Add-on clomiphene citrate benefits women with anovulation, PCOS

Adding clomiphene citrate (CC) to letrozole improves ovulation as opposed to letrozole alone in women with polycystic ovarian syndrome (PCOS) or anovulatory infertility, findings from a study suggest.

Ovulation rate with the combination regimen was 84 percent whereas with letrozole alone, the corresponding rate was 71.4 percent. A comparison between arms yielded a rate ratio (RR) of 1.81 (95 percent confidence interval [CI], 1.11–2.96).

The difference persisted among women with a BMI >30 (80.1 percent vs 68.9 percent; RR, 1.82; 95 percent CI, 1.05–3.14; p=0.03). [ESHRE 2025, abstract O-126]

Compared with letrozole alone, the letrozole-CC combination led to a numerically higher live birth rate (33 percent vs 25.5 percent; RR, 1.28; 95 percent CI, 0.75–2.17). However, the study was not powered to detect a difference in this outcome, noted Dr Rachel Mejia from the University of Iowa Carver College of Medicine, Iowa City, Iowa, US, who presented the findings at ESHRE 2025.

The combo and monotherapy arms had similar clinical pregnancy rates (34 percent vs 27 percent; p=0.359). There were two twin pregnancies in each arm.

Despite the trend towards a higher miscarriage rate with the combination regimen (RR, 1.70, 95 percent CI, 0.47–6.17), Mejia noted that this is still below the rate observed in the general population.

The side effect profiles in both arms were similar, with most participants reporting none or acceptable side effects. Headaches and hot flashes were the most common side effects.

An acceptable treatment alternative

“PCOS is the most common endocrine disorder in reproductive-age women and the most common cause of anovulatory infertility. The treatment of infertility in women with PCOS focuses on ovulation induction,” said Mejia.

“Multiple treatment regimens have been used with varying success. However, the question remains if there are other medical alternatives without proceeding to gonadotropins or in vitro fertilization, as both are associated with increased costs and risks,” she continued.

In their pilot study, ovulatory rates improved with the letrozole-CC combination over one treatment cycle. [Fertil Steril 2019;111:571-578.e1] “Based on the results of this trial, we wanted to look at a larger cohort that would reflect clinical practice, where we escalate doses up to three cycles, ultimately to get more outcome data on the significance,” said Mejia.

“We hypothesized that combined therapy with letrozole and CC is more effective than letrozole monotherapy in achieving ovulation in multiple cycles,” she continued.

The study included 190 women aged 18–40 years with a diagnosis of both infertility and PCOS. They were randomized 1:1 to letrozole 2.5 mg alone or with CC 50 mg daily on cycle days 3–7. Letrozole dose was increased if indicated in subsequent cycles in both arms based on ovulatory response and ultrasound findings. Dose was increased immediately if anovulatory and there was no follicular development. Participants could complete up to three treatment cycles.

“In conclusion, a majority of women achieved ovulation over three cycles in both arms with no significant difference in the percentage of women who ovulated. However, per treatment cycle, the combination was associated with more ovulatory cycles than letrozole alone,” said Mejia.

“The combination of letrozole and CC is an acceptable alternative with higher per cycle ovulation rate vs letrozole alone, particularly in women with a BMI >30. It was well tolerated and safe. This could be another treatment option for anovulatory women,” she concluded.