Development of External Genitalia and Disorders of Sexual Differentiation

Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai
DEVELOPMENT OF EXTERNAL GENITALIA
DISORDERS OF SEXUAL DIFFERENTIATION

MODERATORS:
Professors:
• Prof. Dr. G. Sivasankar,M.S., M.Ch.,
• Prof. Dr.A. Senthilvel,M.S., M.Ch.,
Asst Professors:
• Dr. J. Sivabalan,M.S., M.Ch.,
• Dr. R. Bhargavi,M.S., M.Ch.,
• Dr. S. Raju, M.S., M.Ch.,
• Dr. K. Muthurathinam,M.S., M.Ch.,
• Dr. D.Tamilselvan,M.S., M.Ch.,
• Dr. K. Senthilkumar,M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai.
2

NORMAL SEXUAL DIFFERENTIATION
 Jost paradigm
Establishment of chromosomal sex at fertilization
Development of undifferentiated gonads into testis and ovaries
Differentiation of internal ducts and external genitalia…1
3

NORMAL GENOTYPIC DEVELOPMENT
 Chromosomal sex
Y chromosome determines the destiny of the bipotential gonad…1
TDF…most distal aspect of the Y-unique region of short arm of Y
chromosome, adjacent to the pseudoautosomal boundary
SRY – function as molecular switch
- Expressed and functions in the supporting cells of the
developing male urogenital ridge > cord formation > develop into
Sertoli cells
4

GENES INVOLVED IN GONADAL DIFFERENTIATION
5

NORMAL PHENOTYPIC DEVELOPMENT
6

GONADAL DIFFERENTIATION
• 1. In Males
• Differentiation of sertoli cell (7th week) MIS production
regression of Mullerian ducts.
• MIS acts locally and unilaterally.
• Formation of Leydig cell (9th week) testosterone
production virilization of wolffian duct structures, UGS &
Genital tubercle and descend of testis.
7

8

GONADAL DEVELOPMENT
• 2. In Females
• Absent SRY Ovary differentiation
No MIS NO testosterone
Proliferation of Reggresion of
Mullerian duct wolffian duct
Uterus Epoophoron
Fallopian tube Paroophoron
Upper 2/3 of vagina Gartener’s duct
9

GONADAL DEVELOPMENT
10

PHENOTYPIC DIFFERENTIATION
11

FORMATION OF INTERNAL REPRODUCTIVE TRACT
 MALE
SC > MIS > Suppress MD
LC > Testo. > develop. WD
• 10 Week – Degeneration of MD is complete & WD become more prominent
• Adjacent to testis – convolusions of the ducts organize to form the
epidydamis
• WD of epidydamis joins proximally rete testis and distaly with the UGS >
Develop into SV
12

 FEMALE
No testo > WD regress
No MIS > maintain MD > devolope into female internal
reproductive tract
• Cephalic ends forms fallopian tubes on either sides
• Caudal ends fuses to form uterus
• Contact b/w MD and UGS induces formation of UVP >
ultimately forms lumen of vagina
13

FORMATION OF EXTERNAL REPRODUCTIVE TRACT
Undifferentiated stage of external genitalia consists of
1. Genital tubercle
2. Genital (urethral ) folds
3. Genital swelling
14

• In males
• 7-8 weeks - Masculinization of male fetus…1
• 10 week – increase distance between genital tubercle and anal folds can
be seen
- Genital tubercle thickens and elongates > penis
- Urethral folds fuse from posterior to anterior over the urethral groove
- Genital swelling migrates posterior to genital tubercle and fuses > scrotum
• 12th-13th week - masculinization of external genitalia completes with
closure of Elongated urogenital cleft…2
-
15

16

In Females
• In female fetus the absence of circulating testosterone
maintains the appearance of the Female
external genitalia.
17

18

19

Abnormal sexual differentiation
Classification
 Disorders of gonadal differentiation
 True hermafroditism > Ovotesticular DSD
 Masculanized female / female hermaphroditism > 46 XX DSD.
 Under masculanized male / male hermaphroditism > 46 XY DSD
 Unclassified forms
20

