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Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism

ABSTRACT

Background

Cardiometabolic risk is high in patients with hypogonadism. Visceral adiposity index (VAI) and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio are the practical markers of atherosclerosis and insulin resistance and independent predictors of cardiaovascular risk. To date, no study has evaluated VAI levels and TG/HDL-C ratio in hypogonadism.

Subjects and methods

A total of 112 patients with congenital hypogonadotrophic hypogonadism (CHH) (mean age, 21.7 ± 2.06 years) and 124 healthy subjects (mean age, 21.5 ± 1.27 years) were enrolled. The demographic parameters, VAI, TG/HDL-C ratio, asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured for all participants.

Results

The patients had higher total cholesterol (p = 0.04), waist circumference, triglycerides, insulin, and HOMA-IR levels (p = 0.001 for all) than the healthy subjects. VAI and ADMA and TG/HDL-C levels were also higher in patients than in healthy subjects (p < 0.001 for all). VAI was weakly correlated with ADMA (r = 0.27, p = 0.015), HOMA-IR (r = 0.22, p = 0.006), hs-CRP (r = 0.19, p = 0.04), and total testosterone (r = −0.21, p = 0.009) levels, whereas TG/HDL-C ratio was weakly correlated weakly with ADMA (r = 0.30, p = 0.003), HOMA-IR (r = 0.22, p = 0.006), and total testosterone (r = −0.16, p = 0.03) levels. Neither VAI nor TG/HDL-C ratio determined ADMA, HOMA-IR, and hs-CRP levels.

Conclusions

The results of this study demonstrate that patients with hypogonadism have elevated VAI and TG/HDL-C ratio. These values are significantly correlated with the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance. However, the predictive roles of VAI and TG/HDL-C ratio are not significant. Prospective follow-up studies are warranted to clarify the role of VAI and TG/HDL-C ratio in predicting cardiometabolic risk in patients with hypogonadism.

Hypogonadism; cardiometabolic risk; visceral adiposity index; triglyceride/high-density lipoprotein cholesterol ratio

INTRODUCTION

Hypogonadism is a syndrome characterized by low testosterone levels and a clinical spectrum of poor libido, energy loss, muscle atrophy, and depression. In addition to fertility disturbance, cardiometabolic risk is increased in patients with hypogonadism (11. Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency: III Cardiovascular disease. J Androl. 2009;30:477-94.,22. 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(3):843-50.). The prevalence of cardiac and metabolic disorders, such as type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity, are significantly increased in these patients (22. 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(3):843-50.,33. 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(4):490-4.). However, the mechanism by which cardiometabolic risk increases in patients with hypogonadism remains to be completely elucidated. Inflammation, insulin resistance, and endothelial dysfunction are the major contributors to increased cardiometabolic risk in hypogonadism (44. Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007;30(11):1029-34.

5. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149(6):601-8.

6. Traish AM, Saad F, Guay AT. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009;30(1):23-32.

7. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92(11):4254-9.
-88. Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian J Androl. 2008;10(2):214-8.). In our previous studies, we observed that even young patients with hypogonadism exhibit endothelial dysfunction, inflammation, and insulin resistance (99. Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, et al. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2011;164(5):759-64.

10. Meric C, Sonmez A, Aydogdu A, Tapan S, Haymana C, Basaran Y, et al. Osteoprotegerin, fibroblast growth factor 23, and vitamin D3 levels in male patients with hypogonadism. Horm Metab Res. 2014;46(13):955-8.
-1111. Sonmez A, Haymana C, Aydogdu A, Tapan S, Basaran Y, Meric C, et al. Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. Endocr J. 2015;62(7):605-13.). However, none of the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance are sufficiently robust to be used as prognostic tools. Thus, a simple, widely available, relatively inexpensive, and generally reproducible marker to predict cardiometabolic risk in patients with hypogonadism is needed.

