This document provides an overview of reproductive embryology and urogenital development from weeks 5-8 of gestation. It discusses the key structures and events in bladder, genital, and gonadal development in both males and females. It also reviews common disorders of sex development and the genetic basis for differences in male versus female development. Case examples are presented and analyzed.

1. Reproductive Embryology
Catherine Keegan, M.D., Ph.D.
Spring 2009
M1 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 structures
develops from the urogenital sinus?
Vas deferens
Seminal vesicle
Prostate
Appendix testicle

7. The bladder trigone Mullerian ducts
develops 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 of
gestation is the
indifferent stage
Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. ed

11. Source Undetermined
Migration of primordial germ
cells 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
Differentiation
Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.

13. Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.

14. Para- Mesonephric
mesonephric duct
duct remnants in
remnants in females
males
Epoophoron
Appendix Paroophoron
testis
Prostatic Gartner’s cyst
utricle
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 normal
Y 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 virilization
Blue = DHT
Brown = 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 center
Normal 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 month
2nd month
Requires Insl3
term
7th month
Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.

24. The testicles descend to the level of
internal 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 males
Source 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-reductase
deficiency has the following features except:
Seminal vesicle
Vas deferens
Fallopian tubes
Testicles
J. Park
Severe perineal hypospadias

37. This patient with 5-alpha-reductase
deficiency 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., 2009
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Slide 6: Carlson. Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.
Slide 7: Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. Ed
Slide 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. Ed
Slide 13: Source Undetermined; Larsen. Human Embryology. Philadelphia : Churchill Livingstone/Elsevier, 2009. 4th ed. Ed
Slide 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. Ed
Slide 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 Undetermined
Slide 29: Source Undetermined
Slide 30: Source Undetermined
Slide 35: John Park
Slide 38: John Park
Slide 39: John Park