Both clomiphene citrate (Clomid) and letrozole (Femara) are oral medications used to treat infertile women who have ovulation problems. Women with ovulation disorders and especially those with polycystic ovarian syndrome (PCOS) often have absent or irregular menses. They do not ovulate or ovulate infrequently.
These medications work in different ways to help the pituitary gland release more follicle-stimulating hormone (FSH) and therefore improve the stimulation of developing follicles (egg sacs) in the ovaries. For over 50 years, clomiphene citrate has been the drug of choice to help patients ovulate. Ovulation rates are generally good, however the pregnancy rates remain relatively low, so there may be certain indications to consider letrozole instead.
For over a decade letrozole has been used mainly to treat various types of breast cancer. Letrozole is in a class of drugs called aromatase inhibitors. It works by blocking the aromatase enzyme that is responsible for converting testosterone into estrogen in several tissues including the ovaries. The resulting drop in blood estrogen levels then stimulates the pituitary gland to increase the output of FSH. The increase in FSH can result in the development of a mature follicle in the ovary and subsequent ovulation of an egg.
Clomiphene citrate (Clomid) is an anti-estrogen drug that fools the estrogen receptors in the hypothalamus and pituitary into thinking that estrogen levels are low. Clomid's anti-estrogenic properties cause an increased secretion of FSH that results in ovulation in most cases. However, the anti-estrogenic activity of Clomid on the cervix and the uterine lining often causes decreased cervical mucus production and poor development of the uterine lining. These anti-estrogenic effects are the main reason that women who ovulate with Clomid don't always conceive, explaining the relatively poor pregnancy rates. In contrast, letrozole is relatively short acting and has no direct anti-estrogenic effects on the uterine lining or cervical mucus. There is some evidence suggesting a reduced rate of twins with letrozole (approximately 5%) compared to Clomid (approximately 6 to 10%). Both medications can cause minor and temporary side effects such as hot flashes, mood changes, blurred vision, nausea, bloating and headache.
A recent research study published in the New England Journal of Medicine compared the live birth rates of PCOS patients using letrozole versus Clomid. They found that women taking letrozole had significantly more live births than those who received Clomid (27.5% versus 19.1%), and also had higher ovulation rates. (N Engl J Med 2014 371: 119-129)
Many doctors are more comfortable using Clomid since letrozole is not approved by the FDA as an infertility drug and its use in this fashion is still considered 'off label'. Over the past decade the vast majority of the studies done thus far concerning the safety of letrozole have been very reassuring. However there was one abstract that did suggest a slight increase in birth effects after treatment with letrozole. However the design of this study revealed major flaws in methodology which weakened the data. Nonetheless, the drug manufacture, Novartis, sent a warning letter to physicians, for liability reasons, asserting that it was approved only for breast cancer patients, therefore discouraging it's use for ovulation induction. Many subsequent studies have shown letrozole to be effective for ovulation induction and the incidence of birth defects was no different than with Clomid.
Summary: For many years Clomid has been the first line oral infertility treatment for women with ovulation disorders and PCOS, but aromatase inhibitors, such as letrozole, might result in better pregnancy rates. There is reassuring evidence that letrozole is a safe alternative in the treatment of infertility.