Menustral Cycle Flashcards

1
Q

What are the aims of the menstrual cycle?

A
  • selection of oocyte
    -regular spontaneous ovulation
    -correct number of chromosomes in eggs
  • cyclical changes in the vagina, cervix, and fallopian tube
  • preparation of the uterus
  • support of the fertilised dividing egg
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2
Q

What are controls of the menstrual cycle?

A
  • pulsatile secretion of GnRH from anterior pituitary in the hypothalamus
  • To secrete FSH and LH in a pulsatile manner
  • these act on antral follicle to produce the selection of a dominant follicle
    -the antral follicle produces estrogen and progesterone which feeds back to the hypothalamus (negative feedback) but on day 12-14 there’s positive feedback.
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3
Q

What are the features of normal menstrual cycle?

A

-the length of a 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 menstrual cycle is 28 days
-menstruation lasts 3-8 days, written 7/28 or 5-6/27-32

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4
Q

What happens in the menstrual cycle?

A

Day 1: bleeding
Day 1-14 : follicular phase is the growth of follicles until ovulation, this phase is dominated by the selection of the follicle and the prime hormone is estrogen.
Day 14: ovulation after ovulation the reminder of the follicle in the ovary forms a corpus luteum
Day 14-28 : corpus luteum produces progesterone which is called luteal phase
If there is no pregnancy the cycle starts again.

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5
Q

What phase has variable feedback?

A
  • follicular phase (1-14), positive feedback of oestrogen.
    -if oestrogen levels are maintained over 300pmol for 48 hours switched to positive feedback, which results in LH surge.
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6
Q

What hormone controls follicular phase?

A

-oestrogen

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7
Q

What hormone controls luteal phase?

A

-progesterone

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8
Q

outline the different stages of the menstrual cycle.

A

Late luteal/early follicular stage:
- progesterone declines(no pregnancy and corpus luteum dies), negative feedback is removed so selectively raises FSH levels again = inter-cycle rise

Mid follicular:
- Dominant follicle releases E2, increases E2 , removes -ve feedback, FSH falls

Mid cycle:
- 2 days of E2 >300pmol = positive feedback =LH surge=
LH surge triggers ovulation = oocyte released from corpus luteum

Mid luteal:
-high progesterone = corpus luteum releases progesterone
- negative feedback so low LH/FSH , LH levels are needed for corpus luteum to survive = decline in LH levels = corpus luteum dies = corpus luteum releases progesterone so progesterone levels decline = negative feedback = increase in intracycle FSH levels and cycle begins again.

=> in pregnancy progesterone levels are high so no negative feedback and raise in FSH to start a new cycle = prevents menstruation and multiple pregnancy

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9
Q

Why is intra cycle rise and fall in FSH important?

A
  • allows selection of a singe follicle
  • rise needed to recruit the antral follicles into menstrual cycle
    -as they grow and release estrogen this feedback negatively and FSH starts to drop
    -FSH drop allows dominant follicle to survive and the remainder to die off, as follicles need FSH to grow.
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10
Q

What is the FSH threshold hypothesis?

A

-one follicle from the group of antral follicles is at the right stage at the right time
- it has the most FSH receptors
-this becomes the dominant follicle which goes to ovulate - this is known as selection.

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11
Q

What is Oestrus(heat) cycle?

A
  • cyclic appearance of behavioural sexual activity (heat or oestrus)
  • they do not menstruate , endometrium is reabsorbed if not fertilised
    -day 0 of the oestrous cycle is the day of beginning sexual receptivity.
    -ovulation usually occurs early in cycle as high oestrogen levels stimulates behaviour as well as exerting positive feedback
    -Different species have different lengths of cycles
  • Rabbits have no oestrous cycle and are induced by mating so can conceive at anytime.
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12
Q

What cells make is DHEA made?

A

Theca cells

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13
Q

What makes progesterone?

A

corpus luteum

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14
Q

What cells make ostrogen?

A

Granulosa

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15
Q

What are the different types of breeding cycles in animals?

A
  1. polyestrus - heat several times a year, continuous breeders, ie: cow primates, rat
  2. monoestrus - only one breeding cycle a year/season, ie: Ewe, Nanny, Doe
  3. seasonal polyestrus -> long day breeders and short day breeders. The specific environmental cue determines the breeding like longer or shorter light hours.
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16
Q

what cells produce inhibin?

A

sertoli and granulosa

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17
Q

What is the structure of inhibin?

