Development+of+the+Reproductive+System

=**Objectives**=


 * 1. Define/Describe:**

__Urogenital Sinus (Three Portions)__ Vesicular portion- most superior, forms bladder. Pelvic portion- middle, forms prostatic urethra Phallic portion- forms penile urethra and cowper's glands.

__Mesonephric Duct__ Formed with the mesonephric kidney during kidney development.

In duct system development, mesonephric ducts form the efferent ductules in the male as well as remnants in the form of the appendix of the epididymis and the paradidymis.

In the female duct system development, the absence of testosterone causes the mesonephric ducts to regress, leaving remnants such as appendix vesiculosa, epoophron, paraoophoron, and duct/cysts of Gartner.

__Wolffian Duct__ Another name for mesonephric duct. Comes from the mesonephric kidneys.

__Paramesonephric Duct__ Formed during the 6th week of development as a longitudinal invagination of coelomic mesothelium on the surface of the urogenital ridge lateral to the mesonephric duct. Forms a solid cord of cells that reach the urogenital sinus between the enterence of mesonephrid ducts and then recanalizes, leaving a funnel-shapped cranial end open into the coeloic cavity and a closed caudal end into the urogenital sinus.

In males, Mullerian-inhibiting substance (MIS) causes the paramesonephric ducts to degenerate, leaving remnants in the form of the prostatic utricle (homologue to vagina) and the appendix to the testis (superior pole of testis).

In females, the absence of MIS permitsthe development of the paramesonephric duct into the female duct system. Wnt-4 is necessary for paramesonephric duct development, and Wnt-7a is necessary for Hoxd 10-13 gene expression. The cranial end of the paramesonephric duct forms the uterine tubes with the cranial opening becoming the fimbriated infundibulum. The caudal ends move medially and ventrally to the mesonephric duct and fuse together in the midline to form the uterovaginal perimordium which gives rise to the vagina and uterus. As the ducts migrate toward the midline, the associated tissue that is carried with them form the broad ligament and forms the boundaries of the rectouterine and vesicouterine pouches.

__Mullerian Duct__ Another name for paramesonephric duct.

__Uterovaginal Primordium__ The fused portions of the paramesonephric ducts that are the primordial uterus, cervix, and upper portion of vagina.

__Sinovaginal Bulb__ Two of these epithelium-derived structures are induced to form by the bulging out of the sinus tubercule.

__Primary Sex Cords__ Also known as Gonadal cords, these are coelomic mesothelium in origin, proliferating on the medial aspect of the mesonephric ridge. In males, they move into the medulla of the forming testis and the germ cells migrate into them, forming rudimentary seminiferous tubules.

__Cortical Cords (Secondary Sex Cords)__ In the female ovarian development, these are outgrowths of mesothelium, remaining in the cortical region of the gonadal ridge, that contain the germ cells that will develop into oogonia.

__Seminifernous Tubule__ After the 7th week of development, the Primary sex cords will differentiate into the seminiferous tubules. They contain the spermagonia from the primordial germ cells, fetal sertoli cells that are epithelial in origin, and fetal leydig cells that are mesenchymal in origin. On the dorsolateral side, they make contact with the mesonephric ducts via the mesonephric tubules, allowing differentiation of rete testis and efferent tubules.

__Ovarian Follicle__ An ovarian follice consists of an ovum, which originates from the endodermal lining of the yolk stalk, and the surrounding follicular cells, which are mesothelial (coelomic epithelium) and mesenchymal (from mesonephric tubules) in origin.

__Tunica Albuginea__ The coelomic ridge of epithelium on the surface of the cortex of the developing gonads becomes the tunica albuginea after the ingrowth and formation of the primary and/or secondary sex cords.


 * 2. Describe the situation (location) of the embryonic gonad as it begins its development. What is the origin of the autonomic innervation and vascular supply of the developing gonad (both blood and lymphatic).**

The embryonic gonads begin their formation just ventral to the developing metanephric kidneys.

Sympathetic autonomic innervation is supplied by the least splanchnic nerve (T12) which goes through the aortico-renal prevertebral ganglion. Parasympathetic autonomic innervation is supplyed by the vagus nerve (CNX).

The least splanchnic nerve follows the gonadal artery which supplies the gonads.


