Females display an increased incidence of autoimmune diseases, with a sexual dimorphism in the immune response. The autoimmune diseases involve both genetic and environmental factors and the autoimmune process is characterized by the breakdown of tolerance in subjects with genetic susceptibility, with subsequent target (organ-specific and not) injury, that, in turn, elicits repairing mechanisms. Increasing evidence in the literature suggests an important role of the microenvironment on the immune system activity and of sex steroids in this context. Sex steroids may act at the multiple steps of the autoimmune process with different (and contrasting) effects, depending on the type of the steroid (natural or synthetic), the concentration and co-presence of the ligands and the binding to their specific receptors. Regarding the effectors of the immune system, different actions of sex steroids depend on the type of immunocytes involved (with final stimulatory or inhibitory actions). To complete the scenario, sex steroids may influence the whole process through multiple, contrasting and time-dependent pathways, for instance, modulating the autoimmune destroying process and/or stimulating the reparation. The clinical resulting effect is a balance of these complex and contrasting modifications. In this chapter we will summarize the fundamental and clinical aspects of the neuroendocrine-immune interactions in three main autoimmune diseases, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA) (see Reference 1 for more details).
The tolerance against self-antigens is a highly regulated process, involving both B and T-cells  Thymic negative selection (central deletion) eliminates the danger of pathogenic autoimmune T-cell, whereas peripheral mechanisms inactive T-cells which escape thymic deletion , (Table 1).
The professional antigen presenting cells (APCs) control the tight balance between tolerance and immunity. Dendritic cells (DCs) represent a family of professional APCs that are derived from hematopoietic precursors and have the capacity to induce antigen-specific T-cell responses.
The mechanisms causing loss of tolerance in autoimmune diseases remain elusive. Autoimmunity develops when genetically predisposed individuals encounter environmental agents that trigger the disease. Sex steroids influence this process at different levels.
A sexual dimorphism in the immune response has been described. The immune system (antibody and cell-mediated response) is more active in females, protecting from infectious diseases and conferring a greater longevity . Sex steroids influence immune cell development in primary lymphoid tissues and have immunomodulatory effects on both peripheral T-cell and B-cell subsets in adult life. Recent evidence suggests that tolerogenic DCs can be programmed by a variety of factors, including innate immune receptor signaling, cell–cell interactions, and micro-environmental cues (e.g., steroid hormones, cytokines, and other soluble mediators). Tolerogenic DC populations regulate immune responses through numerous potential mechanisms, including altered co-stimulatory molecule expression, inhibition of proinflammatory mediators (e.g., IL-12, TNF-α, NO, NF-κβ), enhanced production of immunoregulatory factors (e.g., IL-10, TGF-β, IDO, arginase), or increased expansion and/or differentiation of Tregs . Sex steroids are divided in androgens (testosterone T,5-α-dihydrotestosterone DHT, dehydroepiandrosterone sulphate DHEAS, dehydroepiandrosterone DHEA, androstenedione A), oestrogens (17β-estradiol E2, estrone E1, estriol E3) and progesterone (P).
Sex steroid receptor in the immune system
Classical steroid actions are mediated through receptors that belong to the nuclear hormone receptor superfamily . Transcription-independent actions can be mediated by membrane associated receptors (mR). Estrogens interact with two receptors, ER-α (ESR1) and ER-β (ESR-2), from NR3A1 and NR3A2 genes located on chromosome (Ch) 6 and 14, respectively. Estrogen receptors are expressed in thymocytes, thymic epithelial cells and mature peripheral B- and T-lymphocytes . Splenic B-cells express classical ER-α, but not ER-β . ER-α66 and ER-α46 splice variant are expressed in human monocytes and macrophages . mER in mice have been demonstrated in macrophages and T-cells .
Progesterone has 3 isoforms of receptors (PRs) (PR-A, PR-B, and PR-C, from the NR3C3 gene located at Ch 11. The presence of PRs has been detected in about 21% of lymphocytes , immature DCs , activated peripheral blood lymphocytes of females, peripheral NK cells and tissue macrophages ; mPR were detected in T-lymphocytes .
The androgens act through the androgen receptor (AR), from the NR3C4 gene located on Ch X. ARs are present in bone marrow (BM) stromal cells , thymocytes  and immature DCs . Splenic T cells and macrophages express mAR .
In summary, the presence of the steroid receptors in immune cells supports the hormonal action in the development and modulation of the immune system. During physiological pregnancy, P and E2 reach high concentrations (up to 100 times higher) compared to normal levels: there is a thymic involution, a Th1 to Th2 shift and an increased expression of FoxP3; thymus size normalizes in the 1st month postpartum . Systemic lupus erythematosus (SLE), a Th2-mediated disease is exacerbated by pregnancy; whereas RA and MS, Th1-mediated diseases, improve during pregnancy [20, 21].
Systemic lupus erythematosus
The prevalence of SLE is higher in females (F:M=9-10:1), during the reproductive phase. SLE is less common before the menarche (with a ratio F:M=3-4:1) and after the menopause .
Genetic variation of the IRF5 (a protein related to IFN-α production) and Stat4 (an IFN-α-inducible intracellular signalling molecule) has been reported to be associated with risk of SLE, suggesting that IFN-α and Th1/Th17 pathways interact with genetic and hormonal actions . Risk of SLE is also related to the gene UBE2L3 (a co-activator of PRs and other sex steroid receptors) .
Central and peripheral B-cell tolerance mechanisms involved in the control of survival, differentiation and activation of autoreactive B- and T-cells are altered in SLE [25, 26]. In SLE, autoAb-containing ICs activate pDCs through these same pathways to induce IFN-α, which is believed to act on multiple immune cell types to break tolerance and amplify autoimmunity.
Oestrogen and their catechol metabolites play an important role in SLE . Interactions among TNF, IFN-γ, E2, and IFN-α may regulate the expression of IFN-inducible (IFI) genes . E2 upregulated six pathways that control T-cell function including IFN-α signalling . In an interesting study, T cells cultured in medium containing 2-fluoroE2 showed a significant increase in the amount of CD40 ligand (CD40L) on the cell surface. The binding of CD40L (on Th cells) to CD40 protein (on APCs) is a well known co-stimulatory signal that induces a variety of downstream pathways supporting autoimmune B cells. The estrogen receptor antagonist ICI 182,780 blocked the estrogen dependent increases in SLE T cell CD40L mRNA and cell surface protein, suggesting that E2 worked through the ER .
