INTERSEX

1. INTERSEX Dr. Ahmed Al Sayyad CHEO / University of Ottawa

2. Sexual Differentiation • Gonadal differentiation at 6-8 wk gestation • TDF gene (Y-chromosome): • stimulates gonads towards testicular differentiation • Absence of TDF: • gonads differentiate into ovaries

3. Phenotypic Differentiation • Begins around 8th week of gestation • Wolffian duct from mesonephros • Müllerian duct from coelomic epithelium • Endocrine effect during this phase is crucial: • paracrine action of hormones produced by ipsilateral gonad • testis (MIS, T)  male internal genitalia • ovary (nil)  female internal genitalia

4. Endocrine Effects on Phenotypic Development • Müllerian-inhibiting substance: • produced by fetal testes • found on chromosome 19 • Causes almost complete regression of Müllerian duct derivatives: • utriculus masculinus, appendix testis • Important in testicular differentiation

5. Endocrine Effects on Phenotypic Development • Testosterone: • produced by fetal Leydig cells • Regulates male phenotypic development • Multiple steps in effect of testosterone: • production, 5-alpha reductase, AR • T  Wolffian duct (male internal genitalia) • DHT  male external genitalia (includes prostate)

6. Endocrine Effects on Phenotypic Development • Wolffian duct: • requires testosterone for development • epididymis, vas deferens, seminal vesicle • Müllerian duct: • does not require hormonal stimulation • does require MIS be absent • oviduct, uterus, cervix, upper vagina

7. External Genitalia - Differentiation(8-16 wk gestation) • Male (requires DHT): • labioscrotal fold = scrotum • urethral fold / groove = urethra • genital tubercle = glans penis • Female (requires nil): • labioscrotal fold = labia majora • urethral fold = labia minora • genital tubercle = glans clitoris

8. External Genitalia Development

9. Clinical Assessment - History • Maternal androgen exposure: • endogenous (hormone producing tumors) • exogenous (medication) • Family history: • AGS / infant death • abnormal sexual development • infertility / amenorrhea • parental consanguinity

10. Clinical Assessment - Physical Examination • Abdominal exam • rectal exam to feel for uterus • Inguinal / scrotal exam for gonads • if palpable = testis • Phallic size • Urethral orifice location • Hyperpigmentation of labioscrotal folds • excess ACTH (AGS)

11. Clinical Assessment - Further Testing • Lab: • karyotype (72 hour) • serum 17 OH-progesterone • Radiography: • genitogram • abdominal / pelvic ultrasound • Operative: • endoscopy of urogenital sinus • laparoscopy/laparotomy and gonadal biopsy

12. Intersex Classification • Classification based on gonadal status: • Over-androgenized female (ovary + ovary)* • Under-androgenized male (testis + testis)* • True hermaphrodite (ovary + testis) • Mixed gonadal dysgenesis (testis + streak) • Pure gonadal dysgenesis (streak + streak)) * “pseudo-hermaphrodite” is being phased out

13. Over-androgenized Female • Most common form of intersex • Karyotype = 46 XX • TDF gene not present • Ovarian tissue only • Normal female internal genitalia • External genitalia virilized: • potency of androgen • time of exposure • duration of exposure

14. Over-androgenized Female • Congenital adrenal hyperplasia (CAH) comprises majority of cases • Exposure to maternal androgens is rare but can occur

15. Over-androgenized Female (CAH) • Most common inheritance pattern in CAH is autosomal recessive • Enzymatic deficiency results in reduced production of glucocorticoids • Lack of feedback inhibition on hypothalamus and pituitary: •  ACTH production •  adrenal androgen release

16. Over-androgenized Female (CAH) • 21-hydroxylase deficiency most common • 50% of patients “salt losers” • death at 7-10 days post-natally (adrenal crisis) • serum 17- hydroxyprogesterone assay • Medical management of CAH crucial: • corticosteroid ± mineralocorticoid • prevent death and metabolic complications • allow normal development of 2° sexual characteristics, fertility

17. Over-androgenizedFemale (CAH) • Female gender assignment usual: • controversy with Prader V • Müllerian structures always present • Surgical intervention (?): • feminizing genitoplasty ± vaginoplasty • Antenatal treatment may minimize degree of virilization

