The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials

BMC Medicine

Benjamin J Cowling¹  Guy Freeman¹  Shiu Lun Au Yeung¹  C Mary Schooling¹ 

[1] Department of Community Medicine, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Units 624-627, Core F, Cyberport 3, 100 Cyberport Road, Hong Kong, Hong Kong SAR, China

关键词: testosterone;    statins;    inflammation;    diabetes;    cholesterol;    cardiovascular;    androgen;   

Others  :  857164
DOI  :  10.1186/1741-7015-11-57

 received in 2012-07-31, accepted in 2013-02-28,  发布年份 2013

【 摘 要 】

Background

Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.

Methods

A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.

Results

Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).

Conclusions

Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases.

See commentary article here http://www.biomedcentral.com/1741-7015/11/58 webcite

【 授权许可】

   
2013 Schooling et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC: Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med 2005, 165:725-730.
• [2]Gotto AM Jr, Moon JE: Recent clinical studies of the effects of lipid-modifying therapies. Am J Cardiol 2012, 110:15A-26A.
• [3]Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C: Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des 2012, 18:1519-1530.
• [4]Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, et al.: Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010, 375:735-742.
• [5]Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK: Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011, 305:2556-2564.
• [6]Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008, 359:2195-2207.
• [7]Deng J, Wu Q, Liao Y, Huo D, Yang Z: Effect of statins on chronic inflammation and nutrition status in renal dialysis patients: a systematic review and meta-analysis. Nephrology (Carlton) 2012, 17:545-551.
• [8]Lee PY, Scumpia PO, Byars JA, Kelly KM, Zhuang H, Shuster JS, Theriaque DW, Segal MS, Reeves WH, Brantly ML: Short-term atorvastatin treatment enhances specific antibody production following tetanus toxoid vaccination in healthy volunteers. Vaccine 2006, 24:4035-4040.
• [9]Shyamsundar M, McKeown ST, O'Kane CM, Craig TR, Brown V, Thickett DR, Matthay MA, Taggart CC, Backman JT, Elborn JS, McAuley DF: Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med 2009, 179:1107-1114.
• [10]Parker RA, Clark RW, Sit SY, Lanier TL, Grosso RA, Wright JJ: Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors. J Lipid Res 1990, 31:1271-1282.
• [11]Tobert JA, Bell GD, Birtwell J, James I, Kukovetz WR, Pryor JS, Buntinx A, Holmes IB, Chao YS, Bolognese JA: Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase, in healthy volunteers. J Clin Invest 1982, 69:913-919.
• [12]Dobs AS, Sarma PS, Schteingart D: Long-term endocrine function in hypercholesterolemic patients treated with pravastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Metabolism 1993, 42:1146-1152.
• [13]Smals AG, Weusten JJ, Benraad TJ, Kloppenborg PW: The HMG-CoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity. J Steroid Biochem Mol Biol 1991, 38:465-468.
• [14]MacDonald JS, Gerson RJ, Kornbrust DJ, Kloss MW, Prahalada S, Berry PH, Alberts AW, Bokelman DL: Preclinical evaluation of lovastatin. Am J Cardiol 1988, 62:16J-27J.
• [15]Dobs AS, Schrott H, Davidson MH, Bays H, Stein EA, Kush D, Wu M, Mitchel Y, Illingworth RD: Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia. Metabolism 2000, 49:1234-1238.
• [16]Dobs AS, Miller S, Neri G, Weiss S, Tate AC, Shapiro DR, Musliner TA: Effects of simvastatin and pravastatin on gonadal function in male hypercholesterolemic patients. Metabolism 2000, 49:115-121.
• [17]Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS: Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011, 34:828-837.
