Open Access

Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review)

  • Authors:
    • Quanjun Niu
    • Junhang Hao
    • Zhen Li
    • Huiping Zhang
  • View Affiliations

  • Published online on: September 25, 2024     https://doi.org/10.3892/mmr.2024.13339
  • Article Number: 215
  • Copyright: © Niu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease whose etiology is not fully understood. Defective peripheral immune tolerance and subsequent mis‑differentiation and aberrant infiltration of synovium by various immune cells, especially helper T (Th) cells, play an important role in the development of RA. There are significant sex differences in RA, but the results of studies on the effects of sex hormones on RA have been difficult to standardize and hormone replacement therapy has been limited by the potential for serious side effects. Existing research has amply demonstrated that cellular immune responses are largely determined by sex and that sex hormones play a key role in Th cell responses. Based on the aforementioned background and the plasticity of Th cells, it is reasonable to hypothesize that the action of sex hormones on Th cells will hopefully become a therapeutic target for RA. The present review discussed the role of various Th cell subsets in the pathogenesis of RA and also explored the role of sex hormones on the phenotype and function of these aberrantly regulated immune cells in RA as well as other pathologic effects on RA.

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease with chronic polyarticular inflammation as the main clinical manifestation. The pathogenesis of RA is associated with the production of autoantibodies such as anti-immunoglobulin G (IgG) and citrullinated proteins (1). The main pathological features of RA are synovial hyperplasia of the joint cavity, thickening of the lining layer, formation of vascular opacities and infiltration of a variety of autoimmune cells and activated inflammatory cells, which in turn cause the destruction of cartilage and bone tissues, ultimately leading to joint deformity and loss of function (2,3).

The pathogenesis of RA involves dysregulation of both intrinsic and adaptive immunity. In adaptive immunity, T cells and B cells are involved to varying degrees in the pathogenesis of RA. B cells accumulate in the synovium of inflamed RA and secrete rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), which are involved in the inflammatory process (4). Helper T (Th) cells are a diverse group of CD4+ T cell subsets that play a crucial role in the immune system. Intrinsic defects in the naive CD4+ T cells cause cellular mis-differentiation, leading to irreversible tissue-tolerant destruction as a key pathogenesis of RA (2).

A systematic analysis of global, regional and national burden studies of RA from 1990–2017 showed that the global age-standardized point prevalence and annual incidence of RA in 2017 were 246.6 [95% uncertainty interval (UI) of 222.4–270.8] and 14.9 (95% UI of 13.3–16.4), respectively, which increased by 7.4% (95% UI 5.3–9.4) and 8.2% (95% UI 5.9–10.5) from 1990, respectively (all estimates presented as counts and age-standardized rates per 100,000 population) (5). The data in this systematic analysis also showed that the prevalence of RA was highest in developed countries, followed by India and South America, and appeared to be lower in rural areas compared with urban settings, suggesting that population characteristics, socioeconomic or environmental risk factors influence the prevalence of RA (5). Women make up the majority of patients with RA, with a ratio of up to 4:1 or more to men (68). The influence of specific events such as menopause, the number of parturiency and breastfeeding on the risk of developing RA, as well as the sex ratio of patients with RA, all contribute to the role of sex hormones in RA. This role has been explored from as early as the last century and clinical trials have confirmed the anti-inflammatory effects of sex hormones in RA and the significant improvement of symptoms (9). However, hormone replacement therapy (HRT) has since declined substantially due to potentially serious side effects such as increased risk of coronary heart disease, breast cancer and stroke (10,11). Currently glucocorticoids are widely used with the treatment of RA, but sex hormones have not been included in the treatment regimen for RA. A recent study of female patients with RA treated with tocilizumab, an IL-6 receptor antibody and/or traditional disease-modifying anti-rheumatic drugs found that exogenous sex hormone use appeared to be associated with higher remission rates (12). Although epidemiologic investigations and mechanistic studies remain contradictory, the effect of sex hormones on RA is evident. Few articles have looked at Th cells to illustrate the role of sex hormones in RA and repairing Th cell defects during asymptomatic autoimmunity may be the next cutting-edge intervention in RA. Exploring the effect of sex hormones on RA from Th cells may be another research proposal for using sex hormones to treat RA.

Materials and methods

The present study used ‘rheumatoid arthritis’, ‘T cells’ and ‘sex hormone’ as the key words and collected relevant information from different databases, including PubMed (https://pubmed.ncbi.nlm.nih.gov), Web of Science (https://ras.cdutcm.edu.cn:7080/s/cn/clarivate/webofscience/G.https/wos/woscc/basic-search), Springer (https://link.springer.com), Science Direct (https://www.sciencedirect.com), ACS (https://pubs.acs.org/?locale=zh_CN), Wiley (https://onlinelibrary.wiley.com) and CNKI (https://www.cnki.net). Inclusion criteria were: Clinical studies, laboratory studies (including purely experimental animal studies or in vitro cellular studies, combined animal and in vitro cellular studies), meta-analyses and bioinformatics studies validated with clinical or laboratory data, regardless of the languages of publication. Exclusion criteria were: Studies that were repeatedly published, clinical trials from which no relevant data could be extracted, newspapers, conferences, comments and other information without experimental data, studies that were low quality or had incorrect assertions or conclusions and different reports on the same issue (these have been retained for comparison and discussion purposes).

Immunology of RA

The immunopathogenesis of RA spans decades and is characterized by defective immune responses, primarily involving pro-inflammatory cytokines and alterations in peripheral immune tolerance, especially Th cells (13,14). Genetic and environmental factors are major risk factors for RA and shared epitope-positive HLA-DRB1 alleles and PTPN22 variants are associated with the development of RF and ACPA (15,16). Although these studies have taken less account of the effect that other factors have on this process, they have revealed the relationship between these genes and autoantibodies and the effect of this process on RA. T cells recognize citrullinated antigens in the context of HLA-DRB1*04 and B cells respond by producing large amounts of citrullinated proteins (17,18). B cells can also play an important role as antigen-presenting cells (APCs) to self-reactive T cells (19,20). There are several important stages in the transition from a healthy state to clinical RA, which a high-quality review from Nature Immunology categorized as the systemic breakdown of self-tolerance, the transition from asymptomatic autoimmunity to tissue inflammation and the transition from acute synovitis to prolonged chronic synovitis (2).

Specifically, individuals with genetic and environmental risks begin with the recognition of modified protein antigens and the appearance of autoantibodies (phase I). Following a prolonged period of asymptomatic autoimmunity and immune system remodeling, cell-intrinsic changes in metabolic networks and DNA instability drive T cell differentiation to tissue-invasive short-term effector T cells and protective macrophage failure, followed by disruption of tissue tolerance and the development of early synovitis (phase II). The transformation of synovial stromal cells to self-invasive effector cells transforms synovitis from acute to chronic destructive, leading to destruction of articular cartilage and bone (phase III). In the vast majority of cases, the destruction of tissue tolerance is irreversible (2).

Th cells in RA background

The second phase of RA is clinically marked by synovial inflammation, which is closely related to cell-intrinsic defects in CD4+ T cells, caused by mis-differentiation during the conversion of initially resting CD4+ T cells into memory T cells and effector T cell (2123). Specifically, naive CD4+ T cells are transformed into highly proliferative, tissue-invasive and pro-inflammatory T cells rather than relatively quiescent memory T cells; initial self-tolerance is disrupted, the disease process shifts localization and a variety of immune cells infiltrate the synovium (Fig. 1). Activated CD4+ T cells make up a large proportion of inflammatory cells in synovial tissue and are involved in the pathologic process of RA. A reduced naive CD4+ T cell frequency is the strongest predictor of the development of synovitis in patients with ACPA-positive populations (24).

Naive CD4+ T cells are activated and differentiated into various Th cell subpopulations in response to antigenic stimulation and cytokine signaling and their differentiation process is dependent on the expression of specific transcription factors induced by specific cytokines. These Th cells exert varying degrees of disease-promoting or protective effects.

Role of Th cell subsets in the pathogenesis of RA and experimental arthritis
Th1 cells

Initially, Th1 cells were hypothesized to play a dominant role in the development of RA due to the high expression levels of interleukin-12 (IL-12) and interferon-gamma (IFN-γ) found at sites of inflammation and the positive correlation of IL-12 levels with disease activity observed in the serum and synovial fluid of a significant proportion of patients with RA (25,26). In addition, most CD4+ T cells infiltrating the synovium express IFN-γ, which subsequently activates macrophages and induces tumor necrosis factor-alpha (TNF-α) production (25). However, the Th1 phenotype does not explain the full mechanism of RA development because of the higher susceptibility to collagen-induced arthritis (CIA) in IFN-γ-deficient mice and IFN-γ receptor-deficient mice (27,28), as well as the lack of efficacy of IFN-γ monoclonal antibodies in the majority of patients with RA (29).

Th2 cells

The proposed Th1/Th2 model was used to explain RA pathology in early studies. In arthritis dominated by Th1 cells, IL-4 secreted by Th2 cells prevents disease and induces a switch from a Th1-type to a Th2-type response. IL-4 deficiency is essential for disease induction in animal models of CIA (30). Treatment of CIA mice using mesenchymal stem cells (MSC) in combination with IL-4 restored synovitis symptoms to the level of healthy controls (31). Later, the hypothesis that the Th1/Th2 model is dominant began to change due to the emergence of anti-inflammatory regulatory T (Treg) cells that produce growth transformation factor-beta (TGF-β) and pro-inflammatory Th17 cells that produce IL-17 (32).

Th17 cells

Multiple molecules are involved in the differentiation process of Th17 cells and the combination of these molecules with each other generates pathogenic and non-pathogenic Th17 cell subpopulations with varying degrees of pro- and anti-inflammatory properties (33,34). In patients with RA, both in vivo and in vitro anti-TNF-α treatment induced the production of the anti-inflammatory factor IL-10 by Th17 cells, suggesting that TNF-α may have an inhibitory effect on IL-10 production by Th17 cells (35). Although Th17 cells and their effector molecules play a positive role in the maintenance of immune homeostasis in the body, they are also involved in the pathology of a variety of autoimmune diseases. Peripheral blood mononuclear cells (PBMC) from patients with RA had a large number of Th17 cells and their proportion correlated with the progression and activity of RA (36,37). IL-17-deficient and blocked mice exhibited resistance to CIA while ameliorating disease severity in a mouse model of CIA (38,39). IL-22 is an important cytokine produced by Th17 cells and IL-22(−/-) mice had severely reduced splenic germinal centers and their CIA severity was also significantly reduced (40).

Th17 cells expressing the receptor activator of NF-κB ligand (RANKL), an osteoclast-activating factor, stimulate localized bone resorption by regulating the migratory state and functional changes of mature osteoclasts through cell-to-cell contacts and this may be the mechanism by which Th17 cells mediate inflammatory bone destruction (41). As IL-17 blockade has therapeutic potential for RA and clinical trials have been conducted to explore the feasibility of this treatment approach. For instance, a study has shown that IL-17 blocking drugs such as secukinumab and ixekizumab are effective in the treatment of RA, but their efficacy appears to be inferior to that of already existing biologics such as anti-TNF-α and anti-IL-6 (42).

Treg cells

Treg cells play a crucial role in maintaining autoimmune tolerance by secreting the anti-inflammatory cytokine IL-10 and the immunosuppressive molecule TGF-β (43,44). However, the number of Treg cells in the synovial fluid of patients with RA with persistent joint inflammation is significantly increased, suggesting that Treg cell function is altered in patients with RA (45). This is supported by other studies which have found that Treg cell regulation is reduced in both peripheral blood and synovium in patients with RA (4648). Forkhead box protein 3 (Foxp3) is a key transcription factor for Treg cells and TNF-α dephosphorylation inhibits the transcriptional activity of Foxp3, disabling Foxp3+ Treg cells in patients with RA (46). In arthritic conditions, CD25(lo)Foxp3(+) T cells lose Foxp3 expression and transdifferentiate into inflammatory Th17 cells (49). The regulatory capacity of Treg cells in an inflammatory environment is reduced or lost, so that Treg cells isolated from active patients with RA cannot prevent effector T cells from secreting pro-inflammatory cytokines such as IFN-γ and TNF-α (47,48), which may be a vicious cycle. In addition, studies have shown that MSC has a favorable effect on the regulatory function of Treg cells in the context of RA (50,51).

