Normal Development of the Urogenital System

Christi Hughart, D.O.

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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• – 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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• 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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• 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.

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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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).

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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• 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.

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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Renin-Angiotensin System

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

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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– 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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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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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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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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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.