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 tow of the organic sex
criteria
 TRANSSEXUALITY:
Discordance between oganic sex and psychological
sex components
 CLASSIFICATION OF
INTERSEXUALITY
1. Virilization of genitically female foetus
Female pseudohemaphroditism
2. Incomplete musculinization of genitically male
foetus
Male pseudohermaphroditism (XY-FEMALE)
3. The presence of both ovarian and testicular tissue
in the same individual
True hermaphroditism
4. Chromosomal abnormality
Mixed gonadal dysgenesis ( 45,X0 / 46,XY)
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 EXCESS MATERNAL
ANDROGENS ANDROGENS
Congenital adrenal
 Maternal androgen
hyperplasia
secreting tumours
 21 -hydrxylase deficiency
(ovary, adrenal)
 11-hydroxylase
deficiency  Maternal ingestion of
 3ß-hydroxysteroid androgenic drugs
dehydrogenase deficiency
 21-hydrxylase deficiency
congenital adrenal hyperplasia
Cholesterol
Pituitary
Pregnenolone
Progesterone ACTH
17-OH progesterone
Adrenal cortex

21-hydroxylase

Cortisol Androgens Cortisol Androgens
 Congenital adrenal
hyperplasia
 The commonest cause of genital
ambiguity at birth
 21-Ohas deficiency is most
common form
 Autosomal reccessive
 Salt wasting form may be lethal in
neonates
 SERUM 17OH-progesterone
(21OHase)
  SERUM deoxycorticosterone,
11-deoxycotisol (11- OHase)
 Treatment : cortisol replacement
and ? Surgery
Drugs with Androgenic side effects
ingested during pregnancy
- Testosterone
- Synthetic progestins
- Danocrine
- Diazoxide
- Minoxidil
- Phenetoin sodium
- Streptomycin
- Penicillamine
 Male pseudohermaphroditism
(XY- FEMALE)
Failure to produce Failure to utelize
testosterone testosterone
 Pure XY gonadal  5-alpha-reductase
dysgenesis (swyer’s deficiency
syndrome)
 Anatomical testicular  Androgen receptor
failure (testicular deficiency
regression syndrome) * Complete androgen
 Leydig-cell agenesis Insensitivity
 Enzymatic testicular * Incomplete androgen
failur Insensitivity
 Swyer’s syndrome
46, XY

No SRY OR its receptors

STREAK GONADS
- NO MIF (Uterus +)
- NO SEX STEROIDS

Female Female
external Internal
Genitalia Genitalia
 Testicular regression syndrome
(congenital anorchia)
46-XY/SRY

Testis  MIF
(self destruction)

± testosterone
± DHT

Female or ± Male
ambiguous Internal
External genitalia
genitalia
 Leydig-cell agenesis
46-XY/SRY

TESTIS  MIF
( partial/ complete absence
Of leydig-cells)

No or  testosterone
No or  DHT

Female or ± Male
ambiguous Internal
external Genitalia
Genitalia
 Testicular enzymatic
46-XY/SRY failure

Testis  MIF Autosomal recessive enzyme

(defects in testosterone deficiency :
Synthesis) -20-22 desmolase
-3-ß-ol-dehydrogenase
-17-  -hydroxylase
 testosterone precursors -17,20-desmolase
DHT -17-ß –hydroxysteroid
oxyreductase
Ambiguous Male
External Internal
Genitalia Genitalia
 46-XY/SRY 5-alpha-reductase
deficiency
Testis  MIF

Testosterone

5--rductase

DHT

Female or Male Internal

Ambiguous Genitalia
external Genitalia
 46-XY/SRY
Testicular feminization
TESTIS  MIF syndrome
Testosterone
5--reductase

DHT

Absent androgen
receptors

Female Male
External Internal
Genitalia Genitalia
Incomplete form  Ambigious genitalia
 Diagnosis of XY Female
Testosterone concentration

