Download external genitalia -

Prof. M.C.Bansal
MBBS,MS,MICOG,FICOG
Professor OBGY
Ex-Principal & Controller
Jhalawar Medical College & Hospital
Mahatma Gandhi Medical College, Jaipur.
Defining Sex and Gender
Gender identity (Psychological sex)
Inner sense of owns maleness / femaleness.
 Sex of rearing
 Gender role
Sexual identity (Organic sex)
The biologic sexual differentiation
 Chromosomal sex
 Gonadal sex
 Internal genital sex
 External genital sex
 Hormonal sex
Human sexual differentiation
Chromosomal sex
Gonadal sex
Internal genital sex
External genital sex
SEX ASSIGNMENT
Sex of rearing
Gender identity
and role
Gonadal development
SRY-gene (TDF)
Short arm of Y chromosome
Present
Absent
Bipotential
Gonad
Receptors
For H -Y antigen
TESTES
2 X chromosomes
OVARY
Male development
Leydig
cells
Sertoli
cells
Mullerian inhibiting
factor
Testosterone
Wollfian duct
5a-reductase
DHT
Male internal
Genital organs
Urogenital sinus
Regrsession of
Muuleian ducts
Male external genitalia
Female development
Neutral
Development
Urogenital sinus
Female external genitalia
. Lower part of vagina
Absence of androgen exposure
Mullerian ducts
Female internal genital
Organs
. Most of upper vagina
. Cervix and uterus
. Fallopian tubes
Summary of Normal Sex
Differentiation





genetic sex is determined at fertilization.
testes develop in XY fetus, ovaries develop in XX
fetus.
XY fetus produces MIS and androgens and XX fetus
does not.
XY fetus develops Wolffian ducts and XX fetus
develops Mullerian ducts.
XY fetus masculinizes the female genitalia to make it
male and the XX fetus retains female genitalia.
INTERSEX
An individual in whom there is discordance between
chromosomal, gonadal, internal genital, and
phenotypic sex or the sex of rearing

INTERSEXUALITY:
Discordance between any two of the organic sex
criteria
 TRANSSEXUALITY:
Discordance between organic sex and psychological
sex components
CLASSIFICATION OF INTERSEXUALITY
Disorders of fetal Endocrinology
CLASSIFICATION OF INTERSEXUALITY
Primary gonadal defect – Swyer syndrome
How many children are born with
intersex conditions?

A conservative estimate is that 1 in 2000 children
born will be affected by an intersex condition

98 % of affected babies are due to congenital
adrenal hyperplasia
FEMALE
PSEUDOHERMAPHRODITISM
EXCESS FETAL
ANDROGENS
Congenital adrenal hyperplasia
 21 -hydrxylase deficiency
 11-hydroxylase deficiency
 3ß-hydroxysteroid
dehydrogenase deficiency
EXCESS MATERNAL
ANDROGENS

Maternal androgen secreting
tumors (ovary, adrenal)
 Maternal ingestion of
androgenic drugs
Congenital Adrenal Hyperplasia
 It is a familial disorder of adrenal steroid
biosynthesis with autosomal recessive mode of
inheritance.
 The defect is expressed as adrenal enzyme
deficiency.
 5 major Enzymes deficiency are clinically
important
 21-Hydroxylase
 11-b-Hydroxylase
 17-a-Hydroxylase
 3-b-Hsteroid hydrogenese
 20,22 Desmolase deficiency
CAH
 The
most frequent is steroid 21hydroxylase deficiency, accounting for
more than 90 percent of cases.
 The enzyme deficiency causes reduction
in end-products, accumulation of
hormone precursors & increased ACTH
production.
The clinical picture reflects the effects of
inadequate production of cortisol &
aldosterone and the increased production
of androgens & steroid metabolites.
Biochemistry

Steroid 21-hydroxylase (CYP21, also termed
CYP21A2 and P450c21) is a cytochrome P-450
enzyme located in the endoplasmic reticulum.

It catalyzes the conversion of 17hydroxyprogesterone to 11-deoxycortisol, a
precursor of cortisol, and the conversion of
progesterone to deoxycorticosterone, a precursor
of aldosterone.

Owing to this loss of enzyme function, patients
with 21-hydroxylase deficiency cannot synthesize
cortisol efficiently, and as a result, the adrenal
cortex is stimulated by corticotropin and
overproduces cortisol precursors.
Contd…

Cortisol is an adrenal steroid hormone that
is required for normal endocrine function.
Production begins in the second month of
fetal life. Poor cortisol production is a
hallmark of most forms of CAH. Inefficient
cortisol production results in rising levels of
ACTH, which in turn induces overgrowth
(hyperplasia) and overactivity of the
steroid-producing cells of the adrenal
cortex. The defects causing adrenal
hyperplasia are congenital (i.e., present at
birth)
Contd…

Some of these precursors are diverted to the
biosynthesis of sex hormones, which may
cause signs of androgen excess, including
ambiguous genitalia in newborn girls and
rapid postnatal growth in both sexes.

