Letrozole appears to be more effective, and associated with fewer maternal side effects, than clomiphene in the treatment of infertility in women with polycystic ovary syndrome (PCOS), a double blind trial has found.

A total of 750 women, aged 18-40 years, with PCOS but without other impediments to fertility were recruited. Modified Rotterdam criteria (anovulation with hyperandrogenism or polycystic ovaries) were used to define PCOS. Participants were randomised to receive letrozole (n = 374) or clomiphene (n = 376). Blinding was possible as both treatments were given for five days starting early in the follicular phase of the menstrual cycle. The maximum number of treatment cycles was five.

The primary outcome was live birth. The secondary outcomes were ovulation, pregnancy loss, singleton birth and congenital abnormality.

Women given letrozole were more likely to conceive (41.2% vs 27.4%; P <0.001) and to have a live birth (27.5% vs 19.1%), rate ratio 1.44 (95% CI:1.10-1.87; P = 0.007) than those treated with clomiphene. Pregnancy loss rates were similar (31.8% vs 29.1% respectively; P = 0.65).

Women given clomiphene had more twin pregnancies compared with those treated with letrozole but the difference was not statistically significant (7.4% vs 3.4%; P = 0.32). The time to pregnancy and duration of pregnancy were similar.

Two serious adverse events were recorded in women given letrozole (ruptured corpus luteum cyst and ovarian cyst) and one in women given clomiphene (ovarian torsion).

Five infants were born with significant congenital abnormality four of whom (3.9%) were conceived following letrozole treatment: cerebral palsy with hydrocephalus; spina bifida with imperforate anus; hemimegalencephaly with partial cerebral dysgenesis; and one case of ventricular septal defect. The one (1.5%) anomaly associated with clomiphene was atrial septal defect with ventricular septal defect and pulmonary stenosis. Although the difference between the groups was not statistically significant given the group size a potential difference cannot be ruled out, the researchers caution.

PCOS is the most common cause of anovulatory infertility in women. The standard first-line treatment to induce ovulation is clomiphene which selectively blocks the action of oestrogen at the level of the hypothalamus. The aromatase inhibitor letrozole, which blocks oestrogen production at the level of the ovary, appears to be more effective and associated with fewer adverse effects.

Letrozole, better known as an adjuvant treatment for breast cancer, does seem to have real potential in the treatment of women with PCOS and sub-fertility. However, questions about teratogenesis will need to be resolved before it can be recommended for regular use.

‘Further study with larger numbers of infants is needed to clarify the safety and teratogenic risks with letrozole relative to those with other infertility therapies,’ the study authors conclude.

Dr Chris Barclay