Minimal changes were observed in the lupus nephritis using ER-α deficient (ER-α knock out, AERKO) mice exposed to E2, whereas E2 treatment in wild-type mice induced a lupus phenotype with accelerated death, increased kidney damage, Th2-type cytokines and autoAb production . DHT administration lowered anti-DNA Ab levels and improved the prognosis; P treatment modestly worsened survival in mice . The treatment with medrossiprogesterone acetate markedly decreased death, kidney damage, suppressing pathogenic Th1-related anti-dsDNA IgG2a in the serum and kidneys . Androgen deficiency induced premature death .
Not all lupus features occur in a similar way (immune complex glomerulonephritis vs focal sialadenitis, renal vasculitis, and periarticular inflammation); E2 stimulates Ab production and immune complex phenomena but inhibits T cell mediated organ pathologies . E2 may play a modulatory role depending on its conversion to downstream mitogenic proinflammatory 16α-OH-E1 or naturally occurring anti-estrogens such as 2-OH-E1.
In SLE females, serum E1 levels and urinary levels of 16α-OH-E1 are increased (the conversion to the mitogenic 16α-OH-E1 is upregulated) , serum P is reduced  and an androgen deficiency (T and DHEA) is present [36-39]. Increased incidence of SLE has been reported in hypogonadal states in males . Women taking oral contraceptives (OC, estrogens and P) demonstrated no increased risk to develop SLE , although exogenous estrogens might exacerbate lupus activity . The OC use should be considered only for inactive SLE. Pregnane progestin contraception (with chlormadinone acetate 10 mg/day and cyproterone acetate 50 mg/day) is well tolerated .
Hormonal replacement therapy (HRT) increases the risk of developing SLE/discoid lupus in postmenopausal women . SLE tends to flare during pregnancy and puerperium, directly depending on the disease activity before conception . SLE disease activity scores increased in the 2nd trimester and decreased in the 3rd trimester .
Dehydroepiandrosterone (DHEA) (200 mg/day) reduced flares by 16% compared with placebo, enabling reduction of steroids . In Chinese women, DHEA reduced serum IL-10 . However, in a recent meta-analysis, authors concluded that DHEA had a modest impact with not consistent effect on SLE disease activity (as measured by SLE disease activity index, SLEDAI) . Testosterone therapy (150 g patches, twice weekly) did not significantly affect disease activity in SLE females .
Fulvestrant (ICI 182,780,selective ER down-regulator) therapy (250 mg intramuscular) in patients with moderately active SLE significantly improved SLEDAI . Raloxifene was well tolerated in patients with inactive SLE, maintaining femoral neck and spinal bone mineral density (BMD) in patients receiving corticosteroids .
Tibolone (progestogen derived from 19-nortestosterone) is one of the available options for HRT in SLE. Tibolone (2.5 mg/day) in post-menopausal patients with inactive or stable SLE did not affect the flares and controlled hypoestrogenism related symptoms .
Multiple sclerosis (MS) is more frequent in young females (F:M=3-2:1) . Men have a later onset of disease (when testosterone is low) , and have a poor prognosis . Gender differences in brain damage have been found (both white matter and intra-cortical lesions) .
The role of IL-12, IL-13 and IL-23 has been evaluated in EAE . Perivascular IL-17-producing T-cells are present in brain lesions of active MS patients . FoxP3+ Treg cells may limit the expansion of encephalitogenic T-cells .
The C57BL/6 mice show no sex difference in the manifestation of EAE. SJL mice presented increased incidence in female. Ovariectomy led to an earlier EAE onset and treatment with estrogens (E3>E2) delayed the onset itself. Treatment with pregnancy-level E2 (mediated by ERα) reduced subsequent neurologic disease, through suppression of Th1 and Th17 cell .
Clinical EAE was induced by orchidectomy . Oral tolerance induction of EAE in male B10.PL mice was blocked by castration . The myelin basic protein (MBP)-primed T cells from female and castrated male mice, but not from male mice, produced proinflammatory molecules, such as NO, IL-1β, and IL-6 in astroglia . Androgen-selected T-cell lines secreted less IFN-γ and more IL-10 than untreated cell lines . EAE susceptibility in females is influenced by specific proinflammatory effects of IL-13, in part through up-regulation of Th1-inducing cytokines and MHC II on CD11b+ macrophages .
In EAE, several studies have demonstrated the potent suppressive effects of estrogens . Naive cells are more sensitive to sex hormones than differentiated effector cells. E2 diminished EAE clinical manifestations in C57BL/6 IL-4, IL-10, and IFN-γ KO mice, suggesting that these Th2 cytokines are dispensable for the oestrogen protective effect in mice . Low E2 doses reduced the capacity of myelin-reactive T-cells to initiate disease, suggesting autoimmunity in females is dependent on homeostatic levels of oestrogen .
In the presence of E1, E2 and E3, human CD4+ T-cell clones from MS patients showed an enhancement of IL-10 secretion , whereas the secretion of TNF was biphasic (enhanced at low but inhibited at high concentrations). E2 treatment decreased frequency of DCs in the brain of EAE mice, reducing TNF-α, IFN-γ and IL-12 production . E2 have multiple effects on DC function, including inhibition of homing and migration, suppression of antigen presentation and shifting cytokine production towards a Th2 profile. Estrogen effects may be mediated by TGF-β . Sustained sub-pregnancy E2 levels prevented clinical and histological signs of EAE, probably due to expansion of Tregs. E2 induced dependent increase in FoxP3 expression . E2 treatment reduced the production of IL-17 . E2 treatment did not protect against EAE or suppress IL-17 production in PD-1 gene deficient mice . E2 (pregnancy levels) decreased disease-mediating chemokine receptors in a model of EAE . The protective effect of E2 in animals with EAE was abolished in AERKO mice but not in BERKO mice . ER-alpha agonist (propyl pyrazole triol) and selective estrogen receptor modulators (SERMs) (raloxifene and WAY-138923) but not ER-beta selective agonist suppressed clinical symptoms of disease .
