Delayed Puberty

Delayed puberty is absence of testicular enlargement (volume under 4 mL) by age 14 in boys, and absence of breast development (Tanner B2) by age 13 in girls, which is 2 to 2.5 standard deviations above the mean age of onset. Primary amenorrhoea is no menarche by age 15 (or 3 years after thelarche). Delayed puberty is commoner in boys (about 3% of adolescents).

Causes:

• Constitutional delay of growth and puberty (most common): 60 to 65% of boys and 30% of girls. A normal variant with delayed bone age and a positive family history in 50 to 75%. Eventually, normal puberty and fertility.
• Functional hypogonadotropic hypogonadism: chronic illness (coeliac disease, inflammatory bowel disease, cystic fibrosis, sickle cell disease, thalassaemia, chronic kidney disease, juvenile arthritis, HIV), malnutrition, eating disorders, excessive exercise, stress, hypothyroidism, diabetes, and glucocorticoid use.
• Permanent hypogonadotropic hypogonadism (central, 10 to 20%): Kallmann syndrome and isolated congenital hypogonadotropic hypogonadism, CNS tumours (craniopharyngioma), cranial radiotherapy, pituitary disease and hypopituitarism, hyperprolactinaemia, and syndromes (Prader-Willi, CHARGE, Bardet-Biedl).
• Hypergonadotropic hypogonadism (primary gonadal failure): Klinefelter syndrome, Turner syndrome, gonadal dysgenesis, chemotherapy (alkylating agents) and radiotherapy, bilateral torsion or anorchia, autoimmune oophoritis, galactosaemia, and Noonan syndrome (males).
• Other: androgen insensitivity (complete form gives primary amenorrhoea with breast development but absent pubic hair), Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome, normal breasts and pubic hair, absent uterus), transverse vaginal septum and imperforate hymen (cryptomenorrhoea).

Consequences: short stature, reduced peak bone mass and osteoporosis risk, psychosocial distress (bullying, depression, social withdrawal), poor self-esteem, and in permanent cases infertility.

Presentation:

• Boys: prepubertal testes (under 4 mL), small genitalia, no pubic hair, short stature relative to peers, and concerns about appearance. Constitutional delay is often associated with a previous slower growth in mid-childhood.
• Girls: no breast development by 13, absent menarche by 15, short stature, or lack of growth spurt.

Clues to the cause:

• Constitutional delay: family history, otherwise healthy, height below the mid-parental target for age but growth velocity normal, delayed bone age (at least 1.5 to 2 years), and height approximating the delayed bone age.
• Chronic disease: gastrointestinal symptoms, cough, joint pain, weight loss, poor appetite, pallor, fatigue, and chronic medications.
• Hypogonadotropic hypogonadism: anosmia, mirror movements (Kallmann syndrome), cryptorchidism and micropenis (congenital onset), cleft lip/palate, hearing loss, headaches, visual field loss, galactorrhoea, and polyuria.
• Primary gonadal failure: syndromic features (Turner stigmata, tall eunuchoid habitus in Klinefelter), history of treatment for cancer, autoimmune conditions.
• Eating disorder and athletes: low BMI, restrictive eating, intense training, and amenorrhoea.

Examination: height, weight, BMI, arm span, height velocity, Tanner stage and testicular volume, olfaction, thyroid, midline defects, visual fields, dysmorphic features, and signs of chronic illness. Genital examination for micropenis (stretched penile length under 2.5 SD for age), cryptorchidism, and hypospadias.

Red flags: neurological symptoms, visual disturbance, features of pituitary deficiency, bone pain or fractures, and eating disorder.

The main challenge is separating constitutional delay from permanent hypogonadotropic hypogonadism, since both show low gonadotropins and low sex steroids.

Initial tests:

• Bone age (delayed in constitutional delay), CBC, ESR/CRP, creatinine and electrolytes, liver enzymes, tissue transglutaminase IgA and total IgA (coeliac), TSH and free T4, prolactin, IGF-1, and karyotype in girls with hypergonadotropic hypogonadism (and boys with small firm testes).
• LH, FSH, and oestradiol or testosterone (early morning): high FSH (above 10 to 20 IU/L) indicates primary gonadal failure, and low levels suggest central causes or constitutional delay.
• Basal LH on an ultrasensitive assay above 0.3 IU/L indicates early puberty onset.
• Inhibin B (above 35 pg/mL in boys suggests constitutional delay) and AMH (higher in constitutional delay).
• hCG stimulation test (hCG 1500 to 2000 units IM daily for 3 days, or 5000 units once, with testosterone measured) tests Leydig cell function.
• GnRH agonist stimulation (leuprolide 20 micrograms/kg SC), with LH at 3 to 4 hours above 5 IU/L supporting constitutional delay.
• Brief low-dose testosterone priming (testosterone enanthate 50 to 100 mg IM) can also help identify who will progress spontaneously.

