Achieving a Successful Pregnancy with PCOS 3 rd Annual Friedman Fellows Symposium November 13 th 2010 Achieving a Successful Pregnancy with PCOS 3 rd Annual Friedman Fellows Symposium November 13 th 2010 Takako Araki MD 1, Rony Abdallah MD 2, Zev Rosenwaks MD 2, Leonid Poretsky MD 1 1 Division of Endocrinology and Metabolism, Beth Israel Medical Center, New York 2 The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York

Polycystic Ovary Syndrome (PCOS) PCOS is characterized by anovulation, hyperandrogenism, and polycystic ovarian morphology. PCOS was initially described by Stein Leventhal in Prevalence : 7-8% of reproductive age women PCOS is the most common cause of infertility in reproductive age women

Clinical Manifestations of PCOS Peripubertal onset Cutaneous : – Hirsutism, Acne, Male pattern baldness Reproductive : – Amenorrhea/Oligomenorrhea, Infertility, Early pregnancy loss Metabolic : – Obesity, Insulin resistance, type2 diabetes (10% by age 40s), and cardiovascular disease

Biochemical Manifestations of PCOS Elevated total/free testosterone, androstenedione, progesterone, dehydroepiandrosterone sulfate (DHEAS), Decreased sex hormone binding globulin (SHBG) Increased insulin levels Elevated LH/FSH ratio.

Diagnostic Criteria NIH Criteria 1990 Rotterdam Criteria 2003 Androgen Excess and PCOS Society Criteria 2006  None of the criteria addressed insulin resistance and metabolic manifestations

NIH (1990) Anovulation or oligo-ovulation Clinical and/or biochemical hyperandrogenism Rotterdam (2003) (Two out of three) Anovulation or oligo-ovulation Clinical and/or biochemical hyperandrogenism Polycystic ovaries (morphology) Androgen Excess and PCOS Society (2006) Ovarian dysfunction (either) Anovulation or oligo-ovulation Polycystic ovaries (morphology) Clinical and/or boichemical hyperandrogenism

Etiology/Hypotheses of PCOS Central Hypothesis (1,2) : abnormal GnRH pulse can ↑LH pulse amplitude and frequency, and change ratio of LH/FSH Ovarian Hypothesis (3,4) : Intrinsic ovarian functional defects of theca cells(P 450c 17) and granulosa cells (aromatase) Adrenal Hypothesis (5,6,7) : Increased androgen production during puberty can decrease FSH production → stimulate ovarian hyperandrogenism Dual-defect (8) : Two independent defects; elevated LH and hyperinsulinemia can cause synergetic action in the ovary Programming (9,10) : Intrauterine hyperinsulinemia and hyperandrogenemia can program female reproduction and possibly produce a phenocopy of PCOS Genetic (11,12,13) : PCOS has strong familial clustering

Insulin related ovarian regulatory system Poretsky, L., et al., Endocr Rev, (4): p

Synergistic effect of Insulin and LH/hCG on ovarian growth Poretsky, L., et al., Endocr Rev, (4): p

Treatment of infertility in PCOS Lifestyle Modification Medical Therapy – Clomiphene citrate – Gonadotropin/GnRH – Metformin – Thiazolidinediones – Glucagon-like peptide-1 agonists IVF/IVM

Lifestyle Modification Weight loss (5-10% over 6 months) is effective in re-establishing ovarian function in >50% of obese PCOS women. StudyWeight lossOutcomes kg12 out of 13 + ovulations 11 out of 13 + pregnant Hollman kg80% ovulation rate 29% pregnancy androstenedione, insulin testosterone, estradiol Huber-Buckholz kg (2-5% loss)9 out of 15 + ovulations 2 out of 15 + pregnant Hoeger % loss30% increased ovulation rate Decreased hirsutism score

Clomiphene Citrate Clomiphene is a partially selective estrogen receptor modulator. Induces a change in GnRH pulse frequency, increases FSH level, promotes follicular development Used for ovulation since 1960s High ovulation rate (60-85%), 30-40% pregnancy rate

Clomiphene Citrate 4-10% risk of ovarian hyperstimulation syndrome (OHSS) There is a discrepancy between ovulation rate and pregnancy rate. Obese PCOS women tend to have clomiphene resistance. Clomiphene is the current first-line therapy (Thessaloniki ESHRE/ASRM consensus 2008).

