Beyond Fertility – The Effects of Progesterone on Pain Management, Immune Function, and Bone Remodeling

This is our third blog post about progesterone, which is a fascinating hormone produced by the adrenal glands, reproductive organs, and brain in men and women.¹ Yes - men need progesterone too, even though progesterone is often thought of as a female hormone required for a healthy pregnancy and fertility. While progesterone is produced in the most robust amounts during pregnancy, progesterone is an important hormone that supports general health in both women and men.²

Progesterone is a sex hormone, and there are three classes of sex hormones – androgens, estrogens, and progestogens. Progesterone is one of the progestogen hormones.³ Like all other sex hormones, progesterone is derived from cholesterol after cholesterol is converted to the steroid hormone pregnenolone in the mitochondria.

Progesterone is the most abundant hormone produced by the reproductive glands, and it affects fertility, immune function, pain management, bone health, and more.^1,4 In women, progesterone is primarily synthesized by the corpus luteum in the ovary during the second half of the menstrual cycle (after ovulation), the adrenal glands daily, and the placenta during pregnancy.¹

The red line in the graph below demonstrates the salivary progesterone level present during an average optimal menstrual cycle:

In men, progesterone is predominately produced by the adrenal glands and testes and is a precursor for testosterone production. Therefore, a low progesterone level in a man could be due to dysfunction in the adrenal glands or the reproductive organs.¹

Here is an illustration of the Androgen Pathway, including progesterone:

Consider reviewing our first two blog posts, which offer the latest evidence-based information about the effects of progesterone on fertility, gut motility, healthy skin & hair, metabolism, and more!

Continue reading below to learn more about the importance of maintaining an optimal salivary progesterone level in women and men and how progesterone affects natural opioid levels, pain management, bone health, and immune function.

Progesterone and Pain Management

Progesterone is a sex hormone that also acts as a neuro-steroid since progesterone receptors are widely expressed throughout the nervous system. Many studies have suggested that sex differences influence pain perception in men and women. Researchers speculate pain perception might be different between men and women due to their varying levels of and responses to opioids and steroid hormones.⁴

Clinical studies in humans have discovered that women are less sensitive to pain in the luteal phase of their menstrual cycle compared to the follicular phase. The luteal phase begins after ovulation when progesterone levels are much higher. The researchers describe the phenomenon as a state of “luteal analgesia,” during which there is a significant reduction in the emotional component of pain and reduced brain activation in response to painful stimuli.⁴

The significant changes in hormone levels during pregnancy also appear to modulate the opioid system to reduce pain. Decreased pain sensitivity during pregnancy, or “pregnancy-induced analgesia,” has been demonstrated in many studies. Furthermore, a study of patients undergoing elective Caesarean section showed higher progesterone levels correlated with lower pain levels during and after the surgery.⁴

Sex hormones, including progesterone, directly affect central opioid activity. Scientists have determined that increased levels of progesterone trigger activation of the opioid system in the spinal cord, increase the natural release of endogenous opioids, and decrease sensitivity to pain. According to a study by Kondo et al., progesterone receptors in the central nervous system also play a role in the development of neuropathic pain.⁴

Recent data suggest that prescribed bioidentical progesterone might increase the expression of delta-opioid receptors in the spinal cord and other areas to reduce pain. While changes in pain sensitivity as a result of progesterone administration are still controversial, the research appears promising for pain management.⁴

Progesterone, COVID-19, and Immune Function

Progesterone affects and modulates a wide range of biological processes, including the function of the immune system. Progesterone receptors are present on many immune cells, which suggests these cells respond to natural progesterone levels and progesterone-based treatments.⁵ Nearly all human immune cells express estrogen receptors, progesterone receptors, or both, including natural killer cells, macrophages, dendritic cells, and T lymphocytes (T cells).^5,6,7

The impact of progesterone on the immune system is probably most clear within the context of maternal immune tolerance. The high levels of immune-modulating progesterone that are produced during a healthy pregnancy play a significant role in the phenomenon known as maternal immune tolerance. The implantation of the “non-self” human embryo after fertilization is considered an immunological and biological paradox - a miracle - because the immune system is expected to naturally attack foreign objects or tissues.⁴ The potent anti-inflammatory effects of progesterone are crucial to preventing a mother’s immune system from rejecting and harming the fetus during pregnancy.^8,9

Research has established progesterone offers multi-layered anti-inflammatory benefits in the brain, gastrointestinal tract, uterus, lungs, and many other tissues.^1,9,10 Progesterone reduces lipid peroxidation, oxidative stress, the release of inflammatory cytokines, and cellular apoptosis.⁹

