Abstract
Purpose
Low cholesterol levels and statin drugs may protect against prostate cancer with a worse prognosis. Their protective mechanism is unknown, but has been hypothesized to be related to cholesterol’s role as a sex steroid hormone precursor. We evaluated whether serum testosterone and estradiol differ by cholesterol or cholesterol-lowering drug use.
Materials and methods
Testosterone and estradiol were measured for 1,457 male participants in the Third National Health and Nutrition Examination Survey. We estimated multivariable-adjusted geometric mean hormone concentration by quintiles of cholesterol concentration and by cholesterol-lowering drugs use.
Results
Across quintiles of cholesterol, testosterone level did not differ (mean, 95% confidence interval (CI); Q1: 5.25, 5.02–5.49, Q5: 5.05, 4.76–5.37 ng/ml; p-trend = 0.32), whereas estradiol levels were lower (Q1: 38.7, 36.9–40.5; Q5: 33.1, 31.8–34.5 pg/ml; p-trend < 0.0001). Neither testosterone (no: 5.12, 4.94–5.30, yes: 4.91, 4.33–5.57 ng/ml, p = 0.57) nor estradiol (no: 35.9, 34.8–37.1; yes: 33.9, 29.4–39.2 pg/ml; p = 0.39) differed by cholesterol-lowering drugs use.
Conclusion
Testosterone did not differ by cholesterol or cholesterol-lowering drug use. Estradiol was lower in men with higher cholesterol, but did not differ by cholesterol-lowering drug use. Our results suggest that the lower risk of advanced prostate cancer among statin users is not readily explained by a cholesterol-mediated effect of statins on sex hormone levels.
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References
Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM (2005) Statins and cancer prevention. Nat Rev Cancer 5(12):930–942
Solomon KR, Freeman MR (2008) Do the cholesterol-lowering properties of statins affect cancer risk? Trends Endocrinol Metab 19(4):113–121
Nelson WG (2007) Prostate cancer prevention. Curr Opin Urol 17(3):157–167
Hall SA, Page ST, Travison TG et al (2007) Do statins affect androgen levels in men? Results from the Boston area community health survey. Cancer Epidemiol Biomarkers Prev 16(8):1587–1594
Farnsworth WH, Hoeg JM, Maher M et al (1987) Testicular function in type II hyperlipoproteinemic patients treated with lovastatin (mevinolin) or neomycin. J Clin Endocrinol Metab 65(3):546–550
Mastroberardino G, Costa C, Gavelli MS et al (1989) Plasma cortisol and testosterone in hypercholesterolaemia treated with clofibrate and lovastatin. J Int Med Res 17(4):388–394
Jay RH, Sturley RH, Stirling C et al (1991) Effects of pravastatin and cholestyramine on gonadal and adrenal steroid production in familial hypercholesterolaemia. Br J Clin Pharmacol 32(4):417–422
Azzarito C, Boiardi L, Zini M et al (1992) Long-term therapy with high-dose simvastatin does not affect adrenocortical and gonadal hormones in hypercholesterolemic patients. Metabolism 41(2):148–153
Purvis K, Tollefsrud A, Rui H et al (1992) Short-term effects of treatment with simvastatin on testicular function in patients with heterozygous familial hypercholesterolaemia. Eur J Clin Pharmacol 42(1):61–64
Dobs AS, Miller S, Neri G et al (2000) Effects of simvastatin and pravastatin on gonadal function in male hypercholesterolemic patients. Metabolism 49(1):115–121
Santini SA, Carrozza C, Lulli P et al (2003) Atorvastatin treatment does not affect gonadal and adrenal hormones in type 2 diabetes patients with mild to moderate hypercholesterolemia. J Atheroscler Thromb 10(3):160–164
Bohm M, Herrmann W, Wassmann S, Laufs U, Nickenig G (2004) Does statin therapy influence steroid hormone synthesis? Z Kardiol 93(1):43–48
Dobs AS, Schrott H, Davidson MH et al (2000) Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia. Metabolism 49(9):1234–1238
Hyyppa MT, Kronholm E, Virtanen A, Leino A, Jula A (2003) Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial. Psychoneuroendocrinology 28(2):181–194
Ormiston T, Wolkowitz OM, Reus VI, Johnson R, Manfredi F (2004) Hormonal changes with cholesterol reduction: a double-blind pilot study. J Clin Pharm Ther 29(1):71–73
