The Menstrual Cycle I Flashcards
(20 cards)
What controls the menstrual cycle?
The HPG axis
What is a key requirement to maintain the HPG axis
Pulsatile release of both GnRH and gonadotrophins. This maintains the HPG axis which in turn maintains fertility.
If you GnRH continuously, you stop the release of gonadotrophins, and cause the cessation of the complete cycle.
What is the length of the Menstrual Cycle
The length of the menstrual cycle is the number of days between the first day of menstrual bleeding of one cycle to the onset of menses of the next cycle
Median duration of MC is 28 days, with most cycles between 25-30 days.
Menstruation lasts 3-8 days.
MC<21 days = polymenorrheic
MC>35 days = oligomenorrheic
The luteal phase is fixed for 14 days independent on the lifecycle of the corpus luteum. Someone with a varied cycle is due to a varied follicular phase.
The menstrual cycle is typically most irregular around extremes of reproduction such as menarche and menopause.
Which steroids are made where?
Oestrogen is made in the granulosa cells. This is because the enzyme responsible for converting androgens (androstenedione/testosterone) to oestrogens (oestradiol, oestrogen) is found in the granulosa cell. This enzyme is aromatase. The gonadotropin that drives this conversion is FSH.
Majority of the androgens are made in the theca cells. In theca cells, the gonadotropin LH modulates the production of androgens.
Describe the menstrual cycle
Late luteal – early follicular
• The death of the CL results in the drop in progesterone production
• Normally, progesterone negatively feedbacks to the hypothalamus and pituitary to inhibit FSH
• The decline in progesterone causes FSH to be released this stimulates follicles
Mid follicular
• Growth of the antral follicles = antral follicles are producing E2
• As E2 rises, this re exerts negative feedback onto FSH = FSH falls
• The rise and fall in FSH allows selection of the dominant follicle
Mid Cycle
• The dominant follicle produces LOTS of oestrogen
• Sustained oestrogen of around 48 hours (2 days) + has to exceed the threshold >300pmol
• Feedback switches negative to positive = LH surge
• The LH surge brings about ovulation of the dominant follicle
Mid Luteal
• The remainder of follicle becomes the corpus luteum = produces a lot of progesterone
• This exerts negative feedback = keeps FSH + LH low
• In addition, there are high levels of inhibin to maintain the low levels of FSH
• In the luteal phase, you also have a peak of oestrogen coming from the CL
• But progesterone dominates over oestrogen and negative feedback is maintained in the mid luteal phase
What does all mammals have?
• All mammals have cyclical ovarian function & the same reproductive system (in terms of HPG axis) to produce a mature egg and the necessary sex steroids
What is the menstrual cycle?
• Menstrual cycles occur only in humans, primates (apes and monkeys) & is named for the regular appearance of menses i.e. shedding of the endometrial lining
Define the Oestrus cycle
Oestrus cycle in animals named because of:
o The cyclic appearance of behavioural sexual activity (heat or oestrus)
o It is a period of sexual receptivity and sexual activity shown in their behaviour
o They do not menstruate – the endometrium is reabsorbed if fertilization does not occur
o Day 0 of the oestrous cycle is the day of beginning of sexual receptivity
o Ovulation usually occurs early in cycle as high oestrogen levels stimulate sexual behaviour as well as exerting positive feedback
o 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
o Rabbits have no oestrous cycles and are induced to ovulate by mating and can conceive at any arbitrary moment.
Describe Inhibin
Inhibin is a hormone produced by sertoli cells in the testes and the granulosa cells in the ovaries.
It is a disulphide-linked protein dimer with a common alpha subunit with different beta subunits, giving rise to two forms: inhibin A and inhibin B. The subunits are members of the TGF-beta superfamily of proteins.
Both forms specifically suppress FSH secretion without affecting LH secretion.
Describe Activin
Activin is a hormone from the follicular fluid which stimulate FSH secretion.
Activin can take 3 forms depending on the beta-chain composition.
Describe Follistatin
Follistatin is another FSH-suppressing protein from the follicular fluid. It binds to activin with high affinity and neutralises the FSH-stimulating ability of activin.
Explain inhibin and activins role
Remember: Inhibins always inhibit FSH, whereas Activins always stimulate FSH. The activity of Activins can be further regulated by how much Follistatin is present in the follicular fluid which could bind it and reduce its activity.
