Aromatase inhibitor
Encyclopedia
Aromatase inhibitors are a class of drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

s used in the treatment of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....

 in postmenopausal
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...

 women. AIs may also be used off-label to treat or prevent gynaecomastia in men.

Aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is 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...

 is the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 which synthesizes estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

. As 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.

Types of AIs

There are 2 types of aromatase inhibitors (AIs) approved to treat breast cancer:
  • Irreversible steroidal inhibitors, such as exemestane
    Exemestane
    Exemestane is a drug used to treat breast cancer. It is a member of the class of drugs known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors , and are called ER-positive. They may also be called estrogen-responsive,...

     (Aromasin), forms a permanent and deactivating bond with the aromatase enzyme.

  • Non-steroidal inhibitors, such as anastrozole
    Anastrozole
    Anastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...

     (Arimidex), inhibits the synthesis of estrogen via reversible competition for the aromatase enzyme.

Mode of action

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is 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...

, which converts androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...

s into estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

s 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 bodies estrogen is produced in the conversion of androgens to estrogen by the aromatase enzyme in peripheral tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

 (outside the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

), and also a few CNS sites in various regions within the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

. Estrogen is produced and acts locally via action of the aromatase enzyme in these tissues, but any circulating estrogen, which exerts systemic
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...

 estrogenic effects in men and women, is the result of estrogen escaping local metabolism
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

 and spreading to the circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...

.

Members

Available aromatase inhibitors (AIs) include:

Selective

  • Anastrozole
    Anastrozole
    Anastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...

     (Arimidex)

  • Letrozole
    Letrozole
    Letrozole is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery.Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme...

     (Femara)

  • Exemestane
    Exemestane
    Exemestane is a drug used to treat breast cancer. It is a member of the class of drugs known as aromatase inhibitors. Some breast cancers require estrogen to grow. Those cancers have estrogen receptors , and are called ER-positive. They may also be called estrogen-responsive,...

     (Aromasin)

  • Vorozole
    Vorozole
    Vorozole is an imidazole based competitive inhibitor of the aromatase enzyme. It underwent clinical testing for evaluation for use as an antineoplastic agent; however it was withdrawn from testing when no difference was detected in the duration of median survival as compared to the progestational...

     (Rivizor)

  • Formestane
    Formestane
    Formestane belongs to a class of drugs known as 2 aromatase inhibitors. It is used in the treatment of estrogen-receptor positive breast cancer in post-menopausal women. It is available as an intramuscular depot injection ....

     (Lentaron)

  • Fadrozole
    Fadrozole
    Fadrozole is an aromatase inhibitor that has been introduced in Japan for the treatment of breast cancer.It is selective....

     (Afema)

Other

  • 4-Hydroxyandrostenedione

  • 1,4,6-Androstatrien-3,17-dione
    1,4,6-Androstatrien-3,17-dione
    1,4,6-Androstatrien-3,17-dione is a potent irreversible aromatase inhibitor that inhibits estrogen biosynthesis by permanently binding and inactivating aromatase in adipose and peripheral tissue. It is used to control estrogen synthesis....

     (ATD)

  • 4-Androstene-3,6,17-trione
    4-Androstene-3,6,17-trione
    4-Androstene-3,6,17-trione is a drug or nutritional supplement that may increase the testosterone-estrogen ratio, but has no proven effect on body composition...

     ("6-OXO")

Cancer

In contrast to premenopausal women, in whom most of the estrogen is produced in the ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...

, in postmenopausal women estrogen is mainly produced via the enzyme aromatase 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. When aromatase inhibitors are used in premenopausal women, the decrease in estrogen activates the hypothalamus and pituitary axis to increase gonadotropin secretion, which in turn stimulates the ovary to increase androgen production. This counteracts the effect of the aromatase inhibitor. Ongoing areas of clinical research is optimizing adjuvant hormonal therapy in postmenopausal women with breast cancer. Although tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...

 (SERM
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...

) had been the traditional drug treatment of choice, the ATAC trial has shown that clinical results are superior with an AI in postmenopausal women with localized breast cancer that is estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...

 positive.

Investigational/off-label

Bodybuilders who take anabolic steroids may also use AIs, such as anastrozole
Anastrozole
Anastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...

, to avoid estrogenic effects, such as gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...

, via preventing their elevated levels of testosterone from being converted to excess estrogen. Although anastrozole is reported by steroid users to work well in preventing and also reversing minor symptoms of gynecomastia, only the selective estrogen receptor modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...

, tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...

, has been shown to be more successful at treating pubertal gynecomastia than placebo. These results are not unexpected due to the significant etiological differences in steroid-induced gynecomastia (excess estrogen) and pubertal gynecomastia (hypersensitive tissue). Tamoxifen has been reported to be effective in treating both groups, showing the acute anti-estrogen action of tamoxifen on the affected tissue provides faster relief in the initial stages of treatment, especially as nipple pain or sensitivity is common in the steroid group, often occurring independently of tissue growth.

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 assay
Enzyme assay
Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.-Enzyme units:...

s, with white mushroom having shown the greatest ability to inhibit the enzyme. AIs have also been used experimentally in the treatment of adolescents whose predicted adult height was low.

Side effects

Side effects include an increased risk for developing osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 and joint disorders such as arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, arthrosis and arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....

. Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors, but also have another serious side effect, osteonecrosis of the jaw
Osteonecrosis of the jaw
Osteonecrosis of the jaw is a severe bone disease that affects the maxilla and the mandible. Various forms of ONJ have been described over the last 160 years, and a number of causes have been suggested in the literature...

. 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, and liver dysfunction. Patients with liver, kidney or adrenal abnormalities are at a higher risk of developing adverse events.
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