T follicle helper (Tfh) cells

Tfh cells are characterized by high expression of the chemokine receptor C-X-C motif chemokine receptor 5, the transcription factor Bcl6, inducible co-stimulatory molecule and the co-inhibitory molecule programmed cell death protein 1 (PD-1). Once the naive CD4+ T cells are activated by APCs, IL-6 and IL-21, they differentiate into Tfh cells (52). Tfh cells help B cells produce relevant antibodies in patients with RA. Transplantation of MSC into CIA mice prevented the progression of arthritis by suppressing the number and function of Tfh cells (53). patients with RA express high levels of IL-21 in serum (54,55) and the percentage of Tfh cells is also positively correlated with disease activity (55). After 1 month of drug treatment, the percentage of PD-1+ Tfh cells was significantly decreased in drug-responsive patients with RA (55). In the synovium of IL-21R-deficient RA model mice, fewer Tfh cells and more Th17 cells were found in comparison with the control, as well as low levels of RANKL expression, suggesting that IL-21 plays an important role in the disease process of RA through Tfh cell proliferation and RANKL induction rather than Th17 cell function (56,57).

Sex hormones and Th cell response

The thymus is a key site for the production of a number of types of T cells and the effects of sex hormones on the thymus were recognized as early as the last century when it was observed that the thymus is enlarged in male castrated mice and shrinks following the administration of androgens (58). Compared with men, women have a higher absolute number of CD4+ T cells and show stronger T-cell responses and B-cell responses to antigens, which contributes to autoimmunity (59). Women are more inclined to develop T-cell-mediated autoimmune diseases, whereas men are more susceptible to cancer and infectious diseases (60), which has been commonly described as an immunostimulatory effect of estrogens and an immunosuppressive effect of androgens, which is clearly an oversimplified description. The effect of sex hormones on the immune system and immune disorders is complex and can be influenced by a combination of factors such as genetics, the relative expression of hormone receptor subtypes, hormone concentrations, the tissues in which they are found and the stage of life (Table I).

Table I.

Sex hormones and Th cell response.

Table I.

Sex hormones and Th cell response.

First author/s, yearSex hormoneObject of studyMedicineConcentration and timeKey results(Refs.)
Kim et al, 2019EstrogensCD4-ERα knockout mice//ERα inhibits the Tfh cell response and GC reaction to control autoantibody production.(68)
Guo et al, 2019 Naïve CD4+T cells isolated from the spleen and MLNs of C57BL/6 miceERB041 (an ERβ specific agonist)100 nM,60 minERβ activation enhanced Treg differentiation and TGF-β1/Smad signaling in CD4 + T cells and promoted immunosuppression.(69)
Maret et al, 2003 Ovariectomized (OVX) mice, ERα and ERβ genes destroy miceE20.1 mg/60 days (Subcutaneous implants release particles)E2 administration in OVX mice resulted in a T cell proliferative and Th1 cell response and IFN-γ and T-bet production. ERα, but not ERβ, was necessary for the enhanced E2-driven Th1 cell responsiveness.(70)
Lambert et al, 2005 Naïve CD4+T cells isolated from the spleen of OVX mice and ERα-deficient miceE210−9M (272.4 pg/ml), 12–16 hE2 increased IL-4 and GATA-3 mRNA levels from CD4+ T cells, which is dependent on Erα.(71)
Polanczyk et al, 2005 E2-treated mice; pregnant miceE22.5 mg/60 days (subcutaneous implants release particles)E2 enhances the expression of FoxP3 and the inhibitory function of Treg cells in pregnant mice.(72)
Tai et al, 2008 E2-treated mature OVX and immature mice; pregnant miceE2100 ng/per mouse (subcutaneous injection)E2 expanded Treg cells in different tissues and increased the expression of Foxp3 gene and IL-10 gene.(73)
Haghmorad et al, 2014 E2-treated OVX mice; pregnant miceE215 mg/21 days (subcutaneous implants release particles)Pregnancy and gestational levels of estrogen decrease the expression levels of Th1 and Th17 cell transcription factors T-bet and ROR-γt and the expression levels of Th1 and Th17 cytokines IFN-γ, TNF-α, IL-17 and IL-23 in the spleen of mice.(74)
Dragin et al, 2016 ERα-knockout mice; healthy human thymus tissueE2200 µg/dayEstrogen upregulates the number of methylated CpG sites in the AIRE promoter via ERα, causing AIRE expression to fall below the threshold, thereby increasing the susceptibility of women to autoimmune diseases.(83)
Zhu et al, 2016AndrogensAR deficient mice; human neonatal thymus tissueDihydrote stosterone0–10 mg/60 days (subcutaneous particles); 100 mg/per mouse (subcutaneous injection)In mice and humans, the expression of AIRE in the thymus is higher in males than in females.(82)
Androgens recruit AR to the AIRE promoter region, enhancing AIRE transcription, improving immune tolerance and producing more effective negative selection of self-reactive T cells.
Gandhi et al, 2022 AR-deficient mice, oxp3 fate-mapping mice5α-dihydrotes tosterone15 mg/60 days (subcutaneous implants release particles)Androgen can increase Foxp3 expression and stabilize the suppressive function of Treg cells through AR signaling.(85)
Vargas-Villavicencio et al, 2006 Male mice with gonadectomy//IL-4 and IL-10 mRNA levels were markedly decreased in response to castration, compared with intact unaffected mice.(86)
Xia et al, 2022 Rats with allergic asthma5α-dihydrotes tosterone0.5 mg/kg/3 day (oral)Androgen decreased the high levels of IL-4, IL-5 and IL-33 in bronchoalveolar lavage fluid.(87)
Kalidhindi et al, 2021 CD4 cells isolated from castrated mice//AR binds a conserved region within the phosphatase, PTPN1 and consequent up-regulation of PTPN1 then inhibits IL-12 signaling in CD4 T cells and inhibits Th1 cell differentiation.(88)
Quispe Calla et al, 2015Progestational hormoneDC isolated from human peripheral blood mononuclear cellsmedroxypr ogesterone acetate2×10−3 M, 24 hThe ability of medroxyprogesterone acetate-treated DC to promote CD4(+) and CD8(+) T cell proliferation was reduced.(94)
Mao et al, 2010 Mature and immature female mice; pregnant micePg2 mg/mouse (subcutaneous injection)Midterm pregnancy doses of Pg increased CD4(+)CD25(+) Treg cell proportion and IL-10 expression and also enhanced their inhibitory function.(95)
Pg has the ability to transform CD4(+)CD25(−) T cells intoo CD4(+)CD25(+) Treg cells.
Hierweger et al, 2019 Spleen cells from non-pregnant and pregnant micePg10−6 M; 48 hPg induced conventional CD4+T cell death, but had no lethal effect on CD4+ Treg cells.(96)
Hughes et al, 2009 SLE model miceDepot medroxypr ogesterone acetate10 mg/6 weeks, 30 weeks (subcutaneous injection)Progestational hormone reduces the accumulation of pathogenic antibodies associated with nephrogenic Th1 cells.(98)
Carreno et al, 2005PRL13 days old fetal liver cells, 15 days old fetal thymus cellsPRL10 ng/ml, 7 daysPRL induces thymus T cell development and hepatic lymphoid progenitor cell survival, proliferation and differentiation.(100)
Legorreta-Haquet et al, 2016 Treg cells and effector T cells isolated from PMBC of SLE patientsPRL50 ng/ml, 5 daysThe percentage and function of Treg cells are decreased in SLE patients compared with healthy individuals. PRL decreased the inhibition of Treg cells and increased IFN-γ secretion.(101)
Dimitrov et al, 2004 Whole blood cells from healthy individualsPRL20 ng/mlPRL promotes CD4+T and CD8+ T cells to produce more TNF-α, IFN-γ and IL-2.(102)
Lentz et al, 2022HCGNaïve CD4+T cells isolated from the spleen and inguinal and para-aortic lymph nodes of CBA/J miceurine-derived HCG (uHCG), recombinant HCG (rHCG)uHCG:250 IU/ml rHCG:100 IU/ml, both 24hHCG increased the frequency of Treg cells. With the involvement of IL-2, both interfere with the differentiation of CD4 + T cells into pro-inflammatory Th17 cells and induces anti-inflammatory characteristics in already differentiated Th17 cells.(104)
Diao et al, 2017 CD4+T cells isolated from PMBC of women with recurrent implantation failurehuman urinary HCG50 IU, 72 hHCG increased the proportion of FoxP3+ Tregs cells expressing TGF-β.(106)
Sha et al, 2017 Patients with unexplained recurrent spontaneous abortionCombinati on therapy of HCG plus IGBefore 14 weeks gestation: IG 0.3 g/3 weeks; HCG 2000 U/2 days (intramuscular injection). After 13 weeks of gestation: The HCG dose was gradually reduced and eventually discontinuedCombined therapy resulted in decreased Th17/Treg ratio and Treg bias in peripheral blood and increased levels of Treg cells and related cytokines IL-10 and TGF-β1.(105)
Iqbal et al, 2006FSHBone marrow and macrophages in C57BL6J miceFSH100 ng/ml, 18 hFSH directly stimulates the production of TNF-α by myeloid granulocytes and macrophages.(108)
Qian et al, 2020 The periodontal ligament cells in a healthy personFSH30 ng/ml, 24 hFSH significantly increased the expression and secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in human periodontal ligament cells.(109)

[i] Th, helper T; ER, estrogen receptor; Tfh, T follicle helper; MLNs, mesenteric lymph nodes; TGF-β, growth transformation factor-beta; Treg, regulatory T; OVX, ovariectomized; E2, estradiol; GATA-3, GATA binding protein 3; Foxp3, Forkhead box protein 3; IL, interleukin; T-bet, T-box expressed in T cells; ROR-γt, retinoic acid receptor-related orphan receptor γt; IFN-γ, interferon-γ; CpG, cytosine-phosphate-guanosine; AIRE, autoimmune regulatory gene; RA, rheumatoid arthritis; RANKL, receptor activator of NF-κB ligand; DC, dendritic cells; Pg, progesterone; SLE, systemic lupus erythematosus; PRL, prolactin; TNF-α, tumor necrosis factor-alpha; HCG, human chorionic gonadotropin; u, urine-derived; r, recombinant; PMBC, peripheral blood mononuclear cell; IU, international unit; IG, immunoglobulin; FSH, follicle-stimulating hormone.

Estrogen

Women have three main natural estrogens, estrone, estradiol (E2) and estriol, with E2 being its most potent form. In studying the role of estrogen in autoimmune diseases, Cutolo et al (61) conclude that estrogen may promote B-cell-driven diseases, while T-cell-driven diseases may be inhibited by estrogen. Estrogen is mainly mediated by two specific intracellular receptors namely estrogen receptors (ER) α and β and a membrane G-protein coupled receptor. There are significant differences in the distribution of ERα and ERβ in immune cells and tissues and the complex effects of estrogen on the immune system are partly due to the fact that the expression of one receptor relative to the other may alter the action of estrogen (62). For example, in a mouse model of systemic lupus erythematosus (SLE), ERα has significant pro-inflammatory effects, whereas ERβ exhibits anti-inflammatory and immunosuppressive effects (6365). ERβ expression is also significantly reduced in T cells from patients with SLE and inflammatory bowel disease (66,67). In addition, it has been found that ERα controls the production of autoantibodies to prevent autoimmunity by inhibiting the reaction of Tfh cells (68), while ERβ enhances immunosuppression by promoting the differentiation of Treg cells (69).