Low Normal
Male level
Concentration of
Testosterone precurcers DHT

High Low Low Normal

Testicular Absent testes or 5 -reductase Testicular

enzyme Absent leydig-cell Deficiency Feminization
Failure Syndrome
Surgical exploration
 MIXED GONADAL DYSGENESIS
 Combined features of Turner’s
syndrome and male
pseudohermaphroditism
 Short stature
 Streak gonad on one side with
a testis on the other
 Unicornuate uterus & fallopian
tube- side of streak gonad
 Karyotype 46XY / 45X0
 Considrable variation in the
sexual phenotype
 TRUE HERMAPHRODITISM
• Gonads :
- ovary one side and testis on the other or
- bilateral ovotestis
• Karyotype :
46,XX most common(57%); XY(13%) and XX/XY(30%)
• Internal genitalia :
Both mullerian and wolffian derivates
• Phenotype is variable
• Gonadal biopsy is required for confirming diagnosis
TRUE HERMAPHRODITISM
 DYSEMBROGENESIS
genital ambiguity with associated
anomalies
 Can occur in both genitic males and genitic females
 Most common genital malformation :
- Penoscrotal transposition
- Agenesis of phallus in a genitic male
 Coexistence of other caudal or urologic abnormalities
should strongly suggest dysembryogenisis
 CLINICAL PRESENTATION
OF INTERSEXUALITY
 AT BIRTH
Ambiguous genitalia
 DURING CHILDHOOD
Heterosexual features
 AT ADOLESSCENCE
Delayed or Heterosexual Puberty
 AMBIGUOUS GENITALIA AT BIRTH

The external genital Any one of the following :

organs look unusual,  A small, hypospadiac
making it impossible phallus and unilaterally
to identify the sex of undescended gonad.
the newborn from its  An enlarged phallus with
outward appearance. bilaterally impalpable
gonads.
 An enlarged phallus and
a vagina in the same
infant.
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.
 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 testes until proven otherwise
 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)
 A PROTOCOL FOR INVESTIGATION
OF A NEWBORN WITH AMBIGUOUS
GENITALIA
Karyotype all

Palpable gonad

NO YES

CAH Sreen
. Biochemical profile
Positive Negative . US / MRI /? genitogram
- US / MRI . ? Gonadal biopsy
-? Genitogram
TA US Genitogram
 Sex assignment
General guidelines
• Sex assignment should be decided after
detailed assessment, investigations and
accurate diagnosis
• Complete gender assignment by age 18
months
 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
 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
Before surgery After surgery
 Concluding remarks on
Management of newborn with genital
ambiguity
The causes of ambiguous genitalia are many and
complex, so it is important to approach the treatment
of children with this disorder in a systematic fashion.
 Evaluation should be done expeditiously, and
parents should be kept informed during the
evaluation to help them understand the embryologic
anomaly that led to their child's genital ambiguity.
 Endocrine supplementation should be instituted
when necessary, and a pediatric surgeon should be
actively involved in assigning the child's sex of
rearing as well as performing any necessary
reconstructive surgery.
 INTERSEXUALITY PRESENTING AT
ADOLESCENCE
Primary amenorrhea Ambiguous genitalia
- Complete androgen - Neglected congenital
insesitivity (TFS) adrenal hyperplasia
- Congenital anorchia - Mixed gonadal dysgenesis
- Partial androgen resistance
( early testicular
regression syndrome) - Congenital anorchia ( Late )
- Testicular enzymatic failure
- Complete leydig-cell
agenesis - Leydig cell agenesis
( incomplete)
- Some forms of enzymatic
testicular failure - True hermaphrotidism
 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
 INTERSEXUALITY PRESENTING
AT ADOLESCENCE
Surgical aspects of manegement
 Clitoral reduction
 Removal of gonads in the presence of Y
chromosome
 Vaginal repair and construction
Before surgery After surgery
GONADECTOMY
VAGINAL CREATION
Vaginal dilatation
McIndoe Vaginoplasty
William’s vulvo-vaginoplasty
Colovaginoplasty
 Transsexualism
 Transsexualism occurs when a person strongly
believes that he or she belong to the opposite
sex.
 This is typically a lifelong feeling and results in
varied degrees of physical/external changes
 These patients should be referred to the
psychiatrist
 Concluding remarks
Management of adolescent with
intersex
 By following an approach that is based on a few embryological;
physiological and anatomical principles-and with a minimum of
tests- the clinician can arrive at a prompt and accurate diagnosis
in patients with intersexuality
 If such a patient is managed correctly, she or he may live a
happy, well adjusted life and may even be fertile
 If the patient is managed incorrectly, she or he may be doomed to
live as a sexual freak in loneliness and frustration
 Gynecologists, endocrinologists, plastic surgeons, urologists
and psychiatrists should be actively involved in the management
of these patients
Abnormal Development
Abnormal Development
Intrauterine exposure to abnormal hormone levels:
 Animal studies: Spatial learning tasks
– Observational studies indicate:
 female rats use landmarks (pictures), male rats use geometric
cues (angles)
 in the absence of landmarks, female rats use geometric cues
 male rats almost exclusively used geometric cues
– Experimental studies indicate:
 depriving newborn male rats of testosterone, and administering
estrogen to newborn female rats -> produces reversal of these
sex typed behaviors
Abnormal Development
Intrauterine exposure to abnormal hormone levels:
 Resnick et al. (1993)
– 422 twin pairs, of which 51 opposite-sex pairs, 15-70 yrs
– completed Sensation-Seeking Scale
– Speculated that intrauterine testosterone would affect females in
opposite sex pairs
– Finding:

