SEXUAL DIFFERENTIATION: ORDER AND DISORDER

SEXUAL DIFFERENTIATION: ORDER AND DISORDER Chuck Metcalfe, PGY 5 University of British Columbia Department of Urologic Sciences Urology Grand Rounds December 12, 2012 OBJECTIVES REVIEW THE CLASSIFICATIONS/NOMENCLATURE OF DSD OVERVIEW OF NORMAL SEXUAL DIFFERENTIATION REVIEW THE ABNORMAL SEXUAL DIFFERENTIATION CAUSES EVALUATION AND SURGICAL MANAGEMENT OF DISORDERS OF SEXUAL DIFFERENTIAION REVIEW SEXUAL ASSINGMENTS AND PHYSCOLOGICAL IMPLICATIONS 1&

CASE PRESENATION CASTER SEMENYA SOUTH AFRICAN 800 M RUNNER WORLD CHAMPION 2009 INVESTIGATED AND SUSPENDED FOR PRESUMED ABNORMAL TESTOSTERONE LEVELS/SUSPICION OF DRUG USE 2&

CLASSIFICATION OF INTERSEX INTERSEX TERM NO LONGER USED CHANGED TO DISORDER OF SEXUAL DIFFERENTIOATION CLASSIFICATION OF DSD OLD TERMS: NEW CLASSIFICATION INTERSEX MALE PSEUDO HERMAPHODITE FEMALE PSEUDO HERMAPHODITE TRUE HERMAPHODITE XY SEX REVERSAL DSD 46 XY DSD 46 XX DSD OVOTESTICULAR DSD 46 XY GONADAL DYSGENESIS 3&

DSD WHAT DOES THIS MEAN? 46 XY DSD! UNDERMASCULINIZED MALE 46 XX DSD! OVERMASCULINIZED FEMALE OVOTESTICULAR DSD! TRUE HERMAPHODITE MULTI-STEP PATHWAY CHROMOSOMES DETERMINE GENES GENES DETERMINE GONADS GONADS DETERMINE HORMONES HORMONES NEED RECEPTORS RECEPTORS NEED ORGANS 4&

GENETICS SRY DISCOVERED IN 1990 FROM TDF LOCUS ON Y CHROMOSOME XX MALES AND XY FEMALES ACTIVATES DOWNSTREAM GENE EXPRESSION BIPOTENTIAL FETUS AN AWFUL LOT OF WORK GOES INTO TRYING TO DEVELOP AWAY FROM BEING FEMALE DEFAULT BATHED IN ESTROGEN REQUIRES ANDROGEN TO DEVELOP MALE STRUCTURES REQUIRES MIS TO INHIBIT FEMALE STRUCTURES FUNDAMENTAL ASPECT OF PHYSIOLOGY AND PATHOPHYSIOLOGY 5&

GONADS DIFFERENTIATION STARTS IN 6 TH WEEK DEVELOPMENT OF SERTOLI CELLS MIS FROM SERTOLI AT 7-8 WEEKS PARACRINE ASYMMETRICAL OVARIAN PATHWAY ABSENCE OF MIS POORLY UNDERSTOOD 2 ND X REQUIRED TURNER S SYNDROME INTERNAL GENITALIA WOLFFIAN = MESONEPHRIC MESONEPHRIC FOR KIDNEY DEVELOPMENT = WOLFFIAN FOR GENITALS MULTIPLE EMBRYOLOGIC SEQULAE MÜLLERIAN = PARAMESONEPHRIC DEVELOPS IN 6 TH WEEK LATERAL TO MESONEPHRIC DUCTS 6&

ANDROGENS TESTOSTERONE BY 9 WEEKS PEAK AT 13 WEEKS ANDROGEN RECEPTOR VIRILIZATION OF WOLFFIAN DUCT PASSIVE DIFFUSION TISSUE CONVERSION TO DHT INCREASED AFFINITY TO AR UG SINUS, PROSTATE, GENITALIA 2 DISTINCT ENZYMES 5ΑR 1 : SKIN AND HAIR 5ΑR 2: PROSTATE CLONED AND MAPPED TO X CHROMOSOME External Genitalia GLANS URETHRAL FOLD LABIO-SCROTAL SWELLING 7&

EVALUATION OF AMBIGIOUS GENATALIA HISTORY HISTORY IF INFANT DEATH IN FAMILY HISTORY OF INFERTILITY/AMENORRHEA/ HIRSUTISM MATERNAL MEDS (STEROIDS/ CONTRACEPTIVES) PE PALPABLE GONADS HYPOSPADIUS (MEATAL POSITION) STRETCHED PENILE LENGTH EVALUATION OF AMBIGIOUS GENATALIA HYPOSPADIUS AND SINGLE PALPABLE UDT- 15% SINGLE NON PALPABLE UDT-50% BILATERAL PALPABLE UDT-16% BILATERAL NON PALPABLE UDT-50% INCREASED WITH PROXIMAL VS DISTAL HS 65% VS. 5-8% 8&

