INTERSEX PPT BY PROF. (DR). T.K. NASKAR, DEPT. OF GYANAECOLOGY & OBSTETRICS, MEDICAL COLLEGE & HOSPITAL, CALCUTTA, WEST BENGAL INDIA.

1. INTERSEX
Prof. (Dr.) Tapan Kr. Naskar
Dept. of Gynaecology & Obstetrics
Medical College, Kolkata.
1

2. Defining Sex and GenderDefining 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
2

3. Human sexual differentiation
Chromosomal sex
Gonadal sex
External genital sexInternal genital sex
SEX ASSIGNMENT
Gender identity
and role
Sex of rearing
3

4. Gonadal development
SRY-gene (TDF)
Short arm of Y chromosome
Bipotential
Gonad
2 X chromosomesReceptors
For H -Y antigen
OVARYTESTES
Present Absent
4

5. Leydig
cells
Sertoli
cells
Testosterone Mullerian inhibiting
factor
Wollfian duct 5a-reductase
Urogenital sinus
Regrsession of
Muuleian ducts
Male external genitalia
Male internal
Genital organs
DHT
TESTIS
Male
development
5

6. Urogenital sinus
Female external genitalia
. Lower part of vagina
OVARY
Mullerian
ducts
Female internal genital
Organs
. Most of upper vagina
. Cervix and uterus
. Fallopian tubes
Neutral
Development
Absence of androgen exposure
Female
development
6

7. 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.
7

8. 8

9. Sertoli
Cell
Leydig
Cell
5α - reductase
AMH DIHYDROTESTOTERON
E
TESTOSTERONE
Inhibitis Mullerian
duct development
Promotes Wollfian
duct development
Masculinizes ext. genitalia
9

10. 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.
10

11. INTERSEX
Definitions : Intersex may be
defined as the presence of both
Male & Female external & / or
internal genital organs in the same
individual causing confusion in the
diagnosis of sex.
11

12. GENDER?
12

13. Intersex Contd….
Incidence : 1/2000
Determination of Sex : Following factors are
to be considered – Chromosomal sex,
external & internal anatomic sex, Gonadal
Sex, (Genetic, Hormonal, Psychological sex &
sex of rearing) also.
13

14. Intersex Contd….
In new born -- by ext. genital organ.
In adolescent – ext. genital organ +
sex of rearing, psychogenic sex &
appearance of sec. sex characters
are to be considered.
14

15. Intersex Contd….
Classification
Traditional
Female intersex
Male intersex
True Hermaphrodite
Now a days
2006 46XX DSD
46XY DSD
SEX Chromosome DSD
15

16. 46 XX DSD
Gonadal (Ovarian)
Development Disorder
Ovo-Testicular disorder
(True Hermaphrodite)
Testicular Disorder
(46XX Male Sex reversal)
Gonadal Dysgenesis
Androgen Excess
Other Disorder of
Genital Development
Cloacal extrophy
MRKH
MURCS.
Fetal Origin
Feto-Placental
Maternal Origin
21 Hydroxylase
3 β Hydroxy Steroid
11 β Hydroxylase
Aromatase
P 450-OR
Drug Ingestion
Preg. Luteoma
Theca LuteinSex Chromo.
DSD
45, X – Turner & Variants
47, XXY – Kline Feltar & Variants
45, X/ 46, XY-Mixed Gonadal Dys., Ovo testicular DSD
46, XX / 46,XY (Chimerism, Ovo Testicular DSD.
46XY DSD
Gonadal ( (Testicular)
Development Disorder
Gonadal dysgenesis
Complete –(Swyer Syndrome)
Partial
Testicular Regression
Syndrome
Ovo- Testicular DSD
Disorder of Androgen
Synthesis
5 α Reductase , 17 α Hydroxylase , 3 β Hydroxy Steroid de hydrogenase
17 β Hydroxy Steroid de hydrogenase , P 450 OR , StAR Steroid acute
Regulatory protein
Disorder of
Androgen Action
Androgen insensitivity
Syndrome
Complete AIS
Partial AIS
LH receptor defect – leydig cell hypoplasia
Disorder of AMH & its receptor Hernia uterine inguinalae
16