 female opposite sex twin pairs more disinhibited, experience seeking,

greater overall sensation seeking
 male opposite sex twins did not differ from male same sex twins
Abnormal Development
Congenital Adrenal Hyperplasia (CAH)
 genetic defect leading to excessive production of androgens
 girls exposed to excessive androgens prenatally
 (taking synthetic steriods prenatally can produce similar condition to CAH)
 Results:
– masculinization of the genitals (which can be surgically corrected)
– masculinization of the brain (based on interviews with subject, mother,
teachers):
 more tomboyish than unaffected sisters
 more aggressive than unaffected sisters
 increased likelihood of masculinized gender identity
Abnormal Development
Congenital Adrenal Hyperplasia (CAH)
 Berenbaum, Resnick, & Hines
– Given a choice of toys CAH girls chose masculine type toys (e.g., cars)
– CAH girls, compared to unaffected sisters, superior at:
 spatial manipulation task

 spatial rotation task

 disembedding task

– CAH girls did not differ from unaffected sisters on perceptual and verbal
tasks
Abnormal Development
Intrauterine exposure to abnormal hormone levels:
 Ehrhardt et al. (1984)
– Participants:
 13 males, 15 females exposed to synthetic progesterone prenatally

 22 males, 15 females exposed to progesterone and estrogen prenatally

 matched unexposed controls

– underwent comprehensive psychological exam including sex dimorphic

behavior
– Findings:
 hormone exposed males did not differ from controls
 hormone exposed females showed greater stereotyped feminine behavior (e.g.,
more interest in doll play, feminine clothing, less interest in physical play)
Abnormal Development
Turner Syndrome:
 affects females only, 1:2500
 “XO” instead of “XX”
 Characteristics:
– short stature (approx. 4’8”), short neck with webbed appearance, low
hairline at the back of the neck, low set ears
– fail to develop breasts at puberty
– incomplete ovary development: do not menstruate
– internal reproductive organs do not develop normally
– cognitive skills?
Abnormal Development
Turner Syndrome:
– cognitive skills:
 normal intelligence

 difficulty with visual spatial tasks (mental rotation), mathematics

 verbal skills normal

Abnormal Development
Triple X Syndrome:
 affects females only, often asymptomatic
 “XXX” instead of “XX”
 Characteristics:
– small head, tall stature
– menstrual irregularities, delayed puberty, premature menopause, infertility
– Cognitive skills?
Abnormal Development
Triple X Syndrome:
– Cognitive skills:
 rare: mental retardation, more “X”, more mental retardation

