A normal menstrual cycle requires a precisely timed series of
events that interrelate to allow for regular ovulation. These
events are important to understand since they allow physicians
to manage your fertility care. They include:
* (1) development of a monthly pool of recruitable follicles.
Only the recruited follicles will respond to the signal to mature,
which is a hormone named follicle stimulating hormone (FSH). Research
suggests that this small group of recruitable follicles present
at the onset of a cycle has actually been prepared specifically
for the cycle over a 3-6 month period of time.
No recruited follicle will enter more than one cycle of maturation,
so that if a follicle begins to mature with FSH stimulation the
follicle will either ovulate or will degenerate during that month.
Clinical importance
Fertility medications called human menopausal gonadotropins (menotropins)
have FSH as their active ingredient stimulating egg maturation.
In the presence of excess amounts of FSH all recruitable follicles
may develop simultaneously. At the time of maturation in cycles
using fertility medication, there may be more than 10-25 mature
eggs in the ovaries as compared to only one mature egg in the
usual natural cycle.
The goal of menotropin therapy generally is to mature as many
eggs as possible. Since only that month's recruited follicles
can respond to FSH and develop you are not using eggs that would
ever enter another cycle. Therefore, you will not have early menopause
due to menotropin therapy.
* (2) FSH concentration increases a few days prior to the onset
of menstrual flow.
Circulating FSH concentration changes throughout the cycle such
that only one mature egg is usually produced at ovulation. FSH
concentration increases prior to the onset of menstrual flow which
rescues some of the eggs within that month's recruitable pool
of follicles from degeneration. These eggs begin to mature.
Within the first 5-7 days of the cycle one of the developing follicles
out competes the others for available FSH. This becomes the "dominant
follicle" that normally goes on to ovulate.
It is uncommon for 2 eggs to mature simultaneously in a cycle,
with the twinning rate for natural cycles in the USA about 1 in
80 to 1 in 90 pregnancies.
Circulating FSH concentration decreases as ovulation approaches
to enhance atresia (degeneration) of the maturing nondominant
follicles
Clinical importance
Fertility medications used to increase the number of fully matured
eggs during a given cycle should be initiated prior to the selection
of the dominant follicle. This will enhance the yield of fully
mature eggs.
* (3) the growth rate and hormonal function of the dominant
follicle changes during the cycle
A sudden rapid increase in both the follicular diameter (size)
and the circulating estrogen concentration (function) occurs just
prior to complete egg maturation. The increase in diameter is
identifiable by ultrasound. The increase in estrogen level is
identifiable with close monitoring of blood estradiol concentrations.
Clinical importance
Monitoring findings from ultrasounds and the woman's bloodwork
allows the infertility specialist to interpret changes in egg
development and adjust therapy.
* (4) circulating leutinizing hormone (LH) concentration increases
dramatically about 36 hours (one and a half days) prior to ovulation
This sudden increase in LH concentration, the "LH surge,"
is the trigger for both "the egg" to undergo its final
maturational step and for "the ovary" to undergo the
final changes required to release the mature egg into the pelvis.
Clinical importance
Injections of hCG (Profasi) when the egg(s) is mature can mimic
the LH surge since the hCG and LH molecules are very similar.
Actually hCG and LH occupy the same cellular receptors to accomplish
their biologic response. The hCG injection triggers ovulation
about one and a half days later.
Detection of the LH surge (as LH excreted in urine) is the basis
for the commercially available ovulation predictor kits (purchased
in the pharmacy).
* (5) the follicular cyst rapidly changes following ovulation
under the influence of increased LH to become a "corpus luteum"
cyst.
A major difference between the follicular cyst (prior to ovulation)
and the corpus luteum cyst (following ovulation) is hormone production.
The predominant sex steroid produced by the follicular cyst is
estrogen and that of the corpus luteum cyst is progesterone.
