Twenty One Flashcards
(35 cards)
What are primordial oogonia? Describe their lifecycle before birth and until puberty.
Primordial oogonia are the germ cells that eventually develop into oocytes. At about the
middle of our fetal life, ( if you happen to be XX with normal ovaries), there are about 7
million of these oogonia that developed due to mitotic activity. Unfortunately, most of
these have to go. Mitosis then stops, and there are no more new oocytes ever produced.
Eventually, there are only 2 million oocytes at birth and then only 400,000 at puberty. The
unlucky ones just degenerate into atretic follicles.
During fetal development, the oocytes that are remaining start the process of meiosis, and
basically just stop in prophase 1 until the time of ovulation. This is due to some kind of
maturation-inhibiting factor in the follicular fluid, putting the brakes on the meiosis. Refer
to the picture of the ovary. We will go through the stages of folliculogenesis.
Describe primordial follicles. Primary follicles. Secondary follicles. Graafian follicles.
Primordial Follicles are resting or inactive oocytes. They consist of the oocyte surrounded by a single layer of flattened follicular (soon to be granulosa) cells, and a basement membrane around the follicular cells. Remember the oocyte is resting in prophase. If these cells don’t become atretic, they advance on to…
Primary Follicles, which have a larger oocyte, and this mucopolysaccharide coating secreted by the oocyte called the zona pellucida. There are also cytoplasmic processes extending from the granulosa cells to the egg to probably nourish it. The surrounding follicular cells start to proliferate and become more cuboidal. after stimulation with FSH (more on this later). A thecal layer forms outside of the basement membrane and the
granulosa cells proliferate even more.
Secondary Follicles are when you start to see a cavity (antrum) form in the middle of some of the follicular/granulosa cells. This follicular fluid contains steroids, growth factors cytokines.
Graafian Follicles (tertiary) develop from continued FSH stimulation. The antrum (cavity) is quite large and causes a bulging on the surface of the ovary. The oocyte is sitting on a platform of granulosa cells called the cumulus oophorus. The granulosa cells that were initially and still surounding the egg are called the corona radiata. Now there are two thecal layers, an internal and external layer with the internal layer surrounding the basement membrane. The basement membrane has no vessels penetrating it, so everything from the vascular thecal layers reaches the granulosa cells and the oocyte via diffusion.
What is ovulation? What triggers it? Describe the process.
Ovulation is the release of the oocyte from the ovary, triggered by the LH surge. This LH surge completes the first meiotic division right before ovulation. The result is an oocyte and the first polar body. This polar body is in the perivitelline space, which is the space within the zona pelucida. The second meiotic division occurs at the time of fertilization where there is a second polar body given off from the oocyte. Ovulation is a complex process. It is not due to increasing pressure in the follicle, causing an explosion of the egg into the pelvis. What happens is that the follicular wall is thinned out by collagenases and
plasmin which are proteolytic enzymes dissolving the follicular wall. The oocyte is extruded with the corona radiata, cumulus oophorus cells, and the follicular fluid.
What is the corpus luteum? What is its function? What does it become?
Corpus Luteum is what remains of the follicle (literally “yellow body”). Both the theca
layer and the granulosa cells become lutineized, the latter producing progesterone. If
pregnancy results, then the corpus luteum supports the pregnancy until 8-10 weeks. If no
pregnancy results, the corpus luteum becomes scarred and fibrosed and is then called a
Corpus Albicans.
What are the 3 types of estrogen? What is its origin?
Estradiol is the star here (“di”meaning two hydroxyl groups). It is the most potent and
most abundant estrogen around. It is mostly from granulosa cells as we will soon learn.
Estriol (three hydroxyl groups…hence the tri) is usually seen in pregnancy. Estrone (one
hydroxyl group) is the weakest. It is usually made in peripheral tissue from
androstenedione, seen in menopausal patients, and possibly obese patients.
What are the progestins? What is their origin? What do they become? What is the significance of 17 alpha hydroxyprogesterone?
Progestins
Look at the steroid pathway figure. You can see how progesterone (the major progestin) is
not only a major steroid itself, but it is also a precurser to the estrogens and androgens.
Another big test topic is 17 alpha hydroxyprogesterone. This is the steroid that builds up
in congential adrenal hyperplasia caused by 21 hydroxylase deficiency.
What are androgens? Examples? Are they secreted from the ovary? What are some other hormones involved in the ovary?