In peripheral T cells, low concentrations of E2 induce T cells to express T-box transcription factor expressed in T cells (T-bet) and IFN-γ to promote the Th1 response and ERα, but not ERβ, is required for this process (70). E2 levels are consistently elevated during pregnancy and high concentrations of E2 affect CD4+ T cell polarization by enhancing the expression of Th2-related genes (GATA3 and IL-4) and Treg-related genes (Foxp3, IL-10 and TGF-β), while inhibiting the expression of Th1-related genes (T-bet, IL-2, TNF-α and IFN-γ) and Th17-related genes (ROR-γ T, IL-6, IL-17 and IL-23) expression (7174). By contrast, the decline in ovarian function and rapid decline in circulating estrogen during menopause are associated with an increase in pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β (75,76). The addition of E2 at ovulation level to PBMC of postmenopausal women in vitro can inhibit the release of these pro-inflammatory factors (77).

Androgens

Androgens mainly include testosterone, dihydrotestosterone and dehydroepiandrosterone (DHEA) and the biological actions of androgens are mediated by the androgen receptor (AR) (78). Androgens have recognized immunosuppressive effects, in large part because of their ability to inhibit cytokine production and impair T cell effector activity (79,80).

The autoimmune regulatory gene (AIRE) provides strong protection against autoimmune disease and the effect of androgens on them is stronger in males than in females (81). Androgens recruit AR to the AIRE promoter region, enhancing AIRE transcription, improving immune tolerance and producing more effective negative selection of self-reactive T cells (82). By contrast, estrogen promotes autoimmunity by decreasing AIRE expression through ERα upregulation of AIRE methylation (83). The number of Treg cells is significantly higher in men than in women (84) and the androgen/AR pathway can stabilize the inhibitory function of Treg cells by enhancing Foxp3 expression (85). In addition, androgens regulate Th2 cytokine production and mRNA levels of IL-4 and IL-10 are reduced in gonadectomized male mice (86), but in Th2 cell-mediated allergic asthma, the androgen/AR pathway restricts Th2 cytokine release (87,88). Androgens/AR may inhibit the differentiation of CD4+ T cells into Th1 cells through a direct increase in protein tyrosine phosphatase non-receptor type 1, a phosphatase that inhibits Th1 differentiation, thus effectively preventing male autoimmunity (89). Androgen deficient men also showed higher levels of IL-1β, IL-2, TNF-α and CD4+/CD8+ T cell ratios (90). In turn, TNF-α has been shown to have an inhibitory effect on testosterone synthesis in the testis by inhibiting important enzymatic steps in the adrenal and gonads (91).

Other sex hormones

Progesterone (Pg) is a female sex hormone that plays a key role in establishing and maintaining the pregnancy process and has powerful immunomodulatory properties (92). T cells express Pg receptors (PR-a, PR-b and PR-c) and membrane Pg receptors (mPRa, mPRb and mPRg) (93). Pg reduces T cell proliferation by impairing the ability of dendritic cells to stimulate T cell proliferation (94). In mouse experiments, administration of a comparable dose of Pg in midgestation promotes CD4+CD25+ Treg cell proliferation and enhances the inhibitory function of CD4+CD25+Treg cell by increasing IL-10 expression (95). High levels of Pg during pregnancy selectively induce conventional CD4+ T cell death and CD4 + Treg cell enrichment (96). In human studies, Pg enhances anti-inflammatory responses and immune tolerance by inducing Th2 and Treg cell subsets during pregnancy (97). In addition, Pg inhibits the differentiation of naive CD4+ T cells to Th1 and Th17 cells (98,99).

Prolactin (PRL) is also involved in immunomodulation and has been shown to favor the survival and differentiation of T-cell progenitors (100). PRL reduces the inhibitory function of Treg cells (101) and SLE patients have elevated PRL receptor expression in Treg cells but decreased Treg cell percentage and function (100). It was observed that co-culturing T cells with PRL led to more production of Th1-related cytokines such as TNF-α, IFN-γ and IL-2 (102).

Human chorionic gonadotropin (HCG) peaks in early pregnancy. Studies demonstrate that HCG regulates Th1/Th2 balance (103), interferes with Th17 differentiation and induces its anti-inflammatory profile, increases the frequency of Treg cells (104) and enhances the inhibitory capacity of Tregs by increasing the secretion of IL-10 and TGF-β (105107). Follicle stimulating hormone (FSH) is closely related to female ovulation and its level directly reflects the ovarian function status. Studies have found that FSH promotes the high expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α (108,109).

Effects of sex hormones on RA

Globally, RA occurs more commonly in women (68). The ratio of female to male prevalence is >4 before the age of 50 years and after the age of 60 years, this value decreases to <2 (110). Disease activity and progression is also usually more severe in women than in men (111), but pregnancy puts female patients in remission. The sex differences in the prevalence of RA have led to the investigation and study of the role of sex hormones in the pathologic process of the disease, which has evolved from initial comparisons of prevalence between men and women to later studies of the specific mechanisms of the role of specific reproductive factors in RA; however, the effect of such factors on RA has not yet been fully elucidated.

Estrogen

Regardless of sex, decreased androgen levels and increased estrogen levels are found in the synovial fluid of patients with RA (112,113). This phenomenon may be due to the activation of peripheral tissue aromatase stimulated by elevated inflammatory factors (TNF-α, IL-6 and IL-1) in the synovium and promotes the peripheral conversion of androgens to estrogens (114,115). Injection of glucocorticoids into the joints suppresses their serum estrogen androgen levels compared with baseline before injection therapy, but this tends to be reversible (116). Other studies have shown that in synoviocytes from patients with RA, estrogen hydroxylated metabolites have pro-inflammatory activity and pathogenic effects that cause synovial hyperplasia (117,118). Although these reports show a pro-RA effect of estrogen, a growing body of research suggests that the protective effect of estrogen on RA is dose-dependent and that estrogen deficiency is more likely to bring about joint inflammation and cause bone erosion. For example, estrogen deficiency induces T cell proliferation and prolongs active T-cell lifespan via IFN-γ, which leads to bone loss (119). Ovariectomized (OVX) mice have normal T cell numbers in the bone marrow, but have more RANKL-expressing CD3+ T cells and B cells (120). In MRL/lpr mice (with a genetic susceptibility similar to human RA), estrogen deficiency may induce the activation of RANKL-carrying CD4+ T cells, leading to osteoclastogenesis and bone resorption (121). Treatment of CIA mice with E2 led to a decrease in the number of Th17 cells and IL-17(+) γδ T cells in the joints but an increase in the number of Th17 cells and IL-17(+) γδ T cells in the draining lymph nodes, suggesting that E2 mediates the prevention of migration of these two types of cells from the lymph nodes to the joints (122). In addition, estrogen antagonizes acid-sensing ion channel 1α-induced mitochondrial stress and protects against cartilage damage in OVX rats with adjuvant arthritis (123).

As aforementioned, the immunizing effects of estrogen are closely related to the relative expression of ER. The expression of ER mRNA in synovial tissues of patients with RA was significantly higher than that in healthy non-inflammatory synovial tissues and the relative expression ratio of ERα/ERβ mRNA was significantly lower (124). Treatment with E2 improved synovial inflammation and joint destruction in mice with arthritis and reduced the number of Th17 cells in the joints, both of which are dependent on Erα (125,126). Recent studies have also revealed the effects of ERβ on bone. Xu et al (127) show that bone mass decreases in male mice with osteoblast ERβ deletion, but has no effect on bone mass in female mice, suggesting that the mechanism by which osteoblast ERβ regulates bone modeling varies by sex.

Androgens

Androgens are generally considered to be a natural anti-inflammatory agent with immunosuppressive effects (79,80). Serum androgen levels and synovial androgen metabolism levels are decreased in patients with RA regardless of sex (113,128) and serum androgen levels are negatively correlated with RA disease activity (129,130). Therefore, the deficiency of androgen regulating the immune system is considered to be related to the onset of RA. Androgen deprivation has been found to increase the risk of RA when androgen deprivation is administered to patients with prostate cancer (131,132) and the longer the duration of treatment deprivation, the higher the risk (131). In terms of improving clinical and chemical indicators of immune response in men with RA, several studies have demonstrated the beneficial effects of testosterone therapy (129,133). Animal studies have also shown that both physiologic and pharmacologic concentrations of testosterone produce anti-inflammatory effects on joint inflammation in rats (134,135). In addition, polarization of RA synovial macrophages activates intracellular androgens, which contribute to the suppression of local inflammation (136). Anti-TNF-α and anti-IL-6 treatment of synoviocytes from patients with RA both attenuate androgen suppression (137,138) and methotrexate (MTX) treatment also improves testosterone levels in rats with adjuvant-induced arthritis (139).

Other studies have also provided evidence that androgens ameliorate RA, such as the study by Stark et al (140) which found that the cytochrome B5 type A (CYB5A) single nucleotide polymorphism (SNP) increases androgens in women and is associated with a reduced genetic risk of RA in women, but the CYB5A SNP is not associated with RA risk in men. Overexpression of CRF6-interacting factor 1, a nuclear protein that interacts with the AR, was found by Park et al (141) to attenuate activation of Th17 cells and osteoclast differentiation and reduce arthritic symptoms and histological manifestations in CIA mice. By inhibiting cellular immunity and autoantibody formation, exogenous DHEA ameliorated the severity of acute and chronic antigen-induced arthritis in mice (142). However, DHEA treatment at 50 mg/day for 12 consecutive weeks did not show any greater improvement in patients with RA compared with the placebo group (143).

Other sex hormones

Studies using next-generation sequencing show that Pg-induced transcriptomic changes are significantly enriched in genes associated with pregnancy-regulated diseases (for example, multiple sclerosis, RA and psoriasis), suggesting a potential role for Pg in the immunomodulation of pregnancy-induced diseases (144). Experimental studies have demonstrated the inhibitory effect of Pg on matrix metalloproteinase activity produced by fibroblast-like synoviocytes (145). M2000 is a novel nonsteroidal anti-inflammatory drug with immunosuppressive effects that improves clinical symptoms and increases serum Pg levels in patients with RA (146).

Luteinizing hormone (LH) levels are significantly lower in both male and postmenopausal female patients with RA compared with healthy controls (147149), but are not associated with disease activity (148). In a study using the gonadotropin-releasing hormone antagonist ASP1707 in combination with MTX for the treatment of RA, a 90% decrease in plasma LH concentrations was found in 90% of patients treated with ASP1707, but no clinical benefit was demonstrated and there were no significant changes in levels of TNF-α, matrix metalloproteinase 3 and IL-6 (150).

FSH levels increase during the perimenopausal period due to negative feedback in the gonadal axis (151) and FSH secretion promotes the production of TNF-α, which increases the number of osteoclast precursors in the bone marrow (103), but this does not affected osteoclastogenesis (152). High FSH levels have been found to be associated with an increased risk of RA and are positively correlated with RA disease activity (153). However, earlier studies have shown that serum FSH is significantly lower in postmenopausal women with RA compared with healthy controls (149).

PRL has a well-recognized immunostimulatory effect (154); increased serum PRL has been reported in patients with RA (155,156) and breastfeeding may exacerbate the condition of patients with RA through PRL effects (154).

Influence of special periods and special events of women on RA

Menopause

Following menopause, estrogen levels plummet and testosterone levels begin to decline and postmenopausal women have a higher pro-inflammatory immune status (157). The peak incidence of RA in women is roughly during their menopausal years (158) and menopausal status is associated with the progression of joint function decline and deterioration (159). Early age at menopause has long been recognized to be associated with an increased risk of RA (160,161) and women with menopausal age in their 40s have more than double the risk of RA (160). Postmenopausal women are at increased risk of ACPA-positive RA, especially in early menopause when estrogen plummets (162,163). Treatment with E2 in postmenopausal women with RA significantly increased the salivation of crystallizable fragments of IgG and induced its capacity for anti-inflammatory effects (164).

