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Menopause and aging: Changes in the immune system—A review
Maturitas 67 (2010) 316–320
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Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Menopause and aging: Changes in the immune system—A review Cátia Morgado Gameiro a , Fatima Romão a , Camil Castelo-Branco b,∗ a
Department of Gynaecology and Obstetrics, Garcia de Orta’s Hospital, Almada, Portugal Clinic Institute of Gynecology, Obstetrics and Neonatology, Faculty of Medicine-University of Barcelona, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 28 June 2010 Received in revised form 3 August 2010 Accepted 10 August 2010
Keywords: Menopause Sex steroids Immune system Cytokines Aging Immunosenescence
a b s t r a c t Background: The higher risk of women developing autoimmune diseases suggests that immune system is mediated by sex steroids. Objective: To review the effects of aging and menopause in immune system. Methods: A systematic review of in vitro, animal and human studies involving aging and menopause and immune system was carried out. An electronic search based on Internet search engines, MEDLINE (1966–June 2010) and the Cochrane Controlled Clinical Trials Register was done. Results: After crossing-cleaning the reference lists, a total of 688 studies dealing with immune system and menopause were identified. Of them, 30 were considered selectable. The concept of immunosenescence reflects changes in both cellular and serological immune responses throughout the process of generating specific response to foreign antigens. This may be related with a higher incidence of infectious and chronic diseases. After menopause, there is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increase in response of the immune blood cells to these cytokines, a decrease in CD4 T and B lymphocytes and a decrease in the cytotoxic activity of NK cells. Additionally, IL-6 is a key factor in bone resorption and also seems to be associated with other diseases more common after menopause such as diabetes, atherosclerosis and cardiovascular disease. Conclusions: Most of the studies suggested that in addition to age, in postmenopausal women, changes of the immune system have been attributed to estrogen deprivation. Furthermore, recent studies point out changes in immune response related to use or cessation of hormone replacement at menopause. © 2010 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The immune and endocrine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Gender and the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Aging and the immunologic response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Menopause, estrogen deprivation and the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Institut Clínic de Ginecologia, Obstetrícia i Neonatología, University of Barcelona, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 93 227 54 36; fax: +34 93 227 93 25. E-mail address: [email protected] (C. Castelo-Branco). 0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2010.08.003
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1. Introduction Climacteric complaints vary significantly among countries, with North American and European people reporting higher rates of symptoms than Asian women [1,2]. The fact that gender influences the immune system has long been recognised. The difference between both sexes has many explanations, such as an influence of sex hormones and an influence of different endocrine pathways [3]. The higher risk of women developing autoimmune diseases suggests that these diseases are somehow mediated by sex steroids. The concept of immunosenescence reflects changes in the cellular and humoral immune response and throughout the process of generating specific response to the foreign antigens [4]. The natural immune defences of the organism are also reduced because of the fragility of the skin and decrease of the production of antibodies. The dysfunction of the immune system associated with age may be reflected in a higher incidence of infectious and chronic diseases [5]. Accordingly, low levels of estrogen, observed in castrated animals or in postmenopausal women, have been shown to mitigate the immune response and predispose to disease and infection [6,7]. In this review, an attempt is made to summarize the major published reports on the relationship between immune system and aging and menopause and to emphasize points that still need further clarification and additional research. 2. Material and methods 2.1. Search design A systematic review of in vitro, animal and human studies involving immune system and menopause was carried out. To identify all of the articles that describe a relationship between immune system and menopause, the following search strategy was designed: (aging OR gender medicine OR menopause) and immune system. This strategy was adapted and applied to different Internet search engines, to the MEDLINE database (1966–June 2010) and the Cochrane Controlled Trials Register. There was no language or date restriction. This search was further supplemented by a hand-search of reference lists of selected review papers. One reviewer (CCB) independently evaluated the eligibility of the trials. One reviewer (CMG) extracted the data from the selected articles using a prefixed protocol (information was gathered on the characteristics of participants in the trial, the intervention and how the results were measured). Of the reviewed articles, those that did not establish a relationship between menopause and immune system, literature reviews or those whose purpose was not to demonstrate a therapeutic impact were not considered. Finally an additional search of articles dealing with hormone replacement during menopause and inflammation markers retrieved 22 additional articles. 3. Results After crossing-cleaning the reference lists, a total of 688 studies dealing with immune system and menopause were identified. Of them, 30 were considered selectable and were allocated according their focus in one of the following topics: immune system and endocrine system, gender, aging and menopause for further review. 3.1. The immune and endocrine system The immune system provides the defence against infections, takes control of internal homeostasis and guarantees the recognition of self or non-self, developing mechanisms and strategies of their own protection. Innate immunity is the mechanism of
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resistance to disease which is not specific for any pathogen. It includes: anatomical, physiological, phagocytic and inflammatory barriers. Natural Killer‘s (NK) are cells of the innate immunity system that represent an important line of protection against tumour and infected cells. The adaptive immunity is a mechanism of resistance with a highly specific and great memory competence. It includes the humoral system, in which the contact of an antigen with the lymphoid system stimulates B lymphocytes, resulting in plasma cells and memory cells that produce high amounts of antibodies specific for each antigen, and the cellular response, where T lymphocytes play an important role. Cytokines are regulatory proteins, produced by different cell types acting in an autocrine, endocrine and paracrine way in response to many stimuli. Immune memory is a secondary antibody response that is typically faster and more intense. It is the imbalance between stimulating and inhibiting immunity factors that may lead to disease such as autoimmune‘s diseases and immunodeficiency. The interaction between the endocrine and immune system is based on the observation of several common mechanisms: (1) cells of both systems have receptors to cytokines, neuropeptides and neurotransmitters, (2) immune–neuroendocrine products are found in both systems, (3) endocrine mediators modulate the immune system, and finally (4) immune structures mediators may affect the endocrine system [8]. Steroid hormones may affect the immune response by influence gene expression in cells that have receptors for these hormones [10]. Moreover, immune cells via receptors, may bind to steroids, growth hormone, estradiol and testosterone. The hypothalamic–pituitary–thyroid axis can be inhibited by IL-1, tumor necrosis factor (TNF) and IL6 and the hypothalamic–pituitary–adrenal axis may influence immune function with glucocorticoids suppressing the maturation, differentiation and proliferation of immune cells [9]. The hypothalamic–pituitary axis can also modulate the immune function (Fig. 1). Gonadotropin-releasing hormone (GnRH) is also involved in the process of developing and modulating the immune system [11]. 3.2. Gender and the immune system Females are more prone to autoimmune diseases, although the reasons for this susceptibility are not fully understood. Immunization studies in both mice and humans suggest that females produce higher titter of antibodies, tend to mount more vigorous immune response [10] and have higher levels of CD4+T cells [10,11] and serum Ig M. Sex hormones appear to be partly responsible for the observed differences between genders, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immunesupressors [10–12]. Several physiological, pathological and therapeutic conditions may change the serum estrogens levels including the menstrual cycle, pregnancy, menopause, aging, the use of corticosteroids, oral contraceptives (OC) and hormonal replacement treatment (HRT) and thus induce changes in immunity. The immune response, both cellular and humoral, is modified according to the different phases of the menstrual cycle [13]. The menstrual phase is associated with suppression of NK cells [14]. In the follicular phase there is a domain of the cellular immune response. During the pre-ovulatory period, there is a decrease in cytolytic activity of NK cells [15] and during the luteal phase there is a change in the cellular immune response towards humoral. In humans it appears that estrogens on its own do not play a significant role in the etiology of either Rheumatoid Arthritis (RA) or Multiple Sclerosis (MS), but there are indications that it may be important in Systemic Lupus Erythematosus (SLE). Additionally, androgens play an important role in some autoimmune diseases.
