• Open Access
    Review

    The influence of reproductive hormones on systemic lupus erythematosus

    Ruchi Sachdeva
    Rahul Pal*

    Explor Immunol. 2022;2:351–362 DOI: https://doi.org/10.37349/ei.2022.00055

    Received: December 14, 2021 Accepted: March 31, 2022 Published: June 07, 2022

    Academic Editor: Satish Kumar Gupta, Indian Council of Medical Research, India

    This article belongs to the special issue Human Reproduction: Involvement of the Immune System

    Abstract

    Humans are afflicted by a wide spectrum of autoimmune disorders, ranging from those affecting just one or a few organs to those associated with more systemic effects. In most instances, the etiology of such disorders remains unknown; a consequence of this lack of knowledge is a lack of specific treatment options. Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder; pathology is believed to be antibody-mediated, and multiple organs are targeted. Periods of disease “flares” are often followed by long periods of remission. The fact that SLE is more commonly observed in females, and also that it more particularly manifests in females in the reproductive age group, has quite naturally drawn attention to the potential roles that hormones play in disease onset and progression. This review attempts to shed light on the influences that key hormones might have on disease indicators and pathology. Databases (Google Scholar, PubMed) were searched for the following keywords (sometimes in certain combinations), in conjunction with the term “lupus” or “SLE”: autoantibodies, recurrent abortion, polycystic ovarian syndrome (PCOS), preeclampsia, pre-term delivery, estrogens, progesterone, androgens, prolactin, leptin, human chorionic gonadotropin (hCG). Cited publications included both research articles and reviews.

    Keywords

    Autoimmune diseases, systemic lupus erythematosus, sex steroids, prolactin, leptin, human chorionic gonadotropin, reproductive dysfunction

    Introduction

    Systemic lupus erythematosus (SLE, or lupus) is a systemic autoimmune disorder that can affect many organs, including the skin, joints, the central nervous system, and the kidneys. With the exception of monogenic lupus, a complex interaction of inherent and environmental factors is believed to contribute to disease onset [1, 2]; some such factors are outlined in Figure 1.

    A complex interaction between inherent and environmental factors is believed to contribute to the onset of SLE in most instances. UV: ultraviolet light

    SLE is characterized by aberrant activation of the innate and adaptive immune systems, causing the accumulation of autoantibodies and inflammatory immune cells [3]. More than a hundred different autoantibody specificities have been described in lupus; ribonucleoproteins [for example, Smith (Sm), Ro, La], nucleic acids [for example, double-stranded DNA (dsDNA)], and lipids are often targeted [4]. While several of the antibody specificities observed in lupus have been documented in other autoimmune diseases as well, antibodies against dsDNA and the Sm protein are characteristic of lupus [5]. Interestingly, some common autoantibody specificities (such as anti-nuclear, anti-Ro, anti-La, and anti-phospholipid antibodies) can be detected in serum many years before clinical onset, whereas others (like anti-dsDNA and anti-Sm antibodies) appear closer to the appearance of overt disease [6]. Several investigations have revealed evidence for the association of anti-dsDNA autoantibodies with glomerulonephritis, one of the most serious consequences of the disease [7].

    SLE predominantly affects women in their reproductive years [8], prompting investigations into the role reproductive hormones play in disease onset and progression. A higher incidence of premature ovarian failure has been observed in SLE patients [9, 10], the precise reasons for which remain unknown. Interestingly, patients with polycystic ovarian syndrome (PCOS) express many of the antibodies found in SLE patients [11], prompting speculation that PCOS could have an autoimmune etiology. Higher rates of preeclampsia have been observed in SLE patients [12, 13]. Several recent reports indicate that pregnancies in SLE patients are also characterized by a higher incidence of pre-term delivery [14, 15].

    The presence of anti-Sjögren’s-syndrome-related antigen A (anti-SSA)/Ro and anti-SSB/La antibodies during pregnancy is associated with an increased risk of neonatal lupus, a condition that arises due to transplacental autoantibody transport [16]. Autoantibodies of several specificities have been associated with recurrent abortion in SLE patients [17]. More particularly, the presence of anti-phospholipid antibodies is linked with recurrent pregnancy loss, fetal loss, and stillbirth in women with SLE [18, 19].

    Hormones and SLE

    Steroid hormones can have strong immune-modulatory effects, a fact that may explain, to an extent, the female preponderance of lupus. The effects of 17β-estradiol, testosterone, progesterone, dehydroepiandrosterone/dehydroepiandrosterone sulfate on disease incidence and severity have been described [20, 21]. Steroid hormones can potentially modulate the T-helper 1 (Th1)/Th2 cytokine balance. For example, progesterone causes Th2 polarization [22], and Th2-related cytokines [particularly interleukin-10 (IL-10) and IL-6] play major roles in the progression of lupus; levels of these cytokines are reportedly higher in SLE patients than in healthy individuals, and levels of IL-10 correlate with anti-dsDNA antibody titers [23].

    Pregnancy presents a potentially high-risk condition for lupus, and pregnancy-associated disease flares have been reported [21, 24]. These observations are in line with data suggesting that pregnancy (at least notionally) is believed to constitute a Th1-to-Th2 immune skew and that autoantibodies constitute prime drivers of pathology in SLE. In normal pregnancies, levels of estrogens and progesterone progressively increase from the first trimester of pregnancy, reaching peak levels in the third trimester. Estrogens, at “physiological” levels, potentiate both Th1 and Th2 responses, whereas, at “supra-physiological” levels (such as those achieved in the third trimester), they suppress Th1 responses while promoting Th2 responses; such a milieu would favor the production of immunoglobulins. That said, while some studies describe heightened disease activity in the second trimester, there appears some discordance with levels of estrogens and progesterone [21].

