Disorders of Sexual Differentiation PDF

Intersex : celebrating the beauty in difference Sexual determination and differentiation Nicos Skordis Prof Paediatrics GEMD program 2023  the plan Explain the difference between genetic and phenoty...

Intersex : celebrating the beauty in difference Sexual determination and differentiation Nicos Skordis Prof Paediatrics GEMD program 2023  the plan Explain the difference between genetic and phenotypic sex Explain sex determination and differentiation Describe the process of sexual differentiation Outline some of the common causes of ambiguous (unusual) genitalia  Sexual Determination & Differentiation Sexual Determination Genetically controlled process dependent on the ‘switch’ on the Y chromosome Chromosomal determination of male or female Sexual Differentiation The process by which internal and external genitalia develop as male or female The two processes are contiguous and consist of several stages  sex differentiation Determined by the gonadal tissue fertilisation present ovarian or testicular genotypic sex Morphology of the external genitals gonadal sex phenotypic sex Genetic sex as determined by the presence of the XX (female) or the gender identity XY (male) genotype in somatic cells The individual’s deeply held personal sense of their own gender as male or female, neither or both. External manifestations of gender, expressed through one’s name, pronouns, clothing, haircut, behaviour, voice, or body characteristics. The chromosomal, hormonal, and anatomic determinants which result in characterizing people as male or female An individual’s enduring physical and emotional attraction to another person  Gonadal Sex SRY gene creates the testis In the absence of Y chromosome ovaries develop Sex determining region Y (SRY) switches on briefly during embryo development (>week 7) to make the gonad into a testis. In its absence an ovary is formed Testis develops cells that make 2 important hormones: Sertoli cells produce anti-Mullerian hormone (AMH) Leydig cells make Testosterone Products of the testis influence further gonadal and phenotypic sexual development  Gonadal Development After fertilisation a pair of gonads develop which are bipotential. Their precursor is derived from common precursors called the genital ridge primordia (3½ - 4½ weeks) Mullerian duct Genital Wolffian ridges duct  Gonadal Development 3 waves of cells invade the genital ridge: 1. Primordial Germ Cells – become Sperm (male) or Oocytes (female) 2. Primitive Sex Cords – become Sertoli cells (male) or Granulosa cells (female) 3. Mesonephric Cells – become blood vessels and Leydig cells (male) or Theca cells (female)  1. Primordial Germ Cell migration A cluster of cells in the epithelium of the yolk sac expands by mitosis at around 3 weeks and then migrate to the genital ridge - completed by 6 weeks  2 - Primitive sex cords ( Sertoli / Granulosa ) Primitive Wolffian duct medullary cords (mesonephric) Cells from the germinal epithelium migrate inwards as columns called Aorta the primitive sex cords Genital ridge viewed from above Mullerian duct Primitive sex (paramesonephric) cords Male SRY expression Female Penetrate medullary mesenchyme No SRY & surround primordial germ cells Sex cords condense in the cortex to form testis cords – precursor of as small clusters around primordial seminiferous tubules. germ cells – precursor of ovarian Eventually become Sertoli Cells follicle which express AMH Eventually become Granulosa cells  3 – Mesonephric cells Originate in the mesonephric primordium In males they act under the influence of pre-sertoli cells (which themselves express SRY) to form… Vascular tissue Leydig cells (synthesize testosterone) Basement membrane – contributing to formation of seminiferous tubules In females without the influence of SRY they form… Vascular tissue Theca cells (synthesize Androstenedione which is a substrate for Estradiol production by the granulosa)  Gonadal sex summary The differentiation of the gonad into a testis or ovary involves many genes Invading cells become Primordial germ cells Spermatozoa Primitive sex cords Sertoli cells (SRY, AMH) Mesonephric cells Leydig cells (Androgens) Invading cells become Primordial germ cells Oocytes Primitive sex cords Granulosa cells Mesonephric cells Theca cells  sexual differentiation 2 processes occurring: Internal External differentiation differentiation Internal Development of reproductive organs phenotypic sex External genitalia  Internal Reproductive Organs Two main structures