Menstrual Cycle Flashcards
In males, negative feedback of FSH and LH is from what?
what about in females? (caveat?)
Testostorone
Estrogen but it also positive feedback as well.
Puberty in the girls involves:
Thelarche?
Adrenarche?
Menarche?
breast development
increase in adrenal androgen secretion
beginning of menstrual cycles
Gonadotropin levels through the life of the female?
increases in gonadotropin during the 2nd trimester (mostly FSH)
early postnatal time (mostly FSH)
puberty they rise, leading to the reproductive years and monthly surges of LH
Menopause (high of both but more FSH.. low estrogen removes negative feedback so elevated gonadotropin)
What’s to note about the oscillatory patterns of GnRH secretion in puberty for females?
somehow it starts in the REM sleep of females. that’s when we start seeing higher levels and in a pulsatile manner
What does the ovarian cycle consists of?
Endometrial cycle?
Follicular + Luteal
Menstrual phase (Menses), proliferative, secretory
Oocyte –> graafian follicle?
Primary oocyte that has been replicated.. it’s arrested in meiosis 1 prophase 1.
then the follicle grows and a mix of cells that surround the oocyte and form the follicles.
the most undeveloped stage of the follicle is the “primordial follicle”.. it’s surrounded in cells called “pregranulosa cells”
when they differentiate enough to become granulosa cells, we consider that follicle the primary follicle. (UNILAMINAR –> one layer of granulosa)
follicle continues and you get additional layers of granulosa cells and theca cells are going to show up… this is the secondary follicle (MULTILAMINAR PRIMARY FOLLICLE)
then we get a small antrum, which helps distinguish between secondary and early tertiary follicle.. also see a ton of granulosa cells, and closest to the oocyte is called the corona radiata (also have theca interna and externa) (CALLED SECONDARY FOR ANATOMY)
Graafian follicle –> bigger antrum, corona radiata still there, we also have a cumulus oophorus which connects the oocyte to the wall.. theca cells are proliferating and we have the theca interna and theca externes.
granulosa cells are most similar to what in males?
sertoli cells
closely tied to the oocyte providing nutrients.
at the LH surge, what happens to the gamete?
when does this happen?
we pass prophase one and we go through meiosis and it’s arrested one more time in metaphase of meiosis 2.
going from early tertiary follicle (2ndary) to Graafian follicle
When do we go from 2N to N for the gamete?
what else forms during this process?
second meiotic division is completed upon fertilization.
1 egg and 2-3 polar bodies are going to happen when this happens.
What marks the dependency of gonadotropin?
the development of the antrum
what’s happening constantly in the woman?
what is chosen?
what happens to the ones that aren’t chosen?
there are going to be different follicles at different stages.
there are going to be some mix of primary and secondary (antrum or no antrum) and it needs to be ongoing because the development of the follicle doesn’t happen fast, so there should be this constantly going on so selection can happen faster
the ones that are selected are the antrums are bigger.
the rest that doesn’t qualify or meet the quota are lost through atresia.
What’s the difference in antral follicles with their size and dependency on FSH?
early antral follicles are dependent on FSH for normal growth –> secrete very low levels of estrogen which is important to the negative feedback
large antral follicles (the ones we want to select) are HIGHLY dependent on their growth and sustained viability.
What are mural granulosa cells?
what’s to note about androgens and this?
what happens to this and the theca cells after ovulation?
in the growing antral cells, not only do we have theca cells that are going to be androgens to be converted to estrogen, but we also are dependent on the sterotidogenic activity of Mural Granulosa cells
as they grow, that population becomes highly steroidogenic.
this population are going to be remaining after ovulation and differentiate to corpus luteum
Dominant follicle?
as FSH levels drop, the rapidly growing follicles progressively undergo atresia until there is one survivor left.
the largest follicle with the MOST FSH receptors of the recruited crop becomes the dominant follicle!
Periovulatory period?
what happens at the start of the periovulatory period and goes throughout the process of ovulation?
what happens during this?
time from the onset of the LH surge to ovulation –> lasts 32-36 hours
at the same time, we’re going to have that with the LH surge there is luteinization
changing theca and granulosa cells to produce tons of progesterone, along with estrogen, within a few days after ovulation
induces dramatic changes in the dominant follicle that involves its rupture, ovulation of the corona radiate-oocyte complex, and biogenesis of the corpus luteum from what remains.
what happens to the dominant follicle during the periovulatory period?
