Pcos Slide Presentation

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Polycystic Ovary Syndrome Polycystic Ovary Syndrome

Mark Perloe, M.D Mark Perloe, M.D. ..
PCOS PCOS Overview Overview
Definition
Ultrasound Findings
Hypothalamic-Pituitary-Ovarian Axis abnormalities
Insulin resistance
Diagnosis
Treatment Options
Fertility
Menstrual disturbances
Hirsutism
PCOS PCOS Objectives Objectives
To provide an overview of current thinking and
research
To help you better understand this condition
To allow you to be an active participant in your
patients medical care
PCOS PCOS Definition Definition
POLYCYST OVARY SYNDROME is a
generic description for a broad spectrum
of clinical and morphological findings in
women with an endocrine dysfunction,
specifically abnormal androgen production
and metabolism.
PCOS PCOS Symptoms Symptoms
0 20 40 60 80
Infertility
Biphasic BBT
Dysmenorrhea
Amenorrhea
Abnormal menses
Cyclic Menses
Virilization
Hirsutism
Obesity
Percent
Goldzieher JW, et al: JCEM 22:325, 1962
PCOS PCOS Health Risks Health Risks
More likely to have hysterectomy
Dahlgren E, et al: Fertil Steril 57:505, 1992
Coronary heart disease risk factors significantly
Talbott E, et al:Arterioscler Thromb Vasc Biol 15:821, 1995
TC, LDL-C, & TG in IR & NIR
Talbott E, et al: J Clin Epidemiol 51:415, 1998, Melrow D, et al: Hum Reprod 11:1848, 1996
Blood pressure with insulin level and is in
obese PCOS women
Conway GS, et al: Clin Endocrinol 37:119.1992
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PCOS PCOS Sequelae Sequelae
Relative risk of MI 7.4 times age matched controls
Dahlgren E, et al: Acta Obstet Gynecol Scand 71:599, 1992
Risk of diabetes associated death (3.6 O.R.)
Pierpont T, et al: J Clin Epidemiol 51:581, 1998
More extensive CVD on heart catheterization
PCOa present in 42% of CVD patients
Birdsall MA, et al: Ann Intern Med 126:32, 1997
Hyperinsulinemia Hyperinsulinemia CVD Risk Factors CVD Risk Factors
Endothelium dysfunction (impaired NO vasodilation)
Disorders of coagulation & fibrinolysis
Plasminogen activator inhibitor-1
Plasminogen activator activity
Fibrinogen levels
Activation of coagulation
Hypertension
Dyslipidemia
PCOS Findings PCOS Findings
Biochemical
Androgen
Testosterone
DHEAS
Androstenedione
17OH progesterone
SHBG
LH
Insulin/Glucose
PAI-1
Lipids
Ultrasound
Necklace sign
Ovarian volume
Antral follicle count
Doppler blood flow
changes
Physical
Obesity
Hirsutism
Acanthosis
Abnormal menses
Acne
PCOS PCOS Insulin Connection Insulin Connection
30% of obese PCOS women have glucose tolerance
by their 30s
Insulin-mediated glucose uptake is 35-40%
glucose-stimulated insulin release ( -cell function)
50% of PCOS women demonstrate post-receptor
defect
insulin, steroidogenesis and LH release
Dunaif A, et al: J Clin Invest 96:801, 1995
Insulin Receptor Pathways
Insulin Resistance Gene Chip Insulin Resistance Gene Chip
210 genes in metabolic
pathways related to insulin
resistance
Transciptions factors
Cytoskeletal
components
Fat oxidation
Fat storage Fat uptake
Glucose storage Glucose oxidation
Glucose uptake Signaling
Walder K, et al: Ann NY Acad Sci 967:274, 2002
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PCOS PCOS Ultrasound Ultrasound
1078 reproductive age women screened by US
183 (17%) demonstrated PCO appearance
80% had irregular or absent cycles
19.7% had regular cycles
AndersY et al: Contacept Fertil Sex 23:415, 1995
PCO appearance associated with testosterone,
androstenedione and glucose clearance
Najmabadi, et al: Fertil Steril 67:631, 1997, Dewally D, et al: Ann Ny Acad Sci 587:206, 1993
Androgen production, action & control Androgen production, action & control
Pituitary ACTH, LH
GnRH-a, birthcontrol pills,
progesterone
Adrenal DHEAS,
Androstendione, Testosterone
Dexamethasone
Ovary Androstendione,
Testosterone
Spironolactone, metformin,
thiazolidinediones
Testosterone conversion
5-reductase enzyme
Finasteride
Androgen receptor
Flutamide, spironolactone,
CPA
Hair Follicle
Vaniqa
PCOS PCOS Exercise Exercise
Peripheral muscle cells metabolize 80% of glucose
Aerobic exercise
3-4x/wk 20-30 min/session
Burns 100-200 kcal
40% improvement in insulin sensitivity within 48 hrs.
DeFronzo RA, et al: Diabets 36:1379, 1987; Segal KR, et al: J Appl Physiol 71:2502, 1991
Role of Dietary Nutrients Role of Dietary Nutrients
Interact with hormonal signals to govern the expression of
genes encoding proteins involved in energy metabolism,
cell differentiation, and cell growth
Govern the tissue content and activity of different proteins
by functioning as regulators of gene transcription, nuclear
RNA processing, mRNA degradation, and mRNA
translation, as well as functioning as posttranslational
modifiers of proteins
FFA have a very strong direct influence on the molecular
events that govern gene expression
Clarke S, et al: Ann NY Acad Sci 967:283, 2002
Is obesity related to high fat diets? Is obesity related to high fat diets?
A substantial decline in the percentage of energy
from fat during the last 2 decades has corresponded
with a massive increase in the prevalence of
obesity. Diets high in fat do not appear to be the
primary cause of the high prevalence of excess
body fat in our society, and reductions in fat will
not be a solution.
Willet WC, et al: Am J Med 113S:47S, 2002
The Diet The Diet Dilemna Dilemna

