OCP in PCOS · Monophasic levonorgestrel Monophasic norethindrone, triphasic levonorgestrel Triphasic gestodene, biphasic desogestrel, monophasic desogestrel Monophasic cyproterone

OCP in PCOS

Dr. Sonia MalikProgramme 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

Copyright ©2003 The Endocrine Society

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

PCO

Hyperandrogenism

Chronic Anovulation

HPCO

PCO-CA

HCA-PCO

HCA

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

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Wikipedia

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


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Estrogen Progestin (mg) Commercial Names

Monophasic EE 35 Norethindrone 1Norethindrone 0.5Ethynodiol 1Noregastimate .25Cryproterone 2

Orthonovum 1/35Ovcon 35Demulen 1/35Orthocyclean.25Gynofen, Diane 35

EE 30 Norethindrone 1.5Noregestrel 0.15Desogetrel .15Levonorgestrel .1Gestodene .75 Drosperinone 3Norethindrone 1Levonorgestrel .1Desogetrel 1.5Gestodene .75Drosperinone 3

EE 20

Loestrin 21 1.5/30Lo-OvralDesogen, MarvelonNevlen, NordetteGynera, MinuletYasminLoestrin 21 1/20Alesse, LevliteMircette, MercilonMerilane, HormonatteYaz

EE 15 Gestodene 0.6 Melodia

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


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Estrogen Progestin (mg) Commercial Names

Biphasic EE 30/40 Desogetrel .025-0.125Levonorgestrel .125-.75EE 30/40/30Triphasic

EE 35

EE 25

Noregastimate .18-.25

Noregastimate .18-.25

EE 30/40/30 Gestodene .05-0.1

GracialTrilevlen, Triphasil

OrthocycleanOrthocyclean LOTrigynera, Tri-Minulet

S.Nader, and E.Diamanti-Kandarakis

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

Actions of Combined Oral Contraceptives

Estrogen Components (ethinyl-estradiol) Suppression of Follicle- Stimulating Hormone Stabilization of endometriumPotentiation of progestin actionSuppression of dominant follicle formationIncrease in sex hormones binding globulinDecrease in free androgen

Progestin Component (Variable component to preparation)Suppression of luteinizing hormoneInhibition of luteinizing hormone surge Unreceptive endometriumHostile Cervical mucusdecrease in ovarian androgen secretionpossibly androgen-blocking effects



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 todihydrotestosterone and

Binding of dihydrotestosterone to androgen receptors

Oligoanovulation

Copyright ©2003 The Endocrine Society

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

PCO

Hyperandrogenism

Chronic Anovulation

HPCO

PCO-CA

HCA-PCO

HCA

Hyperandrogenism

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 levonorgestrelMonophasic norethindrone, triphasic levonorgestrelTriphasic gestodene, biphasic desogestrel, monophasic desogestrelMonophasic cyproterone acetate

Androgencity according to relative binding affinities to androgen receptors in rats from most to least andogenic-LevonorgestrelGestodeneDesogestrelNorgestimate

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

LevonogestrelGestodeneDesogetrelNorgestimate

Progestins with anti-andogenic effectsDrospirenone (+)Cyproterone acetate (++)

Efficacy of OCP’S

Comparison of efficacy and safety of metformin, oral contraceptive combination of ethinylestradiol and drospirenone alone or in combination in polycystic ovarian syndrome

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

• 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.


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

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 fasting glucose.

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

Comparison of metformin versus oral contraceptive pill with outcome of improved menstrual

pattern.




[email protected]

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

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

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.


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• 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.

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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.

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

OCP & Antagonist protocol

Side effects

• Weight gain

• Increased insulin resistance

• Increased blood sugar

• VTE

• CVD


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Adverse Effects of the Common Treatments for Polycystic Ovary Syndrome: A Systematic Review and Meta-AnalysisJuan 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 MuradJCEM 2013

• 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


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• 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.


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Comparison of metformin versus oral contraceptive pill with outcome of severe adverse

events (requiring stopping of medication).




[email protected]

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.


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© 2015 Southend Fertility & IVF 28

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.

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.


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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)


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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).


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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.


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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 (cyproteroneacetate, 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.

• Use of direct hair removal methods are recommended along with COCs as fist-line therapy (Grade A, EL 1).


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


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

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• In adolescents with hyperandrogenism, if glucose intolerance is not

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


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• 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.


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To conclude,



Thank you


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Documents

OCP in PCOS · Monophasic levonorgestrel Monophasic norethindrone, triphasic levonorgestrel Triphasic gestodene, biphasic desogestrel, monophasic desogestrel Monophasic cyproterone