EAE-protective effects of E2 were abrogated in B cell-deficient (muMT−/−) mice . E2 treatment of wild type mice selectively up-regulated expression of PD-L1 on B cells and increased the percentage of IL-10-producing CD1dhighCD5+ regulatory B cells. Upregulation of PD-L1 was critical for E2-mediated protection since E2 did not inhibit EAE in PD-L1−/− mice. The results demonstrate a requirement for B cells in E2-mediated protection against EAE involving ERα and PD-1/PD-L1 negative co-stimulatory pathway. E2-primed B cells may represent an important regulatory mechanism in MS, with significant implications for women receiving current MS therapies that cause B-cell depletion . Other studies demonstrated that ER-α was dispensable for the E2 improvement in EAE model . Treatment with either ER-α or ER-β ligand was neuroprotective, reducing demyelination, with preserved axon numbers in white matter and decreased neuronal abnormalities in gray matter. It is possible to dissociate the anti-inflammatory effect from the neuroprotective effect of estrogen treatment (neuroprotective effects of oestrogen treatment do not necessarily depend on anti-inflammatory properties) .
Oral 17α-ethinyl estradiol (EE, a semisynthetic estrogen compound) and androstenediol (5-AED, rank of binding ERβ > ERα AR), like E2, suppressed EAE induction and severity [81, 82].
Progesterone has shown variable effects in EAE. In rats, while EE inhibited EAE, the progestagen medroxyprogesterone acetate augmented disease activity . In C57BL/6 females, 20-100 mg P before EAE induction attenuated disease severity (inflammation, demyelination and axonal pathology . Regarding remyelination, P treatment after onset of EAE fosters CNS myelin regeneration, involving suppression of IL-2 and IL-17 .
In susceptible female Lewis rats ovariectomized, E2 limited both EAE behavioral impairments and inflammation. On the contrary, P-treated rats had more severe sensorimotor deficits with increased inflammatory infiltrates and apoptotic neurons. Interestingly, co-administration of E2 with P prevented the consequences of P, including neuronal apoptosis . Progesterone has been also associated with enhancement of EAE . Testosterone and DHT were shown to have protective effects in EAE (both males and females) by directly promoting the production of IL-10 at the expense of IFN-γ from myelin reactive CD4+ lymphocytes [62, 88]. In mice, female and castrated male MBP-primed T cells expressed both α4 and β1 integrin. Interestingly, the expression of β1 was absent in male MBP-primed T cells . Male sex hormones (T and DHT), but not female sex hormones (E2 and P), were able to suppress the mRNA expression of β1 in female MBP-primed T cells . Fluasterone (HE2500, a synthetic androstene derivative), and androstenetriol (HE2200, a natural androstene hormone) delayed the onset of EAE and prevented the relapses .
Approximately 40% of women with MS reported worsening of symptoms at menopause . One study reported beneficial effects in 75% of MS patients with HRT . In women with MS, the rate of relapses declined during pregnancy, especially in the 3rd trimester (from 0.7 before pregnancy to 0.2/woman/year in the 3rd trimester), and increased during the 3 months postpartum (1.2/woman/year) before returning to the pre-pregnancy rate . Serial magnetic resonance imaging (MRI) examinations did not show differences in brain lesion activity during ovarian cycle [93, 94]. Changes in the P/E2 luteal (PEL) ratio were significantly related to the corresponding changes in the number and volume of enhancing lesions: increased PEL values corresponded to increased MRI activity . The T/E2 ratio in the follicular phase showed a significant positive correlation with the mean MRI activity (measured as number and volume of enhancing lesions) of the next 3 months . Other authors did not confirm these results . Hormonal fluctuations during menstrual cycles may be associated with exacerbations of MS symptoms, with a premenstrual worsening .
Oral contraceptives do not affect the risk of developing MS. In a case-control study, the incidence of MS was 40% lower in recent users of OCs (mainly EE plus a progestagen) compared with nonusers . OC use in women with relapsing-remitting MS is associated with a milder disabling course . The observations indicate that MS patients do not need to stop OCs, unless other risks (such as thrombosis or neoplasia) become significant .
E3 treatment (pregnancy levels, 8 mg/day) in patients with relapsing remitting MS decreased the number and volume of inflammatory lesions on monthly cerebral MRI , increased IL-5 levels (by CD4+, CD8+ T-cells) and IL-10 (by CD64+ monocytes/macrophages) and decreased TNF (by CD8+ T-cells) in stimulated mononuclear cells .
The preventive effect of combined E2/progestagen (17β-E2 transdermal 75 μg once a week + oral nomegestrol acetate 10 mg/day, for 3 months after delivery) on post-partum relapses is currently being tested in a randomized, placebo-controlled European trial (POPART’MUS study) .
Gonadal function in MS patients may be variable, ranging from hyper- to hypo-function depending on the course of the disease, the presence of relapse and the concurrent therapy. Both hyperandrogenism and low testosterone concentrations have been reported in females and males [94, 104]. Hormonal abnormalities are present in 56% of patients, consisting of decreased P level, increased E2 level or both . Treatment with T gel (100 mg/day) in men with relapsing-remitting MS was associated with improvement in cognitive performance and a slowing of brain atrophy, with no significant effect on gadolinium-enhancing lesion numbers .
The prevalence of RA is higher in females than in males (F:M=4:1). Predisposition to RA has been linked to the major histocompatibility complex (MHC) class II HLA-DRB1 locus, and in particular to the HLA-DR4 genes such as DRB1*0401, DRB1*0404, and DRB1*0405 .
Reduced central tolerance to type II collagen (CII) in AIRE-KO mice manifested as increased CD4 T-cell help to B-cells for cross-reactive autoAb production and enhanced type II collagen induced arthritis (CIA) . Cells that are primed by DCs, such as B-cells, Th1 and Th17 cells are being considered as additional targets for immune-based therapy . Multiple factors induced by IL-17 seem to promote bone resorption, extracellular matrix degradation, synovium proliferation, angiogenesis, and recruitment and activation of immune cells for bone erosion and articular destruction in RA joints.
Ovariectomy of female DBA/1 mice increased arthritis induced with CII ; E2, E3 and 2-methoxyestradiol presented positive effects . An ER-alpha agonist propylpyrazoletriol (PPT) in female DBA/1 ovariectomized mice ameliorated the disease in CIA . Raloxifene and E2 treatment decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis in CIA in B10.Q-ncf1*/*mice . Addition of E2 or raloxifene to dexamethasone-treatment in CIA in female DBA/1-mice prevented generalized bone loss and induced a marked improvement in the arthritic disease .
Pregnancy-level P had little effect on joint swelling or serum TNF-α and PGE2, but reduced the beneficial effects of pregnancy level estrogen, acting primarily at the level of joint inflammation (on the effector phase of immune injury), rather than induction of autoimmunity .