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Fig. 1. Pathways overlaps between the nervous, immune and endocrine systems. ACTH; adrenocorticotropic hormone, CRH: corticotrophin releasing hormone; TNF: tumour necrosis factor; VIP: vasoactive intestinal peptide.
Testosterone may be protective against some several autoimmune diseases such as MS, diabetes, SLE and Sjogren’s syndrome [10]. The suppressive role of progesterone seems to be supported by the knowledge that many autoimmune diseases as RA and MS, may improve during pregnancy and worsen after delivery. By the other hand, LES which has a strong humoral component tends to get worse. Hormonal effects on immune system may not be limited to steroidal sex hormones. Prolactin, which is found in higher levels in women, is another hormone that seems to be implicated in regulation of the immune response. The presence of prolactin receptors on peripheral T and B lymphocytes may reflect the importance of this hormone [10].
also decreased contributing to a greater number of neoplastic and infectious diseases [16]. The inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Therefore, the increasing quantity of free radicals can lead to DNA mutation or other severe cell changes [19]. 3.4. Menopause, estrogen deprivation and the immune system Besides age, in postmenopausal women changes of the immune system have been attributed to estrogen deprivation. In these stage of women’s life there is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increasing response of the body’s cells to these cytokines, a decrease in CD4 T and B lymphocytes and in the cytotoxic activity of NK cells [9,20].
3.3. Aging and the immunologic response Among body’s systems, nervous, endocrine and the immune are the ones that suffers more changes with aging. The immune system undergoes changes in lymphocyte subsets, in cytokines, in immunological tolerance, among other functions [16]. The concept of immunosenescence reflects changes in cellular and humoral immune response specific to foreigner antigens [17]. The natural immune defences of the body are also reduced due to the fragility of the skin and the decrease of antibody produced by mucous membranes. The immune system dysfunction associated with age seems to be related with a higher incidence of infectious and chronic diseases such as hypertension, diabetes mellitus, autoimmune diseases, heart disease and atherosclerosis [16]. These changes are probably associated with several immune alterations occurring when the individual grows older (Table 1): changes in immune tolerance, an increase of autoantibodies; decline in function of NK cells, B lymphocytes and especially the T lymphocytes [18]. Another characteristic of immunosenescence is a chronic state of basal inflammatory activity that may result from increased production of pro-inflammatory cytokines such as IL6, TNF-alfa and free radicals [18,16]. Moreover, molecules like cytokine IL2 and INFgama related to activation and proliferation of T lymphocytes are
Table 1 Frailty in the elderly: some clinical characteristics and biological correlates. Clinical
Biological correlates
Muscle weakness Fatigue Inactivity Slow and/or unsteady gait
Increased blood levels of catabolic cytokines C-reactive protein ↑ Interleukin-6 ↑ Elevated markers of blood coagulation: D-dimer ↑ Factor VIII ↑ Reduced hemoglobin levels Normocytic subclinical anemia
Weight loss Loss of appetite Reduced endurance Impaired cognition
Growth hormone ↓ Insulin-like growth factor-1 ↓ Testosterone ↓ Dehydroepiandrosterone ↓ Estradiol ↓ Cortisol production (especially postmenopausal women) ↑
LH, FSH
Body composition changes: Sarcopenia Osteoporosis Visceral protein decrease: Transthyretin ↓ Retinol-binding protein ↓ Serum albumin ↓
C.M. Gameiro et al. / Maturitas 67 (2010) 316–320 Table 2 Effects of estrogen therapy on inflammation markers.
4. Conclusion and perspective
Marker
Result
Author Refs.
