Menstrual Cycle I

Question 1

What are the 6 aims of the MC? (6)

Answer 1

• selection of single haploid
  -regular spontaneous ovulation
  -correct number of chromosomes in egg
  -Cyclical changes in the vagina, cervix and fallopian tube
• Preparation of the uterus
• Support of the fertilised dividing egg

Question 2

What is the key requirement to maintain the HPO axis? (2)

Answer 2

-pulsatile GnRH
- regular/ pulsatile gonadotrophins

Question 3

The normal menstrual cycle (5)

Answer 3

• The length of a menstrual cycle = number of days b/w 1st day of menstrual bleeding of one cycle to the onset of menses of the next cycle
• Median duration of cycle =28 days with most cycles b/w 25-30 days
  *Menstruation lasts 3-8 days, written as 7/28 or 5-6/27-32

*MC<21 days=polymenorrheic; MC>35days=oligomenorrheic
*Menstrual cycle typically most irregular around extremes of reproductive life i.e menarche and menopause

Question 4

Menstrual cycle day/phase diagrams (7)

Answer 4

images

LL: dec. p+e2
EF: dec. p+e2, inc. FSH+LH surge -> intracycle rise of FSH (recruits early antral follicles) (MENSES)
MF: inc. e2 (inc. oestrogen- granulosa cells release from follicles), steady p(-tive feedback from oestreogen = dec. FSH)
LF: peaks of all
EL: drops
ML: highs for p+e2 (from CL, gran,+ theca)
LL: restart

Question 5

Which steroids are made where? (2 cell gonadotrophin theory) (3)

Answer 5

Theca: predom. all the enzymes responsible for formation of progesterone family and androgen family (due to LH receptors)

Granulosa: androgens converted to oestrogen because aromatase only present here (FSH receptors)

Corpus Luteum: mixture of both

Question 6

What are the roles of FSH? (5)

Answer 6

-cyclical recruitment of FSH
-GC multiplication
-Stimulation of E2 - leading to prolif of endometrium
-DF selection
-Introduction of LH receptors

Question 7

What are the roles of LH? (3)

Answer 7

-Completion of Meiosis I in oocyte and start of meiosis II
-Ovulation
-CL formation w/ accompanying progesterone production

Question 8

The menstrual cycle mini diagrams (4)

Answer 8

LL/EF: prog declines (CL dies if no pregn) = selectively raises FSH = intercycle rise

MF: E2 rises (-ve feedback) = FSH falls

Mid cycle: 2 days of E2 (>300pmol = +ve feedback- length of time +threshold) = LH Surge

ML: high prog = -tive feedback = low LH/FSH, P overcomes E2

Question 9

Oestrus vs menstrual cycle (wider reading) - (7)

Answer 9

Menstrual cycles occur only in humans, primates and snakes for the regular appearance of menses I.e. shedding

Oestrus cycle in animals named because of:
* The cyclic appearance of behavioural sexual activity (heat or oestrus)
* They do not menstruate – the endometrium is reabsorbed if fertilisation does not occur
* Day 0 of the oestrous cycle is the day of beginning of sexual receptivity (=poly babies)
* Ovulation usually occurs early in cycle as high oestrogen levels stimulate sexual behaviour as well as exerting positive feedback
* Different species have different lengths of cycles
‒ Some are poly-oestrous i.e. go into heat several times/year (cats, cows, pigs);
others are di-oestrous (twice/year) and some have only one breeding season/year i.e. mono-estrous (eg. Bears, foxes, wolves) and usually in spring
* Rabbits have no oestrous cycles and are induced to ovulate by mating and can conceive at any arbitrary moment

Question 10

Types of breeding cycles in animals (5)

Answer 10

Polyestrus: The animal can cycle during the entire year, independently of environmental cues. (e.g. primates, rat, sow, cow)

Monoestrus: These are animals which have only one cycle per year. (e.g. wolf and fox.

Seasonsal polyoestrus: These animals only cycle during a determined season, in response to specific environmental
cues, such as an increase or decrease of light hours.

• Short day breeders start cycling as the days get shorter in the fall (e.g. ewe, nanny and doe)

-Long day breeders start cycling as the days are getting longer in the spring (e.g. mare)

Question 11

HPO

Answer 11

Image

Question 12

Inhibin (4)

Answer 12

1985 purified Inhibin = produced by testis (Sertoli cells ) and ovary (granulosa cells)
» Disulphide-linked protein dimers
» Common α-subunit with different β-subunits giving two forms of Inhibin
» Both forms specifically suppress (INHIBIT) FSH secretion by pituitary w/o affecting LH secretion

Question 13

Activins - 1986

Answer 13

1986 – isolated Activins from follicular fluid which stimulate (ACTIVATE) FSH secretion

Question 14

Follistatin -1987

Answer 14

1987- Follistatin – binds to activin with high affinity » neutralises FSH-stimulating ability of activins (suppressed FSH indirectly, by preventing stim.)

