Intersex : A practical approach to diagnosis of ambiguous genitali [warda]

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this is a trial to simplify the subject of intersexuality for juniour gynecologists

this is a trial to simplify the subject of intersexuality for juniour gynecologists

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  • 1. Osama M. Warda, MD Professor of Obstetrics & Gynecology Mansoura University-EGYPT osama warda,MD INTERSEXUALITY: PRACTICAL APPROACH TO DIAGNOSIS OF AMBIGUOUS GENITALIA
  • 2. NORMAL SEXUAL DIFFERENTIATION Effect of Sex Chromosomes on Gonadal Differentiation. Proper Functioning of the Differentiated Testes {ovaries not important}. Response of End-organs to Testicular activity.
  • 3. Effect of Sex Chromosome on Gonadal Differentiation Sex chromosome has only one function to perform in sexual development ; i.e. to determine the final morphology of the undifferentiated gonad; Presence of (Y) gonads are testes. Absence of (Y) gonads are ovaries. A normal male must have 1-X & 1-Y while a normal female must have 1-X & 1-X. osama warda,MD
  • 4. Mechanism by Which the Y Chromosome Promotes Testicular Differentiation This is done through a single determinant gene called Testicular Determinant Factor (TDF). TDF is present on distal short arm of Y-chromos. TDF begins its action at 6-7 weeks. Loss of TDF leads to gonadal dysgenesis. TDF transfer to X-chromosome leads to XX-male. TDF produces its actions via encoding &expressing 3 proteins; H-Y-antigen ,ZFY-&SRY. ------------------------ H-Y= histocompitability antigen on Y : ZFY= zinc finger protein: SRY=sex determining region Y osama warda,MD
  • 5. Proper Functioning of the Differentiated Testes The testes produce their intrauterine function by producing 2 substances: 1- testosterone 2- antimullerian hormone (AMH) Testosterone gives rise to development of: 1- external genitalia ( di-hydro testosterone) 2- Wollfian ducts (testosterone) AMH gives rise to: 1- inhibition of the mullerian structures. 2- descent of the testes into scrotum. 3- extra-mullerian function. osama warda,MD
  • 6. ABNORMAL SEXUAL DIFFERENTIATION * The standard classification of individuals with intersexuality (Hermaphroditism) proceeds according to gonadal morphology (Speroff, 1999): I- True hermaphrodite = posses both ovarian & testicular tissue II- Female pseudo-hermaphroditism = posses ovaries + masculine external genitalia III- Male pseudo-hermaphroditism = posses testes + external ( and sometimes internal) genitalia take on female phenotype. osama warda,MD
  • 7. ETIOLOGY OF INTERSEXUALITY I- Disorders of fetal endocrinology: A- Masculinized females (female pseudohermaphrodite): 1-Conginital adrenal hyperplasia 2- Elevated androgens in maternal circulation 3- Aromatase (P450 arom) deficiency B- Incompletely Masculinized male (Male pseudohermaphrodite) 1- androgen insensitivity syndromes 2- 5 αααα - reductase deficiency 3- enzymatic testosterone biosynthesis defect 4- gonadotropin resistant testes 5- AMH deficiency. osama warda,MD
  • 8. ETIOLOGY OF INTERSEXUALITY II- Disorders of gonadal development A- Male pseudo-hermaphroditism: 1- Primary gonadal defect (Swyer’s syndrome) 2- Anorchia B- True hermaphroditism C- Gonadal dysgenesis 1- Turner syndrome 2- Mosaicism 3- Normal karyotype (Noonan Syndrome) osama warda,MD Cont.
  • 9. MASCULINIZED FEMALES : Congenital Adrenal Hyperplasia Incidence: the most common, 45% (Speroff, 1999): Types 1- 21 hyroxylase deficiency ( the commonest) 2- 11 β hyroxylase deficiency 3- 3 β hydroxy-steriod dehydrogenase deficiency 4- 17 α hyroxylase deficiency (very rare) Clinical picture 1- simple virilising type 2- salt losing type 3- hypertensive type osama warda,MD
