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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)
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
bipotential gonads
urogenital sinus
Wolffian duct
Müllerian duct
testes ovaries
vas deferens
seminal vesicle
epididymidis oviduct
uterus prostate
T+
MIH+
T-
MIH-
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
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
DISTURBANCES
IN
GONADAL ORGANOGENESIS AND
SOMATIC SEXUAL DIFFERENTIATION
DISORDERS OF SEX DIFFERENTIATION / DEVELOPMENT
(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
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)