    Lupus-prone mice have been extensively employed to elucidate the roles hormones play in disease onset and progression, as well as the genes they might influence. For example, microarray analysis in intact male and female New Zealand black (NZB) × New Zealand white (NZW) F1 mice, as well as in gonadectomized mice with/without steroid supplementation, has revealed that estrogens and androgens can influence genes in a differential manner in the two sexes [25].

    A role for pituitary hormones has also been envisaged. While most studies appear to suggest heightened luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in male SLE patients, and LH levels in female patients [26], the relevance of these observations remains unclear. Evidence of the possible influence of gonadotropins on disease activity has been obtained in lupus-prone Swiss inbred (SWR) × NZB F1 mice; the administration of gonadotropin-releasing hormone (GnRH) antagonists to ovariectomized female mice enhances survival, while GnRH agonists drive autoreactive responses [27]. As described in more detail below, an abundance of data suggest a role for prolactin in autoimmune diseases in general, and in lupus in particular [28].

    Estrogens

    Dendritic cell-derived type 1 interferons (IFNs) are believed to drive lupus progression, and mechanistic links between estrogens and the IFN signature have been described [29].

    Estrogens are generally considered to have immune-stimulatory effects. Besides being present in reproductive tissues, estrogen receptors (ERs, ERα and ERβ) are also widely expressed in most cells of the immune system, exerting influence on both innate and adaptive immune responses [30]. The role of ERs in lupus has been studied in various murine models of disease. Ovariectomized NZB × NZW F1 mice treated with the potent ERα agonist propyl pyrazole triol develop autoantibodies and proteinuria with enhanced kinetics. The ERβ agonist diarylpropionitrile, on the other hand, reduces levels of some immunoglobulin G (IgG) anti-dsDNA autoantibody subclasses but does not reduce total IgG, proteinuria, or mortality. These studies indicate that, while ERα signaling may have immune-stimulatory effects, ERβ signaling could be immunosuppressive, to an extent [31]. In line with this data, ERα deficiency has been shown to reduce autoantibodies levels and glomerulonephritis, and to improve survival in female and male NZB × NZW F1 mice [32]. Further, targeted deletion of ERα specifically in B cells leads to decreases in both the production of pathogenic autoantibodies and the development of nephritis in these mice [33]. Interestingly, a sex-dependent effect of ERα deficiency has been observed in lupus-prone mice [34].

    Levels of ERα messenger RNA (mRNA) are heightened in peripheral blood mononuclear cells (PBMCs) from SLE patients [35]. While T cells from SLE patients display numerous defects in homeostasis, phenotype, signaling, metabolism, and function [36], evidence suggests that estrogen could contribute to these outcomes [37], with receptor polymorphisms also exerting some influence [38]. That estrogen suppresses extracellular signal-regulated kinase (ERK) phosphorylation in phorbol 12-myristate 13-acetate + ionomycin-stimulated T cells from SLE patients with inactive or mild disease but not with moderate or active disease [39] is significant in light of the fact that downregulation of the ERK pathway is known to induce DNA demethylation [40], and DNA hypomethylation is a characteristic epigenetic aberration in SLE [41, 42].

    Estrogen increases expression levels of the activation markers calcineurin and CD154 on T cells from women with SLE but not from healthy women, which is an indication of increased sensitivity of the former [43]. While estradiol tightly regulates calreticulin levels in T cells derived from healthy individuals, such control is lost in T cells from SLE patients, which is a fact that could contribute to abnormal T cell function [44]. Estradiol treatment of T cells from SLE patients (but not of healthy T cells) leads to increased expression of Fas ligand (FasL) and caspase-8, indicating that the steroid may induce cell death by activating the extrinsic pathway of apoptosis under appropriate conditions [45]. This is an observation of some significance, given that aberrant apoptosis has been implicated in lupus initiation and progression. Of particular relevance is the fact that apoptotic blebs contain endogenous toll-like receptor (TLR) ligands, some of which signal via TLR-7 and TLR-9; such signaling has been implicated in disease progression [46]. Stimuli that aid the processes that induce additional cell death would be expected to contribute to disease-driven pathological events, including effects on the reproductive system.

    Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, a member of the TNF superfamily) is a proinflammatory, multifunctional cytokine which induces the release of several inflammatory mediators including IL-6, a cytokine associated with renal damage in SLE [47]. Treatment of PBMCs derived from patients of lupus nephritis with estrogen increases TWEAK mRNA levels, an effect negated by an ERα inhibitor (methyl-piperidino-pyrazole) or an ER antagonist (fulvestrant). Co-administration of TWEAK short hairpin RNA (shRNA) attenuates renal pathology and decreases serum IL-6 levels in estrogen-treated ovariectomized lupus-prone mice [48].

    These studies indicate that estrogen plays important immune-modulatory roles in lupus, acting via several mediators to accelerate the disease course.

