For this article, we’ve invited Dr. Tanya Lee, a naturopathic doctor and herbalist, to share with us the ways in which fluctuations in the hormone progesterone have been linked to symptom flares or reductions in various autoimmune conditions. She also explains whether or not progesterone therapy is a realistic option for mitigating symptoms, and gives us a glimpse into why autoimmune disease might be so much more prevalent in women.
The impact of hormones in autoimmune disease is represented by the clear female predominance in a number of autoimmune conditions. Female to male ratios of specific autoimmune diseases include primary biliary cirrhosis 16:1, antiphospholipid syndrome 12:1, systemic lupus erythematosus (SLE) 9-10:1, and multiple sclerosis 2:1. (1, 2) Other autoimmune conditions with female predominance include Hashitmoto’s thyroiditis, Graves’ disease, scleroderma, Sjorgens’s syndrome. (2)
The hormonal influence on autoimmune disease is highlighted by the fact that the onset of most female-dominant autoimmune diseases occur after puberty. For example, the ratio between female:male risk of SLE and thyroiditis before puberty is lower (3-4:1) than after puberty (9:1), and other female-dominant autoimmune conditions, such as Sjorgen’s syndrome and primary biliary cirrhosis, are extremely rare before puberty. (2)
The role of female hormones in autoimmune disease is also represented in the fluctuations in symptom severity throughout the different phases of the menstrual cycle. (3) Pregnancy is an excellent example of how sex hormones can influence our immune activity. Pregnancy requires the changes in the immune system to achieve a state of balance between protecting the baby from infection, and preventing mother’s immune system from being triggered to attack the foreign DNA expressed by the developing fetus. (4) This balance has been found to be achieved through the influence by both estrogen and progesterone. In pregnancy, progesterone and estrogen levels increase by 5 to 10-fold and drop steeply after childbirth. (2, 5) While estrogen plays a significant role in these changes, progesterone will be the focus of this article.
Progesterone and Autoimmune Disease
Progesterone is a hormone that is secreted abundantly during the second half of our menstrual cycle, and continues to rise throughout pregnancy. During pregnancy, progesterone rises 10-fold in the maternal bloodstream and 100-fold within the placenta. (3) Progesterone is generally considered an anti-inflammatory hormone and high levels of progesterone is considered one of the strongest signals that influences the balance of the immune system seen in pregnancy. (6, 7) A study by Shah et. al observed that administration of progesterone (P4) to healthy, pregnant women reduced markers of inflammation within the maternal bloodstream. (8)
The hormonal influence in RA is represented by the symptomatic changes that occur within the menstrual cycle, the reduction of symptoms during pregnancy, and the increase in flares after childbirth. (9, 10) An increased risk after menopause (45-75 years) has also been observed, specifically in non-child bearing women. (11) The rapid drop in progesterone that occurs postpartum may contribute to the increase in RA flares after delivery. (12) An earlier study by Valentino et. al found women with RA exhibited significantly lower progesterone levels during the luteal phase of the menstrual cycle compared to the control group. (13) In RA, one of the most significant contributors to inflammation is the cytokine Th17; progesterone has been found to suppress Th17, suggesting its protective role in RA. (6) At this point, evidence supporting the use of progesterone alone for use in RA are lacking, and the results of existing studies are inconsistent. (11, 14, 15)
MS is an autoimmune condition targeting the insulation layer of the nerves (called the myelin sheath) contained in the central nervous system. An autoimmune flare results in “demyelination” of nerves which contributes to the core neurological symptoms presenting in MS. Progesterone has been known to be neuroprotective, anti-inflammatory and to hold pro-myelinating properties, making this hormone a therapy of interest in MS. (16) Similar to rheumatoid arthritis, the hormonal impact of progesterone on disease activity is represented by the reduction of symptoms during pregnancy, and the increase in flares after childbirth. (2) These animal models of MS have shown that progesterone can suppress inflammatory Th17 cells, increase anti-inflammatory cells, reducing the severity of disease. (17) One animal study found that treatment with progesterone at the onset of disease relieved demyelination and symptoms of MS. (18) A current human clinical trial is ongoing to determine the effects of using high-dose progestin after childbirth on MS flares. (19)
Systemic Lupus Erythematosus
The typical onset of SLE occurring between puberty to menopause and the high female:male dominance (9:1) suggests hormones play a role in the risk and activity of SLE. (11) Women with SLE appear to have lower progesterone levels compared to controls, SLE flares are known increase during pregnancy and in females with low progesterone, and early puberty is considered an independent risk factor for SLE; these examples point to the role of both excess estrogen and low progesterone in SLE risk and severity. (2, 11, 20) A dose-dependent link has been established between estrogen-containing hormone replacement therapy (HRT) and oral contraceptive (OCP) use, and the risk for SLE flares. (22, 23) Progestin-only (synthetic progesterone) containing forms of OCP and HRT do not appear to increase risk of SLE flares and actually have been found to provide relief in symptoms related SLE flares. (24) A recent study found that progestogens (bioidentical progesterone and synthetic DMPA) both appear to suppress inflammatory markers IFN-a, which is a known inflammatory marker in SLE. (25) This indicates that modifying progesterone levels may be a considerable target for improving risk and activity of SLE. Considering high-estrogen containing OCP is linked to increased risk for clotting, coupled with the pre-existing risk for clotting in SLE patients (specifically those with high anti-phospholipid antibodies), progesterone-only OCPs should be considered for SLE patients seeking oral forms of birth control. (2)
Based on the existing research and its wide use as a safe HRT, progesterone may be a viable treatment option for specific autoimmune diseases including RA, MS and SLE. Research has found that activity of progesterone on progesterone (PR) and glucocorticoid (GR) receptors on immune cells is dose-dependent and extremely high levels of progesterone (pregnancy levels) may be required for activation. (2) This is important because GR activation has been proposed to be the main anti-inflammatory mechanism of progesterone, and corticosteroids which bind to the same GRs are the standard treatment for inflammatory flares in autoimmune disease. (26) Perhaps dosing progesterone at levels mimicking pregnancy may show more consistent, positive, results in studies. (21)
Remember, autoimmune diseases are complex, multifactorial conditions that are influenced by a number of physiological and environmental triggers. Treatment (including hormonal) considerations should always be based on your individual requirements. A good clinician should take into account the category of autoimmune disease (i.e. whether it is of female-dominant type) and associated risks, your symptom presentation, outcomes of progesterone testing as well as a detailed history of your health, including menstrual cycles and fertility. All of these factors together should act as a clinical guide to determine if progesterone support may be a treatment of value in your case.
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