PHYSIOLOGY AND PATHOLOGY OF SEXUAL DIFFERENTIATION

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1 PHYSIOLOGY AND PATHOLOGY OF SEXUAL DIFFERENTIATION Prof. Dr med. Jolanta Słowikowska-Hilczer Department of Andrology and Reproductive Endocrinology Medical University of Łódź, Poland

2 Sexual determination and differentiation are sequential processes starting with the establishment of genetic sex at conception, followed by differentiation of bipotential gonad into testis or ovary (gonadal sex), differentiation of internal and external genitalia during embryogenesis (genital sex), development of male or female habitus during puberty (phenotypic sex) and finally determination of brain (psychic) sex, appearing as gender identity, role, sexual orientation.

3 STRUCTURE OF CHROMOSOME Y Yp Euchromatin Yq Pseudoautosomal region 1 SRY Centromer AZFa AZFb AZFc Heterochromatin 7 Pseudoautosomal region 2

4 Genital ridge WT1 (chr. 11) SF1 (chr. 9) Bipotential gonad SRY SOX9 (chr. 19) DAX1 (chr. X) Testis Ovary

5 DIFFERENTIATION OF GONADS

6 aorta primordial germ cells genital ridge hindgut mesonephric duct sex cords mesothelial epithelium medullar part paramesonephric duct cortical part Reprinted from: Embriologia, H.Bartel, PZWL, 1995

7 TESTIS 6-7 week OVARY 7-8 week cortical cords tubuli seminiferi tubuli recti rete testis trace of rete ovary ductus efferentes epididymal tubule Trace of paramesonephric duct primary oocytes derivative of rete ovary Reprinted from: Embriologia, H.Bartel, PZWL, 1995

8 DIFFERENTIATION OF INTERNAL SEX ORGANS

9 bipotential gonads Wolffian duct Müllerian duct urogenital sinus testes ovaries epididymidis vas deferens prostate seminal vesicle T+ MIH+ T- MIH- oviduct uterus

10 CG testosterone LH 12 week 24 week birth

11 MIH - Müllerian Inhibiting Hormone MIF - Müllerian Inhibiting Factor MIS - Müllerian Inhibiting Substance AMH - Antimüllerian Hormone A glycoprotein member of the transforming growth factor β (TGF- β) family.

12 Differentiation of male internal sex organs Presence of T TESTIS Presence of MIH Wolffian ducts Müllerian ducts epididymidis vasa deferentia seminal vesicles upper vagina uterus oviducts

13 Differentiation of female internal sex organs Lack of T OVARY Lack of MIH Wolffian ducts Müllerian ducts epididymidis vasa deferentia seminal vesicles upper vagina uterus oviducts

14 DIFFERENTIATION OF EXTERNAL SEX ORGANS

15 genital tubercle genital fold 4 week A B cloacal membrane genital tubercle genital fold 5 week labial swelling anus C Reprinted from: Embriologia, H.Bartel, PZWL, 1995

16 clitoris joining of labial labia minora swellings labia majora 10 week H commisure of labia I glans penis uretheral orifice uretheral orifice mons pubis peneal raphe scrotal raphe 12 week perineum J hymen vaginal opening K Reprinted from: Embriologia, H.Bartel, PZWL, 1995

17 Testosterone dependent Dihydrotestosterone dependent 5α-reductase

18 DISTURBANCES IN GONADAL ORGANOGENESIS AND SOMATIC SEXUAL DIFFERENTIATION DISORDERS OF SEX DIFFERENTIATION / DEVELOPMENT (DSD)

19 TRUE HERMAPHRODITISM OVOTESTICULAR DSD OVOTESTIS TESTIS / OVARY

20 MALE PSEUDOHERMAPHRODITISM 46,XY or 45,X/46,XY DSD

21 Classification of male pseudohermaphroditism Disturbace of testicular organogensis Agenesis or dysgenesis Regression Inadequate testosterone production Testosterone biosynthetic defects: Deficiency of 20,22-lyase, 3β-hydroxysteroid-dehydrogenase, 17α-hydroxylase, 17,20-lyase, 17β-ketoreductase Leydig cell hypoplasia or agenesis Hypothalamo-pituitary-testicular insufficiency Disturbances of hypothalamus or pituitary CG/LH receptor unresponsiveness Peripheral unresponsiveness to androgens End-organ resistance Complete or partial androgen insensitivity 5α-reductase deficiency