    Prolactin

    Hyperprolactinemia is observed in several autoimmune diseases and is believed to contribute to pathological outcomes [28]. Prolactin appears to participate in the pathogenesis of SLE by influencing both the innate and adaptive arms of the immune system. Hyperprolactinemia has been documented in 20–30% of SLE patients, and a correlation has been drawn between serum prolactin levels and disease activity. In particular, evidence suggests that prolactin plays a role in the pathogenesis of lupus nephritis, as well as in the neuropsychiatric, serosal, hematologic, articular, and cutaneous manifestation of the disease [49]. Increased levels of prolactin are observed in 12% of patients with the anti-phospholipid syndrome, and levels correlate with miscarriage in pregnant patients [50].

    SLE patients express an increased frequency of the prolactin gene’s –1149 G allele; following incubation with phytohemagglutinin, SLE lymphocytes carrying the allele express enhanced prolactin mRNA levels [51].

    Given that several pathologies in SLE are believed to be autoantibody-mediated, the fact that increases in serum levels of prolactin in SLE patients coincide with disease flares (with levels reducing upon disease remission), and also that prolactin levels correlate with serum levels of dsDNA antibodies [52], is clearly significant. While the prolactin receptor is expressed at higher levels on pro-B cells derived from lupus-prone mice [53], the full implications of this observation are at present unclear. In pregnant SLE patients, heightened levels of prolactin are linked with poor maternal-fetal outcomes [54]. Significantly, the presence of anti-prolactin antibodies (found in a certain percentage of SLE patients) correlates with lower disease activity in non-pregnant patients [55] and better outcomes in pregnant patients [56]. Further evidence of the pathological effects mediated by prolactin comes from the use of bromocriptine (a dopamine receptor agonist that blocks the release of prolactin) in lupus-prone mice and SLE patients; in pregnant SLE patients, bromocriptine reduces disease relapse, improves outcomes, and allows for the reduction in concurrent steroid administration [57].

    Progesterone

    Studies indicate that progesterone mediates immunological effects distinct from estradiol and testosterone [58]. Progesterone appears to counteract many of the effects of estradiol, thereby ameliorating the risk of lupus-like disease [59]. Some of these processes may be compromised in lupus; for example, inadequate estrogen-induced priming of progesterone receptors in the reproductive tissue of lupus-prone mice has been observed [60]. The fact that female SLE patients have lower levels of progesterone during ovulatory menstrual cycles [61] may also be a contributing factor.

    Treatment of pre-morbid female NZB × NZW F1 mice with medroxyprogesterone acetate decreases circulating IgG2a anti-dsDNA antibody levels and the deposition of anti-DNA antibodies in the kidney [62]; though IgG1 anti-dsDNA antibodies reportedly increased in this study as well in other studies upon progesterone treatment, this isotype is considered less pathogenic in terms of its association with lupus nephritis [63].

    In nuclear progesterone receptor knockout B6.Nba2 mice (C57BL/6 mice homozygous for the Nba2 autoimmunity locus), heightened levels of pathogenic class-switched IgG2c autoantibodies are observed, indicating that the steroid mediates protective effects [64]. However, other studies report that treatment of both male and female NZB × NZW F1 mice with progesterone leads to increased levels of serum anti-DNA IgG antibodies [65], while treatment with medroxyprogesterone has no beneficial effects [66].

    Testosterone

    It is believed that testosterone works to dampen the effects of lupus in both males and females. Low plasma levels of testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate have been observed in female SLE patients, with concentrations inversely correlating with disease severity [67]. While the administration of testosterone-like anabolic steroids in women may induce a degree of disease amelioration [68], such treatment can be accompanied by undesirable, masculinizing side effects.

    Of interest is the fact that hypogonadism in men is a risk factor for the development of SLE [69], and testosterone supplementation has been shown to be beneficial in some cases [70]. Autoantibody levels in SLE males correlate with specific polymorphisms of the androgen receptor [71]. In PBMCs isolated from SLE patients, testosterone reduces the generation of IgG antibodies (including anti-dsDNA autoantibodies), possibly via a suppressive effect on the production of IL-6 [72].

    Several studies have described the beneficial effects of androgen supplementation in lupus-prone mice. Administration of testosterone to castrated mice of both sexes reduces levels of anti-DNA antibodies and glomerulonephritis and enhances survival; the benefits of androgen supplementation are evident in intact male mice as well [73]. Oral administration of dehydroisoandrosterone (another anabolic steroid) to female NZB × NZW F1 mice also reduces levels of anti-dsDNA antibodies and prolongs survival [74]. Some evidence suggests that the immunosuppressive and ameliorative effects of different androgens in NZB × NZW F1 mice may not be related to their endocrine properties [75].

    Additional evidence in support of the idea that androgens play a protective role in lupus comes from observations that treatment of female lupus-prone mice with flutamide (an androgen receptor blocker) accelerates mortality [76].

    Leptin

    Leptin is secreted by adipocytes, the placenta, and the stomach, and is a sexually dimorphic cytokine/hormone, with its levels being higher in females. It regulates appetite and is believed to serve as a link between metabolism and immune function [77, 78]. Though not considered part of the classic reproductive hormonal axis, leptin exerts multiple influences on reproductive tissues. For example, it works to enhance levels of GnRH receptors in the pituitary, and also promotes granulosa cell and theca cell function in females, and testicular development in males [79]. It is proinflammatory in nature, and affects the survival, activation, differentiation, and function of T and B lymphocytes, and modulates autoreactive responses in many disease models [80].

    While levels of leptin are higher in SLE patients than in healthy individuals [81], correlations with disease severity are not always apparent. An inverse correlation between the levels of serum leptin and androstenedione has been reported, indicating that leptin could contribute to the hypoandrogenicity observed in SLE patients [82].

