Embryology, Urethral Folds

Development

The urogenital system arises from the intermediate mesenchymal tissue (intermediate mesoderm forms kidneys and ureters) and forms the urogenital ridge on both sides of the aorta.[1]

Development of the urogenital ridge begins with three sets of tubular nephric structures, from cranial to caudal: pronephros, mesonephros, and the metanephros.  

Pronephros

• This is the most cephalad, or cranial most, set of tubes
• Mostly regresses 

Mesonephros

• Located in the midsection of the embryo
• It eventually develops into the mesonephric tubules and the mesonephric duct or Wolffian duct. 

Metanephros

• Gives rise to the adult kidney 
• Development occurs from an outgrowth from the caudal mesonephric duct (ureteric bud) as well as from the condensation of the metanephric blastema.  

Metanephric Blastema - Derivatives

• Distal convoluted tubules
• Proximal convoluted tubules
• Podocytes - glomerular capillaries
• Ascending thick limbs of Henle
• Descending thick limbs of the loop of Henle
• Thin limbs of the loop of Henle
• Epithelial cells lining the Bowman's capsule 

Ureteric Bud - Derivatives

• Ureters
• Major and minor calyces
• Collecting tubules 
• Collecting ducts

Steps in Renogensis

1. Retinoic acid-dependent reciprocal induction process
2. the metanephric blastema forms from the cranial-caudal patterning in the tail of the embryo within the intermediate mesoderm
3. The ureteric bud form from growth factors secreted by metanephric blastema at the caudal portion of the mesonephric duct.
4. The proliferation of the ureteric bud occurs, resulting in differentiation of the metanephric blastema. Once differentiation occurs, the glomeruli and tubules of the kidney form.
5. If there are any perturbations in any of these events (i.e., any mutations of either metanephric or ureteric factors or retinoic acid signaling disruption), inhibition of the ureteric bud growth and renal hypoplasia/agenesis may occur. If there is overproliferation or even duplication of these structures, a gain of function of the inductive factors may occur. 

The urethra is a part of the urogenital system, urethra develops from the endoderm of the urogenital sinus.[2] The urethra runs from the neck of the urinary bladder to the external urethra orifice. The male urethra divides into four parts prostatic, membranous, bulbar, and penile part.[3] 

Some Potential Malformations that may occur with errors during development:

• Bladder exstrophy
  • Cause: Ventral abdominal wall defect during embryogenesis - overdeveloped cloacal membrane
  • Clinical Findings: herniation of bladder and urethra, incontinence, widely separated pubic symphysis, for males, the penis may become shortened with a dorsal curvature and possible epispadias, for females there may be a bifid clitoris with labia that is separated anteriorly as well as possible epispadias. 
    • Associated malformations may also consist of omphalocele, low set umbilicus, anteriorly displaced anus, indirect inguinal hernia, possible hip dysplasia, cardiac dysplasia, and bicornuate uterus. 
  • Diagnosis: primarily clinical, although prenatal ultrasound can provide visualization of the abnormality.
  • Treatment: surgery.
• Epispadias
  • Cause: Malformation due to malpositioning genital tubercle, which then causes urethral tubularization to be incomplete on the dorsal penis (when associated with exstrophy of the bladder). May also result from chronic pressure (i.e., transurethral indwelling catheter that eventually erodes the urethra)
  • Clinical Findings: division and exposure of the urethra of the dorsal surface and associated with a curvature of the penis; Urinary incontinence.
  • Diagnosis: clinical
  • Treatment: surgery 
• Hypospadias
  • Cause: Ectopic location of the urethral meatus from a failure of urethral foreskin and folds to fuse on the ventral surface of the penis.[4]
  • Genetic, endocrine, and environmental factors have been implicated; Occurs in 1 in 250 newborn males.[5]
  • Clinical Features:'hooded' abnormal foreskin, ventral penile curvature with two possible mental openings
  • Diagnosis: clinical
  • Treatment: Depends on the severity; may be treated surgically. 
• Posterior Urethral Valves
  • Cause: males- malformation where membranous folds obstruct the membranous and prostatic urethra 
  • Clinical Features: urinary tract obstruction in newborn male (most common), pulmonary hypoplasia resulting in respiratory distress, bladder distention causing abdominal distention; if the presentation is late: UTI leading to urosepsis, failure to thrive, diurnal enuresis, and difficulty voiding
  • Diagnosis: voiding cystourethrogram
  • Treatment: first-line is primary valve ablation; second-line- vesicostomy
• Webbed Penis
  • Cause: malformation with the growth of the scrotum; the urethra is typically unaffected 
  • Clinical Features: during erect, there is webbing between the tip of the penis and scrotum; potential erectile dysfunction 
  • Diagnosis: clinical
  • Treatment: surgery 

