Pseudohermaphroditism

Definition

"A pseudo-hermaphrodite is an individual with the genetic constitution and gonads of one sex and the genitalia of the other."

• Ganong's Review of Medical Physiology

Levels of Sexual Determination

• Quick Compendium of Clinical Pathology, p. 382

Classification

1. True hermaphroditism - both ovarian and testicular gonadal tissue
2. Male pseudohermaphroditism - testicles only
3. Female pseudohermaphroditism - ovarian tissue only
4. Mixed gonadal dysgenesis - underdeveloped or imperfectly formed gonads

Female Pseudohermaphroditism

• Karyotype: 46,XX
• Gonads: Ovaries (present and functional)
• Phenotype: Virilized external genitalia - clitoral hypertrophy, partial fusion of urogenital/labioscrotal folds
• The individual is a genetic female exposed to excessive androgens in utero (between the 8th-13th weeks of gestation)

Causes:

1. Congenital Adrenal Hyperplasia (CAH) - the most common cause
   • Enzyme deficiencies: 21-hydroxylase (accounts for ~90% of cases), 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase
   • These enzyme deficiencies result in overproduction of androgenic intermediary steroids, masculinizing the developing XX fetus
   • These infants cannot synthesize cortisol and are prone to salt loss; they require cortisol replacement (and fludrocortisone if mineralocorticoid-deficient)
2. Exogenous androgens administered to the mother during pregnancy
3. Androgen-secreting maternal tumors (adrenal or ovarian)

"In 90% of cases, deficiency of 21-hydroxylase causes ACTH to stimulate the secretion of excessive quantities of adrenal androgen, which masculinizes the developing female."

• Schwartz's Principles of Surgery

Male Pseudohermaphroditism

• Karyotype: 46,XY
• Gonads: Testes (present, usually bilateral)
• Phenotype: Feminized or ambiguous external genitalia; duct structures may differentiate as phenotypic female

Causes:

1. Androgen Insensitivity Syndrome (AIS) / Testicular Feminization
   • Due to defects or mutations in the androgen receptor (AR) gene on the X chromosome
   • Complete AIS: External genitalia resemble that of a woman; testes may be found in the inguinal canal
   • Partial/Mild AIS: Ambiguous or male-appearing genitalia
   • Serum testosterone is normal-to-elevated; LH is normal-to-elevated; 5α-reduction of testosterone to DHT is intact
   • AR gene mutation found in >95% of complete AIS cases
2. 5α-Reductase Deficiency ("penis at twelve syndrome")
   • The enzyme converting testosterone to dihydrotestosterone (DHT) is absent
   • Born with ambiguous female genitalia; variable virilization occurs at puberty when testosterone surges
   • Autosomal recessive
3. Inadequate testosterone production due to biosynthetic errors in the testis
4. Defective testicular development
   • Testes also fail to produce Mullerian Inhibiting Substance (MIS), so these genetic males develop female internal genitalia as well
5. Reifenstein Syndrome - a form of partial androgen insensitivity

Key Clinical Points

• Incidence of genital ambiguity: ~1 in 4,500 births
• Priority in newborns with ambiguous genitalia: Rule out CAH first - it is the only life-threatening condition in this group
• A gonad found in the labial or inguinal region almost always contains testicular tissue
• In male pseudohermaphroditism (especially AIS), undescended testes have a risk of malignant degeneration and should be resected (after full family counseling)
• In mixed gonadal dysgenesis, dysgenetic gonads carry a high risk of gonadoblastoma and should be removed

Diagnosis and Management

1. Karyotype / genetic background and family history
2. Physical examination, pelvic ultrasound, and chromosome studies
3. Biochemical studies (serum/urine) to evaluate enzyme defects (e.g., 17-OHP for 21-hydroxylase deficiency)
4. Laparoscopy and gonadal biopsy when needed

• Gender assignment must be avoided before expert evaluation
• Management should be at a center with a multidisciplinary team (pediatric endocrinologist, urologist, geneticist, psychologist)
• All individuals should receive a gender assignment after appropriate assessment
• Open communication with patients and families is mandatory
• Electrolyte correction and hormonal replacement are started promptly in CAH cases

• [Berek & Novak's Gynecology](Berek & Novak's Gynecology, pp. 146, 369)
• [Robbins, Cotran & Kumar Pathologic Basis of Disease](Robbins, Cotran & Kumar - Pathologic Basis of Disease, p. 169)
• [Schwartz's Principles of Surgery, 11th Ed.](Schwartz's Principles of Surgery, p. 1774)
• [Ganong's Review of Medical Physiology, 26th Ed.](Ganong's Review of Medical Physiology)
• [Quick Compendium of Clinical Pathology, 5th Ed.](Quick Compendium of Clinical Pathology, p. 382)