PHYSIOLOGY AND PATHOLOGY OF SEXUAL DIFFERENTIATION Prof. Dr med. Jolanta Słowikowska-Hilczer Department of Andrology and Reproductive Endocrinology Medical University of Łódź, Poland
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.
STRUCTURE OF CHROMOSOME Y Yp Euchromatin Yq 1 2 3 4 5 6 Pseudoautosomal region 1 SRY Centromer AZFa AZFb AZFc Heterochromatin 7 Pseudoautosomal region 2
Genital ridge WT1 (chr. 11) SF1 (chr. 9) Bipotential gonad SRY SOX9 (chr. 19) DAX1 (chr. X) Testis Ovary
DIFFERENTIATION OF GONADS
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
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
DIFFERENTIATION OF INTERNAL SEX ORGANS
bipotential gonads Wolffian duct Müllerian duct urogenital sinus testes ovaries epididymidis vas deferens prostate seminal vesicle T+ MIH+ T- MIH- oviduct uterus
CG testosterone LH 12 week 24 week birth
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.
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
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
DIFFERENTIATION OF EXTERNAL SEX ORGANS
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
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
Testosterone dependent Dihydrotestosterone dependent 5α-reductase
DISTURBANCES IN GONADAL ORGANOGENESIS AND SOMATIC SEXUAL DIFFERENTIATION DISORDERS OF SEX DIFFERENTIATION / DEVELOPMENT (DSD)
TRUE HERMAPHRODITISM OVOTESTICULAR DSD OVOTESTIS TESTIS / OVARY
MALE PSEUDOHERMAPHRODITISM 46,XY or 45,X/46,XY DSD
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
NORMAL TESTES TESTICULAR DYSGENESIS I. PURE STREAK GONAD STREAK GONAD II. MIXED III. PARTIAL UNDERDEVELOPED TESTIS STREAK GONAD UNDERDEVELOPED TESTIS UNDERDEVELOPED TESTIS
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
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
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
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
Disturbances in differentiation of male sex organs hypothalamus pituitary LH TESTIS MIH T 5 reductase DHT (dihydrotestosterone)
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
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
Disturbances in differentiation of male sex organs hypothalamus pituitary LH TESTIS MIH T 5 reductase DHT androgen receptor
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
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
TESTICULAR DESCENT
CRYPTORCHIDISM internal orifice of inguinal canal external orifice of inguinal canal Reprinted from: Podstawy embriologii człowieka, PC. Williams, CP.Wendell-Smith, PZWL, 1972
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
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)