Aromatase deficiency is a condition characterized by reduced levels of the female sex hormone estrogen and increased levels of the male sex hormone testosterone.

Females with aromatase deficiency have a typical female chromosome pattern (46,XX) but are born with external genitalia that do not appear clearly female or male. These individuals typically have normal internal reproductive organs, but develop ovarian cysts early in childhood, which impair the release of egg cells from the ovaries (ovulation). In adolescence, most affected females do not develop secondary sexual characteristics, such as breast growth and menstrual periods. They tend to develop acne and excessive body hair growth (hirsutism).

Men with this condition have a typical male chromosome pattern (46,XY) and are born with male external genitalia. Some men with this condition have decreased sex drive, abnormal sperm production, or testes that are small or undescended (cryptorchidism).

There are other features associated with aromatase deficiency that can affect both males and females. Affected individuals are abnormally tall because of excessive growth of long bones in the arms and legs. The abnormal bone growth results in slowed mineralization of bones (delayed bone age) and thinning of the bones (osteoporosis), which can lead to bone fractures with little trauma. In affected individuals, the body does not respond correctly to the hormone insulin, so people with aromatase deficiency can have abnormally high blood sugar (glucose), a condition known as hyperglycemia. In addition, people with armoatase deficiency can have excessive weight gain and a fatty liver.

Women who are pregnant with fetuses that have aromatase deficiency often experience mild symptoms of the disorder even though they themselves do not have the disorder. These women may develop hirsutism, acne, an enlarged clitoris (clitoromegaly), and a deep voice. These features can appear as early as 12 weeks of pregnancy and go away soon after delivery.

Mutations in the CYP19A1 gene cause aromatase deficiency. The CYP19A1 gene provides instructions for making an enzyme called aromatase. This enzyme converts a class of hormones called androgens, which are involved in male sexual development, to different forms of estrogen. In females, estrogen guides female sexual development before birth and during puberty. In both males and females, estrogen plays a role in regulating bone growth and blood glucose levels. During fetal development, aromatase converts androgens to estrogens in the placenta, which is the link between the mother's blood supply and the fetus. This conversion in the placenta prevents androgens from directing sexual development in female fetuses. After birth, the conversion of androgens to estrogens takes place in multiple tissues.

CYP19A1 gene mutations that cause aromatase deficiency decrease or eliminate aromatase activity. A shortage of functional aromatase results in an inability to convert androgens to estrogens before birth and throughout life. As a result, there is a decrease in estrogen production and an increase in the levels of androgens, including testosterone. In affected individuals, these abnormal hormone levels lead to impaired female sexual development, unusual bone growth, insulin resistance, and other signs and symptoms of aromatase deficiency. In women who are pregnant with an affected fetus, excess androgens in the placenta pass into the woman's bloodstream, which may cause her to have temporary signs and symptoms of aromatase deficiency.

Normal Function

The CYP19A1 gene provides instructions for making an enzyme called aromatase. This enzyme converts a class of hormones called androgens, which are involved in male sexual development, to different forms of the female sex hormone estrogen.

In cells, aromatase is found in a structure called the endoplasmic reticulum, which is involved in protein production, processing, and transport. The activity (expression) of aromatase varies among different cell types depending on the cells' need for estrogen. In females, aromatase is most active in the ovaries, where it guides sexual development. In males, aromatase is most active in fat (adipose) tissue. In both males and females, estrogen plays a role in regulating bone growth and blood sugar (glucose) levels. During fetal development, aromatase converts androgens to estrogens in the placenta, which is the link between the mother's blood supply and the fetus. This conversion in the placenta prevents androgens from directing sexual development in female fetuses. After birth, the conversion of androgens to estrogens takes place in multiple tissues.

Health Conditions Related to Genetic Changes

Aromatase deficiency

More than 20 mutations in the CYP19A1 gene have been found to cause aromatase deficiency. This condition is characterized by reduced levels of estrogen and increased levels of androgens. These abnormal hormone levels lead to impaired sexual development in affected females and unusual bone growth, insulin resistance, and other signs and symptoms in both males and females with the condition. CYP19A1 gene mutations that cause aromatase deficiency decrease or eliminate aromatase activity. A lack of aromatase function results in an inability to convert androgens to estrogens before birth and throughout life. As a result, there is a decrease in estrogen production and an increase in the levels of androgens, including testosterone. In women who are pregnant with an affected fetus, excess androgens in the placenta pass into the woman's bloodstream, and may cause her to have temporary signs and symptoms of aromatase deficiency.

Aromatase excess syndrome

More than 10 rearrangements of genetic material involving the CYP19A1 gene have been found to cause aromatase excess syndrome. This condition is characterized by the increased conversion of androgens to estrogen. As a result, affected males have enlarged breasts (gynecomastia) and short stature; affected females can have irregular menstrual periods and short stature.

Several types of genetic rearrangement involving the CYP19A1 gene can cause aromatase excess syndrome. Some genetic rearrangements that cause aromatase excess syndrome duplicate parts of the CYP19A1 gene, doubling some of the instructions used for making the enzyme. As a result, more enzyme than normal is produced. Other genetic rearrangements, called deletions, remove (delete) parts of the CYP19A1 gene and a nearby gene. The remaining DNA is then fused together, creating a fusion gene composed of parts of two different genes. These fusion genes always contain part of the CYP19A1 gene, but can involve a piece of one of several other genes. As a result of these fusion genes, the CYP19A1 gene is active (expressed) in tissues where it is not normally expressed so more aromatase than normal is produced. Another type of rearrangement, called an inversion, occurs when DNA is broken in two places and the resulting piece of DNA is reversed and reinserted into the chromosome. Inversions involving the CYP19A1 gene and a nearby gene also result in the production of a fusion gene. These fusion genes lead to increased aromatase production.

The increase in aromatase production caused by CYP19A1 gene rearrangements leads to increased estrogen production, which results in the signs and symptoms of aromatase excess syndrome.

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Other Names for This Gene

• ARO
• ARO1
• aromatase
• CP19A_HUMAN
• CPV1
• CYAR
• CYP19
• CYPXIX
• cytochrome P-450AROM
• cytochrome P450 19A1
• cytochrome P450, family 19, subfamily A, polypeptide 1
• cytochrome P450, subfamily XIX (aromatization of androgens)
• estrogen synthase
• estrogen synthetase
• flavoprotein-linked monooxygenase
• microsomal monooxygenase
• P-450AROM

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The prevalence of aromatase deficiency is unknown; approximately 20 cases have been described in the medical literature.