Development of the Male and Female Reproductive System 2024-2025 PDF

Development of the Urogenital System Page 1 of 36 Dennis J. Goebel, Ph.D. DEVELOPMENT OF THE MALE AND FEMALE REPRODUCTIVE SYSTEM LECTURE LEARNING OBJECTIVES 1 Describe male and female gonadal development Desc...

Development of the Urogenital System Page 1 of 36 Dennis J. Goebel, Ph.D. DEVELOPMENT OF THE MALE AND FEMALE REPRODUCTIVE SYSTEM LECTURE LEARNING OBJECTIVES 1 Describe male and female gonadal development Describe the role of the Y chromosome and SRY gene expression in determining male and female phenotype development of the internal and external genital system. Describe the timing and development of the indifferent-stage of gonadal development. Define the germ source for the primordial germ cells. Describe the role of the primordial germ cells in the induction of gonadal development into the indifferent gonad from the genital ridge. Describe the formation of the primitive sex cords in the development of the indifferent gonad. 2. Describe the development of the testis Describe the timing and chromosomal signaling events that lead to the differentiation of the indifferent gonad into the testis. Describe the differentiation of the primitive sex cords into the medullary cords and their development into the rete testis and the testis cords in the forming testis. Describe the development of the testis cords into the seminiferous tubules. Describe the germ-source of the interstitial cells of Lydig and their significance in furthering differentiation of the duct system in the testis. Describe the contents and the differentiation of the sex cords into the rete testis and seminiferous tubules. 3. Describe the development of the ovaries Describe the fate of the primitive medullary sex cords in the developing ovary. Know that the primitive germs cells undergo extensive mitosis. Describe the formation of the cortical cords of the ovary and their role in differentiating into follicular cells to and their formation of a primary follicular cells. Know the role of the follicular cells in arresting the first meiotic division at prophase until ovulation. Know that the surface epithelium or the testis forms a thick tunica albuginea, whereas in the female the majority of the epithelium contributes to the formation of the follicular cells and results in the formation of a very thin tunica albuginea. 4. Describe the fate of the paramesonephric and mesonephric ducts in the development of the internal male and female reproductive structures. Understand the origin of the paramesonephric (Müllerian) ducts and their relationship with the mesonephric ducts during the “indifferent stage” of development. Understand the molecular signaling events required for the genital duct formation in the male and its dependence upon the Y chromosome. Development of the Urogenital System Page 2 of 36 Dennis J. Goebel, Ph.D. Understand the fate of the distal portion of the mesonephric (wolffian) duct in the male and female. Male Know that the sinus tubercle will give rise to the formation of the distal part of the vagina and its hymen in the female and that its remnant will form the seminal colliculus on the prostate gland in the male. Know that in the male that the mesonephric ducts and tubules associated with the testis are dependent upon SRY signaling and FGF9 release (to prevent the local regression of the mesonephric duct and tubules) to form the ductus deferens, epididymis and the efferent ductules, seminal vesicles and ejaculatory ducts of the testis. Know that SRY expression in the male causes the release of antimüllerian inhibiting factor which signals the paramesonephric duct to regress to form 2 remnants, the prostatic utricle and the appendix of the testis. Female Understand that the lack of SRY release in the female results in the inhibition of FGF9 transcription factor release, which in turn results in the regression of the regional mesonephric duct and tubules. Understand the formation of the uterus and the vagina from the paramesonephric ducts Understand the role of the paramesonephric duct in the induction of the sinovaginal bulbs. Understand the 3 regions of the female paramesonephric and their derivatives. Know that the paramesonephric ducts association with the urogenital membrane is required for the induction of the sinovaginal bulb in the female. Know the derivatives produced by the sinaovaginal bulbs. Know that the paramesonephric duct develops into the fimbriae, uterine tubes uterus, cervix and the upper 1/3 of the vagina. Know the remnants of the degenerated mesonephric system in the female. Know the germinal source of the forming muscular layers of the uttering tubes, uterus and vagina. Understand the formation of the broad ligament and the resulting approximation of the right and left paramesonephric ducts. Know the subdivisions of the broad ligament and the two pelvic compartments that it forms. 5. Describe the fate of the paramesonephric and mesonephric ducts in the development of the external male and female reproductive structures Understand the timing for the formation of the “indifferent stage” of external genital development. Understand the developmental progression of the cloacal folds and their derivatives. Understand the relationship of the genital swellings to the cloacal folds and their fate in the male and female fetus. Development of the Urogenital System Page 3 of 36 Dennis J. Goebel, Ph.D. Male Describe the formation of the male external genitalia and its dependence upon androgen signaling. Understand the formation of the urethral groove and its involvement in generating the penile urethra. Understand the source and process involved in forming the external urethral meatus and navicular fossa of the penis. Understand the anatomical region responsible for the formation of the scrotum. Female Understand the development of the female external genitalia and its dependence upon estrogen. Know the derivatives of the genital tubercle, urethral folds and genital swellings of the female fetus. Know the fate of the urogenital groove in the female fetus. Understand the mechanism and anatomical pathway for the descent of the testis from the pelvic cavity into the scrotum. 