C-reactive protein (CRP)
Increase CRP in healthy women Decrease CRP in women No change in CRP in healthy women Inhibit IL-1 induced expression of CAMs Lower soluble CAMs in healthy women Inhibit MCP-1 expression
[34–40]
Lower soluble MCP-1 in healthy women Inhibit TNF-␣ gene expression Lower soluble TNF-␣ in women Inhibit IL-6 expression Increase soluble IL-6 in healthy women No change in soluble IL-6 in healthy women
[50,52,53]
Cell adhesion molecules (CAMs)
Monocyte chemoattractant protein-1 (MCP-1)
Tumor necrosis factor (TNF)-␣
Interleukin (IL)-6
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[42,43] [36,41] [44,45] [35–37,46–50] [45,51]
[54] [39,55] [45,56] [37,38] [34,39]
Low levels of estrogen and DHEA sulfate in postmenopausal women result in decreased number of cells secreting ITF-G contributing to the decline of immunologic reactivity. A significant increase of cytokines IL-1 and IL-6 were also detected after menopause. Several studies have also shown an increase in circulating levels of IL-6 and TNF-alfa after natural and surgical menopause [21–23]. Consequently, attenuated immune response and higher susceptibility to microbial invasion and infection are more common in postmenopausal women [6,7]. Cytokines are also involved in the mechanisms of ovarian follicle loss, whether it occurs at a normal or accelerated rate. If the immune processes proceed continuously rather than cyclically, premature ovarian failure occurs [24]. Women with premature ovarian failure have decreased NK cells and increased T and B lymphocytes [21]. There are studies relating the increase of pro-inflammatory cytokines and bone loss that arises in postmenopausal women. In fact IL6 is a key factor in bone reabsortion by osteoclast activation and also seems to be associated with other diseases that occur more in menopause such as diabetes, atherosclerosis and cardiovascular diseases [16,25–27]. IL1 and TNF-alfa have also been shown to increase bone reabsortion through indirect or direct modulation of osteoclasts [28]. IL7 is another cytokine that appears to be associated with the increased IL-6 and bone metabolism but more studies are needed to prove it [26]. Hormone therapy in postmenopausal women is effective in alleviating vasomotor symptoms, genital atrophy, and contributes for the inhibition of bone loss. Potentially beneficial effects of hormone therapy on other systems need further investigation being its effects on immune system matter of controversy (Table 2). In addition, recent studies indicate several changes in immune response, either with starting of hormone therapy or with its suspension [29–31]. Epidemiological and clinical studies indicate the normalization of the cellular immune response after hormonal replacement, thus being a potential factor influencing development and course of autoimmune disorders and neoplasms [9,32]. The effects of this therapy on humoral immunity are still inconsistent. Its also seems that soymilk and supplemental isoflavones modulate B cells populations and appear to be protective against DNA damage in postmenopausal women [33].
Gender and its specific hormones influences the immune system, with estrogens as enhancers of the humoral immunity and androgens and progesterone as natural immunesupressors. Thus the effect of steroid hormones should be viewed in a two-way interaction between the immune and endocrine system. The function of the immune system undergoes changes associated with age such as in the subsets of lymphocytes, the patterns of secretion of cytokines, in immunological tolerance, among other functions. This seems to be associated with a higher incidence of infectious and chronic degenerative diseases. Besides age, in postmenopausal women changes in the immune system have been attributed to estrogen deprivation. There is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increasing response of the body’s cells to these cytokines, a decrease in CD4 T and B lymphocytes and in the cytotoxic activity of NK cells. Thus attenuated immune response and higher susceptibility to microbial invasion and infection are characteristic in postmenopausal women. In addition, IL-6 has been related to bone resorption by osteoclast activation and also seems to be associated with other diseases that occur more often in menopause such as diabetes, atherosclerosis and cardiovascular disease. IL7 is another cytokine that might be associated with IL-6 and bone turnover but more studies are needed previously to drawn definitive conclusions. Epidemiological and clinical studies indicate a positive action on cellular immune response of hormonal replacement at menopause, thus being a potential influence on the development and course of autoimmune disorders and neoplasms. However, the exact role of hormone therapy on humoral immunity need further well designed studies. Contributors Cátia Morgado Gameiro: reference search, extracted data from references, design and write the manuscript; Fatima Romão: reference search, review the manuscript; Camil Castelo-Branco: reference search, extracted data from references, assess the eligibility of the trials and design and review the manuscript. Competing interest Camil Castelo-Branco, as corresponding author confirm that either (a) no financial conflict of interest exists with any commercial entity whose products are described, reviewed, evaluated or compared in the manuscript, or (b) a potential conflict of interest exists with one or more commercial entities whose products are described, reviewed, evaluated or compared in the manuscript through the existence of one or more of the following relationships: the author is a full or part-time employee of a company; has an existing or optional equity interest in a company; owns or partly owns patents licensed to a company; has an ongoing retainer relationship (consultantship, speaker, etc.) with a company for which he/she receives financial remuneration; or has received financial compensation for this publication or for the work involved in this publication. Provenance and peer review Not commissioned, externally peer reviewed. References [1] Dennerstein L. Well-being, symptoms and the menopausal transition. Maturitas 1996;23(2):147–57.
