What are the causes and treatments of delayed puberty?

Causes of Delayed Puberty

Delayed puberty results from three major pathophysiologic categories: constitutional delay of growth and puberty (CDGP), hypogonadotropic hypogonadism (central/hypothalamic-pituitary dysfunction), and hypergonadotropic hypogonadism (primary gonadal failure). 1, 2, 3

Constitutional Delay of Growth and Puberty (CDGP)

• CDGP is the most common cause of delayed puberty, particularly in males, representing a normal variant in pubertal timing with favorable outcomes for final height and reproductive capacity 3, 4
• This condition is characterized by short stature, delayed skeletal maturation (delayed bone age), and a familial pattern of late puberty 3, 5
• Growth velocity remains delayed until immediately before puberty onset, then rapidly accelerates 3
• CDGP is a diagnosis of exclusion—all pathological causes must be ruled out first 3, 6

Hypogonadotropic Hypogonadism (Central Causes)

Functional (Reversible) Hypogonadotropic Hypogonadism

• Chronic systemic illnesses cause transient delay in hypothalamic-pituitary-gonadal axis maturation, including 1, 3:
  • Malnutrition and anorexia nervosa 1, 3
  • Celiac disease 3
  • Inflammatory bowel diseases 3
  • Chronic kidney disease 7, 3
  • Chronic asthma and other chronic diseases of childhood 5, 8

Permanent Hypogonadotropic Hypogonadism

• CNS structural abnormalities require MRI evaluation to exclude 3:

  • Pituitary tumors (prolactinomas are most common pituitary adenomas in adolescents, though rare before puberty) 7
  • Craniopharyngiomas and other sellar/suprasellar masses 3
  • Trauma or radiation-induced hypothalamic-pituitary injury 9, 3

• Kallmann syndrome presents as isolated hypogonadotropic hypogonadism, often with anosmia 3

• Panhypopituitarism involves multiple pituitary hormone deficiencies beyond gonadotropins 3

• Hyperprolactinemia inhibits gonadotropin secretion via suppression of hypothalamic kisspeptin, presenting with delayed or arrested puberty, galactorrhea, and menstrual disturbances in girls 7

Hypergonadotropic Hypogonadism (Primary Gonadal Failure)

• Chromosomal abnormalities are identified through genetic analysis 3:

  • Turner syndrome (45,X) in females 7, 3
  • Klinefelter syndrome (47,XXY) in males 3

• Iatrogenic premature ovarian insufficiency results from chemotherapy or radiation exposure, presenting with hypergonadotropic hypogonadism requiring pubertal induction 7

• Primary testicular failure from cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy 9

• Autoimmune ovarian or testicular failure 3

Biochemical Differentiation

• Low testosterone (males) or estradiol (females) with elevated FSH and LH indicates hypergonadotropic hypogonadism (primary gonadal failure) 1, 3

• Low sex steroids with low or inappropriately normal FSH and LH indicates hypogonadotropic hypogonadism (central cause) 1, 3

• Baseline hormone measurements at age 13-14 years help differentiate these categories, though distinguishing CDGP from permanent hypogonadotropic hypogonadism remains challenging with static testing alone 1, 3

Critical Pitfalls

• Do not assume CDGP without excluding pathological causes—chronic illness, hormonal deficiencies, and structural CNS abnormalities must be ruled out 3, 6

• Measure prolactin in all patients with delayed puberty, as hyperprolactinemia is easily treatable but frequently overlooked 7

• Assess thyroid function and exclude hypothyroidism, which independently causes growth failure and delayed puberty 7

• Evaluate nutritional status and metabolic control (sodium, bicarbonate) in patients with chronic disease, as these directly impact pubertal progression 7, 1

• Obtain bone age assessment to evaluate skeletal maturation and predict final height potential 1, 2