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Disorders of sex
development
(DSD)
It is a complex topic but actually if you understand it,
it will be very simple.
Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
Hormones
Chromosomal Sex
Genes associated with sex determination
 SRY (sex-determining region Y gene) is responsible for testis
formation and called TDF (testis-determining factor).
 Mutation in SRY gene may occurs and result in sex reversal As
it absent in Y chromosome result in XY female And it’s
present in X chromosome result in XX male And this prove that
SRY gene is TDF.
Sinclair et al 1990
Chromosomal Sex
Presence of SRY gene Testis formation
Absence of SRY gene ovary formation
(Passive)
• During the first 6 weeks the gonadal ridge, germ
cells  bipotential sex development.
• Ovarian differentiation needs at least two X
chromosome ( this explain dysgenetic ovary in 45
X0 turner). Haqq et al 1994
Gonadal development
1. In Males
• Differentiation of sertoli cell (7th week)  MIS production
regression of Mullerian ducts.
• MIS acts unilaterally.
• Formation of leydige cell (9th week)  testosterone
production  proliferation of wolffian duct and descend of the
testis.
Gonadal development
• Testosterone  dihydrotestosterone (higher affinity to
androgen receptors) by intracellular 5α-reductase.
• Disorders of androgen receptors or 5α-reductase lead
to a spectrum of phenotypic abnormalities in the
genetic male.
Andersson et al, 1991
Gonadal development
2. In Females
• Absent SRY Ovary differentiation
No MIS NO testosterone
Proliferation of Mullerian duct
• Uterus
• Fallopian tube
• Upper 4/5 of vagina
Reggresion of wolffian duct
• Epoophoron and
paroophoron
• Gartener’s duct
Phenotypic differentiation
Malefemale
Phenotypic differentiation
Undifferentiated stage
• Before the 8th week of gestation the urogenital tract is
identical in the two sexes.
• Undifferentiated stage of external genitalia consists of
1. Genital tubericle
2. Genital (urethral ) folds
3. Genital swelling
Phenotypic differentiation
In males
• Androgen  -masculinization of the external genitalia
(12th-13th week).
-penile growth and testicular descent
(3rd trimester) Doymer et al 1994.
Phenotypic differentiation
In Females
• In the female fetus the absence of circulating
testosterone maintains the appearance of the Female
external genitalia at the 6-week gestational stage.
Doymer et al 1994
Gender Identity
• Gender identity;- the identification of self as
either male or female.
• Is complex, poor understood and multifactorial.
• Androgen has major role in brain imprint.
• Postnatal environmental factors and learning
appear to have an important effect.
Reiner et al 2004
Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
Definition of DSD
Conditions involving the following elements
• Sex chromosome anomalies as Turner syndrome.
• Disorder of gonadal developments as ovitestes
• Disorders of internal reproductive organs
• Disorders of external genitalia ( ambigious)
It was called intersex but this term is not accurate
and showed be avoided.
Hughes et al 2006
Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular DSD)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
• Seminiferous tubule dysgenesis
Seminiferous tubule dysgenesis
1. Klinefelter syndrome
• The Most common DSD.
• Genotype;- Male with at least Y + at least 2 X
chromosomes (47XXY (classic), 48XXXY,48XXYY,…..
Mosaic 46XY/47XXY)
• Gonads;- Small firm atrophic testes with small number of
leydig cells Azospermic except in mosaic.
• Hormones;-low normal Testosterone , Increase FSH and
LH, Increase estrogen.
• Phenotype; normal male external genitalia Not ambiguous
• Special features
• Complications
1. High incidence of
breast cancer (8 times).
2. Predispose to sertoli
and leydig cell tumour
3. Infertility
• Management
1. Androgen replacement
2. Surveillance for
testicular tumor and
breast carcinoma.
Staessen et al 2003
Klinefelter syndrome
Cont…Seminiferous tubule dysgenesis
2. 46,XX male
Due to translocation of Y chromosomal material, including SRY
(TDF) to the X chromosome.
