INTERSEX �& �IT’S MANAGEMENT

DR ACHARA AMAECHI PETER

VISITING LECTURER, DEPATMENT OF O & G, COLLEGE OF HEALTH SCIENCES, BINGHAM UNIVERSITY

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OUTLINE

• DEFINITION/INTRODUCTION
• NORMAL SEXUAL DIFFERENTIATION
• CLASSIFICATION OF INTERSEX
• CLINICAL PRESENTATION OF INTERSEX
• INVESTIGATION OF NEWBORN WITH AMBIGOUS GENITALIA
• TREATMENT OF NEWBORN WITH AMBIGOUS GENITALIA
• SEX ASSIGNMENT
• INTERSEX AT ADOLESCENCE
• TRANSEXUALISM
• CONCLUSION

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DEFINITION/INTRODUCTION

DEFINITIONS

• INTERSEX: An individual in whom there is discordance between chromosomal, gonadal, internal genital, and phenotypic sex or the sex of rearing

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• INTERSEXUALITY:

Discordance between any two of the organic sex criteria

• TRANSSEXUALITY:

Discordance between organic sex and psychological sex components

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• In intersex, there is:
• A state of confusion in the determination of the sex of an individual.
• Male and female sex organs occurring together in a single person.
• Condition of external genitalia in which there is question about sex of baby
• How many children are born with intersex condition?
• 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

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DEFINING 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

Human sexual differentiation

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Chromosomal sex

Gonadal sex

External genital sex

Internal genital sex

SEX ASSIGNMENT

Gender identity

and role

Sex of rearing

NORMAL SEXUAL DIFFERENTIATION

Involves:

1. Establishment of chromosomal sex at fertilization
2. Development of the undifferentiated gonads into testes or ovaries
3. Differentiation of the internal ducts and external genitalia

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UNDIFFERENTIATED UROGENITAL TRACT

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8 wks

10 wks

Undifferentiated External genitalia

DIFFERENTIATION TIMELINE

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GONADAL DEVELOPMENT

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SRY-gene (TDF)

Short arm of Y chromosome

Bipotential Gonad

2 X chromosomes

Receptors

For H -Y antigen

OVARY

TESTES

Present

Absent

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Y chromosome

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Leydig

cells

Sertoli

cells

Testosterone

Mullerian inhibiting

factor

Wollfian duct

5a-reductase

Urogenital sinus

Regression of

Mullerian ducts

Male external genitalia

Male internal

Genital organs

DHT

TESTIS

Male development

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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

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.

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CLASSIFICATION OF INTERSEXUALITY

• 1. Chromosomal level:
• Turners syndrome [xo] & Turner mosaic
• Tripple x – female
• Klinefelter syndrome
• XYY males
• Abberation in sex determining gene
• 2. Disorder in gonadal differentiation:
• True hermophrodite
• Pure gonadal dysgenesis
• Mixed gonadal dysgenesis
• 3. Absent anti – mullerian hormone [AMH]:
• Persistent Mullerian Duct syndrome

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• 4. End – organ resistance to androgen:
• Absence of androgen receptors
• 5ἀ - reductase deficiency
• 5. Male pseudohermophroditism:
• Leydig cell hypoplasia
• Defect in testosterone synthesis
• 6. Female pseudohermophroditism:
• Congenital adrenal hypperplasia [CAH]
• Exogenous androgen
• Idiopathic

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FEMALE PSEUDOHERMAPHRODITISM

EXCESS FETAL ANDROGENS

Congenital adrenal hyperplasia

 21 -hydrxylase deficiency

 11-hydroxylase deficiency

 3ß-hydroxysteroid

dehydrogenase deficiency

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EXCESS MATERNAL ANDROGENS

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• Maternal androgen secreting tumors (ovary, adrenal)

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 Maternal ingestion of androgenic drugs

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CONGENITAL ADRENAL HYPERPLASIA [CAH]

• It is a familial disorder of adrenal steroid biosynthesis with autosomal recessive mode of inheritance.
• The defect is expressed as adrenal enzyme deficiency.
• 5 major Enzymes deficiency are clinically important
• 21-Hydroxylase
• 11-b-Hydroxylase
• 17-a-Hydroxylase
• 3-b-Hsteroid hydrogenese
• 20,22 Desmolase deficiency

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CAH

• The most frequent is steroid 21-hydroxylase deficiency, accounting for more than 90 percent of cases.
• The enzyme deficiency causes reduction in end-products, accumulation of hormone precursors & increased ACTH production.
• The clinical picture reflects the effects of inadequate production of cortisol & aldosterone and the increased production of androgens & steroid metabolites.

