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
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
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
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
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
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
46.
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
48.
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
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
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
63.
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 mutationmale
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
68.
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
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
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
Sexual differentiation is a very complex process which normally proceeds sequentially through complex genetic and hormonal interactions. According to the Jost paradigm 3 steps must occur: establishment of chromosomal sex at fertilization, which determines development of the undifferentiated gonads into testes or ovaries, and subsequent differentiation of the internal ducts and external genitalia as a result of endocrine functions associated with the type of gonad present.
Now, we’ve known since the 1950’s that the Y chromosome possesses genetic material which determines the destiny of the bipotential gonad.
This is a genetic map of the short arm of the human Y chromosome. SRY is an evoultionarily conserved gene on the Y chromosome of mammals.
In 1991 Koopman and coworkers introduced the Sry gene into XX mouse embryos and demonstrated it was capable of giving rise to testicular development in the transgenic mice. Genetic and molecular data have established that SRY can be equated to the TDF
HMG high mobility group
Primordial germ cells recognized in the 3rd week migrate in 5th week.
In males a second line of primordial cells of steroidogenic mesenchyme…
Testosterone enters androgen target tissue and either binds to androgen receptor in cell nuclei or is converted by 5a-reductase to DHT.
The local source of androgen is important for wolffian duct development, which does not occur if testosterone is supplied only via the peripheral circulation. In some cells like those in the UG sinus, testosterone is converted to dihydrotestosterone intracellular 5a-reductase.
Remember estrogens are not required for normal female differentiation of the reproductive tract but they can interfere with male differentiation.
Differentiation of the wolffian and mullerian duct and UG sinus in male and female.
Schematic diagram of external genitalia in the indifferentiated period.
Before the 8th week of gestation the UG tract is identical ini the two sexes. In the male fetus, sertoli cells produce MIS, which acts locally and unilaterally to suppress the mullerian ducts, and leydig cells produce testosterone, which permits local development of the wolffian structures.
By 10 weeks gestation, degeneration of the mullerian ducts is almost complete in the male and the wolffian ducts have become more prominent. In the female the absence of testosterone regression of wolffian ducts.
Timetable of normal sexual differentiation.
By 12-13 weeks gestation, the genitalia of the male fetus is completed with closure of the elongated UG cleft.
In female in absence of testosterone the external genetalia are maintained at the 6 week gestational age.
A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter's syndrome). The karyotype was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low normal. Note normal virilization with long legs and gynecomastia (B, C). The testes were small and firm and measured 1.8 × 0.9 cm. Testicular biopsy revealed a severe degree of hyalinization of the seminiferous tubules and clumping of Leydig cells. D, A 48-year-old male with 47,XXY Klinefelter's syndrome with severe leg varicosities.
At least one Y and two X to be Klinefelter’s.
ICIS intracytoplasmic sperm injection
Characterized by …
Patients typically present for evaluation of gynecomastia.
Androgen replacement and reduction mamoplasty in selected pts.
Lack of germ cell elements obviates testicular biopsy & ICSI (intracytoplasmic sperm injection)
Rapid attrition rate of oocytes thought due to inadequate protective layer of follicular cells which usually surround the germ cells; streaks typically located in broad ligament.
Both estrogen and androgens are decreased and LH and FSH are increased.
Dx. Frequently made because of amenorrhea.
Y chromosome predisposes to masculinization and gonadoblastoma, therefore timely excision of streaks in Y mosaic is advised.
Human growth hormone between 12-15 yrs, and exogenous hormone therapy to induce puberty and to maintain normal female endocrine status is begun.
Pregnancy is realistic possibility with current assisted reproductive technology.
Phenotypic spectrum with XO/XY extends from females with Turners (25%), to those with ambiguous genetalia, to, rarely those appearing as normal males.
Denys-Drash syndrome nephropathy, HTN, and progressive renal failure.
75% raised male; hypospadius and chordee in about 80%.
Virtually all have UG sinus present and most have uterus present.
2/3 are 46,XX karyotype but 46,XY and mosaics occur less commonly.
Fallopian tubes present on the side of ovary and vas deferens present adjacent to testis.
A 17-year-old true hermaphrodite with bilateral scrotal ovotestes and a 46,XX sex chromosome constitution in cultures of peripheral blood and skin, perineal hypospadias (partially repaired in photograph), moderate bilateral gynecomastia and pubic hair (recently shaved in picture), sparse axillary hair, a high-pitched voice, and absent facial hair. Height was 168 cm. Urinary 17-ketosteroid level was 1.3 mg/day; urinary gonadotropin levels were elevated. A male type of urethra, bilateral scrotal fallopian tubes and ovotestes, and rudimentary bicornuate uterus and vagina attached to the posterior urethra were seen at operation. The photomicrographs show histopathology of the ovarian and testicular portion of one ovotestis. B, Immature seminiferous tubules lined with Sertoli cells and spermatogonia and Leydig cells. C, Ova and follicles. (From Grumbach MM, Barr ML. Cytologic tests of chromosomal sex in relation to sexual anomalies in man. Recent Prog Horm Res 1958; 14:255–334.)
