Progesterone

Progesterone is a steroid and sex hormone that is created endogenously (by our own bodies) in the female reproduction organs, adrenal glands, adipose tissue, and nervous tissue, especially the brain. It is the primary hormone in the steroid class progestogens. Although widely known to play a large role in the menstrual cycle and pregnancy, scientists are just beginning to understand the enormous range of effects progesterone can have on the human body and its many systems.

Progesterone vs. Progestins
Progestins is a general term for substances or medications that produce some or all of the effects of progesterone. Progestins are used by pharmaceutical companies in medications and contraceptives. They are purposefully created to differ in structure from progesterone for patenting purposes (it is often not possible to patent a chemical as it exists in nature) and in order to create desired side-effects such as those that prevent pregnancy from occurring.

Women that take progestins should be aware that these hormones do not perfectly mimic natural progesterone, because they can cause unwanted side-effects, ranging in severity from acne to increased risk of breast cancer.

Bio-Identical Progesterone and BHRT
Many functional medicine doctors have begun supplementing patients with imbalanced hormone levels with bio-identical hormone replacement therapy (BHRT). The term "bio-identical" distinguishes these hormone supplements from the more conventionally used synthetic hormones created by pharmaceutical companies, because unlike the latter, bio-identical hormone supplements are identical in molecular structure to the natural hormones our bodies create. Whereas hormone replacement therapy (HRT) is widely known and highly conventional among mainstream medicine, BHRT is most often only heard of in functional or integrative medicine. A practitioner who uses BHRT will likely measure your hormone levels via saliva or blood sample, and prescribe your hormones through a compounding pharmacy.

Bio-identical progesterone is synthesized from the naturally occurring diosgenin in wild yams or from the stigmasterol found in soy beans and can be taken as a transdermal cream, pill, or vaginal gel. Over-the-counter progesterone supplements exist, but are likely too weak to be effective, and therefore a prescription is needed.

Although bio-identical progesterone is sometimes considered more "natural" than progestins because its molecular structure is identical to endogenous progesterone, both progestins and bio-identical progesterone are synthesized by humans. Many believe bio-identical progesterone to be safe, but more long-term research studies are needed to confirm this.

Follicular Phase
At the beginning of a woman's cycle, the hypothalamus begins to secrete Gonadotropin Releasing Hormone (GnRH), stimulating the pituitary to create Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which travel to the ovaries. FSH causes follicles in the ovaries to begin to mature. Several follicles, each of which stores an egg, begin to grow as they mature, and in the process release estrogen. This estrogen produces a negative feedback during the first 10 days of the cycle that tells to the pituitary to inhibit the release of LH. It is important to note that low levels of estrogen will inhibit the release of LH from the pituitary, while high levels will stimulate it.

Ovulation
As estrogen continues to rise due to the maturing follicles, it also causes FSH levels to fall steadily (low estrogen levels trigger the release of FSH). Around day 10 of the cycle, estrogen levels reach a threshold which stops the negative feedback of LH and begins a positive one resulting in the secretion of LH by the pituitary. The resulting spike in LH triggers the most mature follicle to release an egg (or oocyte); this is called ovulation.

Luteal Phase
After ovulation, the empty follicle will begin to die. This dying follicle is called a corpus luteum. As the corpus luteum degrades, it secretes three hormones: estrogen, inhibin, and progesterone. Inhibin provides a negative feedback to the pituitary to suppress the production of FSH. Progesterone provides a similar feedback to prohibit the release of GnRH, which in turn decreases the levels of LH and FSH. It also stimulates endometrial growth (the interior lining of the uterus).

As the corpus luteum degenerates, it will secrete fewer and fewer hormones, and progesterone, estrogen, and inhibin will steadily decrease. In the absence of fertilization, the decreasing levels of progesterone can no longer maintain the lining of the uterine wall, so the wall dies and sheds out of the body, resulting in menstruation. This decrease in progesterone also allows for the secretion of GnRH to begin again, and the cycle repeats.

Progesterone only exists in high levels during the second half of the menstrual cycle, the Luteal Phase. In the absence of fertilization, the corpus luteum will last for 11 to 17 days; it is during these days a woman can expect progesterone levels to be highest.

Exogenous Progesterone, Preventing Ovulation, and Contraceptives
Many contraceptives use progestins (synthetic progesterone) to prevent ovulation. They can also prevent pregnancy by thickening the cervical mucus, which blocks sperm from entering the uterus, and thinning the lining of the uterine wall, which prevents implantation of a fertilized egg (although endogenous progesterone helps to thicken this lining, the slightly different structure of some progestins results in the opposite effect). The most common form of birth control, combined oral contraceptive pills, also simply called "The Pill," uses progestins and estrogen to prevent pregnancy.

