Week 6 - Female Reproductive System

Question 1

GnRH

Answer 1

gonadotropin releasing hormone

produced in the hypothalamus – brain

Stimulates FSH and LH secretion by the anterior pituitary gland.

Question 2

FSH

Answer 2

follicle stimulating hormone

produced in the anterior pituitary – brain

Stimulates follicle maturation in the ovaries.

Question 3

LH

Answer 3

Luteinising hormone

produced in the anterior pituitary – brain

Stimulates release of the ovum from the mature ‘graafian’ follicle and conversion of the remaining follicle into the corpus luteum structure.

Question 4

Estrogen

Answer 4

the major female hormone and responsible for building the endometrium.

Mostly produced by the follicles

mostly has a negative feedback effect on GnRH, LH and FSH secretion (ie. high levels of estrogen reduce GnRH and MAINLY FSH secretion, except during mid cycle-ovulation when estrogen negative feedback flips to estrogen positive feedback AND high levels of estrogen increase GnRH and FSH secretion)

Question 5

Progesterone

Answer 5

produced by follicles

stabilises the endometrium
Helps implantation of a fertilised ovum.
High levels of progesterone have a negative feedback effect on the hypothalamus to reduce GnRH secretion and MAINLY LH secretion (to prevent ovulation).

Question 6

Inhibin

Answer 6

a hormone that INHIBITS only FSH secretion

Question 7

How does the HPO system work?

Answer 7

1. GnRH neurons reside in the hypothalamus
2. Neurons have terminal projections in the median eminence
3. GnRH is released from the nerve terminals in the ME
4. GnRH travels through the hypothalamic-hypophyseal portal (blood) system to the anterior pituitary
5. GnRH stimulates LH and FSH production by gonadotroph cells in the AP

Question 8

GnRH secretion

Answer 8

GnRH is secreted in pulses

LH is therefore also secreted as pulses (1:1 relationship with GnRH)

But FSH is secreted continuously
(different vesicles contain LH & FSH)

Question 9

Menstrual cycle

Answer 9

1. Follicular phase
2. Luteal phase

Question 10

Follicular phase

Answer 10

1. Low levels of oestrogen stimulate FSH release (-ve feedback)
2. FSH stimulates the maturation of
   many ‘primary’ follicles.
3. Only the most dominant oestrogen secretor develops into the Graafian follicle (contains the ovum)
4. Secondary and mature follicles
   increase plasma oestrogen
5. High plasma oestrogen mid-cycle stimulates LH release (+ve feedback)
6. LH causes the Graafian follicle to
   rupture and release the ovum

Question 11

Luteal phase

Answer 11

1. The ruptured follicle becomes the corpus luteum which secretes progesterone and oestrogen
2. If the ovum is not fertilised, progesterone and oestrogen secretion stops and the endometrium sheds (menstruation)

Question 12

Post - Menopause

Answer 12

1. Fail to recruit follicles by FSH
2. Reduced oestrogen and progesterone levels in plasma (only small amounts of oestrogen and progesterone are synthesised in other organs) [& inhibin]
3. Negative feedback on hypothalamus and pituitary
4. Increased GnRH (causes hot flushes)
5. Increased FSH and LH (due to lack of overriding negative feedback)

Cessation of menstruation (~50 yo)

No development of the endometrial lining and no menstruation

Question 13

Low endogenous levels of oestrogen
and progesterone lead to …..

Answer 13

• Headaches
• Mood disturbances
• Depression
• Fragile bones
• Risk of cardiovascular disease
• Change in immune function
• Vaginal dryness
• Thinning/dull hair
• Weight gain
• Bone pain (eg. Sore back)
• Loss of muscle tone
• Loose teeth, and more….

