RS 1 - Development of Reproductive Systems

- New individual sets aside from the other cells of the body - the somatic cells - very early in development
- The primordial germ cells are formed in the epiblast during the second embryonic week and find their way to the primordial gonads, which develop into ovaries or testes
- In a complex interaction with somatic cells the gonad of germ cells first multiply by mitosis, then undergo meiosis to form haploid gametes
- In the female = ovum
- In the male = sperm

- Ova = limited number that can be supported through preparation for fertilisation and long gestation as necessary to nurture the embryo and foetus. Unless pregnant, a woman of reproductive age will produce 12-14 ova per year, a total of about 400 over a reproductive life-span of nearly 40 years from puberty to menopause
- Sperm = continuous production to exploit intermittent female fertility. Only a tiny proportion of sperm will survive the journey through the female tract, so very large numbers must be produced. A young man will produce about 7000 sperm a second.

1. Gonads = site of gamete production.
- Female = ovary
- Male = testis
2. Internal genitalia = transport, storage, nutrition and development
- Female = provide an environment within which sperm may travel to and fertilise the ovum, the conceptus can implant to form a placenta, and the embryo can develop to term
- Male = Collect and mature continuous sperm production and produce other components of semen
3. External genitalia = transfer of gametes
- Female = introduction of sperm to female reproductive tract and the formation of a birth canal through which the foetus may be delivered
- Male = deliver the semen via ejaculation into the vagina

- Production of gametes, and the mechanisms of gestation and parturition are co-ordinated by hormones
- The hypothalamus, anterior and posterior pituitary gland, the gonads, and the placenta produce hormones that are involved in reproductive processes
- Many other hormones are involved to a lesser degree in reproductive processes as they affect virtually every body system

Hypothalamus = produces peptides releasing factors:
- GnRH
- PRH
- PIH
Posterior pituitary gland:
- Produces oxytocin (through neural control from the hypothalamus)
Anterior pituitary gland = produces gonadotrophins
- FSH = follicle stimulating hormone
- LH = luteinising hormone
- Prolactin
Gonads = produce the gonadal steroids
- Testosterone
- Oestrogens (oestradiol, oestrone and oestriol)
- Progesterone
- Also produce inhibin
Placenta
- Human chorionic gonadotrophin (hCG)
- Human placental lactogen (hPL)
- Oestrogens
- Progesterone

- Germ cells arise in the wall of the yolk sac ~ 3 weeks post-fertilisation
- Migrate by amoeboid action to the primitive gonad 5th-6th week of gestation
- Germ cells induce and influence the development into testis or ovary

- Formed by condensation of mesenchymal calls (medulla) surrounded by epithelial cells (cortex)
- Superficial and medial to the mesonephric tissue
- Columns of cells from the mesonephros and coelomic epithelium form the primitive medullary cords and sex cords respectively by penetrating the mesenchyme
- Indifferent (no sex)

- XY germ cells
- Germ cells express the SRY gene at the end of the 6th week (on the Y chromosome) which influences the subsequent masculinisation
- Encodes 'testis determining factor' TDF, which mediates gene expression
- Primitive sex cords proliferate and penetrate deep into the medulla
- Sex cords meet the mesonephric cords and so form the definitive testis cords.
- The germ cells enter these cords, which will in the adult give rise to seminiferous tubules within which sperm will be formed - connected to the urinary system
- Sertoli cells differentiate from the surface epithelium and express the SRY gene
- Leydig cells differentiate from the mesenchyme = begin to secrete testosterone by 8th week → influences sexual differentiation
- Tunica albuginea separates cord from surface

- XX germ cells colonise the cortex of the primordial gland = don't go deep
- Surface epithelium continues to proliferate
- Primary sex cords degenerate and secondary sex cords develop from the mesothelium
- Germ cells migrate to the new sex cords
- Germ cells become surrounded by clusters of mesenchymal cells to form primordial follicles
- A primordial follicle is composed of a single oocyte from the primordial germ cell and a single layer of follicular cells from the mesothelium, which surround the oocyte
- Cortex develops even if no germ cells arrive

- Foetus has primordia for both male and female internal ducts
- Mesonephric (Wolffian) = male
- Paramesonephric (Mullerian) = female

Male
- Mullerian duct growth inhibited by Mullerian inhibitory hormone (MIH) secreted Sertoli cells
- Leydig cells secrete testosterone
- Mullerian ducts regress and the Wolffian duct develop
- The seminephrous cords join the Wolffian ducts at the rete testis and the remainder of each duct forms the epididymis, vas deferens and seminal vesicles

Female
- Wolffian ducts regress spontaneously
- Mullerian duct develops into oviducts, uterus, cervix and possible upper vagina
- If there are no gonads at all, Mullerian ducts develop

- Primordia bipotential
- 5 mesenchymal swellings, covered by ectoderm develop around the cloacal membrane
- One genital tubercle
- 2 Urogenital / urethral folds
- 2 genital swellings

Male:
- Dihydrotestosterone (DHT) is formed from testosterone secreted by Leydig cells and is responsible for the development of the male external genitalia
- Genital tubercle swells to form the phallus, which becomes the glans of the penis
- Urethral folds fuse ventrally to form the shaft of the penis
- Genital swellings fuse to form, the scrotum

Female:
- Develops due to the absence of testosterone
- Genital tubercle forms the clitoris
- Urethral folds form the labia minora
- Genital swellings for the labia majora
- No hormonal influence