Androgens
Testosterone is secreted by the ovary, but not in large quantiaties. Androstenedione and
Dehydroepiandrosterone (DHEA) are also secreted, but mostly act as precursors. There are
several other factors in the ovary that are involved with autocrine and paracrine-like
activities. Some examples are insulin-like growth factors, cytokines etc.
Describe the two cell theory of estrogen synthesis? Which hormones are important? When are they active? What reactions occur in which cells? What is the role of inhibin? How is feedback regulated? What enzymes are important?
Estrogen, for being such an important hormone, has a very round-about way of how it is
synthesized. The two cell theory explains this. The two cells being the granulosa cells and
the theca interna cells…both surround the oocyte and can be seen in the figure of the ovary.
(The theca interna cells are on the other side of the basement membrane, shown as squiggly
lines that are unmarked). The theca interna cells are analogous to the Leydig cells in the
testis, they both have LH receptors and they both are the predominant sites for androgen
production in the gonads, stimulated by LH. Granulosa cells are analogous to the Sertoli
cells in the testis. Both surround the germ cells, and respond to FSH. Granulosa cells also
make a hormone called inhibin, which inhibits the production of FSH.
For some reason, granulosa cells were not endowed
with the enzyme 17-hydroxylase and can not make
androgens, which are the precursors for estrogen.
(follow this through on the steroid pathway “chicken
wire” diagram). What happens is that the
androstenedione produced in the theca interna cells is
used as a precursor in the granulosa cells, and is
aromatized to estrogen by the enzyme called
armoatase. FSH and a small amount of LH secreted
during the first half of the menstrual cycle stimulate
the production of estrogen. This increasing estrogen
synergizes with FSH to help make some LH receptors
on the granulosa cells too…this will be important
later in the menstrual cycle.
FSH and LH both work on the cells using cyclic
AMP as a second messenger. Estradiol can inhibit
LH and FSH at both the hypothalamus and pituitary.
Inhibin is also a suppressor for FSH, working at the
hypothalamic/pituitary level.
Describe the cellular mechanism of estrogen and progesterone.
Both the estrogens and progestins enter the cell by diffusion and bind to nuclear receptors.
After binding to the receptors, two of the receptor/hormone pairs join (dimerize) and then,
the dimerized pair join to the hormone response element (HRE) on the DNA. mRNA is
then produced and you know the rest of the protein synthesis story. Apparantly, there is a
heat shock protein (HSP) bound to the receptors before the steroids bind to them. After the
steroid binds to the receptor, the receptor dumps the HSP and changes its configuration
and marches with the newly bound steroid to the nucleus to go make protein.
What are the main actions of the estrogens?
The main actions of the estrogens are as follows:
Growth stimulation of the uterus, fallopian tubes, vagina, and endometrium (too much can lead to endometrial cancer) and mammary gland ducts.
Moisturizes the vagina and causes the cervix to secrete thin, watery mucus
Helps with follicular growth and with the formation of LH receptors on the granulosa cells
Prevents osteoporosis at menopause
Stimulates bone growth and closes the epiphyses (if too soon, patient will have shorter overall height)
Decreases total cholesterol, LDL cholesterol, but increases HDL
Increases clotting factors
Decreases glucose tolerance
Increases sex hormone binding globulin, thyroxine binding globulin, and transcortin
Increases the number of progesterone receptors
What are the main actions of progestins?
Produces secretory endometrium for implantation of blastocyst.
Turns cervical mucus viscous and scant
Stimulates the alveolar and lobular development of the breasts
Antagonizes aldosterone, therefore decrease sodium retention
Increase body temperature
Increases ventilation
Decreases bowel and uterine motility
What are the main actions of the androgens?
Increase in pubic and axillary hair in women
Excesses can cause increased midline hair (mustache, beard, male escutcheon etc.) also referred to as hirsutism
Increased bone formation
Precursors for estrogens
Increase in libido
What are the 3 faces of the ovarian cycle? How long do they last?
There are 3 phases to this. I will use the typical 28 day cycle (that really isn’t so typical clinically) to explain
- follicular phase (lasts about 14 days but is variable. This is what may cause variation in cycle length)
- ovulation
- luteal phase (lasts about 14 days…is NOT as variable as the follicular phase)
Describe the follicular phase of the ovarian cycle including the hormones involved, what they do, where they act, what cells are involved, etc.
