Clinical data | |
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Trade names | Femara, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a698004 |
License data | |
Routes of administration | By mouth |
Drug class | Aromatase inhibitor; Antiestrogen |
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Pharmacokinetic data | |
Bioavailability | 99.9% |
Protein binding | 60%, mainly to albumin |
Metabolism | pharmacologically-inactive metabolites Bis(4-cyanophenyl)methanol and 4,4'-dicyanobenzophenone. [3] |
Elimination half-life | 2 days [3] |
Excretion | Kidney [3] |
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CAS Number | |
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IUPHAR/BPS | |
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UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.200.357 |
Chemical and physical data | |
Formula | C17H11N5 |
Molar mass | 285.310 g·mol−1 |
3D model (JSmol) | |
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Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. [1]
It was patented in 1986 and approved for medical use in 1996. [4] In 2021, it was the 222nd most commonly prescribed medication in the United States, with more than 1 million prescriptions. [5] [6] It is on the World Health Organization's List of Essential Medicines. [7]
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. [8]
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. [9] 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. [10] [11]
Letrozole has been used for ovulation induction by fertility doctors since 2001, because it has fewer side-effects than clomiphene (Clomid) and less chance of multiple gestation.[ citation needed ] A study of 150 babies following treatment with either letrozole alone or letrozole and gonadotropins presented at the American Society of Reproductive Medicine 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. [12] A larger, follow-up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene. [13] 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. [14] 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; [15] however, such off-label uses are legal in many countries such as the US and UK. [16] [17]
Tests have shown that the efficacy of first-trimester medical abortions (using misoprostol) can be improved by including letrozole in the drug regimen. [18] [19] [20]
Letrozole is considered a performance enhancing drug by the World Antidoping Agency (WADA), as are other aromatase inhibitors, despite not having any documented evidence for enhancing performance, because it may be used to counteract the side effects of anabolic steroids. [21]
Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation. [22]
The most common side effects are sweating, hot flushes, arthralgia (joint pain), and fatigue. [22]
Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, [8] which is why in certain patient populations such as post-menopausal women or osteoporotics, bisphosphonates may also be prescribed.[ citation needed ]
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. [22]
Letrozole is an orally active, nonsteroidal, selective aromatase inhibitor and hence an antiestrogen. It prevents 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 corticosteroids.[ citation needed ]
Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
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First | Testolactone | 250 mg 4x/day p.o. | ? | Type I | ? |
100 mg 3x/week i.m. | ? | ||||
Rogletimide | 200 mg 2x/day p.o. 400 mg 2x/day p.o. 800 mg 2x/day p.o. | 50.6% 63.5% 73.8% | Type II | ? | |
Aminoglutethimide | 250 mg mg 4x/day p.o. | 90.6% | Type II | 4,500 nM | |
Second | Formestane | 125 mg 1x/day p.o. 125 mg 2x/day p.o. 250 mg 1x/day p.o. | 72.3% 70.0% 57.3% | Type I | 30 nM |
250 mg 1x/2 weeks i.m. 500 mg 1x/2 weeks i.m. 500 mg 1x/1 week i.m. | 84.8% 91.9% 92.5% | ||||
Fadrozole | 1 mg 1x/day p.o. 2 mg 2x/day p.o. | 82.4% 92.6% | Type II | ? | |
Third | Exemestane | 25 mg 1x/day p.o. | 97.9% | Type I | 15 nM |
Anastrozole | 1 mg 1x/day p.o. 10 mg 1x/day p.o. | 96.7–97.3% 98.1% | Type II | 10 nM | |
Letrozole | 0.5 mg 1x/day p.o. 2.5 mg 1x/day p.o. | 98.4% 98.9%–>99.1% | Type II | 2.5 nM | |
Footnotes:a = In postmenopausal women. b = Type I: Steroidal, irreversible (substrate-binding site). Type II: Nonsteroidal, reversible (binding to and interference with the cytochrome P450 heme moiety). c = In breast cancer homogenates. Sources: See template. |
The antiestrogen 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. [23]
Letrozole is sometimes used as a treatment for gynecomastia, although it is probably most effective at this if caught in an early stage (such as in users of anabolic steroids). [24] [25] [ unreliable source? ]
Some studies have shown that letrozole can be used to promote spermatogenesis in male patients with nonobstructive azoospermia. [26]
Letrozole has also been shown to delay the fusing of the growth plates in mice. [27] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature. [28]
Letrozole has also been used to treat endometriosis. [29]
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. [30] 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. [29]
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 regard 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. [31]
Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.
Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.
Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth.
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.
Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.
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 exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.
Exemestane, sold under the brand name Aromasin among others, is a medication used to treat breast cancer. It is a member of the class of antiestrogens known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors (ERs), and are called ER-positive. They may also be called estrogen-responsive, hormonally-responsive, or hormone-receptor-positive. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.
Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.
Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
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 inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development.
Testolactone is a non-selective, irreversible, steroidal aromatase inhibitor which is used as an antineoplastic drug to treat advanced-stage breast cancer. The drug was discontinued in 2008 and is no longer available for medical use.
Antihormone therapy is a type of hormone therapy that suppresses selected hormones or their effects, in contrast with hormone replacement therapy, which encourages hormone activity.
Gynecomastia 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. Gynecomastia can cause significant psychological distress or dysphoria.
An estrogen-dependent condition can be that relating to the differentiation in the steroid sex hormone that is associated with the female reproductive system and sex characteristics. These conditions can fall under the umbrella of hypoestrogenism, hyperestrogenim, or any sensitivity to the presence of estrogen in the body.
Steroidal aromatase inhibitors are a class of drugs that are mostly used for treating breast cancer in postmenopausal women. High levels of estrogen in breast tissue increases the risk of developing breast cancer and the enzyme aromatase is considered to be a good therapeutic target when treating breast cancer due to it being involved in the final step of estrogen biosynthetic pathway and also its inhibition will not affect production of other steroids. Aromatase Inhibitors are classified into two categories based on their structure, nonsteroidal and steroidal; the latter resemble the structure of androstenedione. Steroidal aromatase inhibitors irreversibly inhibit the enzyme by binding covalently to the binding site of aromatase so the substrate cannot access it.
A progonadotropin, or hypergonadotropin, also known as a gonad stimulant, is a type of drug which increases the secretion of one or both of the major gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This, in turn, results in increased function and maintenance of the gonads and increased gonadal steroidogenesis of sex hormones such as androgens, estrogens, and progestogens. Progonadotropins are the functional opposites of antigonadotropins. They have clinical applications in the treatment of hypogonadism and infertility. Conversely, hypergonadotropic effects can occur as a side effect of some drugs. Examples of progonadotropic drugs include gonadotropin-releasing hormone (GnRH) agonists when administered in a pulsatile manner, antiestrogens such as tamoxifen, clomifene, fulvestrant, and aromatase inhibitors like anastrozole, and, only in men, pure antiandrogens such as flutamide, bicalutamide, enzalutamide, and apalutamide.
Triphenylchloroethylene, or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions.
Non-Steroidal Aromatase Inhibitors (NSAIs) are one of two categories of aromatase inhibitors (AIs). AIs are divided into two categories, steroidal aromatase inhibitors and non-steroidal aromatase inhibitors that is based on their mechanism of action and structure. NSAIs are mainly used to treat breast cancer in women. NSAIs binding is a reversible process where NSAIs binds to the aromatase enzyme through non-covalent interactions. When aromatase inhibitors (AIs) are used to treat breast cancer the main target is the aromatase enzyme which is responsible for the high estrogen level.
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.
Female fertility agents are medications that improve female’s ability to conceive pregnancy. These agents are prescribed for infertile female who fails to conceive pregnancy after 1-year of regular and unprotected sexual intercourse. The following will cover the advancements of female fertility agents, major causes of female infertility. Next, it emphasizes on common female fertility agents in terms of their mechanism of action, side effects, fetal consideration and clinical application and ended up by the introduction of supplements and herbal medicines for female infertility.