 delayed development of speech and language skills

 language related learning disabilities, e.g., dyslexia

Abnormal Development
Klinefelter Syndrome:
 affects males only, 1:500 to 1:1000, often asymptomatic
 “XXY” instead of “XY”
 Characteristics:
– small external genitalia, sterile
– feminized appearance: enlarged breasts, slightly curved hips and waist,
lack of body or facial hair, but also taller and more overweight than
unaffected fathers and brothers
– low or absent sex drive
– may be passive and/or shy
– Cognitive skills?
Abnormal Development
Klinefelter Syndrome:
– Cognitive skills:
 below average intelligence

 delayed onset of speech

 difficulty learning to read and write

 life-long and pervasive difficulty with language

Abnormal Development
XYY syndrome:
 affects males only, 1:1000
 Characteristics:
– tall, about 3 inches taller than normal on average
– severe acne
– normal fertility, normal sexual drive
– Increased aggressiveness?
– Cognitive skills?
Abnormal Development
XYY syndrome:
– Increased aggressiveness?
 famous serial murder case: Richard Speck, 1970s, murdered 8 women

 subsequent studies indicate inconsistent findings

– Cognitive skills:
 intelligence within normal range

 some learning and school related difficulties

Abnormal Development
 True hermaphrodism:
– possessing both male and female sexual anatomy
– example: one ovary, one testis, vaginal opening and
penis
 Pseudohermaphrodism:
– ovaries or testes, but not both
– if ovaries, then male external sexual anatomy
– if testes, then female external sexual anatomy
Abnormal Development

How should a child be raised if it (he/she) is

born with ambiguous genitalia? In other
words, what criteria should be used to
decide whether the child should be raised as
a boy or a girl?
Abnormal Development
Androgen Insensitivity Syndrome (AIS):
 XY genetics, raised as girls
 body unable to detect and respond normally to androgens
 complete AIS:
– normal external female appearance
– feminized external genitalia, short, blind-ending vagina
– absence of internal female genitalia - no fallopian tubes, uterus, or cervix

– undescended testes
– at puberty, normal female development (e.g., breasts)
– female gender identity, heterosexual orientation
 estradiol did not masculinize the brain!

 Explanations: culture overrides biology? Both testosterone and estradiol

required to masculinize the brain?

 incomplete AIS
Abnormal Development
5-alpha reductase syndrome: Guevedoces ("eggs-at-12")
 XY genetics, raised as girls
 unable to convert T to dihydrotestosterone
 Complete:
– feminized external genitalia, short, blind-ending vagina
– uterus and fallopian tubes absent - normal secretion of Mullerian
inhibiting factor
– testes, epididymis, vas deferens, seminal vesicles intact
– often misdiagnosed as AIS at birth (if ambiguous genitalia)
Abnormal Development
5-alpha reductase syndrome: Guevedoces ("eggs-at-12")
– at puberty: females begin to masculinize
 penis enlargement

 shoulders broaden, hips narrow

 no breast development

 facial hair growth

 adams apple becomes more prominent

– gender identity?
Abnormal Development
5-alpha reductase syndrome: Guevedoces ("eggs-at-12")
– Gender identity
– Imperato-McGinley et al. (1979)
 examined 38 subjects with 5 alpha-reductase deficiency
 all born with female genitalia, 18 raised unambiguously as girls
 normal plasma testosterone levels for a male
 Finding:
– during or after puberty 17 of 18 changed to male gender identity/gender
role
– suggests that exposure to normal male levels of T in utero and at puberty
contributes to male gender identity
– suggests that exposure to normal male levels of T in utero and at puberty
overrides the sociocultural influence of being raised as girls
Abnormal Development
Persistent Mullerian duct syndrome:
 XY
 inability to synthesis Mullerian-inhibiting hormone
 insensitivity to Mullerian-inhibiting hormone
 presence of uterus and fallopian tubes
 otherwise normal males
Abnormal Development
Ablatio penis:
 John Money (1975)
– reported case XY male
– penis lost at 7months due to accident, raised female
– had identical twin brother
– at age 9 female gender identity disorder
 Later follow-up:
– psychological problems
– gender identity confusion
– male gait
 Dr. M.Sasmito Djati
(associate professor)
e-mail : msdjati@ub.ac.id