A highly specific agonist of the ER-β (called ERB-041) had a strong beneficial effect in the Lewis rat adjuvant-induced arthritis (AIA) model . HE3286 (17α-ethynyl-5-androstene-3β, 7β, 17β-triol) is a novel metabolically stabilized, orally bio-available derivative of an active DHEA metabolite (androstene-3β, 7β, 17β-triol, AET). It was used in CIA, reducing clinical signs of disease and proinflammatory signals, including IL-6 and matrix metallopeptidase 3, with increased Tregs [117, 118].
Female sex has a negative effect on RA, but the menopausal state with lower steroid hormone levels is responsible for the differences in outcome between men and women . A reduced blood androgen concentration has been found in RA .
The age at RA diagnosis was lower in Polish patients with the ER-α rs9340799 (A allele) as well as in patients with ER-α rs2234693 (TT and TC genotypes) . An ERα polymorphism (Pvu II and Xba I restriction fragment length) affected the course of RA in Japanese patients . The polymorphism of the ER-β (rs1256049, Rsa, in exon 5) was more frequent in female Japanese RA patients . A CA repeat polymorphism in ERβ has been associated to the presence of RA . The CAG repeat polymorphism (with a lower number of repeats, shorter allele) in the AR gene was associated with the presence of articular erosions in RA patients .
OC use was not associated with changes in the disease course in patients with RA. 41% of woman with RA are taking the OC. Flares before menses were 28% in patients with RA.
Prior HRT did not increase the risk to develop RA. HRT markedly improved bone mineral density and reduced bone resorption markers in RA . In addition, HRT had marginal beneficial effects on the articular index, pain score, and morning stiffness . Treatment with HRT suppressed erythrocyte sedimentation rate (ESR) and elevated haemoglobin concentration, with a better clinical outcome assessed by response on the Disease Activity Score 28 . Therefore HRT is useful to prevent postmenopausal osteoporosis in women with RA. Young women with RA can undergo pregnancy and/or use OC.
RA joint involvement tends to improve during pregnancy . The improvement generally starts during the 1st trimester and continues during the 2nd and 3rd trimesters. A pregnancy-induced remission is experienced by 75% of patients with RA, in more than half of the cases, remission is complete, but a flare-up occurs in more than 60% after delivery . In the 3rd-trimester of normal pregnancy, ex vivo monocytic IL-12 production was about 3-fold and TNF-α production was approximately 40% lower than postpartum values, supporting RA remission during pregnancy . Significantly higher concentrations of soluble TNF receptor 2 and IL-1ra were measured in pregnant compared with non pregnant women . Compared with non pregnant patients and other pregnant women, RA patients showed elevated levels of Th2 lymphocyte markers . RA with onset after the initiation of aromatase inhibitor therapy has been reported .
Serum E2 and E1 levels are similar in female RA patients compared with controls . In male RA patients, E2 levels were higher than healthy men, and E2 levels were positively correlated with inflammation . Androgens (DHEAS, T and DHT) are markedly lower in inflammatory diseases, playing an unfavorable role [136, 137]. The low androgen/oestrogen ratio might have a pathogenic role in patients with RA . High local levels of oestrogens in inflamed synovial tissue and synovial fluid, particularly in relation to androgens, are proinflammatory in RA . The presence of ARs and ERs has been demonstrated in synovial macrophages in RA [140, 141]. PR has been identified in inflammatory cells from synovial tissue in RA . Synovial macrophages present enzymes of steroid metabolism (including 17β-OH steroid dehydrogenase and 5α-reductase) that transform steroid precursors, leading to accumulation of T and E2 and formation of biologically active derivatives, especially DHT . A better response to treatment in RA patients with ER gene polymorphism (rs9340799 AA and rs2234693 TT) has been observed after 12 months of therapy with leflunomide . No correlation between CAG repeat polymorphism in the AR gene and response to leflunomide has been found in women with RA . There is no evidence to promote the use of estrogens in preventing or treating RA in females .
Increasing evidence in the literature indicates an immunomodulatory role of sex steroids in the pathogenesis of autoimmune diseases. The results of the clinical trials will give the basis in order to better define the use of sex steroids in combination with current therapeutic drugs in autoimmunity [147, 148]. Sex steroid receptor modulating drugs are a promising class of therapeutic agents that will provide new approaches in these pathologies.
Antonio Martocchia, Silvia Raja, Manuela Stefanelli, Anna Cocca, Paolo Falaschi – S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy
Corresponding Author: Antonio Martocchia, MD, PhD, Email: email@example.com
Martocchia A, Stefanelli M, Cola S, Falaschi P. Sex Steroids in Autoimmune Diseases. Curr Top Med Chem 2011; 11: 1668-83.
Poletaev AB, Stepanyuk VL, Gershwin ME. Integrating immunity: the immunculus and self-reactivity. J Autoimmun 2008; 30: 68-73.
Wu Y, Zheng Z, Jiang Y, Chess L, Jiang H. The specificity of T cell regulation that enables self-nonself discrimination in the periphery. Proc Natl Acad Sci USA 2009; 106: 534-9.
De León-Nava MA, Nava K, Soldevila G, López-Griego L, Chávez-Ríos JR, Vargas-Villavicencio JA, Morales-Montor J. Immune sexual dimorphism: Effect of gonadal steroids on the expression of cytokines, sex steroid receptors, and lymphocyte proliferation. J Steroid Biochem Molecul Biol 2009; 113: 57-64.
Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-95.
Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI. Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998; 25: 1305-12.
Benten WPM, Stephan C, Wunderlich F. B cells express intracellular but not surface receptors for testosterone and estradiol. Steroids 2002; 67: 647-54.
Murphy AM, Guyre PM, Wira CR, Pioli PA. Estradiol regulates expression of estrogen receptor ERa46 in human macrophages. PLoS One 2009; 4: e5539. doi: 10.1371/journal.pone.0005539
Benten WPM, Lieberherr M, Giese G, Wunderlich F. Estradiol binding to cell surface raises cytosolic free calcium in T cells. FEBS Lett 1998; 422: 349-53.
Szekeres-Bartho J, Polgar B, Kozma N, Miko E, Par G, Barakonyi A, Palkovics T, Papp O, Varga P. Progesteronedependent immunomodulation. Chem Immunol Allergy 2005; 89: 118-25.
Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, Tonelli L, Sternberg EM. Progesterone inhibits mature rat dendritic cells in a receptor mediated fashion. Int Immunol 2007; 19: 287-96.
Gilliver SC. Sex steroids as inflammatory regulators. J Steroid Biochem Mol Biol 2010; 120: 105-15.