6. Describe the descent of the testis Understand the formation of the gubernaculum and its role in the formation of the process vaginalis and for guiding the testis through the inguinal canal from the pelvic cavity into the scrotum. Understand the androgen-dependent signaling of the formation of the extra- abdominal-portion of the gubernaculum in the male. Describe the formation of the process vaginalis and its relationship with the muscles and fascia of the anterior abdominal wall and the peritoneal cavity. Describe the layers of the spermatic cord. Understand the timeline for the descent of the testis into the scrotum, the fate of the process vaginalis following its descent and the remaining remnant forming the tunica vaginalis. Define the mesothelial layers of the tunica vaginalis. 7. Understand the clinical relevance’s resulting from development malformations related to the urogenital systems. Understand the reasoning for the malformations of the uterus and vagina for the following, Uterus dideiphys with double vagina, Uterus arcuatus, Uterus bicomis, Uterus bicomis unicollis, Cervical atresia and Vaginal atresia. Define Hypopadias and Epispadias. Describe the reasoning and incidence for the malformations that lead to urorectal and rectiovagional fistulas. Understand the path way of an indirect hernia in the male and the roll that the process vaginalis plays in the process. Describe a urachal fistula, a urachal cyst and a urachal sinus and their consequences. Describe the possible ectopic urethral openings in the female. Development of the Urogenital System Page 4 of 36 Dennis J. Goebel, Ph.D. Lecture Outline I. Development of the genital system in the male and female A. General overview 1. The role of the SYR gene in determining the fate of the male and female genital systems. 2. Concepts of the “Indifferent stage” of genital development B. Development of the indifferent gonad 1. Formation of genital ridges 2. Migration of primordial germ cells from the epiblast a. Timing of the migration of the primordial germ cells. b. Signaling by the arriving primitive sex cells to generate primitive sex cords within the forming indifferent gonad. C. Gonad differentiation: Overview 1. Development of the testis: Proliferation of the primitive sex (testis) cords forming medullary cords. a. Base of the testis cords gives rise to the rete testis b. Surface of the genital ridge forms the tunica albuginea c. Testis cords mature i. Become U-shaped and become continuous with the rete testis ii. Primordial germ cells and sustentacular cells migrate in. d. Migration of the interstitial cells of Lydig to the testis cords i. Testis cords canalize into seminiferous tubules at puberty D. Development of the ovary: Overview 1. Indifferent gonad, primitive medullary cords dissociate into irregular clusters containing primitive germ cells. 2. Proliferation and of germ cells forming primodial germ cells. 3. Proliferation of the surface epithelium forms cortical cords a. Cortical cords dissociate to form follicular cells that encircle primordial oocytes forming primordial follicles E. Development of genital ducts 1. Formation of the paramesonephric duct a. Features of the paramesonephric duct b. Relationship with mesonephric duct c. Induction of the sinus tubercle 2. The mesonephric duct a. In male: forms seminal vesicles, ejaculatory ducts, ductus deferens epididymis and efferent ductules. b. In female: degenerates 3. Overview of molecular signaling of the genital ducts: a. In male (XY) activates SRY transcription factor-dependent pathways (promotes maturation of mesonephric duct differentiation). b. In female (XX), absence of Y chromosome results in degeneration of mesonephric duct and promotes paramesonephric duct differentiation. 4. Male genital ducts Development of the Urogenital System Page 5 of 36 Dennis J. Goebel, Ph.D. a. Mesonephric tubules i. Epigenital tubules form efferent ductules ii. Paragenital tubules degenerate b. Derivatives of the mesonephric duct (wolffin) c. Paramesonephric duct degenerates. i. Remnants of paramesonephric duct in the male 5. Female genital ducts: a. WNT4 dependent signaling i. Promotes development of ovaries and estrogen production i. Inhibits testosterone synthesis & release iii. Inhibits synthesis of Antimüllerian inhibiting factor a. Allows for differentiation of the paramesonephric duct b. Absence of SRY transcription factor prevents differentiation of mesonephric duct i. Remnants of the mesonephric duct c. Development of paramesonephric duct: Overview i. Derivatives of the paramesonephric duct ii. Approximation of the rt and left paramesonephric duct iii. Repositioning of the paramesonephric duct within the broad ligament d. Overview of the formation of the uterus and vagina: i. Origin of the myometrium ii. Induction of the sinovaginal bulbs e. Formation of the hymen II. Development of external genitalia A. The Indifferent stage (weeks 4-7): formation of the cloacal folds and their derivatives 1. Formation of the cloacal folds 2. Formation of the genital tubercle 3. Formation of the