Question 14

Anti-menopause treatment (hormone delivery)

Answer 14

one of the solutions to the problems associated with menopause includes administering exogenous hormones that the body can no longer produce endogenously

methods incude:
IUD
pills
patches
subcutaneous implants (the bar)
nasal spray
vaginal ring/tablet/cream

Question 15

Two different types of the contraceptive pill

Answer 15

1. The combined oestrogen and progestin pill
2. The progestin only pill

Rule of thumb:
* Oestrogens should not be given without progestins to women with a uterus
* In the absence of progestins, oestrogens cause hyperproliferation (abnormally rapid growth) of the endometrium of the uterus which increases the risk of endometrial cancer
* Not a problem in post-hysterectomy women

Question 16

Oestrogen component (combined pill)

Answer 16

Natural oestrogen is more potent than modified oestrogens, but is not well absorbed from the gut and is rapidly cleared
* Original combined pill used high oestrogen dose (150-50 ug), but this was associated with a high incidence of side effects.
* Magic number for oestrogen dose = 20 ug (effective and few side effects).
* <20 ug = insufficient contraceptive effect

Question 17

Progestin component (combined or progestin only pill)

Answer 17

progesterone
* Short half life (5 m)
* 100-200 mg

norethisterone
* Long half life (5-14h)
* Other family members with slightly modified structures
* 0.35 mg

levonorgestrel
* Long half life (~24h)
* 0.03/0.15 mg

cyproterone acetate
* Long half life (2-3 d)
* Potent anti-androgen with progestin activity
* Also drospirenone
* 2 mg

Question 18

How does ‘the pill’ work?

Answer 18

High plasma estrogen
* Inhibits secretion of FSH (and to a lesser extent, LH) via -ve feedback (hypo & pit)
* Inhibits follicle maturation & ovulation

• Also keeps the endometrial lining thin – if the lining is too thin it cannot support the implantation of a fertilised egg

High plasma progestin
* Inhibits synthesis of LH at the hypothalamus (-ve feedback),
* Prevents LH surge required for ovulation, also…
* Thickens cervical mucus
* Forms a mucus ‘plug’ around the cervix
* Prevents sperm from gaining access to the uterus

if its very fluid, it enhances sperm penetration. if its thick, it prevents sperm penetration.

Question 19

Hormone replacement for menopause

Answer 19

Estrogen
* Artificially add estrogen (increase plasma levels)
* Negative feedback on hypothalamus and pituitary
* Reduces GnRH, FSH and LH (stops hot flushes)
* Replaces lost estrogen so maintains normal functioning of all other cells that have estrogen receptors

Progestin
* Artificially add progesterone (increased plasma levels)
* Mimics luteal phase
* Negative feedback on hypothalamus
* Reduces GnRH secretion (stops hot flushes)
* No effect on plasma estrogen levels or cells containing estrogen receptors. Generally positive effect on cells containing progesterone receptors.

Question 20

Why choose to take the progestin only pill over the combined pill?

Answer 20

Women who have contraindications to taking oestrogen
* History of hypertension
* History or stroke
* History of thromboembolism (DVT)

BUT the progestin only pill is not
recommended for women with a
history of clots!!!

Question 21

Problem with progestin only pill?

Answer 21

• Irregular vaginal bleeding
• ‘potentially’ higher contraceptive failure rate

Question 22

Why would you choose to administer very high progestin doses?

Answer 22

Emergency or ‘morning after’ contraceptive pill

Levonorgestrel 1.5 mg (compared to 0.15 mg)
 Must be taken within 3-5 days (85% reduction in conception within 3 days)
Works by:
 Preventing LH surge
 prevents/delays ovulation
 Only works if taken 2 days before the LH surge
 Does NOT alter the capacity for ovum fertilisation or
implantation and DOES NOT effect the fetus.
 Major side effects are menstrual irregularities, nausea & vomiting (if vomiting occurs within several hours, another pill is needed).

Ulipristal 30 mg (does not need to be taken with food)
 Must be taken within 3-5 days (85% reduction in conception within 3 days)
Works by:
 Inhibiting progesterone binding to its receptor (exact mechanism unknown)
 Prevents or delays ovulation
 Effect on implanted fertilised egg is unknown.
 Major side effect is menstrual irregularities. Nausea & vomiting are less common than for levonorgestrel)

Question 23

Why would you deliberately inhibit
hormone production or action?

