Menopause Booklet

T H E M E N O PA U S E
JANUARY - 2010
List of Office Bearers of FOGSI for the year 2009
Dr. C.N. Purandare Dr. Gupte Sanjay Anant

President President Elect
Dr. Shirish Patwardhan Dr. Narendra Malhotra

Senior Vice President Immediate Past President
Dr. Alka Kriplani Dr. P.K. Shah

Second Vice President Secretary General
Dr. Hara Pattanaik Dr. Nozer Sheriar

Third Vice President Deputy Secretary General
Dr. Madhuri Patel Dr. H.D. Pai

Jt. Secretary Treasurer
List of Chairpersons of the Committees of FOGSI 2009
1. Dr. Parag Biniwale 10. Dr. Ragini Agrawal 19. Dr. Sarita Bhalerao
Chairperson (2008 - 2010) Chairperson (2009-2011) Chairperson (2009-2011)
Young Talent Promotion Foods & Drugs Committee Quiz Committee
Committee
20. Dr. Madhuri Patel
2. Dr. V. K. Poddar 11. Dr. Ritu Joshi Chairperson (2009)
Chairperson (2008 – 2010) Chairperson (2009-2011) Study on Female Breast Committee
Reproductive Endocrinology Family Welfare Committee
Committee 21. Dr. Sujata Misra
12. Dr. Ameet Patki Chairperson (2009-2011)
3. Dr. Sheela V. Mane Chairperson (2009-2011) Medical Disorders in Pregnancy
Chairperson (2008 – 2010) Perinatology Committee Committee
Safe Motherhood Committee
13. Dr. Kiran Kurtkoti 22. Dr. Jayprakash Shah
4. Dr. Pragnesh Shah Chairperson (2009-2011) Chairperson (2009-2011)
Chairperson (2009-2011) Medical Termination of Pregnancy Imaging Science Committee
Endoscopy Committee Committee
23. Dr. Manju Gita Mishra
5. Dr. S. Shantha Kumari 14. Dr. Bharati Dhorepatil Chairperson, (2007 – 2009)
Chairperson, (2008 - 2010) Chairperson (2009 – 2011) Medical Education Committee
Medical Nomenclature / Norms, Clinical Research Committee
Research Records Committee 24. Dr. Deepika Deka
15. Dr. Harshad Parasnis Chairperson (2007 – 2009)
6. Dr. Dilip B. Walke Chairperson (2009-2011) Genetic & Fetal Medicine
Chairperson, (2008 - 2010) Oncology & Trophoblastic, Committee
Ethics & Medico Legal Committee Tumours Committee
25. Dr. Jayant Rath
7. Dr. Manish R. Banker 16. Dr. D.K. Pattnaik Chairperson (2007- 2009)
Chairperson (2008– 2010) Chairperson 2005-2009 International Academic Exchange
Infertility Committee Public Awareness Committee Committee
8. Dr. Maninder Ahuja 17. Dr. Kusum Gopal Kapoor 26. Dr. Laxmi Shrikhande
Chairperson (2009-2011) Chairperson (2009-2011) Chairperson (2007 – 2009)
Geriatric Gynaecology Committee Rural Obstetric Committee HIV & AIDS Committee
9. Dr. Alpesh Gandhi 18. Dr. Roza Olyai

Chairperson (2009-2011) Chairperson (2009 - 2011)
Practical Obstetric Committee Adolescent Health Committee
THE FEDERATION OF OBSTETRIC AND GYNAECOLOGICAL SOCIETIES OF INDIA

Model Residency CHS., Ground Floor,, 605 Bapurao Jagtap Marg, Jacob Circle, Mahalaxmi East, Mumbai - 400 011.
Tel.: (91 22) 2302 1648, 2302 1654, 2302 1343 Fax : (91 22) 2302 1383 Email- [email protected]
The Menopause FOGSI Focus
President's Message
Dr. C. N. Purandare
“It does not matter how slowly you go so long as you do not stop”
- Confucius, Chinese philosopher & reformer (551 BC - 479 BC)
Menopausal years are increasingly important as one third of women's life is spent in menopause.
Menopause is growing to become a significant public health issue in India. This FOGSI FOCUS is
designed to give you a glimpse into the scope of clinical practice in this exciting & rewarding area of
women's health. The aim of this FOCUS is to increase knowledge of every gynecologist to the constant
change and evolution that is occurring in managing menopause and to suit the fast changing needs of our
female patients.
There are a lot of modifications and newer molecules for managing menopause and choices now
available to us as practitioners for our patients. The aim is to approach Menopause in a holistic manner
and ensure that a healthy lifestyle and mindset is the way to positive health for our patients. The purpose is
to be able to deal with the subject with much depth and details, and hence all details of symptomotology
along with life style changes, nutrition and exercise and all the different types of hormone therapy are
highlighted in this FOGSI FOCUS.
I would like to thank all of you for your support during this year, Emcure Pharamceuticals for agreeing to
print this important FOCUS and Dr. Mandakini Parihar for doing an excellent job in editing this FOGSI
FOCUS on Menopausal Health.
I wish you all a very happy 2010.
With regards,
Dr. C. N. Purandare
1
Messages from Vice President of FOGSI
Dr. Shirish Patwardhan,

Dear Friends,
Namskar and Greetings and Best Wishes for the New Year from FOGSI, AMOGS and
POGS! It is my proud privilege to extend Best Wishes for FOGSI Focus on Menopause
which is edited by Dr. Mandakini Parihar. I am sure that with all the hard work put in by
you and your team, it would be a great help to fellow FOGSIANS.
While caring for the clients, many of us neglect our own health. This is indeed a serious issue. Let us ensure
that all our constituent Society's are Anemia Free to begin with. Let us not forget our staff and see to it that
our Hospital / Clinic too are Anemia Free. Do join in for Earning – Energy – Enthusiasm (E Cube) or
Sexcellence Workshop held in Leh every May and in Society's which request for it.
Wishing all the members Srimanti and Anand in years to come.
Professor Alka Kriplani

It is a pleasure to know that FOGSI Focus on Menopause is being released. FOGSI Focus is
a very good endeavour for the practicing Gynaecologists as they provide ready clinical
material for the FOGSI Members. Its scientific contents are comprehensive and useful in
day-to-day practice.
Menopause is a pertinent subject. With so many women entering menopause, dealing

with the problems associated with it, is relevant in today's practice. This issue of FOGSI Focus addresses
all the problems related to menopause for which Dr. Mandakini Parihar is praiseworthy. I am quite sure
that this issue will be of immense benefit for all the FOGSI members who will find it useful for day-to-day
patient care.
I wish all the best.
Dr. H. P. Pattanaik
I am happy to know that, the new FOGSI FOCUS is going to be realesed at AICOG 2010,
Guwahati. This FOCUS is devoted to Menopausal Health. Menopause as you know today
is of great importance so far as health of the mature women is concerned. With added
years to life, women today in post menopausal years want a much better quality of life,
free from hot flushes, neurological, cardiological and above all osteoporotic problems. We
gynaecologists have a great role in serving and treating these ailments of these elderly
women to make them more useful to the society.
With emmergence of new drug, modalities particularly low dose HRT and alternative therapies like
phytoestrogens and nutraceuticals we have lot many things in our hand to treat menopausal problems.
This issue of the FOGSI FOCUS is dedicated to all these menopausal problems and the treatment
modalities offered. Dr. Mandakini Parihar has done an excellent job as editor.
I hope the FOGSIans will be immensely benefited from this issue.
Happy new year.
2
Editorial
Dr. Mandakini Parihar
Knowledge rests not upon truth alone, but upon error also.
-Carl G. Jung
Menopause is the permanent cessation of reproductive fertility. The term was originally coined to
describe this reproductive change in human females, where the end of fertility is traditionally indicated by
the permanent stopping of monthly menstruation or "menses". While menopause used to mean
withdrawal from active life for many women, this is not true today. Women may experience a wide range
of feelings, from anxiety and discomfort, to release and relief. Most adapt to the changes and continue to
live well and remain healthy through these transitions.
Most of today's women will live 25 to 30 years-one third of their lives-after menopause. An understanding
of the body's changes during this phase of life can ease the transition, and equally important, better
prepare us to safeguard our patients health during the later years. In this FOGSI FOCUS-ON
MENOPAUSE, we are discussing all that is relevant to manage menopausal women effectively and
improve the quality of their life by addressing their health needs and preventing diseases. The focus is
divided into different sections to cover all the relevant topics. In Basic Understanding of Menopause,
covers the reproductive endocrinology of hormones, the details of the New staging systems, along with
the Symptoms and System Manifestations. There is detailed discussion on the silent killer Osteoporosis
and all forms of effective therapies are discussed. The science of hormone therapy discusses all options for
effective menopause management with the latest evidence regarding HT and dispelling all the myths and
facts associated with all the different studies on menopausal health and finally a holistic approach to these
important years with tips on diet and exercise during menopause. Many mistakes were made by us in
managing menopausal women and we have now corrected those mistakes today. Setting up of a
menopausal clinic and preventing cancer should form an integral part of our management protocols
which are discussed in the FOCUS.
There are risks and costs to a program of action, but they are far less than the long-range risks and costs of
comfortable inaction. So let us use this knowledge to empower ourselves for better understanding of the
menopausal years and work towards a better quality of life in these autumn years for our patients.
I would like to thank our President, Dr. C. N. Purandare for giving me the opportunity to be the editor of
this important FOGSI FOCUS and to all the contributors for their well researched and timely chapters. A
special thanks to my family for their never-ending support and Emcure Pharmaceuticals for burning the
midnight oil to get this focus released on time.
With warm regards
3
Thoroughly Modern Granny
I have a little granny,

She's really very old,
but also unconventional
in the most unusual mould
She doesn't wear her spectacles

perched upon her nose,
she's into contact lenses
and varnishes her toes
How I sometimes wish,

she'd stay and tuck me into bed,
she's off to study yoga
and standing on her head
Unlike all other grannies

who are home before it is dark,
she is dressed up in her track suit,
jig-jogging in the park
She goes for day trips with her Gang,

the over-sixties club,
they racket down the country side
and end up in the pub
I really love my granny

and I think she's really great.
And if, this is what growing old is like,
I simply cannot WAIT
4
Index
Section 1 - Understanding Menopause

1. Basics of Reproductive Hormones - Dr. Hemaleka Kumarasamy ......................................................... 6
2. Physiological changes in Menopause and the quality of life - Dr. Sucheta Kinjawdeker, Dr. Anu Vij ..... 10
3. Staging of Menopause - Dr. Behram Anklesaria .................................................................................. 15
Section 2 - Symptoms and System Manifestations in Menopause

4. Pshchological & Cognitive Functions - Dr. P. K. Shah, Dr. Sonal Yadav ................................................ 18
5. Vasomotor Problems - Dr. Sujata Misra, Dr. Ritu Joshi ...................................................................... 21
6. Uro -Genital Complaints - Dr. Nirmala Vaze, Dr. Pravin Mundada ..................................................... 25
7. Bone Health in Menaopause - Dr. H. P. Pattnaik ................................................................................... 29
8. Candiovascular Dysfunction - Dr. Urvashi Jha, Dr. Indranil Ganguli .................................................. 31
Section 3 - The Silent Killer Osteoporosis

9. Osteoporosis - the extent of the problem - Dr. Jaishree Gajraj .............................................................. 37
10. Measurement of Bone Quatity & Quality - Dr. Anand Parihar, Dr. Deepti Mhatre,
Dr. Ketki Kulkarni............................................................................................................................... 39
11. Role of Calcium Vitamin D and Micronutrients in bone health - Dr. Smita Kokare ................................... 44
12. Role of Estrogen in Prevention & Treatment of Osteoporosis - Dr. C. N. Purandare, Dr. Madhuri Patel,
Dr. Nikhil Purandare .......................................................................................................................... 47
13. Anti- resosptive agents for prevention & Treatment of Osteoporosis - Dr. Mohini Prasad ........................ 51
14. Anabolic drugs and newer therapies in treatment of Osteoporosis - Dr. Ranu Patni .................................. 59
Section 4 - The science of hormone Therapy in Menopause

15. Risk assessment and Investigations - Dr. Atul Munshi ............................................................................ 62
16. Hormone Therapy Preparation, Routes of Administration,
Indication & Contraindications - Dr. Mandakini Parihar, Dr. Manisha Damani,
Dr. Hemaleka Kumarasamy .............................................................................................................. 68
17. Current Recommendations for Replacement
(a) ERT - Dr. Meeta Singh .................................................................................................................... 74
(b) Tibolone - Dr. Jaideep Malhotra, Dr. Ruchika Garg ..................................................................... 78
(c) Androgen Replacement - Dr. Sunila Khandelwal ............................................................................ 82
18. Role of Phytoestrogens - when and for how long ? - Dr. Madhuri Patel, Dr. Nikhil Purandare,
Dr. Khyati Patel ................................................................................................................................... 85
Section 5 - Facts & Myhts of Different Studies on Menopause

19. WHI Study - Dr. Jyoti Unni ................................................................................................................... 90
20. HERS Study - Dr. Survarna Khadilkar ................................................................................................ 92
21. PAM - newer insights in therapy - Dr. Suchitra Pandit, Dr. Rana Khan,
Dr. Priti Vyas ....................................................................................................................................... 99
22. THEBES Study - Dr. Rashmi Shah ....................................................................................................... 106
Section 6 - Holistic Approach to Menopause

23. Diet & Nutrition - Dr. S. S. Mehendale, Dr. Shirish Patwardhan ....................................................... 109
24. Exercise - how soon - how far? - Dr. Manindra Ahuja ............................................................................ 112
25. Setting up of an One step Menopause Clinic - Dr. Sonia Malik .............................................................. 118
26. Prevention of cancer - Dr. Alka Kriplani, Dr. Beenu Kushwah ........................................................... 121
5
1 Basics of Reproductive Hormones
Dr. Hemaleka Kumarasamy
DNB., DGO
Clinical Associate, Mandakini fertility center and IVF clinic, Mumbai
Introduction:
Diagnosis and appropriate management of reproductive dysfunction is facilitated by a
comprehensive knowledge of the physiological origin and the mechanism of action of the various
hormones. Hormones are generally recognized to be chemical signals in a complex system of internal
biologic communication, and the reproductive hormones are rather specifically involved in virtually
every facet of reproductive function in both males and females. A substantial fraction of reproductive
dysfunction is caused by the inappropriate release of a hormone or hormones by the source
endocrine gland or by aberrant reception of the hormone by its target tissue. Menopause is end stage
of cessation of ovarian hormone production.
Steroidogenesis:
An understanding of the steroidogenic pathway is a necessary prerequisite for physicians interested in
reproductive endocrinology.
Cholesterol or other substrates as acetate form the basis for steroidogenesis in the gonadal and adrenal
tissues. Cholesterol is transported into mitochondria where the side chain cleavage enzymes at the
inner mitochondrial membrane can cleave the cholesterol side chain to form pregnenolone. The
pregnenolone is further metabolized into progesterone. By side chain cleavage progesterone and
pregnenolone are further metabolized to androgens by enzymes present in the smooth endoplasmic
reticulum. In the 5pathway pregnenolone is converted to DHEA, in the 4 pathway progesterone is
converted to androstenedione and ultimately further metabolized to testosterone and from
testosterone to estrogens. All this happens under the influence of gonadotropins from the pituitary,
which is further under hypothalamic control.
Fig 1: The pathways for steroid biosynthesis
6
Role of Estrogens:
1. Vaginal cornification
2. Enlargement of uterus
3. Breast-Enlargement, increased vascularity,
pigmentation of areola, epithelial growth
4. Modulates pituitary hypothalamic axis
5. Negative feedback of FSH
6. Ovarian follicular growth
7. Myometrial hypertrophy and development of gap junctions in pregnancy
8. Endometrial proliferation, increased vascularity, and fluid retention
9. Fallopian tubes-hypertrophy, increased vascularity, enhanced ciliary activity.
10. Reduces bone resorption, increase bone formation
11. Alteration in lipid balance or bile salt production
12. Reduces urinary calcium secretion, inhibit bone reabsorption
13. Stimulation of hepatic protein synthesis-globulin, fibrinogen, TBG,TeBG
14. Increase in factors 2,7,10, fibrinogen, decrease in Antithrombin 3 activity.
15. Increase HDL, triglyceride, decrease in LDL
16. Salt and water retention
Role of Progesterones:
1. Converts endometrium into secretory phase
2. Makes cervical mucus thick and impermiable to sperm
3. Maintanance of pregnancy
4. Decreases contractility of uterine smooth muscle
5. Fetus metabolises placental progesterone in the
production of adrenal steroids
6. Raises Epidermal growth factor 1
7. Thermogenic function during ovulation
8. Relaxes smooth muscles
9. Regulates immune response
10. Reduces gall bladder activity
11. Acts in conjunction with estrogen for breast development
Role of Androgens
1. Regulation of the differentiation of male phenotype during embryonic development
2. Development and maintanence of male secondary sexual charecteristics beginning at the time of
puberty
3. Support of spermatogenesis
4. General anabolic and growth promoting effects
5. Behavioural effects
6. Regulation of gonodotrophin secretion
7. Females-axillary and pubic hair, axillary sweating, apocrine glands
7
Fig 2: Reference ranges for Estradiol and progesterone in menstrual cycle expressed in mass
and molar concentration
Fig 3: Progesterone levels (black line) during menstrual cycle
Endocrinology of perimenopausal women:

During the perimenopause, midcycle estrogen concentrations have been observed to be normal or
increased, and levels of progesterone and androgens have been observed to be normal or decreased,
independent of major changes in sex hormone-binding globulin
Sherman and associates1,2 followed six women for several years, including the time of their last
menstrual period, and noted:
(1) A monotropic rise in follicle-stimulating hormone (FSH) occurred even with normal menstrual
cycles
(2) Occasional anovulatory cycles occurred
(3) The last menstrual period occurred immediately after an ovulatory cycle.
The increase in FSH that occurs during the menopause transition has been attributed to a loss of
ovarian Inhibin B along with aging. 3,4
Age at which the FSH rise first appears may not necessarily correlate with menopause. Longitudinal
studies have shown that an increase in FSH occurs as early as the early 40s in normal women. Along
with the elevation in FSH, there is a lesser, but still significant, rise in perimenstrual levels of luteinizing
hormone (LH). In comparison to midreproductive age women, women in the menopausal transition
have higher levels of FSH and LH but not lower estrogen levels. Therefore, elevated FSH
concentrations are not due to low estrogen but are likely to be caused by other factors, such as inhibin
B.
8
Changes in estrogenic environment

An important but often clinically frustrating aspect of peri-menopause is that estradiol levels do not
gradually decrease; instead, they fluctuate greatly around the normal range until menopause, when
no more responsive follicles are available. The anovulatory cycles often seen may be associated with
elevated levels of estradiol. Thus, as a woman ages, there is not a downward spiral in the estrogenic
milieu, but instead a roller coaster in estrogen production. The perimenopausal fluctuations in
estradiol may result from the aging ovary's being less responsive to FSH
Changes in the progesterone milieu
Both normal5,6 and decreased7 levels of progesterone secreted by the corpus luteum have been
observed in the perimenopause. Further clarification regarding perimenopausal progesterone levels
would be clinically very useful, because if decreased levels of progesterone are associated with
increased levels of estradiol, this may also predispose women to dysfunctional uterine bleeding and
endometrial hyperplasia.
Changes in the growth hormone and insulin like growth factors

Age itself may be a more important factor affecting GH concentration than estrogen alone. Recent
studies have shown that a decrease in somatotropic axis activity is detectable before any changes
occur in menstrual cyclicity or decreased production of estradiol. Older, regularly cycling women (age
42–46) have lower daytime GH concentrations than younger, regularly cycling controls (age 19–34).
This occurred in the older women despite higher estradiol levels on the day of sampling (compared
with their younger controls) and overall normal parameters of gonadal hormones. It remains to be
shown whether the changes in function of the somatotropic axis and hormonal environment affect
sensitivity to insulin. This is an important association to be determined, because during the
perimenopause, insulin sensitivity decreases, especially when there is weight gain. Wing and
colleagues noted a direct correlation with perimenopausal weight gain and insulin resistance. Thus,
aging is associated with decreased GH and IGF-1 levels, decreased insulin sensitivity, increased
insulin resistance and weight gain.
Menopausal changes- summary

The climacteric or perimenopausal period normally begins as early as 40 years of age with
commencement of the regression of ovarian function. Depletion of primordial ovarian follicles results
in diminution of estradiol levels leading to intermittent menstrual irregularities, vasomotor symptoms,
and genital atrophy. As a result of the decrease in estradiol negative feedback and diminished levels of
inhibin, there is increased secretion of FSH. The postmenopausal ovary secretes androgens but
virtually no estrogen and that is what causes all the symptomatology in menopausal years.
Suggested Reading
1. Sherman BM, West JH, Korenman SG: The menopausal transition: Analysis of LH, FSH, estradiol and progesterone concentrations during
menstrual cycles of older women. J Clin Endocrinol Metabol 42: 629, 1976
2. Chang RJ, Judd HL: The ovary after menopause. Clin Obstet Gynecol 24: 181, 1981
3. Sherman BM, Korenman SG: Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest 55: 669, 1975
4. Welt CK, McNicholl DJ, Taylor AE et al: Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab
1999 Jan;84(1):105-11.
5. Reyes FI, Winters JS, Faiman C: Pituitary-ovarian relationship preceding the menopause: A cross-sectional study of serum FSH, LH, prolactin,
estradiol and prog
6. Lenton EA, Landgren B, Sexton L et al: Normal variation in the length of the follicular phase of the menstrual cycle: Effect of chronological age. Br
J Obstet Gynecol 91: 681, 1984
7. Lenton EA, Sexton L, Lee S et al: Progressive changes in LH and FSH and LH:FSH ratios in women throughout reproductive life. Maturitas 100:
35, 1988
9
2 MENOPAUSE: Understanding the Change
Dr. Sucheta Kinjawadekar
Consultant Obstetrician & Gynecologist,
Navi Mumbai
Dr. Anu Vij

Secretary NMOGS
Consultant Obstetrician and gynecologist,
Navi Mumbai
Menopause, also known as “the change” or “change of life,” is a normal part of a woman's life. The years
leading up to that last period, when women might be experiencing menopausal symptoms like changes in
their monthly cycles or hot flushes, are called the menopausal transition.
Changes at Midlife
The medical definition of menopause is the end of menstruation, so menopause can only be
diagnosed after the fact. But the bodily changes leading up to menopause may take place over a
decade. Most women reach menopause between the ages of 45 and 55.
Changes to Expect
Some women continue to menstruate normally until the onset of menopause and then simply cease
to have periods. But for most women, the transition is not so orderly.
1) Changing Hormonal Patterns

Menopause results from loss of ovarian sensitivity to gonadotropin stimulation, which is directly
related to follicular decline and dysfunction. Thus, the variable cycle length during perimenopause
can be due to anovulation or to irregular maturation of follicles.
Despite having no pelvic pathology and continue to be ovulatory, a shorter menstrual cycle is the
most common change 4. Because follicles, which are stimulated by FSH during the first part of the
menstrual cycle, have declined in number, less recruitment of oocytes occurs and the follicular phase
shortens accordingly. However, once ovulation occurs, the luteal phase remains fairly constant, at 14
days.
As aging progresses follicles become more resistant to gonadotropin stimulation, circulating FSH and
LH levels increase. Elevated FSH and LH lead to ovarian stromal stimulation, resulting increase in
estrone levels and a decrease in estradiol levels.
Inhibin levels also drop during this time because of the negative feedback of elevated FSH levels.5
With the commencement of menopause and a loss of functioning follicles, the most significant change
10
in the hormonal profile is the dramatic decrease in circulating estrogen levels. Without a follicular
source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and
adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation.
Testosterone levels also decrease with menopause,6 but this decrease is not as marked as the decline in
17- estradiol.7
With cessation of ovulation, estrogen production (by stromal and extragonadal sites) continue,
unopposed by progesterone production by a corpus luteum. Perimenopausal and menopausal
women are thus often exposed to unopposed estrogen for long periods, which can lead to
endometrial hyperplasia.
The laboratory indication that menopause has occurred is the measure of an elevated FSH level. A
slightly elevated FSH level in a perimenopausal women may not be a reliable indicator of menopause
because of the wide variation of FSH and LH levels in response to increased release of gonadotropin-
releasing hormone (GnRH) by the hypothalamus and increased pituitary sensitivity to GnRH.
Measuring FSH and LH levels again in the perimenopausal patient after 2-3 months is helpful in
establishing whether the woman is progressing through menopause. Women with elevated, but not
postmenopausal, FSH levels are still at risk for pregnancy and contraception should still be used until
FSH levels remain in the postmenopausal range
Because estrogen plays many roles in the female body -- including maintenance of bone density,
stimulation of breast tissue, and nurture of the vaginal membranes -- its loss has numerous
ramifications, collectively known as the "Change."
Menopause at a glance
11
Changes in the Menstrual Cycle
The perimenopausal years may be marked by skipped menstrual periods, heavier or lighter than
usual bleeding, and changes in the frequency of cycles. During some menstrual cycles are
anovulatory cycles.
Muscle Tone and Elasticity

Skin and mucous membranes in various parts of the body become drier As the body ages and the
estrogen level declines, the fatty layer beneath the skin surface that makes the skin appear supple and
youthful begins to shrink from a loss of elasticity and moisture. The outer skin layer is now looser than
the deeper layers, and begins to fold and wrinkle. The skin may also develop a rougher texture.
Vaginal Changes are the first sign of approaching menopause for some while many do not notice
changes until five to ten years after menopause. As estrogen levels drop, the vulva and vagina lose
elasticity, resulting in vaginal dryness, itching and a shrinking process known as vaginal atrophy
Vaginal membranes also become thinner, hold less moisture, and lubricate more slowly. The thinner
vaginal lining becomes more susceptible to tears, vaginal infections, and painful intercourse.
Breast Changes - Glandular tissue shrink and loss of elasticity causes the breasts to droop and flatten.
Nipples become smaller and flatter and may lose their erectile properties.
Women who have been bothered by breast tenderness and cysts related to the menstrual cycle are
often relieved to find that these symptoms disappear after menopause.
Abdominal wall tone may lessen gradually, resulting in a protruding stomach
Hair, Bones, and Teeth

Hair all over the body can change in texture and quantity. The increased effects of the body's
androgens can result in darker, thicker and wiry body hair on the pubis, underarms, face, chest, lower
abdomen, and back.
A loss of luster occurs because individual hair shafts begin to thin and dry as a result of hormonal changes.
The replacement process for normal daily hair loss becomes slower.
Bone strength- As estrogen and progesterone levels fall drastically, the bones begin to lose mass.
Osteoporosis strikes at least half of all women age 50 and older leaves a woman vulnerable to bone
fractures, especially in the hip, spine, and wrist. In fact, by the time a woman is 80, she may have lost
40 percent of her bone mass.
Teeth and the mouth are similarly affected. Dental problems that can occur around midlife, such as
receding gums or loose teeth.
"Classic" Menopausal Changes

Hot flashes, flushes, or night sweats are the most common. Some experience a simple warming
sensation throughout the body, Others feel acute flushes that begin with a sensation of pressure in the
head similar to a headache, which then leads to a feeling of heat or burning in the face, neck, and
chest, followed immediately by an outbreak of sweating. In most cases, hot flashes are mild and
disappear after a year or two.
12
The exact physiological cause of this upset is not yet known. The feeling may be precipitated by a
hormonally induced imbalance in the body's temperature- control center.
Short term memory loss has been cited as a problem. Forgetfulness may be related to stress or lack of
sleep.
Emotional issues - Though there is no increase in serious psychiatric disorders minor emotional
distress, however, may be a natural response to the changes a woman faces during this period.
Hot flashes may keep one up at night, leading to chronic sleep deprivation which can reduce one's
mental and coping abilities. Vaginal changes that result in painful intercourse may interfere with one's
sexual pleasure and psychological health.
Weight gain, is not directly related to menopause. There is a natural redistribution of fat over the
abdomen and hips. Weight gain most likely results from reduced muscle tone, reduced physical
activity, increased appetite .
Cardiovascular Health
A women's risk of cardiovascular disease rises dramatically after menopause .The younger a woman
is when her ovaries stop functioning, the greater her risk for MI.
Thus menopause itself is a risk factor for cardiovascular disease, along with high blood pressure,
smoking, family history, poor diet, high blood cholesterol, diabetes, and obesity.
Bladder Control
Women in peri - and postmenopause may experience mild stress incontinence, urge incontinence.
These problems occur when declining estrogen levels cause cell deterioration and diminished muscle
control in the urethra, bladder, and vagina.
Repeated UTIs, are also common. The deterioration of cells in the urinary tract produces an easily
torn and bruised surface, creating an hospitable environment for the bacteria.
Effect of Menopausal Symptoms on Overall Quality of Life

Women feel their quality of life is severely compromised by menopausal symptoms but further
studies concluded that menopause brings about a significant decrease in quality of life that is
independent of other factors, such as age, marital status and other socio demographic variables.
Many scales are now developed to quantify quality of life (QOL). These are questionare based on
physical, psychological /emotional, changes/ symptoms Perceived by affected population. Total score
is calculated to evaluate pre and post HRT status and evaluate benefit of HRT.
13
Suggested Reading
1. McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas. Jan 1992;14(2):103-15. [Medline]
2. Cramer DW, Harlow BL, Xu H, et al. Cross-sectional and case-controlled analyses of the association between smoking and early menopause.
Maturitas. Sep 1995;22(2):79-87. [Medline].
3. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect. Jan-Feb 1998;30(1):24-9, 46. [Medline].
4. Santoro N, Brown JR, Adel T, et al. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. Apr
1996;81(4):1495-501. [Medline].
5. Lenton EA, de Kretser DM, Woodward AJ, et al. Inhibin concentrations throughout the menstrual cycles of normal, infertile, and older women
compared with those during spontaneous conception cycles. J Clin Endocrinol Metab. Dec 1991;73(6):1180-90. [Medline].
6. Smith KE, Judd HL. Menopause and postmenopause. In: DeCherney AH, Pernoll ML, eds. Current Obstetric and Gynecologic Diagnosis and
Treatment. 8th ed. Appleton & Lange; 1994:1030-1050.
7. Wells G, Herrington DM. The Heart and Estrogen/Progestin Replacement Study: what have we learned and what questions remain?. Drugs
Aging. Dec 1999;15(6):419-22. [Medline].
8. Grady D, Cummings SR. Postmenopausal hormone therapy for prevention of fractures: how good is the evidence?. JAMA. Jun 13
2001;285(22):2909-10. [Medline].
9. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene:
results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. Aug 18
1999;282(7):637-45. [Medline].
10. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.
Fracture Intervention Trial Research Group. Lancet. Dec 7 1996;348(9041):1535-41. [Medline].
11. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal
osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. Oct 13
1999;282(14):1344
14
3 Staging of Menopause
Dr. Behram S. Anklesaria
M.D., D.G.O., D.F.P, A.T.M.F.(USA), Millennium F.I.C.O.G.,
President, 2004-2005 , Federation of Obstetrics & Gynecological Societies of India (FOGSI)
Executive Board Member, 2007-2009,
International Federation of Obstetrics and Gynecology (F.I.G.O.)
Menopause is an important part in a woman's life, a time of transition from reproductive years to non-
reproductive years. It is defined as a period when menstrual function stops completely. However, patient
may present with symptoms for many years before the actual stopping of the monthly periods. For a few
preceding years there are a lot changes occurring and patient would present with symptoms many years
before menopause will set in. it is important for us to realize the different stages of menopause.
In 1997, when this staging system was first published, long term HRT was popular in the West.
Subsequently this staging has been widely published, in India and abroad. (See references.) In 2008, it
was adopted by the Indian Menopause Society and presented at the World conference of the International
Menopause Society at Madrid. Meanwhile, WHI and other studies, considerably reduced the popularity
of long term HRT. However our staging system has become even more relevant, because HRT and other
interventions are now critically 'time bound'. For example, the “window of opportunity” period for
initiation of long term HRT, happens to correspond exactly with “Stage II” of this system!
Individualized management of 40+ women with their diverse cultural and regional needs is not possible
without Clinical Categorisation. Individualisation of treatment involves another more important aspect.
The same `patient' develops different needs at various `stages' of menopause. A good physician will
encourage the `patient' to report regularly and will alter the management to suit her ever changing needs.
This simple scientific `staging system', widely disseminated, has helped us to do just that.
Table1: Stages of Menoapuse, Dr. Behram. S. Anklesaria, 1997
Stage
STAGES Stage I Stage II B Stage III
IIA
Roughly 3-5 years before ONE Up to five years From five years
YEARS after the after menopause
the menopause YEAR
menopause up to her life time.
* Menstrual irregularity M C * Local atrophic III A: Late
E O changes atrophic changes
* Vasomotor instability N N * Late III B: Ischemic
EVENTS O F psychosomatic heart disease
* Early psychosomatic P I symptoms III C:
symptoms A R (see detailed Osteoporosis
U M staging) III D: Very late
S A complications:
E T e.g.. Cerebro–
I Vascular
O accidents,
N Alzheimer’s
disease, etc.
ESTABLISH
ACTION TREAT ! PREVENT !
COMMUNICATION !
15
Stages of Menopause in Detail
Stage 1:
From the Earliest Perminenopausal Symptom
(Usually Vasomotor Instability or Menstrual Irregularity)
To Menstrual Cessation (Menopause)
Stage 2:
“FIVE YEARS AFTER MENOPAUSE”
Stage 2: A
“From the cessation of menstruation Up to one Year,”
(That is up to confirmation of Menopause by WHO definition.)
The main symptoms of menopause during this stage are URETHRAL Syndrome and Vasomotor
Instability.
Stage 2: B
From end of 2: A, up to Four Years, the usual Symptoms are:
(a) Atrophic Symptoms, Vaginitis, Dyspareunia
(b) Urinary Symptoms, e.g. Urgency, SUI
(c) Weight gain , Abnormal Weight Distribution
(d) Skin and Hair changes
(e) Genital Prolapse
(f) Late Psychological Symptoms
(g) Sexual Disorders.
Stage 3:
From five years after menopause up to her life time.
III A: Late atrophic changes III B: Ischemic heart disease
III C: Osteoporosis III D: Very late complications:
e.g. Cerebro –Vascular accidents, Alzheimer's disease, etc.
Practical Usage:
The Five Year Rule of the Thumb
• Each stage duration is highly variable, but a rough five years per stage calculation is clinically useful
• Consider the case of lady 'A' who reaches her menopause at say age 50
• From 45 – 50 she is in stage I when she needs initial counseling
• From 50-55 she will be in stage II : The window of opportunity
• From 55 to 70 she will go through the earlier stage III complications which could have been prevented!
• At 70+ she enters stage III D and beyond. She now needs very different management than the earlier
stages
The author has presented here, his staging system, first published in India in 1997. Four years later in
2001, the `Stages of Reproductive Ageing Workshop (STRAW) and the American Society for
Reproductive Medicine published another staging system. This is an excellent system for
Reproductive Ageing, useful for managing infertility problems of older women. However, in dealing
with symptomatic and preventive aspects of menopause, we feel that our older staging system is
superior.
16
2) STRAW SYSTEM (Stages of Reproductive Aging Workshop)

The early climacteric years
Signs and Symptoms
Flushes Night sweats
Fertility Menstrual cycle problems
Contraception Uterine Bleeding
PMS
Breast Carcinoma
Final Menstrual Period (FMP)
-2 -1 +1 +2
Stages:
Menopausal Transition Postmenopausal Transition
Terminoloy: Late Early* Late
Early
Perimenopause
Duration of Stages: Variable a b until demise
1
yr 4 yrs
≥
Amen x 12 mos
Menstrual Cycles: Variable cycle length 2 skipped cycles and none
(> 7 days different an interval of
from normal) amenorrhea (≥ 60 days)
Endocrine: FSH FSH
Executive Summary: Stages of Reproductive Aging Workshop. Menopause 2001:8:402-407 (STRAW).
Summary:
The most important sociomedical change of the present era has been the dramatic increase in life
expectancy and the subsequent rise of “older” populations. Woman's liberalization, emancipation
and professionalism have led to spreading concepts of Menopause as a 'Positive' change. Greatly
encouraging is the rising awareness of the benefits of life style changes. Estrogen therapy for treatment
and prevention has become complicated. However the most important development has been the
crucial importance of the TIMING of various interventions in Menopause Management. That is why
our 'Staging of Menopause' has now become the best method to understand the symptomology, the
complications and the management of a woman's best years – the Menopause!
Questions for the Reader:

• Why is Stage I known as the Stage of Communication?
• Why is Stage II Extremely Important for the Initiation of Modern HT?
• Which of the complications of Stage III can be or cannot be prevented by HT?
Suggested Reading
1. “Menopause” published by Orient Longman; edited by Dr. Usha Krishna & Duru Shah, 1996, Page13,.Chapter by Dr. B. S. Anklesaria.
2. HRT for "Mature" Women using a Clinical Staging System : Dr. B. S. Anklesaria in Gujarat Medical Journal, Volume 54, Dec. 1997.
3. Executive Summary: Stages of Reproductive AgeingWorkshop (STRAW) Menopause 2001; 8: 402 - 407.
4. “Menopause” Current Concepts, edited by Dr. C.N. Purandare, 2004, Page 201, Chapter by Dr. B. S. Anklesaria.
5. Maturitas : Proceedings of the International Menopause Society Conference, MADRID, 2008, “Staging of Menopause: The Indian Mantra'' by
Dr. B. S. Anklesaria.
6. JEFFCOATE : Principles of Gynecology Seventh International Edition, 2008, Page 863: Staging of Menopause by Dr. B. S. Anklesaria.
17
4 Psychological and Cognitive Functions in Menopause
Dr. P. K. Shah
(M.D., F.I.C.O.G., F.C.P.S., F.I.C.M.U.,
F.I.C.M.C.H., D.G.O., D.F.P.)
Professor & Unit Head
Department of Obstetrics & Gynaecology
Seth G. S. Medical College & K.E.M. Hospital
Dr. Sonal P. Yadav

