DETAIL DESCRIPTION REGARDING DISORDERS OF SEXUAL DEVELOPMENT

1. DR ANKIT GUPTA
MD, PEDIATRICS
KIMS, KARAD

2. CASE SCENARIO
 A 4O week full term baby born via
normal vaginal delivery was examined
Child was normal except child had
hypospadias with bilateral testis in the
inguinal region
Child discharged
 Was the management wrong?

3. Normal Sexual
Differentiation
1. Establishment of chromosomal sex
at fertilization
2. Development of the undifferentiated
gonads into testes or ovaries
3. Differentiation of the internal ducts
and external genitalia

4. Chromosomal Sex
 TDF was mapped to the
most distal aspect of the Y-
unique region of the short
arm of the Y chromosome,
adjacent to the
pseudoautosomal
boundary
 Sry is localized to the
smallest region of the Y
chromosome capable of
inducing testicular
differentiation in humans
and in mice
 Sry appears to be capable
of recognizing specific
sites on DNA, and, by
binding and producing
bending of the DNA, it is
able to activate
downstream gene
expression

5. Other Important Genes
 WT-1 : originally isolated in experiments that identified an
oncogene on chromosome 11 as being involved in the
etiology of Wilms' tumor. Research on WT-1 in the mouse
suggests that it exerts its effects upstream of SRY and is
likely to be necessary for commitment and maintenance of
gonadal tissue
 SF-1: a nuclear receptor, is expressed in all steroidogenic
tissue and appears to be a regulator of müllerian
inhibiting substance (MIS)

6.  SOX-9 gene: identified in patients with
camptomelic dysplasia, a congenital disease of
bone and cartilage formation that is often
associated with XY sex reversal
 SOX-9 HMG-box amino acid sequence has 71%
similarity to that of SRY.
 Expression of the gene in adults is greatest in the testes
and is thought to be involved in gonadal differentiation

7. Other Important Genes
 DSS (DAX-1) (dosage-sensitive sex
reversal). Found in XY females with
duplication of this gene
Suggests duplicated X chromosome causes XY sex
reversal by expressing a double dose of the gene
normally subject to X inactivation. Screening of XY
females with a normal Sry gene detected a
submicroscopic duplication designated DSS
Implicated in adrenal hypoplasia congenita
 WNT4 (factor in ovarian pathway)
 Thought to repress the biosynthesis of gonadal androgen in
female mammals, therefore is suppresses male sexual
differentiation (Hughes, NEJM, 351(8),Aug 19, 2004. 792-798

8. Gonadal Stage of
Differentiation
 During the first 6 weeks of embryonic
development structures are bipotential in both
46,XY and 46,XX embryos
 Migration of the germ cells begins in the 5th week
of gestation through the mesentery to the medial
ventral aspect of the urogenital ridge
 SRY initiates the switch that induces the
indifferent gonad toward testicular organogenesis
In the absence of SRY, ovarian
organogenesis results
 Development of testis
Requires short arm of Y chromosome which
contains SRY gene

9.  Sex can be identified at 8-10 weeks
because of presence of testis around 7
weeks which leads to formation of
external genitilia
 Females
Both long and short arms contains gene for
development of ovaries
R – spondin1 – necessary for development
of ovaries
Other genes are DAX1 and WNT4

10.  Presence of WT1 gene may lead to Denys –
Drash syndrome
 Deletion affecting short arm of X
chromosome may lead to turner syndrome
 Mutation of R-spondin 1 may lead to
testicular development in 46, XX individuals

11.  If X chromosome carries SRY gene
XX males
 If Y chromosome don’t carries SRY
gene
XY females
 Sertoli cells produce Antimullerian
hormone (AMH) that causes female
system to regress

12. DUCTS
 WOLFIAN DUCTS – In presence of
testis testosterone is converted in
dihydrotestosterone.
 Testosterone – wolffian ducts into
seminal vesicles, epididymis and vas
deferens
 Dyhydrotestosterone – required for
development of external genitilia

13.  Mullerian ducts – Sertoli cell of testis
secrete AMH which cause regression of
mullerian ducts
 In absence of testis mullerian ducts
develops into fallopian tube, uterus and
upper third of vagina
 A functional androgen receptor,
produced by an X linked gene, is
required for testosterone and THT to
induce their effects