Clinically speaking, the follicular phase begins with the menstrual cycle. I realize that it
seems more intuitive to end with the menstrual cycle, but from now on, you will refer to the
first day of menses as day #1. Basic scientists often refer to ovulation (or the LH peak), as
starting points, so don’t be confused.
To confuse you even more, the follicular phase actually starts in the prior luteal phase
phase when a crop of oocytes are getting all excited about being the DOMINANT
FOLLICLE! About 3 to 12 of these oocytes are selected (by FSH stimulation) to be the
dominant follicle, but like in the TV show, only one (generally speaking) gets to be the sole
survivor. FSH stimulates the growth of these select few, and via the two-cell hypothesis,
they start to secrete estrogen. These follicles secrete estrogen and by doing so, start
inhibiting FSH production, essentially starving themselves for that which is making them
grow. The dominant follicle, however, wins because it has more FSH receptors (by
chance) than any of the others. By having the most receptors, it needs less FSH than the
others and survives while the others become atretic and are lost forever.
Later in the follicular phase, we see progesterone just getting started. This is due to the
stimulation of the granulosa cells with LH. (FSH induces LH receptors on the granulosa
cells). Estrogen levels start reaching their peak just before ovulation, and in fact get the
ovulatory process going. Read on.
What causes ovulation? When?
About 14 to 24 hours after the peak in estradiol, there is a surge of LH, which causes ovulation. This occurs about 10-12 hours after the peak in LH. This is ingenious because the follicle is actually telling the brain that it is ready for ovulation, thus getting the timing down perfectly.
Describe the luteal phase. What cells are involved and what are they producing? What happens if pregnancy occurs? What happens if it does not occur? What regulates this?
This is the second half of the cycle, typically around 14 days in length, and the least
variable of the two halves. After the LH surge, the theca and granulosa cells become
luteinized, and the structure is then called the corpus luteum. The big product here is
progesterone, and a good amount of estradiol is produced too. The corpus luteum’s
survival is dependent on whether or
not pregnancy results. The hormone
HCG (human chorionic gonadotropin)
is what maintains the corpus luteum.
If pregnancy occurs, the HCG rescues
the corpus luteum from its demise, if
no pregnancy, the corpus luteum’s
progesterone production peaks at 7
days after ovulation, and then
decreases. The pregnancy itself, via
HCG, maintains the corpus luteum
and progesterone production to
ultimately maintain itself. Think of
progesterone as “pro gestation”.
If there is no pregnancy (and no
HCG), then the corpus luteum shrinks,
progesterone declines, and FSH levels
start to rise again, hence recruiting a
new crop of contestants for next
cycle’s dominant follicle. Remember
when we read about the cycle actually
starting in the prior luteal phase?
Well, hopefully it makes sense now.
Describe the neuroendocrine control of LH/FSH secretion. What are the pulses like?
Our existence here on this planet has a lot to do with an important hormone called GnRH or
gonadotropin releasing hormone. Located in the arcuate nucleus in the hypothalamus, a
group of cells (which actually migrated from the olfactory region of the nose along the
olfactory nerve) is what controls this process. These cells secrete pulses of GnRH, which
ultimately drive the FSH and LH levels. They are influenced by many factors such as
ovarian steroids and opiates, to name a few. It is the pulsatile secretion of GnRH which
causes LH and FSH to be secreted in a pulsatile fashion as well. Generally, the pulses are
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more frequent but smaller in the follicular phase compared to the luteal phase, with a slight
increase in frequency observed, as you get closer to ovulation.
Describe the action of estradiol on the hypothalamus and pituitary.
Well, both actually. In the follicular phase, the slowly rising estradiol levels prime the
hypothalamus and pituitary so that LH levels rise slightly, rather than decline by negative
feedback. This is to get the pituitary geared up for the big LH surge. As the levels of
estradiol rise, and we see the presence of progesterone, we have everything ready for the
LH surge. When there is at least 200 pg/ml of estradiol, and progesterone present, there is
a positive feedback on the hypothalamus and pituitary causing the LH surge. The peak in
follicular estrogen is the trigger for the LH surge..the ovary’s way of telling the brain it is
ready for the LH surge. The presence of progesterone augments the LH surge.
In the luteal phase, the increased production of progesterone, estradiol and inhibin from
the corpus luteum cause a negative feedback on GnRH, LH and FSH.
There are SEVERAL other factors involved with this process, a great deal at the ovarian
level. There are several autocrine and paracrine factors, feedback loops etc. that all help
produce a single dominant follicle in women. You know the most important details.