 * 3. Describe the origin and migratory path of the primordial germ cells.**

The primordial germ cells originate in the yolk sac endoderm. Under the influence of BMP-4 and chemotactic factors, they migrate into the forming urogenital ridge, and then into the primary sex cords (gonadal cords). If the embryo is XX, the germ cells will migrate into the secondary (cortical) sex cords.


 * 4. Explain the roles of the SRY locus, Testis-Determining Factor, androgenic hormones, Anti-Mullerian Factor (or Mullerian Inhibiting Substance), in the development of the reproductive systems.**

SRY is located on the short arm of the Y chromosome. It is responsible for inducing the production of TDF.

Testis Determining Factor is responsible for the formation of the primary sex cords and differentiation of the gonad into testis. Lack of TDF results in an ovary.

Anti-Mullerian Factor (MIS) is responsible for inhibiting the development of the paramesonephric duct system and causing its degeneration.


 * 5. Describe the migration of coelomic epithelial (mesothelial) cells into the mesenchyme of the gonad to produce the primary sex cords in the testes and the primary and secondary sex cords in the ovary. What ultimately develops from each generation of cords.**

Mesothelial cells proliferate on the medial side of the mesonephros in the 5th week, then extend fingerlike epithelial cords into the underlying mesenchyme-- this creates an external cortex region, and an internal medullary region.

The primary sex cords will grow into the medulla, ultimately forming testis. The secondary sex cords (cortical sex cords) remain in the cortical region, ultimately breaking down to form ovarian follicles.


 * 6. What are the components and origin of each component of the seminiferous tubule, straight tubules, rete testes, efferent ductules, ductus epididymis, and ductus deferens?**

Seminiferous Tubule(outer primary sex cord origin) consists of Sertoli cells (coelomic epithelium), Spermatogonia (Yolk sac endoderm, with interstitial Leydig cells surrounding it (Mesenchymal origin).

Straight Tubules are partly of sex cord origin and partly of mesonephric tubular origin.

Rete Testes are of inner gonadal cord origin, where they have branched into the medulla and anastomosed.

Efferent Ductules are created where the rete testis becomes continuous with 15-20 mesonephric tubules.

Ductus Epididymus and Ductus Deferens originate from the mesonephric duct, and are directed by Hox genes (10-10, and 11-13, respectively).


 * 7. Describe the formation of the seminal vesicle and the prostate.**

The seminal vesicle forms from a lateral outgrowth of the caudal portion of the mesonephric duct.

The prostate is a result of multiple endodermal outgrowths of the prostatic urethra into surrounding mesenchyme. The epithelium differentiates into glandular cells, whereas the mesenchyme differentiates into dense stroma and smooth muscle. This happens under the influence of testosterone on the mesenchyme, and is positionally directed by Hoxd-13.


 * 8. What is the origin of the interstitial cells of the testis, theca interna of the ovarian follicle, and interstitial gland of the ovary.**

Interstitial cells of the testis and ovary arise from mesenchyme.


 * 9. What is the primary determinant of genotypic (genetic) and phenotypic (morphologic) sex in humans?**

Genotypic sex is determined at fertilization. XX for females, XY for males. Phenotypic sex is not manifested until the 7th week of gestation during gonadal differentiation.

In male XY genotype, the Sry gene produces testis-determining factor (TDF) which triggers inhibition of the Dax-1 gene and permits testis formation. In female XX genotype, expression of Dax-1 gene suppresses formation of testicular structures and permits indifferent gonad to form ovaries. Unlike testis, presence of germ cells is necessary for ovarian development; if primordial germ cells fail to migrate, then the indifferent gonad regresses into streak ovaries.

The embryonic sertoli cells produce MIS, which prevents development of the paramesonephric duct system, as well as Meiosis-Inhibiting Factor, which prevents spermatogenesis and meiosis.
 * 10. What substance (hormones) does the embryonic testis produce? What does each substance do in the body?**

The embryonic Leydig cells produce testosterone and androstenedione in response to placental HcG. The testosterone secreted is responsible for the convolution and formation of the duct system in weeks 9-14.


 * 11. Why does the testis use a duct system and the ovary does not?**

The testis duct system develops from the preformed mesonephric duct, whereas the ovary initiates growth of the paramesonephric ducts. These paramesonephric "ducts" begin as grooves in the lateral aspect of the mesonephros, eventually folding closed to form funnel-like structures, open cranially and fused caudally.

