presentation on approach to intersex

1. Dr. Sandip Gupta
PGT, PEDIATRICS
B.S.M.C.H.

2. Definition
 When the external genitalia do not appear completely male or
completely female .
 Incidence:1in 2000 live births
 Most cases present in newborn period
 Social and medical emergency

3. When to suspect
 Micropenis: Stretched penile







length<2.5cm in a term newborn
Asymmetry of labioscrotal folds
A penis with B/L nonpalpable testis
U/L cryptorchidism with hypospadias
Perineoscrotal or penoscrotal
hypospadias with or without microphallus
even if testes are descended.
Apparently female external genitalia with
clitoromegaly or inguinal hernia
Overtly abnormal genitals like cloacal
exstrophy
Discordance of external genitalia with
prenatal karyotype.

4. Disorder of Sexual Differentiation(DSD)
 Also known as disorder of sexual development (Nelson) is
defined as a congenital condition in which development of
chromosomal,gonadal & anatomical sex is different.
 Preferred over older terminology such as ambiguous
genitalia, pseudohermaphroditism and intersex
 Atypical development of genetic, gonadal and phenotypic sex
 Includes disorders grouped under 4 major headings
 46,XX virilized female
 46,XY undervirilized male
 Gonadal differentiation and chromosomal disorders

5. Types
46,XX virilized female
46,XY undervirilized male
 Congenital adrenal hyperplasia  Defects in testicular differentiation
 21-hydroxylase deficiency,
 Defects in testicular biosynthesis
 11-hydroxylase deficiency
 Defects in androgen action
 3 beta hydroxysteroid
dehydrogenase deficiency
 Aromatase deficiency(fetal and
maternal)
 Glucocorticoid receptor gene
mutation
 Virilizing maternal conditions
 CAH
 Adrenal/ovarian tumors
 Drugs-progestin,androgen
Ovotesticular DSD
 XX
 XY
 XX/XY chimera
Sex chromosome DSD
 45X(turner syndrome)
 47XXY(klinefelter syndrome)
 45,X/46,XY(mixed gonadal
dysgenesis)
 46,XX/46XY

6. Incidence
 The exact data on the incidence and prevalence of
conditions causing ambiguous genitalia are limited.
 Congenital adrenal hyperplasia accounts for most of the
cases
 Incidence of CAH 1 in 15000, AIS 1 in 20,000 (Avery’s
disease of newborn 9th ed)

7. Incidence-India
Etiology and clinical profile of ambiguous genitalia studied (n=109)
1) Genetic females with virilisation or FPH –27.5 %(n=30)
 Congenital adrenal hyperplasia (CAH) was the underlying cause in all cases
of FPH
Salt wasting form - 23/30
Simple virilising form – 7/30
2) Genetic males undervirilised or MPH –52.3 %(n=57)
Androgen insensitivity syndrome - 28% (16/57)
5- alpha reductase deficiency - 23%(13/57) .
3) Disorder of gonadal differentiation- 10.1%(n=11)
Gonadal dysgenesis – 9/11
True hermaphrodite – 2/11
4) Syndromic form of ambiguous genitalia- 1.8% (n=2)
Rajesh R. Joshi, Sudha Rao, Meena Desai. Etiology and clinical profile of ambiguous genitalia-an
overview of 10 years experience. Indian Pediatrics, 2006;43:974-979.

8. Embryology
 Sexual differentiation-3 stages
1. Determination of chromosomal sex (at conception)
2. Gonadal differentiation (at 6-7 wks of gestation)
3. Phenotypic sex determination (at 8-12 wks of gestation)
 Stage 1 depends upon sex chromosome complement of
fertilizing sperm
 Stage 2 depends upon SRY gene of Y chromosome
 Stage 3 depends upon testosterone and Mullerian Inhibiting
Factor (MIF)

9.  Gonad develops from
 Somatic cells (arise from mesonrphric cells and coelomic
epithelium)- sertoli cells/granulosa cells
 Germ cells (arise from yolk sac and migrate to genital ridge)Leydig cell/theca cell

10. Embryology
 Testicular development is guided by TDF which is encoded
by the SRY gene on the short arm of the Y chromosome.
 Under the influence of the TDF ,germ cells in the genital ridge
differentiate into Sertoli cells which secrete MIS (causes
regression of the mullerian ducts) and Leydig cells which
produce testosterone (promotes maturation of spermatogonia
and regulates male phenotype).