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PCOS PCOS Diet & Weight Loss Diet & Weight Loss
Hypocaloric diets insulin resistance
10-20% protein, ~50% carbohydrates
< 30% total fat, < 10% saturated fat
ADA nutritional recommendations: Diabetes Care 20S:14, 1997
Further improvement with 5-10kg weight reduction
Two fold glucose disposal rate with 16% weight
Niskanen L, et al: J Obes Relat Metab Disord 20:154, 1996
PCOS PCOS Dietary Recommendations Dietary Recommendations
Focus on lowering dietary fat as a means for promoting
negative energy balance has led to an underestimation of
the potential role of dietary composition in promoting
reductions in energy intake and weight loss
Roberts SB, et al:J Am Coll Nutr 21:140S, 2002
Diets based on low-GI foods produced greater weight loss
than did equivalent diets based on high-GI foods.
Brand-Miller JC, et al: Am J Clin Nutr 76:281,2002
Low GI diet more effect than low fat in obese children
Spieth LE, et al: Arch Ped Adol, 154:947, 2000
PCOS PCOS Dietary Dietary Sequalae Sequalae
Diets with a high glycemic load and a low cereal
fiber content increase risk of diabetes in women.
Salmeron J, et al: JAMA 277:472, 1997
Exacerbation of the proinflammatory process may
be a mechanism whereby a high intake of rapidly
digested and absorbed carbohydrates increases the
risk of ischemic heart disease, especially in
overweight women prone to insulin resistance
Willet WC, et al: Am J Clin Nutr 75:492 2002
Improvements in menstrual cyclicity were
associated with greater decreases in insulin
resistance and fasting insulin.
Norman RJ, et al: J Clin Endocrinol Metab 88:812 2003
The glycemic index appears to be a better predictor
of the metabolic effects of a diet than the sugar
content.
Jenkins DJ, et al: Curr Opin Clin Nutr Metab Care 6:165, 2003
Substitute nonhydrogenated unsaturated fats for saturated
and trans-fats
omega-3 fatty acids from fish, fish oil supplements, or
plant sources
fruits, vegetables, nuts, and whole grains
refined grain products.
Simply lowering the percentage of energy from total fat in
the diet is unlikely to improve lipid profile or reduce CHD
incidence.
Willet WC, et al: JAMA 288:2569, 2002
PCOS PCOS Dietary Goals Dietary Goals
Consume more foods
rich in complex
carbohydrates
monounsaturated fat
fiber
with a ratio of omega-6 to
omega-3 fatty acids
Reduce
Total caloric intake
Saturated fat
Cholesterol
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PCOS PCOS FFA & Insulin Resistance FFA & Insulin Resistance
FFA release from adipose tissue or failure of FFA using
tissues to remove them normally, lead to TG
delivery of FFA to muscle muscle glucose uptake and
utilization
IR correlates with intramuscular TG store
Lipotoxicity: Intracellular TG linked to pancreatic -cell
failure
Ziegler O, et al: Diabetes Metab 27:261, 2001
Diabetes Prevention Program Diabetes Prevention Program
3,234 people with impaired GTT followed 3 years
BMI 34
Low fat diet and exercise (150 minutes/wk)
58% reduction of diabetes risk (71% for 60 & older)
Loss of 5-7% of body weight (15 pounds)
Metformin 850 mg twice daily
31% reduction of diabetes risk
Loss of 5% of body weight
PCOS PCOS Medical Therapy Benefits Medical Therapy Benefits
Metformin appetite, BP, PAI-1, plasma lipids
TZD (thiazolidinedione) FFA, TG, LDL-oxidation, PAI-1,
BP
Metformin & TZD may be combined
Hypoglycemia results from diet and too little, not too
much metformin or TZD
insulin may improve menstrual cyclicity
endometrial cancer risk
androgens
Diabetes Epidemic Diabetes Epidemic
Diabetes afflicts 16 million Americans
20% of those age 20 or older
95% type II
Prevalence tripled last 30 years
Risk 5 times with BMI > 30
Compared to whites, black adults have 60% greater
risk and Hispanic adults have 90% greater risk
PCOS PCOS Fertility Treatment Options Fertility Treatment Options
Diet
Exercise
Insulin sensitizer
Ovulation induction
Clomiphene/letrozole
Gonadotropins
GnRH-agonist/gonadotropins
Ovarian drilling
