The Menstrual Cycle II Flashcards
(28 cards)
How does the switch to positive feedback occur?
At the end of the follicular phase, E2 feedback becomes positive & persistent (300pM, 48 hours) causing an exponential rise in LH that has to exceed a threshold. This is the LH surge.
The LH surge lasts for 36-48 hours and triggers ovulation.
How quickly is LH cleared from serum?
rapidly.
This contrasts with HCG which is cleared slowly & binds with great affinity to LH receptors.
Where are LHr found on the dominant follicle at the end of the follicular phase?
Both theca and granulosa cells of the dominant follicle
Describe the preovulatory follicle prior to the LH surge
The outer cortex of the ovary consists of many primordial follicles. As follicles activate and grow, they move towards the medulla of the ovary where there is rich blood supply.
When the dominant follicle grows, it moves back towards the surface of the ovary, ready for ovulation. This is when it is known as the preovulatory follicle.
The preovulatory follicle bulges underneath the ovarian surface epithelium and comprises of the theca interna, theca externa, and mural granulosa cells, which is resting beneath the basement membrane.
The egg is surrounded by cumulus granulosa cells
Briefly describe the preovulatory follicle following LH stimulation immediately prior to ovulation
The LH surge induces significant changes in the preovulatory follicle, allowing it to prepare for ovulation.
When the LH surge happens, there is a breakdown of the ovarian surface epithelium, the basement membrane and digestion of theca and granulosa cells at the apex of the ovary. This allows the surface to rupture, and the egg to be released.
In addition to this, towards the inner part of the ovulatory follicle, you have the breakdown of the basement membrane, which has kept the mural granulosa cells intact. This allows the invasion of blood vessels into the follicle and brings inflammatory cytokines and leukocytes which will continue the process of ovulation.
The cumulus-oocyte complex will detach from the mural granulosa cells and undergo certain changes.
What factors are responsible for holding the oocyte in meiotic arrest?
cGMP from cumulous cells enter oocytes, via gap junctions, to inhibit oocyte cAMP phosphodiesterase PDE3A activity. This is because PDE3A normally degrades cAMP. Therefore, the inhibition helps cAMP levels high.
High cAMP within the cumulus-oocyte complex keeps the maturation promoting factor (MPF) inactive.
Other factors involved are hydrogen peroxide, nitric oxide, and calcium.
What happens within 3-12 hours of the LH surge?
1) Detachment of COC from surrounding mural GC, followed by cumulus cell expansion, and the formation of a unique extracellular matrix between cumulus cells comprised of long chains of hyaluronan. This process is known as mucification.
The visco-elastic properties of the cumulus cells matrix are important for successful ovulation as it allows the egg to be picked up successfully and travel through the oviduct. It also allows penetration of sperm.
2) Resumption of meiosis I
LH decreases cGMP production and closes the gap junctions between cumulus cells. This allows the activation of PDE3A, which degrades and decreases the levels of cAMP, and activates the maturation promoting factor (MPF).
This activates pathways leading to the breakdown of the nuclear membrane of the primary oocyte, which is known as germinal vesicle breakdown (GVBD), and subsequently causes the resumption and completion of meiosis I and the release of the 1st polar body.
Chromosomes of secondary oocyte immediately enter 2nd meiotic division, form the 2nd metaphase spindle, and arrest again.
What happens when Meiosis I is completed?
Meiosis I is completed with half chromosomes but nearly all the cytoplasm remains in the secondary oocyte.
The remaining chromosomes move with a small amount of cytoplasm to form the discarded polar body (PB)
Chromosomes of secondary oocyte immediately enter 2nd meiotic division, form the 2nd metaphase spindle, and arrest again.
The arrest is maintained by cytostatic factor.
Meiosis II is only completed upon fertilisation.
Why is there an unequal division of cytoplasm in Meiosis?
There is a need to conserve all the material synthesised for the oocyte as it is used to take the zygote through growth and fertilisation.
What occurs at around 12-18 hours after the peak of LH surge?
Ovulation.
The LH surge induces the expression of progesterone receptors in the granulosa cells and results in the luteinisation of DF cells (both GC and TC become granulosa luteal cells and theca luteal cells respectively).
As E2 production falls, P is stimulated.
Blood flow to the follicle increases and new vessels appear in avascular GC.
Prostaglandin and Proteolytic enzymes (collagenase and plasmin) increase in response to LH and progesterone. Their function is to digest the collagen in the follicle wall to allow it all to be ruptured so the egg can be released and picked up by the oviduct.
Prostaglandins-E and -F and HETE reach a peak level in follicular fluid.
Prostaglandin stimulates proteolytic enzymes which digest the follicle and ovary wall, allowing the release of the egg.
HETE stimulates angiogenesis (growth of new blood vessels) and hyperemia (increases blood flow)
Whilst the follicle wall is being digested, an appearance of apex or stigma on the ovary wall can be observed. This is the point of the dominant follicle closest to the ovarian surface where digestion occurs.
