INTERSEXINTERSEX

Dr. Ahmed Al SayyadDr. Ahmed Al Sayyad

CHEO / University of OttawaCHEO / University of Ottawa

Sexual DifferentiationSexual Differentiation

Gonadal differentiation at 6-8 wk Gonadal differentiation at 6-8 wk gestationgestation

TDF gene (Y-chromosome):TDF gene (Y-chromosome):• stimulates gonads towards testicular stimulates gonads towards testicular

differentiationdifferentiation Absence of TDF:Absence of TDF:

• gonads differentiate into ovariesgonads differentiate into ovaries

Phenotypic DifferentiationPhenotypic Differentiation

Begins around 8Begins around 8thth week of gestation week of gestation Wolffian duct from mesonephrosWolffian duct from mesonephros MMüüllerian duct from coelomic epitheliumllerian duct from coelomic epithelium Endocrine effect during this phase is Endocrine effect during this phase is

crucial:crucial:• paracrine action of hormones produced by paracrine action of hormones produced by

ipsilateralipsilateral gonad gonad • testis (MIS, T) testis (MIS, T) male internal genitalia male internal genitalia• ovary (nil) ovary (nil) female internal genitalia female internal genitalia

Endocrine Effects on Endocrine Effects on Phenotypic DevelopmentPhenotypic Development

MMüüllerian-inhibiting substance:llerian-inhibiting substance:• produced by fetal testesproduced by fetal testes• found on chromosome 19found on chromosome 19

Causes almost complete regression of Causes almost complete regression of MMüüllerian duct derivatives:llerian duct derivatives:• utriculus masculinus, appendix testisutriculus masculinus, appendix testis

Important in testicular differentiationImportant in testicular differentiation

Endocrine Effects on Endocrine Effects on Phenotypic DevelopmentPhenotypic Development

TestosteroneTestosterone::• produced by fetal Leydig cellsproduced by fetal Leydig cells

Regulates male phenotypic developmentRegulates male phenotypic development Multiple steps in effect of testosterone:Multiple steps in effect of testosterone:

• production, 5-alpha reductase, ARproduction, 5-alpha reductase, AR• T T Wolffian duct (male internal Wolffian duct (male internal

genitalia)genitalia)• DHT DHT male external genitalia (includes male external genitalia (includes

prostate)prostate)

Endocrine Effects on Endocrine Effects on Phenotypic DevelopmentPhenotypic Development

Wolffian duct:Wolffian duct:• requires testosterone for developmentrequires testosterone for development• epididymis, vas deferens, seminal epididymis, vas deferens, seminal

vesiclevesicle MMüllerian duct:üllerian duct:

• does not require hormonal stimulationdoes not require hormonal stimulation• does require MIS be absentdoes require MIS be absent• oviduct, uterus, cervix, upper vaginaoviduct, uterus, cervix, upper vagina

External Genitalia - External Genitalia - DifferentiationDifferentiation (8-16 wk gestation)(8-16 wk gestation)

Male (requires DHT):Male (requires DHT):• labioscrotal fold = scrotumlabioscrotal fold = scrotum• urethral fold / groove = urethraurethral fold / groove = urethra• genital tubercle = glans penisgenital tubercle = glans penis

Female (requires nil):Female (requires nil):• labioscrotal fold = labia majoralabioscrotal fold = labia majora• urethral fold = labia minoraurethral fold = labia minora• genital tubercle = glans clitorisgenital tubercle = glans clitoris

External Genitalia External Genitalia DevelopmentDevelopment

Clinical Assessment - Clinical Assessment - HistoryHistory

Maternal androgen exposure:Maternal androgen exposure:• endogenous (hormone producing tumors)endogenous (hormone producing tumors)• exogenous (medication)exogenous (medication)

Family history:Family history:• AGS / infant death AGS / infant death • abnormal sexual development abnormal sexual development • infertility / amenorrhea infertility / amenorrhea • parental consanguinityparental consanguinity

Clinical Assessment - Clinical Assessment - Physical ExaminationPhysical Examination