Concomitant aldosterone deficiency may
lead to salt wasting with consequent failure
to thrive, hypovolemia, and shock.
21-hydrxylase deficiency
congenital adrenal hyperplasia
Cholesterol
Pregnenolone
Progesterone
17-OH progesterone
Pituitary
ACTH
Adrenal cortex
21-hydroxylase
Cortisol
Androgens
Cortisol

Androgens
21-hydrxylase deficiency
congenital adrenal hyperplasia
Most common type, accounts for >80% of
cases.
Incidence is 1:5000 to 1:15000 live birth.
Gene is located on the short arm of
chromosome 6 near the C4 locus in close
association with HLA genes.
Heterozygous carriers can be detected by
ACTH stimulation test.
Contd..
It is characterized by reduced production
of cortisol and aldosterone and increased
production of progesterone;
17-OH-progesterone, and sex steroids.
The urinary steroid metabolites
(17-ketosteroids and pregnanetriol) are
elevated above normal levels.
Contd..
Decreased secretion of aldosterone results in
salt loss with hyponatremia and
hyperkalemia; plasma renin activity is
therefore elevated.
In partial enzyme deficiencies, the
aldosterone deficiency is not expressed, and
patients remain normonatremic and
normokalemic.
The excess androgens causes virilization of
girls & ambiguous genitalia & dark scrotum
in boys.
Contd…
There are 3 forms:
1. classic early virilization type with or
without salt-losing crisis(typically identified
at birth because of genital ambiguity)
2.Salt wasting (in which there is
impairment of mineralocorticoid as well as
glucocorticoid secretion),
3. non-classic type with late-onset
virilization(in which heterosexual
development occurs at the expected age of
puberty).
Contd…
Male babies with non salt-losing nonclassic type remains asymptomatic till
late childhood when they may show signs
of sexual precocity.
Because members of the same family may
have classic, non-classic & asymptomatic
forms, the disorder may be due to allelic
variations of the same enzyme.
Mass neonatal screening using filter
paper blood sample for 17-OHProgesterone is used in the USA.
CLINICAL MANIFESTATIONS
1. In classic form(girls are born with ambiguous genitalia)
having
 enlarged clitoris
 fusion of the labioscrotal folds and the urogenital sinus.
 The internal female organs (including the uterus,
fallopian tubes, and ovaries) develop normally because
they are not affected by the increased androgen levels.
 early pubic hair and rapid growth in childhood precocious
puberty or failure of puberty to occur (sexual infantilism:
absent or delayed puberty)
 excessive facial hair
 Virilization
 menstrual irregularity in adolescence
 infertility due to anovulation
 shallow vagina
clitoromegaly
labioscrotal fusion
Marked virilization with
hypospadiac-appearing phallus
2. In salt wasting 21hydroxylase deficiency
hyponatremia
hyperkalemia
hypotension
CLASSICAL CAH
Contd…
 During childhood, untreated girls with either the
classic or salt wasting form grow rapidly but have
advanced bone ages, enter puberty early, experience
early closure of their epiphyses, and ultimately are
short in stature as adults. CAH, with appropriate
therapy, is the only inherited disorder of sexual
differentiation in which normal pregnancy and
childbearing are possible.

Boys :
-no overt signs of the disease
except variable and subtle hyperpigmentation
and penile en-largement
BOYS WITH CAH
 Are unrecognized at birth because their genitalia are
normal.
 They are not diagnosed until later, often with a salt
wasting crisis resulting in dehydration, hypotension,
hyponatremia and hyperkalemia or later in childhood
with early pubic hair & phallic enlargement
accompanied by accelerated linear growth and
advancement of skeletal maturation.
 High blood pressure & hypokalemia may occur in
those with 11-b-hydroxylase deficiency and 17-ahydroxylase deficiency due to the accumulation of the
mineralocorticoid desoxycorticosterone
(Williams Textbook of Endocrinology, 10th ed, 2003)
11-hydroxylase (P450c11) deficiency
 Accounts for 5-10% of cases of CAH.
 Gene is located on the long arm of chromosome 8.
 caused by mutations in the CYP11B1 gene.
 It is characterized by low plasma renin activity &
elevation of serum 11-Deoxycortisol and 11deoxycorticosterone.
 Because of the strong mineralocorticoid activity of
deoxycorticosterone, the condition is characterized by
salt retention, hypertension & hypokalemic alkalosis.
 The elevated plasma androgens may cause virilization
of the female fetus.
3ß-hydroxysteroid dehydrogenase deficiency







