6 - DEVELOPMENT OF THE REPRODUCTIVE SYSTEM AND HORMONAL CONTROL OF REPRODUCTION

Question 1

How does development of the sexual phenotype occur?

Answer 1

• Development of the internal and external reproductive system is controlled by:
1) Genotype (usually XX or XY).
2) Hormones.
• Usually results in a binary sexual phenotype of male or female.
• Differences in Sexual Development (DSD) do occur and may be undiagnosed until puberty, intercourse or trying to start a family.
• Sex assignation at birth is based on external anatomy.

Question 2

How are gonads created?

Answer 2

• Primordial Germ Cells (PGCs) migrate from the yolk sac, into the embryo in the gut, along the mesentery, (which attaches the gut to the wall) into the urogenital ridge around week 6 of pregnancy to create:

1) Ovarian tissue (if their genetic background is XX).
2) Testicular tissue (if their genetic background is XY).

• Gonadal tissue can start to express hormones:

1) Ovaries express oestrogen.
2) Testes express testosterone.

Question 3

INTERNAL SEXUAL DIFFERENTIATION: XX

Answer 3

At 20 weeks (fetal period) XX
• a lack of testosterone leads to degeneration of Mesonephric duct (Wolffian)
• Oestrogen (and receptors) maintains the Paramesonephric duct
• Remaining Mesonephric duct becomes the oviducts, uterus and upper part of vagina.

Question 4

INTERNAL SEXUAL DIFFERENTIATION: XY

Answer 4

In XY fetuses at 16 weeks:
• Anti-Mullerian Hormone (AMH) stimulates degeneration of Paramesonephric ducts
• Testosterone (and receptors) maintains mesonephric duct
• Mesonephric duct becomes the epididymis and vas deferens.

Question 5

EXTERNAL GENITALIA

Answer 5

• At early stages the external genitalia is visible as a genital tubercle
• At 7 weeks (9 weeks since last menstrual period) the genital tubercle is bigger in females than males
• This can lead to mistaken sex assignation in early prenatal scan

Question 6

EXTERNAL SEXUAL DIFFERENTIATION - XX

Answer 6

XX growth : Oestrogen
• Genital tubercle (orange) becomes the clitoris
• Genital fold (purple) becomes the Labia minora and urethral and vaginal orifices
• Genital swelling (green) becomes the Labia majora

Question 7

EXTERNAL SEXUAL DIFFERENTIATION - XY

Answer 7

XY growth: Dihydrotestosterone
• Genital tubercle becomes the glans penis
• Genital fold forms the orethral fold and raphe
• Genital swelling forms the scrotum

Question 8

SEX STEROIDS

Answer 8

• Made from cholesterols, i.e. Low-Density Lipoproteins from diet or de novo.
• Androgens: testosterone from testes & adrenal cortex.
• Oestrogens: ovaries, placenta & testosterone.
• Progestins: ovaries & placenta.
• XX and XY systems use the same hormones.
• Variations in form & function of body are related to:
1) Quantity.
2) Structures present.
3) Receptors and mediators.

Question 9

PUBERTY: INITIATION OF REPRODUCTIVE CYCLE

Answer 9

1. As the brain matures, it starts to produce Gonadotrophin releasing Hormone (GnRH) from the hypothalamus.
2. Gonadotrophins are released from the Anterior Pituitary
   • Luteinising Hormone (LH)
   • Follicle Stimulating Hormone (FSH)
3. LH and FSH stimulate gonadal development and the release of Testosterone, Oestrogen and Progesterone
4. T, O and P have effects on the function of the reproductive tissues and the system: Growth + Secondary sex characteristics

Question 10

FEMALE REPRODUCTIVE CYCLE

Answer 10

• Female gonads (ovary) are a site of endocrine production. Also produces growth factors and regulatory peptides (eg inhibin ).
• Female reproduction is influenced by stress more than the male reproductive system. May be related to up to 50% of cases of female infertility

Question 11

Which 3 activities does the reproductive cycle control, in regards to fertility?

Answer 11

1. Ovarian cycle (maturation of the oocyte)
2. Uterine cycle (suitable implantation environment)
3. Cervical cycle (controls sperm entry)

Question 12

What happens in the menstrual cycle?

Answer 12

• Rising levels of FSH at puberty stimulate follicles to develop in the ovary.
• The follicle cells surrounding the oocytes are stimulated by FSH and LH to synthesise oestrogens, principally B-oestradiol, which enters the circulation and promotes skeletal and muscular growth and development of female secondary sexual characteristics (e.g. breast development).
• FSH levels are controlled by negative feedback – the follicle cells secrete inhibin in response to FSH which inhibits FSH release.