14.  The differentiation of Sertoli cells is
associated with the production of
AMH (MIS), a glycoprotein encoded
by a gene on the short arm of
chromosome 19
 Primordial cells of steroidogenic
mesenchyme remain among the
testicular cords and represent future
Leydig cells, which differentiate at 8
to 9 weeks

15. Gonadal Function
 The initial endocrine function of the fetal testes is the
secretion of AMH by the Sertoli cells at 7 to 8 weeks'
gestation
 Testosterone secretion by the fetal testes is
detectable shortly after the formation of Leydig cells
in the interstitium at approximately 9 weeks' gestation
 testosterone peaks at 13 weeks and then declines
 testosterone enters target tissues by passive diffusion
 DHT binds to the androgen receptor with greater
affinity and stability than does testosterone
 the gene encoding the androgen receptor has been cloned and
mapped to the X chromosome between the centromere and q13
 Estrogen synthesis is detectable in the female embryo
just after 8 weeks of gestation

16. Undifferentiated Urogenital
Tract
8 wks
10
wks Undifferentiated External genitalia

17. Differentiation Timeline

18. Psychosexual
Differentiation Gender identity: the identification of self
as either male or female
 Gender role: aspects of behavior in which
males and females appear to differ
 Gender orientation: choice of sexual
partner (heterosexual, homosexual, or
bisexual)
 Cognitive differences

19. Disorders of Gonadal
Differentiation and
Development

20. REVISED NOMENCLATURE
PREVIOUS CURRENTLY ACCEPTED
MALE PSEUDOHERMAPHRODITE 46, XY DSD
FEMALE PSEUDOHERMAPHRODITE 46, XX DSD
TRUE HERMAPHRODITE OVOTESTICULAR DSD
XX MALE 46, XX TESTICULAR DSD
XY FEMALE 46, XY COMPLETE
GONADAL DYSGENESIS

21. COMMON DISORDERS
 Congenital adrenal hyperplasia
 Androgen insensitivity syndrome
 Mixed gonadal dysgenesis
 Clitoral/labial anomalies
 Hypogonadotropic hypogonadism
 46 XY SGA males with hypospadias

22. CHROMOSOMAL DISORDERS
 KLINEFELTER SYNDROME
 TURNER SYNDROME
 XX MALENESS
 MIXED GONADAL DYSGENESIS OR
PURE GONADAL DYSGENESIS

23. Klinefelter's syndrome
(Williams Textbook of Endocrinology, 10th
ed, 2003)

24. Seminiferous Tubule Dysgenesis
(Klinefelter's syndrome)
 Syndrome characterized by eunuchoidism, gynecomastia,
azoospermia, increased gonadotropin levels, and small, firm testes,
47,XXY karyotype
 Nondisjunction during meiosis
 1 of 1000 liveborn males
 Associated with 48,XXYY; 49,XXXYY; 48,XXXY; 49,XXXXY; 46,XY/47XXY
 Gynecomastia can be quite marked at pubertal development
 8 X risk for breast carcinoma compared with normal males
 Seminiferous tubules degenerate and are replaced with hyaline
 Fertility, with the benefit of ICSI, has been reported in one patient
 decreased androgens prevents normal secondary sexual development
○ Poor muscle development, the fat distribution is more female than
male.
○ Normal amounts of pubic and axillary hair, but facial hair is sparse.
○ Patients tend to be taller than average, due to disproportionately
long legs

25.  Predisposed to malignant neoplasms of extragonadal germ
cell origin.
 Androgen supplementation to improve libido & reduction
mammoplasty
 surveillance for breast carcinoma

26. 46,XX maleness
 Occurs in 1 of every 20,000 males
 Testicular development in subjects who have two X
chromosomes and lack a normal Y chromosome.
 Most of these subjects have normal male external
genitalia, but 10% have hypospadias and all are infertile
80% are Sry positive and rest are Sry negative
Sry -positive group rarely have genital abnormalities, but they
have phenotypic features of Klinefelter's syndrome
 Shorter (mean height, 168 cm) and have more normal
skeletal proportions than Klinefelter’s patients
 Due to translocation of Y chromosomal material,
including SRY, to the X chromosome
 Infertile  lack of germ cell elements

