Delayed Puberty

• Hypergonadotropic hypogonadism (high LH/FSH) means primary gonadal failure — Turner syndrome, Klinefelter syndrome, gonadal dysgenesis, prior chemotherapy or radiation, autoimmune oophoritis.
• Hypogonadotropic hypogonadism (low or inappropriately normal LH/FSH) means the hypothalamus or pituitary is not signalling — constitutional delay of growth and puberty (much the most common cause, and a normal variant), Kallmann syndrome (with anosmia), functional suppression from malnutrition, intense exercise, chronic illness or eating disorders, and pituitary lesions including prolactinoma.
• Constitutional delay is characterised by a bone age delayed to match height age, a positive family history and eventual normal puberty; it is a diagnosis of exclusion rather than an assumption.

Hypergonadotropic (primary gonadal failure)

• Sex chromosome aneuploidy: Turner syndrome (45,X and mosaics) with streak gonads; Klinefelter syndrome (47,XXY) with seminiferous tubule hyalinization — the single most common genetic causes tested.
• 46,XX / 46,XY gonadal dysgenesis: streak gonads with normal female external genitalia and a Müllerian uterus in 46,XY complete gonadal dysgenesis (Swyer syndrome), which is why these patients present with primary amenorrhea and high FSH; Y-containing dysgenetic gonads carry gonadoblastoma risk.
• Acquired gonadal injury: alkylating chemotherapy (cyclophosphamide), gonadal or total-body irradiation, bilateral torsion, mumps orchitis, autoimmune oophoritis (often with APS-1), galactosemia.

Hypogonadotropic (central)

• Constitutional delay of growth and puberty: a maturational lag of the GnRH pulse generator, strongly familial, and by far the most common cause overall.
• Congenital GnRH deficiency: Kallmann syndrome (anosmia; ANOS1/KAL1 X-linked, FGFR1, PROK2), normosmic idiopathic hypogonadotropic hypogonadism (GNRHR, KISS1R, TAC3), CHARGE syndrome, Prader–Willi, combined pituitary hormone deficiency.
• Structural/infiltrative pituitary-hypothalamic disease: craniopharyngioma, prolactinoma, germinoma, Langerhans cell histiocytosis, cranial irradiation, iron overload from transfusion-dependent thalassemia or hemochromatosis.
• Functional suppression: energy deficit from anorexia nervosa, high-volume endurance or gymnastics training, celiac disease, inflammatory bowel disease, cystic fibrosis, chronic kidney disease, poorly controlled diabetes, untreated hypothyroidism, chronic glucocorticoids or opioids.

Non-modifiable risk factors

• Family history of late puberty in a parent or sibling (the classic constitutional-delay stem), male sex (boys present far more often), karyotypic abnormality, prior gonadotoxic chemotherapy or radiation, congenital midline/olfactory defects, history of micropenis or cryptorchidism in infancy.

Modifiable risk factors

• Caloric deficit and low body weight, over-training, undiagnosed or undertreated chronic inflammatory disease, hypothyroidism, hyperprolactinemia, and opioid or glucocorticoid exposure. The USPSTF recommends screening adolescents aged 12–18 for major depressive disorder (B recommendation); it concluded that evidence is insufficient to recommend routine screening for eating disorders in asymptomatic adolescents (I statement), so eating disorders are usually detected clinically when weight loss, amenorrhea, or growth failure prompt evaluation.

• Normal axis: GnRH neurons originate in the olfactory placode and migrate along olfactory axons into the hypothalamus during fetal life. After a transient neonatal minipuberty, central inhibition produces the childhood juvenile pause. Puberty begins when kisspeptin-producing KNDy neurons (kisspeptin/neurokinin B/dynorphin) restore pulsatile GnRH release, which drives pituitary LH and FSH, then gonadal sex steroids and inhibin B.
• Constitutional delay: the pulse generator reactivates late but normally. Gonadotropins are low because they have not yet risen, not because they cannot — hence delayed bone age tracking with height age, and eventual spontaneous, complete puberty.
• Kallmann syndrome: failed migration of GnRH neurons with olfactory axons explains why anosmia and absent olfactory bulbs on MRI travel with the endocrine defect; ANOS1 deletions add unilateral renal agenesis and mirror movements (synkinesia).
• Functional suppression: negative energy balance lowers leptin and raises CRH/cortisol, silencing kisspeptin drive. The axis is structurally intact and recovers with weight restoration or treatment of the underlying illness.
• Primary gonadal failure: loss of gonadal steroid and inhibin B negative feedback disinhibits the pituitary, so FSH rises first and highest — the biochemical signature of Turner and Klinefelter.
• Why the phenotype looks as it does: absent sex steroid means no Tanner progression, no pubertal growth spurt, and no bone mineral accrual. Estradiol — including estradiol aromatized from testosterone in boys — is the signal that both accelerates growth and ultimately fuses the epiphyses. Without it, growth plates stay open and slow linear growth continues, producing eunuchoid proportions: arm span exceeding height and a lower segment longer than the upper segment. Low peak bone mass follows from the same estrogen deficiency.

