W4 - The Menstrual Cycle

Question 1

What are the aims of the menstrual cycle?

Answer 1

• selection of a single oocyte
• correct number of chromosomes in eggs i.e. haploid
• regular spontaneous ovulation
• cyclical changes in the vagina, cervix and Fallopian tube
• preparation of the uterus
• support of the fertilised dividing egg

Question 2

Why does GnRH have to be pulsatile?

Answer 2

They infused an animal with pulsatile GnRH and measured LH in the blood - it was keeping up. When GnRH was given continuously, there was a decline in LH.

Question 3

What are the basic stages of the menstrual cycle?

Answer 3

*In a 28-day cycle day 1 is typically the 1st day of menses
1st stage
*Follicular phase = growth of follicles up to ovulation → dominated by oestradiol production from follicles
2nd stage
*Luteal phase = formation of corpus luteum from the empty follicle → dominated by progesterone production from corpus luteum

Question 4

How are the two phases separated by ovulation?

Answer 4

• 2 phases separated by ovulation
• Cycle begins on day 1=first day of bleeding
• Next 14 days are follicular phase i.e. growth of antral follicles
• Ovulation occurs at end of the follicular phase (i.e. in the middle of the cycle)
• Remnant of the follicle becomes the corpus luteum
• Next 14 days are luteal phase i.e dominated by corpus luteum
• Menstruation occurs at the end if there is no pregnancy

Question 5

How does the hypothalamic/ pituitary/ ovarian axis work?

Answer 5

Luteal phase=Negative feedback → Progesterone

Follicular phase=variable
1. Release of negative
feedback
2. Negative feedback then
reinstated, then
3. Switch from negative to
positive feedback

Question 6

What is the Inter-cycle rise in FSH?

Answer 6

The inter-cycle rise and fall in FSH is very important because it allows selection of a single follicle, which will go onto become the dominant follicle that will ovulate

Question 7

What is the window of opportunity?

Answer 7

Preantral growth does not require Gonadotrophin. Once they reach a certain size, they need FSH to continue growing. As FSH rises, a cohort of follicles that’s been growing will be recruited into the menstrual cycle and continue their growth. As they continue growing, they produce oestrogen. With the feedback to the hypothalamus, it decreases FSH. As FSH decreases, these follicles will die off apart from one. This rise and fall in FSH produces a window of opportunity.

Question 8

How do follicles get selected?

Answer 8

• Raised FSH present a “window” of opportunity to recruit
  antral follicles that are at the right stage to continue growth
• FSH threshold hypothesis
  – One follicle from the group of antral follicles in ovary is just at the
  right stage at the right time to survive declining FSH
  – This becomes the dominant follicle which 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
  How does the dominant follicle survive the fall in FSH?

Question 9

What is dominant follicle selection?

Answer 9

• As FSH falls, LH increases. Dominant follicle acquires LH receptors on granulosa
  cells
• Other follicles do not, so they loose their stimulant and die
  *(look at the steroidogenesis slide in the folliculogenesis lecture)

Question 10

What are dominant follicles?

Answer 10

Dominant follicle survives fall in FSH by
* increases sensitivity to FSH 
increased FSH receptors
* increased numbers of granulosa cells
» 2-5 million GC in EFP and 50-100
million at ovulation
» increases E2 production because
of increased aromatase levels
» 200x more E2 in DF than in others
* acquisition of LH receptors
» the LHR (LH receptor) gene is
switched on by FSH

Question 11

What is the LH surge?

Answer 11

• Throughout follicular phase E2 feedback was negative
• At end of follicular phase if E2 levels raised for long enough
  (48h) and high enough (>300pM) enough → feedback switches
  from negative to positive
• Causes massive release of LH from pituitary
• Exponential rise in LH in serum
• Triggers ovulation cascade
• Egg is released
• Above result in changes in follicle cells = luteinisation i.e. formation of
  the corpus luteum
• Corpus luteum has both luteinised granulosa and theca cells
• E2 production falls, but still produced and P is stimulated & dominates

Question 12

What is ovulation?

Answer 12

• ovulation occurs via cascade of events:
  – blood flow to the follicle increases dramatically
  – appearance of apex or stigma on ovary wall
  – Local release of proteases and inflammatory mediators
  – Enzymatic breakdown of protein of the ovary wall
• 12-18 hrs after peak of LH, the follicle wall is digested
  and ovulation occurs with release of cumulus-oocyte
  complex (COC)

Question 13

What is ovulation cont?

Answer 13

• Oocyte with cumulus cells is extruded from the ovary
• Follicular fluid may pour into Pouch of Douglas
• egg ‘collected’ by fimbria of Fallopian tube
• egg progresses down tube by peristalsis and action of cilia

Question 14

What is meiosis and extrusion of the polar body?

Answer 14

• In response to the LH surge, the nucleus of the oocyte in the
  dominant follicle completes the first meiotic division.
• ½ the chromosomes are put into a small “package” in the egg
  called the 1st polar body
• The egg (with most of the cytoplasm) is now a secondary oocyte
• The 1st polar body plays no further part in the process and does
  not divide again
• Oocyte begins the 2nd meiotic division, but arrests again.
  The polar body will no longer play a part in the arrest again - sometimes you can get a division of the polar body, usually you don’t.

Question 15

What are secondary oocytes?

