Hormones of the menstrual cycle
While this article is dense, it lays the groundwork for many future articles especially around PCOS, PMS, recurrent miscarriages, and cyclical symptoms such as migraines and even autoimmune flares. You will find a summary of key takeaways and a brief overview of why this matters for your overall health (and for natural contraception and family planning) in this related post.
Before we get into hormone patterns throughout the menstrual cycle, let’s go over a few basics starting with follicular development, the very first phase of the menstrual cycle.
Non-cyclical follicular development
Primordial follicles: Near birth, germ cell cysts that formed between the 5th and 20th weeks of pregnancy in developing female fetuses become primordial follicles. Each one of these follicles contain an oocyte (immature egg) and a single layer of ovarian follicular epithelial cells known as granulosa cells. At birth, around 1 to 2 million primordial follicles reside in the ovaries and remain in a state of arrested development (Prophase I of meiosis) until recruitment during the woman’s reproductive years.
Primary follicles: At the beginning of each ovulation cycle, a number of primordial follicles are recruited and begin maturing in a process known as folliculogenesis. The morphology of the granulosa cell layer changes from flat to cuboidal in shape after recruitment and the follicles begin developing a second layer of granulosa cells during primary follicular development. By the end of primary follicular development, the granulosa layer is several cell layers thick and the zona pellucida, the outer membrane of the mature egg, is defined. Primary follicles also develop follicular stimulating hormone (FSH) receptors but don’t respond to FSH until they mature to the antral stage. Meiosis I is completed during primary follicular development.
Secondary follicles: During this stage of development, more granulosa cell layers are formed along with a layer of cells surrounding the granulosa layer known as thecal cells and because of this, secondary follicles are able to generate estradiol. The key feature distinguishing a mature secondary follicle from a primary follicle entering secondary follicle development is presence of the follicular antrum, a fluid filled space that appears within the granulosa layer. Meiosis II starts during secondary follicular development, but meiosis II isn’t completed unless the follicle is fertilized.
It is still not well understood how primordial follicles are recruited for development into secondary follicles, but what is known is that these phases of follicular development don’t rely on follicular stimulating hormone (FSH) for growth.
Cyclical follicular development
Tertiary (antral or Graafian) follicles: Antral follicles (as opposed to pre-antral follicles) respond to follicular stimulating hormone (FSH) and these follicles are able to be further recruited for development into the mature egg released at ovulation. A few days before your period starts, progesterone and estradiol levels start to drop, and follicular stimulating hormone (FSH) begins to rise stimulating further development of antral follicles. We will revisit this piece of follicular development later in this post.Before leaving follicular development, we will look at the role of testosterone and estradiol in the developing follicles and the brain’s role in follicular development and ovulation.
Testosterone and estrogen production in developing follicles
The thecal cell layer contains enzymes that convert cholesterol into androstendione and testosterone and one other androgen (dihydrotestosterone). These androgens cross between the thecal cell layer and the granulosa cell layer by diffusion. The granulosa cells contain the enzyme aromatase, specifically CYP19A1. This enzyme belongs to the P450 cytochrome family of enzymes and converts testosterone made by the thecal cells into estradiol and androstenedione made by the thecal cells into estrone. Estrone is converted into estradiol within the granulosa cells by another enzyme, 17beta-hydroxysteroid dehydrogenase (17B-HST).
Even though the granulosa cells make estradiol, in the absence of thecal cells to supply the testosterone to the aromatase enzyme for conversion, follicles that haven’t yet matured to secondary follicles are unable to create estradiol on their own as they don’t have the necessary testosterone supply to generate the estradiol.
As antral follicles continue growing in size, these follicles produce larger and larger quantities of estradiol, which is part of an important feedback loop with FSH (follicular stimulating hormone).
The brain’s role in follicular development and ovulation
Two glands within the brain play a key role in ovulation. The hypothalamus gland releases gonadotropin releasing hormone (GnRH) at a specific tempo throughout the menstrual cycle. In response to low estradiol and low progesterone just before menstruation, the pulsed release of GnRH slows down and this prompts the pituitary gland to release more FSH.