Question 15

How do we know that Inhibins act selectively on FSH? - ovx sheep study (3)

Answer 15

Experiment using ovx sheep: GnRH agonist (activating) injected in the presence and absence of Inhibin

ovx= control + avoid intrinsic control of hormones
sheep = mono-ovulatory (like us)

= complete absence of FSH in inhibin induced sheep (no change in LH), compared to normal sheep

Images

Question 16

Inhibin and activist subtypes (3)

Answer 16

Biosynthesis of inhibins and activins occurs from 3 genes, makes precursor protein:
» α- protein, specific for Inhibin
» βA- protein, can form either Activin/Inhibin
» βB- protein, can form either Activin/Inhibin

Inhibins take 2 forms depending on β-chain composition
» Inhibin A and Inhibin B

Activins take 3 forms depending on β-chain composition
» Activin A (βA-homodimer), Activin B (βB-homodimer) & Activin AB (βAβB-heterodimer)

Inhibin: Inhibits FSH sec. =
-InhibinA- alpha and BetaA subunits
-InhibinB- alpha and BetaB subunits

Activin: stimulates FSH sec. =
-ActivinA- BetaA and BetaA subunits
-ActivinAB- BetaA and BetaB subunits
-ActivinB- BetaB and BetaB subunits

Question 17

Follicle stage and production of inhibin and Activin - rat study proof (4)

Answer 17

image

-Granulosa cells produce diff. amounts of each, going through the menstrual cycle.
-Activins: high FSH in EFP correlation
-Inhibins: low FSH in LFP correlation

used rats - used rabbit serum and antiserum (checking what happens when you block inhibin) = raised FSH con. in rats w/antiserum, as it binds w/ inhibin
= INHIBIN needed w/E2 in LAP to inhit FSH

Question 18

AMH - role in ovaries? (6)

Answer 18

-glycoprotein and member of the TGFβ superfamily

In males expressed from week 8 of development
» causes regression of the Müllerian ducts by a wave of apoptosis.

1980s: found to be expressed in rodent ovaries

Over the last decade a new and interesting role for AMH has emerged in the ovary

It is expressed by ovarian granulosa cells with levels peaking in selectable follicles (large preantral and small antral follicles) » then decreasing

AMH production in preantral follicles is variable, but has been detected from the primary stage onwards – species variation?

Question 19

AMH distribution in follicles (2)

Answer 19

IHC of adjacent section using anti-AMH staining

found higher staining (higher AMH levels) in small antral follicles compared to the big one

Question 20

AMH as a regulator of normal follicle growth and development (3)

Answer 20

AMH has 2 windows of action on folliculogenesis:
1) Inhibits transition from primordial to primary follicles

2) Inhibits FSH-dependent cyclical recruitment of follicles by inhibiting FSH-stimulated aromatase and FSH receptor expression → in the normal cycle would act to prevent over-recruitment of growing follicles

(over-recruitment = quicker depletion = earlier menopause)

Question 21

Explain the window of opportunity (5)

Answer 21

Raised FSH = presents a window of opportunity

FSH threshold hypothesis:
- one follicle from the group of antra, follicles in the ovary is just at the right stage at the right time…
– This becomes the dominant follicle which survives fall in FSH and goes onto ovulate
– Known as “selection”
– Can be in either ovary
* Oestradiol levels rise reinstating negative feedback at pituitary causing FSH levels to fall prevents further follicle growth

Question 22

How does the dominant follicle survive the fall in FSH? Follicular phase gonadotrophins (3)

Answer 22

Image- intercycle rise in FSH

-As FSH falls, LH increases
- Dominant follicle acquires LH receptors on granulosa cells
- Other follicles do not, so they lose their stimulant = die

Question 23

Which type of receptor is present in the Granulosa and Theca and what steroids are produced consequently? (4)

Answer 23

Granulosa:
receptors: FSHr and then LHr acquired from MF phase in dominant follicle
steroids: FSH drives oestrogen production in F phase and LH drives Progesterone in L phase

Theca cells:
receptors: LHr
steroids: LH drives Androgens and Progesterones

Question 24

Integration of feedback and the menstrual cycle - graph data of Inhibin (6)

Answer 24

Inhibin B:
-highest in early-mid FP (ratio of activin: inhibin)
-declines in LFP (small peak at LH surge)
-zero in luteal phase.

Inhibin A:
-increases in late FP with highest levels in luteal phase (being made by CL) – contributes to inhibition of FSH in this phase
-dramatic decline in Inhibin A end of the luteal phase allows for increase in FSH

interlinked with activin (feedback)

Question 25

Which section of teh cycle varies most and how do you know? (2)

Answer 25

Follicular phase
The luteal phase is relatively constant at 14 days due to the fixed life-span of the corpus luteum.

Question 26

What type of feedback does high E2 exert?

Answer 26

positive feedback

Question 27

What type of feedback does low E2 exert?

Answer 27

negative feedback

Question 28

What type of feedback does proges. exert?

Answer 28

negative feedback

Question 29

Hormonal Effects on the Reproductive Tract (4)

Answer 29

Characteristic changes occur due to varying conc.’s of E2 & P in
different parts of MC
» Endometrium (grow, thin or shed)
» Oviduct/Fallopian tubes
» Cervix
» Vagina - changes in vaginal epithelial cells