Tolle Causam

Tanya Lee, ND

We are just beginning to understand the complex nature of the immune system and the cross-talk between the immune system and other systems in the body. The influence of sex hormones is not limited to reproductive tissues; they also exert effects on peripheral systems such as the immune system. In the context of autoimmune disease, there is a known female predominance of many autoimmune diseases. Some examples of female-to-male ratios of specific autoimmune diseases include 16:1 for primary biliary cirrhosis; 12:1 for antiphospholipid syndrome; 9-10:1 for systemic lupus erythematosus (SLE); and 2:1 for multiple sclerosis.^1,2 Other autoimmune conditions with female predominance include Hashimoto’s thyroiditis, Graves’ disease, scleroderma, and Sjögren’s syndrome.²

The female predominance of autoimmune disease is highlighted by the fact that the onset of most female-dominant autoimmune diseases occurs following puberty. The ratio of female-to-male risk of SLE and thyroiditis before puberty is lower (3-4:1) than after puberty (9:1), and other autoimmune diseases, such as Sjögren’s syndrome and primary biliary cirrhosis, are extremely rare in pediatric populations.² Autoimmune diseases whose onset typically occurs before puberty, eg, type 1 diabetes mellitus, appear to exhibit no female polarization.² The role of female hormones in autoimmune disease is also observed in symptom severity fluctuations throughout the different phases of the menstrual cycle.³

Both genetic and environmental factors contribute to the risk of autoimmune disease: when genetic risk is high, environmental factors become less influential on the onset and severity of disease progression. Although hormone status may play a role in the risk of developing disease, research has thus far found that modulating hormones appears to impact disease activity far more than disease risk.² While sexual dimorphism of autoimmune disease includes many hormonal factors, female prevalence of certain autoimmune diseases suggest that sex hormones such as estrogen and progesterone are key players in the development and activity of the female-prevalent autoimmune diseases.

Pregnancy is an excellent example for viewing how sex hormones may influence the immune system. There is a dramatic change in hormones during pregnancy, with progesterone and estrogen levels increasing 5-10-fold within the maternal circulation, and then dropping suddenly drop postpartum, alongside significant immunological shifts both during and after pregnancy.² During pregnancy, the immune system must achieve a unique state of equilibrium: being strong and active at the maternal-fetal interface, while also maintaining a state of immunosuppression within the maternal circulation so as to not react to the partially allogenic cells of the fetus. During pregnancy, the uterine lining (the decidua) is an immunologically intense area, tightly regulated in order to ensure the survival of the fetus. Specialized uterine natural killer cells and monocytes are inactivated when encountering the unique HLA-G expression of fetal trophoblastic cells, but are active at disabling any foreign pathogen threatening the fetus.⁴ Other known mechanisms of this pregnancy paradox include T-helper-2 (Th2) dominance, upregulation of anti-inflammatory cytokines and immunosuppressive proteins, downregulation of the classical complement pathway, and the blockage of fetal antigen exposure to the maternal immune system.^2,5

The local protective effects of the maternal-fetal interface appear to be influenced by estrogen and progesterone. While estrogen as well as other steroids play a large role in the totality of the immunological paradox of pregnancy and the development and progression of autoimmune disease, this article will focus on the effects of progesterone on the immune system during pregnancy and in female-prevalent autoimmune disease.

Progesterone’s Broad Actions

Progesterone & the Immune System

Progesterone is a steroid hormone produced by the corpus luteum, uterus, adrenal glands, and the brain. Progesterone (P4) binds to many different receptors on both reproductive and non-reproductive tissues; these receptors include membrane-bound progesterone receptors, intracellular progesterone receptors, and glucocorticoid receptors, which are expressed on human immune cells including mast cells, natural killer (NK) cells, macrophages, dendritic cells, and both CD4+ and CD8+ type cells.^2,3 P4 is generally considered an anti-inflammatory hormone. Some of its known anti-inflammatory mechanisms include the suppression of proinflammatory Th1 and Th17 differentiation, T-regulatory (T-reg) cell induction and expansion (immune modulating), as well as polarization towards Th2 differentiation and activity.⁶