involved… Mullerian ducts most important in female inhibited in the male by AMH Wolffian ducts most important in the male stimulated by testosterone lack of stimulation by testosterone means regression in female Development of male internal genitalia Wolffian duct develops into male internal genitalia by influence of TESTOSTERONE At 7 week Mullerian duct regresses by the influence of ANTI-MULLERIAN HORMONE At 9 week  Wolffian ducts form the urinary tract in both sexes Under Testosterone stimulation from testis in male, they form the main parts of the anatomy that permit passage of sperm into the penis: body and tail of epididymis, the vas deferens, seminal vesicles and ejaculatory ducts Lack of stimulation in female (no Testosterone) - Wolffian ducts disappear Development of female internal genitalia Mullerian duct develops into female internal genitalia without any hormones At 7 week In the absence of anti-mullerian hormone, Mullerian duct develops into female internal genitalia in a genetic (46 XY) & At 9 week gonadal male fetus(SRY)  Internal sexual differentiation in female No Y chromosome, so no SRY, so no testis No testis, so no AMH No inhibition of the Mullerian ducts, which form uterine tubes, uterus and upper 1/3 of vagina Upper ends of ducts stay open and form ends of uterine tubes and lower portions fuse to form single cavity uterus Internal Sexual Differentiation Male Female  External differentiation Male: Testo converted to DHT ( Dihydrotestosterone) by 5 alpha reductase in male skin and tissue = penis, scrotum and prostate Female: in the absence of DHT clitoris, labia and lower 2/3 vagina  5-α-reductase & external differentiation DHT also binds to the testosterone receptor, but is more potent than testosterone Testosterone Dihydrotestosterone DHT causes differentiation of the male external genitalia: Clitoral area enlarges into penis Labia fuse and become ruggated to form scrotum Prostate forms  External differentiation DHT causes development of male external genitalia Testes descend from the abdominal cavity into the scrotum In the absence of androgens the external genitalia are feminized  Sex Differentiation Summary XY undiff XX gonad testis SRY ovary Leydig Sertoli cells AMH cells Testosterone DHT Regression Differentiation Mullerian Regression of and growth Fusion of Lack of Wolffian of mullerian ducts growth of labial androgen ducts ducts differentiate Wolffian scrotal folds leads to and grow duct structures growth of vagina, into uterine seminal vesicles phallus labia & tubes, and vas and prostate clitoris uterus and deferens upper 1/3 of vagina  Disorders of Sexual Differentiation Gonadal dysgenesis - Sexual differentiation is incomplete. Usually missing SRY in male, or partial or complete deletion of second X in female. Also used as a general description of abnormal development of the gonads. Sex reversal - Phenotype does not match genotype, ie may be male genotypically but externally look like a female. Intersex - Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine. Patients prefer to be known as someone with a ‘disorder of sexual differentiation’ or DSD. Terms such as ‘pseudohermaphrodite’ and, ‘testicular feminisation’ are now obsolete.  Intersex Disorders of Sexual Differentiation True hermaphrodite Ovotesticular DSD Male pseudohermaphrodite 46, XY DSD Female pseudohermaphrodite 46, XX DSD XX male / XX sex reversal 46, XX testicular DSD XY sex reversal 46, XY complete gonadal dysgenesis Pediatrics 2006  Intersex Disorders of Sexual Differentiation True hermaphrodite Ovotesticular DSD Male pseudohermaphrodite 46, XY DSD Female pseudohermaphrodite 46, XX DSD XX male / XX sex reversal 46, XX testicular DSD XY sex reversal 46, XY complete gonadal dysgenesis Pediatrics 2006  Ovid – Latin poet 1st century BC Metamorphosis : Salmacis and Hermaphrodite The sleeping Hermaphrodite, by Bernini 1620, Louvre True hermaphrodite – Ovotesticular DSD Rare disorder – the infant is born with gonads of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes)  During puberty virilization in the female or gynecomastia in the male Presence of vagina Dysgenetic testicular tissue  46, XY DSD what happens if in 46 XY... no male hormones are made or detected? - how would this happen? Male pseudohermaphrodite  Incomplete virilization in a 46 ΧΥ male Testosterone biosynthetic defect 5 alpha reductase deficiency – no DHT Androgen Insensitivity Syndromes – Androgen Receptor  HCG stimulation Hormone before after Testosterone(nmol/l) 2.4 4.85 DHEA-S (μmol/l) 2.02 2.58 Androstenedione 17.3 33.2 (nmol/l ) DHT (nmol/)l 0.04 0.20 R80Q R80Q 46, XY - 17β-HSD deficiency  46, XY DSD what happens if testosterone is made but not DHT? – 5 a reductase deficiency – testes form, AMH acts, testosterone acts internal structures form, external do not may have ambiguous genitalia/intersex due to action of Testosterone alone OR may appear mainly female Clinical manifestation of 5 a reductase deficiency at birth What happens at puberty At puberty levels of Testosterone become very high and may mimic DHT effects causing virilisation At puberty Guevedoces (πέος στα 12) 5 alpha reductase deficiency what happens if male hormones are inactive ?? Androgen Insensitivity Syndromes – Testes develop – Mullerian ducts regress as AMH still made – No Wolffian duct development as no Testosterone action – DHT still made , but no action so …. female external genitals What happens at puberty? Estrogen from testes and conversion of androgens from adrenals to Estrogen cause breast development What would patient present with?  Androgen insensitivity syndrome (AIS) – 46, XY Complete AIS - incidence 1:20,000 Appear completely female at birth and assigned female gender Have undescended testes Diagnosis? Usually present with inguinal hernia in childhood OR primary amenorrhoea in adolescence. Lack of body hair is a clue. Ultrasound : No uterus, karyotype : 46, XY with elevated Testosterone Never responded to androgen so appear and often feel female. Partial AIS - incidence unknown as is probably a spectrum Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris. Surgery was universal but now fortunately considered optional or at least best delayed. Decisions made on potential. Very difficult for parents.  Androgen Insensitivity Syndromes Complete Partial  Quigley scale Mild Partial Complete Familial form of 46,XY with PAIS X-linked recessive trait Mutations in the androgen receptor ( AR) gene the phenotypic spectrum ranges from those with normal female external genitalia, through those with genital ambiguity to that of a normal male with infertility  Isolated AMH Insufficiency: The Persistent Müllerian Duct Syndrome Persistence of Müllerian derivatives, uterus, and Fallopian tubes, in otherwise completely virilized 46,XY males Bilateral cryptorchidism Defect in either gene coding for AMH or it's receptor, AMH receptor type II (AMHRII) PMDS is inherited as an autosomal recessive trait One or both testes may make it into the inguinal canal or the scrotum, dragging the uterus along Unilateral cryptorchidism with a hernia containing the uterus on the opposite side, a condition known as “hernia uteri inguinalis.” Ultrasound pelvic examination to display Müllerian organs is the diagnostic method of choice  46 , XX DSD what happens if –XX female is exposed to high levels of androgens in utero –how might this happen –Congenital Adrenal Hyperplasia most commonly : 1 in 5000 to 1 in 15000  Congenital adrenal hyperplasia (CAH) XY undiff XX gonad testis SRY ovary Leydig Sertoli cells AMH cells Testosterone DHT Regression Differentiation Mullerian Regression of and growth Fusion of Lack of Wolffian of mullerian ducts growth of labial androgen ducts ducts differentiate Wolffian scrotal folds leads to and grow duct structures growth of vagina, into uterine seminal vesicles phallus labia & tubes, and vas and prostate clitoris uterus and deferens upper 1/3 of vagina  Congenital Adrenal Hyperplasia Completeness of the block varies If enzyme completely absent, the baby will be sick with salt wasting from lack of aldosterone - sepsis like picture at first 2 weeks of life – can be lethal Often children may be wrongly gender assigned at birth because of ambiguous (unusual) genitalia. Treatment with glucocorticoids to correct feedback Prader scale Steroidogenesis – adrenals ACTH Failure to synthesize Cortisol / Aldosterone Elevated precursor (17OHP) and metabolites 46, XX CAH patient raised as a male 46, XO / 46, XY Mixed Gonadal Dysgenesis Testis unilateral – may be undescended Streak gonad contralateral May have Mullerian duct remnants Incomplete virilization 46, XO / 46, XY Mixed Gonadal Dysgenesis Neonate 1 Male sex of rearing 46, XO / 46, XY Mixed Gonadal Dysgenesis 45, XO / 46, XY Mixed Gonadal Dysgenesis Neonate 2 Female sex of rearing October 2016 http://www.independent.co.uk/life-style/health-and- families/intersex-celebrating-the-beauty-in-difference- a7339656.html Stigmatization faced by people who underwent intersex surgeries to correct ambiguous genitalia