genital swellings B. Androgen dependent development of the male external genitalia (weeks 7-12) 1. Elongation of the genital tubercle to form the phallus a. Formation of the urethral groove and urethral plate (weeks 4- 7, from the indifferent stage) b. Closure of the urethral folds to form the penile urethra c. Recanalization of the glans forming the external urethral meatus and navicular fossa 2. Development of the scrotum a. Growth and migration of the scrotal swellings C. Development of the female external genitalia (weeks 7-12) 1. Development is dependent upon estrogen a. Formation of the urethral groove and urethral plate (weeks 4- 7, from the indifferent stage) i. Formation of the clitoris from the genital tubercle Development of the Urogenital System Page 6 of 36 Dennis J. Goebel, Ph.D. ii. Formation of the labia minora from the urethral folds iii. Non-closure of the urogenital grove forms the vestibule iv. Labia major differentiates from the genital swellings III. Formation of the inguinal canals (and the descent of the testis) A. Mesothelial covering of the testis, formation of the gubernaculum and process vaginalis. 1. Testis remain retroperitoneal 2. Formation and attachment of the gubernaculum 3. Formation of the process vaginalis and the formation of the spermatic cord fascial layers 4. Regression of the paramesonephric ducts and the descent of the testis though the deep inguinal ring. B. Descent of the testis into the scrotum IV. Clinical Relevance A. Uterine and Vaginal defects 1. Uterus didelphys 2. Uterus arcuatus 3. Uterus bicornis 4. Atresia defects of the uterus B. Female external genitalia defects 1. Atresia of the hymen C. Developmental defects of the male external genitalia 1. Hypospadias and glandular hypospadias 2. Epispadias with or without exstophy D. Congenital indirect hernia in the male E. Failure of the descent of the testis into the scrotum Development of the Urogenital System Page 7 of 36 Dennis J. Goebel, Ph.D. I. DEVELOPMENT OF THE GENITAL SYSTEM IN THE MALE AND FEMALE General Overview: The differentiation of the gonads and the external genitalia are dependent upon the Y chromosome, which contains the sex- determining region (SRY gene) on its short arm. Its expression signals downstream genes that determine the fate of the rudimentary sexual organs. Two key points to highlight here are: 1. SRY expression (XY-male) signals male development (formation of the testis, prostate seminal vesicles, ejaculatory duct and male external genitalia. In the absence of the Y chromosome (e.g, XX- female), development defaults to the formation of the ovaries, uterus, oviducts/fimbriae, vagina, and the female external genitalia (see Figure 1). *Very thin tunica albuginea Figure 1: Sadler 16.21 2. Sexual differentiation in the developing fetus does not begin until the 7th week of gestation. Prior to this period, the appearance of the primordial male and female gonadal and external genitalia are indistinguishable from each other. This will be a common theme for the development of these tissues, and will be referred to as the “Indifferent stage” of sexual development (see Figure 1). A. Development of the “indifferent gonad” 1. Gonad development begins during the 5th week, where a condensation of mesoderm develops on the inferior-medial side of the developing mesonephric kidney & duct. Proliferation of the epithelium and underlying mesoderm in Development of the Urogenital System Page 8 of 36 Dennis J. Goebel, Ph.D. this region generates a pair of longitudinal genital ridges (see Figure 2B below and Figure 3 on the next page). Figure 2: Sadler 16.18 2. Source, migration and induction properties of the primordial germ cells: During the 3rd week, primordial germ cells (indifferent at this stage) migrate from the epiblast of the embryo, via the primitive streak, and make their way to the endoderm of the yolk sac in close proximity to the allantois (see Figure 2A). a. During the 4th week the primordial germ cells migrate through the dorsal mesentery of the hindgut and by the 5th week, they reach the primitive gonads (see Figure 2B). b. The arrival of the primordial germ cells signals an inductive response to the primitive gonads to begin to differentiate whereby, the epithelium of the genital ridge begins to penetrate the underlying mesoderm to form irregular-shaped primitive sex cords (see Figure 3). i. Note, failure of the arrival of the primordial germ cells to the gonadal ridge prevents gonadal development. Development of the Urogenital System Page 9 of 36 Dennis J. Goebel, Ph.D. ii. At this stage, the male or female gonads are indistinguishable from each other, and are classified as being indifferent gonads. Figure 3: Sadler 16.19 B. Gonad differentiation begins during the 7th week of development and its differentiation is dependent upon the germ cell’s sex chromosomal signature (e.g. XY male, XX female). In the male, the Y chromosome contains the SRY gene, that encodes for the production and release of testis determining factor. This signals the primordial gonadal tissue to form the testis. In the absence of a Y chromosome, the indifferent gonadal tissue will default to forming a pair of ovaries. 