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21-hydrxylase deficiency�congenital adrenal hyperplasia

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Pituitary

ACTH

Adrenal cortex

🡅🡅

Androgens

Cortisol

Cholesterol

Pregnenolone

Progesterone

17-OH progesterone

21-hydroxylase

Androgens

Cortisol

CAH

• The commonest cause of genital ambiguity at birth
• 21-hydroxylase deficiency is most common form
• Autosomal recessive
• Salt wasting form may be lethal in neonates
• ↑SERUM 17OH-progesterone (21OHase)
• ↑SERUM deoxycorticosterone, 11-deoxycotisol (11-OHase)
• Treatment : cortisol replacement and ? Surgery

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DRUGS WITH ANDROGENIC SIDE EFFECT �INGESTED DURING PREGNANCY

• Testosterone
• Synthetic progestins
• Danocrine
• Diazoxide
• Minoxidil
• Phenytoin sodium
• Streptomycin
• Penicillamine

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MALE PSEUDOHERMAPHRODITISM (XY- FEMALE)

Failure to produce testosterone

 Defects in testicular

steroidogenesis

 Gonadotropin-resistant

testes (LH receptor mutation)

 Congenital lipoid adrenal

hyperplasia

 Defective synthesis,

secretion, or response to

anti-mullerian hormone

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Failure to utilize testosterone

 Androgen receptor deficiency

* Complete androgen Insensitivity (TFS)

* Incomplete androgen Insensitivity

 5-alpha reductase deficiency

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PURE GONADAL DYSGENESIS� (SWYER’S SYNDROME)

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46, XY

No H-Y OR its receptors

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

Female Internal Genitalia

Female external

Genitalia

TESTICULAR REGRESSION SYNDROME�(CONGENITAL ANORCHIA)

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46-XY/SRY

Testis 🢧 MIF

(self destruction)

± testosterone

± DHT

± Male Internal genitalia

Female or

ambiguous

External

genitalia

LEYDIG-CELL AGENESIS

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46-XY/SRY

TESTIS 🢧 MIF

( partial / complete absence

Of leydig-cells)

No or 🡇 testosterone

No or 🡇 DHT

± Male

Internal

Genitalia

Female or ambiguous external Genitalia

TESTICULAR ENZYMATIC FAILURE

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46-XY/SRY

Testis 🢧 MIF

(defects in testosterone

Synthesis)

↑ testosterone precursors ↓DHT

Male Internal Genitalia

Ambiguous

External

Genitalia

Autosomal recessive enzyme deficiency : 20-22 desmolase

3-ß-ol-dehydrogenase 17- β -hydroxylase 17,20-desmolase 17-ß –hydroxysteroid oxyreductase

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5-alpha-reductase �deficiency

46-XY/SRY

Testis 🢧 MIF

Testosterone

🡇5-α-reductase

Male Internal Genitalia

Female or Ambiguous external Genitalia

🡇DHT

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Testicular feminization syndrome

46-XY/SRY

TESTIS 🢥 MIF

Testosterone

5-α-reductase

DHT

Absent androgen receptors

Male Internal Genitalia

Female

External

Genitalia

Incomplete form 🢧 Ambigious genitalia

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DIAGNOSIS OF XY FEMALE

Testosterone concentration

Normal

Male level

DHT

Normal

Low

Testicular

Feminization

Syndrome

5 α-reductase

Deficiency

Low

Concentration of

Testosterone precursors

Low

High

Absent testes or

Absent Leydig -cell

Testicular

enzyme

Failure

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
• Considerable variation in the sexual phenotype

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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

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TRUE HERMAPHRODITISM

DYSEMBRYOGENESIS�GENITAL AMBIGUITY WITH ASSOCIATED ANOMALIES

• Can occur in both genetic males and genetic females
• Most common genital malformation :
• Peno-scrotal transposition (scrotum is located above penis)
• Agenesis of phallus in a genetic male
• Coexistence of other caudal or urologic abnormalities should strongly suggest dysembryogenisis

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CLINICAL PRESENTATION�OF INTERSEXUALITY

• AT BIRTH

Ambiguous genitalia

• DURING CHILDHOOD

Heterosexual features

• AT ADOLESCENCE

Delayed or Heterosexual Puberty

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AMBIGUOUS GENITALIA AT BIRTH

The external genital organs look unusual, making it impossible to identify the sex of the newborn from its outward appearance.

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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.

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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.

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EVALUATION AND MANAGEMENT OF THE NEWBORN WITH AMBIGUOUS GENITALIA

• Medical and psychosocial emergency to be handled with great sensitivity toward the family
• Goals:
• precise diagnosis of the intersex disorder
• assign a proper sex of rearing based on the diagnosis
• determine the status of the child's anatomy
• delineate the functionality of genitalia and reproductive tract
• Valuable history points:
• infant death
• infertility
• amenorrhea
• hirsutism
• maternal medications (i.e. steroids , OCP), during pregnancy

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• Physical examination: the presence of one or two gonads
• Distinctly palpable gonad along the pathway of descent is highly suggestive of a testis