11. Embryology
Wolffian duct develops into the following:
 Epididymis
 Vas deferens
 Ejaculatory duct and seminal vesicles

12. Embryology
 In the absence of the Y chromosome , gonads differentiate
into ovaries at around 11-13 weeks gestation.
 Absence of MIS leads to persistence of mullerian
structures which develop into:
 Fallopian tubes
 Uterus
 Cervix
 Vagina

14. Embryology
 Undifferentiated external genitalia includes the following:
 Urogenital tubercle
 Urogenital swelling
 Urogenital folds

15. Embryology
 In males DHT leads to development of these three structures
into :
 Glans penis
 Scrotum
 Penile shaft
 In absence of DHT, these structures develop into
 Clitoris
 Labia majora
 Labia minora

16. Embryology
 True hermaphroditism have both testicular and ovarian tissue
in the gonads.
 In patients with pure gonadal dysgenesis,both gonads are
streak gonads.
 Patients with mixed gonadal dysgenesis have a testis on one
side and a streak gonad on the other

18. History
 Maternal drug ingestion esp. in 1st trimester




(androgen, antiandrogen, progestins, antiseizure medication.)
H/O virilization in mother may suggest androgen producing
tumour (adrenal or ovarian,) placental aromatase
deficiency,CAH.
Past h/o early death of infants may suggest a previously missed
androgenital deficiency
Family h/o affected sibling or family member
(CAH, hypospadias, infertility, delayed puberty
, cryptorchidism, consanguinity)
Neonatal death.

19. External genitalia Examination
 Streched penis length,
 width of corpora,
 presence of chordee,
 position of the urethral meatus,
 presence of vaginal opening
 pigmentation &symmetry of scrotum
&labioscrotal fold
 Anogenital ratio>0.5 is an indicator of
1st trimester androgen exposure.
CAH with ambiguous genitalia

20. External genitalia Examination
 Gonadal size ,position & descent should be noted a gonad
below inguinal ligament is ususally a testis.
 Abnormal genital development with cliteromegaly or
apparently well formed penis with an empty scrotum should
raise concern of virilised female with CAH.
 Bimanual rectal exam may reveal mullerian strucures cervix or
uterus in midline.
 Associated anomalies should be noted.
(WAGR, SMITH-LEMLI-OPITZ, ROBINOW,GOLDENHAR
SYNDROME)
Ambiguous genitalia in CAH

21. Investigations
 Serum electrolytes
 Blood sugar
 Hormonal study
 Karyotyping
 Ultrasonography
 Genitogaphy,
 Sinogram
 CT
 MRI
 Exploratory laprotomy/ Laproscopy

22. DIAGNOSTIC ALGORITHM

23. Algorithm for evaluation of 46,XX DSD
Ambiguous genitalia
46 XX Karyotype
Uterus present
17 Hydroxy progesterone
Normal
Ovotestis on USG
Biopsy:
Ovarian folicles &
testicular tubules
Hermaphroditism
(Bisexual gonads)
Increased
CAH
Normal
Matrnal virilization/
Exogenous androgen exposure
Maternal virilizing disorders:
Medications: Progestins
Tumors (adrenal/ovarian)
Luteomas of pregnancy
Aromatase deficiency

24. Algorithm for evaluation of 46,XY DSD
Ambiguous genitalia
Karyotype 46 XY
USGlvis
Pelvis
No uterus
Uterus present
hCG stimulation test
N/ T & DHT:
AIS(Ar mutation
analysis)/
Idiopathic
Normal T & DHT
: 5 alpha reductase
deficiency
Gonadal biopsy:
•True hermaphordite
•Persistent mullerian duct
syndrome
T and DHT:
LH/FSH :partial gonadal dysgenesis,
leydig cell hypoplasia
Precursor steroids : T-biosynthesis
defect

25. Ultrasonography
 Identify müllerian structures- uterus, ovaries, fallopian tubes
and upper half of vagina
 Allows visualization of a neonate's adrenal glands - enlarged in
infants with congenital adrenal hyperplasia (CAH) - have a
cribriform appearance.
 Normal ultrasonographic findings of the adrenal glands do not
exclude a diagnosis of CAH.

26. Genitography
 Helps to determine ductal anatomy.
 In a neonate with ambiguous genitalia, a catheter can be
inserted into the urethra - Contrast is injected to outline the
internal ductal anatomy.
 Findings - normal urethral anatomy, a müllerian remnant in a
male, a common urogenital sinus, or normal female internal
genitalia
 CT and MRI - may help identify internal anatomy
 Endoscopic examination of genitourinary tract .