Visceral adiposity index (VAI) is a mathematical model based on simple anthropometric [body mass index (BMI) and waist circumference (WC)] and metabolic [triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)] parameters and is considered as a simple surrogate marker of visceral adipose dysfunction (1212. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al. Visceral Adiposity Index. Diabetes Care. 2010;33(4):920-2.). VAI is strongly associated with visceral adiposity measured using magnetic resonance imaging and cardiovascular and cerebrovascular events (1212. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al. Visceral Adiposity Index. Diabetes Care. 2010;33(4):920-2.). Recent data also indicate that hypertriglyceridemia and low HDL-C are key components of the metabolic syndrome and are strongly predictive of coronary artery disease (1313. Carey VJ, Bishop L, Laranjo N, Harshfield BJ, Kwiat C, Sacks FM. Contribution of high plasma triglycerides and low high-density lipoprotein cholesterol to residual risk of coronary heart disease after establishment of low-density lipoprotein cholesterol control. Am J Cardiol. 2010;106(6):757-63.,1414. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, et al. Triglycerides and the risk of coronary heart disease: 10158 incident cases among 262525 participants in 29 Western prospective studies. Circulation. 2007;115(4):450-8.). The TG/HDL-C ratio is another practical marker of atherosclerosis and insulin resistance and an independent predictor of cardiovascular risk (1515. Dobiasova M, Frohlich J. The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FERHDL). Clin Biochem. 2001;34(7):583-8.

16. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Intern Med. 2001;161(3):361-6.
-1717. McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D, et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol. 2005;96(3):399-404.). The role of TG/HDL-C ratio in predicting cardiometabolic risk has been tested in several metabolic disorders, such as diabetes mellitus, hypertension, chronic kidney disease, and nonalcoholic fatty liver disease (1818. Vega GL, Barlow CE, Grundy SM, Leonard D, DeFina LF. Triglyceride-to-high-density-lipoprotein-cholesterol ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men. J Investig Med. 2014;62(2):345-9.

19. Onat A, Can G, Kaya H, Hergenç G. “Atherogeni index of plasma” (log10 triglyceride/high-density lipoprotein-cholesterol) predicts high blood pressure, diabetes, and vascular events. J Clin Lipidol. 2010;4(2):89-98.

20. Sung KC, Ryan MC, Kim BS, Cho YK, Kim BI, Reaven GM. Relationships between estimates of adiposity, insulin resistance, and nonalcoholic fatty liver disease in a large group of nondiabetic Korean adults. Diabetes Care. 2007;30(8):2113-8.
-2121. Sonmez A, Yilmaz MI, Saglam M, Unal HU, Gok M, Cetinkaya H, et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids Health Dis. 2015;14:29.).

To date, no studies have investigated VAI and TG/HDL-C ratio in patients with hypogonadism. Therefore, we designed the present study to answer the following questions: 1. Do VAI and TG/HDL-C ratio differ between patients with hypogonadism and healthy subjects? 2. Are insulin resistance, inflammation, and endothelial dysfunction associated with VAI and TG/HDL-C ratio?

SUBJECTS AND METHODS

This retrospective analysis was performed by evaluating the database of the Department of Endocrinology and Metabolism, Gulhane Military Medical Academy School of Medicine, Ankara, Turkey. Military service is compulsory for all young men in Turkey, and Gulhane Military Medical Academy School of Medicine is the tertiary medical center for military recruits. Patients with hypogonadism are referred to the Department of Endocrinology and Metabolism for both treatment and follow-up. Some of these patients, generally those living in rural regions, have never received treatment. A total of 273 young patients with hypogonadism were registered between 2007 and 2012. Of these, 64 patients were excluded because of a history of androgen replacement; 27 because of high testosterone levels (200–300 ng/dL); 16 because of liver, kidney, or pulmonary disease; 22 because of a diagnosis other than hypogonadotropic hypogonadism (CHH; i.e., primary hypogonadism, panhypopituitarism, or pituitary adenoma); and 32 because of incomplete data on demographic and metabolic parameters. A total of 112 treatment-naive patients (mean age, 21.7 ± 2.06 years) with congenital CHH were included. The control group included 124 age- and BMI-matched healthy subjects (mean age, 21.5 ± 1.27 years).

