Anormal Seksüel Gelişim - İnterseks - www.jinekolojivegebelik.com

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Anormal Seksüel Gelişim - İnterseks - www.jinekolojivegebelik.com

  1. 1. <ul><li>Thursday 14th August 2003 </li></ul><ul><li>David Galvin </li></ul>Ambiguous Genitalia
  2. 2. <ul><li>Normal Sexual Differentiation has 3 stages: </li></ul><ul><ul><li>Establishment of chromosomal sex </li></ul></ul><ul><ul><li>Development of the undifferentiated gonads </li></ul></ul><ul><ul><li>Differentiation of internal ducts & genitalia </li></ul></ul>Introduction Jost, 1973
  3. 3. <ul><li>Y chromosome necessary for testes development. </li></ul><ul><li>Testis-determining factor (TDF) </li></ul><ul><li>SRY (Sex-determining Region of Y chromosome) Sinclair 1990 </li></ul><ul><li>Mutations in this gene lead to alterations in sex differentiation. </li></ul>Introduction
  4. 4. Normal Sexual Differentiation Genital Ridge Bipotential Gonad SF-1 SF-1 Ovary Follicular Cells Theca Cells Follicles Mullerian Duct Female Genitalia Leydig Cells Sertoli Cells SF-1 SF-1 Testosterone AMH Testis Mullerian Duct Regression Wolffian Duct Genital Tubercle Urogenital Sinus Male Internal Genitalia Penis Prostate DHT
  5. 5. <ul><li>The embryo is bipotential up until 6 weeks </li></ul><ul><li>Primordial germ cells are seen at week 3 on the posterior wall of the secondary yolk sac </li></ul><ul><li>These germ cells then migrate to the urogenital ridge </li></ul><ul><li>The presence of SRY initiates testicular cord development, its absence ovarian cord. </li></ul>Gonadal Differentiation
  6. 7. <ul><li>Sertoli cells noted at week 6 to 7 </li></ul><ul><li>Blood-testis barrier created by a BM </li></ul><ul><li>Sertoli cells produce Mullerian Inhibitory Substance (MIS) </li></ul><ul><li>Leydig cells differentiate at week 8 to 9 </li></ul>Testicular Differentiation Basement Membrane Fibroblasts Spermatogonia ↓ ↑ ↑
  7. 8. <ul><li>Ovarian cords develop in the absence of SRY </li></ul><ul><li>2 X Chromosomes are necessary for normal development (ovarian dysgenesis in 45 XO) </li></ul><ul><li>They appear to differentiate granulosa cells into the protective granulosa cell layer </li></ul><ul><li>Germ cells undergo exhaustive mitosis creating 20 million cells by 20 weeks </li></ul>Ovarian Differentiation
  8. 9. <ul><li>2 hormones necessary for male differentiation </li></ul><ul><ul><li>MIS (Mullerian Inhibitory Substance) </li></ul></ul><ul><ul><ul><li>TGF family, Ch.19, Fibrosis of Mullerian tissue except prostatic utricle and appendix testis </li></ul></ul></ul><ul><ul><ul><li>Allows Wolffian development under the influence of testosterone </li></ul></ul></ul><ul><ul><li>Testosterone ( produced by Leydig cells at week 8-9) </li></ul></ul><ul><ul><ul><li>Testosterone diffuses in to target organs stimulating virilisation </li></ul></ul></ul>Gonadal Function - Testis
  9. 10. <ul><li>In the Urogenital sinus, prostate and penis, 5 α reductase is present and converts testosterone to DHT. </li></ul><ul><li>The androgen receptor binds DHT with much greater affinity than testosterone, so DHT is the active androgen in these tissues </li></ul><ul><li>5 α reductase type 2 is the primary enzyme in the prostate </li></ul>Gonadal Function - Testis
  10. 11. <ul><li>Oestrogen synthesis is detectable at 8 weeks </li></ul><ul><li>Oestrogens are NOT necessary for normal female differentiation but in males, they can inhibit the effects of MIS on Mullerian tissue </li></ul>Gonadal Function - Ovary
  11. 13. <ul><li>Male </li></ul><ul><ul><li>Identical Urogenital tract until week 8 </li></ul></ul><ul><ul><li>Mullerian ducts degenerated by week 10 </li></ul></ul><ul><ul><li>Epididymis and rete testis form and join the urogenital sinus to form the seminal vesicles </li></ul></ul><ul><ul><li>External genitalia develop under the influence of DHT </li></ul></ul>Phenotypic Differentiation