When progesterone binds to its receptor, it blocks the inflammatory NF-kB pathway and inhibits COX-2 to significantly decrease inflammation. Progesterone also affects the production of several pro-inflammatory cytokines, including TNF-α, IFN-γ, and IL-12.⁹ Progesterone stimulates the release of the anti-inflammatory cytokine IL-10 and blocks the degranulation of neutrophils and natural killer cells.^1,4,9 Treatment of T-cells with progesterone shifts them from a Th1 to Th2-type response and induces the synthesis of IL-10, IL-13, and IL-27. In B cells, progesterone supports and optimizes the production of protective antibodies.⁹

Progesterone also has the ability to bind to glucocorticoid receptors (cortisol receptors) to reduce inflammation. Research shows there are higher numbers of glucocorticoid receptors than progesterone receptors in immune cells. Thus, progesterone-induced glucocorticoid receptor stimulation likely offers a robust alternate pathway by which progesterone may modulate the function of the immune system.¹¹

Progesterone also significantly alters cellular signaling and activity to beneficially affect the outcome of mucosal infections along the genital, gastrointestinal, and respiratory tracts.⁵ Progesterone receptors are expressed in lung tissue, and the presence of progesterone affects the vasodilation of blood vessels, controls the relaxation/contraction of smooth muscles to support inhalation, regulates inflammatory cytokines, and may reduce ACE2 expression in the lungs since it reduces ACE2 expression in uterine tissue.¹²

Progesterone regulates many cellular responses during lung infections, which may explain some of the significant differences in clinical outcomes between men and women with COVID-19.¹³ Research shows the treatment of other respiratory infections (such as Influenza A) with progesterone promotes the repair and regeneration of damaged lung tissue by increasing the production of the epidermal growth factor amphiregulin, elevating levels of TGF-b, IL-6, IL-22, and increasing the numbers of regulatory CD39 þ Th17 cells in the lungs.⁵

The research data available thus far provides significant evidence that progesterone and its related compounds profoundly affect mucosal immunity and the pathogenesis of pulmonary infections, including COVID-19.⁵

Early treatment of COVID-19 with estradiol and progesterone enhanced antibody production, reduced the production of pro-inflammatory cytokines and reduced the severity of symptoms in a randomized, placebo-controlled trial.¹³

In another recent clinical trial, researchers administered a 5-day progesterone protocol to men hospitalized with moderate to severe COVID-19. Those who received progesterone required three fewer days of supplemental oxygen and 2.5 fewer days of hospital stay compared with the control subjects.¹⁴ The anti-inflammatory and immunomodulatory effects of progesterone are nonspecific and generally support the phenomenon of immune tolerance.¹⁵

The educated use of prescribed bioidentical progesterone and supporting healthy progesterone levels may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages, with the caveat that the effects of progesterone on innate immune cells may diverge depending upon its concentration.^11,15 As always, optimal and balanced hormone levels are the goal since both high and low hormone levels can contribute to dysfunction.

Progesterone and Bone Health

Bone health is affected by steroid hormones and their fluctuations throughout life in men and women. Common reproductive disorders, including infertility, are often associated with low bone mineral density and suboptimal bone strength. While it is well known that estrogen and testosterone play a major role in promoting bone health, research shows other hormones, including progesterone, have a significant impact on bone physiology.^16,17

Research shows progesterone stimulates bone formation and slows down bone resorption (breakdown), which is a process known as bone remodeling.¹⁰

What is bone remodeling?

Bone remodeling is a normal daily process that is required to maintain healthy bones. Bone remodeling includes bone resorption, which is the breakdown of bone, and bone formation. Yes, bone must be broken down before stronger and healthier bone can be produced. Ideally, these two processes are balanced during adulthood, so bone formation is equivalent to bone resorption.

In individuals with low hormone levels, such as women in menopause or young women without a menstrual cycle, bone resorption occurs at a faster rate than bone formation, leading to a decrease in bone mineral density. Depending on the severity of the reduction in bone mineral density, individuals may develop osteopenia, osteoporosis, or a bone fracture due to suboptimal hormone levels.^16,18

Effects of Progesterone on Osteoclasts and Osteoblasts

An osteoclast is a specialized bone cell that breaks down bone in a process known as bone resorption. Osteoclasts do not survive very long, only days to weeks. Osteoclasts have progesterone receptors, and preliminary evidence suggests progesterone reduces osteoclastic activity, but the direct effect of progesterone on osteoclasts has not yet been thoroughly explored.^10,16

