SP0045 Oestrogens, immune response and autoimmune diseases

Abstract

Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors. Several physiological, pathological and therapeutic conditions may change the serum oestrogen milieu including the menstrual cycle, pregnancy, postpartum period, menopause, elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, use of glucocorticoids, oral contraceptives, and steroid hormonal replacements. Cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve also sex hormone circadian synthesis and levels. Abnormal regulation of aromatase activity (i.e. increased activity) by inflammatory cytokines production (i,e, TNF-alpha, IL-1, IL-6) may partially explain the abnormalities of peripheral oestrogen synthesis in RA (i.e. increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus srythematosus (SLE). In the synovial fluids of RA patients the increased oestrogen concentration are observed in both sexes and are more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, that is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation. Epidemiological evidence indicates that during the fertile age women are more often affected by rheumatic diseases than men, particularly autoimmune diseases. As a matter of fact, rheumatic disorders with autoimmune involvement such as RA or SLE, result from the combination of several predisposing factors, that include the relationships between epitopes of the trigger agent (i.e. virus), the status of the stress response system including the hypothalamic-pituitary-adrenocortical axis (HPA) and mainly the effects of the gonadal hormones (hypothalamic- pituitary-gonadal axis - HPG). The pre-or post-menopausal serum sex hormonal status is a further factor influencing the rate of rheumatic diseases. It is therefore important, whenever possible, to evaluate epidemiologic data broken down into age (for example 10 year age band) and sex-specific group before making inferences. Obviously, sex hormones seem to play an important role as modulators of both disease onset and perpetuation and show circadian rhythms together with cortisol. Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors. Low concentrations of gonadal and adrenal androgens [testosterone (T)/dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), respectively] levels, as well as reduced androgens/estrogens ratio, have been detected in serum and body fluids (i.e. blood, synovial fluid (SF), smears, salivary) of male and female RA patients, as well as in SLE, supporting the possible pathogenic role for the decreased levels of the immune-suppressive androgens. However, respect to serum levels of estrogens, interestingly they are not significantly changed which is in strict contrast to androgen levels in RA patients (reduced). As a matter of fact, sex hormones can exert also local actions (paracrine) in the tissues in which they are formed or enter the circulation and both T and 17-beta estradiol seem to exert dose and time-dependent effects on cell growth and apoptosis. These effects, as well as important influences on gene promoter of Th1/Th2 cytokines and the recently discovered increased SF oestrogen concentrations, might suggest new interesting roles for estrogens at least in RA. Finally estrogens exert important epigenetic actions on cell proliferation. Estrogens act as key factors in cellular proliferation and differentiation as well as cancer development and progression (prostate). The expression of oestrogen receptor (ER)-b appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERβ expression in prostate cancer cells. These observations highlights that the strategy of merging epigenetic and hormonal therapies might be beneficial also in inflammatory/autoimmune diseases (synovial tissue).