Aromatase inhibitor | |
---|---|
Drug class | |
![]() Anastrozole, a non steroidal aromatase inhibitor and a widely used drug in the treatment of breast 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 |
In Wikidata |
Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, [1] [2] 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.
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 such, AIs are estrogen 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 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. [3] 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. Tamoxifen (a SERM) traditionally was the drug treatment of choice, but the ATAC trial (Arimidex, Tamoxifen, Alone or in Combination) showed that in women with localized estrogen receptor-positive breast cancer, women receiving the AI anastrozole had better results than the tamoxifen group. [4] Trials of AIs used as adjuvant therapy, 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. [5]
Aromatase inhibitors have been approved for the treatment of gynecomastia in children and adolescents. [6]
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. [7]
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. [8] 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. [9] 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, [10] [11] and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events. [12]
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. [13]
Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
---|---|---|---|---|---|
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. |
There are two types of aromatase inhibitors approved to treat breast cancer: [14]
Aromatase inhibitors (AIs) include:
In addition to pharmaceutical AIs, some natural elements have aromatase inhibiting effects, such as damiana leaves.
The development of aromatase inhibitors was first pioneered by the work of British pharmacologist Angela Brodie at the University of Maryland School of Medicine, first demonstrating efficacy of Formestane in clinical trials in 1982. [15] The drug was first marketed in 1994. [16]
Investigations and research has been undertaken to study the use of aromatase inhibitors to stimulate ovulation, and also to suppress estrogen production. [17] Aromatase inhibitors have been shown to reverse age-related declines in testosterone, including primary hypogonadism. [18] 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. [19] [20] AIs have also been used experimentally in the treatment of adolescents with delayed puberty. [21]
Research suggests the common table mushroom has anti-aromatase [22] 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. [23] However the study was relatively small (2,018 patients participating) and limited to Chinese women of southeast China.
The extract from the herb damiana (Turnera diffusa) has been found to suppress aromatase activity, including the isolated compounds pinocembrin and acacetin. [24] [ better source needed ] [25] [ 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 |
Anastrozole, sold under the brand name Arimidex among others, is a 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.
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 been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.
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 reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into estrogens. The enzyme aromatase can be found in many tissues including gonads, brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer. It is an important factor in sexual development.
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.
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.
Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of 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.
Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.
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. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.
Arzoxifene is a selective estrogen receptor modulator (SERM) of the benzothiophene group which was never marketed. It is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.
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.
A hormone-receptor-positive (HR+) tumor is a tumor which consists of cells that express receptors for certain hormones. The term most commonly refers to estrogen receptor positive tumors, but can also include progesterone receptor positive tumors. Estrogen-receptor-positive tumors depend on the presence of estrogen for ongoing proliferation.
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 unease.
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.
Kathleen I. Pritchard, is the head of oncology at Sunnybrook Health Sciences Centre in Toronto, Canada, specializing in breast cancer therapies, and leading the clinical trials division of the centre. She has authored numerous studies on women's health, breast cancer, hormone replacement therapy, public health, and research methodology. According to Thomson Reuters, Pritchard was one of the most cited researchers in the world in 2014 and 2015.
Estrogen deprivation therapy, also known as endocrine therapy, is a form of hormone therapy that is used in the treatment of breast cancer. Modalities include antiestrogens or estrogen blockers such as selective estrogen receptor modulators (SERMs) like tamoxifen, selective estrogen receptor degraders like fulvestrant, and aromatase inhibitors like anastrozole and ovariectomy.
A hormone-sensitive cancer, or hormone-dependent cancer, is a type of cancer that is dependent on a hormone for growth and/or survival. Examples include breast cancer, which is dependent on estrogens like estradiol, and prostate cancer, which is dependent on androgens like testosterone.
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.