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[2] Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burgr HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol Obstet 2000;96(3):351–8. [3] Grossman CJ, Roselle GA, Mendenhall CL. Sex steroid regulation of autoimmunity. J Steroid Biochem Mol Biol 1991;40:649–59. [4] Weiskopf D, Weinbereger B, Grubeck-Loebenstein B. Theaging of the immune system. Transpl Int 2009;22(November (11)):1041–50. [5] Krabbe KS, Pedersen M, Brunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol 2004;39(5):687–99. [6] Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev 1996;17(4):369–84. [7] Medeiros SF, Oliveira VN, Yamamoto MMW. Epidemiologia clínica do climatério. Reprod Clim 2003;18(1):79–86. [8] Basedovsky HO, Del Rey A. Immune–neuro–endocrine interactions: facts and hypotheses. Endocr Rev 1996;17(1):64–102. [9] Medeiros SF, Alexandre M, Nince APB. Efeitos da terapia hormonal na menopausa sobre o sistema imune. Rev Brás Ginecol Obestet 2007;29(11):593–601. [10] Goldsby AR, Kindt JT, Osborne AB.Kuby immunology. Fourth ed. 2000. p. 508–9. Chapter 20. [11] Ho HN, Wu MY, Chen HF, et al. In vivo CD3+CD25+ lymphocyte subpopulation is down-regulated without increased serum-soluble interleukin-2 receptor (sIL-2R) by gonadotropin releasing hormone agonist (GnRH-a). Am J Reprod Immunol 1995;33(1):134–9. [12] Cutolo M, Capellino S, Sulli A, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci 2006;1089(November):538–47. [13] Faas M, Bouman A, Moes H, Heineman MJ, de Leij L, Schuiling G. The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil Steril 2000;74(5):1008–13. [14] Shakhar K, Shakhar G, Rosenne E, Ben-Eliyahu S. Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity. Br J Cancer 2000;83(12):1630–6. [15] White HD, Crassi KM, Givan AL, et al. CD3+CD8+CTL activity within the human female reproductive tract: influence of stage of menstrual cycle and menopause. J Immunol 1997;158(6):3017–27. [16] Tonet AC, Nóbrega OT. Immunosenescence: the association between leukocytes, cytokines and chronic diseases. Rev Bras Geriatr Gerontol 2008;11(2):259–73. [17] Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int 2009;22(November (11)):1041–50. Epub 2009 July 16. [18] Grolleau- Julius A, Ray D, Yung RL. The role of epigenetics in agin and autoimmunity. Clin Rev Allergy Immunol 2010;39(August (1)): 42–50. [19] Khansari N, Shakiba Y, Mahmoidi M. Chronic inflammation and oxidative stress as a major cause of age-related disease and cancer. Recent Pat Inflamm Allergy Drug Discov 2009;3(1):73–80. [20] Giglio T, Imro MA, Filaci G, et al. Immune cell circulating subsets are affected by gonadal function. Life Sci 1994;54(18):1305–12. [21] Kamada M, Irahara M, Maegawa M, et al. Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am J Obstet Gynecol 2001;184(3):309–14. [22] Yasui T, Maegawa M, Tomita J, et al. Changes in serum cytokine concentrations during the menopausal transition. Maturitas 2007;56(4):396–403. [23] Cioffi M, Esposito K, Vietri MT, et al. Cytocine patern in postmenopauce. Maturitas 2002;41:187–92. [24] Coulam CB, Stern JJ. Immunology of ovarian failure. Am J Reprod Immunol 1991;25(4):169–74. [25] Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev 2002;23(1):90–119. [26] Toshiyuki Y, Hirokazu U, Masayo Y, et al. Associations of interleukin-6 with interleukin 1Beta, interleukin-8 and macrophage inflammatory protein 1Beta in midlife women. Cytokine 2008;41:302–6. [27] William B, Ershler S, Harman M, Even T. Immunologic aspects of osteoporosis. Dev Comp Immunol 1997;21:487–99. [28] Pacifici R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996;11:1043–51. [29] Straub RH, Hense HW, Andus T, Scholmerich J, Riegger GA, Schunkert H. Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study. J Clin Endocrinol Metab 2000;85(3):1340–4. [30] Brooks-Asplund EM, Tupper CE, Daun JM, Kenney WL, Cannon JG. Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women. Cytokine 2002;19(4): 193–200. [31] Blum M, Zacharovich D, Pery J, KitAi E. Lowering effect of estrogen replacement treatment on immunoglobolins in menopausal women. Rev Fr Gynecol Obstet 1990;85(4):207–9.
[32] Stopinska-Gluszack U, Waligóra J, Grazela T, et al. Effect of estrogen/progesterone hormone replacement therapy on natural killer cell cytotoxicity and immunoregulatory cytokine release by peripheral blood mononuclear cells of postmenopausal womem. J Reprod Immunol 2006;69(1):65–75. [33] Ryan-Borchers TA, Park JS, Chew BP, McGuire MK, Fournier LR, Beerman KA. Soy isoflavones modulate immune function in helthy postmenopausal women. Am J Clin Nutr 2006;83(5):1118–25. [34] Koh KK, Schenke WH, Waclawiw M, Csako G, Cannon III RO. Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women. Circulation 2002;105:1531–3. [35] Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins. The postmenopausal estrogen/progestin interventions (PEPI) study. Circulation 1999;100:717–22. [36] Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001;85:619–25. [37] Herrington DM, Brosnihan KB, Pusser BE, et al. Differential effects of estrogen and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001;86:4216–22. [38] Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999;19:893–9. [39] Walsh BW, Cox DA, Sashegyi A, Dean RA, Tracy RP, Anderson PW. Role of tumor necrosis factor-␣ and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women. Am J Cardiol 2001;88:825–8. [40] Silvestri A, Gebara O, Vitale C, et al. Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 2003;107:3165–9. [41] Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation 2002;106:1224–8. [42] Sattar N, Perera M, Small M, Lumsden MA. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet 1999;354:487–8. [43] Modena MG, Bursi F, Fantini G, et al. Low-grade inflammation and estimates of insulin resistance during the menstrual cycle in lean and overweight women. J Clin Endocrinol Metab 2005;90:3230–5. [44] Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest 1996;98:36–42. [45] Miller AP, Feng W, Xing D, et al. Estrogen modulates inflammatory mediator expression and neutrophil chemotaxis in injured arteries. Circulation 2004;110:1664–9. [46] Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002;105:1436–9. [47] Lamon-Fava S, Posfai B, Schaefer EJ. Effect of hormonal replacement therapy on C-reactive protein and cell-adhesion molecules in postmenopausal women. Am J Cardiol 2003;91:252–4. [48] Koh KK, Bui MN, Mincemoyer R, Cannon III RO. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol 1997;80:1505–7. [49] Koh KK, Blum A, Hathaway L, et al. Vascular effects of estrogen and vitamin E therapies in postmenopausal women. Circulation 1999;100:1851–7. [50] Koh KK, Jin DK, Yang SH, et al. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001;103:1961–6. [51] Pervin S, Singh R, Rosenfeld ME, Navab M, Chaudhuri G, Nathan L. Estradiol suppresses MCP-1 expression in vivo: implications for atherosclerosis. Arterioscler Thromb Vasc Biol 1998;18:1575–82. [52] Stork S, Baumann K, von Schacky C, Angerer P. The effect of 17 betaestradiol on MCP-1 serum levels in postmenopausal women. Cardiovasc Res 2002;53:642–9. [53] Koh KK, Son JW, Jin DK, et al. Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels. Int J Cardiol 2001;81:43–50. [54] Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R. Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J Clin Invest 1999;104:503–13. [55] Koh KK, Ahn JY, Jin DK, et al. Effects of continuous combined hormone replacement therapy on inflammation in hypertensive and/or overweight postmenopausal women. Arterioscler Thromb Vasc Biol 2002;22:1459–64. [56] Sukovich DA, Kauser K, Shirley FD, DelVecchio V, Halks-Miller M, Rubanyi GM. Expression of interleukin-6 in atherosclerotic lesions of male apoE-knockout mice. Arterioscler Thromb Vasc Biol 1998;18:1498–505.