    Leptin levels in NZB × NZW F1 mice correlate with disease, and administration of leptin accelerates both autoreactivity and the onset of renal pathology. Conversely, the administration of anti-leptin antibodies ameliorates disease and enhances animal survival. The fact that leptin significantly inhibits Treg function probably contributes to its deleterious effect in these mice [83].

    Anti-dsDNA antibody levels are lower in leptin-deficient lupus-prone mice; such mice also exhibit decreases in histological aberrations in the kidney [84]. Leptin deficiency also protects mice from the pristane-induced lupus-like disease [83].

    Leptin induces the transcription of retinoid-related orphan receptor-γt (RORγt), thereby driving Th17 responses in humans and lupus-prone mice [85]. These findings assume importance given the fact that Th17 cells mediate inflammation and lupus-related pathologies [86].

    Leptin, along with a high-fat diet, also promotes the development of lupus-associated comorbidities, specifically in NZB × NBW F1 mice; along with accelerated proteinuria, increased pro-inflammatory high-density lipoprotein scores, as well as atherosclerosis, are observed [87]. Correlating with these observations is the fact that leptin is associated with an increased risk of atherosclerosis in women with SLE [88].

    Leptin enhances the phagocytotic uptake of apoptotic cells by macrophages and may therefore serve to increase the presentation of self-antigen to T cells [83, 89]. Further, it promotes the survival of autoreactive T cells in lupus-prone mice [90].

    Data from both humans and mice, therefore, suggest that strategies targeting leptin could form the basis of new therapeutics in SLE.

    Human chorionic gonadotropin

    Case studies describe the occurrence of SLE in healthy women receiving ovulation-inducing agents which include human chorionic gonadotropin (hCG) [91]. Further, ovarian hyperstimulation syndrome (OHSS, a complication sometimes observed in women undergoing assisted reproductive techniques) has been linked with the use of hCG [92]; OHSS is characterized by thrombotic events (a pathology also observed in SLE), providing these observations relevance. Whether hCG-stimulated estradiol is subsequently responsible for OHSS is a matter of some debate [93].

    Several pieces of additional evidence, albeit some indirect, suggest a possible role of hCG in the onset and/or progression of systemic autoimmunity. The presence of hCG in non-pregnant SLE patients, and also in male SLE patients has been observed [94]. Reports also suggest that pregnant SLE patients in the first trimester [95], as well as the second and third trimesters [96], exhibit significantly enhanced levels of serum hCG compared with healthy pregnant females. Heightened levels of hCG during pregnancy are associated with an increased risk of pre-eclampsia, an affliction associated with antiphospholipid syndrome and adverse pregnancy outcomes [97], which are pathological sequelae also associated with SLE.

    Recent studies from our lab have shown that hCG specifically stimulates inflammation and autoimmune responses in non-pregnant, lupus-prone mice. Administration of hCG heightens global autoreactivity in these mice; titers of antibodies to dsDNA, as well as to several lupus autoantigens and phospholipids are enhanced, and animal survival is significantly compromised. Specifically, in splenic cell cultures from lupus-prone mice, hCG demonstrates synergistic effects with TLR ligands as well as with T cell receptor (TCR) stimuli; collectively, costimulatory markers on B cells are up-modulated and T cell proliferative responses are enhanced, as is the secretion of lupus-associated cytokines. In lupus-prone mice, these effects are specifically associated with the enhanced phosphorylation of the mitogen-activated protein (MAP) kinase p38. Significantly, the addition of hCG along with either TLR ligands or anti-CD3 + anti-CD28 antibodies also significantly enhances the secretion of potentially pathogenic autoantibodies [98].

    Though much remains to be discovered, evidence is strongly suggestive of the possibility that, counter to its described immunosuppressive/immunomodulatory effects in normal pregnancy [99], hCG drives, or is at least associated with, events that are known to precipitate lupus pathology.

    Conclusions

    The fact that several reproductive hormones significantly affect the clinical manifestation of SLE is now abundantly clear; sex and age both influence hormone-driven outcomes. That said, considerable challenges remain. While disease models either out of convenience or necessity frequently tend to be reductionist in nature, studying the influence of individual hormones in isolation and designing investigations that permit the appreciation of consecutive or concurrent hormonal cross-influences represents the next frontier. No doubt, enhanced understanding will lead to therapeutics with higher efficacy and diminished toxicity.

    Abbreviations

    dsDNA:

    double-stranded DNA

    ERs:

    estrogen receptors

    GnRH:

    gonadotropin-releasing hormone

    hCG:

    human chorionic gonadotropin

    IgG:

    immunoglobulin G

    IL-10:

    interleukin-10

    mRNA:

    messenger RNA

    NZB:

    New Zealand black

    NZW:

    New Zealand white

    OHSS:

    ovarian hyperstimulation syndrome

    PBMCs:

    peripheral blood mononuclear cells

    SLE:

    systemic lupus erythematosus

    Sm:

    Smith

    Th1:

    T-helper 1

    TLR:

    toll-like receptor

    TWEAK:

    tumor necrosis factor-like weak inducer of apoptosis

    Declarations

    Acknowledgments

    The authors acknowledge the National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex (New Delhi, India) for digital access to online databases.

    Author contributions

    RS and RP wrote the manuscript which RP then edited.

    Conflicts of interest

    The authors declare that there are no conflicts of interest.

