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Embryology, Genitourinary


Embryology, Genitourinary

Article Author:
Sabrina Libretti
Article Editor:
Narothama Aeddula
Updated:
6/5/2020 1:12:46 PM
For CME on this topic:
Embryology, Genitourinary CME
PubMed Link:
Embryology, Genitourinary

Introduction

The embryological formation of the intermediate mesoderm derived urogenital system begins as two separate, yet interwoven processes:

A. Development of the urinary system from the nephrogenic cord.

B. Development of the reproductive system from the gonadal ridge.

The interplay between multiple genes and hormones is essential for both systems to develop properly. As such, a mutation or misstep in any portion of the cascade of events can cause a double, absent, or malformed structure. Knowledge of urogenital embryology is paramount for the accurate diagnosis and treatment of a myriad of conditions.

Development

Urinary System

The urinary system begins forming during the 4th week of gestation. At the end of week 4, a nephrogenic cord has formed, giving rise to three kidney systems:

A. The pronephros in the cervical region

B. Mesonephros in the thoracic and lumbar region

C. The metanephros, which will ultimately transform into the functional kidneys.

The most cranially positioned kidney system, the pronephros, is nonfunctional and regresses by the end of the fourth week of gestation as the more caudal kidney systems begin to form. The nephrotome is a vestigial excretory unit present with the pronephros. The mesonephros exists as the embryonic kidney in the lumbar region from weeks 4 to 8, and its remnants go on to form several structures in the male genital system. The mesonephric cord creates vesicles from provesicular cell masses, which make contact laterally with the collecting system of the mesonephros, the mesonephric (Wolffian) duct. The fusion of these vesicles with the Wolffian duct, and acquisition of a lumen, forms the tubules of the nephron.[1] The functioning adult kidney, the metanephros, appears during week 5 and exists in the sacral region, becoming fully functional as early as the eleventh week and is fully formed at week 32. The permanent kidneys develop from both the ureteric bud and the metanephric mesoderm (blastema), which form the collecting system and excretory units, respectively. The ureteric bud, an outgrowth of the mesonephric duct near its junction with the cloaca, dilates to form the renal pelvis, and major calyces after invading metanephric tissue. After several generations of buds, absorption of the third and fourth generations forms the minor calyces and, eventually, the renal pyramid. The ureters and 1 to 3 million collecting tubules also originate from the ureteric bud. The cells of metanephric tissue cap covering the collecting ducts form the renal vesicles, which give rise to S-shaped tubules that acquire capillaries to form glomeruli, the proximal end of which forms Bowman’s capsule. The excretory tubule lengthens to form the proximal convoluted tubule, the loop of Henle, and the distal convoluted tubule. With the expansion of the abdomen and growth of the lumbar and sacral regions, the kidneys separate and ascend between weeks 6 and 9.

The cloaca is the shared component of the anorectal and urogenital passages at the 5th week of gestation that subdivides into two separate channels during the 6th and 7th weeks.[2] The cloaca splits into the urogenital sinus anteriorly and the anal canal posteriorly, separated by the urorectal septum, the tip of which forms the perineal body.[3] The anterior portion of urogenital sinus will become the urinary bladder, and inferior portion of the pelvic and penile urethra in males, while the pelvic part of urogenital sinus will become the prostatic and membranous portions of the urethra in males and urethra and vaginal vestibule in females. The cranial part of the urethra will form with paraurethral (Skene’s) glands in females, homologous to the male prostate gland, which formed from the epithelium of the prostatic urethra that penetrated the surrounding mesenchyme. Bartholin’s glands, also known as the greater vestibular glands, are homologous to the bulbourethral (Cowper’s) glands in the male, both originating from the urogenital sinus.