M. S. (Obste and Gyaec)
Post M.S. Registrar
Department of Obstetrics & Gynaecology
Seth G. S. Medical College & K.E.M. Hospital
Menopausal health is gaining importance as longevity in women has increased, while the age of
menopause has remained the same. We are experiencing a relatively new phenomenon: we can expect to
become old. We are on the verge of becoming a rectangular society. This is a society in which nearly all
individuals survive to advanced age.
The Menopause is that point in time when permanent cessation of menstruation occurs following the loss
of ovarian activity.
Climacteric, an older, more general and less precise term indicates the period of time when a woman
passes from the reproductive stage of life through the perimenopausal transition and the menopause to
the postmenopausal years.
Symptomatology: Most Indian studies locate the median age at 48 years, while those from the west
reveal the same to be about 51.
(WHO Scientific Group 1981)1,2. Vasomotor instability symptoms like hot flush are the most common
symptoms in menopausal patients. Other symptoms include urogenital problems, Psychological
symptoms and other major systemic features due to estrogen deficiency.
Psychological symptoms such as anxiety, irritability, depression and insomnia are most common just
before the onset of menopause.
Mechanism of psychological symptoms in menopausal women:

Sex steroids have been shown to have a modulatory role on brain monoamine receptors. Falling
estrogen level may contribute directly to mood changes and psychosomatic symptoms.
But the view that menopause has a deleterious effect on mental health is not supported in the
psychiatric literature, or in surveys of the general population3,4. A negative view of mental health at the
time of the menopause is not justified; many of the problems reported at the menopause are due to
life events5,6. Thus, there are problems encountered in the early post menopause that are seen
frequently, but their causal relation with estrogen is unlikely. These problems include fatigue,
nervousness, insomnia, depression, irritability, joint and muscle pain, dizziness and palpitations.
18
In the American SWAN study, the prevalence of mood changes increased from the premenopause to
the early perimenopausal, from about 10% to 16%7. There are three possible explanations: 1.The
decline in estrogen at menopause affects neurotransmitters that regulate mood. 2. Mood is adversely
affected by vasomotor symptoms (domino theory). 3. Mood is affected by the vicissitudes of life that
are commonly prevalent around menopause.
Cognition and Alzheimer's Disease:

Up to 3 times as many women as men develop Alzeihmer's Healthy Brain
disease. Estrogen is capable of protecting central nervous Cerebral

Cortex
system functions by means of multiple mechanisms. For

example estrogen protects against neuronal cytotoxicity
Ventricles
induced by oxidation; estrogen reduces the serum
concentration of amyloid P component (the glycoprotein Hippocampus
Mild
found in Alzeihmer's neurofibrillay tangles); and estrogen Alzheimer's Disease
increases synapses and neuronal growth, especially Cortical

Shrinkage
8,9
dendritic spine density . Case control and cohort findings
have indicated that Alzeihmer's disease and related Moderately
Enlarged
dementia occurred less frequently perhaps as much as Ventricles
60% less in estrogen users and the effect was greater with Shrinking
10
Severe Hippocampus
increasing dose and duration of use . WHI concluded that Alzheimer's Disease
Estrogen Progestin therapy increase risk for probable Severe

Cortical
Shrinkage
dementia in women 65 years and older and didn't prevent
mild cognitive impairment. But this hypothesis was Severely
Enlarged
derecognized by WHI itself in view of older age, preexisting Ventricles
cardiovascular disease and established atherosclerosis Severe

Shrinkinge of
Hippocampus
which itself increase the risk of vascular dementia11. Zandi
et al concluded that a reduction in the risk of Alzeihmer's requires long term treatment initiated at least
10 years before symptoms of dementia appear. The favorable effect of hormone therapy on cognition
and risk of Alzeihmer's disease appear to be limited to women who initiate treatment close to their
menopause.
Treatment:
A negative view of mental health at the time of the menopause is not justified; many of the problems
reported at the menopause are due to life events. Thus, there are problems encountered in the early
post menopause that are seen frequently, but their causal relation with estrogen is unlikely. Thus the
overall quality of life reported by women can be improved by better sleep and alleviation of hot
flushing. However it is still uncertain whether estrogen treatment has an additional direct
pharmacologic antidepressant effect or whether the mood response is totally an indirect benefit of
relief from physical symptoms and, consequently, improved sleep.
The short-term administration of unopposed estrogen to patients with Alzheimer's disease has been
reported to improve cognitive performance. Most revealing is a prospective cohort study of the men
and women living in Cache Country, Utah. Hormone therapy provided about a 41% reduced risk of
developing Alzeihmer's with any use and an 83% reduction with 10 or more years of use. Most
importantly, if women had initiated hormone therapy within a period of time that encompassed 10
19
years before the development of clinical symptoms, there was no effect. The Utah strongly suggests
that hormone therapy must be used for a significant duration of time very early in the
postmenopausal period in order to have an impact on the risk of Alzeihmer's disease.
Conclusion:
So the most common cause of perimenopausal mood problems is already existing depression12,13, but
there does exist a small population of women whose moods are sensitive to hormonal changes.
The perimenopausal transition, therefore, is not a cause of clinical depression; however, labile
emotions do seem to be improved in many women administered hormone therapy.
Suggested Reading
1. Wyon J B et al 1966. Population Index 32: 328 – 329

2. Randhawa I et al 1987. Median age of menopause in a sample of Indian women. Indian J Pub Health 31:40
3. Hunter M, The South East England longitudinal study of the climacteric and postmenoapuse, Matritas 14:17, 1992.
4. Oldenhave A, Jaszmann LJB, et al, impact of climacteric on well being, Am J Obstet Gynecol 168:772, 1993
5. Dennerstein L, smith AMA et al Psychological wee\ll being, mid life and the menoapuse, Maturitas 20:1, 1994.
6. Mitchell ES, Woods NF symptom experiences of midlife women: observations from the Seattle midlife women's health study. Maturitas 25:1,
1996
7. Bromberger JT, Assmann SF et al Persistent mood symptoms in a multiethnic community cohort of pre and perimenoapusal women, Am J
Epidemiol 158:347, 2003
8. Rhodin JA, Thomas TN, Clark L in vivo cerebrovascular actions of amyloid beta peptides adn the protective effect of conjugated estrogens J
Alzeihmer's Dis 5:275:2003
9. Diaz Brinton R et al The women's Health initiative estrogen replacement therapy is neurotrophic and neuroprotective. Neurobiol Aging 21:475,
2003.
10. Paganini hill A et al Estrogen replacement therapy and risk of Alzeihmer's disease. Arch Intern Med 156:2213, 1996
11. Rapp SR et al WHIMs JAMA 289:2662,2003.
12. Dennerstein L, Lehert P, Burger HG et al Mood and the menoapuse transition, J Nerv Ment Dis 187:685, 1999
13. Bromberger JT, Assmann SF et al Persistent mood symptoms in a multiethnic community cohort of pre and perimenoapusal women, Am J
Epidemiol 158:347, 2003
20
5 Vasomotor Problems
Dr. Sujata Misra
MD; FICOG
Associate Professor, OBGYN, SCB Medical College Cuttack
Chairperson, Medical Disorders in Pregnancy Committee, FOGSI
Academic Counsellor, Postgraduate Diploma in
Maternal and Child Health, IGNOU
Dr. Ritu Joshi

MD
HOD Dept of OBGYN. Fortis Hospital, Jaipur
Chairperson, Family Wellfare Committee, FOGSI
The vasomotor phenomenon is viewed as the hallmark of female climacteric experienced by most
postmenopausal women. Hot flush and night sweats are the most disruptive symptom of estrogen decline
in pre and post menopausal women and the classic symptom associated with estrogen deficiency is the
hot flush.
Incidence
Hot flushes are experienced by at least one half of all women during natural menopause and by even
more women after surgical menopause.1 Exact estimates of the prevalence are hampered by
inconsistencies and differences in methodologies, cultures and definitions.2
It shows a cultural variation with western countries reporting between 60-80% (USA 82%, Sweden
60%, Australia 62%) 3-5 whereas the eastern countries report lower rates of 10-30 percent (Indonesia
10-20%, Chinese 10-25%, Indian 20-30%).
Hot Flush
This symptom is described as 'recurrent transient periods of
flushing, sweating and a sensation of heat, often accompanied
by palpitations, feelings of anxiety and sometimes followed by
chills.6
There is a sudden onset of reddening of the skin over the head,

neck and chest accompanied by a feeling of intense body heat
which, at times, is concluded by profuse perspiration. The
duration varies from a few seconds to several minutes and,
rarely for an hour. The frequency may be rare to recurrent. The
entire episode usually lasts for 1 to 3 months and may recur as many as 30 times per day, although 5 to
10 times per day is probably more common.
They are more frequent and severe at night (after awakening the woman from sleep) and during
times of stress. In a cool environment, hot flushes are fewer, less intense, and shorter in duration as
compared to that in a warm environment.7
21
Although the flush can occur in the premenopausal phase, it is a major feature of postmenopausal
period, lasting in most women for 1-2 years but in some (approximately 25%) for longer than 5 years.
In cross sectional surveys, up to 40% of premenopausal women and 85% of menopausal women
report some vasomotor complaints.8
Hot flushes may be accompanied by fatigue, nervousness, anxiety, irritability, depression and
memory loss.9 Hot flushes that occur at night, referred to as night sweats are believed to interrupt sleep
patterns. Early in the menopausal transition, vasomotor instability may manifest as an intermittent
sleep disturbance in the absence of obvious hot flushes..
Overweight women report more hot flushing, perhaps reflecting the effect of body fat causing a higher
core body temperature.10
Physiology
Hot flushes are implicated to originate in the hypothalamus and is brought about by a decline in
estrogen. However, all hot flushes are not due to estrogen deficiency. They may be secondary to
diseases, including pheochromocytoma, carcinoid, leukemias, pancreatic tumors and thyroid
abnormalities.11
When the clinical situation is not clear and obvious, estrogen deficiency as the cause of hot flushes
should be documented by elevated levels of FSH. Prescribing estrogen inappropriately (in the
presence of normal levels of gonadotropins) only temporarily postpones the symptoms due to a
placebo effect.
The flush is accompanied by a discrete and reliable pattern of physiological changes.12 It coincides
with a surge of LH and is preceded by a subjective prodromal awareness that a flush is beginning. This
aura is followed by measurable increased heat over the entire body surface. However, its relationship
to LH surge and temperature changes within the brain is not clearly understood. The observation that
hot flushes occur even after hypophysectomy indicates that it is not dependant on nor directly due to
LH release. It is probably secondary to hypothalamic changes in the neurotransmitters that increase
neuronal and autonomic activity.13
Physiologically, hot flushes correspond to marked, episodic increase in the frequency and intensity of
gonadotropin-relasing hormone (GnRH) pulses from the hypothalamus. It is postulated that this
increased pulsatile activity is a marker for some central disturbances of the body temperature
regulating center that is responsible for the hot flushes.14 With the increase in body surface
temperature, there are changes in skin conductance, followed by a fall in core temperature. It is
basically a sudden inappropriate excitation of heat release mechanism.
Release of hypothalamic neuropeptides/neurotransmitters from tonic inhibilitory influence of

estrogens are currently implicated in the pathogenesis of vasomotor symptoms.15 Noradrenergic
neurones have been shown to be present in the medial preoptic area of the hypothalamus,16 are
known to modulate LHRH section17 and thermoregulation.18 There is considerable incidence for
estrogen modulation of the central noradrenergic activity.19 Though plasma norepinephrine levels do
not show any change during hot flushes,20 Freedman RR showed increased plasma concentrations of
3methoxy 4 hydroxy phenylglycol (MHPG- the main metabolite of brain norepinephrine) before hot
flushes.21
22
Other neurotransmitters thought to be involved in the pathogenesis of vasomotor symptoms are the
opioids and tachykinins. Like noradrenergic neurons, opoids containing neurons bind estrogen,21
and influences thermoregulation22. In post menopausal women proopiomelanocortin (POMC)
mRNA levels decline
Management:
Counselling is of paramount importance. Many women have mild hot flushes that they do not feel
require therapy. The patients can be advised that, without treatment, the symptoms usually subside
slowly over a period of 3-5 years.23 A striking and consistent finding in most studies dealing with
menopause and hormonal therapy is a marked placebo response (at least 51% in the first weeks of
treatment)24 in a variety of symptoms, including flushing.
Treatment (Steroidal)
Estrogen replacement therapy results in the reduction of hot flushes in most women in a matter of
days. After oophorectomy, a higher dose of estrogen is commonly needed. In women without risk
factors for cardiovascular disease; low dose oral contraceptives can be used with excellent results.
Alternatively, the daily estrogen dose can be increased stepwise to as high as the equivalent of 2.5mg
of conjugated estrogens to resolve persistent hot flushes. The estrogen dose should be tapered slowly
over a period of months to no more than 1.25mg of conjugated estrogen per day, because the risk of
cardiovascular disease actually may be increased in women taking larger doses.25
In women in whom hormone replacement is contraindicated effective alternatives are

medroxyprogesterone (10-30mg daily orally)26 or megestrol acetate (20-40mg daily orally)27
If either of these progestins result in intolerable side effects, the use of alternative progestins may be
considered, though very few data exist regarding their efficacy.
Treatment (Non Steroidal)

One of the best studied is the L2-adrenergic agonist, Clonidine. This drug probably works through
both central and peripheral mechanism and can be given either orally (0.05mg twice daily) or by a
transdermal patch (0.1mg weekly)28
Formulations containing a combination of phenobarbital, ergotamine and belladonna, used in the

past, are currently not recommended. In addition to having a marked sedative effect and they can
potentially be habit forming. Morever, controlled studies show little long-term effectiveness of this
treatment.
Suggested Reading
1. Weinstein L, Hormonal therapy in the patient with surgical menopause. Obst. Gynecol 1990;75:475-505
2. Kronnenburg F, Hot flushes: epidemiology and physiology, Ann NY Acad Sci 592:52, 1990
3. Fledman BN, Voda A and Gronseth E. The prevalence of hot flush and associated variables among perimenopausal women, Res. Nur Health
1985; 8:261-68
4. Hagstad A and Janson PO. The epidemiology of climacteric symptoms Ada Obst Gynecol Scand Suppl 1986; 134:59-65
5. Guthrie JR, Dennerstein L, Hooper JL et al. Hot flushes, menstrual status and hormone levels in a population-based sample of midlife women.
Obst Gynecol 1996; 88(3):437-42
6. Kronnenberg F, Hot flushes epidemiology and physiology. Ann NY Acad Sci 1990; 592:52-1990
7. Kronnenberg F, Barnard RM, Modulation of menopausal hot flushes by ambient temperature. J Therm Biol 17:43, 1992
8. Oldenhave A, Jaszmann LJB, Haspels AA, Everaerd WTAM, Impact of climacteric on well being, Am J obst Gynecol 168:772, 1993
23
9. Utian WH, Biosynthesis and physiologic effects of estrogen and pathophysiologic effects of estrogen deficiency; review, Am J Obstet Gynecol
1989, 161:1828-1831
10. Randolph JF et al, Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size and menopausal states. J. Clin,
Endocrinol, Metab 88:1516, 2003.
11. Wilkn JR, Flushing reactions : consequences and mechanism Ann Intern Med 95:468, 1981
12. Fredman RR, Physiology of hot flushes, Am J Hum Biol 13:453,2001.
13. Freedman RR, Biochemical metabolic and vascular mechanism in menopausal hot flushes, Fertil Steril 70:332, 1998.
14. Ravnikar, V. Physiology and treatment of hot flushes, Obst Gynecol 1990; 75 35-85
15. Lopez FJ, Finn PD, Lawson MA, Regulation of the hypothalamic pituitary – gonadal axis. Role of gonadal steroids and implications for the
menopause. In menopause: Biology and Pathobiology. Lobo RA, Kelsey J, Marcus R Eds. Academic Press 2000; 33-60.
16. More RY and Bloom FE. Central catecholamine neuron systems: Anatomy-and physiology of the norepinephrine and epinephrine systems.
Annu Res 1979;2:113-68.
17. Kordon C, Drouva SV, Martinez de la Escalera G et al. Role of classic and peptide neuromediators in the neuroendocrine regulation of luteinizing
hormone and prolactin. In the physiology of reproduction Knobil E and Neill JD. Eds. Raven Press: New York 1994;1621-81
18. Van Tiemhoven A, Scott NR and Hillman PE. The hypothalamus and thermoregulation: A review. Poult Sci 1979;58:1633-39
19. Insel PA and Motulskey HJ. Physiologic and pharmacologic regulation of adrenergic receptors.
20. Kronenberg F, Cote LJ, Linkie DM et al. Menopausal hot flashes: Thermoregulatory, cardiovascular and circulating catecholamine and LH
changes. Maturitas 1984;6:31-43.
21. Freedman RR. Biochemical, metabolic and vascular mechanisms in menopausal hot flushes. Fertil Steril 1998;70(2)1.6.
22. Akesson TR and Micevych PE. Endogenous opioid immunoreactive neurons of the venteromedial hypothalamic nucleus concentrate estrogen in
male and female rats. J Neurosci Res 1991;28:359-66.
43. Francesconi R and Mager M. Theroregulatory effects of centrally administered bombesin, bradykinin andmethionine-enkephalin. Brain Res Bull
1981;7:63-68.
23. Kronenberg F, Hot flushes: epidemiology and physiology. Ann NY Acad Sci 1990; 592:52-86
24. Mac Lennan AH, Henry D, Hills S, Moore V, Oral estrogen replacement therapy versus placebo for hot flushes, Menstrual Disorders Module of the
Cochrane database of Systematic Reviews, 2000.
25. Stampfer MJ, Colditz GA, Willete WC et al. Postmenopausal estrogen therapy and cardiovascular disease: ten year followup from the Nurses
Health Study. N Engl J Med 1991; 324:756-762
26. Cedars MI, Lu JK, Meldrum DR. et al Treatment of endometriosis with a long acting gonadotropin relasing hormone agonist plus
medroxyprogesterone acetate. Obst gynecol 1990; 75:641-645.
27. Erlik Y, Meldrum DR, Lagasse LD, et al. Effect of megestrol acetate on flushing and bone metabolism in post menopausal women. Maturitas
1981; 3:167-172.
28. Edington RF, Chagnon JP, Steinberg WM. Clonidine for menopausal flushing, CMAJ 1980; 123:23-26
24
6 Uro-Genital Complaints
Dr. Nirmala Vaze
FRCOG (London), FICMCH (India)
Dr. Pravin Mundada

MBBS, MD
Signs of atrophic changes in the urinary and genital organs due to estrogen deficiency play a very
important role and contribute significantly towards the loss of physical & psychological well being. The
complaints in the lower urinary tract occur within first 5 to 10 years after menopause. Estimated 10 - 40%
of post menopausal women suffer with these symptoms but only 20 - 25 % of them seek medical advise1.
Female genital tract & lower urinary system both develop from primitive urogenital sinus during
embryonic phase. Estrogen & progesterone receptors are present in urethra, bladder, pelvic musculature,
vagina & urogenital ligaments2. During menopause estrogen deficiency affects both systems. The changes
are mild in early years of menopause and marked in later years of menopause. Response to HRT is limited
when marked structural damage occurs.
Anatomical changes in the genital tract in menopause -

• Vulva - Atrophic vulval skin, gaping of introitus, shrinkage of labia, disappearance of hair follicles
• Vagina - Dryness, shortening, disappearance of rugae, pale vaginal lining, smaller caliber, loss of
elasticity
• Cervix - Stenosis, atresia of cervical canal, reduced cervical secretion
Urogenital Complaints are divided into genital and urinary complaints.
Genital Complaints:
Post menopausal bleeding, vaginal dryness, vaginal discharge, vulvovaginal itching, vaginal
infection, dyspareunia, prolapse, loss of libido, genital herpes, labial atrophy.
Management -
• Detailed history including duration of symptoms, severity & recurrence, relevant past medical history,
drug intake should be taken.
• Examination of vulva, vagina, cervix for any apparent lesion, atrophic changes, labial fusion,
adhesions, introital stenosis, pale vagina, urethral caruncle, genital prolapse.
25
Lab findings & investigations -
• pH of vagina > 5
• Cytology of upper vagina - abundant parabasal cells & reduced superficial cells
• Infective agents - candida, trichomonas & other bacteria
• TVS - thin endometrium
• Out patient endometrial sampling
• Hysteroscopy, D & C
Treatment - Local benign lesions should be treated according to the causes. Different operative
procedures for prolapse & relevant management for any malignant cause of post menopausal
bleeding should be followed. HRT can be prescribed in benign cases where it is indicated, provided
there is no contra indication, in minimum effective doses, for a short duration with regular follow up &
counseling of the patient. Topical estrogen preparations are preferred in patients with urogenital
complaints because of greater absorption across thin and atrophic vaginal epithelium. Low dose oral
estrogen (conjugated estrogen, estradiol, & estriol), local estrogen pessaries, cream, & tablets have
been used with beneficial effects on vaginal symptoms3 & for senile vaginitis with little or no side
effects. Estradiol vaginal ring has shown better compliance, less side effects, it is safe & well tolerated3.
Urinary Complaints:
1] Recurrent Urinary Tract Infection
2] Urinary Incontinence
3] Dysurea
4] Increased Urinary frequency
Incidence of urological complaints amongst Indian menopausal women is 35 %, 74%, & 60%
respectively according to different authors4,5.
1] Recurrent Urinary Tract Infection is the most common bacterial infection in elderly. Estrogen
deficiency causes atrophy of epithelium of urethral opening, defective closure mechanism, resulting
in ascending infection from periurethral bacterial flora. Although E. Coli is most common organism,
other gram +ve organisms are also responsible. Polymicrobial infections are found in 10-20% of
cases6. Predisposing factors are instrumentation, catheterization, other morbid conditions such as –
diabetes, malignancy, chronic debility and use of steroids.
Most UTI in elderly are asymptomatic. However when symptoms do occur, the virulence of organism
is often similar as found in younger population.
3] Dysurea & 4] Frequency comes under urethral syndrome
Treatment is aimed at treating infective elements with appropriate antibiotics . Supportive local
estrogen therapy is the main stay.
2] Urinary Incontinence is mainly of two types – Stress and Urge Incontinence.

In 2005, Oskay UY et al in their study of 500 post menopausal women reported that 68.8% of women
had urinary incontinence, amongst those 28.8% had severe urethral incontinence required to use
26
pad. They also reported that amongst these 37.2% of women had SUI, 32.3% had urgency
incontinence & 30.5% had mixed incontinence7.
a] Stress Urinary Incontinence [SUI]

In SUI there is passage of few drops of urine during activities that increases abdominal pressures like
coughing, sneezing, laughing, walking, lifting without any detrusor activity. Pressure in bladder
exceeds pressure in urethra due to increase in intra abdominal pressure rather than detrusor
contraction. Urethral incompetence is due to urethral hypermobility [80-90%], or intrinsic sphincter
dysfunction [10-20%].
Management -
Proper pre operative evaluation is mandatory. Social stigma & embarrassment often prevents ladies
from presenting their problems. Market & Opinion research International [MORI]8, estimated that
there were 2.5 million female sufferers in UK alone in 1991. Detail history is very important as there is
often discrepancy between symptoms & uro dynamic findings. Patient should be examined with full
bladder. It is important to elicit leakage of urine & the degree with rise in intra abdominal pressure.
Investigations & Diagnosis -

• Urine- routine & culture
• Bonney's & Q- tip test to cofirm urethral hypermobility.
• Bladder ultrasound - pre & post void volume
• Electromyography of pelvic floor
• Uro dynamic studies - not mandatory in all cases of SUI, no advantage in genuine SUI, indicated in
mixed aetiology, helps in finding out actual site of defect, mode of treatment & prevention of
unnecessary surgical intervention.
Treatment -
i] Conservative -
Pelvic floor exercises, physiotherapy, Kegel's exercise, vaginal cones, Bio feed back & external
stimulation, mechanical devices [ Contiform, Interol]
ii] Surgical -
1] Vaginal surgery - anterior colporraphy, Kelly's repair
2] Retropubic surgery - Colposuspension - open or laparoscopic, 5 yr. follow up success rate is 90%
& 56.7% respectively
3] Paraurethral injection of collagen or other biodegradable materials
4] Sling operations - Mid urethral- TVT [Tension free Vaginal Tape] or TOT [Trans Obturator Vaginal
tape], most popular, long term effects are awaiting
b] Urge Incontinence -
It is strong, sudden need to urinate followed by bladder contraction resulting in leakage, regardless of
the amount of urine in the bladder. It is mostly because of detrusor instability. In post menopausal
women it may get exaggerated because of recurrent UTI & weakness of internal urethral sphincter.
27
Management -
History in detail & examination to rule out any local causes is must.
Investigations -
• Urine - Routine & Culture
• Ultrasound
• Cystoscopy- to rule out stones & malignancy
• Uro Dynamic Studies in doubtful cases
Treatment -
• Diet
• Antibiotics
• Kegels Exercises
• Bladder Retraining
• Drugs -
- Anticholinergics - Oxybutamine, Tolterodine, solifenacin, Darifenacin
- Antispasmodics
- Tricyclic Anti depressants
- Chemodenervation of Bladder by Submucosal injection of Botulinum Toxin
- Surgery-as last resort, augmentation enteroplasty
- Sacral nerve stimulation
Conclusion -
Urogenital problems in menopausal women needs more and more attention. Active diagnosis, timely
intervention can prevent atrophic vaginitis, various routes of HRT may be used as appropriate to the
individual. Alternative therapies, encouragement of continuation of sexual activity in preventing
vaginal atrophy & shrinkage helps in physical & psychological well being. With good understanding
and co operation between gynaecologist, surgeon & urologist, more & more defects will be corrected
by latest technologies, which will help in alleviating the lives of distressed women.
Suggested Reading
1] Clinical practice of menopausal medicine: How & Why? Menopause and the role of hormone therapy in Indian women. 3rd National revised
consensus meeting guidelines of IMS, Published 2008.
2] Trivedi P., Duddhiya U., Meghal T., Pai P., - Urogynaecological management of menopause- Page 213, Menopause- Current Concepts,
Published- 2004
3] Henriksson L., et al. A comparative multicenter study of the effects of continuous low dose estradiol released from a new vaginal ring verses estriol
vaginal pessaries in post menopausal women with symptoms & signs of urogenital atrophy. Am. J. obstet gynaecol 1994; 171; 624-32
4] Anklesaria B.S. et al, Staging, Symptoms & urological problems in the climacteric, In: Menopause- Krishna U., Shah D., eds, Orient Longman
2004; Ch.2: 11-24
5] Shah D., et al, Symptoms of Menopause, In: Anklesaria B.S., ed, modern Management of Menopause 2007; Chap 4: 10-15
6] Singh R., Urogenital problems in Menopause, Page-296, Progress in Ob/Gy 2. Published 2004
7] Oskay UY et al Acta Obstet Gynaecol Scand Jan 2005; 84[1]: 72-78
8] Market & Opinion research International [MORI], 1991, UK
28
7 Bone Health in Menopause

Dr. H. P. Pattanaik
MD, FICOG, FICMCH
Vice-president, FOGSI – 2009
Secretary General, IMS – 2010
Chairperson, Geriatric Gynaecology Committee,
FOGSI (2004-2008)
Consultant Gynaecologist,
SCB Medical College, Cuttack
Bone health is a major concern for women particularly in the post menopausal period. Human bone is a
dynamic tissue which undergoes continuous breakdown, repair and remodeling. Bone loss occurs when
the rate of bone dissolution exceeds that of bone formation. Maximum bone density occurs in women in
their mid-thirties & skeletal bone mass start decreasing after about age 40 i.e. in the perimenopausal
period.
Human bone consists of 80% cortical bone and 20% trabecular bone. The cortical bone consists of the
dense, compact outer layer and the trabecular bone forms the inner mesh work. Cortical bone seen
mainly in the shaft of long bones and trabecular bone seen in vertebrae, epiphysis of long bones and iliac
crests. Trabecular bone is metabolically more active and more affected by factors leading to bone loss.
The important minerals in bone are calcium salt and phosphates. 90% of body calcium are in bone &
mainly as crystalline hydroxyapatite. Bone remodeling takes place by osteoblasts - the bone forming cells
& osteoclasts – the bone resorbing cells.
Osteoporosis is gradual microscopic reduction of bone tissue leading to fragility of bone finally to
increased risk of fractures. This usually starts in forties in both sexes and there after in women with ovarian
failure when there is accelerated bone loss due to oestrogen deficiency. It is estimated that in old women
about two third of bone loss is due to menopause and one third to ageing. This is mainly due to
osteoclastic activity. The trabecular bones breakdown and there is no bone structure on which new bone
formation can occur. Osteoporosis commonly affects the callus bone than the cortical bone.
In the immediate postmenopausal age the bone loss is as high as 5% on the trabecular bone and 1.5% of
cortical bone every year. The age related bone loss is 1% per year. The accelerated bone loss lasts about 2
to 4 years. It has been estimated that women loose 35% of the cortical bone and 50% of the trabecular
bone in their lifetime.
Oestrogen inhibit osteoclastic activity and thus slows down bone loss but has no action on osteoblastic
activities and so can't form new bone. Testosterone & progesterone appear to stimulate osteoblast and
thereby possibly stimulate bone growth.
Calcium deficiency contributes to 25% of increased bone loss. So, menopausal women should take 1200-
1500mg of calcium daily. Daily dietary intake of standard American diet gives 700mg of calcium. Calcium
carbonate is the most widely prescribed salt. But its absorption is reduced in low gastric acid content i.e.
hypochlorhydria which usually occurs in post menopause. The preferred calcium is calcium aminoacid
chelate which does not require gastric acid for its absorption.
Magnesium is important for the formation of a functional bone matrix. Magnesium converts vitamin D to
29
its active form D3 which helps in absorption of calcium. Women with poor bone health may be deficient in
D3. Menopausal women are deficient in magnesium. Folic Acid and Vitamin B6 (Pyridoxin) have a
pivotal role in promoting bone health. They help in metabolism and excretion of homocystein.
Hyperhomocysteinaemia is associated with defective bone formation and with cardiovascular disease.
Menopausal women show impaired ability to metabolise and excrete homocysteine also they are low in
folic acid and vitamin B6.
Manganese, silicon and vitamin K are necessary for construction of bone matrix around which bone
mineralisation occurs. Vitamin K is found low in individuals with significant bone loss. Overdose of
Vitamin K affects clotting mechanism so daily intake should be 200 µg approximately.
Zinc and copper are also important minerals for bone health that tend to be low in menopausal women.
Both enhance the effectiveness of vitamin D which promotes calcium absorption. Zinc and copper must
be supplemented in proper ratio or else it may affect proper bone formation.
Micronutrient Boron supplementation reduces calcium loss in post menopausal women. Vitamin C play
vital role in immune support and also helps in building bone matrix and connective tissue.
Soy intake is linked with bone health. Dietary soy intake is associated with decrease rate of bone loss.
Isoflavone, the active ingredient of soy, given in 55-90mg daily to postmenopausal women for 6 months
slows down bone loss.
Ostrogen supplementation in form of hormone replacement therapy was advocated for prevention of
osteoporosis and promotion of bone health in post menopausal women. HRT has fallen out of grace
because of infamous(?) WHI trial and today low dose HRT are recommended.
Phytoestrogens or oestrogens derived form plants sources are promoted for bone health particularly in
this post WHI era when postmenopausal women are apprehensive about HRT. Femarelle (DT 56a) is a
promising molecule which is extensively tried in different countries and proves to be effective for
prevention and treatment of osteoporosis.
Hormones play pivotal role in remodeling of bones alongwith several vitamins and minerals.
Supplementing key nutrients along with balanced diet and exercise programme are integral part of bone
health in menopause.
Suggested Reading
1. Burnell JM, Baylink DJ, Chestnut CH, and Teubner, EJ. "The role of skeletal calcium deficiency in postmenopausal osteoporosis." Calcif Tissue
Int. 1986; 38(4):187-92.
2. Heaney RP. "Absorbability of calcium sources: the limited role of solubility." Calcif Tissue Int.1990; 46:300-304.
3. Shikari M, Kushida K, Yamazaki K, et al. "Effect of 2 year's treatment of osteoporosis with 1 alpha-hydroxy vitamin D3 on bone mineral density
and incidence of fracture: a placebo-controlled, double-blind prospective study." Endocr J 1996; 43(2):211-20.
4. Editorial. "Vitamin D Supplementation in the elderly." Lancet 1987; 1(8528): 306-7
5. Joosten E, van den Berg A, Riezler R, et al. "Metabolic evidence that deficiencies of vitamin B12, folate, and vitamin B6 occur commonly in
elderly people". Am J Clin Nutr 1993;58(4):468-76(addendum 1994; 60(1):147).
6. Wilson,T, Katz JM, and Gray DH. "Inhibition of active bone resorption by copper." Calcif Tissue Int 1981;33(1):35-9.
7. Yamaguchi M, and Sakashita T. "Enhancement of vitamin D3 effect on bone metabolism in weaning rats orally administered zinc sulphate." Acta
Endocrinol 1986;111(2):285-8.
8. Hyams D, and Ross E. "Scurvy, megaloblastic anaemia and osteoporosis." Br J Clin Pract 1963;17:334-40.
9. Kalu DN, Masoro EJ, Yu BP, et al. "Modulation of age-related hyperparathyroidism and senile bone loss in Fischer rats by soy protein and food
restriction." Endocrinology 1988;122:1847-1854.
10. Erdman J, Stillman R, Lee K, and Potter S. "Short-term effects of soybean isoflavones on bone in postmenopausal women." Second International
Symposium on the Role of Soy in Preventing and Treating Chronic Disease. Brussels, Belgium, 1996.
11. Agnusdei D, Crepaldi G, Mazzuoli G, et al. " A double blind, placebo-controlled trial of ipriflavone for prevention of postmenopausal spinal bone
loss." Calcif Tissue Int. 1997;61(2):142-7.
12. Sekharan PK, “Estrogen and Bone.” An update on Menopause 2008; 62
30
8 Cardiovascular Dysfunction in Menopause

Dr. Urvashi Prasad Jha
Director Max Institute of OBGyn
Max Hospitals
Chairperson AICC, RCOG North Zone India
Dr. Indrani Ganguli

HOD Department of OBGyn
Ganga Ram Hospital, Delhi
The incidence of cardiovascular disease (CVD) increases with age in women as well as in men. In women
there is an additional risk due to the menopause consequent to the loss of ovarian function1
Globally, it is also the leading cause of morbidity and mortality in women (54% in women vs 43% in men)
Although, the death rate has fallen in men, it has increased in women because of the rising prevalence of
hypertension, diabetes mellitus, sedentary habits, obesity and less decline in smoking.
Cardiovascular disease (particularly coronary artery disease and stroke) is the most common cause of
death amongst postmenopausal women.2 Before menopause, the extent of atherosclerosis in a woman is
equivalent to that of a man 10–15 years younger to her. However, after menopause the risk of a fatal
myocardial infarction secondary to atherosclerosis of the coronary vessels doubles.3,4 Similarly, the risk of
stroke resulting from atherosclerosis of the carotid artery triples in postmenopausal women.5,6
Epidemiologic studies have noted that 16 percent of women die of a stroke, whereas only 8% of men die
of a stroke.7
These high rates of disease amongst women have been shown to result from a decrease in the estrogen
level, with a consequent increase in atherogenic risk factors.8 Specifically, there is an increase in the total
cholesterol level, low-density lipoprotein, (LDL cholesterol) level and lipoprotein(a); a decrease in the
high-density lipoprotein, (HDL cholesterol) level; increased thrombotic tendency; and an occasional
development of insulin resistance.9 This insulin resistance is extremely important given that diabetes
mellitus is associated with a doubling of the risk of an ischemic stroke and an 8-fold higher risk of coronary
artery disease.10,11
A constellation of risk factors which include android adiposity with androgenic hormone profile, higher
LDL:HDL ratio, increased insulin resistance and raised blood pressure is found commonly in the Asian
community. This is probably genetic and helps to explain the increased prevalence of coronary disease in
both sexes with the development of symptomatic coronary disease in Asians approximately 10 years
earlier than in Europeans.12
31
Biological Effects
There are a number of mechanisms by which HT benefits the cardiovascular system.
1. HT affects lipids and lipoproteins, which are important for the development of atheromatous disease.
These effects vary according to the type of estrogen or progesterone used and their route of
administration.
2. Oral estrogens reduce LDL cholesterol and appear more effective than transdermal oestradiol.15 Oral
estrogens are also more effective than transdermal estradiol in increasing HDL cholesterol. This
increase in HDL may be negated by the addition of a progestogen with androgenic properties.16
3. Transdermal estradiols reduce triglycerides, whereas oral estrogens increase them.17 The addition of
androgenic progesterone prevents any rise in triglycerides.17
There may also be reductions in lipoprotein(a); changes in LDL particle size and clearance and
reductions in LDL oxidation. Overall the various changes in the lipids and lipoproteins seen with HT
are probably beneficial.
4. Estrogens also affect glucose and insulin metabolism. Estrogens increase pancreatic insulin secretion,
insulin sensitivity and insulin elimination.18
Androgenic progestogens may oppose these effects but non-androgenic progestogens do not.18
5. Estrogens affect body fat distribution by helping to prevent the postmenopausal increase in central
(android) fat.19
6. Estrogen affects coagulation and fibrinolysis, increasing both pro-coagulant and fibrinolytic activity
but at high doses may result in over all increase in thrombogenesis 20.
7. Estrogens have direct effects on arteries through various genomic and non-genomic mechanishms.21
These include effects on the vascular endothelium, on ion channels and on the renin angiotensin
aldosterone system.
At appropriate physiological doses, estradiol probably improves vascular remodeling, but at

inappropriately high doses it may have adverse effects and cause plaque progression or instability.22
Specific studies concerning premature cardiac events and death in younger premenopausal women
in Indian context need to be highlighted or conducted.
Cardiovascular Risk and HT