Dosiou C, Hamilton AE, Pang Y, Overgaard MT, Tulac S, Dong J, Thomas P, Giudice LC. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 2008; 196: 67-77.
Bellido T, Jilka RL, Boyce BF, Girasole G, Broxmeyer H, Dalrymple SA, Murray R, Manolagas SC. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest 1995; 95: 2886-95.
Kovacs W, Olsen N. Androgen receptors in human thymocytes. J Immunol 1987; 139: 490-3.
Butts C, Bowers E, Horn C, Shukair SA, Belyavskaya E, Sternberg EM. Inhibitory effects of progesterone differ in dendritic cells from female and male rodents. Gender Med 2008; 5: 434-47.
Benten WP, Lieberherr M, Stamm O, Wrehlke C, Guo Z, Wunderlich F. Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages. Mol Biol Cell 1999; 10: 3113-23.
Vargas-Villavicencio JA, De León-Nava MA, Morales-Montor J. Immunoendocrine mechanisms associated with resistance or susceptibility to parasitic diseases during pregnancy. Neuroimmunomodulation 2009; 16: 114-21.
Lahita RG. The influence of sex hormones on the disease systemic lupus erythematosus. Springer Semin Immunopathol 1986; 9: 305-14.
Holmdahl R. Estrogen exaggerates lupus but suppresses T-cell dependent autoimmune disease. J Autoimmunity 1989; 2: 651-6.
Richez C, Barnetche T, Miceli-Richard C, Blanco P, Moreau JF, Rifkin I. Role for interferon regulatory factors in autoimmunity. Joint Bone Spine 2010; 77: 525-31.
Connolly JJ, Hakonarson H. Role of cytokines in systemic lupus erythematosus: recent progress from GWAS and sequencing. J Biomed Biotechnol 2012; 2012: 798924 doi: 10.1155/2012/798924.
Jacobi AM, Zhang J, Mackay M, Aranow C, Diamond B. Phenotypic characterization of autoreactive B cells-checkpoints of B cell tolerance in patients with systemic lupus erythematosus. PLoS One 2009; 4: e5776. doi: 10.1371/journal.pone.0005776.
Kim WU, Min SH, Hwang SH, Yoo SA, Kim KJ, Cho CS. Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus. Clin Exp Immunol 2010; 161: 453-8.
Khan WA, Uddin M, Khan MW, Chabbra HS. Catecholoestrogens: possible role in systemic lupus erythematosus. Rheumatology 2009; 48: 1345-51.
Lee HM, Mima T, Sugino H, Aoki C, Adachi Y, Yoshio-Hoshino N, Matsubara K, Nishimoto N. Interactions among type I and type II interferon, tumor necrosis factor, and betaestradiol in the regulation of immune response-related gene expressions in systemic lupus erythematosus. Arthritis Res Ther 2009; 11: R1 doi: 10.1186/ar2584.
Walters E, Rider V, Abdou NI, Greenwell C, Svojanovsky S, Smith P, Kimler BF. Estradiol targets T cell signaling pathways in human systemic lupus. Clin Immunol 2009; 133: 428-36.
Rider V, Jones S, Evans M, Bassiri H, Afsar Z, Abdou NI. Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol 2001; 28: 2644-9.
Feng F, Nyland J, Banyai M, Tatum A, Silverstone AE, Gavalchin J. The induction of the lupus phenotype by estrogen is via an estrogen receptor-alpha-dependent pathway. Clin Immunol 2010; 134: 226-36.
Roubinian JR, Papoian R, Talal N. Androgenic hormones modulate autoantibody responses and improve survival in murine lupus. J Clin Invest 1977; 59: 1066-70.
Hughes GC, Martin D, Zhang K, Hudkins KL, Alpers CE, Clark EA. Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum 2009; 60: 1775-84.
Talal N. Natural history of murine lupus. Modulation by sex hormones. Arthritis Rheum 1978; 21: S58-63.
Carlsten H, Nilsson N, Jonsson R, Backman K, Holmdahl R, Tarkowski A. Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol 1992; 144: 190-202.
Weidler C, Harle P, Schedel J, Schmidt M, Scholmerich J, Straub RH. Patients with rheumatoid arthritis and systemic lupus erythematosus have increased renal excretion of mitogenic estrogens in relation to endogenous antiestrogens. J Rheumatol 2004; 31: 489-94.
Medeiros PB, Febronio MV, Bonfa E, Borba EF, Takiuti AS, Silva CAA. Menstrual and hormonal alterations in juvenile systemic lupus erythematosus. Lupus 2009; 18: 38-43.
Lahita RG, Bradlow HL, Ginzler E, Pang S, New M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987; 30: 241-48.
Folomeev M, Dougados M, Beaune J. Plamsa sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus 1992; 1: 191-5.
Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin Exp Immunol 2000; 121: 448-52.
Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, Mestanza-Peralta M, Lara-Reyes P, Seuc AH, Cravioto MD. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 2539-49.
Bernier MO, Mikaeloff Y, Hudson M, Suissa S. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum 2009; 61: 476-81.
Chabbert-Buffet N, Amoura Z, Scarabin PY, Frances C, Lévy DP, Galicier L, Wechsler B, Blétry O, Piette JC, Gompel A. Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Contraception 2011; 83: 29-37.
Holroyd CR, Edwards CJ. The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus. Climacteric 2009; 12: 378-86.
Gimovsky ML, Montoro M. Systemic lupus erythematosus and other connective tissue diseases in pregnancy. Clin Obstet Gynecol 1991; 34: 35-50.
Doria A, Cutolo M, Ghirardello A, Zampieri S, Vescovi F, Sulli A, Giusti M, Piccoli A, Grella P, Gambari PF. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum 2002; 47: 202-9.
Nordmark G, Bengtsson C, Larsson A, Karlsson FA, Sturfelt G, Ronnblom L. Effects of dehydroepiandrosterone supplement on health-related quality of life in glucocorticoid treated female patients with systemic lupus erythematosus. Autoimmunity 2005; 38: 531-40.
Chang DM, Chu SJ, Chen HC, Kuo SY, Lai JH. Dehydroepiandrosterone suppresses interleukin 10 synthesis in women with systemic lupus erythematosus. Ann Rheum Dis 2004; 63: 1623-6.
Hartkamp A, Geenen R, Godaert GL, Bijl M, Bijlsma JW, Derksen RH. Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial. Ann Rheum Dis 2010; 69: 1144-7.
