Delayed onset of puberty

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Delayed onset of puberty is defined in boys by testicular volume < 4 mL or length < 2.5 cm by 14 years of age; it is defined in girls by absence of breast development by 13 years of age or menarche by 15 years of age. The most common cause is constitutional delay of growth and puberty (CDGP). Other causes include congenital or acquired conditions that impair gonadotropin-releasing hormone (GnRH) and/or gonadotropin release (hypogonadotropic hypogonadism) and primary failure of the gonads to produce sex hormones (hypergonadotropic hypogonadism). Clinical evaluation involves a focused history and physical examination, including a pediatric growth assessment and sexual maturity rating. Initial diagnostic evaluation includes laboratory testing (gonadotropin and sex hormone levels) and a bone age assessment. Targeted testing to determine the underlying cause is based on clinical presentation and initial testing. Management includes treatment of underlying causes and expectant management in patients with CDGP. Hormonal therapy may be indicated to stimulate pubertal development.

Constitutional delay of growth and puberty (most common) ^[2][3][4]

• Likely genetic cause
• Delayed puberty occurs due to delay in pulsatile hypothalamic GnRH release.

Hypogonadotropic hypogonadism ^[2][3][4]

See also "Etiology of male hypogonadism."

• Congenital
  • Idiopathic hypogonadotropic hypogonadism, including Kallmann syndrome
  • Genetic syndromes (e.g., Prader-Willi syndrome, CHARGE syndrome)
• Acquired
  • Functional causes
    • Undernutrition or excessive exercise (e.g., in anorexia nervosa, REDs)
    • Chronic diseases (e.g., inflammatory bowel disease, hypothyroidism, cystic fibrosis)
    • Medications (e.g., glucocorticoids)
  • CNS causes
    • CNS tumors (e.g., craniopharyngioma, pituitary adenoma, germinoma)
    • Brain injury (e.g., traumatic brain injury, radiation injury)
    • Intracranial infections (e.g., encephalitis, meningitis)
    • Infiltration (e.g., in Langerhans cell histiocytosis)

Hypergonadotropic hypogonadism ^[2][3][4]

See also "Etiology of male hypogonadism" and "Etiology of primary ovarian insufficiency."

• Congenital
  • Klinefelter syndrome
  • Down syndrome
  • Gonadal dysgenesis (e.g., in Turner syndrome)
  • Anorchia
  • LH and FSH receptor defects
  • Androgen insensitivity syndrome
• Acquired
  • Chemotherapy
  • Gonadal radiation
  • Infection (e.g., mumps)
  • Gonadal trauma or surgery
  • Autoimmune disease

Hypergonadotropic hypogonadism is a more common cause of delayed puberty in girls than in boys. ^[4]

The clinical presentation depends on the underlying condition.

Focused history ^[2][3][4]

• Pubertal development: timing and sequence of development of any secondary sexual characteristic
• Past medical history
  • Developmental delay
  • Chronic medical conditions
  • History of chemotherapy and/or radiation
  • CNS trauma or infection
  • Gonadal injury or infection (e.g., testicular torsion, mumps)
  • Cryptorchidism
• Family history
  • Timing of parental puberty, including:
    • Maternal menarche
    • Timing of paternal final adult height
  • Genetic and/or endocrine disorders
  • Infertility
• Focused review of symptoms
  • CNS symptoms (e.g., headaches, vision changes)
  • Anosmia or hyposmia
  • Symptoms of eating disorders
  • Signs of excessive exercise
  • Symptoms of estrogen deficiency
  • Symptoms of hyperprolactinemia (e.g., galactorrhea)
  • Features of chronic disease, e.g.:
    • Gastrointestinal symptoms (e.g., diarrhea, abdominal pain)
    • Symptoms of hypothyroidism or symptoms of hyperthyroidism
    • Arthralgia

Focused examination ^[2][3][4][5]

• Pediatric growth assessment
  • Standard pediatric growth parameters (e.g., height, weight, and BMI)
  • Growth velocity
  • Midparental height
• Evaluation for physical changes during puberty
  • Sexual maturity rating
  • Genital examination
    • Testicular examination: for location, volume, and texture ^[4]
    • Vaginal examination: for signs of hypoestrogenism (e.g., thin and/or pale mucosa)
• Evaluation for underlying cause, e.g.,
  • Thyroid examination
  • Assessment for dysmorphic features suggesting genetic syndromes
  • Neurological examination: for suspected CNS pathology

Approach ^[2][3][4]

Evaluate for delayed onset of puberty in boys if there is no testicular growth by 14 years of age. Evaluate for delayed onset of puberty in girls if there is no thelarche by 13 years of age or menarche by 15 years of age.

• All patients
  • Obtain initial studies, including early morning gonadotropin levels and bone age radiography.
  • Girls ≥ 15 years of age without menarche: See also "Diagnostics for amenorrhea."
• Prepubertal or normal FSH, LH, testosterone, and/or estradiol
  • Perform targeted testing for hypogonadotropic hypogonadism.
  • Suspected CDGP
    • Normal LH, FSH: Consider repeat testing in 1–3 months.
    • Prepubertal LH, FSH: Consider observation or trial of hormonal therapy; see "Management."
• Elevated FSH (with or without LH); : Perform targeted testing for hypergonadotropic hypogonadism.
• Diagnostic uncertainty: Refer to a specialist (e.g., endocrinology, genetics).

Distinguishing between CDGP and congenital hypogonadotropic hypogonadism is challenging. Refer for specialist evaluation in the case of diagnostic uncertainty. ^[3][4]

Initial diagnostic studies ^[2][3][4]

• Laboratory studies
  • LH, FSH
  • Testosterone (boys)
  • Estradiol (girls)
  • If abnormal growth velocity: TSH, prolactin, IGF-1
• Bone age radiography: delayed (less than the patient's chronological age)

Targeted testing ^[2][3][4]

Obtain targeted testing based on clinical presentation and initial studies. Consult a specialist (e.g., endocrinology, genetics) as needed.

Hypogonadotropic hypogonadism

• Signs of hypothyroidism or signs of hyperthyroidism: TSH
• Suspected growth hormone deficiency (e.g., ↓ growth velocity): IGF-1
• CNS symptoms: prolactin, MRI brain
• Suspected chronic systemic illness
  • General: CBC, CMP, ESR
  • Specific: diagnostics for diabetes, diagnostics for celiac disease, diagnostics for inflammatory bowel disease
• Genetic testing (e.g., for Kallmann syndrome, Prader-Willi syndrome, CHARGE syndrome)

Hypergonadotropic hypogonadism

• Karyotype: to assess for genetic syndromes (e.g., Turner syndrome, Klinefelter syndrome)
• Pelvic or testicular ultrasound: to assess presence and location of gonads
• Testing for autoimmune disorders (e.g., type 1 diabetes, Hashimoto disease)

• CDGP: Eventual pubertal progression and normal adult height are expected. ^[2][3][4]
  • Initiate expectant management; repeat evaluation in 1–3 months. ^[4]
  • Patients with psychological stress
    • Consider trial of hormone therapy to initiate puberty. ^[4]
    • If no response after 6 months, refer to pediatric endocrinology for evaluation of persistent hypogonadotropic hypogonadism.
• Pathologic causes of hypogonadism ^[3][4]
  • Treat the underlying cause (e.g., thyroid disorders, eating disorders).
  • Nonreversible causes: Refer to pediatric endocrinology for hormonal therapy to stimulate development of secondary sexual characteristics and growth spurt.
    • Testosterone (for boys)
    • Estrogen (for girls) ^[3]