Week 9 (Repro) physiology Flashcards
Where are primordial follicles formed?
cortex of the ovary
Are primordial follicles diploid or haploid?
diploid
What happens to form primordial oocytes?
(diploid) oogonia undergoes mitosis and become primoridal oocytes
primordial follicle growth initiation
- Oocyte will grow in size
- the granulosa cells undergo mitosis and increase in number
resting state and primordial follicle growth initiation
- Majority of them will undergo atresia
Once growth initiates the oocyte cannot stop and return to resting state.
- majority will undergo atresia (follicle death)
-
1st meiotic arrest (when?)
At birth
2nd meiotic arrest (when?)
ovulatory follicles (oocytes) - before fertilisation
Primary follicle is also?
pre-antral
p
primary follicle layers
- an oocyte
- layers of granulosa cells
- basement membrane
- thecal cells
antral follicle
the antral cavity forms
last follicle before ovulation
Graafian/pre-ovulatory
How is an ovulation of one oocyte regulated?
There’s competition between follicles of all stages, this ensures that only one follicle matures to become the Graafian follicle.
- the rest undergoes atresia
step-wise development of follicles
- independent primordial follicle - NO meiotic divisions
- primary oocyte - can undergo 1 meiotic division
- early antral oocyte - can be fertilised, 1 cell division
- mid antral oocyte - can undergo multiple cell divisions
- pre-ovulatory oocyte- can grow to a baby
Which step of folliculogenesis - can start cell division
antral follicle
Which step of folliculogenesis - mature enough to grow to a baby
Graafian follicle
- fully support post-fertilisation development
What releases GnRH?
hypothalamus
What does the pituitary release in response to GnRH
FSH and LH
When is FSH required?
antral follicle growth
When is LH required?
stimulate final stage of follicle growth (late-antral)
required for ovulation
early stage of follicle development - endocrine feedbacks
- early follicles produce low levels of oestrogen
- low oestrogen +ve feedback —-> Hypth. and Pit.
- INCREASE FSH
later stage of follicle development - endocrine feedbacks
- As follicles are more developed, they release more oestrogen
- high oestrogen will have negative feedback to H. and P.
- P. will release less FSH, LH is unaffected
what does high oestrogen affect?
lower FSH but unaffected LH
how does more developed follicles gain competitive advantage?
- Initially: Ahead follicle will get more sensitive to FSH - more receptors
- The ahead follicle will undergo rapid growth - produce more oestrogen
- FSH levels will fall
- Since the follicle is developed its growth can depend on LH.
- Other follicles will undergo atresia due to low FSH.
Follicles moving through antral stage increasingly release….
oestrogen
- stimulate the uterus and support pregnancy
oestrogen production dependent on?
both LH and FSH
LH contribution to oestrogen production
outlayer - thecal cells
binds to LH receptor and activate PKA via ATP-cAMP pathway
PKA stimulates conversion from cholesterol to androgen
FSH contribution to oestrogen production
androgen will move from outer layer - thecal cells
to granulosa cells.
FSH binds to FSH receptor stimulate cAMP pathway
stimulates gonadal aromatase - androgen to oestrogen
androgen example
androstenedione
oestrogen example
oestradiol
PCOS apparent symptom on imaging
many follicles seem to mature, but are all very small
PCOS criteria
- appearance of polycystic ovaries
- ovulation is abnormal or absent
- high levels of androgen - hyperandrogenaemia
PCOS criteria if no apparent polycystic ovaries
hyperandrogenaemia and abnormal ovulation
what’s the FSH endocrine issue with PCOS
Early stage follicles respond improperly to FSH
- problem with competition
- follicles do not mature properly
- multiple follicles that are not fully developed
- lack of dominant follicle
What could be a kind of treatment to deal with refractory response to FSH in PCOS
stimulate the system with excess FSH
LH issue in PCOS
Anovulatory patients have abnormally high LH
- excess LH will act on early-mid antral follicles
PCOS - LH lead to twins?
issue with development and selection - multiple follicles that mature
Severe cases of LH in PCOS
- The eggs do not mature properly, thus cannot fully support post-fertilisation development.
- anovulation - no ovulation
Why does anovulation occur in PCOS
severe case of PCOS where follicles cannot ovulate properly
- the oocyte is retained in the corpus luteum after improper ovulation.
abnormal corpus luteum in PCOS
since the follicles are underdeveloped
the CL formed are not fully functional.
Corpus luteum effect on LH and FSH
normal CL will secrete mainly progesterone and oestrogen:
- high progesterone level will have negative feedback to H. and P.
- lowers FSH and LH levels
why high LH in PCOS (abnormal corpus luteum)?
immature CL will lead to lower progesterone production
- reduced negative feedback
- HIGH FSH and LH.
increased androgen production in PCOS (where?)
mainly in thecal cells.
more androgen is produced due to:
1. high LH
2. thecal cells become more
High androgen affects progesterone effects
High androgen will antagonise progesterone’s negative feedback to hypothalamus.
- androgen will desensitive H. and P. to progesterone feedback.
- Thus GnRH level is not regulated properly.
metabolic disorder in PCOS patients
PCOS patients are more prone to weight gain
Obese PCOS patients have lower post-prandial energy thermogenesis, reduced energy expenditure.
There will be insulin resistance: hyperinsulinaemia as a consequence.
A potential in treating insulin resistance in PCOS (sheep)
- administering insulin
- increased PPT and energy expenditure
PCOS effect on obesity, obesity effect on PCOS
PCOS patients gain weight easier and insulin resistance.
obese patients often have worse PCOS outcomes - more likely to have anovulation.
how does obesity and IR affect PCOS
- sensitise thecal cells to LH
- upregulating androgen production
PCOS cause - genetic predisposition
Statistics: 20-40% of offsprings of PCOS parents develop PCOS
Case: PCOS Pregnant mother
- high androgen in circulation
- predisposes her daughter to PCOS
GWAS usage in finding genetic causes of PCOS
Genome-wide association study:
some genes show strong association with PCOS symptoms:
- FSH receptors
- insuline receptors
epigenetics significance in PCOS
genome involved in: LH and insulin signalling
more methylation - more gene suppression
This means that some PCOS symptoms are reversible through epigenetic therapy.
Further therapy to anovulatory infertility (refractory to FSH)
Raise FSH levels by reducing oestrogen negative feedback:
1. clomiphene citrate: oestrogen antagonist (bind to oestrogen receptor)
2. letrozole - inhibit aromatase
clomiphene citrate effect
inhibit oestrogen feedback/signalling
letrozole effect
reduce oestrogen synthesis
further therapy to IR in PCOS
metformin: decrease plasma glucose
sensitises insulin signalling
evolutionary benefits of PCOS?
1.PCOS amplifies metabolic outcome - eg. prone to weight gain:
Obesity could help survival in times of privation?
2.PCOS leads to Less fertility - help in childbearing -> better survival?
3.hyperandrogenism leads to increased muscle and bone mass.
