Polycystic ovary syndrome, insulin-sensitizing drugs and infertility

1
Polycystic ovary syndrome, insulin-sensitizing
drugs and infertility
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Introduction

• PCOS affects 610 of women of childbearing age
  (3.55.0 million women in the U.S.)
• Usual symptoms are irregular menstrual cycles,
  excessive body hair, obesity and infertility.
• Pathogenesis is due to reduced sensitivity to
  insulin for which the body compensates by
  elevated levels of this hormone. High Insulin
  levels are involved in excessive androgen
  production and ovulation disorders.
• Anovulation is estimated to cause 40 of female
  infertility, with most cases being euestrogenic
  anovulation due to PCOS.
• Women with PCOS have increased risk of developing
  type 2 diabetes, HTN and heart disease

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Introduction

• Given the strong evidence that insulin plays a
  significant role in PCOS, it is reasonable to
  assume that reducing insulin levels may help
  restore normal reproductive function.
• Weight loss.
• Improved nutrition.
• Exercise.
• Insulin sensitizing agents ?

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HyperInsulinemic insulin resistance and PCOS

• Numerous studies have documented that both lean
  and obese women with PCOS are insulin-resistant.
• There is little evidence at this time to suggest
  that surrogate markers for insulin
  resistancesuch as fasting insulin, glucose, or
  glucose-to-insulin ratioare useful predictors of
  the ovulatory response to insulin-sensitizing
  drugs.
• From a practical viewpoint, it is reasonable to
  regard all women with PCOS as being
  insulin-resistant, and it is the authors'
  practice in the clinical setting not to attempt
  to document or quantify insulin resistance.

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HyperInsulinemic insulin resistance and PCOS

• In obese women with PCOS, efforts to induce
  weight loss through diet and exercise may enhance
  ovulation.
• It is reasonable to recommend lifestyle
  modification, including a weight-reducing diet
  and exercise, as first-line therapy for all obese
  women with PCOS.
• The unfortunate reality in the United States is
  that many obese women with PCOS do not lose
  weight, and, when fertility is an issue, do not
  wish to delay conception for even a brief period
  of lifestyle modification.

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Insulin-sensitizing drugs for initial ovulation
induction

• Metformin
• Works by activating glucose transporters which
  allows passage of glucose into hepatic and muscle
  cells. Peripheral insulin resistance ?, serum
  glucose levels ?.
• Most studies of metformin have demonstrated that
  at a dose of 500mg X 3/d it increases menstrual
  cyclicity, improves spontaneous ovulation and
  promotes fertility.
• Moghetti et al (n32, follow up of 26 months)
  demonstrated sustained normalization of menses in
  41.
• Studies that failed to show improvement were
  short or conducted on women with morbid obesity.

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Comparison of ISD with CC

• Usual recommendation is to start treatment with
  CC and to institute ISDs only with failure.
• No head-to-head trial exists.
• Multicenter study - Nestler et al.(NEJM 1998) In
  an unselected group of obese women, addition of
  CC to Metformin demonstrated increase in
  ovulation (34 vs. 8).

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ISD as adjuvants to CC ovulation induction

• Induction of ovulation in women with PCOS
• Nestler et al - NEJM 1998. Met VS Placebo 34 and
  4, with addition of CC - 90 and 8. (n35
  MetCC, n25 CC).
• Metformin increases both spontaneous and CC
  induced ovulation rates.

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ISD as adjuvants to CC ovulation induction

• Failures of induction of ovulation with CC
• Multicenter DBL, PCR trial(Vandermolen Fertil
  Steril 200175)
• Failures of 150mg CC.
• MET or Placebo for 7 wks and then addition of CC
  50mg/d increased by 50mg increments with
  anovulation.
• 75 ovulation with MET (n12)VS. 27 in Placebo
  (n15).
• Conception rates of 58 VS. 13.

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ISD as adjuvants to Gonadotropin ovulation
induction

• One study evaluated CC resistant women with PCOS.
  (De Leo. Fertil Steril 199272)
• Women randomized to receive MET or no treatment 1
  month prior to ovulation induction with FSH.
• Plasma levels of Estradiol and number of
  follicles lt15mm was significantly lower in MET
  treated group
• MET may reduce hyperstimulation with FSH.

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ISD for IVF

• Metformin increases the number of mature oocytes
  retrieved from women with PCOS undergoing IVF-ET.
• 500mgX2 started on day 1 of leuprolide supression
  and continued to the day of pregnancy test.
• ? mature oocytes, ? fertilization rates, ? number
  of embryos produced.

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ISD and early pregnancy loss

• Women with PCOS have higher rates of pregnancy
  loss (30-50)
• Hyperinsulinemia has been implicated as an
  independent risk factor for early pregnancy loss.
• Jakubowicz et al, J Clin Endocrinol Metabol 2002
  87524-9. Retrospective analysis of women with
  PCOS with/without metformin. Early pregnancy loss
  in MET group 8.8 VS 41.9 off MET.
• Prospective controlled studies are lacking.

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B

• Before institution of Metformin check renal and
  hepatic function.
• Usual side effects are gastrointestinal - in
  10-25 and are usually transient.

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Algorithm for the use of Metformin in the
induction of ovulation in women with PCOS
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Summary

• Insulin resistance plays a key role in PCOS.
• Improving Insulin resistance increases ovulation.
• Sufficient scientific data exists to support the
  use of ISD to treat the infertility associated
  with PCOS.
• No FDA Approval for ISD for this indication.

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