EVALUATION OF AMBIGIOUS GENATALIA INVESTIGATIONS CBC, LYTES, BUN/CR (emergently) T/DHT 17 OH PROGESTERONE KARYOTYPE ULTRASOUND GENITOGRAM CYSTOSCOPY MRI LAPAROSCOPY GENITAL BIOPSY DISORDERS OF SEXUAL DIFERENTIATION 1) 46 XX DSD CAH MATERNAL ESTROGEN 2) 46 XY DSD DISORDERS OF T PRODUCTION DISORDERS OF T CONVERSION DISORDERS OF ABNORMAL ANDROGEN RECEPTORS 3) DISORDERS OF GONADAL DIFF KLINEFELTER,TURNERS 46 XX MALE PURE/MIXED GONADAL DYS 4) OVOTESTICULAR DSD 9&

ABNORMAL DIFFERNTIATION 46 XX DSD (OVERVIRULIZED FEMALE) 1) CONGENITAL ADRENAL HYPERPLASIA 2) MATERNAL EXTROGENS CONGENITAL ADRENAL HYPERPLASIA 3 BROAD CATEGORIES 1) SALT WASTING VIRILIZATION AND SALT WASTING CLASSIC PRESENTATION AT 10-21 DAYS WT LOSS, DEHYDRATION, HYPOTENSION, HYPERKALEMIA 2) SIMPLE VIRILIZATION MALES PRESENT AT 2-3 YEARS WITH ISOSEXUAL PRECOCITY 3) NON-CLASSIC NEITHER SALT WASTING NOR VIRILIZATION 75% SALT WASTING; 25% NON SALT WASTING 10&

CONGENITAL ADRENAL HYPERPLASIA 21-HYDROXYLASE DEFICIENCY 95% CASES CAH MAJORITY OF AMBIGUOUS GENITALIA 1/15,000 US TO 1/490 IN ALASKAN ESKIMOS GENE IS CYP-21 10 DIFFERENT MUTATIONS DESCRIBED AR TRANSMISSION 11&

21-HYDROXYLASE DEFICIENCY 12&

21-HYDROXYLASE DEFICIENCY DIAGNOSIS ELEVATED PLASMA PROGESTERONE AND 17-HYDROXYPROGESTERONE IMMUNOASSAY FOR MORE RAPID DIAGNOSIS URINARY 17 KETOSTEROIDS PELVIC ULTRASOUND MÜLLERIAN STRUCTURES 21-HYDROXYLASE DEFICIENCY HYDROCORTISONE SUPPLEMENTATION SUPPLY DEFICIENCY SUPPRESS ACTH EMPIRICAL DOSE PATIENT, LABS, BP FEMINIZING GENITOPLASTY CONTROVERSIAL CLITOROPLASTY 3-12 MONTHS OF AGE LONG TERM FERTILITY FOR WELL MANAGED PROPHYLACTIC ADRENALECTOMY MOST SEVERE CASES; FAILED MEDICAL MANAGEMENT 13&

ABNORMAL DIFFERENTIATION 46 XY DSD (UNDERVIRULIZED MALE) ABNORMALITIES OF T PRODUCTION ABNORMALITIES OF T CONVERSION ABNORMALITIES OF T RECEPTORS 46 XY DSD ABNORMALITIES OF T PRODUCTION ENZYMES POSSIBLITIES, ALL VERY RARE 14&

46 XY DSD ABNORMALITIES OF T CONVERSION 5 ALPHA REDUCTASE DEFICENCY 40 DIFFERENT MUTATIONS VARIABLE NEONATAL PHENOTYPE PENOSCROTAL HYPOSPADIUS TO MARKEDLY AMBIGOUS GENITALIA ABSENCE OF MULLERIAN STRUCTURES UROGENITAL SINUS/LABIOSCROTAL FUSION NORMAL WOLFFIAN STRUCTURES NORMAL VAS AND EPIDIDYMIS T NEEDDED FOR WOLF/DHT NEEDED FOR EXTERNAL GENITALIA 5 ARi Familial Incomplete Male Pseudohermaphroditism, Type 2 Decreased Dihydrotestosterone Formation in Pseudovaginal Perineoscrotal Hypospadias Patrick C. Walsh, M.D., James D. Madden, M.D., Mary J. Harrod, Ph.D., Joseph L. Goldstein, M.D., Paul C. MacDonald, M.D., and Jean D. Wilson, M.D. N Engl J Med 1974; 291:944-949 15&

5AR de/ DHT 5 ARi Effects of Finasteride (MK-906), a 5α-Reductase Inhibitor, on Circulating Androgens in Male Volunteers GLENN J. GORMLEY, ELIZABETH STONER, ROGER S. RITTMASTER, HALL GREGG, DAVID L. THOMPSON, KENNETH C. LASSETER, PETER H. VLASSES, and EVAN A. STEIN JCEM 1990 70: 1136-1141; 1989 Finasteride started human trials Decreased levels of DHT 1990 Well tolerated medication T/DHT ratio returned to normal after stopping medication 16&

5 ARi Decreased prostate size Increased max flow rates Effective chronic therapy for Benign Prostatic Hyperplasia Finasteride vs. Placebo 900 men, daily dose for 12 months Placebo, 1 mg and 5 mg Significant decrease in total urinary symptom score Increase of 1.6 ml/second in max flow rate 19% decrease in Prostatic volume 17&

46 XY DSD ANDROGEN RECEPTOR AND POST RECEPTOR DEFECTS MOST COMMON IDENTIFIABLE CAUSE 46 XY WITH TESTES SPECTRUM OF PHENOTYPES SEVERITY OF RECEPTOR DISORDER COMPLETE! NORMAL FEMALE PARTIAL ANDROGEN INSENSITVITY COMPLETE ANDROGEN INSENSITIVITY 46 XY-BILATERAL TESTES FEMALE APPEARING EXTERNAL GENETAILIA ABSENCE OF MULLERIAN STRUCTURES USUALLY DIAGNOSED SECONDARY TO PRIMARY AMENORRHEA OR TESTES AT INGUINAL HERNIORRHAPHY RAISED AS FEMALES 18&

PARTIAL ANDROGEN INSENSIVITY VARIED AMBIGUITY OF EXTERNAL GENTALIA RANGE FROM HYPOSPADIUS AND A PSEUDOVAGINA TO GYNECOMASTIA AND AZOOSPERMIA TWO TYPES OF RECEPTOR DEFECTS 1. DECREASED NUMBER OR NORMALLY FUNCTIONING AR 2. NORMAL RECEPTOR BUT DECREASED BINDING AFFINITY MANAGEMENT INDIVIDUALIZED DEPENDING ON DEGREE OF AMBIGUITY OVOTESTICULAR DSD (TRUE HERMAPHODITE) BOTH OVARIAN AND TESTICULAR TISSUE TESTICULAR TISSUE Developed seminiferous tubules OVARIAN TISSUE Primordial follicles 1 TESTES/1 OVARY, ONE OR TWO OVOTESTES PHENOTYPE VAIRED MOST AMBIGOUS, BUT VIRILIZED 75% ARE RAISED AS MALES 60% ARE 46 XX 19&

OVOTESTICULAR DSD DIFFERENTIATION OF THE INTERNAL DUCTS AS VARIABLE AS EXTERNAL GENITALIA INTERNAL DUCTS RELATED TO FUNCTION OF IPSILATERAL GONAD POTENTIAL FOR FERTILITY IF RAISED AS FEMALES AND APPROPRIATE DUCTAL STRUCTURES 20&

GONADAL DYSGENESIS MIXED GONADAL DYSGENESIS 2 ND MOST COMMON DIAGNOSIS MOST HAVE 45 XO/46XY MAY BE PHENOTYPICALLY ASYMMETRIC CONTRALATERAL STREAK GONAD GONADAL DYSGENESIS PHENOTYPE VARIABLE TURNER S TO AMBIGIOUS TO RARE MALE PHALLIC ENLARGEMENT, UG SINUS, LABIOSCROTAL FUSION UNDESCENDED TESTES (INTRAABDOMINAL) MULLERIAN STRUCTURES PRESENT -IPSILATERAL STREAK GONAD 21&

DSD AND TUMORS HIGHEST RISK IN COMPLETE DYSGENESIS -30% TUMOR BY 30 YRS OF AGE -INCOMPETE DYGENESIS UP TO 15% -REQUIRE Y CHROMOSOME TO BE AT RISK GERM CELL MALIGNANT DEGENERATION -SEMINOMA AND NON-SEMINOMA ALL DYSGENETIC GONADS TO BE REMOVED -SCROTAL TESTES AT DECREASED RISK DSD and TUMORS HIGHEST RISK Complete gonadal dysgenesis Partial gonadal dysgenesis with non scrotal gonad Partial androgen insensitivity and non scrotal gonad INTERMEDIATE Partial androgen insensitivity with scrotal gonad LOW Complete Androgen Insensitivity Ovotesticular DSD 22&

