Aromatase

Aromatase, also called estrogen synthetase or estrogen synthase, is an is_associated_with::enzyme responsible for a key step in the is_associated_with::biosynthesis of is_associated_with::estrogens. It is a member of the is_associated_with::cytochrome P450 superfamily, which are is_associated_with::monooxygenases that catalyze many reactions involved in is_associated_with::steroidogenesis. In particular, aromatase is responsible for the aromatization of is_associated_with::androgens into is_associated_with::estrogens. The aromatase enzyme can be found in many tissues including is_associated_with::gonads, is_associated_with::brain, is_associated_with::adipose tissue, is_associated_with::placenta, is_associated_with::blood vessels, is_associated_with::skin, and is_associated_with::bone, as well as in tissue of is_associated_with::endometriosis, is_associated_with::uterine fibroids, is_associated_with::breast cancer, and is_associated_with::endometrial cancer. It is an important factor in is_associated_with::sexual development.

Function
Aromatase is localized in the is_associated_with::endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by is_associated_with::hormones, is_associated_with::cytokines, and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms is_associated_with::androstenedione to is_associated_with::estrone and is_associated_with::testosterone to is_associated_with::estradiol). These steps include three successive is_associated_with::hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.

Genomics
The gene expresses two transcript variants. In humans, the is_associated_with::gene CYP19, located on is_associated_with::chromosome 15q21.1, encodes the aromatase enzyme. The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.

CYP19 is present in an early-diverging is_associated_with::chordate, the is_associated_with::cephalochordate is_associated_with::amphioxus (the Florida is_associated_with::lancelet, Branchiostoma floridae), but not in the earlier diverging is_associated_with::tunicate is_associated_with::Ciona intestinalis. Thus, the aromatase gene evolved early in chordate evolution and does not appear to be present in nonchordate is_associated_with::invertebrates (e.g. is_associated_with::insects, is_associated_with::molluscs, is_associated_with::echinoderms, sponges, is_associated_with::corals). However, is_associated_with::estrogens may be synthesized in some of these organisms, via other unknown pathways.

Activity
Factors known to increase aromatase activity include age, is_associated_with::obesity, is_associated_with::insulin, is_associated_with::gonadotropins, and alcohol. Aromatase activity is decreased by is_associated_with::prolactin, is_associated_with::anti-Müllerian hormone and the common herbicide is_associated_with::glyphosate. Aromatase activity appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer, endometriosis, and uterine fibroids.

Role in sex-determination
Aromatase is generally highly present during the differentiation of ovaries. It is also susceptible to environmental influences, particularly temperature. In species with is_associated_with::temperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring. Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at a male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see is_associated_with::sex reversal). In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD (for challenges to this argument, see is_associated_with::temperature-dependent sex determination). It varies from species to species whether it is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures.

Role in neuroprotection
Aromatase in the brain is usually only expressed in is_associated_with::neurons. However, following penetrative brain injury of both mice and zebra finches, it has been shown to be expressed in is_associated_with::astrocytes. Furthermore, it has also been shown to decrease is_associated_with::apoptosis following brain injury in zebra finches. This is thought to be due to the is_associated_with::neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines, interleukin-1β (IL-1β) and is_associated_with::interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.

Aromatase excess syndrome
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to is_associated_with::gynecomastia, and in girls to is_associated_with::precocious puberty and is_associated_with::gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase. It is inherited in an autosomal dominant fashion. It has been suggested that the pharaoh is_associated_with::Akhenaten and other members of his family may have suffered from this disorder, but more recent genetic tests suggest otherwise. It is one of the causes of familial precocious puberty—a condition first described in 1937.

Aromatase deficiency syndrome
This syndrome is due to a mutation of gene CYP19 and inherited in an is_associated_with::autosomal recessive way. Accumulations of androgens during pregnancy may lead to is_associated_with::virilization of a female at birth (males are not affected). Females will have primary is_associated_with::amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure.

Inhibition of aromatase
The inhibition of aromatase can cause is_associated_with::hypoestrogenism (low estrogen levels). The following natural elements have been found to have inhibiting effects on aromatase.


 * is_associated_with::Apigenin,
 * is_associated_with::Catechin,
 * Chalcones,
 * is_associated_with::Eriodictyol,
 * is_associated_with::Isoliquiritigenin,
 * is_associated_with::Mangostin,
 * is_associated_with::Myosmine,
 * is_associated_with::Nicotine,
 * is_associated_with::Resveratrol,
 * is_associated_with::Vitamin E,
 * is_associated_with::Zinc.

Extracts of certain (white button variety: is_associated_with::Agaricus bisporus) is_associated_with::mushrooms have been shown to inhibit aromatase in vitro.

Pharmaceutical aromatase inhibitors
is_associated_with::Aromatase inhibitors, which stop the production of estrogen in is_associated_with::postmenopausal women, have become useful in the management of patients with is_associated_with::breast cancer whose lesion was found to be is_associated_with::estrogen receptor positive. Inhibitors that are in current clinical use include is_associated_with::anastrozole, is_associated_with::exemestane, and is_associated_with::letrozole. Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems.