Obstetrics and Gynaecology chapters
Gonadal steroidogenesis, precocious and delayed puberty, and ambiguous genitalia
How the gonads and adrenals make sex steroids, which enzyme defects cause ambiguous genitalia, the DSD conditions (Turner, Swyer, androgen insensitivity, 5-alpha-reductase deficiency, CAH) and the work-up of early and late puberty.
- Sex steroids are all made from cholesterol; the first and rate-limiting step is desmolase (P450scc) with StAR moving cholesterol into mitochondria; an enzyme block causes a lack of products and a pile-up of precursors.
- The commonest 46,XX DSD is 21-hydroxylase CAH (virilised girl, salt-wasting in two-thirds); the commonest 46,XY DSD is complete androgen insensitivity (female body, no uterus, testes in the groin).
- Precocious puberty: before 8 in girls, 9 in boys (central = GnRH-driven; peripheral = always pathological); delayed puberty: no signs by 14 (low or high gonadotrophins).
On this page
Overview
Disorders of sex development (DSD) are conditions where chromosomal, gonadal or anatomical sex does not develop in the usual way. They may present:
- at birth with ambiguous genitalia,
- at puberty with primary amenorrhoea, absent puberty or unexpected virilisation.
To understand them you need two things: normal sex differentiation and the steroid synthesis pathway. This chapter also covers precocious and delayed puberty.
Normal sex differentiation
| Step | Male (46,XY) | Female (46,XX) |
|---|---|---|
| Gonad | SRY gene on Y → testis | No SRY → ovary |
| Internal ducts | Sertoli cells make AMH → Müllerian ducts regress; Leydig testosterone keeps Wolffian ducts (epididymis, vas, seminal vesicle) | No AMH → Müllerian ducts form tubes, uterus, upper vagina; no testosterone → Wolffian ducts regress |
| External genitalia | Dihydrotestosterone (DHT), made from testosterone by 5-alpha-reductase, forms penis and scrotum | No androgen → female external genitalia |
- hCG from the placenta drives fetal Leydig cells to make testosterone early in pregnancy.
- Female is the default: without a testis (AMH plus androgen), development is female.
The uterus depends only on the absence of AMH, and the external genitalia depend on androgen action (DHT). Work out any DSD by asking: was AMH made, and did androgens act?
"AMH removes the uterus; testosterone keeps the Wolffian ducts; DHT builds the outside."
Steroidogenesis
All sex steroids, cortisol and aldosterone come from cholesterol.
- StAR protein moves cholesterol into the mitochondria (control point).
- Desmolase (P450scc, CYP11A1) cuts the side chain: cholesterol → pregnenolone. This is the rate-limiting step.
- 3-beta-hydroxysteroid dehydrogenase: pregnenolone → progesterone.
- 17-alpha-hydroxylase (CYP17) sends steroids towards cortisol and sex steroids (17-hydroxyprogesterone, then androgens).
- 21-hydroxylase: progesterone → 11-deoxycorticosterone (aldosterone path) and 17-hydroxyprogesterone → 11-deoxycortisol (cortisol path).
- 11-beta-hydroxylase: makes corticosterone and cortisol.
- 17-beta-HSD: androstenedione → testosterone.
- Aromatase (CYP19): androgens → oestrogens (granulosa cells, fat, placenta).
- 5-alpha-reductase (target tissue): testosterone → DHT.
A block causes too little of what comes after and too much of what comes before. In the adrenal, low cortisol raises ACTH, the glands enlarge (hyperplasia), and the backed-up precursors are pushed into the androgen pathway.
Congenital adrenal hyperplasia (CAH): enzyme table
| Enzyme deficient | Cortisol | Aldosterone | Androgens | Blood pressure, salts | Genitalia |
|---|---|---|---|---|---|
| 21-hydroxylase (over 90%) | Low | Low (salt-losing form) | High | Salt loss: low Na, high K, shock | XX virilised; XY normal or early virilisation |
| 11-beta-hydroxylase | Low | Low, but 11-deoxycorticosterone high | High | Hypertension, low renin | XX virilised |
| 17-alpha-hydroxylase | Low | Mineralocorticoids high | Low (no sex steroids) | Hypertension, hypokalaemia | XY undervirilised (female-looking); XX no puberty |
| 3-beta-HSD | Low | Low | Low (weak DHEA only) | Salt loss | Female-like genitalia |
In 17-alpha-hydroxylase deficiency a "girl" presents at puberty with primary amenorrhoea, no breast development and high blood pressure with low potassium. Do not confuse it with 21-hydroxylase deficiency, which causes virilisation and salt loss.