A
  • disulphide-linked protein dimers
    -common alpha subunit with different beta subunits giving two forms of inhibin
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18
Q

What is the function of inhibin?

A

both forms specifically supress FSH secretion by pituitary without affecting LH secretion.

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19
Q

What is the function of activin?

A

to stimulate FSH (opposite effect to inhibin)

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20
Q

What is the function of Follistan?

A

same as inhibin, supresses FSH production but it does this by binding to activin with high affinity and neutralises FSH stimulating ability.

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21
Q

How do we know inhibin selectively acts on FSH?

A

Experiment using ovariectomized (Ovx) sheep, GnRH agonist was injected in the presence and absence of inhibin, showed drop in FSH but LH stayed the same.

Ovariectomised to prevent gonad released hormones such as oestrogen and testosterone related negative feedback causing change in LH and FSH levels - as a control

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22
Q

What are subtypes of inhibin A and inhibin B?

A

alpha and beta A chain = inhibin A
alpha and beta B chain = inhibin B
Alpha subunit the same in both

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23
Q

What are the subtypes of Activin A,AB, and B?

A

Activin A: Beta A and Beta A (homo dimer)
Activin AB : Beta A and Beta B (hetrodimer)
Activin B: Beta B and Beta B (homodimer)

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24
Q

What stage of the follicular stage does activin correlate with?

A

increased FSH in early follicular stage

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25
Q

What stage of the follicular stage does inhibin correlate with?

A

Low FSH in Late follicular stage.

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26
Q

What are characteristics of AMH?

A
  • glycoprotein
  • member of TGF - beta superfamily
  • males: expressed at 8 weeks and causes regression of the mullerian ducts by a wave of apoptosis
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27
Q

What is the newly found role of AMH in females?

A
  • found in ovarian granulosa cells with levels peaking in selectable follicles (large preantral and small antral follicles)
    -AMH production in preantral follicle is variable and has been detected from primary stage.
  • AMH production in small antral follicle is higher than in larger antral follicles
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28
Q

What is the role of AMH in normal follicle growth and development?

A
  1. inhibits transition from primordial to primary follicles
  2. inhibits FSH - dependent cyclical recruitment of follicles by inhibiting FSH stimulated aromatase and FSH receptor expression -> in the normal cycle would act to prevent over recruitment of growing follicles.
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29
Q

How does follicular selection happen(FSH hypothesis)?

A
  • raised FSH presents a ‘window’ of opportunity
  • one follicle from the group of antral follicles in ovary is just at the right stage at the right time
  • this becomes the dominant follicle which survives fall in FSH and goes on to ovulate (known as selection), and can occur in either ovary.
    -follicular phase is driven by oestrogen so oestrogen levels rise reinstating negative feedback at pituitary causing FSH levels to fall preventing further follicle growth
30
Q

So how does the dominant follicle survive the fall in FSH caused by negative feedback?

A

As FSH falls , LH increases (negative feedback)
the dominant follicle aquires LH receptors on granulosa cells allowing it to grow whereas other folllicles do not so they lose their stimulant and die.

31
Q

Which type of receptors are present in the granulosa?

A

-FSH receptors
-acquired LH receptors mid follicular phase and onwards in dominant follicle (DF)

32
Q

What steroids are produced in Granulosa cells?

A

FSH drives oestrogen production
LH drives progesterone production
(cant produce androgen bc they dont have aromatase enzyme)

33
Q

Which type of receptors are present in Theca cells?

A

LH receptors
NOT FSH receptors

34
Q

What steroids are produced in the Theca cells?

A

LH drives progesterone
Androgens

35
Q

When is inhibin A levels increased?

A

increases in late follicular phase, with highest levels in luteal phase, contributes to the inhibition of FSH in this phase. The dramatic decline in inhibin A at the end of the luteal phase allows for increase in FSH .

36
Q

When is inhibin B levels increased?

A

early -mid follicular phase, and declines in LFP , zero in luteal phase.

37
Q

The relation between the ratio of Inhibin A and Inhibin B:

A

Indirectly proportional
ratio in early follicular phase IB levels high and IA levels low and LFP IA levels high and IB levels low

38
Q

How does characteristic changes occur in the reproductive tract?

A

due to hormonal changes in oestrogen and progesterone in different parts of the menstrual cycle.
=>endometrium changes and follicular changes and relate it to menstrual cycle!