27. Turner’s Syndrome (45,XO)
 No oocytes remain in the ovaries, which
become streaks
 Fertility = 60% pregnancy rate w/ART
 Ovum donation for those with bilateral
streaks
 1 in 2500 live births
 60% are 45,XO and 40% are mosaics
 Y chromosomal material
masculinization & gonadoblastoma
(30%)
 33% - 60% have structural or
positional abnormalities of the kidney
 horseshoe kidney = 10%,
 duplication or renal agenesis= 20%
 malrotation= 15%
 multiple renal arteries = 90%
 Four classic features:
○ female phenotype
○ short stature
○ lack of secondary sexual characteristics
○ a variety of somatic abnormalities:
Cubitus valgus
Wide spaced nipples
Broad chest (shield)
Webbed neck
Short stature
peripheral edema at birth, short 4th metacarpal,
hypoplastic nails, multiple pigmented nevi,
coarctation of the aorta, and renal anomalies

28. Mixed gonadal dysgenesis
(MGD)
 Characterized by a unilateral testis, often intra-
abdominal
 Contralateral streak gonad
 Persistent müllerian structures with varying inadequate
masculinization
 Most are 45,XO/46,XY, the most common form of Y
chromosome mosaicism
 Second most common cause of ambiguous genitalia after
CAH
 Dysgenetic or streak gonad is associated with ipsilateral
müllerian derivatives (uterus, fallopian tube)
 Well-differentiated testis with functional Sertoli and Leydig
cells will have ipsilateral wolffian but no müllerian ducts
no germ cells so infertility is the rule

29.  Increased risk of developing gonadoblastoma or
dysgerminoma of 15% to 20%
Also increased risk for Wilm’s tumor and
association with Denys-Drash
 Endocrine function of testis is normal post-
pubertally
Fetal testis dysfunction may account for
ambiguous genitalia
 90% to 95% of 45,X/46,XY mosaicism have
normal-appearing male genitalia

30. True Hermaphroditism
46,XX
 Individuals who have
both testicular tissue
with well-developed
seminiferous tubules
and ovarian tissue with
primordial follicles,
which may take the
form of one ovary and
one testis or, more
commonly, one or two
ovotestes.
 External genitalia and
internal duct structures of
true hermaphrodites
display gradations
between male and female
(Williams Textbook of Endocrinology, 10th ed, 2003)

31. True Hermaphroditism
 In most patients, the external genitalia are ambiguous
but masculinized to variable degrees, and 75% are
raised as male
 Internal ductal development are influenced by
ipsilateral gonad
Fallopian tubes are consistently present on the side of
the ovary
a vas deferens is always present adjacent to a testis
Fallopian tube is present with 66% of ovotestes, vas or
both in 33%
Most have urogenital sinus and and uterus

32.  80% of those raised as male have
hypospadias and chordee
 Ovaries usually on left in normal
position, testis usually on right and
located anywhere along path of
descent
 60% of gonads palpable in canal or
labia are ovotestes

33. True Hermaphroditism
 Ovarian portion of the ovotestis is frequently
normal, whereas the testicular portion is typically
dysgenetic
 66% of patients are 46 XX
 Gonadal tumors is approximately 10% in 46,XY
true hermaphroditism and 4% in 46,XX true
hermaphroditism
 Most important aspect of management in true
hermaphroditism is gender assignment
 Sex assignment should be based on the
functional potential of external genitalia, internal
ducts, and gonads, according to the findings at
laparoscopy or laparotomy.

34.  Unlike patients with most other
forms of gonadal dysgenesis, true
hermaphrodites have the potential
for fertility if raised as female with
the appropriate ductal structures
 Males, remove ovaries and/or
ovotestis and mullerian duct
structures consider gonadectomy
 Females remove all testicular and
wolffian structures

35. Female
Pseudohermaphroditism
 46,XX individuals with
ovaries have a partially
masculinized phenotype
and ambiguous genitalia
 CAH is most common
cause
 Uncommon etiologies:
Maternal ingestion of
androgens
Virilizing tumors in the mother
labioscrotal fusion
clitoromegaly
Marked virilization with
hypospadiac-appearing
phallus

36. (Williams Textbook of Endocrinology, 10th ed, 2003)