This is a very rare disorder that results in accumulation of DHEA,
which is converted to testosterone in peripheral tissues.
Enzyme defects in adrenal and ovary in autosomal –recessive fashion
Caused by mutations in the HSD3B2 gene encoding the 3ß-HSDII
enzyme affects the synthesis of glucocorticoids, mineralocorticoids, and
sex steroids.
Cortisol ↓ & aldosterone ↓
Dehydroepiandrosterone ↑↑  the external genitalia ambiguity
It can cause virilization of female fetus and leads to ambiguous genitalia
in the newborn.
A diagnosis based on baseline and ACTH-stimulated changes in
steroid levels is not accurate ; indeed, in adult women, an apparent lateonset 3ß-hydroxysteroid dehydrogenase deficiency is almost always, if
not always, a secondary response to anovulation and polycystic ovaries,
accompanied by hyperinsulinemia
17-hydroxylase deficiency
 Genetic defect is on chromosome 10.
 Corticosterone, 11-deoxycorticosterone ↑
 Presents with similar features of those of 11-Hydroxylase
deficiency except that Androgens are low, so no
virilization in girls & genitalia is ambiguous in boys.
 Hypertension (due to hypernatremia and hypervolemia),
hypokalemia
 Infantile female external genitalia & primary amenorrhea
ESSENTIALS OF DIAGNOSIS
 Increased linear growth with advanced bone age and
eventual short stature
 Pseudohermaphorditism in girls due to androgen
virilizing effect
 Isosexual precocity in boys with small infantile testes.
 Adrenal crisis with salt-loss & metabolic acidosis or
Hypertension & hypokalemic alkalosis.
 Low cortisol with high androgens, ACTH and steroid
precursors e.g. 17-OH-Progest. or 11-Deoxycortisol.
 Diagnosis is confirmed by measurement of ACTH,
Cortisol, Aldosterone, 17-OH-progesterone,
Testosterone & urinary 17-ketosteroids.
 Needs alertness for the possibility in all babies with
Diarrhea & Vomiting, hypoglycemia or  BP.
Diagnosis


Classic 21-hydroxylase deficiency is characterized by
markedly elevated serum levels of 17hydroxyprogesterone, the main substrate for the enzyme.
The gold standard for differentiating 21-hydroxylase
deficiency from other steroidogenic enzyme defects is the
corticotropin (cosyntropin) stimulation test,measuring
base-line and stimulated levels of 17-hydroxyprogesterone.
corticotropin (cosyntropin) stimulation test :
The most commonly used stimulatory test involves
measurement of 17-hydroxyprogesterone 30 minutes after
administration of a bolus of 250 mg of synthetic
cosyntropin (Cortrosyn).
Contd…
In normal women - this value seldom exceeds 400 ng/dL.
Patients with classic 21-hydroxylase deficiency - achieve peak levels of
3,000 ng/dL or higher.
Patients with nonclassic 21-hydroxylase deficiency-achieve levels of 1,500
ng/dL or more.
Heterozygous carriers
- achieve peak levels up to
about 1,000 ng/dL.
In hirsute women with hypertension, 11-deoxycortisol levels can be
determined during the test. If both 11-deoxycortisol and 17hydroxyprogesterone levels are increased, the rare 11-hydroxylase
deficiency is present. Only measurements of several steroid precursors
after corticotropin stimulation can identify individuals with nonclassic
forms of 3-HSD deficiency.
The elevated levels of 17-hydroxyprogesterone present in all forms of 21hydroxylase deficiency are rapidly suppressed by administration of
exogenous corticoids. Even a single dose of a glucocorticoid such as
dexamethasone will suppress 17-hydroxyprogesterone in CAH but not
in virilizing ovarian and adrenal neoplasms.
CONGENITAL ADRENAL HYPERPLASIA - Diagnosis

Normal infant :100ng/dl (17 -hydroxyprogesterone)

Affected infants : 3,000 - 40,000ng/dl ↑

The severity of hormonal abnormalities
: depends on the type of 21-hydroxylase def

Salt wasting : 17-hydroxyprogesterone: 100000ng/dl

In adult , random 17-hydroxyprogesterone (17-OHP)
: baseline - 200ng/dl ↓

Levels greater 200ng/dl, but less than 800 ng/dl
-> Corticotropin stimulation test
Lab Findings

Demonstration of inadequate production of cortisol and/or
aldosterone in the presence of accumulation of excess
concentrations of precursor hormones is diagnostic.

In 21-hydroxylase deficiency, very high serum 17hydroxyprogesterone is characteristic together with very high
urinary pregnanetriol (metabolite of 17-hydroxyprogesterone).

Both are accompanied by elevated 24-hour urinary 17ketosteroids, the urinary metabolites of adrenal androgens.
Other tests
 Salt wasting forms of adrenal hyperplasia are
accompanied by low serum aldosterone, hyponatremia,
hyperkalemia and elevated plasma renin activity
indicating hypovolemia.
In contrast hypertensive forms of adrenal hyperplasia
(11-b-hydroxylase deficiency and 17-a-hydroxylase
deficiency) are associated with suppressed plasma renin
activity and hypokalemia
 A karyotype
is essential in the evaluation of the infant with
ambiguous genitalia in order to establish the
chromosomal sex.

