Hormone replacement and contraceptive therapy in autoimmune diseases

doi:10.1016/j.jaut.2011.11.002

Journal of Autoimmunity

Volume 38, Issues 2–3, May 2012, Pages J170-J176

https://doi.org/10.1016/j.jaut.2011.11.002 Get rights and content

Abstract

Sex hormones, including estrogens, influence the immune system in a complex manner, playing an important role in the pathophysiology of autoimmune diseases. Estrogen receptors can be found in almost all cells, including those of the adaptive and innate immune systems. Depending on the relative preponderance and stimulation of different receptors in various tissues, estrogens may demonstrate pro-inflammatory or anti-inflammatory properties. Traditionally, exogenous estrogens were considered to have the potential of worsening the autoimmune processes and hence were avoided in patients with rheumatic diseases. Recent studies have demonstrated the efficacy of exogenous hormone therapies, either in the form of oral contraceptives or post-menopausal hormonal replacement therapy, in the majority of patients with rheumatic diseases. However, caution needs to be exercised as a higher incidence of mild to moderate flares of systemic lupus erythematosus was noted with hormonal replacement therapy in the large randomized controlled trial, HRT-SELENA. Exogenous estrogens can also increase the risk of thrombosis in patients with positive antiphospholipid antibodies and should be avoided in this subgroup. This review will discuss the current evidence on the efficacy, safety and impact of exogenous sex hormone therapies in patients with autoimmune rheumatic diseases.

Highlights

► The sex hormones play a significant role in the pathophysiology of autoimmune rheumatic diseases. ► Hormonal therapies (OCs and HRT) are effective in the majority of patients with rheumatic diseases. ► However, their use should be avoided in women with severe active SLE and hypercoaguable states. ► HRT led to an increase in mild to moderate SLE flares in the HRT-SELENA trial. ► OCs may improve RA disease activity and are an effective and safe option for young women with RA.

Section snippets

Estrogens and systemic lupus erythematosus

The major concerns over use of estrogens in systemic lupus erythematosus (SLE) were induction or exacerbation of the disease. Animal data have shown harmful effects of estrogens in SLE models. Estrogens augment murine B-cell survival and autoreactivity and exacerbate murine SLE in some models. However, the effects of estrogens on murine disease are variable [1]. In the NZB/NZW murine SLE model, removal of estrogen or addition of androgen improves survival [2]. In contrast, estrogen has diverse

Estrogens and rheumatoid arthritis

In animal models of arthritis, estrogens have beneficial effects, retarding arthritis progression [60], [61]. In human rheumatoid arthritis, the role of estrogens is less clear as both pro- and anti-inflammatory effects have been reported. Rheumatoid arthritis is two to three times more common in women compared to men. Higher disease activity scores have been reported in women compared to men [62]. On the other hand, rheumatoid arthritis tends to improve during periods of high estrogen levels,

Other autoimmune diseases

The evidence for any beneficial or harmful role for estrogens and other sex hormones is very limited and sometimes contradictory for other autoimmune diseases. Two studies suggested beneficial role of exogenous estrogens (including hormone replacement therapy) on endothelial function in patients with systemic sclerosis [82], [83]. In contrast, one case report described progression of Raynaud’s phenomena to severe systemic sclerosis after use of OCs [84]. Behcet’s disease is associated with

Conclusion

The autoimmune rheumatic diseases affect young women, especially SLE. The pathophysiology of these diseases is complex and sex hormones may have variable effects. Care should be exercised in using hormone replacement therapy in SLE given the increased risk of mild to moderate flare. OCs cannot be recommended for women with SLE with hypercoagulability. Women with active and severe SLE, history of thrombosis, anticardiolipin antibody and/or lupus anticoagulant positivity are at high risk and

