Menstrual cycle (repro)

Question 1

Aims of menstrual cycle

Answer 1

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

Question 2

Control of menstrual cycle

Answer 2

• hypothalamus releases pulsatile GnRH and LHRH to the anterior pituitary
• the pituitary then releases pulsatile FSH and LH to the ovary
• this causes positive feedback of oestrogen and progesterone to be released back to the pituitary gland and hypothalamus (this is what antral follicle does)
• GnRH has to be pulsatile

Question 3

overview of cycle

Answer 3

• 2 phases separated by ovulation
• in a 28 day cycle, 1 day is typically the 1st day of menses (bleeding)
• menstruation lasts 3-8 days (7/28)
• regular cycle should have no more than 4 days variation every month
• the follicular phase then occurs for 14 days which is the growth of antral follicles
• ovulation occurs on day 14 and is dominated by estradiol production from follicles
• Luteal phase then happens for the last 14 days where there is a formation of corpus luteum from the remnant of the follicle
• this is dominated by progesterone production from corpus luteum
• menstruation occurs at the end if there is no pregnancy

Question 4

hypothalamic/ pituitary/ ovarian axis

Answer 4

• luteal phase is negative feedback of progesterone
• follicular phase is variable
• release of negative feedback
• negative feedback then reinstated
• then switch from negative to positive feedback

Question 5

hormones during menstrual cycle

Answer 5

late luteal/early follicular phase:
- progesterone declines
- selectively raises FSH 
- causes inter-cycle rise
mid follicular phase:
- E2 increases
- negative feedback causing FSH to fall
mid cycle:
- 2 days of E2 
- >300 pmol
- causes positive feedback and therefore a surge in. LH
mid luteal phase:
- high progesterone 
- negative feedback causes low LH and FSH 
- Progesterone overcomes E2

Question 6

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
• this will go onto become the dominant follicle that will ovulate

Question 7

Follicle selection

Answer 7

• 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
• this is 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 8

Dominant follicle selection

Answer 8

• for the inter cycle rise in FSH, as FSH falls, LH increases
• dominant follicle acquires LH receptors on granulosa cells
• other follicles do not, so they loose their stimulant and die

Question 9

Dominant follicle

Answer 9

Dominant follicle survives fall in FSH by:

• increased sensitivity to FSH leads to increased FSH receptors
• increased numbers of granulosa cells (2-5 million GCs 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 LH receptor gene is switched on by FSH)

Question 10

Steroidogenesis

Answer 10

Order of the mechanism:

• Acetate
• Cholesterol C27 in the theca and granulosa
• using side chain cleavage enzyme goes to pregneneolone C21 in theca and granulosa cells
• goes to progesterone C21 in theca and granulosa cells
• goes to androgens (testosterone/C19 androstenedione) using 17alpha hydroxyls and 17,20 lyase in theca only
• goes to oestrogens C18 using aromatase in granulosa only

Question 11

LH surge

Answer 11

• throughout follicular phase E2, feedback was negative
• at the end of follicular phase if E2 levels raised for long enough (48hr) and high enough (>300pM)
• 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
• results in changes in follicle cells which leads to luteinisation ie formation of the corpus luteum
• corpus luteum has both luteinised granulosa and theca cells
• E2 production falls, but still produced and P is stimulated and dominates

Question 12

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 hours after peak of LH, the follicle wall is digested and ovulation occurs with release of cumulus-oocyte complex (COC)
• Oocyte with cumulus cell is extruded from the ovary
• follicular fluid may pour into Pouch of Douglas
• egg ‘collected’ by fimbria of Fallopian tube
• egg processes down the tube by peristalsis and action of cilia

Question 13

Meiosis

Answer 13

• in response to the LH surge, the nucleus of the oocyte in the dominant follicle completes the first meiotic division
• 1/2 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
• 1st polar body plays no further part in the process and does not divide again
• oocyte begins the 2nd meiotic division, but arrests again

Question 14

Secondary oocyte

Answer 14

• unlike sperm we only want a singe 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 to the tube

Question 15

Corpus luteum formation

Answer 15

• after ovulation is 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 16

Secretions of CL

Answer 16

progesterone:
- supports oocyte in its journey
- maintains the CL 
- prepares the endometrium 
- controls cells in Fallopian tubes
- alters secretions of cervix
oestradiol:
- for endometrium

Question 17

demise of CL

Answer 17

• if fertilisation doesn’t 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

Signs of ovulation

Answer 18

• 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 gf LMP
  signs:
• tender breasts
• abdominal bloating
• light spotting
• changes in cervical mucus
• slight pain or ache on one side of the abdomen

Question 19

Ovulation prediction kits

Answer 19

• fertile period spans 6 days and is affected by:
• lifespan of the egg (up to the 24hr after ovulation)
• lifespan of sperm (median 1.5days but sperm can survive up ton 5 days In the sperm supportive mucus of fertile days of cycle
• sperm survival is dependent on the type and quantity of mucus within cervix and the quality. of the sperm
• E3G is urinary metabolite of estradiol allowing women to identify days of high fertility leading up to ovulation

Question 20

main points

Answer 20

• inter cycle rise in FSH followed by slow decline
• slow rise in LH in follicular phase to exponential mid cycle rise
• 2 peaks in estradiol different shapes
• single luteal phase rise in progesterone

Question 21

Glossary

Answer 21

• 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.