The classic stem

• A 14-year-old boy who is the shortest in his class with no testicular enlargement (prepubertal volume <4 mL, length <2.5 cm), whose father "grew after high school" — constitutional delay.
• A 13-year-old girl with no breast budding, or a 15-year-old with breasts but no menarche. ACOG defines primary amenorrhea as no menses by age 15 with secondary sexual characteristics, or by 13 without them.

Core findings and their mechanism

• Tanner stage 1 genitalia/breasts with declining height percentile: absent gonadal steroid output.
• Eunuchoid body proportions and delayed bone age: unfused epiphyses from absent estrogen effect on the growth plate.
• Adrenarche may be present (pubic hair, axillary odor) even when gonadarche is absent, since adrenal androgens are independently regulated — a frequent point of confusion.

Cause-specific clues

• Anosmia or hyposmia, cleft lip/palate, mirror movements, unilateral renal agenesis: Kallmann syndrome. Micropenis and cryptorchidism in infancy point to congenital GnRH deficiency rather than constitutional delay.
• Short stature with webbed neck, low posterior hairline, shield chest, cubitus valgus, short fourth metacarpal, neonatal lymphedema, murmur of bicuspid aortic valve or coarctation: Turner syndrome.
• Tall stature with long limbs, small firm testes, gynecomastia, and learning or language difficulty: Klinefelter syndrome; puberty often starts and then arrests.
• Headache, visual field loss, galactorrhea, polyuria/polydipsia: sellar or suprasellar mass (craniopharyngioma, germinoma, prolactinoma).
• Low BMI, bradycardia, lanugo, parotid enlargement, dental erosion, or chronic diarrhea, weight loss and iron-deficiency anemia: functional suppression from an eating disorder, celiac disease or inflammatory bowel disease.

Step 1 — history, growth chart, Tanner staging

• Plot height velocity, calculate mid-parental target height, ask about anosmia, headache/vision, GI symptoms, exercise volume, and parental pubertal timing.

Step 2 — initial labs and imaging

• Bone age: radiograph of the left hand and wrist. Bone age delayed and roughly equal to height age with preserved growth potential is the hallmark of constitutional delay.
• LH and FSH (ultrasensitive assay) plus morning total testosterone in boys or estradiol in girls — this is the branch point named in the overview.
• Screen for systemic and endocrine causes: TSH/free T4, prolactin, IGF-1, CBC, CMP, ESR/CRP, tissue transglutaminase IgA with total IgA.

Step 3 — direct the workup by gonadotropin level

• High LH/FSH → karyotype is the confirmatory test. 45,X (or mosaic) confirms Turner; 47,XXY confirms Klinefelter. In Turner, add echocardiography and renal ultrasound per the international Turner syndrome consensus guideline.
• Low or inappropriately normal LH/FSH → MRI of the hypothalamus and pituitary when there are neurologic signs, hyperprolactinemia, anosmia, or multiple pituitary hormone deficiencies. Formal olfactory testing supports Kallmann; absent olfactory bulbs/sulci on MRI is the imaging finding.
• In girls with breast development but amenorrhea, pelvic ultrasound assesses Müllerian anatomy (outflow obstruction, Müllerian agenesis, androgen insensitivity).

Distinguishing constitutional delay from congenital GnRH deficiency

• There is no gold-standard single test. Supportive of permanent deficiency: prior micropenis/cryptorchidism, anosmia, very low inhibin B, and blunted response to GnRH or GnRH-agonist stimulation. In practice the diagnosis is confirmed by longitudinal observation — spontaneous progression establishes constitutional delay retrospectively, so it remains a diagnosis of exclusion.

Immediate priorities

• Exclude and treat a dangerous underlying cause first: a sellar mass, an eating disorder with hemodynamic instability, or a newly identified Turner patient with aortic coarctation. Correct hypothyroidism and treat hyperprolactinemia (dopamine agonist, e.g., cabergoline) before attributing delay to the gonads.

Constitutional delay

• Reassurance plus observation with 4–6-month growth and Tanner reassessment is appropriate and sufficient in most boys.
• Short-course low-dose androgen for significant psychosocial distress: an injectable testosterone ester (testosterone enanthate or cypionate) at low dose monthly for roughly 3–6 months jump-starts virilization and the growth spurt without compromising adult height. This is a widely used, guideline-suggested option (a weak recommendation based on low-quality evidence; the Endocrine Society testosterone guideline is written for adult men and addresses adolescent constitutional delay only as a suggestion), supported by pediatric endocrine consensus practice.