Pregnancy

Pregnancy has been found to have a protective effect on the development and disease activity of RA, with any number of births being significantly associated with a reduced risk of RA, but no such protective effect was found in nulliparous women (165), which, as previously described, is perhaps associated with high estrogen and Pg concentrations (166,167). A large population-based Swedish study showed that ACPA-positive patients are unlikely to experience disease improvement from pregnancy (168), possibly because pregnancy in ACPA-positive patients failed to cause elevated ACPA-IgG galactosylation (169). CD4+CD25+ Treg cell levels are significantly higher in patients with RA during pregnancy than at 8 weeks postpartum and CD4+CD25+ Treg cell frequency is negatively correlated with RA disease activity in both periods (170). Experimental studies demonstrate that pregnancy protects mice from CIA, with Treg cells playing a considerable role and that transfer of Treg cells from pregnant ‘protected’ mice is sufficient to confer protection to non-pregnant mice (171). Fertility is affected in patients with RA (172,173) and anti-Müllerian hormone is currently the most reliable biomarker of ovarian reserve. A number of studies have demonstrated that serum anti-Müllerian hormone levels are not reduced in patients with RA compared with healthy controls (174,175), suggesting that reduced fertility in patients with RA may not be caused by decreased ovarian reserve function.

Breastfeeding

Studies on the role of breastfeeding in RA show conflicting results. The incidence of RA is significantly higher in postpartum breastfeeding women, with ~90% of patients experiencing an onset in the first 3 months postpartum and a decrease in the following 9 months, which also suggests that elevated PRL is associated with episodes and recurrences of RA (154,176). However, prolonged breastfeeding (>12 months) has been found to be associated with a reduced risk of RA (177,178). A subsequent systematic review and meta-analysis covering 1,672 RA cases from six studies show that breastfeeding is associated with a lower risk of RA regardless of whether breastfeeding is longer or shorter than 12 months (179). Hormone levels fluctuate greatly in postpartum women, with a sudden drop in estrogen and Pg and an increase in PRL levels and coupled with the fact that PRL has been little studied in RA, there is still a large gap to be filled in terms of the effects of breastfeeding on RA and its causes.

HRT and oral contraceptive (OC)

A study based on an epidemiologic survey of RA evaluating the relationship between postmenopausal HRT use and RA risk showed a reduced risk of ACPA-positive RA but no association with ACPA-negative RA in postmenopausal women who used HRT compared with those who did not (180). OC has also shown a protective effect against ACPA-positive RA only and the earlier the first exposure to OC, the lower the odds ratio for RA (180,181). No correlation with the risk of ACPA-negative RA is found for either HRT or OC (180,182) and these differences suggest the existence of different hormone-related etiologic pathologies for ACPA-positive and ACPA-negative RA. However, these results have not been fully harmonized, as a meta-analysis of 17 studies showed that OC did not provide protection against the risk of RA in women (183) and a number of large cohort studies have failed to identify an association between OC or HRT use and the risk of RA (177,184,185).

Conclusion and future research prospects

The present study found that androgens and Pg had a more definite inhibitory effect on immune response and RA compared with other sex hormones, whereas the protective effect of estrogen on RA appears to be dose-dependent, but the sex differences and specific mechanisms of action of these hormones remain to be investigated. These hormones regulate immune and inflammatory responses by modulating CD4+ T-cell differentiation to promote the balance between Th1/Th2 and Th17/Treg cells and altering Th-cell function and alleviate the joint symptoms of RA by modulating the balance between osteoclasts and osteoblasts to ameliorate bone destruction. From epidemiologic investigations of female-specific events on the risk of RA and mechanistic studies of RA-hormones, it is not difficult to find a common feature that an acute decline in ovarian function and estrogen drives RA progression. However, the role of estrogen combined with Pg in RA is controversial, as not all studies have shown favorable results (9,181,186). Finally, little is known about the role of hormones such as LH and FSH in the RA disease process; are their effects and mechanisms of action on RA worthy of attention?

In addition, studies of hormone therapy for RA are quite limited and the findings are inconclusive. Regardless of sex, androgen-assisted treatment of RA has a limited effect on disease activity, but brings improvements in quality of life (143,187189). The addition of estrogen to pre-existing therapy in postmenopausal women with RA seems to bring some relief from the disease, but this is associated with serum estrogen levels (9,190) and more studies show that estrogen is well suited to ameliorate bone loss and increase bone density in postmenopausal women with RA (9,191193). In addition, two studies of the gonadotropin-releasing hormone antagonist, cetrorelix, for the short-term treatment of RA found that cetrorelix has a rapid anti-inflammatory effect, but it is only in patients with RA and with high gonadotropin levels that adjunctive treatment with cetrorelix can show a rapid improvement in the disease (194,195).

Differences in hormone levels and regulation between men and women, as well as multiple life stages and specific events in women, have made the study of sex hormones in disease difficult and complicated the findings, with high or low levels of a particular hormone appearing to be associated with disease. In addition, the level of expression of the hormone receptor proteins may also cause the hormones to act differently and it needs to be verified whether these differences in action have an effect on RA pathogenesis or, conversely, whether RA activity causes changes in the expression of the hormone receptor proteins.

The failure of T cell tolerance is attributed to endogenous cellular abnormalities already present in the naive T cells that shift the differentiation program to favor the production of short-term effector T cells over long-lived memory T cells. Current therapeutic strategies for RA are focused on controlling inflammation and by recognizing that RA undergoes a period of relatively stable impaired immune tolerance prior to the onset of inflammation and the associated molecular features of this period, it is possible to identify upstream therapeutic targets that can abort the disease process before irreversible tissue damage occurs. The role of sex hormones in the immune system was recognized at an early stage and it is now clear that Th cell responses are regulated by sex hormone levels and that sex hormones not only directly affect T cell transcriptional profiles, but also influence T cell responses and alter CD4+ cell differentiation by controlling gene expression in thymic epithelial cells and regulating innate immune cells (196). However, despite the a number of advances in the study of the effects of sex hormones on T cells, there are still a number of unanswered questions, especially in RA, where epidemiologic investigations are still contradictory and controversial and the study of the mechanisms of sex hormone effects on Th cells has not been carried out extensively or intensively.

Nonetheless, existing research has also revealed new areas for combating RA. Future studies may be able to devise a way to limit the targets of action of sex hormones to make T cell differentiation more stable or to correct mis-differentiation, which would be an important step in the effective use of sex hormones as an immunotherapy, but also a lengthy process that needs to be precisely controlled.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

QN wrote and revised the manuscript; JH reviewed and edited the manuscript; ZL reviewed and edited the manuscript; HZ conceptualized the article and reviewed the manuscript. All authors have read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Malmstrom V, Catrina AI and Klareskog L: The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting. Nat Rev Immunol. 17:60–75. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Weyand CM and Goronzy JJ: The immunology of rheumatoid arthritis. Nat Immunol. 22:10–18. 2021. View Article : Google Scholar : PubMed/NCBI

3 

Scherer HU, Haupl T and Burmester GR: The etiology of rheumatoid arthritis. J Autoimmun. 110:1024002020. View Article : Google Scholar : PubMed/NCBI

4 

Wu F, Gao J, Kang J, Wang X, Niu Q, Liu J and Zhang L: B Cells in Rheumatoid Arthritis: Pathogenic mechanisms and treatment prospects. Front Immunol. 12:7507532021. View Article : Google Scholar : PubMed/NCBI

5 

Safiri S, Kolahi AA, Hoy D, Smith E, Bettampadi D, Mansournia MA, Almasi-Hashiani A, Ashrafi-Asgarabad A, Moradi-Lakeh M, Qorbani M, et al: Global, regional and national burden of rheumatoid arthritis 1990–2017: A systematic analysis of the Global Burden of Disease study 2017. Ann Rheum Dis. 78:1463–1471. 2019. View Article : Google Scholar : PubMed/NCBI

6 

Galarza-Delgado DA, Azpiri-Lopez JR, Colunga-Pedraza IJ, Cárdenas-de la Garza JA, Vera-Pineda R, Wah-Suárez M, Arvizu-Rivera RI, Martínez-Moreno A, Ramos-Cázares RE, Torres-Quintanilla FJ, et al: Prevalence of comorbidities in Mexican mestizo patients with rheumatoid arthritis. Rheumatol Int. 37:1507–1511. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Cardiel MH, Pons-Estel BA, Sacnun MP, Wojdyla D, Saurit V, Marcos JC, Pinto MR, Cordeiro de Azevedo AB, da Silveira IG, Radominski SC, et al: Treatment of early rheumatoid arthritis in a multinational inception cohort of Latin American patients: The GLADAR experience. J Clin Rheumatol. 18:327–335. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Castillo-Canon JC, Trujillo-Caceres SJ, Bautista-Molano W, Valbuena-García AM, Fernández-Ávila DG and Acuña-Merchán L: Rheumatoid arthritis in Colombia: A clinical profile and prevalence from a national registry. Clin Rheumatol. 40:3565–3573. 2021. View Article : Google Scholar : PubMed/NCBI

9 

D'elia HF, Larsen A, Mattsson LA, Waltbrand E, Kvist G, Mellström D, Saxne T, Ohlsson C, Nordborg E and Carlsten H: Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol. 30:1456–1463. 2003.PubMed/NCBI

10 

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. JAMA. 288:321–333. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA. 291:1701–1712. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Daraghmeh DN, Hopkins AM, King C, Abuhelwa AY, Wechalekar MD, Proudman SM, Sorich MJ and Wiese MD: Female reproductive status and exogenous sex hormone use in rheumatoid arthritis patients treated with tocilizumab and csDMARDs. Rheumatology (Oxford). 62:583–595. 2023. View Article : Google Scholar : PubMed/NCBI

13 

Gomez-Puerta JA, Celis R, Hernandez MV, Ruiz-Esquide V, Ramírez J, Haro I, Cañete JD and Sanmartí R: Differences in synovial fluid cytokine levels but not in synovial tissue cell infiltrate between anti-citrullinated peptide/protein antibody-positive and -negative rheumatoid arthritis patients. Arthritis Res Ther. 15:R1822013. View Article : Google Scholar : PubMed/NCBI

14 

Van Den Broek M, Dirven L, Klarenbeek NB, Molenaar TH, Han KH, Kerstens PJ, Huizinga TW, Dijkmans BA and Allaart CF: The association of treatment response and joint damage with ACPA-status in recent-onset RA: A subanalysis of the 8-year follow-up of the BeSt study. Ann Rheum Dis. 71:245–248. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, Klareskog L and Dahlqvist SR: A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther. 6:R303–R308. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Johansson M, Arlestig L, Hallmans G and Rantapää-Dahlqvist S: PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res Ther. 8:R192006. View Article : Google Scholar : PubMed/NCBI

17 

Ge C and Holmdahl R: The structure, specificity and function of anti-citrullinated protein antibodies. Nat Rev Rheumatol. 15:503–508. 2019. View Article : Google Scholar : PubMed/NCBI

18 

Kissel T, Reijm S, Slot LM, Cavallari M, Wortel CM, Vergroesen RD, Stoeken-Rijsbergen G, Kwekkeboom JC, Kampstra A, Levarht E, et al: Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications. Ann Rheum Dis. 79:472–480. 2020. View Article : Google Scholar : PubMed/NCBI

19 

Shlomchik MJ, Craft JE and Mamula MJ: From T to B and back again: Positive feedback in systemic autoimmune disease. Nat Rev Immunol. 1:147–153. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Yan J, Harvey BP, Gee RJ, Shlomchik MJ and Mamula MJ: B cells drive early T cell autoimmunity in vivo prior to dendritic cell-mediated autoantigen presentation. J Immunol. 177:4481–4487. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Weyand CM and Goronzy JJ: Immunometabolism in early and late stages of rheumatoid arthritis. Nat Rev Rheumatol. 13:291–301. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Weyand CM, Shen Y and Goronzy JJ: Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med. 125:36–43. 2018. View Article : Google Scholar : PubMed/NCBI

