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Association between testosterone and lipid profiles under statin therapy and its clinical impact on the cardiovascular event risk

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Abstract

Statin therapy may decrease the levels of serum steroid hormones, including testosterone and cortisol, accompanied by lowering low-density lipoprotein cholesterol (LDL-C) levels, which remains to be investigated. The aim of this study is to examine the association between steroid hormones and lipids under statin therapy and its clinical impact on the cardiovascular event risk from a viewpoint of steroid hormone metabolism. Using a population dataset extracted from the standard versus intEnsive statin therapy for hyper-cholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study, we analyzed the correlation between steroid hormones and lipid profiles at registration and 1 year after registration, comparing between male patients with or without cardiovascular events (CV events) within 4 years (CV events + ; n = 100, and CV events − ; n = 100, respectively) after prognostic score matching. The risk for CV events was evaluated using conditional logistic regression analysis. Testosterone levels were lower in the CV events + group than in the CV events − group at registration (5.2 ± 2.2 vs. 7.6 ± 4.1 ng/mL, p < 0.001). Testosterone levels were lowered to 5.1 ng/mL on average in proportion with LDL-C lowering, and Δtestosterone was correlated with ΔLDL-C during 1 year after registration. Cortisol levels were not correlated with LDL-C levels. In addition, testosterone levels at 1 year after registration were not associated with cardiovascular event risk. In male hypercholesterolemic patients with diabetic retinopathy, testosterone levels were positively correlated with LDL-C levels, which were mildly lowered in proportion with LDL-C lowering under mild statin therapy. This decrease in testosterone levels under statin therapy was not related to the increase in cardiovascular event risk.

Clinical trial registration: UMIN 000003486. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000004199.

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Data availability

The data that support the findings of this study are available from the EMPATHY data center, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the EMPATHY Investigators.

References

  1. Health at a Glance 2019. Data by OECD Indicators. https://www.oecd-ilibrary.org/docserver/4dd50c09-en.pdf?expires=1586492868&id=id&accname=ocid195240&checksum=5EFD1362A8160A23F7846ACFFA573CA6 (Accessed 10 April 2020).

  2. Ference BA, Graham I, Tokgozoglu L, Catapano AL (2018) Impact of lipids on cardiovascular health: JACC health promotion series. J Am Coll Cardiol 72:1141–1156

    Article  CAS  Google Scholar 

  3. Martin SS, Blumenthal RS, Miller M (2012) LDL cholesterol: the lower the better. Med Clin North Am 96:13–26

    Article  CAS  Google Scholar 

  4. Taguchi I, Iimuro S, Iwata H, Takashima H, Abe M, Amiya E, Ogawa T, Ozaki Y, Sakuma I, Nakagawa Y, Hibi K, Hiro T, Fukumoto Y, Hokimoto S, Miyauchi K, Yamazaki T, Ito H, Otsuji Y, Kimura K, Takahashi J, Hirayama A, Yokoi H, Kitagawa K, Urabe T, Okada Y, Terayama Y, Toyoda K, Nagao T, Matsumoto M, Ohashi Y, Kaneko T, Fujita R, Ohtsu H, Ogawa H, Daida H, Shimokawa H, Saito Y, Kimura T, Inoue T, Matsuzaki M, Nagai R (2018) High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 137:1997–2009

    Article  CAS  Google Scholar 

  5. Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S, Kitagawa K, Kitakaze M, Kitazono T, Kurabayashi M, Miyauchi K, Murakami T, Murohara T, Node K, Ogawa S, Saito Y, Seino Y, Shigeeda T, Shindo S, Sugawara M, Sugiyama S, Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K, Yamagishi M, Yamazaki T, Yo S, Yokote K, Yoshida K, Yoshimura M, Yoshimura N, Nakao K, Nagai R, Investigators EMPATHY (2018) Intensive treat-to-target statin therapy in high-risk Japanese patients with hypercholesterolemia and diabetic retinopathy: report of a randomized study. Diabetes Care 41:1275–1284

    Article  CAS  Google Scholar 

  6. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, Steering CommitteeInvestigators FOURIER (2017) Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 376:1713–1722

    Article  CAS  Google Scholar 

  7. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Muñoz D, Smith SC Jr, Virani SS, Williams KA Sr, Yeboah J, Ziaeian B (2019) 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. Circulation 140:e563–e595

    PubMed  PubMed Central  Google Scholar 

  8. Olsson AG, Angelin B, Assmann G, Binder CJ, Björkhem I, Cedazo-Minguez A, Cohen J, von Eckardstein A, Farinaro E, Müller-Wieland D, Parhofer KG, Parini P, Rosenson RS, Starup-Linde J, Tikkanen MJ, Yvan-Charvet L (2017) Can LDL cholesterol be too low? Possible risks of extremely low levels. J Intern Med 281:534–553

    Article  CAS  Google Scholar 

  9. Chen C, Zhai H, Huang G, Cheng J, Xia F, Zhao L, Chen Y, Chen Y, Han B, Li Q, Jiang B, Wang N, Lu Y (2018) Is lower low-density lipoprotein cholesterol associated with lower androgen and erectile dysfunction in men? Nutr Metab Cardiovasc Dis 28:1304–1310