The DSD conditions
Terminology (Chicago consensus 2006)
| Old term | Current term |
|---|---|
| Intersex | DSD |
| Male pseudohermaphrodite, undervirilised male | 46,XY DSD |
| Female pseudohermaphrodite, virilised female | 46,XX DSD |
| True hermaphrodite | Ovotesticular DSD |
| XX male | 46,XX testicular DSD |
| XY sex reversal | 46,XY complete gonadal dysgenesis |
The old terms are still asked. Pseudohermaphrodite = one type of gonad but genitalia of the other appearance. True hermaphrodite = both ovarian and testicular tissue in the same person.
46,XX DSD: congenital adrenal hyperplasia (21-hydroxylase)
- Commonest cause of ambiguous genitalia in a newborn girl.
- Excess fetal adrenal androgen: enlarged clitoris, fused, scrotal-looking labia, the vagina and urethra may open as a single channel. Internal organs (ovaries, uterus) are normal.
- About two-thirds are salt-losing: vomiting, dehydration, low sodium, high potassium and collapse in the first days or weeks; this is life-threatening.
- Diagnosis: raised 17-hydroxyprogesterone.
In any newborn with ambiguous genitalia, check sodium, potassium and glucose early: salt-losing CAH can kill within days.
- Treatment: lifelong hydrocortisone, plus fludrocortisone if salt-losing. Genital surgery is now decided individually by a multidisciplinary team; early surgery is controversial.
- Non-classic (late-onset) CAH presents in young women with hirsutism and irregular periods and mimics PCOS.
46,XY DSD
Complete androgen insensitivity syndrome (CAIS)
- Commonest 46,XY DSD; X-linked androgen receptor defect.
- Testes form (SRY) and make AMH → no uterus, tubes or upper vagina.
- Testosterone is made but cannot act → female external genitalia; some testosterone is aromatised → normal breasts.
- Presents at puberty with primary amenorrhoea, scanty pubic and axillary hair, short blind vagina; or earlier with inguinal hernia containing a testis.
- Management: honest disclosure with psychological support, gonadectomy (small tumour risk, can wait until after puberty) then HRT, vaginal dilators before considering surgery. Infertile.
Partial androgen insensitivity: limited receptor response, so ambiguous genitalia at birth.
5-alpha-reductase deficiency
- XY with normal testes, testosterone and AMH, but no DHT in the skin.
- Ambiguous or female-looking genitalia at birth; at puberty the surge of testosterone causes virilisation (deep voice, muscle, phallic growth). No uterus.
46,XY complete gonadal dysgenesis (Swyer syndrome)
- Testes fail to form (SRY mutation in about 15%); streak gonads make no hormones.
- No AMH → uterus, tubes and vagina present; no testosterone → female external genitalia.
- Presents with delayed puberty and primary amenorrhoea, high FSH and LH.
- Gonads must be removed when diagnosed: high risk of gonadoblastoma and other germ cell tumours. Puberty induced with oestrogen; pregnancy possible with donor eggs.
Sex chromosome conditions
Turner syndrome (45,X)
- Commonest sex chromosome problem in females: about 1 in 2,500 live female births; mosaicism is common.
- Streak ovaries (stroma only) → no oestrogen → delayed puberty, primary amenorrhoea, high FSH and LH (hypergonadotrophic).
- Short stature, webbed neck, wide carrying angle (cubitus valgus), shield chest, history of middle ear infections.
- Coarctation of the aorta, bicuspid aortic valve, renal anomalies, deafness, autoimmune thyroid disease, inflammatory bowel disease.
- Treatment: growth hormone in childhood, oestrogen to induce puberty, then HRT. Pregnancy possible with egg donation but risky (aortic dissection).
- Mosaic women may have some periods but an early menopause.
Mixed gonadal dysgenesis (often 45,X/46,XY): a streak gonad and a testis; variable genitalia; gonadectomy because of tumour risk.
Ovotesticular DSD: both ovarian and testicular tissue; genitalia depend on how much testicular function there is; Müllerian structures usually absent on the testis side.
Klinefelter syndrome (47,XXY): the commonest sex chromosome cause of male subfertility; small testes, very low or absent sperm count and high FSH and LH (testicular failure).
Quick comparison: primary amenorrhoea with a DSD
| Condition | Karyotype | Breasts | Uterus | Pubic hair | Gonad |
|---|---|---|---|---|---|
| Turner | 45,X | Absent | Present (small) | Normal (adrenal) | Streak |
| Swyer | 46,XY | Absent | Present | Normal or sparse | Streak |
| CAIS | 46,XY | Present | Absent | Scanty | Testes |
| MRKH | 46,XX | Present | Absent | Normal | Normal ovaries |
| 17-alpha-hydroxylase | 46,XY or XX | Absent | Absent (XY)/present (XX) | Sparse | Testes or ovaries |
Approach to a baby with ambiguous genitalia
- Treat as a medical and social emergency; do not assign sex in a hurry and avoid guessing in front of the family.
