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.
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.
Letrozole has been used for ovarian stimulation by fertility
doctors since 2001—having fewer 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). Despite
this, India banned the usage of Letrozole in 2011, citing potential
risks to infants.
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
Some studies have shown that Letrozole can be used to promote
spermatogenesis in male patients suffering from nonobstructive
Letrozole has also been shown to delay the fusing of the growth
plates in mice. When used with growth hormone, Letrozole has been
shown therapeutic 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
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
Letrozole is contraindicated in women having a pre-menopausal
hormonal status, during pregnancy and lactation.
The most common side effects are sweating, hot flashes, arthralgia
(joint pain), and fatigue.
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.