27. Genetic Evaluation
 KARYOTYPE
 FISH
 Presence of SRY
 X and Y probes for gonadal biopsies
 Specialized molecular genetic tests
 Mutation analysis of 21-hydroxylase gene
 Androgen receptor sequencing
 Y chromosome microdeletions

28. Endocrinal Evaluation
Hypothalamic/pituitary/gonadal Axis:
• Gonadotropins: LH, FSH
• Gonadal response: Testosterone, DHT, estrogen
Adrenal function:
• Electrolytes, 17-OH-P
• DHEAS
• Cortisol
Response to challenges:
• GnRH stimulation
• HCG stimulation

29. hCG stimulation test
 Evaluation of gonadal axis in children
 Dynamic & reliable test for leydig cell evaluation in boys
 Assess testosterone secretion by testes
 500 IU of hCG given i/m daily for 3 days
 Serum testosterone, DHT, DHEA, androsteedione, LH & FSH
are measured at baseline and then 24 hr after 3rd day
 Collection of 24 hr urine before & after three doses of hCG
used in analysis of steroid profile to detect testosterone
biosynthesis defect

30. Interpretation
 2 to 20 times rise in testosterone
1)adequate rise indicates presence of functioning testes
2)if rise is blunted –enzymatic defect in testosterone synthesis,
gestational loss of testicular tissue, LH receptor mutation
3) ↑ T:DHT ratio(>20:1)- 5 alpha reductase def
 Raised LH,FSH denotes anorchia or primary gonadal failure
 Increased precursor steroid denotes biosynthesis defect

31. GnRH stimulation test
 Assess the pituitary function and degree of pubertal maturation
in DSD
 Evaluation of B/L cryptorchidism (along with hCG stimulation
test)
Method: Serum LH, FSH, estradiol, testosterone and SHBG
collected, followed by 2.5mcgm/kg GnRH iv is given, then
above samples collected at 30 and 60 min.

32. Interpretation
 In normal cases FSH&LH values rise at 30 min and later
decline at 60 min
 Initially there is predominant FSH response with progressive
increase in LH response with pubertal maturation
 In primary gonadal failure the basal gonadotropins are
elevated with exaggerated response to GnRH

33. MANAGEMENT

34. DSD Team Participants
 Pediatrician
 Medical Geneticist
 Pediatric Urologist
 Pediatric Endocrinologist
 Gynecologist
 Pediatric Psychologist
 Cytogeneticist
 Social Worker

35. General guidelines for gender
assignment
 Try to match the baby’s sex assignment to the chromosomal
and gonadal sex if possible
 Try to anticipate pubertal development
 Consider future function when planning surgeries
 Try to preserve fertility
 Respect the opinions of well-informed parents

36. Treatment
Treatment options include :
 Reconstructive surgery
 Hormone therapy

37. Reconstructive surgery
 Goals
Cosmetic
 to make a boy’s or a girl’s genitalia look natural
 restoring sexual function
 May need repeated surgeries later in life

38. Reconstructive surgery
 For girls : sexual function of organs is often not compromised
despite any ambiguous appearance.
 Depending on severity options are :
 Uncovering vagina hidden under skin
 Removing excess masculine tissue around the
clitoris(clitoral reduction) – done once hormone replacement
therapy has begun
 Testis should be removed soon after birth if female sex of
rearing is decided

39. Reconstructive surgery
 For boys : surgery is complicated but often successful. It
includes :
 Lengthening of the incomplete penis
 Undescended testis that is to be retained is best brought
down into the scrotum at the time of initial gonadal biopsy
 Correction of chordee and urethroplasty in boys with
hypospadias is usually performed between 6 and 18 months
of age

40. Hormone therapy
 Depending on severity of condition, hormone therapy alone
may be enough to correct the initial hormonal imbalance.
 Ability of the gonads to produce appropriate hormones for sex
of rearing is a factor in sex assignment.
 Advantageous to retain a gonad appropriate to the assigned sex
if it is likely to function adequately.