Gordon C, Wallace DJ, Shinada S, Kalunian KC, Forbess L, Braunstein GD, Weisman MH. Testosterone patches in the management of patients with mild/moderate systemic lupus erythematosus. Rheumatology 2008; 47: 334-8.
Abdou NI, Rider V, Greenwell C, Li X, Kimler BF. Fulvestrant (Faslodex), an estrogen selective receptor downregulator, in therapy of women with systemic lupus erythematosus. Clinical, serologic, bone density, and T cell activation marker studies: a double-blind placebo-controlled trial. J Rheumatol 2008; 35: 797-803.
Mok CC, To CH, Mak A, Ma KM. Raloxifene for postmenopausal women with systemic lupus erythematosus: a pilot randomized controlled study. Arthritis Rheum 2005; 52: 3997-4002.
Vieira CS, Pereira FV, de Sá MF, Paulo LJ, Martins WP, Ferriani RA. Tibolone in post-menopausal women with systemic lupus erythematosus: a pilot study. Maturitas 2009: 62: 311-6.
Nicot AB. Gender and sex hormones in multiple sclerosis pathology and therapy. Front Biosci 2009; 14: 4477-515.
Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol 1994; 36(s): S6-S11.
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116: 117-34.
Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, Barachino L, Morra A, Rinaldi L, Romualdi C, Perini P, Battistin L, Gallo P. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol 2007; 64: 1416-22.
Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233-40.
Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM. Interleukin-17 production in central nervous systeminfiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008; 172: 146-55.
Buenafe AC, Andrew S, Afentoulis M, Offner H, Vandenbark AA. Prevention and treatment of experimental autoimmune encephalomyelitis with clonotypic CDR3 peptides: CD4(+)FoxP3(+) T-regulatory cells suppress interleukin-2-dependent expansion of myelin basic protein-specific T cells. Immunol 2010; 130: 114-24.
Lelu K, Laffont S, Delpy L, Paulet PE, Perinat T, Tschanz SA. Estrogen receptor alpha signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J Immunol 2011; 187: 2386-93.
Bebo BF, Zelinka-Vincent E, Adamus G, Amundson D, Vandenbark AA, Offner H. Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 1998; 84: 122-30.
Bebo BF, Adlard K, Schuster JC, Unsicker L, Vandenbark AA, Offner H. Gender differences in protection from EAE induced by oral tolerance with a peptide analogue of MBP-Ac1-11. J Neurosci Res 1999; 55: 432-40.
Brahmachari S, Pahan K. Gender-specific expression of b1 Integrin of VLA-4 in myelin basic protein-primed T cells: implications for gender bias in multiple sclerosis. J Immunology 2010; 184: 6103-13.
Bebo BF, Schuster JC, Vandenbark AA, Offner H. Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells. J Immunol 1999; 162: 35-40.
Sinha S, Kaler L, Proctor TM, Teuscher C, Vandenbark AA, Offner H. IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis. J Immunol 2008; 180: 2679-85.
Offner H, Polanczyk M. A potential role for estrogen in experimental autoimmune encephalomyelitis and multiple sclerosis. Ann NY Acad Sci 2006; 1089: 343-72.
Ito A, Bebo BF, Matejuk A, Zamora A, Silverman M, Fyfe-Johnson A, Offner H. Estrogen treatment down-regulates TNF production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout mice. J Immunol 2001; 167: 542-52.
Bebo BF, Fyfe-Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H. Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol 2001; 166: 2080-9.
Gilmore W, Weiner LP, Correale J. Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997; 158: 446-51.
Liu HY, Buenafe AC, Matejuk A, Ito A, Zamora A, Vandenbark AA, Offner H. Estrogen inhibition of EAE involves effects on dendritic cell function. J Neurosci Res 2002; 70: 238-48.
Dhandapani KM, Wade FM, Mahesh VB, Brann DW. Astrocyte-derived transforming growth factor mediates the neuroprotective effects of 17β-estradiol: involvement of nonclassical genomic signaling pathways. Endocrinology 2005; 146: 2749-59.
Wang C, Dehghani B, Li Y, Kaler LJ, Vandenbark AA, Offner H. Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1. Immunology 2009; 126: 329-35.
Subramanian S, Matejuk A, Zamora A, Vandenbark AA, Offner H. Oral feeding with ethinyl estradiol suppresses and treats experimental autoimmune encephalomyelitis in SJL mice and inhibits the recruitment of inflammatory cells into the central nervous system. J Immunol 2003; 170: 1548-55.
Polanczyk M, Zamora A, Subramanian S, Matejuk A, Hess DL, Blankenhorn EP, Teuscher C, Vandenbark AA, Offner H. The protective effect of 17β-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-α. Am J Pathol 2003; 163: 1599-605.
Morales LBJ, Loo KK, Liu HB, Peterson C, Tiwari-Woodruff S, Voskuhl RR. Treatment with an estrogen receptor α ligand is neuroprotective in experimental autoimmune encephalomyelitis. J Neurosci 2006; 26: 6823-33.
Bodhankar S, Wang C, Vandenbark AA, Offner H. Estrogen-induced protection against experimental encephalomyelitis is abrogated in the absence of B cells. Eur J Immunol 2011; 41: 1165-75.
Garidou L, Laffont S, Douin-Echinard V, Coureau C, Krust A, Chambon P, Guery JC. Estrogen receptor α signaling in inflammatory leukocytes is dispensable for 17β-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 2004; 173: 2435-42.
Tiwari-Woodruff S, Morales LBJ, Lee R, Voskuhl RR. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment. Proc Natl Acad Sci USA 2007; 104: 14813-8.
Subramanian S, Matejuk A, Zamora A, Vandenbark AA, Offner H. Oral feeding with ethinyl estradiol suppresses and treats experimental autoimmune encephalomyelitis in SJL mice and inhibits the recruitment of inflammatory cells into the central nervous system. J Immunol 2003; 170: 1548-55.
Arnason BG, Richman DP. Effect of oral contraceptives on experimental demyelinating disease. Arch Neurol 1969; 21: 103-8.
Garay L, Deniselle MC, Lima A, Roig P, De Nicola AF. Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis. J Steroid Biochem Mol Biol 2007; 107: 228-37.
Yu HJ, Fei J, Chen XS, Cai QY, Liu HL, Liu GD. Progesterone attenuates neurological behavioral deficits of experimental autoimmune encephalomyelitis through remyelination with nucleus-sublocalized Olig1 protein. Neurosci Lett 2010; 476: 42-5.
