Abnormalities of sexual differentiation

1. Abnormalities of sexual differentiation N. Ambalavanan MD Jan 2004 Material based on Chapter 47, Part 4 of Fanaroff and Martin, 7th Edition, 2002

2. What’s normal in a term newborn? • Female: • Vaginal opening fully visible: 3-4 mm slit or stellate orifice with heaped-up mucosa • Clitoris width 2-6 mm • Absence of gonads in labia majora or inguinal region • Male: • Urethra at tip of glans (may be inferred by a fully developed foreskin) • Penis of normal stretched length (2.5-5 cm) and diameter (0.9-1.3 cm) • Bilateral testes of normal size (8-14 mm) in the scrotal sacs

3. Ambiguous genitalia: what is it? Evaluation of intersex problem required for: • Male-appearing genitalia with micropenis, mod/severe hypospadias, bilateral cryptorchidism, or two mild defects (e.g. mild hypospadias and unilateral cryptorchidism) • Female-appearing genitalia with posterior labial fusion, clitorimegaly, or a labial or inguinal mass

4. Basic concepts • Fetal sex differentiation: • Occurs at 7-14 weeks’ fetal age only • Is innately female and does not require ovaries or estrogens • As a male requires: • Sex-determining region of Y (SRY) gene • Bilateral testes producing mullerian inhibiting substance (MIS/MIF/AMH) and testosterone • 5a-reductase enzyme (external genitalia) • Testosterone and dihydrotestosterone receptor (internal and external genitalia)

5. Human Gonadal Development and Differentiation Genital ridge Wolffian D. Male int genit. Testis Genit. Tub. Urogen. Sinus Penis Prostate SOX-9 SRY Leydig cells Testosterone DHT AMH Mullerian Duct Regression SF-1 WT-1 SF-1 Sertoli cells Bipotential gonad DSS Follicular cells Theca cells Mullerian Duct Female Internal Genitalia SF-1 Follicles Ovary

6. It’s a boy! (or..girl!)… maybe… • Evaluation is a medical and psychosocial emergency • Why? • Diagnose CAH before an adrenal crisis • Designate correct gender • Correct problems early for correct body image and gender identity • Provide genetic counseling for the future • Identification of children at higher risk for gondal tumor

7. What should you do at the birth of a baby? • Careful evaluation of genitalia of all neonates (does not need to be overtly ambiguous for diagnostic evaluation) • Defer gender assignment • Discuss with parents: “The genitalia are unfinished in their development, and we will need a few days to perform some studies to determine which sex your baby was intended to be” • Most of the diagnostic evaluation for gender assignment can be done within 3 days.

8. Diagnostic evaluation - 1 • History: • Maternal androgens, drugs, teratogens • Affected relatives, sibs who died in infancy (CAH?) • Consanguinity

9. Diagnostic evaluation - 2 • Physical examination: • Genitalia • Gonads • Rectal • Hyperpigmentation • Turner syndrome? • Dysmorphic features?

10. Diagnostic evaluation - 3 • Chromosomes: • Rapid test for X and Y chromosomes • Karyotype • Contact laboratory personally and ask for result ASAP • Buccal smears are no longer recommended

11. Diagnostic evaluation - 4 • Anatomic evaluation • Ultrasound • Uterus seen? • seen in 94% of normal females • If no uterus, suggests MIS production by testes • If uterus +, suggests bilateral ovaries or gonads that do not produce MIS • Intrapelvic gonads sometimes seen • Endoscopy • Retrograde genitography • Anatomy of urethra and vagina. • Presence of cervix confirms mullerian duct structures

12. Diagnostic evaluation - 5 • Biochemical evaluation If patient is: • XX with mullerian ducts: 17 OHP, 11-deoxycortisol, 17OHPe, T • XX without mullerian ducts: T, E2, LH, FSH • XY with mullerian ducts: T, E2, LH, FSH • XY without mullerian ducts: T, DHT, LH, FSH

13. Management • Gender Assignment: • Usually made when chromosome status and mullerian duct status are known • Occasionally need to defer until biochemical results are known • Consultation with pediatric urologist and endocrinologist necessary • If bilateral ovaries are present, usually reared as female • Males with poor androgen insensitivity difficult to assign • Psychological counseling to family (and later to patient)

14. Management • Management of CAH if present • Female: surgical correction of ambiguous genitalia (procedure depending on age) • Male: • Testosterone for micropenis • Course of HCG followed by orchiopexy if necessary for cryptorchidism • No circ if hypospadias • Do not remove mullerian structures • Gonadectomy if streak or dysgenetic gonads with Y chromosome (risk of malignancy high from infancy)

15. Congenital Adrenal Hyperplasia • Defect in the adrenocortical synthesis of cortisol from cholesterol • Low cortisol elevates ACTH • Consequences of impaired synthesis of hormones (glucocorticoids, mineralocorticoids, gonadal sex steroids) and overproduction of precursors or side products

16. Steroid Biosynthetic Pathway Cholesterol Pregnenolone (Pe)  17-OH Pe  DHEA  D5-Androstenediol Progesterone (Pr)  17-OH Pr  Androstenedione  Testosterone 11-DeOxCorticost 11-DeOxCortisol Dihydrotestosterone Corticosterone Cortisol 18-OH Corticost Aldosterone MineralocorticoidsGlucocorticoidsAndrogens 3b-HSD 21-OH ase 5a-Reductase 11-b OH ase

17. Congenital Adrenal Hyperplasia • 21-Hydroxylase deficiency • 90% of CAH • diagnosed by increased 17-OHP • Simple virilizing (partial) and salt-wasting (complete absence of enzyme) • Abnormal virilization of female fetus • Males may develop penile enlargement, accel growth etc postnatally • 11b-hydroxylase similar to 21-hydroxylase deficiency; but with hypertension • 3b-OHSD deficiency leads to ambiguous genitalia in males and females

18. Rare syndromes • True hermaphroditism: • co-existence of ovarian and testicular tissue either in the same or opposite gonads • 60% are 46 XX; 20% are 46XY or 45 X/46XY and rest are mosaics/chimeras