Transcript Managing high undescended testes and complicaitons of
Embryology of Sexual differentiation in Intersex Minki Baek, M.D., PhD.
Konkuk University College of Medicine Seoul, Korea Catholic symposium 2009
Contents
Embryology
• • •
Chromosomal sex Sex determination: gonad Sex differentiation: int. / ext. genitalia Classification & Diagnosis
EMBRYOLOGY
Remind… Sexual bipotentiality
• •
Gonad Internal ducts / external genitalia
Female development:
autonomous
Hormone action
• •
Locally Critical period
Sexual bipotentiality
Undifferentiated gonad Internal duct External genitalia T MIS testis ovary Wolffian Müllerian T DHT Virillization Feminization
Female development: autonomous
XX XY XY XY castrate castrate castrate testosterone castrate testis Female Female Wollffian Müllerian Wollffian
**
sex development is constitutively
‘female’
**
Jost.
Rec Progr Horm Res,
1953
Ext Int Gonad 46XX Ovarian development (Oogonia) 46XY Gonad SRY 5 7 9 10 Testicular development Seminiferous tubules Sertoli cell Leydig cell Int Primary follicle Maximum germ cells (7,000,000) Remaining germ cells (2,000,000) 12 15 25 40 Ext
TDF (testis determining factor)
• • H-Y antigen (histocompatibility Y): male-to-female skin graft rejection
ZFY (zinc finger gene on Y chromosome):
•
Y specific DNA in XX male, Y chromosome deletion in XY female
SRY
(sex determining region of Y)
“SRY ”
rather than Y chromosome
•
SRY transcript: testis-specific
•
XX male: SRY(+) XY female: SRY(-)
•
SRY transgenic XX mice: testis development
Other genes
• • • SF1: differentiation of gonad, regulator of MIS WT1 (Wilms’ tumor gene): differentiation of gonad / kidney
SOX9:
differentiation of gonad, up-regulation of AMH
• •
DAX1: XY female with normal SRY (X chromosome duplication) WNT4: XY female (anti-testis)
Gonadal formation, initiation
thickening of coelomic mesoderm (histologically indifferent)
•
medial aspect of the urogenital ridge
mesonephric cells of the primitive kidney
WT1 gene if, mutation(+): renal disorders + gonadal dysgenesis ex) Frasier syndromes, Denys-Drash syndromes
Gonadal development
Male
•
Seminiferous tubules (7wks) condensation of primary sex cord
• •
Sertoli cell (7wks) Leydig cell (9wks) Interstitial cells from mesenchyme
Female
•
Ovarian development (start at 11wks): Oogonia
primary follicle
maximum germ cell (7,000,000)
remaining germ cell (2,000,000)
•
4wks later than male, complete at late pregnancy period
Ext Int M / W M Gonad Ovarian development (Oogonia) 46XX 46XY Gonad Int M / W SRY 5 Testicular development 7 9 10 Seminiferous tubules Sertoli cell MIS Leydig cell T DHT W Ext Virilization Feminization Primary follicle Maximum germ cells (7,000,000) Remaining germ cells (2,000,000) 12 15 25 40 Maximum T Testis descent Phallic growth
Internal duct
Autonomous
M, differentiation W, regression
MIS (-)
Persistent M. duct syndrome Müllerian + Wolffian (hernia uteri inguinalis)
MIS
M, regression
Testosterone
W, differentiation High concentration Local action
External genitalia
Androgen 10 weeks
Genital tubercle enlargement
Autonomous
Hormone during sex differentiation
Female
•
NOT require estrogen Male
•
Testosterone & DHT High concentration Local action Critical period AR (androgen receptor)
Male sex development
maximum levels ≈ 10 nmol/L
Testis descent
Transabdominal migration (1 st )
•
relaxin Insulin-like peptide, produced by testis If mutation(+), bilateral cryptorchidism
Ilioinguinal descent (2 nd )
•
androgen-dependent ex) hypogonadotrophic hypogonadism syndromes of androgen insensitivity
Androgen
•
Autonomous (early)
•
by stimulation Placental hCG secretion Fetal pituitary gland LH
Kallmann syndrome
congenital hypogonadotrophic hypogonadism
Defect in gonadotropin secretion, testosterone↓↓
•
Wolffian duct derivates (+)
•
Microphallus, cryptorchidism
Why ?
