Hypogonadism in Male Children (Infancy Through Adolescence)

Background

• Hypogonadism in male children refers to decreased testicular function compared to age-appropriate testes function.
  • Hypogonadism may be associated with disruption of ≥ 1 hormone levels of the hypothalamic-pituitary-testicular axis and/or disorder of spermatogenesis.
  • Clinically, hypogonadism in male children can result in ambiguous or abnormal genitalia in infants or delayed or arrested pubertal development in adolescents.
• Hypogonadism in children may be present at birth (fetal-onset hypogonadism) or may occur after birth (postnatal-onset hypogonadism).
• Hypogonadism can be classified according to the location of the dysfunction along the hypothalamic-pituitary-testicular axis.
  • Primary hypogonadism (hypergonadotropic hypogonadism) is caused by primary testicular failure due to impaired Leydig cell function and results in low testosterone levels, impairment of spermatogenesis, and elevated gonadotropin levels.
  • Secondary hypogonadism (hypogonadotropic hypogonadism) is caused by central defects of the hypothalamus or pituitary gland and results in low or normal gonadotropin levels and low testosterone levels (inadequate gonadotropic stimulation of Leydig cells).
  • Combined primary and secondary hypogonadism is caused by combined primary and secondary testicular failure and results in low testosterone levels, impaired spermatogenesis, and variable gonadotropin levels (depending on whether primary or secondary testicular failure is predominant).

Evaluation

• Evaluation should be based on a thorough history and physical examination.
• Diagnostic testing varies based on age of presentation.
  • In neonates and infants < 6 months old presenting with abnormal external genitalia:
    • Measure serum hormone levels including testosterone level, anti-Müllerian hormone (AMH), and inhibin B levels.
      • Persistently low levels (compared to age-appropriate normal values) suggests hypogonadism.
      • Normal levels rule out testicular dysfunction.
    • Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to distinguish between primary and secondary hypogonadism.
      • Elevated levels of LH and FSH suggests primary hypogonadism.
      • Low or inappropriately normal levels of LH and FSH suggests secondary hypogonadism, except in patients with mutations in LH beta or FSH beta when affected gonadotropin is undetectable, but the other gonadotropin level is high.
      • LH and FSH may be high, low, or normal in combined primary and secondary hypogonadism, depending on the predominant underlying process.
  • In infants > 6 months old and prepubertal boys presenting with abnormal external genitalia:
    • Measuring testosterone and gonadotropins is usually not useful for diagnosis of secondary hypogonadism because levels decline after age 6 months and remain low until puberty.
    • Diagnosis of hypogonadism can be made by measuring other hormone levels, including AMH and inhibin B.
      • Persistently low levels of AMH and inhibin B (compared to age-appropriate normal values) suggests hypogonadism.
      • AMH and inhibin B levels may be normal if hypogonadism is caused by Leydig cell specific dysfunction.
  • In adolescents and postpubertal male children presenting with signs and symptoms of delayed puberty:
    • Measure morning testosterone levels, AMH, and inhibin B levels.
      • Persistently low levels (compared to age-appropriate normal values) suggests hypogonadism.
      • Normal levels rule out testicular dysfunction
    • Measure LH and FSH levels to distinguish between primary and secondary hypogonadism.
    • Consider human chorionic gonadotropin (hCG) stimulation tests to assess:
      • presence of functional testicular tissue
      • defects in testosterone synthesis and action
• Results of various serum hormone level tests can help determine etiology of fetal-onset hypogonadism and postnatal-onset hypogonadism.
• To confirm diagnosis and identify etiology of hypogonadism in children of all ages, consider further testing, including:
  • Additional blood tests to identify conditions such as hemochromatosis, pituitary hormone deficiencies, or hyperprolactinemia and tests to discriminate secondary hypogonadism from constitutional delay of growth and puberty
  • Urine tests to detect steroidogenic defects
  • Genetic testing, including karyotype analysis, to identify chromosomal abnormalities and congenital causes of hypogonadism
  • Imaging tests to estimate skeletal age, measure testicular volume and position, detect tumors such as prolactinomas and characteristics of congenital disorders
  • Semen analysis and sperm count

Management

• For male neonates with primary or secondary hypogonadism, the goal of treatment is to correct physiological abnormalities, such as micropenis or cryptorchidism.
  • The standard therapy for neonates with micropenis is testosterone therapy, such as testosterone enanthate or cypionate 25 mg intramuscular injection every 4 weeks for 3 months.
  • For management of cryptorchidism in neonates, surgical correction is necessary.
• For management of hypogonadism in male adolescents:
  • Treatment should be started at the age of pubertal onset (about 12 years old). Delaying treatment past age 14 years may reduce height potential and peak bone mass.
  • The goals for treatment include:
    • Induce and maintain male secondary sexual characteristics at the appropriate age
    • Optimize pubertal growth spurt and development of normal body proportions
    • Achieve optimal fat to muscle ratio and bone mineral density
    • Enable adequate growth of genitalia
    • Reduce cardiovascular risk (includes improvement of lipid profile and reduction of risk for metabolic syndrome)
    • Promote normal male psychosocial and psychosexual maturation and well-being
  • For management of primary hypogonadism, testosterone therapy is the only viable treatment option.
  • For management of secondary hypogonadism:
    • Testosterone therapy is the primary treatment to initiate development of secondary sexual characteristics.
    • Testosterone therapy may result in accelerated skeletal maturation; if growth hormone deficiency is a concern, consider initiating treatment with human growth hormone, prior to testosterone therapy.
  • Testosterone formulations and dosing are dependent on the age at diagnosis.
    • In patients diagnosed at or near puberty (about 12 years old):
      • Give an initial dose of testosterone enanthate or cypionate 50 mg intramuscular injection every 4 weeks, and increase the dose by 25-50 mg every 6-12 months.
      • Once the monthly dose is > 150 mg, consider splitting into every 2 weeks.
      • Continue to titrate up over 2-3 years until the final adult dose of 100-250 mg once every 2-4 weeks is reached.
      • The aim of testosterone treatment is to mimic the natural progression of puberty. Increasing the dosage too quickly can lead to abrupt virilization and fusion of the epiphyseal before the full height is achieved.
      • Monitor patients on testosterone therapy every 3-6 months for changes in genital maturation, height velocity, and body composition.
    • In patients with a late diagnosis who have completed puberty and reached near-adult height, scaling may not be needed. The suggested dose in these patients is testosterone enanthate or cypionate 150-250 mg intramuscular injection once every 2-4 weeks.
    • Continue testosterone treatment through adulthood.
• Follow-up
  • Monitoring in male children receiving testosterone therapy for induction of puberty should include regular assessments of the following:
    • growth
    • pubertal progression
    • bone age
    • serum total testosterone levels
    • hematocrit (if > 54%, discontinue testosterone then restart when < 54%)
    • lipid profile
    • bone density, including lumbar spine and femoral neck
  • Perform a clinical assessment of genital maturation, height velocity, and changes in body composition every 3-6 months.
  • Evaluate bone age annually throughout childhood in prepubertal and pubertal male children until epiphyseal closure occurs and adult height is achieved.