23 

Wu B, Goronzy JJ and Weyand CM: Metabolic fitness of t cells in autoimmune disease. Immunometabolism. 2:e2000172020. View Article : Google Scholar : PubMed/NCBI

24 

Ponchel F, Burska AN, Hunt L, Gul H, Rabin T, Parmar R, Buch MH, Conaghan PG and Emery P: T-cell subset abnormalities predict progression along the Inflammatory Arthritis disease continuum: Implications for management. Sci Rep. 10:36692020. View Article : Google Scholar : PubMed/NCBI

25 

Paunovic V, Carroll HP, Vandenbroeck K and Gadina M: Signalling, inflammation and arthritis: crossed signals: The role of interleukin (IL)-12, −17, −23 and −27 in autoimmunity. Rheumatology (Oxford). 47:771–776. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Kim W, Min S, Cho M, Youn J, Min J, Lee S, Park S, Cho C and Kim H: The role of IL-12 in inflammatory activity of patients with rheumatoid arthritis (RA). Clin Exp Immunol. 119:175–181. 2000. View Article : Google Scholar : PubMed/NCBI

27 

Chu CQ, Swart D, Alcorn D, Tocker J and Elkon KB: Interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17. Arthritis Rheum. 56:1145–1151. 2007. View Article : Google Scholar : PubMed/NCBI

28 

Geboes L, De Klerck B, Van Balen M, Kelchtermans H, Mitera T, Boon L, De Wolf-Peeters C and Matthys P: Freund's complete adjuvant induces arthritis in mice lacking a functional interferon-gamma receptor by triggering tumor necrosis factor alpha-driven osteoclastogenesis. Arthritis Rheum. 56:2595–2607. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Sigidin YA, Loukina GV, Skurkovich B and Skurkovich S: Randomized, double-blind trial of anti-interferon-gamma antibodies in rheumatoid arthritis. Scand J Rheumatol. 30:203–207. 2001. View Article : Google Scholar : PubMed/NCBI

30 

Ortmann RA and Shevach EM: Susceptibility to collagen-induced arthritis: Cytokine-mediated regulation. Clin Immunol. 98:109–118. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Haikal SM, Abdeltawab NF, Rashed LA, Abd El-Galil TI, Elmalt HA and Amin MA: Combination Therapy of Mesenchymal Stromal Cells and Interleukin-4 Attenuates Rheumatoid Arthritis in a Collagen-Induced Murine Model. Cells. 8:8232019. View Article : Google Scholar : PubMed/NCBI

32 

Steinman L: A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 13:139–145. 2007. View Article : Google Scholar : PubMed/NCBI

33 

Krebs CF and Steinmetz OM: CD4(+) T Cell Fate in Glomerulonephritis: A Tale of Th1, Th17, and Novel Treg Subtypes. Mediators Inflamm. 2016:53938942016. View Article : Google Scholar : PubMed/NCBI

34 

Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, Monticelli S, Lanzavecchia A and Sallusto F: Pathogen-induced human TH17 cells produce IFN-ү or IL-10 and are regulated by IL-1β. Nature. 484:514–518. 2012. View Article : Google Scholar : PubMed/NCBI

35 

Evans HG, Roostalu U, Walter GJ, Gullick NJ, Frederiksen KS, Roberts CA, Sumner J, Baeten DL, Gerwien JG, Cope AP, et al: TNF-α blockade induces IL-10 expression in human CD4+ T cells. Nat Commun. 5:31992014. View Article : Google Scholar : PubMed/NCBI

36 

Penatti A, Facciotti F, De Matteis R, Larghi P, Paroni M, Murgo A, De Lucia O, Pagani M, Pierannunzii L, Truzzi M, et al: Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 19:1032017. View Article : Google Scholar : PubMed/NCBI

37 

Van Hamburg JP, Asmawidjaja PS, Davelaar N, Mus AM, Colin EM, Hazes JM, Dolhain RJ and Lubberts E: Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 63:73–83. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Nakae S, Nambu A, Sudo K and Iwakura Y: Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 171:6173–6177. 2003. View Article : Google Scholar : PubMed/NCBI

39 

Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA and van den Berg WB: Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 50:650–659. 2004. View Article : Google Scholar : PubMed/NCBI

40 

Corneth OB, Reijmers RM, Mus AM, Asmawidjaja PS, van Hamburg JP, Papazian N, Siegers JY, Mourcin F, Amin R, Tarte K, et al: Loss of IL-22 inhibits autoantibody formation in collagen-induced arthritis in mice. Eur J Immunol. 46:1404–1414. 2016. View Article : Google Scholar : PubMed/NCBI

41 

Kikuta J, Wada Y, Kowada T, Wang Z, Sun-Wada GH, Nishiyama I, Mizukami S, Maiya N, Yasuda H, Kumanogoh A, et al: Dynamic visualization of RANKL and Th17-mediated osteoclast function. J Clin Invest. 123:866–873. 2013.PubMed/NCBI

42 

Tlustochowicz W, Rahman P, Seriolo B, Krammer G, Porter B, Widmer A and Richards HB: Efficacy and safety of subcutaneous and intravenous loading dose regimens of secukinumab in patients with active rheumatoid arthritis: Results from a randomized phase II study. J Rheumatol. 43:495–503. 2016. View Article : Google Scholar : PubMed/NCBI

43 

Corthay A: How do regulatory T cells work? Scand J Immunol. 70:326–36. 2009. View Article : Google Scholar : PubMed/NCBI

44 

Rudensky AY: Regulatory T cells and Foxp3. Immunol Rev. 241:260–268. 2011. View Article : Google Scholar : PubMed/NCBI

45 

Zhang R, Miao J, Zhang K, Zhang B, Luo X, Sun H, Zheng Z and Zhu P: Th1-like treg cells are increased but deficient in function in rheumatoid arthritis. Front Immunol. 13:8637532022. View Article : Google Scholar : PubMed/NCBI

46 

Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B, et al: Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med. 19:322–328. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Walter GJ, Fleskens V, Frederiksen KS, Rajasekhar M, Menon B, Gerwien JG, Evans HG and Taams LS: Phenotypic, functional, and gene expression profiling of peripheral CD45RA+ and CD45RO+ CD4+CD25+CD127(low) Treg cells in patients with chronic rheumatoid arthritis. Arthritis Rheumatol. 68:103–116. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Kommoju V, Mariaselvam CM, Bulusu SN, Ganapathy CK, Narasimhan PB, Thabah MM and Negi VS: Conventional Tregs in treatment-naive rheumatoid arthritis are deficient in suppressive function with an increase in percentage of CXCR3 and CCR6 expressing Tregs. Immunol Res. 72:396–408. 2024. View Article : Google Scholar : PubMed/NCBI

49 

Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA and Takayanagi H: Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 20:62–68. 2014. View Article : Google Scholar : PubMed/NCBI

50 

Gonzalez-Rey E, Gonzalez MA, Varela N, O'Valle F, Hernandez-Cortes P, Rico L, Büscher D and Delgado M: Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis. 69:241–248. 2010. View Article : Google Scholar : PubMed/NCBI

51 

Pedrosa M, Gomes J, Laranjeira P, Duarte C, Pedreiro S, Antunes B, Ribeiro T, Santos F, Martinho A, Fardilha M, et al: Immunomodulatory effect of human bone marrow-derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients. J Tissue Eng Regen Med. 14:16–28. 2020. View Article : Google Scholar : PubMed/NCBI

52 

Ji LS, Sun XH, Zhang X, Zhou ZH, Yu Z, Zhu XJ, Huang LY, Fang M, Gao YT, Li M and Gao YQ: Mechanism of follicular helper T cell differentiation regulated by transcription factors. J Immunol Res. 2020:18265872020. View Article : Google Scholar : PubMed/NCBI

53 

Liu R, Li X, Zhang Z, Zhou M, Sun Y, Su D, Feng X, Gao X, Shi S, Chen W and Sun L: Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis. Sci Rep. 5:127772015. View Article : Google Scholar : PubMed/NCBI

54 

Ma J, Zhu C, Ma B, Tian J, Baidoo SE, Mao C, Wu W, Chen J, Tong J, Yang M, et al: Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis. Clin Dev Immunol. 2012:8274802012. View Article : Google Scholar : PubMed/NCBI

55 

Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L and Jiang Y: High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Exp Immunol. 174:212–220. 2013. View Article : Google Scholar : PubMed/NCBI

56 

Kwok SK, Cho ML, Park MK, Oh HJ, Park JS, Her YM, Lee SY, Youn J, Ju JH, Park KS, et al: Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum. 64:740–751. 2012. View Article : Google Scholar : PubMed/NCBI

57 

Jang E, Cho SH, Park H, Paik DJ, Kim JM and Youn J: A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25-T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol. 182:4649–4656. 2009. View Article : Google Scholar : PubMed/NCBI

58 

Olsen NJ, Watson MB, Henderson GS and Kovacs WJ: Androgen deprivation induces phenotypic and functional changes in the thymus of adult male mice. Endocrinology. 129:2471–2476. 1991. View Article : Google Scholar : PubMed/NCBI

59 

Xu D, Wu Y, Gao C, Qin Y, Zhao X, Liang Z, Wang Y, Feng M, Zhang C, Liu G and Luo J: Characteristics of and reference ranges for peripheral blood lymphocytes and CD4+ T cell subsets in healthy adults in Shanxi Province, North China. J Int Med Res. 48:3000605209131492020. View Article : Google Scholar : PubMed/NCBI

60 

Wilkinson NM, Chen HC, Lechner MG and Su MA: Sex differences in immunity. Annu Rev Immunol. 40:75–94. 2022. View Article : Google Scholar : PubMed/NCBI

61 

Cutolo M, Sulli A and Straub RH: Estrogen metabolism and autoimmunity. Autoimmun Rev. 11:A460–A464. 2012. View Article : Google Scholar : PubMed/NCBI

62 

Chakraborty B, Byemerwa J, Krebs T, Lim F, Chang CY and McDonnell DP: Estrogen receptor signaling in the immune system. Endocr Rev. 44:117–141. 2023. View Article : Google Scholar : PubMed/NCBI

63 

Bynote KK, Hackenberg JM, Korach KS, Lubahn DB, Lane PH and Gould KA: Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice. Genes Immun. 9:137–152. 2008. View Article : Google Scholar : PubMed/NCBI

64 

Li J and Mcmurray RW: Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. Clin Immunol. 123:219–226. 2007. View Article : Google Scholar : PubMed/NCBI

65 

Svenson JL, Eudaly J, Ruiz P, Korach KS and Gilkeson GS: Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin Immunol. 128:259–268. 2008. View Article : Google Scholar : PubMed/NCBI

66 

Maselli A, Conti F, Alessandri C, Colasanti T, Barbati C, Vomero M, Ciarlo L, Patrizio M, Spinelli FR, Ortona E, et al: Low expression of estrogen receptor beta in T lymphocytes and high serum levels of anti-estrogen receptor alpha antibodies impact disease activity in female patients with systemic lupus erythematosus. Biol Sex Differ. 7:32016. View Article : Google Scholar : PubMed/NCBI

67 

Pierdominici M, Maselli A, Varano B, Barbati C, Cesaro P, Spada C, Zullo A, Lorenzetti R, Rosati M, Rainaldi G, et al: Linking estrogen receptor β expression with inflammatory bowel disease activity. Oncotarget. 6:40443–40451. 2015. View Article : Google Scholar : PubMed/NCBI

68 

Kim DH, Park HJ, Park HS, Lee JU, Ko C, Gye MC and Choi JM: Estrogen receptor α in T cells suppresses follicular helper T cell responses and prevents autoimmunity. Exp Mol Med. 51:1–9. 2019. View Article : Google Scholar : PubMed/NCBI