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Menopause and aging: Changes in the immune system—A review Cátia Morgado Gameiro a , Fatima Romão a , Camil Castelo-Branco b,∗ a
Department of Gynaecology and Obstetrics, Garcia de Orta’s Hospital, Almada, Portugal Clinic Institute of Gynecology, Obstetrics and Neonatology, Faculty of Medicine-University of Barcelona, Hospital Clinic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 28 June 2010 Received in revised form 3 August 2010 Accepted 10 August 2010
Keywords: Menopause Sex steroids Immune system Cytokines Aging Immunosenescence
a b s t r a c t Background: The higher risk of women developing autoimmune diseases suggests that immune system is mediated by sex steroids. Objective: To review the effects of aging and menopause in immune system. Methods: A systematic review of in vitro, animal and human studies involving aging and menopause and immune system was carried out. An electronic search based on Internet search engines, MEDLINE (1966–June 2010) and the Cochrane Controlled Clinical Trials Register was done. Results: After crossing-cleaning the reference lists, a total of 688 studies dealing with immune system and menopause were identified. Of them, 30 were considered selectable. The concept of immunosenescence reflects changes in both cellular and serological immune responses throughout the process of generating specific response to foreign antigens. This may be related with a higher incidence of infectious and chronic diseases. After menopause, there is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increase in response of the immune blood cells to these cytokines, a decrease in CD4 T and B lymphocytes and a decrease in the cytotoxic activity of NK cells. Additionally, IL-6 is a key factor in bone resorption and also seems to be associated with other diseases more common after menopause such as diabetes, atherosclerosis and cardiovascular disease. Conclusions: Most of the studies suggested that in addition to age, in postmenopausal women, changes of the immune system have been attributed to estrogen deprivation. Furthermore, recent studies point out changes in immune response related to use or cessation of hormone replacement at menopause. © 2010 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The immune and endocrine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Gender and the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Aging and the immunologic response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Menopause, estrogen deprivation and the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Institut Clínic de Ginecologia, Obstetrícia i Neonatología, University of Barcelona, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 93 227 54 36; fax: +34 93 227 93 25. E-mail address: [email protected] (C. Castelo-Branco). 0378-5122/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2010.08.003
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1. Introduction Climacteric complaints vary significantly among countries, with North American and European people reporting higher rates of symptoms than Asian women [1,2]. The fact that gender influences the immune system has long been recognised. The difference between both sexes has many explanations, such as an influence of sex hormones and an influence of different endocrine pathways [3]. The higher risk of women developing autoimmune diseases suggests that these diseases are somehow mediated by sex steroids. The concept of immunosenescence reflects changes in the cellular and humoral immune response and throughout the process of generating specific response to the foreign antigens [4]. The natural immune defences of the organism are also reduced because of the fragility of the skin and decrease of the production of antibodies. The dysfunction of the immune system associated with age may be reflected in a higher incidence of infectious and chronic diseases [5]. Accordingly, low levels of estrogen, observed in castrated animals or in postmenopausal women, have been shown to mitigate the immune response and predispose to disease and infection [6,7]. In this review, an attempt is made to summarize the major published reports on the relationship between immune system and aging and menopause and to emphasize points that still need further clarification and additional research. 2. Material and methods 2.1. Search design A systematic review of in vitro, animal and human studies involving immune system and menopause was carried out. To identify all of the articles that describe a relationship between immune system and menopause, the following search strategy was designed: (aging OR gender medicine OR menopause) and immune system. This strategy was adapted and applied to different Internet search engines, to the MEDLINE database (1966–June 2010) and the Cochrane Controlled Trials Register. There was no language or date restriction. This search was further supplemented by a hand-search of reference lists of selected review papers. One reviewer (CCB) independently evaluated the eligibility of the trials. One reviewer (CMG) extracted the data from the selected articles using a prefixed protocol (information was gathered on the characteristics of participants in the trial, the intervention and how the results were measured). Of the reviewed articles, those that did not establish a relationship between menopause and immune system, literature reviews or those whose purpose was not to demonstrate a therapeutic impact were not considered. Finally an additional search of articles dealing with hormone replacement during menopause and inflammation markers retrieved 22 additional articles. 3. Results After crossing-cleaning the reference lists, a total of 688 studies dealing with immune system and menopause were identified. Of them, 30 were considered selectable and were allocated according their focus in one of the following topics: immune system and endocrine system, gender, aging and menopause for further review. 3.1. The immune and endocrine system The immune system provides the defence against infections, takes control of internal homeostasis and guarantees the recognition of self or non-self, developing mechanisms and strategies of their own protection. Innate immunity is the mechanism of
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resistance to disease which is not specific for any pathogen. It includes: anatomical, physiological, phagocytic and inflammatory barriers. Natural Killer‘s (NK) are cells of the innate immunity system that represent an important line of protection against tumour and infected cells. The adaptive immunity is a mechanism of resistance with a highly specific and great memory competence. It includes the humoral system, in which the contact of an antigen with the lymphoid system stimulates B lymphocytes, resulting in plasma cells and memory cells that produce high amounts of antibodies specific for each antigen, and the cellular response, where T lymphocytes play an important role. Cytokines are regulatory proteins, produced by different cell types acting in an autocrine, endocrine and paracrine way in response to many stimuli. Immune memory is a secondary antibody response that is typically faster and more intense. It is the imbalance between stimulating and inhibiting immunity factors that may lead to disease such as autoimmune‘s diseases and immunodeficiency. The interaction between the endocrine and immune system is based on the observation of several common mechanisms: (1) cells of both systems have receptors to cytokines, neuropeptides and neurotransmitters, (2) immune–neuroendocrine products are found in both systems, (3) endocrine mediators modulate the immune system, and finally (4) immune structures mediators may affect the endocrine system [8]. Steroid hormones may affect the immune response by influence gene expression in cells that have receptors for these hormones [10]. Moreover, immune cells via receptors, may bind to steroids, growth hormone, estradiol and testosterone. The hypothalamic–pituitary–thyroid axis can be inhibited by IL-1, tumor necrosis factor (TNF) and IL6 and the hypothalamic–pituitary–adrenal axis may influence immune function with glucocorticoids suppressing the maturation, differentiation and proliferation of immune cells [9]. The hypothalamic–pituitary axis can also modulate the immune function (Fig. 1). Gonadotropin-releasing hormone (GnRH) is also involved in the process of developing and modulating the immune system [11]. 3.2. Gender and the immune system Females are more prone to autoimmune diseases, although the reasons for this susceptibility are not fully understood. Immunization studies in both mice and humans suggest that females produce higher titter of antibodies, tend to mount more vigorous immune response [10] and have higher levels of CD4+T cells [10,11] and serum Ig M. Sex hormones appear to be partly responsible for the observed differences between genders, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immunesupressors [10–12]. Several physiological, pathological and therapeutic conditions may change the serum estrogens levels including the menstrual cycle, pregnancy, menopause, aging, the use of corticosteroids, oral contraceptives (OC) and hormonal replacement treatment (HRT) and thus induce changes in immunity. The immune response, both cellular and humoral, is modified according to the different phases of the menstrual cycle [13]. The menstrual phase is associated with suppression of NK cells [14]. In the follicular phase there is a domain of the cellular immune response. During the pre-ovulatory period, there is a decrease in cytolytic activity of NK cells [15] and during the luteal phase there is a change in the cellular immune response towards humoral. In humans it appears that estrogens on its own do not play a significant role in the etiology of either Rheumatoid Arthritis (RA) or Multiple Sclerosis (MS), but there are indications that it may be important in Systemic Lupus Erythematosus (SLE). Additionally, androgens play an important role in some autoimmune diseases.