17. OVO TESTICULAR DISORDER
(True hermaphrodite)
Previously it was called true hermaphrodite
so many combination – usually Rt testis, Lt
ovary,mostly 46, XX, 7% 46,XY,10-40% are
mosaics.most having vagina, uterus can be
normal / functional, hypoplastic, vestigial or
absent. Ext. genitalia – ambiguous to
isolated hypospadias. virilization reared as
male.3/4th
developgynaecomastia.at puberty
menstruate..AD. Probable cause is –
translocation of testis determining gene
from Y to X chrom. or an autosome.
17

18. TESTICULAR DISORDER(DSD)
(46XXsex reversal)
46, XX sex reversal – may be of 2 types – SRY +ve
& SRY –ve. In 90% cases it is due to abnormal
recombination between distal portion of short
arm of X & Y & transfer of SRY from Y to X, during
male meiosis.
SRY +ve. – usually male. Short stature sterile.
Normal male pattern of hair distribution.
cryptorchid testis,Gynaecomastia,hypogonadism.
SRY –ve. – ambiguous genitalia,
gynaecomastia,or fail to masculinise fully after
puberty.
18

19. GONADAL DYSGENESIS
Streak gonad. Normal in stature usually no
somatic abnormality. 46, XX-autosomal
gene also play important in ovarian
differentiation.
19

20. 20

21. FETAL ORIGIN OF ANDROGEN
EXCESS – (CAH)
Mostly due to 21 Hydroxylase, 11 β, 3 β
Hydroxy steroid dehydrogenase.
Patho physiology - cotisol production
ACTH from pituitary Adrenal hyperplasia
steroid hormon proximal to block alternate
pathway Andorgens.
21

22. CAH contd….. (21 OH)
Types :
Diagnosis: More serious & less serious verities -- in neonates with CAH 17 OHP
will
be 3500 ng /dl. Where as in normal it is < 100 ng/dl.
ACTH challenge tests 17OHP will be > 10,000 ng. / dl. Or by genotyping from amniotic
cells or CVS.
Least serious verities : 17OHPR only slightly raised. Serum DHEAS
normal. In children morning values >82 ng./dl. Is diagnostic. In adult – morning values
<200 ng./dl. Exclude the diagnosis. Level >800 ng./dl. Are virtually diagnostic. If the level
of 17OHP is in between <200 - >800 ng./dl. It needs ACTH challenge test & the 17 OHP
will be >1500 ng./dl. (synthetic ACTH i.e. COSYNTROPIN – 1µg/m2
. or 0.25 mg.
More serious – Salt wasting virilisation + dehydration
Less serious - simple virilizing masculinization of Ext. Genitalia
Least serious - non classical at adulthood hirsutism,
mens. irregularity, Precautious puberty.
22

23. 11 β Hydroxylase deficiency
Types
Diagnosis : Serum Deoxy Cortisol, Deoxycortico sterone, Testosterone.
3 β Hydroxysteroid dehydrogenase
2 types of 3 β HSD isoenzyme- type I & II.
Type I : - Mediates activities in placenta, skin, breast, prostate.
Type II: - Mediates activities in Adrenals, Ovaries & Testis.
Two types : -
SEVERE
SIMPLE VIRILISING Hypertension is due to minerelo
corticoids. HypokalemiaLate onset (milder)
Salt wasting -- diagnosis by – serum 17 α OH pregnenolone.
Non Salt wasting -- concentration after ACTH Stimulation. .
23

24. TREATMENT OF CAH
Principle : Supply of cortisol to suppress
ACTH & its consequences.
•Preg. Mother : Prevent virilization of
female fetus.
•Neonates : Prevent death
•Newborn : Normal growth.
•Adult : Hirsutism & PCO.
24

