Normal Development of the Urogenital System

1. 0 Normal Development of the Urogenital System Christi Hughart, D.O.

2. 0 Kidney Development • 3 embryonic kidneys (from intermediate mesoderm)- • Pronephros- transient (week 3-5), nonfunctional, 5-7 paired segments. • Mesonephros- transient (week 4- month 4), excretory organ while metanephros begins development. Form renal corpuscles. • Formation of nephric ducts/wolffian ducts (controlled by Pax2, Lim 1) precedes development of mesonephric tubules. • Small number of elements from mesonephros persist to form reproductive tract. • Males- efferent ductules of testes, epididymis and vas- wolfian origin. • Females- nonfunctional mesosalpingeal structures.

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4. 0 • Metanephros- definitive kidneys • Form as ureteric buds (from distal end of nephric duct) (RET-GDNF-GFR alpha 1 pathway). • Penetrates metanephric mesenchyme at 28 days to begin nephron formation- lobulated appearance. • Autosomal recessive polycystic kidney disease- (1/5,000) progressive, cysts form from collecting ducts. (RF in infancy or childhood). • Autosomal dominant polycystic kidney disease- (1/500-1/1,000) cysts form from all segments of nephron. (RF in adulthood). • Metanephric mesoderm forms nephron or excretory unit (glomerulus, proximal tubule, loop of Henle, distal tubule)- form from metanephric mesenchyme. Develop in stages I-IV. • Older nephrons on inner part of kidney, newer at periphery.

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6. 0 • Collecting system (collecting ducts, calyces, pelvis, ureter)- formed from ureteric bud. • Week 6= 16 branches, week 7= minor calyces formed, week 32= 1-3 million branches. • Duplication of the ureter- due to early splitting of the ureteric bud. • Ectopic ureter- one ureter opens into bladder and other into vagina, urethra, or vestibule. • Multicystic dysplastic kidney- numerous ducts surrounded by undifferentiated cells- nephrons fail to develop and ureteric bud fails to branch- collecting ducts never form- • may cause involution of kidney or renal agenesis (also occurs if ureteric bud fails to contact metanephric mesoderm). • B/L renal agenesis (1/10,000)- Potter sequence- anuria, oligohydramnios, hypoplastic lungs (other associated anomalies).

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8. 0 • Definitive kidney functional at 12 weeks- urine passed into amniotic cavity and mixes with amniotic fluid- fluid swallowed by fetus and recycles (placenta excretes waste). • Renal maturation continues after birth but nephrogenesis is complete before birth.

9. 0 Renal Ascent • Week 6-9- ascend to lumbar site below adrenals. • Thought to be due to differential growth of lumbar and sacral regions of embryo. • Vascularized by succession of transient aortic branches- degenerate- final pair remaining is renal arteries (may have accessory renal arteries if some persist). • Horseshoe kidney (1/600 births)- inferior poles fuse, across ventral side of aorta, fused lower pole stuck under IMA. • Cross-fused ectopy- one kidney fuses to contralateral one and ascends to opposite side.

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11. 0 Renal Vascular Development • Angiogenic Hypothesis- derived from branches off aorta and other pre-existing extrarenal vessels. • Vasculogenic Hypothesis- originate in situ from vascular progenitor cells (VEGF).

12. 0 Bladder (Urogenital Sinus) • 3rd week- cloacal membrane bilaminar (endoderm and ectoderm). • 4th week- neural tube and tail grow dorsally and caudally to project over cloacal membrane (embryo folding)- cloacal membrane now ventral. • 5th-6th weeks- partitioning of cloaca into anterior urogenital sinus and posterior anorectal canal by midline fusion of 2 lateral ridges of cloacal wall and by descending urorectal septum. (some believe this septum formation and fusion of cloacal membrane never occur). • 24th day- nephric (wolffian) duct fuses with cloaca- • Cephalad vesicourethral canal- bladder and pelvic urethra. • Caudal urogenital sinus- phallic urethra for males, distal vaginal vestibule for females.