1. Duplications of the uterus
- Result from lack of fusion of paramesonephric ducts
- May be entirely double or slightly indented in the middle
2. Uterus bicornis
- Uterus has 2 horns entering a common vagina
- Relatively common
3. Hypospadias
- Fusion of the urethral folds is incomplete and abnormal openings of the urethra occur along the inferior aspect of the penis
- 3-5/1000 births
4. Micropenis
- Occurs when there is insufficient androgen stimulation for growth of the external genitalia
- Usually caused by primary hypogonadism or hypothalamic or pituitary dysfunction

- Germ cells migrate to the primitive gonadal cortex
- Proliferate rapidly by mitosis
- Maximum number reached by mid gestation (7 million)
- Most die during gestation
- Remaining 2 million all enter meiosis before birth
- Meiosis stops at an early stage to form a primary oocyte, surrounded by a single layer of granulosa cells (for support), forming the primordial follicle.
- No new follicles can ever arise
- At puberty follicles begin to develop further

- At puberty a small number of follicles begin to develop further
- Each month one or two complete development to mature ovum = this is the reproductive cycle
- The release of the resulting ovum - ovulation - is the start of a very short period of fertility (36 hrs or so)

- Three stages to the reproductive cycle
- Around 28 days long
- Starts on the first day of bleeding (but actually the end of the last cycle)

1. Preparation
- At the beginning of the cycle = days 0-12
- A small number of follicles begin to develop further
- Primordial follicles develop to pre-antral follicles
→ zona pellucida ( glycoprotein shell) forms around the primary oocyte
→ the single granulosa layer and the primary oocyte enlarge in size to form a multilaminar follicle
→ The surrounding ovarian cortex forms the secretory theca interna and theca externa
→ Towards the end of this phase the most advanced late preantral follicles develop receptors for oestrogen and FSH on the granulosa cells and LH on the theca cells
- Antral (secondary) follicle
→ A fluid filled cavity called the antrum develops within the granulosa cell layer
→ Theca secretes an increasing amount of oestrogens
- At the beginning of the cycle, under the influence of FSH and LH one or two follicles grow to 20mm
- Pre-ovulatory follicle
→ Capable of rupture to release ovum
→ LH surge triggers rupture
- Just before ovulation, the preovulatory follicle completes the first meiotic division
- This forms the secondary oocyte and the first polar body
- The secondary oocyte begins the second meioisis but goes into arrest at the second metaphase stage
- Rapid expansion of follicular fluid and the granulocytes synthesise progesterone
- The secondary oocyte becomes free floating within the expanded preovulatory follicle

2. Ovulation = days 12-14
- Secondary oocyte ruptures out of the preovulatory follicle
- Ovulated oocyte composed of a mature haploid oocyte that is capable of fertilisation and has the majority of cytoplasm and organelles, and the first polar body, which is a small haploid cell that degenerates
- Period of fertility approximately 24-36 hours

3. Wait and see = days 14-28
- After fertilisation the follicle regroups to form the corpus luteum
- GRows under the influence of LH
- Secretes oestrogen and progesterone
- Dies after 14 days
- In higher primates the lining of the uterus is shed at the end of an unsuccessful cycle = menstruation

The ovary has 3 components:
1. Surface
- Simple cuboidal epithelium called the germinal epithelium (nothing to do with germ cells)
2. Cortex
- Composed of connective tissue stroma supporting thousands of follicles
- Also supports preovulatory, postovulatory and degenerating follicles
3. Medulla
- Composed of supporting stroma
- Contains rich network of vessels and nerves that enter the ovary from the mesovarium

- Germ cells colonise the sex cords in the medulla of the gonad
- Before birth proliferate by mitosis, forming spermatogonia
- At puberty the cords hollow out to form seminiferous tubules. There are 250-750 of these per testis
- Diploid spermatogonia cluster around the edges
- The number of spermatogonia maintained by mitosis = available up to a beyond 70 years
- Mitotic divisions are incomplete in spermatogonia, so that daughter cells remain connected by thin cytoplasmic bridges. These bridges remain until spermatozoa are released into the lumen of the seminiferous tubule
- The primary spermatocytes undergo meiosis to form 4 haploid spermatids, moving towards the lumen as it does so
- Spermatids are released into the seminiferous tubules
- They undergo remodelling/maturation as they pass down the tubule through the rete testis, ducti efferentes and epidydymus. This is called spermiogenesis
- The fully mature spermatozoa are stored in the epididymus until they are ejaculated or broken down

- The whole process of sperm production takes about 70 days
- New groups of spermatogonia arise every 16 days
- All stages of the process are occuring at the same time in different sections of the tubule = spermatic wave

- Secretions of the seminal vesicle (60%) = seminal fluid
- Secretions of the prostate (20%) = seminal fluid
- Sperm via the vas deferens
- Secretions from the bulbo-urethral gland

- Mixed by emission in the vagina by ejaculation
- 3.5ml contains 350M sperm

- Fibrous septa divide each testis into about 300 lobules, each containing 1-4 seminiferous tubules that produce sperm
- Seminiferous tubules are closed loops with a specialized epithelium and contain 2 types of cells
→ spermatognoia
→ sertoli cells that support developing sperm and secrete testicular fluid into the tubules
- Between the seminiferous tubules are the vessel and clusters of testosterone secreting Leydig (interstitial) cells
- The loops of seminiferous tubules drain into the rete testis = convuluted networks of ducts, lined by simple cuboidal cells with microvilli
- Sperm pass from the rete testis to the epididymus via 15 efferent ductules liked by ciliated epithelium