Effects of Menopause on Autoimmune Diseases

Miranda A Farage; Kenneth W Miller; Howard I Maibach

Disclosures

Expert Rev of Obstet Gynecol. 2012;7(6):557-571. 

In This Article

What is Known About the Estrogen Deficiency of Menopause & Specific Autoimmune Diseases

It is known that many natural, pathological and therapeutic conditions can change serum estrogen levels, including the menstrual cycle, pregnancy, menopause, use of oral contraceptives, use of hormonal replacement treatment and disease. The estrogen withdrawal of menopause, however, is a significant hormonal transition, and one with numerous physiologic ramifications. The normal immunosenescence evidenced in both sexes may be modulated in some degree by changing levels and forms of endogenous estrogen.

The production of cytokines IL-6, IL-1, and TNF-a increase after menopause, as does the physiological response to those cytokines.[10] There is a postmenopausal decrease in CD4 T and B lymphocytes, as well as decrease in the cytotoxic activity of natural killer cells.[31]

In vitro analysis of three different T-cell signaling proteins (Janus kinase 2 [JAK2], Janus kinase 3 [JAK3], and CD3-z) found that postmenopausal levels were substantially reduced compared with premenopausal levels.[11] In addition, Jurkat T cells exposed to premenopausal levels of E2 also formed significantly more IL-2 producing colonies compared with those exposed to premenopausal levels (75.3 ± 2.2 vs 55.7 ± 2.1 [p < 0.0001]).[11] Studies suggest a normalization of cellular response after hormone-replacement therapy (HRT).[10]

Systemic Lupus Erythematosus

SLE is an autoimmune disorder characterized by the production of pathogenic autoantibodies, primarily to nuclear antigens, as well as dysregulation of both T and B cells.[62] B cells display accelerated maturity.[63] SLE patients exhibit monocyte-derived DCs, which display an activated, proinflammatory phenotype.[63]

SLE has a female preponderance of 9:1. Although there are X-chromosome abnormalities associated with SLE,[64] estrogen itself is strongly implicated in SLE autoimmunity.[10] SLE is associated with a disrupted sex hormone balance characterized by lower amounts of androgens and dramatically higher levels of the estrogen metabolite, 16-hydroxyestrone.[65] Pregnancy worsens the disease;[23] incidence of SLE diminishes after menopause.[36,42,66] Administration of an estrogen receptor (ER) blocker (fulvestrant) to human female SLE patients produces clinical improvement[67] as does treatment with testosterone.[68]

Increased risk has been associated with higher lifetime levels of estrogen exposure. In a cohort of 238,308 adult women evaluated prospectively over 27 years, the 262 women diagnosed with SLE over the course of the study were analyzed for relative risk factors. Increased risk was associated with early menarche (aged less than 10 years; relative risk: 2.1; 95% CI: 1.4–3.2) and oral contraceptive use (relative risk: 1.5; 95% CI: 1.1–2.1).[69] Menstrual irregularity increased risk of SLE diagnosis in a Japanese case–control study.[70] Menstrual cycles of abnormal length (either long and short) increased risk as well.[71] Estradiol treatment of mouse lupus-prone strains produces disease onset, increases autoantibody production, and increases risk of mortality.[23]

Hormonal fluctuations also appear to influence the course of SLE. Dual studies evaluated the course of disease in early-onset SLE patients versus late-onset patients; later-onset patients (after the age of 50 years) had lower incidences of renal disease, arthritis, malar rash and photosensitivity compared with patients who were younger at diagnosis.[72] Younger patients had a more aggressive disease course as well, with time from symptom onset to diagnosis being 3 years compared with 5 years in older patients.[72] Similar results were observed in a study of 125 Chinese SLE patients.[73] A pooled analysis that compared 714 late-onset patients with 4700 early-onset patients confirmed earlier results, finding also a lower incidence of purpura, alopecia and Raynaud's phenomenon in the late-onset group. The late-onset group, however, had a higher prevalence of rheumatoid factor, with antibodies to ribonucleoprotein and sphingomyelin less frequently.[74]

