Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when using external testosterone. They may also be used for chemoprevention in high risk women.
|Synonyms||Estrogen synthesis inhibitors; Estrogen synthase inhibitors; Estrogen blockers|
|Use||Breast cancer, infertility, precocious puberty, medical abortion, gynecomastia, endometriosis, short stature, others|
|Chemical class||Steroidal; Nonsteroidal|
Aromatase is the enzyme that catalyzes a key aromatization step in the synthesis of estrogen. It converts the enone ring of androgen precursors such as testosterone, to a phenol, completing the synthesis of estrogen. As hormone positive breast and ovarian cancers require estrogen to grow, AIs are taken to either block the production of estrogen or block the action of estrogen on receptors.
In contrast to premenopausal women, in whom most of the estrogen is produced in the ovaries, in postmenopausal 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. the adipose tissue of the breast) with aromatase inhibitors has been proven to be an effective treatment for hormone-sensitive breast cancer in postmenopausal women. Aromatase inhibitors are generally not used to treat breast cancer in premenopausal women because, prior to menopause, the decrease in estrogen activates the hypothalamus and pituitary axis to increase gonadotropin secretion, which in turn stimulates the ovary to increase androgen production. The heightened gonadotropin levels also upregulate the aromatase promoter, increasing aromatase production in the setting of increased androgen substrate. 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. Although tamoxifen (a SERM) traditionally was the drug treatment of choice, but the ATAC trial showed that AI gives superior clinical results in postmenopausal women with localized estrogen receptor positive breast cancer. Trials of AIs in the adjuvant setting, when given to prevent relapse after surgery for breast cancer, show that they are associated with a better disease-free survival than tamoxifen, but few conventionally-analyzed clinicals trials have shown that AIs have an overall survival advantage compared with tamoxifen, and there is no good evidence they are better tolerated.
Aromatase inhibitors such as testolactone have been approved for the treatment of gynecomastia in children and adolescents.
Ovarian stimulation with the aromatase inhibitor letrozole has been proposed for ovulation induction in order to treat unexplained female infertility. In a multi-center study funded by the National 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 with gonadotropin but not with clomiphene.
In women, side effects include an increased risk for developing osteoporosis and joint disorders such as arthritis, arthrosis, and joint pain. Men do not appear to exhibit the same adverse effects on bone health. Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors, but also have another serious side effect, osteonecrosis of the jaw. As statins 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. 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, and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.
Mechanism of action
Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens 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 the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced in peripheral tissues (outside the CNS), and also a few CNS sites in various regions within the brain. Estrogen is produced and acts locally in these tissues, but any circulating estrogen, which exerts systemic estrogenic effects in men and women, is the result of estrogen escaping local metabolism and spreading to the circulatory system.
|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.
|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.
|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.
|Fadrozole||1 mg 1x/day p.o.|
2 mg 2x/day p.o.
|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.
|Type II||10 nM|
|Letrozole||0.5 mg 1x/day p.o.|
2.5 mg 1x/day p.o.
|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.|
Aromatase inhibitors (AIs) include:
Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production. Aromatase inhibitors have been shown to reverse age-related declines in testosterone, including primary hypogonadism. Extracts of certain mushrooms have been shown to inhibit aromatase when evaluated by enzyme assays, with white mushroom having shown the greatest ability to inhibit the enzyme. AIs have also been used experimentally in the treatment of adolescents with delayed puberty.
Research suggests the common table mushroom has anti-aromatase 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 and green tea had a 90% lower incidence of breast cancer. However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.
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