Disorders of Gonadal Differentiation And Development
A ) Seminiferous tubule dysgenesis
Klinefelter's syndrome
46, XX male
B) Syndromes of gonadal dysgenesis
Turner's syndrome
Pure gonadal dysgenesis
Mixed gonadal dysgenesis
Partial gonadal dysgenesis (dysgenetic male
pseudohermaphroditism)
C) Bilateral vanishing testis/testicular regression
syndromes
21

MASCULINIZED FEMALE
(FEMALE PSEUDOHERMAPHRODITISM)
A) Congenital adrenal hyperplasia
• 21-hydroxylase
• 11β-hydroxylase,
• 3β-hydroxysteroid dehydrogenase deficiencies
B) Maternal androgens
22

UNDERMASCULINIZED MALE
(MALE PSEUDO HERMAPHRODITISM)
A) Leydig cell agenesis, unresponsiveness
B) Variants of congenital adrenal hyperplasia affecting corticosteroid and
testosterone synthesis
StAR deficiency (congenital lipoid adrenal hyperplasia)
3β-Hydroxysteroid dehydrogenase deficiency
17α-Hydroxylase deficiency
C) Disorders of testosterone biosynthesis
17,20-Lyase deficiency
17β-Hydroxysteroid oxidoreductase deficiency
23

D) Disorders of androgen-dependent target tissue
 Androgen receptor and postreceptor defects
 Syndrome of complete testicular feminization
 Syndrome of partial androgen resistance
 Androgen resistance in infertile men
E) Disorders of testosterone metabolism by peripheral
tissues
 5α-Reductase deficiency
 Disorders of synthesis, secretion, or response to
müllerian-inhibiting substance
F) Persistent müllerian duct syndrome
24

Unclassified Forms
In males
Micropenis
In females
Mayer-Rokitansky-Kuster-Hauser
syndrome
25

Disorders Of Gonadal Differentiation
1.Seminiferous tubule dysgenesis
a. klinefelter’s syndrome
b. 46 xx male
2.Syndrome of gonadal dysgenesis
a.Turner’s syndrome
b. pure gonadal dysgenesis
c. mixed gonadal dysgenesis
d. partial gonadal dysgenesis
3. bilateral vanishing testis/testicular regression
syndromes
26

KLINEFELTER SYNDROME
 Most common major abnormality of sexual differentiation
 Genotype : Male with at least Y + at least 2 X chromosomes
(47 XXY (classic), 49 XXXYY, 48 XXYY
Exagerated form is a/w 48 XXXY , 49 XXXXY
Mosaic form – 46 XY/47XXY …milder version
27

• Phenotype : Normal male external genitalia Not ambiguous
• 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.
28

SPECIAL FEATURES
29

Classic 47, XXY
• Cause : d/t non disjunction during meiosis
• Incidence: 1 in 600 live born males
• Testis are firm and small …< 3.5cm length
• Histology : Lyedig cells +…
• Low normal testosterone
• Elevated plasma estrodial (gyneacomastia)
• Azoospermia…
• Abnormal secondary sexual development
• Muscle development is poor
• Feminine fat distribution
• Facial hair is sparse ( pubic and axillary hairs normal)
30

Complications
• Ca. Breast - 8 X
• Risk : Extra gonadal GCT, Leydig and Sertoli cell tumors
• Neuropsychiatric evaluation
- Depressed verbal ability
- limitations in frontal excecutive functioning
31

Management
• Androgen supplementation - improve libido
• Reduction mammoplasty
• Surveillance for breast ca and testis tumor
• Assisted reproductive technique – offers potential fertility to
non-mosaic klinefelters
32

46,XX MALES
• INCIDENCE :1 in 20,000 males
• Characterized by testicular development in subjects who have
two X chromosomes and lack a normal Y chromosomes
Due to translocation of Y chromosomal material, including
SRY(TDF) to the X chromosome…
33

• Gonads - Small firm atrophic testes with small number of
leydig cells >>>>> Azospermic
• Phenotype - Normal male external genitalia, Not ambiguous
but 10 % hypospadias.
• Hormones - Low normal Testosterone, Increase FSH and
LH, Increase estrogen.
34

