The menstrual cycle

Question 1

What are the aims of the menstrual cycle?

Answer 1

selection of a single oocyte

regular spontaneous ovulation every month

correct number of chromosomes in eggs

cyclical changes in the vagina, cervix and fallopian tube; this allows sperm to enter and the egg to be released from the follicle to travel down the tube and meet the sperm for fertilisation

preparation of the uterus, ready to receive an embryo if fertilisation occurs; must also be able to shed the uterus if an embryo isn’t received to allow for the cycle to occur again

support of the fertilised dividing egg

Question 2

In what rhythm is GnRH, FSH and LH secretion occurring?

Answer 2

Pulsatile

Question 3

What do FSH and LH act on in women and why?

Answer 3

Follicles in the antral phase of folliculogenesis

Selects dominant follicle out of cohort

The follicle produces oestrogen and progesterone which feedback on the hypothalamus/ pituitary to control the secretion

Question 4

What are the 2 phases of the menstrual cycle separated by ovulation and what happens in ovulation?

Answer 4

Follicular phase 
1st phase up to 14th day
Dominant follicle is selected 
Oestrogen is prime hormone involved
growth of follicles up to ovulation

Ovulation then occurs at the end of the follicular phase on day 14 - release of dominant follicle’s egg into fallopian tube

Luteal phase
2nd phase starting on 14th day
formation of corpus luteum from the empty follicle
progesterone production from corpus luteum

So follicular phase involves growth of follicle and luteal phase is dominated by corpus luteum

Question 5

How many days is an ideal cycle?

What happens on the 1st day of the cycle?

What happens if there is no fertilization/ pregnancy by the 28th day?

Answer 5

28

Bleeding begins

The whole cycle starts again at day 28

Question 6

Describe the feedback control in males

and then females in both the luteal and follicular phases

Answer 6

Males - only negative feedback by testosterone

Females

Luteal phase Only negative feedback by progesterone

Follicular phase
Variable

Release of negative feedback

Negative feedback then reinstated

Switch from negative to positive feedback

Question 7

Describe the menstrual cycle from the beginning of the follicular phase

Answer 7

1. Progesterone exerts -ve feedback on hypothalamus; release of this feedback when CL dies, so gonadotrophins in pituitary release FSH and LH
2. FSH causes early antrum follicles at right stage/ size to start growing, so granulosa and theca cells multiply and produce oestrogen. Oestrogen exerts -ve feedback on pituitary and hypothalamus so FSH drops and all the antral follicles (having lost their stimulus) die; the dominant one survives as it has acquired LH receptors
3. The dominant follicle then grows at an exponential rate. It produces a lot of oestrogen; when oestrogen levels are sustained (for more than 48 hours; over 300 picomoles of it in circulation), you get a switch to positive feedback, causing a big surge in LH which triggers ovulation of dominant follicle and leutinization of follicle to form CL
4. The CL produces a lot of progesterone so -ve feedback is exerted. Oestrogen is still produced by the dominant follicle but progesterone is the dominant hormone, reinstating the –ve feedback.

CL dying when there is no pregnancy starts cycle again

Question 8

What is crucial to selecting the dominant follicle?

Answer 8

Both the rise and fall of FSH

The rise is crucial to recruit the antral follicles into the menstrual cycle.

The fall allows for the dominant follicle to survive when the other follicles in the cohort are dying due to lack of FSH.

Question 9

Why do we only want 1 follicle to ovulate?

Answer 9

We are designed to hold 1 foetus only.

Question 10

What is pre-antral growth and how do the follicles grow when in this stage?

Answer 10

Pre-antral growth (cohort of follicles initiating growth from the resting stage) occurs up to early antral stages, all the time in a slow and sustained way

Question 11

How are follicles recruited into the menstrual cycle?

Answer 11

The cohort of follicles that have grown 1-2mm, have an antrum, have good thecal vasculature are selected to grow, since they now need FSH to continue growing. They are at the right stage and size to respond to the inter-cycle rise in FSH (-ve feedback lifted as CL dies) and grow. This ‘recruits’ follicles into the menstrual cycle

Question 12

What happens after a cohort of follicles are recruited?

Answer 12

They grow 

produce oestrogen

-ve feedback

FSH drops 

only dominant follicle survives

any other follicle of right size/ shape cannot grow as FSH has dropped

Question 13

Why does the dominant follicle survive?

Answer 13

FSH threshold hypothesis

One follicle from the group of antral follicles in ovary (can be in either ovary) is just at the right stage at the right time to be selected

Thought that dominant follicle has the most number of FSH receptors/ has them very effectively coupled to downstream signalling (so needs least FSH to respond by producing oestrogen/ grow granulosa cells)

Question 14

So how does dominant follicle survive the fall in FSH?

Answer 14

In the dominant follicle the gene that produces LHr switches on, so it acquires LH receptors on it’s granulosa cells; it can now respond to LH. It also increases FSHr’s so FSH is captured even if levels are falling (i.e. increased sensitivity to FSH) + increases no. of granulosa cells. Other follicles do not do this.

As FSH falls, LH rises (surge caused by switch to positive feedback when a lot of oestrogen is produced by the dominant follicle)

Question 15

What are the receptor rules?

Answer 15

Theca always has LHr, never FSHr
LH drives androgen and progesterone production from theca

Granulosa have FSHr
Selected dominant follicle has LHr’s acquired at the end of the window of opportunity (window in which dominant follicle is selected)
From mid-follicular phase onwards

FSH and then LH drive oestrogen production in follicular phase + progesterone production later on

Question 16

Where does progesterone form from specifically? Why only there?