Progesterone in Pregnancy

Progesterone is secreted by the corpus luteum in the early stages of pregnancy, and later by the placenta after week 8 of gestation. P4 levels rise 10-fold within the maternal circulation and 100-fold within the placenta.³ This high concentration of P4 is strong enough to signal through the glucocorticoid receptor, which is thought to be one of the mechanisms for the immunosuppressive effect seen during pregnancy.⁷ The surge of P4 is credited for Th2 shift, for the expansion and production of the Th2-promoting cytokine, interleukin (IL)-4, the increased expression of uterine NK cells, the suppression of inflammatory cytokine, Th17, and the induction of the T-reg cells during pregnancy.^2,3 A recent study by Shah et al observed that administration of progesterone to healthy, pregnant women suppressed the production of interferon-gamma (IFN-γ), a promoter of Th1-mediated immunity. The study also found that mifepristone, a progesterone receptor antagonist, induced IFN-γ expression.⁸

Progesterone & Autoimmune Disease

The transient modification of the immune system during pregnancy and the clear influence of pregnancy on the presentation of different autoimmune conditions serves as a gateway for our understanding of the role progesterone plays in autoimmune disease. While research specifically studying the effects of natural P4 is still lacking, a strong backbone of evidence suggests that therapeutic use of P4 in certain autoimmune diseases may be beneficial in modulating the activity of the disease.

Rheumatoid Arthritis

The hormonal influence in rheumatoid arthritis (RA) is illustrated by the symptomatic changes that occur with the fluctuations of the menstrual cycle, the remission of symptoms during pregnancy, and the increase in flares in the postpartum period.^9,10 RA onset typically occurs after menopause (45-75 years) and nulliparity appears to increase the risk of developing RA, suggesting that estrogen and progesterone may play a protective role in the risk and disease activity of RA.¹¹ The rapid withdrawal of progesterone postpartum may contribute to the increase in risk of RA in susceptible women after delivery.¹² In RA, there is a marked increase in the inflammatory Th17; as discussed, progesterone has been found to induce T-reg cells, suppress Th17 and Th1 differentiation, and promote Th2 dominance, suggesting its protective role in RA. An earlier study by Valentino et al found that women with RA exhibited significantly lower progesterone levels during the luteal phase of the menstrual cycle as compared to healthy controls.¹³

However, there is very little in the way of evidence supporting the use of progesterone alone for managing the risk and activity of RA. In fact, many studies (both in vivo and human) fail to show consistent results regarding the influence of P4 in RA, with many showing no amelioration of symptoms of RA by hormone replacement therapy (HRT).^11,14,15

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune condition targeting the central nervous system, driven by myelin-specific CD4+ Th1 cells and inflammatory cytokines. Considering the Th2-promoting effect of progesterone, and its known neuroprotective, anti-inflammatory and pro-myelinating properties, this hormone has been a therapy of interest for modulating disease activity in MS.¹⁶ Similar to RA, the hormonal impact of progesterone on disease activity in MS is represented by the amelioration of symptoms during pregnancy and the increase in disease flares within the postpartum period.² The immunomodulatory effect of progesterone can be observed in animal models of experimental autoimmune encephalitis (EAE) – the in-vivo representation of MS. These animal models have shown that, at the onset of EAE, progesterone can suppress inflammation by reducing proinflammatory IL-2, IL-17, and IL-23, and increasing B-cells and anti-inflammatory IL-10, thereby reducing the severity of disease progression.¹⁷ In another in-vivo model of demyelination, Ye et al found that treatment of progesterone at the onset of disease ameliorated demyelination and the resulting neurobehavioral deficits.¹⁸

An ongoing human clinical trial plans to determine the effects of high-dose progestin administration on postpartum MS flares at the onset of the postpartum period.¹⁹

Systemic Lupus Erythematosus

The typical onset of SLE, occurring between menarche and menopause, as well as the high female:male dominance (9:1) of this disease, suggest that hormones play a role in the development and activity of SLE.¹¹ Early menarche is considered an independent risk factor for SLE, and initial SLE flares in women have been linked to low P4, indicating a pathogenic role of estrogen and a protective role of P4 in both the risk and activity of SLE.¹¹ Symptoms of SLE have been found to be exacerbated by pregnancy, with SLE flare rates higher in pregnant patients compared to non-pregnant patients.²⁰ SLE flares have been associated with Th2 dominance and increased humoral activity, a state that is favorable for other autoimmune conditions, such as RA and MS.³ However, there is also evidence that pregnancy itself does not influence the risk of SLE flares and that the biggest risk factor for SLE flares during pregnancy is the severity of disease activity 6 months prior to conception, as well as the discontinuation of medication at the onset of pregnancy.²¹ Therefore, high circulating levels of hormones may not actually influence disease activity in SLE, as compared with autoimmune conditions such as RA and MS.

