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Clomid has long been the initial drug of choice for management of anovulation. However, it is well known that clomid has disadvantages related to its anti-estrogenic properties. At the level of the hypothalamus and pituitary, clomid’s anti-estrogenic properties cause increased secretion of pituitary hormones (gonadotropins) that result in ovulation when the medication is working properly. However, anti-estrogenic activity at the level of the cervix and uterus causes decreased mucous production and poor development of the uterine lining respectively. Letrozole, one of a class of drugs called aromatase inhibitors, works by inhibiting the enzyme responsible for the formation of estrogen in various tissues including brain, ovaries, and fat. Because it is relatively short acting, and has no direct anti-estrogenic effects on the uterine lining or cervical mucous, studies have suggested a trend toward higher pregnancy rates compared to clomid. Some studies have shown that when clomid treatment fails to achieve pregnancy, letrozole often succeeds. There is also some evidence supporting a reduced rate of twins with letrozole (approximately 5%) compared to clomid (approximately 10%).
Traditionally, when clomid fails to result in pregnancy, and other causes of infertility have been ruled out, patients are counseled to consider injectable pituitary hormones (gonadotropins). The disadvantages of this approach include the need for daily injections, requirement for careful monitoring including ultrasound and laboratory testing, a 20% chance of multiple birth, and a possibility of developing ovarian hyperstimulation. In certain circumstances, letrozole may offer a safer, simpler alternative to using gonadotropins. However, one of the disadvantages of letrozole is that it is not FDA approved for use as an ovulation-stimulating agent. It is approved for use in breast cancer patients because it lowers estrogen production by inhibiting one of the enzymes required for the formation of estrogen.
Who is most likely to benefit from a trial with letrozole?
1) A patient with failure to ovulate regularly who has failed to conceive during a trial with clomid. Patients with polycystic ovarian syndrome are ideal candidates for treatment with letrozole. However if these patients have failed to ovulate in response to clomid, they are unlikely to respond favorable to letrozole.
2) Patients who have been treated with clomid and found to have poor cervical mucous production or thin endometrium.
3) Patient’s known to have endometriosis make ideal candidates for a trial of letrozole because these patients are more inclined to have endometriotic implants stimulated by the high levels of estrogen stimulated by clomid. Stimulation with letrozole results in lower estrogen levels and is therefore less likely to activate endometriotic implants. Because letrozole has a short half-life, there is time during the treatment cycle for the endometrium to develop more normally.
4) Patients with unexplained infertility make ideal candidates for treatment with letrozole.
One of the concerns about letrozole is that it has not been studied as extensively as clomid. While clomid has been in use clinically since the early 1960’s, there has been ample opportunity to study its effects and prove its safety. While most of the studies done thus far concerning the safety of letrozole have been reassuring, one abstract did suggest a slight increase in locomotor defects and cardiac anomaly in the infants conceived after treatment with letrozole. However, the design of this study revealed major methodological flaws, which weakened the data and conclusions, presented. Because our clinical experience with letrozole for ovulation induction spans only about 10 years, it is important to exercise caution when using it for ovulation induction. Patients who are being treated with letrozole should have a quantitative beta-HCG test done immediately before starting a treatment cycle to assure that they are not pregnant.