Menstrual Cycle II Flashcards

1
Q

There is selection and exponential growth of the dominant follicle. How does the switch to positive feedback occur?

A

LH surge lasts for 36-48 hours & triggers ovulation (timing varies from species-species)
» LH surge relatively precise
predictor of timing of
ovulation

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2
Q

LH is rapidly cleared from serum in contrast to..

A

CG which is cleared
slowly & binds with great affinity to LHCGR

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3
Q

What causes a surge in LH?

A

Oestradiol release…?

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4
Q

Where are LHr found on the follicle at this stage?

A

Theca and Granulosa.

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5
Q

What makes the hCG?

A

Blastocysts

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6
Q

What happens in order for ovulation to take place?

A

( a) Preovulatory follicle prior to the LH surge

b) Preovulatory follicle following LH stimulation immediately prior to ovulation. )
Loss of OSE & breakdown of underlying basal lamina and GC & TC at apex to allow for rupture.
GC basal lamina is disrupted allowing extension of
blood vessels into GC layer and for infiltration of
theca cells & leukocytes into GC compartment. COC
detaches from surrounding GC to expand.

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7
Q

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

A
  • High cAMP → keep maturation promoting factor (MPF) inactive
    ‒ cGMP enters oocytes from cumulus cells via gap junctions to inhibit oocyte cAMP phosphodiesterase PDE3A activity (PDE3A normally degrades cAMP)
    ‒ H2O2/NO/calcium
    ‒ other cells/ ovarian environment & integrity of the follicle?
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8
Q

Within 3-12hr of LH surge, we see:

A
  1. Detachment of COC from surrounding
    mural GC, followed by cumulus cell
    expansion – formation of unique
    extracellular matrix between cumulus
    cells (aka “mucification”)
    – Comprised of long chains of hyaluronan
    – Visco-elastic properties of CC matrix important for successful ovulation, ovum pick
    up by oviducts and penetration of sperm
  2. cGMP production and closure of gap junctions
  3. Activation of PDE3A → ↓cAMP → activation of
    pathways leading to breakdown of nuclear
    membrane in primary oocyte aka germinal vesicle
    breakdown (GVBD)
  4. Resumption of meiosis in oocyte → completion of
    Meiosis I & release of 1st polar body
  5. Arrests again in Metaphase II Cell (2006), Volume 126, Issue 1
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9
Q

What happens during meiosis in the oocyte?

A

Early oocytes classified as immature i.e. at
germinal vesicle (GV) or metaphase 1
stage
- Meiosis I is completed with half
chromosomes but nearly all cytoplasm
remaining in the secondary oocyte
- Remaining chromosomes move with small
bag of cytoplasm to form discarded polar
body (PB)

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10
Q

Why is there unequal division of the cytoplasm?

A

All the organelles/mitochondria (maternal mitochondria) come from the the mature secondary oocyte.
Need to conserve for the oocyte all the relevant material

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11
Q

LH/hCG surge leads to

A

Activation of PDE3A which dcereases cAMP production–>

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12
Q

Chromosomes of secondary oocyte immediately enter 2nd meiotic division, form the 2nd metaphase spindle and arrest. This arrest is maintained by

A

Cytostatic factor (protein
complex). Egg is ovulated in this arrested
state

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13
Q

When is meiosis 2 completed?

A

When the egg is fertilised

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14
Q

What does LH surge induce?

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)

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15
Q

As there is an LH surge, what happens to E2 and Progesterone?

A

E2 production falls and P is stimulated (P & 17α-OHP)

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16
Q

What happens to blood flow when there is an LH surge?

A

Blood flow to the follicle increases & new vessels appear in
avascular GC

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17
Q

What happens to prostaglandins and proteolytic enzymes when there is an LH surge?

A

Prostaglandins and proteolytic enzymes eg collagenase and
plasmin, are increased in response to LH and progesterone.

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18
Q

What do proteolytic enzymes do?

A

Digest collagen in follicle wall

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19
Q

what is the stigma?

A

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

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20
Q
A

Cascade of events → release of COC → Ovulation

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21
Q

Increased secretion of chemokine/cytokines from GC & TC
triggers massive infiltration of leukocytes from circulation →

A

acute inflammatory response

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22
Q

Ovulation occurs in which ovary?

A

In humans – ovulation occurs randomly from either ovary during
a given cycles, some indication more common from right ovary

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23
Q

Which hormone is essential for ovulation?

A

Progesterone essential for ovulation
» Progesterone inhibitor (RU486) suppress ovulation

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24
Q
A

Prostaglandins-E and -F and hydroxyeicosatetraenoic acid (HETE metabolite of arachidonic acid) reach a peak level in follicular fluid just prior to ovulation

25
Q

Prostaglandins stimulate..

A

proteolytic enzymes (proteases)

26
Q

HETEs may stimulate

A

angiogenesis and hyperemia (↑blood flow)

27
Q

Follicle Rupture/Ovulation

A

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

28
Q

What is involved in rupture of the ovarian wall?

A

LH surge, LH binds to receptor, activates PA (plasminogen activator)
PA converted to plasmin
Plasmin activates collagenase via MMP-1,2
Collagenase disrupts fibril network of theca &
tunica albuginea & promotes digestion of
basement membrane of follicle and OSE
TNF induces cell death, proteolysis, stigma
formation and eventual follicular rupture

29
Q

ovulation

A

econdary 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
 Ciliated cells are controlled by which hormones?***
 Residual part of follicle collapses into space left by
fluid – a clot forms and whole structure become
corpus luteum

30
Q
A

The follicular fluid is
“inflammatory”

31
Q

Complications of inflammatory follicular fluid

A

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!

