Menstrual Cycle II Flashcards

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1
Q

What do high sustained levels of oestrogen do?

A

Switch feedback from negative to positive

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2
Q

How long does the LH surge last?

A

36-48 hours

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3
Q

What does the LH surge do?

A

Triggers ovulation - the surge must exceed a threshold for ovulation

leads to breakdown of surface epithelium of the basement membrane and digestion of theca and granulosa cells - allows invasion of blood vessels into the follicle because granulosa cells don’t have any vasculature.

LH surge allows the follicle to rupture and release the egg

LH surge induces expression of progesterone receptor (PR) in GC in all species and results in luteinisation of DF cells (both granulosa and theca) – they become luteal cells

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4
Q

How is LH cleared from the serum?

A

Rapidly compared to hCG which is cleared slowly because it has a greater affinity to LHr

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5
Q

What can the LH surge be used for?

A

To predict ovulation

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6
Q

Where are the primordial follicles usually found?

A

In the outer cortex

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7
Q

What happens as the primordial follicles grow?

A

They will move into the ovary - near the rich blood supply

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8
Q

Where does the DF follicle move?

A

It will move back up to the surface of the ovary for ovulation

DF is under the ovarian surface epithelium, resting on the basement membrane

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9
Q

What factors are responsible for holding the oocyte in meiotic arrest?

A

o High cAMP within follicle → keeps maturation promoting factor (MPF) inactive

o cGMP enters oocytes from cumulus cells via gap junctions to inhibit oocyte cAMP phosphodiesterase PDE3A activity (PDE3A normally degrades cAMP) – keeps cAMP high

o H2O2/NO/calcium

o other cells/ ovarian environment & integrity of the follicle?

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10
Q

What are the effects of LH within the 3-12 hours of the LH surge?

A
  • Detachment of COC (cumulus oocytes complex) from surrounding mural GC, followed by cumulus cell expansion – formation of unique extracellular matrix between cumulus cells (aka “mucification”)
  • ↓cGMP production and closure of gap junctions – LH binds to its receptors and triggers a pathway that degrades cGMP/not favour cGMP production
  • Activation of PDE3A → ↓cAMP → activation of pathways leading to breakdown of nuclear membrane in primary oocyte aka germinal vesicle breakdown (GVBD)
  • Resumption of meiosis in oocyte → completion of Meiosis I & release of 1st polar body
  • Arrests again in Metaphase II
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11
Q

What is produced at the end of meiosis I?

A
  • Both oocytes will have half the chromosomes but one oocyte will have almost all of the cytoplasm - there’s unequal division
  • The oocyte will no cytoplasm is called a polar body
  • one oocyte has all the cytoplasm because it has double the organelles because the sperm only brings chromosomes
  • Chromosomes of secondary oocyte immediately enter 2nd meiotic division, form the 2nd metaphase spindle and arrest
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12
Q

What maintains the secondary oocyte arrest?

A

cytostatic factor (protein complex)

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13
Q

What happens right before ovulation?

A
  • LH surge induces expression of progesterone receptor (PR) in GC in all species and results in luteinisation of DF cells (both granulosa and theca) – they become luteal cells
  • E2 production falls and progesterone is stimulated (both P & 17α-OHP)
  • Blood flow to the follicle increases & new vessels appear in avascular GC
  • Prostaglandins and proteolytic enzymes eg collagenase and plasmin, are increased in response to LH and progesterone - Digest collagen in follicle wall
  • appearance of apex or stigma on ovary wall
    o Stigma= point of the dominant follicle closest to the ovarian surface where digestion occurs
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14
Q

When does ovulation occur?

A

12-18 hours after the peak of LH surge

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15
Q

How does the follicle rupture/ovulation occur?

A

• No increase in intra-follicular pressure. Progressive weakening of stigma region and OSE overlying follicle prior to rupture – fundamental aspect

  • LH stimulates secretion of Plasminogen Activator (PA) by binding to its receptors
  • PA converts plasminogen into plasmin – plasmin activates collagenase
  • Collagenase disrupts fibril network of theca & tunica albuginea & promotes digestion of basement membrane of follicle and OSE
  • TNFa induces cell death, proteolysis, stigma formation and eventual follicular rupture – reinforces this pathway
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16
Q

What is the structure of the ovarian wall where the DF rests?

A

OSE=simple layer of epithelial cells, which is supported by a basement membrane that lies over the TA (held together by desmosomes and gap/tight junctions). Preferential growth of the DF brings it in close apposition with the OSE.

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17
Q

What happens during ovulation?

A
  • Secondary oocyte (arrested in metaphase II) with cumulus cells is extruded from the 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
  • Residual part of follicle collapses into space left by fluid – a clot forms and whole structure become corpus luteum (CL has luteinised granulosa and theca cells)
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18
Q

What is associated with ovulation?

A

Inflammation:
• The follicular fluid is “inflammatory”
• Inflammation definitely present, but too much is detrimental
• Higher “inflammation markers” in FF associated with decreased pregnancy rate (specifically C Reactive Protein, CRP)
• Gingivitis associated with poorer IVF outcomes (study found out)

19
Q

How does the ovulatory wound heal?

A
  • Ovary faces monumental task of repairing damage caused by follicle rupture after each ovulation
  • Basic steps are known but the underlying mechanisms are still unknown
  • Interestingly the ovulation wounds scar, but not for long – quick resolution
  • Maybe steroidogenic environment helps – oestrogen is a mitogen
  • Recently identified stem cell/progenitor population that may contribute to maintenance of OSE
20
Q

What are the signs of ovulation?

