Aromatase Deficiency

Overview

Epidemiology

• Prevalence unknown 
• Fewer than 20 cases worldwide have been reported to date.

Genetics

• Karyotype: normal
• Etiology: mutation in the CYP19A1 gene, which plays a major role in aromatase enzyme synthesis
• Inheritance pattern: autosomal recessive

Pathophysiology

• The enzyme aromatase is needed to convert androgens (including testosterone) into estrogens.
  • Normally, aromatase is present in the placenta, ovaries, testes, adipose tissue, skin, and brain.
  • Estrogen levels are maintained by aromatase activity in the ovaries of women of childbearing age and in the adipose tissue of men and postmenopausal women.
• Mutation causes ↓ aromatase enzyme production → impaired estrogen biosynthesis due to inability to convert androgens into estrogen → ↓ estrogen and ↑ testosterone
• The placenta of a developing fetus with aromatase deficiency also lacks aromatase.
• Placenta fails to convert precursor androgens to estrogens → dehydroepiandrosterone sulfate (DHEAS) from fetal adrenal glands is converted to testosterone and androstenedione rather than estrogen.
• Uninhibited and excessive androgens cause virilization of the female fetus and of the mother.

Clinical Presentation

Clinical Phenotype

• Characteristics of the mother
  • Virilization begins during pregnancy, between the 12th and 30th week of gestation:
    • Acne
    • Deepening of voice
    • Hirsutism (excessive hair growth in male-like pattern)
    • Clitoromegaly
  • Symptoms resolve spontaneously shortly after giving birth.
• Characteristics of females (46,XX):
  • Pseudohermaphroditism (external genitalia resembles that of opposite sex)
  • Ambiguous/masculinized genitalia noted at birth
    • Labioscrotal fusion
    • Greatly enlarged phallus with a single meatus at its base
    • Present by 12th week of gestation
  • Female reproductive organs present
  • Normal growth and development in infancy and childhood
  • Signs of lack of estrogen and excessive testosterone noticed at pubertal age
    • Absent growth spurt
    • Progressive virilization
    • Delayed or lack of onset of puberty
    • Absence of breast development
    • Primary amenorrhea
    • Hypergonadotropic hypogonadism: ↑ follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with ↓ estrogen levels
    • Clitoromegaly
    • Acne
    • Normal axillary and pubic hair development
• Characteristics of males (46,XY):
  • Tall stature with continued linear growth into adulthood
  • No pubertal growth spurt
  • Eunuchoid body habitus (disproportionately long limbs relative to trunk)
  • Delayed epiphyseal closures
  • Progressive genu valgum (“knock knees”)
  • Normal male external genitalia
  • Normal sexual development and maturation
  • May have low libido in adulthood
  • Possible cryptorchidism (undescended testes)
  • Varying levels of spermatogenesis and fertility

Associated conditions

• Osteoporosis in men and women due to estrogen deficiency
• Glucose intolerance/diabetes
• Dyslipidemia
• Obesity
• Fatty liver disease
• Acanthosis nigricans (thickened, darkened skin)

Diagnosis and Management

Diagnosis

• History and physical examination
• Labs:
  • Pregnant women
    • ↓↓ Estriol and estradiol levels
    • ↑↑ Testosterone concentration
  • Girls in infancy/early childhood
    • ↑ FSH
    • Undetectable estrogen levels
  • Girls of pubertal age
    • Undetectable estrogen levels 
    • ↑↑ FSH and LH
    • ↑ Testosterone and androstenedione
  • Boys
    • ↑ FSH and LH
    • ↑ Testosterone
    • Undetectable estrogen levels
    • ↑ Basal insulin
    • ↓ Low HDL/LDL cholesterol ratio with ↓↓ HDL
• Imaging:
  • Urogenitogram may show urogenital sinus (only 1 opening/exit for both tracts).
  • Ultrasound shows enlarged polycystic ovaries. 
  • X-rays of pelvis and extremities show lack of epiphyseal fusion.
• Genetic testing

Management

• Females:
  • Surgical correction of ambiguous genitalia and urogenital sinus when present
  • Estrogen replacement starting as early as 2 years of age with close monitoring:
    • Maintains bone density
    • Decreases formation of ovarian cysts
    • In excess, can accelerate bone age and induce premature breast development
  • Estrogen increased at pubertal age (10–12 years of age) to induce:
    • Breast development
    • Growth spurt (normal height may be reached with treatment)
    • Menstrual cycles 
    • Regression of ovarian cysts
    • Increased bone density
  • Progesterone replacement therapy added within 2 years of pubertal level estrogen replacement to prevent endometrial hyperplasia
  • Combination oral contraceptives started at approximately 14 years of age for maintenance therapy
• Males:
  • Transdermal estradiol replacement beginning around age 14–16 years, or at time of diagnosis
  • Estrogen replacement necessary for:
    • Epiphyseal closure
    • Increasing and maintaining bone density
    • Improving sexual desire
    • Improving insulin resistance
    • Improving lipid profile
    • Normalizing LH, FSH, and testosterone levels
  • Life-long estrogen replacement
  • Monitoring for development of gynecomastia is necessary.
• All individuals:
  • Calcium and vitamin D supplementation
  • Genetic counseling

Differential Diagnosis

• True hermaphroditism: also known as ovotesticular disorder of sexual development (ODSD). The condition is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Patients have ambiguous genitalia at birth, with both male and female reproductive organs that can be seen on imaging. Karyotyping and gonadal biopsy help confirm the diagnosis. Treatment involves surgical reconstruction, removal of abnormal gonad, and hormone replacement therapy. 
• Congenital adrenal hyperplasia (CAH): consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme used in cortisol and/or aldosterone synthesis. This deficiency results in an increased formation of androgens with virilization of the external female genitals and is the most common cause of ambiguous genitalia in 46,XX genotypic females. All forms of CAH are characterized by low levels of cortisol, high levels of adrenocorticotropic hormone (ACTH), and adrenal hyperplasia. Surgical correction of ambiguous genitalia and lifelong glucocorticoid replacement therapy are needed.