Two categories
SRY-positive (90%)
SRY-negative
SRY positive : rarely have genital abnormality…1
- Hypogonadism
- Gynacomastia
- Azoospermia
- Hyalinization of seminiferous tubules
- Altered hormonal level at puberty (low testo, ^ FSH/ LH)…2
- Shorter
- Normal skeletal proportions
35

MANAGEMENT
• Androgen replacement
• Reduction mammoplasty
• Screening for Breast ca. and testis ca.
36

Disorders Of Gonadal Differentiation
1.Seminiferous tubule dysgenesis
a. klinefelter’s syndrome
b. 46 xx male
2.Syndrome of gonadal dysgenesis
a.Turner’s syndrome
b. pure gonadal dysgenesis
c. mixed gonadal dysgenesis
d. partial gonadal dysgenesis
3. bilateral vanishing testis/testicular regression
syndromes
37

TURNER SYNDROME
• INCIDENCE -1 in 2500 live births
• Common cause of primary amenorrhea…
• Cause : Secondary to loss of X chromosome through
Non disjunction in gamatogenesis or an error in meiosis
12-20% - isochromosome X
30-40% - Mosaicism ( 45X/46XX, 45X/46XY )
38

 Diagnosed prenatally by ultrasound / Karyotyping
o Nuchal translucency
o Lymphedema
o Cystic hygroma
o Coarctation of aorta
o Renal anomalies
39

 Genotype : 45XO , Mosaic (45XO/46XX, 45XO/46XY).
 Gonads : fibrous streaks ( white, fibrous structure 2-3 cm long
and 0.5 cm wide located in the broad ligament…
 Hormones : Decrease androgen and estrogen, increase in FSH
and LH
 Phenotype : well –differentiated, external genitalia, vagina and
müllerian Derivatives > Not ambiguous
40

41

• Paramount Importance - identification of Y chromosomal
material Or 45,X/46XY mosaicism
• Gonadoblastoma & in-situ GCT - 12 %
• Renal abnormalities ( 33%-60% )…
- Multiple renal A. 90 %
- Horse shoe kidney 10%
- Duplication or Renal agenesis 20%
- Malrotation 15%
42

TREATMENT
• Identification of Y chromosome { FISH / PCR }…
• Timely Prophylactic Gonadectomy in Y mosaic turner
• Ultrasound screening for renal and cardiac abnormality
• Human growth hormone Therapy
• Assisted reproductive technique
43

GONADAL DYSGENESIS
44

46,XX COMPLETE (PURE) GONADAL DYSGENESIS
 Normal female external genitalia
 Normal Mullerian ducts structures
 Bilateral streak gonads
 Sexual infantilism
 Normal height
 Normal karyotype
45

• Familial 46 XX gonadal dysgenesis – AR…
• T/t : Proper cyclical hormone replacement with
estrogen/ progesterone
• GH & gonadectomy not required
46

46,XY COMPLETE (PURE) GONADAL DYSGENESIS
(SWEYER SYNDROME)
Etiology
• Abnormality of the SRY gene that eliminates SRY function, or
loss of another gene downstream from SRY that is necessary
for SRY protein action
• Absence of testicular determination > Ovarian differentiation
• Mutaion DHH gene / 9p24
• Present in their teens with delayed puberty and amenorrhea
47

 Characteristics
• normal female genitalia
• well developed mullerian structures
• bilateral streak gonad
• complete absence of testicular determination
• sexual infantilism
• Amenorrhea
• Breast development is usually absent
• Gonodotrophin is elevated
48

49

 Histology
streak gonad with fibrous connective tissue resembling wavy
ovarian stroma but without follicles
 Risks
- Germ cell tumors 30% in 30 yrs ; M/C- Gonadoblastoma
other: Embryonal carcinoma
Endodermal sinus tumor
Choriocarcinoma
Immature teratoma
50

 Management
- Removal of both streak gonads
- Proper cyclic hormone replacement with
estrogen and progesterone
51

PARTIAL GONADAL DYSGENESIS
 Characteristics
• Pts with abnormal sex differentiation have Two Dysgenetic testis upto
variable proportion
• Karyotype : 45,X/46,XY OR 46,XY
• External Genital abnormalities…1
• Persistent mullerian structures…2
• Histology: testis composed of immature hypo plastic semniferous
tubules and persistent stroma
• Risk : Gonadal malignancy 46% at 40 yrs (GB/Dysgerminoma), DDS
52

