| Aromatase inhibitor | |
|---|---|
| Drug class | |
 Anastrozole, anon steroidal aromatase inhibitor and a widely used drug in the treatment ofbreast cancer. | |
| Class identifiers | |
| Synonyms | Estrogen synthesis inhibitors; Estrogen synthase inhibitors; Estrogen blockers |
| Use | Breast cancer,infertility,precocious puberty,medical abortion,gynecomastia,endometriosis,short stature, others |
| ATC code | L02BG |
| Biological target | Aromatase |
| Chemical class | Steroidal;Nonsteroidal |
| Legal status | |
| In Wikidata | |
Aromatase inhibitors (AIs) are a class of drugs that block the enzyme aromatase, which is responsible for convertingandrogens intoestrogens.[1] They are primarily used in the treatment ofhormone receptor-positive breast cancer, particularly inpostmenopausal women,[2] but can also be used inpremenopausal women when combined with ovarian suppression therapy.[3] AIs are also used in men for conditions such asgynecomastia andhormone-sensitive cancers,[4] and may be usedoff-label to manage estrogen levels duringtestosterone therapy.[5] Additionally, they are sometimes used forchemoprevention in individuals at high risk of developing breast cancer.[6]
Aromatase is theenzyme that catalyzes a key aromatization step in the synthesis ofestrogen. It converts theenone ring of androgen precursors such as testosterone, to a phenol, completing the synthesis of estrogen. As such, AIs areestrogen synthesis inhibitors. Because hormone-positive breast and ovarian cancers are dependent on estrogen for growth, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.
In contrast topremenopausal women, in whom most of the estrogen is produced in theovaries, inpostmenopausal women estrogen is mainly produced in peripheral tissues of the body. Because some breast cancers respond to estrogen, lowering estrogen production at the site of the cancer (i.e. theadipose tissue of the breast) with aromatase inhibitors has been proven to be an effective treatment for hormone-sensitive breast cancer in postmenopausal women.[7] Aromatase inhibitors are generally not used to treat breast cancer in premenopausal women because, prior to menopause, the decrease in estrogen activates thehypothalamus andpituitary axis to increasegonadotropin secretion, which in turn stimulates the ovary to increaseandrogen production. The heightened gonadotropin levels also upregulate the aromatase promoter, increasing aromatase production in the setting of increased androgensubstrate. This would counteract the effect of the aromatase inhibitor in premenopausal women, as total estrogen would increase.
Ongoing areas of clinical research include optimizing adjuvant hormonal therapy in postmenopausal women with breast cancer.Tamoxifen (aSERM) traditionally was the drug treatment of choice, but the ATAC trial (Arimidex,Tamoxifen,Alone or inCombination) showed that in women withlocalizedestrogen receptor-positive breast cancer, women receiving the AIanastrozole had better results than the tamoxifen group.[8] Trials of AIs used asadjuvant therapy, when given to prevent relapse after surgery for breast cancer, show that they are associated with a betterdisease-free survival than tamoxifen, but few conventionally-analyzed clinicals trials have shown that AIs have anoverall survival advantage compared with tamoxifen, and there is no good evidence they are better tolerated.[9]
Aromatase inhibitors have been approved for the treatment of gynecomastia in children and adolescents.[10]
Ovarian stimulation with the aromatase inhibitorletrozole has been proposed forovulation induction in order to treat unexplained female infertility. In a multi-center study funded by theNational Institute of Child Health and Development, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation (i.e., twins or triplets) but also a lower frequency of live birth, as compared withgonadotropin but not withclomiphene.[11]