18. Under-androgenized Male • Very diverse group • Karyotype = 46 XY • Testicular tissue only • Lack of fetal virilization from wide variety of defects or deficiencies • Phenotypic range broad • may even resemble normal female

19. Under-androgenized MaleAndrogen Insensitivity • Most common form of UAM • Assay serum testosterone, DHT: • usually after HCG stimulation • Fibroblast cultures of genital skin: • absence of DHT binding • PCR can be done to detect receptor abnormalities

20. Under-androgenized MaleAndrogen Insensitivity • Testicular feminization (complete AI): • phenotypically normal female with a short vagina • Presentation: • primary amenorrhea • testes found in inguinal hernias in female • Maintenance of female gender appropriate with estrogen supplementation • Testicles should be removed (cancer risk)

21. Under-androgenized MaleAndrogen Insensitivity

22. Under-androgenized MaleAndrogen Insensitivity • Incomplete insensitivity: • phenotype can run the gamut • clitoromegaly, partial fusion of labio-scrotal folds, short blind ending vagina • Female gender assignment  gonadectomy: • prevent virilization in puberty • obviate cancer risk • In males  early genital reconstruction

23. Under-androgenized MaleEnzymatic defects • Wide variety of potential defects: • abnormal testosterone synthesis • inadequate conversion to DHT • Phenotype: • no Müllerian structures (MIS present) • under-virilized external genitalia

24. Under-androgenized MaleEnzymatic defects • 5- reductase deficiency prevents conversion of T to DHT • Autosomal recessive inheritance • Phenotypically severe perineoscrotal hypospadias with undescended testes • T/DHT ratio may aid in diagnosis

25. Under-androgenized Male • Primary Hypogonadism • baseline high levels of gonadotropins • do not respond to HCG stimulation • Hypogonadotropic Hypogonadism • baseline low levels of gonadotropins • respond to HCG stimulation

26. True Hermaphroditism • Uncommon: 10% of intersex • Karyotype: • 60-70% 46XX • remainder 46XY or a mosaic • Characterized by presence of ovarian and testicular tissue • Gender assignment based on anatomical findings (75% male)

27. True Hermaphroditism • Internal genitalia conform to ipsilateral gonad: • vas with testicle • fallopian tube with ovary • either (both) with ovotestis • Contradictory gonadal / ductal tissue should be removed once gender assigned • External genitalia reconstructed according to gender assignment

28. True Hermaphroditism • Gonadal configuration can vary: • testis one side, ovary other side • ovotestis with contralateral normal testis or ovary • bilateral ovotestes

29. Mixed Gonadal Dysgenesis • Second most common cause of intersex • Karyotype: • 46XY/45XO mosaic • Unilateral testis with dysgenetic (streak) gonad contralaterally • Testis has Sertoli and Leydig cells but no germinal elements • Risk of gonadoblastoma

30. Mixed Gonadal Dysgenesis • Internal genitalia variable (±MIS) • External genitalia: • hypospadias • partial labioscrotal fusion • undescended testes • Gender assignment: • female most common (bilateral gonadectomy) • male if markedly virilized and orchiopexy feasible

31. Pure Gonadal Dysgenesis • Bilateral dysgenetic (streak) gonads • Present as females with sexual infantilism: • external genitalia are not ambiguous • Immature Müllerian structures are present: • low levels of fetal MIS

32. Pure Gonadal Dysgenesis • Turner’s syndrome: • 45 XO • characteristic phenotype • Swyer’s syndrome: • 46 XY • at risk for gonadoblastoma (30%) • 46 XX: • low tumor risk

33. Other Genetic Abnormalities • Klinefelter’s syndrome: • male phenotype • impaired sexual maturation • gynecomastia • azoospermia • Typical karyotype 47 XXY

34. Other Genetic Abnormalities • XX Sex reversal • rare phenotypic males with 46XX karyotype • often have hypospadias and gynecomastia • usually fragments of Y chromosome short arm found in distal short arm of X chromosome

35. Summary • Intersex is a challenging and complicated situation, but when understood can often be dealt with effectively • Many potential medical, social, and psychological ramifications • Multidisciplinary approach involving urology, endocrinology, genetics and social work is essential