OCP in PCOS

Dr. Sonia Malik

Programme Director
Southend Fertility & IVF
Chairperson, FOGSI Infertility Committee
Immediate Past President, Indian Fertility Society
AIM
• Why OCP’S act in PCOS
• When to be given: INDICATIONS
• Which one to be given: SELECTION
CRITERIA
• Adjuncts: METFORMIN,SPIRANOLACTONE,
ANTIANDROGENS
• Efficacy
• Side effects
• Recommendations
PCO
Hyperandro
genism
Chronic
Anovulation
HPCO
PCO-CA
HCA-PCO
HCA

Legro, R. S. Endocr Rev 2003;24:302-312

Copyright ©2003 The Endocrine Society

 4

OCP
• The combined oral contraceptive pill
(COCP), often referred to as the birth
control pill or colloquially as "the pill",
is a birth control method that includes
a combination of an estrogen
(estradiol) and a progestogen
(progestin). The estrogen component is
generally ethinyl estradiol in a dose of 15 -
30mg and it is the progesterone that is
variable.
© 2015 Southend Fertility & IVF
Wikipedia
 Low Dose[<50-ug ethinyl estradiol(EE)combined oral contraceptives 5

Estrogen Progestin (mg) Commercial Names

Monophasic EE 35 Norethindrone 1 Orthonovum 1/35

Norethindrone 0.5 Ovcon 35
Ethynodiol 1 Demulen 1/35
Noregastimate .25 Orthocyclean.25
Cryproterone 2 Gynofen, Diane 35
EE 30 Norethindrone 1.5 Loestrin 21 1.5/30
Noregestrel 0.15 Lo-Ovral
Desogetrel .15 Desogen, Marvelon
Levonorgestrel .1 Nevlen, Nordette
Gestodene .75 Gynera, Minulet
Drosperinone 3 Yasmin
EE 20 Norethindrone 1 Loestrin 21 1/20
Levonorgestrel .1 Alesse, Levlite
Desogetrel 1.5 Mircette, Mercilon
Gestodene .75 Merilane, Hormonatte
Drosperinone 3 Yaz
EE 15 Gestodene 0.6 Melodia

© 2015 Southend Fertility & IVF

 Low Dose[<50-ug ethinyl estradiol(EE)combined oral contraceptives 6

Estrogen Progestin (mg) Commercial Names

Biphasic EE 30/40 Desogetrel .025-0.125 Gracial

Triphasic EE 30/40/30 Levonorgestrel .125-.75 Trilevlen, Triphasil
EE 35 Noregastimate .18-.25 Orthocyclean
EE 25 Noregastimate .18-.25 Orthocyclean LO
EE 30/40/30 Gestodene .05-0.1 Trigynera, Tri-Minulet

S.Nader, and E.Diamanti-Kandarakis

Human Reproduction Vol.22, No.2 pp. 317–322, 2007

© 2015 Southend Fertility & IVF

 Actions of Combined Oral Contraceptives
Estrogen Components (ethinyl-estradiol)
Suppression of Follicle- Stimulating Hormone
Stabilization of endometrium
Potentiation of progestin action
Suppression of dominant follicle formation
Increase in sex hormones binding globulin
Decrease in free androgen

Progestin Component (Variable component to preparation)

Suppression of luteinizing hormone
Inhibition of luteinizing hormone surge
Unreceptive endometrium
Hostile Cervical mucus
decrease in ovarian androgen secretion
possibly androgen-blocking effects

S.Nader, and E.Diamanti-Kandarakis

Human Reproduction Vol.22, No.2 pp. 317–322, 2007
 OCP’S
 Reduce hyperandrogenism by promoting direct
negative feedback on LH secretion, which results in
decreased ovarian synthesis of androgens.
 They increase liver production of sex hormone-binding
globulin and subsequently decrease circulating free
androgen.
 Cause reduction in adrenal androgen secretion and
inhibition of peripheral conversion of testosterone to
dihydrotestosterone and
 Binding of dihydrotestosterone to androgen receptors
PCO
Hyperandro
genism Hyperandrogenism
Chronic
Anovulation
HPCO
PCO-CA
HCA-PCO Oligoanovulation
HCA

Legro, R. S. Endocr Rev 2003;24:302-312

Copyright ©2003 The Endocrine Society

Indications for use
• Menstrual disturbances
• Hirsutism
• Acne
• ART
Selection Criteria

 Depends on the age and

 requirement of the patient.
 Least androgenic
 Androgenicity of combined oral contraceptive progestin's
Androgenicity according to sex hormone binding globulin elevation from most to least androgenic