41. Prediction of fertility
 Ovaries are generally functional but testicular tissue is
generally dysgenetic
 XX patients with CAH have a reasonably high probability of
being fertile since they have a uterus and 2 normal ovaries
 Women with 46,XX ovotesticular DSD are occasionally fertile

42.  Pts with gonadal dysgenesis, partial AIS, 17-OHD are infertile
either because testis are abnormal or there is no uterus
 If child has no chance of fertility and genitalia are sufficiently
well developed to function as male, male sex of rearing is
advised
 Pts with ovotesticular DSD should be raised as female after
removing the testicular tissue and leaving the ovary in place

44. Hormone Biosynthesis Pathway

45. Congenital Adrenal Hyperplasia
 Incidence – 1 in 12000
 Most common cause of ambiguous genitalia in female newborn

Autosomal recessive inheritance

No sex prediliction
 21-hydroxylase deficiency - common cause of CAH

Young women may present with symptoms of polycystic
ovarian syndrome

46. CAH due to 21-OH deficiency
Classic salt wasting
Classic simple
virilizing
Males
Females
Males
Females
Age at dx
Birth-6mo
Birth-1mo
2-4 yr
Birth-2yr
External
genitalia
Normal
Ambiguous
Normal
Ambiguous
Nonclassic
Males
Females
Child to adult
Normal
Usually
normal; may
have
clitoromegal
y
Aldosterone
Low
Normal
Normal
Cortisol
Low
Low
Normal
17-OHP
Basal>20,000 ng/dL
Basal> 10,000 – 20,000
ng/dL
ACTH stimulated 1,500 –
10,000 ng/dL
% of normal
0
1-2
20-50
21-OH
activity
Pediatrics Endocrinology, Mechanisms, Manifestations and Management, Ora H. Pescovitz, Erica A.
Eugster, 2004 by Lippincott Williams & Wilkins.

47. Management
 Medical –
Stablisation of general condition
Correction of electrolyte abnormalities
After stabilisation – replacement of glucocorticoid and / or
mineralocorticoids depending on the general condition
 Glucocorticoid replacement :
 Hydrocortisone – 10-15mg/m2/d
 Prednisolone – 2.5-6mg/m2/d
 Mineralocorticoid replacement :
 9 fluorohydrocortisone – 0.1-0.2mg/d

48. Management
 Surgical –
Females with severe virilisation – early recession of clitoris
followed by vaginoplasty
Mild virilisation – medical treatment is adequate
NEWBORN SCREENING PROGRAMME

49. Antenatal management (CAH)

50. 5 alpha reductase deficiency
 Autosomal recessive
 Male have small phalus or ambiguous genitalia with with
perineoscrotal hypospadias,bifid scrotum, inguinal,labio/scrotal
testis.
 Mullerian structures regress & wolffian duct derivaties
present.
At puberty they present with primary amenorrhoea and may
experience virilization
Diagnosis is done by increased testosteron to DHT ratio .

51. Treatment
 Medical management –
Males – testosterone enanthenate 25 mg i.m. monthly X 3mths
may increase penile length
Females - estrogen replacement therapy should be initiated at a
bone age of 12 years or once an increase in gonadotropins is
observed
Dose is tailored to reach adult replacement levels over a 3-4
year range

52. Surgical treatment
 Females
Feminizing genitoplasty - gonadectomy, restructuring of the
labioscrotal folds into labia, and reduction or recession of the
phallus
 Males
Urethroplasty (Perineoscrotal hypospadias repair is typically a
multistage procedure.)
Repair of bifid scrotum
Chordee repair
Orchiopexy

53. Androgen insensitivity syndrome(AIS)
 Also known as Androgen receptor defects
 M/c form of male DSD
 Frequency 1/20,000 genetic males
 X linked recessive disorder
 Two types
complete AIS
Partial AIS(k/a Reifenstein syndrome)

54. Clinical presentation
 Extreme failure of virilization
 Genetic male invariably reared as female since birth
 Testes may be intra-abdominal/inguinal
 AMH causes regression mullerian ducts.
 Normal breast (due to peripheral aromatization of testosterone)
 Primary amenorrhoea
 Absent pubic hair

55. Investigation
 Serum Gonadotropins
LH & FSH leading to testosterone &estrogen
 hCG stimulation test (Twofold or greater increase in
testosterone level in response to HCG suggests normal
functioning testicular tissue and helps rule out a defect in
testosterone biosynthesis)

56. Treatment
 Remove inguinal hernias
 Gonadectomy before or immediately after completion of
puberty (increased risk of gonadoblastoma)
 Estrogen replacement
 Vaginal reconstruction or vaginoplasty may be needed
 Supportive counseling for infertility
 Genetic counseling for family members