Letrozole, sold under the brand name Femara among others, is an

aromatase inhibitor Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone ex ...

medication that is used in the treatment of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Breast cancer

Letrozole is approved by the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women.Drugs.com: for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.

Comparison with tamoxifen

Tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

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.

Ovulation induction

Letrozole has been used for ovulation induction by fertility doctors since 2001, because it has fewer side-effects than

clomiphene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a cours ...

(Clomid) and less chance of multiple gestation. A study of 150 babies following treatment with either letrozole alone or letrozole and gonadotropins presented at the

American Society of Reproductive Medicine The American Society for Reproductive Medicine (ASRM) is a nonprofit, multidisciplinary organization for advancement of the science and practice of reproductive medicine. The society has its headquarters in Washington, D.C and its administrati ...

2005 Conference found no difference in overall abnormalities but did find a significantly higher rate of locomotor and cardiac abnormalities among the group having taken letrozole compared to natural conception. A larger, follow-up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene. That study also found no significant difference in the rate of overall abnormalities, but found that congenital cardiac anomalies was significantly higher in the clomiphene group compared to the letrozole group. Despite this, India banned the usage of letrozole in 2011, citing potential risks to infants. In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India and also stated that letrozole's use for infertility was illegal worldwide; however, such

off-label use Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...

s are legal in many countries such as the US and UK.

Contraindications

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

Side effects

The most common side effects are sweating,

hot flash Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, an ...

es,

arthralgia Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

(joint pain), and

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

. Generally, side effects include signs and symptoms of

hypoestrogenism Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiova ...

. There is concern that long term use may lead to

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...

, which is why in certain patient populations such as post-menopausal women or osteoporotics,

bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...

s may also be prescribed.

Interactions

Letrozole inhibits the liver enzyme

CYP2A6 Cytochrome P450 2A6 (abbreviated CYP2A6) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine and ...

, and to a lesser extent

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

, ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...

'', but no relevant interactions with drugs like

cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 r ...

and

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

have been observed.

Pharmacology

Pharmacodynamics

Letrozole is an

orally active Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

, selective

and hence an

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or ...

. It prevents

aromatase Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...

from producing

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

s by

competitive Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indivi ...

, reversible binding to the

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...

of its

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

unit. The action is specific, and letrozole does not reduce production of

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are inv ...

Research

The antiestrogen action of letrozole has been shown to be useful in pretreatment for termination of pregnancy, in combination with

misoprostol Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. Misoprostol is taken by mouth w ...

. It can be used in place of

mifepristone Mifepristone, also known as RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of ...

, which is expensive and unavailable in many countries. Letrozole is sometimes used as a treatment for

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...

, although it is probably most effective at this if caught in an early stage (such as in users of

anabolic steroid Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects ...

s). Some studies have shown that letrozole can be used to promote spermatogenesis in male patients with nonobstructive

azoospermia Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen ...

. Letrozole has also been shown to delay the fusing of the

growth plates The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...

in mice. When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature. Letrozole has also been used to treat

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...

. Endometrial stromal sarcomas are hormonally sensitive tumors as it is represented that letrozole reduces serum estrogen levels. Letrozole is well-tolerated and is a good option for long-term management of this disease. Also in a study on Uterine myoma the volume was successfully reduced by use of an aromatase inhibitor. Rapid onset of action and avoidance of initial gonadotropin flare with an aromatase inhibitor. Letrozole has been documented to be safe and effective for improving height and pubertal outcomes in children living with constitutional delay in growth and puberty, and is better than testosterone with regards to improvement in testicular volume and delaying bone-age progression. This was documented in a meta-analysis published by Dutta et al. which analyzed data from 7 different randomized controlled trials.

References

External links

* {{Portal bar , Medicine Aromatase inhibitors Benzonitriles Hormonal antineoplastic drugs Novartis brands Triazoles World Anti-Doping Agency prohibited substances