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14. 0 • Primitive trigone- day 33- right and left common excretory ducts (mesonephric) fuse midline as this triangular area. • Smooth muscle develops from the bladder dome and extends to base and urethra. • Bladder body- endoderm and surrounding mesenchyme, trigone- mesoderm. • Week 12- urachus involutes into median umbilical fold. • Week 21- bladder epithelium 5 cell layers thick.

15. 0 Ureter • Complete lumen at 28 days- transient luminal obstruction at 37-40 days and recanalizes starting at the midureter. • 37-39 days- Chwalla’s membrane- 2 cell thick layer over ureteric orifice. • 12 weeks- smooth muscle and elastic fibers (smooth muscle begins at UVJ and ascends)- occurs later than bladder. • 14 weeks- transitional epithelium-occurs by epithelial-mesenchymal interaction.

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17. 0 Renin-Angiotensin System • Responsible for fetal glomerular filtration, urine production, growth/development of kidney and ureter (mothers treated with ACE-inh- oligohydramnios, hypotension, anuria).

18. 0 Genital Development • Genital ridge mesenchyme- primitive sex cords- after 6 wks develop different fates in male/female (paramesonephric/mullerian ducts also form): • SRY (sex-determining region of Y chromosome)- differentiate into Sertoli cells, 7th week- testis cords/rete testes, puberty- seminiferous tubules. • Sertoli cells secrete MIS (mullerian-inhibiting substance)- regression of mullerian ducts at weeks 8-10 (remnants= appendix testis, prostatic utricle). • Week 9-10- Leydig cells form testosterone. • Stimulates wolffian ducts to form vas (8-12 weeks).

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21. 0 • Absent SRY- differentiate into ovarian follicles. • Primitive sex cords degenerate and secondary sex cords form- forms ovarian follicles. • Germ cells become oogonia and enter first meiotic division as primary oocytes (puberty- oocytes resume gametogenesis due to monthly gonadotropin surges). • Wolffian ducts degenerate. • No MIS in females so no regression of mullerian ducts- mullerian ducts form fallopian tubes, uterus, and upper 2/3 vagina.

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23. 0 Prostate/Seminal Vesicle • Prostate/bulbourethral glands- from urethra/urogenital sinus (10-12 weeks)- at puberty testosterone rises and prostate size increases. • Seminal Vesicle- (10th week) sprout from distal mesonephric ducts in response to testosterone.

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25. 0 External Genitalia • Mesodermal cells form rudiments of external genitalia. • They spread around cloacal membrane to form swellings. • 5th week- cloacal folds develop on either side of cloacal membrane- meet anteriorly to form midline swelling called genital tubercle. • Cloacal folds differentiate into urogenital folds and anal folds. • Labioscrotal folds form on each side of urogenital folds. • Urethral groove and urethral plate fuse to form penile urethra. • Females- no androgen receptor signaling by DHT- perineum doesn’t lengthen and labioscrotal and urethral folds do not fuse at midline. • Phallus bends inferiorly- becomes clitoris. • Urethral folds- labia minora. • Labioscrotal folds- labia majora.

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28. 0 Gonadal Descent • Testicles/ovaries lie near kidney before gonadal differentiation- held there by 2 loose ligaments- • Ventral- gubernaculum. • Dorsal- cranial suspensory ligament (CSL). • Males (week 10-15)- at inguinal region- gubernaculum enlarges, CSL regresses. • Inguinoscrotal migration (7th month)- gubernaculum descends to scrotal location and is hollowed out by peritoneal diverticulum (processus vaginalis). • Females- ovary moves cranially- CSL develops, gubernaculum involutes. • Ovaries suspended in broad ligaments of uterus. (3rd month). • “Female gubernaculum” becomes round ligament.

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30. 0 References • Campbell-Walsh Urology- Ninth Edition (2007), Vol. 4, Chapter106- Normal Development of the Urogenital System. • Langman’s Medical Embryology- Ninth Edition (2000), Chapter14- Urogenital System.