The Menstrual Cycle

The menstrual cycle refers to the regular changes in the activity of the ovaries and the
endometrium that make reproduction possible. The endometrium is the layer of tissue
lining the inside/entire(?) of the uterus of the uterus. This lining consists of a functional
layer, which is subject to hormonal changes and is shed during menstruation and a thin
basal layer which feeds the overlying functional layer.

The menstrual cycle actually consists of two interconnected and synchronized processes:
the ovarian cycle, which centers on the development of the ovarian follicles and ovulation,
and the uterine or endometrial cycle, which centers on the way in which the functional
endometrion thickens and sheds in response to ovarian activity.

Menarche, which refers to the onset of the first menstrual period, usually occurs during
early adolescence as part of puberty. Following menarche, the menstrual cycle occurs on a
monthly basis, pausing only during pregnancy, until a person reaches menopause, when her
ovarian function declines and she stops having menstrual periods. The monthly menstrual
cycle can vary in duration from 20 to 35 days, with an average 28 days. Each menstrual cycle
begins on the first day of menstruation, and this is usually referred to as day one of the
cycle. Ovulation, or the release of the oocyte from the ovary, usually occurs 14 days before
the first day of menstruation (i.e., 14 days before the next cycle begins). So, for an average
28-day menstrual cycle, this means that there are usually 14 days leading up to ovulation
(i.e., the preovulatory phase) and 14 days following ovulation (i.e., the postovulatory phase).

During these two phases, the ovaries and the endometrium each undergo their own set of
changes, which are separate but related. As a result, each phase of the menstrual cycle has
two different names to describe these two. For the ovary, the two weeks leading up to
ovulation is called the the ovarian follicular phase, and this corresponds to the menstrual
and proliferative phases of the endometrium. Similarly, the two weeks following ovulation is
referred to as the ovarian luteal phase, which also corresponds to the secretory phase of the
endometrium.

So, let’s first focus on the preovulatory period, starting with the ovarian follicular phase. This
phase starts on the first day of menstruation and represents weeks one and two of a four-
week cycle. The whole menstrual cycle is controlled by the hypothalamus and the pituitary
gland, which are like the masterminds of reproduction. The hypothalamus is a part of the
brain that secretes gonadotropin-releasing hormone, or GnRH, which causes the nearby
anterior pituitary gland to release follicle stimulating hormone, or FSH, and luteinizing
hormone, or LH. Before puberty, gonadotropin-releasing hormone is released at a steady
rate, but once puberty hits, gonadotropin-releasing hormone is released in pulses
sometimes more and sometimes less. The frequency and magnitude of the gonadotropin-
releasing hormone pulses determine how much follicle stimulating hormone and luteinizing
hormone will be produced by the pituitary. These pituitary hormones control the
maturation of the ovarian follicles, each of which is initially made up of immature sex cells
or primary oocyte, surrounded by layers of theca and granulosa cells, the hormone-
secreting cells of the ovary. Over the course of the follicular phase, these oocyte-containing
groups of cells, or follicles, grow and compete for a chance at ovulation.

During the first ten days, theca cells develop receptors and bind luteinizing hormone, and in
response secrete large amounts of the hormone androstenedione, an androgen hormone.
Similarly, granulosa cells develop receptors and bind follicle stimulating hormone, and in
response produce the enzyme aromatase. Aromatase converts androstenedione from the
theca cells into 17β-estradiol, which is a member of the estrogen family.

During days 10 through 14 of this phase, granulosa cells also begin to develop luteinizing
hormone receptors, in addition to the follicle stimulating hormone receptors they already
have. As the follicles grow and estrogen is released into the bloodstream, increased
estrogen levels act as a negative feedback signal telling the pituitary to secrete less follicle
stimulating hormone.

As a result of decreased follicle stimulating hormone production, some of the developing

follicles in the ovary will stop growing, regress and die off. The follicle that has the most
follicle stimulating hormone receptors, however, will continue to grow, becoming the
dominant follicle that will eventually undergo ovulation. This dominant follicle continues to
secrete estrogen, and the rising estrogen levels make the pituitary more responsive to the
pulsatile action of gonadotropin-releasing hormone from the hypothalamus. As blood
estrogen levels start to steadily climb higher and higher, the estrogen from the dominant
follicle now becomes a positive feedback signal – that is, it makes the pituitary secrete a
whole lot of follicle stimulating hormone and luteinizing hormone in response to
gonadotropin-releasing hormone.