25. Treatment of CAH contd….
Couples at risk of having CAH – IVF,
collects cells at 6-8 stage i.e. 3 days after
oocyte retrieval- PCR – unaffected cells
transferred 2 days later i.e at the
Blastocyst stage.
Prenatal T/t c Dexamethasone up to
1.5mg daily in divided doses. Ideally T/t
should start at 4-5 wks of gestation &
not later than 9 wks.
25

26. Treatment of CAH contd…..
Neonate :
I.V. 10-20ml /kg of 0.9% saline, 2-4mg/kg 10%
Dextrose, Kalemia by insulin & glucose. Stress
dose of Hydrocortisone 50-100 mg/m2
I.V. i.e.
25mg – followed by 50-100 mg/m2
in divided
doses i.e. 4 hrly. Additional stress dose is needed
until the infant is stable & feeding normally. If salt
wasting CAH is confirmed Fludro Cortisone up to
0.3mg/day & Na supplementation 1-3mg daily are
required.
26

27. Treatment of CAH Cont..
Children : Hydrocortisone (Cortisol) 12-
18ml/m2
daily . Fludrocortisone is needed in a
dose of 0.05-0.2 mg daily.
Clitoroplasty Adrenalectomy.
Adult : T/t c long acting glucocorticoids
(Dexamethasone/ Prednisone) 0.25-0.75 mg HS
daily.
During pregnancy : T/t c hydrocortisone is
preferred.
27

28. FETO PLACENTAL ORIGIN OF
ANDROGEN EXCESS
AROMATASE : It helps conversion of
andogens (DHEA, Testosterone,
Androstenedione) to estrogens. (E1, E2, E3 ). Rare
AR disorder. With ambiguous genitalia at birth &
puberty. Absent breast development &
multicystic ovaries c maternal hirsutism during
2nd
½ of preg. & regresses later.
P450-OR : AR, virilised, due to “Back door
path way” of Androgen excess. -- Prenatal
screening of Trisomy 21 revel low maternal E3
level.
28

29. Maternal causes of Androgen
excess
Early preg.- labio scrotal fushion & clitoromegaly.
After 12 weeks- only clitoromegaly.
Drug ingestion by mother: Danazole or c progestins for
Th. Abortion, but other than progesterone, 17 OH
progesterone but not with OCP fetal virilisation.
29

30. Drugs with Androgenic side effects
ingested during pregnancy
- Testosterone
- Synthetic progestins
- Danocrine
- Diazoxide
- Minoxidil
- Phenetoin sodium
- Streptomycin
- Penicillamine
30

31. Pregnancy leuteoma : hyperplastic masses, solid,
androgens virilisation.if the mother not
virilised the fetus usually does not .
Theca lutein cyst : seen in multiple preg. H
mole,Rh iso.& DM- serum Testosterone
,Androstenedione are elevated.
31

32. OTHER DISORDERS OF GENITAL
DEVELOPENT
TYPES :
Cloacal extrophy
MRKH SYNDROME
MURCS association.
32

33. • Cloacal extrophy- rare disorder, rectum,vagina &
urinary tract share a common everted orifice
accompanied by omphalocele & imperforated anus.
• MRKH-absent of vagina,absent/hypoplastic ut,&
normal/hypoplastic tubes.Normal breast & pubic hair
at puberty c amenorrhoea.
• MURCS association-
Mulleriana/hypoplasia,unilateral renal agenesis /
• ectopy,cervico thoracic dysplasia.cleft lip/palate,
• ovarian agenesis
33

34. XY DISORDER OF DSD
Male pseudo hermaphrodite : Abnormalities of
gonadal development fetal Androgen synthesis
due to enz. Problems, androgen receptors
problems, LH receptors problem causing Leydig
cells hypoplasia – or from mutations affecting
AMH or its receptors.
34