The bladder begins development during weeks 4 to 7. Initially, the bladder is continuous with allantois, and when the lumen becomes obliterated, the urachus functions to connect the apex of the bladder with the umbilicus. Involution of the cloaca and embryonic allantois form the urachus, whose remnant is the median umbilical ligament.[4]

Genital System

All fetuses begin with undifferentiated gonads, which will develop into either the ovaries in females or the testes in males. Although morphologically indistinguishable at this stage, unisex gonads are known as ‘bipotential’ because of the ability to transform into an ovary or testis depending if the individual possesses an XX or XY chromosome, respectively.[5] The genetic sex of the embryo is determined based on the sperm and egg that come together during fertilization, but fetal gonads will not acquire male or female morphological characteristics until week 7 of gestation. The initial appearance of the gonads is the genital (gonadal) ridges formed by the proliferation of the epithelium and condensation of underlying mesenchyme. The development of testes in males and ovaries in females relies on the induction by primordial germ cells from the yolk sac to the genital (gonadal) ridges during 4th through 6th weeks. These primordial cells arrive at the primitive gonads at week 5 and invade the gonadal ridge during week 6.[6] The presence of the SRY gene (sex-determining region on the chromosome) on the short arm of the Y chromosome (Yp11) influences the development into testes, while the gonads will become ovaries in its absence. The presence of estrogen is paramount in the formation of external genitalia in females, whereas testosterone drives the development of male external genitalia. 

The formation of the gonads begins at embryonic day 10, and the expression of Sry protein, also known as the testes-determining factor, begins between days 10 and 11. The undifferentiated genital system consists of two pairs of ducts at week 7: the mesonephric (Wolffian) and paramesonephric (Mullerian) ducts. The paramesonephric ducts arise on the anterolateral surface of the urogenital ridge. In males, the paramesonephric ducts regress under the influence of anti-Mullerian hormone (AMH), also referred to as Mullerian inhibiting substance (MIS), produced by Sertoli cells beginning in weeks 8 to 10. Testosterone secreted by Leydig cells beginning at week 9 causes the mesonephric ducts to differentiate into the epididymis, vas deferens, ejaculatory duct, and seminal vesicles.[7] Testosterone is also involved in the masculinization of the urogenital sinus and external genitalia into the penis and scrotum, after conversion to dihydrotestosterone catalyzed by the enzyme 5a-reductase.[6] In females, the absence of AMH and the influence of estrogen leads to the formation of the uterine (Fallopian) tubes from the cranial portion of the paramesonephric ducts, and the upper third of the vagina, cervix, and uterus from the caudal portion, which is complete by the end of the first trimester. The endometrium of the uterus originates from simply epithelium, while the myometrium and perimetrium covering the uterus originate from surrounding mesenchyme.[8]

The genital tubercle forms from a pile of mesenchymal cells from the cloacal folds and is positioned cranially to the opening of the urogenital sinus. The genital tubercle will elongate under the influence of androgens to become the phallus in males and the clitoris in females in the absence of androgens.[6] The genital tubercle pulls together the urethral folds (from the cloacal folds), to form the urogenital folds, which will fuse in the midline to become the shaft of the penis in males or the unfused labia minora in females. The scrotum in males is homologous to the labia majora in females, as they share a common origin, the labioscrotal swellings. The labioscrotal swellings initially appear in week 4, lie lateral to the genital tubercle, and migrate caudally and medially during weeks 9 to 11 to form the scrotum by week 12. Estrogens are essential for the development of the clitoris, labia, and lower vagina. The processus vaginalis from the evagination of the peritoneum of the abdominal cavity forms the inguinal canal after protrusion into the scrotal swelling.[9] Descent of the testes is prompted by intra-abdominal pressure causing its migration through the abdominal wall via the inguinal canal by 28 weeks gestation and should reach the scrotum by week 33. Coverings of the testis include the peritoneal layers derived from the processus vaginalis, and derivatives of the anterior abdominal wall: transversalis fascia (internal spermatic fascia), internal oblique muscle (cremasteric fascia and muscle), and external oblique muscle (external spermatic fascia).

Cellular

Interactions between epithelium and mesenchyme (embryonic connective tissue) are necessary for the development of all organs of female and male urogenital systems, except for the gonads.[10] While the development of the genital organs (the epididymis, vas deferens, seminal vesicle, penis and prostate in males; the uterine tubes, uterus, cervix, vagina, and clitoris in females), relies on hormones, the development of urinary system structures (kidney, ureter, and bladder) is hormone-independent.[10]

The urogenital system is formed from intermediate mesoderm, while the lining of the urethra, urinary bladder, and reproductive system is composed of endoderm. Primordial germ cells that migrated from the epiblast through the primitive streak then appear at the primitive gonads at the beginning of week 5, to invade the genital ridges at week 6, as stated above.