SEXUAL ASSIGNMENT John-Joan Case David (Bruce) Reimer born 1965 (Identical twin)?phimosis at age 6 months Severe Cautery Injury to penis Consulted Dr. Money (Hopkins) OR at 22 mo,bilat orchiectomy, urethostomy Raised as a girl (Ideal control w/twin brother) Traumatic visits to Dr.Money Suicidal age 14, parents reviled Age 15 decided to be male (David) Married, stepfather.suicide age 38 SEXUAL ASSIGNMENT TWO DIFFERENT SCHOOLS OF THOUGHT 1. MONEY AND ASSOCIATES PROACTIVE APPROACH, GENDER SPECIFIC ROLE PLAY, EARLY SURGICAL THERAPY. EXPOSURE TO ANDROGENS IN UTERO/GENETIC SEX SECONDARY TO SPECIFIC SOCIAL CONTEXT SOCIAL AND CHARACTERISTICS OF EXTERNAL GENITALIA MOST IMPORTANT FACTORS (MONEY ET AL. J SEX MARITAL THER 1987) 23&

SEXUAL ASSIGNMENT 2. DIAMOND AND SIGMUNDSON SEXUAL IDENTITY DOES NOT DEPEND ON EXTERNAL GENITALIA GENETIC IMPRINT ON CENTRAL NERVOUS SYSTEM IN UTERO/EARLY CHILDHOOD POST PUBERTAL HORMONAL CHANGES COINCIDE WITH IMPRINT GENETIC IMPRINTING UNKNOWN CRITICAL PERIOD ANDROGENS EXPOSURE ON DEVELOPING BRAIN MAY BE STRONGEST PREDICTOR TESTOSTERONE SPIKE @ 14-16 WEEKS GESTATION testosterone in male fetus and infant 61 HUTSON ET AL. J UROL 2002 24&

GENETIC IMPRINTING 46 XX- CAH, RAISED AS FEMALES MORE TOMBOYISH BEHAVOIR/ROUGH PLAY VS. OTHER GIRLS (Berenbaum, S.A. Psycol Sci 1992, Money et al. Pschoneuroendocrinology, 1987) HIGHER RATES OF BISEXUAL/HOMOSEXUAL TENDENCIES (Erhnhardt, A.A. Science 1984) ANIMAL STUDIES Female rates with exposed to perinatal testosterone reveal male mating behaviors (Ward,IL. J Physio Psychology 1980) Postnatal testosterone treatment within 1-6 months correlate strongly with male behaviors (Hrabovszky, Z. J Urol 2002) SEXUAL ASSIGNMENT WILL ALWAYS BE CONTROVERSIAL PHYSICAL/ PSYCHOSOCIAL ISSUES ARE VAST MULTITEAM APPROACH ENDOCRINOLOGIST PEDIATRIC UROLOGIST PEDIATRIC GYNECOLOGIST PSYCIATRIST GENERAL SURGERY GENDER DYSPHORIA FEELING THAT ONES GENDER IS INCORRECT (DeVries et al. Pediatric Endo. 1997) 25&

CASE CASTOR SEMENYA SUSPENDED BY IAAF UNTIL FURTHER STUDIES COULD BE PREFORMED IAAF HANDLED CASE VERY POORLY SEMENYA WAS TOLD SHE WAS UNDERGOING STANDARD DOPING TESTS EXTREME STRESS TO CASTOR AND FAMILY, INTENSE SCRUTINY AND HUMILIATION 26&

HYPERANDRODROGENISM IAAF/IOC WOMEN PRODUCE 1/10 TH TESTOSTERONE THAN MALES NORMAL RANGE FOR MALE TESTOSTERONE >10MMOL/L ONLY FEMALES WHO HAVE TESTOSTERONE LEVELS BELOW THE NORMAL MALE RANGE OR WHO HAVE AND ANDROGEN RESISTANCE CONDITION ARE PERMITTED TO PARTICIPATE IN WOMEN S COMPETITION (IAAF 2011) HYPERANDRODROGENISM IDENTIFIED ATHLETES MUST UNDERGO: CLINICAL EXAM ENDOCRINE EXAM AND/OR FULL EXAM (GENETIC TESTING, IMAGING, PSYCHOLOGICAL EVAL) IF DOES NOT PASS EVALUATION A THERAPEUTIC PROPOSAL IS ISSUED BANNED FROM COMPETITION UNTIL T IS LOWERED 27&

