Achieving a Successful Achieving a Successful Pregnancy with PCOSPregnancy with PCOS  33rdrd Annual Friedman Fellows Annual Friedman Fellows

Symposium November 13Symposium November 13thth 2010 2010

  Takako Araki MDTakako Araki MD  11, Rony Abdallah MD, Rony Abdallah MD  22, , 

Zev Rosenwaks MDZev Rosenwaks MD  22, Leonid Poretsky MD, Leonid Poretsky MD  11

1Division of Endocrinology and Metabolism, Beth Israel Medical Center, New York

2The 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 1935.

• 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-ovulationClinical and/or biochemical hyperandrogenism

• Rotterdam (2003) (Two out of three)Anovulation or oligo-ovulationClinical and/or biochemical hyperandrogenismPolycystic 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(P450c17) 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, 1999. 20(4): p. 535-82.

Synergistic effect of Insulin and LH/hCG on ovarian growth

Poretsky, L., et al., Endocr Rev, 1999. 20(4): p. 535-82.

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.

Study Weight loss Outcomes

1995 6.3 kg 12 out of 13 + ovulations11 out of 13 + pregnant

Hollman 1996 5.6 kg 80% ovulation rate29% pregnancyandrostenedione, insulintestosterone, estradiol

Huber-Buckholz 1999 6.3 kg (2-5% loss) 9 out of 15 + ovulations2 out of 15 + pregnant

Hoeger 2004 6.8% loss 30% increased ovulation rateDecreased 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 (37.5-50.0 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 N duration ovulation

Ratepregnancyrate

live birth

Palomba 2005

102Lean PCOS

6 months M = C M > C

Neveu 2007 154All PCOS

9 months M > C M = C

Legro 2007 626All PCOS

6 months M = C M << C

Zain 2009 115Obese PCOS

6 months M = C M = C M < C

Baran 2010 61Obese PCOS

3 months M < C M = C

M : metformin, C : clomiphene

Live Birth PredictionBasic clinical information can predict live birth rate with either

metformin, clomiphene, or combination (14)

Rausch, M.E., et al. J Clin Endocrinol Metab, 2009. 94(9): p. 3458-66.

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. 10-15% 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. 2.5-5% 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 40-

50% 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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