  • 10. MASCULINIZED FEMALES : Congenital Adrenal Hyperplasia Common clinical manifestation A- Masculinization of external genitalia 1- Clitoris 2- Labioscrotal 3- Labia majoa 4-Vagina 5- Progressive virilisation post-natal >>>>(heterosexual precocious puberty) B- Metabolic disorders 1- salt losing type (aldosterone deficiency) 2- hypertensive type 3- hypoglycemia osama warda,MD Cont.
  • 11. DIAGNOSIS A- prenatal: 1- CAH is autosomal recessive 2- detection of elevated amniotic fluid levels of (17 OHP , 21 deoxycortisol & androstendione) 3- molecular genetic diagnosis ( CVS) most accurate. B- Postnatal: 1- clinical: ambiguous genitalia - no palpable testes 2- 17 OHP in blood 3- plasma renin activity 4- urinary 17 ketosteriod 5- others (karyotype, USS) osama warda,MD Cont. MASCULINIZED FEMALES : Congenital Adrenal Hyperplasia
  • 12. osama warda,MD This girl with CAH was 8 years old and was admitted to MUH for plastic correction. She was 3years old when her mother noticed the masculine change of vulva. Note how can the clitoris and labia minora can turn into penis, while the labia majora turns into scrotum-like structure.
  • 13. MASCULINIZED FEMALES : Congenital Adrenal Hyperplasia Treatment A- Medical: 1- hydrocortisone (10 mg/day) OR 2- prednisone (3.5-5 mg/m2 surface area] monitoring of treatment by 17 OHP (range 500 – 4000 ng/dl) B- Surgical: 1- general consideration Patient is genetically female and potentially fertile Surgical correction must be after medical control Parents must be counseled about the procedure 2- surgical procedures: Reduction of clitoris size (amputation, clitoral recession) Division of labio-scrotal folds (introito-plasty) osama warda,MD Cont.
  • 14. Incompletely Masculinized Males Androgen Insensitivity Syndromes 1- Complete androgen insensitivity; testicular feminization [Morris syndrome]*. 2- Incomplete androgen insensitivity (Reifenstein syndrome] 3- 5 α reductase deficiency --------------------------- * Note that the complete androgen insensitivity does not present as ambiguous genitalia but presents at puberty as primary amenorrhea as the phenotype and genitalia are like normal females osama warda,MD
  • 15. Incompletely Masculinized Males Androgen Insensitivity Syndromes Management A- Diagnosis: Clinical, hormonal profiles. B- General consideration: 1- Rearing as female 2- Other members of the family must be investigated (x-linked diseases) 3- Patients are sterile female C- Treatment options: 1-Gonadectomy (malignancy is a risk) 2- Neo-vagina (when needed) 2- Psychotherapy osama warda,MD Cont.
  • 16. Disorders of Gonadal Development Abnormal gonado-genesis may occur as a result of structural defect or disease related catastrophes leading to loss of fetal gonadal function. Abnormal gonadal development is classified as follows: A- Male pseudohermaphroditism 1- Bilateral testicular dysgensis (Swyer syndrome) 2- Anorchia B- True hermaphroditism C- Gonadal dysgensis 1- Turner syndrome 2- Mosaicism 3- Normal karyotype (Noonan syndrome) osama warda,MD
  • 17. CAH 3B - dehydrogenase block in male Androgen: Normal or slight increase Signs of adrenal failure Normal 17OHP laparatomy gonadectomy 1- incomplete androgen insensit. 2-5a. reductase def. 3-true herma. 4- mixed gond. dysg. 5- abnorm. androg. synth. Normal androgen Normal 17 OHP X-Y Karyotype Karyotype, Androgen, 17OHP. osama warda,MD Managment of Ambiguous Genitalia
  • 18. Managment of Ambiguous Genitalia CAH 21-hydroxylase 11B-hydroxylase IncreaseAdrogens Increase17OPH Elevated androgens in maternal circulation Laparotomy Gonadectomy truehermaphrod. or gonadal dysgenesis Normal Adrogens Normal 17OPH XXKaryotype Y - Contianing Abnormal Karyotype Karyotype, Androgen, 17OHP osama warda,MD Cont.
  • 19. osama warda,MD