1) where does the ovum do as it goes closer to the wall?
2) what happens to this structure?
3) what does the antrum become continuous with then?
follicle presses against the wall of ovary and forms bulge called the STIGMA
LH surge induces release of cytokines and hydrolytic enzymes from the theca and granulosa cells –> breaks down follicle wall, tunica albuginea, surface epithelium
antrum cavity becomes continuous with peritoneal cavity
what happens to the basal lamina of the mural granulosa cells during the periovulatory period
what do granulosa cells produce to increase the blood supply to the new corpus luteum
enzymatically degraded and blood vessels and outer lying theca can push into the granulosa cells.
angiogenic factors including Vascular Endothelial Growth Factor, angiopoietin 2, basic fibroblast growth factor
Corpus Luteum life span?
what can save it? how long does it last then?
What is it highly similar to? how so?
life span of 14 days unless rescued by human chorionic gonadotropin (hCG) which originates from the implanting embryo from part of the placenta.
if rescued, corpus luteum will remain viable for as long as the pregnancy.
hCG is highly similar to LH.. it can produce high levels of progesterone
Follicular Atresia, when does this happen?
what’s lost?
What persists?
occurs at any time of the development
losing granulosa cells and oocytes that weren’t selected. (makes sense since they’re providing nutrients for the gametes
Thecae cells persist and repopulate the cellular storm of the ovary
throughout the lifespan, how many dominant follicles are going to be ovulated?
400-500
Summary of folliculogenesis (includes all 3 phases)
follicular phase –> recruitment/growth of atrial follicles –> selection of dominant follicle –> growth of dominant follicle until ovulation
LH surge causes –> ovulation
Luteal phase –> hormonal secretion by the corpus luteum
What causes the LH surge?
estrogen, positive feedback mechanism from estrogen from the dominant follicle
Follicle needs what to complete its development? what happens to these levels as time goes on?
when does the follicle growing technically start and end?
what do granulosa cells increase the production of and what does this do in turn?
FSH.. they decline but it selects for the cells for high sensitivity to find the dominant follicle.
start of menses, end on LH surge (around 14 days)
estradiol –> stimulates endometrium to undergo continuous growth and maturation
rapid rise of estradiol triggers the surge of LH, which causes ovulation
what does the increase of estradiol from the granulosa cells match up with in the endometrial cycle?
proliferative phase
rapid rise of estradiol triggers the surge of LH, which causes ovulation
Luteal phase?
what do luteal cells produce? what does this lead to?
what does it coincide with in the endometrial phase?
follicle transforms into a corpus luteum
luteal cells produce progesterone and estrogen and inhibin, which stimulate further endometrial growth and development
secretory phase
Inhibin in females is going to be coming from what source of cells?
what does it feed too?
What receptors do they have?
granulosa cells.. which are feeding into anterior pituitary to regulate FSH.
granulosa cells have receptors for FSH and LH
Hypothalamic Pituitary Ovarian Axis?
include: CNS, HP, AP, Theca cells, Granulosa cells, Reproductive tract
hypothalamus releases GnRH –> ant pity for FSH and LH
LH stimulates Theca cells –> produce androgens in the follicular phase and a little bit of progesterone
Androgens go to the granulosa cells and are converted to estradiol and to estrogen through aromatase.
granulosa cells make progesterone / estrogen.
Granulosa create inhibins which negatively regulate the anterior pituitary (FSH)
Granulosa also create activins which activate the ant pity to create more FSH
Granulosa cells have receptors for both FSH and LH.
progesterone and estrogen are then going to positively regulate the reproductive tract, but also negatively regulating the ant pity and hypothalamus.
which one affects the CNS? progesterone or estrogen
Estrogen.
Explain the cellular events that result in synthesis and secretion of gonadotropins
which subunits are made
what does estrogen do from the follicular stage on this synthesis?
what about estrogen and progesterone in the luteal phase?
Inhibin?
Activin?
