ORIGINAL R ESEARCH AR TICLE
The Effect of Testosterone and Fenofibrate, Administered Alone or in Combination, on Cardiometabolic Risk Factors in Men with Late-Onset Hypogonadism and Atherogenic Dyslipidemia Robert Krysiak,1 Wojciech Gilowski1,2 & Bogusław Okopien1 1 Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland 2 Cardiology Department, Chrzanow District Hospital, Chrzanow, Poland
Keywords Androgens; Atherogenic dyslipidemia; Fibrates; Hypogonadism; Insulin resistance; Testosterone replacement. Correspondence R. Krysiak, Department of Internal Medicine and Clinical Pharmacology, Medical University w 18, 40-752 Katowice, of Silesia, Medyko Poland. Tel./Fax: +48-32-2523902; E-mail: [email protected]
doi: 10.1111/1755-5922.12139
SUMMARY Introduction: Oral testosterone was found to reduce plasma levels of HDL cholesterol. No previous study has examined the effect of fibrates, known to increase HDL cholesterol, in patients with low testosterone levels requiring testosterone replacement. Aims: The study included three age-, weight-, and lipid-matched groups of older men with atherogenic dyslipidemia and late-onset hypogonadism, treated with oral testosterone undecanoate (120 mg daily, n = 15), micronized fenofibrate (200 mg daily, n = 15), or testosterone plus fenofibrate (n = 18). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were assessed before and after 16 weeks of therapy. Results: Apart from an increase in plasma testosterone and a reduction in HDL cholesterol, testosterone undecanoate tended to decrease hsCRP and to improve insulin sensitivity. Fenofibrate administered alone increased HDL cholesterol, reduced triglycerides, decreased insulin resistance, reduced circulating levels of uric acid, hsCRP, and fibrinogen, as well as increased plasma levels of homocysteine. The strongest effect on testosterone, HOMA1-IR, uric acid, hsCRP, and fibrinogen was observed if fenofibrate was administered together with testosterone. Testosterone–fenofibrate combination therapy was also devoid of unfavorable effect on HDL cholesterol and homocysteine. Conclusions: Our study shows that fenofibrate produces a stronger effect on cardiometabolic risk factors in men with late-onset hypogonadism and atherogenic dyslipidemia than oral testosterone undecanoate. The obtained results suggest that this group of patients may benefit the most from the combined treatment with oral testosterone undecanoate and micronized fenofibrate.
Introduction Testosterone levels decline with aging, especially after 40 years of age, because of an age-related attrition in testicular Leydig cells and slowing of the hypothalamic gonadotropin-releasing hormone pulse generator [1]. Because of an increase in sex hormonebinding globulin, the decline is more pronounced for bioavailable testosterone (2–3% per year) than for total testosterone (1.6% per year) [2]. Consequently, a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult men [3]. Moreover, aging in men is often accompanied by a decrease in muscle mass and strength, an increase in abdominal fat (especially visceral fat), insulin resistance, an atherogenic lipid profile, a decrease in libido and pubic hair, osteopenia, decreased cognitive performance, depression, insomnia, perspiration, and a decrease in the general sense of well-being [4,5]. Recent clinical trials have demonstrated that low circulating testosterone levels are associated with increased cardiovascular morbidity and mortality [6,7]. The rate of decline in
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testosterone levels varies in different individuals and some middle-aged and elderly men may develop late-onset hypogonadism (LOH), defined as a clinical and biochemical syndrome associated with advancing age, which is characterized by typical symptoms and deficiency in serum testosterone levels [5]. The prevalence of low testosterone levels and the symptoms of its deficiency is higher in men with comorbidities such as obesity, type 2 diabetes, hypertension, dyslipidemias, cardiovascular disease, asthma, and chronic obstructive pulmonary disease [1,8,9]. Because the symptoms of LOH are similar to those of hypogonadism in young men, testosterone therapy has become a popular option for its therapy [9]. In numerous studies, testosterone replacement was able to improve libido, sexual function, central obesity, glycometabolic control, mood, and muscle strength [8,10,11]. Unfortunately, no previous study has investigated the effect of testosterone therapy on cardiovascular morbidity or mortality, and therefore, the causality of the relationship between low testosterone levels and cardiovascular disease is unclear. Although observational studies show a consistent association of low
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testosterone with adverse lipid profiles [12,13], the question whether testosterone therapy exerts a beneficial effect plasma lipids remains uncertain. Moreover, in some studies, testosterone decreased circulating levels of HDL [14–16], considered to have a protective effect against coronary heart disease [17]. Taking into account the high prevalence of dyslipidemias in the general population [18], many men with LOH require treatment with lipid-lowering agents. However, to the best of our knowledge, no previous study has investigated the impact of concurrent treatment with testosterone and any hypolipidemic agent. The aim of this study was to compare the effect of fenofibrate, known to increase HDL cholesterol [19], administered alone or in combination with testosterone, and the effect of testosterone monotherapy on plasma lipid levels and plasma levels of other cardiometabolic risk factors in nondiabetic patients with LOH and atherogenic dyslipidemia.