Developing antral follicles have FSH receptors and require FSH for growth. In theory, the larger and the faster that antral follicles grow the better able they are to bind more FSH, and this effectively starves out smaller, slower growing follicles.
Larger and quickly growing antral follicles also produce more estradiol than smaller antral follicles, therefore, larger follicles outcompete smaller and slower growing follicles because increasing estradiol levels during follicular development results in lower concentrations of FSH in the bloodstream. As estradiol levels go up, the hypothalamus increases the tempo of its pulsed release of GnRH and this reduces the amount of FSH the pituitary expresses in the negative feedback loop. Larger follicles also contain more FSH receptors and are able to more effectively recruit FSH, which is necessary for developing follicles. In this way, a single follicle typically outcompetes all other follicles during each menstrual cycle resulting in atresia (death) of the remaining developing follicles and release of a single egg at ovulation.
When fraternal twins or multiplets are born, it is because more than one follicle achieved ovulation in that cycle.
Figure 1 below shows the different stages of follicular development and highlights where FSH dependent development (cyclical development) begins.
Figure 1. Stages of follicular development starting with the primordial follicle.
Blue = granulosa cells and red = theca cells
Historically, it has been postulated that once estradiol levels reach a critical threshold, the amount of GnRH secreted by the hypothalamus increases, and this prompts the surge of luteinizing hormone (LH) stimulating release of the mature ovum. Typically (but not always) there is also a spike in FSH at the time of ovulation, and it is thought this is due to switching of the negative feedback loop to a positive feedback loop once estradiol reaches a critical threshold.
Ovulation: Pre-ovulatory rise in progesterone prompts ovulation
Historically, it was thought that the LH surge causes the follicle to release the mature ovum (egg) in a reversal of the negative feedback loop between estradiol and the pulse of GnRH which suppresses release of both FSH and LH from the pituitary.
What is interesting is that new research points to a rise in progesterone levels preceding ovulation, and this prompts release of LH from the pituitary. Based on my own at-home hormone monitoring of urinary metabolites of estradiol and progesterone plus LH and FSH, my own observations demonstrate this pre-ovulatory temporal rise in progesterone, and in fact, if this new theory proves correct, this goes a long way in explaining the sudden shift in the electrolyte composition of vaginal secretions at ovulation.
Progesterone levels just prior to ovulation are much lower than levels mid-luteal phase, and so it is likely that the adrenal cortex rather than the developing follicles are producing the progesterone necessary to prompt the surge in luteinizing hormone (LH). It is also of note that high levels of progesterone (like those produced during the luteal phase and during pregnancy) inhibit ovulation. In in-vitro fertilization, when progesterone is given at levels to simulate the blood concentration seen during the luteal phase, this prompts the “vanishing follicle” phenomenon suggesting that a low progesterone concentration is vitally important to successful ovulation.
This theory may also explain why women under stress don’t ovulate. It is common for women who develop a cold or illness peri-ovulatory to have either delayed ovulation or an anovulatory cycle. Other forms of stress (mental, over-exercise, disturbances to the circadian rhythm) are also known to delay ovulation. Considering that pregnenolone is the precursor to both cortisol and progesterone, this progesterone rise theory as the key event leading to ovulation evolutionarily fits the concept of conserving eggs or preventing reproduction when conditions aren’t favorable as elevated demands for cortisol during times of high stress would deplete the body’s ability to create progesterone.
Ovulation: The LH surge
The high levels of LH luteinize the granulosa cells of the follicle left behind on the surface of the ovary at the time the ovum bursts forth. During the LH surge, the basement membrane separating the theca cells from the granulosa cells also dissolves in response to the high concentrations of LH producing the corpus luteum (Latin for yellow body, so called because of the high concentration of carotenoids, including lutein, that create the yellow color when viewed under a microscope). This process takes a few days to complete, and this leads to the bell-shaped curve of progesterone in the body during the luteal phase as we will talk about next.