Gonadotropin/GnRH Human recombinant FSH is the often used preparation High ovulation rate (70%) and pregnancy rate (30%) Risk of multiple pregnancies (25-30%) and OHSS Step-up low dose FSH induction protocol has been safer for monofollicular development; decreased risk of OHSS with same ovulation rate and pregnancy rate compared to high initial dose FSH protocol.

Gonadotropin/GnRH Current recommendation – start from low dose of FSH ( IU daily) with step-up regimen (Thessaloniki ESHRE/ASRM 2008). Gonadotropin therapy is high cost, needs frequent monitoring of estradiol levels and sonographic follow up.

Metformin Insulin sensitizers target metabolic abnormalities to improve ovulation and fertility in PCOS women. Metformin is a category B drug for pregnancy Metformin enhances AMPK pathway, increases IGFBP-1 level; no evidence of anti-inflammatory effects. Initial study was done by Velazquez in 1994, which showed increased pregnancy rate. Numerous studies have been conducted with inconclusive data of metformin as the first therapy until mid 2000s.

Metformin vs. Clomiphene Metformin or Clomiphene, inconclusive which would be the first-line therapy Total Ndurationovulation Rate pregnancy rate live birth Palomba Lean PCOS 6 monthsM = CM > C Neveu All PCOS 9 monthsM > CM = C Legro All PCOS 6 monthsM = CM << C Zain Obese PCOS 6 monthsM = C M < C Baran Obese PCOS 3 monthsM < CM = C M : metformin, C : clomiphene

Live Birth Prediction Basic clinical information can predict live birth rate with either metformin, clomiphene, or combination (14) Rausch, M.E., et al. J Clin Endocrinol Metab, (9): p

Thiazolidinediones (TZDs) TZDs are PPAR-γ ligands used as insulin sensitizers In human ovary, TZDs directly inhibit ovarian androgen production by regulating ovarian steroidogenic enzymes TZDs also stimulate StAR protein, 3β HSD, and inhibit aromatase

Thiazolidinediones (TZDs) (cont’) Several studies showed that troglitazone improved insulin resistance and ovulation, however it was removed from the market because of hepatotoxicity Rosiglitazone/Pioglitazone improve ovulation, however there is concern about cardiovascular risk TZDs do not cause weight loss TZDs are pregnancy category C drugs

Glucagon-like peptide-1 (GLP-1) agonists GLP-1 is an incretin hormone derived from GI tract GLP-1 enhances glucose-dependent insulin secretion, delays gastric emptying GLP-1 controls central appetite stimulation, therefore induces weight loss A pilot study showed that GLP-1 improved ovulation (50%), produced moderate weight loss, and decreased testosterone levels (15) GLP-1 agonists may have a role to play in the treatment of PCOS

In-vitro fertilization (IVF) Indication: Failure of non-pharmacologic and clomiphene citrate treatment+ failure of Gonadotropin/IUI High success rate of pregnancies, however, women with PCOS tend to be hypersensitive to gonadotropin therapy, therefore have an increased rates of multiple pregnancies and OHSS. The clinical pregnancy and implantation rates in PCOS women are 30-35% and 10-15%, respectively.

In-vitro fertilization (IVF) Numerous IVF/induction protocols have been attempted to decrease OHSS. Damario et al presented data of dual pituitary suppression therapy to normalize LH/FSH ratio with significant decrease of OHSS (16).

In-vitro maturation (IVM) Since multifollicular development is the goal of ovarian stimulation for IVF, PCOS patients often present therapeutic challenge. With in vitro maturation (IVM), immature follicules are collected, then matured in the laboratory before being fertilized. Compared to IVF, IVM requires less ovarian stimulation, therefore decreases risks of OHSS.