A portion of the data for this study population was previously published (99. Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, et al. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2011;164(5):759-64.

10. Meric C, Sonmez A, Aydogdu A, Tapan S, Haymana C, Basaran Y, et al. Osteoprotegerin, fibroblast growth factor 23, and vitamin D3 levels in male patients with hypogonadism. Horm Metab Res. 2014;46(13):955-8.
-1111. Sonmez A, Haymana C, Aydogdu A, Tapan S, Basaran Y, Meric C, et al. Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. Endocr J. 2015;62(7):605-13.). None of the control subjects had a chronic disorder or used any medications, including over-the-counter drugs. All subjects provided informed consent, and the Local Ethical Committee of Gulhane School of Medicine approved the study. This study has been registered with Clinicaltrials.gov (NCT02111434).

Detailed medical histories of all patients were obtained before the study. Height, weight, and WC were measured with the subjects in their underwear. BMI was computed as the ratio of weight to the square of height (kg/m2). WC was measured on the line between the iliac crest and the lower costal margin parallel to the ground after subjects exhaled. The pubertal developments of the subjects were assessed according to the Tanner stages. CHH diagnosis was based on a history of failure to undergo spontaneous puberty before 18 years of age and was confirmed with tests demonstrating low serum total testosterone and normal or low gonadotropin levels. Pituitary hormones were evaluated in all patients to exclude panhypopituitarism, and pituitary or hypothalamic mass lesions were excluded by evaluation with magnetic resonance imaging.

Sample collection and laboratory measurements

For biochemical analyses, all blood samples were collected from the antecubital veins between 08:00 and 09:00 h after overnight fasting. The samples were centrifuged for 15 min at 4,000 × g, aliquoted, and immediately frozen at −80°C for analyses. Fasting plasma glucose, total cholesterol, TG, and HDL-C levels were measured by the enzymatic colorimetric method using an Olympus AU-2700 autoanalyzer with reagents from Olympus Diagnostics (GmbH, Hamburg, Germany). Low-density lipoprotein cholesterol level was calculated using Friedewald’s formula (2222. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of lowdensity lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499-502.). Serum basal insulin, total testosterone, follicle-stimulating hormone, and luteinizing hormone levels were measured by the chemiluminescence method using a UniCel DxI 800 Access Immunoassay System (Miami, FL, USA). Complete blood count was obtained using the Olympus AU-2700 autoanalyzer (GmbH). Insulin sensitivity was calculated by the homeostatic model assessment-insulin resistance (HOMA-IR) using the following formula: HOMA-IR = (insulin × glucose)/405 (2323. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med. 2002;19(7):527-34.). Plasma high-sensitivity C-reactive protein (hs-CRP) levels were determined in 58 patients and 69 control subjects. Plasma asymmetric dimethylarginine (ADMA) levels were determined in 59 patients and 33 control subjects using the enzyme-linked immunosorbent assay kit (Immundiagnostik, Bensheim, Germany). The minimum detectable concentration of ADMA was 0.05 µmol/L. The hs-CRP level was determined in serum by the immunoturbidimetric fixed rate method using the Olympus AU-2700 autoanalyzer (GmbH). The intra- and inter-assay coefficients of variation were 5.8% and 3.1%, respectively. The minimum detectable concentration of hs-CRP was 0.07 mg/L. VAI was calculated using the following sex-specific equation (1313. Carey VJ, Bishop L, Laranjo N, Harshfield BJ, Kwiat C, Sacks FM. Contribution of high plasma triglycerides and low high-density lipoprotein cholesterol to residual risk of coronary heart disease after establishment of low-density lipoprotein cholesterol control. Am J Cardiol. 2010;106(6):757-63.):

Statistical analysis

All data were recorded in a computer database and analyzed using the SPSS 18.0 program (SPSS, Inc., Chicago, IL, USA). Results are expressed as means ± standard deviation. The variables were assessed for normality using the Kolmogorov–Smirnov test, and the equality of variance was evaluated using the Levene’s test. Inter-group differences were analyzed using the Student’s t-test and Mann–Whitney U test as appropriate. The correlations were performed using the Pearson’s or Spearman’s correlation tests. Differences were considered significant at a p value of < 0.05.

