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Urogenital embryology
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Urogenital embryology Presentation Transcript

  • 1. Reproductive Embryology Catherine Keegan, M.D., Ph.D.Spring 2009M1 Embryology
  • 2. Topics• Bladder and ureter development• Genital development• Cases
  • 3. Objectives• Understand the key events during urogenital development• Understand the origin of major structures that comprise the urogenital system• Understand major differences between male and female gonadal development – Both internal and external genitalia• Be familiar with common disorders of sex development and their genetic basis
  • 4. Division of the cloacal region 5 weeks 6 weeks 8 weeks Controversy over existence of “urorectal septum” Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 5. The prostate develops as an outgrowth of the urogenital sinus epithelium Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. ed Urogenital sinus: prostate, bulbourethral gland Ureteric bud: ureter Mesonephric duct: seminal vesicle, vas deferens
  • 6. Which of the following structuresdevelops from the urogenital sinus? Vas deferens Seminal vesicle Prostate Appendix testicle
  • 7. The bladder trigone Mullerian ductsdevelops from which Mesonephric ducts of the following Urogenital sinus structures? Ureteric buds Langman. Medical Embriology. Lippincott, 2004. 9th ed. Mesonephric ducts fuse with urogenital sinus and migrate caudally to form the trigone Common excretory duct = name for mesonephric duct distal to ureteric bud
  • 8. Developmental abnormalities of the urogenital sinus Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 9. Gonadal Development• Sexual determination – Genetic events that bring about male or female gonadal development• Sexual differentiation – All subsequent morphogenetic and physiologic events that establish functional sexuality, sexual dimorphism, and secondary sex characteristics
  • 10. The first 7 weeks ofgestation is theindifferent stage Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. ed
  • 11. Source UndeterminedMigration of primordial germcells to urogenital ridges Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. ed Indifferent stage Mesonephric duct = Wollfian duct Paramesonephric duct = Mullerian duct
  • 12. Sexual Determination No MIS Sertoli cells No Testosterone Leydig cells Sexual DifferentiationCarlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 13. Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 14. Para- Mesonephricmesonephric ductduct remnants inremnants in femalesmales EpoophoronAppendix ParoophorontestisProstatic Gartner’s cystutricle Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. ed
  • 15. Formation of uterus and vagina Langman. Medical Embriology. Lippincott, 2004. 9th ed.Paramesonephric (Mullerian) ducts fuse to form uterus and upper 1/3 of vagina
  • 16. In the presence of a structurally normalY chromosome, the following structures would be expected to develop:• Mullerian derivatives• Ovaries• Wolffian derivatives• Uterus, cervix and upper 1/3 of the vagina
  • 17. Virilization of male genitalia Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Effects of Testosterone and DHT mediated by Androgen Receptors
  • 18. Male virilizationBlue = DHTBrown = Testosterone Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 19. Formation of external genitalia Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 20. Formation of the urethra Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 21. Hypospadias Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed. meatus Raphe off centerNormal midline raphe J. Park J. Park
  • 22. Developmental anomalies of the uterus Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 23. Testicular descent 3rd month2nd month Requires Insl3 term 7th month Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
  • 24. The testicles descend to the level ofinternal inguinal ring by which time point during gestation? Sixth week Third month Sixth month Ninth month
  • 25. Disorders of Sex Development: Terminology• Sex reversal (Determination) – 46, XX males – 46, XY females – Complete gonadal dysgenesis• Ambiguous genitalia (Differentiation) – Partial gonadal dysgenesis – True hermaphrodites • Both testicular and ovarian tissue – Pseudohermaphrodites • Phenotype of external genitalia is inconsistent with gonadal sex• Gene-based approach• DSD consensus statement
  • 26. SRY Source Undetermined• Primary sex determining gene on Y chromosome – Located near pseudoautosomal region• Transcription factor – DNA-binding and DNA-bending HMG box – Thought to activate SOX9 expression• Translocation of SRY causes 46 XX males and 46 XY females – 80% of XX males are SRY positive• 15% of patients with complete gonadal dysgenesis have SRY mutations – Most in HMG box
  • 27. SRY translocation Pairing of X and Y chromosomes in pseudoautosomal region during meiosis Rare crossing over causes translocation of SRY to X chromosome: XY females or XX malesSource Undetermined
  • 28. SOX9 Source Undetermined• SRY-related protein – SRY-box = SOX – Multiple family members• Strongly expressed in male gonads, expression downregulated in females• Activates male specific genes (MIS)• Human mutations in SOX9 cause campomelic dysplasia – XY sex reversal and skeletal dysplasia
  • 29. Which of the following is not true of the SRY (the Sex-determining Region of the Y- chromosome) gene? It is a transcription factor that activates male- specific gene expression. A translocation of the SRY gene to the X chromosome during paternal meiosis or a mutation in the SRY gene are both mechanisms that can lead to complete male-to-female sex reversal (46, XY female). It is located on the short arm of the Y chromosome near the pseudoautosomal region. It causes regression of the mesonephric (Wolffian) ducts.