1. Development of the testis: In response to the Y chromosome signaling (by the release of testis determining factor), the primitive sex cords continue to proliferate and penetrate deep into primitive genital ridge to form the medullary-cords (also called testis cords) ”See Figure 4A on the next page). a. At the base of the genital ridge (dorsal to the forming medullary cords) the cords develop into smaller tubules that give rise to the rete testis (see Figure 4A on the next page). b. During this time, a fibrous connective tissue thickening begins to form on the ventral surface of the developing testis, just beneath the parietal peritoneum covering of the body wall. It will become the tunica albuginea. Development of the Urogenital System Page 10 of 36 Dennis J. Goebel, Ph.D. i. The tunica albuginea (translates to” white dress”) continues to thicken over the next 6 weeks (see Figure 4A & B below). Figure 4: Sadler 16.20 c. During the 4th month, the testis cords become “U- shaped” and their extremities become continuous with the developing rete testis (Figure 4B). At this time, the testis cords now contain primordial germ cells and sustentacular cells of Sertoli. The latter, are derived from the surface epithelium of the gland. d. Paralleling the timing of the formation of the testis cords, interstitial cells of Leydig are formed around the testis cords, from the surrounding mesoderm. By the eighth week of development, these cells begin to synthesize and release testosterone to further influence sexual differentiation of the genital ducts and the external genitalia. i. Testis cords remain solid (without a lumen) until the onset of puberty, when they will “canalize”, and then become seminiferous tubules. Development of the Urogenital System Page 11 of 36 Dennis J. Goebel, Ph.D. ii. The future seminiferous tubules link up with the neighboring rete testis tubules and then join up with the forming efferent ductules (which form from the retained mesonephric tubules and duct: See Figure 4B on the previous page). Their linkage to the “genital duct system” via the rete testis is described on page 15 (section 4) of these notes. 2. The descent of the testis into the scrotum will be discussed later in these notes, in Section IIIB. C. Development of the ovaries: Differentiation of the indifferent ovary begins during the 4th week of development. Unlike the testis, the ovaries do not migrate outside of the peritoneal cavity, and are suspended off of the posterior pelvic wall by a mesentery (Mesovarium), and to assure ovulation following puberty, form a very thin tunica albuginea. 1. In absence of a Y chromosome in the female embryo, the primitive medullary sex cords of the indifferent gonad dissociate into irregular clusters (containing primitive germ cells) and migrate into the medullary region of the future ovary. 2. By the 4th month, the primordial germ cells have undergone extensive mitosis and have produced up to 2 million primordial follicles (oogonia) in the pair of ovaries. 3. During this period the epithelium of the female gonad continues to proliferate. By the 7th week, the epithelium will give rise to the formation of cortical cords, which then penetrate into the proximal underlying mesoderm (See Figure 5a). a. During the 12th week, the cortical cords begin to dissociate and form isolated cell clusters of cells, which proliferate and then encircle each primary oocyte (a primordial germ cell) with a single layer of epithelium. These cells will become follicular cells (see Figure 5B). Development of the Urogenital System Page 12 of 36 Dennis J. Goebel, Ph.D. i. Once the oocyte becomes encircled by follicular cells it becomes a primordial follicle. Figure 5: Sadler 16.22 b. At 4 months, each primordial follicle enters the first meiotic division (prophase, entering the diploid stage). i. The surrounding follicular cells then release oocyte maturation inhibitor, which arrests the process of meiosis at prophase, until puberty begins. D. Development of the Genital Ducts: During the “indifferent staging” of urogenital development, the male and female embryo contain two sets of genital ducts, the mesonephric and the paramesonephric ducts. 1. The paramesonephric duct (also called the müllerian duct) forms from a longitudinal invagination of the epithelium located on the anterior-lateral surface of the urogenital ridge (see Figure 2 on page 8, and Figure 5 above). a. Cranially, the paramesonephric duct remains open to the abdominal cavity and each is capped with a funnel-like opening in both the male (see Figure Development of the Urogenital System Page 13 of 36 Dennis J. Goebel, Ph.D. 7A) and female embryo (see Figures 6 and 7B on the next page). Figure 6: Moore 12-34B b. The paramesonephric duct crosses the mesonephric duct ventrally in the male and female (see Figures 6, 7A & B) and at its caudal end, merges with its partner before opening into the urogenital sinus (see Figure 6). c. The entrance of the paramesonephric duct into the UG Sinus initiates the formation of a raised tubercle into the UG sinus (called the sinus tubercle) surrounding the duct’s opening. i. In the male the sinus tubercle becomes seminal colliculus (located on the posterior wall of the prostatic urethra). Development of the Urogenital System Page 14 of 36 Dennis J. Goebel, Ph.D. Figure 7: Sadler 16.23 ii. In the female, the sinus tubercle will give rise to a pair of sinovaginal bulbs (see Figure 6 on the previous page), which will form the distal part of the vagina and the hymen (more on this later in these notes). 2. The mesonephric duct (also called the wolffian duct): The distal portion of the mesonephric duct relies upon signaling from the “Y” chromosome to contribute to the formation of the gonadal duct systems in the male. In the absence of the “Y” chromosome, this portion of the mesonephric duct degenerates in the female embryo. 