37. Congenital Adrenal
Hyperplasia Error in cortisol biosynthesis pathway
 The most commonly recognized syndromes result
from a deficiency of one of the terminal two enzymes
of glucocorticoid synthesis (21-hydroxylase or 11-
hydroxylase)
 Formation of hydrocortisone is impaired, causing a
compensatory increase in the secretion ACTH enhances
formation of adrenal steroids proximal to the enzymatic
defect and a secondary increase in the formation of
testosterone, the active androgen in CAH
 21-hydroxylase is responsible for 95% of cases of CAH
 Incidence is 1 in 5,000 to 1 in 15,000 in the United States
and Europe. The highest incidence, 1 in 490, in the
Alaskan Eskimo

38. HORMONE SYNTHESIS

39. CONGENITAL ADRENAL
HYPERPLASIA

40. CAH: 21-Hydroxylase
Deficiency Three categories:
 (1) salt wasters (patients with virilization and aldosterone deficiency),
 (2) simple virilizers (patients with virilization, but without salt
wasting),
 (3) nonclassic patients (those without evidence of virilization or salt
wasting).
 21-hydroxylase gene ( CYP-21 ) is located on chromosome
6p,
 transmitted in an autosomal recessive pattern
 Mutations leading to conversion of the active CYP-21
gene into the inactive gene occur in 65% to 90% of
cases of classic 21-hydroxylase deficiency (i.e., salt
wasting and simple virilizing forms) and in all
nonclassic cases
 Gene deletions are responsible for 10% to 35% of the
remainder of mutations that produce 21-hydroxylase
deficiency
 75% present with salt wasting and 25% with simple
virilization

41. Prader Classification of
Virilization

42. CAH: 21-Hydroxylase
Deficiency Salt-losing variant of CAH  symptoms begin
within the first few weeks after birth, with failure to
regain birth weight, progressive weight loss, and
dehydration
 In severely affected infants, adrenal crises
occur within the first 10 to 21 days of life
 Vomiting is prominent and can be so extreme
that a mistaken diagnosis of pyloric stenosis
is made, particularly in the male.

43.  Death ensues from hyperkalemia,
dehydration, and shock
 Masculinization of the untreated
female; pubic and axillary hair
develop prematurely, acne appears,
and the voice deepens
 Isosexual precocity (2-3 yo) is
hallmark for non-salt wasting males
“little Hercules”

44. CAH: Diagnosis of 21-Hydroxylase
Deficiency
 Plasma levels of progesterone and 17-
hydroxyprogesterone are markedly elevated
 Urinary 17-ketosteroids and pregnanetriol are
elevated.
 The diagnosis may be made biochemically with
the use of radioimmunoassay of plasma 17-
hydroxyprogesterone
Replaced the more cumbersome 24-hour urine collection
of metabolites (e.g., pregnanetriol).
 A pelvic ultrasound study demonstrating the
presence of müllerian tissues is confirmatory.

45. CAH: 3β Hydroxysteroid
Dehydrogenase (3β-HSD) Deficiency
 Affects the early steroid biosynthesis in adrenals and
gonads
inability to convert 3β-hydroxysteroids to 3-ketosteroids
females exhibit mild clitoromegaly and labial fusion with
symptoms of aldosterone and cortisol deficiency
 Autosomal recessive inheritance pattern
 Increased serum levels of 17-
hydroxypregnenolone and
dehydroepiandrosterone (DHEA) are diagnostic
 Treatment is similar to that of patients with 21-
hydroxylase deficiency
 Testosterone in males

47. CAH: 11 β-Hydroxylase
Deficiency Accounts for about 5% of cases
 mutations in the CYP-11B1 gene
 Hypertension is common in patients with this type
of CAH
due to increased serum levels of deoxycorticosterone
(DOC).
 The diagnosis can be confirmed by increased
plasma levels of 11-deoxycortisol and 11-DOC.
 Urinary 17-ketosteroids and 17-hydroxycorticoids
are increased.
 The treatment with glucocorticoid is identical
to that of patients with 21-hydroxylase
deficiency

49. CAH: Treatment
 Early diagnosis could prompt prenatal
treatment to prevent virilization
Prenatal diagnosis is made by amniotic
fluid 17-hydroxyprogesterone
Diagnosed by chorionic villous cells at 8-
10 weeks or amniotic cells at 16-17 weeks.
BUT treatment should be instituted at 5-6
weeks of gestation
Currently, it is not possible to confirm the
diagnosis before therapy is initiated