SEXUAL ASIGNMENTS 46 XX DSD (CAH/MATERNAL ESTROGENS) FEMALE DIAGNOSIS DIFFERENCE BETWEEN SALT LOSING VS. SIMPLE VIRILIZING CONDITIONS ISSUES: ENLARGED CLITORIS LABIAL FUSION UG SINUS/SHORT VAGINA 28&

GOALS OF SURGERY GENITAL APPEARANCE COMPATIBLE WITH GENDER UNOBSTRUCTED URINARY EMPTYING GOOD ADULT SEXUAL AND REPRODUCTIVE FUNCTION RECOMMENDED TIMING FOR SURGERY IS 2-6 MO AND THEN USUALLY REVISION VAGINOPLASTY IN ADOLESCENCE (CONSENSUS STATEMENT ON 21-OH DEF, CLAYTON ET AL. 2002) CLITOROPLASTY 1930 FIRST REPORTED CASE, WAS AMPUTATION UNTIL 1970 S DR.PIPPI SALLE-CORPOREAL SPARING DISMEMBERED TECHNIQUE 29&

CLITORPLASTY 8 PATIENTS FU-6-12 MO ALL CASES RETAINED DESIRED COSMETIC APPERANCE ALL GLANS PRESERVED NO EVIDENCE OF PAINFUL ERECTIONS PIPPI SALLE ET AL. J UROL 2007 30&

46 XY DSD- CAIS External female genitalia, bilateral testes, absence of mullerian structures 100% of patients regarded themselves as female 100% attracted to males in adolescence (93% in adulthood) 78% reported satisfaction with sexual function 46 XY DSD-CAIS SURGICAL PROCEDURES 40% HAD UNDERGONE VAGINOPLASTY AVERAGE AT OF OR 18 YRS OLD NO PTS REQUIRED CLITOROPLASTY RANGE OF LENGTH OF CLITORIS 2-15MM NORMAL XX FEMALE 16+/-4.3 MM 100% OF PTS RECEIVED GONADECTOMY PRIOR TO AGE 21 31&

46 XY DSD-5 AR deficient AUTOSOMAL RECESSIVE NORMAL T=NORMAL SV,VAS,EPIDYMIDES, ED NO DHT = SEVERE GENITAL AMBIGUITY CLITORAL-LIKE PHALLUS BIFID SCROTUM PSUEDOVAGINA PS/PERINEAL HS TESTES-INTRABDO OR W/IN CANAL 46 XY DSD- 5 AR DEFICEINCY ELEVATED LEVELS OF T AT PUBERTY SECONDARY SEXUAL CHARATERISTICS PHALLIC ENLARGEMENT +/- TESTES DECENT PENIS AT TWELVE IF RAISED AS FEMALE, LARGEST REPORTS SHOW 56-63% OF PTS UNDERGO GENDER ROLE CHANGES FEMALE!MALE AFTER PUBERTY (COHEN-KETTENIS, P. ACHR SEX BEHAVIOR 2005) TODAY, ONCE DIAGNOSE KNOW, SUGGESTED ALL TO BE RAISED AS MALES (HUGHES ET AL. CONSENSUS STATEMENT 2006) 32&

NOT SO CLEAR. 46 XY DSD- PAIS MIXED GONADAL DYSGENESIS OVOTESTICULAR DSD 14 pts with PAIS 5/14 living as men, 9/14 as women 11 pts with partial gonadal dysgenesis 7/11 living as men, 4/11 as women 14 pts true hermaphodites 9/14 living as men, 5/14 as women NOT SO CLEAR. FEMALE DIAGNOSIS Median 2 OR s Low self-reported body image MALE DIAGNOSIS Multiple OR s (0->10) Low self reported body image 33&

NOT SO CLEAR. SEXUAL ASSIGNMENT SURGICAL MORATORIUM ALL SURGERY (UNLESS MEDICAL EMERGENCY) SHOULD BE DEALYED UNTIL CHILD ABLE TO MAKE OWN DECISIONS SURGERY IS DAMAGING, MUTILATING, ONLY COSMETIC (PACIFIC CENTER FOR SEX AND SOCIETY) 34&

DSD WILL ALWAYS BE CONTROVERSIAL MUST CONSIDER PSYCHSOCIAL WELL BEING GENDER IDENTITY SEXUAL APPEARANCE SEXUAL FUNCTION POSSIBILE FERTILITY MINIMIZE NUMBER OF SURGICAL PROCEDURES CASTER SEMENYA South African flag bearer at Opening Ceremonies 2012 Olympic Silver medalist 35&

THANKS TO DR.MACNEILY FOR OVERSEEING PRESENTAION 36&