    Ethical approval

    Not applicable.

    Consent to participate

    Not applicable.

    Consent to publication

    Not applicable.

    Availability of data and materials

    Not applicable.

    Funding

    This work was supported by core grants of the National Institute of Immunology, Aruna Asaf Ali Marg, JNU Complex (New Delhi, India). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Copyright

    © The Author(s) 2022.

    References

    Catalina MD, Owen KA, Labonte AC, Grammer AC, Lipsky PE. The pathogenesis of systemic lupus erythematosus: harnessing big data to understand the molecular basis of lupus. J Autoimmun. 2020;110:102359. [DOI] [PubMed]
    Parks CG, de Souza Espindola Santos A, Barbhaiya M, Costenbader KH. Understanding the role of environmental factors in the development of systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2017;31:30620. [DOI] [PubMed] [PMC]
    Mohan C, Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol. 2015;11:32941. [DOI] [PubMed]
    Yaniv G, Twig G, Shor DB, Furer A, Sherer Y, Mozes O, et al. A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients. Autoimmun Rev. 2015;14:759. [DOI] [PubMed]
    Tan EM, Smolen JS, McDougal JS, Butcher BT, Conn D, Dawkins R, et al. A critical evaluation of enzyme immunoassays for detection of antinuclear autoantibodies of defined specificities. I. Precision, sensitivity, and specificity. Arthritis Rheum. 1999;42:45564. [DOI] [PubMed]
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:152633. [DOI] [PubMed]
    Rekvig OP. The dsDNA, anti-dsDNA antibody, and lupus nephritis: what we agree on, what must be done, and what the best strategy forward could be. Front Immunol. 2019;10:1104. [DOI] [PubMed] [PMC]
    Murphy G, Isenberg D. Effect of gender on clinical presentation in systemic lupus erythematosus. Rheumatology (Oxford). 2013;52:210815. [DOI] [PubMed]
    Ceccarelli F, Orefice V, Perrone G, Pirone C, Perricone C, Truglia S, et al. Premature ovarian failure in patients affected by systemic lupus erythematosus: a cross-sectional study. Clin Exp Rheumatol. 2020;38:4504. [PubMed]
    Medeiros MM, Silveira VA, Menezes AP, Carvalho RC. Risk factors for ovarian failure in patients with systemic lupus erythematosus. Braz J Med Biol Res. 2001;34:15618. [DOI] [PubMed]
    Hefler-Frischmuth K, Walch K, Huebl W, Baumuehlner K, Tempfer C, Hefler L. Serologic markers of autoimmunity in women with polycystic ovary syndrome. Fertil Steril. 2010;93:22914. [DOI] [PubMed]
    Dao KH, Bermas BL. Systemic lupus erythematosus management in pregnancy. Int J Womens Health. 2022;14:199211. [DOI] [PubMed] [PMC]
    Seo MR, Chae J, Kim YM, Cha HS, Choi SJ, Oh S, et al. Hydroxychloroquine treatment during pregnancy in lupus patients is associated with lower risk of preeclampsia. Lupus. 2019;28:72230. [DOI] [PubMed]
    Simard JF, Chaichian Y, Rossides M, Wikstrom AK, Shaw GM, Druzin ML. Preterm delivery phenotypes in systemic lupus erythematosus pregnancies. Am J Perinatol. 2019;36:9648. [DOI] [PubMed]
    Davidov D, Sheiner E, Wainstock T, Miodownik S, Pariente G. Maternal systemic lupus erythematosus (SLE) high risk for preterm delivery and not for long-term neurological morbidity of the offspring. J Clin Med. 2021;10:2952. [DOI] [PubMed] [PMC]
    Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol. 2011;40:2741. [DOI] [PubMed] [PMC]
    D’Ippolito S, Ticconi C, Tersigni C, Garofalo S, Martino C, Lanzone A, et al. The pathogenic role of autoantibodies in recurrent pregnancy loss. Am J Reprod Immunol. 2020;83:e13200. [DOI] [PubMed]
    Di Prima FA, Valenti O, Hyseni E, Giorgio E, Faraci M, Renda E, et al. Antiphospholipid syndrome during pregnancy: the state of the art. J Prenat Med. 2011;5:4153. [PubMed] [PMC]
    Pantham P, Abrahams VM, Chamley LW. The role of anti-phospholipid antibodies in autoimmune reproductive failure. Reproduction. 2016;151:R7990. [DOI] [PubMed]
    Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. 2018;9:2279. [DOI] [PubMed] [PMC]
    Doria A, Cutolo M, Ghirardello A, Zampieri S, Vescovi F, Sulli A, et al. Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus. Arthritis Rheum. 2002;47:2029. [DOI] [PubMed]
    Joachim R, Zenclussen AC, Polgar B, Douglas AJ, Fest S, Knackstedt M, et al. The progesterone derivative dydrogesterone abrogates murine stress-triggered abortion by inducing a Th2 biased local immune response. Steroids. 2003;68:93140. [DOI] [PubMed]
    Gröndal G, Gunnarsson I, Rönnelid J, Rogberg S, Klareskog L, Lundberg I. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol. 2000;18:56570. [PubMed]
