HDL Cholesterol Subfractions and the Effect of Testosterone Replacement in Hypogonadism

Abstract

Metabolic disorders and cardiovascular events are increased in hypogonadism. Serum HDL composition is a better cardiovascular predictor than the HDL counts. However, there is no information about the HDL subfractions in patients with hypogonadism. We designed a prospective study to investigate the HDL subfractions in treatment naïve subjects with hypogonadism and the effects of 2 different testosterone replacement regimens on the HDL subfractions. Seventy young male patients with congenital hypogonadotropic hypogonadism (CHH) and 70 age and BMI-matched healthy males were enrolled in the present study. The patients were assigned to receive intramuscular injections of testosterone esters 250 mg every 3 weeks and transdermal testosterone applications 50 mg daily. Biochemical investigations including HDL subfractions and insulin resistance were done. Patients with CHH had higher levels of insulin, HOMA-IR, WC, triglyceride, and diastolic blood pressure. Although, the HDL cholesterol concentrations were similar in both groups, hypogonadal patients had lower HDL2 and higher HDL3 levels. The total testosterone levels were independent determinants of the HDL2 subfractions. During the follow-up, a significant increase in the BMI and WC values and a significant decrease in the levels of total cholesterol, HDL cholesterol, and HDL3 were observed. No difference was present between the 2 treatment arms. These results show that patients with hypogonadism have unfavorable HDL compositions in addition to the other dysmetabolic features. However, testosterone replacement for about six months neither improves the metabolic problems nor the HDL composition. Mechanistic studies are warranted to better understand the cardiovascular effects of unfavorable HDL compositions in hypogonadism.