Permanent hypogonadism (either type)

• Boys: escalating testosterone replacement (injectable or transdermal) titrated upward over 2–3 years to mimic physiologic puberty, then adult replacement — consistent with Endocrine Society testosterone therapy guidance.
• Girls: low-dose estradiol, preferably transdermal, escalated gradually, with a progestin added after about 2 years of estrogen or once breakthrough bleeding occurs, to prevent unopposed-estrogen endometrial hyperplasia.
• Turner syndrome: growth hormone for stature, then estrogen initiation at an age-appropriate time, per the international Turner consensus guideline.

Fertility-directed and surgical management

• Sex steroids alone do not induce spermatogenesis or ovulation. Fertility in hypogonadotropic hypogonadism requires gonadotropin therapy (hCG with FSH) or pulsatile GnRH.
• Prophylactic gonadectomy for dysgenetic gonads containing Y material because of gonadoblastoma risk.

Avoid

• High-dose or prolonged androgen/estrogen in a child with open epiphyses — accelerates bone age and prematurely fuses growth plates, costing adult height.
• Long-term unopposed estrogen in a girl with a uterus.
• Committing to lifelong therapy before the constitutional-delay-versus-permanent-deficiency question has been resolved.

Of the untreated disease

• Reduced adult height or, paradoxically, tall eunuchoid stature: absent estrogen means the epiphyses never fuse on schedule, so long bones keep growing while the growth spurt never occurs.
• Low peak bone mass, osteopenia and adult fracture risk: sex steroids drive adolescent bone mineral accrual, and the window is finite — this is the strongest argument against indefinite "watchful waiting."
• Infertility: intrinsic in gonadal dysgenesis and Klinefelter; potentially reversible in hypogonadotropic hypogonadism with gonadotropin or pulsatile GnRH therapy.
• Psychosocial morbidity: bullying, depression, and impaired body image, which independently justify treatment.
• Missed underlying disease: an unrecognized craniopharyngioma or germinoma progressing to visual loss, panhypopituitarism, or pituitary apoplexy — an emergency presenting with thunderclap headache, ophthalmoplegia and hypotension from adrenal insufficiency.
• Turner-specific: aortic dissection from bicuspid valve/coarctation-associated aortopathy is a true emergency; also renal anomalies, hypothyroidism, and sensorineural hearing loss.
• Klinefelter-specific: gynecomastia with increased breast cancer risk, and metabolic syndrome.
• Y-containing gonadal dysgenesis: gonadoblastoma, the reason for prophylactic gonadectomy.

Of treatment

• Premature epiphyseal fusion from excessive androgen or estrogen dosing — signalled by bone age advancing faster than chronologic age; monitor bone age serially.
• Testosterone: erythrocytosis (rising hematocrit), acne, priapism, mood lability, and sleep apnea aggravation.
• Estrogen: venous thromboembolism, and endometrial hyperplasia or carcinoma if given unopposed to a girl with a uterus.
• Refeeding syndrome in a severely malnourished adolescent whose delay is functional — hypophosphatemia with arrhythmia and heart failure is an emergency.
• Ovarian hyperstimulation or multiple gestation with gonadotropin-based fertility induction.

• The single best next step in almost every stem is a bone age radiograph of the left hand/wrist plus LH and FSH. Gonadotropin level is the branch point; bone age separates delayed maturation from a fixed height deficit.
• Delayed puberty + anosmia = Kallmann syndrome. Mechanism: GnRH neurons fail to migrate with olfactory axons from the olfactory placode. Look for the added ANOS1 features — unilateral renal agenesis and mirror movements.
• Short girl, no breasts, high FSH → order a karyotype, not an MRI. Tall boy, small firm testes, gynecomastia, high FSH/LH → Klinefelter (47,XXY). A phenotypic girl with a uterus, streak gonads and high FSH who turns out to be 46,XY is Swyer syndrome.
• Constitutional delay is the most common cause and a normal variant, but it is a diagnosis of exclusion — bone age delayed to match height age plus a positive family history, confirmed by eventual spontaneous progression.
• Adrenarche is independent of gonadarche. Pubic and axillary hair can be present with Tanner 1 breasts or prepubertal testes; its presence does not exclude delayed puberty. This is the classic distractor.
• Sex steroids do not restore fertility. In hypogonadotropic hypogonadism, spermatogenesis or ovulation requires hCG plus FSH or pulsatile GnRH — a favourite second-order question.
• Estrogen closes the growth plates, including estrogen aromatized from testosterone in boys. Over-dosing androgen therefore shortens adult height; short-course, low-dose therapy is the suggested approach for boys with constitutional delay and significant distress.
• Always add a progestin to long-term estrogen in a girl with a uterus, and always gonadectomize dysgenetic gonads containing Y material because of gonadoblastoma risk.