Azzarito C, Boiardi L, Vergoni W, Zini M, Portioli I (1996) Testicular function in hypercholesterolemic male patients during prolonged simvastatin treatment. Horm Metab Res 28(4):193–198
Dobs AS, Sarma PS, Schteingart D (1993) Long-term endocrine function in hypercholesterolemic patients treated with pravastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Metabolism 42(9):1146–1152
Heller RF, Miller NE, Lewis B et al (1981) Associations between sex hormones, thyroid hormones and lipoproteins. Clin Sci (Lond) 61(5):649–651
Heller RF, Wheeler MJ, Micallef J, Miller NE, Lewis B (1983) Relationship of high density lipoprotein cholesterol with total and free testosterone and sex hormone binding globulin. Acta Endocrinol (Copenh) 104(2):253–256
Dai WS, Gutai JP, Kuller LH et al (1984) Relation between plasma high-density lipoprotein cholesterol and sex hormone concentrations in men. Am J Cardiol 53(9):1259–1263
Hamalainen E, Adlercreutz H, Ehnholm C, Puska P (1986) Relationships of serum lipoproteins and apoproteins to sex hormones and to the binding capacity of sex hormone binding globulin in healthy Finnish men. Metabolism 35(6):535–541
Lichtenstein MJ, Yarnell JW, Elwood PC et al (1987) Sex hormones, insulin, lipids, and prevalent ischemic heart disease. Am J Epidemiol 126(4):647–657
Stefanick ML, Williams PT, Krauss RM et al (1987) Relationships of plasma estradiol, testosterone, and sex hormone-binding globulin with lipoproteins, apolipoproteins, and high density lipoprotein subfractions in men. J Clin Endocrinol Metab 64(4):723–729
Barrett-Connor E, Khaw KT (1988) Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 78(3):539–545
Kiel DP, Baron JA, Plymate SR, Chute CG (1989) Sex hormones and lipoproteins in men. Am J Med 87(1):35–39
Nanjee MN, Rajput-Williams J, Samuel L, Wootton R, Miller NE (1989) Relationships of plasma lipoprotein concentrations to unbound, albumin-bound and sex hormone-binding globulin-bound fractions of gonadal steroids in men. Eur J Clin Invest 19(3):241–245
Freedman DS, O’Brien TR, Flanders WD, DeStefano F, Barboriak JJ (1991) Relation of serum testosterone levels to high density lipoprotein cholesterol and other characteristics in men. Arterioscler Thromb 11(2):307–315
Khaw KT, Barrett-Connor E (1991) Endogenous sex hormones, high density lipoprotein cholesterol, and other lipoprotein fractions in men. Arterioscler Thromb 11(3):489–494
Kato I, Nomura A, Stemmermann GN, Chyou PH (1992) Determinants of sex hormone levels in men as useful indices in hormone-related disorders. J Clin Epidemiol 45(12):1417–1421
Tchernof A, Labrie F, Belanger A et al (1997) Relationships between endogenous steroid hormone, sex hormone-binding globulin and lipoprotein levels in men: contribution of visceral obesity, insulin levels and other metabolic variables. Atherosclerosis 133(2):235–244
Zmuda JM, Cauley JA, Kriska A et al (1997) Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former multiple risk factor intervention trial participants. Am J Epidemiol 146(8):609–617
Wranicz JK, Cygankiewicz I, Rosiak M et al (2005) The relationship between sex hormones and lipid profile in men with coronary artery disease. Int J Cardiol 101(1):105–110
Nordoy A, Aakvaag A, Thelle D (1979) Sex hormones and high density lipoproteins in healthy males. Atherosclerosis 34(4):431–436
Deutscher S, Bates MW, Caines MJ et al (1986) Determinants of lipid and lipoprotein level in elderly men. Atherosclerosis 60(3):221–229
Van Pottelbergh I, Braeckman L, De Bacquer D, De Backer G, Kaufman JM (2003) Differential contribution of testosterone and estradiol in the determination of cholesterol and lipoprotein profile in healthy middle-aged men. Atherosclerosis 166(1):95–102
Mendoza SG, Zerpa A, Carrasco H et al (1983) Estradiol, testosterone, apolipoproteins, lipoprotein cholesterol, and lipolytic enzymes in men with premature myocardial infarction and angiographically assessed coronary occlusion. Artery 12(1):1–23