 Treatment
- Gender assignment
- Surveillance for malignancy
53

MIXED GONADAL DYSGENESIS
• 2nd most common cause of ambiguous genitalia (M/C : CAH)
• Result of anaphase lag during mitosis
• Karyotype : 45XO/46,XY
• Characterized by
Unilateral testis (intraabdominal)
Contra-lateral streak gonad and
Persistent mullerian structures with
Inadequate masculinization…
54

 TYPES…
1. Phenotypic female with Turner’s
syndrome 25%
2. With ambiguous genitalia
3. Normal male genitalia –rare
55

 Risks
• Testis lack germinal element so infertility is the rule
• Gonadal tumor (gonadoblastoma, dysgerminoma) 15%-
20%
• Wilms tumor - 50%
56

 SYNDROMES
1. DDS
> WT1 gene > XX/XY mosaicism
- Nephropathy : early onset proteinuria, HTN, progressive renal failure
- Willms tumour : B/L, favourable triphagic histology
- Genital abnormality : ambiguity, hypospadias, cryptorchidism
 interesting and consistent finding with DDS - Calyceal blunting
without obstruction
57

2) FRASIER SYNDROME
 CONSIDERED – girl with steroid resistant nephrotic syndrome,
primary amenorrhea and puberty delay
Due to mutations in the alternative splice donor site of exon 9 on
WT1…1
• Nephropathy ( FSGS)–later > More gradual progressive to renal
failure
• No known predisposition to Willms tumor
• Gonadoblastoma – 60%
58

 MANAGEMENT
• Gender assignment…
• Appropriate gonadectomy
• Screening for Wilms tumor / Gonadoblastoma
59

GONADAL DYSGENESIS
Pure Mixed partial
Bilateral Dysgenetic testis Two dysgenetic testes
streak contralateral streak gonads
gonad
Female Ambiguous Ambiguous
(Not Ambiguous)
60

Testis Streak gonad
(Often Intra-abdominal)
MIS and testosterone NO MIS and testosterone
ipsilateral wolffian duct Mullerian duct differentiation
differentiation and müllerian Ipsilateral uterus, fallopian tube
ducts regression
61

GENDER ASSIGNMENT
Depends on
• Function of the external genitalia and
• Gonads (anatomy not fertility).
Male > Orchiodopexy plus screening for germ tumour Or
gonadectomy and androgen replacement
Female > Orchidectomy & hormonal replacement
62

BILATERAL VANISHING TESTIS
TESTICULAR REGRESSION SYNDROMES
• Karyotype : 46,XY
• Absent testes with clear evidence of testicular function at some
point during embryogenesis…
Etiology - Genetic mutation, a teratogen, or bilateral torsion.
Diagnosis: Elevated FSH/LH and castrate testosterone levels
63

 3 PHENOTYPES
MOST SEVER
• Before 60-70 days
Gestation MIS secreted but
before the elaboration of
androgen.>>>>> phenotypic
female with no internal
genital 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.
Testicular regressions
syndrome
bilateral vanishing testes
syndrome
64

• After liberation of MIS and incomplete elaboration
of androgen
• Ambiguous genitalia
• Absent gonads and internal ductal structures
INTERMEDIATE
65

• On surgical exploration
 Rudimentary cord structures are usually identified
 Biopsy of their distal ends demonstrates no
recognizable testicular tissue
 Atrophic epididymal remnants are occasionally seen
66

3 ) Ambiguous genitalia
- Individualized assessment to determine gender
assignment
MANAGEMENT:
1 ) Phenotypic females
- Estrogen supplementation at expected puberty
- Vaginal dilation or vaginoplasty
2 ) Phenotypic males
- long-term androgen replacement
67

TRUE HERMAPHRODITISM (OVOTESTICULAR)
Both testicular tissue with well develop seminiferous tubules and
ovarian tissue with primordial follicles are present, which may
take form of one ovary and one testis or more commonly one or
two ovotestis
• CAUSE - a partial defect in testis determination results in both
testicular and ovarian maldevelopment
• Karyotype : variable, Not helpful for diagnosis.
- 46 XX karyotype 60%
- Mosaics (46 XX/46 XY) 33%
- 46 XY 7%
68

