Clomiphene for anovulatory infertility

Clinical question

How effective is clomiphene for inducing pregnancy in women with polycystic ovary syndrome (PCOS) presenting as oligomenorrhea or anovulation?

Bottom line

Three small studies show clomiphene induces pregnancy in woman with PCOS. For every 6 women treated, 1 more will become pregnant. Recent larger studies comparing newer agents to clomiphene suggest complications are rare. Clomiphene might be more beneficial in those with body mass index (BMI) ≥ 30 kg/m².

Evidence

• Systematic review of RCTs of antiestrogens in PCOS¹:

  • -In 3 RCTs (N = 133) that examined clomiphene (50 to 250 mg/d, 1 to 5 cycles) versus placebo, the pregnancy rate was higher with clomiphene (20% vs 3%); the number needed to treat (NNT) was 6. Live births and miscarriages were not reported.
  • -Limitations: small sample, variable dosing and number of cycles, high dropout rate, poor adverse event reporting.
• Systematic review of insulin-sensitizing drugs in PCOS²:

  • -In a subgroup analysis of clomiphene versus metformin, for those with BMI ≥ 30 kg/m² (2 RCTs, N = 500), clomiphene was superior to metformin for pregnancy (NNT = 7) and live birth (NNT = 5) rates; for those with BMI < 30 kg/m² (3 RCTs, N = 349), metformin was superior to clomiphene for pregnancy (NNT = 8); the effect on live births was unclear.
  • -There was substantial heterogeneity in trials’ reporting of pregnancy and live births.
  • -Adding metformin to clomiphene improved pregnancy rates (NNT = 13; 11 RCTs) with no effect on birth rates.

Context

• Most guidelines recommend clomiphene as first-line therapy in PCOS.^3–5

• A systematic review of aromatase inhibitors in PCOS (26 RCTs, N = 5560) found letrozole improved live births over clomiphene (29% vs 18%, NNT = 10). Questions about selective reporting and publication bias limit application.^4,6 Letrozole is not approved for infertility in Canada.

• A systematic review of 7 RCTs demonstrated no benefit of clomiphene in unexplained infertility.⁷

• One systematic review reported ovarian hyperstimulation syndrome occurred in 2 of 1095 patients treated with clomiphene with or without adjunct therapy.²

• An RCT of 626 women reported 6% multiple pregnancies with clomiphene, 0% with metformin, and 3% with both.⁸

• Metformin alone² improves pregnancy rates compared with placebo (NNT = 9).

Implementation

Clomiphene is inexpensive, well-tolerated, safe, and effective. Contraindications include liver disease or dysfunction, endometrial carcinoma, ovarian cysts (not PCOS), undiagnosed uterine bleeding, and pregnancy.^9,10 Treatment should be initiated at 50 mg daily on cycle days 2 to 5 (follicular phase) and continued for 5 consecutive days with increases of 50 mg in subsequent cycles if anovulation persists. The Society of Obstetricians and Gynaecologists of Canada³ and the Food and Drug Administration¹⁰ advise 100 mg or less, but up to 250 mg is used in some specialty practices.¹¹ Ovulation can be confirmed with a luteal serum progesterone level > 25 nmol/L. In women who ovulate, 52% do so taking 50 mg, 22% taking 100 mg, and fewer with subsequent increases.¹¹ Anovulatory women should be treated for 6 cycles before considering alternate methods of ovulation induction.¹²

Tools for Practice

Tools for Practice articles in Canadian Family Physician (CFP) are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in CFP are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice@cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.