Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Disorders of sex development

10,262 views

Published on

intersex
DSD

Published in: Health & Medicine
  • To get professional research papers you must go for experts like ⇒ www.HelpWriting.net ⇐
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • I think you need a perfect and 100% unique academic essays papers have a look once this site i hope you will get valuable papers, HelpWriting.net
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • The recovery program is giving me the chance that I was seeking to change my life and to free me of the bulimia. For the first time in my life I feel that I am not alone trying to surpass my bulimia. I have real knowledges about my illness and how to beat them. I feel supported, pleased and liberated, with less fears and insecurities of my image. ♥♥♥ http://scamcb.com/bulimiarec/pdf
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • The Bulimia Recovery Program, We Recovered, You CAN TOO! ◆◆◆ http://t.cn/A6Pq6KF6
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • How to use "The Scrambler" ot get a girl obsessed with BANGING you... ★★★ http://t.cn/AijLRbnO
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

Disorders of sex development

  1. 1. Disorders of sex development (DSD)
  2. 2. It is a complex topic but actually if you understand it, it will be very simple.
  3. 3. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  4. 4. Hormones
  5. 5. Chromosomal Sex Genes associated with sex determination  SRY (sex-determining region Y gene) is responsible for testis formation and called TDF (testis-determining factor).  Mutation in SRY gene may occurs and result in sex reversal As it absent in Y chromosome result in XY female And it’s present in X chromosome result in XX male And this prove that SRY gene is TDF. Sinclair et al 1990
  6. 6. Chromosomal Sex Presence of SRY gene Testis formation Absence of SRY gene ovary formation (Passive) • During the first 6 weeks the gonadal ridge, germ cells  bipotential sex development. • Ovarian differentiation needs at least two X chromosome ( this explain dysgenetic ovary in 45 X0 turner). Haqq et al 1994
  7. 7. Gonadal development 1. In Males • Differentiation of sertoli cell (7th week)  MIS production regression of Mullerian ducts. • MIS acts unilaterally. • Formation of leydige cell (9th week)  testosterone production  proliferation of wolffian duct and descend of the testis.
  8. 8. Gonadal development • Testosterone  dihydrotestosterone (higher affinity to androgen receptors) by intracellular 5α-reductase. • Disorders of androgen receptors or 5α-reductase lead to a spectrum of phenotypic abnormalities in the genetic male. Andersson et al, 1991
  9. 9. Gonadal development 2. In Females • Absent SRY Ovary differentiation No MIS NO testosterone Proliferation of Mullerian duct • Uterus • Fallopian tube • Upper 4/5 of vagina Reggresion of wolffian duct • Epoophoron and paroophoron • Gartener’s duct
  10. 10. Phenotypic differentiation Malefemale
  11. 11. Phenotypic differentiation Undifferentiated stage • Before the 8th week of gestation the urogenital tract is identical in the two sexes. • Undifferentiated stage of external genitalia consists of 1. Genital tubericle 2. Genital (urethral ) folds 3. Genital swelling
  12. 12. Phenotypic differentiation In males • Androgen  -masculinization of the external genitalia (12th-13th week). -penile growth and testicular descent (3rd trimester) Doymer et al 1994.
  13. 13. Phenotypic differentiation In Females • In the female fetus the absence of circulating testosterone maintains the appearance of the Female external genitalia at the 6-week gestational stage. Doymer et al 1994
  14. 14. Gender Identity • Gender identity;- the identification of self as either male or female. • Is complex, poor understood and multifactorial. • Androgen has major role in brain imprint. • Postnatal environmental factors and learning appear to have an important effect. Reiner et al 2004
  15. 15. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  16. 16. Definition of DSD Conditions involving the following elements • Sex chromosome anomalies as Turner syndrome. • Disorder of gonadal developments as ovitestes • Disorders of internal reproductive organs • Disorders of external genitalia ( ambigious) It was called intersex but this term is not accurate and showed be avoided. Hughes et al 2006
  17. 17. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  18. 18. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular DSD) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  19. 19. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes • Seminiferous tubule dysgenesis
  20. 20. Seminiferous tubule dysgenesis 1. Klinefelter syndrome • The Most common DSD. • Genotype;- Male with at least Y + at least 2 X chromosomes (47XXY (classic), 48XXXY,48XXYY,….. Mosaic 46XY/47XXY) • Gonads;- Small firm atrophic testes with small number of leydig cells Azospermic except in mosaic. • Hormones;-low normal Testosterone , Increase FSH and LH, Increase estrogen. • Phenotype; normal male external genitalia Not ambiguous