Gq –> PLC –> increasing ca+ and the phosphorylation of PKC through DAG.. PKC modulates transcription for the creation of subunits and secretion of these along with Ca2+
subunits that form FSH and LH.. one alpha subunit, and one B-FSH, one B-LH
follicular stage = increase!.. positive feedback system for LH surge preparation
luteal stage = decrease.. negative feedback.. to go back to normal
inhibin = decrease
activin = increase
GnRH and pulsatile secretion of LH? what about FSH?
high pulsatile frequency of GnRH has a preference for stimulating LH
low pulsatile GnRH have a preference for FSH
during the early follicular phase (lower sensitivity) for LH?
what about during late (higher sensitivity) for LH?
pulses are going to be lower in amplitude
as we move to the late follicular phase (LH surge), then we have an increased sensitivity so you’re releasing more LH
Theca cells have what receptors?
Granulosa?
LH
LH and FSH
Inhibins are produced by granulosa cells of the follicle.. what do they do?
activins?
inhibit FSH production by gonadotrophs in the ant pity
stimulate FSH release from gonadotrophs
Estrogen and feedback at low and high concentrations?
Progesterone low or high?
estrogen negative feedback at both low and high (leads to the LH) surge.. it’s predominated by the high levels of progesterone
progesterone only at high –> luteal phase
Follicular phase, what does estrogen and progesterone do to LH?
what about estrogen and progesterone during the luteal phase?
as gonadotropin levels fall, what happens to the steroid levels?
rapidly increase it
rapidly decrease it to normal levels
drop too.
Where is estrogen coming from?
primarily circulating estrogen in non pregnant women?
ovary, adrenal gland, peripheral conversion in adipose tissue
Estradiol
Estrone to Estradiol is done by what?
17B-hydroxysteroid dehydrogenase
where is estriol made?
from estradiol and estrone to estriol –> weaker form of estrogen made in the liver
What is the goal of the follicular phase?
what cell is closer to blood vessels?
what cell is closer to the oocyte?
what separates both cells?
to produce estrogen
theca cells are closer to the blood vessels, Granulosa cells are closer to the oocyte
separation is the basal lamina.
What is the precursor to estrogen that is created in the theca cells?
how do they go from outer mitochondrial to inner mitochondria and from there how do they go from cholesterol to androstenedione?
Cholesterol.
It’s pulled in through the blood through LDL/HDL receptors or made de novo.
Cholesterol is carried from the outer mitochondrial to the inner mitochondria through the StAR protein and the CYP11A1 (desmolase) –> pregnenolone –> Progesterone –> Androstenedione (through 17a hydroxylase too (CYP17))
Now that we have androstenedione, what can happen to it?
it goes to the granulosa cell which then is changed to testosterone through 17B HSD and then CYP19(aromatase) to convert testosterone to estradiol!
difference between granulosa cells and the Theca cells?
Granulosa does not have 17a-hydroxylase and 17,20 desmolase
but it has aromatase
theca does not have aromatase
What are the relative levels of 17B-HSD in theca cells and granulosa cells?
more in granulosa so tipping the scale for making estradiol in the granulosa
When we have the granulosa cells, what is going to help increase the stimulus to aromatase to make more estradiol?
FSH on the FSH receptor
also LH?
When we have the LH surge, what’s going to happen on the thecal lutein cell and the granulosa lutein cell
Blood vessels are now coming closer to the granulosa cells, so now both the thecal cell and the granulosa cells are close
both cells now can uptake cholesterol
in the thecal cell you’re forming androstenedione which won’t be converted to high levels of estradiol because aromatase is going to be transiently repressed so we’re tipping the system to all the cholesterol in the granulosa cell is going to be making progesterone because of the over expression of 3B-HSD
After the demise of the corpus luteum, what happens?
low levels of progesterone and estrogen
we have the zona compact and the zona spongiosa (both functional layer) which are going to be destroyed in the menstrual phase
the only surviving layer is the zona basalis
Hormonal regulation of basal body temperature (BBT) during menstrual cycle?
Late proliferative phase we have high levels of estrogen… that estrogen is associated with a small decrease in basal body temperature.
when you have an increase in BBT, it’s from the progesterone! so high amounts of progesterone are shown to have thermoregulatory effect to set the setpoint to being higher than normal.