Molecular

BMPs (bone morphogenetic proteins) and their modifiers are invaluable to the formation of the kidney, especially BMP4, expressed in the mesenchyme surrounding the nephric duct, and BMP7 expressed in the metanephric mesenchyme and ureteric buds.[11] The epithelia of the collecting duct derive from the ureteric bud, while the epithelium of the nephron derives from metanephric mesenchyme. The ureteric bud expresses Hoxb, and the metanephric mesenchyme expresses the transcription factors Six2 (a marker for self-renewing nephron progenitors) and Cited 1. FGF2 and BMP7 are essential for the proliferation of metanephric mesenchyme and the production of WT1. As such, deletions in the Fgfr2 receptor produce small kidneys, anomalous branching of the ureteric bud, scant nephrons, and defective stromal mesenchymal patterns.[12] WT1, expressed by mesenchyme of the metanephric blastema, regulates the production of glial-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) by the mesenchyme, which then stimulates the branching and growth of the ureteric bud from the mesonephric duct. RET, the tyrosine kinase receptor for GDNF, and MET, the receptor for HGF, are synthesized by the epithelium of ureteric buds to stimulate its growth.

Upregulation of PAX2 and WNT4 by WNT9B and WNT6 promotes the condensation of the mesenchyme and epithelialization into tubules of condensed mesenchyme, respectively. Wnt signaling is essential for Müllerian duct development, differentiation, and regression, and WNT4 has been deemed the ovary-determining gene. In both males and females, WNT4 and the autosomal gene SOX9 are expressed in the gonadal ridges. SRY and/or SOX9 induce the secretion of FGF9 by the testes that influence the penetration of the gonadal ridge by the tubules of the mesospheric duct. SOX9 becomes upregulated by SRY and activates expression of SF1 (steroidogenesis factor 1), whose role is to stimulate differentiation of Sertoli and Leydig cells.

Interaction of SOX9 and SF1 is essential to raise the concentration of AMH to cause regression of the Müllerian ducts. WNT4 upregulates DAX1, whose role is to suppress SF1 transcriptional activity, inhibiting the function of SOX9; thus, in females, ovaries will develop from the inhibited expression of SOX9 and is not just a passive ‘default’ process.[13] GATA4 and FOG2 are additional protein-coding genes that play a role in male gonadogenesis and maintenance of SRY expression. Hox genes are responsible for the anterior-posterior orientation of the Müllerian duct system. Lastly, sonic hedgehog (Shh) becomes expressed in the genital tubercle, and its signaling is implicated in the formation of the penis.[6] In its absence, there is a disruption of genital tubercle development and a persistent cloaca.

Function

The urinary system, composed of the kidneys, ureters, and urethra, is responsible for filtration of waste, fluid balance, waste elimination, and production of the hormones erythropoietin, renin, and calcitriol necessary for red blood cell production, blood pressure regulation, and vitamin D regulation, respectively. Urine production begins at week 10 after the differentiation of glomerular capillaries. Urine production is necessary for the amniotic fluid volume to cushion the fetus and facilitate proper lung development.

The urinary bladder receives urine from the ureters from the kidneys and to store urine before micturition. The genital system functions to produce ova in females and sperm in males and transport them to come together during fertilization. A zygote will be carried through the fallopian (uterine) tubes for implantation in the uterine cavity. Production of sex hormones, estrogen, and progesterone from ovaries and testosterone from testes, is an essential component of the hypothalamic-pituitary-gonadal axis.

Testing

Various imaging modalities exist to visualize the anatomy of the pelvis. An ultrasound is a cost-effective and minimally invasive imaging modality that can display the structures of the genitourinary system to highlight renal or gonadal abnormalities; this is the first choice when evaluating pediatric patients, as it is painless, widely available, and immediate. Through prenatal imaging, ninety percent of fetal kidneys are identifiable by 17 to 20 weeks gestation and 95% by 22 weeks gestation.[14] 

Ultrasound is essential in the diagnosis of horseshoe kidney, renal agenesis, Wilms’ tumor, polycystic kidney disease, and urachal anomalies. A CT scan can also be performed but at the expense of radiation exposure and may involve contrast dye. MRI, though expensive, can also be employed to visualize structures of the genitourinary system with more detail, and is the gold standard for evaluating uterine anomalies.[15] 

Measurement of the amniotic fluid index aids in the evaluation of the kidney function of the fetus, as too little amniotic fluid, oligohydramnios, results in poor lung development. In contrast, polyhydramnios, too much amniotic fluid, indicates a problem with swallowing, such as esophageal atresia.

