Letrozole - Substitute of Clomiphene Citrate (CC); How good is it?

Originally Araomatase inhibitors are the drugs for breast cancer for their anti estrogen effect. But they are found effective and in some way better for induction of ovulation particularly in PCOS patients. USFDA and now India government has allowed its use in infertility. Though in most of the company literatures the use of the drug in infertility is not mentioned yet!

Aromatase inhibitors are a serious challenge to replace clomiphene as the first line of treatment for anovulatory women. These are non-steroidal compounds that suppress estrogen biosynthesis by blocking the action of the enzyme aromatase which converts androstenedione and testosterone to estrogens.

Letrozole is the most widely used aromatase inhibitor; it is used orally in a dose of 2.5-5mg per day and is free of any side effects.


There are certain advantages of letrozole over Clomiphene citrate (CC)

1.CC blocks and depletes estrogen receptors. Hence it has a negative effect on the cervical mucous and the endometrium. This does not occur with
letrozole,

2.Though initially estrogen production is impaired with aromatase inhibitors eventually with the rise of FSH, estrogen production also increases with development of follicles as a result of which a negative feedback is activated on the hypo¬thalamus which will modulate an overzealous discharge of FSH which in turn is likely to result in monofollicular ovulation with moderate estrogen concentrations. This is all the more likely since letrozole has a much shorter half life (2days) than CC.

3. Though there is statistically significant data to support letrozole for its advantage over CC but it is true that letrozole is an acceptable alternative to CC as an ovulation induction agent in PCOS. Letrozole may be of benefit for patients in whom CC has failed. CC failure can be defined either as lack of ovulation or a thin endometrial lining resulting in failed implantation. Since it is not possible to identify patients who will have a poor response to CC ahead of time, it seems reasonable to use a treatment that is equally effective in inducing ovulation, but without antiestrogenic adverse effects, as a first-line therapy. For letroz to replace CC as the first line of drug for ovulation induction in general probably some more strong evidence is required.
What are the risks of using aromatase inhibitors (Letrozole)

There are certain concerns raised as to the theoretical possibility of accumulation of androgens in a women with PCOS, however there are no reports which indicate towards manifestation or worsening of clinical and biochemical hyperandrogenism following use of letrozole. In fact these increased androgens may have a stimulatory effect in early follicular FSH receptor expression and therefore amplifying FSH response this may explain the relative success of combined letrozole and FSH for ovulation stimulation in improving the response to FSH.

Pregnancy outcome: In an elegant study by Tulandi et al. where in 911 newborns conceived after infertility treatment with letrozole and clomiphene citrate were accessed for congenital malformations, they found that there was no difference in the overall rates of major and minor congenital malformations among the 2 groups. However, it appeared that congenital cardiac anomaly was less frequent in the letrozole group. Till date there is no data to prove Letrozole is teratogenic.

This article is also published in India study Channel