Materials and Methods The participants of the study were recruited among men (55– 79 years old) with atherogenic dyslipidemia, defined as plasma HDL cholesterol less than 40 mg/dL and triglycerides at least 150 mg/dL), complying with lifestyle intervention for at least 3 months before the beginning of the study. To be admitted to the study, they had to meet the criteria of LOH: total testosterone level below 3.0 ng/mL on two different occasions combined with the presence of the following symptoms: decreased frequency of morning erection, erectile dysfunction, and decreased frequency of sexual thoughts. The exclusion criteria were as follows: prostate cancer, severe lower urinary tract symptoms (the American Urological Association International Prostate Symptom Score exceeding 19), baseline prostate-specific antigen greater than 4 ng/mL (or prostate-specific antigen above 3 ng/ mL in men at high risk of prostate cancer), breast cancer, myocardial infarction, acute coronary event, unstable angina, stroke or coronary revascularization procedure within 6 months preceding the study, severe heart failure (classes II–IV according to the New York Heart Association Functional Classification), uncontrolled arterial hypertension, hematocrit exceeding 50%, untreated obstructive sleep aspnea, diabetes mellitus or treatment with any hypolipemic agents within 3 months, concomitant treatment with other drugs known either to affect plasma lipid levels or to interact with testosterone and fibrates, and poor patient compliance. The Bioethical Committee of the Medical University of Silesia approved the study protocol. All enrolled patients provided their written informed consent for the investigation, and the study was performed according to the Declaration of Helsinki. The study population was divided into three age-, weight-, and lipid-matched groups, treated with testosterone and fenofibrate (group 1, n = 15), testosterone alone (group 2, n = 15), or fenofibrate alone (group 3, n = 18). Both testosterone undecanoate (120 mg daily) and micronized fenofibrate (200 mg daily) were administered orally for 16 weeks without any changes in dosage throughout the study. Testosterone undecanoate was given in three equal doses, while fenofibrate once daily. Moreover, throughout the study, the participants continued to comply with lifestyle modifications. Compliance, investigated during each visit,
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was regarded as satisfactory if the number of tablets taken by a patient ranged from 90% to 110%. Venous blood samples were drawn from the antecubital vein, after a 12-h overnight fast, in a quiet temperature controlled room (24–25°C) between 8.00 and 9.00 a.m. (to avoid possible circadian fluctuations in the parameters studied) before and after 16 weeks of treatment. Plasma lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), fasting glucose, and plasma uric acid were assayed by routine laboratory techniques (Roche Diagnostics, Basel, Switzerland). LDL-cholesterol levels were measured directly. Plasma insulin, total testosterone, and dehydroepiandrosterone sulfate (DHEA-S) were determined by enzyme-linked immunosorbent assay (DRG Instruments GmbH, Marburg, Germany). To calculate the homeostasis model assessment 1 of insulin resistance ratio (HOMA1-IR), the following equation was used: (fasting serum glucose [mg/dL] 9 fasting insulin level [lU/mL])/405. Circulating levels of CRP were assessed using a high-sensitivity monoclonal antibody assay (hsCRP) (MP Biomedicals, Orangeburg, New York, United States). Plasma homocysteine levels were determined with the use of enzyme immunoassay (Diazyme, San Diego, CA, USA). Plasma fibrinogen levels were determined with a semi-automated blood coagulation analyzer OPTION 2 Plus using reagents obtained from bioMerieux (Marcy l’Etoile, France). The intraand interassay coefficients of variation for the assessed variables were less than 6.2 and 8.7%, respectively. The distribution of the variables was analyzed using the Kolmogorov–Smirnov test. Outcomes for triglycerides, HOMA1-IR, hsCRP homocysteine, fibrinogen, and hormones were natural-log transformed to meet the assumptions of normality and equal variance. Between-group comparisons were performed using oneway ANOVA followed by the post hoc Bonferroni test. The differences between the means of variables within the same treatment group were analyzed with Student’s paired t-test. Chi-squared test was used to compare associations between categorical variables. Correlations were calculated using Kendall’s tau test. Values of P < 0.05 were considered statistically significant.