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The risk of developing SLE increases with greater concentrations of ethinyloestradiol in the pill formulation and is higher in women using first- or second-generation contraceptives that are known to have higher oestrogen doses compared to more modern drug formulations [99,100]. As predicted by our hypothesis, postmenopausal exogenous oestrogen use also increases women’s SLE risk, and randomized, double-blind controlled trial of hormone replacement therapy in SLE patients slightly increases the risk of mild to moderate flares [101–103]. Oestrogen levels therefore influence not only symptoms of autoimmune disease, but might also be a contributing factor to autoimmune disease incidence, possibly by affecting central and peripheral tolerance induction mechanisms.
Over the past century autoimmune disease incidence has increased rapidly in (post-) industrialised, affluent societies, suggesting that changes in ecology and lifestyle are driving this development. Epidemiological studies show that (i) 80% of autoimmune disease patients are female, (ii) autoimmune diseases co-occur more often in women, and (iii) the incidence of some autoimmune diseases is increasing faster in women than in men. The female preponderance in autoimmunity is most pronounced between puberty and menopause, suggesting that diverging sex hormone levels during the reproductive years are implicated in autoimmune disease development. Using an evolutionary perspective, we build on the hypotheses that female immunity is cyclical in menstruating species and that natural selection shaped the female immune system to optimise the implantation and gestation of a semi-allogeneic foetus. We propose that cyclical immunomodulation and female immune tolerance mechanisms are currently out of balance because of a mismatch between the conditions under which they evolved and (post-)industrialised, affluent lifestyles. We suggest that current changes in autoimmune disease prevalence may be caused by increases in lifetime exposure to cyclical immunomodulation and ovarian hormone exposure, reduced immune challenges, increased reproductive lifespan, changed reproductive patterns, and enhanced positive energy balance associated with (post-)industrialised, affluent lifestyles. We discuss proximate mechanisms by which oestrogen and progesterone influence tolerance induction and immunomodulation, and review the effect of the menstrual cycle, pregnancy, and contraceptive use on autoimmune disease incidence and symptoms.
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Women exposed to FHT and matched women unexposed to FHT enrolled in a national insurance plan.
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ReviewHormone replacement and contraceptive therapy in autoimmune diseases

Abstract

Highlights

Section snippets

Estrogens and systemic lupus erythematosus

Estrogens and rheumatoid arthritis

Other autoimmune diseases

Conclusion

Approach to the study of the role of sex hormones in autoimmunity

Arthritis Rheum

Sex hormone modulation of autoimmunity in NZB/NZW mice

Arthritis Rheum

Incidence of systemic lupus erythematosus. Race and gender differences

Arthritis Rheum

Lupus disease activity associated with menstrual cycle

J Rheumatol

Self-reported flaring varies during the menstrual cycle in systemic lupus erythematosus compared with rheumatoid arthritis and fibromyalgia

Rheumatology (Oxford)

Reproductive and menopausal factors and risk of systemic lupus erythematosus in women

Arthritis Rheum

Combined oral contraceptive use and the risk of systemic lupus erythematosus

Arthritis Rheum

Postmenopausal estrogen therapy and the risk for developing systemic lupus erythematosus

Ann Intern Med

Oral contraceptives and systemic lupus erythematosus

Arthritis Rheum

Malignant hypertension and antiphospholipid antibodies as presenting features of SLE in a young woman using oral contraceptives

Br J Rheumatol

Risk factors for developing systemic lupus erythematosus: a case-control study in southern Sweden

Rheumatology (Oxford)

Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study

Arthritis Rheum

Female systemic lupus erythematosus in Miyagi Prefecture, Japan: a case-control study of dietary and reproductive factors

Tohoku J Exp Med

Shingles, allergies, family medical history, oral contraceptives, and other potential risk factors for systemic lupus erythematosus

Am J Epidemiol

Patients with rheumatoid arthritis and systemic lupus erythematosus have increased renal excretion of mitogenic estrogens in relation to endogenous antiestrogens

J Rheumatol

Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity

Lupus

Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity

Lupus

Hormonal contraception: state of the art and future perspectives

Minerva Ginecol

Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal outcome

Nephrol Dial Transplant

Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies

Br J Rheumatol

Lupus and pregnancy studies

Arthritis Rheum

Frequency of fractures in women with systemic lupus erythematosus: comparison with United States population data

Arthritis Rheum

Hormonal supplementation as treatment for cyclical rashes in patients with systemic lupus erythematosus

J Rheumatol

Combined oral contraceptives in women with systemic lupus erythematosus

N Engl J Med

A trial of contraceptive methods in women with systemic lupus erythematosus

N Engl J Med

Can women with systemic lupus erythematosus safely use exogenous estrogens?

J Clin Rheumatol

Oral contraceptives in systemic lupus erythematosus: side-effects and influence on the activity of SLE

Scand J Rheumatol

Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus

Arthritis Rheum

Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients

Contraception

Epidemiology of the contraceptive pill and venous thromboembolism

Thromb Res

Lupus nephritis and Raynaud’s phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies

Clin Rheumatol

Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke

Stroke

Oral contraceptives and the risk of myocardial infarction

N Engl J Med

Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study

Lancet Neurol

Depot medroxyprogesterone acetate contraception in women with medical problems

J Reprod Med

Musculoskeletal complications of systemic lupus erythematosus in the Hopkins Lupus Cohort: an update

Arthritis Care Res

Review
Hormone replacement and contraceptive therapy in autoimmune diseases