Answer 23

1. Pregnancy termination
2. Treatment of Oestrogen receptor (ER) positive or ‘overexpressing’ breast cancers

Question 24

Pregnancy termination (antiprogestin)

Answer 24

• Competitive inhibitor of the progesterone receptor
• Two fold higher affinity for the progesterone receptor than progesterone itself
• Used as the first of a 2 step series of pills designed to medically terminate pregnancies
• Take a 200 mg tablet of mifepristone
• Causes breakdown of the decidua (what used to be the uterine endometrium)
• Take a prostaglandin pill (which causes uterine contractions)

Question 25

How are oestrogens made?

Answer 25

1) Cholesterol is converted to progesterones (influence of LH)
2) Progesterones are converted to androgens (LH)
3) Androgens are converted to oestrogens (via aromatase UNDER influence of FSH)

Question 26

Aromatase inhibitors

Answer 26

Letrozole and Anastrozole

they inhibit the action of the p450 aromatase using the aromatase inhibitors. they are effectively inhibiting the synthesis of estrogens by reversibly competitively binding (competing with testosterone) to the aromatase enzymes.
they reduce the plasma concentrations of thos endogenous estrogens. by reducing conc of estrogens in the body you are reducing the effect of those estrogens on cancer growth.

Question 27

How do oestrogens work?

Answer 27

1. Oestrogen enters the cell by passive diffusion
2. Binds to the oestrogen receptor (ER)
3. Conformational change in the receptor
4. Dimerizes with another oestrogen-bound ER
5. Enters the nucleus
6. Binds to the oestrogen responsive element (ERE) on DNA
7. Conformational change allows binding of coactivators
8. Binding of coactivators promotes gene transcription

Question 28

Oestrogen receptor inhibition (tamoxifen)

Answer 28

1. Tamoxifen is metabolised to several ‘active’ forms (eg. 4-hydroxy tamoxifen) by liver CYP2D6 & 3A4
2. 4-OH-Tam enters the cell
3. Competitively binds to the oestrogen receptor (ER)
4. NO conformational change in the receptor
5. Dimerizes with another 4-OH-Tam bound ER
6. Enters the nucleus
7. Binds to the oestrogen responsive element (ERE) on DNA
8. Lack of conformational change prevents binding of coactivators
9. No gene transcription

Acts as an ER antagonist in breast tissue (to slow breast cancer
growth) but acts as a partial agonist in the endometrium & bone

Question 29

Where are other Oestrogen receptors located (ERα and β)

Answer 29

brain, bones, fat, cardiovascular system, immune cells

Question 30

Hypothalamic-Pituitary-Ovarian (HPO)

Answer 30

HPO regulates female reproductive function.

involves the hypothalamus releasing GnRH, which stimulates the pituitary gland to release FSH and LH, which then influence ovarian follicle development and ovulation.

These hormonal interactions control the menstrual cycle and fertility.

Question 31

Sex hormone production in follicles

Answer 31

LH stimulates cholesterol uptake & androgen synthesis in the theca cells.

Theca cells:
acetate -> cholsterol -> pregnenolone ->androstenenedione (into blood and granulosa cells) -> testosterone (into grandusa cells as aromatase)

FSH stimulates granulosa cells to convert androgens to estradiol

Granulosa cells:
Androstenenedione -> aromatase -> estradiol (to blood and follicular fluid as estrogen)

Question 32

Overview of whole cycle

Answer 32

Follicular Maturation:
- ovarian follicles release estrogen
- lots of estrogen signal to hypothalamus to release GnRH

LH Surge:
- when estrogen levels reach a certain threshold the pit releases a surge of LH
- triggers final maturation of graafian follicle which is ready to release egg

Ovulation:
- The peak of LH activity initiates the rupture of the mature ovarian follicle, releasing the egg into the fallopian tube.
- is when a woman is most fertile, and it marks the middle of the cycle.

Corpus Luteum Formation:
- After ovulation, the remaining part of the follicle transforms into the corpus luteum, a temporary endocrine structure that produces progesterone.
- Progesterone prepares the uterine lining for potential embryo implantation.

If fertilization does not occur, the corpus luteum regresses, progesterone levels drop, and the menstrual cycle begins again. The LH surge is a key event in the precise coordination of hormonal changes that regulate the menstrual cycle and enable successful reproduction.