Clomiphene citrate (CC) is the most commonly used oral agent for the induction of ovulation. It is a nonsteroidal
selective estrogen receptor modulator that has predominant antiestrogenic action resulting in long-lasting
estrogen receptor depletion. Side effects include antiestrogenic effects systemically and on the endometrium and cervical mucous.
Letrozole is a potent, nonsteroidal,
aromatase inhibitor, originally used for postmenopausal
breast cancer therapy, at present its only registered indication. We hypothesized that
letrozole could mimic the action of CC without depletion of
estrogen receptors. As there is no
estrogen receptor antagonism, antiestrogenic effects such as poor cervical mucus and thin endometrium are not expected with
aromatase inhibitor treatment. In addition, because
estrogen receptors in the brain are not depleted, normal negative feedback occurs with
letrozole and generally results in monoovulation. We and others have demonstrated the success of
aromatase inhibition in inducing ovulation in women with
polycystic ovarian syndrome.
Letrozole may be very effective for ovulation induction and pregnancy in cases of CC resistance. When used together with
follicle-stimulating hormone (FSH)
injections,
letrozole resulted in a significant reduction in the FSH dose needed for controlled ovarian hyperstimulation.
Aromatase inhibitors likely increase ovarian sensitivity to FSH, and may be useful in poor responders and in women undergoing ovarian stimulation for in vitro fertilization. The safety of
letrozole in pregnancy outcome studies has been demonstrated by examination of spontaneous pregnancy loss, multiple pregnancy rates, and congenital anomalies compared with a control group of
infertility patients treated with CC. In addition, new data suggest that CC may result in cardiac anomalies and other
birth defects and in low birth weight babies. We believe
aromatase inhibitors are acceptable alternatives to CC as first line oral agents for ovulation induction or controlled ovarian stimulation.