Researchers have investigated the effects of progesterone on osteoblasts more substantially. Osteoblasts are specialized bone cells that build bone, and a healthy osteoblast can be active for months. Like osteoclasts, osteoblasts also express the progesterone receptor. Since the expression of progesterone receptors on osteoblasts is stimulated by estrogen, some of the effects on bone physiology attributed to estrogen may be due to progesterone.¹⁶

Studies show low doses of progesterone increase osteoblastic production of TGF-β1, TGF-β2, TGF-β3, and bone-specific alkaline phosphatase regardless of the estrogen level. Progesterone also regulates the function of metalloproteinases, which may have local beneficial effects on bone remodeling.¹⁶

Effects of Progesterone on Bone Mineral Density

A meta-analysis of randomized controlled trials of more than 1000 menopausal women reported that treatment with estrogen plus progesterone led to a more significant increase in lumbar bone mineral density than treatment with only estrogen.¹⁶

Research also shows premenopausal women with lower bone mineral density tend to have significantly lower progesterone levels during their menstrual cycles despite regular menstrual cycles and normal estrogen levels. Furthermore, studies of healthy fertile premenopausal women with ovulatory menstrual cycles discovered levels of bone formation and resorption markers change across the menstrual cycle. Increased levels of markers of bone formation and, therefore, higher osteoblastic activity are present during the luteal phase when the salivary progesterone level is robust.¹⁶

In women, research shows estrogen and progesterone work together to maintain optimal bone health. Overall, estradiol prevents bone resorption by osteoclasts, while progesterone increases bone formation by osteoblasts while also reducing bone resorption.^9,10

A small clinical trial that included men with asthma demonstrated progesterone therapy markedly increases bone mineral density in men too. When present at an optimal level, progesterone improves bone strength, but elevated levels of progesterone can be detrimental to bone mineral density, particularly in men, since high progesterone levels can suppress the signaling pathways that induce testosterone production. Thus, it is best to ensure your salivary progesterone level is optimal at all times.¹⁶

We hope you have enjoyed learning more about progesterone and the impacts this fascinating hormone has on health in women and men!

Optimal salivary progesterone levels support fertility, healthy skin and hair, balanced mood, healthy gut function, immune resilience, neuroprotection, nerve function, bone strength, pain management, and more in women AND men. Research suggests optimal salivary progesterone levels may improve the health of those with chronic pain, infertility, Alzheimer’s disease, diabetic neuropathy, osteopenia, COVID-19 and other infections and inflammatory conditions, osteoporosis, gastrointestinal issues, hypertension, and other health concerns. Consider asking your doctor to order a saliva hormone panel soon!

Fura-Mag™ is a physician-formulated, highly bioavailable magnesium and vitamin B6 supplement that supports stress management, adrenal function, healthy menstrual cycles, and optimal progesterone levels.*

Flavo PlexC™ is a potent blend of vitamin C, bioflavonoids, and organic plant extracts that supports immunity, a healthy adrenal response, and optimal saliva hormone levels.*

* This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.

YOU MAY ALSO ENJOY

THE BENEFICIAL EFFECTS OF OPTIMAL SALIVARY PROGESTERONE LEVELS ON FERTILITY IN MEN AND WOMEN

The word progesterone means “promoting gestation,” and progesterone is often considered a female hormone since high progesterone levels are present during healthy pregnancy. But - progesterone is also an important hormone that supports fertility and general health in men... In men, progesterone, which is a precursor for testosterone production, is predominately produced by the adrenal glands and the testes. Continue reading this blog post to learn more about the beneficial effects of optimal salivary progesterone levels on fertility in women and men.

SIGNS AND SYMPTOMS OF A HIGH TESTOSTERONE LEVEL (HYPERANDROGENISM) IN WOMEN AND MEN

Many men believe the higher the testosterone level, the better, but high testosterone levels can cause harm. Too much of a good thing is not always good, even in men!  And - it is well-known that high testosterone levels in women are associated with numerous health concerns. Thus, testosterone is a hormone that must be present at an optimal level because abnormally high free testosterone levels can cause significant health issues.

THE BENEFITS OF SALIVA HORMONE TESTING

If you could choose, would you rather spit into a tube or have a needle jabbed into your arm to measure your hormone levels? We suspect you would rather not get stuck with a needle, and you do have a choice! Saliva hormone testing offers many benefits, including painless collection in the comfort of your home at any time. Saliva hormone tests can help determine the underlying cause(s) of PMS, insomnia, anxiety, fatigue, infertility, migraines, weight gain, hot flashes, hair loss, and many other health concerns.