32
Q

How does the ovulatory wound heal?

A

Ovary faces monumental task of repairing damage caused by
follicle rupture after each ovulation. the ovulation wounds scar, but not for long – quick
resolution.

Maybe steroidogenic environment helps – mitogenic
(oestrogen). Recently identified stem
cell/progenitor population that may
contribute to maintenance of OSE (Ng et al (2014) Nature Cell Biology 16:745-757)

33
Q

Signs of ovulation include:

A
  • 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 LMP- to see normal temperature)
  • Tender breasts
  • Abdominal bloating
  • Light spotting
  • Changes in cervical mucus
  • Slight pain or ache on one side of the abdomen
34
Q

Cervical Mucus Ovulation Sign

A

Immediately after menstruation, the cervical mucous is scant and viscous.
- In late follicular phase, ↑ E2 levels, the cervical
mucous becomes clear, copious and elastic
- Quantity ↑ 30 fold compared to EFP
- The stretchability/elasticity of cervical mucous
evaluated between two glass slides and
recorded as the spinnbarkeit
- After ovulation, ↑progesterone levels, the cervical mucous
again becomes thick, viscous and opaque and ↓ quantity
produced

35
Q

Menstrual Cycle Apps & Ovulation Prediction

A

The mean follicular phase length was 16.9 days (95% CI: 10-30) and mean luteal phase length was 12.4 days (95% CI: 7-17)
Mean cycle length was 28 days (range: 23–35); 34% of women believed they had a 28-day cycle, but only 15% did.

36
Q

Why shouldn’t we only rely on Apps to track ovulation?

A

Ovulation day varies considerably for any given menstrual cycle length. In order to identify the fertile period it is important to track physiological parameters such as basal body temperature and not just cycle length.

37
Q

What is measured in ovulation prediction kits?

A

LH levels (some use E3G). E3G is urinary metabolite of
oestradiol, allowing women to identify days of high fertility
leading up to ovulation

38
Q

Fertile period spans….. and is affected by….

A

6 days

  1. Lifespan of the egg → up to 24h after ovulation
  2. 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
39
Q

After ovulation, remaining granulosa enlarge, become
vacuolated in appearance, and accumulate a yellow pigment
called

A

Lutein

40
Q

What hormones are produced by CL?

A

progesterone
inhibin a
androgens
oestrogens

41
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)

42
Q

CL demise..

A

In humans and higher primates NOT due to luteolytic agents
but loss of luteotrophic support (i.e. below threshold levels
of LH enough for maintenance for a whilst)

43
Q

When does CL degrade?

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 is essential to initiate a new cycle

44
Q

Summarise 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

45
Q

How is effect of prostaglandins proved?

A

Use of prostaglandin synthetase inhibitors decreases
amount of menstrual bleeding
» Average duration of menstrual flow
is 4-6 days (range 2-8 days)
» Average amount of menstrual blood
loss is 30ml with >80ml abnormal

46
Q

What is anovulation?

A

common cause of infertility in women- affecting up to 40% of infertile women

47
Q

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

48
Q

Luteinized unruptured follicle syndrome (LUF)

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
» Diagnose using repeated transvaginal ultrasound
» LUF occurs in women with normal menstrual cycle at rate of 5% but in
infertile women at rate of >25% (reviewed Duffy et al, 2019, Endocrine Reviews,
40:369-416)
» Linked to dysregulation of ovulation associated inflammatory changes
– e.g. reduction in prostaglandin synthesis/action. EVIDENCE: Patients treated with
high dose prostaglandin synthetase inhibitors (eg Indomethacin) → block in
prostaglandin production and follicular rupture
– 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

49
Q

What are NSAIDs normally used for?

A

NSAIDs commonly used for relieving pain, lowering fever and
reducing swelling

50
Q

How do NSAIDs work?

A

by suppressing prostaglandins, the essential
stimulators of inflammation

51
Q
A

Concept of ovulation as an “inflammatory response” → concern
regarding effects of NSAIDs and ovulation

52
Q

Ovarian follicle expresses 2 types of prostaglandin synthase –

A

PTGS1 (constitutive) and PTGS2 (inducible)

53
Q

When is PTSG2 expression increased? What is the effect of NSAID on this?

A

↑PTSG2 expression just before ovulation. Administration of NSAID that specifically inhibit PTGS2 → delayed follicle
rupture & oocyte release

54
Q
A

Most studies of NSAID inhibition of ovulation use doses that are
at or above the maximum dose prescribed

55
Q

Ovulation and Ovarian Cancer

A

Epithelial ovarian cancer (EOCs) most common cause of death from gynaecological
malignancy in developed world

56
Q

What do EOCs comprise of?

A

EOCs comprise heterogenous group, most lethal form is high-grade serous cancer
(HSGC)

57
Q

10-25% of OvCa is associated with hereditray genetic mutations e.g.

A

BRCA1 or BRCA2
mutations

58
Q

For many years most accepted hypothesis of EOC carcinogenesis was the
“incessant ovulation” theory

A

Ovulation traumatises the OSE, hence increasing error during cell replication
» Epidemiological evidence that women with high number of life-time ovulations
at increased risk of EOC eg. nulliparous women, those with early menarche and
late menopause
» Long-term use of oral contraception reduces OvCa risk