    Article  CAS  Google Scholar 

  10. Schooling CM, Au Yeung SL, Freeman G (2013) Cowling BJ (2013) The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med 11:57

    Article  CAS  Google Scholar 

  11. Santini SA, Carrozza C, Lulli P, Zuppi C, Tonolo GC, Musumeci S (2003) Atorvastatin treatment does not affect gonadal and adrenal hormones in type 2 diabetes patients with mild to moderate hypercholesterolemia. J Atherosclero Thromb 10:160–164

    Article  CAS  Google Scholar 

  12. Dobs AS, Miller S, Neri G, Weiss S, Tate AC, Shapiro DR, Musliner TA (2000) Effects of simvastatin and pravastatin on gonadal function in male hypercholesterolemic patients. Metabolism 49:115–121

    Article  CAS  Google Scholar 

  13. Kloner RA, Carson C 3rd, Dobs A, Kopecky S, Mohler ER 3rd (2016) Testosterone and cardiovascular disease. J Am Coll Cardiol 67:545–557

    Article  CAS  Google Scholar 

  14. Hackett G, Kirby M (2018) Erectile dysfunction and testosterone deficiency as cardiovascular risk factors? Int J Clin Pract 72(2):e13054

    Article  Google Scholar 

  15. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P (2004) Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 89:5462–5468

    Article  CAS  Google Scholar 

  16. Kapoor D, Clarke S, Channer KS, Jones TH (2007) Erectile dysfunction is associated with low bioactive testosterone levels and visceral adiposity in men with type 2 diabetes. Int J Androl 30:500–507

    Article  CAS  Google Scholar 

  17. Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S, Kitagawa K, Kitakaze M, Kitazono T, Kurabayashi M, Miyauchi K, Murakami T, Murohara T, Node K, Ogawa S, Saito Y, Seino Y, Shigeeda T, Shindo S, Sugawara M, Sugiyama S, Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K, Yamagishi M, Yamazaki T, Yo S, Yokote K, Yoshida K, Yoshimura M, Yoshimura N, Nakao K, Nagai R, Investigators EMPATHY (2019) Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: exploratory analysis of the standard versus intensive statin therapy for patients with hypercholesterolaemia and diabetic retinopathy study. Diabetes Obes Metab 21:791–800

    Article  CAS  Google Scholar 

  18. Hansen BB (2008) The prognostic analogue of the propensity score. Biometrika 95:481–488

    Article  Google Scholar 

  19. Hajage D, De Rycke Y, Chauvet G, Tubach F (2017) Estimation of conditional and marginal odds ratios using the prognostic score. Stat Med 36:687–716

    Article  Google Scholar 

  20. Carr BR, Simpson ER (1981) Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland. Endocr Rev 2:306–326

    Article  CAS  Google Scholar 

  21. Carr BR, Parker CR Jr, Ohashi M, MacDonald PC, Simpson ER (1983) Regulation of human fetal testicular secretion of testosterone: low-density lipoprotein-cholesterol and cholesterol synthesized de novo as steroid precursor. Am J Obstet Gynecol 146:241–247

    Article  CAS  Google Scholar 

  22. Baspınar O, Bayram F, Korkmaz S, Aksu M, Kocer D, Dizdar OS, Simsek Y, Toth PP (2016) The effects of statin treatment on adrenal and sexual function and nitric oxide levels in hypercholesterolemic male patients treated with a statin. J Clin Lipidol 10:1452–1461

    Article  Google Scholar 

  23. Illingworth DR, Kenny TA, Orwoll ES (1982) Adrenal function in heterozygous and homozygous hypobetalipoproteinemia. J Clin Endocrinol Metab 54:27–33

    Article  CAS  Google Scholar 

  24. Marceau K, Abel EA (2018) Mechanisms of cortisol—substance use development associations: hypothesis generation through gene enrichment analysis. Neurosci Biobehav Rev 92:128–139

    Article  CAS  Google Scholar 

  25. Elsaied MA, Masallat D, Abdel-Hamid IA (2019) Correlation of adiponectin with testosterone in patients with and without type 2 diabetes and erectile dysfunction. Am J Mens Health 13:1557988318807049

    Article  Google Scholar 

  26. Akishita M, Fukai S, Hashimoto M, Kameyama Y, Nomura K, Nakamura T, Ogawa S, Iijima K, Eto M, Ouchi Y (2010) Association of low testosterone with metabolic syndrome and its components in middle-aged Japanese men. Hypertens Res 33:587–591

    Article  CAS  Google Scholar 

  27. Dozio E, Barassi A, Dogliotti G, Malavazos AE, Colpi GM, D’Eril GV, Corsi MM (2012) Adipokines, hormonal parameters, and cardiovascular risk factors: similarities and differences between patients with erectile dysfunction of arteriogenic and nonarteriogenic origin. J Sex Med 9:2370–2377

