Aromatase Deficiency

Aromatase deficiency is an uncommon condition marked by very low or absent levels of the enzyme aromatase activity in the body. It is an autosomal recessive disorder caused by various mutations in the CYP19 (P450arom) gene, which can result in ambiguous genitalia and delayed puberty in females, continued growth into adulthood, and osteoporosis in males, as well as virilization in pregnant mothers. As of 2020, fewer than 15 cases have been documented in genetically male individuals and at least 30 cases in genetically female individuals.

Signs and symptoms

The deficiency leads to the virilization of XX fetuses. Symptoms typically emerge during adolescence or early adulthood. The absence of estrogen results in primary amenorrhea and increased height. The greater than expected height occurs because estrogen usually causes the fusion of the epiphyseal growth plates in the bones, and without it, the patient continues to grow. The gonadotropins LH and FSH are both elevated, and patients exhibit polycystic ovaries. Additionally, the low estrogen levels increase the risk of osteoporosis.

Female

• After birth, female infants often show ambiguous genitalia, including labioscrotal fusion, clitoromegaly, and phallic genitalia. Hyperandrogenism is present at birth, along with low estrogen levels in the blood. However, they have normal internal female genitalia. Documented cases have shown Prader scale ratings between II and V, with most classified as IV (11 out of 23 cases) or III (7 out of 23 cases). Some 46,XX individuals are assigned male at birth due to sufficiently virilized genitalia, and a male gender identity persisted in some of these cases.

  
  

• During puberty, progressive signs of virilization, such as increased body hair, can be observed, along with puberty failure due to the lack of estradiol action. The disruption of the LHRH-LH/FSH axis results in delayed bone age without a growth spurt.

  
  

• In adulthood, symptoms include virilization, absence of breast development, primary amenorrhea, infertility, and multicystic ovaries.

  
  

• Other symptoms include hypergonadotropic hypogonadism, polycystic ovaries, hypoplastic ovaries, and tall stature.

  
  

Male

Symptoms typically appear in adulthood:

• Tall stature, osteopenia, osteoporosis, Type II Diabetes, hyperinsulinemia, acanthosis nigricans, lipid metabolism disorders, and impaired liver function.

During pregnancy

During pregnancy, a baby with Aromatase Deficiency can cause the mother to become virilized, leading to a deeper voice, cystic acne, excessive hair growth, cliteromegaly, and hirsutism. The mother also experiences increased circulating testosterone levels. However, these symptoms usually subside after childbirth.

Complications

Pregnant mother

Aromatase is an enzyme that synthesizes estrone (E1) and estradiol (E2) from Androstenedione and Testosterone respectively. During pregnancy, the placenta, which is fetal tissue, produces large amounts of intermediates in the biosynthesis of estrogens, androstenedione and testosterone, but cannot convert them to estrogens due to the lack of aromatase. The accumulated androgen levels in the mother can rise up to 100 times higher than normal, leading to virilization of both the mother and the fetus. The mother may experience cystic acne, voice deepening, and hirsutism, but these symptoms typically resolve after delivery.

If the fetus is male, it will develop normal male genitalia and grow normally, showing secondary male sexual characteristics. If the fetus is female, it will be born with ambiguous genitalia, such as labioscrotal fusion and a significantly enlarged phallus.

Female

Females lacking aromatase cannot produce estrone or estradiol, leading to a significant buildup of androgens in the blood. This disrupts the LHRH-LH/FSH axis, potentially causing polycystic ovaries in adulthood. Without estrogen, high levels of circulating LH and FSH result in hypergonadotropic hypogonadism.

During adolescence, females begin to exhibit virilization and hair growth in various areas, but they cannot menstruate without estradiol, leading to primary amenorrhea, clitoromegaly, and lack of breast development. Puberty does not progress, resulting in an absence of growth spurts and delayed bone age. Without intervention, the excess androgens can lead to polycystic ovary development.

Male

Males with aromatase deficiency grow normally into adulthood. However, the very low circulating estrogen levels (<7 pg/mL) cause elevated FSH and LH levels in the blood. High androgen levels do not promote skeletal muscle growth harmoniously like estrogen, resulting in a eunuchoid body habitus.

These individuals are typically tall and continue linear bone growth into adulthood. Without estrogen, epiphyseal plates do not fuse properly, allowing continuous height increase. Estrogen is crucial for bone homeostasis, and its deficiency leads to osteopenia and osteoporosis in the lumbar spine and cortical bone. Estrogen may also be linked to abnormal lipid profiles and hyperinsulinemia in men, though the exact mechanism is unclear.

Cause

Gene Mutation

Aromatase deficiency is an autosomal recessive condition, with most mutations occurring in the highly conserved regions of the gene. Both homozygous and heterozygous mutations have been found at various locations on the exon of the P450 arom (CYP19) gene on chromosome 15p21.1. Additionally, mutations in cytochrome P450 oxidoreductase (POR), necessary for aromatase's enzymatic activity, can also cause aromatase deficiency.

Diagnosis

A fetus may be suspected of having aromatase deficiency if the pregnant mother shows signs of virilization. A female infant can be diagnosed physically due to abnormal genitalia and hormonal blood tests. The diagnosis is considered for any virilized 46,XX child when congenital adrenal hyperplasia is ruled out. In males, the condition might be suspected in late teens or twenties if they exhibit continued linear growth and bone pain. Extremely low estrogen levels and high androgens are diagnostic markers for aromatase deficiency in both genders. Testosterone levels in the urine may be normal or elevated.

Treatment

In males, transdermal estradiol replacement facilitates epiphyseal plates closure, enhances bone density, promotes skeletal maturation, normalizes FSH and LH levels, and reduces insulin blood concentration.

In females, hormonal replacement therapy, such as cyclic oral therapy with conjugated estrogen, results in breast development, menses, pubertal growth spurts, resolution of ovarian cysts, suppression of elevated FSH and LH levels in the blood, and proper bone growth. Ambiguous genitalia, clitoromegaly, and ovarian cysts can be surgically removed (provided it is not illegal).