Results At the start of the study, there was no difference between the treatment groups in terms of age, weight, medical background, and laboratory characteristics. Demographic data and baseline results are shown in Tables 1 and 2. Two patients treated with testosterone undecanoate and fenofibrate stopped participating in the study because of increased transaminase activity and increased hematocrit. One subject receiving fenofibrate was withdrawn from the study because of noncompliance with the study protocol. Another patient (treated with testosterone) withdrew his content and therefore did not complete the study. Neither significant adverse effects nor any complications were reported throughout the entire study period in the remaining participants. Testosterone undecanoate administered alone increased plasma testosterone levels by 65% (P < 0.001), reduced plasma HDL cholesterol by 12% (P < 0.05), as well as insignificantly reduced plasma levels of hsCRP ( 14%, P = 0.086) and HOMA1-IR ( 11%, P = 0.098). Testosterone undecanoate produced no effect
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Table 1 Baseline characteristics of participantsa
Variable
Testosterone
Fenofibrate
Combined therapy
Number of patients Age [years; mean (SD)] Body mass index [kg/m2; mean (SD)] Waist circumference [cm; mean (SD)] Smokers [n (%)] Metabolic syndrome [n (%)] Treated hypertension [n (%)] Systolic blood pressure [mmHg; mean (SD)] Diastolic blood pressure [mmHg; mean (SD)]
14 67 (4) 28.8 (2.6)
14 68 (5) 29.1 (2.4)
16 68 (5) 28.3 (2.2)
98 (5)
99 (5)
97 (4)
5 (36) 12 (86)
4 (29) 12 (86)
5 (31) 14 (88)
10 (71)
10 (71)
11 (69)
127 (7)
128 (7)
125 (8)
83 (4)
82 (4)
81 (4)
a
Only data of patients who completed the study were included in the final analyses.
on plasma levels of DHEA-S, total and LDL cholesterol, triglycerides, glucose, uric acid, fibrinogen, and homocysteine (Table 2). Fenofibrate administered alone increased plasma levels of HDL cholesterol by 22% (P < 0.01), decreased plasma levels of triglycerides by 42% (P < 0.001), as well as insignificantly reduced plasma levels of total ( 13%, P = 0.056) and LDL ( 10%, P = 0.083) cholesterol. Moreover, fenofibrate reduced circulating levels of uric acid by 19% (P < 0.05), hsCRP by 29% (P < 0.001), and fibrinogen by 16% (P < 0.05), decreased HOMA1-IR by 20% (P < 0.01), as well as increased plasma homocysteine by 24% (P < 0.05). The drug did not affect plasma testosterone, DHEA-S, and glucose (Table 2). Testosterone–fenofibrate combination reduced plasma levels of LDL cholesterol by 19% (P < 0.01), total cholesterol by 21% (P < 0.01), and triglycerides by 44% (P < 0.001). Moreover, 16 weeks of testosterone–fenofibrate combination therapy increased plasma testosterone by 94% (P < 0.001), reduced HOMA1-IR by 38% (P < 0.001), as well as decreased circulating levels of uric acid by 40% (P < 0.001), hsCRP by 45% (P < 0.001), and fibrinogen by 28% (P < 0.01). No changes in DHEA-S, HDL cholesterol, fasting glucose, and homocysteine were observed (Table 2). The combination therapy was superior to (1) testosterone undecanoate alone and fenofibrate alone with regard to circulating levels of testosterone, uric acid, hsCRP, and fibrinogen as well as HOMA1-IR; (2) testosterone undecanoate alone in affecting total cholesterol, LDL cholesterol, HDL testosterone, and triglycerides; (3) fenofibrate alone in affecting plasma homocysteine. Fenofibrate alone was superior to testosterone undecanoate alone in affecting HDL cholesterol, triglycerides, hsCRP, uric acid, and fibrinogen, as well as inferior to testosterone undecanoate in affecting plasma testosterone (Table 2). At entry, there was a correlation between plasma levels of uric acid, hsCRP, homocysteine, fibrinogen, and plasma levels of total cholesterol (r values between 0.31 [P < 0.05] and 0.41