How Progestins & Progesterone Prevent Ovulation
The chemical process by which progesterone and progestins prevent ovulation centers around their ability in the Follicular Phase to stop the release of Luteinizing Hormone (LH) by the anterior pituitary. Progesterone/progestins naturally create a negative feedback to the Hypothalamus, causing the latter to inhibit the release of Gonadotropin Releasing Hormone (GnRH). Without enough GnRH to stimulate the release of LH from the pituitary, LH levels will not spike as they usually do around day 13-14 in the cycle, and ovulation will not occur.

Endogenous Progesterone Levels in Luteal Phase when Ovulation Fails
This failure to ovulates means no follicle will release an egg and degrade into a corpus luteum. The corpus luteum (CL), or dying follicle, is the main source of endogenous progesterone in the female cycle, therefore without the CL, endogenous progesterone levels will remain low during the second half of the cycle. Women taking either progestins or exogenous bio-identical progesterone at certain levels should be aware that this process halting the production of endogenous progesterone may be taking place, especially for those trying to conceive and because this hormone plays an important role not only in reproduction, but in the brain as well (see "Progesterone in the Brain" below).

There is currently no research suggesting universally "safe" levels of exogenous bio-identical progesterone doses that will not prevent ovulation from occurring. The hormone feedback loops that are integral to the female cycle are incredibly complex and sensitive, and exogenous progesterone is metabolized at different rates in different females. These factors make ovulation-safe levels very difficult to predict.

Reference Ranges
Reference ranges vary slightly by lab; the following is an example of reference ranges for progesterone levels in blood serum used by the Mayo Clinic: *Reference intervals are based on central 90% of healthy population

Progesterone & Estrogen: A Balancing Act
One of the reasons it is difficult to measure the effects of progesterone and estrogen is that these two primary female sex hormones work in concert with each other, and it is therefore often the case that their ratio is more important than their independent levels. Many of the functions of estrogens are countered by progesterone including tissue growth, inflammation, immune function, and uterine muscle contraction. When progesterone does not exist in sufficient levels in the body, it results in "estrogen dominance," which can lead to breast cancer, endometriosis, and other pathologies. It is in establishing the correct levels of both estrogens and progesterone that a healthy homeostasis is achieved and the pathogenesis of endometriosis, infertility, cancer, and more can be diminished.

Inflammation
Although estrogen has some anti-inflammatory effects, it most often functions as a pro-inflammatory hormone. Progesterone, on the other hand, which often down-regulates estrogen-mediated actions, functions as a powerful anti-inflammatory steroid. Both are critical in maintaining a normal menstrual cycle and healthy pregnancies. Estrogen's inflammatory effects in the absence of progesterone's anti-inflammatory actions are necessary for stimulating the shedding of the uterine wall in menstruation, and some scientists even describe menstruation itself as an "acute inflammatory response of ESCs [endometrial stromal cells] to progesterone withdrawal."

Progesterone's anti-inflammatory effect has also been found to aid in recovery from traumatic brain injury in rats, fight gingivitis in monkeys, and decrease signs of autoimmune encephalomyelitis (EAE) in mice. It is known to suppress pro-inflammatory cytokines, such as the inhibition of IL-6 and IL-8 in the inflammatory response to lipopolysaccharides in human uterine cervical fibroblasts.

It is unknown whether progesterone functions independently as an anti-inflammatory, or whether it must work in concert in estrogen to have this effect.

Progesterone Resistance & Inflammation in Endometriosis
Endometriosis is a condition in which tissue grows not only on the internal walls of the uterus, but also on the ovaries, fallopian tubes, and external uterine walls, resulting in pain and sometimes infertility. Research suggests that the etiology of endometriosis centers around a disruption of estrogen-progesterone homeostasis in the uterus, caused by "progesterone resistance," which leads to increased inflammation. This progesterone resistance may lead to increased production of estrogen and pro-inflammatory cytokine presence including IL-1β, TNF-α, LIF, IL-6, IL-8, IL-11, NF-kB, p53, and STAT3. While these cytokines aid in embryonic implantation, levels that are too high or last too long can lead to aberrant outcomes like endometriosis. Through studying the effects of progesterone on endometriosis and other conditions related to estrogen-dominance, many researchers are optimistic about the development of future treatments.

Understanding the Effects of Progesterone and Estrogens
Deciphering the roles of progesterone and estrogen is extremely difficult because both can have a wide range of effects. Both hormones can have pro- and anti-inflammatory functions, depending on the physiological circumstances. Both can also lead to one outcome at low levels and the opposite outcome at high levels (see negative/positive feedback in "Role in the Menstrual Cycle" above).