This surge of follicle stimulating hormone and luteinizing hormone usually happens a day or
two before ovulation and is responsible for stimulating the rupture of the ovarian follicle
and the release of the oocyte. You can think of it this way: for most of the follicular phase,
the pituitary saves its energy, then when it senses that the dominant follicle ready for
release, the pituitary uses all its energy to secrete enough follicle stimulating hormone and
luteinizing hormone to induce ovulation.

While the ovary is busy preparing an egg for ovulation, the uterus, meanwhile, is preparing
the endometrium for implantation and maintenance of pregnancy. This process begins with
the menstrual phase, which is when the old endometrial lining, or functional layer, from the
previous cycle is shed and eliminated through the vagina, producing the bleeding pattern
known as the menstrual period. The menstrual phase lasts an average of five days and is
followed by the proliferative phase, during which high estrogen levels stimulate thickening
of the endometrium, growth of endometrial glands, and emergence of spiral arteries, which
grow a little under the influence of estrogen from the basal layer to feed the growing
functional endometrium.

Rising estrogen levels also help change the consistency of the cervical mucus, making it
more hospitable to incoming sperm. The combined effects of this spike in estrogen on the
uterus and cervix help to optimize the chance of fertilization, which is highest between day
11 and day 15 of an average 28-day cycle.

Following ovulation, the remnant of the ovarian follicle becomes the corpus luteum, which
is made up of luteinized theca and granulosa cells, meaning that these cells have been
exposed to the high luteinizing hormone levels that occur just before ovulation. Luteinized
theca cells keep secreting androstenedione, and the luteinized granulosa cells keep
converting it to 17β-estradiol, as before. However, luteinized granulosa cells also respond to
the low luteinizing hormone concentrations that are present after ovulation by increasing
the activity of cholesterol side-chain cleavage enzyme, or P450scc for short. This enzyme
converts more cholesterol to pregnenolone, a progesterone precursor. So luteinized
granulosa cells secrete more progesterone than estrogen during the luteal phase.
Progesterone acts as a negative feedback signal on the pituitary, follicle stimulating
hormone and luteinizing hormone.

At the same time, luteinized granulosa cells begin secreting inhibin, which similarly inhibits
the pituitary gland from making follicle stimulating hormone. Both of these processes result
in a decline in estrogen levels, meaning that progesterone becomes the dominant hormone
present during this phase of the cycle. Together with the decreased level of estrogen, the
rising progesterone level signals that ovulation has occurred and helps make the
endometrium receptive to the implantation of a fertilized gamete.

Under the influence of progesterone, the uterus enters into the secretory phase of the
endometrial cycle. During this time spiral arteries continue to grow, and the uterine glands
begin to secrete more mucus. After day 15 of the cycle, the optimal window for fertilization
begins to close. The cervical mucus starts to thicken and becomes less hospitable to the
sperm. Over time, the corpus luteum gradually degenerates into the nonfunctional corpus
albicans. The corpus albicans doesn’t make hormones, so estrogen and progesterone levels
slowly decrease. When progesterone reaches its lowest level, the spiral arteries collapse,
and the functional layer of the endometrium prepares to shed through menstruation. This
shedding marks the beginning of a new menstrual cycle and another opportunity for
fertilization.
All right, so as a quick recap - the menstrual cycle begins on the first day of menstruation.
For an average 28-day menstrual cycle, the changes which occur in the ovary during the first
14 days are called the follicular phase. Ovulation usually occurs at day 14, as a result of the
estrogen-induced surge and luteinizing hormone. The last 14 days of the cycle are the luteal
phase, during which progesterone becomes the dominant hormone. While the length of the
follicular phase can vary, the luteal phase almost always precedes the onset of menses by 14
days. The uterus also goes through its own set of changes. During the first 14 days of the
cycle, the endometrium goes through the menstrual phase and the proliferative phase, and
during the last 14 days it goes through the secretory phase.