  21. 21. • Special features • Complications 1. High incidence of breast cancer (8 times). 2. Predispose to sertoli and leydig cell tumour 3. Infertility • Management 1. Androgen replacement 2. Surveillance for testicular tumor and breast carcinoma. Staessen et al 2003 Klinefelter syndrome
  22. 22. Cont…Seminiferous tubule dysgenesis 2. 46,XX male Due to translocation of Y chromosomal material, including SRY (TDF) to the X chromosome. • Gonads;- Small firm atrophic testes with small number of leydig cells  Azospermic • Hormones;-low normal Testosterone , Increase FSH and LH, Increase estrogen. • Phenotype; normal male external genitalia Not ambiguous but 10 % hypospadias. • Complication and Management as Klinefelter but shorter and normal skeletal proportions. Fechner et al 1993
  23. 23. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes • Syndromes of gonadal dysgenesis
  24. 24. Turner syndrome • Incidence of 1 in 2500 live births. • Genotype 45XO , Mosaic (45XO/46XX ,45XO/46XY). • Gonads fibrous streaks (no surviving germ cells) • Hormones Decrease both androgen and estrogen, increase in FSH and LH • Phenotype; normal female external genitalia ( well- differentiated external genitalia, vagina and müllerian derivatives) Not ambiguous Epstein, et al 1990 • Renal anomlies 33% (structural or positional ); Horseshoe kidney or renal agenesis , and malrotation. Hall et al , 1990
  25. 25. Turner syndrome Low set ear
  26. 26. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes • Syndromes of gonadal dysgenesis
  27. 27. Syndromes of gonadal dysgenesis • Abnormality of SRY gene that affects SRY function  fundamental abnormality of gonadal development. • Karyotyping is variable XX or XY. • Gonads can be ‘streak’ gonad or dysgenetic. • failure of the Gonads to produce testosterone and MIS results in an entirely female phenotype. • Partial gonadal dysgenesis may be unilateral or bilateral, and so gives rise to varying degrees of sexual ambiguity.
  28. 28. Pure Mixed partial Bilateral streak gonads Female (Not Ambiguous) Dsygenetic testis contralateral streak gonad Ambiguous Two dysgenetic testes Ambiguous Gonadal dysgenesis
  29. 29. Mixed gonadal dysgenesis Testis (Often Intra-abdominal) MIS and testosterone ipsilateral wolffian duct differentiation and müllerian ducts regression Streak gonad NO MIS and testosterone Mullerian duct differentiation Ipsilateral uterus fallopian tube Davidoff and Federman, 1973
  30. 30. • Gender assignment depends on function of the external genitalia and gonads (anatomy not fertility). Female Orchidectomy and hormonal replacement Male Orchiolysis and pexy plus screaning for germ tumour Or gonadectomy and androgen replacement
  31. 31. Disorders of Gonadal Differentiation • Seminiferous tubule dysgenesis 1. Klinefelter syndrome 2. 46,XX male • Syndromes of gonadal dysgenesis 1. Turner syndrome 2. Pure gonadal dysgenesis 3. Mixed gonadal dysgenesis 4. Partial gonadal dysgenesis (dysgenetic male pseudohermaphroditism) • Bilateral vanishing testis/testicular regression syndromes Bilateral vanishing testis/testicular regression syndromes
  32. 32. Bilateral vanishing testis/testicular regression syndromes • 46,XY • Absent testes with clear evidence of testicular function at some point during embryogenesis. • Due to genetic mutation, a teratogen, or bilateral torsion. • Diagnosis: Elevated FSH/LH and castrate testosterone levels; 46 XY Migeon et al 1994
  33. 33. Most sever Before60-70 days gestation MIS secreted but before the elaboration of androgen. phenotypic female with no internal genital structures testicular regression syndrome Intermediate After liberation of MIS and incomplete eloberation of androgen  ambiguous genitalia, absent gonads and internal ductal structures Least sever Late after complete anatomic development of the male external genitalia  phenotypic males with fully developed wolffian structures but an empty scrotum, and microphallus. bilateral vanishing testes syndrome 3 phenotypes according to the time that vanishing occur.
  34. 34. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  35. 35. True Hermaphroditism (Ovotesticular) • Both testicular and ovarian tissue, either in separate gonads or coexisting in the same gonad as an ovotestis. • Karyotype variable  Not helpful for diagnosis. • Phenotype Ambiguous genitalia with tendency to masculinization (75% are raised as male). • Internal organs are variable and according to the present gonad • Pregnancy documented in female only. (Berkovitz et al, 1991)
  36. 36. True Hermaphroditism (Ovotesticular) Management • Gender assignment based on the functional potential of external genitalia, internal ducts, and gonads, according to the findings at laparoscopy or laparotomy. • If the patient is to be raised as female, all testicular and wolffian tissue should be removed. • If a male gender is assigned, all ovarian and müllerian tissue should be removed • Gonadectomy at puberty with androgen replacement due to the high risk of malignancy and no hope for fertility. Starceski et al, 1988