  12. 14. <ul><li>Male </li></ul><ul><ul><li>Anal folds and genital tubercle move apart at week 10 </li></ul></ul><ul><ul><li>Genital tubercle forms the penis </li></ul></ul><ul><ul><li>Urethral folds fuse to form the urethra </li></ul></ul><ul><ul><li>These folds are surrounded by prostate at the bladder </li></ul></ul><ul><ul><li>Urogenital swellings fuse posteriorly to form the scrotum </li></ul></ul><ul><ul><li>Penile growth and testicular descent occur in the third trimester under the influence of testosterone </li></ul></ul>Phenotypic Differentiation
  13. 16. <ul><li>Female </li></ul><ul><ul><li>Wolffian ducts regress due to lack of testosterone </li></ul></ul><ul><ul><li>Mullerian ducts grow in the absence of MIS </li></ul></ul><ul><ul><li>Cephalic end forms Fallopian tubes </li></ul></ul><ul><ul><li>Caudal end fuses to form the Uterus </li></ul></ul><ul><ul><li>Meets the Urogenital sinus to form the Uterovaginal plate and ultimately the vaginal lumen </li></ul></ul>Phenotypic Differentiation
  14. 17. <ul><li>Female </li></ul><ul><ul><li>Genital tubercle develops into the clitoris </li></ul></ul><ul><ul><li>Genital swellings become the labia majora </li></ul></ul><ul><ul><li>Urethral folds become the labia minora </li></ul></ul><ul><ul><li>The Introitus develops between the urethral folds </li></ul></ul>Phenotypic Differentiation
  15. 19. <ul><li>Classified by Grumbach and Conte (1998) </li></ul><ul><ul><li>Disorders of Gonadal Differentiation and Development </li></ul></ul><ul><ul><li>Female Pseudohermaphroditism </li></ul></ul><ul><ul><li>Male Pseudohermaphroditism </li></ul></ul><ul><ul><li>Unclassified forms </li></ul></ul>Abnormal Sexual Development - “Intersex”
  16. 20. <ul><li>Seminiferous Tubule Dysgenesis (Klinefelters) </li></ul><ul><ul><li>Most common major abnormality </li></ul></ul><ul><ul><li>47 XXY (1 in 1000 males), also 47 XXYY or mosaic 46XY/47XXY </li></ul></ul><ul><ul><li>Seminiferous tubules degenerate and are replaced by hyaline </li></ul></ul><ul><ul><li>Small firm testes, azoospermia, female body habitus, abnormal secondary sexual characteristics (tall, no facial hair) </li></ul></ul><ul><ul><li>Leydig cells are present but testosterone is low-normal, raised FSH/LH and raised oestrogen (gynaecomastia - x8 increase in breast ca. & EG-GCT) </li></ul></ul><ul><ul><li>Treat with androgens / reduction mammoplasty / cancer surveillance </li></ul></ul>Disorders of Gonadal Differentiation May be oligospermic and fertile (ICSI)
  17. 21. <ul><li>II. 46 XX Males (sex reversal) </li></ul><ul><ul><li>1 in 20000 males, 2% of infertile males. (All Infertile) </li></ul></ul><ul><ul><li>Normal testes and ext. genitalia, but 10% have hypospadias </li></ul></ul><ul><ul><li>80% SRY positive - like Klinefelters but smaller and normal proportions </li></ul></ul><ul><ul><li>Probably translocation of Y chromosome material to X chromosome or mutation of a X chromosome gene </li></ul></ul>Disorders of Gonadal Differentiation
  18. 22. <ul><li>III. Turners Syndrome (45 X0) </li></ul><ul><ul><li>Presence of one functioning X Chromosome </li></ul></ul><ul><ul><li>1 in 2500 females. Mosaicism 45 X/46 XX (10%) or 45 X/46 XY (3%) </li></ul></ul><ul><ul><li>Oocytes degenerate leaving streak gonads (in broad lig.) at birth </li></ul></ul><ul><ul><li>Reduced Oestrogen, Raised FSH/LH. No pubertal development. </li></ul></ul><ul><ul><li>Management includes: </li></ul></ul><ul><ul><ul><li>Give Growth Hormone to Children and Oestrogens at puberty. </li></ul></ul></ul><ul><ul><ul><li>Up to one third may have functioning ovaries - so pregnancy is possible. </li></ul></ul></ul><ul><ul><ul><li>Remove Streak gonads in Mosaic patients </li></ul></ul></ul>Disorders of Gonadal Differentiation Features: 1. Female Phenotype 2. Short Stature 3. No Secondary Sexual Characteristics 4. Somatic Abnormalities - Webbed Neck - Broad Chest - Short Ring finger Occult Y Ch. Material: Predisposed to Virilisation and Gonadoblastoma (30%) and other GCT (50%). Renal Anomalies: 90% Multiple Renal Arteries 20% Renal agenesis/Duplication 15% Malrotation 10% Horseshoe kidney