In women, side effects include an increased risk for developingosteoporosis and joint disorders such asarthritis,arthrosis, andjoint pain. Men do not appear to exhibit the same adverse effects on bone health.[12]Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors, but also have another serious side effect,osteonecrosis of the jaw. Asstatins have a bone strengthening effect, combining a statin with an aromatase inhibitor could help prevent fractures and suspected cardiovascular risks, without potential of causing osteonecrosis of the jaw.[13] The more common adverse events associated with the use of aromatase inhibitors include decreased rate of bone maturation and growth,infertility, aggressive behavior,adrenal insufficiency,kidney failure,hair loss,[14][15] and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.[16]
Aromatase inhibitors work by inhibiting the action of the enzymearomatase, which convertsandrogens intoestrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is theovaries inpremenopausal women, while inpost-menopausal women most of the body's estrogen is produced in peripheraltissues (outside theCNS), and also a few CNS sites in various regions within thebrain. Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exertssystemic estrogenic effects in men and women, is the result of estrogen escapinglocal metabolism and spreading to thecirculatory system.[17]
| Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
|---|---|---|---|---|---|
| First | Testolactone | 250 mg 4x/dayp.o. | ? | Type I | ? |
| 100 mg 3x/weeki.m. | ? | ||||
| Rogletimide | 200 mg 2x/dayp.o. 400 mg 2x/dayp.o. 800 mg 2x/dayp.o. | 50.6% 63.5% 73.8% | Type II | ? | |
| Aminoglutethimide | 250 mg mg 4x/dayp.o. | 90.6% | Type II | 4,500 nM | |
| Second | Formestane | 125 mg 1x/dayp.o. 125 mg 2x/dayp.o. 250 mg 1x/dayp.o. | 72.3% 70.0% 57.3% | Type I | 30 nM |
| 250 mg 1x/2 weeksi.m. 500 mg 1x/2 weeksi.m. 500 mg 1x/1 weeki.m. | 84.8% 91.9% 92.5% | ||||
| Fadrozole | 1 mg 1x/dayp.o. 2 mg 2x/dayp.o. | 82.4% 92.6% | Type II | ? | |
| Third | Exemestane | 25 mg 1x/dayp.o. | 97.9% | Type I | 15 nM |
| Anastrozole | 1 mg 1x/dayp.o. 10 mg 1x/dayp.o. | 96.7–97.3% 98.1% | Type II | 10 nM | |
| Letrozole | 0.5 mg 1x/dayp.o. 2.5 mg 1x/dayp.o. | 98.4% 98.9%–>99.1% | Type II | 2.5 nM | |
| Footnotes:a = Inpostmenopausal women.b = Type I:Steroidal,irreversible (substrate-binding site). Type II:Nonsteroidal,reversible (binding to and interference with thecytochrome P450hememoiety).c = Inbreast cancerhomogenates.Sources: See template. | |||||
There are two types of aromatase inhibitors approved to treat breast cancer:[18]
Aromatase inhibitors (AIs) include:
In addition to pharmaceutical AIs, some natural elements havearomatase inhibiting effects, such asdamiana leaves.[19]
The development of aromatase inhibitors was first pioneered by the work of British pharmacologistAngela Brodie at theUniversity of Maryland School of Medicine, first demonstrating efficacy ofFormestane in clinical trials in 1982.[20] The drug was first marketed in 1994.[21]
Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production.[22] Aromatase inhibitors have been shown to reverse age-related declines in testosterone, includingprimary hypogonadism.[23] Extracts of certainmushrooms have been shown to inhibit aromatase when evaluated byenzyme assays, withwhite mushroom having shown the greatest ability to inhibit the enzyme.[24][25] AIs have also been used experimentally in the treatment of adolescents with delayed puberty.[26]
Research suggests the commontable mushroom has anti-aromatase[27] properties and therefore possible anti-estrogen activity. In 2009, a case-control study of the eating habits of 2,018 women in southeast China revealed that women who consumed greater than 10 grams of fresh mushrooms or greater than 4 grams of dried mushrooms per day had an approximately 50% lower incidence of breast cancer. Chinese women who consumed mushrooms andgreen tea had a 90% lower incidence of breast cancer.[28] However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.
The extract from the herbdamiana (Turnera diffusa) has been found to suppress aromatase activity, including the isolated compoundspinocembrin andacacetin.[29][better source needed][30][better source needed]
| Species Name | Common name | Family | Type |
|---|---|---|---|
| Aesculus glabra | Ohio buckeye | Hippocastanaceae | Plant |
| Agaricus bisporus | Baby button mushroom | Agaricaceae | Fungus |
| Allium sp. | White onions | Liliaceae | Plant |
| Alpinia purpurata | Red ginger | Zingerberaceae | Plant |
| Brassica oleracea | Cauliflower | Brassicaceae | Plant |
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