Abdominal examAbdominal exam• rectal exam to feel for uterusrectal exam to feel for uterus

Inguinal / scrotal exam for gonadsInguinal / scrotal exam for gonads• if palpable = testisif palpable = testis

Phallic sizePhallic size Urethral orifice locationUrethral orifice location Hyperpigmentation of labioscrotal foldsHyperpigmentation of labioscrotal folds

• excess ACTH (AGS)excess ACTH (AGS)

Clinical Assessment - Clinical Assessment - Further TestingFurther Testing

Lab:Lab:• karyotype (72 hour)karyotype (72 hour)• serum 17 OH-progesteroneserum 17 OH-progesterone

Radiography:Radiography:• genitogramgenitogram• abdominal / pelvic ultrasoundabdominal / pelvic ultrasound

Operative:Operative:• endoscopy of urogenital sinusendoscopy of urogenital sinus• laparoscopy/laparotomy and gonadal laparoscopy/laparotomy and gonadal

biopsybiopsy

Intersex ClassificationIntersex Classification

Classification based on gonadal status:Classification based on gonadal status:• Over-androgenized female (ovary + ovary)*Over-androgenized female (ovary + ovary)*

• Under-androgenized male (testis + testis)*Under-androgenized male (testis + testis)*• True hermaphrodite (ovary + testis)True hermaphrodite (ovary + testis)• Mixed gonadal dysgenesis (testis + streak)Mixed gonadal dysgenesis (testis + streak)• Pure gonadal dysgenesis (streak + streak))Pure gonadal dysgenesis (streak + streak))

* “pseudo-hermaphrodite” is being phased out* “pseudo-hermaphrodite” is being phased out

Over-androgenized Over-androgenized FemaleFemale

Most common form of intersexMost common form of intersex Karyotype = 46 XXKaryotype = 46 XX TDF gene not presentTDF gene not present Ovarian tissue onlyOvarian tissue only Normal female internal genitaliaNormal female internal genitalia External genitalia virilized: External genitalia virilized:

• potency of androgen potency of androgen • time of exposuretime of exposure• duration of exposureduration of exposure

Over-androgenizedOver-androgenized FemaleFemale

Congenital adrenal hyperplasia (CAH) Congenital adrenal hyperplasia (CAH) comprises majority of casescomprises majority of cases

Exposure to maternal androgens is Exposure to maternal androgens is rare but can occurrare but can occur

Over-androgenized Over-androgenized Female Female (CAH)(CAH)

Most common inheritance pattern in Most common inheritance pattern in CAH is autosomal recessiveCAH is autosomal recessive

Enzymatic deficiency results in Enzymatic deficiency results in reduced production of glucocorticoidsreduced production of glucocorticoids

Lack of feedback inhibition on Lack of feedback inhibition on hypothalamus and pituitary:hypothalamus and pituitary: ACTH productionACTH production adrenal androgen releaseadrenal androgen release

Over-androgenized Over-androgenized FemaleFemale (CAH) (CAH)

21-hydroxylase deficiency most common21-hydroxylase deficiency most common• 50% of patients “salt losers”50% of patients “salt losers”• death at 7-10 days post-natally (adrenal crisis)death at 7-10 days post-natally (adrenal crisis)• serum 17- hydroxyprogesterone assayserum 17- hydroxyprogesterone assay

Medical management of CAH crucial:Medical management of CAH crucial:• corticosteroid ± mineralocorticoidcorticosteroid ± mineralocorticoid• prevent death and metabolic complications prevent death and metabolic complications • allow normal development of 2allow normal development of 2° sexual ° sexual

characteristics, fertilitycharacteristics, fertility

Over-androgenizedOver-androgenized FemaleFemale (CAH) (CAH)

Female gender assignment usual:Female gender assignment usual:• controversy with Prader Vcontroversy with Prader V

MMüllerian structures always present üllerian structures always present Surgical intervention (?):Surgical intervention (?):

• feminizing genitoplasty ± feminizing genitoplasty ± vaginoplastyvaginoplasty

Antenatal treatment may minimize Antenatal treatment may minimize degree of virilizationdegree of virilization

