How should I evaluate and manage an otherwise healthy adolescent who presents with delayed puberty (age >13 years in girls or >14 years in boys)?

Evaluation and Management of Delayed Puberty in Adolescents

Begin with targeted hormone testing (FSH, LH, testosterone in boys or estradiol in girls, TSH, and prolactin) to differentiate between constitutional delay, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism, as this distinction drives all subsequent management decisions. 1, 2

Initial Clinical Assessment

Define the Problem

• Delayed puberty is defined as absence of testicular enlargement (volume <4 mL) by age 14 years in boys or absence of breast development by age 13 years in girls. 2, 3, 4
• Document Tanner staging meticulously: absence of both axillary and pubic hair indicates Tanner stage 1 (pre-pubertal status). 2
• In boys, measure testicular volume with an orchidometer; volumes <4 mL at age 14+ indicate delayed puberty. 5, 2
• In girls, breast development (thelarche) is the first sign; its absence at age 13+ warrants evaluation. 5, 6

Critical History Elements

• Family history of late puberty strongly suggests constitutional delay of growth and puberty (CDGP), the most common cause. 3, 7
• Document growth velocity and plot on growth curves; poor growth velocity suggests pathologic causes rather than CDGP. 2, 4
• Screen for chronic systemic illness (inflammatory bowel disease, celiac disease, chronic kidney disease) as these cause transient hypogonadotropic hypogonadism. 5, 1
• Assess nutritional status, weight changes, and exercise patterns to identify functional hypothalamic amenorrhea or eating disorders. 1, 8
• Ask about chemotherapy or radiation exposure, which causes iatrogenic hypergonadotropic hypogonadism. 5, 1
• Review medications: antipsychotics and antiepileptics can cause hyperprolactinemia. 8

Physical Examination Priorities

• Measure height, weight, and calculate BMI; plot on growth charts to assess growth trajectory. 2, 4
• Examine for dysmorphic features suggesting Turner syndrome (girls) or Klinefelter syndrome (boys). 1, 6
• Check for anosmia (inability to smell), which indicates Kallmann syndrome. 1, 4
• Look for galactorrhea, which indicates hyperprolactinemia. 1, 8
• Assess for signs of chronic illness or malnutrition. 5, 1

Diagnostic Laboratory Evaluation

Mandatory First-Line Tests

Draw the following hormones between cycle days 3-6 in girls with any menses, or at any time in amenorrheic patients or boys: 8

• FSH and LH: Elevated levels (FSH >40 mIU/mL) indicate primary gonadal failure (hypergonadotropic hypogonadism); low or inappropriately normal levels indicate central causes (hypogonadotropic hypogonadism). 1, 4
• Testosterone (boys) or estradiol (girls): Low sex steroids with elevated gonadotropins = primary gonadal failure; low sex steroids with low gonadotropins = central hypogonadism. 1, 2
• TSH and free T3: Hypothyroidism independently causes growth failure and delayed puberty and is easily treatable. 5, 1
• Prolactin: Hyperprolactinemia inhibits gonadotropin secretion and presents with delayed or arrested puberty; measure in all patients as it is frequently overlooked but easily treatable. 1, 8
  • Critical pitfall: Never draw prolactin immediately after stress, breast examination, sexual activity, or seizure; obtain a morning resting sample. 8
• Bone age (hand/wrist X-ray): Delayed bone age supports CDGP; normal or advanced bone age suggests pathologic hypogonadism. 5, 2

Interpretation Algorithm

If FSH and LH are elevated (>40 mIU/mL):

• Diagnosis is hypergonadotropic hypogonadism (primary gonadal failure). 1, 4
• Confirm with repeat FSH 4 weeks later (two elevated values required). 8
• Obtain karyotype in girls to identify Turner syndrome and in boys with small testes. 1, 6
• Consider history of chemotherapy/radiation exposure causing iatrogenic premature ovarian insufficiency. 5, 1

If FSH and LH are low or inappropriately normal:

• Diagnosis is hypogonadotropic hypogonadism (central cause). 1, 4
• Differentiate between CDGP (most common, especially in boys) versus permanent hypogonadotropic hypogonadism. 3, 7
• Order brain MRI to exclude CNS structural abnormalities (pituitary tumors, craniopharyngioma) if: 1, 2
  • Headaches, visual disturbances, or other neurologic symptoms present
  • Prolactin >100 µg/L
  • Anosmia (suggests Kallmann syndrome)
  • Lack of progression after initial treatment
• Measure IGF-1 if growth velocity is abnormal to assess for growth hormone deficiency. 5, 4