The incidence of cardiovascular disease (CVD) increases with age in women as well as in men. In
women there is an additional increase in risk due to the menopause. This is due to the loss of ovarian
function.1 Globally, it is also the leading cause of morbidity and mortality in women (54% in women
vs 43% in men). Although, the death rate has fallen in men, it has increased in women because of the
rising prevalence of hypertension, diabetes mellitus, sedentary habits, obesity and smoking.
There are a number of mechanisms by which HT may benefit the cardiovascular system.
1. HT affects lipids and lipoproteins, which are relevant to the development of atheromatous disease.
These effects vary according to the type of estrogen or progesterone used and their route of
administration
2. Oral estrogens reduce LDL cholesterol and appear more effective than transdermal oestradiol.15 Oral
estrogens are also more effective than transdermal oestradiol in increasing HDL cholesterol. This
increase in HDL may be negated by the addition of a progestogen with androgenic properties.16
3. Transdermal estradiol reduces triglycerides, whereas oral estrogens increase them.17 The addition of
androgenic progesterone does not prevent any rise in triglycerides.17
There may also be reductions in lipoprotein(a); changes in LDL particle size and clearance and
reductions in LDL oxidation. Overall the various changes in the lipids and lipoproteins seen with HT
are beneficial.
32
4. Estrogens also affect glucose and insulin metabolism. Estrogens increase pancreatic insulin secretion,
insulin sensitivity and insulin elimination.18
5. Estrogens affect body fat distribution by helping to prevent the postmenopausal increase in central
(android) fat.19
6. Estrogens affect coagulation and fibrinolysis, increasing both pro-coagulant and fibrinolytic activity
but at high doses may result in over all increase in thrombogenesis.20
7. Estrogens have direct effects on arteries through various genomic and non-genomic mechanisms.21
These include effects on the vascular endothelium, on ion channels and on the renin-angiotensin-
aldosterone system.
At appropriate physiological doses estradiol probably improves vascular remodeling, but at

inappropriately high doses it may have adverse effects and cause plaque progression or instability.22
Primary Prevention
Epidemiological data and observational studies have demonstrated a 35–50% reduction of
cardiovascular events in postmenopausal women on traditional HT.
However the results of the Woman's Health Initiative (WHI) a large prospective randomized
controlled double blind study has confirmed that there is no primary cardio-protection in healthy
women who take continuous combined CEE 0.625 mg and 2.5 mg MPA. The increase in cardiac
events in the first year in the WHI trial could well be because the trial was dealing with a mean age
group of women who were 63.3 years of age and were really an at-risk population. This observation is
similar to the HERS trial on women with documented preexisting CHD where the mean age was 67
years. Women should be informed during counseling that this data need not necessarily apply to
women in their 50s.
In the meanwhile consideration should be given to switching to micronized progesterone, preferably

by the vaginal or the rectal route if acceptable to the women, since these are known to be more lipid
friendly and more physiological.
Coronary Artery Disease

The majority of observational and preclinical studies support the potential benefits of systemic
ET/EPT in reducing coronary heart disease (CHD) risk. Most RCTs have not. Emerging data suggest
that these disparities in findings may be related to the timing of initiation of ET/EPT in relation to the
proximity of menopause. Neither ET nor EPT reduced overall CHD incidence in the WHI study. The
role of ET/EPT in primary prevention of CHD remains unclear when considered for perimenopausal
and early postmenopausal women if initiated early after reaching menopause and continued for a
number of years thereafter. Thus, ET/EPT use for primary prevention needs further evaluation.
Data do not currently support recommendations for use of EPT regimens in secondary prevention of
CHD. Pending additional data, the use of ET/EPT is not recommended as a single or primary
indication for coronary protection in women of any age.
HT & Hypertension
ET plays a part in the synergic action with the antihypertensive drugs in reducing blood pressure
values and ensures an improvement in the metabolic profile. This effect is of great value in lowering
the cardiovascular risk in hypertensive postmenopausal patients. Increase in systolic blood pressure
(SBP) over time is significantly lower in postmenopausal women taking ET than in those not taking
ET. This difference is intensified at older ages.
33
HT does not pose a threat to postmenopausal women with underlying hypertension. The
transdermal/non oral form of estrogen is recommended. Tibolone and raloxifene can be
recommended without any adverse effect.
Venous Thromboembolism
Observational studies and RCTs have found a significant increase in the risk of venous
thromboembolism (VTE) in postmenopausal women using systemic ET/EPT. The RCTs found an
increased hazard ratio (HR) for VTE with both EPT and ET use. VTE risk appears during the first 1--2
years after initiation of therapy and decreases over time. In the WHI, excess VTE risk associated with
EPT and ET use was low overall and even lower in women younger than 60 years when randomized
to HT. Lower doses of oral estrogens may be safer than higher doses.
Stroke
Both ET and EPT appear to increase the risk of ischemic stroke in postmenopausal women, but RCT
data have not been fully consistent in this regard. The WHI EPT and ET arms demonstrated an
increased risk, whereas some other large trials have not. The absolute risk of stroke, however, is lower
in women aged 50--59 years (one additional stroke per 10,000 women per year of ET) or within 5
years of menopause (three additional strokes per 10,000 women per year of EPT) than in older
women more distant from menopause. HT should be particularly avoided for women who have an
elevated baseline risk of stroke.
Are there Pharmacological Alternatives to Traditional HT for Cardioprotection?23,24

The short answer to that is that no single agent has yet been demonstrated.
The relationship between estrogen and cardiovascular disease is far more complex than initially
realized. Till more data is available, HT should be used for non coronary disease concerns. HT is
approved and effective for the treatment of perimenopausal symptoms and osteoporosis.
With respect to cardiovascular disease, women and their physicians should follow AHA/ACC
guidelines including lipid-lowering therapy in women with hyperlipidemia-an established
intervention of CAD which is still underutilized. Statins have been found to be more effective in
women than in men in major primary and secondary prevention trials of statins like 4S (Scandinavian
Simvastatin Survival Study), CARE (Cholesterol and Recurrent Events), LIPID (Long-Term
Intervention with Pravastatin in Ischemic Disease), and WOSCOPS (West of Scotland Coronary
Prevention Study).
Beneficial effects of tibolone on lipid profile and coagulation factors are well documented in human
trials but the randomized control trials with tibolone on reduction of cardiovascular events are not yet
available.
Antioxidants
Role of antioxidants is not established for prevention of CAD in women.
Summarized Recommendations for HT from American Heart Association AHA13
34
Primary Prevention
• EPT is not recommended for primary cardioprevention as demonstrated by the WHI trial randomized
controlled clinical trial.
• There is insufficient data to suggest therefore that HT should be initiated for the sole purpose of
primary prevention of CVD.
• Initiation and continuation of HT should be based on established non coronary benefits, risks and
patient preference
Secondary Prevention
• HT should not be initiated for the purpose of primary or secondary prevention of CVD.
• The decision to continue or stop HT in women with CVD who have been undergoing long term HT
should be based on established non coronary benefits and risks and patient preference.
• If a woman develops an acute CVD event or is immobilized whilst undergoing HT, it is prudent to
consider discontinuance of the HT or to consider VTE (venous thromboembolism) prophylaxis while
she is hospitalized to minimize risk of VTE associated with immobilization. Re-institution of HT should
be based on established non coronary benefits and risks as well as patient preference.
CVS Risk Factors and Role of HT in the Indian Context14,25,26

Certain risk factors are more prevalent in Indian women that may alter the recommendations
regarding HT use in Indian women. This would however further require validating these suggestions
prior to changing clinical practice:
a) Atherogenic dyslipidemia (increased triglycerides, low HDL, and increased small dense LDL-C).
b) Insulin resistance syndrome (hyper tension, diabetes mellitus, central obesity,
Lp(a) and atherogenic dyslipidemia).
c) Low level of HDL is a strong predictor of CAD in Indian women.
d) Increased levels of Lp(a) and homocysteine are more prevalent in Indians, which predisposes them to
premature CAD.
e) In HERS I trial, women who were in the highest quartile of Lp(a) and received HT had impressive
54% decrease in the cardiovascular events. Although no Indian trials with the effect of HT on CHD
are available, it may be possible to assume that benefits of HT may be greater in Indian women.
However, this would require hard clinical evidence prior to making a recommendation.
f) Indian women with a high risk factor (diabetes mellitus, family history of CAD, hypertension, and
insulin resistance syndrome) should be subjected to special investigations such as Lp(a) and
homocysteine assays along with lipid profile, PAI-I and C-reactive protein (CRP).
g) We could consider adding HT to statins in certain subset of women like those with high Lp(a) after a
fully informed counseling session which clarifies the lack of firm Indian evidence but is based on the
subset beneficial effect seen in the HERS I trial.
h) Syndrome X, where symptoms of angina with ECG changes and stress tests like stress thallium or
stress echo show evidence of reversible ischemia with normal coronary angiogram, may be benefited
with HT. Again this is an area for clinical research. AHA/ACC recommends lifestyle changes.
Key Points
a) Pregnancy and preconception periods are optimal time to review common cardiac risk factor status
and health behavior to reduce cardiovascular disease in future.
b) A physician should focus on educating women about CVD risk and should uniformly apply proven
CHD risk-reduction therapies with established benefits in women. Postmenopausal women should
understand that the importance of a lipid profile for cardiac health is similar to a pap smear for cervical
cancer prevention.
35
c) Assessment of carotid atherosclerosis as a surrogate marker of general atherosclerosis by
measurement of intimal medial thickness by B-mode carotid sonography may be utilized before
giving a prescription of HT to diagnose subclinical atherosclerosis in certain subset of patients.
d) The use of statins and aspirin should be recommended as first line measures.
e) HT can have beneficial effects on CHD if started in younger women closer to menopause. Low dose
HT may be initiated in older postmenopausal women if otherwise indicated for non-cardiac benefits.
f) Benefits of HT in preventing atherosclerosis occur only when the therapy is started during the early
postmenopausal years, known as the “window of opportunity” before advanced atherosclerosis
develops.
g) Initiation and continuation of HT should be based on established non-coronary benefits and risks and
patient preference. AHA also recommends life style changes and healthy diet for preventing CHD.
h) Mind modulation by Yoga and pranayama are good suggestions for prevention of CHD along with
diet and exercise, avoidance of excessive alcohol, stress and smoking.
Suggested Reading
1. Stevenson JC. Menopausal hormone therapy. In: Wenger NK, Collins P, eds, Women and Heart Disease London: Taylor and Francis
2005;375–90.
2. American Heart Association. 2000 Heart and Stroke Facts: Statistical Update. Dallas: American Heart Association; 1999.
3. Greendale GA, Lee NP, Arriola ER. The menopause. Lancet 1999;353:571–80.
4. Kannel WB, Wilson PW. Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995;155:57–61.
5. American Heart Association. Heart and Stroke Facts: 1995 Statistical Supplement. Dallas: American Heart Association; 1994:11.
6. Rothwell PM, Slattery J, Warlow CP. Clinical and angiographic predictors of stroke and death from carotid endarterectomy: systemic review. BMJ
1997;315:1571–7.
7. Bonita R. Epidemiology of stroke. Lancet 1992;339:342–4.
8. Finucane FF, Madans JH, Bush TL, et al. Decreased risk of stroke among postmenopausal hormone users: results from a national cohort. Arch
Intern Med 1993; 153:73–9.
9. Kritz-Silverstein D, Barrett-Connor E, Wingard DL. Hysterectomy, oophorectomy, and heart disease risk factors in older women. Am J Public
Health 1997;878:676–80.
10. Whisnant JP, Wiebers DO, O'Fallon WM, et al. A population-based model of risk factors for ischemic stroke. Neurology Rochester, Minnesota
1996;47:1420–8.
11. Laakso M, Ronnemaa T, Lehto S. Does NIDDM increase the risk for coronary heart disease similarly in both low-and high-risk populations?
Diabetologia 1995;38:487–93.
12. Oakley CM. The modern management of the menopause¯a perspective for the 21st century. Berg G, Hammar M, eds. 1994;Chap. 27:251–4.
13. Mosca L, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart
Association. Circulation 2001; 104:499–503.
14. Reedy KS, Salim Y. Emerging epidemic of cardiovascular disease in developing countries. Circulation 1998;97:596–601.
15. Godsland IF. Effects of post menopausal hormone therapy on lipid, lipoprotein, and apolipoprotein(a) concentrations: analysis of studies
published from 1974–2000. Fertil Steril 2001;75:898–915.
16. Stevenson JC. Lipid metabolism In: Genazzaui AR, ed. Hormone Replacement Therapy and Cardiovascular Disease Carnforth: Parthevon
Publishing, 2005:27–35.
17. Crook D, Cust MP Ganger KF, et al. Comparison of transdermal and oral estrogen/progestin hormone replacement therapy; effects on serum
lipids and lipoproteins. Am J Obstet Gynecol 1992;166:950–5.
18. Spencer CP, Godsland IF, Cooper AJ, et al. Effects of oral and transdermal 17B estradiol with cyclical oral norethindrone acetate on insulin
sensitivity, secretions and elimination in post menopausal women. Metabolism 2000;49:742–7.
19. Gambaciani M, Ciaponi, Cappaglli B, et al. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal
women. J Clin Endocrinol Metabolism 1997;82:414–7.
20. Winkler UH. Menopause, hormone replacement therapy and cardiovascular disease: a review of haematoserological findings. Fibrinolysis
1992;6(Suppl 3):5–10.
21. Stevenson JC. Cardiovascular effects of estrogens. J Steroid Biochemical Biol 2000; 74:387–93.
22. Wingrones CS, Gurr E, Godsland IF, Stevenson JC. 17 beta-estradiol enhances release of matrix metalloproteinase 2 from human vascular
smooth muscles cells. Biochim Biophys Acta 1998;1406:169–74.
23. Lissin LW, Cooke JP. Phytoestrogens and cardiovascular health. J Am Coll Cardiol 2000;35:1403–1410.
24. Mosca L, et al. Design and method of the Raloxifene Use for The (RUTH) study. Am J Cardiol 2001;88:392–395.
25. Enas A Enas, et al. Coronary artery disease in women. Indian Heart Journal.
26. Anand SS, et al. Difference in risk factors, atherosclerosis, and Coronary artery disease between ethnic groups in Canada: The Study of Health
Assessment and Risk in Ethnic groups (SHARE). Lancet 2003;356:279–284
36
9 Osteoporosis Extent of the Problem
Dr. Jaishree Gajraj

MD DGO FRCOG ( UK ) FRCS ( Ed )
Sr. Consultant Obstetrician & Gynaecologist
Apollo & Fortis Malar Hospitals
MANGAI Women's Health Exclusive Chennai
Bone loss with ageing is an universal phenomenon resulting in low skeletal mass. This along with
microarchitectural deterioration of bone tissue leads to enhanced bone fragility and in turn to increased
fracture risk. Strength of bone in the elderly woman is mainly determined by the quantity of bone mass.
Bone mass itself is believed to be influenced by the genetic profile, calcium intake and physical activity.
Osteoporosis is a chronic disease that can affect people of any age but perhaps has major implications in
the elderly. It is frequently referred to as a silent killer but the condition itself has to be recognized by
clinicians as a silent epidemic.
Perimenopausal osteoporosis is caused by oestrogen deficiency which increases the rate of bone turnover
along with an excessive resorption and inadequate formation at each remodeling site. The consequence
of such an imbalance in remodeling is an acceleration in the loss of bone mass leading to progressive
thinning and disruption of trabecular architecture. There is therefore a resultant disproportionate loss of
bone strength.
Osteoporosis becomes clinically apparent very often only when an individual sustains a fragility fracture,
by which time the disease is well established. No precise longitudinal data are known but a realistic
estimate would be 1 in 3 women and 1 in 8 men over the age 50 would be affected by osteoporosis
worldwide. Whilst breast cancer is diagnosed in every 8 th woman, every 3 rd woman is diagnosed to
have some degree of osteoporosis.
Without doubt osteoporosis is a clinical and public health problem - but what is the extent
of the problem
Life Expectancy
Globally life expectancy at birth has doubled in the last half century. Approximately 580 million men
and women are over 60 years of age and by 2020 this figure is believed to touch 1 billion(1) of this 1
billion atleast 50% would be post menopausal women. In India the percentage increase in the elderly
population by the year 2050 as compared to 1999 is expected to be 242%
From an average of 30 years in the late 1940s life expectancy has currently increased to well above
60. The number of women in the age group 50 - 59 years is projected to increase from 36 million in
2000 to 63 million in 2020.(2)
An inevitable fallout of this is the fact that women spend atleast one third of their life post menopause
and are therefore more susceptible to Osteoporosis.
37
Osteoporosis
The actual risk of osteoporosis and osteoporosis related fractures varies from one country to another.
In the United Kingdom there are over 200,000 osteoporotic fractures each year, a number which is
expected to double over the next 50 years.( 3 ) In the USA the estimated lifetime risk of hip fracture to a
white American woman is approximately 15% and 70% of postmenopausal women are osteoporotic
by 80 yrs of age.
Seventy per cent of the 1.3 million fractures that occur annually in the USA in patients aged 45 years
or older are attributable to osteoporosis. From the age of 50 years a woman has 32% risk of vertebral
fracture, 16% risk of lower arm fracture and 15% risk of Hip fracture
In India, 30 million women suffer from osteoporosis of which 50% are postmenopausal. Indians have
a lower peak bone mass than their North American or European counterparts. Osteoporotic fractures
occur 10-20yrs earlier in Indians as compared to Caucasians.
The International Osteoporosis Foundation quotes that an approximate 36 million Indian women will
be affected by this condition by the year 2013.Indian men and women are estimated to have a lower
bone density as compared to Americans and Europeans.( 4 ) This high prevalence is probably related to
nutritional Vitamin D and Calcium deficiency. In certain ethnic groups lack of exposure to sunlight can
result in suboptimal levels of Vit D. Diabetes, Hypothyroidism, certain chronic infections,
environmental and genetic factors can all influence the onset, progression and severity of
Osteoporosis
80% of the urban Indian population has Vit D levels below 20 ng / ml as against the ideal 30 ng / ml. A
region wise study also showed the Vit D levels amongst South Indians was 6 to 20 ng / ml compared
to 2 to 12 ng / ml in North Indians. Vit D deficiency surprisingly is present in healthy children in the age
group 10 to 18 years. 35% of these children had Vit D levels below 8 ng / ml.
Conclusion
Osteoporosis is now identified as one of the most important diseases affecting the human race, along
with hypertension and diabetes mellitus. Advances in technology and communication have resulted
in a downward trend in mortality in India. Analysis of the disease pattern shows an epidemiologic
transition from communicable to non communicable diseases. Unfortunately preventable diseases
form a major proportion of the mortality figures .Whilst atleast 50% of Indian women above the age of
45 are believed to suffer from Osteoporosis atleast 1 in 4 of those who sustain an osteoporotic fracture
will die within a year !!
Facts and figures although difficult to digest help us to understand the extent of the problem and
perhaps implement strategies to detect , prevent and treat osteoporosis.
Suggested Reading
1. Family Welfare Programme in India, Year Book, 1996 – 1997. New Delhi 1998
2. United Nations World population Prospects The 2000 revision. Comprehensive tables ( Vol 1 ) 2001
3. The Guideline Development Group Osteoporosis : Clinical Guidelines for Prevention and Treatment. London.Royal College of Physicians of
London 1999
4. Gupta A ,Osteoporosis in India – the nutritional hypothesis,Metabolic Bone Disorders, Indian Society for Bone and Mineral Research, Ed.Mithal
A, Rao D S, Zaidi M. 1998 ; 115 – 132
38
Measurement of Bone Quality And Quantity

10
- Clinical Uses & Recent Advances
Dr. Anand Parihar, MD, DMRD
Director, Mandakini Imaging Centre, Mumbai
Hon Professor Radiology
K. J. Somaiya Medical College & Hospital, Mumbai
President, Association of Medical Consultants
Dr. Deepti Mhatre, MD

Clinical Associate, Mandakini Centre
Chembur Mumbai
Dr. Ketki Kulkarni, MD

Clinical Associate, Mandakini Centre
Chembur Mumbai
“A stitch in time saves nine”

- Old English proverb
Introduction
Osteoporosis is called a silent killer, as it comes unannounced. The first time a person is diagnosed
with osteoporosis is when they present with a fracture. Osteoporosis is an abnormal reduction in bone
mass and bone deterioration leading to increased fracture risk. Bone is a living, growing tissue, and
throughout our lifetime, new bone cells grow and old bone cells break down to make room for the
new, stronger bone. It is postulated that 20% of the people who get a hip fracture will die within one
year of the fracture. The relationship between low bone mineral density (BMD) and fracture risk is
analogous to the relationship between high serum cholesterol and risk of myocardial infarction.
Osteoporosis develops as a result of mismatch between the osteoblastic and osteoclastic activity i.e.
the old bone breaks down faster than the new bone can replace it. As this happens, the bone loses
minerals. The measurement of bone mineral density is hence used as a marker for osteoporosis.
Women who have gone through menopause are more likely to get osteoporosis than men or younger
women. Methods that can give us an idea of the bone mineral density will be able to help us detect
osteopenia and hence prevent osteoporosis in patients.
Definition of osteoporosis
WHO definition of osteoporosis is based on BMD levels
1. Normal-bone density within 1SD of young adult mean.
T score>-1=BMD within normal range.
2. Low bone mass (osteopenia) bone density –1 to-2.5 SD below young adult mean.
T score –2.5 to –1. Increased risk of fracture but not osteoporosis
39
3. Osteoporosis – 2.5 SD or more below young adult mean
T score more than-2.5 - Severe established osteoporosis - Bone density >2.5 SD below young
adultmean and one or more broken bones
T-Score Means: Young Normal Reading

This is comparing the patients reading with that of a young healthy 30year old adult of the same sex.
This is a comparison between the solidness of the bones with average young healthy population and
is measured in standard deviations (SD)
Z-Score means: Age matched reading

This measures the patient's own reading with what should be normal for his/her age, size and sex.
Since the BMD is low in elderly, age matched reading are misleading.
Bone strength is the maximal load that can be applied before fracture occurs and is influenced by-
1) Mass
2) Geometry
3) Architecture
4) Bone tissue quality.
Bone tissue quality depends on degree of mineralization and matrix characteristics. The determinants
of bone strength are as follows:
1) Bone mineral density. (BMD)
2) Bone dimensions - External diameters Predicts 55% of variance of bone strength
3) Cortical thickness
4) Bone micro-architecture
Bone Mineral Density

Serial BMD testing is an essential component of osteoporosis management and therefore high quality
and cost-effective patient care requires that healthcare providers receive valid BMD reports from
adequately trained interpreters. There are different methods of testing for bone quality using bone
density measurements. BMD is most commonly used, non-invasive measure of early diagnosis of
osteoporosis. The reports for BMD are mentioned as T-scores and Z-scores. Values obtained at
proximal femur and lumbar spines are used to diagnose osteoporosis by applying criteria established
by WHO. BMD predicts approximately 66-74%of variance of bone strength, and BMD corresponds
to the ratio between bone mineral content (hydroxyapatite) and bone scanned area.
This is done by:

1. Dual-energy X-ray absorptiometry (DEXA). This is considered today as the gold standard in
BMD measurements especially in case of suspected osteoporosis. The purpose of monitoring medical
therapies is to ensure reduction of future fracture risk, stabilize or increase bone mass, and preserve or
improve bone quality and strength. Central DEXA assessment of the hip or spine is currently the “gold
standard” for serial assessment of BMD. However, biological changes in bone density are small
compared to the inherent error in the test itself, and interpretation of serial bone density studies
depends on appreciation of the smallest change in BMD that is beyond the range of error of the test.
This least significant change (LSC) varies with the specific instrument used, patient population being
40
assessed, measurement site, technologist's skill with patient positioning and test analysis, and the
confidence intervals used. Changes less than 3 to 6% at the hip and 2 to 4% at the spine from test to
test may be due to the precision error of the testing itself.
2. Quantitative Ultrasound - using a peripheral bone like the calcaneum, tibia, patella or the phalynx
for measuring the BMD. This is the most cost effective measures of doing screening BMD for the
general population and detection of patients at risk. Peripheral skeletal sites do not respond in the
same magnitude as the spine and hip to medications and thus are not appropriate for monitoring
response to therapy at this time.
3. Quantitative Computed Tomography - is most commonly used for measuring the spine but can
be used for other sites as well. Trabecular BMD of the lumbar spine can be used to monitor age-,
disease-, and treatment- related BMD changes in men and women. Precision of acquisition should be
established by phantom data and analysis precision by re-analysis of patient data.
Table: Comparison between the different methods of doing BMD
unit of Uses
Technique Site measurement Advantages/disadvantages
DXA Lumbar spine, area density Diagnosis, Very low radiation

proximal femur, g/cm2 monitoring exposure, precise, quick.
transverse Disadvantage-APspine
body, forearm, measurements influenced
heel, phalanges. by degenerative chances
and other artifacts. Two
dimensional only.
QCT lumbar spine, Volumetric Diagnosis, More sensitive than DEXA.
hip, forearm density(g/cm3) monitoring Directly measures trabecular
bone loss in central aspect of
vertebral body. 3-dimentional.
Disadvantages-high
radiation exposure, less
presice, more expensive.
Qualitative Heel, patella, Speed of sound, Risk Inexpensive,
USG tibia. broad band, assessment. easily transportable.
USG attenuation. No radiation.
Bone Micro-architecture is assessed by -

1. Histo-morphology - two dimensional evaluation of micro-architecture provides information of bone
quality including structure and turnover.
2. Micro-computed tomography (micro CT) – shows the three dimensional micro architecture of bone
as well as the relative bone volume and trabecular thickness.
Bone tissue quality showing the degree of mineralization

Nano-indentation technique applies to investigate tissue quality by measuring both hardness and
elasticity of dry and wet bone tissue with a high spatial resolutionEvaluation of bone strength for
different parts of skeleton
41
• Compression of vertebral body or proximal tibia
• 3-4 point bending test of long bones
• Shear test of femoral neck
• Load deflection curve
Clinical applications
Bone quality and strength is important for the diagnosis of certain conditions and also for evaluation
of the treatment
• Post menopausal osteoporosis

• Family history of osteoporosis
• Surgical menopause
• Premature menopause
• Primary hypo or hyperthyroidism
• Hypogonadism
• Life style factors
- low calorie intake
- smoking
- alcohol overuse
- lack of exercise
- chronic immobility
• Certain medications
- long term >5 months steroid therapy
- GnRH agonist therapy
• Osteopenia apparent on X-ray
• Medical conditions like Celiac disease, Crohn's disease
The Importance of screening for osteoporosis

Early detection of low bone mass is the most important step in prevention and treatment. If there is
osteopenia or osteoporosis, a person can take action and remedial measures with life style
modifications to stop the progression of bone loss. If acted upon early, prevention is possible. The best
remedy for osteoporosis is regular exercise and proper nutrition.
Newer Applications and Advances

1. To determine the diagnostic accuracy of mandibular and maxillary bone density in detecting
osteoporosis using receiver operating characteristic (ROC) analysis. Density of the premolar region
reaches a fair diagnostic accuracy, which might improve when including additional factors in the
analysis and refining the densitometric tool.5
2. The role of the dental surgeon in detecting osteoporosis: the OSTEODENT study.6
Those with osteoporosis tended to have a low OSIRIS score and a thinned cortical mandibular
border. The area under the ROC curve for using both cortical width and OSIRIS to predict
osteoporosis was 0.90 (95% CI = 0.87 to 0.92). Dentists have a role to play in the detection and
referral of patients at high risk of osteoporosis.
42
3. Advanced imaging of bone macrostructure and microstructure in bone fragility and fracture repair.7
The methods available to quantitatively assess macrostructure include computed tomography and,
particularly, volumetric quantitative computed tomography. Methods for assessing microstructure of
trabecular bone include high-resolution computed tomography, microquantitative computed
tomography, high-resolution magnetic resonance imaging, and micromagnetic resonance imaging.
These new techniques help to illustrate the process of fracture-healing by defining the skeletal
response to innovative therapies and assessing biomechanical relationships. Research into the
molecular and cellular pathways focusing on bone fragility and fracture-healing has led to new
potential treatments to aid in fracture-healing.
4. Investigating new BioMEMS techniques for early detection of osteoporosis.8 The biomarkers provide
a promising challenge of clinical proteomics for early disease detection. Different techniques like
optical and electrochemical testing are been studied comparatively. New peaks have been identified
in UV-visible spectroscopy at 420nm and high sensitivity is achieved by electrochemical technique
with ng/ml to pico/ml level detection of bonemarkers. An electrochemical technique is found to be the
best suitable for developing a new bioMEMS chip.
Take home message: Osteoporosis - Facts
• 30 million women in India suffer from osteoporosis and expected to rise to 36 million by 2013.
• It is a silent killer
• 12-20% patients will die within one year of a hip fracture
• 30-50% of women and 15-30% of men will suffer from osteoporotic fracture in their lifetime
• In women over 45years, osteoporosis accounts for more days spent in hospital than any other
disease.
Suggested Reading
1. Brian Lentle, Jerilyn Prior. Osteoporosis- what a clinician expects to learn from patients BMD Test.Radiology- 2003;228:620-628
2. Leon Lenchick, P.Rochims, D. Sartoris. Current Concepts in Osteoporosis. Am Journal Roentgenol -1998;168:905-911.
3. Hou YL, Liao EY, Wu XP et al. Effects of the sample size of reference population on determining BMD reference curve and peak BMD and
diagnosing osteoporosis Osteoporos Int. 2008 Jan;19(1):71-8. Epub 2007 Aug 3.
4. Durosier C, Hans D, Krieg MA et al. Combining clinical factors and quantitative ultrasound improves the detection of women both at low and
high risk for hip fracture.Osteoporos Int. 2007 Dec;18(12):1651-9. Epub 2007 Jul 11.
5. Nackaerts O, Jacobs R, Devlin H, et al. Osteoporosis detection using intraoral densitometry. Dentomaxillofac Radiol. 2008 Jul;37(5):282-7.
6. Devlin H, Allen P, Graham etal. The role of the dental surgeon in detecting osteoporosis: the OSTEODENT study. Br Dent J. 2008 May
24;204(10):E16; discussion 560-1. Epub 2008 Apr 18.
7. Kalpakcioglu BB, Morshed S, Engelke K, Genant HK. Advanced imaging of bone macrostructure and microstructure in bone fragility and fracture
repair. J Bone Joint Surg Am. 2008 Feb;90 Suppl 1:68-78
8. Singh K, Kim KC. Investigating new BioMEMS techniques for early detection of osteoporosis. Conf Proc IEEE Eng Med Biol Soc.
2007;2007:2265-8 (EPub)
43
The Role of Calcium and Vitamin D
11
and Micronutrients in Bone Health
Dr. Smita Kokare
M.D., D.G.O.
Clinical Associate,
Mandakini IVF Centre and Fertility Clinic , Mumbai
There is growing interest in the role of calcium supplied in different vehicles on indices of bone health in
the population in general. Micronutrients encompass vitamins and minerals and a variety are implicated
in the maintenance of bone health.
Ca and vitamin D
An adequate intake of calcium, lifelong, is necessary for the acquisition of peak bone mass and
maintenance of bone health. The skeleton contains 99% of the body's Ca stores, when the exogenous
supply is inadequate, bone tissue is reabsorbed from the skeleton to maintain serum ca at a constant
level.
Type and timing of Ca supplements

Dairy products (e.g., milk, cheese, and yogurt) are the most common sources of dietary calcium.
Calcium supplements may be used if patients are unable to consume adequate amounts of calcium
through foods. The two most common calcium supplements are calcium carbonate and calcium
citrate. Calcium phosphate and calcium gluconate are also available. Calcium carbonate contains
40% elemental calcium, the highest amount available among calcium formulations; it should be
taken with food to maximize absorption capacity by providing an acidic environment. This option is
cost-effective and may be preferred for most patients. Calcium citrate may be taken with or without
food, but it is more expensive, contains less elemental calcium (21%), and is available in fewer
formulations. Calcium citrate may be beneficial for patients with achlorhydria and those taking
histamine H2-receptor antagonists or proton-pump inhibitors.
There is growing support for the effect of Ca supplementation on the suppression of both PTH
secretion and bone resorption, but controversy still remains as to the optimum timing of
supplementation administration
Table 1:Dietary Reference Intakes For Calcium
Group Calcium(mg/day)
0-6months 210
6m-1yr 270
1-3yrs 500
4-8yrs 800
9-18yrs 1,500
19-50yrs 1,200
>50yrs 1,500
Women, pregnant or lactating 1,500
44
In an interesting study presented by S Oetolani, Istito Auxologico Italiano, Milan, Italy, and associates,
a three way randomised study of 12 postmenopausal women was undertaken comparing no
treatment with 2 different dosing schedules of Ca (1 dose of 1200mg at evening or 2 doses of 600mg
at 12 hr interval). The aim of the study was to determine whether two separate doses of calcium lead
to more steady suppression of bone resorption. Results indicated that serum Ca was increased and
serum PTH reduced by Ca administration with either dosing schedule as compared with placebo and
although overall suppression of PTH and bone resorption obtained with 2 daily doses of 600mg of
calcium is similar to that of a single dose 1200mg, repeated doses provides a more steady suppression
of bone resorption .
Another important paper is one presented by Palbertazzi and co-workers, University of Hull UK
comparing two types of Ca preparations (ossein hydroxyapatite [OHC]v/s tri-Ca phosphate). Both
preparations derived from porcine bone powder, but the second supplement type had the organic
matrix destroyed by ashing. The study involved 153 postmenopausal osteopenic women who were
randomised into 1of 3 treatment groups. Measurements of bone resorption performed at baseline 3
months and 6 months and bone density at baseline and 6 months. Results indicated that both the
OHC and TCP supplements significantly reduced marker of bone resorption compared with placebo
group, but the effect was not as marked in the TCP group. Spine BMD was found to be increased by
0.5%with OHC and decreased with both placebo (0.8%) and TCP (0.7%).
Vitamin D promotes bone formation by improving intestinal absorption of Ca and phosphate and by
stimulating maturation and mineralisation of the osseous ground substance - the osteoid. A daily
allowance of 400-800 IU is required for healthy bone.
High dietary levels of phosphates (found for example in many carbonated drinks) are associated with
a negative calcium balance.
Magnesium
Hypomagnesemia is one of the possible factors in osteoporosis. Food sources
rich in magnesium are green leafy vegetables, unpolished grains, nuts, milk and
meat.
Vitamin A
Vitamin A has many roles in maintenance of health. While it is important for normal vision, high
vitamin A intake is associated with a higher risk for fractures as it is a vitamin D and Ca antagonist.
Consuming a diet rich in fruit and vegetables is a reasonable way to meet vitamin A needs rather than
taking supplements.
Vitamin K
It is now apparent that Vit K not only affects blood clotting but also plays a role in bone metabolism
and potential protection against osteoporosis. Vitamin K is required for the gamma-carboxylation of
osteocalcin. Studies suggest that long term use of coumarin based anticoagulants such as warfarin
adversely affects vertebral BMD and fracture risk. Vegetables particularly dark green leafy vegetables
are rich source of vitamin K.
Other micronutrients and dietary components

So many other nutrients and dietary factors are important for long term bone health. These include
zinc, copper, manganese, boron, vitamin C, The B vitamins, potassium sodium and phytoestrogenes.
Phytoestrogens are plant substances that have similar effects like those of estrogens and help in
45
preventions of osteoporosis.
Other important groups are isoflavones and lignans. Isoflavones are found in soybeans, other
legumes (beans and peas). The major isoflavones are genistein and daidzein. The major ligans are
entrolactone and entrodiol found cereals, vegetables and fruit.
Suggested Reading
1. Ortolani S, Scott A, Cherubini R. Comparison of single verses repeated daily administration of oral Ca to suppress bone resorption in
postmenopausal women Osteoporos Int 2002;13(suppl1):Program and abstracts of the IOF World congress on Osteoporosis; May 10-
14,2002;Lisbon, Portugal.
2. AlbertazziP,Steel SA, Purdie DA, HowarthE. Comparison of effects of two different types of calcium supplementation on markers of bone
metabolism in a postmenopausal osteopenic population with low calcium intake: double blind, placebo controlled trail. Osteoporos Int
2002;13(suppl1):Program and abstracts of the IOF World congress on Osteoporosis;May 10-14,2002;Lisbon ,Portugal.
3. Bolland MJ, Barber PA, Doughty RN, et al Vascular events in healthy older women receiving calcium supplementation : randomised controlled
trail .BMJ 2008;336:262-266
4. Pearson DA. Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Pract.2007
Oct;22(5):517-44.
46
Role of Estrogen in Prevention and

12
Treatment of osteoporosis
Dr. C. N. Purandare
MD (BOM), MA Obst. (Ireland),
DGO, DFP, D.Obst.RCPI (Dublin),
FICOG, FRCOG (U.K.), FICMCH, PGD,MLS
PRESIDENT FOGSI 2009, SECRETARY GENERAL FOGSI 2004 - 2008
ASSOC. EDITOR JOURNAL FOGSI, Consultant Obst. & Gyn.
St.Elizabeth Hospital and BSES Hospital, Mumbai
Ex.Hon. Professor Obst. & Gyn., Grant Medical College & J. J. Hospital, Mumbai 400 008
Dr. Madhuri Patel

