The female reproductive system includes all of the internal and external organs that help with reproduction. The internal sex organs are the ovaries, which are the female gonads, the fallopian tubes, two muscular tubes that connect the ovaries to the uterus, and the uterus, which is the strong muscular sack that a fetus can develop in. The neck of the uterus is called the cervix, and it protrudes into the vagina. At the opening of the vagina are the external sex organs, and these are usually just called the genitals and they’re in the vulva region. They include the labia, the clitoris, and the mons pubis.
The ovaries are a pair of white-ish organs about the size of walnuts. They’re held in place, slightly above and on either side of the uterus and fallopian tubes by ligaments. Specifically, there’s the broad ligament, the ovarian ligament, and the suspensory ligament. And the suspensory ligament is particularly important because the ovarian artery, ovarian vein, and ovarian nerve plexus pass through it to reach the ovary. If you slice the ovary open and look at it (don’t try this at home) there’s an outer layer called the cortex, which has ovarian follicles scattered throughout it, and an inner layer called the medulla, which contains most of the blood vessels and nerves.
At birth, the ovarian cortex has around two million follicles - that’s roughly the population of Paris - and they’re called primordial follicles. Each primordial follicle has a single immature sex cell called the primary oocyte at the core, and a layer of follicular cells surrounds this. The primary oocyte has 46 chromosomes, but eventually it has to turn into a gamete with only 23 chromosomes. To do this, the primary oocytes have to complete meiosis 1, and in a person’s lifetime only about 400 successfully do that. This process of oocyte development follows that of follicular development, which can be broken into three stages.
The first stage lasts from infancy to puberty, and during this stage the primary oocyte remains stuck in the prophase step of meiosis 1. So, in other words, the cell is living, but not dividing. Meanwhile, the primordial follicle turns into a primary follicle, meaning that the follicular cells that surround the primary oocyte develop into granulosa cells.
The second stage of follicular development begins for a few lucky primary follicles with the first menstrual cycle in puberty, and a few more primary follicles go into the second stage with each subsequent menstrual cycle. In the second stage, the primary follicles develop into secondary and eventually tertiary, or graafian follicles. In a secondary follicle, the primary oocyte is still in the prophase step of meiosis 1, but now the follicle has additional layers of granulosa cells, as well as theca cells. Theca cells make androstenedione, a sex hormone precursor, and granulosa cells use the enzyme aromatase to convert it into estradiol - a member of the estrogen family, as well as progesterone.
In a graafian follicle, a central cavity called the antrum forms within the follicle, and the granulosa cells secrete a nourishing fluid for the primary oocyte directly into that antrum. The second stage takes roughly 70 to 85 days and results in a few fast-growing graafian follicles. The third stage of follicular development starts when the graafian follicles are ready and occurs during the follicular phase of the menstrual cycle.
So let’s briefly switch gears and go over the highlights of the menstrual cycle to put that follicular phase into context. The menstrual cycle starts on the first day of menstrual bleeding, lasts 28 days on average from then. Assuming a 28-day cycle, the follicular phase makes up the first two weeks of the menstrual cycle, and the luteal phase, the last two weeks. These two phases are separated by ovulation, which is when the follicle ruptures and releases an oocyte that is ready to be fertilized. This usually occurs on day 14 of a 28 day cycle.
The menstrual cycle is ultimately controlled by the hypothalamus, which is at the base of the brain. Before puberty, the hypothalamus constantly secretes small amounts of a hormone called gonadotropin-releasing hormone, or GnRH. That GnRH travels to the nearby pituitary, which secretes two hormones of its own - follicle stimulating hormone, or FSH, and luteinizing hormone, or LH. Once puberty hits, the hypothalamus starts to secrete GnRH in pulses, sometimes more and sometimes less, and pituitary FSH and LH make the ovarian follicles develop.
The amount of GnRH can be mapped out like a wave over time, and the frequency and amplitude of the waves of GnRH determine how much FSH and LH get produced by the pituitary. LH binds to LH receptors on theca cells, making them secrete androstenedione. FSH binds to FSH receptors on granulosa cells and they make aromatase and, as a consequence, estrogen. Serum levels of estrogen and progesterone act as feedback for the command center in the brain, which adjusts its hormone production according to the phases of the menstrual cycle.
During the follicular phase of each menstrual cycle, the few fast-growing graafian follicles enter the third stage of development. Pituitary FSH makes the follicles grow and the granulosa cells produce more estrogen. In addition to estrogen, the granulosa cells also secrete a hormone called activin, which stimulates FSH production, as well as binding to FSH receptors, and the activity of granulosa cell aromatase as well. So early in the follicular phase, a small rise in FSH, leads to a large increase in estrogen.
However, estrogen acts as a negative feedback signal – that is, it tells the pituitary to secrete less FSH and LH. Less FSH means that there is only enough left to stimulate one follicle. The follicle that has the most FSH receptors hoards most of this hormone, and becomes the dominant follicle. It usually takes about a week for a dominant follicle to get selected, and after that happens, the rest of the follicles regress and die off. The dominant follicle keeps secreting estrogen for the rest of the follicular phase. The steady increase in estrogen makes the pituitary more responsive to the pulsatile action of hypothalamic GnRH.
When blood estrogen levels reach 200 picograms/milliliter, dominant follicle estrogen becomes a positive feedback signal – that is, it makes the pituitary secrete a whole lot of FSH and LH in response to GnRH. This triggers the primary oocyte within the dominant follicle to finally complete meiosis 1, and turn into a secondary oocyte, which has 23 chromosomes. The dominant follicle completes its third stage of development in a blaze of glory called ovulation. That’s when the nearly 2 centimeter sized follicle ruptures and releases the tiny secondary oocyte into the fallopian tube. The secondary oocyte stops in metaphase of meiosis 2, and waits for fertilization as the menstrual cycle transitions into the luteal phase.
The luteal phase makes up the second half of the menstrual cycle - week 3 and week 4, of the 4-week cycle. Right after ovulation, while the LH levels are still high, the remains of the follicle turn into the corpus luteum, which is made up of luteinized granulosa and theca cells. Luteinized granulosa cells secrete inhibin, which inhibits the pituitary gland from making FSH. Without FSH, estrogen levels fall, and the amount of LH goes back to the level before ovulation.