Granulosa cells are cells that line the inside of both of these
cysts and are capable of producing either estrogen or progesterone.
Cholesterol is the starting material for either of these hormones
and cholesterol's molecular structure is changed using proteins
called enzymes. The activity of the enzymes that change cholesterol
into either estrogen or progesterone can be enhanced or suppressed
within these granulosa cells.
Under conditions present prior to ovulation the granulosa cells
produce mostly estrogen and under the conditions present following
ovulation these cells produce mostly progesterone.
Prior to ovulation, the high circulating estrogen concentrations
act on the endometrium (uterine lining) to stimulate growth that
results in an increased endometrial thickness. Following ovulation,
the high circulating concentration of progesterone acts on the
endometrium to stabilize it and prepare it for the implantation
of an embryo.
Clinical importance
Inadequate progesterone effect during the luteal phase of the
menstrual cycle (a "luteal phase defect") can be treated
with supplemental progesterone (oral micronized progesterone,
vaginal suppositories, vaginal gel applicator, or by injection
in an oil base). Supplemental hCG can be given as injections every
few days following ovulation to enhance the ovary's own progesterone
production. Clomiphene citrate in the follicular (preovulatory)
phase may increase the final size of the follicle prior to ovulation
so that there are more granulosa cells to then produce progesterone
in the luteal phase.
Supplemental progesterone for a luteal phase deficiency is usually
continued until about 10-12 weeks gestation (8-10 weeks from fertilization).
The placenta takes over progesterone production from the ovarian
corpus luteum during this time, so that further supplementation
is not necessary.
* (6) the "window of uterine receptivity" is a short
period of time during which embryos may implant into the uterus
During this period of uterine receptivity the endometrial lining
is ideally prepared to allow for embryo implantation. In most
cases embryos will only implant and grow normally if present in
the cavity during this window of receptivity.
Progesterone is believed to be the major determinant of the window
of receptivity, however, many other candidate hormones and protein
messengers are also being considered as the research on molecular
mechanisms of implantation continues to grow
The duration of the window of uterine receptivity in humans is
thought to be about 3 days
Clinical importance
During cycles of In Vitro Fertilization (including frozen embryo
transfer cycles and donor egg cycles involving egg recipients)
the success rate (in terms of implantation or pregnancy) relates
to the hormonal preparation of the endometrium (uterine lining).
If progesterone production, or the uterine response to the progesterone
produced, is not adequate then the lining of the uterus may be
inadequate for embryo implantation. This situation can lead to
either infertility if the lining does not become receptive or
recurrent pregnancy loss if the lining is receptive for implantation
but the embryo cannot develop normally.
* (7) menses occur if a pregnancy is not achieved
LH stimulates the enzymes within the corpus luteum cyst to produce
progesterone for only about 2 weeks following ovulation. If the
woman becomes pregnant the placental cells that grow into the
uterine lining and establish contact with the maternal circulation
produce a hormone called human chorionic gonadotropin (hCG). The
hCG molecule produced by placental cells (syncytiotrophoblast
cells) is structurally similar to LH and shares the same receptors
on the ovary to produce similar biologic responses.
In a pregnancy cycle, the maternal circulation begins to have
a detectable hCG concentration about 7 to 8 days after fertilization
(fertilization occurs within a day or so of ovulation). This hCG
then takes over (by acting like LH) the stimulation of progesterone
production by the corpus luteum cyst.
If the woman does not become pregnant, then there is no hCG to
take over the role of LH in the support of the corpus luteum cyst.
Thus, the corpus luteum cyst deteriorates, the progesterone concentration
supporting the uterine lining declines and the uterine lining
that has grown in preparation for pregnancy is shed (as the menstrual
flow).
Clinical importance
Menstrual flow sometimes becomes a monthly reminder associated
with the pain and frustration often felt by couples with an infertility
problem.
More information on the events involved in Ovulation are available here.
More information on the causes and treatments of miscarriages is available here.
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