Question 13

What happens in oogenesis?

Answer 13

• Lifetime supply of oocytes is made in utero.
Mitosis:
• Occurs in early foetal life.
• Gives rise to primary oocytes.
Meiosis I:
• Begins during foetal development.
• After puberty, primary oocytes complete meiosis I, which produces a secondary oocyte and a first polar body that may or may not divide again.
Meiosis II:
• The secondary oocyte begins meiosis II.
• A secondary oocyte (and first polar body) is ovulated.
• After fertilisation, meiosis II resumes.
• The oocyte splits into an ovum and a second polar body.
• The nuclei of the sperm cell and the ovum unite, forming a diploid (2n) zygote.

Question 14

Ovarian cycle

Answer 14

• The follicles will mature with an increase of FSH and oestrogen.
• Oocyte in the follicular phase, released at ovulation.
• What is left of the follicle after the egg leaves becomes the corpus luteum (which secretes both estrogen and progesterone).
• If no implantation occurs, the corpus luteum will regress and steroid levels drop, and menstruation occurs.

Question 15

UTERINE CYCLE

Answer 15

Proliferative phase (follicular): 
• Oestrogen levels increase from maturing follicles

• Secretive phase (luteal):
• Progesterone and Oestrogen control. Prevents FSH and LH release. (low Oestrogen levels)
• Progesterone from maturing follicles, then the corpus luteum.
• Progesterone stimulates secretion of nutritive substance
• Progesterone and Oestrogen increase growth of uterine lining

Question 16

CERVICAL CYCLE

Answer 16

Luteal phase:
• Progesterone thickens cervical mucus to create a cervical plug, trapping sperm
Periovulatory/ovulatory phase:
• Oestrogen increase changes mucus fibres to a more linear conformation to allow sperm to follow the fibres up.
• Consistency of mucus is more fluid and slippery
• Mucus alkaline to promote sperm survival
• Sperm can survive several days in cervix.

Question 17

What happens during hormonal changes in early pregnancy?

Answer 17

• Early Pregnancy Factor is found in the bloodstream within hours of conception.
• It is an immunosuppressant and helps to stimulate trophoblast (placental) growth during the peri-implantation period.

• Maternal menstrual & 'pregnancy' hormones change:
1) There is an increase in:
• Progesterone (P).
• Oestrogen (E).
• human Chorionic Gonadotrophin (hCG).
2) There is a decrease in:
• Gonadotrophin Releasing Hormone (GnRH).
• Follicle Stimulating Hormone (FSH).
• Luteinising Hormone (LH).

Question 18

How is pregnancy maintained?

Answer 18

• The first key events of pregnancy are:

1) Maintenance of pregnancy.
2) Formation and growth of the placenta.

• Pregnancy hormones are initially released by the corpus luteum after ovulation and the key hormones are:
1) Human Chorionic Gonadotrophin.
2) Progesterone.
3) Oestrogen.
• Placenta will take over production from CL.

Question 19

PRODUCTION OF SPERM

Answer 19

• Production of sperm (spermatogenesis) can take 65- 75 days , depending on the individual. Genetically controlled.
• It consists of 6 stages/segments:
1. A-spermatogonium
2. B-spermatogonium
3. Primary spermatocyte (= spermatocyte order I)
4. Secondary spermatocyte (= spermatocyte order II)
5. Spermatid
6. Sperm cell (= spermatozoon)
• Sperm degenerate if they do not pass through the stages in time
• Number of spermatogonic stem cells stimulated in controlled by the endocrine system

Question 20

What are Leydig & Sertoli cells?

Answer 20

• Leydig/interstitial cells are responsible for testosterone production.
• Sertoli/sustentacular cells:
1) Are tree-shaped; extend from basal lamina to lumen, forming a barrier to protect sperm from immune system.
3) Support germ cell development.
4) Enable phagocytosis of excess fluid.

Question 21

How are male hormones regulated?

Answer 21

• Hypothalamus produces GnRH = stimulates FSH and LH production.
• FSH acts on nutritive, supportive Sertoli cells.
• Sertoli cells produce inhibin which is negatively feedbacking on the function of the adenohypophysis and testosterone (like oestrogen).
• Testosterone will inhibit anterior pituitary and hypothalamic production of GNRH & gonadotrophins.
• LH acts on Leydig cells to produce testosterone, and regulate testosterone more locally in the testes.
• Testosterone acts on Sertoli cells, which then start to produce oestrogen.
• Oestrogen is then bound to the Leydig cells, which inhibits the production of testosterone.