Testosterone
autonomous secretion, early
•
Wolffian duct differentiation, 8-9 weeks
Placental hCG secretion
Fetal pituitary gland LH
•
Phallic growth, testis descent
CLASSIFICATIONS
Classification
Disorders of gonadal differentiation
Seminiferous tubule dysgenesis
Klinefelter’s syndrome 46, XX male Syndrome of gonadal dysgenesis
Turner’s syndrome Pure gonadal dysgenesis Complete (pure) gonadal dysgenesis Mixed gonadal dysgenesis Dysgenetic male pseudohermaphroditism = partial gonadal dysgenesis Bilateral vanishing testes/testicular regression syndrome
True HP Female PH… Male PH…
Campbell-Walsh Urology 9 th edition
Classification
Disorders of gonadal differentiation
Seminiferous tubule dysgenesis
Klinefelter’s syndrome (XXY, XXXY,…) 46, XX male (XX+SRY) Syndrome of gonadal dysgenesis
Turner’s syndrome (45 XO, 45XO/46XX, 45X/46XY ) Pure gonadal dysgenesis (46XX) Complete (pure) gonadal dysgenesis (46XY) Mixed gonadal dysgenesis (45XO/46XY) Dysgenetic male pseudohermaphroditism (45XO/46XY, 46XY) = partial gonadal dysgenesis Bilateral vanishing testes/testicular regression syndrome (46XY)
True HP Chromosome Female PH… Hormone Male PH… Hormone
Campbell-Walsh Urology 9 th edition
Classification, by gonad
Disorders of gonadal differentiation
Seminiferous tubule dysgenesis
Klinefelter’s syndrome (XXY, XXXY,…) 46, XX male (XX+SRY) Syndrome of gonadal dysgenesis
Turner’s syndrome (45 XO, 45XO/46XX, 45X/46XY ) Pure gonadal dysgenesis (46XX) Complete (pure) gonadal dysgenesis (46XY) Mixed gonadal dysgenesis (45XO/46XY) Dysgenetic male pseudohermaphroditism (45XO/46XY, 46XY) = partial gonadal dysgenesis Bilateral vanishing testes/testicular regression syndrome (46XY)
True HP Chromosome Female PH… Hormone Male PH… Hormone
Campbell-Walsh Urology 9 th edition
Disorders of gonadal dysgenesis
histological Dx: “Dysgenetic gonad”
Mixed GD
•
2 nd common (after CAH)
•
45XO/46XY
•
unilateral. testis + streaky gonad
Pure GD
•
bilateral streaky gonads
•
45XO (Turner’s synd), 46XX XX: necessary for ovarian maintenance
•
46XY (Swyer’s synd)
True hermaphroditism
histological Dx “Ovotestis / Ovary + Testis”
46XX (80%), 46XX/XY (10%), 46XY (10%) Internal ducts
•
correlated to ipsilat. gonadal fxn local hormonal action
Gender assignment
•
variable ext. genitalia, 75% raised as male
•
gonadal tumor: 4-10%
•
potential for fertility, 46XX with appropr. Int. ducts
Female pseudohermaphroditism
Fetal androgen Maternal androgen CAH adrenal tumor, ovarian tumor
Male pseudohermaphroditism
Defect in androgen biosynthesis Defect in androgen metabolism 17 β-OH-dehydrogenase deficiency, … 5 α-reductase deficiency Resistance to androgen, incomplete Partial AIS Resistance to androgen, complete Complete AIS
True hermaphroditism
Both testicular and ovarian tissue XX, XY, XX/XY
Disorders of gonadal differentiation
Mixed gonadal dysgenesis Pure gonadal dysgenesis 45XO/46XY Turner’s syndrome (46XO), Swyer’s syndrome (46XY), 46XX
CAH
Ovary Abnormal testosterone ↑↑
Why ?