Under-androgenized MaleUnder-androgenized Male

Very diverse groupVery diverse group Karyotype = 46 XYKaryotype = 46 XY Testicular tissue onlyTesticular tissue only Lack of fetal virilization from wide Lack of fetal virilization from wide

variety of defects or deficienciesvariety of defects or deficiencies Phenotypic range broad Phenotypic range broad

• may even resemble normal femalemay even resemble normal female

Under-androgenized MaleUnder-androgenized MaleAndrogen InsensitivityAndrogen Insensitivity

Most common form of UAMMost common form of UAM Assay serum testosterone, DHT:Assay serum testosterone, DHT:

• usually after HCG stimulationusually after HCG stimulation Fibroblast cultures of genital skin:Fibroblast cultures of genital skin:

• absence of DHT bindingabsence of DHT binding PCR can be done to detect PCR can be done to detect

receptor abnormalitiesreceptor abnormalities

Under-androgenized MaleUnder-androgenized MaleAndrogen InsensitivityAndrogen Insensitivity

Testicular feminization (complete AI):Testicular feminization (complete AI):• phenotypically normal female with a short phenotypically normal female with a short

vaginavagina Presentation:Presentation:

• primary amenorrhea primary amenorrhea • testes found in inguinal hernias in femaletestes found in inguinal hernias in female

Maintenance of female gender appropriate Maintenance of female gender appropriate with estrogen supplementationwith estrogen supplementation

Testicles should be removed (cancer risk)Testicles should be removed (cancer risk)

Under-androgenized MaleUnder-androgenized MaleAndrogen InsensitivityAndrogen Insensitivity

Under-androgenized MaleUnder-androgenized MaleAndrogen InsensitivityAndrogen Insensitivity

Incomplete insensitivity:Incomplete insensitivity:• phenotype can run the gamutphenotype can run the gamut• clitoromegaly, partial fusion of labio-scrotal clitoromegaly, partial fusion of labio-scrotal

folds, short blind ending vaginafolds, short blind ending vagina Female gender assignment Female gender assignment

gonadectomy:gonadectomy:• prevent virilization in puberty prevent virilization in puberty • obviate cancer riskobviate cancer risk

In males In males early genital reconstruction early genital reconstruction

Under-androgenized MaleUnder-androgenized MaleEnzymatic defectsEnzymatic defects

Wide variety of potential defects:Wide variety of potential defects:• abnormal testosterone synthesisabnormal testosterone synthesis• inadequate conversion to DHTinadequate conversion to DHT

Phenotype:Phenotype:• no Mno Müllerian structures (MIS present)üllerian structures (MIS present)• under-virilized external genitaliaunder-virilized external genitalia

Under-androgenized MaleUnder-androgenized MaleEnzymatic defectsEnzymatic defects

5-5- reductase deficiency prevents reductase deficiency prevents conversion of T to DHTconversion of T to DHT

Autosomal recessive inheritanceAutosomal recessive inheritance Phenotypically severe Phenotypically severe

perineoscrotal hypospadias with perineoscrotal hypospadias with undescended testesundescended testes

T/DHT ratio may aid in diagnosisT/DHT ratio may aid in diagnosis

Under-androgenized MaleUnder-androgenized Male

Primary HypogonadismPrimary Hypogonadism• baseline high levels of gonadotropinsbaseline high levels of gonadotropins• do not respond to HCG stimulationdo not respond to HCG stimulation

Hypogonadotropic HypogonadismHypogonadotropic Hypogonadism• baseline low levels of gonadotropinsbaseline low levels of gonadotropins• respond to HCG stimulation respond to HCG stimulation

True HermaphroditismTrue Hermaphroditism

Uncommon: 10% of intersexUncommon: 10% of intersex Karyotype:Karyotype:

• 60-70% 46XX60-70% 46XX• remainder 46XY or a mosaicremainder 46XY or a mosaic

Characterized by presence of Characterized by presence of ovarian and testicular tissueovarian and testicular tissue