35. Disorders of Gonadal
(Testicular) Development
Complete Gonadal Dysgenesis: (SWYER SYNDROME) 46,
XY, looks Female as no AMH & Androgens due to
streak gonads ,needs gonadectomy .T/t c Estrogen
for breast development delayed sexual
maturation. Pubic hair, ut, tubes, vagina all are
normal. Pr. amenorrhoea, needs donar oocytes &
IVF.
Partial Gonadal Dysgenesis : Mullerian structure ±,
ext. genitalia female / ambiguous / male.
35

36. Swyer’s syndrome
46, XY
No SRY OR its receptors
STREAK GONADS
- NO MIF
(Uterus +)
- NO SEX
STEROIDS Female
Internal
Genitalia
Female
external
Genitalia
36

37. • Testicular Regression syndrome : fetal testis
+ve, lost at birth. Normal male ext. genitalia
small phallus or incomplete masculinization.
Partly / Completely absence of Testicular
Tissue – Seminiferous tubules, Sertoli cells
enveloped in Fibrous strands C no visible
germs cells.
37

38. Testicular Regression Syndrome
(Congenital Anorchia)
46-XY/SRY
Testis  MIF
(self destruction)
± testosterone
± DHT
± Male
Internal
genitalia
Female or
ambiguous
External
genitalia 38

39. DISORDER OF ANDROGEN
SYNTHESIS
5α Reductase deficiency: AR 46, XY, perineal
hypospadious. small penis, shallow vagina-failed
labioscrotal fusion,inguinal testis. Type I & II.
serum Testn
. & Testn
. / DHT ratio. Usually Testn
is
normal but Testn
/ DHT >10 in infant & ≥ 20 in old
& children and adult are diagnostic. Confirmed by
hCG stimulation test – Gonadectomy – Clitroro &
vagino plasty – Estrogen therapy. Can be reared
as male also c Testn
. Supplementation.
-
-
-
-
-
39

40. 5-alpha-reductase5-alpha-reductase
deficiencydeficiency46-XY/SRY
Testis  MIF
Testosterone
5-∝-rductase
Male Internal
Genitalia
Female or
Ambiguous
external Genitalia
DHT
40

41. Contd….
17α hydroxylase deficiency: Female ext.
genitalia, blind vagina & intra abdominal testis.
3β HSD deficiency : Incomplete masculinization,
hypospadious, female ext. genitalia.
17β HSD Deficiency : Testis - severely under
virilised ext. genitalia i.e. female ext. genitalia
ambiguity micro penis, inguinal testis. T/t –
Gonadectomy – estrogen therapy.
P450 OR deficiency : 46, XY, under virilised male.
41

42. Contd….
Steroid Acute regulatory (StAR) Protein
deficiency : Female ext. genitalia. Severe
adrenal insufficiency (vomiting, diarrhoea,
volume depletion, Na+
, K+
). Females are
normally developed at birth – because the
prepubartal ovary, unlike the adrenals & testis
is relatively dormant & thus may escape cellular
damage from cholesterol accumulation.
42

43. Disorders of Androgen action
CAIS : Short vagina, breast & clitoris, ill developed labia,
inguinal gonads. T/t – Gonadectomy after puberty is
completed (16-18),no pubic & axillary hair. Creation of
vagina – hormone therapy.
IAIS : No Mullerian structure. Uunder developed male int.
genitalia / labio scrotal fold. Normal breast development.
Ambiguous genitalia in new born. Axillary and pubic hair is
normal.
REIFENSTEIN SYNDROME : Infertile man c bifid scrotum
& Perineo scrotal hypospadious. No prostate. Normal
pubic & axillary hair but little chest or facial hair,
gynaecomastia. T/t – high dose of Testn
/ DHT can achieve
grater phallic growth.
43

44. 44

45. 45

46. 46

47. LH RECEPTOR DEFECTS
AR, 46, XY, due to inactivating mutation
in the LH/hCG receptor. Completely Ext.
female genitalia to nearly normal male
genitalia. Female at birth lac of
pubic hair & breast development or c
ambiguous genitalia.
47

48. DISORDER OF AMH &
RECEPTORS
Rare AR disorder due to failure of Mullerian
duct regression. Normal male c inguinal
hernia containing uterus, tubes, cryptorchid
testis.
48