 Prenatal diagnosis of adrenal hyperplasia is possible
through biochemical and genetic tests.
Imaging Studies




A pelvic ultrasound: in the infant with
ambiguous genitalia to demonstrate the
presence or absence of a uterus or associated
renal anomalies
A urogenitogram is often helpful to define the
anatomy of the internal genitalia.
A CT scan of the adrenal gland to R/O bilateral
adrenal hemorrhage in the patient with signs
of acute adrenal failure
A bone age study is useful in the evaluation of
the child who develops precocious pubic hair,
clitoromegaly, or accelerated linear growth.
CONGENITAL ADRENAL HYPERPLASIA – Management
GOALS

According to the clinical course & hormonal level

Purpose
: Normal growth, B.Wt, pubertal development, optimal
adult height

Growth velocity, body Wt velocity, bone age maturation

Classic 21-OH def
-> glucocorticoid : adrenal androgen secretion ↓
-> mineralocorticoid : electrolytes & plasma renin activity
MODE OF TREATMENT
Steroid replacement
 Supportive therapy when needed
 Treatment is life-long
 Plastic surgery for ambiguous genitalia at early
age
 Genetic counseling
 Psychological support

Treatment(1)-Glucocorticoids

Patients with classic 21-hydroxylase deficiency
require long-term glucocorticoid treatment to
inhibit excessive secretion of corticotropinreleasing hormone and corticotropin by the
hypothalamus and pituitary, respectively, and to
reduce elevated levels of adrenal sex steroids.
 In children, the preferred drug is hydrocortisone
(i.e., cortisol itself ) in maintenance doses of 10 to
20 mg per square meter of body-surface area per
day in three divided doses.
Treatment(2)-Glucocorticoids

Doses of up to 100 mg per square meter per day
are given during adrenal crises and life-threatening
situations.
 Even these maintenance doses exceed physiologic
cortisol secretion (7 to 9 mg per square meter per
day in neonates and 6 to 8 mg per square meter
per day in children and adolescents).
 The efficacy of treatment is best monitored by
measuring 17-hydroxyprogesterone and
androstenedione levels at a consistent time in
relation to the administration of medication.
Treatment(3)-Glucocorticoids

The therapeutic goal is to use the lowest dose of
glucocorticoid that adequately suppresses adrenal
androgens and maintains normal growth and
weight gain.
 Children should also undergo radiography
annually to determine bone age, and their linear
growth should be carefully monitored.
 Older adolescents and adults may be treated with
prednisone (e.g., 5 to 7.5 mg daily in two divided
doses) or dexamethasone (total, 0.25 to 0.5 mg
given in one or two doses per day).
Treatment(1)-Mineralocorticois

Infants with the salt-wasting form of 21hydroxylase deficiency require supplemental
mineralocorticoid (usually 0.1 to 0.2 mg of
fludrocortisone daily) and sodium chloride (1 to 2
g or 17 to 34 mmol of sodium chloride chloride
daily in addition to glucocorticoid treatment).
 Older infants and children usually do not require
sodium chloride supplements, and they often have
reduced requirements for fludrocortisone.
Treatment(2)-Mineralocorticoids

Plasma renin activity levels or direct renin
immunoassays may be used to monitor the
adequacy of mineralocorticoid and sodium
replacement, taking into account the age-specific
reference ranges for each laboratory.
 Hypotension, hyperkalemia, and elevated renin
levels suggest the need for an increase in the dose,
whereas hypertension, edema, tachycardia, and
suppressed plasma renin activity signify
overtreatment with mineralocorticoids.
NEW TRENDS OF T/T
A New approach therapy is the
combined use of 4 drugs:

glucocorticoid (to suppress ACTH and adrenal
androgen production),

mineralocorticoid (to reduce angiotensin II
concentrations),

aromatase inhibitor (to slow skeletal
maturation),

flutamide (an androgen blocker to reduce
virilization)
Management of Ambiguous
Genitalia