    Article  CAS  Google Scholar 

  28. Rasul S, Ilhan A, Reiter MH, Baumgartner-Parzer S, Kautzky-Willer A (2011) Relations of adiponectin to levels of metabolic parameters and sexual hormones in elderly type 2 diabetic patients. Gend Med 8:93–102

    Article  Google Scholar 

  29. Høst C, Gormsen LC, Hougaard DM, Christiansen JS, Pedersen SB, Gravholt CH (2014) Acute and short-term chronic testosterone fluctuation effects on glucose homeostasis, insulin sensitivity, and adiponectin: a randomized, double-blind, placebo-controlled, crossover study. J Clin Endocrinol Metab 99:E1088-1096

    Article  Google Scholar 

  30. Senmaru T, Fukui M, Okada H, Mineoka Y, Yamazaki M, Tsujikawa M, Hasegawa G, Kitawaki J, Obayashi H, Nakamura N (2013) Testosterone deficiency induces markedly decreased serum triglycerides, increased small dense LDL, and hepatic steatosis mediated by dysregulation of lipid assembly and secretion in mice fed a high-fat diet. Metabolism 62:851–860

    Article  CAS  Google Scholar 

  31. Bolanos-Garcia VM, Nunez R (2003) On the structure and function of apolipoproteins: more than a family of lipid-binding proteins. Prog Biophys Mol Biol 83:47–68

    Article  CAS  Google Scholar 

  32. Morita S (2016) Metabolism and modification of apolipoprotein B-containing lipoproteins involved in dyslipidemia and atherosclerosis. Biol Pharm Bull 39:1–24

    Article  CAS  Google Scholar 

  33. St-Pierre AC, Cantin B, Dagenais GR, Mauriège P, Bernard PM, Després JP, Lamarche B (2005) Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Québec Cardiovascular Study. Arterioscler Thromb Vasc Biol 25:553–559

    Article  CAS  Google Scholar 

  34. Koba S, Hirano T, Ito Y, Tsunoda F, Yokota Y, Ban Y, Iso Y, Suzuki H, Katagiri T (2006) Significance of small dense low-density lipoprotein-cholesterol concentrations in relation to the severity of coronary heart diseases. Atherosclerosis 189:206–214

    Article  CAS  Google Scholar 

  35. Soisson V, Brailly-Tabard S, Helmer C, Rouaud O, Ancelin ML, Zerhouni C, Guiochon-Mantel A, Scarabin PY (2013) A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 75:282–288

    Article  CAS  Google Scholar 

  36. Keevil BG, Adaway J (2019) Assessment of free testosterone concentration. J Steroid Biochem Mol Biol 190:207–211

    Article  CAS  Google Scholar 

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Acknowledgement

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Funding

Restart-up research funding by The University of Tokyo (2018).

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Atsuko Nakayama, Hiroyuki Morita & Issei Komuro

  2. Clinical Research Promotion Center, The University of Tokyo, Tokyo, Japan

    Takuya Kawahara

  3. Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine, Tokyo, Japan

    Hiroshi Itoh

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  1. Atsuko Nakayama
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Contributions

Conceptualization: AN. Data curation: TK, HI, and IK. Formal analysis: AN. Funding acquisition: AN. Methodology: AN, HM, and TK. Project administration: AN. Supervision: HI and IK. Writing—original draft: AN. Writing—review and editing: HM.

Corresponding authors

Correspondence to Atsuko Nakayama or Hiroyuki Morita.

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Conflict of interest

H.I. reports grants and personal fees from Shionogi & Co., Ltd during the course of the study, and grants and personal fees from Takeda Pharmaceutical Co. Ltd, Nippon Boehringer Ingelheim Co., Ltd, Daiichi Sankyo Co., Ltd, MSD K.K., Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd and Taisho Toyama Pharmaceutical Co., Ltd, as well as grants from Sumitomo Dainippon Pharma Co., Ltd, Astellas Pharma Inc., Kyowa Hakko Kirin Co., Ltd, Teijin Pharma Ltd, Mochida Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan K.K. and personal fees from Nipro Corporation and SBI Pharmaceuticals Co., Ltd outside the submitted work. I.K. reports personal fees from Shionogi & Co., Ltd during the course of the study, grants and personal fees from Takeda Pharmaceutical Co. Ltd, Nippon Boehringer Ingelheim Co., Ltd, Astellas Pharma Inc., Daiichi Sankyo Co., Ltd, and Otsuka Pharmaceutical Co., Ltd and grants from MSD K.K., Shionogi & Co., Ltd, GlaxoSmithKline K.K., Sanofi K.K., Genzyme Japan K.K., Sumitomo Dainippon Pharma Co., Ltd, Mitsubishi Tanabe Pharma Corporation and Bristol‐Myers Squibb Co. outside the submitted work.

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Nakayama, A., Morita, H., Kawahara, T. et al. Association between testosterone and lipid profiles under statin therapy and its clinical impact on the cardiovascular event risk. Heart Vessels 36, 1794–1803 (2021). https://doi.org/10.1007/s00380-021-01872-5

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