MD (BOM), D.G.O., FICOG,
Joint Secretary FOGSI , 2009
Chairperson Study on Female Breast Committee, FOGSI
Consultant Obstetrician & Gynecologist, Mumbai
Ex. Associate Professor, GMC, Mumbai
Chairperson Medico-legal committee, MOGS
Dr. Nikhil Purandare

MD, MRCOG, MRCPI, MICOG, D.G.O.
Specialist Registrar OBGY, Ireland
Introduction
Osteoporosis is a systemic skeletal disease characterized by low bone mass and a deterioration of
micro-architecture of bone tissue, leading to enhanced bone fragility which results into increase in the
fracture rate even with little or no trauma. It is the most prevalent bone problem in the elderly and has
become a major global public health problem due to tremendous increase in the elderly population
throughout the world. Because of this demographic change, the number of hip fractures occurring in
the world each year will increase approximately 6 fold from 1990 to 2050 and the proportion
occurring in Europe and North America will fall from 50% to 25% as the number of old people in
developing countries increase1. It has a lot of impact on national economy. Twenty five million people
suffer from osteoporotic fractures in U.S.A. and more than 1.3 million fractures occur per year in
U.S.A. It is estimated that annual health costs due to fractures in U.S.A. amount to 10 billions U.S.
dollars, DM 1 billion in Germany and 500 million £ in U.K.2
Effects of Estrogen on bone

Estrogens in women are essential for the formation and maintenance of sufficient bone mass.
Osteoclasts and osteoblasts have estrogen receptors. Estrogen act both directly and indirectly on
osteoblasts. Estrogen directly inhibits lysosomal enzyme production in the osteoclasts and thus
decreases bone resorption. Indirectly estrogen inhibits maturation of osteoclasts from osteoclastic
precursor cells. Osteoblasts precursors produce several cytokines, some that stimulate and others that
inhibit osteoclast activity. The osteoblast derived osteoclast Stimulatory factors are interleukins (12-1,
12-2, 12-6, 12-11) where production of interleukins are inhibited by estrogen in bone. Osteoblast
derived osteoclast-inhibiting factor i.e. transforming growth factor β (TGF-β ), the production of which
47
is stimulated by estrogens. After menopause due to estrogen deficiency the above process is reversed
hence there is increased in the bone resorption.
Prevention and treatment of Osteoporosis

1. Primary prevention: To ensure that each woman achieve peak bone mass, provided prevention
should start at menarche and adolescent years. A combination of adequate and appropriate
nutrition, physical exercise and healthy life style will help to achieve optimal peak bone mass.
2. Secondary prevention is to diagnose osteoporosis and preventive measure to be taken for prevention
of osteoporotic fracture and further deterioration of the disease.
3. Tertiary prevention is by preventing further osteoporotic fracture where osteoporotic fracture has
already occurred in the past.
Estrogen Replacement Therapy (ERT) in The Prevention and Treatment of Osteoporosis

Estrogen therapy is one of the most commonly prescribed treatment for the prevention of
postmenopausal osteoporosis and for a treatment of established bone loss. Multiple trials have
demonstrated the positive effect of estrogen in the improvement of the bone mineral density and
lower doses have also proven efficacious with fewer side effect. Hence, many experts recommend
that all women should use ERT after the menopause. But general treatment is obviously unrealistic
hence, all experts agree that ERT is necessary when osteoporosis or risk factors for the disease already
exists.
The prevention of Osteoporosis is very important because once osteoporosis sets in bones can never
be completely restored and ERT after osteoporosis can prevent only further bone loss.
Mechanism of Action
The main action of estrogen is at the cellular levels where it inhibits the osteoclasts and thus decreases
bone resorption. Estrogen has also been shown to antagonize PTH stimulation of bone resorption,
increases calcium absorption from gastrointestinal tract and renal calcium conservation.
Numerous studies have shown that all estrogens, irrespective of the mode of administration are
effective in maintaining BMD.3, 4
Table 1 : Shows commonly used estrogens recommended with doses which preserves bone density
Oral Conjugated Equin Estrogen (Premarin) 0.625 mg
Estradiol Valerate 2 mg
Estropipate 0.625 mg
Popemerize Estrogen Sulphate (Harmogen) 1.5 mg
Transdermal Estradiol 50µg twice weekly
Percutaneous Estradiol Gel 1.5 mg daily
Subcuatenous Estradiol 50 mg, 6 monthly
Despite the multitude of published studies on ERT / HRT in postmenopausal women, only 15
observational studies included fracture as a study endpoint. These trials reported that there was
reduction in fracture risk in postmenopausal women who used ERT / HRT compared to case
controls4. Epidemiological studies of ERT indicates that when ERT was taken for more than 5 years
there was 50 to 60 percent decrease in fractures of arm and hip5 and when estrogen was
48
supplemented with calcium, an eighty percent reduction in vertebral compression fracture was
observed.6 It has been observed that the more potent estrogen and its esters and CEE have a
protective effect on bone turnover, but not estriol.
In the postmenopausal women estradiol levels vary greatly from undetectable upto 25 pg/ml. The
skeleton effects of endogenous serum estradiol were assessed in 274 women 65 years and older who
participated in the study of osteoporotic fractures. Women who had estradiol levels from 10 to 25 pg /
ml had 4.9%, 9.6%, 7.3% and 6.8% greater BMD at the total hip, calcaneous, proximal radius and
spine, respectively compared to women whose estradiol levels were less than 5 pg/ ml7. It has been
observed that estradiol blood level of 40 to 60 pg / ml is required to protect against bone loss3. Women
with premature menopause (less than 40 years), alcohol consumption and cigarette smoking will
require higher doses of ERT.
Commencement of ERT
Since the greatest damage of bone mass occurs in the first few years after menopause, ERT is most
beneficial when instituted as early as possible. However, even at later age when significant amount of
bone mineral mass already have been lost, ERT can prevent further bone loss. When ERT was given
in women over the age of 65 years, it has been documented to protect against fractures 8. Optimum
treatment should start as soon as possible after the last menstrual period and should continue at least
for 8 to 10 years. Some experts even suggest that ERT should be used until the end of life which can
provide maximum protection.
There is a risk of endometrial hyperplasia and carcinoma when estrogen alone is taken for a long time
in an intact uterus. Hence, progestrogen supplementation for ten or more days in each month is given
to reduce endometrial proliferation. Smith and Studd reported endometrial hyperplasia in 5 – 6
percent cases of endometrial biopsis carried out in women with long term unopposed estrogen
therapy 9. Progestrogens that have been clinically assessed for such protection are norethisterone (5
mg), medroxy progesterone acetate (5 mg) dydrogesterone (10mg) and Levonorgestrel ( 75 mcg).
Some studies have reported that when progrestrone is added to oestrogen, progestrone can lead to
an apparent synergistic increase in bone formation associated with a positive balance of calcium10,11.
While other studies have failed to find a greater impact on bone, comparatively estrogen alone to
estrogen plus progrestrone.12
Some studies have reported that addition of testosterone to an estrogen therapy has additional
beneficial effect on bone.13, 14 Others have reported a greater increase in bone density with an estrogen
– androgen combination compared with estrogen alone, but blood estrogen levels were higher than
those associated with standard postmenopausal hormonal therapy. 15
In the Women's Health Initiative (WHI) studies, the risk of breast cancer associated with estrogen with
or without progestrone was evaluated. The risk of breast cancer was slightly increased with combined
estrogen and progestin after 3 years of use. When estrogen alone was given in women with
hysterectomies did not increase the risk of breast cancer compared to placebo in other portion of the
hormonal replacement trial of WHI study. Other several studies also found a link between duration of
estrogen and progestrone use and breast cancer risk.16, 17 Addition of progestin increases the risk of
breast cancer compared to estrogen alone, because it has been observed that mitotic activity in the
breast during normal menstrual cycle is greatest when progestrone levels are highest.
49
Effects of Stopping ERT
The protective effect of estrogen rapidly dissipates after treatment is stopped because estrogen
withdrawal is followed by rapid bone loss, similar to that after menopause.18 In a Swedish case-control
study, most of the beneficial effects of ERT was lost five years after discontinuing the treatment.19
Hence, maximum protection against osteoporotic fractures requires life long therapy.
It is recommended to measure the bone density in treated women when they are in their late 60s as
some of these women may have failed to respond to ERT. Hence, treatment in such cases can be
modified. Along with ERT sufficient amount of calcium, vitamin D and physical activity are also
necessary.
Largest trials by Women's Health Institute (WHI) reported adverse effects of estrogen and
progestrogen therapy. These include an increase incidence of thromboembolic phenomenon,
cardiovascular disease and strokes. Hence, the trial's using continuous combine HRT in WHI have
been stopped after 5 years. Therefore, today we recommend use of alternatives like Tibolone and
SERMS, which have been successfully used for the prevention of postmenopausal osteoporosis.
Conclusion
Estrogen therapy had proven to increase bone mineral density at all skeleton sites. Prevention and
treatment of osteoporosis and estrogen therapy has been supported by a wealth of data which
includes a meta-analysis of 22 estrogen trials, Cohort studies, results of the WHI and Million Women
study and trials with bone mineral density outcome. However, use of estrogen therapy has its
attendant risks and therefore the risk to benefit ratio should be carefully weighed for each individual
woman.
Suggested Reading
1. Cooper C, Campion G, Melton III IJ. Hip fractures in the elderly: a world-wide projection. Osteoporosis Int 1992;2:285-289
2. Robert A Henry. Hormone Replacement Therapy and Menopause. Shering AG 3rd edn D-113342 Berlin 2000; 67-68
3. O 'Connell MB, Pharmacokinetic and pharmacologic variations between different estrogen product J. Clin Pharmacol: 1995 : 35 : 185.
4. Marcus R et al. Antiresorptive treatment of postmenopausal osteoporosis : Comparison of study designs and outcomes in large clinical trials with
fracture as an endpoint. Endocr Rev 2002 : 23 : 16-37.
5. Michaesson K, Baron JA et al. On behalf of the Swedish Hip fracture study group, HRT and risk of hip fracture. Population based case control
study Br Med J 1998: 316: 1858
6. Smith and Studd. The Menopause and Hormonal Replacement Therapy. Martin Dunitz, London, 1994.
7. Ettinger B, Pressman A, Sklaria P et al Associations between low levels of serum estradiol, bone density and fractures among elderly women. The
study of oestesporosis factures J Clin Endocrinol Metab 1998 : 83 : 2234 : 43.
8. Christiansen C, et al. 17β estradiol and continuous norethisterone: A unique treatment for established osteoporosis in elderly women. J Clin
Endocrinal Metab 1990; 71 : 836-41.
9. Armamento – Villareal R, civitelli R. Estrogen action on the bone mass of postmenopausal women is dependent on body mass and initial bone
density J Clin Endocri Metab 1995, 80: 776
10. Selby PL, Peacock M et al Early effect of ethinyl estradiol and norethisterone treatment in postmenopausal women on bone resorption and
calcium regulating hormone Clin Sci 1985, 69: 265
11. Munk – Jensen M, Nielsen S.P. Reversal of postmenopausal vertebral bone loss by estrogen and progestrogen : a double blind placebo controlled
study. BMJ 1988, 296” 1150.
12. Cauley JA, Selley DG, Enbsrud K. Ettinger B. Black D. Cummings SR, for the study of osteoprootic Fractures Research Group, Estrogen
replacement therapy and fractures in older women, Ann Intern Med 1995; 122: 9.
13. Garnett T. Studd J, et al. The effect of plasma estradiol levels on increased in vertebral and femoral bone density following therapy with estradiol
and estradiol with testosterone implant J. Obst Gyn 1992; 79:968.
14. Watts NB, Notelovitz M, et al. Comparision of oral estrogens and estrogen plus androgens on bone mineral density, menopause symptoms and
lipid-lipoprotein profiles in surgical menopause J Obst Gyn 1995; 85: 529.
15. Davis SR, Mccloud P, Strauss BJG, Burger H. testosterone enhances estradiol effects on postmenopausal bone density and sexuality, Maturitas
1995: 21: 227.
16. Schairer C, Lubrin J, Troisi R et al Menopausal estrogen and estrogen – progestrone replacement therapy and breast cancer risk. JAMA 2000 :
283 : 485 – 91.
17. Ross Rk, Paganini – Hill A, Wan P et al Wffect the hormonal replacement therapy on breast cancer: estrogen verses estrogen plus progestin J Natl
Cancer Inst. 2000 : 92 : 328 : 32.
18. Lindsay R, MacLean A, Kraszewski A, Clark AC, Garwood J.Bone response to termination of estrogen treatment, Lancet 1978; 1:1325
19. Michaesson K, Baron JA, Farahmand BY, Johnell O, Magnusson C, Persson PG. On behalf of the Swedish Hip Fracture Study Group, Hormone
replacement therapy and risk of hip fracture population based case-control study, Br Med J 1998; 316:1858
50
Anti Resorptive Agents for Prevention and

13
Treatment of Post Menopausal Osteoporosis
Dr. Mohini N. Prasad

DORCP(Dublin), FRCOG (London),
Consultant Obstetrician and Gynecologist
Dr.P R Desai Hospital Bangalore, India.
Past President Bangalore Society of Obstetrics
and Gynacology.
Secretary Bangalore Chapter IMS
Osteoporosis has been defined as a systemic, skeletal disease characterized by low bone mass and micro
architectural deterioration of bone tissue with a consequent increase in bone fragility.
Osteoporosis is a silent disease until it is complicated by fractures - fractures that can occur following
minimal trauma. These fractures are common and place an enormous medical and personal burden on
aging individuals and a major economic toll on the nation. Osteoporosis can be prevented and can be
diagnosed and treated before any fracture occurs. Importantly, even after the first fracture has occurred,
there are effective treatments to decrease the risk of further fractures. Hence, prevention, detection, and
treatment of osteoporosis should be a mandate of primary care providers.
Periosteum Periosteum
Strong, dense compact bone
Spongy bone
Thin, week
compact bone
Thin, broken
spongy bone
Normal bone Osteoporotic bone
51
Synopsis of Major Recommendations to the Clinician
For postmenopausal women and men age 50 and older:
• Counsel on the risk of osteoporosis and related fractures.
• Check for secondary causes.
• Advise on adequate amounts of calcium (at least 1200 mg/d, including supplements if
necessary) and vitamin D (800 to 1000 IU per day of vitamin D3 for individuals at risk of
insufficiency).
• Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of
falls and fractures.
• Advise avoidance of tobacco smoking and excessive alcohol intake.
• In women age 65 and older and men age 70 and older, recommend BMD testing.
• In postmenopausal women and men age 50-70, recommend BMD testing when you have
concern based on their risk factor profile.
• Recommend BMD testing to those who have suffered a fracture, to determine degree of
disease severity.
• Initiate treatment in those with hip or vertebral (clinical or morphometric) fractures.
• Initiate therapy in those with BMD T-scores < -2.5 at the femoral neck, total hip, or spine by
DXA, after appropriate evaluation.
• Initiate treatment in postmenopausal women and in men age 50 and older with low bone
mass (T-score -1 to -2.5, osteopenia) at the femoral neck, total hip, or spine and 10-year hip
fracture probability ≥3% or a 10-yr all major osteoporosis-related fracture probability of ≥
20% based on the US-adapted WHO absolute fracture risk model.
• Current FDA-approved pharmacologic options for osteoporosis prevention and/or
treatment are bisphosphonates (alendronate, ibandronate, risedronate, and zoledronate),
calcitonin, estrogens and/or hormone therapy, raloxifene and parathyroid hormone (PTH 1-
34).
• BMD testing performed in DXA centers using accepted quality assurance measures is
appropriate for monitoring bone loss (recommendation every 2 years). For patients on
pharmacotherapy, it is typically performed two years after initiating therapy and at 2-year
intervals thereafter.
Universal Recommendations for All Patients

Several interventions to reduce fracture risk can be recommended to the general population. These
include an adequate intake of calcium and vitamin D, lifelong participation in regular weight-bearing
and muscle-strengthening exercise, avoidance of tobacco use, identification and treatment of
alcoholism, and treatment of other risk factors for fracture such as impaired vision.
52
• Adequate Intake of Calcium and Vitamin D

1. Calcium - Lifelong adequate calcium intake is necessary for the acquisition of peak bone mass and
subsequent maintenance of bone health.
2. Vitamin D - Vitamin D plays a major role in calcium absorption, bone health, muscle performance,
balance, and risk of falling.
3. Regular Weight – Bearing Exercise - Among its many health benefits, weight-bearing and muscle-
strengthening exercise can improve agility, strength, posture, and balance, which may reduce the risk
of falls. In addition, exercise may modestly increase bone density.
4. Fall Prevention - In addition to maintaining adequate vitamin D levels and physical activity, as
described above, strategies to reduce falls include, but are not limited to, checking and correcting
vision and hearing, evaluating any neurological problems, reviewing prescription medications for
side effects that may affect balance and providing a check list for improving safety at home. Wearing
undergarments with hip pad protectors may protect an individual from injuring the hip in the event of
a fall. Hip protectors may be considered for patients who have significant risk factors for falling or for
patients who have previously fractured a hip.
5. Avoidance of Tobacco Use and Excessive Alcohol Intake - Advise patients to avoid tobacco
smoking. The use of tobacco products is detrimental to the skeleton as well as to overall health. The
NOF strongly encourages a smoking cessation program as an osteoporosis intervention.
Recognize and treat patients with excessive alcohol intake. Moderate alcohol intake has no known
negative effect on bone and may even be associated with slightly higher bone density and lower risk of
fracture in postmenopausal women. However, alcohol intake of 3 or more drinks per day is
detrimental to bone health, increases the risk of falling, and requires treatment when identified.
Pharmacologic Therapy
Medications used to prevent and treat osteoporosis fall into two categories: drugs that inhibit bone
resorption (antiresorptive agents) and drugs that stimulate bone formation (anabolic agents).
53
Current FDA-approved pharmacologic options for the prevention and/or treatment of
postmenopausal osteoporosis include, in alphabetical order: bisphosphonates (alendronate,
alendronate plus D, ibandronate, risedronate, and risedronate with 500 mg of calcium carbonate,
zoledronate), calcitonin, estrogens (estrogen and/or hormone therapy), estrogen agonist/antagonist
(raloxifene), and parathyroid hormone [PTH (1-34), teriparatide].
Who Should Be Treated?
Postmenopausal women and men age 50 and older presenting with the following should be treated:
• A hip or vertebral (clinical or morphometric) fracture
• Other prior fractures and low bone mass (T -score between -1.0 and -2.5 at the femoral neck, total hip,
or spine)
• T -score < -2.5 at the femoral neck, total hip or spine after appropriate evaluation to exclude
secondary causes
• Low bone mass (T -score between -1.0 and -2.5 at the femoral neck, total hip, or spine) and
secondary causes associated with high risk of fracture (such as glucocorticoid use or total
immobilization)
• Low bone mass (T -score between -1.0 and -2.5 at the femoral neck, total hip, or spine) and 10-yr
probability of hip fracture ≥
3% or a 10-yr probability of any major osteoporosis related fracture ≥
20%
based on the U.S.-adapted WHO algorithm.
Anti Resorptive Agents

Antiresorptive agents reduce bone loss by decreasing osteoclastic boneresorption. While these
therapies have no direct effect on osteoblast function and do not stimulate new bone formation,
increases in BMD are observed. Antiresorptive agents slow remodeling and reduce the number and
depth of resorption sites. Bone formation exceeds bone resorption at these sites, leading to a refilling
of the remodeling space, more complete bone mineralization, and overall increases in BMD.
Before choosing the most appropriate antiresorptive therapy for a given patient, it is important to
understand the benefits of these agents with respect to BMD and fracture risk and any nonbone
benefits and risks.
• Bisphosphonates
Bisphosphonates are structural analogues of pyrophosphate, a naturally occurring bone resorption
inhibitor. Bisphosphonates have a strong affinity for the hydroxyapatite crystals in bone, where they
act as potent inhibitors of bone resorption by decreasing osteoclast recruitment, activity, and life span.
• Alendronate - Alendronate sodium is approved by the FDA for the prevention (5 mg daily and 35 mg
weekly) and treatment (10 mg daily and 70 mg weekly [Tablet or liquid formulation] or 70 mg weekly
54
with 2,800 IU and 5600 IU of vitamin D3) of osteoporosis in postmenopausal women. Alendronate
reduces the incidence of spine, hip and wrist fractures by about 50% over 3 years in patients with a
prior spine fracture. It reduces the incidence of spine fractures by 48% over 3 years in patients without
a prior spine fracture. Alendronate is also approved to increase bone mass in men with osteoporosis
and for the treatment of men and women receiving glucocorticoids in a daily dose of 5 mg or greater of
prednisone and who have low bone mass. In addition to tablet formulation, alendronate is available
as a liquid with 70 mg in 75ml, to be followed by at least 2 oz of plain water.
• Ibandronate -
Ibandronate sodium as 2.5 mg per day orally, 150 mg per month orally, and 3 mg every 3 months by
intravenous injection are approved by the FDA for the treatment of postmenopausal osteoporosis.
The oral preparations are also approved for the prevention of postmenopausal osteoporosis.
Ibandronate reduces the incidence of spine fractures by about 50% over 3 years.
• Risedronate -
Risedronate sodium (5 mg daily dose; 35 mg weekly dose; 35 mg weekly dose packaged with 6 tablets
of 500 mg calcium carbonate, or 75 mg on two consecutive days every month) is approved by the
FDA for the prevention and treatment of postmenopausal osteoporosis. Risedronate reduces the
incidence of spine fractures by 41-49% and non-spine fractures by 36% over 3 years in patients with a
prior spine fracture. Risedronate is approved for treatment to increase bone mass in men with
osteoporosis and for the prevention and treatment of osteoporosis in men and women who are either
initiating or continuing systemic glucocorticoid treatment (daily dose equivalent to 5 mg prednisone
or greater) for chronic disease.
• Zoledronate -
Zoledronate (5 mg by intravenous infusion over at least 15 minutes once yearly) is approved by the
FDA for the treatment of osteoporosis in postmenopausal women. Zoledronate reduces the incidence
of spine fractures by 70%, hip fractures by 41%, and non-vertebral fractures by 25% over 3 years.
• Side Effects and Administration of Bisphosphonates

Side effects are similar for all oral bisphosphonate medications and include gastrointestinal problems
such as difficulty swallowing, inflammation of the esophagus and gastric ulcer. There have been
reports of osteonecrosis of the jaw (particularly following intravenous bisphosphonate treatment for
patients with cancer) and of visual disturbances, which should be reported to the healthcare provider
as soon as possible. The level of risk for osteonecrosis in patients being treated for osteoporosis with
bisphosphonates is not known, but appears extremely small for at least up to 5 years.
Alendronate and risedronate must be taken on an empty stomach, first thing in the morning, with 8
ounces of plain water (no other liquid), at least 30 minutes before eating or drinking. Patients should
remain upright (sitting or standing) during this interval as well. Ibandronate should be taken on the
same day each month, at least 60 minutes before first food, drink (other than plain water) or
medication of the day. Patients using the liquid formulation should swallow one bottle (75 ml) and
follow with at least 2 oz of plain water. Other instructions remain the same. Ibandronate tablets must
be taken on an empty stomach, first thing in the morning, with a glass of plain water. Patients must
remain upright for at least one hour after taking the medication. Ibandronate, by intravenous injection
over 15 to 30 seconds, should be given once every 3 months. Serum creatinine should be checked
55
before each injection. Zoledronate, 5 mg in 100 ml, is given once yearly by intravenous infusion over
at least 15 minutes. Patients may be pre-treated with acetaminophen to reduce the risk of an acute
phase reaction (arthralgia, headache, myalgia, fever). These symptoms occurred in 32% of patients
after the first dose, 7% after the second dose, and 3% after the third dose.
• Calcitonin
Salmon calcitonin is FDA-approved for the treatment of osteoporosis in women who are at least 5
years postmenopausal. It is delivered as a single daily intranasal spray that provides 200 IU of the
drug. Subcutaneous administration by injection also is available.
Adverse reactions associated with the injectable form, including local reactions, flushing, and rash,
and rare systemic allergic-type reactions have limited its use. Adverse effects are rare with the
intranasal formulation and consist mostly of nasal complaints of dryness, soreness, irritation, itching,
and epistaxis. Nasal examinations should be performed before treatment begins and whenever nasal
complaints occur. Should severe ulcerations of the nasal mucosa develop, the drug must be
immediately discontinued.
Calcitonin is thought to have some analgesic effects and has been used for pain management in
osteoporotic patients with acute compression fractures. The mechanism underlying this is not well
understood, but increases in
Studies in postmenopausal women with low BMD have demonstrated increases in spine BMD of 1-
3% after therapy with 200 IU of calcitonin nasal spray. Significant changes in hip BMD have not been
seen.
• Estrogen/Hormone Therapy
Estrogen/Hormone therapy is approved by the FDA only for the prevention of Osteoporosis. The
Woman's Health Initiative (WHI) found that 5 years of HT (Prempro®) reduced the risk of clinical
vertebral fractures and hip fractures by 34% and other osteoporotic fractures by 23% (20).
The Women's Health Initiative (WHI) reported increased risks of myocardial infarction, stroke,
invasive breast cancer, pulmonary emboli and deep vein phlebitis during 5 years of treatment with
Premarin and medroxyprogesterone. Subsequent analysis of these data showed no increase in
cardiovascular disease in women starting treatment within 10 years of menopause. In the estrogen
only arm of WHI, no increase in breast cancer incidence was noted over 7.1 years of treatment.
Because of the risks, ET/HT should be used in the lowest effective doses for the shortest duration to
meet treatment goals. When ET/HT use is considered solely for prevention of osteoporosis, the FDA
recommends that approved non-estrogen treatments should first be carefully considered.
• Estrogen Agonist/Antagonist
Raloxifene – Raloxifene is a selective estrogen receptor modulator which has mixed agonist and
antagonist effects on estrogen receptors throughout the body. Raloxifene is approved by the FDA for
both prevention and treatment of osteoporosis in postmenopausal women. Raloxifene reduces the
risk of spine fracture by 30% in patients with and by 55% in patients without a prior spine fracture,
over 3 years.
56
Raloxifene decreases low-density-lipoprotein (LDL) cholesterol concentrations by 8-10% but has a

neutral effect on triglycerides and does not increase high-densitylipoprotein (HDL) cholesterol. The
true effect of raloxifene on cardiovascular outcomes is being tested in a large prospective trial of high-
risk post-menopausal women, the Raloxifene Use for The Heart (RUTH) trial
Raloxifene, like estrogen, increases the risk of venous thromboembolism (VTE) up to threefold and is
contraindicated in women with a history of thrombosis. The most common adverse effects associated
with raloxifene are leg cramps and hot flashes. Raloxifene should not be used in postmenopausal
women with hot flashes, since it can make the symptoms worse.
• Parathyroid Hormone
PTH(1-34) is approved by the FDA for the treatment of osteoporosis in postmenopausal women at
high risk for fracture. PTH (1-34) is an anabolic (bone-building) agent when administered by daily
subcutaneous injection. PTH (1-34) in a dose of 20 µ g daily was shown to decrease the risk of spine
fractures by 65% and non-spine fractures by 53% in patients with osteoporosis, after an average of 18
months of therapy. PTH(1-34) is indicated to increase bone mass in men with primary or
hypogonadal osteoporosis who are at high risk of fracture.
PTH (1-34) is well tolerated, although some patients experience leg cramps and dizziness. Because
PTH (1-34) caused an increase in the incidence of osteosarcoma in rats, patients with an increased
risk of osteosarcoma (e.g., patients with Paget's disease of bone) and those having prior radiation
therapy of the skeleton, bone metastases, hypercalcemia, or a history of skeletal malignancy should
not receive PTH (1-34) therapy. The safety and efficacy of PTH (1-34) has not been demonstrated
beyond 2 years of treatment. Since PTH (1-34) is used for a maximum of 2 years, it is common
practice to follow PTH (1-34) treatment with an anti-resorptive agent, usually a bisphosphonate, to
maintain or further increase BMD.
Combination Antiresorptive Therapy

Several combinations have been evaluated in small randomized controlled trials (e.g., raloxifene-
alendronate, risedronate-HRT, and alendronate-HRT). Results of studies evaluating these
combination therapies have been conflicting. In some trials, greater increases in BMD were seen with
combination therapy compared with either agent alone. The impact of combination therapy on
fracture risk is unknown, however. Further studies with fractures as an endpoint are needed before
combination therapy can be recommended. Therapy with both a bisphosphonate and HRT or ERT
may be appropriate in post-menopausal women with osteoporosis and menopausal symptoms (e.g.,
vasomotor symptoms).
Monitoring Effectiveness of Treatment

In addition to important lifestyle changes and institution of non-pharmacologic interventions,
patients often require the use of FDA-approved pharmacologic therapies for the prevention and
treatment of osteoporosis. With use of all therapeutic interventions, it is imperative to ask patients
about adherence to their therapy and encourage continued and appropriate compliance with their
osteoporosis therapies to reduce fracture risk.
57
1. Bone Mineral Density
2. Central DXA
3. QCT
4. pDXA, pQCT and QUS.
5. Biochemical Markers of Bone Turnover
Changes in markers of bone turnover can be seen as early as three months. These markers can be
used for early monitoring of the response to drug therapy, and their measurement may help with
patient compliance. Measurements should be obtained at baseline and repeated after three to six
months of therapy. Decreases of approximately 50% from baseline values are expected with
antiresorptive drug therapy.
Conclusion
When pharmacologic agents are required to prevent or treat osteoporosis, bisphosphonates have
shown the greatest benefit in preventing bone loss and decreasing fracture rates. If these agents are
not tolerated well, SERMs may be considered for prevention and SERMs or calcitonin for treatment.
Estrogen should not be used for the sole purpose of osteoporosis prevention; however, short-term use
is acceptable for women who are also having vasomotor symptoms or in whom the benefits outweigh
the risks. PTH may offer another treatment alternative.
Osteoporosis needs lifelong management and adherance to therapy is a must to gain benefit and
reduce risk of fractures.
Increasing knowledge of the mechanisms that regulate bone cell activity will provide sources for
potential new therapeutic strategies. Thus future approaches may include local regulators such as
cytokines (which are essential in bone metabolism), modification of hormone receptors and
pharmacogenetics.
Suggested Reading
1. Current Approaches to the Prevention and Treatment of Postmenopausal Osteoporosis – Sheryl L. Follin, Laura B. Hansen Am J Health-Syst
Pharm 60(9):883-901,2003
2. The Prevention and Treatment of Osteoporosis: A Review - Felicia Cosman Medscape General Medicine 7(2):73, 2005
3. National Osteoporosis Foundation. America's Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. National Osteoporosis
Foundation, Washington, DC, pp. 1-55, 2002
4. Osteoporosis: Review of the Evidence for Prevention, Diagnosis and Treatment and Cost-Effective Analysis. Osteoporos Int 8 (Supplement 4),
1998
5. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes for calcium, phosphorus, magnesium,
vitamin D and flouride. Washington, D.C.: National Academy Press; 1997
6. Dawson-Hughes B, Tosteson ANA, Melton LJ, Baim S, Favus MJ, Khosla S, Lindsay L. Implications of absolute fracture Risk assessment for
osteoporosis practice guidelines in the U.S. Osteoporos Int DOI 10.1007/s000198-007-0559-5
7. Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis J Bone Miner Res 9:1137-1141, 1994
58
Anabolic Drugs and Newer Therapies

14
in Treatment of Osteoporosis
Dr. Ranu Patni

Gynaecologist and Gynaec. Onco-Surgeon
Secretary , Indian Menopause Society
Fortis Escorts Hospital, Jaipur
Introduction
In the present perspective, the goals of treatment of Osteoporosis should be to -
- Prevent fractures
- Stabilize / achieve an increase in bone mass
- Relieve symptoms of fractures and skeletal deformity
- Maximize physical function ( e.g. halt progressive deformity)
Over the past two decades, therapies for osteoporosis have evolved very fast. Anabolic drug therapy
is the most recent medication that has been approved by FDA.
FDA approved Anabolic drug therapy1,2

Teriparatide{Recombinant Human Parathyroid Hormone ( PTH 1-34 )
FDA has approved Teriparatide for the treatment of postmenopausal osteoporosis and in men with
idiopathic or hypogonadal osteoporosis who are at high risk for fracture or who have failed or been
intolerant of previous osteoporosis therapy. The recommended dose is 20mcg daily subcutaneously.
This has been shown to reduce the risk of vertebral and non-vertebral fractures in postmenopausal
women by 65% and 54% respectively over a 19 month treatment period (level 1 evidence). Observed
side effects have been mild and transient and include nausea and orthostatic hypotension. Transient
and asymptomatic hypercalcemia has also been observed. Teriparatide is contraindicated in patients
with Paget's disease, with open epiphysis, with a history of irradiation involving the skeleton or with
an undefined elevation of alkaline phosphatase of skeletal origin. Efficacy and safety of Teriparatide
have been assessed for two years and are presently unknown thereafter. Pretreatment measurement
of serum levels of PTH, 25 hydroxycholcalceferol, creatinine, calcium and phosphorus is
recommended. Monitoring patients on treatment for hypercalcemia and hypercalceuria should be
considered. American Association of Clinical Endocrinologists ( AACE) and National Osteoporosis
Foundation (NOF) do not recommend concomitant use of antiresorptive agents with Teriparatide at
present as it may alter the BMD and bone turnover response.
Non- FDA approved drugs for Osteoporosis-

Calcitriol2- This synthetic Vitamin D analogue which promotes calcium absorption has been approved
by the FDA for managing hypocalcemia and metabolic bone disease in renal dialysis patients. It is also
approved for use in hypoparathyroidism both surgical and idiopathic and
pseudohypoparathyroidism. No reliable data demonstrate a reduction of risk for osteoporotic
fractures.
59
Other Bisphosphonates2- ( Etidronate, Pamidronate, Tiludronate) Most of these bisphosphonates are
currently approved for conditions other than Osteoporosis like Paget's disease, hypercalcemia of
malignancy and Myositis Ossificans.
PTH (1-34)2- Approved in some European countries for treatment of Osteoporosis in women. In one
clinical study PTH (1-84) effectively reduced the risk of vertebral fractures at a dose of 100mcg/day.
Sodium Fluoride2- Through a process that is still unclear, Sodium Fluoride stimulates the formation of
new bone. The quality of bone mass thus developed is uncertain, and the evidence that reduces
fracture risk is conflicting and controversial.
Tibolone2- This tissue specific agent is indicated for treatment of vasomotor symptoms of menopause
and for prevention of Osteoporosis in Europe but is not approved for use in the USA.
Strontium Ranelate – Strontium is adsorbed onto the bone surface and increases bone strength by
being incorporated in a dose dependent manner into bone tissue to change the crystal structure but
without altering mineralization(3). In a randomized controlled trial of postmenopausal women with
osteoporosis treatment with Strontium Ranelate increased BMD in a dose dependent way by 1.4%-
3% per year compared with placebo(4). New vertebral fractures were reduced by 44% after 2 years in
women on the highest dose (2gm). The treatment was well tolerated and the larger dose was
suggested for clinical use. The use of Strontium normally regarded as a trace element may offer an
alternative way of decreasing bone resorption; however at present, Strontium is not approved for use.
Growth factors - Identification of factors that act on receptors for osteoclast attachment or function -
such as λ
γβ3 integrin, receptor activator of nuclear factor kB ligand (RANKL) or the soluble ligand
Osteoprotegerin may allow the development of receptor antagonists. Clinical testing of
Osteoprotegerin indicates a positive effect on BMD in postmenopausal women(5).
Cathepsin K - Degradation of bone matrix is mediated by Cathepsin K, an osteoclast protease that

appears to act specifically on bone collagen(6). An inhibitor of Cathepsin K may be useful as an
antiresorptive drug.
Cytokines - Most cytokines are implicated as enhancers of osteoclast activity and subsequently of bone
resorption. Blockade of cytokine activity especially IL-1 or IL-6 may have effect on bone turnover
since tumour necrosis factor á is one of the most important cytokines that modify bone resorption. But
relative non-specificity and subsequent effects on other organs may limit their usefulness.
New SERM - Two new drugs for osteoporosis were featured at the International Osteoporosis
Foundation (IOF) World Congress on Osteoporosis at Rio de Janerio, Brazil on May 26, 2004- a new
generation SERM, Lasofoxifene and Strontium Ranelate. Lasofoxifene (0.5mg/day) resulted in-
a) A significant increase in lumbar BMD (up by an average of 2.2% compared with a fall
of- 0.25% in the placebo group over the same time frame)
b) Significant reduction in biochemical markers of bone metabolism.
c) A significant reduction in LDL Cholesterol from an average of 129mg/dl in the placebo
group to 106mg/dl.
60
Other approaches for the future

Future approaches may include genetic modification and pharmacogenetic methods developed as a
result of our still increasing knowledge of the genetics of bone diseases. A number of genes have been
identified as possibly being associated with Osteoporosis and fractures, although results are
inconsistent. Variations in the collagen, estrogen receptor and vitamin D receptor genes merit
mentioning as they have been associated with BMD and fractures in elderly women with implications
of functional importance for the collagen polymorphism.
Suggested Reading
1) AACE Osteoporosis Guidelines. Endocr Prac 2003; 9 (No. 6).