An acute inflammatory response also occurs as GC and TC increase their secretion of chemokines and cytokines, triggering massive infiltration of leucocytes from circulation.
This causes the progressive weakening of the stigma region and OSE overlying the follicle.
There is no increase intra-follicular pressure.
Is progesterone essential for ovulation?
Yes, progesterone inhibitor suppresses ovulation.
Explain what occurs to cause the rupture of the ovarian wall?
LH would bind to receptors on the ovarian surface epithelium.
This would stimulate the secretion of Plasminogen Activator (PA)
PA converts plasminogen –> plasmin
Plasmin activates collagenase via MMP-1,2
Collagenase disrupts the fibril network of theca & the tunica albuginea and promotes the digestion of the basement membrane of the follicle and ovarian surface epithelium.
This is reinforced by the release of TNF-alpha which induces cell death, proteolysis, stigma formation and eventual follicular rupture.
What happens at ovulation?
The secondary oocyte (arrested at metaphase II) with cumulus cells is extruded from the ovary.
Follicular fluid may pour into the Pouch of Douglas
The egg is collected by fimbria of the uterine tube.
The egg progresses down the tube by peristalsis and the action of cilia, which is controlled by progesterone.
The residual part of the follicle collapses into the space left by fluid. A clot forms and the whole structure becomes the corpus luteum.
The corpus luteum contains luteinising granulosa and theca cells.
What is inflammation associated with ovulation?
The follicular fluid is inflammatory.
The presence of macrophages indicates a functional role in ovulation and repair.
Inflammation is present, but too much is detrimental.
Higher inflammation markers in FF are associated with decreased pregnancy.
Gingivitis (inflammation of gums) is associated with poorer IVF outcomes.
Does the ovulatory wound heal?
Ovary repairs damage caused by follicle rupture after each ovulation.
The basic steps are known, but the underlying mechanisms are still unknown.
The ovulation wounds scar but not for long as it is a quick resolution.
A steroidogenic environment may help repair. Oestrogen promotes cell growth.
The stem cell/progenitor population may also contribute to the maintenance of the OSE.
Signs of Ovulation
slight rise in basal body temperature (0.5-1 degree) - you need to keep a chart of basal body temp from day 1 of last menstrual period to observe a rise - as day to day life, basal body temp fluctuates.
tender breasts abdominal bloating light spotting changes in cervical mucus slight pain/ache on one side of the abdomen
Describe the cervical mucus in the menstrual cycle
The cervical mucus changes throughout MC
• 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 in LFP compared to EFP
• After ovulation, ↑progesterone levels, the cervical mucous again becomes thick, viscous and opaque and ↓ quantity produced (egg white)
Use of Menstrual Cycle Apps
- The use of apps that record detailed menstrual cycle data presents a new opportunity to study the menstrual cycle
- The mean follicular phase length was 16.9 days and mean luteal phase length was 12.4 days
- Ovulation day varies considerably for any given menstrual cycle length, thus it is not possible for calendar/app methods that use cycle-length information alone to accurately predict the day of ovulation.
- To identify the fertile period, it is important to track physiological parameters such as basal body temperature and not just cycle length.
Describe Ovulation Prediction Kits
Measures predominantly LH, some measure metabolites of oestradiol (oestradiol triggers LH surge).
This allows women to identify days of high fertility leading up to ovulation.
The fertile period spans 6 days and is affected by
o Lifespan of the egg → up to 24h after ovulation
o Lifespan of sperm → median = 1.5days but sperm can survive up to 5 days in the sperm-supportive mucus of fertile days of the cycle
sperm survival is dependent on the type & quantity of mucus within cervix AND the quality of the sperm
What happens after ovulation?
After ovulation, the remaining granulosa cells enlarge, become vacuolated in appearance, and accumulate a yellow pigment called lutein.
Angiogenesis occurs to form new capillaries.
The luteinised GC combined with the newly formed theca lutein cells and surrounding stroma in the ovary to become the corpus luteum (CL)
What hormones are produced by the corpus luteum?
progesterone
inhibin A
androgens
oestrogens
What is the job of the corpus luteum
To support and implant the embryo until the placenta is established
What determines the life-span of the corpus luteum?
It depends on the continued LH support or hCG from pregnancy (luteotrophic support)
The process is not well understood.
In humans and higher primates, the demise of the CL is not due to luteolytic agents but the loss of luteotrophic support.
If there is no pregnancy, CL undergoes luteolysis and forms a scar tissue called the corpus albicans.
Cell death occurs, vasculature breaks down, CL shrinks.
The removal of Cl is essential to initiate a new cycle.
How does menstruation occur?
• Progesterone withdrawal results in increased coiling and constriction of spiral arterioles in the endometrium (womb lining)
• Endometrium releases prostaglandins that cause contractions of uterine smooth muscle and sloughing of degraded endometrial tissue
o Use of prostaglandin synthetase inhibitors decreases the amount of menstrual bleeding
o Average duration of menstrual flow is 4-6 days (range 2-8 days)
o Average amount of menstrual blood loss is 30ml
o >80ml = abnormal
