Clomiphene citrate for unexplained subfertility in women

Cochrane Database Syst Rev. 2000;(3):CD000057. doi: 10.1002/14651858.CD000057.


Background: The effectiveness of clomiphene citrate has been clearly demonstrated in the treatment of sub-fertility associated with oligo-ovulation. The multiple pregnancy rate associated with clomiphene, however, is elevated at approximately 10%. Additional side effects associated with clomiphene use also include hot flashes, mood swings, headaches and visual disturbances. A variety of publications have raised the question of increased ovarian cancer risks associated with clomiphene use. Understanding the effectiveness of clomiphene in this patient group is therefore, extremely important.

Objectives: To determine the effectiveness of clomiphene citrate given to women with unexplained subfertility, in a dose range of 50-250 mg for up to 10 days. The primary outcome was clinical pregnancy.

Search strategy: RCTs were identified using the search strategies developed for the menstrual disorders and subfertility group. See review group for more information.

Selection criteria: Randomized controlled trials were included if they were relevant to the clinical question posed and reported data in treated and untreated groups. Cohort studies were excluded.

Data collection and analysis: Eleven potentially relevant trials were identified, of which six were included in this review. All trials were assessed for quality in terms of method of randomization, completeness of follow up, presence or absence of cross-over and co-intervention.

Main results: Clomiphene appeared to be superior to no treatment or placebo. The common odds ratios for clinical pregnancy per patient and per treatment cycle were 2.37 (1.22-4.62) and 2.5 (1.35-4.62) respectively. Although there was some clinical heterogeneity between studies, the results were statistically homogeneous (p>0.1). These data suggest statistically and clinically significant improvement in pregnancy rate following clomiphene citrate in women with unexplained infertility.

Reviewer's conclusions: Although the absolute treatment effect is small, given the low cost and ease of administration, clomiphene citrate appears to be a sensible first choice treatment for women with unexplained infertility. However, in making this treatment choice, concerns of long-term use and ovarian cancer risk, multiple pregnancy risk and minor symptoms should be discussed. Given the extensive use of clomiphene in ovulatory women and recent concerns associated with long term use, a definitive trial with adequate power is warranted to establish effectiveness in women with unexplained subfertility.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Clomiphene / therapeutic use*
  • Female
  • Fertility Agents, Female / therapeutic use*
  • Humans
  • Infertility, Female / drug therapy*
  • Randomized Controlled Trials as Topic


  • Fertility Agents, Female
  • Clomiphene