69 

Guo D, Liu X, Zeng C, Cheng L, Song G, Hou X, Zhu L and Zou K: Estrogen receptor β activation ameliorates DSS-induced chronic colitis by inhibiting inflammation and promoting Treg differentiation. Int Immunopharmacol. 77:1059712019. View Article : Google Scholar : PubMed/NCBI

70 

Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A, Dupont S, Chambon P, Druet P, Bayard F and Guéry JC: Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells. Eur J Immunol. 33:512–521. 2003. View Article : Google Scholar : PubMed/NCBI

71 

Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB and Estes DM: Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 175:5716–5723. 2005. View Article : Google Scholar : PubMed/NCBI

72 

Polanczyk MJ, Hopke C, Huan J, Vandenbark AA and Offner H: Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol. 170:85–92. 2005. View Article : Google Scholar : PubMed/NCBI

73 

Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, Zhao L, An X, Du X, Chen X, et al: Induction of regulatory T cells by physiological level estrogen. J Cell Physiol. 214:456–464. 2008. View Article : Google Scholar : PubMed/NCBI

74 

Haghmorad D, Amini AA, Mahmoudi MB, Rastin M, Hosseini M and Mahmoudi M: Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. J Neuroimmunol. 277:85–95. 2014. View Article : Google Scholar : PubMed/NCBI

75 

Pfeilschifter J, Koditz R, Pfohl M and Schatz H: Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 23:90–119. 2002. View Article : Google Scholar : PubMed/NCBI

76 

Sinatora RV, Chagas EFB, Mattera FOP, Mellem LJ, Santos AROD, Pereira LP, Aranão ALC, Guiguer EL, Araújo AC, Haber JFDS, et al: Relationship of inflammatory markers and metabolic syndrome in postmenopausal women. Metabolites. 12:732022. View Article : Google Scholar : PubMed/NCBI

77 

Ralston SH, Russell RG and Gowen M: Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women. J Bone Miner Res. 5:983–988. 1990. View Article : Google Scholar : PubMed/NCBI

78 

Lucas-Herald AK and Touyz RM: Androgens and androgen receptors as determinants of vascular sex differences across the lifespan. Can J Cardiol. 38:1854–1864. 2022. View Article : Google Scholar : PubMed/NCBI

79 

Kwon H, Schafer JM, Song NJ, Kaneko S, Li A, Xiao T, Ma A, Allen C, Das K, Zhou L, et al: Androgen conspires with the CD8(+) T cell exhaustion program and contributes to sex bias in cancer. Sci Immunol. 7:eabq26302022. View Article : Google Scholar : PubMed/NCBI

80 

Yang C, Jin J, Yang Y, Sun H, Wu L, Shen M, Hong X, Li W, Lu L, Cao D, et al: Androgen receptor-mediated CD8(+) T cell stemness programs drive sex differences in antitumor immunity. Immunity. 55:1268–1283. e92022. View Article : Google Scholar : PubMed/NCBI

81 

Berrih-Aknin S, Panse RL and Dragin N: AIRE: A missing link to explain female susceptibility to autoimmune diseases. Ann N Y Acad Sci. 1412:21–32. 2018. View Article : Google Scholar : PubMed/NCBI

82 

Zhu ML, Bakhru P, Conley B, Nelson JS, Free M, Martin A, Starmer J, Wilson EM and Su MA: Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun. 7:113502016. View Article : Google Scholar : PubMed/NCBI

83 

Dragin N, Bismuth J, Cizeron-Clairac G, Biferi MG, Berthault C, Serraf A, Nottin R, Klatzmann D, Cumano A, Barkats M, et al: Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest. 126:1525–1537. 2016. View Article : Google Scholar : PubMed/NCBI

84 

Afshan G, Afzal N and Qureshi S: CD4+CD25(hi) regulatory T cells in healthy males and females mediate gender difference in the prevalence of autoimmune diseases. Clin Lab. 58:567–571. 2012.PubMed/NCBI

85 

Gandhi VD, Cephus JY, Norlander AE, Chowdhury NU, Zhang J, Ceneviva ZJ, Tannous E, Polosukhin VV, Putz ND, Wickersham N, et al: Androgen receptor signaling promotes Treg suppressive function during allergic airway inflammation. J Clin Invest. 132:e1533972022. View Article : Google Scholar : PubMed/NCBI

86 

Vargas-Villavicencio JA, Larralde C and Morales-Montor J: Gonadectomy and progesterone treatment induce protection in murine cysticercosis. Parasite Immunol. 28:667–674. 2006. View Article : Google Scholar : PubMed/NCBI

87 

Xia T, Ma J and Sun Y and Sun Y: Androgen receptor suppresses inflammatory response of airway epithelial cells in allergic asthma through MAPK1 and MAPK14. Hum Exp Toxicol. 41:96032712211213202022. View Article : Google Scholar : PubMed/NCBI

88 

Kalidhindi RSR, Ambhore NS, Balraj P, Schmidt T, Khan MN and Sathish V: Androgen receptor activation alleviates airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma. Am J Physiol Lung Cell Mol Physiol. 320:L803–L818. 2021. View Article : Google Scholar : PubMed/NCBI

89 

Kissick HT, Sanda MG, Dunn LK, Pellegrini KL, On ST, Noel JK and Arredouani MS: Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation. Proc Natl Acad Sci USA. 111:9887–9892. 2014. View Article : Google Scholar : PubMed/NCBI

90 

Klein SL, Jedlicka A and Pekosz A: The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis. 10:338–349. 2010. View Article : Google Scholar : PubMed/NCBI

91 

Hong CY, Park JH, Ahn RS, Im SY, Choi HS, Soh J, Mellon SH and Lee K: Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha. Mol Cell Biol. 24:2593–2604. 2004. View Article : Google Scholar : PubMed/NCBI

92 

Druckmann R and Druckmann MA: Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol. 97:389–396. 2005. View Article : Google Scholar : PubMed/NCBI

93 

Scarpin KM, Graham JD, Mote PA and Clarke CL: Progesterone action in human tissues: Regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl Recept Signal. 7:e0092009. View Article : Google Scholar : PubMed/NCBI

94 

Quispe Calla NE, Ghonime MG, Cherpes TL and Vicetti Miguel RD: Medroxyprogesterone acetate impairs human dendritic cell activation and function. Hum Reprod. 30:1169–1177. 2015. View Article : Google Scholar : PubMed/NCBI

95 

Mao G, Wang J, Kang Y, Tai P, Wen J, Zou Q, Li G, Ouyang H, Xia G and Wang B: Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice. Endocrinology. 151:5477–5488. 2010. View Article : Google Scholar : PubMed/NCBI

96 

Hierweger AM, Engler JB, Friese MA, Reichardt HM, Lydon J, DeMayo F, Mittrücker HW and Arck PC: Progesterone modulates the T-cell response via glucocorticoid receptor-dependent pathways. Am J Reprod Immunol. 81:e130842019. View Article : Google Scholar : PubMed/NCBI

97 

Robinson DP and Klein SL: Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav. 62:263–271. 2012. View Article : Google Scholar : PubMed/NCBI

98 

Hughes GC, Martin D, Zhang K, Hudkins KL, Alpers CE, Clark EA and Elkon KB: Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum. 60:1775–1784. 2009. View Article : Google Scholar : PubMed/NCBI

99 

Hughes GC and Choubey D: Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol. 10:740–751. 2014. View Article : Google Scholar : PubMed/NCBI

100 

Carreno PC, Sacedon R, Jimenez E, Vicente A and Zapata AG: Prolactin affects both survival and differentiation of T-cell progenitors. J Neuroimmunol. 160:135–145. 2005. View Article : Google Scholar : PubMed/NCBI

101 

Legorreta-Haquet MV, Chavez-Rueda K, Chavez-Sanchez L, Cervera-Castillo H, Zenteno-Galindo E, Barile-Fabris L, Burgos-Vargas R, Álvarez-Hernández E and Blanco-Favela F: Function of treg cells decreased in patients with systemic lupus erythematosus due to the effect of prolactin. Medicine (Baltimore). 95:e23842016. View Article : Google Scholar : PubMed/NCBI

102 

Dimitrov S, Lange T, Fehm HL and Born J: A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines. Brain Behav Immun. 18:368–374. 2004. View Article : Google Scholar : PubMed/NCBI

103 

Tsampalas M, Gridelet V, Berndt S, Foidart JM, Geenen V and Perrier d'Hauterive S: Human chorionic gonadotropin: A hormone with immunological and angiogenic properties. J Reprod Immunol. 85:93–98. 2010. View Article : Google Scholar : PubMed/NCBI

104 

Lentz LS, Stutz AJ, Meyer N, Schubert K, Karkossa I, von Bergen M, Zenclussen AC and Schumacher A: Human chorionic gonadotropin promotes murine Treg cells and restricts pregnancy-harmful proinflammatory Th17 responses. Front Immunol. 13:9892472022. View Article : Google Scholar : PubMed/NCBI

105 

Sha J, Liu F, Zhai J, Liu X, Zhang Q and Zhang B: Alteration of Th17 and Foxp3(+) regulatory T cells in patients with unexplained recurrent spontaneous abortion before and after the therapy of hCG combined with immunoglobulin. Exp Ther Med. 14:1114–1118. 2017. View Article : Google Scholar : PubMed/NCBI

106 

Diao LH, Li GG, Zhu YC, Tu WW, Huang CY, Lian RC, Chen X, Li YY, Zhang T, Huang Y and Zeng Y: Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells. Am J Reprod Immunol. 77:2017. View Article : Google Scholar : PubMed/NCBI

107 

Schumacher A, Heinze K, Witte J, Poloski E, Linzke N, Woidacki K and Zenclussen AC: Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance. J Immunol. 190:2650–2658. 2013. View Article : Google Scholar : PubMed/NCBI

108 

Iqbal J, Sun L, Kumar TR, Blair HC and Zaidi M: Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci USA. 103:14925–14930. 2006. View Article : Google Scholar : PubMed/NCBI

109 

Qian H, Jia J, Yang Y, Bian Z and Ji Y: A follicle-stimulating hormone exacerbates the progression of periapical inflammation through modulating the cytokine release in periodontal tissue. Inflammation. 43:1572–1585. 2020. View Article : Google Scholar : PubMed/NCBI

110 

Kvien TK, Uhlig T, Odegard S and Heiberg MS: Epidemiological aspects of rheumatoid arthritis: The sex ratio. Ann N Y Acad Sci. 1069:212–222. 2006. View Article : Google Scholar : PubMed/NCBI

111 

Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F, Skakic V, Badsha H, Peets T, Baranauskaite A, et al: Women, men, and rheumatoid arthritis: Analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res Ther. 11:R72009.PubMed/NCBI

112 

Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M, Cutolo M and Straub RH: Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J Rheumatol. 30:2597–2605. 2003.PubMed/NCBI

113 

Nieminen P, Hamalainen W, Savinainen J, Lehtonen M, Lehtiniemi S, Rinta-Paavola J, Lehenkari P, Kääriäinen T, Joukainen A, Kröger H, et al: Metabolomics of synovial fluid and infrapatellar fat pad in patients with osteoarthritis or rheumatoid arthritis. Inflammation. 45:1101–1117. 2022. View Article : Google Scholar : PubMed/NCBI

114 

Schmidt M, Weidler C, Naumann H, Anders S, Schölmerich J and Straub RH: Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes-androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5alpha-reduced androgens. Arthritis Res Ther. 7:R938–R948. 2005. View Article : Google Scholar : PubMed/NCBI

115 

Capellino S, Straub RH and Cutolo M: Aromatase and regulation of the estrogen-to-androgen ratio in synovial tissue inflammation: Common pathway in both sexes. Ann N Y Acad Sci. 1317:24–31. 2014. View Article : Google Scholar : PubMed/NCBI