Assisted Reproductive Technology (IVF)
PCOS PCOS Ovarian Drilling Ovarian Drilling
Spontaneous ovulation
60-95%
Pregnancy
60-85%
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PCOS PCOS Ovarian Drilling Ovarian Drilling
Disadvantages
Adhesion formation
Interceed not beneficial
Requires surgery
1/3 require ovulation
medications
POF risk
Less successful in smokers
25% vs 95%
Advantages
High success rate
Prolonged response
Multiple births
OHSS
Dose, duration ovulation
induction
PCOS PCOS Injectable Injectable Gonadtropins Gonadtropins
Birth control pretreatment
GnRH-agonist vs antagonist
Low dose treatment (multidose vials)
Low dose hCG
Avoiding Multiple Births and OHSS Avoiding Multiple Births and OHSS
Follicular reduction
Conversion to IVF
Oocyte cryopreservation
Cycle cancellation
Metformin Metformin GRS Treatment Criteria GRS Treatment Criteria
8 or fewer menses per year
Hirsutism or elevated androgens
Acanthosis nigricans
History of gestational diabetes
PCO appearing ovaries
Family history of diabetes
Fasting insulin over 10 miu/ml; 2 hour over 50 miu/ml
Hypoglycemic response on 2hr IGTT
Metformin Metformin Who Gets Pregnant? Who Gets Pregnant?
93.7% had normal FBS
50% had insulin < 15 miu/ml
89% had normal testosterone levels
Labtests dont predict who gets pregnant!
PCOS PCOS GRS Metformin Protocol GRS Metformin Protocol
Metformin 500 mg XR qd wk 1; bid wk 2; tid wk 3;
followed by metformin 850 mg bid
Take with full glass of water/milk at middle of meal
Monitor BBTs, u-hCG if 16 day temp rise seen
Re-evaluate @ 3 months
Additional time
Increased metformin to tid or add Avandia/Actos (check ALT)
Letrozole/clomiphene
Ovarian drilling
Low dose injectables
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PCOS PCOS Metformin & Ovulation Metformin & Ovulation
61 PCOS women with BMI >28
26 women received - Placebo
35 women received - Metformin
1500 mg/day
1 14 28 35
Prog. >25 nmol/L
1 ovulated
14 ovulated
P<0.001
Nestler et al. N Engl J Med 1998
Ovulation Induction Ovulation Induction
Metformin With Clomiphene Metformin With Clomiphene
25 women received -
Placebo
1 5 10 18
2 ovulated
P<0.001
Nestler et al. N Engl J Med 1998
21 women received - Metformin
1500 mg/day
19 ovulated
CC
50 mg
Metformin Improves Pregnancy Rates Metformin Improves Pregnancy Rates
OGTT offered to women with obesity, AN, GDM, FHX or
CC failure
51 had hyperinsulinemia
Group 1: Metformin alone (n=11), Met+CC (n=17), Group 2: CC
alone (n=23) for 7.5 months average
Ovulation (82% vs 78%) and pregnancy rates (63% vs 36%, NS)
Pregnancy in women who ovulated appeared higher in metformin
patients (75% vs 44%, p=0.054)
Lavoie HB, et al. Abstract P2-426 Endocrine Society, 2001
Pregnancies Following Metformin in Pregnancies Following Metformin in
PCOS PCOS
Anovulatory patients (N=48) with PCOS
Metformin 500 mg b.i.d. 6 weeks, t.i.d. thereafter
Clomiphene added if anovulatory at 12 weeks
31/48 (64.5%) resumed spontaneous menses
16/31 (52%) conceived within the first six months
3/16 (19%) had spontaneous abortions
19/48 (40%) suffered gastrointestinal related side-effects,
including diarrhea, abdominal cramping, and nausea
Heard MJ, et al: Abstract 140, Society of Gynecologic Investigation, 2001
Metformin Reduces Metformin Reduces Pregnancy Pregnancy Loss in Loss in
PCOS PCOS
Retrospective study of PCOS women who became
pregnant
Group 1: received metformin during pregnancy (n=101)
Group 2: control (n=31)
Early loss rate 12.9% vs 41.9% (p=0.001)
Prior SPAB: 15.7% vs 58.3% (p=0.005)
Jakubowicz DJ, et al: abstract P2-427, Endocrine Society, 2001
PCOS PCOS Conclusion Conclusion
We know how to speak many falsehoods which
resemble real things, but we know, when we will
how to speak true things.
Hesiod
Everything should be made as simple as possible,
but not simpler.
Albert Einstein

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Polycystic Ovary Syndrome Polycystic Ovary Syndrome

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