Gender assignment based on Gender assignment based on anatomical findings (75% male)anatomical findings (75% male)

True HermaphroditismTrue Hermaphroditism

Internal genitalia conform to ipsilateral Internal genitalia conform to ipsilateral gonad:gonad:• vas with testiclevas with testicle• fallopian tube with ovaryfallopian tube with ovary• either (both) with ovotestiseither (both) with ovotestis

Contradictory gonadal / ductal tissue Contradictory gonadal / ductal tissue should be removed once gender assignedshould be removed once gender assigned

External genitalia reconstructed External genitalia reconstructed according to gender assignmentaccording to gender assignment

True HermaphroditismTrue Hermaphroditism Gonadal configuration can vary:Gonadal configuration can vary:

• testis one side, ovary other sidetestis one side, ovary other side• ovotestis with contralateral normal testis ovotestis with contralateral normal testis

or ovaryor ovary• bilateral ovotestesbilateral ovotestes

Mixed Gonadal DysgenesisMixed Gonadal Dysgenesis

Second most common cause of intersexSecond most common cause of intersex Karyotype:Karyotype:

• 46XY/45XO mosaic46XY/45XO mosaic Unilateral testis with dysgenetic (streak) Unilateral testis with dysgenetic (streak)

gonad contralaterallygonad contralaterally Testis has Sertoli and Leydig cells but no Testis has Sertoli and Leydig cells but no

germinal elementsgerminal elements Risk of gonadoblastomaRisk of gonadoblastoma

Mixed Gonadal DysgenesisMixed Gonadal Dysgenesis

Internal genitalia variable (±MIS)Internal genitalia variable (±MIS) External genitalia:External genitalia:

• hypospadiashypospadias• partial labioscrotal fusionpartial labioscrotal fusion• undescended testesundescended testes

Gender assignment:Gender assignment:• female most common (bilateral female most common (bilateral

gonadectomy)gonadectomy)• male if markedly virilized and orchiopexy male if markedly virilized and orchiopexy

feasiblefeasible

Pure Gonadal DysgenesisPure Gonadal Dysgenesis

Bilateral dysgenetic (streak) Bilateral dysgenetic (streak) gonadsgonads

Present as females with sexual Present as females with sexual infantilism:infantilism:• external genitalia are external genitalia are notnot ambiguous ambiguous

Immature MImmature Müllerian structures are üllerian structures are present:present:• low levels of fetal MISlow levels of fetal MIS

Pure Gonadal DysgenesisPure Gonadal Dysgenesis

Turner’s syndrome:Turner’s syndrome:• 45 XO45 XO• characteristic phenotype characteristic phenotype

Swyer’s syndrome:Swyer’s syndrome:• 46 XY46 XY• at risk for gonadoblastoma (30%) at risk for gonadoblastoma (30%)

46 XX:46 XX:• low tumor risklow tumor risk

Other Genetic Other Genetic AbnormalitiesAbnormalities

Klinefelter’s syndrome:Klinefelter’s syndrome:• male phenotypemale phenotype• impaired sexual maturationimpaired sexual maturation• gynecomastiagynecomastia• azoospermiaazoospermia

Typical karyotype 47 XXYTypical karyotype 47 XXY

Other Genetic Other Genetic AbnormalitiesAbnormalities

XX Sex reversalXX Sex reversal• rare phenotypic males with 46XX rare phenotypic males with 46XX

karyotypekaryotype• often have hypospadias and often have hypospadias and

gynecomastiagynecomastia• usually fragments of Y chromosome usually fragments of Y chromosome

short arm found in distal short arm of short arm found in distal short arm of X chromosome X chromosome

SummarySummary

Intersex is a challenging and Intersex is a challenging and complicated situation, but when complicated situation, but when understood can often be dealt with understood can often be dealt with effectivelyeffectively

Many potential medical, social, and Many potential medical, social, and psychological ramificationspsychological ramifications

Multidisciplinary approach involving Multidisciplinary approach involving urology, endocrinology, genetics and urology, endocrinology, genetics and social work is essentialsocial work is essential