Intersex made easy Anmar Nassir Dr. Anmar Nassir, FRCS(C) Canadian board in General Urology Fellowship in Andrology (U of Ottawa) Fellowship in EndoUrology and Laparoscopy (McMaster Univ) Assisstent Prof Umm Al-Qura Consultant Urology King Faisal Specialist Hospital Anmar Nassir

Intersex It is part of Genital abnormalities: Intersex Hypospedias Extophy- epispadias Undescended testicle Hernias & Hydroceles

Sexual development: Genetic Gonadal Phenotypic

Cascade of events Schematic representation of the interaction between the seven major factors in sexual development.

Pioneering intrauterine experiments Alfred Jost , A. Arch. Anat. Microsc. Morphol. Exp. 1947 Background Pioneering intrauterine experiments During wartime in the 1940's / France. He showed that by removing the gonadal ridges : both the internal and external genitalia - female lines irrespective of the genetic sex.

In a second series - inserted a crystal of testosterone - external genitalia in all cases masculinized although the Mullerian ducts persisted concluded female was the pathway of default normal masculinization to occur, the testes must secrete, in addition to testosterone, another substance which was responsible for suppression of the Mullerian ducts We now know this as (AMH)

Internal genitalia TDF - SRY gene Male differentiation Begins 6th wk Female differentiation is the default Begins 8th wk Suppressed w AMH But the 2nd X Requires local T Contribution of the wolffian and müllerian ducts and the urogenital tract.

Ian A. Aaronson, DJU, 1999

External genitalia DHT for fusion LS GU sinus (prostate) Phallus Normal sexual development in the male and female.

Intersex Categories By Allen 1976 Ovary only Testis only Ovary + Testis Testis + Streak gonad Streak + Streak gonad Female pseudohermaphrodite Male pseudohermaphrodite True hermaphrodite Mixed Gonadal dysgenesis Pure gonadal dysgenesis

? Case Baby born – looked phenotypically male Circumcised at day 1 or 2 & sent home Came back to hosp. on day 5 Collapsed floppy kid Dehydrated Low Na ?

CAH 46 XX

Sever clitoromegaly in sever CAH F Mild clitoromegaly in mild CAH F

Intersex Categories By Allen 1976:

Female pseudohermaphrodite This is the most common type forms 60-70% of all intersex cases presenting during the neonatal period

Desoxycorticosterone Minerlocorticoid Glucocoticiod Sex Steroid Pregnenlolone Progesterone Desoxycorticosterone Corticosterone 18 OH Corticosterone Aldosterone Cholesterol Desmolase 3 B HSD 21 OH 11 OH 18 OH Desmolase 17 a OH 17 OH Pregnenlolone 17 OH Progesterone 11 Desoxycortisol Cortisol 3 B HSD 21 OH 11 OH DeHydroEpiAndrosterone Androstendione Testosterone Estradiol 3 B HSD

CAH/ Adreno-genital Syndrome Autosomal recessive inheritance, 1:10000 live birth. Six types of CAH exist, only types I - IV are virilising causing female pseudohermaphrodites.

Desoxycorticosterone 11 Desoxycortisol Types of CAH: Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD IV 17 a OH Progesterone 17 OH Progesterone Androstendione I II 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol III 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

Pseudohermaphrodite CAH In female Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

21 Hydroxylase Deficiency: Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD Androstendione 17 a OH Progesterone 17 OH Progesterone Testosterone Estradiol 21 OH 21 OH 90 % of CAH 1 : 50,000 births 50-70 % salt wasting Female = ambiguous, Hyperpig Male = virlization Desoxycorticosterone 11 Desoxycortisol 11 OH Depend on the degree 11 OH Hydrocortisone bolus IV 50 mg Then Maintenance Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

11 Hydroxylase Deficiency: Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 5 % of CAH HTN Female = ambiguous, Hyperpig Male = virlization 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

3 B Hydroxy steroid DH Deficiency: Weak Androgen Desmolase Cholesterol Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone Survival is rare due to more proximal enzyme bloke 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

Intersex Categories By Allen 1976 Ovary only Testis only Ovary + Testis Testis + Streak gonad Streak + Streak gonad Female pseudohermaphrodite Male pseudohermaphrodite True hermaphrodite Mixed Gonadal dysgenesis Pure gonadal dysgenesis

Male pseudohermaphrodite Insufficient T Enzymatic def. CAH (pitut/hypoth. Abn) End organ failure 5 a reductase def. dec. receptor MIS deficiency

Pseudohermaphrodite CAH In Male 20 a OH lase Cholesterol 17 , 20 Desmolase 17 a OH Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH 17 keto R Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

17 Hydroxylase Deficiency: Desmolase Cholesterol Desmolase 17 a OH HTN Hypokalemic alkalosis Female = Normal Male = Ambiguous Pregnenlolone 17 OH Pregnenlolone DeHydroEpiAndrosterone 3 B HSD 3 B HSD 3 B HSD 17 a OH Progesterone 17 OH Progesterone Androstendione 21 OH 21 OH Desoxycorticosterone 11 Desoxycortisol 11 OH 11 OH Testosterone Estradiol Corticosterone Cortisol 18 OH 18 OH Corticosterone Aldosterone

5 alpha Reductase Deficiency Pseudovaginal perineoscrtal Hypospadias AR 46 XY Wolffian duct terminate into vagina b/o no DHT b/o normal T

Case Beautiful 14 yr old female w primary ammenorrhea ?

Blind vagina No internal female organ T fm

Male pseudo male XY