If prolactin is elevated:

• Levels >100 µg/L or any elevation with headaches/visual changes mandates endocrine or neurosurgical referral for possible pituitary adenoma. 8
• Hyperprolactinemia inhibits GnRH secretion and is a reversible cause of delayed puberty. 1

Additional Testing Based on Clinical Context

• In girls with hyperandrogenic signs (hirsutism, acne): measure testosterone, androstenedione, and DHEA-S to screen for PCOS, adrenal tumors, or non-classical congenital adrenal hyperplasia. 8
• In chronic kidney disease patients: correct metabolic acidosis (serum bicarbonate ≥22 mEq/L), optimize nutrition, and control secondary hyperparathyroidism before considering treatment. 5
• In cancer survivors: measure FSH and estradiol, but discontinue any hormone therapy prior to testing; AMH may provide additional ovarian reserve information. 8

Management Approach

Constitutional Delay of Growth and Puberty (CDGP)

CDGP is a diagnosis of exclusion after ruling out pathologic causes. 3, 7

Indications for treatment:

• Patient or family distress about the delay. 2
• Bone age assessment confirms delayed skeletal maturation. 2
• Pathologic causes have been excluded. 2

Treatment protocol for boys:

• Low-dose testosterone enanthate intramuscularly for 3-6 months to "jump-start" puberty. 2, 3
• Monitor for spontaneous resumption of pubertal progression and endogenous gonadotropin secretion. 3
• If no spontaneous progression occurs, consider permanent hypogonadotropic hypogonadism and continue escalating doses. 3

Treatment protocol for girls:

• Begin pubertal induction between ages 11-12 years to facilitate positive psychosocial adaptation and keep pace with peers. 5
• Use transdermal 17β-estradiol as first-line therapy (superior uterine development compared to oral ethinyl estradiol, critical for cancer survivors with pelvic radiation). 5
• Start with 1/8 of a patch weekly for 0-6 months, then escalate to 1/4 patch for 6-12 months, then 1/2 patch, mimicking physiological puberty over 2-3 years. 5
• Use oral 17β-estradiol only if transdermal route contraindicated (poor compliance, chronic skin graft-versus-host disease). 5
• Add cyclic progestin after 12-24 months of estrogen or once breakthrough bleeding occurs. 5

Permanent Hypogonadotropic Hypogonadism

• Continue sex hormone treatment in escalating doses until completion of pubertal development and growth. 3
• Refer to pediatric endocrinology for long-term management. 2

Hypergonadotropic Hypogonadism

• Requires pubertal induction with hormone replacement therapy as spontaneous puberty will not occur. 5, 1
• In girls with iatrogenic premature ovarian insufficiency, early estrogen exposure (ages 11-12) optimizes uterine development and reduces miscarriage risk in future pregnancies. 5
• Refer to pediatric endocrinology for initiation and monitoring. 2

Referral Indications

Refer to pediatric endocrinology if: 2

• Persistently abnormal hormone levels (elevated FSH/LH or prolactin >100 µg/L)
• Confirmed hypogonadism (hypergonadotropic or permanent hypogonadotropic)
• Lack of progression after initial 3-6 month treatment course
• Concerns about final height and bone health
• Testosterone >5 nmol/L or rapid virilization (suggests tumor) 8

Critical Pitfalls to Avoid

• Do not assume chemotherapy-induced amenorrhea equals menopause; hormone levels are unreliable during tamoxifen treatment. 8
• Do not measure prolactin post-ictally or after stress/breast examination; wait 24 hours and obtain morning resting sample. 8
• Do not delay pubertal induction in confirmed hypogonadism beyond age 13 in girls or 14 in boys, as this worsens psychosocial outcomes and may compromise final height. 5
• Do not use oral ethinyl estradiol for pubertal induction in cancer survivors with pelvic radiation; transdermal 17β-estradiol achieves superior uterine development. 5
• Do not forget to assess bone mineral density in patients with prolonged hypogonadism or functional hypothalamic amenorrhea. 5, 8