Improvements in the surgical correction of genital
anomalies over the past two decades have led to
earlier use of single-stage surgery — between two
and six months of life in girls with 21-hydroxylase
deficiency, a time when the tissues are maximally
pliable and psychological trauma to the child is
minimized.
 The long-term outcomes of the newer surgical
procedures have yet to be evaluated.
SURGICAL T/T
 Infants with CAH may require surgical
evaluation and, if needed, corrective surgery.
 Traditional approach is clitroplasty early in life,
followed by vaginoplasty after puberty.
 Some female infants with adrenal hyperplasia
are only mildly virilized and may not require
corrective surgery if they receive adequate
medical therapy to prevent further virilization.
Prenatal diagnosis and t/t
 Done by chorionic villus sampling at 8-12 wk &
amniocentesis at 18-20 wk.
 HLA typing in combination with measurement of 17OH-progesterone & androstenedion in amniotic fluid is
used for antenatal diagnosis.
 Prenatal treatment of 21-hydroxylase deficiency
prevents intrauterine virilization of female fetuses.
 According to the protocol proposed by Carlson et al,
the mother is treated with dexamethasone (20 m/kg/d
in 3 divided doses) as soon as the pregnancy is
recognized to suppress fetal ACTH secretion & prevent
the fetal adrenal gland from overproducing adrenal
androgens.
Incompletely Masculized Males
Male pseudohermaphroditism
(XY- FEMALE)
Failure to utilize
testosterone
 Androgen receptor
deficiency
* Complete androgen
Insensitivity (TFS)
* Incomplete androgen
Insensitivity
 5-alpha reductase deficiency
Failure to produce
testosterone
 Defects in testicular
steroidogenesis
 Gonadotropin-resistant
testes (LH receptor mutation)
 Congenital lipoid adrenal
hyperplasia
 Defective synthesis,
secretion, or response to
anti-mullerian hormone
What is AIS?

A genetic condition where affected people have male chromosomes &
male gonads with complete or partial feminization of the ext. genitals

An inherited X-linked recessive disease with a mutation in the
Androgen Receptor (AR) gene resulting in:
–
–

Functioning Y sex chromosome
Abnormality on X sex chromosome
Types
1.
CAIS (completely insensitive to AR gene)
-External female genitalia
-Lacking female internal organs
2.
PAIS (partially sensitive-varying degrees)
-External genitalia appearance on a spectrum (male to female)
MAIS (mildly sensitive, rare)
-Impaired sperm development and/or impaired masculinization
Also called Testicular Feminization
3.
Normal Sexual Development
MALE
Sex Chromosome = XY
Gonads = Testes
External Genitalia = Male
FEMALE
Sex Chromosome = XX
Gonads = Ovaries
External Genitalia = Female
Normally chromosome sex determines gonad sex which determines
phenotypic sex
WHAT HAPPENS IN AIS?
Androgen Receptor Gene

AIS results from mutations in the androgen receptor gene, located
on the long arm of the X chromosome (Xq11-q12)

The AR gene provides instructions to make the protein called
androgen receptor, which allows cells to respond to androgens,
such as testosterone, and directs male sexual development

Androgens also regulate hair growth and sex drive

Mutations include complete or partial gene deletions, point
mutations and small insertions or deletions
The Process of Sexual Development

In AIS the chromosome sex and gonad sex do not agree with the
phenotypic sex

Phenotypic sex results from secretions of hormones from the
testicles

The two main hormones secreted from the testicles are
testosterone & mullerian duct inhibitor
– Testosterone is converted into dyhydrotestosterone
– Mullerian duct inhibitor suppresses the mullerian ducts &
prevents the development of internal female sex organs in
males

Wolffian ducts help develop the rest of the internal male
reproductive system and suppress the Mullerian ducts
– Defective androgen receptors cause the wolffian ducts &
genitals
to be unable to respond to the androgens
testosterone & DHT
AIS Fetus Development
• Each fetus has non-specific genitalia for the first 8 weeks
after conception
• When a Y-bearing sperm fertilizes an egg an XY embryo
is produced and the male reproductive system begins to
develop
• Normally the testes will develop first and the Mullerian
ducts will be suppressed and testosterone will be
produced
• Due to the inefficient AR gene cells do not respond to
testosterone and female genitalia begin to form
 The amount of external feminization depends on the
severity of the androgen receptor defect
 CAIS: complete female external genitalia
 PAIS: partial female external genitalia
 MAIS: Mild female external genitalia, essentially
male
46-XY/SRY
TESTIS  MIF
Testicular feminization
syndrome
Testosterone
5--reductase
DHT
Absent androgen
receptors
Female
External
Genitalia
Male
Internal
Genitalia
Incomplete form  Ambiguous genitalia
Complete Androgen Insensitivity
Testicular
Feminization SD (female phenotype)
– female-appearing external genitalia, and absence of müllerian derivatives
 Blind ending vagina, reduced pubic hair
1
in 20-60,000 males, X-linked trait
In
utero loss of androgen, & MIS secretion means loss of
internal genitalia
2%
of males with an inguinal hernia have Complete androgen
sensitivity so vaginoscopy pruden
Usually
diagnosed amenorrhea, absence of pubic hair or
hormonal profile
Gonadectomy
and Oestrogen replacement therapy
Incomplete Androgen Insensitivity
(Reifenstein’s Syndrome)