39
Q

how are theca and granulosa cells different?

A
  • have different receptors for different hormones
  • have different enzymes
40
Q

What enzymes does theca cells have?

A

Aromatase for conversion of testosterone to oestrogen

41
Q

What enzyme does granulosa cells have?

A

testosterone -> oestrogen by aromatase

42
Q

How does negative feedback switch to positive feedback and lead to LH surge occur?

A

At the end of follicular phase oestrogen levels become persistent (300pM for 48hrs) this cause the switch from negative to positive feedback and causes LH surge.

43
Q

How long does the LH surge last?

A

Lasts 36-48 hours and triggers ovulation.

44
Q

What takes longer to be cleared from the serum LH or hCG and why?

A

hCG takes longer to be cleared bc it has higher affinity to LHR than LH.

45
Q

Where are LH receptors found?

A

granulosa has both LHR and FSHR whereas Theca has only is only LHR no FSHR

46
Q

How does LH surge change preovulatory follicle?

A

before LH surge:
granulosa cell has no blood vessels supplying it and the barriers around it prevents the oocyte leaving.

After LH surge:
loss of oocyte surface epithelium and breakdown of underlying basal lamina and GC and TC allowing rupture
GC basal lamina is distrupted allowing extension of blood vessels into GC layer and for infiltration of theca cells and leukocytes into GC compartment, Cumulus cell oocyte complex (COC) detaches.
you need all these cells to enter for ovulation to occur and the remaining becomes corpus luteum.

47
Q

What regulates meoitic arrest?

A
  • oocytes are in meoitic arrest since fetus
    -cGMP enters oocytes from cumulus cells via gap junctions to inhibit oocytes phosphodiesterase PDE3A activity (PDE3A normally degrades cAMP)
  • maintained by high cAMP -> keep maturation promoting factor (MPF) inactive = meiotic arrest
    -H2O2/NO/ calcium
    -other cells/ ovarian environment and integrity
48
Q

What causes resumption of meotic arrest?

A

LH surge - within 3-12 hours of LH surge:
-detachment of COC from surrounding mural GC, cumulus cell expansion and formation of unique extracellular matrix between cumulus cells
-decreases cGMP production and closure of gap junctions
- actiavtion of PDE3A -> decreased cAMP - activation of maturation promoting factors and pathways leading to breakdown of nuclear membrane in primary oocyte aka germinal vesicle breakdown (GVBD)
- resumption of meiosis in oocyte -> completion of meiosis and release of first polar body
-arrest again at metaphase II at this stage egg is ovulated in this arrested state.

49
Q

what factors are involved in the breaking of follicle wall to release COC for ovulation?

A
  • LH surge = LH stimualtes secretion of plasminogen activator which converts plasminogen to plasmin which activates prostaglandins and proteolytic enzymes, eg: collagenase and plasmin are increased in response to LH and progesterone and they digest collagen in follicle wall
  • all the different layers from OSE , basement menbrane, theca externa and interna need to be broken.
50
Q

What is the stigma or Apex on ovary wall?

A

point of the dominant follicle closest to the ovarian surface where digestion occurs.

51
Q

How does the process of ovulation actually happen?

A
  • secondary oocyte (arrested at metaphase II) with cumulus cells is extruded from ovary
  • follicular fluid may pour into pouch of Douglas
  • egg ‘collected’ by fimbria of uterine tube
    -egg progresses down tube by peristalsis and action of cilia
  • ciliated cells are controlled by hormone
  • residual part of follicle collapses into space left by fluid - a clot forms and whole structure become corpus luteum.
52
Q

what indicates ovulation

A

inflammation
but too much is detrimental , ie FF is an inflammatory marker associated with decreased pregnancy

53
Q

How does ovulatory wound heal?

A

follicle rupture after each ovulation causes damage but wound scars are quickly healed
recently discovered stem cell populations may contribute to maintenance of OSE

54
Q

What are some signs of ovulation?

A
  • slight rise in basal body temp
  • tender breasts
  • abdominal bloating
  • light spotting
    -changes in cervical mucus
  • slight pain or ache on one side of the abdomen
55
Q

What are changes in cervical mucus that are signs of ovulation?

A
  • cervical mucus changes throughout MC
  • late follicular phase: increased oestrogen levels: clear, copious and elastic mucus
  • after ovulation : increased progesterone levels : thick, viscous and opaque and less produced.
56
Q

How can you track MC?