• [18]Levine GN, D'Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, Milani RV, Sagalowsky AI, Smith MR, Zakai N: Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 2010, 60:194-201.
• [19]Groth KA, Skakkebaek A, Host C, Gravholt CH, Bojesen A: Klinefelter syndrome - a clinical update. J Clin Endocrinol Metab 2013, 98:20-30.
• [20]Grossman CJ: Interactions between the gonadal steroids and the immune system. Science 1985, 227:257-261.
• [21]Sakiani S, Olsen NJ, Kovacs WJ: Gonadal steroids and humoral immunity. Nat Rev Endocrinol 2012, 9:56-62.
• [22]Snider H, Lezama-Davila C, Alexander J, Satoskar AR: Sex hormones and modulation of immunity against leishmaniasis. Neuroimmunomodulation 2009, 16:106-113.
• [23]Pergola C, Rogge A, Dodt G, Northoff H, Weinigel C, Barz D, Radmark O, Sautebin L, Werz O: Testosterone suppresses phospholipase D, causing sex differences in leukotriene biosynthesis in human monocytes. FASEB J 2011, 25:3377-3387.
• [24]Verhagen AP, de Vet HC, de Bie RA, Kessels AG, Boers M, Bouter LM, Knipschild PG: The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol 1998, 51:1235-1241.
• [25]Duleba AJ, Banaszewska B, Spaczynski RZ, Pawelczyk L: Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial. Fertil Steril 2006, 85:996-1001.
• [26]Banaszewska B, Pawelczyk L, Spaczynski RZ, Dziura J, Duleba AJ: Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab 2007, 92:456-461.
• [27]Banaszewska B, Pawelczyk L, Spaczynski RZ, Duleba AJ: Comparison of simvastatin and metformin in treatment of polycystic ovary syndrome: prospective randomized trial. J Clin Endocrinol Metab 2009, 94:4938-4945.
• [28]Bohm M, Herrmann W, Wassmann S, Laufs U, Nickenig G: Does statin therapy influence steroid hormone synthesis? Z Kardiol 2004, 93:43-48.
• [29]Hyyppa MT, Kronholm E, Virtanen A, Leino A, Jula A: Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial. Psychoneuroendocrinology 2003, 28:181-194.
• [30]Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL: The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab 2009, 94:103-108.
• [31]Raja-Khan N, Kunselman AR, Hogeman CS, Stetter CM, Demers LM, Legro RS: Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial. Fertil Steril 2011, 95:1849-1852.
• [32]Kazerooni T, Shojaei-Baghini A, Dehbashi S, Asadi N, Ghaffarpasand F, Kazerooni Y: Effects of metformin plus simvastatin on polycystic ovary syndrome: a prospective, randomized, double-blind, placebo-controlled study. Fertil Steril 2010, 94:2208-2213.
• [33]Rashidi B, Abediasl J, Tehraninejad E, Rahmanpour H, Sills ES: Simvastatin effects on androgens, inflammatory mediators, and endogenous pituitary gonadotropins among patients with PCOS undergoing IVF: results from a prospective, randomized, placebo-controlled clinical trial. J Investig Med 2011, 59:912-916.
• [34]Ose L, Davidson MH, Stein EA, Kastelein JJ, Scott RS, Hunninghake DB, Campodonico S, Insull W, Escobar ID, Schrott HG, Stepanavage ME, Wu M, Tate AC, Melino MR, Mercuri M, Mitchel YB: Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group. Clin Cardiol 2000, 23:39-46.
• [35]Gao L, Zhao FL, Li SC: Statin is a reasonable treatment option for patients with Polycystic Ovary Syndrome: a meta-analysis of randomized controlled trials. Exp Clin Endocrinol Diabetes 2012, 120:367-375.
• [36]Raval AD, Hunter T, Stuckey B, Hart RJ: Statins for women with polycystic ovary syndrome not actively trying to conceive. Cochrane Database Syst Rev 2011, 10:CD008565.
• [37]Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, D'Agostino R, Vasan RS: Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011, 96:2430-2439.
• [38]Bancroft J: The endocrinology of sexual arousal. J Endocrinol 2005, 186:411-427.
