Aromatase inhibitors (AIs) are a class of

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

used in the treatment of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

postmenopausal Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

women and in men, and

gynecomastia Gynecomastia (also spelled gynaecomastia) 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. Updated by Brent Wisse ( ...

in men. They may also be used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...

to reduce estrogen conversion when supplementing testosterone

exogenously In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogen ...

. They may also be used for

chemoprevention Chemoprevention (also chemoprophylaxis) refers to the administration of a medication for the purpose of preventing disease or infection. Antibiotics, for example, may be administered to patients with disorders of immune system function to preven ...

in women at high risk for breast cancer.

Aromatase 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 ...

is the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that catalyzes a key aromatization step in the synthesis of

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

. 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 inhibitor An estrogen synthesis inhibitor is a type of drug which inhibits the enzymatic synthesis of estrogens, such as estradiol. They include: * Aromatase inhibitors (CYP19A1 inhibitors): inhibit the synthesis of estrogens from androgens * CYP17A1 inhibi ...

s. 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.

Medical uses

Cancer

In contrast to

premenopausal Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...

women, in whom most of the estrogen is produced in the

ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

, in

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 Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...

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 The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

and pituitary axis to increase

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...

secretion, which in turn stimulates the ovary to increase

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

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 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 b ...

(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 Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...

-positive breast cancer, women receiving the AI

anastrozole 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 ca ...

had better results than the tamoxifen group. 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 Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...

than tamoxifen, but few conventionally-analyzed clinicals trials have shown that AIs have an

overall survival Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...

advantage compared with tamoxifen, and there is no good evidence they are better tolerated.

Gynecomastia

Aromatase inhibitors have been approved for the treatment of gynecomastia in children and adolescents.

Ovulation induction

Ovarian stimulation with the aromatase inhibitor

letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most common ...

has been proposed for

ovulation induction Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles Ovulation Induction Retrieved on Mars 7, 2010 to reverse anovulation or oligoovulation. S ...

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

but not with clomiphene.

Side effects

In women, side effects include an increased risk for developing

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

and joint disorders such as arthritis,

arthrosis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...

, and

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

. Men do not appear to exhibit the same adverse effects on bone health.

Bisphosphonates Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...

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 (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws (the maxilla and the mandible). Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature. Oste ...

. 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 Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...

, aggressive behavior, adrenal insufficiency,

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

, 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 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 ...

, which converts

s into

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

women, while in

post-menopausal Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...

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 A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

. 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 The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

Types

There are two types of aromatase inhibitors approved to treat breast cancer: * Irreversible steroidal inhibitors, such as

exemestane 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 h ...

(Aromasin), forms a permanent and deactivating bond with the aromatase enzyme. * Nonsteroidal inhibitors, such as the triazoles

(Arimidex) and

(Femara), inhibit the synthesis of estrogen via reversible competition.

Members

Aromatase inhibitors (AIs) include:

Non-selective

* Aminoglutethimide (Elipten, Cytadren, Orimeten) *

Testolactone Testolactone (, ) (brand name Teslac) is a non-selective, irreversible, steroidal aromatase inhibitor which is used as an antineoplastic drug to treat advanced-stage breast cancer.

(Teslac)

Selective

Anastrozole 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 ca ...

(Arimidex) *

Letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most common ...

(Femara) *

Exemestane 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 h ...

(Aromasin) *

Vorozole Vorozole (developmental code name R-76713; former tentative brand name Rizivor) is a triazole based competitive inhibitor of the aromatase enzyme. It underwent clinical testing for evaluation for use as an antineoplastic agent; however it was wi ...

(R-76713; Rivizor) *

Formestane Formestane, formerly sold under the brand name Lentaron among others, is a steroidal, selective aromatase inhibitor which is used in the treatment of estrogen receptor-positive breast cancer in postmenopausal women. The drug is not active orally ...

(Lentaron) * Fadrozole (Afema)

Unknown

* 1,4,6-Androstatrien-3,17-dione (ATD) * 4-Androstene-3,6,17-trione ("6-OXO") In addition to pharmaceutical AIs, some natural elements have aromatase inhibiting effects, such as

damiana ''Turnera diffusa'', known as damiana, is a shrub native to southern Texas in the United States, Central America, Mexico, South America, and the Caribbean. It belongs to the family Passifloraceae. Damiana is a relatively small, woody shrub tha ...

leaves.

History

The development of aromatase inhibitors was first pioneered by the work of British pharmacologist

Angela Brodie Angela Hartley Brodie (28 September 1934 – 7 June 2017) was a British biochemist who pioneered development of steroidal aromatase inhibitors in cancer research. Born in Lancashire (now Greater Manchester), Brodie studied chemical patholo ...

at the

University of Maryland School of Medicine The University of Maryland School of Medicine (abbreviated UMSOM), located in Baltimore City, Maryland, U.S., is the medical school of the University of Maryland, Baltimore and is affiliated with the University of Maryland Medical Center and Me ...

, first demonstrating efficacy of

in clinical trials in 1982. The drug was first marketed in 1994. 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 Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins ...

. Extracts of certain

mushrooms A mushroom or toadstool is the fleshy, spore-bearing fruiting body of a fungus, typically produced above ground, on soil, or on its food source. ''Toadstool'' generally denotes one poisonous to humans. The standard for the name "mushroom" is ...

have been shown to inhibit aromatase when evaluated by

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 The quantity or concentration of an enzyme can be expressed in molar amounts, as with a ...

s, 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

Research suggests the common table mushroom has anti-

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 Green tea is a type of tea that is made from '' Camellia sinensis'' leaves and buds that have not undergone the same withering and oxidation process which is used to make oolong teas and black teas. Green tea originated in China, and since the ...

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. The extract from the herb

(Turnera diffusa) has been found to suppress aromatase activity, including the isolated compounds

pinocembrin Pinocembrin is a flavanone, a type of flavonoid. It is an antioxidant found in damiana, honey, fingerroot, and propolis Propolis or bee glue is a resinous mixture that honey bees produce by mixing saliva and beeswax with exudate gathere ...

and

acacetin Acacetin is a 4′- ''O''-methylated flavone of the parent compound apigenin, found in ''Robinia pseudoacacia ''Robinia pseudoacacia'', commonly known in its native territory as black locust, is a medium-sized hardwood deciduous tree, belon ...

Natural aromatase inhibitors

References

External links

* {{Assisted reproductive technology Hormonal antineoplastic drugs Progonadotropins