• •
Wolffian duct(-) Virillization(+)
1. Timing
of the action •
Wolffian duct differentiation, 8-9 weeks
•
CAH start
•
External genitalia differentiation, 9-13 weeks
2. not effective
as much as direct & local effusion from testis
Androgen biosynthesis/metabolism
“Double sex reversal”
•
17 βHSD3 deficiency
•
5 αRD2 deficiency
female ext. genitalia at birth
marked Virilization at puberty (by isoenzymes)
* *
AIS
(androgen insensitivity synd.)
resistance to androgen (abnormal AR), bilateral normal testes
Complete AIS
•
Testicular feminization syndrome
•
female genitalia
Partial AIS
•
commonest cause of male PH
•
wide-range phenotype ambiguous genitalia ~ normal male genitalia with infertility
Chromosome Female pseudohermaphroditism
CAH Maternal androgen
Male pseudohermaphroditism
Defect in androgen biosynthesis Defect in androgen metabolism Partial AIS Complete AIS
True hermaphroditism*
46XX 46XY Both testicular and ovarian tissue 46XX 80% 46XY 10% 46XX/XY 10%
Disorders of gonadal differentiation*
Mixed gonadal dysgenesis Pure gonadal dysgenesis 46XO/XY (mc), XO, XY, XXY XX, XO, XY
Gonad
Ovary Testis Testis + Ovary / Ovotestis W / M Testis + DG DG + DG
Int
M W W W ± none W / M M
Ext
Variable Variable Variable Variable Female Variable Variable Female
Ambiguous genitalia Gonad Palpable, bi Non-palpable Palpable, uni Chromosome Susp. Ds.
Dx methods 46XY 46XX Male PH Female PH 17OH-P hCG stimulation No response high T ↑ T/DHT low high normal Ovary(+) 46XX 80% 46XY 10% 46XX/XY 10% 46XO/XY True H Mixed GD Imaging/endocrine test, laparotomy/laparoscopy, biopsy Dx Defect in androgen syn.
5αRD 2 def AIS CAH Maternal androgen True H Mixed GD
Ambiguous genitalia Gonad Palpable, bi Non-palpable Palpable, uni Chromosome Susp. Ds.
Dx methods 46XY 46XX Male PH Female PH 17OH-P hCG stimulation No response high T ↑ T/DHT low high normal Ovary(+) 46XX 80% 46XY 10% 46XX/XY 10% 46XO/XY True H Mixed GD Imaging/endocrine test, laparotomy/laparoscopy, biopsy Dx Defect in androgen syn.
5αRD 2 def AIS CAH Maternal androgen True H Mixed GD
Ambiguous genitalia Gonad Palpable, bi Non-palpable Palpable, uni Chromosome Susp. Ds.
Dx methods 46XY 46XX Male PH Female PH 17OH-P hCG stimulation No response high T ↑ T/DHT low high normal Ovary(+) 46XX 80% 46XY 10% 46XX/XY 10% 46XO/XY True H Mixed GD Imaging/endocrine test, laparotomy/laparoscopy, biopsy Dx Defect in androgen syn.
5αRD 2 def AIS CAH Maternal androgen True H Mixed GD
Ambiguous genitalia Gonad Palpable, bi Non-palpable Palpable, uni Chromosome Susp. Ds.
Dx methods 46XY 46XX Male PH Female PH 17OH-P hCG stimulation No response high T ↑ T/DHT low high normal Ovary(+) 46XX 80% 46XY 10% 46XX/XY 10% 46XO/XY True H Mixed GD Imaging/endocrine test, laparotomy/laparoscopy, biopsy Dx Defect in androgen syn.
5αRD 2 def AIS CAH Maternal androgen True H Mixed GD
True HP 46XX
46XO/46XY Mixed GD
Conclusion
Investigation of intersex
Normal sexual development Chromosome / Gonad / Hormone Understanding abnormal process
Classification
according to the Gonad