• [39]Do C, Huyghe E, Lapeyre-Mestre M, Montastruc JL, Bagheri H: Statins and erectile dysfunction: results of a case/non-case study using the French Pharmacovigilance System Database. Drug Saf 2009, 32:591-597.
• [40]de Graaf L, Brouwers AH, Diemont WL: Is decreased libido associated with the use of HMG-CoA-reductase inhibitors? Br J Clin Pharmacol 2004, 58:326-328.
• [41]Ding EL, Song Y, Malik VS, Liu S: Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006, 295:1288-1299.
• [42]Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y: Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med 2012, 172:144-152.
• [43]Davis SR, Braunstein GD: Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med 2012, 9:1134-1148.
• [44]Herbst KL, Calof OM, Hsia SH, Sinha-Hikim I, Woodhouse LJ, Buchanan TA, Bhasin S: Effects of transdermal testosterone administration on insulin sensitivity, fat mass and distribution, and markers of inflammation and thrombolysis in human immunodeficiency virus-infected women with mild to moderate weight loss. Fertil Steril 2006, 85:1794-1802.
• [45]Miller KK, Biller BM, Schaub A, Pulaski-Liebert K, Bradwin G, Rifai N, Klibanski A: Effects of testosterone therapy on cardiovascular risk markers in androgen-deficient women with hypopituitarism. J Clin Endocrinol Metab 2007, 92:2474-2479.
• [46]Giltay EJ, Toorians AW, Sarabdjitsingh AR, de Vries NA, Gooren LJ: Established risk factors for coronary heart disease are unrelated to androgen-induced baldness in female-to-male transsexuals. J Endocrinol 2004, 180:107-112.
• [47]Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA: Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011, 96:3007-3019.
• [48]Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases Hepatology 1986, 6:807-813.
• [49]Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S: Adverse events associated with testosterone administration. N Engl J Med 2010, 363:109-122.
• [50]Eyben FE, Graugaard C, Vaeth M: All-cause mortality and mortality of myocardial infarction for 989 legally castrated men. Eur J Epidemiol 2005, 20:863-869.
• [51]Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA: Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005, 90:6516-6522.
• [52]Ajayi AA, Mathur R, Halushka PV: Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995, 91:2742-2747.
• [53]Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, Eyawo O, Guyatt G, Berwanger O, Briel M: Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM 2011, 104:109-124.
• [54]Li JY, Li XY, Li M, Zhang GK, Ma FL, Liu ZM, Zhang NY, Meng P: Decline of serum levels of free testosterone in aging healthy Chinese men. Aging Male 2005, 8:203-206.
• [55]Johnson L, Barnard JJ, Rodriguez L, Smith EC, Swerdloff RS, Wang XH, Wang C: Ethnic differences in testicular structure and spermatogenic potential may predispose testes of Asian men to a heightened sensitivity to steroidal contraceptives. J Androl 1998, 19:348-357.
• [56]Jin B, Turner L, Zhou Z, Zhou EL, Handelsman DJ: Ethnicity and migration as determinants of human prostate size. J Clin Endocrinol Metab 1999, 84:3613-3619.
• [57]Mirzaei M, Truswell AS, Taylor R, Leeder SR: Coronary heart disease epidemics: not all the same. Heart 2009, 95:740-746.
• [58]Hall SA, Page ST, Travison TG, Montgomery RB, Link CL, McKinlay JB: Do statins affect androgen levels in men? Results from the Boston area community health survey. Cancer Epidemiol Biomarkers Prev 2007, 16:1587-1594.
• [59]Stanworth RD, Kapoor D, Channer KS, Jones TH: Statin therapy is associated with lower total but not bioavailable or free testosterone in men with type 2 diabetes. Diabetes Care 2009, 32:541-546.
• [60]Akduman B, Tandberg DJ, O'Donnell CI, Hughes A, Moyad MA, Crawford ED: Effect of statins on serum prostate-specific antigen levels. Urology 2010, 76:1048-1051.