116 

Weitoft T, Larsson A and Ronnblom L: Serum levels of sex steroid hormones and matrix metalloproteinases after intra-articular glucocorticoid treatment in female patients with rheumatoid arthritis. Ann Rheum Dis. 67:422–424. 2008. View Article : Google Scholar : PubMed/NCBI

117 

Capellino S, Montagna P, Villaggio B, Soldano S, Straub RH and Cutolo M: Hydroxylated estrogen metabolites influence the proliferation of cultured human monocytes: possible role in synovial tissue hyperplasia. Clin Exp Rheumatol. 26:903–909. 2008.PubMed/NCBI

118 

Schmidt M, Hartung R, Capellino S, Cutolo M, Pfeifer-Leeg A and Straub RH: Estrone/17beta-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis. Arthritis Rheum. 60:2913–2922. 2009. View Article : Google Scholar : PubMed/NCBI

119 

Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, Sierra O and Pacifici R: Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci USA. 100:10405–10410. 2003. View Article : Google Scholar : PubMed/NCBI

120 

Garcia-Perez MA, Noguera I, Hermenegildo C, Martínez-Romero A, Tarín JJ and Cano A: Alterations in the phenotype and function of immune cells in ovariectomy-induced osteopenic mice. Hum Reprod. 21:880–887. 2006. View Article : Google Scholar : PubMed/NCBI

121 

Yoneda T, Ishimaru N, Arakaki R, Kobayashi M, Izawa T, Moriyama K and Hayashi Y: Estrogen deficiency accelerates murine autoimmune arthritis associated with receptor activator of nuclear factor-kappa B ligand-mediated osteoclastogenesis. Endocrinology. 145:2384–2391. 2004. View Article : Google Scholar : PubMed/NCBI

122 

Andersson A, Grahnemo L, Engdahl C, Stubelius A, Lagerquist MK, Carlsten H and Islander U: IL-17-producing үδT cells are regulated by estrogen during development of experimental arthritis. Clin Immunol. 161:324–332. 2015. View Article : Google Scholar : PubMed/NCBI

123 

Zai Z, Xu Y, Qian X, Li Z, Ou Z, Zhang T, Wang L, Ling Y, Peng X, Zhang Y and Chen F: Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis. J Transl Med. 20:5612022. View Article : Google Scholar : PubMed/NCBI

124 

Ishizuka M, Hatori M, Suzuki T, Miki Y, Darnel AD, Tazawa C, Sawai T, Uzuki M, Tanaka Y, Kokubun S and Sasano H: Sex steroid receptors in rheumatoid arthritis. Clin Sci (Lond). 106:293–300. 2004. View Article : Google Scholar : PubMed/NCBI

125 

Engdahl C, Borjesson AE, Forsman HF, Andersson A, Stubelius A, Krust A, Chambon P, Islander U, Ohlsson C, Carlsten H and Lagerquist MK: The role of total and cartilage-specific estrogen receptor alpha expression for the ameliorating effect of estrogen treatment on arthritis. Arthritis Res Ther. 16:R1502014. View Article : Google Scholar : PubMed/NCBI

126 

Andersson A, Stubelius A, Karlsson MN, Engdahl C, Erlandsson M, Grahnemo L, Lagerquist MK and Islander U: Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis. Arthritis Res Ther. 17:322015. View Article : Google Scholar : PubMed/NCBI

127 

Xu X, Yang H, Bullock WA, Gallant MA, Ohlsson C, Bellido TM and Main RP: Osteocyte estrogen receptor β (Ot-ERβ) regulates bone turnover and skeletal adaptive response to mechanical loading differently in male and female growing and adult mice. J Bone Miner Res. 38:186–197. 2023. View Article : Google Scholar : PubMed/NCBI

128 

Sims NA, Dupont S, Krust A, Clement-Lacroix P, Minet D, Resche-Rigon M, Gaillard-Kelly M and Baron R: Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-beta in bone remodeling in females but not in males. Bone. 30:18–25. 2002. View Article : Google Scholar : PubMed/NCBI

129 

Bove R: Autoimmune diseases and reproductive aging. Clin Immunol. 149:251–264. 2015. View Article : Google Scholar

130 

Cutolo M, Sulli A, Pizzorni C, Craviotto C and Straub RH: Hypothalamic-pituitary-adrenocortical and gonadal functions in rheumatoid arthritis. Ann N Y Acad Sci. 992:107–117. 2003. View Article : Google Scholar : PubMed/NCBI

131 

Yang DD, Krasnova A, Nead KT, Choueiri TK, Hu JC, Hoffman KE, Yu JB, Spratt DE, Feng FY, Trinh QD and Nguyen PL: Androgen deprivation therapy and risk of rheumatoid arthritis in patients with localized prostate cancer. Ann Oncol. 29:386–391. 2018. View Article : Google Scholar : PubMed/NCBI

132 

Drevinskaite M, Dadoniene J, Miltiniene D, Patasius A and Smailyte G: Association between androgen deprivation therapy and the risk of inflammatory rheumatic diseases in men with prostate cancer: Nationwide Cohort Study in Lithuania. J Clin Med. 11:20392007. View Article : Google Scholar

133 

Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C and Sulli A: Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis. Ann N Y Acad Sci. 966:131–142. 2002. View Article : Google Scholar : PubMed/NCBI

134 

Ganesan K, Selvam R, Abhirami R, Raju KV, Manohar BM and Puvanakrishnan R: Gender differences and protective effects of testosterone in collagen induced arthritis in rats. Rheumatol Int. 28:345–353. 2008. View Article : Google Scholar : PubMed/NCBI

135 

Ganesan K, Balachandran C, Manohar BM and Puvanakrishnan R: Effects of testosterone, estrogen and progesterone on TNF-α mediated cellular damage in rat arthritic synovial fibroblasts. Rheumatol Int. 32:3181–3188. 2012. View Article : Google Scholar : PubMed/NCBI

136 

Martin CS, Crastin A, Sagmeister MS, Turner JD, MacDonald L, Kurowska-Stolarska M, Scheel-Toellner D, Taylor AE, Gilligan LC, Storbeck K, et al: Inflammation dynamically regulates steroid hormone metabolism and action within macrophages in rheumatoid arthritis. J Autoimmun. 147:1032632024. View Article : Google Scholar : PubMed/NCBI

137 

Weidler C, Struharova S, Schmidt M, Ugele B, Schölmerich J and Straub RH: Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: A prerequisite for local androgen deficiency. Arthritis Rheum. 52:1721–1729. 2005. View Article : Google Scholar : PubMed/NCBI

138 

Straub RH, Harle P, Yamana S, Matsuda T, Takasugi K, Kishimoto T and Nishimoto N: Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: A randomized, double-blind, placebo-controlled study. Arthritis Rheum. 54:1778–1785. 2006. View Article : Google Scholar : PubMed/NCBI

139 

Jurcovicova J, Svik K, Scsukova S, Bauerova K, Rovensky J and Stancikova M: Methotrexate treatment ameliorated testicular suppression and anorexia related leptin reduction in rats with adjuvant arthritis. Rheumatol Int. 29:1187–1191. 2009. View Article : Google Scholar : PubMed/NCBI

140 

Stark K, Straub RH, Rovensky J, Blažičková S, Eiselt G and Schmidt M: CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women. Arthritis Res Ther. 17:562015. View Article : Google Scholar : PubMed/NCBI

141 

Park JS, Choi SY, Hwang SH, Kim SM, Choi J, Jung KA, Kwon JY, Kong YY, Cho ML and Park SH: CR6-interacting factor 1 controls autoimmune arthritis by regulation of signal transducer and activator of transcription 3 pathway and T helper type 17 cells. Immunology. 156:413–421. 2019. View Article : Google Scholar : PubMed/NCBI

142 

Rontzsch A, Thoss K, Petrow PK, Henzgen S and Bräuer R: Amelioration of murine antigen-induced arthritis by dehydroepiandrosterone (DHEA). Inflamm Res. 53:189–198. 2004. View Article : Google Scholar : PubMed/NCBI

143 

Sandoughi M, Kaykhaei MA, Langarizadeh E and Dashipour A: Effects of dehydroepiandrosterone on quality of life in premenopausal women with rheumatoid arthritis: A preliminary randomized clinical trial. Int J Rheum Dis. 23:1692–1697. 2020. View Article : Google Scholar : PubMed/NCBI

144 

Hellberg S, Raffetseder J, Rundquist O, Magnusson R, Papapavlou G, Jenmalm MC, Ernerudh J and Gustafsson M: Progesterone dampens immune responses in in vitro activated CD4(+) T cells and affects genes associated with autoimmune diseases that improve during pregnancy. Front Immunol. 12:6721682021. View Article : Google Scholar : PubMed/NCBI

145 

Khalkhali-Ellis Z, Seftor EA, Nieva DR, Handa RJ, Price RH Jr, Kirschmann DA, Baragi VM, Sharma RV, Bhalla RC, Moore TL and Hendrix MJ: Estrogen and progesterone regulation of human fibroblast-like synoviocyte function in vitro: implications in rheumatoid arthritis. J Rheumatol. 27:1622–1631. 2000.PubMed/NCBI

146 

Jahanbakhshi M, Babaloo Z, Mortazavi-Jahromi SS, Shokri MM, Ahmadi H and Mirshafiey A: Modification of sexual hormones in rheumatoid arthritis patients by M2000 (β-D-mannuronic Acid) as a Novel NSAID with immunosuppressive property. Endocr Metab Immune Disord Drug Targets. 18:530–536. 2018. View Article : Google Scholar : PubMed/NCBI

147 

Tengstrand B, Carlstrom K and Hafstrom I: Bioavailable testosterone in men with rheumatoid arthritis-high frequency of hypogonadism. Rheumatology (Oxford). 41:285–289. 2002. View Article : Google Scholar : PubMed/NCBI

148 

Tengstrand B, Carlstrom K and Hafstrom I: Gonadal hormones in men with rheumatoid arthritis-from onset through 2 years. J Rheumatol. 36:887–892. 2009. View Article : Google Scholar : PubMed/NCBI

149 

Cevik R, Em S, Gur A, Nas K, Sarac AJ and Colpan L: Sex and thyroid hormone status in women with rheumatoid arthritis: Are there any effects of menopausal state and disease activity on these hormones? Int J Clin Pract. 58:327–332. 2004. View Article : Google Scholar : PubMed/NCBI

150 

Takeuchi T, Tanaka Y, Higashitani C, Iwai M, Komatsu K, Akazawa R and Lademacher C: A phase 2a, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral gonadotropin-releasing hormone antagonist, ASP1707, in postmenopausal female patients with rheumatoid arthritis taking methotrexate. Mod Rheumatol. 31:53–60. 2021. View Article : Google Scholar : PubMed/NCBI

151 

Weitzmann MN and Pacifici R: Estrogen deficiency and bone loss: An inflammatory tale. J Clin Invest. 116:1186–1194. 2006. View Article : Google Scholar : PubMed/NCBI

152 

Belenska-Todorova L, Zhivkova R, Markova M and Ivanovska N: Follicle stimulating hormone and estradiol alter immune response in osteoarthritic mice in an opposite manner. Int J Immunopathol Pharmacol. 35:205873842110161982021. View Article : Google Scholar : PubMed/NCBI

153 

Zhang X, Qiao P, Guo Q, Liang Z, Pan J, Wu F, Wang X and Zhang L: High follicle-stimulating hormone level associated with risk of rheumatoid arthritis and disease activity. Front Endocrinol (Lausanne). 13:8628492022. View Article : Google Scholar : PubMed/NCBI

154 

Vieira Borba V and Shoenfeld Y: Prolactin, autoimmunity, and motherhood: when should women avoid breastfeeding? Clin Rheumatol. 38:1263–1270. 2019. View Article : Google Scholar : PubMed/NCBI