- Check for salt-losing CAH: electrolytes, glucose, blood pressure.
- Karyotype, 17-hydroxyprogesterone, pelvic ultrasound (uterus? gonads?), hormone tests.
- A multidisciplinary team: paediatric endocrinologist, surgeon, psychologist, geneticist.
Precocious puberty
- Onset of puberty before 8 years in a girl or before 9 years in a boy.
| Type | Mechanism | Causes | Tests |
|---|---|---|---|
| Central (true, gonadotrophin-dependent) | Early activation of GnRH pulses | Usually idiopathic in girls; up to 25% CNS malformation or brain tumour (more common in boys) | LH and FSH raised and rise further after GnRH stimulation; MRI brain |
| Peripheral (pseudo, gonadotrophin-independent) | Sex steroids from outside the HPO axis | Always pathological: oestrogen-secreting ovarian tumour (granulosa cell), ovarian cysts, exogenous oestrogen, adrenal tumour, CAH (in boys), hCG-secreting tumour | LH and FSH suppressed; no rise after GnRH |
- Effects: early breast and hair growth, early growth spurt, advanced bone age; early epiphyseal fusion cuts final height.
- Central type is treated with a GnRH agonist (continuous), which switches the axis off until a suitable age; peripheral type is treated by removing the cause.
In central precocious puberty the sequence of puberty is normal, just early. In peripheral puberty the sequence may be odd (for example vaginal bleeding before breast development).
Delayed puberty
- No secondary sexual characteristics by 14 years (girls).
| Type | Gonadotrophins | Causes |
|---|---|---|
| Constitutional delay | Low for age | Often a family history; puberty comes eventually, but other causes must be excluded first |
| Hypogonadotrophic hypogonadism | Low | Anorexia, excessive exercise, chronic illness (diabetes, renal failure), Kallmann syndrome, pituitary tumour |
| Hypergonadotrophic hypogonadism | High | Turner syndrome, gonadal dysgenesis, POI after chemotherapy or radiotherapy |
- Tests: FSH, LH, oestradiol, prolactin, TSH, karyotype, bone age, pelvic ultrasound, MRI if central.
- Treat the cause; induce puberty with low-dose oestrogen (transdermal preferred), adding progestogen once bleeding starts if there is a uterus.
Expect: SRY, AMH, testosterone and DHT in normal differentiation; the steroid pathway with desmolase as the rate-limiting step; 21-hydroxylase deficiency as the commonest cause of ambiguous genitalia in a girl, its salt-wasting crisis and raised 17-hydroxyprogesterone; 11-beta and 17-alpha-hydroxylase deficiency with hypertension; CAIS (XY, breasts, no uterus, scanty hair, X-linked); 5-alpha-reductase deficiency virilising at puberty; Swyer and Turner with streak gonads and high FSH; gonadectomy for Y-containing streak gonads; old versus new DSD terms; age cut-offs for precocious (8 and 9) and delayed (14) puberty; central versus peripheral precocious puberty and GnRH agonist treatment.
Quick revision
- Cholesterol → pregnenolone (desmolase, StAR) is rate-limiting.
- 21-OH deficiency: virilised XX, salt loss, high 17-OHP; hydrocortisone ± fludrocortisone.
- 11-beta and 17-alpha deficiency: hypertension.
- CAIS: XY, female body, breasts, no uterus, scanty hair, testes; gonadectomy and HRT.
- 5-ARD: XY, ambiguous at birth, virilises at puberty.
- Swyer: XY streak gonads, uterus present; remove gonads.
- Turner: 45,X; short; streak ovaries; coarctation.
- Precocious: girls under 8, boys under 9; central vs peripheral.
- Delayed: none by 14; low vs high FSH.
Written by The House Job from standard references (Gynaecology by Ten Teachers; Guyton and Hall Textbook of Medical Physiology).
FAQ
Why does a woman with CAIS have breasts but little pubic hair?
Her testes make plenty of testosterone, some of which is converted to oestrogen to grow breasts, but her androgen receptors do not respond, so androgen-dependent hair is scanty.
Why is 21-hydroxylase deficiency dangerous in the first weeks of life?
In the salt-losing form neither aldosterone nor cortisol is made, so the baby loses sodium, retains potassium and can collapse with shock unless treated with steroids and salt replacement.
Why does Swyer syndrome have a uterus but CAIS does not?
In Swyer syndrome the gonads never become testes, so no AMH is made and the Müllerian ducts persist; in CAIS normal testes secrete AMH and the uterus regresses.
Why is a GnRH agonist used to treat central precocious puberty?
Given continuously it desensitises the pituitary, lowering FSH and LH so sex steroids fall, puberty halts and early fusion of the growth plates is delayed, protecting adult height.