Processes of sexual differentiation, growth, development, puberty, reproduction, and ageing
Sexual differentiation
- Chromosomal -> gonadal -> phenotypic sex, in that order
- SRY (Yp11.3) -> testis -> Sertoli + Leydig
- Sertoli: AMH -> Mullerian regression
- Leydig: testosterone -> Wolffian (epididymis, vas, seminal vesicle)
- 5-alpha-reductase -> DHT -> external virilisation (phallus, scrotum, prostate)
- No SRY -> ovary; needs two intact X
- Ovary is an active WNT4/RSPO1 pathway, not a default
- No AMH -> Mullerian persists (tubes, uterus, upper vagina)
- Internal ducts follow the ipsilateral gonad; external genitalia follow circulating androgen
Puberty
- Girls: thelarche -> pubarche -> peak growth velocity -> menarche
- Growth peak precedes menarche - only ~5 cm left after it
- Boys: testicular enlargement (>4 mL) -> pubarche -> penile growth -> growth spurt
- Spurt ~2y later than girls, from a larger prepubertal base -> ~13 cm adult height difference
- Tanner/Marshall stages 1-5
- Adrenarche (DHEAS, age 6-8) is independent of gonadarche - pubarche alone is not puberty
Growth
| Phase | Driver |
|---|---|
| Infantile (0-2y) | Nutrition, insulin |
| Childhood | GH/IGF-1 + thyroid hormone |
| Pubertal | Sex steroids + GH |
- Oestrogen closes the epiphyses in both sexes (aromatised testosterone in males)
- Aromatase deficiency or ER-alpha mutation -> tall man with unfused epiphyses
Reproductive ageing
- Female: fixed oocyte pool - 7M at 20 weeks gestation, 1-2M at birth, ~400 ovulated
- Menopause = 12 months amenorrhoea; mean 51y. Premature ovarian insufficiency if <40y
- inc FSH, dec AMH. AMH measures reserve, not fertility
- Male: no abrupt cessation - testosterone falls ~1%/yr from ~40y, SHBG rises
- Total testosterone falls less than free - measure free/calculated
Timing of puberty
- Normal onset: girls 8-13y, boys 9-14y
- Secular trend to earlier thelarche (adiposity, ?endocrine disruptors); menarche age near-stable ~12.5-13y
- Precocious puberty F>M ~10:1
- Girls: >90% idiopathic central. Boys: organic cause in a large minority
- Delayed puberty M>F presenting; constitutional delay commonest cause in both
- POI ~1% of women; menopause mean 51y
Trigger of puberty
- Pulsatile GnRH resumes 2-3y before clinical onset, nocturnal-predominant -> LH/FSH -> gonadal steroids
- Brake release: MKRN3 loss-of-function (paternally imprinted - inherited from father) = commonest known monogenic CPP
- Also KISS1/KISS1R and NKB gain-of-function, DLK1
- Permissive: leptin/fat mass, general health, genetics (~50-80% of timing variance)
- Sex steroids drive the spurt via GH amplification, then fuse the plates
Precocious puberty - central (GnRH-dependent)
- Consonant sequence, LH pubertal/detectable
- Idiopathic (most girls)
- Hypothalamic hamartoma = commonest organic cause
- Secretes TGF-alpha -> ectopic GnRH pulses; gelastic (laughing) seizures
- Optic pathway glioma (NF1), germinoma, cranial irradiation, hydrocephalus, CNS trauma/infection
- Prior chronic sex-steroid exposure (late-treated CAH) -> secondary central activation
Precocious puberty - peripheral (GnRH-independent)
- Non-consonant, LH suppressed
- McCune-Albright - post-zygotic mosaic GNAS activating mutation
- Cafe-au-lait with jagged "coast of Maine" border + polyostotic fibrous dysplasia + autonomous ovarian cysts
- +/- acromegaly, Cushing, hyperthyroidism, phosphaturia
- Familial male-limited precocity (testotoxicosis) - AD activating LHCGR, onset 2-3y, bone age markedly advanced
- CAH, adrenal carcinoma, Leydig/granulosa cell tumour, hCG-secreting tumour (boys only), exogenous steroid
- Severe primary hypothyroidism (Van Wyk-Grumbach) - very high TSH cross-activates FSH-R
- Bone age delayed, not advanced - the one precocity with short stature and slow growth
- Sustained peripheral exposure matures the axis -> superimposed central precocity
CPP progression patterns
- Rapidly progressive / slowly progressive (commoner in girls) / spontaneously regressive
- A period of observation is what separates them - not a test
Staging
- Boys: testicular volume >4 mL (long axis >2.5 cm) is the first sign - orchidometer, +/- scrotal thinning then pigmentation
- Girls: breast bud
- Pubic hair without gonadal enlargement = adrenal or peripheral source
Precocious puberty - assessment
Precocious puberty
- Definition: secondary sexual characteristics <8y girls, <9y boys
- Bone age is the first-line test
- Advanced -> true precocity