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Table 2 The effect of testosterone undecanoate and fenofibrate treatment on steroid hormones, plasma lipids, glucose homeostasis markers, and the investigated cardiometabolic risk factors in men with late-onset hypogonadism and atherogenic dyslipidemiai Variable
Testosterone
Total testosterone [ng/mL; mean (SD)] Baseline 1.7 (0.4) After 16 weeks 2.8 (0.5)c,h DHEA-S [lg/dL; mean (SD)] Baseline 130 (35) After 16 weeks 142 (49) Total cholesterol [mg/dL; mean (SD)] Baseline 236 (25) After 16 weeks 228 (30) LDL-cholesterol [mg/dL; mean (SD)] Baseline 144 (14) After 16 weeks 142 (16) HDL cholesterol [mg/dL; mean (SD)] Baseline 34 (3) After 16 weeks 30 (3)a Triglycerides [mg/dL; mean (SD)] Baseline 259 (41) After 16 weeks 249 (37) Glucose [mg/dL; mean (SD)] Baseline 99 (5) After 16 weeks 99 (6) HOMA1-IR Baseline 3.8 (0.7) After 16 weeks 3.4 (0.6) Uric acid [lmol/L; mean (SD)] Baseline 395 (58) After 16 weeks 383 (60) hsCRP [mg/L; mean (SD)] Baseline 3.7 (0.8) After 16 weeks 3.2 (0.5) Homocysteine [lmol/L; mean (SD)] Baseline 38 (8) After 16 weeks 37 (11) Fibrinogen [mg/dL; mean (SD)] Baseline 407 (60) After 16 weeks 412 (60)
Fenofibrate
Combined therapy
1.6 (0.4) 1.9 (0.4)
1.8 (0.3) 3.5 (0.6)c,d,h
120 (29) 140 (41)
116 (37) 129 (29)
240 (31) 210 (29)
243 (36) 193 (28)b,d
149 (17) 134 (18)
155 (19) 126 (16)b,d
32 (4) 39 (5)b,f
32 (3) 35 (4)a,d
267 (43) 159 (35)c,f
249 (39) 140 (35)c,f
100 (6) 96 (5)
97 (5) 93 (5)
3.5 (0.6) 2.8 (0.4)b
3.7 (0.8) 2.3 (0.4)c,f,g
378 (70) 308 (52)a,d
411 (68) 247 (55)c,f,g
3.8 (0.6) 2.7 (0.5)c,d
4.0 (0.8) 2.2 (0.4)c,f,g
34 (8) 42 (6)a
40 (11) 36 (5)g
420 (58) 351 (61)a,d
396 (62) 285 (69)b,e,g
P < 0.05, bP < 0.01, cP < 0.001 vs. baseline value; dP < 0.05, P < 0.01, fP < 0.001 vs. testosterone-treated patients; gP < 0.05, h P < 0.001 vs. fenofibrate-treated patients. iOnly data of patients who completed the study were included in the final analyses. a
e
[P < 0.001]), LDL cholesterol (r values between 0.32 [P < 0.05] and 0.40 [P < 0.001]), HDL cholesterol (r values between 0.35 [P < 0.01] and 0.49 [P < 0.001]), and triglycerides (r values between 0.37 [P < 0.01] and 0.51 [P < 0.001]). There were also correlations between circulating levels of uric acid, hsCRP, homocysteine and fibrinogen, and HOMA1-IR (r values between 0.38 [P < 0.01] and 0.56 [P < 0.001]), as well as between levels of uric acid, hsCRP, homocysteine and fibrinogen, and testosterone (r values between 0.34 [P < 0.01] and 0.51 [P < 0.001]). The effect of fenofibrate administered alone or in combination with testosterone on uric acid, hsCRP, and fibrinogen correlated
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weakly with the effect of this drug on HOMA1-IR (fenofibrate: r values between 0.40 [P < 0.01] and 0.58 [P < 0.001]; combination therapy: r values between 0.37 [P < 0.01] and 0.59 [P < 0.001]) but not with the effect on plasma lipids. Treatmentinduced changes in uric acid, hsCRP, and fibrinogen inversely correlated with baseline testosterone levels (testosterone: r values between 0.30 [P < 0.05] and 0.48 [P < 0.001]; fenofibrate: r values between 0.42 [P < 0.001] and 0.53 [P < 0.001]; combination therapy: r values between 0.37 [P < 0.01] and 0.50 [P < 0.001]).