2) Clinician's Guide to Prevention and Treatment of Osteoporosis 2008. National Osteoporosis Foundation
3) Bovin G et al. Strontium distribution and interaction with bone mineral in monkey iliac bone after Strontium salt ( S 12911) administration.
Journal of Bone and Mineral Research 1996; 11: 1302-11
4) Meunier PJ, Slosman DO et al. Strontium Ranelate: dose dependent effects in established postmenopausal vertebral osteoporosis- a two year
randomized placebo controlled trial. Journal of Clinical Endocrinology and Metabolism 2002; 87: 2060-6.
5) Bekker PJ et al. The effect of a single dose of Osteoprotegerin in postmenopausal women. Journal of Bone and Mineral Research 2001; 16: 348-
60.
6) Drake FH et al. Cathepsin K but not Cathepsins B, L or S is abundantly expressed in human Osteoclasts. Journal of Biological Chemistry 1996;
271: 12511-6.
7) BologneseMA et al. Lasofoxifene: a next generation SERM for prevention of bone loss in postmenopausal women. Osteoporosis Int 2004; 15.
61
Risk Assessment and Investigations
15
- Prior to Starting Hormone Therapy
Dr. Atul Praful Munshi

M.D., D.G.O.
Consulting Obstetrician & Gynecologist
Sr. Prof. of Obstetrics & Gynecology: Smt. N.H.L. Municipal Medical College, Ahmedabad,
Sr. Vice President : FOGSI- 2007
President (Elect 2010) : Indian Menopausal Society
Governing Council Member : Indian College of OB/GYN.
Past President: Ahmedabad OB/GYN Society,
With many women in or near menopause and multiple news stories of hormone risks, there has been
renewed interest in the treatment of menopause. Each woman entering the menopausal phase is a unique
individual who will experience menopause in her own way with regard to developing menopausal
symptoms and also in the way she reacts to hormone therapy.
“there are many unanswered questions and many gaps in our understanding of the benefits and risks,
so the research studies need to be supported”
– Wall Street Journal, 1/26
Why is RISK ASSESSMENT essential?

It has been estimated that one third of the postmenopausal women in the western countries use
hormone therapy to treat symptoms of menopause and prevent chronic conditions. In developing
countries also there is an increasing trend in its use. Hormone therapy is a double edged sword it does
not suit all women alike and in some the risks may outweigh the benefits. It is important that the
benefits and harms of HT based on scientific evidence should be considered when prescribing HT.
It is also important to consider a small group of younger women who enter the transition and
experience menopausal symptoms. Starting and continuing HT becomes important in women with
premature menopause till they reach the natural age of menopause. The North American
Menopause Society released a revised position statement that said
“the benefits of short term hormone replacement therapy for treatment of menopausal women likely
outweigh the risks for younger women”
Tailoring an individual program for women, which may include HT and other therapeutic options, is
guided by the menopausal risk assessment. It has been seen that women with better socio-economic
status, higher education and urban population are more likely to use HT.
Why are INVESTIGATIONS needed?

Starting hormone therapy requires recognition of risk factors as certain conditions warrant the
cautious use of hormones like estrogen and progesterone. Some investigations are required before
starting and during periodic follow up of women in HT. Clinicians must be aware of the advantages
and disadvantages and discuss them thoroughly with their patients. Evaluation of the menopausal
women with a stratified risk assessment module helps in individualizing the need for hormone
therapy. HT should not be used for treatment of chronic diseases.
62
Table 1: Advantages & Disadvantages of HT
ADVANTAGES OF HT DISADVANTAGES OF HT
•Excellent symptomatic •Increased risk of

management Hotflushes stroke and PE
Night sweats •CHD : doesn't help,
Urinogenital atrophy might hurt
?urinary incontinence •Increased rates of breast Ca
Decreased rates of: •Increased GB disease
•Colon Cancer •Increased rates of lupus
•Osteoporosis •Vaginal bleeding
•?UTI
•?depression
•?dementia
• Preservation of joint movement,
teeth, skin
• Improved HDL to LDL ratio
History and Physical Examination

The risk assessment of the menopausal woman begins with the history and physical examination. The
examiner should ask specifically about classical symptoms of estrogen deficiency including hot
flushes, sleep disturbance, palpitations, dry skin, irritable bladder, and dyspareunia. A thorough
family history of breast carcinoma, coronary heart disease, osteoporosis, early menopause should be
elicited also the use of any unopposed estrogen previously should be kept in mind.
Height, weight, waist circumference, body mass index, waist/hip ratio and blood pressure (who have
optimal BP (<130/80) are rechecked every 2yr & those with normal level (<140/90 mm Hg )
checked yearly. High blood pressure per se is not a contraindication to starting hormone therapy.
should be recorded during the physical examination. It should focus on the genitourinary,
neuroendocrine, skeletal, and cardiovascular systems. Special attention should be directed to the
thyroid, breast, cardiovascular(cardiac murmurs and arterial bruits), pelvic, and rectal examinations.
A screening PAPS smear should be obtained of the exocervix and endocervix using a spatula and
cytobrush to for cervical cancer.1
Assessment should also take into account the women's individual needs and their risk factors.
Risk factors for early menopause:
- Any treatment or surgery that can compromise ovarian functioning
• Pelvic surgery
• Chemotherapy, radiation
• Pelvic endometriosis, adhesions, ovarian surgery
- Familial and genetic factors
• Estrogen receptor and á polymorphism
- Mean age of menopause due to ovarian failure is significantly advanced upto 4 years in
hysterectomized women
- Smoking advances the age of menopause by 2 years
- Recent studies suggest that high levels of galactose consumption and starvation in early
childhood may also have an effect.
63
Risk factors for osteoporosis:
In women without menopausal symptoms, HT should be used only in those women with significant
risk for osteoporosis and in whom alternative therapies have been carefully considered.
Table 2: Risk for Osteoporosis
NONMODIFIABLE METABOLIC / HORMONAL MODIFIABLE
- Leanness - Weight-increased risk

- Approximate risk
- Late menarche / early if thin and decreased
of fracture doubles
menopause if overweight
every 7yrs
- Bilateral oopherectomy - Excessive weight loss
- Family h/o
osteoporotic fracture - Amenorrhea - Smoking
esp hip fracture - Hyperthyroidism
- Low calcium intake
- Glucorticoid excess
- Personal history of
>5mg/day - Vit D deficiency
osteoporotic fracture
- Cushings syndrome
- Untreated early - Inadequate
menopause physical activity
- Ethnicity, genetics - Low bone density
(Modifiable risk factors are those that can be eliminated by a change in lifestyle like regular exercise,
healthy food habits, calcium and vitamin supplementation and so on. They bring about a dramatic
change when considering cardiovascular diseases, osteoporosis and even urinary incontinence in
some.)
In 2005, Osteoporosis Canada Society recommended identifying absolute fracture risk by integrating
the key risk factors for fracture; namely, age, BMD, prior fracture, and glucocorticoid use.2 The 10-
year risk of fragility fractures is thus determined and defined as high if it is greater than 20%, moderate
if it is 10% to 20%, and low if it is less than 10%.3 The additional effect of a pre-existing fragility
fracture or glucocorticoid use moves the patient 1 risk category higher. These guidelines were based
on Swedish data. A more comprehensive calculation of the 10-year absolute fracture risk, now
available from the World Health Organization, incorporates additional risk factors: parental history of
hip fracture, current tobacco smoking, rheumatoid arthritis or other secondary causes of bone loss,
and alcohol intake of 3 or more units daily.4 Absolute fracture risk data be used in determining who
should be treated, as this will target pharmacologic and hormone therapy at those at an increased risk
of fracture.
The goal of management is to prevent fractures and the selection of patients with the highest risk for
fracture targets population most likely to benefit from therapy.
Risk factors for coronary heart disease:

Available evidence demonstrates that initiation of HT should be done with caution in women with
distressing vasomotor symptoms who are more than a decade after menopause because it may be
64
associated with an increased risk of adverse cardiac events. Attention to correction of underlying
cardiovascular risk factors before initiation of HT would be important in these isolated cases.
Table 3: Risk factors for Coronary Disease
NON MODIFIABLE MODIFIABLE
- Age, for every 10 year increase in age risk of - Cigarette smoking

CHO increases three fold - Physical inactivity
- Family history of premature CHD (MI before - Nutrition
55years in men and 65 years in women) increases
- Obesity
risk of MI by two fold
- Psychosocial factors
- Blood pressure
- Lipid level
- Homocysteine level
- Diabetes
Risk factors for Alzheimer's disease:

A better understanding of the factors, or cofactors, that placed the older women at increased risk of
dementia would be helpful in identifying women for whom HT may not be advisable.
- age , family history and apolipoprotein E epsilone 4 allele
- may be autosomal dominant, when uncommon forms of illness that appear before the
seventh decade of life.
- Dominant inheritance is not characteristic of later onset dementia although family history remains risk
factor in this age group
- Poly pharmacy and thyroid disease are two examples of reversible causes of memory loss in older
adults.
Investigations to be carried out:

Diagnosis of menopause:
Hormone level may vary between individuals and their level may fluctuate even from one day to next.
So, hormone level is not always reliable for diagnosis of menopause.
However the postmenopausal range is
S.FSH >30 IU/L
S.LH>30 IU/L
Screening Tests:
Diabetes -
If FBS is high then repeat fasting glucose. Glucose tolerance test should be done in selected cases.
Hyperlipidemias -
Total cholesterol and high-density lipoprotein (HDL) cholesterol should be measured to help
ascertain cardiovascular risk in the menopausal woman. If the total cholesterol concentration is
elevated or the HDL cholesterol concentration is low, a 12-hour fasting lipid profile is needed to
determine the low-density lipoprotein (LDL) cholesterol.
65
HDL(>45mg/dl)
Triglycerides (<150mg/dl)
LDL ( <130mg/dl)
Repeat measurements every 5 years.
Osteoporosis-
Axial DEXA is best validated as the most accurate method of assessing bone density and diagnosis of
osteoporosis. Other investigations include.
Heel ultrasound
Biochemical markers of bone turnover
In few cases homocysteine levels are also checked.
Special circumstances
TSH- for positive history when hot flushes do not subside with hormone therapy
FSH and Estradiol - premature menopause, women on OCP, women who had hysterectomy, doubt as
to the cause of secondary amenorrhea. It need not be done in all cases for diagnosis of menopause.
Endometrial biopsy- post menopausal bleeding, recent irregular bleeding, previous use of unopposed
estrogen in the presence of uterus. It is also indicated if ET>5mm and also for follow up
Test to assess increased risk of thrombosis - women with previous history of unexplained
thromboembolic episodes.
Bone mass measurement - for specific indications only
Liver function tests - in patient with suspected liver disease or recent history of liver disease.
Mammography - Mammography should be performed yearly in perimenopausal and postmenopausal
women to obtain a baseline and evaluate for clinically unrecognized breast cancers.
Alternative therapies
Given the negative press on HRT, many women are considering more “natural” therapies.
“Bioidentical” botanical and dietary supplement products may be considered more “natural” to
consumers, but they are not regulated nor standardized. The most important thing with supplement
use in the management of menopause is to know what your patients are taking, the potential adverse
reactions, and drug/herb interactions.
Active living, alternative therapies and consumption of food rich in phyto estrogens are some areas
which need to be explored in more detail. Benefits and harms need to be re-addressed periodically to
apply newly published evidence and to reassess emerging risk, co-morbidities and need of
individuals.
Menopause is a physiologic event that gives a woman the opportunity to become involved in a
preventive health program. Menopause is not a disease; however, it does cause symptoms in a
significant percentage of women. Medical evaluation with an emphasis on health maintenance and
lifestyle measures is important for menopausal women.
66
Table 4 : Summary
• EARLY MENOPAUSE
• CARDIOVASULAR
RISK ASSESSMENT • OSTEOPOROSIS
• ALZHEIMER`S
• FAMILIAL RISK FOR BREAST CANCER
HISTORY AND • MENOPAUSAL SYMPTOMS

EXAMINATION • HEIGHT, WEIGHT, BODY MASS INDEX,
BP, THYROID, BREAST, CARDIOVASCULAR
SYSTEM, PELVIC AND RECTAL
• PAPS SMEAR
INVESTIGATIONS • DIABETES - FBS

• LIPID PROFILE
• AXIAL DEXA FOR BONE DENSITY IN
HIGH RISK CASES
• OTHERS –
FSH/LH IN PREMATURE MENOPAUSE
ENDOMETRIAL BIOPSY
LIVER FUNCTION TEST
MAMMOGRAPHY
Suggested Reading
1) Assessment of fracture risk - E.MICHAEL LEWIECKI.
2) Consensus, development conf., Am.Jour.Medicine, 1993.
3) Density reporting in Canada. Can Assoc Radiol J, 2001.
4) Delmas PD et al NEJM, 2002.
5) FRAX: WHO fracture assessment tool [Web site]. Sheffield, England: Goodman & Gillman, 2006 edition.
6) Menopause and Osteoporosis Update 2009. ecs Canada.
7) RISK ASSESSMENT OF THE MENOPAUSAL PATIENT, Medical Clinics of North America - Volume 83, Issue 6 (November 1999) -
Siminoski K, Leslie WD, Frame H, Hodsman A, Josse RG, Khan A, et al;
8) Shermn et al, N.Y.Acad. 2001.
67
Menopausal Hormone Therapy
16
Preparation, Routes of Administration, Indications & Contraindications

MD, DGO, FICOG
Director, Mandakini IVF Center, Mumbai
Past Chairperson, Family Welfare Committee, FOGSI
Hon Associate Professor OBS. GYN, K. J. Somaiya Medical College & Hospital, Mumbai
Past president, Navi Mumbai Obs-Gyn Society
Member, Governing Council, ICOG
Member, Managing Committee, ISAR
Dr. Manisha Damani

MD, DGO
Consultant - OBS. GYN
Jalgaon.
Dr. Kumarasamy Hemaleka

DNB., DGO, DNB
Clinical Associate
Mandakini IVF Center
Introduction:
Menopausal years need special attention due to general health problems along with menopausal
changes, which can compound the risks. Menopausal therapy should be part of an overall strategy
including lifestyle recommendations regarding diet, exercise, smoking and alcohol for maintaining
the health of postmenopausal women. Hormone therapy (HT) must be individualized and tailored
according to symptoms and the need for prevention, as well as personal and family history, results of
relevant investigations, the woman's preferences and expectations. The risks and benefits of HT differ
for women around the time of menopause compared to those for older women. HT includes a wide
range of hormonal products and routes of administration, with potentially different risks and benefits.
Women experiencing a spontaneous or iatrogenic menopause before the age of 45 years and
particularly before 40 are at higher risk for cardiovascular disease and osteoporosis. They will benefit
from hormone replacement, which should be given at least until the normal age of menopause.
Counseling should be an important part of the therapy and should be aimed at an holistic approach to
these important years. The benefits and risks of HT should be discussed in detail and in simple terms.
This allows a woman and her physician to make a well-informed decision about HT. HT should not be
recommended without a clear indication for its use.
Indications for HRT

HRT helps to alleviate the unpleasant symptoms associated with the menopause. RCTs have
demonstrated the efficacy of HRT in relieving hot flushes, night sweats, and vaginal dryness. A recent
meta-analysis has also confirmed that HRT reduces the depressed mood associated with the
menopause. Considerable interest has been generated by the more long-term potential benefits of
68
HRT therapy, which include a possible reduction in morbidity and mortality from cardiovascular
disease (both coronary heart disease and stroke), reduction in morbidity and mortality associated
with osteoporosis, and reduction in the cutaneous ageing process. However, evidence and
experience in the various studies conducted on menopausal women now have shown that HT is
indicated only in symptomatic women.
All menopausal women and especially those taking HT should have at least an annual consultation to
include a physical examination, update of medical history, relevant laboratory and imaging
investigations and a discussion on lifestyle. There are no reasons to place mandatory limitations on
the length of treatment. This should be decided at the discretion of the well-informed hormone user
and her health professional, dependent upon the specific goals and an objective estimation of
benefits and risks.
Table 1: Initial Workup before Initiating Estrogen Replacement Therapy
• History and physical examination

• Stool examination
• Pap smear
• Mammogram
• SMA
• Lipid profile
• Blood Glucose- fasting and post prandial
• Liver function tests (with past history of liver disease)
• Endometrial biopsy (in high-risk groups)
Preparations of Estrogen and Progestin and dosage:

There are several classes of estrogens. Naturally occurring estrogens, including estradiol, estrone, and
conjugated estrogens , are the estrogens generally given for replacement therapy. Synthetic
estrogens, including ethinyl estradiol, mestranol, and quinestrol, and the nonsteroidal estrogens,
including diethylstilbestrol and chlorotrianisene, typically are not used for ERT.
Estrogen can be administered through a variety of routes, including oral, intramuscular, topical,
subcutaneous, nasal, and vaginal. Nasal sprays allow direct rapid absorption. Intramuscular injection
is convenient, requiring infrequent administration, but immediate reversal is impossible, and
tolerance may develop. Moreover, very high circulating levels of estrogen may be achieved soon after
administration. Subcutaneous pellets also give sustained release, but immediate reversal may not be
possible because retrieval of the pellet is difficult. Estrogen creams are used extensively in France but
require a wide area of application. Transdermal patches allow direct absorption, but the effect is not
sustained; therefore, the patch must be worn continually and reapplied at appropriate intervals. The
most frequent complication of transdermal delivery is skin irritation. Vaginal suppositories and
creams permit direct absorption but are unacceptable to many women. A low-dose vaginal ring that
delivers 7.5 µgm estradiol per day over a 90-day period provides a local effect without raising serum
estradiol levels above the menopausal range. The oral route is most convenient but is the only mode
of delivery that significantly affects the liver.
69
Table 2: Approximately Equivalent Estrogen Dosages
Administration Method Dosages*

Oral 0.625 mg conjugated equine estrogen
0.625 - 1.25 mg piperazine estrone sulfate
1 mg micronized estradiol - 17ß
Transdermal 0.05 - 0.1 mg estradiol - 17â
Estrogen administration is associated with a number of side effects that may affect compliance.
Initially, most women experience some breast tenderness. If breast discomfort persists, the dosage of
estrogen should be reduced. Some women require much higher doses for alleviation of their
symptoms; young, surgically oophorectomized women often need twice as much estrogen as those
who underwent physiologic menopause. Other side effects include nausea, vomiting, weight gain up
to 5 lb, fluid retention, and heartburn. Fluid retention and weight gain often may be abolished by
restricting salt intake. The most frequent complaint with hormonal replacement is uterine bleeding.
When progesterone is added to the regimen, the incidence of irregular bleeding diminishes markedly.
Table 3: Contraindications to Estrogen Therapy
Strong Relative
Unexplained vaginal bleeding Hypertriglyceridemia
Uncontrolled hypertension Leiomyomas
Impaired liver function Endometriosis
Active thromboembolic disorders Gallbladder disease
Porphyria Pancreatitis
Breast cancer Migraine headaches
Strong family history of breast cancer
Endometrial cancer
Progestin is usually administered only orally. The most commonly prescribed progestin is MPA at a
dose of 10 mg. This dose is not well tolerated in as many as 25% of women. Common complaints
include bloating, depression, premenstrual tension-like symptoms, acne and breast tenderness.
Beginning with a dose of 5 mg and increasing the dose to 10 mg in those women without complaints
reduces the number of women discontinuing therapy. It may even be necessary to decrease the dose
to 2.5 mg in some women. Norgestrel (150 to 500 µg) and norethindrone acetate (1 to 5 mg) are
frequently used in Europe. These 19-norsteroids lower the ratio of high-density to low-density
lipoproteins more than MPA and therefore can effect the lipid profile and hence increase the incidence
of cardiovascular disease. Micronized progesterone is well absorbed, has little or no effect on the lipid
profile and has been approved for use in the United States. Progesterone in vaginal gel form is also
available. Many prefer to use the LNG-IUS for preventing endometrial proliferation. Other
progestins, such as norgestimate, gestodene and transdermal levonorgestrel and norethindrone
acetate are being investigated.
70
Treatment Regimens
Many regimens are being used, none of which is physiologic. Estrogen is usually given with a
progestin to women with a uterus to prevent endometrial hyperplasia. Estrogen is given alone to
women without a uterus to avoid the deleterious effect of progestin on lipoproteins.
Given below are the common regimens.
Regimen Details Comments
Sequential estrogen daily, progestogen withdrawal bleeding every month;

for last 10 -14 days of cycle change to CCEPT after 5 years
Cyclical estrogen on days 1 - 21, withdrawal bleeding every month;

progestogen on days 9 - 21, change to CCEPT after 5 years
nothing on days 22 - 28
Long - cycle estrogen for 3 months, withdrawal bleeding every third

progestogen in 2nd long - term protection of
half month;of third month endometrium uncertain
Continuous estrogen and progestogen no bleeding should occur,

combined continuously and endometrium should remain
atrophic, but many women experience
irregular bleeding for the first few
months. suitable only for women aged
above 54 or psotmenoapusal
Tibolone synthetic derivative of has weak estrogenic, androgenic and

testosterone,given progestogenic properties; does not
continuously stimulate uterine lining, can be used
without progestogen and causes less
breakthrough bleeding than other
regimens; relieves menopausal
symptoms, including bone loss; may
not provide the same protection
against cardiovascular disease because
of its relatively weak estrogenic
effects; suitable only for women aged
over 54 or who have had no periods
for at least 12 months
CCEPT, continuous combined estrogen and progestogen therapy
Alternative Delivery systems for HT

1. Transdermal Administration
The patches first used for transdermal estrogen administration contained an alcohol reservoir; the
estrogen was released through a semipermeable membrane attached to the skin with an adhesive.
The current generation of patches has the hormones dissolved and distributed throughout the
adhesive matrix and hence the skin irritation is less. The patches are designated according to the
amount of estrogen delivered per day: 50 and 100 µg.
71
The effect of steroids on lipids and lipoproteins is determined by the type of steroid, the dose and the
route of administration. The advantage of transdermal route is the beneficial impact on the
lipoprotein profile. English data indicate that the transdermal administration of 50 g of estradiol twice
a week is as effective as 0.625 mg of oral conjugated estrogens, when combined with a progestin in
sequential regimens, on bone density and lipids over a duration of 3 years. The transdermal
administration of 100 g of estradiol combined with a progestin not only increases bone density, but
also reduces the fracture rate in older women who already have significant osteoporosis.
Estradiol Implants
Estradiol pellets are available in doses of 25, 50, and 75 mg for subcutaneous administration twice
yearly. The 25-mg pellet provides blood levels in the range of 40 to 60 pg/mL (150 to 220 pmol/L),
levels, which are comparable with those obtained with the standard oral dose.
Percutaneous Estrogen
Estradiol delivery can be accomplished by applying a gel (estrogel) to the skin, usually over the
abdomen or thighs.
Vaginal Estrogen
Estrogen is absorbed readily from a vagina with immature, atrophic mucosa. The initial absorption is
rapid, and relatively high circulating levels of estrogen are easily reached. As the vaginal mucosa
cornifies, absorption decreases. This decline takes approximately 3 to 4 months, after which lesser but
still significant absorption takes place. European studies demonstrate that vaginal maturation can be
achieved with a vaginal ring (that is left in place for 3 months) having incredibly small doses of
estrogen, with a low-level absorption that is free of systemic effects. This is an acceptable treatment to
relieve atrophic vaginal symptoms in women with contraindications to estrogen treatment.
Progesterone intra Uterine Device – LNG-IUS

The contraceptive levonorgestrel-releasing IUD has been reconfigured in a smaller model releasing as
little as 5 µg of levonorgestrel per 24 hours. The intrauterine presence of the progestin effectively
protects the endometrium against hyperplasia and cancer. The local site of action provides
endometrial protection and escapes systemic progestin side effects. There is irregular breakthrough
bleeding in the first 6 months, and after 1 year, approximately 60% to 70% of the women are
amenorrheic. The levonorgestrel device has the advantage of a 10-year duration of use.
Conclusion
Judicious use of HT in women with symptoms is indicated and should not be denied. Relief of mild
menopausal symptoms may be achieved by short-term therapy tapering to none. When needed, Ht
should be individualized, as there is no one size that fits all. However, HT without any symptoms is no
longer indicated. In view of the side-effects with oral HT, alternative routes are now being
recommended and seem to have lesser complications due to avoiding the first by-pass by the liver.
How long therapy of postmenopausal and oophorectomized women should continue is still a
question that's needs to be answered.
72
Suggested Reading
1. Armstrong BK: Oestrogen therapy after the menopause: Boon or bane? Med J Aust 148: 213, 1998
2. Mashchak CA, Lobo RA, Dozono-Takano R et al: Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet
Gynecol 144: 511, 1992
3. Ross D, Rees M, Godfree V et al: Randomised crossover comparison of skin irritation with two transdermal oestradiol patches. Br Med J 315: 288,
1977
4. Kuhl H: Pharmacokinetics of oestrogens and progestogens. Maturitas 12: 171, 1990
5. Hillard TC, Whicroft SJ, Marsh MS et al: Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss.
Osteoporos Int 4: 341, 1999
6. Lufkin EG, Wahner HW, O'Fallon WM et al: Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 117: 1, 1999.
7. Raudaskoski TH, Lahti EI, Kauppila AJ et al: Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints:
Clinical and endometrial responses. Am J Obstet Gynecol 172: 114, 2005
8. Rigg LA, Hermann H, Yen SSC: Absorption of estrogens from vaginal creams. N Engl J Med 298: 195, 1998.
9. Pschera H, Hjerpe A, Carlström K: Influence of the maturity of the vaginal epithelium upon the absorption of vaginally administered estradiol-
17b and progesterone in postmenopausal women. Gynecol Obstet Invest 27: 204, 1989
10. Johnston A: Estrogens: Pharacokinetics and pharmacodynamics with special reference to vaginal administration and the new estradiol
formulation—Estring. Acta Obstet Gynecol Scand 75 (suppl 163): 16, 2006.
73
Current Recommendations for use of
17 A
Hormone Therapy at Menopause
Dr. Meeta Singh

Vice-President Indian Menopause Society
Consultant, Obstetrician and Gynecologist, Hyderabad
The role of Hormone Therapy at menopause has always evoked a passionate response, be it from the
diehard admirers or the critics. The premature release of the results of the Women's Health Initiative which
were not completely evaluated and analyzed had a major detrimental effort on the use of Hormone
Therapy. However a more detailed sub analysis of the WHI study published in the last three years
correlate with the findings of the observational studies on Hormone Therapy. It is clear that appropriately
timed Hormone Therapy is safe for healthly women in their early post menopause and decreases total
mortality in the age group of 50-59 years(WHI data).
The current recommendations are based on consensus statement issued by International Menopause
Society (2007,2008)1,2. North American Menopause Society(2007)3, Indian Menopause Society
(2004)4,5.
Indications of use of Hormone Therapy.

• The primary indication remains the treatment of vasomotor symptoms.
• HT is indicated for prevention of bone loss in women with premature menopause and secondary
amenorrhea.
• HT should not be recommended without a clear indication for its use.
Issues to be assessed before deciding for Hormone Therapy:

• Age of the woman
• Symptoms of Menopause
• Family history, Past history of medical problems
• Clinical examinations
• Counselling regarding Risk and Benefits
• Routine Screening Tests-CBC, Urine test, Pap smear, S.TSH, Blood Sugar, Lipid Profile, TVS and
Mammogram.
• Tests to be done on indication- FSH, Estradiol, Endometrial Biopsy, BMD, tests to assess increased
risk of thrombosis.
Hormone Therapy:
• The type, dose, regime and route of Hormone Therapy should be based on patient preference,
efficacy in the individual patient, side effects and cost.
• Lower than standard doses of EPT should be considered, such as 0.3 mg of oral conjugated estrogen
or 0.25 to 0.5mg of micronized estradiol, but these have not been tested in long-term trials.
• The long term risk/benefit ratio for non oral administration has not been tested.
74
• Unopposed Estrogen is prescribed for women with Hysterectomy. Progesterone has to be prescribed
along with Estrogen for a woman with uterus.
• Vaginal atrophy may be symptomatic in up to 40% of postmenopausal women, although most
women do not seek medical attention for these symptoms. Dryness is the most common symptom of
vaginal atrophy.
The current position statement suggests that vaginal lubricants and moisturizers are the first-line
therapy for symptoms of vaginal atrophy, and vaginal estrogen therapy should be considered for
women with continued symptoms while receiving conservative therapy. All delivery method of
vaginal estrogen appears equally effective. Low dose vaginal estrogen does not require progesterone
supplements.
Level A evidence refers to data from randomized controlled trials, whereas Level B evidence comes
from case control/observational studies.
HT-Quality of Life and Menopause

In symptomatic postmenopausal women, quality of life and sexuality are improved by HT6, and, in
the presence of symptoms of androgen deficiency, by additional androgen administration.
• There is no evidence that so-called 'natural' products and unregulated hormone products
(compounded bio-identical) significantly improve quality of life.
HT- Coronary Heart Disease, Stroke and Thromboembolism

• HT in women ages 50-59 years does not increase CHD risk in healthy women and may even decrease
the risk in this age group7[A].
• Estrogen-alone therapy in the age group 50-59 was associated with significantly less coronary
calcification(equivalent to a smaller plaque burden),which is consistent with findings of a lower
coronary intervention score in women of this age in the WHI study[A].
• Early harm (more coronary events during the first 2 years of HT) was not observed in the early
postmenopausal period. The number of CHD events decreased with duration of HT in both WHI
clinical trials[A].
• Data derived from randomized controlled trials in the age group 50-59 are similar to the older
observational data suggesting a protective effect of HT on coronary disease[A,B].
• It is unclear at present whether there is a statistical increase in ischemic stroke with standard HT in
healthy women aged 50-59. The WHI data showed no statistically significant increase in risk;
nevertheless, even if statistically increased, as found in Nurses' Health Study, the low prevalence of
this occurrence in this age group makes the attributable risk extremely small[A,B].
• The risk of venous thrombosis approximately two fold higher with standard doses of oral HT, but is a
rare event in that the background prevalence is extremely low in a healthy women under 60 years of
age[A].
• The risk of venous thrombosis is possibly less with Transdermal, compared with oral estrogen
therapy[B].
HT-Breast
• There is wide variation across the world in the incidence of breast cancer and its risk factors.
• There are multiple risk factors for breast cancer, including life-style factors especially alcohol intake,
75
obesity and lack of exercise. These need to be included during counselling to put the magnitude of risk
of HT into an appropriate perspective [B].
• After 5 years' use of combined estrogen and Progestogen, there is a small increase in risk of breast
cancer in North American women of about eight extra cases per 10,000 women per year. However,
no significant increase was seen in women without prior use of HT in the WHI study[A].
• Estrogen-only use does not cause an increase in breast cancer for up to 7 years8. In observational
studies, a small increase in the risk with estrogen-alone therapy appears with long-term use9[B].
• Women using combined HT before a diagnosis of breast cancer have a reduced mortality[B].
• A decline in the incidence of breast cancer in the USA started before the WHI publication and can be
partially related to fluctuation in screening. There has been no decline in breast cancer registration in
the UK following the Million Women Study report, nor in Norway, Canada, the Netherlands and
countries with stable screening programmes[B].
• Combined estrogen and progesterone therapy may cause increased breast density in up to 50% of
postmenopausal women, dependent on the regime (dose, type of progesterone). The effect of
estrogen alone is smaller[A].
• The effect on breast density is dose-related. Ultra-low-dose regimes do not cause any perceptible
change in density[A].
• The average increase in breast density under standard-dose HT is only about 5-10%[A].
• Increased baseline breast density is a risk factor for breast cancer. There are no data to support a direct
association between HT-induced breast density changes and the risk of developing breast cancer.
• Many women who develop breast cancer have no known risk factors other than growing older and
most women with known risk factors do not develop breast cancer.
• Individual risk analysis for breast cancer is strongly recommended in clinical practice.
HT-Bone:-
• Overall, HT is effective in the prevention of all osteoporosis-related fractures, even in patients at low
risk of fracture[A]10.
• Although no head-to-head studies have compared HT to bisphosphonates in terms of fracture
reduction, there is no evidence to suggest that bisphosphonates or any other antiresorptive therapy
are superior to HT.
• It is therefore suggests that, in 50-59 years old postmenopausal women, HT is a cost-effective first-line
treatment in the prevention of osteoporotic fractures.
• Even lower than standard-dose preparations maintain a positive influence on bone indices such as
bone mineral density[A].
• HT has a positive effect on osteoarthritis and the integrity of intervertebral disks.
HT-Cognition:-
• At present, there is no evidence of substantial cognitive decline across the menopausal transition.
However, many women experience cognitive difficulties in association with vasomotor symptoms,
sleep disturbances and mood changes[A].
• Verbal memory performance relates with the objective number of hot flushes women experience but
not to the number of hot flushes they report.
• Clinical trial findings currently find no cognitive benefit among women initiating HT late in the
postmenopausal period (i.e. after age 65).
• Cognitive benefits from estrogen replacement therapy appear to depend on age of initiation11.
76
• Observational studies show a decreased risk of Alzheimer's disease in hormone users and typically
involve women who initiated estrogen therapy early in the menopausal transition.12
• Limited data exist on the effect of Progestogen added to estrogen in the early postmenopause period.
Clinical trial data suggest no cognitive benefit with MPA early in the menopause[A].
No Consensus:-
• There is no consensus whether cessation of Hormone Therapy should be abrupt or tapered.
Evidence based prescription of Hormone Therapy is to start early, use minimum effective dose
judiciously on indication, after appropriate counseling
Suggested Reading
1) International Menopause Society consensus statement climacteric; Vol 12; No 5; Oct 2009
2) IMS updated Recommendations of Post Menopausal Hormone Therapy Climacteric; Vol 10; No 3; June 2003;181-194
3) Position statement on use of Hormone Therap. North American Menopause Societ-2007
4) Menopause and role of HRT in Indian women. A second National Revised Consensus And Policy Development Document 2002 .
5) IMS Insight Science and sense of Hormone Therapy At Menopause
6) Wilkund I, Karberg J, mattson L-A.Quality of life of post menopausal women on regimen of transdermal estradiol therapy: a double blind placebo
controlled study. Am J Obstet Gynecol 1993;168:824-30.
7) Rossouw JE, Prentice RL, Manson JE, at al. Post menopausal hormone therapy and risk of cardiovascular disease by age and years since
menopause. JAMA 2007;2971465-77
8) Stefanick ML,Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in post
menopausal women with hysteroscopy. JAMA 2006;295;1647-57.
9) Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027-
32
10) Jackson RD, Wactawasi-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal
women with hysterectomy: results from the Women's Heallth Initiative randomized trial. J Bone Miner Res 2006;21:817-28
11) Bagger YZ, Tanko LB, Alexanderson P, Qin G, Christiansen C. Early postmenopausal hormone replacement therapy may prevent cognitive
impairment later in life.Menopause 2005;12:12-17.
12) Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement thrapy and incidence Alzheimer's disease on older women the Cache County
Study. JAMA 2002;288:2123-9
77
TIBOLONE : Clinical Recommendations
17 B
and Practical Guidelines
Dr. Jaideep Malhotra,
Vice President, 2010, FOGSI
Chapter secretary, IMS Agra
Consultant, Obsterician and Gynecologist, Agra
Dr. Ruchika Garg

Clinical Associate,
Agra
Introduction
Tibolone has been classified as a selective tisane estrogenic actively regulator (STEAR) (1)
In the light of the results of the Women's Health Initiative (WHI) unopposed estrogen therapy (ET)
trial[2] and after the criticism[3,4] of the findings of the Million Women Study (MWS)[5] there is now room
for reformulation of expert advice as to the use of postmenopausal hormone therapy. Tibolone has a
different profile to conventional ET, oestrogen-progestogen therapy (EPT) and selective oestrogen
receptor modulators (SERMs).
Tibolone has specific effects in different tissues due to tissue-selective metabolism, enzyme regulation
and/or receptor binding and activation. After oral ingestion, tibolone is converted to three active
metabolites : the 3a - OH-and 3b-OH-tibolone metabolites have oestrogenic effects on the bone,
vagina and climacteric symptoms, whilst the D4 isomer has progestogenic and androgenic properties
and prevents stimulation of the endometrium. The breast is also not stimulated due to effects on local
enzyme activity that inhibit formation of active oestrogens.
1. Efficacy:
1.1 Climacteric symptoms
Tibolone controls hot flushes, sweating and other typical symptoms such as insomnia, headache and
fatigue. It has proved as effective as a range of EPT/ET regimens in relieving climacteric symptoms[6-8],
although it may have a somewhat slower onset of action, and can be used as add-back therapy to
relieve oestrogen-deficiency symptoms in women receiveing gonadotrophin-releasing hormone
(GnRH) agonist therapy for myomas or endometriosis[9, 10].
1.2 Urogenital symptoms

Tibolone has been shown to reverse vaginal atrophy (increases in karyopycnotic index and cell
maturation value) and improve cervical mucus[11]. Women treated with it have reported significantly
less vaginal dryness, dyspareunia & urinary symptoms.
78
1.3 Libido & Sexuality

With tibolone, sex hormone binding globulin (SHBG) levels are decreased and therefore free
testosterone levels are significantly increased as opposed to the decrease observed with standard EPT.
DHEAS has also been shown to increase[12]. In addition, the D4 isomer of tibolone has androgenic
effects. These properties of tibolone contribute towards a beneficial effect on sexual well-being,
including improvements in sexual desire, arousability, sexual fantasies and vaginal lubrication[13-15].
Tibolone is more beneficial than oral EPT/ET in this respect.
1.4 Mood & Depression

In a comparative study with EPT, tibolone proved more effective in improving
mood disorders[16].
1.5 Prevention of bone loss

Randomised, controlled studies have shown that tibolone is effective in increasing bone mineral
density (BMD) and preventing bone loss[17,18]. These beneficial effects are seen over long-term (10
years) treatment[19] and in both early and late post-menopausal women, women with established
osteoporosis and women receiving GnRH agonist treatment [9, 10, 20-22].
1.6 Quality of life

Beneficial effects of tibolone on climacteric and urogenital symptoms, sleep, sexual drive and mood,
combined with low rates of vaginal bleeding and breast tenderness, might be expected to result in an
improvement in quality of life.
2. Safety and tolerability

2.1. Breast tolerability
Tibolone causes significantly less breast tenderness and mastalgia than EPT and women are
considerably less likely to stop taking tibolone than EPT for these reasons [6, 7, 17, 23]
2.2 Breast Density

