This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome.
The PCOS, which is diagnosed on the basis of hyperandrogenism, oligo-ovulation with associated oligomenorrhea, and polycystic ovaries on ultrasonography, affects 5 to 10% of reproductive-age women and is the most common cause of anovulatory infertility.
• What are the potential drawbacks to the use of clomiphene citrate for ovulation induction?
Clomiphene citrate, a selective estrogen-receptor modulator that antagonizes the negative feedback of estrogen at the hypothalamus with a consequent increase in ovarian stimulation by endogenous gonadotropin, has been used for this indication for decades. Clomiphene has drawbacks, including its overall poor efficacy (only a 22% rate of live birth with up to six cycles of clomiphene in our previous study), a relatively high multiple-pregnancy rate (3 to 8%) as compared with the rate associated with unassisted conception (<1%), and an undesirable side-effect profile, including mood changes and hot flashes.
• What was the primary outcome of this study comparing clomiphene to letrozole for ovulation induction in infertile women with the polycystic ovary syndrome?
The group of women who received letrozole had more cumulative live births than the group of women who received clomiphene (103 of 374 women [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth with letrozole, 1.44; 95% confidence interval, 1.10 to 1.87). There were no significant between-group differences in live-birth rates according to treatment cycle. The live-birth rates after an anovulatory cycle were similar with and without progestin-induced withdrawal bleeding in both treatment groups.
Morning Report Questions
Q: What were secondary study outcomes?
A: The rates of pregnancy loss after conception were similar in the two treatment groups. The ovulation rate was significantly higher with letrozole than with clomiphene at each monthly visit (P<0.01 for all comparisons) beginning with the second visit. Among patients who ovulated, there was a significantly greater chance of singleton pregnancy with letrozole than with clomiphene (P=0.03). The sex ratio at birth favored girls.
Q: How did adverse events compare between the two treatment groups?
A: Three serious adverse events related to ovarian-cyst formation occurred during infertility treatment: two with letrozole (a ruptured corpus luteum cyst in one patient and hospitalization for the drainage and removal of an ovarian cyst in another patient) and one with clomiphene (ovarian torsion). Clomiphene was associated with a significantly higher incidence of hot flushes; letrozole was associated with significantly higher incidences of fatigue and dizziness. During pregnancy, the most common complication was gestational diabetes, followed by preeclampsia or eclampsia, preterm labor, and premature rupture of membranes, with no significant differences between treatment groups. There were five major congenital anomalies (four with letrozole and one with clomiphene); the between-group difference was not significant (P=0.65).