Abraham Tsur1 , Grant C. Hughes2 and Yehuda Shoenfeld3, 4
(1)
Obstetrics and Gynecology, Sheba Medical Center, Tel Hshomer, Israel
(2)
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA
(3)
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
(4)
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Abraham Tsur
Email: avitsur@gmail.com
1 The Impact of Sex Hormones on the Immune System
The human immune system exhibits sexual dimorphism. Approximately 78 % of patients affected with an autoimmune disease (AD) are women [1]. The female to male ratio may vary from 9:1 and higher in systemic lupus erythematous (SLE), Sjögren’s syndrome and autoimmune thyroid disease, to 3:1 in multiple sclerosis (MS) and rheumatoid arthritis (RA). Only a few ADs are more common in men, but include the spondyloarthropathies, autoimmune diabetes and Guillain-Barré syndrome [2, 3]. Moreover, men and women show different susceptibilities to allergy and infection, and these differences are influenced by hormonal status [4, 5].
The immunomodulatory effects of sex hormones are a major factor leading to the sexual dimorphism described above. Non-hormonal factors are also important. These include sex-dependent expression of genes encoded on X [6] and Y [7] chromosomes, microchimerism [8] and gender related behavioral factors. The hypothesis that sex hormones are a major player associated with sexual immune dimorphism is supported by the observation that many ADs appear, fluctuate or resolve when there are hormonal changes, such as at the beginning of the menstrual cycle, during the cycle, pregnancy or puerperium, and following hormone replacement therapy (HRT) or hormonal contraception [3]. Moreover, the risk of certain allergic diseases and infections is closely associated with hormonal status. At present, there is abundant data regarding the immunomodulatory effect of estrogen, while the data and understanding of the effects of progestogens is lagging behind considerably.
1.1 Progestogens Effects on Different Components of the Immune System
Progestogens, whether natural or synthetic, modulate inflammation, immunity and autoimmunity through direct actions in cells of both the innate and adaptive immune systems. Leukocytes express a broad range of specific hormone receptors, including nuclear and membrane progesterone receptors [9].
Two important targets of progestogen immunomodulation are T cells and B cells. T cells protect against infection by causing the elimination of infected cells and by providing maturation signals to B cells. B cells in turn produce antibodies (Abs), which can neutralize and kill pathogens. In AD, healthy tissues are attacked by T cells and self-reactive Abs, called auto-antibodies (autoAbs). A subset of T cells, T helper (Th) cells, is strongly regulated by progestogens. During pregnancy, high levels of progesterone and estrogens appear to suppress the development and functions of Th1 and Th17 cells while facilitating the development and functions of Th2 cells. Th1 cells are important for defense against intracellular pathogens, but one of their effector molecules, interferon-gamma, appears to be particularly dangerous to the developing fetus [10, 11]. Th17 cells, characterized by production of pro-inflammatory IL-17, are believed to be involved in the chronic inflammation of RA and MS [12], and their activation is associated with recurrent pregnancy loss [13]. During pregnancy, progesterone appears to foster the induction of regulatory Th cells (Tregs) [9], which might prevent harmful responses to the fetus by the maternal immune system [14]. Thus, during pregnancy, progesterone directs the maternal immune response toward increased Treg/Th2 activity and reduced Th1/Th17 activity. While this shift possibly is involved in the remission of rheumatoid arthritis and multiple sclerosis during pregnancy, it could also explain why pregnant women have an increased risk of infection with some intracellular pathogens such as Listeria monocytogenes, HSV-2 and HIV [15–17].
Progesterone and estrogen have important effects on B cell differentiation and effector functions. Progesterone suppresses immunoglobulin class switch recombination and somatic hypermutation in B cells. These two processes are required for B cells to make highly protective Abs or highly pathogenic autoAbs. This may be one mechanism whereby progesterone protects against certain autoAb-mediated ADs. Interestingly, estrogen enhances these same pathways, suggesting that the balance between progesterone and estrogen is an important determinant of outcomes in Ab-mediated responses [18]. During pregnancy, progesterone and other pregnancy hormones might induce remission of rheumatoid arthritis by altering post-translational glycosylation of autoAbs, rendering them less capable of inducing inflammation [19, 20].