Tibolone does not increase mammographic density[23,24]. Naturally occurring increased
mammographic density is considered to be an independent risk factor for breast cancer.
2.3 Breast safety

In contrast to EPT, tibolone does not increase breast tissue proliferation whilst stimulating
apotosis [24,25]. No increased risk of breast cancer has been observed compared with placebo in pooled
data from all phase III/IV trials of tibolone (relative risk (RR) 0.50; 95% confidence interval 0.11-
2.54)[26]. The MWS reported an increased RR of breast cancer with tibolone (RR 1.45; 95%
confidence interval 1.25–1.67), although this was significantly (p<0.0001) less than that seen with
EPT[5].
Randomised controlled trials are awaited before any firm conclusion can be drawn regarding tibolone
and breast cancer.
2.4 Endometrium
Randomised controlled studies show that women given tibolone have significantly less irregular
79
vaginal bleeding and a higher amenorrhoea rate than those given EPT[6,7,27]. In contrast to EPT,
tibolone does not increase the size or volume of myomas[28]. With it standard endometrial surveillance
is not required.
2.5 Cardiovascular
Surrogate endpoint studies for arterial & venous thrombo - embolic disease are inconclusive with
regard to benefit or risk.
2.6 Overall tolerability

Tibolone is well tolerated. It has no major clinical impact on body weight. The most common adverse
events are leucorrhoea, abdominal pain, weight increase, vaginal bleeding and breast pain.
It prevents the increase in body fat mass and the decrease in lean body mass that typically occur in
postmenopausal women[29, 30]
3. Contraindicatoins to tibolone
These should be considered to be the same as for EPT/ET.
Suggested Reading
1. Smith CL, O'Malley BW. Coregulator function : a key to understanding tissue specificity to selective receptor modulators. Endocr Rev 2004; 25 :
45 – 71.
2. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy : the Women's
Health Initiative randomized controlled trial. J Am Med Assoc 2004; 291 : 1701 – 12.
3. Shapiro S. The Million Women Study : potential biases to do not allow uncritical acceptance of the data. Climacteric 2004; 7:3 – 7.
4. Whitehead M, Farmer R. The Million Women Study : critique. Endocrine 2004; 24 : 187 – 94.
5. Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003; 362 : 419 – 27.
6. Hammar M, Christau S, Nathorst-Boos J, Rud T, Garre K.A double-blind randomized trial comparing the effects of tibolone and continuous
combined hormone replacement therapy in post-menopausal women with menopausal symptoms. Br J Obstet Gynaecol 1998;105:904-11.
7. Huber J, Palacios S, Berglund L, et al. The effect of tibolone compared with conjugated equine oestrogens continuously combined with
medroxyprogesterone acetate on bleeding rates, quality of life and tolerability in postmenopausal women. Br J Obstet Gynaecol 2002;109:886-
93.
8. Baracat Ec, Barbosa IC, Giordano MG, et al. A randomized, open-label study of conjugated quine estrogens plus medroxyprogesterone acetate
versus tibolone: effects on symptom control, bleeding pattern, lipid profile and tolerability. Climacteric 2002;5:60-9.
9. Lindsay PC, Shaw RW, Coelingh Bennink HJ, Kovic P. The effect of add back treatment with tibolone (Livial) on patients treated with the
gonadotrophin-releasing hormone agonist triptorelin (Decapeptyl). Fertil Steril 1996; 65 : 342 – 8.
10. Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C. Long-term administration of tibolone plus gonadotrophin- releasing hormone agonist for
the treatment of uterine leiomyomas : effectiveness and effects on vasomotor symptoms, bone mass and lipid profile. Fertil Steril 1999; 72 : 889 –
95.
11. Morris EP, Wilson POG, Robinson J. Rymer JM. Long-term effects of tibolone on the genital tract in postmenopausal women. Br J Obstet
Gynaecol 1999; 106 : 954 – 9.
12. Doren M, Rubig A, Coelingh Bennink HJ, Holzgreve W. Differential effects on the androgen status of postmenopausal women treated with
tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Fertil Steril 2001;75:554-9.
13. Davis SR. The effects of tibolone on mood and libido. Menopause 2002;9:162-70.
14. Palacios S, Menendez C, Jurado R, Castano JC, Vargas JC. Changes in sex behavior after menopause: effects of tibolone. Maturitas
1995;22:155-6.
15. Laan E, van Lunsen RHW, Everaerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women.
Climacteric 2001;4:28-41.
16. Egarter Ch, Huber J, Leikermoser R, et al. Tibolone versus conjugated estrogens and sequential progestogen in the treatment of climacteric
complaints Maturitas 1996;23:55-62.
17. Roux C, Pelissier C, Fechtenbaum J, Loiseau-Peres S, Benhamou CL. Randomized, double-blind, 2 year comparison of tibolone with 17β -
estradiol and norethindrone acetate in preventing postmenopausal bone loss. Osteoporosis Int 2002;13:241-8.
18. Lippuner K, Haenggi W, Birkhauser MH, Casez J-P, Jaeger P. Prevention of postmenopausal bone loss using tibolone or conventional peroral or
transdermal hormone replacement therapy with 17 β -oestradiol and dydrogesterone. J Bone Min Res 1997;12:806-12.
19. Rymer J, Robinson J, Fogelman I. Ten years of treatment with tibolone 2.5 mg daily: effects on bone loss in postmenopausal women. Climacteric
2002;5:390-8.
20. Berning B, Kuijk CV, Kuiper JW, Coelingh Bennink HJT, Kicovic PM, Fauser BCJM. Effects of two doses of tibolone on trabecular and cortical
bone loss in early postmenopausal women: a two-year randomized, placebo-controlled study. Bone 1996;19:395-9.
21. Bjarnason NH, Bjarnason K, Haarbo J, Rosenquist C, Christiansen C, Tibolone: prevention of bone loss in late postmenopausal women. J Clin
Endocrinol Metab 1996;81:2419-22.
80
22. Pavlov PW, Ginsburg J, Kicovic PM, van der Schaaf DB, Prelevic G, Coelingh Bennink HJT. Double-blind, placebo controlled study of the effects
of tibolone on bone mineral densityin postmenopausal osteoporotic women with and without previous fractures. Gynecol Endocrinol
1999;13:230-7.
23. Lundstrom E, Christow A, Svane G, et al. Effects of tibolone and a continuous combined HRT regimen on mammographic breast density. Am J
Obstet Gynecol 2002;186:717-22.
24. Valdivi I, Campodonico I, Tapia A, et al. Effects of tibolone and continuous combined hormone therapy on mamographic breast density and
breast histochemical markers in postmenopausal women. Fertil Steril 2004;81:617-23.
25. Conner P, Christow A, Kersemaekerc W. A comparative study of breast cell proliferation during hormone replacement therapy: effect of tibolone
and continuous combined estrogen progestogen therapy. Climacteric 2004;7:50-8.
26. Helmond FA, Kloosterboer HJ, Safety and teloreability profile of Livial. In: Genazzani AR, editor. Hormone replacement therapy and cancer. The
current status of research and practice. Boaa Raton: The Parthenon Publishing Group; 2002. p. 252-6.
27. Doren M, Rubig A, Coelingh Bennink HJT, Holzgreve W. Impact on uterine bleeding and endometrial thichness: tibolone compared with
continuous combined estradiol and norethisterone acetate replacement therapy. Menopause 1999;6:299-306.
28. Fedele L, Bianch S, Raffaelli R, Zanconato G.A randomized study of the effects of tibolone and transdermal estrogen replacement therapy in
postmenopausal women with uterine myomas. Eur J Obstet Gynecol Reprod Biol 2000;88:91-4.
29. Haenggi W, Lippuner K, Jaeger P, Birkhauser MH, Horber FF. Differential impact of conventional oral or transdermal hormone replacement
therapy or tibolone on body composition in postmenopausal women. Clin Endocrinol 1998;48:691-9.
30. Meeuwsen IB, Samson MM, Duursma SA, Verhaar HJ. The effect of tibolone on fat mass, fat-free mass, and total body water in postmenopausal
women. Endocrinology 2001;142:4813-7.
81
17 C Role of Androgen Replacement
Dr. Sunila Khandelwal

MS, FICMCH, FICOG, FICS
President Indian Menopause Society
Medical Superintendent
Prof. & Head,
Director of Menopause Clinic & Research Unit
Dept. of Obst. & Gyn.
M.G. Medical College & Hospital, Jaipur
Androgens play a primary role in female physiopathology. The age-related decline in the production
of ovarian and adrenal androgens may significantly affect women's health.1 Recognition of cellular
action of androgen and decrease in androgen production in women after menopause has led to
increase use of androgen replacement therapy for post menopausal women.2
Androgen insufficiency, a cluster of symptoms and physical signs indicative in both peri- and
postmenopausal women, include a decrease in mood, diminished energy, depression and impaired
sexuality. These women are at increased risk for 'hypoactive sexual desire disorder' (HSDD).
HSDD is a common clinical consequence of Surgical, chemotherapy induced or natural menopause.3
Reliable biological confirmation of female androgen insufficiency is done by using the free
testosterone index (the ratio of total plasma testosterone/SHBG).4 A value in postmenopausal women
below the lower quatertile of normal for premenopausal women is confirmatory of female androgen
insufficiency.5 A Menopause Rating Scale and urogenital problems interview, combined with a
“Vaginal Health Index”, facilitate early diagnosis and monitoring.6
Effects of androgen therapy -

Positive effects: increased libido, mood sense of well being, decreased
breast tenderness induced by HRT and an additive effect on ERT induced
BMD increments, especially in the spine (both trabecular & cortical).
Negative effects: Long-term use of high doses may result in liver toxicity,
Virilizing effects like seborrhoea, androgenic alopecia, acne, mild
hirsutism, deepening of voice, clitoromegaly&reversal of the positive effect
ERT on lipids (HDL) . Contraindications of testosterone therapy are
focused similarly to those associated with estrogen therapy.
DHEA use can be beneficial in post menopausal women to compensate for Endogenous age related
and accelerated decline in DHEA after surgical menopause. It has anti aging benefits with positive
effect on cognition and skeleton. Six weeks DHEA (50 mg / day) has shown remarkable increase in
perceived physical and psychological well-being in depressed surgically menopausal women. A
synthetic form of this hormone is available as nutritional supplement in tablet (25 mg), capsule (25-50
mg – available in India), cream (1%) and widely used to improve libido & well being in post
menopausal women in USA, Europe & Far East. Close monitoring of serum DHEAS and its
metabolites should be performed frequently during replacement therapy. However long term safety
data for DHEA therapy are lacking.7 Researchers argue that, cessation of estradiol secretion by the
postmenopausal ovary is a physiological event not a deficiency state. The real deficiency is adrenal.
82
They propose that the most physiological intervention is to replace the deficient androgen precursor,
DHEA (HPRT). Within the design of a phase III prospective clinical trial involving 218
postmenopausal women, they transvaginal DHEA was administered. Using highly specific and
sensitive mass spectrometry to measure circulating sex steroids and combined with traditional vaginal
cytology, they demonstrated convincingly that intravaginal DHEA is transformed to estrogen within
vaginal epithelium cells and that there is no detectable increase in circulating estradiol. They described
relief in symptomatic vaginal atrophy and in estrogen-induced changes in vaginal cytology that are
dramatic.8
Tibolone possesses some androgenic activity that can be used to treat vasomotor symptoms,
psychological and libido problems, and for prevention of osteoporosis. In the absence of availability
of other androgen preparations, tibolone can be an option.
As per recommendations of the International Menopause Society, administration of individualized
HT (including androgenic preparations) improves sexuality and overall quality of life. Androgen CO-
therapy should be administered at the lowest dose for the shortest time that meets treatment goal. 9
Whom to consider therapy?

Surgical menopause - androgen replacement should be reserved for women with of severe
androgen insufficiency due to an established cause and with matching clinical signs and symptoms. In
women with bilateral oophorectomy or adrenal failure, androgen replacement has significant
beneficial effects, in particular on health related quality of life and sexual function.
Natural menopause - premature natural menopause, especially with unsatisfactory function that
are on MHT and present with poor compliance, addition of androgen in moderate dosages for short
term (when indicated) promises improved continuation rate.
More research is needed to precisely define androgen insufficiency, recommend an ideal preparation,
and to identify to benefits v/s risk of androgen therapy in post menopausal women.
Androgenic preparations11
Preparations Dose range Frequency Route

Methyltestosterone in combination 1.25 - 2.25 mg Daily Oral
with esterified estrogens 0.625 - 1.25 mg
Methyltestosterone with ethinyl estradiol 3.6 mg - 0.0044 mg Daily Oral
Mixed testosterone esters with estradiol* 50 -100 mg/ml 4 - 6 weekly IM
5 mg
Methyltestosterone alone 5 -10 mg Daily Oral
micronized 2.5 mg Twice/day
(cyclodextrin) SL
Testosterone Undecanoate* 40 mg Every 2nd day Oral

Testosterone implants 50 -100 mg 3 - 6 monthly SC
Testosterone pellets 75 mg 3 - 6 monthly SC
Transdermal Testosterone patch* 150 - 300 µg Every 3rd day Topically
Transdermal Testosterone spray* 12.5 mg/spray Daily Topical
Transdermal Testosterone gel* 1% Daily Topical
Transdermal Testosterone cream* 1% Daily Topical
Dehydroepiandrosterone (DHEA)* 25 -50 mg Daily Oral
Tibolone (Gonadomimmetic) * 2.5 mg Daily Oral
* Available in India
83
Future Prespective
Androgen treatment in postmenopausal women is complex, and it is certain that the debate will
continue until more information is gathered to provide a clearer picture as to whether the beneficial
effects of androgen therapy on libido are countered by detrimental adverse effects on preexisting
conditions such as cancer or cardiovascular disease. An informed consensus can be made when more
equitable comparisons are made within and between animal models and clinical trials. Likewise,
more emphasis placed on understanding differences in dose, duration, and type of treatment, as well
as the method of delivery, and solo versus combined use of androgens with estrogens/progestin's will
help to eliminate uncertainties and to eventually establish a general standard of care for androgen
therapy.
Androgen replacement therapy is the primary choice, especially in younger women, with either
premature ovarian or surgically induced menopause, suffering from loss of well being, fatigue and loss
of libido that are not modified by estrogen therapy.
However, since the above conclusions are extrapolated from relatively short-term studies, it is
important that long-term safety data be obtained for women given testosterone or DHEA
therapeutically.10
Suggested Reading
1. A.R. Genazzani and N. Plucbino Androgen replacement therapy and cardiovascular function Climacteric 2009; 12 (Suppl. 1) 102-107.
2. Androgen therapy in women: Endocrine society, clinical practice guidelines. J. Clin. Endocrinol. Meta. 10; 91;: 369 710, 2006
3. Kingsberg SA, Simon JA, Goldstein I. The current outlook for testosterone in the management of hypoactive sexual desire disorder in
postmenopausal women. J Sex Med 2008; 5:182-193.
4. Androgen therapy in women. European Jour. Of endocrinology 154:1-11; 2006.
5. Testosterone for peri & postmenopausal women. Cochrane database of Systematic reviews 2 ; 2007
6. Health Plan for the adult women.2:1-25; 2006.
7. DHEA therapy for women. Hum Reprod update 13 (3): 239-48,2007.
8. Labrie F, Archer D, Bouchard C, et al, Serum steroid levels during 12 week intravaginal DHEA administration Menopause & intravaginal
Prasterone (DHEA), the physiological and highly efficient treatment of vaginal atrophy. 2009; 16:897-922.
9. “Moderate dosage estrogen-androgen therapy improves continuation rates in postmenopausal women: impact of the WHI reports” 9,3:224-
233.2006
10. James K. Pru, The risks of androgen treatment in postmenopausal women remain controversial: a need for equitable comparisons. 2009; 16(3)
430-431.
11. Third national revised consensus meeting guidelines of Indian Menopause Society. Menopause & the Role of Hormone Therapy in Indian
Women 2008; 192:194.
84
a form of tablet Promensil providing 57 or 85.5 mg isoflavones per day for 6 months resulted in an
increased in BMD of the proximal radius & ulna. 12 In a randomized double blind placebo controlled
trial, Charlottee A et al did not observe an increased in lumber spine BMC or BMD with a daily dose of
80.5 mg. isoflavones in the form of as soy protein given for 24 weeks but they saw a reduction in the
extent of bone loss .13
Anderson J. J. et al observe in the study of 28 premenopausal women with mean age of 24 years, no
significant effects of a soy protein supplement that provided up to 90 mg. of isoflavones for 12 months
and they concluded that isoflavones may be beneficial in attenuating age associated bone loss rather
than in enhancing peak bone mass in younger premenopausal women.14
Phytoestrogens and Cardiovascular disease

Several lines of evidence, including epidemiological clinical trial data and basic science suggest that
the phytoestrogens decreased the risk of cardiovascular disease. However, this association is
confounded by other concomittend dietary differences for e.g. low saturated fat intake in Asian
population, making it difficult to attribute the observed differences in disease rates to phytoestrogens
intake.
Two proposed mechanisms for the hypocholesterolemic effect of phytoestrogen are the upregulation
of LDL receptors and / or the inhibition of endogenous cholesterol synthesis. Isoflavones, particularly
genistein have been reported to alter the activity of growth factors and inhibit cell division and
proliferation 15 with antithrombolytic effect.16 However, several clinical trials with phytoestrogens have
reported inconsistent serum lipid effects. In one study, hypercholesterolemic, postmenopausal
women were randomly assigned to 6 month of 40 gm. protein supplementation / day from casein
nonfat dry milk source, an isolated soy protein source or a soy protein source with approximately half
of the phytoestrogen content removed. Compared to the casein milk protein both soy products
lowered non HDL cholesterol and increased HDL cholesterol significantly.11 While in another study
with moderately hypercholesterolemic postmenopausal women were given 45gm/day of either soy
flour or wheat flour for 12 weeks and observed significant decrease in the cholesterol in both groups .8
Phytoestrogens and Cancer :

Hormone related cancer of breast, ovary, endometrium and colon have been reported to vary from 5
to 20 folds between populations and migrant studies indicated that the differential is largely
attributable to environmental factors rather than genetics. The highest rates of these cancers are
typically observed in population with Western lifestyles that include relatively high fat, meat based,
low fiber diets whereas the lowest rates are observed in Asian Populations with Eastern lifestyles which
include plant – based diets with a high content of phytoestrogens.17 In 1997, Goodman MT et al
reported that among the multiethnic population of Hawaii, soy and fiber consumptions were
associated with a decreased risk off endometrial cancer, a finding that was limited to women who had
never used unopposed estrogens and had never been pregnant.18 Despite the positive association of
the endogenous and exogenous estrogens with the breast, ovarian, endometrial and colon cancers,
phytoestrogens are associated with decreased incidence of these cancers. This can be explained by
either a lack of estrogenicity or estrogen antagonism at these sites in conjunction with other possible
mechanisms. The primary lignans and isoflavones have been shown to exhibit antiestrogenic effects
and reduce the proliferation of cells at concentration higher than those achievable under normal
88
physiological conditions i.e. > 10 ml / L. The antioxidant properties, inhibition of enzymes associated
with cell proliferation and enzymes involved in the production of estrogen from the androgens are
other mechanism for anticarcinogenic effects of phytoestrogens.
Recently in 2009, Temfer CB et al concluded in a meta-analysis of randomized trial that based on the
available evidence, phytoestrogens supplements have a safe side effect profile with moderately
elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia,
endometrial cancer and breast cancer were not significantly increased among phytoestrogen users .20
Conclusion :
Many researchers are of the opinion that there are few risks and many potential benefits from
increasing intake of plant based foods which are good sources of phytoestrogens. However, available
data do not appear to unequivocally support beneficial effects of phytoestrogens and hence many
researchers warn against their wide use in the absence of satisfactory clinical trials. Additionally
questions and issues those remain to be the resolved include when to start (perimenopausal or
menopausal age), optimal dosages and for how long?
Suggested Reading
1) Tidsskar Nor Laegeforea, Phytoestrogens and menopausal symptoms. Pub med U.S. National Liberary of Medicines, National Institutes of
Health 2009 : Nov. 5 : 129 (21) : 2238-39.
2) Kuiper GG, Carlsson B, Grandien K et al, Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors
alpha and beta. Endocrinology 1997 : 3 : 863 – 70.
3) Royal College of Nursing complementary approacher to menopausal symptoms : RCM guidance for nurses, midwives and health visitors
London, 2006, 2 HP: //www.rcn.org.44/publications/pdf/complementary – approaches - menopausal pdf.
4) Adlererentz H, Mazur W, Phytoestrogens and western diseases. Ann Med 1997 : 29 : 95 – 120.
5) Barnes S., Peterson TG, Coward L., Rationale for the use of genistein containing soy matrices in chemoprevention trials for breast and prostrate
cancer. J Cell. Biochem. 1995:22:181-187.
6) Geeta Pandya, Alternative Medicines to HRT, Menopause Current Concepts, FOGSI publications, Editors – Dr. C. N. Purandare, Dr. S. S.
Khadilkar, 2004:10:155-167.
7) Buckler H., Alternative treatments for vasomotor symptoms In : 2004.
8) Murkies AL, Lombart C, Strauss BG et al, Dietary Flour supplementation decreases postmenopausal hot flushes : effect of soy and wheat.
Maturitas : 1995 : 21 : 189-195.
9) Krebs EG, Ensrud KE, Mac Donald R et al, Phytoestrogens for treatment of menopausal symptoms : A systemic review Obstet. Gynecol : 104 (4) :
824 – 36.
10) Adami S., Buf – Lino L., Cervetti R. Et al, Biochemical bone markers and bone mineral density during postmenopausal hormonal replacement
therapy and without vitamin D3 : A prospective controlled randomized study, Clin. Endocrinol Metab. 1997 : 82 : 2476 – 482.
11) Potter SM, Baum JA, Teng H et al, Soy protein and isoflavones; their effects on blood lipids and bone density in postmenopausal women, Am. J.
Clin. Nutr. 1998 : 68 (suppl), 13755-95.
12) CliftonDB, Babar RJ, Fulcher GR et al, The effect of isoflavones extracted from red clover on lipid and bone metabolism Menopause : 2001 : 8 :
259 – 65.
13) Charlotte A, Juliet E. Compston, Nicholas E Day et al, The effects of phytoestrogen isoflavones on bone density in women : A double blind,
randomized, placebo – controlled trial. AJ Cll. Nutrition 2004 : 79 : 2 : 326-333.
14) Anderson JJ, Chen X, Boass A et al, Soy isoflavones ; no effects on bone mineral content and bone mineral density in healthy menstruating
young adult women after one year. J. Am. Coll Nutr. 2002 : 21 : 388-93.
15) Mays J., Remarkable Health Benefits of Soy isoflavones. The nutrition practioner 1999 : 1 (1).
16) Wilcox JN., Bluementhal BF, Thrombotic mechanisms in atherosclerosis : potential impact of soy protein 1991 J. Nutr. 125 (Suppl) : 6315 – 6385.
17) Parkim DM, Cancer of the breast, endometrium and ovary : geographic correlations, Eur. J. Cancer Clin Oncol. 1989 : 25 : 1917 – 25.
18) Goodman MT, wilkens L., Harluin JH et al, Assocciation of soy and fiber consumption with the risk of endometmrial cancer, Am. J. Epidemiol
1997 : 146 : 294-306.
19) Barnes S., Sfakianos J., Coward L et al, Soy isoflavonoids and cancer prevention, underlying biochemical and pharmacological issues, Adv. Exp.
Med. Biol, 1996 : 401 : 87 – 100.
20) Temfer CB, Froese G, Heinze G et al, Side effects of phytoestrogens : A meta - analysis of randomized trials, Oct. 2009 : Am. J. 122 (10) : 939 eg.
89
19 Facts & Myths : WHI
Dr. Jyothi Unni
HOD, Dept of Obs & Gyn,
Jehangir Hospital, Pune
Numerous observational studies seemed to show that Hormone Replacement Therapy(HRT) was
beneficial for the prevention of age related diseases in women such as coronary artery disease and
osteoporosis. However, when two large randomized controlled trials HERS and WHI failed to
demonstrate this protective effect, women world over abruptly stopped taking HRT and clinicians were
wary of prescribing it, even in women who needed it for symptom control. Most of the observational
studies looked at markers such as Lipid profile or Bone Density, whereas the WHI study looked at disease
end points.
The Women's Health Initiative (WHI) study was a randomized, double blind placebo controlled trial,
conducted in 40 centres in the United States. A total of 16,608 postmenopausal women aged 50-79 years
(Mean age 63 years), with an intact uterus were randomized to receive Hormone Replacement
Therapy(HRT) or placebo. Participants received conjugated equine estrogens (CEE) 0.625 mg/d, plus
medroxyprogesterone acetate(MPA) 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
Another arm of the study recruited 10,739 postmenopausal women,aged 50-79 years with prior
hysterectomy. They were randomly assigned to receive 0.625 mg CEE or placebo
The planned duration of this trial was 8.5 years, but the estrogen plus progestogen arm was halted in July
2002 after 5.2 years as it was perceived that the health risks exceeded the benefits. The estrogen alone
arm continued till February 2004 (6.8 years)
The results of the CEE+ MPA arm showed an increase in coronary heart disease(CHD),strokes,
pulmonary embolism (PE) and invasive breast cancers. There was a decrease in colorectal cancers and
hip fractures. When these results were reported in percentages in the lay press, the risks appeared to be
alarmingly high. However, the absolute excess risk (or risk reduction) attributable to estrogen plus
progestogen was low. Over 1 year, 10,000 women taking estrogen plus progestogen compared with
placebo might experience 7 more CHD events, 8 more strokes, 8 more PEs, 8 more invasive breast
cancers, 6 fewer colorectal cancers, and 5 fewer hip fractures.
The fallacies of this trial were many. The mean age of the women was 63 years, with 21% of them being in
the 70-79 year age group. Most clinicians would prescribe HRT to women between the ages of 45 -55,
when symptoms are at their worst. This study had only 287 patients aged 50-54 years and was hence
underpowered to test the cardio-protective effect of HRT in women soon after the menopause.
In the study group, 7.7% of them had prior cardio-vascular disease, 36% were hypertensive,10% were
overweight and 7% were on statins. Hence they were already an 'at risk' population.
90
The WHI study tested only one regime, CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, in postmenopausal
women with an intact uterus. The results may not apply to lower doses of these drugs or to other
formulations and routes of administration of estrogens and progestogens.
This study could not distinguish the effects of estrogen from those of progestogen. The effects of
progestogen may be important for breast cancer and atherosclerotic diseases, including CHD and stroke.
42% of the treatment group dropped out compared with 38% of the placebo group. So, this is one of the
rare studies, where there is a higher drop out rate amongst the active preparation group.
As in the WHI estrogen plus progestogen trial, the main hypothesis of the WHI estrogen-alone trial was
that hormone therapy would reduce the risk of CHD. This did not happen, although early CHD harm,
which could be due to the progestogen, appeared less pronounced.
The estrogen alone arm of the study was discontinued due to increase in stroke risk, without any increase
in breast cancer or CHD. There was an increased risk of stroke among women assigned to both estrogen
alone or estrogen plus progestogen, and this adverse effect is therefore attributable to the estrogen
component of the hormone regimen. It is the only statistically significant adverse effect of estrogen alone.
The rate was 0.12% additional strokes per year of treatment, which is quite low.
In younger women however, i.e women aged 50-59 years, there was a 42% decrease in CHD (16Vs29),
28% decrease in breast cancer (25Vs35) and a 41% decrease in colo-rectal cancer (8Vs 15). There was a
22% increase in Venous Thrombo-embolism (18 Vs 15) and an 8 % increase in strokes. Unfortunately, the
numbers in this age group were small, so no definite conclusions can be drawn.
Subsequently, several authors have looked at various aspects of the WHI data as well as designed studies
of HRT in women in the early post menopausal years. Most authors are now of the opinion that HRT,
particularly estrogen alone is not only safe, but beneficial in the age group where treatment is usually
commenced.
Hormone therapy is the most effective modality for treating menopausal symptoms, and for this
indication, women who do not have contra-indications should not be denied HRT. However, estrogen
and progestogen do have adverse effects, and the dose should be kept low and the duration of treatment
short.
Suggested Reading
1. Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women.
Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321-333.
2. Studd JWW. Benefits and side effects of HRT after the Women's health Initiative(WHI) and Million Women's Study (MWS) reports. Progress in
Obstetrics and Gynaecology 2003;16: 411-420
3. The Women's Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy .The
Women's Health Initiative Randomized Controlled Trial .JAMA. 2004;291:1701-1712.
4. Hulley SB,Grady D.The WHI Estrogen-Alone Trial—Do Things Look Any Better? JAMA. 2004;291:1769-1771.
91
20 Facts & Myths : HERS
Dr. Mrs. Suvarna Satish Khadilkar

MD DGO FICOG
Associate Professor and Head of Unit in ObGyn,
Grant Medical College and Cama and Albless hospital, Mumbai.
Secretary, Mumbai chapter, Indian menopause society
Asst secretary, Editorial board, Journal of Obstet. & Gynae. of India, FOGSI
Chairperson menopause committee, MOGS
Jt secretary AMWI, Mumbai, subject editor AMWI scientific journal
Introduction:
Postmenopausal HRT has witnessed its rise and fall over past several years. The research has been
giving conflicting results and confusing menopause practitioners about various management
protocols. As of the early 2000s, after the publication of the principal results of the two large
randomized trials, the Heart and Estrogen/Progestin Replacement Study (HERS) in 1998 and the
Women's Health Initiative (WHI) trial in 2002, the trend has changed drastically.1,2,3 WHI results
constituted the direct cause of discontinuation of HRT in approximately 30% of postmenopausal
women3. HERS is a study which has given an unexpected set back to HRT for cardioprotection. Thus,
it is important to know how HERS and WHI changed our practices
HERS I :4
Heart and Estrogen/progestin Replacement Study (HERS) Research Group conducted a
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in
postmenopausal women4. Earlier observational studies5,6,7 had found lower rates of coronary heart
disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this
potential benefit has not been confirmed in clinical trials so they conducted a Randomized, blinded,
placebo-controlled secondary prevention trial in Outpatient and community settings at 20 US clinical
centers. A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal
with an intact uterus participated in the study. Mean age was 66.7 years. Either 0.625 mg of
conjugated equine estrogens plus 2.5 mg of medroxy progesterone acetate in 1 tablet daily (n =
1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years. The primary
outcome was the occurrence of nonfatal myocardial infarction (MI) or Fatal CHD. Secondary
cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart
failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease.
All-cause mortality was also considered. 172 women in the hormone group and 176 women in the
placebo group had MI or CHD death Within the overall null effect, there was a statistically significant
time trend, with more CHD events in the hormone group than in the placebo group in year 1 and
fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced
venous thromboembolic events (34 vs 12;) and gallbladder disease (84 vs 62;). There were no
significant differences in several other end points for which power was limited, including fracture,
cancer, and total mortality (131 vs 123 deaths). They concluded that during an average follow-up of
4.1 years, treatment with oral estrogen plus medroxyprogesterone acetate did not reduce the overall
rate of CHD events in postmenopausal women with established coronary disease. The treatment did
increase the rate of thromboembolic events and gallbladder disease. Hence starting this treatment for
92
the purpose of secondary prevention of CHD was not recommended as there was no overall
cardiovascular benefit and a pattern of early increase in risk of CHD events. However, given the
favorable pattern of CHD events after several years of therapy, it could be appropriate for women
already receiving this treatment to continue.
Table 1. Hazard ratios of HERs trial 1998
Clinical Event HAZARD RATIO (95% CONFIDENCE INTERVAL)

HERS (Estrogen + Progestin)
CHD events 0.99 (0.80 - 1.22)
Stroke 1.23 (0.89 - 1.70)
Pulmonary embolism 2.79 (0.89 - 8.75)
Breast cancer 1.30 (0.77 - 2.19)
Colon cancer 0.69 (0.32 - 1.49)
Hip fracture 1.10 (0.49 - 2.50)
Death 1.08 (0.84 - 1.38)
Table 1 shows hazard ratios of HERS trial. For the primary CHD events, outcome of (myocardial
infarction plus CHD death), the three randomized trials (HERS, WHI HRT-EP, and WHI HRT-E)had
similar numbers of events and thus similar power. For the other outcomes, the smaller HERS trial had
fewer events and less precise hazard ratios. These risks are statistically significant but minimal.
Results from HERS and WHI led the USFDA to require a warning of potential harm and to
recommend that estrogen preparations not be used to prevent CHD or be considered first-line
therapy for prevention of osteoporosis. a number of professional societies changed their guidelines to
recommend that hormone therapy not be used for preventing disease, and when used for treating
symptoms that it be at the lowest dose and for the shortest time possible.
Critical analysis of facts about HERS trial:

The mean age of participants in all three randomized trials was in the mid-60s, raising the concern that
these results may not apply to treatment begun early in menopause.4, 8
A 50% increase in cardiovascular events was seen in the first year, followed by fewer events after 2
years of treatment in the hormone therapy group than in the placebo group. Understanding the cause
of this pattern of early increase and late reduction in risk is key to interpreting the HERS results and
reconciling them with the large number of observational and other studies of the cardiovascular
effects of estrogen. The other is that the pattern of early increase and late reduction in risk is coupled
with a gradually progressive beneficial effect due to lipid lowering and other factors is a promising
potential explanation.
Why Early Harm and Late Benefit in HERS trial?