Incomplete male pseudohermaphroditism
Ambiguous 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
 Normal testosterone, LH and testosterone/DHT ratio
All intermediate type of androgen insensitivity
 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
Testing for AIS

Tests
– During Pregnancy
 Chorionic Villus Sampling (9-12 weeks)
 Ultrasound and Amniocentesis (after 16 weeks)
– After Birth
 Presence of XY Chromosomes
– Buccal Mouth Smear
– Blood Test
 Pelvic Ultrasound
 Histological Examination of Testes
Biochemical Testing for
Carriers

Tests
– 1960-70s: Skin biopsies-evaluate androgen binding
capacity
 Carries: 50% androgen binding
 Problem: some cases skipped because mutation did
not always take place in the binding region of the
gene
– 1990s: DNA Testing
 blood or mouth cavity smears
– Now:
 Measure length of base pair repeat region in first
exon of gene and compare it to a female relative’s
repeat region to determine if they are a carrier
Non-Biochemical Testing


Maternal relatives affected by AIS
In an XX female
– Delayed puberty
– Reduced pubic-auxiliary hair
– Asymmetric pubic-auxiliary hair
– Reduced bone density
Treatments


Surgery
– Orchidectomy or gonadectomy
 Removal of the testes
– Vaginal lengthening
– Genital plastic surgery
 Reconstructive surgery on the female genitalia if
masculinization occurs
 Phalloplasty
 Vaginoplasty
– Pressure dilation
 Clitorectomy
Debate
– What age?
– Who decides?
Treatments

Hormone Replacement Therapy (HRT)
– Types
Female: Estrogen
– Progesterone (sometimes take to reduce risk of
breast or uterine cancer)
– postorchidectomy
 Male: Testosterone and DHT
– Form
 Oral, transdermal, implant, injection, vaginally
– Prevents osteoporosis (age 10 or 11)
 Body responds as if it is post-menopausal, thus body
density decreases and osteoporosis occurs

The Androgen Insensitivity Syndromes
5α-redutase
Complete
Incomplete
Reifenstein
Infertile
Inheritance
Autosomal
recessive
X-linked
recessive
X-linked
recessive
X-linked
recessive
X-linked
recessive
Spermatogenesis
Decreased
Absent
Absent
Absent
Decreased
Mullerian
Absent
Absent
Absent
Absent
Absent
Wolffian
Male
Absent
Male
Male
Male
External
Female
Female
Female
Clitomegaly
Male
Hypospadia
Male
Breasts
Male
Female
Female
Gynecomastia Gynecomastia
5-alpha reductase deficiency

Secondary to mutations in the type II gene

Phenotype may vary from penoscrotal hypospadias to, more commonly,
markedly ambiguous genitalia

Normal internal genitalia
: testes secrete T, MIH causes Mullerian ducts to degenerate

Lack of DHT leads to inadequate masculinization of external genitalia at birth
– Testes in labia or inguinal canal
– Urogenital sinus: urethra & blind vagina
– Prostate gland: small or absent

At puberty, lots of T
 testes descend, scrotum darkens, phallus enlarges, muscular &
deep voice
46-XY/SRY
Testis  MIF
5-alpha-reductase
deficiency
Testosterone
5--rductase
DHT
Female or
Ambiguous
external Genitalia
Male Internal
Genitalia
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
Testosterone Biosynthesis

5 enzymes involved in the conversion of cholesterol to
testosterone
–3 in the adrenal & testis
–2 in the testis only
Cholesterol side change cleavage
3β OH steroid Dehydrogenase
17α Hydroxylase
17,20 Lyase Deficiency
17β OH steroid Dehydrogenase
Testicular enzymatic
failure
46-XY/SRY
Testis  MIF
(defects in testosterone
Synthesis)
 testosterone precursors
DHT
Ambiguous
External
Genitalia
Male
Internal
Genitalia
Autosomal recessive enzyme
deficiency :
-20-22 desmolase
-3-ß-ol-dehydrogenase
-17-  -hydroxylase
-17,20-desmolase
-17-ß –OH steroid dehydrogenase
Leydig Cell hypoplasia /LH receptor mutation
-46,XY male karyotype, normal-appearing female phenotype
– Palpable testes but ↑LH and ↓Testosterone
– No stimulation of testosterone with HCG
–spectrum  absent Leydig cells to Leydig cells with abnormal LH receptor
–autosomal recessive trait
– No Mullerian structures / short vagina
–DDx = androgen insensitivity syndrome or a terminal defect in androgen
synthesis.
–Testis histology = absent of Leydig cells in intratubular spaces, normal Sertoli
cells
46-XY/SRY
Leydig-cell agenesis
TESTIS  MIF
( partial/ complete absence
Of leydig-cells)
No or  testosterone
No or  DHT
Female or
ambiguous
external
Genitalia
± Male
Internal
Genitalia
Hernia Uterine Inguinale
(persistant mullerian structures)






