Week 6 - Female Reproductive System Flashcards
GnRH
gonadotropin releasing hormone
produced in the hypothalamus – brain
Stimulates FSH and LH secretion by the anterior pituitary gland.
FSH
follicle stimulating hormone
produced in the anterior pituitary – brain
Stimulates follicle maturation in the ovaries.
LH
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.
Estrogen
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)
Progesterone
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).
Inhibin
a hormone that INHIBITS only FSH secretion
How does the HPO system work?
- GnRH neurons reside in the hypothalamus
- Neurons have terminal projections in the median eminence
- GnRH is released from the nerve terminals in the ME
- GnRH travels through the hypothalamic-hypophyseal portal (blood) system to the anterior pituitary
- GnRH stimulates LH and FSH production by gonadotroph cells in the AP
GnRH secretion
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)
Menstrual cycle
- Follicular phase
- Luteal phase
Follicular phase
- Low levels of oestrogen stimulate FSH release (-ve feedback)
- FSH stimulates the maturation of
many ‘primary’ follicles. - Only the most dominant oestrogen secretor develops into the Graafian follicle (contains the ovum)
- Secondary and mature follicles
increase plasma oestrogen - High plasma oestrogen mid-cycle stimulates LH release (+ve feedback)
- LH causes the Graafian follicle to
rupture and release the ovum
Luteal phase
- The ruptured follicle becomes the corpus luteum which secretes progesterone and oestrogen
- If the ovum is not fertilised, progesterone and oestrogen secretion stops and the endometrium sheds (menstruation)
Post - Menopause
- Fail to recruit follicles by FSH
- Reduced oestrogen and progesterone levels in plasma (only small amounts of oestrogen and progesterone are synthesised in other organs) [& inhibin]
- Negative feedback on hypothalamus and pituitary
- Increased GnRH (causes hot flushes)
- 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
Low endogenous levels of oestrogen
and progesterone lead to …..
- 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….
Anti-menopause treatment (hormone delivery)
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
Two different types of the contraceptive pill
- The combined oestrogen and progestin pill
- 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
Oestrogen component (combined pill)
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
Progestin component (combined or progestin only pill)
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
How does ‘the pill’ work?
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.
Hormone replacement for menopause
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.
Why choose to take the progestin only pill over the combined pill?
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!!!
Problem with progestin only pill?
- Irregular vaginal bleeding
- ‘potentially’ higher contraceptive failure rate
Why would you choose to administer very high progestin doses?
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)
Why would you deliberately inhibit
hormone production or action?
- Pregnancy termination
- Treatment of Oestrogen receptor (ER) positive or ‘overexpressing’ breast cancers
Pregnancy termination (antiprogestin)
- 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)
How are oestrogens made?
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)
Aromatase inhibitors
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.
How do oestrogens work?
- Oestrogen enters the cell by passive diffusion
- Binds to the oestrogen receptor (ER)
- Conformational change in the receptor
- Dimerizes with another oestrogen-bound ER
- Enters the nucleus
- Binds to the oestrogen responsive element (ERE) on DNA
- Conformational change allows binding of coactivators
- Binding of coactivators promotes gene transcription
Oestrogen receptor inhibition (tamoxifen)
- Tamoxifen is metabolised to several ‘active’ forms (eg. 4-hydroxy tamoxifen) by liver CYP2D6 & 3A4
- 4-OH-Tam enters the cell
- Competitively binds to the oestrogen receptor (ER)
- NO conformational change in the receptor
- Dimerizes with another 4-OH-Tam bound ER
- Enters the nucleus
- Binds to the oestrogen responsive element (ERE) on DNA
- Lack of conformational change prevents binding of coactivators
- 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
Where are other Oestrogen receptors located (ERα and β)
brain, bones, fat, cardiovascular system, immune cells
Hypothalamic-Pituitary-Ovarian (HPO)
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.
Sex hormone production in follicles
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)
Overview of whole cycle
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.