Partial gonadectomy possible in female but stimulate the bHCG post op to ensure all testicular tissue removed.
WNT4 also may be cause
A and B, An untreated girl with the non–salt-losing form of congenital adrenal hyperplasia. Androgens caused disproportionate acceleration of bone maturation compared with stature. C, Virilized adult female with non–salt-losing adrenal hyperplasia. The patient had a deep voice, shaved daily, and wore a toupee for baldness. After treatment with cortisone, her 17-ketosteroid levels fell to normal values, her breasts enlarged, she underwent a normal menarche, and hair regrew on her head. Note short stature and short extremities. D, Female pseudohermaphroditism caused by maternal ingestion of an oral progestational compound from the 8th to 12th week of pregnancy. Labioscrotal fusion is sufficient to obscure the vaginal orifice and create a urogenital sinus. Clitoris is enlarged. There is no progressive virilizing tendency. (C, from Wilkins L. The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 3rd ed. Springfield, IL, Charles C Thomas, 1965.)
Inborn error of metabolism
Inborn error of metabolism
Any of the 5 enzymes that lead to cortisol synthesis can be affected.
Clinically pts are divided into 3 categories
Detection much greater since now screening in newborn period
In female with simple virilization female pseudohermaphroditism results and vagina and urethra open into common UG sinus.
Nonclassic present late with hirsuitsm, oligomenorrhea, male pattern baldness, and polycystic ovaries.
Developed in 1958 but in my experience not used much in clinical practice until recently
Little Hercules testes normal size, but enlargement of penis, scrotum, prostate and appearance of pubic hair, acne and deepening of voice.
Often unrecognized in non-salt-wasting males until signs of androgen excess occur.
Dexamethasone suppresses ACTH
Fertility issue supports feminizing genitoplasty in virtually all 46,XY CAH pts.
Dexamethasone suppresses ACTH
Fertility issue supports feminizing genitoplasty in virtually all 46,XX CAH pts.
The degree to which any …
These are tumors that have resulted in masculinization of female fetus
Elevated LH likely responsible for androgen production clitoromegaly
The syndrome entails the presence of testes that "vanish" during embryogenesis and is distinguished from pure gonadal dysgenesis, in which there is no evidence of testicular function in utero.
Possible etiology genetic mutation, teratogen, bilateral torsion.
At puberty males get androgens and females get estrogen supplementation.
Leydig cell aplasia no mullerian structures
defect in any of the five enzymes required for the conversion of cholesterol to testosterone can cause incomplete (or absent) virilization of the male fetus during embryogenesis
Because testosterone production never significant, brain imprinting not a factor in gender assignment.
Because testosterone production never significant, brain imprinting not a factor in gender assignment.
17 b HO- oxidoreductase defficiency late onset of virilization is related to pubertal increase in gonadotropin production, which may partially overcome the block in testosterone biosynthesis
5 different isoenzyme types identified, type 3…
The late onset of virilization is related to the pubertal increase in gonadotropin production, which may partially overcome the block in testosterone biosynthesis
Because the testes produce estradiol, which results in appropriate female changes, it is considered preferable to leave the testes insitu until puberty is complete.
Partial AI X-linked; classically pts have…
Mildest form Infertile male syndrome infertility in otherwise normal male may be manifestation of PAI.
AR defect, Type II on chromosome 2, expressed in high levels in prostate and external genetalia.
Vas terminate in blind ending vaginal pouch.
A, A prepubertal 46,XY child with 5α-reductase-2 deficiency who was raised as a female. B, A postpubertal male with 5α-reductase-2 deficiency who has virilized and changed gender role behavior. (From Peterson RE, Imperato-McGinley J, Gautier T, et al. Male pseudohermaphroditism due to 5α-steroid deficiency. Am J Med 1977; 62:170–191.)
Presence of one or two gonads on exam rules out female pseudohermaphroditism
Because ovaries do not descend…
Study by Kaefer and associates 1999, studied incidence of intersex in pts with chriptorchidism and hypospadius without ambiguous genitalia.
Karyotype usually takes 2-3 days, but can get rapid analysis with FISH (fouorescent in situ hybridizaiton) few hrs.
Study by Kaefer and associates 1999, studied incidence of intersex in pts with chriptorchidism and hypospadius without ambiguous genitalia.
Karyotype usually takes 2-3 days, but can get rapid analysis with FISH (fouorescent in situ hybridizaiton) few hrs.
Diagnostic algorhythm for newborn with ambiguous genitalia based on gonadal palpability, presence or absence of mullerian structures, 17, hydroxyprogesterone concentration, and karyotype
If no testes check for elevated LH or stimulate with hCG to demonstrate testicular tissue.
High quality data regarding long-term psychosocial outcomes of gender assignment are lacking at this point but longitudinal studies are being persued.
46, XX Normal ovaries, mullerian ducts, and reproductive potential.
46, XY if complete androgen insensitivity then female appropriate gender, whereas 5a-reductase deficiency more appropriately male.
Most frequent abnormal karyotype is 45X/46XY mosaicism variable phenotypic pattern.
Ultimately this is a challenging and humbling process to say the least