Download Ambiguous Genitalia Dr. Eve G. Fernandez August 17, 2010 Normal

Ambiguous Genitalia
Dr. Eve G. Fernandez
August 17, 2010
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Normal vs. Ambiguous genitalia – you cannot determine if the external genitalia is that of a male
or a female
Objectives:
Normal Sexual Development:
o Involves three sequential events ……..
o The external genitalia develops automatically in the female direction unless the SRY
gene is present.
o SRY gene builds signal for testosterone development or secretion.
This diagram shows the phenotypic differentiation of the male and female embryos. Initially, in
the fetal stage during the first two months or 8-10 weeks AOG, we have the bipotential gonads
(no differentiation yet whether it is male or female). After 8-10 week AOG, if there is no SRY
gene, it will develop into female structures. With the presence of the SRY gene, male structures
will develop. For both the external genitalia, first there is the genital tubercle, the genital folds
and the genital swelling. Then, for the female structures, there is the clitoris, the labia minora
and majora and the openings. For the males, the penis, scrotum, and the urethral orifice.
GONADAL DIFFERENTIATION SLIDE: MEMORIZE BY HEART!!! (This table is incomplete)
Urogenital ridge
Bipotential gonads
SRY gene
(-)
testes
(+)
ovary
Leydig cells
Testosterone
androgen receptors
Androgen receptors
DHT
o
o
The diagnosis of the patient will depend upon what is absent, what is lacking, and what
is in exist.
From the urogenital ridge, we have the bipotential gonad. The presence of the SRY gene
will develop it into testis; its absence into an ovary. The testis has the Sertoli cells
secrete the anti-Mullerian hormones leading to Mullerian duct regression. (In the
female, they will develop to form the fallopian tubes, uterus, cervix, and the upper
portion of the vagina); the Leydig cells secrete the testosterone which by the action of
the testosterone hormone interacting with the receptors, activate the formation or
development of the Wolffian ducts (In a male, it develops into a system of connected
organs between the efferent ducts of the testis and the prostate, namely the
epididymis, the vas deferens,and the seminal vesicle. The prostate forms from the
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urogenital sinus and the efferent ducts form from the mesonephric tubules; in females it
regresses); and the testosterone via the action of the 5-α reductase enzyme would then
be converted into Dihydrotestosterone (DHT) which is a more potent male hormone
than testosterone. Again, with the action of DHT with the androgen receptor, there is
male differentiation of the urogenital sinus into the male external genitalia.
Ambiguous Genitalia: more information
o Neonate: is it a single disease entity or part of a syndrome?
o ……
o Medical: it is a medical emergency because it can cause death ex. CAH
o Social: how will you classify him or her? Male or female?  Registration system’s
dilemma
A. Unvirilized Male
Differentials
1. Abnormal testicular differentiation – differentiation from the bipotential gonads to testis
a. Gonadal dysgenesis
i. Partial … - due to varied pathology: could be due to gene mutation either in
the SRY gene or somewhere in the differentiation from the bipotential
gonads to the testicular differentiation causing problem in the Leydig or the
sertoli cells leading to problems in the production of testosterone and the
anti-mullerian hormones  failure to gonadal maturation
ii. Mixed….
- Karyotype 45XO  Turner’s Syndrome – most common
chromosomal analysis
- Aka asymmetrical…. That has two components different in
both side of the body (making it asymmetric)
i. Poorly differentiated….  deficiency in
testosterone
ii. Gonadal streak… fibrous tissue because this is
undifferentiated which will not be able to secrete
hormone.
b. Other manifestations or syndrome
- Denys-Drash syndrome  proteinuria or nephropathy;
i. Pathophysiology lies in chromosome 11 anomaly
- WAGR (Wilms Tumor, Aneridia, Genito Urinary
malformation, and Retardation) syndrome 
i. Mutation in the chromosome 11….
ii. please emphasize ONLY 46XY in males……
2. Deficiency in Testicular Hormones
a. Leydig Cell Aplasia (or hypoplasia)- …….
i. Mutation…
ii. Absence or hypoplastic wolfian…
iii. ……..
b. Steroidogenesis deficiencies – for CAH
INSERT DIAGRAM OF STEROIDOGENESIS  I got this from net not from the ppt
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The disease condition is based on the deficiency or lack of the different hormones
present in the process.
PHYSIOLOGY: Cholesterol is the mother compound where aldosterone, cortisol, and
testosterone are derived in the body.
Take note: the pathway does not only go downwards, but each one is related to each
other. The pathway is also sideways, meaning there is retouring or detouring that occurs
in enzyme deficiency.
i. StAR deficiency or congenital lipoid adrenal hyperplasia – the enzyme StAR
protein is deficient  there is no production of other hormones. This is the
rate-limiting step of the pathway.
- testosterone development leading to female external
genitalia.
- Hypoplastic or absent wolfian ducts
- Salt-losing crisis  because the patient does not have
aldosterone and cortisol
- No virilization at puberty because there is no testosterone
- ……
ii. 3β-OH steroid deficiency – salt-losing…
- ……
- ..
- ….
iii. 17α OHP deficiency – you cannot proceed with the pathway once you have
this
- …..
- ….
