Male Delayed Puberty

Background

• Male delayed puberty is the lack of testicular enlargement by 2-2.5 standard deviations older than the population mean, usually age 14 years in boys, though the onset of puberty varies by country, race, and ethnicity.
• Risk factors include the family history of delayed puberty, being significantly underweight, or having congenital midline defects (which predict potential pituitary hormone dysfunction).
• The normal onset of puberty is age 9-14 years, with a typical progression in boys as follows:
  • testicular enlargement
  • then pubic hair and penile growth
  • then growth spurt (peak growth velocity at mean age 13.5 years)
• Pubic and axillary hair may develop prior to puberty as they occur due to adrenal androgen secretion (adrenarche) and are independent of the hypothalamic-pituitary-gonadal (HPG) axis.
• Delayed puberty has several etiologies.
  • Constitutional delay of growth and puberty is the most common cause and is a nonpathologic condition where puberty occurs at the extreme end of the normal spectrum.
  • Hypogonadotropic hypogonadism can be transient due to an underlying medical condition or persistent due to an idiopathic or acquired pituitary disorder and is characterized by low follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
  • Hypergonadotropic hypogonadism is due to gonadal failure or an inability to synthesize or respond to sex steroids and is characterized by elevated FSH and LH.

Evaluation

• Diagnose delayed puberty in boys if testicular enlargement is not present by 2-2.5 standard deviations older than the population mean, traditionally age 14 years.
• Perform a complete physical examination including height, weight, and Tanner staging, and begin evaluation for causes of delayed puberty.
• Testing should begin with an x-ray for bone age and assessment of hypothalamic-pituitary-gonadal axis.
  • Check serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to distinguish hypergonadotropic hypogonadism from other forms of delayed puberty.
  • Consider morning total serum testosterone to assess for the onset of puberty.
  • Check prolactin level to detect hyperprolactinemia, which can be caused by prolactin-secreting pituitary adenoma (prolactinoma) and interrupt normal progression of puberty.
  • Check thyroid function studies (thyroid-stimulating hormone [TSH] and free thyroxine [T4]) to detect hypothyroidism, which can cause a failure of growth and pubertal development.
  • Consider serum insulin-like growth factor 1 (IGF-1) to screen for growth hormone deficiency; if IGF-1 is low and short stature is severe or growth velocity is low, then perform a growth hormone stimulation test.
• Further evaluation depends on the suspected cause based on the results of the bone age, and LH and FSH testing.
  • Constitutional delay of growth and puberty (CDGP):
    • Suspect in boys with bone age delayed ≥ 2 years, low or normal LH and FSH levels, and stimulated LH in pubertal range.
    • Perform additional testing to assist in distinguishing CDGP from hypogonadotropic hypogonadism.
    • Diagnose if puberty begins without treatment or continues after treatment is stopped.
  • Functional hypogonadotropic hypogonadism:
    • Suspect in boys with low LH and FSH levels, evidence of an underlying medical condition, or growth rate < 3 cm/year.
    • Perform additional testing in boys with an evidence or history of chronic disease to determine the underlying cause.
  • Persistent hypogonadotropic hypogonadism:
    • Suspect in boys:
      • with stretched penis length < 5 cm at presentation of delayed puberty, low LH and FSH levels, stimulated LH in the prepubertal range, impaired sense of smell, or no evidence of puberty by age 17-18 years
      • if spontaneous puberty has not occurred after 1 year of testosterone treatment or pubertal development stalls
    • Perform additional testing to assist in distinguishing from CDGP.
    • Consider brain imaging if persistent hypogonadotropic hypogonadism is diagnosed or clinical findings are suggestive of a mass, central nervous disease, hypopituitarism, or if puberty has not begun by age 15 years or after 1 year of testosterone therapy.
  • Hypergonadotropic hypogonadism:
    • Suspect in boys with elevated serum LH and FSH levels or findings of Klinefelter or Noonan syndrome.
    • Consider checking a karyotype in boys with suspected Klinefelter syndrome.

Management

• Constitutional delay of growth and puberty treatment depends on age, the presence of development, and family preference.
  • Options include reassurance, watchful waiting, or pharmacotherapy with testosterone.
  • Assess for a spontaneous onset of puberty after discontinuation of testosterone in boys with suspected constitutional delay of growth and puberty (CDGP).
• Functional hypogonadotropic hypogonadism is managed by treating the underlying cause.
• For persistent hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, or if there is diagnostic uncertainty between CDGP and hypogonadotropic hypogonadism, treatment includes starting low-dose testosterone therapy and increasing gradually to the full adult replacement dose.
• Continue to follow and plot linear growth whether or not treatment is given.
• During treatment, follow bone age and monitor serum testosterone levels (adjust dose to achieve midreference range), height velocity, and virilization.