What are the 3 phases of the uterine/endometrial cycle? Describe the blood supply of the endometrium.
3 phases to know:
1) Menstrual phase-which starts off the cycle
2) Proliferative phase
3) Secretory Phase
Note the blood supply to the
endometrium (the innermost
lining of the uterus). This is
the part that is shed with
menstruation. It is supplied
by a basal artery, which
supplies the inner third of the
endometrium which does not
get shed, and the spiral
artery, which is coiled and supplies the outer 2/3 layer which does get shed.
It is somewhat hard to conceptualize what exactly the differences are between the secretory
and proliferative phases (also referred to the follicular and luteal phases), but I will try to make it clear.
Describe the proliferative or follicular stage of the uterus.
What the uterine lining (endometrium) looks like in the first half of the cycle. Estrogen
stimulates its growth. Estrogen stimulates growth from the basal layer and causes the stroma to
“reinflate” itself. The glands are usually straight, opening into the uterine cavity. There is
increased mitotic activity seen as well. One also sees an increase in ciliated and microvillous
cells.
Describe the secretory or luteal phase of the uterus.
After ovulation, the progesterone “transforms” the proliferatvive phase endometrium into one
that will allow implantation. We start to see the glands filling with secretions (hence the name
“secretory”). There is more glycogen storage in the cells and the spiral arteries become very
tortuous. Note that the endometrial height does not change during this phase. It maxed out at
the time of ovulation. What is different is that the glands and vessles do keep growing, and so
everything gets tortuous and crowded. This peaks at about one week after ovulation, which is
when the embryo decides to implant right into the endometrium. The HCG from the embryo
causes the ovary to make progesterone, to keep this nice endometrial lining just like it is. If
there is no embryo and no HCG, the progesterone level starts dropping. There is constriction
of the spiral arteries, prostaglandin release and necrosis. Basically it all just falls apart and all
the left-over outer 2/3 layer is sloughed off and we are back to a new menstrual phase and a
new cycle. The functional layer (that had the basal artery blood supply) was never shed and
thus begins a new proliferative phase to start the cycle over again.
Describe the change in cervical mucus during the menstrual cycle.
We also see changes in the cervical mucus as well. Estrogen stimulates the production of
copious, watery, thin mucous that resembles egg white. This thin mucus is quite stretchy ,a
characteristic we refer to as “spinnbarkeit”~pronounced spin-bar-kite. A cool word to throw
out at your next social function. This stringy clear mucous helps the sperm get through the
cervical os in its destination to find the lucky egg. This estrogenized mucus also forms a “fern-
pattern” when placed on a slide and allowed to dry. This peaks at the time of ovulation, which
makes sense since it facilitates sperm. The rest of the cycle, the mucus becomes thick and
tacky and blocks the entry into the cervix.
Describe the effect of the sex steroids on vaginal cells.
The sex steroids also influence the vaginal cells. Estrogen keratinizes or cornifies vaginal
cells. They are large, flat and irregularly shaped, with small nuclei. There are few leukocytes.
Progesterone stimulates smaller cells, few cornified cells and more leukocytes.
Describe the rises and falls of FSH and LH that occur from prenatal life to puberty.
1) There is a peak in fetal FSH and LH concentrations in the second trimester of
pregnancy, these levels fall in the third trimester, probably due to negative feedback of
the sex steroids
2) There is a rise in LH and FSH shortly after birth. This is most likely due to the loss of
the maternal sex steroids that the fetus saw during the third trimester. Since there are
no more sex steroids to suppress the gonadotropins, they rise. This also implies that the
hypothalamus-pituitary-ovarian axis is functioning, even in the newborn.
3) FSH and LH remain at low levels until about 6-8 years of age. During this time, the
“gonadostat” is highly sensitive to negative feedback, HIGHLY, meaning very low
levels of estradiol suppress FSH and LH. The gonadostat is a term used to describe
some “setpoint” mechanism that exists in the brain. It is not an actual structure, but
used to describe whatever it is that makes the hypothalamus sensitive to negative
feedback. This will hopefully become clearer as you read on.
4) Whatever supresses the gonadostat is lost prior to puberty. We see increased GnRH
pulses with subsequent increases in LH and FSH secretion as well. LH is the big player
during this stage of life. With the increasing LH and FSH, we start to see the sex
steroids being produced from the ovary and thus the development of the secondary
sexual characteristics.
