Disorders of Sexual Development
A board-focused walkthrough of disorders of sexual development — the SRY → AMH/testosterone → DHT differentiation cascade, then AIS, 5α-reductase deficiency, MRKH, and the CAH enzyme blocks — emphasizing classic vignette buzzwords and next-best-step decisions like 17-OHP screening, karyotyping, electrolyte rescue, and timing of gonadectomy.
Normal Sexual Differentiation: The Framework
Sexual development proceeds in three tiers: chromosomal → gonadal → phenotypic sex. The bipotential gonad becomes a testis only when the SRY gene (Y short arm) activates SOX9/testis-determining factor; without SRY, the default gonad is an ovary. Two testicular cell lines then dictate the internal ducts. Sertoli cells secrete anti-Müllerian hormone (AMH/MIS), which regresses the Müllerian (paramesonephric) ducts — otherwise the uterus, fallopian tubes, and upper vagina. Leydig cells secrete testosterone, which stabilizes the Wolffian (mesonephric) ducts → epididymis, vas deferens, seminal vesicles. Testosterone is converted by 5α-reductase to DHT, which masculinizes the external genitalia and prostate.
The "default" pathway is female: no SRY → ovary; no AMH → Müllerian structures persist; no androgen action → Wolffian ducts regress and external genitalia stay female. Disorders of sexual development (DSD) arise when any step — karyotype, gonad, enzyme, or receptor — is disrupted, creating a mismatch between chromosomal, gonadal, and phenotypic sex. Boards surface these through primary amenorrhea, ambiguous genitalia, or a neonatal salt-wasting crisis.
- SRY (Yp) → testis; its absence → ovary. Wolffian ducts need testosterone; external virilization needs DHT (via 5α-reductase).
- AMH (Sertoli) regresses Müllerian ducts → any patient with functional testes has NO uterus.
- Testosterone → DHT by 5α-reductase; testosterone → estradiol by aromatase.
- 46,XY DSD = undervirilized male: CAIS, 5α-reductase deficiency, 17α-hydroxylase deficiency, gonadal dysgenesis.
- 46,XX DSD = virilized female — most commonly 21-hydroxylase CAH (↑ 17-OHP).
- Absent uterus + normal breasts + primary amenorrhea → CAIS (46,XY) vs Müllerian agenesis / MRKH (46,XX); separate them by karyotype, testosterone, and pubic hair.
- Intra-abdominal or dysgenetic gonads carrying Y material have germ-cell tumor risk (gonadoblastoma) → plan gonadectomy.
Comparison: The Big Four Differentials
| Feature | Complete AIS | 5α-Reductase Def. | 21-OH CAH (46,XX) | MRKH Agenesis |
|---|---|---|---|---|
| Karyotype | 46,XY | 46,XY | 46,XX | 46,XX |
| Inheritance | X-linked recessive | Autosomal recessive (SRD5A2) | Autosomal recessive (CYP21A2) | Sporadic (Müllerian aplasia) |
| Defect | Androgen receptor unresponsive | ↓ DHT synthesis | ↓ cortisol/aldosterone, ↑ androgens | Müllerian duct aplasia |
| Gonads | Testes (undescended/inguinal) | Testes | Ovaries | Ovaries |
| Uterus | Absent (AMH +) | Absent (AMH +) | Present | Absent |
| External genitalia | Female | Female → virilize at puberty | Virilized/ambiguous | Female |
| Testosterone | High (male range) | Normal/high, ↑ T:DHT ratio | ↑ androgens | Female range |
| Pubic/axillary hair | Scant/absent | Present | Present (excess) | Normal |
| Buzzword | Primary amenorrhea, blind vagina | "Penis at 12"/guevedoces | Salt-wasting, ↑ 17-OHP | Renal/skeletal anomalies |
A 16-year-old phenotypic girl presents for primary amenorrhea. She has normal breast development (Tanner IV) but scant pubic and axillary hair. Exam reveals a short, blind-ending vagina; ultrasound shows no cervix or uterus; there are bilateral inguinal masses.
- Diagnosis: Complete Androgen Insensitivity Syndrome (46,XY DSD).