Answer 15

• Unlike sperm we only want a single
  oocyte
• The oocyte is the largest cell in the
  body (sperm are smallest…..but
  fastest!)
• The oocyte has to support all of the
  early cell divisions of the dividing
  embryo until it establishes
  attachment to the placenta
• Spends 2-3 days in the uterine tube
• So the oocyte is now on its way into
  the tube….will it meet a sperm? The
  story continues later….

Question 16

How does the corpus luteum form?

Answer 16

• after ovulation the follicle collapses
• corpus luteum is formed, ‘yellow body’
• progesterone production increases greatly, also E2
• CL contains large numbers of LH receptors
• CL supported by LH and hCG (from implanting embryo, if a pregnancy occurs) which also bind to LHR

Question 17

How do hormones change during pregnancy?

Answer 17

If there is a pregnancy, HcG rises exponentially to very high levels and stays during the first few months then drops down - this coincides with the establishment of the placenta, which takes over the functions of the corpus luteum.

Secretion of CL:
* progesterone:
– supports oocyte in its journey
– Maintains the CL
– prepares the endometrium
– controls cells in Fallopian tubes
– alters secretions of cervix
* oestradiol:
– for endometrium

Demise of CL:
* If fertilisation does not occur,
CL has finite lifespan of 14
days.
* removal of CL essential to
initiate new cycle
* Cell death occurs, vasculature
breakdown, CL shrinks
* Process is not well
understood

Question 18

How does everything apply clinically?

Answer 18

We can use the fact that GnRh controls the whole HPG axis to administer analogues and pulsatile treatment to manipulate levels of LH and FSH. Injections of one or both hormones can also be given directly.

This can be used in IVF/ precoscious puberty etc.

In menopause, with reduction of follicles, hence reduction of estradiol and progesterone inhibition (taking away the feedback loop) , we can replace those hormones with HRT or hormone replacement therapy.
Contraceptive pills - constant negative feedback from these steroids will switch off the axis preventing antral follicle progression and ovulation.

Fertility treatment and induction of ovulation, we can distrupt this negative feedback and allow the endogenous FSH to act and recruit more follicles and grow them up using clomid.

Question 18

What other factors are used in the hypothalamic/pituitary/ovarian axis?

Answer 18

Eg. We get input from adipocytes we get a lot of input in to the HPG axis - need to enter into a certain weight to reach puberty. Underweight people do not have the necessary energy to reproduce.

Similarly overweight means getting insulin resistance - it might affect (directly or indirectly) follicles or gonadotrophin release.

Question 19

What is the menstrual cycle?

Answer 19

• Day 1 is first day of bleeding
  *Menstruation lasts 3-8 days, written in notes as 7/28 or 5-6/27-32
  *Regular cycle should have no more than 4 days variation from month to month

First half = follicular phase
Ovulation happens between
Second half = luteal phase
The follicular phase is variable. The corpus luteum has an inbuilt lifespan of 14 days.

Question 20

How does a patient work out when they are
going to ovulate?

Answer 20

• If cycles are regular then it’s easy
• But if cycles are irregular?
• Question – if a woman
  has a 32-day cycle on
  what day will she
  ovulate?
• If having intercourse 3
  times/week probably
  OK….but many will not be
• Ultrasound monitoring if
  having induction of
  ovulation

Question 21

What are signs of ovulation?

Answer 21

• A slight rise in basal body temperature, typically 0.5 to 1 degree, measured by a thermometer
  – Need to keep a chart of basal body temp from
  day 1 of LMP
  These charts are now used in apps to make it easier to track and follow.
• Tender breasts
• Abdominal bloating
• Light spotting
• Changes in cervical mucus
• Slight pain or ache on one side of the
  abdomen

Question 22

Which hormones are detected when ovulation is predicted?

Answer 22

There are tests we can use to urinate on them to see if we are fertile or not.

Question 23

What do ovulation prediction kits consist of?

Answer 23

• Ovulation prediction kits
  – Fertile period spans 6 days and is affected by:
• Lifespan of the egg → up to 24h after ovulation
• Lifespan of sperm → median=1.5days but sperm can survive up to 5 days in
  the sperm supportive mucus of fertile days of cycle » sperm survival is
  dependent on the type & quantity of mucus within cervix AND the quality of
  the sperm

£25 for 20 tests
E3G is urinary metabolite of
oestradiol, allowing women to
identify days of high fertility
leading up to ovulation

Smily face = peak fertility

Question 24

Starting from the late luteal phase, how are hormones controlled in the menstrual cycle?

Answer 24

At the end of the luteal phase, progesterone is the dominating hormone. It surprises GnRH, LH and FSH. As the corpus luteum dies towards the end of the luteal phase, the progesterone will drop. As we go into the start of the follicular phase, that feedback is released. As prog declines, there will be a selective raise in FSH = inter cycle rise. This is responsible for recruiting those antral follicles into the menstrual cycle.

Mid follicular: As follicles grow, they secrete oestrogen, and as oestrogen rise, they exert negative feedback once again and we get a drop in FSH.

Mid cycle: We are going to switch to positive feedback. As FSH levels drop, the cohort of astral follicles growing will start to die. All except for the one follicle that is selected to be the dominant follicle. As that follicle grows, it pumps out vast amounts of oestrodiol. We now get a positive feedback with a big surge in LH.

Mid luteal: That surge in LH causes ovulation of the dominant follicle and conversion of the remainder of the follicle to the corpus luteum. This is now going to produce high levels of progesterone. Results in negative feedback to lower LH and FSH production. At the end of the luteal phase, if no pregnancy occurs, then that corpus luteum dies, progesterone levels fall and the cycle starts again.