Specialised evaluation:

• MRI of hypothalamus and pituitary, with olfactory bulb assessment, in suspected hypogonadotropic hypogonadism, hyperprolactinaemia, headaches and visual field defects.
• Pelvic ultrasound in girls (uterus, ovaries) and MRI of the pelvis when anomalies are suspected.
• Genetic testing: ANOS1, FGFR1, FGF8, CHD7, GNRHR, TAC3/TACR3, KISS1R, PROKR2 panel for congenital hypogonadotropic hypogonadism, FMR1 for premature ovarian insufficiency, and SOX10.
• DEXA for bone health in prolonged delay.

Observe: if no definite cause is found and bone age is delayed, serial review every 3 to 6 months. If no pubertal progression by age 17 to 18, permanent hypogonadotropic hypogonadism is likely and should be managed as such.

Constitutional delay: observation or short-term treatment

• Reassure and monitor. Treatment is for distress, bullying, or social impact.
• Boys: testosterone enanthate (or cypionate) 50 to 100 mg IM every 4 weeks for 3 to 6 months (some use 4 to 6 months), starting from age 12 to 14. Alternatives are oxandrolone 2.5 mg daily for 3 to 6 months (to boost growth, less available), letrozole 2.5 mg daily for 6 months (raises endogenous gonadotropins and testosterone, improves height prediction, with scarce long-term data), and testosterone gel low-dose. Review for puberty progression and testicular growth (a sign of endogenous puberty) after treatment.
• Girls: transdermal oestradiol 3 to 7 micrograms per day, or oral 17-beta-estradiol 0.25 mg daily, or ethinyl estradiol 2 micrograms per day, given for 3 to 6 months, with reassessment.
• Counsel on adult height (typically normal, with a catch-up on spontaneous puberty).

Permanent hypogonadism: puberty induction

• Boys: testosterone enanthate 25 mg IM monthly (or 50 mg, titrate), increasing every 6 to 12 months by 25 to 50 mg, to reach 100 mg every 2 weeks or 200 mg every 2 to 3 weeks over 2 to 3 years, finishing at adult replacement. For preserving fertility in hypogonadotropic hypogonadism, hCG 500 to 1500 units SC 2 to 3 times weekly with recombinant FSH 75 to 150 units 2 to 3 times weekly from the middle of the induction, or use pulsatile GnRH. Testicular growth and spermatogenesis follow in most.
• Girls: transdermal or oral oestradiol at low dose (transdermal 3 to 7 micrograms/day, oral 0.25 to 0.5 mg daily), increased every 6 months over 2 to 3 years to adult dose (50 to 100 micrograms patch twice weekly or oral 2 mg daily). Add cyclic progestogen after 2 years or on breakthrough bleeding (micronised progesterone 200 mg nightly for 12 days each month). Ethinyl estradiol and combined pills are avoided early. The aim is natural breast development and uterine growth, then maintenance until the average age of menopause.

Chronic illness and functional causes

• Treat the underlying disease (gluten-free diet in coeliac disease, nutritional rehabilitation, control of inflammatory bowel disease), correct hypothyroidism (levothyroxine 2 to 3 micrograms/kg/day), hyperprolactinaemia (cabergoline 0.25 to 0.5 mg twice weekly), and eating disorders (multidisciplinary care). Puberty usually progresses with recovery.

Specific disorders

• Turner syndrome: growth hormone 0.045 to 0.067 mg/kg/day from early childhood, oestrogen at age 11 to 12 with pubertal induction, and cardiac, renal and hearing monitoring.
• Klinefelter syndrome: testosterone when testosterone falls, from around age 12, with fertility counselling and sperm preservation (microdissection testicular sperm extraction).
• Androgen insensitivity (complete): gonadectomy after puberty (given the tumour risk) and oestrogen replacement. Müllerian agenesis: vaginal dilators or surgical neovagina, and psychological support, with options for gestational surrogacy.
• Imperforate hymen or transverse septum: surgical correction.

Bone health

• Calcium 1000 to 1300 mg and vitamin D 800 to 2000 IU daily, weight-bearing exercise, DEXA monitoring, and optimise sex steroid replacement to achieve peak bone mass.

Psychosocial care

• Address anxiety, depression, bullying, and body image. Counsel parents. Support groups and school liaison.

Follow-up

• Review every 3 to 6 months, with Tanner stage, growth, testicular volume, bone age, and psychosocial assessment. Specialist endocrine care until adult service transition.