Monophasic levonorgestrel
Monophasic norethindrone, triphasic levonorgestrel
Triphasic gestodene, biphasic desogestrel, monophasic desogestrel
Monophasic cyproterone acetate

Androgencity according to relative binding affinities to androgen receptors in rats from most to least
andogenic-
Levonorgestrel
Gestodene
Desogestrel
Norgestimate

Andogenicity according to androgen to progestin receptor binding ratio from most to least andogenic

Levonogestrel
Gestodene
Desogetrel
Norgestimate

Progestins with anti-andogenic effects S.Nader, and E.Diamanti-Kandarakis

Drospirenone (+) Human Reproduction Vol.22, No.2 pp. 317–322, 2007
Cyproterone acetate (++)
Efficacy of OCP’S

Comparison of efficacy and safety of metformin, oral contraceptive combination of ethinyl

estradiol and drospirenone alone or in combination in polycystic ovarian syndrome

Jyoti A. Bobde, Deepak Bhosle, Rajesh Kadam, Satish Shelke

Department of Pharmacology, MGM Medical College, Aurangabad, Maharashtra, India
Adjuncts
• Anti androgens
• Diuretics
• Insulin sensetizers

• While OCP’S are effective in reducing the

hyperandrogenic effects and regularising the
periods, insulin sensetizers are effective in
correcting the metabolic dysfunction.
 15

• Improved efficacy of low-dose

spironolactone and metformin
combination than either drug alone in
the management of women with
polycystic ovary syndrome (PCOS): a
six-month, open-label randomized
study.
• Ganie MA, Khurana ML, Nisar S, Shah PA, Shah ZA, Kulshrestha B,
et al. J. Clin. Endocrinol. Metab. 2013; 98 (9): 3599-3607.

© 2015 Southend Fertility & IVF

 Comparison of metformin versus oral contraceptive pill with outcome of fasting insulin.

Comparison of metformin versus oral contraceptive pill with outcome of fasting glucose.

Comparison of metformin versus oral contraceptive pill with outcome of fasting triglycerides.

Michael F. Costello et al. Hum. Reprod. 2007;22:1200-1209

© The Author 2007. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
[email protected]
 Comparison of metformin versus oral contraceptive pill with outcome of improved menstrual
pattern.

Comparison of metformin versus oral contraceptive pill with outcome of hirsutism.

Comparison of metformin versus oral contraceptive pill with outcome of acne.

Michael F. Costello et al. Hum. Reprod. 2007;22:1200-1209

© The Author 2007. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
[email protected]
 18

OCP Pretreatment in ART

• Patients with polycystic ovarian syndrome (PCOS) show a
robust response to gentle stimulation with gonadotropins.
• They are at an increased risk for OHSS.
• PCOS patients have higher peak serum E2 levels, lower
gonadotropin requirements and produce a greater number of
oocytes than normal responders.
• They show proportionately higher numbers of immature
oocytes, lower fertilization rates and poor embryo quality. This
may be secondary to the elevated LH levels these patients
demonstrate in the follicular phase.
• GnRH agonists reduce LH levels in the follicular phase.

• Pre-treatment with OC prior to starting the GnRH agonist:

(1) permits normalization of the LH/FSH ratio
(2) reduces ovarian androgen concentrations and
(3) attenuates the initial flare response to the GnRH agonist.
© 2015 Southend Fertility & IVF
 19

• Damario et al. proposed a "dual-suppression" protocol. High-

responder patients were started on OC for 25 days followed
by s.c. leuprolide acetate 1 mg/d which was overlapped with
the final 5 days of OC administration.
• This approach reduced the cancellation rate and improved the
PR with a low incidence of OHSS.
• Use of the dual method of suppression resulted in
significantly lower E2, total testosterone, DHEA-S and
androstenedione concentrations at the onset of gonadotropin
stimulation in high responders undergoing IVF-embryo
transfer.
• As opposed to GnRH agonist suppression without OC
suppression, the dual method of suppression also resulted in
significantly lower serum LH.
 20

Results: No significant difference was observed between the two groups concerning
dynamics of follicular growth and hormonal values. Clinical and ongoing pregnancy
rates were significantly lower in the OCP group despite same oocyte and embryo
quality. Nevertheless, the cumulative pregnancy rate did not differ between the two
groups. The incidence of OHSS was not statistically significant.
Conclusions: Extended duration of OCP pretreatment, as a first intention IVF
protocol for PCO patients, does not improve the pattern of follicular growth nor the
oocyte and embryo quality.
OCP & Antagonist protocol

Figure 1. Pooled risk ratio and 95% CI for ongoing pregnancy rate per randomized woman in the six randomized control trials
derived from a random effects model. OCP = oral contraceptive pill; M-H = Mantel-Haenszel.