SLE patients have also been evaluated for effect of previous hysterectomy (with and without concomitant oophorectomy). SLE patients (n = 3389) who had undergone hysterectomy were less likely to develop nephritis or positive anti-double-strand DNA antibodies than age-matched SLE patients who had not (odds ratio: 6.66 [95% CI: 3.09–14.38] in European patients and 2.74 [95% CI: 1.43–5.25] in African–American patients). SLE patients with hysterectomy before disease onset had later onset of disease (p = 0.0001).[62]

The role of estrogen, rather than age alone, was investigated by studies which utilized younger SLE patients who underwent ovarian failure produced by cyclophosphamide. Significantly fewer flares were observed in the group with ovarian failure compared with normally menstruating SLE women.[75] The cyclophosphamide group, however, was significantly older than the control group (37.9 years compared with 25.5 years). Other research, however, followed two groups of SLE patients: one early onset and one late onset and concluded that the decrease in disease activity after menopause could not conclusively be determined to be related to hormonal status.[76]

HRT has documented benefits for women with regard to some aspects of aging; and in some cases may be medically necessary.[77] Postmenopausal osteoporosis, for example, directly tied to estrogen deficiency, may require hormonal intervention, shown to reduce the risk of hip fractures by as much as 30%.[78] HRT, however in patients with SLE, which is induced or exacerbated by oral contraceptives has the potential to produce disease flares.

Examination of the effects of HRT in postmenopausal women found that in 351 postmenopausal SLE patients, combined estrogen/progesterone hormone replacement (0.625 mg conjugated estrogen daily, plus 5 mg medroxyprogesterone for 12 days/month) given for 12 months produced only a small increase in the risk of disease flares (0.64 probability in HRT patients vs 0.51 in placebo controls, with most flares mild or moderate [p = 0.01]). HRT use did not significantly increase the risk of severe flares.[77]

An overall assessment of the consequences of SLE in postmenopausal patients looked at damage accrual in SLE as part of the LUMINA (Lupus in Minorities: Nature vs Nurture) study and found that despite the drop in disease activity in the postmenopausal period (with a reduction in the risk of renal disease), overall damage scores were higher due to an increase in cardiovascular disease. Whether higher damage accrual is related to the changing hormones of menopause or due simply to longer disease duration is as yet undetermined.[79] It is known that estrogen promotes SLE through ER-a by inducing IFN-g.[80] Testosterone is most likely protective in SLE patients by driving the Th1 immune pathway.[10]

Although no differences are observed in SLE patients as compared with normal controls with regard to circulating estrogen levels (17b-estradiol), number of ERs or binding affinities of ER to estrogen, blocking of the ERs using fulvestrant in patients with moderately active SLE produced a significant decrease in disease activity (as measured by the SLE disease activity index score).[67]

Female SLE patients have abnormal metabolism of sex hormones, with an increase in the production of 16-hydroxyestrone and metabolites that may produce a chronic state of excessive estrogen.[81] Elevated aromatase activity (an enzyme found in all organ systems and integral to sexual reproduction, that converts androgens into estrogens) is also observed in SLE patients.[36]

The molecular mechanism leading to a gender preponderance in SLE appears to be demethylation of CD40 ligand on CD40+ T cells,[82] which, appearing on an inactive X-chromosome, results in overexpression of CD40 ligand on CD4+ cells.[83] SLE patients are typically characterized by high titers of autoantibodies directed against nuclear antigens, antibodies which have been demonstrated to potentially arise from germline-coded polyreactive antibodies induced to class-switch to IgG by a proinflammatory milieu.[84]

Rheumatoid Arthritis

RA is an autoimmune disease in which multiple components of the immune system produce tissue damage and contribute to systemic inflammation. T cells, B cells and macrophages infiltrate into the inflamed synovial membrane whose resident cells proliferate and differentiate; macrophages and other activated tissue-resident cells begin to produce cytokines which induce B- and T-cell responses that act in concert to erode bone and cause destruction of cartilage. RA is associated with an altered sex hormone balance characterized by lower amounts of androgens and higher estrogens.[65] RA incidence increases with postmenopause, suggesting that decreased E2 levels are involved in disease onset. The incidence of RA incidence peaks in the seventh decade.[85] Pregnancy ameliorates disease activity,[86] however, the postpartum period is a time of high risk for new-onset RA.[87] Aromatase inhibitors, compounds that interfere with estrogen production, trigger onset of RA or produce arthritis flares in both premenopausal and postmenopausal women.[88]