Normal phallus, uterus and tubes in the inguinal hernia sac
Poor sperm and hormone production
Gonad cancer risk
Can be familial
Presumed failure of AMH function
Fertility – rarely preserved
Diagnosis of XY Female
Testosterone concentration
Low
Normal
Male level
Concentration of
Testosterone precurcers
High
Testicular
enzyme
Failure
Low
Absent testes or
Absent leydig-cell
Surgical exploration
DHT
Low
5 -reductase
Deficiency
Normal
Testicular
Feminization
Syndrome
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
Predisposed to malignant neoplasms of extragonadal germ cell origin.
Androgen supplementation to improve libido & reduction mammoplasty
– surveillance for breast carcinoma
Klinefelter's syndrome
(Williams Textbook of Endocrinology, 10th ed, 2003)
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
Disorders of Gonadal Development
Gonadal Dysgenesis
Features:
1. Female Phenotype
2. Short Stature
3. No Secondary Sexual
Characteristics
4. Somatic Abnormalities
Occult Y Ch. Material:
- Webbed Neck
Predisposed to Virilisation
- Broad Chest
and Gonadoblastoma (30%)
- Short Ring finger
and other GCT (50%).
Turners Syndrome (45 X0)
–Presence of one functioning X Chromosome
–1 in 2500 females. Mosaicism 45 X/46 XX (10%) or 45 X/46 XY (3%)
–Oocytes degenerate leaving streak gonads (in broad lig.) at birth
–Reduced Oestrogen, Raised FSH/LH. No pubertal development
–Management includes:

Growth Hormone to Children & estrogens at puberty

Up to one third may have functioning ovaries
Renal Anomalies:
90% Multiple Renal Arteries
20% Renal agenesis/Duplication
15% Malrotation
10% Horseshoe kidney
- so pregnancy is possible

Remove Streak gonads in Mosaic patients
Alternative Names:Bonnevie-Ullrich syndrome; Gonadal dysgenesis;
Monosomy X

Symptoms
Turner syndrome
Karyotype 45,X (60%)
(45,X/46,XX, structural abnormalities of X chromosome)
Short stature (final height 142-147 cm)
Gonadal dysgenesis - streak gonad & sexual infantilism
Skletal abnormalities & dysmorphic face
Cardiac and kidney malformation
Autoimmune ds : Hashimoto’s thyroditis, Addison’s ds
Mild insulin resistance & hearing loss
Lymphedema
Essential hypertension
No mental defect
Impairment of cognitive function : mathematical ability↓
Visual–motor coordination, spatial-temporal processing↓
H. Tuner, 1938
Turner syndrome – work up






IVP or renal USG
Echocardiography
Audiometry
Lipid profile & glucose metabolism (annually)
Annual pelvic examination & appropriate screening for
gonadal neoplasm as an adnexal mass
Expert consultation to pursue further analysis with Xand Y- specific DNA probes
Pure Gonadal Dysgenesis

All subjects with female genitalia, normal mullerian structure &
streak gonads ( with either 46,XX or 46,XY karyotypes)

None of Turner phenotype anomalies
Gonadal dysgenesis
(Williams Textbook of Endocrinology, 10th ed, 2003)
46,XX pure gonadal dysgenesis

Features:
– normal female external genitalia
– normal müllerian ducts with absence of wolffian duct
–
–
–
–


structures
a normal height
bilateral streak gonads
sexual infantilism
normal 46,XX karyotype
streak gonads elevated serum gonadotropins
Management of 46,XX "pure" gonadal dysgenesis:
– cyclic hormone replacement with estrogen and progesterone.
– growth is basically normal so GH is not needed

possibly autosomal recessive trait
46,XY Complete Gonadal
Dysgenesis

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
 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
Gonadal Dysgenesis

Multiple X female (47,XXX)
– Normal development & reproductive
function
– Mental retardation- frequent
– Secondary amenorrhea & eunuchoidism
Mixed Gonadal Dysgenesis
–Mosaicism: 45 XO/ 46 XY
–Second most common cause for Ambiguous
genitalia
–Mostly phenotypic females, but entire spectrum
covered
–Due to lack of MIS production in unilateral
dysgenetic
testis with ipsilateral fallopian tube
–Management includes Gender assignment (2/3
female),
Appropriate gonadectomy & screen for Wilm’s
tumor
Features:
Unilateral testis (undescended)
Contralateral Streak Gonad
Persistent Mullerian Structures
Some masculinisation
Mostly females with;
Enlarged phallus
Labioscrotal folds
Uterus /vagina & tubes
Increased risk of:
Gonadoblastoma (20%)
- testis > streak gonad
Wilm’s tumor
Denys-Drash Syndrome
- Nephropathy /CRF
- Genital Abnormalities
- Wilms tumour
- XX/XY mosaicism
May need prophylactic
bilateral nephrectomy
Mixed Gonadal Dysgenesis