3. Molecular signaling of the genital ducts: a. In the male (XY), the SRY transcription factor prevents the degeneration of the mesonephric (wolffian) ducts and the excretory mesonephric tubules located near the developing genital ridge. These will differentiate into the seminal vesicles, ejaculatory ducts, the ductus deferens, Development of the Urogenital System Page 15 of 36 Dennis J. Goebel, Ph.D. epididymis and the efferent ductules of the testis respectively (See flowchart diagram below). b. In the female (XX), the absence of SRY expression causes the mesonephric (wolffian) duct to degenerate. This in turn enables the X chromosome to stimulate the production of the transcription factor WNT4. WNT4 promotes the differentiation of the paramesonephric (müllerian) ducts into forming the uterine tube, fimbriae, the uterus, cervix and the upper portion of the vagina. (See flowchart diagram below). 4. Male genital ducts: As noted earlier, the mesonephric kidney begins regressing in a cranial-caudal direction around the 6th week. The portion of the mesonephric duct (wolffian) and associated excretory mesonephric tubules near the developing testis are retained by SRY signaling. Stimulates Sertoli cells in the testis to synthesis & release of Antimullerian hormone Anit-Mullerian hormone (AMH) release inhibited Development of the Urogenital System Page 16 of 36 Dennis J. Goebel, Ph.D. a. The mesonephric tubules in the region associated with the developing testis give rise to: i. Epigenital tubules of the mesonephric kidney establish contact with the cords of the rete testis on the cranial pole of the testis and form the efferent ductules of the testis (see Figure 8A&B). ii. Paragenital tubules of the mesonephric kidney (that are not associated with the developing testis) degenerate. Figure 8: Sadler 16.27 b. The mesonephric (wolffian) duct persists, except for the most cranial portion, which regresses to form a blunt ended appendage called the appendix epididymis (see Figure 8B). i. The region of the mesonephric duct, just below the efferent ductules, rapidly elongates and coils to form the epididymis (see Figure 8B). ii. Immediately following the epididymis, the mesonephric duct obtains a thickened smooth muscular coat and becomes the ductus deferens. Development of the Urogenital System Page 17 of 36 Dennis J. Goebel, Ph.D. iii. The distal end of the mesonephric duct gives rise to the seminal vesicle and the ejaculatory duct (See Figure 8B), both associated with the developing prostate gland. c. Remnants of the degenerated paramesonephric duct in the male form two blind-ended sacs called the prostatic utricle and the appendix of the testis (See Figure 8B on the previous page). 5. Female genital ducts: In the absence of a Y chromosome, SRY signaling does not occur. This results in the disinhibition of the X-chromosomal release of the transcription factor WNT4 (See Figure 9). Figure 9: Sadler 16.25 a. The expression of WNT4 is paramount for initiating development of the Female gonadal and reproductive organ anatomy. i. WNT4 promotes the indifferent-gonads to develop into ovaries. This step is essential for the synthesis and release of endogenous estrogen by the ovaries, which in turn, enhances the differentiation of the female internal organs and external genitalia (Figure 9). Development of the Urogenital System Page 18 of 36 Dennis J. Goebel, Ph.D. ii. WNT4 release indirectly inhibits SOX9 production/release. SOX9-inhibition prevents development of the testis, and testosterone synthesis & release (see Figure 9). ii. WNT4 also inhibits the synthesis and release of Anti-müllerian hormone (AMH). This allows for differentiation of the paramesonephric duct to occur, leading to the formation of the fimbriae, uterine tubes, uterus/cervix and the upper-region of the vagina (see Figure 10). b. The absence of SRY transcription factor release by the female embryo, prevents FGF9 factor synthesis and release (see flow chart on page 15). This prevents the mesonephric duct from being signaled to differentiate, and results in the regression of the mesonephric duct in the female (see Figure 10A & B). Figure 10: Sadler 16.24  Development of the Urogenital System Page 19 of 36 Dennis J. Goebel, Ph.D. i. Remnants of the mesonephric ducts in the female, (identified as the epoophoron, the paroophoron) can be found within the mesovarium (a mesentery that suspends the ovary off of the uterine tube) of the adult, and Gartner’s cyst (associated with the vaginal wall (see Figure 10B, on previous page). c. Development of the paramesonephric duct: The paramesonephric duct initially consists of three parts: 1) a cranial vertical-orientated portion that opens into the abdominal cavity; 2) a horizontal part that crosses the regressing mesonephric duct and, 3) a caudal part that fuses with its partner and is anchored at its base to the paramesonephric tubercle of the urogenital membrane (see Figure 10A on previous page). i. The first two parts of the paramesonephric duct will give rise to the fimbriae and uterine tubes, and the third (distal) part will form the uterus, cervix and the upper 1/3rd of the vagina (see Figure 10B on the previous page and Figure 11 below). Figure 11: Sadler 16.30  Development of the Urogenital System Page 20 of 36 Dennis J. Goebel, Ph.D. ii. With the growth of the developing ovaries and their consolidation/migration into the pelvis, the urogenital ridges (containing the second part of the paramesonephric ducts), rotate medial-caudally (See arrows in Figure 12A & 12B). As development progresses, the right and left distal portions of the paramesonephric duct become approximated and fuse together (Figure 12C). iii. The inward migration and fusion of the right and left urogenital ridges forms a transverse- orientated bridge across the floor of the pelvis that will form the broad ligament (of the uterus). Note