    Ruiz-Irastorza G, Lima F, Alves J, Khamashta MA, Simpson J, Hughes GR, et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol. 1996;35:1338. [DOI] [PubMed]
    Gubbels Bupp MR, Jørgensen TN, Kotzin BL. Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus. Genes Immun. 2008;9:4756. [DOI] [PubMed]
    Li J, May W, McMurray RW. Pituitary hormones and systemic lupus erythematosus. Arthritis Rheum. 2005;52:370112. [DOI] [PubMed]
    Jacobson JD, Nisula BC, Steinberg AD. Modulation of the expression of murine lupus by gonadotropin-releasing hormone analogs. Endocrinology. 1994;134:251623. [DOI] [PubMed]
    Shelly S, Boaz M, Orbach H. Prolactin and autoimmunity. Autoimmun Rev. 2012;11:A46570. [DOI] [PubMed]
    Lee MH, Chakhtoura M, Sriram U, Caricchio R, Gallucci S. Conventional DCs from male and female lupus-prone B6.NZM Sle1/Sle2/Sle3 mice express an IFN signature and have a higher immunometabolism that are enhanced by estrogen. J Immunol Res. 2018;2018:1601079. [DOI] [PubMed] [PMC]
    Khan D, Ansar Ahmed S. The immune system is a natural target for estrogen action: opposing effects of estrogen in two prototypical autoimmune diseases. Front Immunol. 2016;6:635. [DOI] [PubMed] [PMC]
    Li J, McMurray RW. Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. Clin Immunol. 2007;123:21926. [DOI] [PubMed]
    Bynoté KK, Hackenberg JM, Korach KS, Lubahn DB, Lane PH, Gould KA. Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice. Genes Immun. 2008;9:13752. [DOI] [PubMed]
    Tabor DE, Gould KA. Estrogen receptor alpha promotes lupus in (NZB × NZW)F1 mice in a B cell intrinsic manner. Clin Immunol. 2017;174:4152. [DOI] [PubMed] [PMC]
    Svenson JL, EuDaly J, Ruiz P, Korach KS, Gilkeson GS. Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin Immunol. 2008;128:25968. [DOI] [PubMed] [PMC]
    Inui A, Ogasawara H, Naito T, Sekigawa I, Takasaki Y, Hayashida Y, et al. Estrogen receptor expression by peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Clin Rheumatol. 2007;26:16758. [DOI] [PubMed]
    Perl A. Review: metabolic control of immune system activation in rheumatic diseases. Arthritis Rheumatol. 2017;69:225970. [DOI] [PubMed] [PMC]
    Walters E, Rider V, Abdou NI, Greenwell C, Svojanovsky S, Smith P, et al. Estradiol targets T cell signaling pathways in human systemic lupus. Clin Immunol. 2009;133:42836. [DOI] [PubMed] [PMC]
    Xie QM, Hu HQ, Li SS, Wang F, Zhang M, Jiang SQ, et al. Association of oestrogen receptor alpha gene polymorphisms with systemic lupus erythematosus risk: an updated meta-analysis. Microb Pathog. 2019;127:3528. [DOI] [PubMed]
    Gorjestani S, Rider V, Kimler BF, Greenwell C, Abdou NI. Extracellular signal-regulated kinase 1/2 signalling in SLE T cells is influenced by oestrogen and disease activity. Lupus. 2008;17:54854. [DOI] [PubMed]
    Lu R, Wang X, Chen ZF, Sun DF, Tian XQ, Fang JY. Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decreases DNA methylation in colon cancer cells. J Biol Chem. 2007;282:1224959. [DOI] [PubMed]
    Richardson B. The interaction between environmental triggers and epigenetics in autoimmunity. Clin Immunol. 2018;192:15. [DOI] [PubMed] [PMC]
    Weeding E, Sawalha AH. Deoxyribonucleic acid methylation in systemic lupus erythematosus: implications for future clinical practice. Front Immunol. 2018;9:875. [DOI] [PubMed] [PMC]
    Rider V, Li X, Peterson G, Dawson J, Kimler BF, Abdou NI. Differential expression of estrogen receptors in women with systemic lupus erythematosus. J Rheumatol. 2006;33:1093101. [PubMed]
    Ward JM, Rider V, Abdou NI, Kimler B. Estradiol differentially regulates calreticulin: a potential link with abnormal T cell function in systemic lupus erythematosus? Lupus. 2013;22:58396. [DOI] [PubMed] [PMC]
    Rastin M, Hatef MR, Tabasi N, Mahmoudi M. The pathway of estradiol-induced apoptosis in patients with systemic lupus erythematosus. Clin Rheumatol. 2012;31:41724. [DOI] [PubMed]
    Shao WH, Cohen PL. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res Ther. 2011;13:202. [DOI] [PubMed] [PMC]
    Michaelson JS, Wisniacki N, Burkly LC, Putterman C. Role of TWEAK in lupus nephritis: a bench-to-bedside review. J Autoimmun. 2012;39:13042. [DOI] [PubMed] [PMC]
    Xue L, Liu Z, Hu J, Huang J, Wen J, Liu Z. Estrogen-induced expression of tumor necrosis factor-like weak inducer of apoptosis through ERα accelerates the progression of lupus nephritis. Rheumatology (Oxford). 2016;55:18808. [DOI] [PubMed]
    Jara LJ, Medina G, Saavedra MA, Vera-Lastra O, Torres-Aguilar H, Navarro C, et al. Prolactin has a pathogenic role in systemic lupus erythematosus. Immunol Res. 2017;65:51223. [DOI] [PubMed]