  37. 37. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  38. 38. Masculinized Female (Female Pseudohermaphrodite) • 46,XX DSD  phenotypic disorder • CAH is the main etiology • Most common cause of ambiguous genitalia. • Autosomal recessive disorder • Deficiency of an enzyme involved in glucocorticoid synthesis increase ACTH  shift to androgen pathway and adrenal hyperplasia  Ambiguous gentalia. New and Levine, 1984
  39. 39. Congenital Adrenal Hyperplasia • Types: (1) salt wasters (patients with virilization and aldosterone deficiency) 75%. (2) simple virilizers (patients with virilization, but without salt wasting) 25%. (3) Non classic patients (those without evidence of virilization or salt wasting) rare. Kohn et al, 1995.
  40. 40. Congenital Adrenal Hyperplasia • The clinical phenotype of CAH depends on the nature and severity of the enzyme deficiency.
  41. 41. Congenital Adrenal Hyperplasia labioscrotal fusion and clitoromegaly. complete virilization of phallus.
  42. 42. Congenital Adrenal Hyperplasia • Diagnosis • Demonstration of inadequate production of cortisol, aldosterone, or both • Demonstration of excess concentrations of precursor hormones; serum 17-hydroxyprogesterone Urinary 17-ketosteroid levels serum 11-deoxycortisol and deoxycorticosterone
  43. 43. Congenital Adrenal Hyperplasia • Salt-wasting forms of CAH: Low serum aldosterone concentrations, hyponatremia , hyperkalemia, and elevated plasma renin activity (PRA). • A karyotype is essential in an infant with ambiguous genitalia, to establish the chromosomal sex
  44. 44. Classification 1. Disorders of Gonadal Differentiation 2. True Hermaphroditism (Ovotesticular) 3. Female Pseudohermaphrodite (Masculinized Female) 4. Male Pseudohermaphrodite (Under-masculinized Male) 5. Unclassified Forms
  45. 45. Male Pseudohermaphrodite (Undermasculinized Male) • 46,XY with differentiated testes. • Varying degrees of feminization phenotypically. • Secondary to:  inadequate secretion of testosterone by the testes.  inability of target tissue to respond to androgen appropriately.  impaired production or action of MIS.
  46. 46. Male Pseudohermaphrodite Undermasculinized Male ( 46,XY DSD) Classifications 1. Leydig Cell Aplasia (Luteinizing Hormone Receptor Abnormality) 2. Disorders of Testosterone Biosynthesis 3. 5α-Reductase Deficiency 4. Androgen Receptor and Postreceptor Defects (testicular feminization) 5. Persistent Müllerian Duct Syndrome (hernia uteri inguinale). LH T DHT Receptor
  47. 47. Male Pseudohermaphrodite Undermasculinized Male ( 46,XY DSD) 5.Persistent Müllerian Duct Syndrome (hernia uteri inguinale). • 46,XY • normal male external genitalia • internal müllerian duct structures. • unilateral or bilateral undescended testes • commonly diagnosed after müllerian tissue is encountered during inguinal herniorrhaphy or orchidopexy.
  48. 48. Cont.. Persistent Müllerian Duct Syndrome • The treatment of persistent müllerian duct syndrome is relatively straightforward, in that all patients are phenotypic males who require orchidopexy. • The vasa deferentia are in close proximity to the uterus and proximal vagina, and preservation of the necessary müllerian structures to avoid injury to the vasa is recommended to preserve fertility Sloan and Walsh, 1976
  49. 49. Outlines • Normal sex development and Embryology • Definition • Classification • Disorders • Workup
  50. 50. Pragmatic Urologic approach to DSD DR Ahmed Abdelhamid
  51. 51. • Classic ambiguous genitalia • Female with palpable gonads • Male with nonpalpable gonads • Hypospadias and cryptorchidism • “Normal” Female or Male Common Neonatal Presentations
  52. 52. DSD TEAM Multidisciplinary 1. Urology 2. Endocrine 3. Genetics 4. Psychology/Psychia try 5. Gynecologist 6. Religious counseling
  53. 53. Questions to be answered • What is the diagnosis • What is the anatomy • What is the function of gonads and reproductive tract • Gender Assignment
  54. 54. Important principles A. Palpable gonad = testis; as ovaries do not descend , Rarely, an ovotestis descent to the inguinal canal. B. Bilaterally impalpable testes or unilaterally impalpable testis and hypospadias should be considered DSD until proven otherwise, whether or not the genitalia appear ambiguous.
  55. 55. Work up • Karyotyping • Hormonal assay; serum electolyte, T, DHT, serum 17-hydroxyprogesterone, • HCG stimulation test ruling out anorchia. • Laparoscopy and gonadal biopsy. • Genitogram and endoscopy to detect urogenital sinus.
  56. 56. Gender assignment Non functioning female better than non functioning male
  57. 57. Role of surgery • Feminising surgery Clitororeduction; Reduction of an enlarged clitoris should be done with preservation of the neurovascular bundle. Separation of the vagina and the urethra is preserved for high confluence anomalies for urogenital sinus repair. Vaginoplasty should be performed during the teenage years.
  58. 58. Role of surgery • Masculinising surgery • Hypospadias surgery. • Excision of Mullerian structures. • Orchiopexy. • Phalloplasty; severe penile inadequacy in DSD patients. • correction of penoscrotal transposition, scrotoplasty • insertion of testicular prostheses.
  59. 59. Thank you

×