• Phenotype : Ambiguous genitalia with tendency to
masculinization (75% are raised as male/ among those raised
as female -2/3 have clitoromegaly).
hypospadias & chordae- 80 %
• Internal organs are variable> related to function of I/L
gonad
• All pts have urogenital sinus ,a uterus is present
• The ovaries found in a normal location mostly on left side
• fallopian tubes are consistently present on the side of
the ovary
• The testis or ovotestes may reside at any path along the
testicular descent mostly on right side
• vas deferens always present adjacent to a testis
69

70

71

• 60 % gonads palpable in inguinal canal/ labioscrotal folds are ovotestis
• Difference in firmness at either end of gonad
• Patterns
1) Admixed : central core containing stroma and a mixture of testicular
and ovarian tissue
2) Compartmentalizes: upper pole – ovarian tissue ; lowe pole –
testicular tissue encapsulated by mantle of ovarian tissue
3) Bipolar: strict polar distribution of ovarian and testicular tissue
72

Management
• Gender assignment based on the functional potential
of external genitalia, internal ducts, and gonads,
according to the findings at laparoscopy or laparotomy.
• True hermaphrodites have the potential for fertility >> If the patient
is to be raised as female, all testicular and wolffian tissue should be
removed. > Pregnancy documented in female only
• 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.
73

MASCULINIZED FEMALE
(FEMALE PSEUDOHERMAPHRODITISM)
46 XX with ovaries have a partially musculinizes phenotype and ambiguous
genitalia
A) Congenital adrenal hyperplasia
• 21-hydroxylase
• 11β-hydroxylase,
• 3β-hydroxysteroid dehydrogenase deficiencies
B) Maternal androgens
74

75

CAH
• Inheritence – AR…
• Cause - defect any of the five enzymes involved in the cortisol
biosynthesis pathway
• 21 OH – 95%
• Clinical pattern
A. Salt wasters – 75%
B. Simple virilization -25 %
C. Nonclassic
76

 Classic salt wasters
 Females
- Enlargement of clitoris and varying degree of labial fusion
- Vagina and urethra opens into a common UGS
- Mullerian structures are normal
- Few weeks – failure to regain weight, progressive weight loss,
vomiting and dehydration with hyperkalemia, hyponatremia and
shock
77

78

• Untreated female
- Progression of masculinization > premature development of
pubic and axillary hairs
- Deepning of voice & Acne
- Rapid somatic maturation : premature epiphysial closure > short
stature
- Breast development and menstruation do not occur > unless
excessive suppression of androgen by steroid therapy
79

 MALES
- Birth : Normal
- Sexual and somatic precocity in first 2-3 years of life
- Testis: Normal in size
- Enlargement of penis, scrotum & prostate
- Early pubic hairs, acne, deepening of voice
- Well developed musculature ( LITTLE HERCULES )
80

 Untreated males
- Short stature
- Infertility : 20-40% …
- Adrenal rest tumurs
81

 Diagnosis
A. Biochemical
Elevated plasma 17- hydroxyprogestrone
Elevated urinary 17- ketosteroid and pregnanetriol
B. Pelvic US
- Mulerian structures
- Cerebriform appearance of adrenal gland
C. Karyotyping
82

 Non-classic form of 21 of Deficiency
- Late onset with variable features
- Female : hirsutism , oligomenorrhea, male pattern baldness,
polycystic ovaries
- Male : oligospermia, subfertility
- Typically lower doses of glucocorticoid are required for management
of non-classic form of CAH
83

CAH
 11 B OH – 5 %...
• Signs and symptoms of androgen excess in childhood/
adolescent
• HTN > DOC…
• Diagnosis :
Elevated Plasma 11-deoxycortisole and 11-DOC
Elevated urinary 17- ketosteroid and 17-hydroxycorticoid
84

CAH
 3B-Hydroxysteroid dehydrogenase
- Affects early steps in steroid biosynthesis in both adrenal and gonads
- 3B hydroxysteroid ≠ 3-ketosteroid > impaired aldosterone, cortisol, sex
steroids
- Mild clitoromegaly, labial fusion with symptoms of aldosterone and cortisone
deficiency
- Diagnosis
Elevated serum DHEA
- Treatment
Minralocorticoid and glucocorticoid supplimentation
85