that the broad ligament contains the paramesonephric ducts at midline and the degenerating mesonephric ducts are positioned lateral to them (Figure 12C). Figure 12: Sadler 16.28 Development of the Urogenital System Page 21 of 36 Dennis J. Goebel, Ph.D. a. The broad ligament contains undifferentiated mesoderm that will contribute to the formation of the muscular layers and supporting connective tissues of the developing tubular structures (e.g., the uterus, cervix uterine tubes and vagina) and provides an outer mesothelial lining that will give rise to the mesentery of the broad ligament and its components (e.g., the mesometrium, mesovarium and mesosalpinx). These will suspend the developing uterus, ovaries and uterine tubes as intraperitoneal structures into the pelvic cavity (see Figure 13 A&B). A B Figure 13 iv. The formation of the broad ligament subdivides the floor of the pelvic cavity into to compartments (pouches): See Figure 12C on the previous page. a. Anterior to the broad ligament it forms the uterovesical pouch. b. Posterior to the broad ligament it forms the uterorectal pouch. Development of the Urogenital System Page 22 of 36 Dennis J. Goebel, Ph.D. d. Formation of the uterus and vagina: Following the fusion of the 3rd part of the paramesonephric ducts, they begin to rapidly expand and lengthen. By the 9th week, the septum separating the right and left tubes (called the uterine septum) begins to canalize (see Figure 14A on the next page) and give rise to the uterus and cervix. i. The smooth muscle layers of the uterus, are provided by the surrounding mesoderm. In the uterus, it forms the myometrium. In addition, this mesoderm also contributes to the formation of the outer muscular layers of the uterine tubes and developing vagina. ii. Meanwhile, the portion of the distal 3rd part of the paired paramesonephric ducts that are fused to the urogenital membrane (UM), signal the growth of a pair of sinovaginal bulbs from the overlaying mesoderm of the urogenital membrane (Figure 14B). They, together with the fused 3rd part of the paramesonephric ducts, continue to lengthen and expand (see Figure 14 below & Figure 15 on the next page). Figure 14: Sadler 16.29 Development of the Urogenital System Page 23 of 36 Dennis J. Goebel, Ph.D. a. During this period, the cranial end of the fused sinovaginal bulbs and the caudal part (below the cervix of the uterus) of the fused paramesonephric duct begins to undergo recanalization to form the vagina Figure 14B&C and 15 B&C. This process is completed around the time of birth. Note that the superior 1/3 of the vagina is derived from the paramesonephric ducts and the inferior 2/3’s is formed from the sinovaginal bulbs of the urogenital membrane. See Figure 14C & Figure 15C below. Figure 15: Sadler 16.30 e. The lumen of the vagina remains separated from the urogenital sinus by a thin double layered membrane (outer epithelial, inner mesodermal) called the hymen (see Figures 14C and 15C on the previous page) that is derived from the urogenital membrane. In most cases, an opening in the hymen occurs via recanalization, prior to birth. Development of the Urogenital System Page 24 of 36 Dennis J. Goebel, Ph.D. II. Development of the external genitalia A. The indifferent stage of external genital development spans weeks 3-6, where mesenchyme from the primitive streak migrates to the cloacal membrane to form a pair of elevated folds called the cloacal folds (See Figure 16A on the next page). 1. The cloacal folds are regionally subdivided, such that the cranial half will become the urethral folds and the caudal half, the anal folds (Figure 16B) 2. At the cranial end of the paired folds form a single midline swelling called the genital tubercle, which will give rise to the penis or clitoris (See Figure 16A on the next page). 3. Lateral to the cloacal folds, a pair of genital swellings appears (see Figure 16A on the next page). These will give rise to the scrotum folds in the male, and the labial majora folds in the female. 4. Note, during this period of development (week 3-6) it is impossible to distinguish the sex of the fetus based upon the appearance of the above mentioned structures (Figure 16). Figure 16: Sadler 16.32 B. Development of the male external genitalia is promoted by the release of androgens secreted by the fetal testis. 1. This results in the rapid elongation of the genital tubercle to form the phallus (e.g., the head of the penis/clitoris). Development of the Urogenital System Page 25 of 36 Dennis J. Goebel, Ph.D. a. The elongation of the phallus pulls the neighboring urethra folds forward, where they will become the lateral walls of the urethral groove (see Figure 17A on the next page). Note, the urethral groove does not extend into the phallus. i. The epithelial lining of the urethral groove is derived from the endoderm and forms the urethral plate. b. By the end of the third month, the urethral folds close over the urethral plate and fuse to form the penile urethra. The seam formed by the joining of the two urethra folds can be identified on the ventral surface of the developed penis and is called the penile raphe. i. Note, at this time, the penile urethra ends at the base of the phallus (now called the glans of the penis). c. The most distal part of the penile urethra is formed during the 4th month, when ectodermal cells arising from the tip of the glans, penetrate inward to form an epithelial cord. This cord will eventually undergo recanalization to create the external urethral meatus and the navicular fossa of the penis (See Figure 17D). Figure 17: Sandler 16.33 Development of the Urogenital System Page 26 of 36 Dennis J. Goebel, Ph.D. 2. Development of the scrotum: In the male the scrotal swellings arise from the inguinal region of the developing fetus. They increase in size moving caudally from the inguinal region and merge with each other at midline to from the scrotal raphe derived from the fusion of the scrotal swellings (see Figure 17). a. Note, that up to week 6 of development, the pair of testis are still retained within the abdominal cavity. Testis decent into the scrotum will be discussed in Section III. B.). C. Development of the female external genitalia. 