50.  Treat mother with dexamethasone
which crosses placenta to prevent
virilization
BUT the long-term effects of
dexamethasone on unaffected fetuses
undergoing treatment prenatally remain
unknown

51. CAH: Treatment
 Post-natally, after control of electrolytes and
blood pressure has been achieved in the acute
setting, maintenance therapy with fludrocortisone
and hydrocortisone should be instituted
 Children with the salt-losing form of the disease
require increased salt intake and
mineralocorticoid treatment in addition to
hydrocortisone therapy
 Genitoplasty at 3 to 6 months of age
 Long-term fertility in males and feminization,
menstruation, and fertility in females can be
anticipated in the well-treated patient

52. Female Pseudohermaphroditism:
Maternal Hormones & Tumors
 Androgen or progestational agent affects the female
fetus
 Function of the strength of the agent, its maternal dosage, and
timing and duration of administration
○ Masculinization occurred in 2% of female infants whose mothers were
treated with progestins during pregnancy to prevent abortion (Ishizura et al,
1962 )
 Rarely, maternal ovarian or adrenal tumor has virilizing
effects on a female fetus
○ arrhenoblastoma
○ hilar cell tumor
○ lipoid cell tumor
○ ovarian stromal cell tumor
○ luteoma of pregnancy
○ adrenocortical carcinoma and adenoma
○ Krukenberg's tumor
 Management is confined to external genital reconstruction

53. 46, XY DSD
 46,XY individuals who exhibit varying
degrees of feminization
phenotypically.
Inadequate secretion of testosterone by the
testes at the necessary period in
development
Inability of target tissue to respond to
androgen appropriately
Impaired production or action of MIS
Deletion of short arm of Y chromosome

54. DEFECTS IN TESTICULAR
DIFFRENTIATION
 DENYS DRASH SYNDROME
 WAGR SYNDROME
 XY PURE GONADAL SYNDROME
 XY GONADAL AGENESIS SYNDROME

55. 46,XY Complete Gonadal
Dysgenesis
 SWYER syndrome
 Characterized by :
 normal female genitalia
 well-developed müllerian structures
 bilateral streak gonads
 nonmosaic karyotype
 Ambiguity of genitalia is not an issue
 Sexual infantilism is the primary clinical problem
 present in their teens with delayed puberty
 An abnormality of the Sry gene function, or loss of another
gene downstream from Sry that is necessary for SRY protein
action

56.  LH elevated  clitoromegaly
 30% risk of germ cell tumor development by age 30
years
 gonadoblastoma is most common
 embryonal carcinoma, endodermal sinus tumor,
choriocarcinoma, and immature teratoma have also been
reported
 Management  removal of both streak gonads and
proper cyclic hormone replacement with estrogen
and progesterone

57. Embryonic Testicular Regression and
Bilateral Vanishing Testes Syndromes
 46,XY karyotype and absent testes but clear
evidence of testicular function during
embryogenesis
 Before 8 weeks – Swyer syndrome
 "embryonic testicular regression" = loss of
testicular tissue within the first trimester and is
associated with ambiguity of external genitalia
 "bilateral vanishing testes syndrome" refers to
individuals in whom male sexual differentiation
of ducts and genitalia took place but loss of
testicular tissue occurred subsequently in
utero

58.  Diagnosis can be made on the basis of a 46,XY
karyotype and castrate levels of testosterone despite
persistently elevated serum LH and FSH
 bilateral vanishing testes syndrome, agonadal XY
phenotypic males with fully developed wolffian structures,
but an empty scrotum, absent prostate, and microphallus
 intermediate point presentation is the 46,XY patient with
absent gonads and internal ductal structures but with
ambiguous genitalia  incomplete elaboration of
androgen
 most severe form, agonadism is discovered in a 46,XY
phenotypic female with no internal genital structures; 
the testis has elaborated MIS but vanishes at 60-70 days
before elaboration of androgen

