Hypogonadism

Hypogonadism is a clinical syndrome associated with impaired function of the gonads. Both males and females can be affected. It is classified as either primary or secondary: Primary hypogonadism (hypergonadotropic hypogonadism) is typically caused by congenital differences (differences of sex development affecting the gonads (e.g., Turner syndrome, Klinefelter syndrome) or acquired gonadal injury (e.g., irradiation, infection). Secondary hypogonadism (hypogonadotropic hypogonadism) is most often caused by pituitary or hypothalamic disorders (e.g, craniopharyngioma, Kallmann syndrome). Characteristic features in males include testicular hypoplasia, gynecomastia, and absent facial hair growth, while females commonly present with amenorrhea. Following clinical evaluation, the diagnosis is confirmed with hormone tests, and genetic testing may be considered. Treatment involves management of the underlying cause and hormone replacement therapy.

Hypogonadism is a clinical syndrome associated with impaired functional activity of the gonads.

Hypergonadotropic hypogonadism (primary hypogonadism)

Hypergonadotropic hypogonadism is caused by insufficient sex steroid production in the gonads.

• Primary gonadal insufficiency: Turner syndrome (females), Klinefelter syndrome (males), anorchia
• Secondary gonadal insufficiency (damage to Leydig cells or ovarian tissue): chemotherapy, pelvic irradiation, trauma/surgery, autoimmune disease (e.g, autoimmune polyglandular syndrome), infections (e.g., mumps, tuberculosis)

Hypogonadotropic hypogonadism (secondary hypogonadism)

Hypogonadotropic hypogonadism is caused by an insufficient gonadotropin-releasing hormone (GnRH) and/or gonadotropin release at the hypothalamic-pituitary axis.

• Genetic disorders
  • Kallmann syndrome
  • Idiopathic hypogonadotropic hypogonadism (IHH): a genetic disorder characterized by a defect in GnRH production/action in the absence of anosmia
  • Prader-Willi syndrome
  • Gaucher disease
• Hypothalamic and/or pituitary lesions
  • Neoplasm (e.g. prolactinoma, craniopharyngioma, astrocytoma)
  • Trauma, surgery, irradiation
  • Infection
• Eating disorders (functional hypothalamic amenorrhea)
• Drugs (e.g., opioids ) ^[1]

Diminished functional activity of the gonads → reduced biosynthesis of sex hormones → impaired secondary sexual characteristics and infertility

• Hypergonadotropic hypogonadism: gonadal insufficiency; → insufficient sex steroid production (↓ testosterone, ↓ estrogen) → increased gonadotropin secretion (↑ FSH and ↑ LH) from the anterior pituitary → lack of negative feedback from the impaired gonads → further ↑ FSH and ↑ LH levels
• Hypogonadotropic hypogonadism
  • In Kallmann syndrome; : impaired migration of GnRH cells and defective olfactory bulb → ↓ GnRH in hypothalamus → ↓ FSH and ↓ LH → ↓ testosterone and ↓ estrogen
  • In hypothalamic and/or pituitary lesions: ↓ pituitary gonadotropins (↓ FSH and ↓ LH) → ↓ testosterone and ↓ estrogen

• Delayed puberty (see “Tanner stages”)
  • ♂
    • Testicular hypoplasia
    • ↓ Body hair growth (e.g., absent facial hair)
    • High-pitched voice
    • Smooth skin (no acne)
    • ↓ Lean body mass
  • ♀: primary amenorrhea
• Developmental abnormalities with genitalia (undescended testes, hypospadias)
• Infertility (↓ sperm count), impotence, and/or ↓ libido
• Secondary amenorrhea
• Examine patient for features of:
  • Klinefelter syndrome: gynecomastia
  • Turner syndrome: webbed neck, short stature
  • Kallmann syndrome: anosmia, absent breast development, uterus is present, syndactyly, cleft palate or cleft lip
  • Prader-Willi syndrome: muscular hypotonia, short stature, facial dysmorphia
  • Gaucher disease: hepatomegaly, splenomegaly, painful bone crisis

• Routine tests
  • ↓ Serum testosterone levels (in males; usually < 300 ng/dL) and ↓ serum estrogen levels (in females)
  • Determine if the source is primary or secondary hypogonadism.
    • Hypergonadotropic hypogonadism: ↑ GnRH, ↑ LH/FSH
    • Hypogonadotropic hypogonadism: ↓ GnRH, ↓ LH/FSH
  • Bone scan may support the diagnosis of hypogonadism: shows ↓ bone density (osteoporosis ) or delayed epiphyseal closure
• Further tests: based on suspected etiology
  • Genetic testing (for, e.g., Klinefelter syndrome, Turner syndrome, Kallmann syndrome)
  • Serum prolactin (↑ in prolactinoma)
  • Pelvic ultrasound (e.g., gonadal dysgenesis in Klinefelter syndrome)
  • Brain MRI: for CNS lesion or Kallmann syndrome (e.g., absent olfactory bulbs in Kallmann syndrome)
  • Adrenocorticotropic hormone stimulation test (ACTH stimulation test): to exclude congenital adrenal hyperplasia

• Treat underlying cause: e.g., surgical excision of tumors, pharmacotherapy for prolactinomas
• Hormone replacement therapy
  • Trigger onset of puberty in prepubertal individuals at appropriate age
    • Testosterone replacement therapy in males
    • Estrogen replacement therapy in females
  • To improve fertility in postpubertal individuals with hypogonadotropic hypogonadism and, if prepubescent, an alternative to triggering onset of puberty and growth
    • Pulsatile luteinizing hormone-releasing hormone (LHRH) or human chorionic gonadotropin (HCG) in males
    • Pulsatile LHRH or gonadotropins in females