• Gonads;- Small firm atrophic testes with small number of
leydig cells  Azospermic
• Hormones;-low normal Testosterone , Increase FSH and
LH, Increase estrogen.
• Phenotype; normal male external genitalia Not ambiguous
but 10 % hypospadias.
• Complication and Management as Klinefelter but shorter and
normal skeletal proportions.
Fechner et al 1993
Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
• Syndromes of gonadal dysgenesis
Turner syndrome
• Incidence of 1 in 2500 live births.
• Genotype 45XO , Mosaic (45XO/46XX
,45XO/46XY).
• Gonads fibrous streaks (no surviving germ cells)
• Hormones Decrease both androgen and estrogen, increase in
FSH and LH
• Phenotype; normal female external genitalia ( well-
differentiated external genitalia, vagina and müllerian
derivatives) Not ambiguous Epstein, et al 1990
• Renal anomlies 33% (structural or positional );
Horseshoe kidney or renal agenesis , and malrotation.
Hall et al , 1990
Turner syndrome
Low set ear
Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
• Syndromes of gonadal dysgenesis
Syndromes of gonadal dysgenesis
• Abnormality of SRY gene that affects SRY
function  fundamental abnormality of gonadal
development.
• Karyotyping is variable XX or XY.
• Gonads can be ‘streak’ gonad or dysgenetic.
• failure of the Gonads to produce testosterone and
MIS results in an entirely female phenotype.
• Partial gonadal dysgenesis may be unilateral or
bilateral, and so gives rise to varying degrees of
sexual ambiguity.
Pure Mixed partial
Bilateral
streak gonads
Female (Not
Ambiguous)
Dsygenetic
testis
contralateral
streak gonad
Ambiguous
Two
dysgenetic
testes
Ambiguous
Gonadal dysgenesis
Mixed gonadal dysgenesis
Testis
(Often Intra-abdominal)
MIS and testosterone
ipsilateral wolffian duct
differentiation and müllerian
ducts regression
Streak gonad
NO MIS and testosterone
Mullerian duct differentiation
Ipsilateral uterus fallopian tube
Davidoff and Federman, 1973
• Gender assignment depends on
function of the external genitalia and
gonads (anatomy not fertility).
Female
Orchidectomy and
hormonal replacement
Male
Orchiolysis and pexy plus
screaning for germ
tumour Or
gonadectomy and
androgen replacement
Disorders of Gonadal Differentiation
• Seminiferous tubule dysgenesis
1. Klinefelter syndrome
2. 46,XX male
• Syndromes of gonadal dysgenesis
1. Turner syndrome
2. Pure gonadal dysgenesis
3. Mixed gonadal dysgenesis
4. Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
• Bilateral vanishing testis/testicular regression
syndromes
Bilateral vanishing testis/testicular
regression syndromes
Bilateral vanishing testis/testicular
regression syndromes
• 46,XY
• Absent testes with clear evidence of testicular
function at some point during embryogenesis.
• Due to genetic mutation, a teratogen, or bilateral
torsion.
• Diagnosis: Elevated FSH/LH and castrate
testosterone levels; 46 XY
Migeon et al 1994
Most sever
Before60-70 days
gestation
MIS secreted but before
the elaboration of
androgen.
phenotypic female
with no internal genital
structures
testicular regression
syndrome
Intermediate
After liberation of
MIS and incomplete
eloberation of
androgen

ambiguous
genitalia,
absent gonads
and internal
ductal structures
Least sever
Late after complete
anatomic development
of the male external genitalia

phenotypic males with fully
developed wolffian
structures but an empty
scrotum, and microphallus.
bilateral vanishing
testes syndrome
3 phenotypes according to the time that vanishing
occur.
Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
True Hermaphroditism (Ovotesticular)
• Both testicular and ovarian tissue, either in
separate gonads or coexisting in the same gonad
as an ovotestis.
• Karyotype variable  Not helpful for diagnosis.
• Phenotype Ambiguous genitalia with tendency
to masculinization (75% are raised as male).
• Internal organs are variable and according to the
present gonad
• Pregnancy documented in female only.
(Berkovitz et al, 1991)
Disorders of sex development
True Hermaphroditism (Ovotesticular)
Management
• Gender assignment based on the functional potential
of external genitalia, internal ducts, and gonads,
according to the findings at laparoscopy or
laparotomy.
• If the patient is to be raised as female, all testicular
and wolffian tissue should be removed.
• If a male gender is assigned, all ovarian and müllerian
tissue should be removed
• Gonadectomy at puberty with androgen replacement
due to the high risk of malignancy and no hope for
fertility.
Starceski et al, 1988
Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
Masculinized Female
(Female Pseudohermaphrodite)
• 46,XX DSD  phenotypic disorder
• CAH is the main etiology
• Most common cause of ambiguous genitalia.
• Autosomal recessive disorder
• Deficiency of an enzyme involved in
glucocorticoid synthesis increase ACTH  shift
to androgen pathway and adrenal hyperplasia
 Ambiguous gentalia.
New and Levine, 1984
Disorders of sex development
Congenital Adrenal Hyperplasia
• Types:
(1) salt wasters (patients with virilization and
aldosterone deficiency) 75%.
(2) simple virilizers (patients with virilization, but
without salt wasting) 25%.
(3) Non classic patients (those without evidence of
virilization or salt wasting) rare.
Kohn et al, 1995.
Congenital Adrenal Hyperplasia
• The clinical phenotype of CAH depends on the
nature and severity of the enzyme deficiency.
Congenital Adrenal Hyperplasia
labioscrotal fusion and clitoromegaly. complete virilization of phallus.
Congenital Adrenal Hyperplasia
• Diagnosis
• Demonstration of inadequate production of
cortisol, aldosterone, or both
• Demonstration of excess concentrations of
precursor hormones;
serum 17-hydroxyprogesterone
Urinary 17-ketosteroid levels
serum 11-deoxycortisol and deoxycorticosterone
Congenital Adrenal Hyperplasia
• Salt-wasting forms of CAH: Low serum
aldosterone concentrations, hyponatremia ,
hyperkalemia, and elevated plasma renin activity
(PRA).
• A karyotype is essential in an infant with
ambiguous genitalia, to establish the
chromosomal sex
Classification
1. Disorders of Gonadal Differentiation
2. True Hermaphroditism (Ovotesticular)
3. Female Pseudohermaphrodite (Masculinized
Female)
4. Male Pseudohermaphrodite (Under-masculinized
Male)
5. Unclassified Forms
Male Pseudohermaphrodite
(Undermasculinized Male)
• 46,XY with differentiated testes.
• Varying degrees of feminization phenotypically.
• Secondary to:
 inadequate secretion of testosterone by the testes.
 inability of target tissue to respond to androgen
appropriately.
 impaired production or action of MIS.
Male Pseudohermaphrodite
Undermasculinized Male ( 46,XY DSD)
Classifications
1. Leydig Cell Aplasia (Luteinizing
Hormone Receptor Abnormality)
2. Disorders of Testosterone Biosynthesis
3. 5α-Reductase Deficiency
4. Androgen Receptor and Postreceptor
Defects (testicular feminization)
5. Persistent Müllerian Duct Syndrome
(hernia uteri inguinale).
LH
T
DHT
Receptor
Disorders of sex development
Male Pseudohermaphrodite
Undermasculinized Male ( 46,XY DSD)
5.Persistent Müllerian Duct Syndrome (hernia uteri
inguinale).
• 46,XY
• normal male external genitalia
• internal müllerian duct structures.
