A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome

Fertil Steril. 2019 Mar;111(3):571-578.e1. doi: 10.1016/j.fertnstert.2018.11.030. Epub 2019 Jan 22.


Objective: To evaluate whether a combination of letrozole and clomiphene citrate (CC) results in higher ovulation rates than letrozole alone in infertile women with polycystic ovary syndrome (PCOS).

Design: Open-label randomized controlled trial.

Setting: Academic medical center using two clinic sites.

Patient(s): Women 18-40 years of age with a diagnosis of infertility and PCOS as defined by the Rotterdam criteria and no other known cause of infertility.

Interventions(s): Participants were randomized in a 1:1 ratio, stratified by age and body mass index, to either 2.5 mg letrozole alone or the combination of 2.5 mg letrozole and 50 mg CC daily on cycle days 3-7 for one treatment cycle.

Main outcome measure(s): Ovulation defined as mid-luteal serum progesterone concentration ≥3 ng/mL.

Result(s): Seventy patients were randomized: 35 to letrozole alone and 35 to letrozole and CC. Results were analyzed according to the intention-to-treat principle. Women who received the combination of letrozole and CC had a statistically higher ovulation rate compared with those who received letrozole alone (27 of 35 women [77%] vs. 15 of 35 women [43%]). There were no serious adverse events or multiple-gestation pregnancies in either group. The side-effects profile was similar in the two treatment groups.

Conclusion(s): The combination of letrozole and CC was associated with a higher ovulation rate compared with letrozole alone in women with infertility and PCOS. Further studies are needed to evaluate the effect on live birth rate.

Clinical trial registration number: NCT02802865.

Keywords: Letrozole; clomiphene citrate; combined therapy; infertility; ovulation induction; polycystic ovary syndrome.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Biomarkers / blood
  • Body Mass Index
  • Clomiphene / administration & dosage*
  • Clomiphene / adverse effects
  • Female
  • Fertility / drug effects
  • Fertility Agents, Female / administration & dosage*
  • Fertility Agents, Female / adverse effects
  • Humans
  • Infertility, Female / diagnosis
  • Infertility, Female / drug therapy*
  • Infertility, Female / physiopathology
  • Iowa
  • Letrozole / administration & dosage*
  • Letrozole / adverse effects
  • Live Birth
  • Ovulation / drug effects*
  • Ovulation Induction / adverse effects
  • Ovulation Induction / methods*
  • Polycystic Ovary Syndrome / diagnosis
  • Polycystic Ovary Syndrome / drug therapy*
  • Polycystic Ovary Syndrome / physiopathology
  • Pregnancy
  • Pregnancy Rate
  • Progesterone / blood
  • Treatment Outcome
  • Young Adult


  • Biomarkers
  • Fertility Agents, Female
  • Clomiphene
  • Progesterone
  • Letrozole

Associated data

  • ClinicalTrials.gov/NCT02802865