PREVENTION
 Prenatal diagnosis
 Chorionic villus sampling ( 9-11 week)
 PCR analysis of free fetal DNA ( circulating throphoblastic cells)
 Treatment of mother
- Dexamethasone > crosses placenta > suppress fetal ACTH >
prevent virilization of genitalia
- Start as soon as pregnancy is conformed, no later than 9 weeks of
LMP, before initial development of external genitalia
86

TREATMENT
 Goals
• To supply deficient hormone
• To supress pitutary ACTH secretion and hence adrenal
androgen and clinical virilization
• To forestall abnormally rapid somatic growth and osseous
advance
• To permit normal gonadal development
• To correct salt-water loss And HTN
87

• Prefered protocol
- Oral hydrocortiosone (10-20 mg/m2 in 3 divided doses), increased
doses in stressful events
- Fludrocortisone ( 0.1-0.2 mg/day)
- Effectiveness of therapy : morning plasma 17-
hydroxyprogesterone
• Genitoplasty – significantly virilizes female …– 3-6 months of age
88

• Interesting finding on MRI – Smaller amygdala
volume…1
• Prophylactic adrenalectomy in selected patients…2
• Males with CAH followed with annual scrotal US –
TESTICULAR ADRENAL REST…3
89

MATERNAL ANDROGENS
• Progestinal agent - threatened abortion 2%
• Danazol - t/t for endometriosis
• Ovarian tumours – arrhenoblastoma, hilar cell tumor, lipoid cell
tumour, ovarianl stromal cell tumor, luteoma of pregnancy,
Kruckenberg tumour
• Adrenal tumours ( rare) – adenoma, adrenocortical carcinoma
• Aromatase deficiency…
90

46, XY DSD
( UNDERMUSCULINIZED MALE )
• 46 XY individual with differentiated testis and varying degree of
feminization
A. Leydig Cell Aplasia ( LH receptor abnormality )
- Karyotye: 46,XY male
- Phenotype :Female, normally appearing
- Inheritance : AR
- Testis palpable in inguinal canal or labia majora
- On Investigation – No Mullerian structures, vagina is short
- Hormone : Low testosterone elevated LH
91

B. Disorders of testosterone biosynthesis
92

• C. Androgen receptor and postreceptor defects
1) Syndrome of complete androgen insensitivity…
- Incidence: 1:20000-60000
- Inheritance : X-linked – point mutation (90%)
- Karyotype – 46 XY
- B/L testis
- Female appearing external genitalia with short and blind vagina
(diminished axillary and pubic hairs)
- Breast development and body habitus feminine
- Absence of Mullerian derivatives
- 50 % have inguinal hernia
93

 Clinical Diagnosis
Primary amenorrhea
Finding testis at inguinal herniorrhaphy
 Vaginal examination – blind ending vagina without cervix
 Pelvic US : absence of Mullerian tissue
94

 Endocrine evaluation
Neonatal : Normal testosterone, DHT, gonadotropins
Puberty : elevated gonadotropins > elevated estradiole >
feminization
 Histology
Testis exhibit incomplete or absent spermatogenesis with normal
or hypoplastic Leydig cells
95

 Management
Leave testis in-situ until puberty
Delayed gonadectomy – seminoma, gonadoblastoma
Cyclic estrogen progestin therapy after gonadectomy
Vaginal dilatation / vaginoplasty : short vagina
96

2) Syndrome of partial androgen insensitivity
- X linked disorder
- Major finding : ambiguity of external genitalia
- Genotype : 46 XY
- Phenotype : MALE with penoscrotal hypospadias, cryptorchidism,
rudimentary wolffian duct structure, gynecomastia, infertility
- Forms
- 1) Reduced number of normally functioning androgen receptors
- 2) Normal receptor number but decreased binding affinity
97

 DIAGNOSIS
 46 XY karyotype, ambiguish external genitalia absence
of Mullerian structures on pelvic US
 Endocrine evaluation
Normal testosterone, gonadotropins
Normal testosterone: DHT ratio
 Serum PCR – confirme diagnosis
98