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Fig. 1. Pathways overlaps between the nervous, immune and endocrine systems. ACTH; adrenocorticotropic hormone, CRH: corticotrophin releasing hormone; TNF: tumour necrosis factor; VIP: vasoactive intestinal peptide.
Testosterone may be protective against some several autoimmune diseases such as MS, diabetes, SLE and Sjogren’s syndrome [10]. The suppressive role of progesterone seems to be supported by the knowledge that many autoimmune diseases as RA and MS, may improve during pregnancy and worsen after delivery. By the other hand, LES which has a strong humoral component tends to get worse. Hormonal effects on immune system may not be limited to steroidal sex hormones. Prolactin, which is found in higher levels in women, is another hormone that seems to be implicated in regulation of the immune response. The presence of prolactin receptors on peripheral T and B lymphocytes may reflect the importance of this hormone [10].
also decreased contributing to a greater number of neoplastic and infectious diseases [16]. The inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Therefore, the increasing quantity of free radicals can lead to DNA mutation or other severe cell changes [19]. 3.4. Menopause, estrogen deprivation and the immune system Besides age, in postmenopausal women changes of the immune system have been attributed to estrogen deprivation. In these stage of women’s life there is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increasing response of the body’s cells to these cytokines, a decrease in CD4 T and B lymphocytes and in the cytotoxic activity of NK cells [9,20].
3.3. Aging and the immunologic response Among body’s systems, nervous, endocrine and the immune are the ones that suffers more changes with aging. The immune system undergoes changes in lymphocyte subsets, in cytokines, in immunological tolerance, among other functions [16]. The concept of immunosenescence reflects changes in cellular and humoral immune response specific to foreigner antigens [17]. The natural immune defences of the body are also reduced due to the fragility of the skin and the decrease of antibody produced by mucous membranes. The immune system dysfunction associated with age seems to be related with a higher incidence of infectious and chronic diseases such as hypertension, diabetes mellitus, autoimmune diseases, heart disease and atherosclerosis [16]. These changes are probably associated with several immune alterations occurring when the individual grows older (Table 1): changes in immune tolerance, an increase of autoantibodies; decline in function of NK cells, B lymphocytes and especially the T lymphocytes [18]. Another characteristic of immunosenescence is a chronic state of basal inflammatory activity that may result from increased production of pro-inflammatory cytokines such as IL6, TNF-alfa and free radicals [18,16]. Moreover, molecules like cytokine IL2 and INFgama related to activation and proliferation of T lymphocytes are
Table 1 Frailty in the elderly: some clinical characteristics and biological correlates. Clinical
Biological correlates
Muscle weakness Fatigue Inactivity Slow and/or unsteady gait
Increased blood levels of catabolic cytokines C-reactive protein ↑ Interleukin-6 ↑ Elevated markers of blood coagulation: D-dimer ↑ Factor VIII ↑ Reduced hemoglobin levels Normocytic subclinical anemia
Weight loss Loss of appetite Reduced endurance Impaired cognition
Growth hormone ↓ Insulin-like growth factor-1 ↓ Testosterone ↓ Dehydroepiandrosterone ↓ Estradiol ↓ Cortisol production (especially postmenopausal women) ↑
LH, FSH
Body composition changes: Sarcopenia Osteoporosis Visceral protein decrease: Transthyretin ↓ Retinol-binding protein ↓ Serum albumin ↓
C.M. Gameiro et al. / Maturitas 67 (2010) 316–320 Table 2 Effects of estrogen therapy on inflammation markers.
4. Conclusion and perspective
Marker
Result
Author Refs.