Georg Griesinger, Christos A. Venetis, Basil Tarlatzis, Efstratios Michaelis Kolibianakis

To pill or not to pill in GnRH-antagonist cycles: the answer is in the data already!
Reproductive BioMedicine Online, Volume 31, Issue 1, 2015, 6–8
http://dx.doi.org/10.1016/j.rbmo.2015.04.001
Side effects
• Weight gain
• Increased insulin resistance
• Increased blood sugar
• VTE
• CVD
 23

Adverse Effects of the Common Treatments for

Polycystic Ovary Syndrome: A Systematic
Review and Meta-Analysis
Juan Pablo Domecq, Gabriela Prutsky, Rebecca
J. Mullan, Vishnu Sundaresh, Amy T. Wang,
Patricia J. Erwin, Corrine Welt, David Ehrmann,
Victor M. Montori, and Mohammad Hassan
Murad
JCEM 2013
© 2015 Southend Fertility & IVF
 24

• Included 22 eligible studies, of which 20

were randomised thus including 1335
patients.
• No study of women with PCOS reported
severe side effects (eg, lactic acidosis,
thromboembolic episodes, liver toxicity,
cancer incidence, or pregnancy loss).
Meta-analysis demonstrated no
significant change in weight in OCP or
flutamide users

© 2015 Southend Fertility & IVF

 25

• Indirect evidence from populations

without PCOS demonstrated no increased
risk of lactic acidosis with Mt,
• only case reports of liver toxicity with
flutamide (no comparative evidence), and
• increased relative risk of VTE with OCP
but very low absolute risk.
• Evidence on mortality, cardiovascular
mortality, and cancer was inconclusive.
• The quality of evidence supporting the
safety of Mt is high considering that
women with PCOS would likely use it after
the standard contraindications.

© 2015 Southend Fertility & IVF

 Comparison of metformin versus oral contraceptive pill with outcome of severe adverse
events (requiring stopping of medication).

Michael F. Costello et al. Hum. Reprod. 2007;22:1200-1209

© The Author 2007. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
[email protected]
 27

Conclusions
• The quality of evidence for the safety of
AA and OCPs is likely lower and
• prescribers should consider other risk
factors such as age and smoking
status, along with patient preferences,
and other considerations.
• In general, all the available treatments
had a low occurrence of side effects
and seemed to be well tolerated.

© 2015 Southend Fertility & IVF

 The guidelines from Endocrine society further
recommend screening contraindications to COC use via
established criteria set by ‘Centers for disease control
and prevention (CDC)- US medical eligibility criteria for
contraceptive use
Legro SR, Arslanian AS, Ehrmann AD, Hoeger KM, et al; Endocrine society. Diagnosis and
Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline.
J. Clin.Endocrinol. Metab. 2013.

Malik S, Jain K, Talwar P, Prasad S, Dhorepatil B, Devi G, et al Management of Polycystic Ovary Syndrome in
India.
Fertil Sci Res 2014.

© 2015 Southend Fertility & IVF 28

 29

Existing guidelines PCOS

 Low-dose COCs as primary treatment option for
improved MI and other menstrual disorders in
women with PCOS. The clinical practice
guidelines from
 Endocrine society,
 ACOG
 RCOG and
 PCOS Australia alliance,
 Recommend use of hormonal contraceptives as
first-line therapy for menstrual abnormalities of
PCOS.

© 2015 Southend Fertility & IVF

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Indian guidelines: Recommendations

• In adults with PCOS showing menstrual irregularity, it is
recommended to include progesterone withdrawal bleeds as first-
line therapy till menopause to avoid the risk of endometrial
proliferative disorders (Grade A, EL 4)
• In adults with PCOS who do not intend to conceive, it is
recommended to use COCs (drospirenone and desogestrel as
progestin component) for the management of menstrual irregularity
(Grade A, EL 1). Drospirenone has been shown to be more
beneficial than desogestrel in Indian conditions.
• In women with PCOS, metformin is not recommended as first-line
therapy for the management of menstrual irregularity (Grade A, EL4)
• In women with PCOS, spironolactone is not recommended for
menstrual irregularity (Grade B, EL 4)