Cellular

Female is the default phenotypic differentiation. Degeneration of the mesonephric duct occurs, allowing for the paramesonephric duct to develop. 

In males, the SRY gene on the Y chromosome is what produces the testis-determining factor, which allows for the development of the testes. As a result, testes then can give rise to Sertoli cells, which produce: Mullerian inhibitory factor (MIF), which suppresses the development of paramesonephric ducts, and Leydig cells, which produce the androgens that are necessary for the development of the mesonephric ducts. 

Male and female genital homologs:

1. Genital tubercle
   1. Dihydrotestosterone --> Glans penis, corpus cavernosum, and spongiosum (Cowper)
   2. Estrogen --> Glans clitoris, vestibular bulbs
2. Urogenital sinus
   1. Dihydrotestosterone --> Bulbourethral glans, prostate 
   2. Estrogen --> Greater vestibular glands (Bartholin), Urethral and paraurethral glands (Skene) [6]
   3. Bladder and urethra
3. Urogenital folds
   1. Dihydrotestosterone --> Ventral shaft of the penis (penile urethra)
   2. Estrogen --> Labia minora
4. Labioscrotal swelling
   1. Dihydrotestosterone --> Scrotum
   2. Estrogen --> Labia majors 

Biochemical

The penis develops from ambisexual genital tubercle during early embryo development (8-18 weeks of gestation) under androgen influence.[7] The absence of androgen leads to the development of the female genital tubercle, which will then develop into the clitoris, which is homologous with the penis except for the "clitoral urethra."[8] It has been shown that the urethra of the penis develops via an "opening zipper" by canalization of the solid urethral plate to form the open urethral groove.[9] 

Females undergo the same process of canalization, forming the open vestibular groove.[8] The "closing zipper" or epithelial fusion of the urethral folds in males occurs within the shaft of the penis and leads to the formation of the urethra.[9][10] The "closing zipper" does not happen in females since it occurs under androgenic stimulation, which is absent secondary to the absence of testes. 

Molecular Level

Development of external genitals occurs by three main pathways:

1. Androgen-dependent 
2. Androgen-independent
3. Endocrine/environmental factors 

Testing

The most common malformations sonographically identified during the prenatal period are congenital abnormalities of the urinary tract and kidneys, with obstructive uropathies being the most common.[11] From 9 to 12 months of pregnancy, the fetal kidneys can be visualized on both sides of the lumbar spine and are easy to see because of their hyperechogenicity during the first trimester.[11] 

Color Doppler can make it even easier to identify both renal arteries. Fetal urine production begins at nine weeks gestation, increasing significantly beyond 16 weeks, at 20 weeks, nearly 90% of amniotic fluid is urine produced by the fetus. The fetal bladder can be visualized from 13 weeks onward. From 15 weeks onwards, visualizing the urogenital system via ultrasound becomes easier due to ongoing differentiation.

It is vital to diagnose abnormalities during the prenatal period and treat any critical obstructions or urinary tract infections (UTIs) for the best potential outcome of the affected child. After diagnosis with prenatal ultrasound, about 60% of affected children have surgery for either urinary tract or renal problems in their first five years of life.[12]

A routine fetal ultrasound of the urogenital tract consists of the assessment for the size, location, and presence of both kidneys and bladder, along with the evaluation of their structure and echogenicity, as well as the development of the external genitalia and amniotic fluid quantity.

Clinical Significance

In-depth and thorough knowledge regarding embryological origin and evolution into adulthood is important in the understanding of the pathophysiology of congenital and acquired anomalies. This knowledge enables clinicians to initiate the treatment options that are most appropriate for the patient. The integration of embryology in the medical curriculum is essential for better patient outcomes.[13]