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Mark Hill's site for this lecture.

  • Understand the development of the gonads in males and females.
  • Understand the chromosomal basis of sex determination.
  • Understand the differences in male/female internal duct development.
  • Understand the origins of the external genitalia.
  • Understand the developmental abnormalities in male and female development.
  • Major abnormalities of the genital system are chromosomal in origin

Stages of sexual differentiation

  1. Developmental of the indifferent gonad (genital ridge); early embryo
  2. Differentiation of gonad into testis or ovary in the late embryo, defining event in sexual differentiation (this step defines the following two steps)
  3. Differentiation of internal genital organs and ducts - late embryo to foetal
  4. Differentiation of external genitalia (just like the internal gonad, it starts off indifferent between genders), foetal
  5. Development of secondary sexual characteristics - puberty; we also get a lot of growth in other systems (e.g. grow in height)


Timeline

  • Week 3-4 - primordial germ cells migrate during gastrulation
    • Junctional region (yolk sac and hindgut junction) in front of the hindgut region has the primordial germ cells, which are among the first cells to migrated into the embryo
  • Week 4 - (24 days) intermediate mesoderm, pronephros primordium
    • Intermediate mesoderm (between paraxial and lateral plate) is where the epithelium and mesoderm of the genital ridge form; primordial cells migrate in here
  • Week 5 - (28 days) mesonephros and mesonephric duct
    • Mesonephric duct is a patterner and an internal structure of the male gonad
  • Week 6 - (35 days) ureteric bud, metanephros, genital ridge
  • Week 7 - (42 days) cloacal divison, gonadal primordium - indifferent to first appearance of testis cords
    • Cloaca divides into dorsal anal and ventral urinary component.
  • Week 8 - (49 days) paramesonephric duct, clear gonadal differentiation
  • Week 9 - (56 days) paramesonephric duct fusion (female)
  • Week 15 - (100 days) primary follicles (ovary)

Three stages in kidney development:

  • Pronephros (in the neck)
  • Mesonephros; in the abdominal area; mesonephric duct medially influences the genital ridge
  • Metanephros; down the bottom of the embryo (last stage in

Mesonephric duct runs down the intermediate mesoderm to the kidney; contributes the entire internal genital tract in males

Adrenal gland forms in the wall of the ____; superior portion contributes to the adrenal gland, inferior portion contributes to the genital ridge. In the genital ridge region, the sertoli cells, leydig cells etc develop. The primordial germ cells have no role to play in sexual differentiation (they're passive observers waiting to make next generation).

Y chromosome

SRY on the Y chromosome, when made by support cells, leads to the differentiation of the male gonad. People with SRY damage/failure of express, will differentiate into female phenotype despite being XY. Y chromosome encodes rubbish, but there are 48 useful genes including this SRY that leads to differentiation of the male phenotype.

X chromosome

  • Huge, important chromosome, encodes many things that are
  • Females are not just "default", there are genes that are required to be activated to
  • X inactivation: need to prevent expression of both X's contributed by parents.
  • Female blood: barr body on the side of the nucleus of white blood cells is from the X chromosome being budded off
  • Look at his link to the useful picture
  • Start off with genital ridge, then the primordial germ cells migrate into this genital ridge. We result in the indifferent genital ridge
  • SRY --> sertoli cells begin to express SRY in males, influencing hormone secretion. The supporting green cells produce AMH. Leydig cells (blue) secrete hormones (testosterone). If SRY is not present, then there is no hormonal support of this process, so you end up with the supporting cell and hormone-secreting cell populations relevant to females.

Germ cell migration

  • We can watch the germ cells of a mouse migrating out of the hindgut region into the genital ridge, to form a blob where the gonad will be
    • If the germ cells don't migrate to the right place, you can get cancers in the various places they end up populating
  • About a thousand germ cells populate these regions in both males and females
  • The thickened region near the peritoneal cavity is where the genital ridge will develop

