Higher Live Births and Ovulation Rates with Letrozole than Clomiphene Citrate in Women with PCOS

30 Nov, 17

Introduction

Polycystic ovarian syndrome (PCOS) is the most common cause of anovulatory infertility, affecting 5 to 10% of the women in reproductive age. Clomiphene citrate (CC) has been traditionally used for ovulation induction in women with PCOS since decades. However it has been associated with a number of drawbacks such as low live birth rate, high multiple pregnancy rate, higher incidence of side effects and a significant proportion of patients with low or no response to CC. There are studies which have found aromatase inhibitors superior to CC as they induce physiologic hormonal stimulation of endometrium, have a better safety profile with lower multiple pregnancy rate. However, letrozole has the potential to cause fetal teratogenicity.

Aim

To compare the efficacy and safety profiles of letrozole with CC in PCOS women.

Method

Study Design

Double-blind, multicenter, randomized trial
750 PCOS women aged between 18 to 40 years were included
PCOS was diagnosed on the basis of modified Rotterdam criteria
Women had ovulatory dysfunction with hyperandrogenism (presence of hirsutism or elevated testosterone level), polycystic ovaries (≥12 follicles <10 mm in diameter) or increased individual ovarian volume (>10 cm³) in ≥1 ovary, or both.
Women had at least one patent fallopian tube and a normal uterine cavity, normal male partner with sperm concentration of at least 14 million/ml and documented motility as per WHO guidelines in atleast 1 ejaculate in the previous year
Women were randomized into letrozole and CC groups in 1:1
Letrozole 2.5 mg daily or CC 50 mg daily was started on day 3 on the menstrual cycle for 5 days upto 5 cycles
The dose was increased in the subsequent cycles in case of poor or no ovulatory response
Maximum daily dose given was letrozole 7.5 mg and CC 150 mg for 5 days
The couples were instructed intercourse 2 to 3 times a week

Primary End Points

Live birth rate

Secondary End Points

Ovulation
Pregnancy loss
Singleton birth
Congenital anomalies

Results

Women in the letrozole group had higher cumulative live birth rates of 27.5% as compared to 19.1% in the CC group (p=0.007) as seen in figure 1.

Figure 1. Cumulative live birth rates

The rates of pregnancy loss were similar in both the groups (31.8% in letrozole group vs 29.1% in CC group; p=0.65)
The letrozole group had a significantly higher cumulative ovulation rate (p<0.001) as shown in figure 2.

Figure 2. Cumulative ovulation rates

Among women who ovulated, letrozole was associated with significantly greater chance of singleton pregnancy (p=0.03)
There were no significant differences in the number of congenital anomalies in both the groups. However letrozole group had 4 major congenital anomalies vs 1 in CC group (p=0.65)
The incidence of hot flushes was higher in the CC group whereas the incidences of fatigue and dizziness was more in the letrozole group as shown in figure 3.

Figure 3. Incidence of adverse events

There were no significant differences in the rates of other adverse events between the groups

Conclusion

The efficacy of letrozole was greater than clomiphene citrate in anovulatory infertility in women with PCOS. Letrozole was associated with higher live births and ovulation rates as compared to CC.

N Engl J Med. 2014 July 10; 371(2):119-129. Doi: 10.1056/NEJMoa1313517.