Pathophysiology

Urinary System

Wilms’ tumor (nephroblastoma) arises in the kidney due to a mutation in the WT1 gene on chromosome 11p13. The thought is that persistent cells of the metanephric mesenchyme/blastema are precursors for the development of 40% of Wilms’ tumor cases.[16] Wilms’ tumor is one component of WAGR syndrome caused by a microdeletion of WT1 and PAX6, which also features aniridia, genitourinary anomalies, and intellectual disability. Common genitourinary anomalies associated with WAGR syndrome include cryptorchidism, a failure of at least one testis to descend, or hypospadias, which is an incomplete fusion of the urethral folds leaving an opening in the ventral aspect of the proximal penis, in males. In females, it may present at streak ovaries, hypoplastic uterus, or septate vagina. Hypospadias commonly presents with chordee, involving the shortening and curving of the ventral penis. Wilms’ tumor is also a feature in several other conditions such as Beckwith-Wiedemann syndrome, Bloom syndrome, Denys-Drash syndrome, and Li Fraumeni syndrome.[17] Autosomal recessive polycystic kidney disease (ARPKD) presents as fluid-filled cysts in the collecting ducts leading to renal failure in childhood, while autosomal dominant polycystic kidney disease (ADPKD) features cysts in any part of the nephron and renal failure in adulthood. Eighty-five percent of cases of ADPKD result from a mutation in the gene PKD1, and the remaining 15% from mutations in PKD2.[18]

Mutations in the GDNF-RET signaling pathway are implicated in the formation of a multicystic dysplastic kidney, in which multiple cysts are present and separated by parenchyma; when present bilaterally, it can cause impaired renal function since the collecting ducts within the nephrons fail to develop. Oligohydramnios is the consequence of the inability of the kidneys to produce urine and is present in conditions such as multicystic kidney disease, bilateral renal agenesis, and renal dysplasia. Too little amniotic fluid causes the fatal Potter sequence, resulting in a fetus with craniofacial abnormalities (cleft lip, flattened face, low-set ears, recessed chin), pulmonary hypoplasia, and clubbed feet, although a child with unilateral renal agenesis can survive via compensatory hypertrophy of the functioning kidney.[19] Urinary issues associated with unilateral renal agenesis include ureteropelvic junction obstruction and vesicoureteral reflux (VUR). If the kidneys cannot ascend properly from the pelvis into their proper lumbar position, a pelvic kidney close to the common iliac artery, or a horseshoe kidney with fused lower poles may be present. The root of the inferior mesenteric artery is responsible for preventing the proper ascent of the kidneys, which commonly presents in Edwards syndrome (trisomy 18) and Turner syndrome.[20]

The bladder exstrophy-epispadias-cloacal exstrophy complex is a constellation of ventral wall defects caused by a developmental abnormality 4 to 5 weeks after conception. Bladder exstrophy exists concomitantly with epispadias, a failure of the lateral body wall folds to close in the midline, leaving the urethral meatus on the dorsum of the penis. Cloacal malformations result from the failure of anorectal and urogenital channels to separate during weeks 6 to 7 of gestation and result in a single perineal opening[2] Diagnosis is made clinically during a newborn examination but can present as hydrocolpos on prenatal ultrasound or MRI. Imaging is warranted, as up to 90% of patients with a cloaca also have a urologic anomaly such as renal agenesis, horseshoe kidney, hydronephrosis, or vesicoureteral reflux.[21] A patent urachus involves the persistence of the embryological connection between the dome of the bladder and the umbilicus, as the allantois failed to breakdown. Urine can drain from the umbilicus if there is a urachal fistula present from the persistence of the lumen of the intraembryonic portion of the allantois, causing delayed cord stump healing and edema around the umbilicus of a newborn. Several other urachal anomalies exist, such as a urachal cyst when a local area of the urachus persists, an umbilical-urachal sinus from a failure of the umbilical end of the urachus to obliterate, and vesicourachal diverticulum caused by incomplete obliteration of the urachus on the bladder side.[4] Additionally, an ectopic ureter can develop if there is abnormal migration of the ureteric bud during its insertion into the bladder.