  19. 23. <ul><li>IV. 46 XX Pure Gonadal Dysgenesis </li></ul><ul><ul><li>Similar to Turner’s Syndrome, but No somatic Effects </li></ul></ul><ul><ul><li>Pure gonadal dysgenesis requiring oestrogen and progesterone HRT </li></ul></ul>Disorders of Gonadal Differentiation
  20. 24. <ul><li>V. Mixed Gonadal Dysgenesis </li></ul><ul><ul><li>Mosaicism: 45 XO/ 46 XY </li></ul></ul><ul><ul><li>Second most common cause for Ambiguous genitalia </li></ul></ul><ul><ul><li>Mostly phenotypic females, but entire spectrum covered </li></ul></ul><ul><ul><li>Due to lack of MIS production in unilateral dysgenetic testis with ipsilateral fallopian tube </li></ul></ul><ul><ul><li>Management includes Gender assignment (2/3 female), Appropriate gonadectomy & screen for Wilm’s tumour </li></ul></ul>Disorders of Gonadal Differentiation Features: Unilateral testis (undescended) Contralateral Streak Gonad Persistent Mullerian Structures Some masculinisation Mostly females with; Enlarged phallus Labioscrotal folds Uterus /vagina & tubes Increased risk of: Gonadoblastoma (20%) - testis > streak gonad Wilm’s tumour Denys-Drash Syndrome - Nephropathy /CRF - Genital Abnormalities - Wilms tumour - XX/XY mosaicism May need prophylactic bilateral nephrectomy
  21. 25. <ul><li>VI. Dysgenetic Male Pseudohermaphroditism </li></ul><ul><ul><li>Bilateral Dysgenetic Testis (produce some testosterone / MIS) </li></ul></ul><ul><ul><li>Either 45 X/46 XY or 46 XY </li></ul></ul><ul><ul><li>Spectrum of Mullerian and Wolffian structures persist </li></ul></ul><ul><ul><li>Increased risk of Gonadoblastoma (45% at 40 years) and Denyd-Drah Syndrome </li></ul></ul>Disorders of Gonadal Differentiation
  22. 26. <ul><li>VII. 46 XY Complete Gonadal Dysgenesis </li></ul><ul><ul><li>Male genotype, Phenotypic females with sexual infantilism </li></ul></ul><ul><ul><li>SRY gene is dysfunctional </li></ul></ul><ul><ul><li>Most present in their teens with delayed puberty </li></ul></ul><ul><ul><li>Raised FSH/LH may lead to increased androgen and clitoromegaly </li></ul></ul><ul><ul><li>Increased risk of germ cell tumours (30% at 30 years) </li></ul></ul><ul><ul><li>Manage with gonadectomy and hormone replacement </li></ul></ul>Disorders of Gonadal Differentiation
  23. 27. <ul><li>VIII. Embryonic Testicular Regression </li></ul><ul><ul><li>46 XY Karyotype with absent testes, but evidence of prior testicular function during embryogenesis </li></ul></ul><ul><ul><li>May be due to mutation or teratogen or bilateral torsion </li></ul></ul><ul><ul><li>Vary from complete female, to male with microphallus, empty scrotum and absent prostate </li></ul></ul><ul><ul><li>Timing of in utero event will influence development of mullerian / wolffian ducts </li></ul></ul><ul><ul><li>No testosterone, high FSH/LH. May have rudimentary cords/nubbins. </li></ul></ul>Disorders of Gonadal Differentiation
