Aromatase deficiency is a rare genetic condition where the body cannot produce enough estrogen, the primary female sex hormone, due to a dysfunctional enzyme called aromatase. This enzyme is responsible for a step in hormone synthesis, and its absence leads to extremely low estrogen levels. Fewer than 50 cases have been reported in the medical literature, making it a difficult disorder to recognize and diagnose. The deficiency prevents the conversion of androgens (male hormones) into estrogens, resulting in a hormonal imbalance characterized by excess androgens and a near-complete lack of estrogen.
The Essential Biological Function of Aromatase
The aromatase enzyme (Cytochrome P450 19A1 or P450arom) catalyzes the final step in the biosynthesis of all estrogens. It belongs to the Cytochrome P450 superfamily. This process involves the conversion of androgen hormones into estrogen hormones through a chemical reaction called aromatization. Specifically, aromatase converts androstenedione into estrone and testosterone into estradiol, the most potent form of estrogen.
The enzyme is expressed in numerous tissues throughout the body, including the brain, adipose (fat) tissue, skin, bone, and the placenta during pregnancy. In women, the ovaries are the major site of activity before menopause, while in men, the enzyme’s function in extragonadal tissues is more significant. Aromatase action is necessary for maintaining bone health, regulating fat and glucose metabolism, and facilitating the proper maturation of growth plates in bones for both sexes.
Genetic Origin of Aromatase Deficiency
Aromatase deficiency is caused by specific mutations in the CYP19A1 gene, which provides the instructions for making the aromatase enzyme. This gene is located on chromosome 15 and is the sole genetic determinant for the enzyme’s production. The deficiency is inherited in an autosomal recessive pattern, meaning an individual must inherit a non-functional copy of the gene from both parents to develop the condition.
A wide variety of mutations have been identified in the CYP19A1 gene, including missense, nonsense, and deletion mutations. These genetic changes typically result in an enzyme that is either completely non-functional or is not produced at all. The resulting absence of aromatase activity halts the conversion of androgens to estrogens, directly causing the hormonal imbalance.
How Symptoms Manifest in Males and Females
The symptoms of aromatase deficiency differ significantly between affected females (46,XX) and males (46,XY), primarily due to the hormonal environment during fetal development and puberty. In affected females, the condition often leads to signs of virilization while still in the womb. This prenatal exposure to high levels of androgens can cause the external genitalia to appear ambiguous or masculinized at birth.
During childhood, affected girls may develop ovarian cysts due to the unregulated secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are not suppressed by estrogen. When they reach adolescence, a lack of estrogen prevents the development of secondary female sexual characteristics, such as breast development, and results in primary amenorrhea (the absence of a menstrual period). They also experience progressive virilization, including the growth of excessive body hair (hirsutism) and acne.
Affected males are typically born with normal external genitalia and undergo an unremarkable male puberty, as their sexual development relies on testosterone. The lack of estrogen becomes noticeable later in life, often presenting as a failure of the epiphyseal growth plates in the long bones to fuse. Since estrogen is necessary for skeletal maturation, its absence leads to continued linear growth well into adulthood, resulting in tall stature and a eunuchoid body proportion.
Both sexes face significant long-term health concerns related to bone and metabolic function. Estrogen is necessary for maintaining bone mineral density, and its absence leads to delayed skeletal maturation, low bone density, and a high risk of developing osteoporosis and fractures. Patients can also develop metabolic issues, including insulin resistance, dyslipidemia, obesity, and non-alcoholic steatohepatitis (fatty liver disease).
Identifying and Treating the Deficiency
Diagnosing aromatase deficiency begins with a detailed assessment of clinical symptoms, followed by specific hormone testing. Blood tests typically reveal a characteristic hormonal profile: extremely low, often undetectable, levels of estrogens (estradiol and estrone) coupled with elevated levels of androgen precursors and testosterone. These results, particularly when combined with physical findings like tall stature or ambiguous genitalia, strongly suggest the presence of the disorder.
The definitive diagnosis is confirmed through genetic testing, which analyzes the CYP19A1 gene for the presence of inactivating mutations. This genetic confirmation is important for differentiating aromatase deficiency from other disorders that can cause similar symptoms, such as congenital adrenal hyperplasia.
Once diagnosed, management centers on hormone replacement therapy (HRT), which is tailored to the patient’s age and sex. The primary treatment involves administering estrogen to replace the missing hormone and reverse the effects of its deficiency. In females, estrogen therapy is used to induce the development of secondary sexual characteristics, regulate menstrual cycles, and prevent ovarian cyst formation. In males, estrogen replacement is primarily aimed at promoting the closure of the growth plates to stop excessive linear growth, improve bone mineral density, and address metabolic issues. The treatment typically requires lifelong monitoring and adjustment of hormone doses to ensure optimal bone health, pubertal development, and metabolic function are maintained.