Aromatase deficiency

Aromatase deficiency (also known as CYP19A1 deficiency or estrogen synthetase deficiency) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations in the CYP19A1 gene, which encodes the aromatase enzyme. Aromatase is responsible for converting androgens (such as testosterone and androstenedione) into estrogens (estradiol and estrone). When this enzyme is absent or non-functional, estrogen cannot be produced, leading to a buildup of androgens and a complete or near-complete lack of estrogen throughout the body. The condition affects multiple body systems and manifests differently depending on sex and age. During pregnancy, excess androgens from the affected fetus can cross the placenta and cause virilization (masculinization) of the mother, including acne, deepening of the voice, and clitoromegaly, which typically resolves after delivery. Affected 46,XX females are born with ambiguous genitalia (disorders of sex development) due to prenatal androgen excess, including clitoromegaly and labial fusion, despite having normal internal female reproductive structures. At puberty, affected females fail to develop breasts, experience primary amenorrhea, and may develop ovarian cysts due to elevated gonadotropins. Affected 46,XY males typically appear normal at birth but present later with tall stature, continued linear growth due to unfused epiphyses, delayed bone age, osteoporosis, and eunuchoid body proportions. Both sexes may develop insulin resistance, dyslipidemia, and hepatic steatosis. Treatment centers on estrogen replacement therapy, which is essential for both sexes. In females, estrogen therapy induces puberty, promotes breast development, establishes menstrual cycles, and protects bone health. In males, low-dose estrogen therapy promotes epiphyseal closure, improves bone mineral density, and may improve metabolic parameters. Surgical correction of ambiguous genitalia may be considered in affected females. Long-term monitoring of bone density, metabolic health, and reproductive function is recommended. Fewer than 30 cases have been reported in the medical literature worldwide.

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