1. The development of female external genitalia is dependent upon estrogen secretion, and occurs over the same time span as the male (differentiation covering weeks 7-12). Estrogen sources are primarily from the developing fetus, however maternal estrogen freely crosses the maternal/fetal blood barrier and will influence genital development as well. 2. Starting from the “indifferent stage (~ weeks 4-7)” of external genitalia development, whereby the cloacal fold has formed the anal fold, urethral folds, and a genital tubercle (see Figure 16 A&B on page 24 of these notes, and Figure 18A), the development of the female external genitalia progresses as follows: Figure 18: Sadler 16.36 Development of the Urogenital System Page 27 of 36 Dennis J. Goebel, Ph.D. a. The genital tubercle elongates only slightly to form the clitoris. b. The urethral folds enlarge, but do not fuse together, to form the labia minora. c. The urogenital groove remains open between the labia minora. This area forms the vestibule of vagina. d. The genital swellings enlarge to form the labia majora (Labium majus). See Figure 18A & B. III. Development of the inguinal canals (and the descent of the testis): A. Toward the end of the second month, the urogenital mesentery covers the ventral surface of the testis and the mesonephros, and associates the testis to the posterior abdominal wall (e.g., they remain retroperitoneal). See Figure 19A. Figure 19: Sadler 16.3 Development of the Urogenital System Page 28 of 36 Dennis J. Goebel, Ph.D. 1. Unlike the ovaries, which remain suspended off the posterior abdominal wall (e.g. are defined as being peritoneal), the testis and the ductus deferens remain retroperitoneal structures throughout their migration from the posterior abdominal wall into the scrotum. 2. Extending from the caudal pole of the gonad (and contained by the gonadal mesentery) is an extracellular- matrix-rich mesenchymal condensation that forms a fibrous band called the gubernaculum in the male (see Figure 20). In the female, this condensation becomes the round ligament. a. The gubernaculum extends from the caudal pole of the testis and passes through the inguinal canal between the transverses abdominis and internal abdominal oblique muscles of the anterior abdominal wall (see Figure 20A). Gubernaculum Gubernaculum testis Gubernaculum Gubernaculum testis Gubernaculum testis Figure 20: Sadler 16.38 Development of the Urogenital System Page 29 of 36 Dennis J. Goebel, Ph.D. b. The gubernaculum acts as a guided path for the forming process vaginalis (an extension of the peritoneal cavity) that extends into the inguinal region (Figure 20 B &C). 3. The formation of process vaginalis: Independent from the descent of the testes, the peritoneal lining of the abdominal cavity forms an invagination on each side of the midline into the anterior abdominal wall called the process vaginalis (see Figure 20B & C). a. The process vaginalis follows the course of the gubernaculum testis to the scrotal swellings. i. The process vaginalis is accompanied by the 3 muscular and fascial layers (collectively known as the spermatic fascia) of the body wall, and is lined by parietal peritoneum (see Figure 21). Figure 21: Sadler 16.39 Development of the Urogenital System Page 30 of 36 Dennis J. Goebel, Ph.D. a. The innermost layer of the spermatic fascia is provided by the transversalis fascia. The middle layer is provided by the internal abdominal oblique muscle and gives rise to the cremasteric muscles. The outer layer is provided by the external abdominal oblique fascia. See Figure 21 above. ii. During this period of development the process vaginalis is continuous with the peritoneal cavity (see Figure 21B & C). 4. Between weeks 6-10, increased levels of androgens signal the paramesonephric ducts to regress, and the testis to begin to descend transabdominally through the deep inguinal ring (see Figure 20B on the previous page). a. At this time, the gubernaculum is signaled to extend an extra-abdominal portion that passes through the inguinal canal (described below) and out to the scrotal swellings (see Figure 20B & C on page 28). B. Descent of the testis into the scrotum: As the testis passes through the internal inguinal ring and, courses through the inguinal canal, it brings the muscles and fascial layers mentioned above ( Section i.a., on the previous page), along with it. 1. These layers will accompany the testis all the way down into the scrotum and will form the spermatic cord. 2. The testis will exit the inguinal canal through the external inguinal ring (above the pubic symphysis) and will follow the posterior wall of the process vaginalis all the way down to its termination in the scrotal swelling. 