    Praprotnik S, Agmon-Levin N, Porat-Katz BS, Blank M, Meroni PL, Cervera R, et al. Prolactin’s role in the pathogenesis of the antiphospholipid syndrome. Lupus. 2010;19:15159. [DOI] [PubMed]
    Stevens A, Ray D, Alansari A, Hajeer A, Thomson W, Donn R, et al. Characterization of a prolactin gene polymorphism and its associations with systemic lupus erythematosus. Arthritis Rheum. 2001;44:235866. [DOI] [PubMed]
    Yang J, Li Q, Yang X, Li M. Increased serum level of prolactin is related to autoantibody production in systemic lupus erythematosus. Lupus. 2016;25:5139. [DOI] [PubMed]
    Legorreta-Haquet MV, Flores-Fernández R, Blanco-Favela F, Fuentes-Pananá EM, Chávez-Sánchez L, Hernández-González R, et al. Prolactin levels correlate with abnormal B cell maturation in MRL and MRL/lpr mouse models of systemic lupus erythematosus-like disease. Clin Dev Immunol. 2013;2013:287469. [DOI] [PubMed] [PMC]
    Jara LJ, Pacheco-Reyes H, Medina G, Angeles U, Cruz-Cruz P, Saavedra MA. Prolactin levels are associated with lupus activity, lupus anticoagulant, and poor outcome in pregnancy. Ann N Y Acad Sci. 2007;1108:21826. [DOI] [PubMed]
    Leaños A, Pascoe D, Fraga A, Blanco-Favela F. Anti-prolactin autoantibodies in systemic lupus erythematosus patients with associated hyperprolactinemia. Lupus. 1998;7:398403. [DOI] [PubMed]
    Leaños-Miranda A, Cárdenas-Mondragón G, Ulloa-Aguirre A, Isordia-Salas I, Parra A, Ramírez-Peredo J. Anti-prolactin autoantibodies in pregnant women with systemic lupus erythematosus: maternal and fetal outcome. Lupus. 2007;16:3429. [DOI] [PubMed]
    Borba VV, Zandman-Goddard G, Shoenfeld Y. Prolactin and Autoimmunity. Front Immunol. 2018;9:73. [DOI] [PubMed] [PMC]
    Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012;11:A50214. [DOI] [PubMed] [PMC]
    Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol. 2014;10:74051. [DOI] [PubMed]
    Dhaher YY, Chan K, Greenstein BD, de Fougerolles Nunn E, Khamashta MA, Hughes GR. Impaired estrogen priming of progesterone receptors in uterus of MRL/MP-lpr/lpr mice, a model of systemic lupus erythematosus (SLE). Int J Immunopharmacol. 2000;22:53745. [DOI] [PubMed]
    Arnalich F, Benito-Urbina S, Gonzalez-Gancedo P, Iglesias E, de Miguel E, Gijon-Baños J. Inadequate production of progesterone in women with systemic lupus erythematosus. Br J Rheumatol. 1992;31:24751. [DOI] [PubMed]
    Hughes GC, Martin D, Zhang K, Hudkins KL, Alpers CE, Clark EA, et al. Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum. 2009;60:177584. [DOI] [PubMed]
    Baudino L, Azeredo da Silveira S, Nakata M, Izui S. Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin Immunopathol. 2006;28:17584. [DOI] [PubMed]
    Wong AH, Agrawal N, Hughes GC. Altered IgG autoantibody levels and CD4+ T cell subsets in lupus-prone Nba2 mice lacking the nuclear progesterone receptor. Autoimmunity. 2015;48:389401. [DOI] [PubMed] [PMC]
    Roubinian J, Talal N, Siiteri PK, Sadakian JA. Sex hormone modulation of autoimmunity in NZB/NZW mice. Arthritis Rheum. 1979;22:11619. [DOI] [PubMed]
    Keisler LW, Kier AB, Walker SE. Effects of prolonged administration of the 19-nor-testosterone derivatives norethindrone and norgestrel to female NZB/W mice: comparison with medroxyprogesterone and ethinyl estradiol. Autoimmunity. 1991;9:2132. [DOI] [PubMed]
    Lahita RG, Bradlow HL, Ginzler E, Pang S, New M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum. 1987;30:2418. [DOI] [PubMed]
    Hazelton RA, McCruden AB, Sturrock RD, Stimson WH. Hormonal manipulation of the immune response in systemic lupus erythematosus: a drug trial of an anabolic steroid, 19-nortestosterone. Ann Rheum Dis. 1983;42:1557. [DOI] [PubMed] [PMC]
    Jiménez-Balderas FJ, Tápia-Serrano R, Fonseca ME, Arellano J, Beltrán A, Yáñez P, et al. High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction. Arthritis Res. 2001;3:3627. [DOI] [PubMed] [PMC]
    Olsen NJ, Kovacs WJ. Case report: testosterone treatment of systemic lupus erythematosus in a patient with Klinefelter’s syndrome. Am J Med Sci. 1995;310:15860. [DOI] [PubMed]
    Tessnow AH, Olsen NJ, Kovacs WJ. Expression of humoral autoimmunity is related to androgen receptor CAG repeat length in men with systemic lupus erythematosus. J Clin Immunol. 2011;31:567. [DOI] [PubMed] [PMC]
    Kanda N, Tsuchida T, Tamaki K. Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum. 1997;40:170311. [DOI] [PubMed]
    Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK. Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J Exp Med. 1978;147:156883. [DOI] [PubMed] [PMC]