• unilateral or bilateral undescended testes
• commonly diagnosed after müllerian tissue is
encountered during inguinal herniorrhaphy or
orchidopexy.
Cont.. Persistent Müllerian Duct
Syndrome
• The treatment of persistent müllerian duct
syndrome is relatively straightforward, in that all
patients are phenotypic males who require
orchidopexy.
• The vasa deferentia are in close proximity to the
uterus and proximal vagina, and preservation of
the necessary müllerian structures to avoid injury
to the vasa is recommended to preserve fertility
Sloan and Walsh, 1976
Outlines
• Normal sex development and Embryology
• Definition
• Classification
• Disorders
• Workup
Pragmatic Urologic
approach to DSD
DR Ahmed Abdelhamid
• Classic ambiguous genitalia
• Female with palpable gonads
• Male with nonpalpable gonads
• Hypospadias and cryptorchidism
• “Normal” Female or Male
Common Neonatal Presentations
DSD TEAM
Multidisciplinary
1. Urology
2. Endocrine
3. Genetics
4. Psychology/Psychia
try
5. Gynecologist
6. Religious
counseling
Questions to be answered
• What is the diagnosis
• What is the anatomy
• What is the function of gonads and
reproductive tract
• Gender Assignment
Important principles
A. Palpable gonad = testis; as ovaries do not
descend , Rarely, an ovotestis descent to the
inguinal canal.
B. Bilaterally impalpable testes or unilaterally
impalpable testis and hypospadias should be
considered DSD until proven otherwise, whether
or not the genitalia appear ambiguous.
Disorders of sex development
Work up
• Karyotyping
• Hormonal assay; serum electolyte, T, DHT, serum
17-hydroxyprogesterone,
• HCG stimulation test ruling out anorchia.
• Laparoscopy and gonadal biopsy.
• Genitogram and endoscopy to detect urogenital
sinus.
Gender assignment
Non functioning
female better than
non functioning
male
Role of surgery
• Feminising surgery
Clitororeduction; Reduction of an enlarged
clitoris should be done with preservation of the
neurovascular bundle.
Separation of the vagina and the urethra is
preserved for high confluence anomalies for
urogenital sinus repair.
Vaginoplasty should be performed during the
teenage years.
Role of surgery
• Masculinising surgery
• Hypospadias surgery.
• Excision of Mullerian structures.
• Orchiopexy.
• Phalloplasty; severe penile inadequacy in DSD
patients.
• correction of penoscrotal transposition,
scrotoplasty
• insertion of testicular prostheses.
Disorders of sex development
Thank you

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Disorders of sex development

  • 2. It is a complex topic but actually if you understand it, it will be very simple.
  • 3. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  • 5. Chromosomal Sex Genes associated with sex determination  SRY (sex-determining region Y gene) is responsible for testis formation and called TDF (testis-determining factor).  Mutation in SRY gene may occurs and result in sex reversal As it absent in Y chromosome result in XY female And it’s present in X chromosome result in XX male And this prove that SRY gene is TDF. Sinclair et al 1990
  • 6. Chromosomal Sex Presence of SRY gene Testis formation Absence of SRY gene ovary formation (Passive) • During the first 6 weeks the gonadal ridge, germ cells  bipotential sex development. • Ovarian differentiation needs at least two X chromosome ( this explain dysgenetic ovary in 45 X0 turner). Haqq et al 1994
  • 7. Gonadal development 1. In Males • Differentiation of sertoli cell (7th week)  MIS production regression of Mullerian ducts. • MIS acts unilaterally. • Formation of leydige cell (9th week)  testosterone production  proliferation of wolffian duct and descend of the testis.