  24. 28. <ul><li>IX. True Hermaphroditism </li></ul><ul><ul><li>Both healthy ovarian and testicular tissue in the form of one of each or one/two ovotestes </li></ul></ul><ul><ul><li>2/3 of patients are raised female as potentially reproductive as females </li></ul></ul><ul><ul><li>Differentiation of both internal and external structures is highly variable </li></ul></ul><ul><ul><li>Internal differentiation depends on the function of the ipsilateral gland </li></ul></ul><ul><ul><li>2/3 have an ovotestis, 2/3 of these having a fallopian tube </li></ul></ul><ul><ul><li>Pregnancy is possible as ovarian tissue is normal, whereas testicular tissue is usually dysgenetic (infertile). </li></ul></ul>Disorders of Gonadal Differentiation
  25. 29. <ul><li>Phenotypic females (46 XX) have ovaries but are partially masculinised with ambiguous genitalia </li></ul><ul><li>Most common cause is Congenital Adrenal Hyperplasia (CAH) </li></ul><ul><li>Rarely maternal ingestion of androgens or virilizing tumours in the mother </li></ul>Female Pseudohermaphroditism
  26. 30. <ul><li>Defect in one of 5 enzymes involved in cortisol synthesis </li></ul><ul><li>Resulting in a decrease in cortisol and an increase in ACTH and other steroids </li></ul><ul><li>95% of cases are due to 21-hyrdroxylase deficiency </li></ul><ul><li>1 in 5000 - 15000 in Western world </li></ul>Congenital Adrenal Hyperplasia
  27. 32. <ul><li>3 types </li></ul><ul><ul><li>Salt Wasters (75%) </li></ul></ul><ul><ul><li>Simple Virilisers (25%) </li></ul></ul><ul><ul><li>Non-classic (<1%) </li></ul></ul>21 Hydroxylase Deficiency
  28. 33. <ul><li>Females: Salt Wasters </li></ul><ul><ul><li>Female pseudohermaphrodite </li></ul></ul><ul><ul><li>Impaired steroidogenesis is an early phenomenon, therefore some masculinisation is present from birth (Prader classification) </li></ul></ul><ul><ul><li>Salt loss leads to weight loss, vomitting, dehydration and failure to thrive, even an adrenal crisis < 2-3/52 </li></ul></ul><ul><ul><li>Progressive masculinisation occurs and epiphysis fuse </li></ul></ul>21 Hydroxylase Deficiency
  29. 35. <ul><li>Males: Virilisers </li></ul><ul><ul><li>Appears normal at birth </li></ul></ul><ul><ul><li>Somatic and sexual precocity < 2-3 years </li></ul></ul><ul><ul><li>“Little Hercules” </li></ul></ul>21 Hydroxylase Deficiency
  30. 36. <ul><li>Diagnosis </li></ul><ul><ul><li>Prenatal: ↑ Amniotic 17 OH Progesterone </li></ul></ul><ul><li>↑ Plasma 17 OH-Progesterone / Progesterone </li></ul><ul><ul><li>↑ Urinary 17-Ketosteroids / Pregnanetriol </li></ul></ul><ul><ul><li>21 Hydroxylase gene on Ch.6 (CYP-21) and a pseudogene (CYP-21P). Mutations lead to inactivation of the active CYP-21 gene </li></ul></ul>21 Hydroxylase Deficiency : Oral steroid to mother suppresses ACTH preventing virilisation : Must be given at week 5, prior to CVS / amniocentesis : 7/8 are treated unecessarily : Effectiveness measured by plasma 17 OH progesterone levels
  31. 37. <ul><li>Other causes: </li></ul><ul><ul><li>11 beta Hydroxylase Deficiency (5%) </li></ul></ul>Congenital Adrenal Hyperplasia Hypertension ↑ Plasma 11 Deoxycortisol
  32. 38. <ul><li>Treatment </li></ul><ul><ul><li>ACTH suppression using Steroids </li></ul></ul><ul><ul><ul><li>Hydrocortisone / deltacortril </li></ul></ul></ul><ul><ul><ul><li>Mineralocorticoid (if salt loser) </li></ul></ul></ul><ul><ul><ul><li>Feminising Genitoplasty at 3 to 6 months </li></ul></ul></ul><ul><ul><ul><li>Adrenalectomy in severe cases where it is more difficult to maintain adrenal suppresion that treat adrenal crisis </li></ul></ul></ul>21 Hydroxylase Deficiency
  33. 39. <ul><li>Other causes: </li></ul><ul><ul><li>11 beta Hydroxylase </li></ul></ul><ul><ul><li>3 beta OH-Steroid Dehydrogenase </li></ul></ul><ul><ul><li>17 Hydroxylase </li></ul></ul><ul><ul><li>11 Hydroxylase </li></ul></ul>Congenital Adrenal Hyperplasia Hypertensive ↑ 11 Deoxycortisol