49. SEX CHROMOSOME DSD
• 45, X Turner syndrome and variants.
• 47, XXY (klinefelter syndrome & variants-)
• 45, X / 46, XY mosaicism (mixed gonadal
dysgenesis)– ambiguous genitalia.
• 46, XX /46, XY mosaicism – (chimerism) – all
chimeras are mosaics, but derived from two
distinct zygotes rather than from a single
zygotes. Abnormal sexual development is
noted.
49

50. MALE OR FEMALE ?
50

51. 51

52. Management of Ambiguous Genitalia
• Diagnosis : History, Cl. Examination, Lab. Investigation.
History : Antenatal period androgen exposure?, maternal virilization during
preg ?, previous affected child / relatives ?, Unusual infant death,
consanguinity?
Phy. Examination : Presence / absence of any dysmorphic feature, hyper
pigmentation , suggested ACTH in CAH.
Are gonads palpable ? If yes it is always testis. Asymmetry of gonads i.e.
gonadal dysgenesis. Length & diameter of phallus ? ≥ 2.5cm & ≥ 0.9cm
(penis). 2-6 mm in length (clitoris). Position of the urethral meatus? Labio
scrotal folds fused?
Lab investigatins : USG, MRI, Cystoscopy, rarely laparoscopy, Karyotyping,
FISH – SRY. 17 OHP, ACTH, Cortisol, DHEA, 17α OH pregnenolone, 11
Deoxy cortisol, electro lytes.
52

53. 53

54. 54

55. CLINICAL PRESENTATION
OF INTERSEXUALITY
• At birth
Ambiguous genitalia
• During childhood
Heterosexual features
• At Adolescence
Delayed or heterosexual puberty
55

56. AMBIGUOUS GENITALIA AT BIRTH
The external genital
organs look unusual,
making it impossible
to identify the sex of
the newborn from
its outward
appearance.
Any one of the following :
• A small, hypospadiac
phallus and unilaterally
undescended gonad.
• An enlarged phallus
with bilaterally
impalpable gonads.
• An enlarged phallus
and a vagina in the
same infant.
56

57. MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
GENERAL GUIDELINES
• Medical and social emergency
• Avoid immediate declaration of sex
• Proper counselling of the parents
• Team management; obstetrician,
neonatologist, pediatric endocrinolgist,
genetist and pediatric surgeon.
57

58. MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
DIAGNOSIS
• History : pregnancy; family
• Detailed examination : abdomen; pelvis; external
genitalia; urethral and anal openings.
Federman’s rule:
A palpable gonad below the inguinal ligament is a testes
until proven otherwise
58

59. MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
Investigations
• Rule out cong. Adrenal hyperplasia:
– Serum electrolytes; 17-OHP level and urinary levels of 17-
ketosteroids
• Karyotype ( buccal smear; blood)
• Pelvic US and sometimes MRI or Genitogram
• Skin biopsy; fibroblast culture to measure 5alpha-
reductase activity or dihydrotestosterone binding
• Laparoscopy
• Gonadal biopsy (laparotomy)
59

60. A PROTOCOL FOR INVESTIGATIONA PROTOCOL FOR INVESTIGATION
OF A NEWBORN WITH AMBIGUOUSOF A NEWBORN WITH AMBIGUOUS
GENITALIAGENITALIA
Karyotype all
Palpable gonad
YESNO
CAH Sreen
Positive
- US / MRI
-?
Genitogram
Negative
. Biochemical profile
. US / MRI /? genitogram
. ? Gonadal biopsy
60

61. Sex assignment
General guidelines
• Sex assignment should be decided after
detailed assessment, investigations and
accurate diagnosis
• Complete gender assignment by age 18
months
61

62. Sex assignment
• Male gender assignment :
- stretched phallus > 2 cm
- erectile tissue
- lack of severe hypospadias
• Female gender assignment :
- inadequate phallus
- cervix and uterus present
In difficult cases; sex assignment should be
to the sex which can be surgically made to be
adequate for coitus
62