- Why: Testes make AMH (→ no uterus) and testosterone, but a defective/unresponsive androgen receptor blocks virilization; peripheral aromatization of testosterone to estrogen still drives breast growth. Scant hair reflects androgen unresponsiveness.
- Next best step: Karyotype (46,XY) + serum testosterone (elevated, male range; LH also high) and pelvic ultrasound to confirm the absent uterus.
- Management: Raise per gender identity (typically female); gonadectomy for germ-cell tumor risk — malignancy risk is low pre-pubertally, so it is commonly deferred until after puberty to allow spontaneous estrogen-driven feminization — followed by estrogen replacement. Care is multidisciplinary with shared decision-making on timing.
A 2-week-old 46,XX neonate, noted at birth to have clitoromegaly and fused labia, now presents with vomiting, poor feeding, lethargy, and hypotension. Labs: Na⁺ 124, K⁺ 6.8, low glucose.
- Diagnosis: Salt-wasting 21-hydroxylase deficiency (CAH) — the most common cause of ambiguous genitalia in a genetic female and the most common form of CAH (~90–95%).
- Why: Blocked cortisol and aldosterone → hyponatremia, hyperkalemia, hypovolemic shock (plus hypoglycemia); precursors shunt to the androgen pathway → adrenal androgen excess → virilization. ↑ 17-hydroxyprogesterone is diagnostic.
- Next best step: This is a resuscitation emergency — draw 17-OHP and electrolytes, then immediately give IV normal saline + dextrose and stress-dose IV hydrocortisone; do not delay treatment for confirmatory labs.
- Management: Maintenance hydrocortisone (glucocorticoid) + fludrocortisone (mineralocorticoid) with sodium chloride supplementation in infancy.
CAH Enzyme Blocks: 21 vs 11β vs 17α
| Enzyme deficiency | Androgens | Mineralocorticoid effect | BP / K⁺ | Genitalia | Key marker |
|---|---|---|---|---|---|
| 21-hydroxylase (most common) | ↑ | ↓ aldosterone (salt-wasting) | ↓ BP, ↑ K⁺ | 46,XX virilized | ↑ 17-OHP |
| 11β-hydroxylase | ↑ | ↑ 11-deoxycorticosterone (DOC) | ↑ BP, ↓ K⁺ | 46,XX virilized | ↑ 11-deoxycortisol, ↑ DOC |
| 17α-hydroxylase | ↓ | ↑ DOC | ↑ BP, ↓ K⁺ | 46,XY undervirilized; 46,XX no 2° sexual characteristics | ↓ androgens & cortisol, ↑ DOC |
- CAH & blood pressure: "11 and 17 → hyperTension" — both accumulate 11-deoxycorticosterone (DOC), a mineralocorticoid; "21 → salt-wasting hypoTension."
- CAH & virilization: "21 and 11 virilize; 17 does not" — 17α-hydroxylase blocks all sex-steroid synthesis, so 46,XY is undervirilized and 46,XX lacks secondary sexual characteristics.
- 5α-reductase deficiency: "penis at 12" / guevedoces — genetic males appearing female at birth who virilize at puberty as testosterone surges.
- CAIS: "testes but no uterus, breasts but no hair" — the androgen receptor is deaf; estrogen (from aromatization) is still heard.
- First tests in ambiguous genitalia: karyotype, pelvic/adrenal ultrasound, 17-OHP, serum electrolytes, testosterone/DHT, and LH/FSH. 17-OHP rapidly screens for the dangerous salt-waster.
- Neonatal salt-wasting crisis is an emergency: give IV saline + glucose and hydrocortisone before confirmatory labs return.
- CAIS & dysgenetic gonads: plan gonadectomy for malignancy risk — timing individualized (typically after puberty in CAIS for feminization; earlier for an intra-abdominal dysgenetic gonad carrying Y material).
- Hormone replacement is matched to the sex of rearing: estrogen after gonadectomy in CAIS; testosterone where a male identity is established.
- 5α-reductase deficiency: internal Wolffian ducts are normal (testosterone-dependent) — only external, DHT-dependent structures are affected; the T:DHT ratio is elevated.
- DSD care is multidisciplinary (endocrinology, urology, genetics, psychology); sex of rearing is individualized.
Practice Reproductive now
Board-style questions, spaced-repetition flashcards, and a Socratic AI tutor — free to start.