Letrozole

Letrozole (INN, trade name Femara) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery.

Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.

Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids.

FDA-approved use
Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women. Side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is why prescriptions of Letrozole are often accompanied by prescriptions of osteoporosis-fighting medications such as bisphosphonates.

Off-label use
Letrozole has been used for ovarian stimulation by fertility doctors since 2001—having less side-effects than clomifene (Clomid) and less chance of multiple gestation. A Canadian study presented at the American Society of Reproductive Medicine 2005 Conference suggests that Letrozole may increase the risk of birth defects. A more detailed ovulation induction follow-up study found that letrozole, compared with a control group of clomiphene, had significantly lower congenital malformations and chromosomal abnormalities at an overall rate of 2.4% (1.2% major malformations) compared with clomiphene 4.8% (3.0% major malformations).

The anti-estrogen action of letrozole has been shown to be useful in pretreatment for termination of pregnancy, in combination with misoprostol. It can be used in place of mifepristone, which is expensive and unavailable in many countries.

The anti-estrogen action of Letrozole is preferred by athletes and bodybuilders for use during a steroid cycle to reduce bloating due to excess water retention and prevent the formation of gynecomastia related breast tissue that is a side effect of some anabolic steroids.

Some studies have shown that Letrozole can be used to promote spermatogenesis in male patients suffering from nonobstructive azoospermia.

Letrozole has also been shown to delay the fusing of the growth plates in mice. When used with growth hormone, Letrozole has been shown thereputic for adolescents and children with short stature.

Letrozole has also been used to treat endometriosis.

Comparison with tamoxifen
Tamoxifen is also used to treat hormonally-responsive breast cancer, but it does so by interfering with the estrogen receptor. However, letrozole is effective only in post-menopausal women, in whom estrogen is produced predominantly in peripheral tissues (i.e. in adipose tissue, like that of the breast) and a number of sites in the brain. In pre-menopausal women, the main source of estrogen is from the ovaries not the peripheral tissues, and letrozole is ineffective.

In the BIG 1-98 Study, of post-menopausal women with hormonally-responsive breast cancer, letrozole reduced the recurrence of cancer, but did not change survival rate, compared to tamoxifen.

Contraindications
Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.

Adverse effects
The most common side effects are sweating, hot flashes, arthralgia (joint pain), and fatigue.

Interactions
Letrozole inhibits the liver enzyme CYP2A6, and to a lesser extent CYP2C19, in vitro, but no relevant interactions with drugs like cimetidine and warfarin have been observed.