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

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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

SRY

AZFb

AZFc

AZFa

1

2

3

4

5

6

7

Pseudoautosomal region 1

Centromer

Heterochromatin

Yp

Yq

Euchromatin

Pseudoautosomal region 2

Genital ridge

Bipotential gonad

Testis Ovary

WT1 (chr. 11)

SF1 (chr. 9)

SRY

SOX9 (chr. 19)

DAX1 (chr. X)

DIFFERENTIATION OF GONADS

Reprinted from: Embriologia, H.Bartel, PZWL, 1995

aorta

primordial germ cells

genital ridge

mesonephric duct

mesothelial epithelium

cortical part

medullar part

paramesonephric duct

sex cords

hindgut

Reprinted from: Embriologia, H.Bartel, PZWL, 1995

tubuli seminiferi

tubuli recti

rete testis

ductus efferentes

epididymal tubule

Trace of paramesonephric duct primary oocytes

trace of rete

ovary

cortical cords

derivative of rete ovary

TESTIS

6-7 week

OVARY

7-8 week

DIFFERENTIATION

OF INTERNAL SEX ORGANS

bipotential gonads

urogenital sinus

Wolffian duct

Müllerian duct

testes ovaries

vas deferens

seminal vesicle

epididymidis oviduct

uterus prostate

T+

MIH+

T-

MIH-

12 week 24 week birth

CG

testosterone LH

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

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Presence of MIH TESTIS Presence of T

Müllerian

ducts

Differentiation of female internal sex organs

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Lack of MIH OVARY Lack of T

Müllerian

ducts

DIFFERENTIATION

OF EXTERNAL SEX ORGANS

A

genital tubercle

genital fold

cloacal

membrane

genital tubercle

genital fold

labial swelling

anus

B

C

4 week

5 week

Reprinted from: Embriologia, H.Bartel, PZWL, 1995

labia minora

labia majora

clitoris

vaginal opening hymen

uretheral orifice mons pubis

commi- sure

of labia

joining of labial

swellings

glans penis

uretheral orifice

peneal raphe

scrotal raphe

perineum

H I

J K

10 week

12 week

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

III. PARTIAL

II. MIXED

I. PURE

TESTICULAR

DYSGENESIS

STREAK GONAD

NORMAL TESTES

STREAK GONAD

STREAK GONAD

UNDERDEVELOPED

TESTIS UNDERDEVELOPED

TESTIS

UNDERDEVELOPED

TESTIS

Disturbances in differentiation of male sex organs

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Lack of MIH TESTIS Lack of T

Müllerian

ducts

Female

internal

sex organs

Female

external

sex organs

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Presence of MIH TESTIS Presence T

Müllerian

ducts

Male & female

poorly

developed

internal sex

organs

Disturbances in differentiation of male sex organs

Ambiguous

external

sex organs

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Presence of MIH TESTIS Lack of T

Müllerian

ducts

Lack of

internal sex

organs

Disturbances in differentiation of male sex organs

Female

external

sex organs

TESTIS

cholesterol

pregnenolone

17α-hydroxypregnenolone

dehydroepiandrosterone

androstendione

progesterone

17α-hydroxyprogesterone

androstendione

testosterone

dihydrotestosterone

3β-HSD 20,22-lyase

17α-hydroxylase

17,20- lyase

17β-HSD

5α-reductase

hypothalamus

pituitary

TESTIS

LH

MIH

T 5 reductase DHT (dihydrotestosterone)

Disturbances in differentiation of male sex organs

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Presence of MIH TESTIS Presence of T

Müllerian

ducts

Male internal sex

organs

Disturbances in differentiation of male sex organs

Poorly developed

male external

sex organs

HYPOSPADIAS

coronal

penile

perineal

Reprinted from: Podstawy embriologii człowieka, PC. Williams, CP.Wendell-Smith, PZWL, 1972

Classification according to

the anatomical site

1. glandular

2. coronal

3. penile (distal, middle,

proximal shaft)

4. penoscrotal

5. scrotal

hypothalamus

pituitary

Disturbances in differentiation of male sex organs

TESTIS

LH

MIH

T 5 reductase DHT

androgen receptor

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Presence of MIH TESTIS Presence of T

Müllerian

ducts

Lack of internal

sex organs

Disturbances in differentiation of male sex organs

Female external

sex organs

Wolffian

ducts

• epididymidis

• vasa deferentia

• seminal vesicles

• upper vagina

• uterus

• oviducts

Lack of MIH TESTIS Presence of T

Müllerian

ducts

Male internal sex

organs and

persistent

Müllerian ducts

Disturbances in differentiation of male sex organs

male

external

sex organs

TESTICULAR DESCENT

internal orifice of

inguinal canal

external orifice of

inguinal canal

CRYPTORCHIDISM

Reprinted from: Podstawy embriologii człowieka, PC. Williams, CP.Wendell-Smith, PZWL, 1972

• vaginal agenesis (Mayer-Rokitansky-Küster syndrome)

• vaginal obstruction

• blockage and distension of the vagina and uterus

• transverse vaginal septum

OTHER DEVELOPMENTAL DISTURBANCES

OF FEMALE SEX ORGANS

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)