A link has been observed between estrogen-containing HRT and oral contraceptive (OCP) use, as well as a dose-dependent relationship between the level of estrogen in HRT/OCPs and the risk for SLE flares in those with active disease.^22,23 SLE patients often experience P4 deficiency during the luteal phase of the menstrual cycle, suggesting that P4 may have a protective role against SLE; however, it is unknown if this is a consequence of the disease or a risk factor.²Progestin-only forms of OCPs and HRT do not appear to increase risk and can even reduce flares of SLE.²⁴High circulating levels of type 1 IFN-α and IFN-ß are a hallmark of SLE.³ A recent study found that progestogens (natural progesterone and synthetic medroxyprogesterone acetate) appear to suppress plasmacytoid dendritic cell production of IFN-α, as well as the activation of the IFN-inducing transcription factor IRF-5.²⁵ This indicates that modifying P4 levels may be an effective target for modulating disease risk and activity of SLE.

While there is some evidence to suggest that there is no conferred difference in the risk of SLE flares between combined and progestin-only OCPs and copper IUDs, other studies suggest that estrogen is an aggravating factor in terms of a link between SLE flares and HRT.² However, especially considering the high risk for thrombosis in SLE patients (specifically those with high anti-phospholipid antibodies), progesterone-only OCPs should be considered for SLE patients seeking oral forms of contraception.²

Clinical Considerations

While many experimental animal models indicate that progesterone may have a large impact on immunological function and disease activity of autoimmune conditions, human clinical trials are greatly lacking. Existing observational studies on the impact of HRT and OCPs on autoimmune disease typically used synthetic progestins to represent P4 activity rather than bioidentical P4, which would typically be the treatment of choice by naturopathic doctors. Considering the influence of physiological P4 on immune function observed in pregnancy when P4 levels are peaked, it may be safe to assume that bioidentical P4 represents a viable treatment option to mimic these effects.

Another consideration are the inconsistent results from using HRT in autoimmune disease. Many of these studies fail to provide treatments that mimic the physiological levels of pregnancy; the activity of progesterone on progesterone- and glucocorticoid receptors (GRs) is dose-dependent, with the latter requiring extremely high levels of P4 (pregnancy levels) for activation.² GR activation has been proposed as the main mechanism of immune modulation by P4, given that these receptors are highly expressed on immune cells and that steroids that bind to the GRs (ie, corticosteroids) are the standard treatment for inflammatory flares in autoimmune disease.²⁶ Perhaps dosing bioidentical progesterone at levels mimicking pregnancy can produce more consistently positive results.

Considering the currently available research, bioidentical progesterone may be a viable option in modifying disease activity in female-dominant autoimmune diseases. Clinicians should base this treatment on the patient’s individual requirements – the category of autoimmune disease (ie, whether it is a female-dominant type) and outcomes of progesterone testing. A detailed history of menstrual cycle activity and fertility should be used to help determine whether progesterone might be a treatment of value for an autoimmune patient.

Autoimmune diseases still remain as complex, multifactorial conditions that are influenced by genetic, stochastic, and environmental triggers. It would be silly to consider hormones to be a sole contributing factor when managing female-dominant autoimmune disease. However, insights into how hormones impact risk and disease activity in autoimmune disease provide clinicians a valuable tool to consider when treating autoimmune patients.

References:

Tanya Lee, ND, received her Bachelor of Science degree (Honours) in Biochemistry and Biomedical Sciences from McMaster University, and was trained as a naturopathic doctor at the Canadian College of Naturopathic Medicine. Dr Lee practices full-time between 2 clinics, located in Toronto and Milton, Ontario. Although her primary-care practice focuses on family medicine, Dr Lee treats a wide variety of conditions, including endocrine disorders, infertility, digestive problems, cardiovascular disease, diabetes, insomnia, and fatigue. She has a special interest in the treatment of autoimmune diseases, as well as pediatric health.

Female-Dominant Autoimmunity: The Role of Progesterone

Tolle Causam