3. Note that, as the testis descends into the scrotum, it will remain positioned beneath the peritoneal covering of the process vaginalis (see Figure 20C & D on page 28 of my notes). Development of the Urogenital System Page 31 of 36 Dennis J. Goebel, Ph.D. 4. Once the testis is fully retracted to the scrotum, the process vaginalis will close off its communication with the peritoneal cavity, usually just prior to birth. a. In doing so, the testis retains a part of the process vaginalis on its ventral surface, (now called the tunica vaginalis). i. The tunica vaginalis is a serous-filled mesothelial-lined sac that invests the ventral surface of the testis. Note that the ventral surface of the testis is covered by visceral peritoneum and the region of the sac that is associated with the scrotum is lined by parietal peritoneum (see Figure 21 on the previous page, and Figure 22 on below). Figure 22: Netter 365B 5. Factors controlling descent of the testes are not fully understood, however the relative timing of descent goes as follows: a. The testis reaches the beginning of the inguinal canal ~ week 12. b. The testis migrates through the inguinal canal between weeks 12- 28. Development of the Urogenital System Page 32 of 36 Dennis J. Goebel, Ph.D. c. The testis usually reaches the scrotum by week 33 however, this time frame can vary out to 2-3 months post-natal). See clinical relevance Section IV. D., on page 35 for details. IV. Clinical Relevance: A. Uterine and Vaginal defects: Duplication of the uterus results from the lack of fusion of the distal portion of the para- mesophrenic ducts (see examples Figure 29A, 29B and 29C on the next page). 1. An extreme case is shown in Figure 29A, where the uterus and the vagina are duplicated through their full extent (This is defined as uterus didelphys). 2. A mild case of this is shown in Figure 29B, where an indentation of the internal region of the fundus of the uterus occurs (this is defined as Uterus arcuatus). 3. The most common case is shown in Figure 29C whereby, the pair of uteri open into a single vagina (this is called uterus bicornis). 4. The second-most common contributor to the malformation of the uterus and vagina involves atresia (closure of a normal opening). Examples of these are shown in Figures 29D-F. Figure 29: Sadler 16.31 Development of the Urogenital System Page 33 of 36 Dennis J. Goebel, Ph.D. B. Congenital anomalies of the female external genitalia: Incomplete opening of the hymen is the most common anomaly in the female reproductive tract. The vaginal orifice (the opening within the hymen) varies in diameter (Figure 31B-E). Complete obstruction by an imperforate hymen (Figure 31F) is due to atresia and is the most common anomaly resulting in obstruction of the female reproductive tract. These membranes will require surgical opening, prior to the onset of monthly menses. Figure 31: Moore 12-46 Development of the Urogenital System Page 34 of 36 Dennis J. Goebel, Ph.D. C. Male external genitalia development problems: 1. Hypospadias occurs when fusion of the urethral folds in the male is incomplete (Figure 30A&C). Urine can escape through these openings during urination. a. Glandular hypospadias: Note: dual urethral openings on the glans of the penis (Figure 30B). 2. Epispadias- (Rare 1/30,000 births) The urethral meatus is located on the dorsum of the penis and is often associated with exstrophy (a congenital malformation where the anterior wall of the bladder, and the abdominal wall in front of it, are both missing). See Figure 30D. Figure 30: Sadler 16.35 Development of the Urogenital System Page 35 of 36 Dennis J. Goebel, Ph.D. D. Hindgut abnormalities: Rectourethral and rectovaginal fistulas occur in 1/5000 live births and usually result from incomplete segregation of the cloaca by the urogenital septum (See Figure 32 A: Urorectro fistula & B: Rectovaginal fistula). Recall that both the hindgut and the urogenital sinus are derived from endoderm. Figure 32: Sadler 15.37 A&B E. Male indirect hernias: 1. Congenital indirect inguinal hernia in the male: Recall that prior to, and during the descent of the testis into the scrotum, the peritoneal cavity is in direct communication with tunica vaginalis of the scrotum by the process vaginalis. Normally, the process vaginalis closes off within the first year after birth. However, if the passageway fails to close, intestinal loops can work their way into the scrotum through this opening and follow the process vaginalis all the way down to the testis (see Figure 33). Pediatricians rigorously check for this during the first year following birth. Figure 33: Sadler Development of the Urogenital System Page 36 of 36 Dennis J. Goebel, Ph.D. 2. Indirect Inguinal Hernia due to the formation of hydroceles: The most common cause for male indirect inguinal hernias from childhood-into adult life, results from an incomplete closure of the process vaginalis. Recall that serous-secreting parietal peritoneum is continuous with the mesothelial lining of the process vaginalis. In some instances, closure of the passageway is not fully achieved, and can result in the formation of small serous–lined cysts along the course of the process vaginalis closure (See Figure 33B on the previous page). Fluid accumulation in these serous-lined cysts (called a hydrocele), weaken the closure and provide an opportunity for the mobile intestines to “blunt dissect” through the cyst-lined path into the scrotum. F. Monitoring for the descent of the testis: At the time of birth, 97% of male born infants have both testis present within the scrotum, and by the third postnatal month, the descent of both testis should be completed. Failure of the testis to descend leaves them vulnerable to higher body-core temperatures that will result in the testis becoming sterile, and lose its ability to synthesize and release testosterone (a condition called cryptorchidism). G. Genetic abnormalities in genital development are numerous and will be described in the year 2 curriculum.