Risks of PCOS Early pregnancy loss Gestational diabetes Pregnancy-induced hypertension and preeclampsia Birth weight (low or high) Risk of PCOS for female offspring Risk of metabolic disorders for offspring Metabolic/cardiac complications for male offspring

Early pregnancy loss (EPL) 3 times higher risk in PCOS (30-50% in PCOS vs % in control) Obesity and hyperinsulinemia are independent risk factors of EPL Mechanism is unclear: possibly, ↓glycodelin, ↓IGFBP-1, ↑plasminogen activator inhibitor- 1 maybe associated risks A few studies showed that metformin decreases the risk of early pregnancy loss (17)

Gestational diabetes (GDM) Higher risk in PCOS women – 40% in PCOS vs. 4% in control Insulin resistance created by changes in diabetogenic hormones during pregnancy (hPL, estrogen, progesterone) as well as baseline insulin resistance - a feature of PCOS Risk of GDM is independent of obesity Metformin appears to reduce the occurrence of GMD (18)

Pregnancy-induced hypertension and preeclampsia (PIHDs) Likely the risk factor of PIHDs – 14% in PCOS vs % in control Underlying hyperinsulinemia appears to be an independent risk factor for PIHDs (19) A recent pilot study demonstrated that continuous use of metformin may reduce risk of PIHDs

Birth weight Birth weight of offspring of PCOS women has been controversial Low birth weight has been associated with the development of type 2 diabetes and cardiovascular disease Numerous studies support the finding that offspring of women with PCOS tend to have low gestational weight However, a recent meta-analysis and a large family study showed there is no difference in birth weight effect between the offspring from PCOS and controls

Risk of PCOS for female offspring Female offspring of PCOS women may have a higher risk of developing PCOS Prenatally androgenized female monkeys exhibit % fewer menstrual cycles than normal females, and 40% have polyfollicular ovaries that resemble the morphology of PCO (20). In a human cross-sectional study, PCOS daughters exhibited ↑LH and ↑testosterone, hyperinsulinemia, and ↑ovarian size during puberty (21).

Risk of metabolic disorders for offspring Offspring of PCOS mothers tend to have metabolic abnormalities in their later life. Prenatally androgenized female monkeys develop metabolic problems characteristic of women with PCOS (↓insulin sensitivity, ↓beta cell function, ↑total body adiposity) Offspring of the early-treated female monkeys exhibited impaired insulin secretion while those of the late-treated females showed ↓insulin sensitivity and ↑adiposity, but preserved insulin secretory function.

Metabolic/cardiac complications for male offspring Male offspring from PCOS women have phenotypes which include ↑hair growth, premature male balding. There is strong evidence that male offspring appear to have high risk of metabolic derangements, including type 2 diabetes, dyslipidemia, and risk of cardiovascular disease.

Metabolic/cardiac complications for male offspring (Cont’) Adult male rhesus monkeys exposed to testosterone in-utero exhibit insulin resistance and impaired insulin secretion (22). A recent study of male offspring of PCOS women found that, compared to control, there was an increase in body wt beginning in early infancy (2-3 months), which persisted into adulthood; insulin resistance developed during adulthood (23).

Genetics/genetic counseling in the future PCOS has strong familial clustering, therefore a genetic etiology is suspected. Lack of reliable associations between genotype and phenotype raises the possibility that inheritance of PCOS, if any, is modified by environmental factors.

Genetics/genetic counseling in the future The strongest evidence of an association of a single gene with PCOS is for nucleotide repeat microsatellite marker D19S884 within intron 33 of the fibrillin-3 gene, however, it is not clear whether on how Fibrillin-3 contributes to the pathogenesis of PCOS (23). Like in other complex diseases, including diabetes, genetic research in PCOS remains challenging and confounded by extreme heterogeneity of PCOS.

Conclusions PCOS is a disease of multiple etiologies and variable phenotypes. Infertility may be present. A variety of methods has been used successfully to achieve pregnancy in women with PCOS. Maintenance of pregnancy is complicated by higher rate of premature spontaneous abortions, risk of gestational diabetes and preeclampsia. With careful treatment and monitoring, today the majority of PCOS women can have successful outcome of their pregnancy.

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