RESULTS

The demographic and biochemical characteristics of the patients and control subjects are given in Table 1. Compared with healthy controls, patients had significantly higher total cholesterol levels (p = 0.04); WC, TG, insulin, and HOMA-IR levels (p = 0.001 for all); and ADMA and TG/HDL-C levels and VAI (p < 0.001 for all). VAI were weakly correlated with ADMA (r = 0.27, p = 0.015), HOMA-IR (r = 0.22, p = 0.006), hs-CRP (r = 0.19, p = 0.04; Figure 1A), and total testosterone (r = −0.21, p = 0.009) levels, whereas TG/HDL-C ratio was weakly correlated with ADMA (r = 0.30, p = 0.003), HOMA-IR (r = 0.22, p = 0.006; Figure 1B), and total testosterone (r = −0.16, p = 0.03) levels. In a stepwise linear regression analysis, neither VAI nor TG/HDL ratio remained in the model to be independent determinants of ADMA or HOMA-IR levels. Total testosterone level was the only significant independent determinant of ADMA level, whereas WC was an independent determinant of HOMA-IR level.

Table 1
Demographic and metabolic parameters of patients with congenital hypogonadotropic hypogonadism and healthy control subjects in this study

Figure 1
(A) Scatter plot diagram of the correlation between visceral adiposity index (VAI) and asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment-insulin resistance (HOMA-IR) levels. (B) Scatter plot diagram of the correlation between triglycerides/high-density lipoprotein cholesterol ratio (TG/HDL-C) and asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment-insulin resistance (HOMA-IR) levels.

DISCUSSION

The results of the present study show that patients with hypogonadism have significantly higher VAI and TG/HDL-C ratio than control subjects. Moreover, VAI and TG/HDL-C ratio are significantly correlated with endothelial dysfunction, insulin resistance, and inflammation (VAI only). However, neither VAI nor TG/HDL-C ratio is applicable as the independent predictor of endothelial dysfunction, inflammation, or insulin resistance in patients with CHH.

Cardiovascular and metabolic disorders, such as obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus, are prevalent in patients with hypogonadism (2424. 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(3):843-50.

25. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, et al. Testosterone and sex hormone binding globulin predict the metabolic syndrome and diabetes mellitus in middle-aged men. Diabetes Care. 2004;27(5):1036-41.

26. Caldas AD, Porto AL, Motta LD, Casulari LA. Relationship between insulin and hypogonadism in men with hypogonadism. Arq Bras Endocrinol Metabol. 2009;53(8):1005-11.
-2727. 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(4):490-4.), but the mechanism by which cardiovascular and metabolic risk increase in hypogonadism is unknown. Inflammation, oxidative stress, insulin resistance, and endothelial dysfunction are the fundamental contributors to increased cardiometabolic risk (44. Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res. 2007;30(11):1029-34.

5. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149(6):601-8.

6. Traish AM, Saad F, Guay AT. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009;30(1):23-32.

7. Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007;92(11):4254-9.
-88. Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian J Androl. 2008;10(2):214-8.). In our previous studies, we reported metabolic derangements and endothelial dysfunction, inflammation, and insulin resistance in young and treatment-naïve patients with hypogonadism (99. Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, et al. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2011;164(5):759-64.