Key words

hypogonadism - testosterone replacement therapy - HDL cholesterol subfractions

• References

• 1 Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab 2006; 91: 843-850
• 2 Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts Male Aging Study. Diabetes Care 2000; 23: 490-494
• 3 Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, Altun B, Barcin C, Taslipinar A, Meric C, Uckaya G, Kutlu M. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol 2011; 164: 759-764
• 4 Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, Lenzi A, Forti G, Mannucci E, Maggi M. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2011; 8: 272-283
• 5 Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, Forti G, Mannucci E, Maggi M. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol 2011; 165: 687-701
• 6 Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2670-2677
• 7 Maneschi E, Morelli A, Filippi S, Cellai I, Comeglio P, Mazzanti B, Mello T, Calcagno A, Sarchielli E, Vignozzi L, Saad F, Vettor R, Vannelli GB, Maggi M. Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. J Endocrinol 2012; 215: 347-362
• 8 Vignozzi L, Cellai I, Santi R, Lombardelli L, Morelli A, Comeglio P, Filippi S, Logiodice F, Carini M, Nesi G, Gacci M, Piccinni MP, Adorini L, Maggi M. Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells. J Endocrinol 2012; 214: 31-43
• 9 Filippi S, Vignozzi L, Morelli A, Chavalmane AK, Sarchielli E, Fibbi B, Saad F, Sandner P, Ruggiano P, Vannelli GB, Mannucci E, Maggi M. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. J Sex Med 2009; 6: 3274-3288
• 10 Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009; 30: 726-733
• 11 La Vignera S, Calogero AE, D’Agata R, Di Mauro M, Tumino S, Condorelli R, Lanzafame F, Finocchiaro C, Giammusso B, Vicari E. Testosterone therapy improves the clinical response to conventional treatment for male patients with metabolic syndrome associated to late onset hypogonadism. Minerva Endocrinol 2008; 33: 159-167
• 12 Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest 2010; 33: 776-783
• 13 Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, Spera G. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010; 7: 3495-3503
• 14 Aydogdu A, Bolu E, Sonmez A, Tasci I, Haymana C, Acar R, Meric C, Taslipinar A, Ozgurtas T, Azal O. Effects of Three Different Medications on Metabolic Parameters and Testicular Volume in Patients with Hypogonadotropic Hypogonadism: 3-Year Experience. Clin Endocrinol (Oxf) 2012; Dec 27 2012 DOI: 10.1111/cen.12135. [Epub ahead of print]
• 15 Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007; 82: 29-39
• 16 Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95: 2560-2575
• 17 Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60: 1451-1457
• 18 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; 8: 109-122
• 19 Forti N, Diament J. High-Density Lipoproteins: Metabolic, Clinical, Epidemiological and Therapeutic Intervention Aspects. An Update for Clinicians. Arq Bras Cardiol 2006; 87: 614-622
• 20 Prospective Studies Collaboration . Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007; 370: 1829-1839
• 21 Ansell BJ, Navab M, Hama S, Kamranpour N, Fonarow G, Hough G, Rahmani S, Mottahedeh R, Dave R, Reddy ST, Fogelman AM. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003; 108: 2751-2756
• 22 Navab M, Reddy ST, Van Lenten BJ, Fogelman AM. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 2011; 8: 222-232
• 23 von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001; 21: 13-27
• 24 Huang Y, von Eckardstein A, Wu S, Assmann G. Cholesterol efflux, cholesterol esterification, and cholesteryl ester transfer by LpA-I and LpA-I/A-II in native plasma. Arterioscler Thromb Vasc Biol 1995; 15: 1412-1418
• 25 Link JJ, Rohatgi A, de Lemos JA. HDL cholesterol: physiology, pathophysiology, and management. Curr Probl Cardiol 2007; 32: 268-314
• 26 Salonen JT, Salonen R, Seppänen K, Rauramaa R, Tuomilehto J. HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation 1991; 84: 129-139
• 27 Franceschini G, Bondioli A, Granata D, Mercuri V, Negri M, Tosi C, Sirtori CR. Reduced HDL2 levels in myocardial infarction patients without risk factors for atherosclerosis. Atherosclerosis 1987; 68: 213-219
• 28 Wallentin L, Sundin B. HDL2 and HDL3 lipid levels in coronary artery disease. Atherosclerosis 1986; 59: 131-136
• 29 Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 1996; 121: 35-43
• 30 Tan KC, Shiu SW, Pang RW, Kung AW. Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins. Clin Endocrinol (Oxf) 1998; 48: 187-194
• 31 Tan KC, Shiu SW, Kung AW. Alterations in hepatic lipase and lipoprotein subfractions with transdermal testosterone replacement therapy. Clin Endocrinol (Oxf) 1999; 51: 765-769
• 32 Yamaguchi K, Ishikawa T, Chiba K, Fujisawa M. Assessment of possible effects for testosterone replacement therapy in men with symptomatic late-onset hypogonadism. Andrologia 2011; 43: 52-56
• 33 Ozata M, Yildirimkaya M, Bulur M, Yilmaz K, Bolu E, Corakci A, Gundogan MA. Effects of gonadotropin and testosterone treatments on lipoprotein(a), high density lipoprotein particles, and other lipoprotein levels in male hypogonadism. J Clin Endocrinol Metab 1996; 81: 3372-3378
• 34 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
• 35 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 36 Widhalm K, Pakosta R. Precipitation with polyethylene glycol and density-gradient ultracentrifugation compared for determining high-density lipoprotein subclasses HDL2 and HDL3. Clin Chem 1991; 37: 238-240
• 37 Lamarche B, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Després JP. Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study. Arterioscler Thromb Vasc Biol 1997; 17: 1098-1105
• 38 Barter PJ. Inhibition of endothelial cell adhesion molecule expression by high-density lipoprotein. Clin Exp Pharmacol Physiol 1997; 24: 286-287
• 39 Langer C, Gansz B, Goepfert C, Engel T, Uehara Y, von Dehn G, Jansen H, Assmann G, von Eckardstein A. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem Biophys Res Commun 2002; 296: 1051-1057
• 40 Tan KC, Shiu SW, Kung AW. Alterations in hepatic lipase and lipoprotein subfractions with transdermal testosterone replacement therapy. Clin Endocrinol (Oxf) 1999; 51: 765-769
• 41 Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899-906
• 42 Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003; 6: 1-7
• 43 Mårin P, Holmäng S, Jönsson L, Sjöström L, Kvist H, Holm G, Lindstedt G, Björntorp P. Effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord 1992; 16: 991-997
• 44 Mårin P, Holmäng S, Gustafsson C, Jönsson L, Kvist H, Elander A, Eldh J, Sjöström L, Holm G, Björntorp P. Androgen treatment of abdominally obese men. Obesity Res 1993; 1: 245-251
• 45 Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD, Channer KS. TIMES2 Investigators . Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011; 34: 828-883
• 46 Liu PY, Wishart SM, Celermajer DS, Jimenez M, Pierro ID, Conway AJ, Handelsman DJ. Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo controlled clinical trial of recombinant human chorionic gonadotropin. Eur J Endocrinol 2003; 148: 55-66
• 47 Dobs AS, Bachorik PS, Arver S, Meikle AW, Sanders SW, Caramelli KE, Mazer NA. Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Clin Endocrinol Metab 2001; 86: 1026-1033
• 48 Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 58: 618-625
• 49 Sonmez A, Taslipinar A, Tapan S, Serdar MA. Comment on: Jones et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 Study). Diabetes Care 2011; 34: 828-837; Diabetes Care 2011; 34: e172
• 50 Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350: 482-492