59. Male
Pseudohermaphroditism
 Leydig Cell Aplasia (Luteinizing Hormone Receptor
Abnormality)
 46,XY male karyotype, normal-appearing female phenotype
 Typically, testes are palpable in the inguinal canals or labia
majora
 no rise in testosterone after HCG stimulation
 spectrum  absent Leydig cells to Leydig cells with abnormal
LH receptor
 autosomal recessive trait
 DDx = androgen insensitivity syndrome or a terminal defect in
androgen synthesis.
 testis histology = absent of Leydig cells in intratubular spaces,
normal Sertoli cells

60. Male
Pseudohermaphroditism

61. Male
Pseudohermaphroditism Disorders of Testosterone Biosynthesis
 Defect in any of the five enzymes  incomplete (or absent) virilization of the
male fetus during embryogenesis
 Inheritance is autosomal recessive
 Cholesterol Side Chain Cleavage Deficiency (StAR
Deficiency)
 a defect in cholesterol transport prevents conversion of cholesterol to
pregnenolone
 46,XY individuals have female or ambiguous external genitalia
○ a blind-ending vaginal pouch
○ intra-abdominal, inguinal, or labial testes
○ absence of müllerian structures & Wolffian ducts are present but
rudimentary
○ severe adrenal insufficiency and salt wasting
 suspect this if nonvirilized female external genitalia with:
○ cortisol and aldosterone deficiency
○ hyponatremia, hyperkalemia, and metabolic acidosis.
 Abdominal CT scanning demonstrates large, lipid-laden adrenal
glands

62. Male
Pseudohermaphroditism 3β-Hydroxysteroid Dehydrogenase Deficiency
 incomplete masculinization with salt-wasting  impaired
aldosterone and cortisol synthesis
○ a small phallus, hypospadias with labioscrotal fusion, a
urogenital sinus, and a blind-ending vaginal pouch. Testes
are often scrotal, and wolffian ducts develop normally
 diagnosis: increased levels of 3β-hydroxysteroids (pregnenolone,
17-hydroxypregnenolone, and DHEA)
 17α-Hydroxylase Deficiency
 conversion of pregnenolone and progesterone to 17-
hydroxypregnenolone and 17-hydroxyprogesterone
 impaired cortisol production ACTH hypersecretion 
increased DOC, corticosterone, and 18-hydroxycorticosterone
in the adrenals (check levels)
 These mineralocorticoids  salt and water retention, HTN, and
hypokalemia
 Fertility has not been reported and inadequate testosterone
production makes androgen imprinting a less significant issue
for these patients
○ Phenotype may dictate gender assignment

64. Male
Pseudohermaphroditism 17,20-Lyase Deficiency
 cortisol and ACTH secretion are normal aldosterone normal
 no HTN
 ambiguous rather than totally female genitalia at birth
○ suspect this dx if absent müllerian derivatives and no defect in
glucocorticoid or mineralocorticoid synthesis.
 17β-Hydroxysteroid Oxidoreductase Deficiency
 similar to 5α-reductase deficiency  normal female phenotype,
no significant virilization
 well-differentiated testes located intra-abdominally, inguinally,
or in the labia and no müllerian structures.
 At puberty phallic growth and male secondary sexual
characteristics
○ Androstenedione  increased to 10 to 15x normal
○ type III 17β-hydroxysteroid dehydrogenase isozyme mutationmale
pseudohermaphroditism

65. PERSISTENCE MULLERIAN
DUCT SYNDROME
 Mullerian ducts persist
 Completely virilized males
 Cryptorchidism is present in 80% of
afftected males
 Treatment is removal of mullerian
structures

66. Androgen Receptor & Post-
Receptor Defects
 Most common definable cause of male pseudohermaphroditism
 All are 46,XY karyotype and have testes
 Three classifications exist that describe the spectrum of phenotypes
 Complete androgen insensitivity
 female-appearing external genitalia, and absence of müllerian
derivatives
○ Blind ending vagina, reduced pubic hair
 1 in 20,000 to 1 in 60,000 males
○ 2% of female with hernia  so vaginoscopy prudent
○ X-linked trait, chromosome Xq11–12, point mutation
 unequivocal female gender identity androgen resistance of brain
tissue
○ No reported female  male gender conversion at puberty
 gonadectomy is key  wait until after puberty
○ 2% to 5% risk of seminoma or gonadoblastoma
○ Testis produces estradiol  feminization
○ Girls with inguinal hernia

