Aromatase deficiency is a rare inherited disorder that prevents the body from producing estrogen. This condition affects individuals assigned male and female at birth, leading to varying physical manifestations due to hormonal imbalances. Fewer than 20 cases have been reported in medical literature as of 2021.
The Role of Aromatase and Genetic Causes
Aromatase is an enzyme that converts androgens, hormones involved in male sexual development, into estrogens, female sex hormones. This conversion process, known as aromatization, occurs in various tissues throughout the body, including the ovaries, testes, placenta, fat tissue, skin, and brain.
Aromatase deficiency results from mutations in both copies of the CYP19A1 gene, which provides instructions for making the aromatase enzyme. These mutations reduce or eliminate enzyme activity, leading to low estrogen levels and an accumulation of androgens like testosterone. The condition is inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated gene copy from each parent to be affected.
Signs and Symptoms in Females
Aromatase deficiency impacts females at different life stages, beginning before birth. During pregnancy with an affected female fetus, the placenta cannot convert fetal androgens into estrogens. These excess androgens cross into the mother’s bloodstream, causing temporary virilization. Symptoms may include cystic acne, increased hair growth, a deepened voice, and an enlarged clitoris, typically appearing as early as 12 weeks of gestation and resolving after delivery.
At birth, female infants with aromatase deficiency often present with ambiguous genitalia, meaning their external genitalia do not appear clearly male or female. This can include features like labioscrotal fusion and an enlarged clitoris. Despite these external changes, internal reproductive organs, such as the uterus, are typically normal.
As affected females grow into childhood and puberty, the lack of estrogen becomes more apparent. They may develop ovarian cysts, which can interfere with the release of egg cells. Puberty often fails to progress normally, resulting in a lack of breast development and the absence of menstrual periods (primary amenorrhea). Continued exposure to high androgen levels can also lead to increased body hair growth (hirsutism) and acne.
In adulthood, long-term estrogen deficiency and unopposed androgen action manifest. Females with aromatase deficiency may experience painful intercourse due to underdeveloped or atrophied vaginal tissues. Infertility is also a common concern due to lack of ovulation and proper uterine development. They are at an increased risk for osteoporosis, a condition characterized by weakened bones, because estrogen plays a role in maintaining bone density.
Signs and Symptoms in Males
Aromatase deficiency in males often goes undiagnosed at birth, as they typically have normal male external genitalia. Symptoms usually become noticeable later in childhood or adolescence, primarily affecting bone growth and metabolism. Males with the condition often exhibit tall stature, exceeding their genetic height potential, because their bone growth plates (epiphyses) do not fuse properly without sufficient estrogen. This prolonged linear growth can also be accompanied by bone pain.
As affected males reach adulthood, the consequences of long-term estrogen deficiency become more pronounced. They commonly develop severe osteoporosis, significantly increasing their risk of bone fractures with minimal trauma. Bones may show slowed mineralization and delayed bone age.
Aromatase deficiency also impacts metabolic health in males. They can develop insulin resistance, where the body’s cells do not respond effectively to insulin, potentially leading to high blood sugar levels (hyperglycemia) and an increased risk of type 2 diabetes. Abnormal lipid profiles and excessive weight gain are also observed. While males with aromatase deficiency generally have male sexual differentiation, some may experience decreased sex drive, abnormal sperm production, or undescended testes, affecting fertility.
Diagnosis and Management
Diagnosing aromatase deficiency involves a combination of hormone evaluations and genetic testing. Initial suspicion often arises from hormone tests showing very low or undetectable levels of estrogen, specifically estradiol, alongside elevated levels of androgens like testosterone. Gonadotropins, such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which regulate hormone production in the gonads, are also found at high levels.
A definitive diagnosis is confirmed through genetic testing, which identifies specific mutations in the CYP19A1 gene. This molecular analysis is accurate and helps distinguish aromatase deficiency from other conditions with similar symptoms, such as congenital adrenal hyperplasia. For female newborns with ambiguous genitalia, ruling out congenital adrenal hyperplasia is an important first step, and maternal virilization during pregnancy can further point towards aromatase deficiency.
Management of aromatase deficiency primarily involves lifelong estrogen replacement therapy for both sexes. Treatment goals differ based on gender and age. For females, estrogen therapy is initiated to induce puberty, promoting breast development and the onset of menstruation. It also helps maintain female secondary sex characteristics and can prevent ovarian cyst formation.
In males, estrogen replacement therapy aims to promote proper bone maturation and achieve epiphyseal closure, which helps normalize height and prevent excessive linear growth. It also works to increase bone mineral density, reducing the risk of osteoporosis and fractures. Estrogen therapy can also help improve metabolic issues like insulin resistance and abnormal lipid profiles.