Female Cycle


In females there is a cyclical pattern of hormone secretion by the ovaries. This pattern of hormone secretion results in the ovulation of a single egg each cycle, and coordinates changes in the uterus so that it is ready to house a developing embryo should that egg become fertilized.


Oocytes develop in follicles

The first step in understanding the female cycle is to describe the events in the ovary. Prior to birth, oogonia stop proliferating, so that at birth, the germ cells that are present in the ovary are all primary oocytes. They have initiated meiosis, but then stopped, and are in a state known as meiotic arrest.

The structure in the ovary that contains the oocyte and support cells is called a follicle. Those that are not developing are called primordial follicles, and consist of an oocyte in meiotic arrest surrounded by a single layer of follicle cells. When a follicle starts to develop, the oocyte enlarges, and the follicle cells differentiate to become rounded granulosa cells which start to proliferate. A layer of glycoproteins called the zona pellucida develops between the granulosa cells and the oocyte. The granulosa cell layer is surrounded by a basement membrane. External to the basement membrane, spindle-shaped theca cells associate with the follicle. Within the granulosa cell layer, a fluid-filled space called the antrum develops.


Events in follicle development

Note that the timing of ovarian events is based upon an average female cycle length of 28 days, however normal cycle length varies from 21 to 35 days.

Throughout the part of her life when her ovaries contain follicles, local signals within the ovary will cause some follicles to develop to the early antral stage. We will call this early development of follicles initial development. Initial development is independent of gonadotropins since it can occur before puberty and at any time during the monthly cycle.

The first part of the hormonally-regulated cycle is called the growth phase. During the growth phase, a cohort of follicles that have undergone initial development are stimulated to develop further by rising concentrations of gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). If a follicle undergoes initial development, but does not receive hormonal support for further development, it will undergo a process of degeneration that is known as atresia. Atresia is the fate for all but a few hundred follicles in the ovary.

By day 7, a dominant follicle is selected from the cohort of growing follicles, while the others undergo atresia. From day 7 through day 14, the dominant follicle becomes a mature follicle, bulging out on the surface of the ovary and enlarging to a final size of 1-3 cm. The egg along with a small cluster of granulosa cells detaches from the wall of the follicle and floats free within the swollen antrum, in preparation for ovulation. Ovulation occurs on day 14: the follicle ruptures and releases the egg to the fluid surrounding the ovary.

Following ovulation, the remaining cells of the follicle differentiate into the corpus luteum. The granulosa cells greatly increase in size, the basement membrane breaks down, and the structure is invaded by blood vessels. The corpus luteum is an important endocrine structure, secreting progesterone and estrogen that is necessary to prepare the uterus for implantation and early pregnancy. The corpus luteum persists as long as there is sufficient hormonal support. In a typical menstrual cycle, it degenerates between day 25 and 28 when LH levels decline. If a fertilized embryo implants in the uterus, the hormone chorionic gonadotropin is made. Chorionic gonadotropin is an LH analogue (meaning it binds to LH receptors) that stimulates the corpus luteum to grow and persist throughout the first trimester of pregnancy. Pregnancy tests are an assay for chorionic gonadotropin in the urine.

The pink timeline below the hormone graph summarizes the important ovarian events. Note that ovulation divides the cycle in half: the first half, when follicles develop is the follicular phase, the second half when the corpus luteum is active is the luteal phase.


Hormonal regulation

hormone graph

There is an interplay between ovarian events and gonadotropin secretion from the anterior pituitary that results in a cyclical pattern of hormone secretion in the female. The graph depicts the relative average daily levels of FSH, LH, estrogen, and progesterone throughout the cycle. Refer to this graph as you go through the web page.


Early follicular phase

The growth phase is stimulated by gonadotropins, which steadily increase at the beginning of the follicular phase. This is because estrogen and progesterone levels decline at the end of the previous cycle, releasing the anterior pituitary from negative feedback inhbition. As in the male, in the early follicular phase there is a division of labor between the gonadotropins: FSH specifically stimulates granulosa cells, while LH specifically stimulates theca cells.