10. Meric C, Sonmez A, Aydogdu A, Tapan S, Haymana C, Basaran Y, et al. Osteoprotegerin, fibroblast growth factor 23, and vitamin D3 levels in male patients with hypogonadism. Horm Metab Res. 2014;46(13):955-8.
-1111. Sonmez A, Haymana C, Aydogdu A, Tapan S, Basaran Y, Meric C, et al. Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. Endocr J. 2015;62(7):605-13.). Patients with hypogonadism have increased fat mass and visceral adiposity, and the latter is associated with an increased risk of developing diabetes, hypertension, dyslipidemia, and atherosclerosis (2828. Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med. 2007;120(3 Suppl 1):S12-8.,2929. Despre’s JP. Intra-abdominal obesity: an untreated risk factor for type 2 diabetes and cardiovascular disease. J Endocrinol Invest. 2006;29(3 Suppl):77-82.). We hypothesized that VAI, as an applicable marker for evaluating visceral adipose function, is useful for assessing increased cardiometabolic risk in patients with hypogonadism.

VAI has been recently developed as a novel sex-specific index based on WC, BMI, TG, and HDL-C (1212. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al. Visceral Adiposity Index. Diabetes Care. 2010;33(4):920-2.). VAI is a marker of visceral adipose dysfunction and is strongly associated with cardiovascular events and type 2 diabetes (1212. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al. Visceral Adiposity Index. Diabetes Care. 2010;33(4):920-2.,3030. Chen HY, Chiu YL, Chuang YF, Hsu SP, Pai MF, Yang JY, et al. Visceral adiposity index and risks of cardiovascular events and mortality in prevalent hemodialysis patients. Cardiovasc Diabetol. 2014;13:136.,3131. Wang Y, He S, He J, Wang S, Liu K, Chen X. Predictive value of visceral adiposity index for type 2 diabetes mellitus: A 15 year prospective cohort study. Herz. 2015;40 Suppl 3:277-81.). VAI is significantly correlated with inflammation and insulin resistance in patients with type 2 diabetes and cardiovascular disorders (1212. Amato MC, Giordano C, Galia M, Criscimanna A, Vitabile S, Midiri M, et al. Visceral Adiposity Index. Diabetes Care. 2010;33(4):920-2.,3232. Amato MC, Pizzolanti G, Torregrossa V, Misiano G, Milano S, Giordano C. Visceral adiposity index (VAI) is predictive of an altered adipokine profile in patients with type 2 diabetes. PLoS One. 20;9(3):e91969.). VAI is also a practical measure for assessing cardiometabolic risk in patients with polycystic ovary syndrome (3333. Amato MC, Verghi M, Galluzzo A, Giordano C. The oligomenorrhoic phenotypes of polycystic ovary syndrome are characterized by a high visceral adiposity index: a likely condition of cardiometabolic risk. Hum Reprod. 2011;26(6):1486-94.).

TG/HDL-C ratio is another clinical indicator of insulin resistance and has been evaluated as a predictor of diabetes and coronary heart disease (3434. Gaziano JM, Hennekens CH, O’Donnell CJ, Breslow JL, Buring JE. Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction. Circulation. 1997;96(8):2520-5.

35. Hadaegh F, Hatami M, Tohidi M, Sarbakhsh P, Saadat N, Azizi F. Lipid ratios and appropriate cut off values for prediction of diabetes: a cohort of Iranian men and women. Lipids Health Dis. 2010;9:85.
-3636. Kannel WB, Vasan RS, Keyes MJ, Sullivan LM, Robins SJ. Usefulness of the triglyceride-high-density lipoprotein versus the cholesterol-high-density lipoprotein ratio for predicting insulin resistance and cardiometabolic risk (from the Framingham Offspring Cohort). Am J Cardiol. 2008;101(4):497-501.). This ratio may serve as a simpler method for identifying insulin-resistant individuals with increased cardiometabolic risk (3737. McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D, et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol. 2005;96(3):399-404.). TG/HDL-C ratio is also correlated with endothelial dysfunction. In our previous study, we showed that TG/HDL-C ratio is a significant determinant of endothelial dysfunction and a simple predictor of cardiovascular outcomes in patients with chronic kidney disease (3838. Sonmez A, Yilmaz MI, Saglam M, Unal HU, Gok M, Cetinkaya H, et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids Health Dis. 2015;14:29.). Low HDL-C and increased TG levels are also well-established features of patients with hypogonadism (99. Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, et al. Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2011;164(5):759-64.,3939. Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care. 2004;27(4):861-8.,4040. Zmuda JM, Cauley JA, Kriska A, Glynn NW, Gutai JP, Kuller LH. 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. 1997;146(8):609-17.).