  34. 40. <ul><li>46 XY individuals with testes but with varying degrees of feminisation </li></ul><ul><ul><li>Leydig Cell Aplasia </li></ul></ul><ul><ul><li>Disorders of Testosterone Biosynthesis </li></ul></ul><ul><ul><li>Androgen Receptor Defects </li></ul></ul><ul><ul><li>Impaired MIS production </li></ul></ul>Male Pseudohermaphroditism
  35. 41. <ul><li>46 XY karyotype but female phenotype </li></ul><ul><ul><li>Palpable testes but ↑ LH and ↓ Testosterone </li></ul></ul><ul><ul><li>No stimulation of testosterone with hCG </li></ul></ul><ul><ul><li>No Mullerian structures / short vagina </li></ul></ul><ul><ul><li>Histology demonstrates no Leydig cells </li></ul></ul>Leydig Cell Aplasia / LH receptor abnormality
  36. 42. <ul><li>5 enzymes involved in the conversion of cholesterol to testosterone </li></ul><ul><ul><li>3 in the adrenal & testis </li></ul></ul><ul><ul><li>2 in the testis only </li></ul></ul>Testosterone Biosynthesis Cholesterol side change cleavage 3 β OH steroid Dehydrogenase 17 α Hydroxylase 17,20 Lyase Deficiency 17 β OH steroid Oxioreductase Dehydrogenase
  37. 43. <ul><li>Commonest cause of Male Pseudohermaphroditism </li></ul><ul><li>46 XY phenotype with normal testes </li></ul><ul><li>Variable external genitalia </li></ul><ul><ul><li>Complete Androgen Sensitivity </li></ul></ul><ul><ul><li>Partial Androgen Sensitivity (Reifenstein’s Syn.) </li></ul></ul>Androgen Receptor Defects
  38. 44. <ul><li>Testicular Feminisation (female phenotype) </li></ul><ul><li>1 in 20-60,000 males, X-linked trait </li></ul><ul><li>In utero loss of androgen, and MIS secretion means loss of internal genitalia </li></ul><ul><li>2% of females with an inguinal hernia have Complete androgen sensitivity </li></ul><ul><li>Usually diagnosed with amenorrhea, absence of pubic hair or hormonal profile </li></ul><ul><li>Gonadectomy and Oestrogen replacement therapy </li></ul>Complete Androgen Sensitivity
  39. 45. <ul><li>Incomplete male pseudohermaphroditism </li></ul><ul><li>Ambiguous genitalia </li></ul><ul><li>Incomplete: normal testosterone, LH and testosterone/DHT ratio </li></ul>Partial Androgen Sensitivity (Reifenstein’s Syndrome)
  40. 46. <ul><li>Medical & Psychological Emergency </li></ul><ul><li>Goal is Accurate diagnosis of Intersex Disorder </li></ul><ul><li>Assign proper sex of rearing: </li></ul><ul><ul><li>Status of child’s anatomy </li></ul></ul><ul><ul><li>Functional potential of genitalia and reproductive tract </li></ul></ul>Evaluation of Ambiguous Genitalia
  41. 47. <ul><li>On Examination: TESTES </li></ul><ul><ul><li>Presence of 1/2 palpable gonads </li></ul></ul><ul><ul><li>Absence of palpable testes or the presence of 1 testes and hypospadias is an intersex disorder until proven otherwise </li></ul></ul><ul><ul><li>Unilateral palpable UDT - 15% are Intersex </li></ul></ul><ul><ul><li>Unilateral implapable UDT - 50% are intersex </li></ul></ul><ul><ul><li>Bilateral UDT and hypospadias - 32% are intersex </li></ul></ul>Evaluation of Ambiguous Genitalia
  42. 48. <ul><li>Need to know: </li></ul><ul><ul><li>Presence or absence of palpable testes / position of urethral meatus and phallus </li></ul></ul><ul><ul><li>Presence of Mullerian structures (U/S) </li></ul></ul><ul><ul><li>Serum 17 OH progesterone </li></ul></ul><ul><ul><li>Karyotype </li></ul></ul>Evaluation of Ambiguous Genitalia
  43. 49. <ul><li>Definitive Laparoscopy and gonadal biopsy </li></ul><ul><li>Cultured Genital skin fibroblasts </li></ul><ul><li>Contrast study of Urogenital sinus </li></ul>Evaluation of Ambiguous Genitalia
  44. 50. <ul><li>Potential for normal sexual functioning </li></ul><ul><li>Fertility potential </li></ul><ul><li>Risk of gonadal malignancy </li></ul><ul><li>Psychosocial well being </li></ul><ul><li>Stable Gender Identity </li></ul>Gender Assignment Meyer-Bahlburg, 1998

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