Hoffman GE, Le WW, Murphy AZ, Koski CL. Divergent effects of ovarian steroids on neuronal survival during experimental allergic encephalitis in Lewis rats. Exp Neurol 2001; 171: 272-84.
Arnason BG, Richman DP. Effects of estrogen, progestin and combined estrogen progestin oral contraceptive preparations on experimental allergic encephalomyelitis. Trans Am Neurol Assoc 1969; 94: 54-8.
Palaszynski KM, Loo KK, Ashouri JF, Liu HB, Voskuhl RR. Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol 2004; 146: 144-52.
Offner H, Zamora A, Drought H, Matejuk A, Auci DL, Morgan EE, Vandenbark AA, Reading CL. A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing remitting EAE. J Neuroimmunol 2002; 130: 128-39.
Holmqvist P, Wallberg M, Hammar M, Landtblom AM, Brynhildsen J. Symptoms of multiple sclerosis in women in relation to sex steroid exposure. Maturitas 2006; 54: 149-53.
Smith R, Studd JW. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J R Soc Med 1992; 85: 612-3.
Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 1998; 339: 285-91.
Pozzilli C, Falaschi P, Mainero C, Martocchia A, D’Urso R, Proietti A, Frontoni M, Bastianello S, Filippi M. MRI in multiple sclerosis during the menstrual cycle: relationship with sex hormone patterns. Neurology 1999; 53: 622-4.
Tomassini V, Onesti E, Mainero C, Giugni E, Paolillo A, Salvetti M, Nicoletti F, Pozzilli C. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neurosurg Psychiatry 2005; 76: 272-5.
Falaschi P, Martocchia A, Proietti A, D’Urso R, Antonini G, Pozzilli C. The modulatory role of the sex steroid balance on the disease activity in female patients with multiple sclerosis. In: Columbus F, ed, Focus on multiple sclerosis research. Nova Science Publisher. 2004, 199-215.
Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD. Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis. Acta Neurol Scand 1999; 99: 91-4.
Zorgdrager A, De Keyser J. The premenstrual period and exacerbations in multiple sclerosis. Eur Neurol 2002; 48: 204-6.
Alonso A, Jick SS, Olek MJ, Ascherio A, Jick H, Hernan MA. Recent use of oral contraceptives and the risk of multiple sclerosis. Arch Neurol 2005; 62: 1362-5.
Sena A, Couderc R, Vasconcelos JC, Ferret-Sena V, Pedrosa R. Oral contraceptive use and clinical outcomes in patients with multiple sclerosis. J Neurol Sci 2012; 317: 47-51.
Dwosh E, Guimond C, Sadovnick AD. Reproductive counselling in MS: a guide for healthcare professionals. Int MS J 2003; 10: 67.
Sicotte NL, Liva S, Klutch R, Pfeiffer P, Bouvier S, Odesa S, Wu T, Voskuhl RR. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 2002; 52: 421-8.
Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol 2003; 171: 6267-74.
Vukusic S, Ionescu I, El-Etr M, Schumacher M, Baulieu EE, Cornu C, Confavreux C, for the POPART’MUS study group. The prevention of post-partum relapses with progestin and estradiol in multiple sclerosis (POPART’MUS) trial: rationale, objectives and state of advancement. J Neurol Sci 2009; 286: 114-8 (see also www.edmus.org/src/proj/studies_popart.html).
Falaschi P, Martocchia A, Proietti A, D’Urso R, Antonini G. High incidence of hyperandrogenism-related clinical signs in patients with multiple sclerosis. Neuroendocrinol Lett 2001; 22: 248-50.
Zakrzewska-Pniewska B, Goiowski M, Zajda M, Szeszkowski W, Podlecka-Pitowska A, Nojszewska M. Sex hormone patterns in women with multiple sclerosis as related to disease activity-a pilot study. Neurol Neurochir Pol 2011; 45: 536-42.
Sicotte NL, Giesser BS, Tandon V, Klutch R, Steiner B, Drain AE, Shattuck DW, Hull L, Wang EJ, Elashoff RM, Swerdloff RS, Voskuhl RR. Testosterone treatment in multiple sclerosis. A pilot study. Arch Neurol 2007; 64: 683-8.
Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis. Genes Immun 2004; 5: 151-7.
Campbell IK, Kinkel SA, Drake SF, van Nieuwenhuijze A, Hubert FX, Tarlinton DM, Heath WR, Scott HS, Wicks IP. Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen-induced arthritis. Arthritis Rheum 2009; 60: 1683-93.
Khan S, Greenberg JD, Bhardwaj N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 566-71.
Holmdahl R, Jansson L, Meyerson B, Klareskog L. Oestrogen induced suppression of collagen arthritis. Long term oestradiol treatment of DBA/1 mice reduces severity and incidence of arthritis and decreases the anti type II collagen immune response. Clin Exp Immunol 1987; 70: 372-8.
Ho TY, Santora K, Chen JC, Frankshun AL, Bagnell CA. Effects of relaxin and estrogens on bone remodeling markers, receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG), in rat adjuvant-induced arthritis. Bone 2011; 48: 1346-53.
Engdahl C, Jochems C, Windahl SH, Borjesson AE, Ohlsson C, Carlsten H, Lagerquist MK. Amelioration of collagen-Induced arthritis and immune-associated bone loss through signaling via estrogen receptor-α, and not estrogen receptor-β or G protein-coupled receptor 30. Arthtritis Rheum 2010; 62: 524-33.
Jochems C, Islander U, Erlandsson M, Engdahl C, Lagerquist M, Gjertsson I, Ohlsson C, Holmdahl R, Carlsten H. Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collageninduced chronic arthritis. BMC Musculoskeletal Disorders 2010; 11: 284. doi: 10.1186/1471-2474-11-284.
Islander U, Jochems C, Stubelius A, Andersson A, Lagerquist MK, Ohlsson C, Carlsten H. Combined treatment with dexamethasone and raloxifene totally abrogates osteoporosis and joint destruction in experimental postmenopausal arthritis. Arthritis Res Ther 2011, 13: R96.
Ganesan K, Balachandran C, Manohar B, Puvanakrishnan R. Comparative studies on the interplay of testosterone, estrogen and progesterone in collagen induced arthritis in rats. Bone 2009; 43: 758-65.
Follettie MT, Pinard M, Keith JC, Wang L, Chelsky D, Hayward C, Kearney P, Thibault P, Paramithiotis E, Dorner AJ, Harris HA. Organ messenger ribonucleic acid and plasma proteome changes in the adjuvant-induced arthritis model: responses to disease induction and therapy with the estrogen receptor-β selective agonist ERB-041. Endocrinology 2006; 147: 714-23.