Progestogens also regulate inflammation through their effects on components of the innate immune system. Upon sensing infection and other triggers, cells of the innate immune system (e.g., dendritic cells and macrophages) release inflammatory mediators and prime the adaptive (memory) response by presenting antigens to immature T cells and B cells. Progesterone appears to program dendritic cells that favor the differentiation of Tregs, but not Th1 or Th17 cells [21]. Importantly, progesterone suppresses the production of several pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6 and IL-23) involved in the pathogenesis of RA by dendritic cells and macrophages. This progesterone action, in concert with up-regulation of endogenous inhibitors of IL-1β and TNF-α, could be an important mechanism of pregnancy-induced RA remission [22]. In MS, progesterone also appears to protect against disease through direct actions on the central nervous system [23]. However, the anti-inflammatory effects of progesterone may also increase the risk for certain infections: Suppression of the innate anti-viral cytokine IFN-alpha by high-level progestogens may explain why pregnant women or women using medroxyprogesterone birth control have a significantly increased risk of acquiring HIV [24].
In summary, Progestogens act on several key components of the immune system to control inflammation, immunity and autoimmunity. During pregnancy, the immunomodulatory actions of progestogens contribute to maternal tolerance of the immunologically semi-allogeneic fetus. Some of these actions may help explain two immunological phenomena associated with pregnancy: the remission of rheumatoid arthritis and multiple sclerosis and increased susceptibility to infection with certain pathogens including HIV.
1.2 Progestogens Effect on Specific Autoimmune Diseases
Progesterone levels vary throughout the different life phases. An initial rise occurs post puberty with the beginning of ovulation and the menstrual cycle. Progesterone levels fluctuate with each subsequent cycle, peaking in the mid-luteal/secretory phase then returning to basal levels during the estrogen-dominant follicular/proliferative phase. The most prominent and prolonged rise in progesterone (and estrogen) levels occurs during pregnancy. After menopause, progesterone levels decline back to their pre-puberty levels. These physiological changes represent an opportunity to examine the effects of progesterone levels on immunity and autoimmune diseases.
Pregnancy is of special interest. The maternal immune system must tolerate the paternal antigens presented by the semi-allogeneic fetus, while maintaining adequate immune defenses to protect both mother and fetus from invading pathogens [25]. Nevertheless the rise of progesterone during pregnancy is accompanied by a rise in the level of estrogens. The only period in which there is a surge of progesterone without a similar surge of estrogen is during the mid luteal phase and this is a limited period of a few days. Therefore examining the impact of progestogens on specific diseases requires a comprehensive view of the different phases and while comparing observations with the mechanism of action of progesterone as described above.
1.2.1 Rheumatoid Arthritis (RA)
Several studies have shown that pregnancy leads to improvement of RA in half to three quarters of patients, followed in many cases with a post partum flare [26, 27]. In addition, it has been demonstrated that during the luteal phase of the ovulatory cycle there is a subjective improvement in morning stiffness and pain accompanying RA [28]. As mentioned above, high systemic progesterone levels during pregnancy may contribute to remission of RA via enhancement of Th2 and Treg activity, decrease of Th1 and Th17 production, and inhibition of the inflammatory cytokines IL-1β, IL-6, TNF-α and IL-23. Interestingly it has been demonstrated that the described improvement occurred more frequently (75 %) in women negative for both ACPA and RF than in women with these antibodies (39 %) [29].
1.2.2 Multiple Sclerosis (MS)
During the second and third trimesters there is a decrease in frequency of MS relapses, followed by an increase in the relapse rate up to 6 months postpartum. The effect of the menstrual cycle on MS is not consistent [30]. As with RA, progesterone may contribute to pregnancy remission of MS through suppression of Th1 and Th17 activity. In addition, progestogens may protect against neuronal damage via non-immunologic mechanisms. Accordingly, a clinical trial is presently being performed examining the potential benefit of progestogens for MS treatment and prevention of relapses [31].