1] Estrogen plus progestin had no real effect on risk for heart disease, and the observed pattern of
changing risk over time was simply the result of chance or confounding
2] It may be due to real but opposing effects of this regimen with time, like lipid lowering effects
3] Decrease in number of women uniquely at risk for a cardiovascular complication from hormone
therapy
93
Statistical perspective of HERS trial:
1] From a statistical perspective, although the final test for trend in the relative hazards over time had a P
value of 0.03, this time-trend analysis was not explicitly specified.
2] There are also concerns about the validity of the year-specific estimates of relative risk that were used
in the time-trend analyses
3] Estimates of risk during individual years of follow-up are less precise than for the entire study period.
For these reasons, the time-trend analyses should be interpreted with caution
4] Because of the statistical uncertainties concerning the time-trend analysis, it is clear that the results
need independent confirmation.
Biological Perspective of HERS trial:

1] In the biological perspective, it is possible that the estrogen replacement in HERS had no effect on risk
for coronary heart disease because it was opposed by a progestin, medroxyprogesterone acetate
2] The overall null effect in HERS is later shown to be due to an early adverse and late beneficial effect,
and if the cause of the early risk can be identified and prevented, many women may still be able to
benefit from estrogen replacement for secondary prevention of coronary heart disease
Risk factors were assessed by a HERS trial group9.These researchers found 11 risk factors: 6 noted by
history (nonwhite ethnicity, lack of exercise, treated diabetes, angina, congestive heart failure, and
more than one previous myocardial infarction) and 5 that were measured (blood pressure, low-
density lipoprotein cholesterol level, high-density lipoprotein cholesterol level, lipoprotein(a) level,
and creatinine clearance). The annual rate of coronary events was 1.3% in women with no risk factors
and 8.7% in women with five or more risk factors (a six-fold increase)
The facts and the myths : comparison of the three landmark trials:
Heart and Estrogen/Progestin Replacement Study (HERS)4, 1998 and the Women's Health Initiative
(WHI) trial 2002 E+P 10 and E only.20088
Coronary Heart Disease

Given the absence of evidence in all three trials that these hormone regimens prevent CHD in these
populations, the previously available evidence in favor of HRT was probably misleading. HRT-EP or
HRT-E does not prevent CHD as previously proposed. To the contrary, there may be a small but
significant increase in CHD in women taking HRT-EP. Both women with preexisting CHD and healthy
women are at risk. HRT-E, on the other hand, does not increase the risk for healthy women
Stroke
Another outcome that is consistent across the three trials is the increased risk of stroke among women
assigned to HRT-E or HRT-EP. Increased stroke is possibly attributable to the estrogen component of
the hormone regimen, since it is the only statistically significant adverse effect of HRT-E4
Pulmonary Embolism
A pattern of increased risk for pulmonary embolism was observed in all three studies4,8,10 although the
risk was attenuated and not statistically significant in the WHI HRT-E trial.8
94
Breast Cancer
The findings of the WHI HRT-E trial differed markedly from the findings of the HERS and WHI HRT-
EP trials with respect to the breast cancer risk4,8 In the estrogen plus progestin trials (HERS and WHI
HRT-EP), the risk for breast cancer was increased about 25%, and in the estrogen-only trial (WHI
HRT-E) it was reduced by 23%. Numerous lines of evidence support an increased risk for breast
cancer with estrogen exposure, including cell culture studies, animal models, many observational
studies, and the fact that estrogen antagonists reduce the risk of developing breast cancer in healthy
women. Thus, this discrepancy was somewhat surprising. Nonetheless, the higher risk for breast
cancer observed in the estrogen plus progestin trials probably represent a harmful effect of the MPA.
The increased risk was statistically significant in WHI HRT-EP. This was matched by a trend of the
same magnitude in HERS and supported by evidence from large observational studies suggesting
that the addition of MPA or another progestin to estrogen may significantly increase risk for breast
cancer
Ovarian Cancer
Dementia
In postmenopausal women 65 years of age or older, HRT-EP significantly
increased risk and resulted in an additional 23 cases of probable dementia
per 10,000 women per year Alzheimer's disease was the most common
classification of dementia. A similar trend was observed in the HRT-E
group, although this did not reach statistical significance.12 When the data
were pooled, HRT significantly increased probable dementia risk12
Hyperlipidemia
This rare side effect is observed in patients with severe familial hypertriglyceridemia. An oral estrogen
regimen can hasten severe hypertriglyceridemia or pancreatitis in women with severely elevated
triglyceride levels13. Therefore, estrogen replacement is a relative contraindication in women with
substantially increased triglyceride levels. Effect on lipid was studied by a group14 as Despite the effect
of lowering low-density lipoprotein cholesterol (LDL-C) levels and raising high-density lipoprotein
cholesterol (HDL-C) levels, combination hormone therapy did not reduce the incidence of coronary
heart disease (CHD) events in the Heart and Estrogen/progestin Replacement Study (HERS).
Another group studied Statin therapy15 in the heart and estrogen/progestin replacement study.Data
from HERS supports the use of statins for secondary prevention in postmenopausal women with a
history of cardiovascular disease. Statins may attenuate the increased cardiovascular risk of hormone
replacement therapy.
Gallbladder Disease
Both WHI trials (HRT-E and HRT-EP) trials showed greater risk of any
gallbladder disease or surgery with estrogen16 In HERS, A total of 147
women (7%) were hospitalized for biliary tract surgery in HERS.
Treatment with estrogen plus progestin resulted in a marginally
significant 38% increase in the relative risk for biliary tract surgery (P
= 0.05). A small absolute difference in risk suggested that for every
185 women treated with estrogen plus progestin, one additional
woman had biliary tract surgery per year17
95
Urinary symptoms:
Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement
Study18. shows that: Incontinence improved in 26% of the women assigned to placebo compared with
21% assigned to hormones, while 27% of the placebo group worsened compared with 39% of the
hormone group (P =.001). This difference was evident by 4 months of treatment and was observed
for both urge and stress incontinence. The number of incontinent episodes per week increased an
average of 0.7 in the hormone group and decreased by 0.1 in the placebo group (P <.001).this group
does not recommend this therapy for the treatment of incontinence.
Benefits of Hormone Replacement Therapy:

Hot Flash
HRT-E or HRT-EP reliably treats hot flashes in most women. Currently, hot flash is the most common
indication of a short course of HRT (<5 years).
Fractures
Both HRT-EP and HRT-E significantly decreased hip, vertebral, and other osteoporotic fractures 8. In
this instance, results of observational studies of estrogen and fracture risk and trials using a surrogate
end-point (bone mineral density) agree with the results of clinical trials of fracture prevention.
Colon Cancer
Colon cancer was significantly less common with hormone treatment in the WHI HRT-EP study but
not in WHI HRT-E for reasons that are not clear.8 It is possible that progestin is the protective hormone
in this case.
Quality of life:
Hlatky MA, 2002 published results of the HERs study pertaining to quality of life.19 Women with
flushing who were assigned to hormone therapy had improved mental health and fewer depressive
symptoms (P =.01) over follow-up compared with those assigned to placebo. Women without
flushing who were assigned to hormone therapy had greater declines in physical function (P =.04)
and energy/fatigue ( P =.03) over follow-up. Quality-of-life scores were significantly lower among
patients with older age, diabetes, hypertension, chest pain or heart failure. These differences in
quality of life among women classified by clinical characteristics were much greater than the effects of
hormone therapy.
As more deliberate and exhaustive analyses of these trials become available, they will likely contribute
to new practice guidelines.
Post WHI and HERS Target Groups for HRT

In women with gonadal dysgenesis and surgical menopause, the duration of estrogen deprivation is
prolonged. Estrogen replacement is recommended for these patients for the reduction of hot flashes
and for long-term prophylaxis against cardiovascular disease, osteoporosis, and target organ
atrophy. A low-dose contraceptive may be offered to nonsmoking women until the age of 45. After
this age, doses of estrogen equivalent to 0.625 mg of conjugated estrogens may be more appropriate
because of a sharp age-related increase in risk for thrombo-embolic events. The clinician should
recommend a continuous estrogen-progestin combination to those with a uterus and an estrogen-
only regimen to women without a uterus.
96
HERS II ::20,21
The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized trial of estrogen
plus progestin therapy after menopause. SO HERS II group examined the effect of long-term
postmenopausal hormone therapy on common noncardiovascular disease outcomes21.:
Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent open-
label observational follow-up for 2.7 years (HERS II). Hence the duration of study was between 1993
and 2000: A total of 2763 postmenopausal women with coronary disease and average age of 67
years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS
II. Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens plus 2.5 mg of
medroxyprogesterone acetate (n = 1380) or placebo (n = 1383) during HERS; open-label hormone
therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at
least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group
and increased from 0% (year 1) to 8% (year 6) in the placebo group. There were 261 deaths among
those assigned to hormone therapy and 239 among those assigned to placebo (RH, 1.10; 95% CI,
0.92-1.31).Treatment for 6.8 years with estrogen plus progestin in older women with coronary
disease increased the rates of venous thromboembolism and biliary tract surgery. Trends in other
disease outcomes were not favorable and should be assessed in larger trials and in broader
population.
The Heart and Estrogen/progestin Replacement Study (HERS)4 found no overall reduction in risk of
coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the
hormone group, findings did suggest a higher risk of CHD events during the first year, and a
decreased risk during years 3 to 5. To determine if the risk reduction observed in the later years of
HERS persisted and resulted in an overall reduced risk of CHD events with additional years of follow-
up. The primary outcome was nonfatal myocardial infarction and CHD death. Secondary
cardiovascular events were coronary revascularization, hospitalization for unstable angina or
congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic
attack, and peripheral arterial disease.
Lower rates of CHD events among women in the hormone group in the final years of HERS did not
persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of
cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to
reduce risk for CHD events in women with CHD20
WHI is a tremendously important contribution to our understanding of menopausal therapy. Most, of,
earlier cohort, retrospective, and prospective observational studies have demonstrated significant,
40% to 60% reductions in coronary heart disease (CHD) in postmenopausal women taking HRT-E
only or combined HRT-EP. These studies also showed reductions in all-cause mortality and
osteoporotic fractures, but showed increases in risk of breast cancer on the order of 20% to 30%.
Several similar studies have demonstrated reduced incidence of Alzheimer's-type dementia in
women who had used HRT-EP versus women who did not. Given the inherent biases that confound
observational studies, randomized clinical trials are needed to establish whether HRT protects against
cardiovascular disease (CVD) or dementias. The HERS and other secondary prevention studies
demonstrated no benefit in women with known CVD initiating HRT 8 to 23 years beyond the
menopause Results from WHI indicate that the combined postmenopausal hormones CEEs,0.625
mg/day, plus MPA, 2.5 mg/day, should not be initiated or continued for the primary prevention of
97
CHD. In addition, the substantial risks for CVD and breast cancer must be weighed against the benefit
for fracture protection in selecting from the available agents to prevent osteoporosis.
Conclusion :
HERS I and II both have not shown any beneficial effect on heart the results must be carefully
interpreted. Thus, out of the struggle to interpret the results of HERS, there will emerge new
hypotheses, research questions, and paradigms about estrogen and heart disease prevention that will
ultimately lead to improvements in the health of all postmenopausal women.
Suggested Reading
1. Ness J, et al: Use of hormone replacement therapy by postmenopausal women after publication of the Women's Health Initiative Trial.J Gerontol
A Biol Sci Med Sci 2005; 60(4):460-462.
2 Hoffmann M, et al: Changes in women's attitudes towards and use of hormone therapy after HERS and WHI. Maturitas 2005; 52(1):11-17.
3. Thunell L, et al: Scientific evidence changes prescribing practice—a comparison of the management of the climacteric and use of hormone
replacement therapy among Swedish gynaecologists in 1996 and 2003. Br J Obstet Gyenaecol 2006; 113(1):15-20.
4. Hulley S, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart
and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280(7):605-613.
5. Psaty BM, Heckbert SR, Atkins D, Lemaitre R, Koepsell TD, Wahl PW,et al. The risk of myocardial infarction associated with the combined use of
estrogens and progestins in postmenopausal women. Arch Intern Med. 1994;154:1333-9.
6. Sidney S, Petitti DB, Quesenberry CP Jr. Myocardial infarction and the use of estrogen and estrogen-progestogen in postmenopausal women.
Ann Intern Med. 1997;127:501-8.
7. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of
cardiovascular disease. N Engl J Med. 1996;335:453-61.
8. Anderson GL, et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative
randomized controlled trial. JAMA 2004; 291(14):1701-1712.
9. Vittinghoff E, Shlipak MG, Varosy PD, Furberg CD, , Khan SS, Blumenthal R, , Hulley S; Heart and Estrogen/progestin Replacement Study
Research Group. Risk factors and secondary prevention in women with heart disease: the Heart and Estrogen/progestin Replacement Study.
2003 Jan 21;138(2):81-9..
10. Writing Group for the Women's Health Initiative Investigators Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women:
Principal Results From the Women's Health Initiative Randomized Controlled Trial JAMA. 2002;288:321-333.
11. Lacey Jr JV, et al: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002; 288(3):334-341.
12. Shumaker SA, et al: Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal
women: Women's Health Initiative Memory Study. JAMA 2004; 291(24):2947-2958.
13. Glueck CJ, et al: Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. J
Lab Clin Med 1994; 123(1):59-64.
14. Shlipak MG, Chaput LA, Vittinghoff E, Lin F, Bittner V, Knopp RH, Hulley SB; Heart and Estrogen/progestin Replacement Study Investigators
Lipid changes on hormone therapy and coronary heart disease events in the Heart and Estrogen/progestin Replacement Study (HERS) Am
Heart J. 2003 Nov;146(5):870-5.
15. Daniel KR, Herrington DM. Statin therapy in the heart and estrogen/progestin replacement study. Minerva Ginecol. 2003 Jun;55(3):209-15.
16. Cirillo DJ, et al: Effect of estrogen therapy on gallbladder disease. JAMA 2005; 293(3):330-9.
17. Hunninghake DB, Agarwal SK, Lin F, Cauley JA, Ireland CC, . Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal
women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2001 Oct 2;135(7):493-501.
18. Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T; HERS Research Group. Postmenopausal hormones and incontinence: the
Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol. 2001 Jan;97(1):116-20.
19. Hlatky MA : Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and
Estrogen/Progestin Replacement Study (HERS) trial. JAMA - 6-FEB-2002; 287(5): 591-7
20. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E,
Wenger N; HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin
Replacement Study follow-up (HERS II). JAMA. 2002 Jul 3;288(1):49-57.
21. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hunninghake
D; HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin
Replacement Study follow-up (HERS II). JAMA. 2002 Jul 3;288(1):58-66.
98
21 The Pan-Asia Menopause Study (PAM Study)
Prof. Dr. Suchitra N. Pandit

MD: DNBE : DFP : FRCOG :
FICOG : MNAMS, B.Pharm
Consultant Obstetrician & Gynaecologist -Kokilaben Dhirubhai Ambani Hospital, Mumbai
Jt.Clinical secretary - MOGS, Vice President - FOGSI ( 2008-09 )
Chairperson-Young Talent promotion committee, FOGSI (2003-2007)
West zone coordinator - ISOPARB
Dr. Rana Khan

DGO(MUHS), DGO(CPS),FCPS
Clinical assistant -
Hinduja Hospital & Research centre
Dr. Priti Vyas

MD,FCPS,DGO
Consultant Obstetrician & Gynaecologist
Sangita Maternity Hospital.
BSES hospital, Andheri, Mumbai
Menopause is the time in a woman's life when her periods cease as the woman's ovaries gradually
stop producing estrogen and progesterone hormones. Average age ranges between 47 to 51 years,
but perimenopausal symptoms can start several years earlier.
Menopausal symptoms, which affect about 70-80% of women, are believed to be due to the changing
hormone levels, particularly estrogen. Leading to altered quality of life. Early menopausal symptoms
include physical, sexual and psychological problems
Physical symptoms include:

Hot flushes, night sweats, palpitations, insomnia, joint aches, headaches, anxiety, depression,
fatigue, backaches, sleeplessness, lack of concentration & confidence, vaginal dryness, aversion for
sex and urinary problems
Later menopausal symptoms include:

Frequency of micturition, urinary infections, dysuria and urinary incontinence. Other symptoms
include effects from changes in collagen production, leading to dryer, thinner, less elastic skin,
thinning of hair, nails and tendons more prone to bruising, coronary heart disease, Alzheimer's
disease and osteoporosis
With the general increase in life expectancy, many women are likely to spend nearly one quarter of
their lives or more in the post menopausal period, a state of estrogen deficiency which leads to various
problems .
99
The overall health and well being of middle-aged women has become a major public health concern
around the world. World Health Organization defines Quality of life (QoL) as an individual's
perception of their position in life in the context of culture and values system in which they live and in
relation to their goal expectations, standards and concerns.6
The study of QoL in the post menopause has become an essential component in clinical practices.
Most studies on QoL of postmenopausal women were conducted in developed countries with
different sociocultural realities, which may influence not only the perception of QoL but also the
experience of menopausal symptoms. Very little information exists about QoL of postmenopausal
women in developing countries.
The Greene Climateric Scale:

The Greene Scale provides a brief measure of menopause symptoms. It can be used to assess changes
in different symptoms, before and after menopause treatment.
Three main areas are measured:

1) Psychological
2) Physical
3)Vasomotor.
HRT, or Ovarian Hormone Therapy -

HRT is supplementation of hormones which are deficient in postmenopausal women. The FDA
recently adopted the term “menopausal hormone therapy” to replace HRT. When estrogen alone is
used, it may also be called “Estrogen Replacement Therapy” (ERT).
"When a subject ceases to be of controversy it ceases to be a subject of interest"

- William Hezlitt
Estrogen perhaps enjoys the status of being one of the most researched molecules in the century and
yet the controversies do not cease.
The Women's health initiative was an important national health study taken in the USA focusing
on strategies for preventing major causes of death, disability & frailty in older women of all races &
socioeconomic background like: Heart disease, breast, colorectal cancer & osteoporosis
15 year study sponsored by National institute of health (NIH) & National hear, lung & blood
institute(NHLBI) N=161,000 women, aged 50-79
Three components : 1) WHI clinical trial 2) Observational study 3) Community prevention study
Primary outcomes were
a.) Osteoporosis - causes fractures leading to increased disability & debility.
b.) Heart disease - leading cause of death in postmenopausal women
c.) Breast cancer -second leading cause of cancer deaths
d.) Colon cancer-third leading cause of cancer deaths
100
Risks Per 10 000 person years on HRT as anaysed by WHI investigators

• 8 extra breast cancers
• 7 extra MI
• 8 extra strokes
• 8 extra PE
• 5 fewer hip fractures
• 6 fewer bowel cancers
• Absolute excess risk of events induced in global index 19 per 1000 (as per WHI study)
“Women's Health Initiative” (WHI) investigators found a 34% decrease in hip fractures in
postmenopausal women taking estrogen and progestin. Estrogens prevent/slow bone
resorption in menopausal women. Bone demineralization occurs earlier in life than one
might think!
Generally, estrogens lower LDL, raise HDL, and increase triglycerides

However, the WHI study demonstrated a significant increase in cardiovascular disease: 29% increase
in MI, 41% increase in stroke after 5.2 yrs of estrogen + progestin use .
After this study was published and perhaps misinterpreted by the media naturally what followed was
the abrupt stoppage of HRT by clinicians for women who were on it, fearing the side effects. Despite
the shortcomings of the study it was the failure on part of clinicians to understand the short comings of
the WHI study and lack of caution in extrapolating data of post menopausal women to peri
& early post menopausal women or women with premature menopause. This resulted in
depriving women who really needed HRT .
So guidelines were later set up to help clinicians decide which women needed HRT and how to assess
the benefits versus risks.
The WHI study had evoked controversies & raised doubts about the efficacy & safety of Hormone
Replacement Therapy (HRT). Most of the studies on Hormone replacement therapy have included
Caucasian women having a Western lifestyle so one study which focussed on women in the Asia
Pacific region was 'The Pan-Asia menopause study (PAM study )'
This was a large prospective randomized, 3 arm multi centric clinical trial evaluating 1028
postmenopausal women in 11 Asian countries, to study the prevalence of vasomotor symptoms
in different ethnic groups and effects and safety, tolerability and side effects of varying doses of
Hormone replacement therapy (HRT) on healthy postmenopausal women (40-65 yrs). This would
also assess if lower doses are as effective as the traditional doses of HRT.
The PAM study was a prospective, three arm, randomized, double-blind clinical trial evaluating 1028
postmenopausal women at 22 investigational centers in 11 Asian countries/territories. Subjects were
randomly assigned to one of three doses of continuous combined conjugated estrogens
(CE)/medroxyprogesterone acetate (MPA): CE/MPA (in mg/day) = 0.625/2.5, 0.45/1.5 or 0.3/1.5.
The treatment period, following baseline evaluations, consisted of six continuous 28-day cycles.
101
The study compromised of the use of varying doses of HRT for -
1) Relief of vasomotor symptoms (VMS) and vaginal atrophy in Asian women of different ethnic
background.
2) To study differential prevalence of quality-of-life categories (domains) in Asian women and changes
after therapy
3) Test the hypothesis that reproductive hormone and lipid profiles differ among the nine ethnic groups
under investigation in the PAM study.
Arm 1
Objective: To evaluate the efficacy of three doses of estrogen/progestin therapy for relief of
vasomotor symptoms (VMS) and vaginal atrophy in Asian women of different ethnic
background; to examine the differences in prevalence of VMS amongst ethnic groups.
Methods: A prospective, randomized, double-blind multinational clinical trial in healthy

postmenopausal women from 11 Asian countries. Following 2 weeks of baseline observations, the
women received one of three conjugated combinations of conjugated estrogens (CEE) and
medroxyprogesterone acetate (MPA) (in mg) daily for 24 weeks: doses 0.625/2.5; 0.45/1.5; or
0.3/1.5. The treatment period, following baseline evaluations, consisted of six continuous 28-day
cycles. The women recorded VMS and uterine bleeding daily on diary cards translated into 10
languages. Vaginal responsiveness was evaluated by the vaginal maturation index (VMI) at baseline
and at week 24.
Results:
Amongst the study population of 1028 postmenopausal women, the VMS-evaluable subpopulation
was about 60% of the total population. Hot flush frequency decreased significantly in all the dose
groups within 4 weeks of treatment. The VMI shifted significantly from immature (parabasal) to
mature (superficial) cells at the end of the treatment.. However, uterine bleeding was consistently less
frequent in the 0.3/1.5mg group. The percentage of women who reported VMS at baseline differed
substantially amongst the different ethnic groups, ranging from 5% in Indonesian women to 100% in
Vietnamese women.
Conclusion:
Asian postmenopausal women respond to CE/MPA therapy. The lowest dose is as effective for VMS
and vaginal responsiveness as the higher doses, and the lowest dose is associated with the most
favorable bleeding pattern. The prevalence of vasomotor symptoms differs among ethnic groups.
Second arm
Objectives - To assess the prevalence of four categories (domains) of menopausal symptoms
as markers for quality of life in nine ethnic groups. To evaluate changes in quality of life
(MENQOL scores) after therapy with three doses of conjugated estrogens
/medroxyprogesterone acetate
Methods - A prospective, randomized, double-blind, multinational clinical trial in 1028 healthy

postmenopausal women of nine ethnic groups from 11 Asian countries/regions. Following 2 weeks of
baseline observation, the women received one of three conjugated estrogens
(CE)/medroxyprogesterone acetate (MPA) doses (in mg) daily for 24 weeks: 0.625/2.5, 0.45/1.5, or
0.3/1.5.
102
At baseline and at the end of weeks 4, 12 and 24 following the start of therapy, the study participants
were asked to record, on a menopause-specific quality of life (MENQOL) questionnaire, 29
menopausal symptoms, as experienced during the preceeding month. The symptoms were
categorized into four domains: vasomotor ,psychosocial, physical and sexual.
Results - The baseline (pretreatment) symptom scores in each of the four domains varied substantially
amongst the different ethnic groups. Overall, Vietnamese and Pakistani women had the highest
baseline scores, i.e. were most afflicted by each set of symptoms in a given domain, and Indonesian,
Malay, Taiwanese and Thai women were least afflicted. In the overall population, intervention
resulted in statistically significant decreases in the scores of all four domains within 4 weeks of
intervention. The beneficial effects were similar in the three dose groups.
Conclusions - The prevalence of four domains of menopausal symptoms, varies considerably among
ethnic groups of Asian women. The MENQOL scores in the overall population were significantly
lowered in the course of the study, indicating an improvement in quality of life. In the absence of a
placebo group, the relative contribution of hormones and placebo in our intervention is unknown.
Third arm
Objectives - Significant differences in the prevalence of menopausal symptoms and in lipid
profiles have previously been reported for nine ethnic groups of postmenopausal Asian
women participating in the Pan-Asia Menopause (PAM) study. Based on these findings, the
hypothesis was tested that reproductive hormone profiles differ amongst the nine ethnic
groups under investigation in the PAM study.
Lipid/lipoprotein profiles, amongst other factors, are associated with the risk of cardiovascular disease
which varies in Asian countries, it was hypothesized that lipid profiles differ in ethnic groups of
postmenopausal Asian women. To add to the limited body of information currently available, the
effects of estrogen/ progestin therapy on lipid/lipoprotein profiles in postmenopausal Asian women
was also investigated.
Methods:
With the same population under study as mentioned earlier, baseline serum samples from
postmenopausal women (n=1020) representing nine ethnic groups were analyzed by electro-
chemiluminescence immunoassay methods {estradiol (E2), follicle stimulating hormone (FSH) and
luteinizing hormone (LH)}
Analysis of lipid profiles was a secondary objective of the PAM study. Total cholesterol, low density
lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), very low density
cholesterol (VLDC-C), triglycerides and lipoprotein(a) were analyzed at a central laboratory by state-
of-the-art methods.
Results The hormone levels for the overall study population (mean ± SD) were: E2 = 74.1 ± 125.1
pmol/l (n = 1015); FSH = 81.2 ± 31.4 IU/l (n = 1013); LH = 36.8 ± 15.6 IU/l (n = 1015). There was
an inverse correlation between log E2 and FSH levels and a positive correlation between FSH and LH
levels. The concentrations of E2, FSH and LH were significantly associated with ethnicity
103
Mean concentrations of total cholesterol, LDL-C, VLDL-C and triglycerides differed significantly
among the nine ethnic groups of postmenopausal women. This difference was independent of body
mass index and age, two factors that also influenced lipid/lipoprotein profiles. Mean HDL-C
concentrations also differed, but this difference was influenced by body mass index in a weak
interaction. All three doses of CE/MPA significantly lowered total cholesterol. Treatment with the high
and middle doses significantly lowered LDL-C, and increased HDL-C, VLDL-C and triglycerides. The
high dose produced a significant decrease in lipoprotein (a).
Conclusion - The levels of FSH, LH and particularly of E2 differ substantially among ethnic groups of
postmenopausal Asian women. The clinical significance, if any, of these differences remains to be
investigated. The inverse correlation of E2 and FSH levels suggests that E2 at the postmenopausal
state still affects pituitary FSH output.
The different lipid/lipoprotein profiles in the nine ethnic groups of postmenopausal Asian women
evaluated here suggest a relationship to differences in the prevalence of cardiovascular disease
reported for different regions in Asia. However, the reported prevalence data on cardiovascular
disease morbidity and mortality in the regions corresponding to the nine ethnic groups are insufficient
to allow qualitative comparisons with the lipid profiles shown in our study. The lipid/lipoprotein
changes in response to estrogen/progestin therapy observed here are consistent with those reported
for Western women.
Conclusions of the PAM study : Prevalence of VMS varied amongst different ethnic groups
studied. The lowest dose of (0.3/1.5 mg/d) was as effective as higher doses for VMS. The
vaginal maturation index also was comparable to higher doses. The spotting and bleeding
patterns were favorable. The breast discomfort was lesser. All the three doses were well
tolerated !!
However more data is needed to correlate the differences in the lipid/lipoprotein profiles in
the nine ethnic groups of postmenopausal Asian women to differences in the prevalence of
cardiovascular disease in different regions in Asia.
Keywords: Menopause; Pan-Asia Menopause Study; Pam Study;

Postmenopausal Asian Women; Hormone Therapy;
Suggested Reading
1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast Cancer and HRT: collaborative reanalysis of data from 51 epidemiological
studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047-1059
2. Dale E, Vessey M P, Hawkins M M, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348:977-80
3. Whelan TJ, Goss PE, Ingle JN, Pater JL, Tu DS, Pritchard K, et al. Assessment of quality of life in MA.17: a randomized, placebo controlled trial of
letrozole after 5 years of tamoxifen in postmenopausal women. J Clin oncol 2005; 23: 6931-40.
4. No author listed. Study protocol for the World Health Organisation project to develop a quality of life assessment instrument (WHOQOL). Qual
Life Res 1993; 2: 153-9.
5. Sturdee D W, Ulrich L G, Barlow D H, Wells M, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen
replacement therapy. Br J Obstet Gynecol 2000; 107: 1392-1400
6. Mosca L, Collins P, Herrington D M, et al. Hormone replacement therapy and cardiovascular disease : a statement for healthcare professionals
from the American Heart Association. Circulation 2001; 104:499-503.
7. Nachtigall LB, Lagrega L, Nachtigall LE. The effect of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness.
Proceedings 81st Annual Meeting US Endocrine Society 1999; June 1999, San Diego.
8. Tice JA, Ettinger B, Ensrud K et al. Phytoestrogen supplements for the treatment of hot flashes: The isoflavone clover extract (ICE) study. A
randomized controlled trial. JAMA 2003; 290:207-214.
9. Collaborative Group on Hormonal Factors in Breast Cancer. Breast Cancer and HRT: collaborative reanalysis of data from 51 epidemiological
104
studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047-1059
10. Dale E, Vessey M P, Hawkins M M, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348:977-80
11. Sturdee D W, Ulrich L G, Barlow D H, Wells M, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen
replacement therapy. Br J Obstet Gynecol 2000; 107: 1392-1400
12. Mosca L, Collins P, Herrington D M, et al. Hormone replacement therapy and cardiovascular disease : a statement for healthcare professionals
from the American Heart Association. Circulation 2001; 104:499-503.
13. Nachtigall LB, Lagrega L, Nachtigall LE. The effect of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness.
Proceedings 81st Annual Meeting US Endocrine Society 1999; June 1999, San Diego.
14. Tice JA, Ettinger B, Ensrud K et al. Phytoestrogen supplements for the treatment of hot flashes: The isoflavone clover extract (ICE) study. A
randomized controlled trial. JAMA 2003; 290:207-214.
15. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women.
Principal results for the Women's Health Initiative Randomized controlled trial JAMA 2002;288:321-333
16. Hulley S,Grady D,Bush T, et al. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in
postmenopausal women. JAMA 1998;280:605-613.
17. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419-427
18. Lowe GD, Upton MN, Rumley A et al. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-
PA, PAI and C-reactive protein - a cross-sectional population survey. Thromb Haemost 2001;86:550-556.
19. Ojoo J, Kastelik J, Morice A. The respiratory system and the menopause. Journal of the British Menopause Society 2001; Vol.7, No.4:168-173.
20. Christopher J. Hainesa, Shu-Min Xingb, Ki-Hyun Parkc, Christian F. Holinkad, Militza K. Ausmanase :Prevalence of menopausal symptoms in
different ethnic groups of Asian women and responsiveness to therapy with three doses of conjugated estrogens/medroxyprogesterone acetate:
The Pan-Asia menopause (PAM) study. Received 10 January 2005; received in revised form 17 March 2005; accepted 22 March 2005. Maturitas
- Volume 52, Issue 1, Pages 35-51 (16 September 2005)
21. N. Taechakraichana a; C. F. Holinka b; C. J. Haines c; R. Subramaniam d; X.W. Tian e; M. K. Ausmanas e Menopause & Hormone Replacement
Climacteric, Volume 10, Issue 3 June 2007, pages 225 -237 Climacteric, 1369-7137,
105
22 THEBES Study : Facts and Myths
Dr. Rashmi S. Shah

DGO; DFP; MD
Ex Senior Deputy Director,
National Institute for Research in Reproductive Health (ICMR)
Founder Secretary, Indian Menopause Society, Mumbai Chapter
Joint Secretary, Indian Menopause Society, 2008-09
Visited menopause clinics in U.K. when awarded
Indian National Science Academy Fellowship
Publications of the results of the Women's Health Initiative (WHI) study in 2003 & 2004 with estrogen (E)
+ progestogen (P) arm and the E only arm led to considerable uncertainties about the role of Hormone
Therapy (HT) among health professionals and women. Use of tibolone in postmenopausal women was
considered to be a good alternative for those postmenopausal women who have concerns about HT.
Tibolone, a synthetic steroid, has a unique clinical profile having estrogenic, androgenic and
progestagenic properties. It has specific effects on different tissues as a result of its tissue-selective
metabolism, enzyme regulation, and/or receptor binding and activation. It regulates estrogenic activity in
a tissue-selective manner, thereby having estrogenic effects on brain, vagina and bone but not on breast or
endometrium. However case reports & a few studies have shown presence of endometrial cancer in
women on tibolone. Hence questions have been raised as to whether there is an association between use
of tibolone and an increased risk of endometrial and breast cancer.
The primarary objective of the THEBES study(1) (Tibolone Histology of the Endometrium and Breast
Endpoints Study) was to confirm the endometrial safety of oral tibolone (1.25 and 2.5 mg/d) and the
secondary objective compare it with continous combined oral CEE plus MPA (0.625/2.5 mg/d). The
vaginal bleeding profile and incidence of breast pain was also studied. The study was a multicentre
randomized, active-controlled, double-blind, parallel-group trial wherein a total of 3224 postmenopausal
women (aged 45-65 years) with an intact uterus received the medication (tibolone 1.25mg, n=792;
tibolone 2.5mg, n = 806; CEE/MPA, n = 1626). Endometrial biopsies were obtained (by pipelle suction
curette) at baseline and repeated after 1 and 2 years of treatment. Results of a few important studies
including THEBES are given below.
Tibolone and endometrium

An open, prospective comparative study was undertaken by Perez-Medina et al(2) in 485 postmenopausal
women for a duration of 36 months in which 249 women received 2.5 mg/day of tibolone and 244
women served as controls, receiving continuous-combined HT. Transvaginal ultrasound, hysteroscopy,
and directed biopsies were performed before treatment was initiated and at the end of the study.
Endometrial polyps were detected in 74 women (33.4%) from the tibolone group and in 22 women
(10.8%) from the HT group (P < 0.01). The frequency of atrophic polyps was significantly higher in the
tibolone group (P < 0.01). The study concluded that tibolone increases by threefold the risk for
endometrial polyps.
Tibolone Consensus Group(3) reported that the endometrial histology in women treated with tibolone
showed no hyperplasia and had a high level of atrophic endometrium (level of evidence: proven).
106
The Million Women Study(4) recruited 7,16,738 postmenopausal women out of which 28,028 ie 9 %
women had last used tibolone. The MWS estimated an increased risk of endometrial cancer in women
who had used tibolone compared with never users of HRT (RR approximately 1.8, 95%CI 1.4 – 2.3). The
risk increased with increasing duration of use. Another study that also cautioned that tibolone may be
associated with an increased risk of endometrial cancer was the UK General Practice Research Database
(GPRD)(5). This study analyzed data of 4995 women who had used used tibolone as their first HRT
product; 10 783 (4.3%) of the users of combined HRT had changed to tibolone at some time during the
study period. The adjusted odds ratio of the risk of endometrial cancer in women who had ever used
tibolone, compared with users of combined sequential HRT, was 1.54 (95% CI 1.03, 2.32). The authors
however mentioned that their data are fragile and residual bias and uncontrolled confounding cannot be
excluded and follow-up time was insufficient to draw any firm conclusions.
The secondary objective of the OPAL study(6) was to assess the effects of tibolone (2.5 mg), continuous
combined CEE/MPA (0.625/2.5 mg), and placebo on the endometrium. The study was a 3-year, three-
arm, international, randomized, double-blind, parallel group, placebo-controlled clinical trial which
enrolled 866 postmenopausal women (aged 45-79 years). At the end of 3 years, data showed no
significant differences between the tibolone, CEE/MPA and placebo groups in the incidence of
proliferation (1.4%, 4.8%, and 0%, respectively), endometrial hyperplasia (0% in all groups), or cancer
(1, 0, and 1 case, respectively) thus demonstrating the endometrial safety profile of tibolone.
In the THEBES study,(1) the incidence and upper one-sided 95% CI for the incidence of abnormal
endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at
end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point
was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively.
The study concluded that that there were no cases of endometrial cancer or endometrial hyperplasia in
women who used 1.25 or 2.5 mg of tibolone.
Ettinger et al(7) randomly assigned postmenopausal osteoporotic women (N=3,519) aged 60-85 years
(mean 68 years) with a uterus to receive either tibolone 1.25 mg/day, or identical placebo for a 3 year
study period to investigate endometrial effects of tibolone. Endometrial thickness was evaluated in all
women and histology was examined in 635 participants with unexpected vaginal bleeding or endometrial
thickness more than 4 mm. Diagnostic biopsies among 499 women receiving tibolone and 136 who were
receiving placebo showed cumulative incidences of endometrial hyperplasia less than 1%. Among the
15% of women whose biopsy showed an endometrial polyp (similar rate in tibolone and placebo), those
receiving tibolone were more than twice as likely to show hyperplasia within the polyp. A marginal
increase in grade 1 endometrioid adenocarcinoma (P=.06 compared with placebo) was found among
women receiving tibolone. The study concluded that tibolone treatment minimally increased endometrial
thickness, hyperplastic polyps, endometrial carcinoma, and vaginal bleeding.
Tibolone and breast
The MWS(4) reported that, compared to never users, the use of various types of estrogen-progestogen
combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88-2.12) than
use of estrogens alone (RR = 1.30, 95%CI: 1.21-1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).
Thus this prospective cohort study that included more than a million women, showed that women using
tibolone had nearly 1.5 times the risk of breast cancer as women who never used HRT. The difference was
statistically significant.
107
A randomized double-blind placebo-controlled LIFT(8) study (n = 4506) on the efficacy of low dose (1.25
mg) tibolone (N = 2249) for the treatment of osteoporosis in elderly women (mean age 68 years), has
shown a statistically significantly decreased risk of breast cancer in the tibolone group compared to
placebo after an average of 2.9 years of follow-up. The tibolone group had a 3.1 fold decreased risk of
invasive breast cancer (RR 0.32, p = 0.015). The incidence of breast cancer observed in the tibolone and
placebo arms was 0.91 and 2.85 per 1000 women-years, respectively. The absolute risk decrease is 1.9
cases of breast cancer per 1000 women treated per year. However, the tibolone group had an increased
risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in
February 2006 at the recommendation of the data and safety monitoring board.
The Tibolone Consensus Group(3) states that there is inconclusive level of evidence regarding the safety of
tibolone. It is shown to cause less breast tenderness and mastalgia than HT and does not increase
mammographic density (level of evidence: proven).
Thus, there are controversial reports about tibolone use in terms of efficacy or cancer risks. Only time will
tell about the safety profile of tibolone option for treating menopausal women.
Suggested Reading
1. Archer DF, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A, den Hollander W, Stathopoulos V, Helmond FA. Endometrial effects of
tibolone. THEBES Study Group. J Clin Endocrinol Metab. 2007; 92(3):911-8
2. Perez-Medina T, Bajo-Arenas J, Haya J, Sanfrutos L, Iniesta S, Bueno B, Castelo-Branco C. Tibolone and risk of endometrial polyps: a
prospective, comparative study with hormone therapy. Menopause. 2003;10(6):534-7.
3. Kenemans P, Speroff L; International Tibolone Consensus Group. Tibolone: clinical recommendations and practical guidelines. A report of the
International Tibolone Consensus Group. Maturitas 2005;16;51(1):21-28.
4. Beral V, Bull D, Reeves G; Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women
Study. Lancet. 2005;365(9470):1543-51.
5. de Vries CS, Bromley SE, Thomas H, Farmer RD. Tibolone and endometrial cancer: a cohort and nested case-control study in the UK.Drug Saf.
2005;28(3):241-9.
6. Langer RD, Landgren BM, Rymer J, Helmond FA; OPAL Investigators. Effects of tibolone and continuous combined conjugated equine
estrogen/medroxyprogesterone acetate on the endometrium and vaginal bleeding: results of the OPAL study. Am J Obstet Gynecol.
2006;195(5):1320-7.
7. Ettinger B, Kenemans P, Johnson SR, Mol-Arts M, Van Os S, Seifert W, Verweij PJ, Cummings SR. Endometrial effects of tibolone in elderly,
osteoporotic women. Obstet Gynecol. 2008 Sep;112(3):653-9.
8. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C, Bilezikian J,
Kerzberg EM, Johnson S, Zanchetta J, Grobbee DE, Seifert W, Eastell R; LIFT Trial Investigators. The effects of tibolone in older postmenopausal
women. N Engl J Med. 2008 14;359(7):697-708.
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23 Holistic Approach to Menopause - Diet & Nutrition
Dr. S. S. Mehendale
Professor and HOD, Dept of Gyn & Obs
Bharati Medical College - Pune
Dr. Shirish Patwardhan

Senior Vice President FOGSI
Menopause is a biological phenomenon in the process of ovarian ageing which occurs in around the age
of 50 in 50 % of women. Most of the women will spend 1/3 of their life time in the post menopausal period.
Therefore apart from management of the menopause related medical problems emphasis should be
given on dietary adjustment to fulfill the best potential of the woman's life. Dietary supplementation of
micro nutrients is essential for improving their bone mass potential and physical fitness.
Calcium and Vit D: - Post menopausal woman's bone mineral density

