Aromatase Excess Syndrome

Aromatase excess syndrome (AES or AEXS) is a rarely diagnosed genetic and endocrine syndrome characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of estrogen sex hormones from androgens, leading to high levels of circulating estrogens and symptoms of hyperestrogenism. It affects both sexes, causing marked or complete phenotypical feminization in males (excluding the genitalia; i.e., no ambiguous genitalia) and hyperfeminization in females.

To date, 30 males and 8 females with AEXS have been documented among 15 and 7 families, respectively, in the medical literature.

Signs and symptoms

Physiological abnormalities include significant overexpression of aromatase and elevated estrogen levels, such as estrone and estradiol, with a high rate of peripheral androgen-to-estrogen conversion. One study found cellular aromatase mRNA expression to be at least 10 times higher in a female patient compared to controls, and the estradiol/testosterone ratio after testosterone injection in a male patient was 100 times greater than controls. Another study showed androstenedione, testosterone, and dihydrotestosterone (DHT) to be low or normal in males, with very low follicle-stimulating hormone (FSH) levels due to estrogen's antigonadotropic effects, while luteinizing hormone (LH) levels were normal.

A recent review noted elevated estrone levels in 94% of patients, while estradiol was elevated in 48%. Estrone is the main elevated estrogen. Over half of patients had low to subnormal androstenedione and testosterone levels, with the estradiol to testosterone ratio >10 in 75% of cases. FSH levels are consistently low, and LH levels are low to normal.

Gynecomastia has been noted in patients with normal estradiol levels, possibly due to in situ conversion of adrenal androgens into estrone and estradiol in breast tissue, where aromatase activity might be high.

AEXS symptoms in males include heterosexual precocity (precocious puberty with inappropriate secondary sexual characteristics), severe prepubertal or peripubertal gynecomastia (breast development), high-pitched voice, sparse facial hair, hypogonadism, oligozoospermia, small testes, micropenis, advanced bone maturation, early peak height velocity, and short final stature due to early epiphyseal closure. Gynecomastia is present in 100% of cases, with 20 of 30 males opting for mastectomy.

In females, AEXS symptoms include isosexual precocity, macromastia, enlarged uterus, menstrual irregularities, accelerated bone maturation, and short final height. Of seven females documented, three had macromastia. Pubertal breast hypertrophy has been noted in two young girls.

Fertility, while often affected, does not always prevent sexual reproduction, as evidenced by vertical transmission of the condition by both sexes.

Cause

The exact cause of AEXS is unclear, but it is linked to inheritable, autosomal dominant genetic mutations in CYP19A1, the gene encoding aromatase. Different mutations lead to varying symptom severity, such as mild to severe gynecomastia. For instance, duplications cause mild gynecomastia, while deletions leading to chimeric genes result in moderate or severe gynecomastia.

Diagnosis

Genetic testing is available to identify CYP19A1 variants associated with AEXS. The National Institutes of Health provides a list.

Treatment

Effective treatments for AEXS include aromatase inhibitors and gonadotropin-releasing hormone analogues for both sexes, androgen replacement therapy with non-aromatizable androgens like DHT in males, and progestogens to suppress estrogen levels in females. Male patients often seek bilateral mastectomy, while females may choose breast reduction if necessary.

Although medical treatment for AEXS is not mandatory, it is advised to prevent complications like excessively large breasts, fertility issues, and increased risks of endometriosis and estrogen-dependent cancers such as breast and endometrial cancers later in life. A case of male breast cancer has been reported.