  • 8. Gonadal development • Testosterone  dihydrotestosterone (higher affinity to androgen receptors) by intracellular 5α-reductase. • Disorders of androgen receptors or 5α-reductase lead to a spectrum of phenotypic abnormalities in the genetic male. Andersson et al, 1991
  • 9. Gonadal development 2. In Females • Absent SRY Ovary differentiation No MIS NO testosterone Proliferation of Mullerian duct • Uterus • Fallopian tube • Upper 4/5 of vagina Reggresion of wolffian duct • Epoophoron and paroophoron • Gartener’s duct
  • 11. Phenotypic differentiation Undifferentiated stage • Before the 8th week of gestation the urogenital tract is identical in the two sexes. • Undifferentiated stage of external genitalia consists of 1. Genital tubericle 2. Genital (urethral ) folds 3. Genital swelling
  • 12. Phenotypic differentiation In males • Androgen  -masculinization of the external genitalia (12th-13th week). -penile growth and testicular descent (3rd trimester) Doymer et al 1994.
  • 13. Phenotypic differentiation In Females • In the female fetus the absence of circulating testosterone maintains the appearance of the Female external genitalia at the 6-week gestational stage. Doymer et al 1994
  • 14. Gender Identity • Gender identity;- the identification of self as either male or female. • Is complex, poor understood and multifactorial. • Androgen has major role in brain imprint. • Postnatal environmental factors and learning appear to have an important effect. Reiner et al 2004
  • 15. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  • 16. Definition of DSD Conditions involving the following elements • Sex chromosome anomalies as Turner syndrome. • Disorder of gonadal developments as ovitestes • Disorders of internal reproductive organs • Disorders of external genitalia ( ambigious) It was called intersex but this term is not accurate and showed be avoided. Hughes et al 2006
  • 17. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  • 18. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular DSD) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  • 19. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes • Seminiferous tubule dysgenesis
  • 20. Seminiferous tubule dysgenesis 1. Klinefelter syndrome • The Most common DSD. • Genotype;- Male with at least Y + at least 2 X chromosomes (47XXY (classic), 48XXXY,48XXYY,….. Mosaic 46XY/47XXY) • Gonads;- Small firm atrophic testes with small number of leydig cells Azospermic except in mosaic. • Hormones;-low normal Testosterone , Increase FSH and LH, Increase estrogen. • Phenotype; normal male external genitalia Not ambiguous
  • 21. • Special features • Complications 1. High incidence of breast cancer (8 times). 2. Predispose to sertoli and leydig cell tumour 3. Infertility • Management 1. Androgen replacement 2. Surveillance for testicular tumor and breast carcinoma. Staessen et al 2003 Klinefelter syndrome
  • 22. Cont…Seminiferous tubule dysgenesis 2. 46,XX male Due to translocation of Y chromosomal material, including SRY (TDF) to the X chromosome. • Gonads;- Small firm atrophic testes with small number of leydig cells  Azospermic • Hormones;-low normal Testosterone , Increase FSH and LH, Increase estrogen. • Phenotype; normal male external genitalia Not ambiguous but 10 % hypospadias. • Complication and Management as Klinefelter but shorter and normal skeletal proportions. Fechner et al 1993
  • 23. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes • Syndromes of gonadal dysgenesis
  • 24. Turner syndrome • Incidence of 1 in 2500 live births. • Genotype 45XO , Mosaic (45XO/46XX ,45XO/46XY). • Gonads fibrous streaks (no surviving germ cells) • Hormones Decrease both androgen and estrogen, increase in FSH and LH • Phenotype; normal female external genitalia ( well- differentiated external genitalia, vagina and müllerian derivatives) Not ambiguous Epstein, et al 1990 • Renal anomlies 33% (structural or positional ); Horseshoe kidney or renal agenesis , and malrotation. Hall et al , 1990
  • 26. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes • Syndromes of gonadal dysgenesis
  • 27. Syndromes of gonadal dysgenesis • Abnormality of SRY gene that affects SRY function  fundamental abnormality of gonadal development. • Karyotyping is variable XX or XY. • Gonads can be ‘streak’ gonad or dysgenetic. • failure of the Gonads to produce testosterone and MIS results in an entirely female phenotype. • Partial gonadal dysgenesis may be unilateral or bilateral, and so gives rise to varying degrees of sexual ambiguity.