As the follicles grow in response to stimulation from the gonadotropins, they also start to secrete increasing amounts of estrogen. The two cell types collaborate in the production of estrogen (see figure below). Granulosa cells express the enzyme aromatase, which converts an androgen precursor to estrogen, however they lack the enzymes to make the androgen precursor. Theca cells lack aromatase, but are able to produce the androgen precursor, which is then converted to estrogen (specifically, estradiol) by the granulosa cells.


follicular

Dominant follicle selection and late follicular phase

On day 7 of the cycle, a dominant follicle is selected and the other follicles in the developing cohort undergo atresia. Note that as the follicle enlarges, estrogen secretion increases and causes negative feedback inhibition, so gonadotropin levels, particularly FSH decline. Additionally, granulosa cells secrete inhibin, a peptide hormone which also inhibits FSH secretion. Dominant follicle selection is thought to occur because negative feedback inhibition limits the amount of FSH. In the late follicular phase, granulosa cells in the dominant follicle start to express LH receptors and respond to LH as well as FSH.


LH surge and ovulation

LH surge

In the late follicular phase, the level of estrogen secretion from the dominant follicle crosses a certain threshold, and the feedback effect of estrogen now switches to positive feedback. This means that estrogen now stimulates LH secretion, which in turn stimulates more estrogen production by the follicle. The result is a rapid rise in LH secretion, the LH surge.

The LH surge triggers the rupture of the dominant follicle, in other words, ovulation. Just prior to ovulation, LH stimulates a small increase in progesterone secretion, which appears to be necessary for ovulation, since ovulation can be blocked by progesterone antagonists (see the page on Contraception). The first division of meiosis occurs just prior to ovulation (the second division occurs after the egg is penetrated by the sperm).


Luteal phase

luteal phase

After ovulation, LH stimulates the formation of the corpus luteum. The corpus luteum secretes high levels of both estrogen and progesterone. The combination of high estrogen together with progesterone causes negative feedback inhibition of gonadotropin secretion, thus preventing maturation and ovulation of other follicles.

The corpus luteum persists as long as LH levels stay above a certain level. Once LH secretion falls below a certain level, the corpus luteum degenerates. The drop in estrogen and progesterone secretion releases the hypothalamus and pituitary from negative feedback inhibition, allowing FSH and LH levels to steadily increase. This starts a new cycle.


Coordination of uterine events

The other important role for estrogen and progesterone is to induce changes in the uterus that will prepare it for implantation by a fertilized embryo. The lining of the uterus, or endometrium, is divided into a functional layer that changes under the influence of estrogen and progesterone, and a basal layer that regenerates the functional layer following menstruation. During the middle and late follicular phase, high levels of estrogen stimulate proliferation in the functional layer (proliferative phase). Estrogen also causes glands in the cervix to secrete a thin, watery mucus.

During the luteal phase, the high levels of progesterone prevent continued proliferation, and stimulate the secretion of nutritive substances by the endometrial glands (secretory phase). Progesterone also causes the cervical glands to secrete a thick mucus that acts as a protective barrier to the uterus.

In a non-fertile cycle, the drop in estrogen and progesterone that occurs following degeneration of the corpus luteum is what triggers menstruation. Menstruation is the shedding of the functional layer of the endometrium. Early on, vasoconstriction in endometrial blood vessels causes ischemia and tissue degeneration. Later during menstruation there is vasodilation to cause a small amount of bleeding, along with myometrial contractions.  The bleeding and the contracitons help to expel the degenerated tissue. The first day of menstruation coincides with the first day of the follicular phase, and it typically lasts about 5 days.  Refer to the blue/green timeline in the figure above to see how the uterine cycle coincides with the ovarian cycle.


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