ADMA is an endogenous inhibitor of nitric oxide synthase and a well-known surrogate marker of endothelial dysfunction (4141. Böger RH, Maas R, Schulze F, Schwedhelm E. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality--an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res. 2009;60(6):481-7.). Elevated ADMA levels in chronic metabolic diseases, such as type 2 diabetes, hypertension, dyslipidemia, and chronic kidney disease predict cardiovascular morbidity and mortality (4242. Chan NN, Chan JC. Asymmetric dimethylarginine (ADMA): a potential link between endothelial dysfunction and cardiovascular diseases in insulin resistance syndrome? Diabetologia. 2002;45(12):1609-16.). We have previously reported elevated ADMA levels in patients with hypogonadism (1010. Meric C, Sonmez A, Aydogdu A, Tapan S, Haymana C, Basaran Y, et al. Osteoprotegerin, fibroblast growth factor 23, and vitamin D3 levels in male patients with hypogonadism. Horm Metab Res. 2014;46(13):955-8.,1111. Sonmez A, Haymana C, Aydogdu A, Tapan S, Basaran Y, Meric C, et al. Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement. Endocr J. 2015;62(7):605-13.), which implies increased endothelial dysfunction in this patient group. Most of the markers, such as ADMA, used to define increased cardiometabolic risk in patients with hypogonadism are time-consuming or costly, which precludes their use in routine daily practice. To our knowledge, the present study is the first to measure VAI and TG/HDL-C ratio in patients with hypogonadism.

Our results show that VAI and TG/HDL-C ratio are significantly increased in patients with hypogonadism and are related to markers of inflammation, insulin resistance, and endothelial dysfunction. However, the roles of VAI and TG/HDL-C ratio in predicting endothelial dysfunction, inflammation, and insulin resistance are not sufficiently robust for these parameters to be applicable in clinical practice to predict cardiometabolic risk in patients with hypogonadism. According to the results, total testosterone level and WC are the only independent determinants of endothelial dysfunction and insulin resistance, respectively.

This study has both limitations and advantages. The study population comprising young, treatment-naïve patients with CHH may not be representative of the general population of patients with hypogonadism. Our small sample size may be another limitation. However, because few patients with hypogonadism reach adulthood without receiving treatment, we believe that the number of the patients in our study is adequate because of the unique conditions of the study population. The advantages of the present study are its homogeneous study population and the lack of confounding factors, such as chronic metabolic disorders and concomitant medications.

In conclusion, the present study shows that patients with hypogonadism have elevated VAI and TG/HDL-C ratio, which are significantly correlated with the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance. However, the predictive roles of VAI and TG/HDL-C ratio for endothelial dysfunction, inflammation, and insulin resistance are not significant. Prospective follow-up studies are warranted to clarify the role of VAI and TG/HDL-C ratio in determining cardiometabolic risk in patients with hypogonadism.

REFERENCES

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    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(4):490-4.
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    Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149(6):601-8.
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    Traish AM, Saad F, Guay AT. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009;30(1):23-32.
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Publication Dates

  • Publication in this collection
    13 Feb 2017
  • Date of issue
    May-Jun 2017

History

  • Received
    21 Jan 2016
  • Accepted
    10 Oct 2016
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