Tools for Practice


#160 Can we count on Clomiphene for Anovulatory Infertility?


CLINICAL QUESTION
How effective is clomiphene for inducing pregnancy in females with polycystic ovarian syndrome (PCOS) presenting as oligomenorrhea or anovulation?

BOTTOM LINE
Three small studies show clomiphene induces pregnancy in females with PCOS. For every six women treated, one more will become pregnant. Recent larger studies comparing newer agents to clomiphene suggest complications are rare. Clomiphene may be more beneficial in those with a BMI ≥30.   


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EVIDENCE
Results presented statistically significant: 
  • Systematic review of Randomized Controlled Trials (RCTs) of anti-oestrogens in PCOS:1  
    • Three RCTs examined clomiphene (50-250 mg/day, 1-5 cycles) versus placebo, 133 patients.   
    • Clomiphene: 
      • Increased pregnancy rate: Clomiphene (20%) versus placebo (3%), Number Needed to Treat (NNT)=6. 
      • Live births and miscarriages: Not reported. 
      • Limitations: Small sample size, variable dosing/cycles, high dropout, poor adverse event reporting.  
  • Systematic review of insulin sensitizing drugs in PCOS (44 RCTs, 3,992 women).2 
    • Clomiphene versus metformin:  
      • Subgroup analysis:  
        • BMI ≥30: Clomiphene superior to metformin for pregnancy NNT=7 and live birth rate NNT=5, (two RCTs, 500 women). 
        • BMI ≤30: Metformin superior to clomiphene for pregnancy NNT=8, (three RCTs, 349 women) live birth unclear. 
      • Significant heterogeneity in trials reporting pregnancy and live births.  
    • Adding metformin to clomiphene: 
      • Improves pregnancy, NNT=13 (11 RCTs).  
      • No effect birth rates.
Context:  
  • Most guidelines recommend clomiphene as first-line therapy in PCOS3,8,9 starting 50mg per day for five days, first dose on day 2-5 of menses. If ovulation is not achieved, dose may be increased to 100mg. Use maximum of six cycles.3,4 
  • Recent systematic review of aromatase inhibitors in PCOS (26 RCTs, 5,560 women) found letrazole improved live birth over clomiphene (29% vs 18%, NNT = 10). Questions about selective reporting and publication bias limit application.7,8  Letrazole is not approved for infertility in Canada. 
  • Systematic review of seven RCTs demonstrated no benefit of clomiphene in unexplained infertility.5 
  • One systematic review reported ovarian hyperstimulation syndrome occurred in 2/1,095 patients treated with clomiphene +/- adjunct therapy.2  
  • RCT of 626 women reported 6% multiple pregnancy with clomiphene, 0% with metformin, and 3% with the combination of the two.6 
  • Metformin alone2 improves pregnancy rate versus placebo, NNT=9. 
April 11, 2016

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Author(s):

  • Christina Korownyk MD CCFP
  • Riley Davidson

1. Brown J, Farquhar C, Beck J, et al. Cochrane Database Syst Rev. 2009 Oct 7; (4):CD002249.

2. Tang T, Lord JM, Norman RJ, et al. Cochrane Database Syst Rev. 2012 May 16; 5:CD003053.

3. SOGC clinical practice guideline. Ovulation induction in polycystic ovarian syndrome. Available at: https://docs.google.com/viewerng/viewer?url=http://sogc.org/wp-content/uploads/2013/01/gui242CPG1005E_000.pdf. Last accessed February 11, 2016.

4. Product Monograph. Available at: http://products.sanofi.ca/en/clomid.pdf. Last accessed February 16, 2016.

5. Hughes E, Brown J, Collins JJ, et al. Cochrane Database Syst Rev. 2010 Jan 20; (1):CD000057.

6. Legro RS, Barnhart HS, Schlaff WD, et al. N Engl J Med. 2007; 356:551-66.

7. Franik S, Kremer JAM, Nelen WLDM, et al. Cochrane Database Syst Rev. 2014 Feb 24; 2:CD010287.

8. NICE fertility evidence update March 2015. Available at: http://www.nice.org.uk/guidance/cg156/evidence/evidence-update-188501869. Last accessed February 9, 2016.

9. Legro RS, Arslanian SA, Ehrmann DA, et al. J Clin Endocrinol Metab. 2013 Dec; 98(12):4565-92.

Authors do not have any conflicts to disclose.