155 

Ram S, Blumberg D, Newton P, Anderson NR and Gama R: Raised serum prolactin in rheumatoid arthritis: genuine or laboratory artefact? Rheumatology (Oxford). 43:1272–1274. 2004. View Article : Google Scholar : PubMed/NCBI

156 

Zoli A, Lizzio MM, Ferlisi EM, Massafra V, Mirone L, Barini A, Scuderi F, Bartolozzi F and Magaró M: ACTH, cortisol and prolactin in active rheumatoid arthritis. Clin Rheumatol. 21:289–293. 2002. View Article : Google Scholar : PubMed/NCBI

157 

Han A, Kim JY, Kwak-Kim J and Lee SK: Menopause is an inflection point of age-related immune changes in women. J Reprod Immunol. 146:1033462021. View Article : Google Scholar : PubMed/NCBI

158 

Humphreys JH, Verstappen SM, Hyrich KL, Chipping JR, Marshall T and Symmons DP: The incidence of rheumatoid arthritis in the UK: Comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register. Ann Rheum Dis. 72:1315–1320. 2013. View Article : Google Scholar : PubMed/NCBI

159 

Mollard E, Pedro S, Chakravarty E, Clowse M, Schumacher R and Michaud K: The impact of menopause on functional status in women with rheumatoid arthritis. Rheumatology (Oxford). 57:798–802. 2018. View Article : Google Scholar : PubMed/NCBI

160 

Beydoun HA, El-Amin R, McNeal M, Perry C and Archer DF: Reproductive history and postmenopausal rheumatoid arthritis among women 60 years or older: Third national health and nutrition examination survey. Menopause. 20:930–935. 2013. View Article : Google Scholar : PubMed/NCBI

161 

Salliot C, Nguyen Y, Gusto G, Gelot A, Gambaretti J, Mariette X, Boutron-Ruault MC and Seror R: Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study. Rheumatology (Oxford). 60:4790–4800. 2021. View Article : Google Scholar : PubMed/NCBI

162 

Alpizar-Rodriguez D, Mueller RB, Moller B, Dudler J, Ciurea A, Zufferey P, Kyburz D, Walker UA, von Mühlenen I, Roux-Lombard P, et al: Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis. Rheumatology (Oxford). 56:1579–1585. 2017. View Article : Google Scholar : PubMed/NCBI

163 

Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM and de Villiers TJ; STRAW + 10 Collaborative Group, : Executive summary of the Stages of Reproductive Aging Workshop + 10: Addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab. 97:1159–1168. 2012. View Article : Google Scholar : PubMed/NCBI

164 

Engdahl C, Bondt A, Harre U, Raufer J, Pfeifle R, Camponeschi A, Wuhrer M, Seeling M, Mårtensson IL, Nimmerjahn F, et al: Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: A potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Res Ther. 20:842018. View Article : Google Scholar : PubMed/NCBI

165 

Guthrie KA, Dugowson CE, Voigt LF, Koepsell TD and Nelson JL: Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis Rheum. 62:1842–1848. 2010. View Article : Google Scholar : PubMed/NCBI

166 

Straub RH: The complex role of estrogens in inflammation. Endocr Rev. 28:521–574. 2007. View Article : Google Scholar : PubMed/NCBI

167 

Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, et al: Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 374:1221–1231. 2016. View Article : Google Scholar : PubMed/NCBI

168 

Orellana C, Wedren S, Kallberg H, Holmqvist M, Karlson EW, Alfredsson L and Bengtsson C; EIRA Study Group, : Parity and the risk of developing rheumatoid arthritis: Results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Ann Rheum Dis. 73:752–755. 2014. View Article : Google Scholar : PubMed/NCBI

169 

Bondt A, Hafkenscheid L, Falck D, Kuijper TM, Rombouts Y, Hazes JMW, Wuhrer M and Dolhain RJEM: ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis. Ann Rheum Dis. 77:1130–1136. 2018.PubMed/NCBI

170 

Forger F, Marcoli N, Gadola S, Möller B, Villiger PM and Østensen M: Pregnancy induces numerical and functional changes of CD4+CD25 high regulatory T cells in patients with rheumatoid arthritis. Ann Rheum Dis. 67:984–990. 2008. View Article : Google Scholar : PubMed/NCBI

171 

Munoz-Suano A, Kallikourdis M, Sarris M and Betz AG: Regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun. 38:J103–J108. 2012. View Article : Google Scholar : PubMed/NCBI

172 

Clowse ME, Chakravarty E, Costenbader KH, Chambers C and Michaud K: Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken). 64:668–674. 2012. View Article : Google Scholar : PubMed/NCBI

173 

Littlejohn EA: Pregnancy and rheumatoid arthritis. Best Pract Res Clin Obstet Gynaecol. 64:52–58. 2020. View Article : Google Scholar : PubMed/NCBI

174 

Lopez-Corbeto M, Martinez-Mateu S, Pluma A, Ferrer R, López-Lasanta M, De Agustín JJ, Barceló M, Julià A and Marsal S: The ovarian reserve as measured by the anti-Mullerian hormone is not diminished in patients with rheumatoid arthritis compared to the healthy population. Clin Exp Rheumatol. 39:337–343. 2021. View Article : Google Scholar : PubMed/NCBI

175 

Brouwer J, Laven JS, Hazes JM, Schipper I and Dolhain RJ: Levels of serum anti-Mullerian hormone, a marker for ovarian reserve, in women with rheumatoid arthritis. Arthritis Care Res (Hoboken). 65:1534–1538. 2013. View Article : Google Scholar : PubMed/NCBI

176 

Hampl JS and Papa DJ: Breastfeeding-related onset, flare, and relapse of rheumatoid arthritis. Nutr Rev. 59((8 Pt 1)): 264–268. 2001.PubMed/NCBI

177 

Karlson EW, Mandl LA, Hankinson SE and Grodstein F: Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses' Health Study. Arthritis Rheum. 50:3458–3467. 2004. View Article : Google Scholar : PubMed/NCBI

178 

Adab P, Jiang C Q, Rankin E, Tsang YW, Lam TH, Barlow J, Thomas GN, Zhang WS and Cheng KK: Breastfeeding practice, oral contraceptive use and risk of rheumatoid arthritis among Chinese women: The guangzhou biobank cohort study. Rheumatology (Oxford). 53:860–866. 2014. View Article : Google Scholar : PubMed/NCBI

179 

Chen H, Wang J, Zhou W, Yin H and Wang M: Breastfeeding and risk of rheumatoid arthritis: A systematic review and metaanalysis. J Rheumatol. 42:1563–1569. 2015. View Article : Google Scholar : PubMed/NCBI

180 

Orellana C, Saevarsdottir S, Klareskog L, Karlson EW, Alfredsson L and Bengtsson C: Postmenopausal hormone therapy and the risk of rheumatoid arthritis: Results from the Swedish EIRA population-based case-control study. Eur J Epidemiol. 30:449–457. 2015. View Article : Google Scholar : PubMed/NCBI

181 

Doran MF, Crowson CS, O'fallon WM and Gabriel SE: The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: A population based study. J Rheumatol. 31:207–213. 2004.PubMed/NCBI

182 

Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, Svejgaard A, Pedersen BV, Wohlfahrt J and Frisch M: Strong combined gene-environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis: A nationwide case-control study in Denmark. Arthritis Rheum. 56:1446–1453. 2007. View Article : Google Scholar : PubMed/NCBI

183 

Qi S, Xin R, Guo W and Liu Y: Meta-analysis of oral contraceptives and rheumatoid arthritis risk in women. Ther Clin Risk Manag. 10:915–923. 2014.PubMed/NCBI

184 

Walitt B, Pettinger M, Weinstein A, Katz J, Torner J, Wasko MC and Howard BV; Women's Health Initiative Investigators, : Effects of postmenopausal hormone therapy on rheumatoid arthritis: The women's health initiative randomized controlled trials. Arthritis Rheum. 59:302–310. 2008. View Article : Google Scholar : PubMed/NCBI

185 

Yuk JS, Seo YS, Im YH and Kim JH: Menopausal hormone therapy and risk of seropositive rheumatoid arthritis: A nationwide cohort study in Korea. Semin Arthritis Rheum. 63:1522802023. View Article : Google Scholar : PubMed/NCBI

186 

D'elia HF and Carlsten H: The impact of hormone replacement therapy on humoral and cell-mediated immune responses in vivo in post-menopausal women with rheumatoid arthritis. Scand J Immunol. 68:661–667. 2008. View Article : Google Scholar : PubMed/NCBI

187 

Cutolo M, Balleari E, Giusti M, Intra E and Accardo S: Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum. 34:1–5. 1991. View Article : Google Scholar : PubMed/NCBI

188 

Booji A, Biewenga-Booji CM, Huber-Bruning O, Cornelis C, Jacobs JW and Bijlsma JW: Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis. Ann Rheum Dis. 55:811–815. 1996. View Article : Google Scholar : PubMed/NCBI

189 

Hall GM, Larbre JP, Spector TD, Perry LA and Da Silva JA: A randomized trial of testosterone therapy in males with rheumatoid arthritis. Br J Rheumatol. 35:568–573. 1996. View Article : Google Scholar : PubMed/NCBI

190 

Hall GM, Daniels M, Huskisson EC and Spector TD: A randomised controlled trial of the effect of hormone replacement therapy on disease activity in postmenopausal rheumatoid arthritis. Ann Rheum Dis. 53:112–116. 1994. View Article : Google Scholar : PubMed/NCBI

191 

Hall GM, Daniels M, Doyle DV and Spector TD: Effect of hormone replacement therapy on bone mass in rheumatoid arthritis patients treated with and without steroids. Arthritis Rheum. 37:1499–505. 1994. View Article : Google Scholar : PubMed/NCBI

192 

Forsblad-D'elia H and Carlsten H: Hormone replacement therapy in postmenopausal women with rheumatoid arthritis stabilises bone mineral density by digital x-ray radiogrammetry in a randomised controlled trial. Ann Rheum Dis. 70:1167–1168. 2011. View Article : Google Scholar : PubMed/NCBI

193 

Pullerits R, D'elia HF, Tarkowski A and Carlsten H: The decrease of soluble RAGE levels in rheumatoid arthritis patients following hormone replacement therapy is associated with increased bone mineral density and diminished bone/cartilage turnover: A randomized controlled trial. Rheumatology (Oxford). 48:785–790. 2009. View Article : Google Scholar : PubMed/NCBI

194 

Kass A, Hollan I, Fagerland MW, Gulseth HC, Torjesen PA and Førre ØT: Rapid anti-inflammatory effects of gonadotropin-releasing hormone antagonism in rheumatoid arthritis patients with high gonadotropin levels in the AGRA Trial. PLoS One. 10:e01394392015. View Article : Google Scholar : PubMed/NCBI

195 

Kass AS, Forre OT, Fagerland MW, Gulseth HC, Torjesen PA and Hollan I: Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheumatoid arthritis (AGRA): A randomized, double-blind, placebo-controlled study. Scand J Rheumatol. 43:22–27. 2014. View Article : Google Scholar : PubMed/NCBI

196 

Brown MA and Su MA: An inconvenient variable: Sex hormones and their impact on T cell responses. J Immunol. 202:1927–1933. 2019. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

December-2024
Volume 30 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Niu Q, Hao J, Li Z and Zhang H: Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review). Mol Med Rep 30: 215, 2024.
APA
Niu, Q., Hao, J., Li, Z., & Zhang, H. (2024). Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review). Molecular Medicine Reports, 30, 215. https://doi.org/10.3892/mmr.2024.13339
MLA
Niu, Q., Hao, J., Li, Z., Zhang, H."Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review)". Molecular Medicine Reports 30.6 (2024): 215.
Chicago
Niu, Q., Hao, J., Li, Z., Zhang, H."Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review)". Molecular Medicine Reports 30, no. 6 (2024): 215. https://doi.org/10.3892/mmr.2024.13339