67. Androgen Receptor & Post-
Receptor Defects
 Partial androgen insensitivity (Reifenstein's
syndrome)
 ambiguity of the external genitalia to varying degrees
○ male with perineoscrotal hypospadias, cryptorchidism, rudimentary Wolffian
duct structures, gynecomastia, and infertility
○ the phenotypic spectrum can range from hypospadias and a pseudovagina to
gynecomastia and azoospermia
 etiology:
○ (1) a reduced number of normally functioning androgen receptors
○ (2) a normal receptor number but decreased binding affinity
 gender assignment is often dictated by phenotype and degree of
virilization
 Infertile male syndrome
 normal male phenotype but are azoospermic or severely oligospermic
 normal to elevated serum testosterone
 normal to elevated LH
 decreased androgen receptor binding to DHT in genital skin fibroblasts

69. Androgen Receptor & Post-
Receptor Defects
 5α-reductase deficiency
 Secondary to mutations in the
type II gene
 Phenotype may vary from
penoscrotal hypospadias to,
more commonly, markedly
ambiguous genitalia
 Elevated mean plasma
testosterone, but low DHT levels
 DHT appears to be critical for the
development of normal external
genitalia in utero
 Testosterone alone appears
sufficient for wolffian duct
development
 Male gender assignment is
generally favored, bearing in
mind that the studies strongly
supporting male gender identity
in this disorder
clitoromegaly with
marked labioscrotal
fusion and small vaginal
introitus
urogenital sinus with
separate urethral and
vaginal openings, and
posterior labioscrotal
fusion

70. (Williams Textbook of Endocrinology, 10th ed, 2003)
55αα-Reductase Deficiency-Reductase Deficiency

71. EVALUATION AND MANAGEMENT OF
THE NEWBORN WITH AMBIGUOUS
GENITALIA
 Medical and psychosocial emergency to be handled with great sensitivity
toward the family
 Goals:
 precise diagnosis of the intersex disorder
 assign a proper sex of rearing based on the diagnosis
 determine the status of the child's anatomy
 delineate the functionality of genitalia and reproductive tract
 Valuable history points:
 infant death
 infertility
 amenorrhea
 hirsutism
 maternal medications (i.e. steroids , OCP), during pregnancy
 Physical examination: the presence of one or two gonads
 Distinctly palpable gonad along the pathway of descent is highly
suggestive of a testis

72. EVALUATION AND MANAGEMENT OF
THE NEWBORN WITH AMBIGUOUS
GENITALIA
 Bilaterally impalpable testes or a unilaterally
impalpable testis and hypospadias should be regarded
as having an intersex disorder until proven otherwise,
whether or not the genitalia appear ambiguous
Unilateral cryptorchid testis and hypospadius,
intersex  30% overall (Kaefer et al, 1999)
○ 15% if the undescended testis was palpable and
50% if it was impalpable
Bilateral undescended testes and hypospadias,
intersexuality 32%
○ only 16% if both gonads were palpable.
○ If one of two undescended testes was impalpable, the
incidence of intersex tripled to 47%, comparable to the rate in
those with a unilateral, impalpable, cryptorchid testis.

73. EVALUATION AND MANAGEMENT OF
THE NEWBORN WITH AMBIGUOUS
GENITALIA
 Posterior urethral meatal position is a strong predictor
of intersex 65%, versus 5% to 8% with a midshaft to
anteriorly located hypospadiac meatus
 Penile size should be assessed and an accurate
measure of stretched penile length recorded.
 Precise means of assessing müllerian anatomy is by
pelvic ultrasound
 Karyotype should be obtained
 Serum studies should be immediately sent to rule out a
salt-wasting form of CAH.
 Serum electrolytes, testosterone and DHT should be
measured early

74. DDx Algorithm

75. Gender Assignment
 Issues related to the diagnosis-specific potential for normal sexual
functioning and fertility and the risk of gonadal malignancy should
be addressed
 In the setting of a 46,XX karyotype, gender assignment is usually
appropriately female
 If the karyotype is 46,XY, the issue is a more complex one and
includes factors such as penile length and evidence of androgen
insensitivity
 The degree of masculinization of the external genitalia appears to vary
with the amount of testicular tissue present
 gender assignment depends on the functional potential of the gonadal tissue,
reproductive tracts, and genitalia

76. PRENATAL MANAGEMENT

77. REVIEW