Aromatase excess syndrome

Overview

Aromatase Excess Syndrome (AEXS) is a rare genetic disorder characterized by increased activity of the enzyme aromatase, which converts androgens (male sex hormones) into estrogens (female sex hormones). This excessive conversion leads to abnormally high levels of estrogen in both males and females, with more noticeable effects in males, including signs of feminization, gynecomastia, and short stature due to premature growth plate closure.

AEXS is inherited in an autosomal dominant pattern and can affect both sexes, though it tends to produce more severe symptoms in males due to the imbalance between androgen and estrogen levels.

Causes

Aromatase Excess Syndrome is caused by genetic mutations or duplications involving the CYP19A1 gene, which encodes the aromatase enzyme. These mutations usually result in increased expression or activity of the enzyme in tissues where it is not normally active at such high levels (e.g., adipose tissue, skin, testis).

This leads to an abnormally high peripheral conversion of androgens to estrogens, even in the absence of elevated aromatase gene expression in typical tissues such as the ovaries or placenta.

Symptoms

In Males:

• Gynecomastia: Abnormal breast development, often appearing in early childhood or puberty

• Decreased facial and body hair

• Short stature: Due to premature epiphyseal (growth plate) closure

• Advanced bone age relative to chronological age

• Reduced fertility or testicular abnormalities in severe cases

In Females:

• May be asymptomatic or show mild signs of early puberty (precocious thelarche)

• Irregular menstrual cycles or excessive estrogen-related symptoms in some cases

Diagnosis

Diagnosis of Aromatase Excess Syndrome involves clinical, hormonal, and genetic evaluation:

• Physical examination: Presence of gynecomastia, advanced growth, or reduced secondary male characteristics

• Hormonal studies:

  • Elevated serum estradiol and estrone levels

  • Low or normal testosterone (with a low testosterone-to-estradiol ratio)

  • Suppressed gonadotropins (LH, FSH) due to negative feedback from high estrogen

• Bone age assessment: Advanced skeletal maturation for age

• Genetic testing: Identification of duplications or rearrangements in the CYP19A1 gene

Treatment

Treatment is aimed at reducing estrogen production or blocking its effects. Options include:

Pharmacologic Therapy:

• Aromatase inhibitors: Such as anastrozole or letrozole, to block the conversion of androgens to estrogens

• Selective estrogen receptor modulators (SERMs): Such as tamoxifen to block estrogen action, particularly in cases of gynecomastia

Supportive Care:

• Surgical correction (e.g., mastectomy) for persistent gynecomastia if medically unresponsive

• Monitoring growth and development during puberty

Prognosis

With early diagnosis and appropriate hormonal therapy, most individuals with Aromatase Excess Syndrome can achieve normal growth and prevent long-term complications. Key prognostic considerations include:

• Effective treatment can reduce gynecomastia and delay premature growth plate fusion

• Long-term fertility is usually preserved with proper hormonal balance

• Untreated cases may result in psychosocial distress, short stature, and potential fertility issues

Ongoing endocrinological monitoring is essential to manage hormone levels and optimize physical development during adolescence and adulthood.