A

apps: Flo

57
Q

How did covid affect MC?

A

cycle length decreased but menses length stayed the same

58
Q

How do ovulation prediction kits (pregnancy tests) work?

A

measure E3G in urine, a metabolite of oestridiol (oestrogen breaks down to produce E3G)
high levels of E3G can help women identify when they are most fertile as it correlates, 6 days before ovulation.
hCG produced in the blastocysts is detected.

59
Q

What factors determine fertile period?

A

-life span of egg : upto 24hours of ovulation
-life span of sperm : can survive upto 5 days dependent on type and quantity of mucus within cervix

60
Q

What happens after ovulation (luteal phase)?

A
  • adter ovulation, remaining granulosa enlarge and accumulate yellow pigment called lutein
  • luitinised granulosa cells combine with newly formed theca lutein cells to become cirpus luteum (CL)
    -CL produces progesterone hence why the luteal phase is driven by this hormone (also produces inhibin A, androgens and oestrogen)
61
Q

What determines life span of corpus luteum?

A

depends on continued LH support or hCG from pregnancy (luetotrophic support)
CL undergoes luteolysis if no pregnancy and forms scar tissue called corpus albicans
removal of CL essential to initiate new cycle

62
Q

Menstruation

A

death of CL causes progesterone withdrawl which results in increased coiling and constriction of spiral arterioles
endometrium releases prostaglandins that cause contractions od uterine smooth muscle and sloughing off of degraded endometrial tissue(menses)
lasts 4-6 days and average of 30ml blood lost

63
Q

How can amount of bleeding be reduced?

A

using prostaglandin synthase inhibitors

64
Q

What are some ovarian causes of anovulation?

A
  • Luteinised unruptured follicle syndrome (LUF)
  • effect of non - steroidial anti inflammatory drugs (NSAIDs)
    -PCOS
65
Q

What are some non-ovarian causes of anovulation?

A

obesity
thyroid disorders

66
Q

LUF and anovulation

A
  • normal follicle growth in follicular phase and normal hormonal profile but absence of follicle rupture and no release of oocyte
  • form a CL with trapped oocyte and luteal phase length is normal
    -diagnose using repeated transvaginal ultrasound
67
Q

How is LUF linked to dysregulation of ovulation and associated inflammatory changes?

A
  • prostaglandin is an inflammatory factor , ovulation is associated with inflammatory factors because when coc ruptures ( LH surge activates plasminogen activators - plasmin - activates prostaglandins and other proteolytic enzymes causes lutienised follicle rupture) so this suggest when there is a failure to rupture (LUF) may be linked to low inflammatory factors such as prostaglandins / reduction in prostaglandin synthesis/acton

Evidence: patients treated with high dose prostaglandin synthetase inhibitors (eg. indomethacin) -> blocks prostaglandin production and follicular rupture
- lack of cytokine- granulocyte colony - stimulating factor 3 (CSF3) has been linked to LUF formation in infertile women
Evidence: a single injection of CSF3 during late follicular phase resulted in ovulation in most of the women

68
Q

NSAIDs and LUF

A

-NSAIDs are pain relieving , and reduce inflammation by suppressing prostaglandins, the main stimulators of inflammation such as prostaglandins so may be linked to LUF
- ovulation is “inflammatory response”

69
Q

What are 2 types of prostaglandin synthase expressed by ovarian follicle?

A
  1. PTGS1 (constitutive)
  2. PTGS2 (inducible)
    -> administration of NSAID that specifically inhibit PTGS2 -> delayed follicle rupture and oocyte release
70
Q

ovulation and ovarian cancer

A
  • epithelial ovarian cancer (EOC) comprises heterogenous group, most lethal form is high grade serous cancer (HGSC)
  • Incessant ovulation theory : ovulation traumatises the OSE hence error during cell replication so higher the number of ovulations higher the EOC risk.
    -long term use of oral contraception reduces OvCa risk.

Basically ovulation scars the ovarian epithelium which induces more errors during cell cycle and replication causing higher risk of epithelium ovarian cancer (EOC) risk

71
Q

What is the role of LH?

A

Completion of meiosis I in oocyte and start of meiosis II
Ovulation
Corpus luteum formation with accompanying progesterone production

72
Q

What is the role of FSH?

A

Cyclical recruitment of FSH
Granulosa cell multiplication
Stimulation of E2 leading to proliferation of endometrium
Dominant follicle selection
Induction of LH receptors