(BMD) depends on peak bone mass, age at menopause and the rate
of calcium loss .out of these three factors peak bone mineral density is
most important factor in the development of post menopausal
osteoporosis. Peak BMD depends on the amount of bone mass
achieved in young age. There is a clear benefit of calcium and vit D
supplementation in post menopausal women as it preserves bone
mass, decreases bone turnover(1). Meta analysis of 20 controlled trials
of calcium therapy in post menopausal women showed that mean rate
of bone loss was 1.17% and 0.13% per year (p<0.001) in 625
untreated women and 857 calcium supplemented women respectively.(2)
Recommended daily dietary intake of calcium is 1000-1500

mg/day. Increased vit D intake in elderly women when given with
calcium preserves bone mass and reduces fracture rate. In double-
blind placebo controlled trial, 187 post menopausal women were
randomly given 1000 mg calcium per day or 1000mg calcium
together with 10000 U vit D. BMD was measured in the forearm,
lumbar spine; femoral neck. There was no difference in the change
in the BMD between the subjects taking calcium alone or calcium
with vit D combined.(3)
There are insufficient data to show that vit D without calcium supplementation has a protective effect
on bones. A supplement of 400-1300 IU of vit D/day is recommended for women who cannot spend
30 minutes/day in sun(4)
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Anti-oxidants nutraceuticals:-
Nutraceuticals are nutrients that not only maintain, support and normalize physiological or metabolic
functions but also potentiate or antagonize them. Antioxidant nutraceuticals glutathione, selenium
and Vit C and E undoubtedly influence and improve many disease process. More research is required
in order to clarify the role and importance of these natural substracts with respect to menopausal
symptoms and post menopausal health.
Vit C: - Cardiovascular disease is a leading cause of death in post menopausal

women. Results from prospective investigatons of the relations between vit C
intake and risk of CHD have been inconsistent to date. In 1980, 85118 women
were assessed for their vit C intake and other nutrients. They were followed for
16 years for development of CHD –there was a modest significant inverse
association between total intake of vit C and risk of CHD (RR O.73 ;95% cl 0.57-
0.94)(5)
Vit E:- It is potent anti oxidant .It prevents oxidation of LDL cholesterol ; so helps In
preventing coronary artery disease.600 IU of vit E is recommended for
reducing the risk of CAD(6)
Magnesium: -
Adequate intake of magnesium is crucial for osteoporosis prevention.
Magnesium deficiency can reduce calcium absorption and retention. Magnesium intake of 600 mg is
sufficient to maintain an adequate magnesium reserve in bone.
B6, B12 and folic
110
controlling hot flushes. Mechanism could be - toning of the blood vessels and thereby preventing
excessive vasodilatation & consequent sweating, a process normally achieved by circulatory
estrogen.
In another study of 40 Gms of soya /day during a 6 month trial revealed an increase in the bone
density of 2.2%. Soya protein decreases serum concentration of total cholesterol and triglycerides.(8)
More scientific work on the amount of soya intake that will reduce the risk of cardiovascular diseases,
osteoporosis, menopause related symptoms is clearly warranted.
To conclude, for the physical fitness a post-menopausal woman must consume fat free milk, green
vegetables, fruits for vit E; dark green leafy vegetables for beta carotene; yellow orange colored
vegetables for vit C; amala, citrus fruits, for protein and omega 3 fatty acids ragi, fish, legumes and
soyabeans in proper proportion.
Apart from this physical activity is essential to improve her health outcome.
Suggested Reading
1. Malabahan AO, holick-vit d and bone health in post menopausal women J.women's health 2003; 12:151-6)
2. Nordin B- nutrition osteoporosis J.B. menopause society 2000; 6:48-53)
3. Cooper L Clifton Bligh P.B. et al Am.J. Clinical nutrition 2003; 77:1324-9
4. Jones KP, Menopause and cognitive function clin obstet and gynecol 2000; 43:148-206
5. Osganian S K Stamfer MJ et al J.Am. Cull cardiol 2003; 42:246-52
6. Cooper K, Kenneth cooper's antioxidant revolution Atlanta,GA Thomas nelson publishers 1994
7. Rapp SR Espeland MB et al effect of estrogen on global cognitive function in post menopausal women JAMA 2003;289:2663-72
8. Potter SM Baum JA et al Isoflavones – Their effects on blood lipids and bone density in post menopausal women Am.J. Clin nutr 1998;
68:13758-13795
111
Holistic Approach to Menopause
24
Exercise in Menopause “How Soon - How Far”
Dr. Maninder Ahuja

Ahuja Nursing Home & Infertility Centre
Faridabad.
Menopause is no pause, it is just a continuous life cycle of a woman where some physiological changes are
occurring but if we are not careful we can change this phase into a pathological one.
In Holistic approach to menopause mainstay is life style modification not only for Quality of life but also
for prevention of diseases.”
Goal and Purpose of Menopause Management

• Health promotion
• Disease prevention
• Disability postponement
And all these can be achieved with timely intervention of exercise and proper diet and
calcium and Vit. D
In this mechanized world the only muscles we are moving are our finger tips for various controls and
only weight we are carrying is our own body weight so no doubt avoidable morbidity and mortality in
all age groups but more so in aging is increasing.
Physical exercise involves many types of exercises but somehow in the present scenario a lay man and
for medical practitioners also it just means walking and yoga. But we have to go beyond walking and
yoga and strength building exercises to have the maximum impact of exercise.
Advantages of exercise in menopause are many fold and when to start would depend upon what is
the clinical problem we are trying to prevent .But as a general rule earlier we start the better it is.
Aging is a complex process involving many variables (e.g., genetics, lifestyle factors, chronic diseases)
that interact with one another, greatly influencing the manner in which we age.
• Participation in regular physical activity (both aerobic and strength exercises) from adolescence itself
elicits a number of favorable responses that contribute to healthy aging and healthy menopause.
Various biological systems of our body respond to exercise and knowledge about these is increasing
day by day... Participation in a regular exercise program is an effective intervention/ modality to
reduce/prevent a number of functional declines associated with aging.
• Land mark of aging when in our body degenerative changes start is at about mid thirties say around
35 years and beyond .Till the age of 25 years we gain our maximum bone mass and from 25 to 35
years it is a plateau , from 35 onwards age we start losing our muscle mass and our BMD. We lose
112
muscle mass at the rate of about 0.4% per year and bone mass at the rate of 0.5 to 0.75% per year and
around the year surrounding menopause this loss increases to even 2-4 % per year. It is not only
muscle and bone which women lose they lose their collagen tissue also. So if we have not started life
style modifications early at least to prevent sarcopenia and osteoporosis we must start at the age of 35
years for reversal of process or slowing down of degenerative changes. For this we have to add
strength building and resistance training in our schedule.
• More ever older individuals (including onto- and nonagenarians) adapt and respond to both
endurance and strength training. Endurance training can help maintain and improve various
aspects of cardiovascular function (as measured by maximal VO2, cardiac output and arteriovenous
O2 difference); as well as enhance sub maximal performance this means that strength and stamina
are both increased. Therefore it is never too late to start.
• Importantly, reductions in risk factors associated with disease states (heart disease, diabetes, etc.)
improve health status and contribute to an increase in life expectancy.
• Kyphosis in menopausal women is a combined effect of weak extensor muscles along with micro
fractures of spine because of osteoporosis and women would have to strengthen their back extensors
with isotonic exercises along with antiresorptive treatment and Vit.D D and calcium to have the
maximum effect.
• Some of the studies also suggest that involvement in regular exercise can also provide a number of
psychological benefits related to preserved cognitive function, alleviation of depression symptoms
and behavior, and an improved concept of personal control and self-efficacy.Intensity and frequency
of hot flushes is also decreased.
• It is important to note that while participation in physical activity may not always elicit increases in the
traditional markers of physiological performance and fitness (e.g., VO2max, mitochondrial oxidative
capacity, body composition) in older adults, it does improve health (reduction in disease risk factors)
and functional capacity.
• Those who are exercising regularly in them all time mortality are reduced.
• Helps in osteoarthritis in reducing pain, increasing range of motion and increasing thick ness of
cartilage.
• Doing exercise in perimenopause and menopausal period reduces incontinence in women at risk of
diabetes. In one study it was seen that 38.3% of the women in the lifestyle intervention group had
stress or urge incontinence, compared to 48.1% of women on metformin and 45.7% of those on
placebo. Stress incontinence was more decreased. Most of the difference in rates of incontinence was
attributable to weight loss.
• According to a literature review by Kramer and Wells (1996) sufficient evidence has accumulated to
warrant an analysis of the relationship between physical activity and estrogen-dependent cancers like
breast and endometrium. The mechanism involved may be any one of the following
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1) Maintenance of low body fat and moderation of extra glandular estrogen,
2) Reduction in number of ovulatory cycles and subsequent diminution of lifetime exposure to
endogenous estrogen,
3) Enhancement of natural immune function,
4) Association of other healthy lifestyle habits.
It is a very well known fact that sooner the better, but for many menopausal conditions women can
start even late .
BETTER LATE THAN NEVER
Thus, the benefits associated with regular exercise and physical activity contributes to a healthier,
independent lifestyle, greatly improving the functional capacity and quality of life in this population.
Types of Exercises:
Exercises are of following types:
• Aerobic like walking, swimming, these mean repetitive movements of major
muscle groups
• Strength building like weight training , and resistance training
• Endurance building brisk walking and weight training.
• Range of movement and stretching exercises e.g. yoga and taichi
• Balance training like taichi and dance.
• Meditation for psychological health
Whenever exercising intensity of exercise is very important and it should be moderate or vigorous
intensity .
How Soon?
Prevention should be started as early as possible as quality of bone is better if life style modifications
and exercise are started early in life .Some of important facts are:
• Before puberty, bone mineral density in boys and girls is similar.

• However, adolescent females achieve peak bone mass at 11 to 14 years of age and it rapidly declines
thereafter,
• Adolescent males continue to increase bone mass until 15 to 16 years of age and then follow a slower
subsequent decline
• Central hormonal factors such as estrogen, appropriate nutrition and local mechanical forces
positively affect bone mass during growth and development.
• Weight bearing exercises during puberty may improve bone mineral content and result in a greater
peak bone mass, which may delay the age at which the osteoporotic fracture limit is reached .Even
doing 50 skipping per day is found to give a better bone quality and delays osteoporosis.
• Prolonged periods of inactivity during youth result in higher osteoclastic activity and bone atrophy,
which may have a serious negative impact on peak bone mass.
• Sedentary lifestyles in childhood may, therefore, contribute to increasing rates of osteoporosis and its
complications later in life.
• To improve good bone health, physicians should recommend appropriate nutrition, including an
age-appropriate vitamin D and calcium
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• Regular weight-bearing physical activity and avoidance of tobacco use.

As far as heart risk is concerned we have to check weight and waist ratio even earlier at 3-4 years of
age.
If we consider in utero origin of diseases then proper maintenance of BMI during pregnancy is
essential so that neither underweight nor overweight children are born.
So exercise is advised during pregnancy also.
Heart risks are being detected by age 7 in overweight kids
Children at risk of future obesity should be examined for body mass index
Rebound. BMI:
Rebound is the age at which body mass index (BMI) reaches its lowest point before increasing through
later childhood, adolescence and adulthood. An earlier BMI rebound age is associated with adverse
risk factors for heart disease as measured at age 7: higher BMI, higher systolic and diastolic blood
pressures, higher serum insulin and leptin levels, higher left ventricular mass and left atrial size. Early
BMI rebound age for children is lower than 4.4 years for boys and 4.2 years for girls. Normal values
are 4.4 to 6.6 years for boys and 4.2 to 5.7 years for girls. All children who start gaining weight
between 3-4 years should be classified as a high risk for future diabetes and heart disease.
This study proves the point that maybe we should start with assessing risk factors much earlier and
there comes the corollary that life style modifications like diet and exercise should start very early in
life.
How Far:
For prevention of osteoporosis as Bone requires the mechanical challenge of physical activity to
remain strong and healthy. An active lifestyle plays an important part in both preventing and treating
osteoporosis.
Early prevention:
Achieving a high peak bone mass during childhood and adolescence provides a good foundation for
skeletal health in later life. Impact activities such as walking, jogging, soccer, tennis, skipping and
dancing help to build a strong skeleton.
BMD preservation in adults:

In early and middle adulthood, the main objective is to maintain bone mineral density. Integrating
seasonal and leisure activities into an exercise routine will help to keep up an active lifestyle.
In impact weight-bearing exercises (e.g. jumping, running, racquet sports, step classes), the
effect of gravity creates a force that loads and challenges the bones, thus helping to build BMD and
prevent osteoporosis. Likewise, muscle strengthening (resistance) exercise has a beneficial effect:
when a muscle contracts, it stimulates the bone to which it is attached.
Two sets of eight to 12 repetitions of each exercise twice a week are enough.
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Post menopause Women:
They experience significant bone loss immediately after menopause. But research has shown that
doing specific exercises (impact weight-bearing and muscle strengthening), especially when
combined with appropriate pharmacologic and dietary interventions, can slow down the rate of loss.
If bone loss in the spine is minimal and the risk of spinal fracture is low, Pilates and/or yoga can
strengthen the back muscles and help maintain good posture.
In the later postmenopausal years, the osteogenic response of bone to exercise is diminished because
first, older women are frequently unable to participate in exercise that is vigorous enough to stimulate
bone, and second, the response to exercise is not as robust as in premenopausal females. Weight-
bearing exercises remain important, although more to minimize bone loss than to increase BMD.
The primary goal of exercise in this age group is to prevent falls and fractures. The specifics of the
exercise program need to be based on overall health status (e.g. presence of arthritis, CVD or other
medical conditions), balance and the degree of bone loss. Routines that incorporate balance and
coordination (such as tai chi and dancing) can be helpful in preventing falls and fractures.
Muscle strengthening exercises:

Large muscle groups, (including back extensors) are also important to improve
posture. These can help maintain function and independence and minimize height
loss and rounding of the back (kyphosis) caused by compression fractures.
People who have advanced osteoporosis (especially if there is a previous history of

spinal fracture) should avoid activities that load the spine during positions of flexion
and/or rotation, since these increase the risk of sustaining a vertebral compression
fracture.
The following movements should be avoided or done with caution:

• Forward bending of the spine, e.g. toe touches traditional abdominal sit-ups
twisting movements (e.g. golf swing)
• Heavy lifting (especially using incorrect techniques such as bending at the waist
instead of the knees)
• Yoga positions requiring extremes of spinal flexion
It is always advisable for your patients with osteoporosis to consult a healthcare professional with an
expertise in this area (e.g. physical therapist), to help them establish an appropriate routine based on
the degree of bone loss and their individual needs.
Studies in old people's homes were done by Fiatarone et al and they showed that it is never too late to
start exercising.
• Positive effects of exercise especially strength building exercises have been seen in as old as hundred
years. Women can start these exercises as late as 100 years of age and can still get the benefit of
exercise by gaining muscle strength. By doing these exercises they were able to perform their routine
daily activities and strength and stamina increased for walking and other activities.
• Various studies have proved now that Postmenopausal women who maintain a regular, moderate to
vigorous exercise program reduce their risk for breast cancer, even if they did not exercise in the past.
• Women who exercise even after cancer breast treatment have a better quality of life.
116
So benefits of exercise start from very early life and go until the time you want to stand erect.
But it is a continuous process so for optimal results aging population should make it an integral part of
their life like brushing of teeth.
Everybody should have at least a pair of dumbbell at home so that minimum required
exercise can be done.
Exercise Prescrition for Total Health in Adults:

• Moderate to severe aerobic activity or brisk walking for 150 min per week or 30 min /day for 5days in
a week
Always banking of these activities can be done that means small 10 minutes episodes of activity can
be accumulated during a day
• Strength and stamina building exercises should be added for 2 or 3 times in a week of 20 min per
session. These exercises should cover all the major muscle groups of body. These exercises can be
combined with balancing exercises.
• Meditation and stretching exercises like Yoga should also be included and can be done as a warm up
exercise.
Conclusion: Exercise should be made an integral part of life but if not early then start at 35 plus and if
not at that time at any age it would be effective and fruitful.
Suggested Reading
1. Fiatarone, M. A., E. F. O'Neill, N. D. Ryan, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N.
Engl. J. Med. 330:1769-1775, 1994.
2. Indian Pediatric 2002; 39: 449-452.
3. Indian Pediatric 2004; 41: 559-575.
4. Frequent, Brisk Exercise After Menopause Lowers Breast Cancer Risk Nancy Larson BMC Cancer Published online October 2, 2009
5. Orchard TJ, Temprosa M, Goldberg R, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes
Prevention Program randomized trial. Ann Intern Med. 2005; 142:611-619.
6. Bone, estrogens and strength training (BEST)Study,Osteoporos Int. 2005;16:2129-2141
7. Fiatarone MA, Effects on skeletal muscle. JAMA. 1990; 263:3029-34
8. Brown, J. Lifestyle Intervention Is Associated With Lower Prevalence of Urinary Incontinence, The Diabetes Prevention Program Diabetes Care
2006; 29:385-390
9. Professional sport activity and micronutrients: effects on bone mass,Nuti R, Martini G, Merlotti D, Valleggi F, De Paola V, Gennari L.J Endocrinol
Invest. 2005;28(10 Suppl):52-60.
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25 Setting Up a one Stop Menopause Clinic
Dr. Sonia Malik

DGO; MD, MICOG.
Indian Representative to Asia Pacific Menopause Federation
Representative Asia-Pacific region for World School of Menopause
Past President Indian Menopause Society.
Vice President, Indian Fertility Society.
Co- Chair, Infertility Committee, AOGD
India is a land of great diversity. There is not only a cultural and traditional divide but also a great
difference in the rich and poor, the urban-rural divide and the geographical landscape of the country also
changes the life style, food habits and disease spectrum of the people. This large difference reflects upon
the medical facilities as well - with state of the art hospitals in the urban cities to primary care centre's with
bare minimal facilities in the villages.
To add to this is India's large population that has crossed the one billion mark with over 71 million men
and 43million women over 60yrs of age. It is estimated that by the year 2026, more than 103 million
women would be over 60yrs of age. The average age of menopause in India is 47.5yrs. presently and the
life expectancy about 71yrs .This means that an average Indian woman would be spending about 23.5yrs
of her age in menopause. Women's health is linked to family planning in India. Health programmes for
women in India are designed and targeted towards reproductive health. (The RCH programme).The
older women in India are a medically marginalised group. The medically deprived status of these older
women who have reached menopause is a result of the thought of policy makers who have till very
recently believed that once a woman's reproductive years are over she no longer needs any specific
programmes
With the entire world now waking up to the realization of ageing and the problems that come with this,
most world organizations and governments are now gearing up to the needs of geriatric medicine and
prophylactic screening programmes for this age group. The Medical Council of India has also issued
directives to all medical colleges to have mandatory menopausal clinics in order to cater to the special
needs of this group of patients. However, seeing the great diversity that exists in the populations across the
country, no definite guidelines have been issued for setting up such a clinic.
This paper attempts to collate the ideas and thoughts of various nations in order to set up An ideal one
stop menopause clinic for the women of India.
Clinical need :
Essentially these clinics are meant for women who are either approaching (perimenopausal)
menopause or are already in their menopause. Perimenopausal women may seek only counseling in
order to prepare them for menopause.
The clinic should offer comprehensive patient friendly services under one roof. The medical, para
medical and non medical staff must be well informed and updated in menopausal health, they must
be sympathetic to the patients and essentially give the same information to them so that the patient is
not confused.
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There are three types of patients who would be attending these clinics:
· Symptomless women seeking screening/counselling only
· Women who have problems pertaining to menopause
· Women who have allied problems as well e.g. heart disease.
The Clinic would ideally have to address the following:

1. Evaluating the needs of the individual patient
2. Identification of her menopausal symptoms and evaluation of risk factors
3. Detection of any pathological conditions
4. Treatment of complications
A one stop menopause clinic is therefore a multispeciality, multidisciplinary “centre”

comprising of the following clinicians:
· Gynaecologist
· General Physician
· Endocrinologist
· Cardiologist
· Orthopaedic Surgeon
· Neurologist
· Physiotherapist/ yoga instructor
· Nutritionist
· Ophtahmologist
· Urologist
· Dentist
· Pschycologist/counsellor
All these must be backed by a good laboratory, Dexa scan, mammography and an ultrasound.
However, passing through this long list of clinicians may be cumbersome and tiresome for elderly
women who will soon shy away from this experience. In a govt. set up this would also be expensive
for the exchequer and privately unaffordable for the patient. It is therefore mandatory for the
gynaecologist to become a “ primary care physician” or a specially trained “menopausal medicine
practioner” (training now being conducted by the Indian Menopause Society). Such specialised
training will help to both identify problems and treat the simple one's by a single clinician.
Components of screening:
1. Detailed history
2. Detailed clinical examination
3. Yearly Pap smear
4. Ultrasound scan TVS for uterus and ovaries
5. Mammogram
6. Uterine and Endocervical sampling if required
7. Dexascan
8. Haemogram, LFT, Lipid profile, Blood sugar
9. Urine, Stool exam.
10. Special tests like Thyroid profile, FSH, Estradiol if required.
119
Treatment:
1. Counselling: Counselling is a very important and integral part of a menopause clinic. The patient
needs to be counseled preferably in her own language, on the following aspects :
· The process of menopausal aging and what to expect as she ages
· The current treatment available for her problems and the side effects
· Advice on nutrition and life style.
· Need for yearly screening and follow up
The clinic must have lots of reading material, pamphlets and visuals to inform the patients about all these
aspects of menopause. These must be constantly updated in order to share the lastest information with the
patients.
2. General treatment like vitamins and minerals: Calcium and vitaminD etc.
3. Specific treatment for condition detected
4. Referal to a specialist when required.
It is important for every clinician dealing with elderly women to know that they may require lower dose of
medication if they are frail or have a low BMI and drug interaction must be well known before prescribing
since they may be on more than one drug for their ailments.
Follow up : Every woman must be asked to come for follow up each year to review her condition and to
change/ update her medication if required. A closer follow up e.g. 3-6 months may be required in
special cases and must be clearly explained to the patient. If the patient is being put on some
treatment e.g. HRT for the first time, she must be called within a month or earlier to review her
acceptability and tolerance to the medication and dosage.
Record Keeping: Record keeping, documentation and patient recall system must be perfect so that
long term follow up is also possible.
Use of Internet: For the urban literate patients, a clinic website, email services may go a long way in
making the clinic truly one stop. All interaction can be carried out on email and may thus save a lot of
time. It may also be possible to set up a helpline through this medium or on phone.
Non health needs:

The aging women would have many non health needs which also need to be highlighted and
explained by the physician since this is an opportunity to meet this group. The greatest need is to
make them aware of housing and environment in order that they do not fall while walking. Non slip
flooring and supports in the toilets are essential to prevent hip fractures. Women must be cautioned
and trained to meet this challenge. Social support and a caregiver network are also very important to
help some of these women tide over the acute stress and depression that they may be going through.
Every clinician wanting to set up a menopausal clinic must ensure that the patient visits are minimal
and maximum benefit is gained through just one primary visit each year. A comprehensive, friendly
approach would go a long way in popularizing such a venture.
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26 Prevention of Cancers in Menopause
Prof. Alka Kriplani,

MD, FRCOG, FAMS, FICOG, FICMCH, FIMSA
Professor and Unit Head, deptt. of
obstetrics and gynecology,
All India Institute of Medical Sciences, Delhi
Dr. Beenu Kushwah

M.D., D.N.B.
Senior Research Associate, deptt. of
obstetrics and gynecology,
All India Institute of Medical Sciences, Delhi
Introduction :
Menopause is a transition with certain hormonal changes in body. Menopause itself is not associated
with an increased risk of developing cancer. However, incidence of most of genital cancers does
increase with age and so as with menopause. In addition, changing hormonal milieu of body and use
of certain drugs to manage menopausal symptoms may increase or decrease a lady's cancer risk.
Many reproductive tract malignancies are preventable. The obstetrician-gynecologist play an
important role in counseling patients on lifestyle factors that can reduce the risk of cancer by not
smoking, eating high fiber foods, restricting fat intake, exercising daily, pay attention to body changes,
and getting regular health check-ups. In this chapter the modalities, which can be used as preventive
measures or as screening tools to prevent or to diagnose these malignancies at an early stage, are
reviewed.
Endometrial Cancer : Menopause age group constitutes major subset of cancer endometrium patients.
Screening of all menopausal females without any symptoms is not recommended. Only high risk
patients presenting with post menopausal bleeding, as it is the most common presenting symptom for
the endometrial carcinoma precursors and frank malignancies, are to be screened (1-3).
Detailed history taking is recommended to exclude any drug intake like HRT and Tamoxifen and
finding out high risk factors such as nulliparity, diabetes, obesity, hypertension and the use of
unopposed oestrogens (4).
Bimanual pelvic examination comes next which should be followed by transvaginal ultrasonograph
(TVS) if required. On TVS, endometrial thickness of 4mm is the cut-off for further evaluation of
endometrium (5).
For endometrial sampling D & C should no longer be used as a first line investigation because of its
low sensitivity (6, 7). Office hysteroscopy with directed biopsy is the gold standard whenever facilities are
available.
Females using Tamoxifen should be followed up with more frequent gynecological examination
because of 2-6 fold increase risk of endometrial cancer, although regular endometrial sampling is not
recommended. Nonetheless, patients presenting with abnormal uterine bleeding should be
thoroughly investigated using hysteroscopy and biopsy as first line investigation (8, 9).
121
Hormone replacement therapy (HRT): ACOG (2004) recommends (grade A) combined HRT can
be used for short duration to relive acute menopausal symptoms with no increased risk of endometrial
carcinoma , however, unopposed estrogen is not to be used in women with intact uterus because of
increased risk of endometrial carcinoma (10).
Cervical Cancer: According to American cancer society, with a regular 3 yearly Pap smear screening, 70
yrs is the appropriate age of exit from routine cervical cancer screening in women who had 3 or more
normal Pap smear in a row and with no abnormality during last 10 yrs.
Pap smear is less efficient at detecting cervical intra-epithelial neoplasia 3(CIN 3) in older women,
more smears are required to detect a case of CIN3 after the age of 50 years,(11) but it is more efficient at
preventing invasive cancer (12).
New recommendations are awaited regarding frequency of cervical screening with the possible use of
universal HPV screening and during post HPV vaccination era.
Ovarian cancer: Ovarian cancer is the deadliest of all genital cancers

mainly because of its late presentation. There is no role of OCPs
chemoprevention and prophylactic oophorectomy in menopause age
group which is meant for hereditary ovarian cancers that occurs in
younger age group.
A variety of modalities have been used to detect ovarian cancer in

asymptomatic women and preventing progression to advanced
disease:
Pelvic examination: As a screening tool for early stage disease pelvic examination lacks both sensitivity
and specificity (13-15).
Tumor markers: The most extensively investigated is CA125; a cut-off of 35IU is most commonly used.
As most of the benign conditions causing increase in CA125 can be excluded in menopausal age
group and it is the serial value which is useful, therefore using an algorithm incorporating age and rate
of change of CA125 as well as absolute value can be an important progress(16).The use of a
combination of markers to increase sensitivity and specificity has been extensively investigated and
some of them include CA72-4(TAG 74),M-CSF, OVX1, LPA, prostacin, osteopontin, inhibin and
kallikrein(17). The use of panel of markers as a first-line test in ovarian screening is an attractive concept.
Ultrasound: Although ultrasound alone is not a good modality to detect ovarian cancer in terms of
sensitivity and specificity, addition of morphologic index and color flow doppler imaging has
enhanced sensitivity and specificity of these modalities(18,19).
Multimodal screening: various studies (20-21) have shown that the highest positive predictive value can
be achieved with multimodal screening, using CA125 as a first-line test, followed by ultrasound if
CA125 is abnormal. The use of multimodal screening to detect early ovarian cancer has three main
advantages: first, using serum screening as a first line test reduces cost. Second, reserving ultrasound
as a secondary test reduces the number of women undergoing transvaginal assessment. Finally,
combining different modalities can achieve sensitivity and specificity comparable to that of the most
sophisticated protocols utilizing color flow Doppler ultrasound and morphological indices.
122
Risk of malignancy index I & II: RMI score=ultrasound score x menopausal score x CA 125 levels in
IU/ml
RMI I & II have been introduced, three studies have compared the two RMI scoring schemes, using
cut-off RMI score above 200 to indicate high malignancy risk (22, 23).Because of its greater
sensitivity, specificity and simplicity, RCOG and ACOG both have recommended use of RMI II for
assessment of an ovarian mass to detect ovarian carcinoma at an early stage, therefore improving
overall survival rates.
Breast Cancer: Both American cancer society (ACS) and ACOG recommends annual mammography
after the age of 40 yrs in an average risk female (24).
Following the release of World Health Initiative data, published in July 2002(25) there were concerns
regarding use of hormone replacement therapy (HRT) and increased risk of breast cancer. ACOG
(2002) recommends that HRT should not be initiated solely for the purpose of prevention of coronary
heart disease and should be used for shortest possible duration for amelioration of menopausal
symptoms.
Vulvo-vaginal Cancer: Although cancer vulva and vagina are rare, there is a defined premalignant
phase called vulvar intra epithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VAIN)
respectively, if identified and managed properly, prevents the development of invasive cancer.
Regular gynecological examination, clinical inspection and biopsy are the hallmark of early diagnosis of
high risk vulval lesions. Visual inspection with colposcopy after application of acetic acid is useful.
Because of keratinized sqamous epithelium of vulva acetic acid needs to be put longer than in cervical
lesions, generally it is for five minutes of 5% acetic acid. Extensive evaluation with the colposcope,
including perianal region is needed to rule out multicentric lesions.
Pap test screening for vaginal cancer is recommended for women with history of hysterectomy for cervical
cancer and CIN.
Colo-rectal cancers: As 90% of population with colorectal carcinoma is above the age of 50 yrs, therefore
ACOG (2007) recommends every 10 yearly screening preferably with colonoscopy after the age of 50
yrs, which need to be earlier and more frequent if risk factors are present.
Conclusion: Menopause is the period during which a lady is confronted with multiple changes in her
body system because of the changing hormonal milieu, besides her age being the risk factor for
developing several genital and non-genital malignancies. Most of these malignancies are not ideally
fit for the screening, however early detection can be as good as it would improve their quality of life
immensely and the overall survival. To conclude, annual gynecological examination of menopausal
age group patients is the single most intervention that needs to be implemented for the best possible
results.
123
Suggested Reading
1. Alberico S, Conoscenti G, Veglio P, Bogatti P,Di Bonito L, Mandruzzato G. A clinical and epidemiological study of 245 postmenopausal
metrorrhagia patients. Clin Exp Obstet Gynecol 1989;16:113-121.
2. Feldman S, Cook EF, Harlow BL, Berkowitz RS. Predicting endometrial cancer among older women who present with abnormal vaginal bleeding.
Gynecol Oncol 1995; 56: 376-381.
3. Miyazawana K. Clinical significance of an enlarged uterus in patients with postmenopausal bleeding. Obstet Gynecol 1983; 61: 148-152.
4. Gredmark T, Kvint S, Havel G, Mattsson LA. Histopathological findings inwomen with postmenopausal bleeding. Br J Obstet Gynaecol 1995;
102: 133-136.
5. Moodley M, Roberts C. Clinical pathway for the evaluation of postmenopausal bleeding with an emphasis on endometrial cancer detection. J
Obstet Gynaecol 2004; 24: 736.
6. Ben-Baruch G, Seidman DS, Schiff E, Moran O, Menczer J. Outpatient endometrial sampling with the Pipelle curette. Gynecol Obstet Invest 1994;
37: 260-262.
7. Kaunitz AM, Maciello A, Ostrowski M, Rovira EZ. Comparison of endometrial biopsy with the endometrial Pipelle and Vabra aspirator. J Reprod
Med 1988; 33: 427-433.
8. Love CD, Muir BB, Scrimgeour JB, Leonard RC, Dillon P, Dixon JM. Investigation of endometrial abnormalities in asymptomatic women treated
with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 1999; 17: 2050-2054.
9. Franchi M, Ghezzi F, Donadello N, Zanaboni F, Beretta P, Bolis P. Endometrial thickness in tamoxifen –treated patients: an independent predictor of
endometrial disease. Obstet Gynecol 1999; 93: 1004-1008.
10. Warren MP, Halpert S. Hormone replacement therapy: controversies, pros and cons. Best Prac Res Clin Endocrinol Metab 2004; 18(3): 317.
11. Gustafsson L, Sparen P, Gustafsson M et al. Low efficiency of cytologic screening for cancer in situ of the cervix in older women. Int J Cancer 1995;
63: 804-809.
12. Sasieni P, Adams J, Cuzick J. Benefits of cervical screening at different ages: evidence from the UK audit of screening histories. Br J Cancer 2003;
89: 88-93.
13. Gordis L. Assessing the validity and reliability of diagnostic and screening tests. In: Epidemiology. 2nd edition. Philadelphia: W.B. Saunders;
2000: 63-81.
14. Andolf E, Jorgensen C, Astedet B. Ultrasound examination for detection of ovarian carcinoma in risk groups. Obstet Gynecol1990; 75: 106-9.
15. Smith LH, Oi RH. Detection of malignant ovarian neoplasm: a review of the literature. I. Detection of the patient at risk; Clinical, radiological and
cytological detection. Obstet Gynecol Surv 1984; 39 (6): 313-28.
16. Skates SJ, Menon U, MacDonald N ET AL. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in
postmenopausal women. J Clin Oncol 2003; 21 (10 suppl): 206-210.
17. Menon U, Jacobs IJ. Tumor markers and screening. In: Berek JS, Hacker NF. (eds) Practical Gynecologic Oncology, 4th edn. Philadelphia, PA;
2005: 43-66.
18. DePriest PD, Shenson D, Fried A et al. A morphology index based on sonographic findings in ovarian cancer. Gynecol Oncol 1993; 51: 7-11.
19. Modesitt SC, Pavlik EJ, Ueland FR, DePriest PD, Kryscio RJ, van Nagell Jr JR. Risk of malignancy in unilocular ovarian cystic tumors less than 10
centimeters in diameter. Obstet Gynecol 2003; 102: 594-599.
20. Menon U, Skates SJ, Lewis S et al. A prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol 2005;
23.
21. Adonakis GL, Paraskeveidis E, Tsiga S, Seferiadis K, Lolis DE. A combined approach for the early detection of ovarian cancer in asymptomatic
women. Eur J Obstet Gynecol Reprod Biol 1996; 65: 221-225.
22. Tingulstad S, Hagen B, Skjeldestad FE, Onsrud M, Kiserud T, Halvorsen T, et al. Evaluation of a risk of malignancy index based on serum CA125,
ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses. Br J Obstet Gynaecol 1996; 103(8): 826-31.
23. Morgante G, La Marca A, Ditto A, De Leo V. Comparison of two malignancy risk indices based on serum CA125, ultrasound score and menopause
status in the diagnosis of ovarian masses. Br J Obstet Gynaecol 1999; 106(6):524-7.
24. Rockville, MD. Screening for breast cancer: recommendations and rational. Agency for Healthcare Research and Quality; 2002.
25. Writing Group for the Women's Health Initiative. Risk and benefits of combined estrogen and progestin in healthy postmenopausal women:
principal results for the Women's Health Initiative randomized controlled trial. JAMA 2002; 288-321.
124
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T H E M E N O PA U S E

Dr. C.N. Purandare Dr. Gupte Sanjay Anant

Dr. Shirish Patwardhan Dr. Narendra Malhotra

Dr. Alka Kriplani Dr. P.K. Shah

Dr. Hara Pattanaik Dr. Nozer Sheriar

Dr. Madhuri Patel Dr. H.D. Pai

List of Chairpersons of the Committees of FOGSI 2009

9. Dr. Alpesh Gandhi 18. Dr. Roza Olyai

THE FEDERATION OF OBSTETRIC AND GYNAECOLOGICAL SOCIETIES OF INDIA

Dr. Shirish Patwardhan,

Wishing all the members Srimanti and Anand in years to come.

Professor Alka Kriplani

Menopause is a pertinent subject. With so many women entering menopause, dealing

Dr. Mandakini Parihar

With warm regards

Dr. Mandakini Parihar

I have a little granny,

She doesn't wear her spectacles

How I sometimes wish,

Unlike all other grannies

She goes for day trips with her Gang,

I really love my granny

Section 1 - Understanding Menopause

Section 2 - Symptoms and System Manifestations in Menopause

Section 3 - The Silent Killer Osteoporosis

Section 4 - The science of hormone Therapy in Menopause

Section 5 - Facts & Myhts of Different Studies on Menopause

Section 6 - Holistic Approach to Menopause

Fig 1: The pathways for steroid biosynthesis

Fig 3: Progesterone levels (black line) during menstrual cycle

Endocrinology of perimenopausal women:

Changes in estrogenic environment

Changes in the growth hormone and insulin like growth factors

Menopausal changes- summary

Dr. Anu Vij

1) Changing Hormonal Patterns

Muscle Tone and Elasticity

Abdominal wall tone may lessen gradually, resulting in a protruding stomach

Hair, Bones, and Teeth

"Classic" Menopausal Changes

Effect of Menopausal Symptoms on Overall Quality of Life

Table1: Stages of Menoapuse, Dr. Behram. S. Anklesaria, 1997

2) STRAW SYSTEM (Stages of Reproductive Aging Workshop)

Questions for the Reader:

Dr. Sonal P. Yadav

Mechanism of psychological symptoms in menopausal women:

Cognition and Alzheimer's Disease:

disease. Estrogen is capable of protecting central nervous Cerebral

system functions by means of multiple mechanisms. For

increases synapses and neuronal growth, especially Cortical

Estrogen Progestin therapy increase risk for probable Severe

cardiovascular disease and established atherosclerosis Severe

1. Wyon J B et al 1966. Population Index 32: 328 – 329

Dr. Ritu Joshi

There is a sudden onset of reddening of the skin over the head,

Release of hypothalamic neuropeptides/neurotransmitters from tonic inhibilitory influence of

In women in whom hormone replacement is contraindicated effective alternatives are

Treatment (Non Steroidal)

Formulations containing a combination of phenobarbital, ergotamine and belladonna, used in the