Association of serum complement (C3, C4) and immunoglobulin (IgG, IgM) levels with hormone replacement therapy in healthy post‐menopausal women

Human Reproduction Association of serum complement (C3, C4) and immunoglobulin (IgG, IgM) levels with hormone replacement therapy in healthy post-menopausal women Mehmet Yilmazer 2 4 Veysel Fenkci 2 4 Semin Fenkci 1 4 Orhan Aktepe 0 4 Murat Sonmezer 3 4 Gulay Kurtay 3 4 0 Department of Microbiology, Afyon Kocatepe University, Faculty of Medicine , Afyon 1 Department of Internal Medicine 2 Department of Obstetrics and Gynecology 3 Department of Obstetrics and Gynecology, Ankara University, Faculty of Medicine , Ankara , Turkey 4 Serum levels of C3 , C4, IgG and IgM during HRT BACKGROUND: Recently published data suggest that hormone replacement therapy (HRT) may increase cardiovascular risk during the early months of therapy. Activation of the immune system is known to be involved in several types of cardiovascular disease. In this cross-sectional study, serum C3, C4, IgG and IgM levels were evaluated in healthy post-menopausal women receiving two different short-term HRT regimens, and in untreated women. METHODS: Serum C3, C4, IgM and IgG levels were assessed in 18 women receiving transdermal 17b-estradiol (50 mg/day) + continuous oral medroxyprogesterone acetate (MPA; 2.5 mg/day), in 56 women taking oral conjugated equine estrogen (CEE; 0.625 mg/day) + continuous MPA, and in 80 control women not receiving HRT. RESULTS: The mean serum C3 level was signicantly higher in women using oral CEE + MPA than in women receiving transdermal 17b-estradiol + MPA, and those not on HRT (P = 0.02 and P < 0.001 respectively). Furthermore, women taking oral CEE + MPA had signicantly higher mean levels of C4 compared with untreated women (P < 0.01). IgG and IgM levels were similar among women either of the two HRT regimens and between women not on HRT. CONCLUSIONS: Oral HRT may be involved in the development of cardiovascular disease through inammatory mechanisms, as suggested by increased serum levels of C3 and C4. C3/C4/hormone replacement therapy/immunoglobulin G/immunoglobulin M Introduction Hormone replacement therapy (HRT) relieves menopausal symptoms such as hot ashes and vaginal atrophy, and also prevents osteoporosis in post-menopausal women (Yasui et al., 2000). Numerous epidemiological studies have suggested that HRT reduces the risk of cardiovascular disease in postmenopausal women (Grodstein et al., 1997; Barret-Connor and Grady, 1998). In contrast, a pooled analysis of short-term randomized clinical trials indicated adverse effects, with a relative risk of 1.39 for cardiovascular events (Hemminki and McPherson, 1997). The recently published Women's Health Initiative (WHI) study showed that the proportion of women experiencing coronary heart diseases was increased by 29% for women taking estrogen plus progestin relative to placebo (Rossouw et al., 2002). The mechanism responsible for the increased cardiovascular risk with HRT use is unclear, but it has been hypothesized that this could be mediated in part through an effect on the inammatory system, which is intensely involved in cardiovascular disease (Ross, 1999). The complement system and immunoglobulins are the main components of humoral immunity. The activation of complement is known to be involved in a number of forms of cardiovascular disease. The results of some clinical studies have suggested that complement activation exacerbates myocardial defect following ischaemic injury (Gardinali et al., 1995), is involved in the generation of spontaneous atherosclerotic lesions (Seifert and Kazatchkine, 1988), and may indeed be an initiating factor in lesion formation (Torzewski et al., 1996). C3, the third complement component, is a cytokine and is produced by activated macrophages (Zimmer et al., 1982), which are the cells mainly concerned with the development of atherosclerotic plaques (Libby, 1995). Previous studies have indicated that serum C3 is a powerful indicator of the risk of myocardial infarction (Muscari et al., 1995; 1998; 2000). Furthermore, there is some evidence suggesting that patients with established atherosclerosis have elevated levels of IgA, IgE, IgG and IgM (Criqui et al., 1987; Muscari et al., 1988). Moreover, elevated levels of IgA, IgE Characteristic Age (years) Duration of amenorrhoea (years) 49.9 6 4.9 (4162) 4.1 6 4.5 (120) 51.9 6 5.1 (4662) 4.8 6 5.3 (118) 4.8 6 2.5 (39) 27.6 6 3.5 (22.432.6) 64.5 6 25.6 (31109) 19.7 6 10.8 (030) 27.6 6 3.8 (22.631.5) 52.5 6 20.6 (2287) 50.2 6 24.2 (21108)c 48.6 6 4.7 (4161)a 3.2 6 3.6 (120) 5.8 6 2.7 (39) 26.8 6 2.8 (22.833.4) 34.7 6 18.0 (1390)b 64.3 6 33.7 (12122)d Values are mean 6 SD (range). aP < 0.05, difference between women receiving CEE + MPA and women receiving 17b-E2 + MPA. bP < 0.05, versus 17b-E2 + MPA group and control group. cP < 0.01, versus control group. dP < 0.001, versus control group. BMI = body-mass index; CEE = conjugated equine estrogen; HRT = hormone replacement therapy; MPA = medroxyprogesterone acetate; 17b-E2 = 17b-estradiol. and IgG are predictive of myocardial infarction (Kovanen et al., 1998). In the present study, serum concentrations of complement (C3, C4), and immunoglobulin (IgM, IgG) were investigated in women treated with two different short-term HRT regimens for menopausal hormone deciency symptoms, and in untreated women. To the best of the present authors' knowledge, this is the rst study to determine the impact of HRT on serum complement (C3, C4) and immunoglobulin (IgM, IgG) levels. Materials and methods A total of 154 healthy post-menopausal patients aged between 41 and 62 years was enrolled in this cross-sectional study between October 2000 and March 2002. All the participating post-menopausal women were normotensive (blood pressure <140/90 mmHg), non-hysterectomized, and had been menopausal for at least 12 months before entering the study. Informed consent was obtained from all women before participating in the study. Women with a history of cardiovascular, rheumatismal, autoimmune and malignant diseases, with acute or chronic infection, and those with a clinically relevant abnormality in laboratory tests of haematological, renal and hepatic functions were excluded from participation. Patients with a body mass index (BMI) >35 kg/m2, caffeine consumption in excess of the equivalent of three cups of coffee per day, or who had been operated on within the past 6 months were also excluded. Additional exclusions included those women who had smoked cigarettes within the past year, had a medical history suggesting a possible contraindication to hormone use, a history of corticosteroid or any immunosuppressor drug use during the previous month. Those women with a plasma triglyceride level >200 mg/dl and total cholesterol level >240 mg/dl were also excluded. In order to investigate the impact of short-term HRT use on the immune system, patients receiving oral or transdermal HRT for a duration of 39 months were involved in the study. For the analyses, 74 women receiving HRT were divided into two groups: group 1 (n (...truncated)