Abnormalities of sexual differentiation

Report
Abnormalities of sexual
differentiation
N. Ambalavanan MD
Jan 2004
Material based on Chapter 47, Part 4 of
Fanaroff and Martin, 7th Edition, 2002
What’s normal in a term newborn?

Female:
– Vaginal opening fully visible: 3-4 mm slit or stellate
orifice with heaped-up mucosa
– Clitoris width 2-6 mm
– Absence of gonads in labia majora or inguinal
region

Male:
– Urethra at tip of glans (may be inferred by a fully
developed foreskin)
– Penis of normal stretched length (2.5-5 cm) and
diameter (0.9-1.3 cm)
– Bilateral testes of normal size (8-14 mm) in the
scrotal sacs
Ambiguous genitalia: what is it?
Evaluation of intersex problem required
for:
1. Male-appearing genitalia with
micropenis, mod/severe hypospadias,
bilateral cryptorchidism, or two mild
defects (e.g. mild hypospadias and
unilateral cryptorchidism)
2. Female-appearing genitalia with posterior
labial fusion, clitorimegaly, or a labial or
inguinal mass
Basic concepts

Fetal sex differentiation:
– Occurs at 7-14 weeks’ fetal age only
– Is innately female and does not require
ovaries or estrogens
– As a male requires:
1. Sex-determining region of Y (SRY) gene
2. Bilateral testes producing mullerian inhibiting
substance (MIS/MIF/AMH) and testosterone
3. 5a-reductase enzyme (external genitalia)
4. Testosterone and dihydrotestosterone
receptor (internal and external genitalia)
Human Gonadal Development and Differentiation
Genital
ridge
SF-1
WT-1
Wolffian D. Male int genit.
Testis
SOX-9
SRY
Bipotential
gonad
DSS
Leydig cells
DHT
SF-1
Sertoli cells
AMH
Mullerian Duct
Penis
Prostate
Regression
Follicular cells
SF-1
Ovary
Testosterone
Genit. Tub.
Urogen. Sinus
Theca cells
Mullerian Duct
Follicles
Female Internal Genitalia
It’s a boy! (or..girl!)… maybe…


Evaluation is a medical and psychosocial
emergency
Why?
1. Diagnose CAH before an adrenal crisis
2. Designate correct gender
3. Correct problems early for correct body image
and gender identity
4. Provide genetic counseling for the future
5. Identification of children at higher risk for
gondal tumor
What should you do at the birth of a baby?

Careful evaluation of genitalia of all neonates
(does not need to be overtly ambiguous for
diagnostic evaluation)
 Defer gender assignment
 Discuss with parents: “The genitalia are
unfinished in their development, and we will
need a few days to perform some studies to
determine which sex your baby was intended
to be”
 Most of the diagnostic evaluation for gender
assignment can be done within 3 days.
Diagnostic evaluation - 1

History:
– Maternal androgens, drugs, teratogens
– Affected relatives, sibs who died in
infancy (CAH?)
– Consanguinity
Diagnostic evaluation - 2

Physical examination:
– Genitalia
– Gonads
– Rectal
– Hyperpigmentation
– Turner syndrome?
– Dysmorphic features?
Diagnostic evaluation - 3

Chromosomes:
– Rapid test for X and Y chromosomes
– Karyotype
– Contact laboratory personally and ask for
result ASAP
– Buccal smears are no longer
recommended
Diagnostic evaluation - 4

Anatomic evaluation
– Ultrasound
• Uterus seen?
– seen in 94% of normal females
– If no uterus, suggests MIS production by testes
– If uterus +, suggests bilateral ovaries or gonads that do not
produce MIS
• Intrapelvic gonads sometimes seen
– Endoscopy
– Retrograde genitography
• Anatomy of urethra and vagina.
• Presence of cervix confirms mullerian duct structures
Diagnostic evaluation - 5

Biochemical evaluation
If patient is:
– XX with mullerian ducts: 17 OHP, 11-deoxycortisol,
17OHPe, T
– XX without mullerian ducts: T, E2, LH, FSH
– XY with mullerian ducts: T, E2, LH, FSH
– XY without mullerian ducts: T, DHT, LH, FSH
Management

Gender Assignment:
– Usually made when chromosome status and
mullerian duct status are known
– Occasionally need to defer until biochemical
results are known
– Consultation with pediatric urologist and
endocrinologist necessary
– If bilateral ovaries are present, usually reared as
female
– Males with poor androgen insensitivity difficult to
assign

Psychological counseling to family (and later
to patient)
Management


Management of CAH if present
Female: surgical correction of ambiguous
genitalia (procedure depending on age)
 Male:
– Testosterone for micropenis
– Course of HCG followed by orchiopexy if
necessary for cryptorchidism
– No circ if hypospadias
– Do not remove mullerian structures
– Gonadectomy if streak or dysgenetic gonads with
Y chromosome (risk of malignancy high from
infancy)
Congenital Adrenal Hyperplasia
Defect in the adrenocortical synthesis
of cortisol from cholesterol
 Low cortisol elevates ACTH
 Consequences of impaired synthesis
of hormones (glucocorticoids,
mineralocorticoids, gonadal sex
steroids) and overproduction of
precursors or side products

Steroid Biosynthetic Pathway
Cholesterol
Pregnenolone (Pe)  17-OH Pe 
DHEA

D5-Androstenediol
3b-HSD
Progesterone (Pr)  17-OH Pr  Androstenedione  Testosterone
21-OH ase
11-DeOxCorticost
11-DeOxCortisol
5a-Reductase
Dihydrotestosterone
11-b OH ase
Corticosterone
Cortisol
18-OH Corticost
Aldosterone
Mineralocorticoids
Glucocorticoids
Androgens
Congenital Adrenal Hyperplasia

21-Hydroxylase deficiency
– 90% of CAH
– diagnosed by increased 17-OHP
– Simple virilizing (partial) and salt-wasting
(complete absence of enzyme)
– Abnormal virilization of female fetus
– Males may develop penile enlargement, accel
growth etc postnatally

11b-hydroxylase similar to 21-hydroxylase
deficiency; but with hypertension
 3b-OHSD deficiency leads to ambiguous
genitalia in males and females
Rare syndromes

True hermaphroditism:
– co-existence of ovarian and testicular
tissue either in the same or opposite
gonads
– 60% are 46 XX; 20% are 46XY or 45 X/46XY
and rest are mosaics/chimeras

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