What keeps the corpus luteum alive?
what does this act similar to?
which produces what?
so what are you going to notice on a pregnant female during the first trimester?
hCG.. acting similar to LH.. which produces progesterone
increased basal body temperature
What happens during the proliferative phase?
what is this phase most dependent on???
It’s right after the menstrual phase
the endometrium is restored by the 5th day of the cycle
proliferating basal stromal cells, epithelial cells, more connective tissue from stromal cells..
DEPENDENT ON ESTROGEN secreted by the developing follicles
What is estrogen doing during the proliferative phase?
what does progesterone do to estrogen?
it’s priming the system for progesterone.. it’s important to induce the expression of progesterone receptors that have an effect on the endometrium too
Progesterone INHIBITS estrogen (so seems contradictory) –> it’s important because if you leave it unchecked you have a risk for developing cancer
so progesterone is designed to put a break on the estrogen so no cancer
what happens during the early secretory phase
parallel to the luteal phase
so a lot of the changes are because of progesterone
during the early phase –> providing a hallmark post-ovulatory period which would be the development of the interdigitating tubes within the nucleolus of the endometrial epithelial cells
What happens during the middle to late secretory phase?
Vascularization of the endometrium increases, glycogen content increases
endometrial glands become ENGORGED by secretions
progesterone promotes the differentiation of the stromal cell into predecidual cells, which must be prepared to form the DECIDUA of the pregnancy
Oral contraceptive pill?
you’re adding more exogenous estrogen or a combo of estrogen/progestin
so if you have excess of these, you’re lowering GnRH from the hypothalamus and lowering FSH and LH from the anterior pituitary
so therefore the low levels are insufficient to stimulate normal folliculogenesis; the low LH levels obviate the LH surge and therefore inhibit ovulation
What is the progestin effect of the OCP?
progestin effect is that while estrogen will help in creating a watery viscous solution that helps sperm to go on and carry on with fertilization, progestin does the EXACT OPPOSITE.. so it’s making the cervical mucus thick and sticky so its kind of a barrier for the sperm to fertilize the egg of the female.
Menorrhagia:
Dysmenorrhea:
Oligomenorrhea:
Amenorrhea:
loss of more than 80mL of blood (no more than 30mL usually)
painful periods
existence of few, irregular periods
Absence of periods
Oligomenorrhea and amenorrhea, what’s causing it?
menorrhagia and dysmenorrhea?
usually an issue in the HP axis
pelvic problems
person has intense abdominal pain associated with period.
pain with intercourse.
trying to get pregnant for 2 years
older sister similar history
Endometriosis
Endometriosis?
what do you see in this?
what are they presented with?
tissue that normally grows inside the uterus grows outside it… so you’ll see endometrial glands and stroma outside of the uterus.
so it’ll respond to steroid hormones and it’ll be painful and go through inflammation and scarring.
chronic pelvic pain, cramps, rectal pain.
common cause of female sterility
Polycystic ovarian syndrome (PCOS)
what is causing it?
3 main things that you’re looking for?
most common cause of infertility
many cysts are the dominant follicles that are supposed to be ovulated and leave, but they’re stuck and producing cysts.
combination of unexplained hyperandrogegism (acne and hirsutism), anovulation (amenorrhea also), polycystic ovary
so HIGH levels of androgen!
PCOS and the axis?
high LH
low FSH
high Testosterone
high androgens promote atresia in developing follicles and disrupt feedback relationships.
absence of menarch. webbed neck, short stature, square chest.
breast buds and female external genitalia. BP normal. small uterus and atretic, fatty ovaries.
what is it
Turner syndrome
what is turner syndrome
genotype?
what does it cause?
levels of FSH and LH
primary hypogonadism –> no germ cells, each gonad consists of connective tissue-filled streak
45X (missing an x)
HIGH FSH AND LH
period irregular. 3 months between period.
hot flashes that wake up at night.
less interested in sex because painful
Perimenopause
Perimenopause
what makes it not menopause?
irregular period, hot flashes, not interested in sex.
menopause should be absent for over 1 year
Menopause is what?
what year does it happen?
when does it occur?
what is it due to?
low levels of FSH and LH?
occurring 12 months after the last menstrual period.
occurs usually at 51 years old
due to reduction of estrogen, low levels of inhibin
no negative feedback of LH and FSH, so high levels of both!!