RA is characterized by a profile of generalized immunosenescence typical with age. Early-onset RA may represent premature immunosenescence,[89] a loss of T-cell diversity and T-cell reactivity, a slide towards proliferative arrest, and significant production of inflammatory cytokines. Levels of autoantibodies increase as well.[85] In addition, RA patients carry large, clonally expanded populations of CD4+ and CD8+ cells; CD4+ clones are consistently autoreactive.[85]

Menopause is associated with an increased risk of disease onset. In a cohort of nearly 32,000 women in Iowa (USA), those who reached menopause before 45 years of age had a higher risk of RA than women who reached menopause after 51 years of age.[90] Similar results were obtained in a study that evaluated 18,326 Swedish women and compared those who entered menopause before 45 to those who reached menopause after 45 years of age.[91]

Another author followed RA patients over a 6-year period; the 209 female patients evaluated were divided into premenopausal and postmenopausal groups. Postmenopausal subjects had greater joint damage as measured radiographically as well as by health assessment questionnaires. In addition, comparison with both premenopausal women and men determined that estrogen deprivation of menopause was a significant factor in the disparity of damage between men and women.[92] Although the use of HRT does not appear to influence the risk of developing RA,[93] HRT improves both symptoms and progression of disease.[94]

Scleroderma

Scleroderma is an autoimmune disease of the connective tissues characterized by a buildup of collagen in body tissues. Typically involving primarily the skin on the hands and face, scleroderma can affect many organ systems, including the heart, lungs, and kidneys. Scleroderma affects mostly women, with onset typically around the same time as menopause; early menopause increases risk.[95] Scleroderma involves significant vasculopathy, which is accentuated by menopause-related loss of estrogen. A prospective Italian study found that the estrogen removal of the postmenopausal period was a risk factor for the development of pulmonary arterial hypertension in scleroderma patients, with relative risk due to postmenopausal state of 5.2 (p = 0.000).[96] Twenty-three postmenopausal scleroderma patients were subsequently treated with HRT for a mean follow-up of 7.5 years. None of the HRT scleroderma patients developed pulmonary arterial hypertension as compared with 19.5% of those not on HRT.[97]

Sjögren's Syndrome

Sjögren's syndrome (SS) is an autoimmune disorder that affects mucous membranes as well as tear ducts and salivary glands but may also impact other organs such as the kidneys, stomach, intestines, vasculature, lungs, liver, pancreas and the CNS. The large majority of SS patients are women, with onset after the age of 40 years. SS is associated with a T-cell infiltration of the exocrine glands with associated autoantibodies.[98] Estrogen suppresses disease development while ovariectomy leads to an SS-like condition with increased epithelial cell apoptosis.[23] Estrogen-deficient mice develop an autoimmune exocrinopathy resembling SS.[99] It is believed that estrogen deficiency may influence autoantigen cleavage in such a way that it results in autoimmune exocrinopathy in postmenopausal women.[99]

Multiple Sclerosis

MS is an episodic autoimmune disease in which autoantibodies attack the CNS, particularly the myelin sheath; symptoms vary with the location of the attack. MS is typically diagnosed in young adulthood. As the target tissue of MS is the CNS, MS has debilitating and systemic effects. More women than men suffer from MS; estrogen influence is also suggested by the fact that MS symptoms improve during pregnancy but worsen postpartum. MS pathogenesis is largely driven by antigen-specific CD4+ Th1 cells, specific for the CNS, which secrete proinflammatory cytokines such as IFN-g, TNF-a and IL-12. Active disease is well-correlated with T-cell production of proinflammatory cytokines.[23] Most (54%) MS patients reported a worsening of symptoms after menopause; 75% of those who had used HRT (at all stages of menopause) reported improvement.[100]

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is an autoantibody-induced inflammation of the liver, although a variety of autoantibodies (directed against specific liver antigens as well as nuclear DNA, mitochondrial antigens, and smooth muscle antigens) are involved. AIH also affects predominantly females, most often with onset in childhood but also postmenopause,[45] although men may be affected more often than women in old age. Autoantibodies are directed against hepatocytes, the putative result of an insidious progressive destruction of the hepatic parenchyma.[45] AIH often ameliorates during pregnancy; many cases, however, are diagnosed in the postpartum period.[101,102]

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