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MANAGEMENT OF NEWBORN WITH AMBIGUOUS GENITALIA

DIAGNOSIS

• History : pregnancy; family
• Detailed examination: Abdomen; pelvis; external genitalia; urethral and anal openings
• Are gonads palpable?
• What is the phallus length?
• What is the position of the urethral meatus?
• To what degree are the labioscrotal folds fused?
• Is there a vagina, vaginal pouch, or urogenital sinus?
• Dehydration, hypotension, hyperpigmentation in adrenal hyperplasia
• Federman’s rule: a palpable gonad below the inguinal ligament is testes until proven otherwise

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EVALUATION AND MANAGEMENT OF THE NEWBORN WITH AMBIGUOUS GENITALIA

• Posterior urethral meatal position is a strong predictor of intersex 65%, versus 5% to 8% with a midshaft to anteriorly located hypospadiac meatus
• Penile size should be assessed and an accurate measure of stretched penile length recorded.
• Precise means of assessing müllerian anatomy is by pelvic ultrasound
• Karyotype should be obtained
• Serum studies should be immediately sent to rule out a salt-wasting form of CAH.
• Serum electrolytes, testosterone and DHT should be measured early

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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)

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TREATMENT

• Sex assignment

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• Counseling

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• Genital reconstruction
• Generally easier to reconstruct as female
• If an inadequate phallus cannot be reconstructed surgically, better in female gender role

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PROTOCOL FOR INVESTIGATION OF NEWBORN �WITH AMBIGOUS GENITALIA

• KARYOTYPE ALL → PALPABLE GONADS?:
• YES: BIOCHEMICAL PROFILE, USS, MRI, ? GENITOGRAM, ? GONADAL BIOPSY
• NO: CAH SCREENING;

→ POSITIVE: USS, ?MRI, ? GENITOGRM

→ NEGATIVE: BIOCHEMICAL PROFILE, USS, MRI, ? GENITOGRAM, ? GONADAL BIOPSY

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TREATMENT: Others

• CAH:
• Cortisol replacement
• Fludrocortisone acetate replacement: mineralocorticoid def. and salt losing

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• Mixed gonadal dysgenesis:
• Gonadectomy of streak gonad

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• True hermaphrodite:
• Inadequate phallus
• Remove testis
• Remove testicular portion of ovotestis
• Rear as female
• Adequate phallus
• Remove all mullerian structures
• Hypospadias repair
• Rear as male

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GENDER ASSIGNMENT

General guidelines

• Sex assignment should be decided after:

–detailed assessment,

–investigations and

–accurate diagnosis

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• Complete gender assignment by age of 18 months

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GENDER ASSIGNMENT

• Male gender assignment :

-stretched phallus > 2 cm

-erectile tissue

-lack of severe hypospadias

• Female gender assignment :

-inadequate phallus

-cervix and uterus present

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• In difficult cases; sex assignment should be to the sex which can be surgically made to be adequate for coitus

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SURGICAL CONSIDERATION

• 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

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INTERSEXUALITY PRESENTING AT ADOLESCENCE

Primary amenorrhea

- Complete androgen insensitivity (TFS)

- Congenital anorchia

( early testicular regression syndrome)

- Complete leydig-cell agenesis

- Some forms of enzymatic testicular failure

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Ambiguous genitalia

- Neglected congenital adrenal hyperplasia

- Mixed gonadal dysgenesis

- Partial androgen resistance

- Congenital anorchia ( Late )

- Testicular enzymatic failure

- Leydig cell agenesis

( incomplete)

- True hermaphrotidism

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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 ἀ-reductase deficiency : Some May seek to change the gender role

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SURGICAL ASPECT OF MANAGEMENT �OF INTERSEX PRESENTING AT ADOLESCENCE

• Clitoral reduction
• Removal of gonads in the presence of Y chromosome
• Vaginal repair and construction

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VAGINAL CREATION

• Vaginal dilatation: with a set of vaginal dilators
• Mcindoe vaginoplasty: the Mcindoe & Reeds vaginoplasty involve creating a cavity b/w bladder and the bowel at the site of natural vagina, and then the cavity is lined by a split thickness skin graft taken from the thigh and applied to a plastic mold. Post op pain and fistula formation are possible complications
• Williams vulvo-vaginoplasty: involves the creation of an external pouch by suturing the labia majora to form a short vertical vagina.

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TRANS-SEXUALISM

• Transsexualism occurs when a person strongly believes that he or she belongs 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

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CONCLUSION

• Multi-disciplinary approach is recommended in intersex management. The gynaecologist, endocrinologist, plastic surgeon, urologist and psychiatrist are important.
• Intersex can present early in infancy or even as late as in adolescence. For those presenting later in life, it’s better not to assign a new sex.
• Removal of streak gonads with Y chromosomes advised, to prevent dysgerminoma.
• Generally, Female phenotype is easier to create than male phenotype.
• Patients with CAH are given cortisol. Oestrogen replacement needed for Turners syndrome.

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Thank you

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