C-reactive protein (CRP)
Increase CRP in healthy women Decrease CRP in women No change in CRP in healthy women Inhibit IL-1 induced expression of CAMs Lower soluble CAMs in healthy women Inhibit MCP-1 expression
[34–40]
Lower soluble MCP-1 in healthy women Inhibit TNF-␣ gene expression Lower soluble TNF-␣ in women Inhibit IL-6 expression Increase soluble IL-6 in healthy women No change in soluble IL-6 in healthy women
[50,52,53]
Cell adhesion molecules (CAMs)
Monocyte chemoattractant protein-1 (MCP-1)
Tumor necrosis factor (TNF)-␣
Interleukin (IL)-6
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[42,43] [36,41] [44,45] [35–37,46–50] [45,51]
[54] [39,55] [45,56] [37,38] [34,39]
Low levels of estrogen and DHEA sulfate in postmenopausal women result in decreased number of cells secreting ITF-G contributing to the decline of immunologic reactivity. A significant increase of cytokines IL-1 and IL-6 were also detected after menopause. Several studies have also shown an increase in circulating levels of IL-6 and TNF-alfa after natural and surgical menopause [21–23]. Consequently, attenuated immune response and higher susceptibility to microbial invasion and infection are more common in postmenopausal women [6,7]. Cytokines are also involved in the mechanisms of ovarian follicle loss, whether it occurs at a normal or accelerated rate. If the immune processes proceed continuously rather than cyclically, premature ovarian failure occurs [24]. Women with premature ovarian failure have decreased NK cells and increased T and B lymphocytes [21]. There are studies relating the increase of pro-inflammatory cytokines and bone loss that arises in postmenopausal women. In fact IL6 is a key factor in bone reabsortion by osteoclast activation and also seems to be associated with other diseases that occur more in menopause such as diabetes, atherosclerosis and cardiovascular diseases [16,25–27]. IL1 and TNF-alfa have also been shown to increase bone reabsortion through indirect or direct modulation of osteoclasts [28]. IL7 is another cytokine that appears to be associated with the increased IL-6 and bone metabolism but more studies are needed to prove it [26]. Hormone therapy in postmenopausal women is effective in alleviating vasomotor symptoms, genital atrophy, and contributes for the inhibition of bone loss. Potentially beneficial effects of hormone therapy on other systems need further investigation being its effects on immune system matter of controversy (Table 2). In addition, recent studies indicate several changes in immune response, either with starting of hormone therapy or with its suspension [29–31]. Epidemiological and clinical studies indicate the normalization of the cellular immune response after hormonal replacement, thus being a potential factor influencing development and course of autoimmune disorders and neoplasms [9,32]. The effects of this therapy on humoral immunity are still inconsistent. Its also seems that soymilk and supplemental isoflavones modulate B cells populations and appear to be protective against DNA damage in postmenopausal women [33].
Gender and its specific hormones influences the immune system, with estrogens as enhancers of the humoral immunity and androgens and progesterone as natural immunesupressors. Thus the effect of steroid hormones should be viewed in a two-way interaction between the immune and endocrine system. The function of the immune system undergoes changes associated with age such as in the subsets of lymphocytes, the patterns of secretion of cytokines, in immunological tolerance, among other functions. This seems to be associated with a higher incidence of infectious and chronic degenerative diseases. Besides age, in postmenopausal women changes in the immune system have been attributed to estrogen deprivation. There is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increasing response of the body’s cells to these cytokines, a decrease in CD4 T and B lymphocytes and in the cytotoxic activity of NK cells. Thus attenuated immune response and higher susceptibility to microbial invasion and infection are characteristic in postmenopausal women. In addition, IL-6 has been related to bone resorption by osteoclast activation and also seems to be associated with other diseases that occur more often in menopause such as diabetes, atherosclerosis and cardiovascular disease. IL7 is another cytokine that might be associated with IL-6 and bone turnover but more studies are needed previously to drawn definitive conclusions. Epidemiological and clinical studies indicate a positive action on cellular immune response of hormonal replacement at menopause, thus being a potential influence on the development and course of autoimmune disorders and neoplasms. However, the exact role of hormone therapy on humoral immunity need further well designed studies. Contributors Cátia Morgado Gameiro: reference search, extracted data from references, design and write the manuscript; Fatima Romão: reference search, review the manuscript; Camil Castelo-Branco: reference search, extracted data from references, assess the eligibility of the trials and design and review the manuscript. Competing interest Camil Castelo-Branco, as corresponding author confirm that either (a) no financial conflict of interest exists with any commercial entity whose products are described, reviewed, evaluated or compared in the manuscript, or (b) a potential conflict of interest exists with one or more commercial entities whose products are described, reviewed, evaluated or compared in the manuscript through the existence of one or more of the following relationships: the author is a full or part-time employee of a company; has an existing or optional equity interest in a company; owns or partly owns patents licensed to a company; has an ongoing retainer relationship (consultantship, speaker, etc.) with a company for which he/she receives financial remuneration; or has received financial compensation for this publication or for the work involved in this publication. Provenance and peer review Not commissioned, externally peer reviewed. References [1] Dennerstein L. Well-being, symptoms and the menopausal transition. Maturitas 1996;23(2):147–57.
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[2] Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burgr HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol Obstet 2000;96(3):351–8. [3] Grossman CJ, Roselle GA, Mendenhall CL. Sex steroid regulation of autoimmunity. J Steroid Biochem Mol Biol 1991;40:649–59. [4] Weiskopf D, Weinbereger B, Grubeck-Loebenstein B. Theaging of the immune system. Transpl Int 2009;22(November (11)):1041–50. [5] Krabbe KS, Pedersen M, Brunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol 2004;39(5):687–99. [6] Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev 1996;17(4):369–84. [7] Medeiros SF, Oliveira VN, Yamamoto MMW. Epidemiologia clínica do climatério. Reprod Clim 2003;18(1):79–86. [8] Basedovsky HO, Del Rey A. Immune–neuro–endocrine interactions: facts and hypotheses. Endocr Rev 1996;17(1):64–102. [9] Medeiros SF, Alexandre M, Nince APB. Efeitos da terapia hormonal na menopausa sobre o sistema imune. Rev Brás Ginecol Obestet 2007;29(11):593–601. [10] Goldsby AR, Kindt JT, Osborne AB.Kuby immunology. Fourth ed. 2000. p. 508–9. Chapter 20. [11] Ho HN, Wu MY, Chen HF, et al. In vivo CD3+CD25+ lymphocyte subpopulation is down-regulated without increased serum-soluble interleukin-2 receptor (sIL-2R) by gonadotropin releasing hormone agonist (GnRH-a). Am J Reprod Immunol 1995;33(1):134–9. [12] Cutolo M, Capellino S, Sulli A, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci 2006;1089(November):538–47. [13] Faas M, Bouman A, Moes H, Heineman MJ, de Leij L, Schuiling G. The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil Steril 2000;74(5):1008–13. [14] Shakhar K, Shakhar G, Rosenne E, Ben-Eliyahu S. Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity. Br J Cancer 2000;83(12):1630–6. [15] White HD, Crassi KM, Givan AL, et al. CD3+CD8+CTL activity within the human female reproductive tract: influence of stage of menstrual cycle and menopause. J Immunol 1997;158(6):3017–27. [16] Tonet AC, Nóbrega OT. Immunosenescence: the association between leukocytes, cytokines and chronic diseases. Rev Bras Geriatr Gerontol 2008;11(2):259–73. [17] Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int 2009;22(November (11)):1041–50. Epub 2009 July 16. [18] Grolleau- Julius A, Ray D, Yung RL. The role of epigenetics in agin and autoimmunity. Clin Rev Allergy Immunol 2010;39(August (1)): 42–50. [19] Khansari N, Shakiba Y, Mahmoidi M. Chronic inflammation and oxidative stress as a major cause of age-related disease and cancer. Recent Pat Inflamm Allergy Drug Discov 2009;3(1):73–80. [20] Giglio T, Imro MA, Filaci G, et al. Immune cell circulating subsets are affected by gonadal function. Life Sci 1994;54(18):1305–12. [21] Kamada M, Irahara M, Maegawa M, et al. Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am J Obstet Gynecol 2001;184(3):309–14. [22] Yasui T, Maegawa M, Tomita J, et al. Changes in serum cytokine concentrations during the menopausal transition. Maturitas 2007;56(4):396–403. [23] Cioffi M, Esposito K, Vietri MT, et al. Cytocine patern in postmenopauce. Maturitas 2002;41:187–92. [24] Coulam CB, Stern JJ. Immunology of ovarian failure. Am J Reprod Immunol 1991;25(4):169–74. [25] Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev 2002;23(1):90–119. [26] Toshiyuki Y, Hirokazu U, Masayo Y, et al. Associations of interleukin-6 with interleukin 1Beta, interleukin-8 and macrophage inflammatory protein 1Beta in midlife women. Cytokine 2008;41:302–6. [27] William B, Ershler S, Harman M, Even T. Immunologic aspects of osteoporosis. Dev Comp Immunol 1997;21:487–99. [28] Pacifici R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996;11:1043–51. [29] Straub RH, Hense HW, Andus T, Scholmerich J, Riegger GA, Schunkert H. Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study. J Clin Endocrinol Metab 2000;85(3):1340–4. [30] Brooks-Asplund EM, Tupper CE, Daun JM, Kenney WL, Cannon JG. Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women. Cytokine 2002;19(4): 193–200. [31] Blum M, Zacharovich D, Pery J, KitAi E. Lowering effect of estrogen replacement treatment on immunoglobolins in menopausal women. Rev Fr Gynecol Obstet 1990;85(4):207–9.
[32] Stopinska-Gluszack U, Waligóra J, Grazela T, et al. Effect of estrogen/progesterone hormone replacement therapy on natural killer cell cytotoxicity and immunoregulatory cytokine release by peripheral blood mononuclear cells of postmenopausal womem. J Reprod Immunol 2006;69(1):65–75. [33] Ryan-Borchers TA, Park JS, Chew BP, McGuire MK, Fournier LR, Beerman KA. Soy isoflavones modulate immune function in helthy postmenopausal women. Am J Clin Nutr 2006;83(5):1118–25. [34] Koh KK, Schenke WH, Waclawiw M, Csako G, Cannon III RO. Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women. Circulation 2002;105:1531–3. [35] Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins. The postmenopausal estrogen/progestin interventions (PEPI) study. Circulation 1999;100:717–22. [36] Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001;85:619–25. [37] Herrington DM, Brosnihan KB, Pusser BE, et al. Differential effects of estrogen and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001;86:4216–22. [38] Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999;19:893–9. [39] Walsh BW, Cox DA, Sashegyi A, Dean RA, Tracy RP, Anderson PW. Role of tumor necrosis factor-␣ and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women. Am J Cardiol 2001;88:825–8. [40] Silvestri A, Gebara O, Vitale C, et al. Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 2003;107:3165–9. [41] Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation 2002;106:1224–8. [42] Sattar N, Perera M, Small M, Lumsden MA. Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet 1999;354:487–8. [43] Modena MG, Bursi F, Fantini G, et al. Low-grade inflammation and estimates of insulin resistance during the menstrual cycle in lean and overweight women. J Clin Endocrinol Metab 2005;90:3230–5. [44] Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest 1996;98:36–42. [45] Miller AP, Feng W, Xing D, et al. Estrogen modulates inflammatory mediator expression and neutrophil chemotaxis in injured arteries. Circulation 2004;110:1664–9. [46] Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002;105:1436–9. [47] Lamon-Fava S, Posfai B, Schaefer EJ. Effect of hormonal replacement therapy on C-reactive protein and cell-adhesion molecules in postmenopausal women. Am J Cardiol 2003;91:252–4. [48] Koh KK, Bui MN, Mincemoyer R, Cannon III RO. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol 1997;80:1505–7. [49] Koh KK, Blum A, Hathaway L, et al. Vascular effects of estrogen and vitamin E therapies in postmenopausal women. Circulation 1999;100:1851–7. [50] Koh KK, Jin DK, Yang SH, et al. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001;103:1961–6. [51] Pervin S, Singh R, Rosenfeld ME, Navab M, Chaudhuri G, Nathan L. Estradiol suppresses MCP-1 expression in vivo: implications for atherosclerosis. Arterioscler Thromb Vasc Biol 1998;18:1575–82. [52] Stork S, Baumann K, von Schacky C, Angerer P. The effect of 17 betaestradiol on MCP-1 serum levels in postmenopausal women. Cardiovasc Res 2002;53:642–9. [53] Koh KK, Son JW, Jin DK, et al. Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels. Int J Cardiol 2001;81:43–50. [54] Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R. Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J Clin Invest 1999;104:503–13. [55] Koh KK, Ahn JY, Jin DK, et al. Effects of continuous combined hormone replacement therapy on inflammation in hypertensive and/or overweight postmenopausal women. Arterioscler Thromb Vasc Biol 2002;22:1459–64. [56] Sukovich DA, Kauser K, Shirley FD, DelVecchio V, Halks-Miller M, Rubanyi GM. Expression of interleukin-6 in atherosclerotic lesions of male apoE-knockout mice. Arterioscler Thromb Vasc Biol 1998;18:1498–505.