    Lucas JA, Ahmed SA, Casey ML, MacDonald PC. Prevention of autoantibody formation and prolonged survival in New Zealand black/New Zealand white F1 mice fed dehydroisoandrosterone. J Clin Invest. 1985;75:20913. [DOI] [PubMed] [PMC]
    Verheul HA, Deckers GH, Schuurs AH. Effects of nandrolone decanoate or testosterone decanoate on murine lupus: further evidence for a dissociation of autoimmunosuppressive and endocrine effects. Immunopharmacology. 1986;11:939. [DOI] [PubMed]
    Walker SE, Besch-Williford CL, Keisler DH. Accelerated deaths from systemic lupus erythematosus in NZB × NZW F1 mice treated with the testosterone-blocking drug flutamide. J Lab Clin Med. 1994;124:4017. [PubMed]
    Procaccini C, Pucino V, Mantzoros CS, Matarese G. Leptin in autoimmune diseases. Metabolism. 2015;64:92104. [DOI] [PubMed]
    La Cava A. Leptin in inflammation and autoimmunity. Cytokine. 2017;98:518. [DOI] [PubMed] [PMC]
    Childs GV, Odle AK, MacNicol MC, MacNicol AM. The importance of leptin to reproduction. Endocrinology. 2021;162:bqaa204. [DOI] [PubMed] [PMC]
    La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4:3719. [DOI] [PubMed]
    Lee YH, Song GG. Association between circulating leptin levels and systemic lupus erythematosus: an updated meta-analysis. Lupus. 2018;27:42835. [DOI] [PubMed]
    Härle P, Pongratz G, Weidler C, Büttner R, Schölmerich J, Straub RH. Possible role of leptin in hypoandrogenicity in patients with systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis. 2004;63:80916. [DOI] [PubMed] [PMC]
    Lourenço EV, Liu A, Matarese G, La Cava A. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci U S A. 2016;113:1063742. [DOI] [PubMed] [PMC]
    Fujita Y, Fujii T, Mimori T, Sato T, Nakamura T, Iwao H, et al. Deficient leptin signaling ameliorates systemic lupus erythematosus lesions in MRL/Mp-Faslpr mice. J Immunol. 2014;192:97984. [DOI] [PubMed] [PMC]
    Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A. Cutting edge: leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol. 2013;190:30548. [DOI] [PubMed] [PMC]
    Garrett-Sinha LA, John S, Gaffen SL. IL-17 and the Th17 lineage in systemic lupus erythematosus. Curr Opin Rheumatol. 2008;20:51925. [DOI] [PubMed]
    Hahn BH, Lourencço EV, McMahon M, Skaggs B, Le E, Anderson M, et al. Pro-inflammatory high-density lipoproteins and atherosclerosis are induced in lupus-prone mice by a high-fat diet and leptin. Lupus. 2010;19:9137. [DOI] [PubMed] [PMC]
    McMahon M, Skaggs BJ, Sahakian L, Grossman J, FitzGerald J, Ragavendra N, et al. High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis. 2011;70:161924. [DOI] [PubMed] [PMC]
    Amarilyo G, Iikuni N, Liu A, Matarese G, La Cava A. Leptin enhances availability of apoptotic cell-derived self-antigen in systemic lupus erythematosus. PLoS One. 2014;9:e112826. [DOI] [PubMed] [PMC]
    Amarilyo G, Iikuni N, Shi FD, Liu A, Matarese G, La Cava A. Leptin promotes lupus T-cell autoimmunity. Clin Immunol. 2013;149:5303. [DOI] [PubMed]
    Ben-Chetrit A, Ben-Chetrit E. Systemic lupus erythematosus induced by ovulation induction treatment. Arthritis Rheum. 1994;37:16147. [DOI] [PubMed]
    Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weich HA, et al. Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab. 1995;80:196771. [DOI] [PubMed]
    Orvieto R. Prediction of ovarian hyperstimulation syndrome: challenging the estradiol mythos. Hum Reprod. 2003;18:6657. [DOI] [PubMed]
    Moncayo R, Moncayo HE. A new endocrinological and immunological syndrome in SLE: elevation of human chorionic gonadotropin and of antibodies directed against ovary and endometrium antigens. Lupus. 1995;4:3945. [DOI] [PubMed]
    de Sousa MJR, Ribeiro R, Syngelaki A, Nicolaides KH. First trimester combined screening in patients with systemic lupus erythematosus: impact of pre-analytical variables on risk assessment. Clin Rheumatol. 2019;38:12515. [DOI] [PubMed]
    Maymon R, Cuckle H, Sehmi IK, Herman A, Sherman D. Maternal serum human chorionic gonadotrophin levels in systemic lupus erythematosus and antiphospholipid syndrome. Prenat Diagn. 2001;21:1435. [DOI] [PubMed]
    Barjaktarovic M, Korevaar TIM, Jaddoe VWV, de Rijke YB, Peeters RP, Steegers EAP. Human chorionic gonadotropin and risk of pre-eclampsia: prospective population-based cohort study. Ultrasound Obstet Gynecol. 2019;54:47783. [DOI] [PubMed] [PMC]
    De A, Sachdeva R, Bose A, Malik M, Jayachandran N, Pal R. Human chorionic gonadotropin influences systemic autoimmune responses. Front Endocrinol (Lausanne). 2018;9:742. [DOI] [PubMed] [PMC]
    Schumacher A, Heinze K, Witte J, Poloski E, Linzke N, Woidacki K, et al. Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance. J Immunol. 2013;190:26508. [DOI] [PubMed]