The duct system in the male system functions primarily as a conduit for the spermatozoa to develop and travel through. However, the duct system in the female is more highly modified to accommodate the additional function of nurturing a fetus until partition in addition to its function as a conduit.

The paramesonephric ducts begin to form laterally to the mesonephric ducts. In the absence of MIS, they will form as lateral invaginations in the mesothelium of the mesonephros, eventually fusing their edges to form grooves. They pass ventrally to the mesonephric ducts to fuse caudally into the uterovaginal primordium, which protrudes dorsally into the urogenital sinus wall, forming a bulge known as the sinus tubercule.
 * 12. Describe the site of formation and method of formation of the paramesonephric ducts.**


 * 13. Describe the path or route of development of the paramesonephric ducts.**

See above answer.


 * 14. Describe the formation and fate of the uterovaginal primordium, sinus tubercle, sinovaginal bulbs, vaginal plate, and hymen.**

The uterovaginal primordium is formed by the fusion of the closed caudal ends of the paramesonephric ducts. Their dorsal protrusion into the UG sinus creates a bump called the Sinus Tubercule.

The sinus tubercule induces the epithelium of the UG sinus to proliferate, creating two ridges known as the sinovaginal bulbs. These bulbs grow together to produce the vaginal plate, which eventually canalizes posterior to anterior to form the vagina. The hymen is the tissue in the fetus separating the uterovaginal primordium from the vaginal plate.


 * 15. Define/describe:**

__Labioscrotal Swellings (genital swellings)__ One of the three locations of mesenchyme located around the cloaca that develop into the external genitalia. The labioscrotal swellings are the most lateral, flanking the urogenital folds.

__Urogenital Folds (urethral folds)__ One of the three locations of mesenchyme located around the cloaca that develop into the external genitalia. The urogenital folds surround the cloacal membrane and are flanked laterally by the labioscrotal swellings.

__Genital Tubercle__ Develops from the genital eminence, one of the three locations of mesenchyme located around the cloaca from which the external genitalia develop. The genital tubercle elongates to form the primordial phallus.

__Phallic Portion of Urogenital Sinus__ Part of the urogenital sinus that forms the lateral walls of the urethral groove of the penile urethra in males and the vestibule in females.

__Cloacal Membrane__ A membrane that covers the urogenical sinus and remains intact until the 8th week.

__Urogenital Membrane__ The anterior urogenital division of the cloacal membrane. Forms when the urorectal septum fuses with the cloacal membrane at the end of the 6th week, forming the urogenital and anal membranes. The urogenital membrane covers the opening of the urogenital sinus between the urogenital folds.


 * 16. Describe the complete formation of the male urethra.**

The urethral folds enlarge and fuse to form the urethral seam which is derived from the endoderm of the urethral plate from the phallic portion of the urogenital sinus. The solid plate recannalizes and loses its connection to the surface, forming the urethra. The ectoderm covers over the seam to form the penile raphe.


 * 17A. Define:**

__True Hermaphrodite__ Has both histologically ovarian and testicular tissue in the same or opposite gonads that are non-functional. Phenotypically, they have ambiguous genitalia. Genotypically, 70% are 46/XX, 20% are 46/XX and 46/XY mosaics, 10% are 46/XY.

__Pseudohermaphrodite__ Female pseudohermaphrodites have ovaries with ambiguous genitalia. Genotypically they are 46/XX and have Barr bodies. Male pseudohermaphrodites have testes with ambiguous genitalia. Genotypically, they are 46/XY and lack Barr bodies.


 * 17B. What are several causes of pseudohermaphrodism?**

Female pseudohermaphrodites are usually caused by excessive amounts of androgens that is usually secondary to congenital adrenal hyperplasia. The androgens cause masculinization of genitalia.

Male pseudohermaphrodites are caused by low testosterone levels and Mullarian-inhibiting substance (MIS) synthesis by fetal testes. This is usually the result of defective testosterone synthesis or defective Leydig cells. Lack of MIS results in varying persistence of paramesonephric structures.


 * 18. Define/describe the condition know as testicular ferminization. Developmental error?**

Also called androgen insensitivity syndrome (AIS). Patients are genetical male 4/XY but are characterized by female external genitalia, with the vagina ending in a blind pouch. Uterus and uterine tubes are absent or rudimentary. At puberty, breasts and female body habitus develops, but there is no menstruation. Testes are usually in the abdomen or inguinal canal.