SYNERGISTIC NUTRIENTS FOR ADRENAL SUPPORT – PART 1

Chronic stress is a frequent underlying cause of low nutrient levels and health issues. In fact, according to the World Health Organization (WHO), approximately 450 million people worldwide are affected by stress-related disorders. Research indicates stress could be responsible for an estimated 70% of visits to primary care providers, which is shocking. Fortunately, the consistent use of a synergistic blend of vitamins, minerals, and herbal extracts that nourish the adrenal glands could support a healthy stress response.*

References:

1. Bulletti C, Bulletti FM, Sciorio R, Guido M. Progesterone: The Key Factor of the Beginning of Life. Int J Mol Sci. 2022;23(22):14138. doi:10.3390/ijms232214138
2. Nagy B, Szekeres-Barthó J, Kovács GL, et al. Key to Life: Physiological Role and Clinical Implications of Progesterone. Int J Mol Sci. 2021;22(20):11039. doi:10.3390/ijms222011039
3. Pompili A, Iorio C, Gasbarri A. Effects of sex steroid hormones on memory. Acta Neurobiol Exp (Wars). 2020;80(2):117-128.
4. Kolatorova L, Vitku J, Suchopar J, et al. Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine. Int J Mol Sci. 2022;23(14):7989. doi:10.3390/ijms23147989
5. Hall OJ, Klein SL. Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites. Mucosal Immunol. 2017;10(5):1097-1107. doi:10.1038/mi.2017.35
6. Collins MK, McCutcheon CR, Petroff MG. Impact of Estrogen and Progesterone on Immune Cells and Host-Pathogen Interactions in the Lower Female Reproductive Tract. J Immunol. 2022;209(8):1437-1449. doi:10.4049/jimmunol.2200454
7. Gutzeit O, Segal L, Korin B, et al. Progesterone Attenuates Brain Inflammatory Response and Inflammation-Induced Increase in Immature Myeloid Cells in a Mouse Model. Inflammation. 2021;44(3):956-964. doi:10.1007/s10753-020-01390-y
8. Weng J, Couture C, Girard S. Innate and Adaptive Immune Systems in Physiological and Pathological Pregnancy. Biology (Basel). 2023;12(3):402. doi:10.3390/biology12030402
9. Azeez JM, Susmi TR, Remadevi V, et al. New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling. Am J Cancer Res. 2021;11(11):5214-5232.
10. Alqudah M, Al-Shboul O, Al Dwairi A, et al. Progesterone inhibitory role on gastrointestinal motility. Physiol Res. 2022;71(2):193-198. doi:10.33549/physiolres.934824
11. Shepherd R, Cheung AS, Pang K, et al. Sexual Dimorphism in Innate Immunity: The Role of Sex Hormones and Epigenetics. Front Immunol. 2021;11:604000. doi:10.3389/fimmu.2020.604000
12. Leach DA, Brooke GN, Bevan CL. Roles of steroid receptors in the lung and COVID-19. Essays Biochem. 2021;65(6):1025-1038. doi:10.1042/EBC20210005
13. Gardinassi LG, Servian CDP, Lima GDS, et al. Integrated Metabolic and Inflammatory Signatures Associated with Severity of, Fatality of, and Recovery from COVID-19 [published online ahead of print, 2023 Feb 28]. Microbiol Spectr. 2023;11(2):e0219422. doi:10.1128/spectrum.02194-22
14. Lovre D, Bateman K, Sherman M, et al. Acute estradiol and progesterone therapy in hospitalised adults to reduce COVID-19 severity: a randomised control trial. BMJ Open. 2021;11(11):e053684. doi:10.1136/bmjopen-2021-053684
15. Fedotcheva TA, Fedotcheva NI, Shimanovsky NL. Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation. Biomolecules. 2022;12(9):1299. doi:10.3390/biom12091299
16. Mills EG, Yang L, Nielsen MF, et al. The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens [published correction appears in Endocr Rev. 2021 Oct 01;:]. Endocr Rev. 2021;42(6):691-719. doi:10.1210/endrev/bnab015
17. Seifert-Klauss V, Prior JC. Progesterone and bone: actions promoting bone health in women. J Osteoporos. 2010;2010:845180. doi:10.4061/2010/845180
18. Shufelt CL, Torbati T, Dutra E. Hypothalamic Amenorrhea and the Long-Term Health Consequences. Semin Reprod Med. 2017;35(3):256-262. doi:10.1055/s-0037-1603581