A
  • A slight rise in basal body temperature, typically 0.5 to 1 degree, measured by a thermometer
  • Tender breasts
  • Abdominal bloating
  • Light spotting
  • Changes in cervical mucus
  • Slight pain or ache on one side of the abdomen
21
Q

Why does the cervical mucus change throughout the MC?

A

it responds to oestrogen and progesterone

22
Q

What is the cervical mucus like after menstruation?

A

scant and viscous

23
Q

What is the cervical mucus like during the late follicular phase?

A
  • because of high estradiol (E2) levels, the cervical mucous becomes clear, copious and elastic.
  • Quantity increases 30 fold compared to early follicular phase
24
Q

What is the cervical mucus like after ovulation?

A

because of ↑progesterone levels from the CL, the cervical mucous again becomes thick, viscous and opaque and ↓ quantity produced

25
Q

What do ovulation prediction kits measure?

A

Urine is used to measure LH and oestradiol (by measuring E3G) – oestradiol triggers LH surge and the surge is right before ovulation

26
Q

What is the lifespan of the egg and sperm?

A
  • egg: up to 24h after ovulation
  • 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
27
Q

How is the corpus luteum form after ovulation?

A
  • After ovulation, remaining granulosa enlarge, become vacuolated in appearance, and accumulate a yellow pigment called lutein.
  • Massive angiogenesis to form new capillaries
  • The luteinized granulosa cells combine with newly formed theca-lutein cells and surrounding stroma in the ovary to become the corpus luteum (CL).
28
Q

What hormones are produced by CL?

A
  • Progesterone
  • Inhibin A
  • Androgens
  • Oestrogens
29
Q

What determines the life-span of the CL?

A

Life span of CL depends on continued LH support or hCG from pregnancy (luteotrophic support)

30
Q

Why does the CL undergo luteolysis and what happens during it?

A
  • CL undergoes luteolysis if no pregnancy and forms a scar tissue called the corpus albicans.
  • Cell death occurs, vasculature breakdown, CL shrinks
  • removal of CL essential to initiate new cycle
31
Q

What happens during menstruation?

A

Progesterone withdrawal results in increased coiling and constriction of spiral arterioles

Endometrium releases prostaglandins that cause contractions of uterine smooth muscle and sloughing of degraded endometrial tissue
• Use of prostaglandin synthetase inhibitors decreases amount of menstrual bleeding

32
Q

What is the average duration of the menstrual cycle and the blood lost from it?

A
  • Average duration of menstrual flow is 4-6 days (range 2-8 days)
  • Average amount of menstrual blood loss is 30ml with >80ml abnormal
33
Q

What can be the causes for anovulation?

A

Can be due to non-ovarian causes eg obesity, thyroid disorders

Ovarian causes can be - primary ovarian insufficiency (POI) aka premature ovarian failure due to loss of follicles OR due to disorders that prevent ovulation:

o Luteinized unruptured follicle syndrome (LUF)
o Effect of non-steroidal anti-inflammatory drugs (NSAIDs)
o Polycystic Ovary Syndrome (PCOS)

34
Q

What is Luteinized unruptured follicle syndrome?

A
  • Normal follicle growth in follicular phase and normal hormonal profile but absence of follicle rupture and no release of oocytes
  • Form a CL with trapped oocyte and luteal phase length is normal
35
Q

How is LUF diagnosed?

A

using repeated transvaginal ultrasound

36
Q

What is LUF linked to?

A

to dysregulation of ovulation associated inflammatory changes

o e.g. reduction in prostaglandin synthesis/action. EVIDENCE: Patients treated with high dose prostaglandin synthetase inhibitors → block in prostaglandin production and follicular rupture
o The lack of cytokine - Granulocyte colony-stimulating factor 3 (CSF3) - has been linked to LUF formation in infertile women. In anovulatory women, a single injection of CSF3 during late follicular phase resulted in ovulation in most of the women

37
Q

What are NSAIDs used for?

A

for relieving pain, lowering fever and reducing swelling.

38
Q

How do NSAIDs work?

A

by suppressing prostaglandins, the essential stimulators of inflammation

39
Q

How many types of prostaglandin synthase does the ovarian follicle express?

A

2 types of prostaglandin synthase – PTGS1 (constitutive) and PTGS2 (inducible)

40
Q

Which prostaglandin synthase increases right before ovulation?

A

↑PTSG2 expression just before ovulation

41
Q

How do NSAIDs act on PTSG2?

A
  • Administration of NSAID that specifically inhibit PTGS2 → delayed follicle rupture & oocyte release
  • PTGS2 inhibitor prevents follicle rupture in women
42
Q

What are the types of ovarian cancers?

A
  • epithelial ovarian cancers
  • germ cell cancers
  • stromal cell cancers
43
Q

Which ovarian cancer has the highest death rates?

A
  • Epithelial ovarian cancers (EOCs) most common cause of death from gynaecological malignancy in developed world
  • EOCs comprise heterogenous group, most lethal form is high-grade serous cancer (HSGC)
44
Q

What is the hypothesis behind how EOCs cause harm?

A

• “incessant ovulation” theory:
o Ovulation traumatises the OSE, hence increasing error during cell replication
o Epidemiological evidence that women with high number of life-time ovulations at increased risk of EOC eg. early menarche and late menopause
o Long-term use of oral contraception reduces OvCa risk

• New evidence that HSGC arises from fimbria of fallopian tube rather than the ovaries – women who had breasts removed due to BRCA genes also had ovaries/tubes removed, analysis of tubes showed tumour arising
o However not sure because both tubes and ovaries have the same embryonic origin, maybe the tumour just arises in the tubes