  • 28. Pure Mixed partial Bilateral streak gonads Female (Not Ambiguous) Dsygenetic testis contralateral streak gonad Ambiguous Two dysgenetic testes Ambiguous Gonadal dysgenesis
  • 29. Mixed gonadal dysgenesis Testis (Often Intra-abdominal) MIS and testosterone ipsilateral wolffian duct differentiation and müllerian ducts regression Streak gonad NO MIS and testosterone Mullerian duct differentiation Ipsilateral uterus fallopian tube Davidoff and Federman, 1973
  • 30. • Gender assignment depends on function of the external genitalia and gonads (anatomy not fertility). Female Orchidectomy and hormonal replacement Male Orchiolysis and pexy plus screaning for germ tumour Or gonadectomy and androgen replacement
  • 31. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes Bilateral vanishing testis/testicular regression syndromes
  • 32. Bilateral vanishing testis/testicular regression syndromes • 46,XY • Absent testes with clear evidence of testicular function at some point during embryogenesis. • Due to genetic mutation, a teratogen, or bilateral torsion. • Diagnosis: Elevated FSH/LH and castrate testosterone levels; 46 XY Migeon et al 1994
  • 33. Most sever Before60-70 days gestation MIS secreted but before the elaboration of androgen. phenotypic female with no internal genital structures testicular regression syndrome Intermediate After liberation of MIS and incomplete eloberation of androgen  ambiguous genitalia, absent gonads and internal ductal structures Least sever Late after complete anatomic development of the male external genitalia  phenotypic males with fully developed wolffian structures but an empty scrotum, and microphallus. bilateral vanishing testes syndrome 3 phenotypes according to the time that vanishing occur.
  • 34. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  • 35. True Hermaphroditism (Ovotesticular) • Both testicular and ovarian tissue, either in separate gonads or coexisting in the same gonad as an ovotestis. • Karyotype variable  Not helpful for diagnosis. • Phenotype Ambiguous genitalia with tendency to masculinization (75% are raised as male). • Internal organs are variable and according to the present gonad • Pregnancy documented in female only. (Berkovitz et al, 1991)
  • 37. True Hermaphroditism (Ovotesticular) Management • Gender assignment based on the functional potential of external genitalia, internal ducts, and gonads, according to the findings at laparoscopy or laparotomy. • If the patient is to be raised as female, all testicular and wolffian tissue should be removed. • If a male gender is assigned, all ovarian and müllerian tissue should be removed • Gonadectomy at puberty with androgen replacement due to the high risk of malignancy and no hope for fertility. Starceski et al, 1988
  • 38. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  • 39. Masculinized Female (Female Pseudohermaphrodite) • 46,XX DSD  phenotypic disorder • CAH is the main etiology • Most common cause of ambiguous genitalia. • Autosomal recessive disorder • Deficiency of an enzyme involved in glucocorticoid synthesis increase ACTH  shift to androgen pathway and adrenal hyperplasia  Ambiguous gentalia. New and Levine, 1984
  • 41. Congenital Adrenal Hyperplasia • Types: (1) salt wasters (patients with virilization and aldosterone deficiency) 75%. (2) simple virilizers (patients with virilization, but without salt wasting) 25%. (3) Non classic patients (those without evidence of virilization or salt wasting) rare. Kohn et al, 1995.
  • 42. Congenital Adrenal Hyperplasia • The clinical phenotype of CAH depends on the nature and severity of the enzyme deficiency.
  • 43. Congenital Adrenal Hyperplasia labioscrotal fusion and clitoromegaly. complete virilization of phallus.