  • 30. Genes that regulate Sexual Differentiation• Androgen receptor (AR)• MIS/MIS-receptor• 5 α-reductase• Steroidogenic enzymes – P450c21 (21-hydroxylase) – Congenital adrenal hyperplasia • Adrenal insufficiency • Virilization of female fetus
  • 31. Androgen Receptor• Nuclear hormone receptor modulates effects of androgens• Mutations cause Complete or Partial Androgen Insensitivity Syndrome• XY sex reversal with female external genitalia and normal testes• Normal production of MIS causes Mullerian duct regression• Lack of virilization due to inability of AR to bind testosterone
  • 32. 5 α-reductase deficiency• Enzyme required to convert Testosterone to Dihydrotestosterone• Elevated Testosterone:DHT ratio• DHT is more potent—higher affinity for AR• Deficiency causes ambiguous genitalia in males• Lack of virilization of male fetus• Normal production of MIS causes regression of Mullerian structures
  • 33. Congenital adrenal hyperplasia • Enzymatic defect in steroidogenesis • Autosomal recessive • Virilization of female fetus due to production of androgenic hormones • Testes absent • Normal Mullerian structures internally J. Park • These patients can present with life threatening adrenal crisis and salt wasting!
  • 34. Persistent Müllerian Duct syndrome• Normal male genitalia• Presence of uterus and fallopian tubes• Usually undergo virilization at puberty• Mutation in MIS (50%)• Mutation in MIS-receptor (50%)
  • 35. A patient with a mutation in the Androgen Receptor gene causing complete loss of function would be expected to have which of the following:• Testicles• Cervix• Fallopian tubes• Completely virilized male external genitalia
  • 36. This patient with 5-alpha-reductasedeficiency has the following features except: Seminal vesicle Vas deferens Fallopian tubes Testicles J. Park Severe perineal hypospadias
  • 37. This patient with 5-alpha-reductasedeficiency has the following features except: Severe perineal hypospadias Seminal vesicle Vas deferens Fallopian tubes Testicles J. Park Derived under the influence of testosterone Testicles produce MIS causing regression of Mullerian duct structures
  • 38. Developmental Sex Disorders• Nomenclature – Moving away from terms such as “intersex” and “hermaphrodite” – DSD • Congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical – 46, XY DSD • Gonadal dysgenesis (SRY mutations) • AIS (partial or complete) • Androgen synthesis defects (5-alpha reductase def.) – 46, XX DSD • Androgen excess (most common 21-hydroxylase CAH) – Sex chromosome DSD • Turner, Klinefelter, mosaic karyotypes
  • 39. DSD counseling• Multidisciplinary Care Team• Gender assignment• What to say to the parents• To operate or not to operate? – Is surgery cosmetic? – Risk of malignancy depends on diagnosis• Psychosocial care – Gender identity – Gender role – Sexual orientation• Disclosure – To other family members – To the child• Support Groups
  • 40. DSD counseling• Gender assignment must be avoided before expert evaluation in newborns• Evaluation and long-term management must be performed at a center with an experienced multidisciplinary team• All individuals should receive a gender assignment• Open communication with patients and families is essential; encourage participation in decision- making• Patient and family concerns should be respected and addressed in strict confidence
  • 41. Cases
  • 42. Patient #1• Prenatal ultrasound: – Oligohydramnios – Cardiac abnormality--heart felt to be enlarged – Fetus thought to be female• IUGR, neonatal hypoglycemia and thrombocytopenia that resolved• No cardiac abnormality found postnatally• Ambiguous genitalia: – Bifid scrotum with palpable gonads – Small phallic structure with urethral opening at base – No uterus, no cervix – Endocrine work-up: Normal testosterone, DHT, normal 17-OHP• Family history noncontributory
  • 43. Questions• Based on the findings, what would you expect the karyotype to be?• What tentative diagnosis would fit these features?• What gender would you assign to this baby?
  • 44. Patient #2• Ambiguous genitalia noted at birth – Prenatal ultrasound female gender• No other medical problems• Family history noncontributory• Primarily female phenotype – Enlarged labia majora with palpable gonads – Clitoral tissue – Vaginal opening visualized – Absent uterus by ultrasound• Endocrine work-up: – Normal 17-hydroxyprogesterone – Normal testosterone and T:DHT ratio – MIS in normal range for male
  • 45. Questions• Based on the findings, what would you expect the karyotype to be?• What tentative diagnosis would fit these features?• What gender would you assign to this baby?
  • 46. Patient #3• 16 year old woman with primary amenorrhea• Some breast and pubic hair development• Pelvic ultrasound: – Small uterus (prepubertal), left ovary not identified, right ovary “normal”• Pelvic MRI: – Similar findings, but slightly enlarged right ovary relative to size of uterus• Karyotype 46, XY “SRY+”• Medical history otherwise unremarkable• Family history noncontributory. Younger sister began menses at age 13
  • 47. Questions• What additional work-up would you perform?• Is there anything concerning about her history or physical exam findings?
  • 48. Author: Catherine Keegan, M.D., Ph.D., 2009License: Unless otherwise noted, this material is made available under the terms of theCreative Commons Attribution – Non-Commercial 3.0 License:http://creativecommons.org/licenses/by-nc/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share,and adapt it. The citation key on the following slide provides information about how you may share and adapt this material.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections,or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement formedical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you havequestions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  • 49. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  • 50. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 6: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 7: Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. EdSlide 9: Langman. Medical Embriology. Lippincott, 2004. 9th ed.Slide 10: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 12: Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. EdSlide 13: Source Undetermined; Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. EdSlide 14: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 15: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 16: Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. EdSlide 17: Langman. Medical Embriology. Lippincott, 2004. 9th ed.Slide 19: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 20: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 21: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 22: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 23: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.; John Park (Both images)Slide 24: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 25: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 28: Source UndeterminedSlide 29: Source UndeterminedSlide 30: Source UndeterminedSlide 35: John ParkSlide 38: John ParkSlide 39: John Park