- Normal with isolated premature pubarche -> observe, no further workup
- Basal LH pubertal -> central; prepubertal/suppressed -> peripheral or benign variant
- Equivocal -> GnRH-agonist (leuprorelin) stimulation test: LH rise = central
- Oestradiol (girls), testosterone (boys), DHEAS + 17-OHP if virilised, hCG, TSH
- Pelvic US: uterine length/volume, endometrial echo, ovarian cyst
- MRI brain
- All boys <8y; all girls <6y; any neurological sign; rapid progression
- *2026 ES guideline: NOT routine in girls 6-8y or boys 8-9y with CPP and no CNS findings* - a change from universal imaging
- Features pointing to an intracranial cause: diabetes insipidus, adipsia, hyperthermia, obesity or cachexia, visual field loss, headache, seizures
- In girls <7y with new breast development, 4-6 months of observation before formal workup
Delayed puberty - assessment
Delayed puberty
- No thelarche by 13y, no testicular enlargement by 14y, or >5y thelarche-to-menarche
- LH/FSH splits it
- High -> primary gonadal failure: Turner, Klinefelter, chemo/RT, autoimmune
- Low -> constitutional delay vs hypogonadotropic hypogonadism (the hardest discrimination - delayed bone age and family history favour constitutional; anosmia = Kallmann)
Central precocious puberty - management
Central precocious puberty
- GnRH agonist - leuprorelin, triptorelin. Continuous exposure desensitises gonadotroph GnRH-R -> LH/FSH shut off
- Transient flare over the first 2-4 weeks - warn about a withdrawal bleed
- Start on a long-acting (3-6 monthly) depot rather than a monthly preparation
- Do not routinely check LH or sex steroids to confirm suppression - monitor growth velocity, Tanner stage, bone age
- Do not routinely add growth hormone
- Stop by chronological age 10-11y (girls) / 11-12y (boys), or bone age 11-12y / 12-13y
- Treat when: rapidly progressive, young at onset, bone age well advanced, predicted adult height compromised, significant distress
- Do not treat: slowly progressive or regressive patterns, older girls with little height at stake
- 2026 guideline explicitly moves away from evaluating and treating everyone who meets the age definition
Peripheral precocity - treat the source
- Excise adrenal/gonadal tumour; glucocorticoid for CAH; thyroxine for Van Wyk-Grumbach
- McCune-Albright: aromatase inhibitor (letrozole, anastrozole) or tamoxifen
- GnRH agonist does nothing - the axis is not driving it
- Testotoxicosis: antiandrogen + aromatase inhibitor (or ketoconazole)
- Add a GnRH agonist once secondary central activation supervenes
Growth - treatment
Growth
- GH indications: GH deficiency, Turner, SHOX deficiency, Prader-Willi, CKD, SGA without catch-up by 2-4y
- Post-cranial-irradiation: treat GH deficiency and the precocity together
Reproductive ageing - management
Reproductive ageing
- MHT for vasomotor symptoms: lowest effective dose, add progestogen if uterus intact
- Start <60y or within 10y of menopause; transdermal oestradiol avoids the first-pass VTE excess
- POI: replace sex steroids until ~51y regardless of symptoms - bone, cardiovascular and cognitive protection
- Testosterone in ageing men only for biochemically confirmed hypogonadism, not for age or symptoms alone
Associations
- Cranial irradiation -> precocious puberty + GH deficiency + hypothyroidism in the same patient
- Early puberty can normalise growth velocity and mask the GHD - treat both or final height is lost
- NF1 - optic pathway glioma -> CPP or GH deficiency
- Obesity - earlier thelarche in girls, later onset in boys
- Turner, Klinefelter - absent or arrested puberty
- Adoption / international migration - unexplained excess of CPP
- Leydig cell tumour - palpable testicular mass, high testosterone, suppressed LH, no contralateral enlargement
- Premature pubarche in girls - later PCOS and insulin resistance
Outcomes
- Untreated rapidly progressive CPP -> early epiphyseal fusion -> tall child, adult height often below the 5th centile
- Slowly progressive or regressive CPP -> normal adult height without treatment
- Isolated premature thelarche/pubarche - usually benign, non-progressive, observe
- After stopping a GnRH agonist: menses return ~12-18 months, fertility unimpaired, no lasting BMD deficit
- Untreated POI -> osteoporosis, premature cardiovascular disease
- Menopause is a diagnosis made in retrospect - FSH is unreliable in the transition
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