For the past 60 years clomifene citrate (CC) has been the first line treatment for those with absent or irregular ovulation but who have normal basal levels of oestradiol (almost all of whom have PCOS).
The action of CC is by blocking hypothalamic oestrogen receptors, signaling a lack of circulating oestrogen to the hypothalamus and inducing a change in the pattern of pulsatile release of gonadotrophin releasing hormone (GnRH) and consequently a discharge of FSH.
Although CC will restore ovulation in approximately 80% of patients it will result in pregnancy in only about 35-40% and 20-25% will not respond at all and are considered to be ‘clomiphene resistant’.
Aromatase inhibitors are non-steroidal compounds that suppress oestrogen biosynthesis by blocking the action of the enzyme aromatase which converts androstendione to oestrogens. Letrozole, the most widely used aromatase inhibitor, is given orally in a dose of 2.5 mg – 5 mg/day and is almost free of side effects. In a large trial, 750 women with anovulatory PCOS were randomized to receive either clomifene or letrozole. A 44% increase in pregnancy rate was achieved by letrozole over clomifene (27.5% vs 19.5%). Twinning rate was non-significantly higher in those who received clomifene (7.4% vs 3.2%) with no significant difference in the rate of congenital abnormalities. The conclusion would seem to be that letrozole can be regarded as a serious competitor to CC for first-line therapy for induction of ovulation.