After ovulation: The luteal phase
The corpus luteum produces progesterone at higher levels than the progesterone spike just before ovulation. Progesterone is the dominant reproductive hormone during the luteal phase. Because progesterone is a more thermogenic hormone than estrogen, it is common for women to see at least a 0.3 degree rise in their basal body temperature (BBT) after ovulation. Sometimes this is a dramatic rise, sometimes a step-like rise over the course of a few days depending on a variety of factors (namely, estradiol to progesterone ratios and also other hormones like thyroid hormone, cortisol levels, etc.).
Progesterone concentrations typically rise in a bell-shaped curve peaking about 7 days after ovulation and beginning to fall again ahead of menstruation. Most healthcare practitioners recommend testing progesterone on cycle day 21 assuming every woman has a 28-day cycle, or more precisely assuming every woman ovulates on cycle day 14. A much better time to measure progesterone is 5 to 7 days after ovulation, and this requires that a woman know when she ovulates. Many Fertility Awareness Methods (FAMs) are available that accurately predict ovulation regardless of whether your goal is pregnancy or simply improved hormonal health and body awareness.
Estradiol concentrations also rise again around the middle of the luteal phase. It is common for women who are tracking their cervical fluid to see another time of estradiol- impacted cervical fluid around 7 to 10 days after ovulation due to rising estradiol concentrations. Like progesterone, estradiol also falls off ahead of menstruation as the corpus luteum begins to atrophy and die in the absence of a pregnancy.
While the rise of estradiol during the follicular phase was necessary to build the uterine lining, the secretion of progesterone during the luteal phase is necessary to maintain that lining. Progesterone is vitally important to nourish a fertilized egg after implantation and before the placenta grows to take over nutrient supply to the developing embryo.
Once the fertilized embryo implants (about 7 to 10 days after conception), human chorionic gonadotropin (hCG) levels begin to rise sustaining the life of the corpus luteum, which continues to release progesterone and estradiol to sustain the uterine lining until the placenta forms.
After ovulation: Menstruation
Menstruation is the result of ovulation. Arbitrarily, the onset of menses is assigned cycle day 1 when in fact follicular development for the next cycle begins just before menses as estradiol and progesterone levels fall allowing for the rise of FSH and the recruitment of new follicles for the next cycle.
As progesterone and estradiol concentrations drop towards the end of the menstrual cycle, GnRH pulses once again slow down stimulating the release of FSH from the pituitary which starts the cycle of recruiting a new cohort of follicles for the next menstrual cycle.
The uterine lining (endometrium) begins to atrophy and slough off the walls of the uterus, and key changes in the quality of cervical mucus and in the position of the cervix allow for the start of menses. Despite its designation as cycle day 1, menses marks the end of the previous ovulatory cycle.
We covered these topics in depth in this article discussing:
- follicular recruitment (just prior to menses)
- follicular development
- luteal phase
- and onset of menses at the end of the cycle/start of a new cycle
We also discussed the brain’s role in ovulation introducing the hypothalamus-pituitary-ovary axis, the hormones released by each of these glands, and how hormonal secretions interplay in feedback loops.
Historically believed to induce ovulation, the role of luteinizing hormone is in fact to luteinize the follicle after ovulation, which allows for the production of progesterone at high concentrations by the luteinized follicle (also known as the corpus luteum).
A low-level surge of progesterone produced by the adrenal glands has been shown in multiple studies to in fact be the hormonal event that triggers ovulation, and this is vastly important to women’s health and reproduction because progesterone creation by the adrenals competes with cortisol creation, and this directly links stress to impaired ovulation, which is observed when women experience illness or major stress events near ovulation. Often ovulation is delayed depending on the magnitude of these events. This particular hormonal event is something we will revisit in future articles around PCOS and anovulatory cycles.
As mentioned at the beginning of this article, you will find a high-level overview of this same topic here where we talk about each of these concepts in brief with key takeaways. You may want to bookmark both of these articles as quick reference for future posts where we revisit these concepts.
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