Male

  • The hormones secreted are important in maintaining the mesonephric duct in males. Genital ridge lies medial to the duct. The rest of the mesonephric duct joins with the dorsal sinus where the urinary bladder will form.
  • Parallel to the mesonephric duct (Wolffian) a paramesonephric duct (Mullerian) forms (these Mullerian ducts form medially to the Wolffian ducts).
  • Male loses all the Mullerian ducts (due to AMH). In a female, the Wolffian ducts are lost, and two large Mullerian ducts are maintained.
    • Testosterone is important in maintaining development of the internal male genital tract
  • In male or female, we select one tube system or the other.
  • Columns of the coelomic space are populated by the primordial germ cells, which are connected to the mesonephric duct
  • All the maturation of the seminiferous tubules will occur at puberty in a male (they're very underdeveloped here)
  • Mesonephric duct forms the vas deferens

Female

  • In the absence of testosterone and AMH, we get a loss of the Wolffian duct and a growth of the paramesonephric duct (which forms the Fallopian tube).
  • Don't see any development of follicles to Graafian follicles (this only happens at puberty)
  • The follicles sit in the cortex of the ovary, while the seminiferous tubules sit in the medulla of the testicle.

Uterus

  • The two midline bits of the Mullerian ducts fuse to form the uterine body.
  • The lateral bits stay suck out, to form the Fallopian tubes
  • Therefore the uterus and Fallopian tubes have the same embryonic origin (vagina is subtley different)
  • Epithelium of uterus = sensitive to sex hormones
  • Epithelium of vagina = not sensitive to sex hormones
  • Mesonephric duct can remain as remnants (cysts in broad ligament)
  • Midline fusion of the uterus can cause abnormalities - midline septum or two separate uteri

Foetal period

Male

  • Differentiation of external genitalia
  • Begin with exactly the same external structures
  • They differentiate from each other under influence of hormones
  • Linked diagram is a good summary
  • Cloaca separates the urinary and rectal regions, and urogenital sinus opens to the periphery, forming a fold externally
  • Male development requires dihydrotestosterone (DHT) - converted from testosterone by enzymes
  • DHT causes the male to generate a genital tubercle. The genital folds begin to fuse in the midlines, along the shaft of the penis. The genital tubercle forms the glans of the penis
  • Animation: folds on the midline - opening goes up to cloacal/urogenital sinus. Folds either side = urethral folds (genital folds)
  • See a septation of the rectal region off, middle folds form the shaft of the penis. Lateral folds form the scrotum.
    • Correct name before foetal period is labioscrotal folds (labia in female, scrotum in male).

Female

  • Again, the same structures to start
  • Inner folds form the inner labia, outer folds form the outer labia.
  • The genital tubercle contributes the clitoris (contributes the glans penis in the male)

Gonadal descent

  • We've formed 1. gonads, 2. internal genital tract, 3. external genitalia. Need to get the gonads into the correct location (still in the posterior abdominal wall).
  • In the female, the descent stops up in the abdominal cavity
  • In the male, the descent continues through the abdominal wall and into the scrotum
  • It occurs late in development
  • It is common for newborns not to have both testes descended
  • Gubernaculum is a ligament that shortens during the foetal period, and part of this shortening aids the descent of the testes
    • Two phases of descent: transabdominal and transinguinal
  • It then pulls down the layers of the body wall into the scrotum
  • Transient cavity anterior to the testis = processus vaginalis, which will eventually close up. Abnormality: remains patent, or as a fluid-filled cyst.
  • This pathway results in a weakness in the abdominal wall (middle age or infants, there can be herniation here)
    • Much easier to repair as an infant than an adult
  • In the female, it's less dramatic. Remember the Fallopian tube does not actually contact the ovary

Postnatal - puberty

  • Girls: 7-13; Boys 9-15.
    • Won't see secondary sex characteristics at the early end of the spectrum, it's a gradual change
  • In males, puberty is related to drop in AMH, which stops mitosis of the primordial germ cells, so it starts making spermatozoa
    • Also, T production at the Leydig cells

Abnormalities

  • Precocious puberty - girls undergo early pregnancy
  • Delayed puberty - boys don't undergo puberty at normal time course. Pubertal arrest - no progress in puberty (endocrine abnormalities)
  • Cryptoorchadism - undescended testis: either on the pathway on descent, gets trapped or an ectopic one where it's found in other locations
  • Hydrocele - fluid filled cavity due to the processus vaginalis not folding properly
  • Female abnormalities are rare - e.g. failure of fusion of paramesonephric ducts (can form different types of uteruses, whose septa may continue into the vagina as well
  • Hypospadia - urogenital folds don't fuse properly, urethral opening occurs along the inferior edge of the penis or back towards the scrotum
  • See his site