  • 44. Congenital Adrenal Hyperplasia • Diagnosis • Demonstration of inadequate production of cortisol, aldosterone, or both • Demonstration of excess concentrations of precursor hormones; serum 17-hydroxyprogesterone Urinary 17-ketosteroid levels serum 11-deoxycortisol and deoxycorticosterone
  • 45. Congenital Adrenal Hyperplasia • Salt-wasting forms of CAH: Low serum aldosterone concentrations, hyponatremia , hyperkalemia, and elevated plasma renin activity (PRA). • A karyotype is essential in an infant with ambiguous genitalia, to establish the chromosomal sex
  • 46. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  • 47. Male Pseudohermaphrodite (Undermasculinized Male) • 46,XY with differentiated testes. • Varying degrees of feminization phenotypically. • Secondary to:  inadequate secretion of testosterone by the testes.  inability of target tissue to respond to androgen appropriately.  impaired production or action of MIS.
  • 48. Male Pseudohermaphrodite Undermasculinized Male ( 46,XY DSD) Classifications 1. Leydig Cell Aplasia (Luteinizing Hormone Receptor Abnormality) 2. Disorders of Testosterone Biosynthesis 3. 5α-Reductase Deficiency 4. Androgen Receptor and Postreceptor Defects (testicular feminization) 5. Persistent Müllerian Duct Syndrome (hernia uteri inguinale). LH T DHT Receptor
  • 50. Male Pseudohermaphrodite Undermasculinized Male ( 46,XY DSD) 5.Persistent Müllerian Duct Syndrome (hernia uteri inguinale). • 46,XY • normal male external genitalia • internal müllerian duct structures. • unilateral or bilateral undescended testes • commonly diagnosed after müllerian tissue is encountered during inguinal herniorrhaphy or orchidopexy.
  • 51. Cont.. Persistent Müllerian Duct Syndrome • The treatment of persistent müllerian duct syndrome is relatively straightforward, in that all patients are phenotypic males who require orchidopexy. • The vasa deferentia are in close proximity to the uterus and proximal vagina, and preservation of the necessary müllerian structures to avoid injury to the vasa is recommended to preserve fertility Sloan and Walsh, 1976
  • 52. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  • 53. Pragmatic Urologic approach to DSD DR Ahmed Abdelhamid
  • 54. • Classic ambiguous genitalia • Female with palpable gonads • Male with nonpalpable gonads • Hypospadias and cryptorchidism • “Normal” Female or Male Common Neonatal Presentations
  • 55. DSD TEAM Multidisciplinary 1. Urology 2. Endocrine 3. Genetics 4. Psychology/Psychia try 5. Gynecologist 6. Religious counseling
  • 56. Questions to be answered • What is the diagnosis • What is the anatomy • What is the function of gonads and reproductive tract • Gender Assignment
  • 57. Important principles A. Palpable gonad = testis; as ovaries do not descend , Rarely, an ovotestis descent to the inguinal canal. B. Bilaterally impalpable testes or unilaterally impalpable testis and hypospadias should be considered DSD until proven otherwise, whether or not the genitalia appear ambiguous.
  • 59. Work up • Karyotyping • Hormonal assay; serum electolyte, T, DHT, serum 17-hydroxyprogesterone, • HCG stimulation test ruling out anorchia. • Laparoscopy and gonadal biopsy. • Genitogram and endoscopy to detect urogenital sinus.
  • 60. Gender assignment Non functioning female better than non functioning male
  • 61. Role of surgery • Feminising surgery Clitororeduction; Reduction of an enlarged clitoris should be done with preservation of the neurovascular bundle. Separation of the vagina and the urethra is preserved for high confluence anomalies for urogenital sinus repair. Vaginoplasty should be performed during the teenage years.
  • 62. Role of surgery • Masculinising surgery • Hypospadias surgery. • Excision of Mullerian structures. • Orchiopexy. • Phalloplasty; severe penile inadequacy in DSD patients. • correction of penoscrotal transposition, scrotoplasty • insertion of testicular prostheses.