- Decreased testosterone production
3. Defects in Androgen Function
a. 5α-reductase deficiency – testosterone is not converted to DHT and there will be no
proper signaling between the hormones (testosterone and DHT) and the androgen
receptors
i. ….
ii. These are the patients who were initially diagnosed as females
iii. Palpable gonads in their inguinals usually the patients were reared as
females but become masculinized at puberty and are usually diagnosed at
this point in the Philippine set-up
iv. Normal 17α OHP ruling out CAH due to 21 hydroxylase defieciency
v. High testosterone level but low DHT
b. Complete androgen insensitivity syndrome (CAIS)
i. X-linked recessive; high testosterone; female external genitalia with
aplastic, rudimenrtary to absent Wolffian duct and Mullerian duct.
c. Partial androgen insensitivity syndrome (PAIS)
i. …
ii. Other S/Sx: reared as females but won’t have monthly menstrual period;
not capable of giving birth.
GONADAL DIFFERENTIATION
Urogenital ridge
Bipotential gonads
Abnormal testicular differentiation
SRY gene
(-)
testes
Leydig cells
Testosterone
(+)
ovary
Deficiency in testicular hormones
androgen receptors
Androgen receptors
DHT
B. Masculinized or Virilized Females
o Two factors:
Defects in Androgen Function
1. Maternal Androgen – may be due to a medication that the mother took during
pregnancy or due to the ovarian or adrenal tumors that produces the male
hormone
2. Fetal Androgen
 Placental Aromatase deficiency…
o Estrogen is not produced due to the deficiency of aromatase
enzyme
 CAH or Congenital Adrenal Hyperplasia – most common cause…
o High 17-OHP is confirmatory of CAH
o When a patient comes to you presenting with ambiguous
genitalia, ALWAYS rule out CAH because it is fatal.
o REVIEW: Physiology and Steroidogenesis and Hormones
produced by the adrenal cortex and medulla
 Cortisol – maintenance of sugar
 Aldosterone – maintenance of BP and salt
concentration, sodium in particular.
 Androgens – for sexual differentiation esp. at the time
of puberty
INSERT DIAGRAM: DHEA I got this from net, not from the ppt
DHEA – (dehydroepiandrosterone) is an endogenous hormone and secreted by the adrenal gland. DHEA
serves as precursor to male and female sex hormones (androgens and estrogens). All of us have
testosterone and androstenedione but only females have the aromatase enzyme which converts the
male hormone to estrogen.
Definition of Terms:
 CAH - …..;
o Most common enzyme deficiency: 21 hydroxylase enzyme. If you block this
enzyme, you cannot produce aldosterone and cortisol  overflowing of
androgen; the patient presents with hypoglycemia, hypotension,
hyponatremia, and hyperkalemia; and masculinization or virilization of the
female infants.
 2 Types:
1. Classic
a. Salt-wasting – life-threatening or fatal if not diagnosed or not treated
because you lack aldosterone and cortisol  adrenal crisis wherein the
patient may present with different disease entity like clinical sepsis;
gastroenteritis since the patient may present with dehydration; …….BUT
REMEMBER THAT THESE ARE ALSO THE S/Sx of CAH.
i. Female patients – ambiguous genitalia
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ii. Male patients – normal genitalia
b. Non-salt wasting or simple virilizing – unlikely be fatal because they don’t
have salt-losing crisis; cortisol is lacking but there is normal production of
aldosterone.
i. Female patients – ambiguous genitalia
ii. Male patients – normal genitalia; but can be differentiated from real
normal male patients because CAH male patients are
hyperpigmented/dark-skinned (mas maiitim sila).
iii. If not treated, males will present with precocious puberty; females
will develop more virilization of their genitalia  clitoris may
become penis
2. Non-classic – increased 17 OHP; normal-looking genitalia; major S/Sx: acne,
hirsutism, infertility
Late Manifestations of CAH:
 Precocious puberty due to the high testosterone level……
 Treatment: (at the emergency room level)  adrenal crisis!
o Correct dehydration.
 IV fluids – give plain NSS (Normal saline solution) which has the
highest sodium concentration to correct hyponatremia
o Replacement of cortisol
 Hydrocortisone as stress dose; and prednisone as maintenance
dose
 Fludcortisone
 ………
 Hydrocortisone and fludcortisone are not available in the
Philippines.
 We give the oral form of prednisone or buy
hydrocortisone/fludcortisone in Singapore, Australia, or US.
INSERT PICTURE: A patient (child) in adrenal crisis
 Hyperpigmentation of the skin
Genetics: autosomal recessive; …..
Pre-natal Treatment: Dexamethasone
 Confirmatory: 17-OHP enzyme
Evaluation:
 History:
o S/Sx in mother
o Unexplained infants death (previous child who died which they though
due to sepsis, think of CAH)
o ….
o …
o GENOGRAM: take note of the presence of parental consanguinity
 Physical Examination
o ………………
o …………….
o ……………..
o Ambiguous genitalia
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Phallus
Labioscrotal folds
Urethral openings
o Urogenital sinus if there is only one or single opening
Diagnosis:…….
o R/o CAH ………….
o Imaging
o Endocrine blood tests
o Genetics
 FISH – Fluorescent in situ hybridization
 Same DNA
Management of Sexual Disorders
o Medically
o Surgically
o Sexual rearing – if you want female sex, remove the testis
 If you want male sex, give testosterone; to bring down the testis,
give GnRH analog.