1.2.3 Systemic Lupus Erythematous (SLE)
Unlike RA, SLE does not tend to remit during pregnancy. It is unclear whether pregnancy induces lupus flares: different studies show different conclusions, some showing that pregnant women are at an increased risk for lupus flares while others have reported that the flare rate is unchanged during pregnancy [32]. However, progestogens and estrogens appear to impact on the risk of developing SLE. There is good evidence from large observational studies that exogenous estrogens increase the risk of SLE, possibly by modulating survival and differentiation of self-reactive B cells and T cells [3]. In contrast, there is emerging evidence from animal models that progestogens may protect against the development of SLE by counteracting estrogen’s effects on B cells and T cells [9]. Chabbert-Buffet et al. [33] have shown that when the effect of progestogens is isolated from the effect of estrogen (in the form of progestin only contraception), there was a reduced rate of SLE flares. Hence, it seems that estrogens promote SLE while progestogens may have a protective effects.
1.2.4 Autoimmune Thyroid Disease (AITD)
Both Hashimoto's thyroiditis (HT) and Graves's disease also show a very high preponderance in females, which like SLE, is attributed in part to sex hormones. The data regarding AITD and sex hormone is scarce relative to other ADs. In a mouse model of AITD [34] estrogen had a protective effect while progesterone appeared to augment the levels of autoimmunity. In a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease, estrogen use was associated with a lower risk of AITD [35]. In summary, it appears that compared to SLE, female sex steroids have different effects on the risk of AITD: progestogens may promote AITD while estrogens may have a protective effect in some patients.
2 Progestagen Hypersensitivity
Another aspect of the interaction of progestogens with the immune system is progestagen hypersensitivity, which may present as autoimmune progesterone dermatitis or cyclic urticaria. This rare condition is characterized by a hypersensitive reaction to endogenous or exogenous progesterone/progestins [36–39].
The clinical presentation of progestogen hypersensitivity is mainly dermal but may also by systemic. Table 13.1 summarizes the different manifestations [37, 38].
Table 13.1
Clinical manifestations of progesterone hypersensitivity
|
Dermal manifestations |
Systemic manifestations |
|
Erythema multiforme |
Progesterone induced anaphylaxis |
|
Eczema |
Premenstrual syndrome |
|
Urticaria |
Dysmenorrhea |
|
Pruritus |
Mastalgia |
|
Angioedema |
Headache |
|
Dermatitis |
Arthralgia |
|
Acne |
Asthma/rhinitis |
Exacerbations occur whenever endogenous or exogenous levels of progestogens rise as detailed in Table 13.2. The most classic manifestation is cyclic—appearing at the end of luteal phase of the ovulatory cycle when progesterone levels are high, resolving a few days after menses [37, 38].
Table 13.2
Timing of exacerbations of progestogens hypersensitivity
|
Due to endogenous progesterones rise |
|
Luteal phase of menstrual cycle when progesterone levels are high |
|
Pregnancy (may lead to both improvement or exacerbation) |
|
Due to exogenous rise in progestins |
|
Contraceptive pills |
|
Postmenopausal Hormone replacement therapy |
The condition is clinically suspected from the cyclic response and/or exacerbation due to external progestins. Confirmations of the diagnosis can be achieved using progesterone skin tests [40, 41].
The classic first line treatment is inhibition of endogenous progesterone secretion by suppression of ovulation. This can be achieved pharmacologically using estrogens, or continuous GNRH agonists. Administration of unopposed estrogens may increase the risk of endometrial carcinoma—thus limiting the use of estrogens [40]. An alternative first line treatment is desensitization with small doses of progesterone [36, 42]. This approach is appropriate for non dermal manifestations such as dysmenorrhea and premenstrual syndrome [36, 43].
The use of high dose systemic steroids is controversial both because inconsistent data regarding benefit [40] and possible side effects.
In a few patients with refractory symptoms, bilateral oophorectomy has been used. This option may succeed in controlling hypersensitivity symptoms but should be considered to be treatment of last resort [40, 44].
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