As we start to get growth of the follicles and we come into the early antral stages, we see activin levels are high at these stages and gradually decline
When you get to the stage that you have growth and selection of the antral follicles, oestrogen causes a negative feedback, you also see an increase in Inhibins being released, which adds to that negative feedback
In the early follicular phase where we have an increase in FSH, you tend to have higher levels of activins, and in the late follicular phase as FSH drops off, you have higher levels of activins
What makes the issue much more complicated it is not the absolute level of Activins and Inhibins, it is the ratio of Activins to Inhibin, which will determine the sensitivity of FSH
Describe AMH in the menstrual cycle
• AMH is a glycoprotein and also a member of the TGFβ superfamily
• In males: expressed from week 8 of development
o causes regression of the Müllerian ducts by a wave of apoptosis.
- It is expressed by ovarian granulosa cells with levels peaking in selectable follicles, and then decreasing
- AMH production in preantral follicles is variable, but has been detected from the primary stage onwards – species variation?
Describe AMH role in the menstrual cycle
AMH as a regulator of normal follicle growth and development
o Prevents over recruitment and growth of follicles
AMH has 2 windows of action on folliculogenesis:
1) Inhibits transition from primordial to primary follicles
o KO studies in mice where AMH is not expressed resulted in all resting primordial follicles to activate + grow
o Mass activation = menopause or premature ovarian failure
o AMH maintains the balance to have normal reproductive lifespan
2) Inhibits FSH-dependent cyclical recruitment of antral follicles by inhibiting FSH-stimulated aromatase and inhibiting FSH receptor expression → in the normal cycle would act to prevent over-recruitment of growing follicles
o It is about a balance: at some point AMH levels will fall, and FSH can overcome this to recruit antral follicles
Explain the window of opportunity
- The initial growth and progression of primordial follicles is FSH independent = does not need gonadotrophins
- So, follicles will grow without gonadotrophins very slowly
- But, they reach a certain point in their growth & development where they need FSH to progress
- As FSH levels start to rise (because progesterone is decreasing + therefore removing the breaks), the follicles that are at the right stage and size will respond to that rise of FSH and will be recruited into the menstrual cycle
- This cohort of follicles will grow exponentially
- The granulosa cell of these follicles will also produce activins which aid and stimulate FSH
- The granulosa cells also produce Oestrogen = negative feedback of FSH = FSH will fall
- The granulosa cells also produce Inhibins = causes FSH to fall
- So, as E increases and Inhibins increases = FSH levels fall
- The dominant follicle has been selected, in spite of FSH falling.
- Any other cohort of follicles cannot grow any further because FSH has dropped
How is the Dominant Follicle selected?
• Raised FSH present a “window” of opportunity
• FSH threshold hypothesis
o One follicle from the group of antral follicles in ovary is just at the right stage at the right time….
o This becomes the dominant follicle which survives fall in FSH and goes onto ovulate
o Known as “selection”
o Can be in either ovary
• Oestradiol levels rise reinstating negative feedback at pituitary causing FSH levels to fall prevents further follicle growth
• As FSH falls = LH increases
• Dominant follicle acquires LH receptors on granulosa cells
• Other follicles do not, so they lose their stimulant & die
• The dominant follicle is able to respond to the increase in LH that is occurring
What receptors are present in Granulosa and theca cells and what steroids are produced as a consequence?
• Granulosa:
Have FSHr, then LHr acquired from mid-follicular phase onwards (in dominant follicle)
FSH drives oestrogen production in follicular phase
LH drives progesterone in luteal phase
• Theca:
Always has LHr, never FSHr
LH drives androgen AND progesterone production from theca
When are the two forms of inhibin present in the menstrual cycle
Inhibin B: highest in early-mid FP (ratio of activin: inhibin) and 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. The dramatic decline in Inhibin A at the end of the luteal phase allows for an increase in FSH.
What happens to GnRH in the luteal phase.
• GnRH amplitude and frequency varies to sometimes to favour synthesis over release
o In luteal phase – gonadotrophin accumulates in the vesicle ready for release at the later stages
Which parts of the female reproductive tract are affecting by varying concentrations of Oestrogen and Progesterone?
o Endometrium
o Oviduct/Fallopian tubes
o Cervix
o Vagina - changes in vaginal epithelial cells