© 2015 Southend Fertility & IVF

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Recommendations
• In adults and adolescents with PCOS, if there is no improvement of
menstrual irregularity with COCs or COCs are not tolerated, it is
recommended to use insulin sensitizers such as metformin (with or
without progestins), but not thiazolidinediones for the management
of menstrual irregularity (Grade A, EL 2). Adolescents
• In adolescents with PCOS, it is suggested to use low- dose COCs
(with or without anti-androgenic progestins- drospirenone and
desogestrel) for the management of MI (Grade A, EL 4).
• Between 12-16 years of age, low-dose COCs only to be used,
• In adults and adolescents with PCOS with menstrual irregularity
and hirsutism, low-dose COCs are suggested (Grade A, EL 2).

© 2015 Southend Fertility & IVF

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Existing guidelines PCOS

 The clinical practice guidelines from
Endocrine society, recommend use of
hormonal contraceptives as first-line therapy
for management of clinical features of
hyperandrogenism such as hirsutism/acne in
women with PCOS.
 The consensus guideline from IAA
recommends the use of hormone therapy
with low-dose EE/CPA or higher doses of
CPA or spironolactone.

© 2015 Southend Fertility & IVF

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Recommendations for management of

Hyperandrogenism in PCOS(Indian)

• In adult women with PCOS who do not intend to

conceive, it is recommended to use low-dose
COCs with anti-androgen progestin (cyproterone
acetate, drospirenone, or desogestrel) for the
management of hirsutism (Grade A, EL 1).
• Cyproterone acetate has been shown to be more
beneficial than other progestins in Indian
conditions.
•MalikUse of direct hair removal methods are
S, Jain K, Talwar P, Prasad S, Dhorepatil B, Devi G, et al Management of Polycystic Ovary Syndrome in India.
recommended along with COCs as fist-line Fertil Sci Res 2014.

therapy (Grade A, EL 1).

© 2015 Southend Fertility & IVF
 34

Recommendations for management of

Hyperandrogenism in PCOS
• If there is no improvement with COCs or COCs are not tolerated, it
is recommended to use spironolactone or finasteride (Grade A, EL
2); spironolactone or finasteride are suggested but recommended to
stop 6 months before planned pregnancy.
• • In women with PCOS, if menstrual irregularity and hirsutism are
diagnosed, low-dose COCs with anti-androgenic activity (CPA,
drospirenone, desogestrel) are suggested (Grade A, EL 2)

• The ideal time to stop hormonal therapy for hyperandrogenism

cannot be established with existing evidence (Grade A, EL 4).
• • In adolescents/children with hyperandrogenism, obesity and signs
of insulin resistance, lifestyle modification is first-line

Malik S, Jain K, Talwar P, Prasad S, Dhorepatil B, Devi G, et al Management of Polycystic Ovary Syndrome in India.
Fertil Sci Res 2014.
• In adolescents with hyperandrogenism, if glucose intolerance is not 35

established by OGTT, metformin should not be started (Grade B, EL 4).

• Due to insufficient evidence, alternative (acupuncture) and complementary
therapeutic options (e.g. myoinositol, omega-3 fatty acids) are not
recommended for the management of hyperandrogenism (Grade B, EL 4).
Acne
• In adults with PCOS, it is suggested to use oral contraceptives (cyproterone
acetate, drospirenone, or desogestrel as progestin component) as first-line
therapy for management of all types of acne lesions (Grade A, EL 1).
Cyproterone acetate has been shown to be more beneficial than other
progestins in Indian conditions.
• In adolescents with PCOS and acne, it is suggested to use oral
contraceptives (cyproterone acetate, drospirenone, or desogestrel as
progestin component) based on the clinical presentation of acne, in
consultation with dermatologist (Grade A, EL

© 2015 Southend Fertility & IVF

 36

To conclude,
• Estrogen–progestin combination therapy (with the
use of a combination OCP) remains the
predominant treatment for MI,hirsutism and acne
in PCOS.
• These agents clearly improve hirsutism and acne
and protect against unopposed estrogenic
stimulation of the endometrium, but their potential
adverse effects on insulin resistance, glucose
tolerance, vascular reactivity, and coagulability are
a concern, particularly now that insulin-lowering
agents are available.
Malik S, Jain K, Talwar P, Prasad S, Dhorepatil B, Devi G, et al Management of Polycystic Ovary Syndrome in India.
Fertil Sci Res 2014.

© 2015 Southend Fertility & IVF

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Thank you

© 2015 Southend Fertility & IVF

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© 2015 Southend Fertility & IVF