REPRO: The Menstrual Cycle

Question 1

What are the aims of the menstrual cycle?

Answer 1

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

Question 2

What is the follicular phase of the menstrual cycle?

Answer 2

It is the first half of the menstrual cycle, up to ovulation (Day 14).
It encompasses the growth of follicles up to ovulation, and is dominated by oestradiol production from the dominant follicle.

Question 3

What is the luteal phase of the menstrual cycle?

Answer 3

It is the second half of the menstrual cycle, from ovulation to the end of the cycle.

It is the formation of the corpus luteum from the empty follicle, and is dominated by progesterone production from the corpus luteum.

Question 4

Describe the Menstrual Cycle.

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

Describe how the feedback in the follicular phase is variable.

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

Describe the feedback control in menstrual cycle.

Answer 6

Late luteal/early follicular:
At the end of the cycle (end of the luteal phase), the corpus luteum is the left-over follicle after ovulation. It is dying and the progesterone it was making falls.

Progesterone was exerting negative feedback on the hypothalamus/pituitary, suppressing GnRH, LH and FSH production (keeping it low). As the progesterone levels fall, the brake on negative feedback is lost but in such a way that it selectively increases FSH levels. This is known as the inter-cycle raise in FSH. - responsible for recruiting the antral follicles to the menstrual cycle.

Mid Follicular:
This stimulates follicles to grow and as they grow (granulosa) they produce oestrogen (e2). As the oestrogen levels rise, they exert NF again and FSH levels fall.

Mid Cycle:
As FSH levels drop the cohort of antral follicles start to die, apart from the dominant antral follicle. As it grows, it pumps a lot of oestradiol (>300pmol over 2 days) then it switches back to PF leading to a big surge of LH.

Mid luteal:
LH surge causes ovulation of dominant follicle and conversion of remainder of follicle to corpus luteum. The corpus luteum produces high levels of progesterone which NF and suppress LH and FSH production. Progesterone dominates.

At the end of the luteal phase, if no pregnancy has occurred that corpus luteal dies, progesterone levels falls and the cycle starts again.

Question 7

Why is the inter-cycle rise and fall in FSH important?

Answer 7

The intercycle rise and fall of FSH is very important because it allows for the selection of a single follicle, which will go onto become the dominant follicle that will ovulate.

Question 8

Describe follicle selection.

Answer 8

The raised FSH presents a ‘window’ of opportunity.

The FSH threshold hypothesis:

• one follicle from the group of antral follicles in the ovary is just at the right stage at the right time
• this becomes the dominant follicle which goes on to ovulate
• this is known as ‘selection’
• it can happen in either ovary

Oestradiol levels rise, reinstating negative feedback at the pituitary, causing FSH levels to drop, preventing further follicle growth.

Question 9

How does the dominant follicle survive the fall in FSH?

Answer 9

As FSH falls, LH increases.
The dominant follicle acquires LH receptors on granulosa cells (LH receptor genes switched on). The dominant follicle also increases sensitivity to FSH by increasing FSH receptors and increases the number of granulosa cells. This causes an increase in oestradiol production due to increased aromatase levels.

Other follicles do not, so they lose their stimulant and die.

Question 10

What are some rules of receptors on follicles?

Answer 10

Theca cells will always have LHr, never FSHr.
- remember that LH drives androgen and progesterone production from theca cells

Granulosa cells will have FSHr, then LHr are required from the midfollicular phase onwards
- FSH and then LH drive oestrogen production in the follicular phase

Question 11

What happens when the dominant follicle is selected?

Answer 11

It grows rapidly, doubling in diameter in seven days, from 7mm to 14mm. It needs masses of growth factors, nutrients and steroids. There is also rapid neoangiogenesis (formation of new blood vessels).
Oestrogen is released from the follicle into the circulation.

Question 12

Describe the LH surge during the menstrual cycle.

Answer 12

Throughout the follicular phase, oestradiol feedback was negative. At the end of the follicular phase, oestradiol levels are raised for long enough (48h) and high enough (>300pM) that feedback switches from negative to positive.

This causes a massive release of LH from the pituitary. There is an exponential rise of LH in the serum. This triggers the ovulation cascade:

• Egg is released
• The remainder of the follicle changes = luteinisation i.e. formation of the corpus luteum.
• Corpus lutuem has both luteinised granulosa and theca cells.
• Oestradiol production falls but still produced and Progesterone is stimulated and dominates.

Question 13

What is the ovulation cascade?

Answer 13

Ovulation occurs via a cascade of events:
- blood flow to the follicle increases dramatically (the increase in vasculature permeability increase intra-follicular pressure)

• an appearance of an apex or stigma in the ovary wall
• the local release of proteases and inflammatory mediators.
• the enzymatic breakdown of the ovary wall
• 12-18 hours after the peak of LH, a hole appears in the follicle wall and ovulation occurs with the release of the cumulus-oocyte complex (COC.)
• the oocyte with cumulus cells is extruded from the ovary under pressure
• follicular fluid may pour into the Pouch of Douglas
• the egg is ‘collected’ by the fimbrae of the fallopian tube
• the egg progresses down the tube by peristalsis and the action of the cilia.