63. INTERSEXUALITY PRESENTING
AT ADOLESCENCE
Primary amenorrhea
- Complete androgen
insesitivity (TFS)
- Congenital anorchia
( early testicular regression
syndrome)
- Complete leydig-cell
agenesis
- Some forms of enzymatic
testicular failure
Ambiguous genitalia
- Neglected congenital adrenal
hyperplasia
- Mixed gonadal dysgenesis
- Partial androgen resistance
- Congenital anorchia ( Late )
- Testicular enzymatic failure
- Leydig cell agenesis
( incomplete)
- True hermaphrotidism
63

64. MANAGEMENT OF INTERSEXUALITY
PRESENTING AT ADOLESCENCE
• Cortisol replacement therapy and ? Corrective
surgery in CAH
• Corrective surgery in drug induced cliteromegally
• In almost all other instances (XY- FEMALE),
whatever the diagnosis is to Maintain the gender
role as female
• In some cases of enzymatic testicular defects or
5 ∝ -reductase deficiency :
Some May seek to change the gender role
64

65. INTERSEXUALITY
PRESENTING AT
ADOLESCENCE
Surgical aspects of
management
• Clitoral reduction
• Removal of gonads in the presence of Y
chromosome
• Vaginal repair and construction
65

66. XX VIRILISATION
SRY (+VE)SRY (-VE)
17-OHP
17-OH Pregnenolone
SRY Translocation
Elevated Normal
CAH
• 21 OH
•11 β OH
•3β HSD
•P450 OR
IMAGING
Normal Abnormal
Luteoma
Theca lutcyst
P450 Aromatase
AMH
hCG Stimulation Test
Normal male testn
response
Ovo testicular DSD
SOX 9 Duplication
MALE
66

67. XY Under virilisation
17-OHP
17-OH Pregnenolone
17α hydroxylase
StAR protine
Partial gonadal dysgenesis
3β HSD
P450 OR
Low / absent
ElevatedNormal
IMAGING
(Testis )
hCG Stimulation test AMH
AbsentPresent
Incomplete AIS
AMH receptor defect
Endocrine disruptor
17 β HSD
LH receptor defect
P450 OR
Normal Abnormal
T/DHT
5 α ruductase
>10 ≤ 10
Normal Low
Partila gonaldal dysgenesis
Testicular regression
OVO testicular DSD
AMH Mutation
67

68. Cl. Management of Children c
ambiguous genitalia
• Stabilization : CAH c 5% dextrose In 0.9% saline,
steroids, Hydrocortisone, mineralocorticoids.
• Family counseling :
• Gender decision : Traditionally early gender
assignment and reconstructive surgery but now a days
it is delayed until patients can decide themselves.
• Long-Term care : Having all or part of y chromosome,
intra abdominal gonads – removed as early as possible
due to chance of gonadoblastoma except in CAIS, in
whom surgery generally postponed until after puberty.
68

69. Sex assignment
• Male gender assignment :
- stretched phallus > 2 cm
- erectile tissue
- lack of severe hypospadias
• Female gender assignment :
- inadequate phallus
- cervix and uterus present
In difficult cases; sex assignment should be
to the sex which can be surgically made to be
adequate for coitus
69

70. SURGICAL CONSIDERATIONS
• Phallic / clitoral reduction if the assigned
sex is female, before 3 years of age
• Removal of intra-abdominal gonads /
streaks in newborns carrying Y
chromosome
• Vaginal construction / repair is better
performed around puberty
70

71. Before surgery After surgery
71

72. 72

73. Phallus with ill-formed glans
Length-2.5cms
Diametre-1cms
73

74. TAKE HOME MESSAGE
• Fundamental Theme in DSD – Either
from excess androgen in female or from
too little androgen in male.
• Any palpable gonads : Think as testis.
• Ambiguous genitalia : Think as CAH.
• It is easy to rear as female than male.
74

75. THANK YOU FOR
PATIENT HEARING.
75