Progesterone and estrogen act on cells by binding to specific receptors. Progesterone binds to two main receptors: PR-A and PR-B. When binding to the latter, progesterone decreases inflammation and increases responsiveness to estrogen, while binding to the former has the inverse effect.

Progesterone as a Neurosteroid
Progesterone not only plays a major role in female reproduction, but has many other important roles in both males and females. One such role is as a powerful neurosteroid. Neurosteroids are steroids synthesized in the brain that regulate the excitability of neurons. It has been shown to be important in myelin repair in rodents in the sciatic nerve. In this study, the administration of progesterone to the site of brain lesions led to the regeneration of new myelin sheaths. Neurosteroids can have powerful effects on both pain perception and inflammation, and research has suggested that female sex hormones like progesterone play a key role in modulating chronic pain. Progesterone has been shown in mice to prevent neurodegeneration, increase muscle strength, and enhance respiratory activity. The same study showed that progesterone blocked pro-inflammatory mediators, lessened Iba1+ microglial cells, and decreased symptoms of brain inflammation in mice. It also reduced the production of nitric oxide and TNF-α. Progesterone is neuroprotective, anti-inflammatory, and promyelinating, and could present great benefits for neurological illnesses. However, other studies have shown higher progesterone levels predict worse outcomes for traumatic brain injury in human females.

In the conclusion of a 2018 survey of literature related to neurosteroids, Del Río et. al. wrote the following:"'The present review shows that fluctuations in steroid hormones, influenced by factors such as age and health status, have consequences at the level of CNS [central nervous system] and PNS [peripheral nervous system]. Utilizing both classical and non-classical pathways, neurosteroids participate in the physiological regulation of neurogenesis, neuronal survival, synaptic function, and myelin formation, thus influencing neuronal plasticity. Because of these effects, neurosteroids will have different modulatory actions, exerting control over mood, cognition, and behavior. Additionally, they have a neuroprotective role in relation to certain neurocognitive pathologies.'"

Pain Modulation
Neurosteroids have been found to affect the sensory nervous system in ways that may prevent central sensitization (the process by which the NS becomes heightened to pain perception), and therefore reduce chronic pain. Researchers believe that both the administration of synthetic neurosteroids and treatments that promote the genesis of endogenous neurosteroids like progesterone could hold great promise for future pain management therapies. The latter has proven successful in several animal studies measuring neuropathic, inflammatory, and post-surgical pain.

Autonomic Nervous System
Progesterone has been shown to bind to receptors in the brainstems of rats that modulate pain as well as those that regulate the autonomic nervous system (ANS), the part of the NS that controls unconscious processes like heart rate, breathing, and digestion. Research has also shown increased autonomic cardiac function in human females during the ovulation phase, when progesterone begins to rise rapidly. However, it is unknown whether this is a result of progesterone alone or progesterone combined with estrogen. The latter theory is supported by studies that have shown autonomic regulation of cardiac function suffers during the Luteal Phase and that estrogen is likely to play a stronger role in sympathetic cardiac balance than progesterone.

Mood
Progesterone is well-known to have a calming effect and promote feelings of "elation and vigor." Some medical experts believe low progesterone to estrogen ratios are often the source of anxiety disorders.

Progesterone and Collagen
The existing medical literature presents conflicting data on the relationship between of female sex hormones and connective tissue, joint laxity and tendons. Much more research is needed, but we do know that these hormones are integral to changes in the tissues of the cervix, endometrium, and other parts of the female reproduction system, especially during pregnancy.

One study has shown progesterone had negative effect on ligament strength, measured by the higher likelihood of anterior cruciate ligament injury in female athletes following ovulation. Other studies support this finding. However, Miller et. al. have shown that "there is no effect of menstrual cycle phase, at rest or in response to an acute bout of exercise, on myofibrillar protein synthesis and muscle collagen synthesis in women." There is evidence that combined oral contraceptives (containing both estradiol and progestins) have an "inhibiting effect on collagen synthesis in tendon, bone, and muscle connective tissue, which may be related to a lower bioavailability of IGF-I [insulin-like growth factor]." Estrogen and/or testosterone are believed to have a protective effect on collagen strength as skin ages.

The results of one analysis of 386 women with Hypermobility Type Ehlers Danlos Syndrome (hEDS), a connective tissue disorder, suggested that hEDS symptoms, including fatigue, improve with the administration of progestins. About one-third of the women reported a worsening of symptoms around menstruation (when both estrogen and progesterone are low). The following two tables are from the aforementioned study:

The influence of Hormones on hEDS Symptoms (hEDS Symptoms: Chronic Pain, Fatigue)
* Combined hormonal contraceptives (estrogen and progestins)