Puberty & Pubertal Disorders

How puberty starts

Gonadarche. Through childhood the hypothalamic GnRH pulse generator is held quiet by central inhibition (after a brief "mini-puberty" in early infancy). At puberty, kisspeptin from hypothalamic neurons (gene KISS1) binds KISS1R (formerly GPR54) on GnRH neurons and lifts the brake. GnRH is released in pulses, at first mainly during sleep, driving LH (theca and Leydig androgen production) and FSH (granulosa aromatase, Sertoli support of spermatogenesis). Inactivating KISS1R mutations cause hypogonadotropic hypogonadism with a normal sense of smell.

Leptin is permissive. Leptin, secreted in proportion to fat mass, signals that energy stores can support reproduction. It does not start puberty alone, but when it is low (anorexia nervosa, intense training, chronic illness, congenital leptin deficiency) GnRH pulses stay suppressed and puberty is delayed.

Adrenarche. From about age 6–8 the adrenal zona reticularis raises DHEA and DHEA-S, producing pubic and axillary hair, body odor and acne. It is independent of the gonadal axis: girls with Turner syndrome still grow pubic hair without breast development.

Normal sequence, Tanner stages and growth

Girls. Thelarche (breast budding) usually comes first, typically at 8–13 years, then pubic hair, the growth spurt and finally menarche about 2–2.5 years after thelarche (US average about 12.5 years). Peak height velocity is early (Tanner 2–3), so little growth remains after menarche.

Boys. The first sign is testicular enlargement to ≥4 mL (long axis ≥2.5 cm) with thin, reddened scrotal skin, typically at 9–14 years; pubic hair and penile growth follow, and peak height velocity comes late (Tanner 4, about 13–14 years), with voice change and facial hair later. This later, longer spurt explains the average 13 cm adult height gap, so mid-parental target height is (father + mother + 13 cm) ÷ 2 for boys and (father + mother − 13 cm) ÷ 2 for girls.

Estrogen closes growth plates. Sex steroids amplify GH and IGF-1 for the spurt, but estrogen fuses the epiphyses in both sexes (in males, from aromatized testosterone). Men with aromatase (CYP19A1) deficiency or estrogen receptor-α loss keep growing with open epiphyses, eunuchoid proportions and osteoporosis. Estradiol is undetectable with aromatase deficiency (estrogen therapy works) but high with receptor loss (therapy fails). Any hypogonadism delays fusion, giving arm span greater than height.

Bone age. A left hand–wrist radiograph: advanced by sex-steroid exposure; delayed in constitutional delay, hypothyroidism, GH deficiency and hypogonadism. Untreated precocious children are tall for age but short as adults because their plates fuse early.

Precocious puberty

Definition. Secondary sexual characteristics before age 8 in girls or 9 in boys. Central precocity is normal-sequence puberty that starts early; peripheral precocity is sex-steroid excess without gonadotropin drive.

Central. Most girls are idiopathic; boys more often have a CNS lesion: hypothalamic hamartoma (ectopic GnRH neurons; gelastic "laughing" seizures), NF1 optic glioma, hydrocephalus, tumors, irradiation or trauma. Long peripheral steroid exposure (late-treated CAH) can trigger secondary central puberty. A depot GnRH agonist (leuprolide, triptorelin, histrelin implant) gives continuous rather than pulsatile stimulation, downregulating pituitary GnRH receptors so LH and FSH fall and adult height is preserved.

Peripheral. 21-Hydroxylase CAH (high 17-hydroxyprogesterone; glucocorticoid treatment) virilizes boys with small testes. Leydig cell tumors form a unilateral testicular mass; granulosa cell tumors secrete estrogen (breasts, vaginal bleeding); adrenal tumors raise DHEA-S; testosterone gel or estrogen cream may be transferred from a caregiver. hCG-secreting germ cell tumors (intracranial, mediastinal as in Klinefelter syndrome) and hepatoblastoma cause precocity only in boys: hCG acts on Leydig-cell LH receptors, but ovarian estrogen synthesis needs FSH as well. Activating LH-receptor mutations cause familial male-limited precocious puberty.

McCune-Albright syndrome. A postzygotic activating GNAS mutation keeps Gsα on (constitutive cAMP). The triad: peripheral precocity from autonomous ovarian cysts (vaginal bleeding), café-au-lait macules with jagged "coast of Maine" borders (NF1: smooth "coast of California") and polyostotic fibrous dysplasia; hyperthyroidism, GH excess, Cushing syndrome and FGF23-mediated phosphate wasting may join. Patients are mosaics, because the germline mutation would be lethal. GnRH agonists do not help; letrozole or tamoxifen blocks estrogen.

Hypothyroidism and benign variants. Severe primary hypothyroidism can cause breast growth, ovarian cysts or testicular enlargement because very high TSH weakly activates FSH receptors (Van Wyk–Grumbach syndrome); uniquely, growth slows and bone age is delayed, and levothyroxine reverses it. Premature thelarche (isolated breast budding, often before age 2) and premature adrenarche (early pubic hair or odor, DHEA-S high for age) have normal growth velocity and bone age and need observation; premature adrenarche in girls is linked to later PCOS and insulin resistance.

Delayed puberty

Definition. No breast development by 13 years in girls, or testes <4 mL by 14 years in boys.

Constitutional delay. The most common cause, especially in boys: short stature with normal growth velocity, a late-blooming parent, delayed bone age matching height age, and gonadotropins low for age but appropriate for bone age. Puberty arrives spontaneously and adult height is near target. Early on it mimics permanent hypogonadotropic hypogonadism, so it is a diagnosis of exclusion; low-dose testosterone or estrogen can jump-start development.

Kallmann syndrome. GnRH neurons arise in the olfactory placode and migrate along olfactory fibers to the hypothalamus. Mutations in ANOS1 (KAL1, X-linked, anosmin-1) or FGFR1 block migration → isolated GnRH deficiency (low LH, FSH, sex steroids) with anosmia and hypoplastic olfactory bulbs; boys may have micropenis or cryptorchidism, and delayed fusion gives tall eunuchoid proportions. Associations: unilateral renal agenesis, mirror movements, cleft lip or palate. The pituitary is normal, so pulsatile GnRH or hCG plus FSH induces fertility; testosterone virilizes but does not produce sperm.

Functional suppression. Energy deficit (anorexia, athletes), chronic disease (IBD, celiac disease, cystic fibrosis), hypothyroidism, hyperprolactinemia and glucocorticoid excess reversibly suppress GnRH; exclude sellar tumors such as craniopharyngioma.

Primary gonadal failure. High LH and FSH with low sex steroids: Turner syndrome (45,X), Klinefelter syndrome (47,XXY; puberty often starts but stalls), gonadal dysgenesis, chemotherapy, radiation. A karyotype is the key test.

Short stature with slow growth velocity is not constitutional delay: think hypothyroidism, GH deficiency, celiac disease or Turner syndrome.