Question 14

How is the oocyte prepared for division and describe Meiosis and Extrusion of the Polar Body?

(the continuation of meiosis after puberty)

Answer 14

• For its formation as a primary oocyte in the foetal ovary up until ovulation, the oocyte has been arrested in the first meiotic division. This permits the oocyte to retain all of the DNA and remain as large as possible during its long wait.
• In response to the LH surge, the nucleus of the oocyte in the dominant follicle completes the first meiotic division.

Question 15

How does the oocyte move from primary to secondary?

Answer 15

• ½ the chromosomes are put into a small ‘package’ in the egg called the first 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 egg is ovulated out with the chromosomes lined up on the spindle.

Question 16

What happens to the secondary oocyte?

Answer 16

• Ovulated egg picked up by fallopian tube and travels down.
• Unlike sperm we only want a single oocyte.
• The oocyte is the largest cell in the body (sperm are smallest but fastest)
• IF the oocyte is fertilised, it has to support all of the early cell divisions of the dividing embryo until it establishes attachment to the placenta.

Question 17

How long does the oocyte spend in the fallopian tube?

Answer 17

About 2-3 days, where if it meets with a sperm, fertilisation will occur.

Question 18

Describe corpus luteum formation.

Answer 18

• After ovulation, the follicle collapses. The corpus luteum is then formed, often called ‘the yellow body’.
• Progesterone production greatly increases, along with oestradiol.
• The corpus luteum contains large numbers of LH receptors. The corpus luteum is supported by LH and hCG (from the implanting embryo, if a pregnancy occurs) which also bind to LH receptor.

Question 19

Describe the secretions of the corpus luteum, and what they do.

Answer 19

PROGESTERONE:

• supports oocyte on its journey
• maintains the corpus luteum
• prepares the endometrium
• controls the cells in the fallopian tubes
• alters secretions in the cervix

OESTRADIOL:
- for the endometrium

Question 20

Describe the demise of the corpus luteum.

Answer 20

If fertilisation doesn’t occur, the corpus luteum has a finite lifespan of 14 days.
The removal of the corpus luteum is essential to initiate the new cycle.

Cell death occurs, there is vasculature breakdown and the corpus luteum shrinks. This process is not yet well understood.

Question 21

What are some clinical applications in the menstrual cycle and what controls them.

Answer 21

Clinical applications centre around the concept of feedback.

• Our understanding of GnRH action and feedback have permitted us to develop pharmacological agents to manipulate the MC. So analogues of GnRH which are not broken down reduce gonadotrophin release or you can give pulatile to stimulate it. –> can be used to delay puberty in precocious puberty.
• Injections of LH/FSH for infertility
• Oral Contraceptive Pill – constant NF prevents LH and FSH release
• Clomid – for infertility treatment
• Replacement of hormones with hormone replacemnent therapy

Question 22

Why is there variation in menstrual cycles?

Answer 22

• 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

Follicular phase is variable. Luteal phase is constant at 14 days.

Question 23

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

Answer 23

• If cycles are regular then it’s easy.
• But if cycles are irregular then its more tricky.
• If having intercourse 3 times/week probably OK….but many will not be.
• Ultrasound monitoring if having induction of ovulation.

Question 24

What are some signs of Ovulation?

Answer 24

• 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 the last menstrual period.
• Tender breasts
• Abdominal bloating
• Light spotting
• Changes in cervical mucus
• Slight pain or ache on one side of the abdomen.

Question 25

How does an ovulation prediction kit work?

Answer 25

• LH is detected.
• E3G is urinary metabolite of oestradiol, allowing women to identify days of high fertility leading up to ovulation.
• The kits are quite expensive.

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.

Question 26

Glossary

Answer 26

• Follicular phase – the phase of the menstrual cycle associated with growth of the follicles and selection of the dominant follicle. It is characterised by oestrogen production.
• Ovulation – the release of a mature haploid oocyte from the dominant follicle in response to a surge in LH
• Luteal phase – the phase of the menstrual cycle associated with formation the corpus luteum after ovulation. It is characterised by progesterone production
• Dominant follicle – the follicle that is selected from the growing cohort of antral follicles to become the pre-ovulatory follicle and release a mature egg at ovulation
• Corpus luteum – the structure formed from the granulosa and theca cells of the follicle after ovulation, which is triggered by the surge in LH and causes luteinisation of the granulosa and theca cells.
• Menses – the shedding of the endometrial tissue lining along with blood
• Polar body – the small structure contains half the chromosomes after the completion of meiosis I.