22 NORMAL TESTES TESTICULAR DYSGENESIS I. PURE STREAK GONAD STREAK GONAD II. MIXED III. PARTIAL UNDERDEVELOPED TESTIS STREAK GONAD UNDERDEVELOPED TESTIS UNDERDEVELOPED TESTIS

23 Disturbances in differentiation of male sex organs Lack of T TESTIS Lack of MIH Wolffian ducts Female internal sex organs Müllerian ducts epididymidis vasa deferentia seminal vesicles Female external sex organs upper vagina uterus oviducts

24 Disturbances in differentiation of male sex organs Presence T TESTIS Presence of MIH Wolffian ducts epididymidis vasa deferentia seminal vesicles Male & female poorly developed internal sex organs Ambiguous external sex organs Müllerian ducts upper vagina uterus oviducts

25 Disturbances in differentiation of male sex organs Lack of T TESTIS Presence of MIH Wolffian ducts Lack of internal sex organs Müllerian ducts epididymidis vasa deferentia seminal vesicles Female external sex organs upper vagina uterus oviducts

26 TESTIS 20,22-lyase 17α-hydroxylase cholesterol pregnenolone 17α-hydroxypregnenolone 17,20- lyase dehydroepiandrosterone 17β-HSD androstendione 3β-HSD progesterone 17α-hydroxyprogesterone androstendione testosterone 5α-reductase dihydrotestosterone

27 Disturbances in differentiation of male sex organs hypothalamus pituitary LH TESTIS MIH T 5 reductase DHT (dihydrotestosterone)

28 Disturbances in differentiation of male sex organs Presence of T TESTIS Presence of MIH Wolffian ducts Male internal sex organs Müllerian ducts epididymidis vasa deferentia seminal vesicles Poorly developed male external sex organs upper vagina uterus oviducts

29

30 HYPOSPADIAS coronal Classification according to the anatomical site penile perineal 1. glandular 2. coronal 3. penile (distal, middle, proximal shaft) 4. penoscrotal 5. scrotal Reprinted from: Podstawy embriologii człowieka, PC. Williams, CP.Wendell-Smith, PZWL, 1972

31 Disturbances in differentiation of male sex organs hypothalamus pituitary LH TESTIS MIH T 5 reductase DHT androgen receptor

32 Disturbances in differentiation of male sex organs Presence of T TESTIS Presence of MIH Wolffian ducts Lack of internal sex organs Müllerian ducts epididymidis vasa deferentia seminal vesicles Female external sex organs upper vagina uterus oviducts

33 Disturbances in differentiation of male sex organs Presence of T TESTIS Lack of MIH Wolffian ducts Male internal sex organs and persistent Müllerian ducts Müllerian ducts epididymidis vasa deferentia seminal vesicles male external sex organs upper vagina uterus oviducts

34 TESTICULAR DESCENT

35

36 CRYPTORCHIDISM internal orifice of inguinal canal external orifice of inguinal canal Reprinted from: Podstawy embriologii człowieka, PC. Williams, CP.Wendell-Smith, PZWL, 1972

37 OTHER DEVELOPMENTAL DISTURBANCES OF FEMALE SEX ORGANS vaginal agenesis (Mayer-Rokitansky-Küster syndrome) vaginal obstruction blockage and distension of the vagina and uterus transverse vaginal septum

38 Diagnostic steps for ambiguous genitalia Family and maternal medical history Medical examination Laboratory evaluation - biochemical analysis (Na, K, glucose) - hormonal determinations (17-OHP, testosterone and DHT in hcg test) Imaging studies of pelvic anatomy Genetic tests (sex chromatin, karyotype, molecular genetic analysis)

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