Answer 16

Granulosa cells; they have the enzyme aromatase which converts androgens to oestrogens

Question 17

How are all steroid enzyme formed? Where do they go upon synthesis?

Answer 17

By sequentially removing C atoms from cholesterol via enzymes; upon synthesis they are distributed to different cellular compartments of follicular cells

Question 18

How are other systems in the body involved in the cycle?

Answer 18

They test fitness of person to reproduce

Signals from adipocytes ensure sufficient weight to start menstrual cycle (anorexia can switch off your axis)

Insulin also involved in the cycle; stress via cortisol

Question 19

How many follicles in a lifetime ovulate? How do the thousands of primordial follicles die?

Answer 19

400

Thousands die via atresia, the degeneration of unovulated follicles

Question 20

What are the steps from dominant follicle selection to oestrogen production?

Answer 20

1. Dominant follicle selected
2. Grows rapidly, doubling in diameter from 7mm to 14mm via growth factors, nutrients and steroids
3. Rapid neoangiogenesis - formation of thecal vasculature to bring growth factors, nutrients and steroids
4. Oestrogen released from follicle

Question 21

What does the exponential rise in LH due to the feedback switch cause? (brief)

Answer 21

Ovulation cascade

1. Egg is released
2. GCs and TCs in follicle undergo luteinisation to form the CL which produces progesterone (becomes dominant hormone)

Question 22

What is the ovulation cascade? (detail)

Answer 22

1. Blood flow increases to follicle due to increased vascular permeability of follicle
2. Intra-follicular pressure also increases
3. Follicles migrate to middle of ovary as they grow (blood supply is in middle), then the dominant follicle migrates to the edge
4. Dominant follicle punctures ovarian wall (can see apex/ stigma in wall), then releases proteases from it’s epithelium causing enzymatic breakdown of protein of ovary wall

Hole appears in ovarian wall 12-18 hours after peak of LH

Question 23

How is the oocyte released from the ovary?

Answer 23

In a cumulus oocyte complex, a big sticky mass

This is extruded under pressure

Can lead to follicular fluid pouring into Pouch of Douglas

Question 24

What allows for the cumulus oocyte complex to be picked up by the fallopian tube?

What are other benefits of the complex?

Answer 24

The fallopian tube and ovary are in close contact. The complex is also sticky.

The complex helps the egg to travel down the fallopian tube and protect the oocyte from harsh conditions

Question 25

How does the egg progress down the tube?

Answer 25

By peristalsis (peristaltic movement of the tube) and action of cilia (waft the egg down

Question 26

How and why have oocytes been in ‘arrest’ since it’s foetal formation?

Why must this arrest be removed?

Answer 26

They have been arrested in the first meiotic division since foetal formation. This allows the oocyte to retain all it’s DNA and remain large during it’s wait.

Arrest must be removed in order to complete the meiosis process to form a haploid gamete (so it can join sperms chromosomes to form a diploid zygote)

Question 27

How does a dominant oocytes nucleus respond to an LH surge?

Answer 27

The oocyte completes it’s first meiotic division and extrudes the polar body

But it does not divide (and complete the second meiotic division – goes into arrest again)

Question 28

What is in the first polar body as opposed to the oocyte?

Answer 28

Some cytoplasm and 1/2 chromosomes

The oocyte has RNA and proteins laid down in it to take the embryo through development until the placenta forms

Question 29

What is the difference between a sperm and eggs function?

Answer 29

Sperm carries DNA a long distance, requiring a lot of energy

The oocyte sustains the embryo

Question 30

When does the oocyte arrest again?

Answer 30

The oocyte arrests after it has began it’s 2nd meiotic division (having lined up and formed the spindle)

This is after it has extruded it’s polar body and is a secondary oocyte

Question 31

When is Meiosis II completed for the oocyte?

Answer 31

When a sperm fertilizes the oocyte having penetrated through the thick zona pellucida of the oocyte (in the cumulus oocyte complex)

Question 32

What happens to the zona pellucida once one sperm has fused with the oocyte?

Answer 32

It changes to prevent other sperm from entering

Question 33

What maintains the CL until the placenta is formed and why does this need to be done?

Answer 33

HCG secreted by the embryo
+ LH

CL required to produce progesterone which acts to support processes in luteal phase
(the oocyte has to support all of the early cell divisions of the dividing embryo until it embeds into the uterus and establishes attachment to the placenta)

2-3 days are spent in the uterine tube

Question 34

What do progesterone and oestradiol secretions from the CL do?

Answer 34

Progesterone:

1. Supports oocytes journey
2. Prepares endometrium of uterus (inner epithelial lining)
3. Controls cells in fallopian tube
4. Alters cervical secretions to aid/ prevent sperm entry

Oestradiol:
1. Prepares endometrium

Question 35

What happens to the corpus luteum if fertilisation doesn’t occur?

Answer 35

1. CL dies - has 14 day lifespan

Vasculature breakdown, CL shrinks, CL disintegrates

Question 36

How long does menstruation normally last? How is this written? How much variation should occur between each cycle from month to month?

Answer 36

3-8 days
7/28
4 days

Question 37

Why is the luteal phase fixed but follicular phase variable?

Answer 37

CL has finite lifespan of 14 days so any variation in the cycle is from the follicular phase

Question 38

How do you time fertilisation?

Answer 38

1. Have a lot of intercourse
2. Work out time of ovulation - can use ovulation test kit which detects LH surge prior to ovulation
3. Ultrasound monitor to see when you have the dominant follicle