Genital System

There are many steps during urogenital formation from which anomalies can arise. Failure of the paramesonephric ducts to fuse can occur at any point in the line of normal fusion can result in uterine malformation, such as uterus arcuatus, a concavity at the uterine fundus due to failure of the fused midline segments to degenerate, and uterus didelphys, a complete duplication of the uterus from complete lack of fusion.[15] Uterus bicornis is a uterine anomaly in which the uterus has two horns entering a common vagina as a result of only a partial fusion of the paramesonephric ducts. Failure of the sinovaginal bulbs to develop results in vaginal atresia, while the failure of them to fuse results in the presence of a double vagina. Hydrocele, the buildup of fluid around the testicle due to a remnant of tunica vaginalis, will present in males as painless scrotal swelling and can be transilluminated by light. The appendix testis is a vestigial remnant of the Mullerian duct located at the anterior-superior pole of the testis, and the Gartner’s duct, epoophoron, and paraoophoron are the remnants of the Wolffian duct in females. Additionally, congenital indirect inguinal hernia results from the failure of the connection between the abdominal cavity and the processus vaginalis to close, allowing loops of the bowel to descend into the scrotum.

The most common cause of ambiguous genitalia is congenital adrenal hyperplasia (CAH), most frequently caused by a 21-hydroxylase deficiency (needed in the formation of cortisol) due to mutations or deletions of CYP21A, in 90% of cases. 17a-hydroxylase deficiency can also cause CAH, though less frequently, resulting in normal female internal and external anatomy at birth but primary amenorrhea or failure of secondary sex characteristics at puberty. In males, small genitalia, undescended testes, or other lack of virilization at puberty may be the first sign.[22] In androgen insensitivity syndrome (AIS), receptors are unresponsive to androgens and ineffective in inducing differentiation of the male genitalia. An XY male will have phenotypically female genitalia, though MIS is present, causing the uterine tubes and uterus to be absent. A micropenis, described as 2.5 standard deviations below the mean penis length when stretched, results from insufficient androgen stimulation or defect in the HPG axis. Inhibition or deficiency of the enzyme 5-a-reductase results in the inability to convert testosterone to dihydrotestosterone, resulting in underdeveloped, albeit external male genitalia. Lastly, XY female gonadal dysgenesis (Swyer syndrome) results from point mutations or deletions of the SRY gene and will present as in females as lack of menstruation and/or secondary sex characteristics at puberty.

Clinical Significance

Many congenital anomalies of the female reproductive system can go unnoticed until child-bearing years when infertility or amenorrhea becomes an issue. Gonadal dysgenesis, the presence of streak gonads instead of functional gonads, can be seen in individuals with Turner syndrome (45, XO), and will likely go unnoticed until reproductive age, as will uterine malformations. An undescended testis may be at any point along the normal path of descent from the abdomen. Detection and expectant management of cryptorchidism are crucial as it associated with infertility and increase the risk of developing testicular germ cell tumors, inguinal hernias, or testicular torsions.[23]

The presence of a cloaca or other anorectal malformation (ARM) should prompt a more thorough exam, as it is one component of the VACTERL association (vertebral anomalies, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects).[24] The inability to correctly diagnose a cloaca in the newborn period could miss obstructing uropathy that can progress to sepsis, acidosis, and renal failure. Surgery to make appropriate perineal openings for the gastrointestinal, gynecologic, and urologic tracts is the mainstay of fixing ARMs. 

The presentation of a Wilms' tumor is usually in an asymptomatic child younger than five years of age with an abdominal mass, which would prompt evaluation with an ultrasound and/or an MRI. At the time of the diagnosis of a Wilms' tumor, lung metastasis is present in 10 to 20% of cases.[17] Although the anomaly predisposes the individual to ureteropelvic junction obstruction, hydronephrosis, urinary tract infections, and tumors, one-third of horseshoe kidney cases are found incidentally.[20] Complications stemming from urachal anomalies include urinary stasis, infection, stone formation, and, although rare, malignancy, necessitating a prompt diagnosis and surgical correction.[4] 

The clinical implications of all urogenital anomalies are too numerous for the scope of this discussion. With that said, the emotional well-being of the patient and their support system should always be addressed when discussing their diagnoses, as many of these conditions can carry severe morbidity and mortality.


References

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