The cause is a defect in the androgen receptors in the genital tubercle, urogenital and labialscrotal folds. As a result, the external genitalia become the female default, even when there is sufficient testosterone secretion. Oviducts, uterus, and upper vagina are missing due to secretion of Mullerian-inhibiting substance (MIS) by the testis, which causes the paramesonephric ducts to disappear.


 * 19. Define/describe the condition of hypospadias; epispadias. Developmental error for each?**

Hypospadias is the most common anomaly of the penis and is characterized by the opening of the external urethral orifice on the ventral surface of the penis. This results from the failure of urogenital folds to fuse at the midnline, usually thought to be the results of inadequate production of androgens by the testis or inadequate receptors sites for the hormone.

Glans hypospadias is and external urethral opening at the base of the glans. Penile hypospadias is an external opening anywhere along the shaft of the penis. Penoscrotal hypospadias is an external urethral orifice at the junction between the penis and scrotum. Perineal hypospadias is an external urethral orifice that incudes the scrotum and length of penile shaft. Severe cases may result in diagnosis of male pseudohermaroditism.

Epispadias is a rare anomaly of the penis and is characterized by the opening of the external urethral orifice on the dorsal surface of the penis. It is frequently involved other severe defects including a small bifid phallus with bladder exstrophy or even cloacal exstrophy involving the entire perineum. The cause of this defect is unknown but does not involve androgens.


 * 20. Describe the underlying developmental errors leading to complete or partial duplication of the uterus and/or vagina.**

Incomplete fusion of Mullarian ducts is the underlying developmental error leading to complete or partial duplication of the uterus. Incomplete recanalization of the sinovaginal plate results in duplication of the vagina.

Bicornuate uterus can be caused either by incomplete fusion of Mullarian ducts or by the retarded growth of one Mullarian duct such that it fails to fuse with the other at the midline.

Septate uterus is characterized by a septum dividing the lumen of the uterus int two and is caused by the failure of wall between the fused Mullarian ducts in the uterovaginal primordium to degenerate.

Unicornuate uterus is characterized by a partial uterus, single oviduct, and vagina. This is caused by the development of a single Mullarian duct.


 * 21. Describe the formation of the inguinal canal.**

The inguinal canal forms in both sexes during the indifferent stage of development around the 7th week. The gubernaculum is a ligament attached to the inferior pole of the developing gonad on the retroperitoneal surface of the abdomen. The gubernaculum passes obliquely in the abdominal wall to the site of the future deep inquinal ring. It goes through the abdominal wall and attaches to the inferior portion of the labialscrotal folds.

The process vaginalis is an evagination of the peritoneum that follows the path of the gubernaculum through the abdominal wall, carrying all the layers of the abdominal wall with it. The deep inguinal ring is formed by the opening in the transversalis fascia. The superficial ring is formed by the opening through the external oblique fascia.


 * 22. Describe the process and path of migration of the testis and ovary.**

The testes descends in three phases: initial, transabdominal, and transinguinal. In the initial descent, the testis enlarges due to the influence of testosterone. The cranial suspensory ligament regresses as the mesonephric kidney degenerates. All this contribute to slight caudal movement, loosening up the testis for transabdominal descent.

During transabdominal descent, the testis descends under the influence of testosterone and Insl-3 to the level of the deep inguinal ring by 26 weeks, partly due to the elongation of the trunk.

Lastly, in transinguinal descent, the testis takes 2-3 days descends through the inguinal canal into the scrotum under the influence of testosterone and the gubernaculum. The testes passes external to the peritoneum and process vaginalis, pulling the vas deferens and vessels with it. As the testes descend, they become ensheathed by the fascial layer of the spermatic cord. Once the testis enters the scrotum, the inguinal canal contracts around the spermatic cord and the testes presses into the process vaginalis. The connecting portion of the process vaginalis degenerates, becoming the tunica vaginalis.

The ovaries descend similar to the testis but does not follow through all three phases. The ovaries descend to the posterior pelvic wall just inferior to the pelvic brim. The process vaginalis forms and usually obliterates long before birth; if it persists, it is called a canal of Nuck.

The gubernaculum attaches to the uterus near the attachment of the uterine tube; it acts as a guide in the wall subjacent to the peritoneum. The cranial portion forms the round ligament of the ovary in the adult and runs between the inferior pole of the ovary and the body of the uterus. The caudal portion forms the round ligament of the uterus, extending through the inguinal canal to attach in labia majora.