Aromatase

Aromatase is an enzyme of the cytochrome P450 superfamily (EC 1.14.14.1), whose function is to aromatize androgens (that is, to selectively increase their aromaticity), producing estrogens. As such, it is an important factor in sexual development.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and catalyzes the last steps of estrogen biosynthesis, three successive hydroxylations of the A ring of androgens. Mutations in this gene can result in either increased or decreased aromatase activity; the associated phenotypes suggest that estrogen functions both as a sex steroid hormone and in growth or differentiation. The gene expresses two transcript variants.^[1]

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Genomics

In humans, the gene CYP19, located on chromosome 15q21.1, encodes the aromatase enzyme. CYP19 is present in an early-diverging chordate, the cephalochordate amphioxus (the Florida lancelet, Branchiostoma floridae), but not in the earlier diverging tunicate Ciona intestinalis. Thus the aromatase gene evolved early in chordate evolution and does not appear to be present in non-chordate invertebrates (e.g. insects, molluscs, echinoderms, sponges, corals). However, estrogens may be synthesized in some of these organisms, via unknown pathways.

Cellular and tissue location

The enzyme is located in the endoplasmic reticulum of the cell and its activity is regulated by tissue specific promoters that are in turn controlled by hormones, cytokines, and other factors. The principal action of the enzyme transforms androstenedione to estrone and testosterone to estradiol. The aromatase enzyme can be found in many tissues including gonads, brain, adipose tissue, placenta, blood vessels, skin, bone, endometrium as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer.

Activity

Factors known to increase aromatase activity include age, obesity, insulin, gonadotropins, and alcohol. Aromatase activity is decreased by prolactin, AMH, and smoking. Aromatase activity appears to be enhanced in certain estrogen-dependent local tissue next to breast cancer, endometrial cancer, endometriosis, and uterine fibroids.

Disorders

Aromatase excess syndrome

A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys it can lead to gynecomastia and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to shortness.

Aromatase deficiency syndrome

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

Aromatase inhibitors

The inhibition of the enzyme leads to profound hypoestrogenism (low estrogen levels). Thus aromatase inhibitors have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive.

References

Further reading