Haffner SM, Mykkanen L, Valdez RA, Katz MS (1993) Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab 77(6):1610–1615
National Cholesterol Education Program (2001) Expert panel on detection evaluation, and treatment of high blood cholesterol in adults. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). NIH publication. The Program, Bethesda, MD
Beers MH, Berkow R, Merck Research L (1999) The Merck manual of diagnosis and therapy. In: Anonymous (ed). Merck Research Laboratories, Whitehouse Station
Rinaldi S, Geay A, Dechaud H et al (2002) Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiol Biomarkers Prev 11(10 Pt 1):1065–1071
Vermeulen A, Verdonck L, Kaufman JM (1999) A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84(10):3666–3672
Gunter EW, Lewis BG, Koncikowski SM (1996) Laboratory procedures used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. Report. Centers for Disease Control and Prevention, Hyattsville, MD
Chumlea WC, Guo SS, Kuczmarski RJ et al (2002) Body composition estimates from NHANES III bioelectrical impedance data. Int J Obes Relat Metab Disord 26(12):1596–1609
American Heart Association (2008) What your cholesterol levels mean. American Hearth Association
Bernini GP, Brogi G, Argenio GF, Moretti A, Salvetti A (1998) Effects of long-term pravastatin treatment on spermatogenesis and on adrenal and testicular steroidogenesis in male hypercholesterolemic patients. J Endocrinol Invest 21(5):310–317
Segarra A, Chacon P, Vilardell M, Piera LL (1996) Prospective case control study to determine the effect of lovastatin on serum testosterone and cortisol concentrations in hyperlipidemic nephrotic patients with chronic renal failure. Nephron 73(2):186–190
Travia D, Tosi F, Negri C et al (1995) Sustained therapy with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors does not impair steroidogenesis by adrenals and gonads. J Clin Endocrinol Metab 80(3):836–840
Selvin E, Feinleib M, Zhang L et al (2007) Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 30(2):234–238
Shannon J, Tewoderos S, Garzotto M et al (2005) Statins and prostate cancer risk: a case–control study. Am J Epidemiol 162(4):318–325
Platz EA, Leitzmann MF, Visvanathan K et al (2006) Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst 98(24):1819–1825
Flick ED, Habel LA, Chan KA et al (2007) Statin use and risk of prostate cancer in the California Men’s Health Study cohort. Cancer Epidemiol Biomarkers Prev 16(11):2218–2225
Jacobs EJ, Rodriguez C, Bain EB et al (2007) Cholesterol-lowering drugs and advanced prostate cancer incidence in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev 16(11):2213–2217
Murtola TJ, Tammela TL, Lahtela J, Auvinen A (2007) Cholesterol-lowering drugs and prostate cancer risk: a population-based case–control study. Cancer Epidemiol Biomarkers Prev 16(11):2226–2232
Friedman GD, Flick ED, Udaltsova N et al (2008) Screening statins for possible carcinogenic risk: up to 9 years of follow-up of 361 859 recipients. Pharmacoepidemiol Drug Saf 17(1):27–36
Edwards JE, Moore RA (2003) Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Fam Pract 4:18
Acknowledgments
This is the 9th paper from the Hormone Demonstration Program funded by the Maryland Cigarette Restitution Fund at Johns Hopkins. Dr. Mondul was supported by a National Research Service Award (T32 CA009314) from the National Cancer Institute, National Institutes of Health. Dr. Selvin was supported by a grant (K01 DK076595) from the National Institutes of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
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Mondul, A.M., Selvin, E., Rohrmann, S. et al. Association of serum cholesterol and cholesterol-lowering drug use with serum sex steroid hormones in men in NHANES III. Cancer Causes Control 21, 1575–1583 (2010). https://doi.org/10.1007/s10552-010-9586-6
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DOI: https://doi.org/10.1007/s10552-010-9586-6