Karyotype 46XY / 45X0
Combined features of Turner’s SD
& male pseudohermaphroditism
Short stature
Streak gonad on one side with a
testis on the other side
Unicornuate uterus & fallopian tubeside of streak gonad
Considrable variation in the sexual
phenotype
Gonadal Dysgenesis
Surgical Removal of Gonadal Tissue

The gonadal tissue having any Y chromosome
component in phenotypic females  removal as soon as
the diagnosis is made to avoid the risk of malignant
gonadal tumor
(except complete androgen insensitivity)
: Laparoscopy or laparotomy

The uterus and tubes should be preserved for the
possibility of pregnancy with donor oocytes
Gonadal Dysgenesis
Hormone Treatment of Patients
Without Ovaries

Starting when the bone age is 12 with unopposed
estrogen ( 0.3mg conjugated estrogens or 0.5mg
estradiol daily)

After 2 years , a sequential program is initiated with
0.625mg conjugated estrogens or 1.0mg conjugated
estrogens
+ 5mg medroxyprogesterone acetate for 14days
(if a uterus is present)

In patients with genetic shortness in stature (e.g.
Turner SD)
 Estrogens treatment is not started
until bone age is 12
(to avoid epiphysial closure)
Gonadal Dysgenesis
Stimulation of Growth

Growth hormone treatment for short stature in turner
syndrome
: Optimal response  an early onset of Tx around age
6~7

Now that the success of GH treatment in recognized &
accepted, an argument can be made for chromosomal
screening by molecular analysis of all growth-retarded
girls
Gonadal Dysgenesis
The Possibility of Pregnancy

In women who have variants of gonadal dysgenesis and
who menstruate, pregnancy can occur

30% incidence of congenital anomalies in the offspring
 amniocentesis or chorionic villus biopsy

Donated oocytes yields excellent results

Fatal aortic events (aneurysm, dissection, or rupture)
can occure during pregnancy in patients with gonadal
genesis. A cardiology consultation with a
echocardiogram is strongly advised
Swyer’s syndrome
(Bilateral dysgenesis of the testes)
46, XY
No SRY OR its receptors
STREAK GONADS
- NO MIF (Uterus +)
- NO SEX STEROIDS
Female
external
Genitalia
Female
Internal
Genitalia
Embryonic Testicular Regression and
Bilateral Vanishing Testes Syndromes

46,XY karyotype and absent testes but clear evidence of testicular
function during embryogenesis
 "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
 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
Spectrum of presentation
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
Testicular regression syndrome
Congenital Anorchia
46-XY/SRY
Testis  MIF
(self destruction)
± testosterone
± DHT
Male
Infantile
External
genitalia
± Male
Internal
genitalia
TRUE HERMAPHRODITISM
• Gonads :
- ovary one side and testis on the other side of the abdomen
- bilateral ovotestis
• Karyotype :
46,XX most common(70%); XY and XX/XY
• Internal genitalia :
Both mullerian and wolffian derivates
• Phenotype is variable
• Gonadal biopsy is required for confirming diagnosis
True Hermaphroditism


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)
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
 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
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.
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
Noonan syndrome

Both affected males and females have apparently normal
chromosome complements and normal gonadal function

The phenotype appearance of Turner syndrome
: short stature, webbed neck, shield chest & cardiac malformations
(esp, pulmonic stenosis)

The trait as autosomal-dominant with variable expression
MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA




GENERAL GIUDELINES
Medical and social emergency
Avoid immediate declaration of sex
Proper counselling of the parents
Team management; obstetrician,
neonatologist, pediatric endocrinolgist,
genetist and paediatric surgeon.
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
MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
DIAGNOSIS

History : pregnancy; family

Detailed examination
; Abdomen; pelvis; external genitalia; urethral and anal openings
– Are gonads palpable?
– What is the phallus length?
– What is the position of the urethral meatus?
– To what degree are the labioscrotal folds fused?
– Is there s vagina, vaginal pouch, or urogenital sinus?
– Dehydration, hypotension, hyperpigmentation in adrenal hyperplasia
DDx Algorithm
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
MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
Investigations
• Pelvic US and sometimes MRI or Genitogram
• Karyotype
• Rule out Cong. Adrenal hyperplasia
Serum electrolytes; 17-OHP level,11-DOC & urinary levels of 17-ketosteroids
•
•
•
Serum androgen (androstenedione, testosterone, DEA, DEAS)
Laparoscopy
Gonadal biopsy (Laparotomy)
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
Parameters of Optimal Gender Policy (Meyer-Bahlberg, 1998)
– Reproductive potential (if attainable at all)
– Good sexual function
– Minimal medical procedures
– An overall gender-appropriate appearance
– A stable gender identity
– Psychosocial well being