Ahlem C, Auci D, Reading C, Frincke J, Stickney D, Nicoletti F. HE3286: a novel synthetic steroid as an oral treatment for autoimmune disease. Ann NY Acad Sci 2009; 1173: 781-90.
Auci DL, Mangano K, Destiche D, White SK, Huang Y, Boyle D, Frincke J, Reading CL, Nicoletti F. Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis. Int J Mol Med 2010; 25: 625-33.
Kuiper S, van Gestel AM, Swinkels HL, de Boo TM, da Silva JA, van Riel PL. Influence of sex, age, and menopausal state on the course of early rheumatoid arthritis. J Rheumatol 2001; 28: 1809-16.
Spector TD, Perry LA, Tubb G, Silman AJ, Huskisson EC. Low free testosterone levels in rheumatoid arthritis. Ann Rheum Dis 1988; 47: 65-8.
Dziedziejko V, Kurzawski M, Safranow K, Drozdzik M, Chlubek D, Pawlik A. Oestrogen receptor polymorphisms in female patients with rheumatoid arthritis. Scand J Rheumatol 2011; 40: 329-33.
Ushiyama T, Mori K, Inoue K, Huang J, Nishioka J, Hukuda S. Association of oestrogen receptor gene polymorphisms with age at onset of rheumatoid arthritis. Ann Rheum Dis 1999; 58: 7-10.
Sato H, Ito A, Gonzalez-Canga A, Okuzawa H, Ugai K, Suzuki M, Namiki T, Ueno K. Association of Rsa polymorphism of the estrogen receptor-b gene with rheumatoid arthritis Rheumatol Int 2012; 32: 2143-8.
Gonzalez-Canga A, Ugai K, Suzuki M, Okuzawa H, Negishi E, Ueno K. Association of cytosine–adenine repeat polymorphism of the estrogen receptor-b gene with rheumatoid arthritis symptoms. Rheumatol Int 2010; 30: 1259-62.
Dziedziejko V, Kurzawski M, Safranow K, Ossowski A, Piatek J, Parafiniuk M, Chlubek D, Pawlik A. CAG Repeat Polymorphism in the Androgen Receptor Gene in Women with Rheumatoid Arthritis J Rheumatol 2012; 39; 10-7.
Forsblad-d’Elia H, 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 2011; 70: 1167-8.
Hall GM, Daniels M, Huskisson EC, Spector TD. A randomised controlled trial of the effect of hormone replacement therapy on disease activity in postmenopausal rheumatoid arthritis. Ann Rheum Dis 1994; 53: 112-6.
Forsblad D’elia H, Larsen A, Mattsson LA, Kvist G, Mellström D, Saxne T, Ohlsson C, Nordborg E, Carlsten H. Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis. J Rheumatol 2003; 30: 1456-63.
Ostensen M, Forger F, Nelson JL, Schumacher A, Hebisch G, Villiger PM. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis 2005; 64: 801-3.
Ostensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol 2007; 29: 185-91.
Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP. IL-12, TNF and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 2001; 86: 4933-8.
Ostensen M, Sicher P, Forger F, Villiger PM. Activation markers of peripheral blood mononuclear cells in late pregnancy and after delivery: a pilot study. Ann Rheum Dis 2005; 64: 318-20.
Bertolini E, Letho-Gyselinck H, Prati C, Wendling D. Rheumatoid arthritis and aromatase inhibitors. Joint Bone Spine 2011; 78: 62-4.
Cutolo M, Balleari E, Giusti M, Monachesi M, Accardo S. Sex hormone status in women suffering from rheumatoid arthritis. J Rheumatol 1986; 13: 1019-23.
Tengstrand B, Carlstrom K, Fellander-Tsai L, Hafstrom I. Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation. J Rheumatol 2003; 30: 2338-43.
Cutolo M, Wilder RL. Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum Dis Clin N Am 2000; 26: 825-39.
Imrich R, Vlcek M, Aldag JC, Kerlik J, Radikova Z, Rovensky J, Vigas M, Masi AT. An endocrinologist’s view on relative adrenocortical insufficiency in rheumatoid arthritis. Ann NY Acad Sci 2010; 1193: 134-8.
Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis. Ann NY Acad Sci 2002; 966: 131-42.
Schmidt M, Hartung R, Capellino S, Cutolo M, Pfeifer-Leeg A, 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 2009; 60: 2913-22.
Cutolo M, Accardo S, Villaggio B, Clerico P, Indiveri F, Carruba G, Fecarotta E, Castagnetta L. Evidence for the presence of androgen receptors in the synovial tissue of rheumatoid arthritis patients and healthy controls. Arthritis Rheum 1992; 35: 1007-15.
Cutolo M, Accardo S, Villaggio B, Clerico P, Bagnasco M, Coviello DA, Carruba G, lo Casto M, Castagnetta L. Presence of estrogen-binding sites on macrophage-like synoviocytes and CD8+, CD29+,CD45RO+, T lymphocytes in normal and rheumatoid synovium. Arthritis Rheum 1993; 36: 1087-97.
Ishizuka M, Hatori M, Suzuki T, Miki Y, Darnel AD,Tazawa C, Sawai T, Uzuki M, Tanaka Y, Kokubun S, Sasano H. Sex steroid receptors in rheumatoid arthritis. Clin Sci (Lond) 2004; 106: 293-300.
Cutolo M, Accardo S, Villaggio B, Barone A, Sulli A, Balleari E, Bason C, Felli L, Granata OM, Amodio R, Castagnetta L. Androgen and estrogen receptors are present in primary cultures of human synovial macrophages. J Clin Endocrinol Metab 1996; 81: 820-7.
Dziedziejko V, Kurzawski M, Safranow K, Chlubek D, Pawlik A. The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics 2011; 12: 41-7. doi: 10.2217/pgs.10.164.
Dziedziejko V, Kurzawski M, Safranow K, Ossowski A, Piatek J, Parafiniuk M, Chlubek D, Pawlik A. Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide. Eur J Clin Pharmacol 2012; 68: 371-7.
Bijlsma JW, Van den Brink HR. Estrogens and rheumatoid arthritis. Am J Reprod Immunol 1992; 28: 231-4.
Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001; 7: 115-21.
Martocchia A, Frugoni P, Indiano I, Falaschi P. A rational approach on the use of sex steroids in multiple sclerosis. Recent Pat CNS Drug Discov 2008; 3: 34-9.