MANAGEMENT
• Depending on the degree of genital ambiguity
• Female gender
- Gonadectomy
- Surgical reconstruction of external genitalia
- Estrogen replacement – at puberty
• Male gender
- t/t of cryptorchidism
- Reduction of gynecomastia
- Genital reconstruction
99

• D. DISORDERS OF TESTOSTERONE METABOLOSM BY
PERIPHERAL TISSUE
1) 5 AR Deficiency…
- Inheritance –AR (type 2AR)
- Karyotype : 46 XY
- Phenotype : vary from normal female to ambiguish genitalia to penoscrotal
hypospadias
- UGS is present with common vaginal and urethral channel
- Labioscrotal fusion
- Vaginal pouch blind and short and Vasa terminates in blind ending vagina
- Testis and epidydamis located in labia, inguinal canal or abdomen
100

101

102

• At puberty
- Partial masculinization occurs
- Increase in muscle mass
- Development of male body habitus
- Increase in phallic size
- Onset of erection
103

• Endocrine evaluation
- Elevated plasma testosterone and low DHT
• Male gender
- Cryptorchidism and hypospadias surgically corrected
- Fertlity IU insemination
• Female gender
- Gonadectomy to prevent virilization
- Estrogen and progestin at puberty
- Vaginoplasty and clitoral reduction at first year of life
104

E) PMDS ( Defect in MIS gene )
• Karyotype : 46 XY
• Phenotype : MALE
- Male normal external genitalia
- U/L or B/L UDT
- B/L fallopian tube
- Uterus
- Upper vagina draining to prostatic utricle
105

 Catogories
1) B/L intraabdominal testis – 60-70%
2) One testis in hernia sac with C/L inguinal hernia – 20-30%
3) TTE with fallopian tubes and uterus -10 %
 30 % patient with TTE have PMDS
106

 Treatment
 All patient are phenotypic male - orchidopexy
 Vasa deferentia are close proximity to uterus and
proximal vagina > preserve Mullerian structures
107

MRKH
• Cause – WT-4 mutation
• Congenital absence of uterus and vagina
• Karyotype: 46 XX
• Phenotype : Female
- Normal external genitalia
- Normal secondary sexual characteristics
- Shallow vagina
- Normal ovaries and fallopian tubes present but only
symmetrical uterine remnant
108

• Primary amenorrhea – m/c presentation
• Infertility and dyspareunia
• Upper urinary tract anomaly : renal agenesis, pelvic kidney,
horseshoe kidney
 atypical form:
- symmetrical uterine remnant with variable endometrial tissue
development > cyclical abdominal pain > hematometra
- Urinary tract anomaly
109

 Treatment
- Neovagina
- Hemiuterus should be removed
110

EVALUATION AND MANAGEMENT
• Team approach
• GOAL
- Precise diagnosis
- Proper assignment of sex
• Proper family history
• Physical examination for presence of one or two gonads
• Patient with B/L impalpable testis or U/L impalpable testis
with hypospadias regarded as DSD until prove otherwise
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• U/L cryptorchised testis incidence of DSD – 30%
15% - Palpable
50% - impalpable
• B/L UDT and hypospadias – 32%
16% – palpable
47% - impalpable
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• Pelvis US –assessment of Mullerian structures
• Karyotyping
• Hormonal study
 Based on physical examination finding, presence or absence
of Mullerian structures on USG, 17 Hydroxyprogesterone
concentration and karyotype – reasonable DD can be
formulated
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GENDERASSIGNMENT
• Parental consent : essential
 46 XX, Musculinised female > female
 46 XY - issue is more complex and includes factors such as penile
length and androgen insensitivity
1) 46 XY + complete androgen insensitivity > Female
2) 46 XY + 5 a reductase deficiency > male
 45 X/ 46XY- variable phenotype – gender assignment depends on the
functional potential of gonadal tissue, reproductive tract and genitalia
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 PARAMETERS OF OPTIMAL GENDER POLICY
• Reproductive potential
• Good sexual function
• Minimal medical procedure
• an overall gender appropriate appearance
• A stable gender identity
• Psychosocial well being
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THANKYOU
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Development of External Genitalia and Disorders of Sexual Differentiation

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