Discussion The major finding of our prospective study is that fenofibrate produced a stronger effect on cardiometabolic risk factors in men with LOH and atherogenic dyslipidemia than oral testosterone undecanoate did. Previously, we observed a multidirectional action of fenofibrate including an improvement in glucose metabolism and the inhibitory action on plasma lipids and other risk factors in various metabolic disturbances, including prediabetes, overt diabetes, and mixed dyslipidemia [20–24]. However, the present study is the first which has shown a beneficial effect of any fibrate in patients with hypogonadism. The fact that the strength with which fenofibrate altered uric acid, hsCRP, and fibrinogen inversely correlated with baseline testosterone levels indicates that the obtained results are in part a consequence of the effect of testosterone on LOH itself. The impact of fenofibrate on uric acid, hsCRP, and fibrinogen cannot be explained by the lipid-lowering potential of this drug. However, the presence of a correlation between the strength of this action and the treatment-induced changes in HOMA1-IR suggests that the pleiotropic effects are, in part, associated with an improvement in insulin sensitivity and may be mediated by free fatty acids. As our previous results show, fenofibrate reduced plasma levels of these acids [21,24] being endogenous ligands for PPAR-a receptors [19]. This association may explain why in the Veterans Affairs High-Density Lipoprotein Intervention Trial, a large clinical study including men with low HDL cholesterol levels and the average age of 64 years, the reduction in coronary heart disease events and related mortality was achieved mainly in individuals with insulin resistance [25]. In comparison with fenofibrate, the effect of testosterone was less pronounced. It should be stressed that when administered orally, testosterone undecanoate is absorbed into the lymphatic system with newly formed chylomicrons, then gets to the systematic circulation, and is rapidly converted into dihydrotestosterone [26]. Although, as recommended, testosterone undecanoate was taken with meals, its absorption in our patients might have been reduced because the participants were required to comply with lifestyle modifications and their fat intake was low. However, the fact that oral testosterone increased plasma testosterone levels as well as slightly reduced HDL cholesterol, which is in line with the observations of other research groups [14–16], based on populations not having to limit their lipid intake, indicates that impaired absorption cannot solely explain a relatively weak effect of testosterone in our study.
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Another interesting finding of our study was that the treatment-induced changes in plasma lipids, insulin sensitivity, and cardiovascular risk factors were strongest in patients receiving the combination therapy. Fenofibrate prevented a testosteroneinduced decrease in HDL cholesterol, while testosterone prevented an unfavorable effect of fenofibrate on plasma homocysteine, attributed to an alteration in creatine-creatinine metabolism and/or changes in methyl transfer [27,28]. Taking into account that increased levels of the investigated variables are associated with the earlier development and accelerated progression of atherosclerosis-related disorders [29–32], men with LOH and atherogenic dyslipidemia may benefit the most from the combined treatment with oral testosterone undecanoate and micronized fenofibrate. It seems that this combined treatment is an interesting therapeutic option particularly in symptomatic males with metabolic syndrome and very low testosterone levels. This study has some limitations. The most important of them is a small number of men participating in the study, its short duration and nonrandomized nature. Moreover, our study measured only surrogates, and its results cannot be easily translated to hard points. Because the study included only nondiabetic subjects, it remains unanswered whether oral testosterone, fenofibrate, and the combined treatment bring any benefits to males with LOH and diabetes. Finally, because testosterone was administered orally, the question of whether route of administration may affect the obtained results requires further studies. In conclusion, fenofibrate was superior to testosterone in improving plasma lipids and insulin sensitivity, and with exception of homocysteine, in reducing the remaining cardiometabolic risk factors. These effects, which are lipid-independent and more potent if both agents are administered together, may delay the onset and progression of atherosclerosis and related disorders.
Acknowledgments This work was supported by the statutory grant of the Medical University of Silesia (grant number NN-1-038/10).
Conflict of Interest The authors declare no conflict of interests.
Author Contributions Robert Krysiak conceived the study, participated in its design, as well as drafted and edited the manuscript. Wojciech Gilowski conducted the literature search, carried out the immunoassays, and performed the statistical analysis. Boguslaw Okopien participated in its design and coordination and provided critical input during manuscript preparations. All authors read and approved the final manuscript.
Institutional Approval The study was approved by the Bioethical Committee of the Medical University of Silesia.
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The Effect of Testosterone and Fenofibrate, Administered Alone or in Combination, on Cardiometabolic Risk Factors in Men with Late-Onset Hypogonadism and Atherogenic Dyslipidemia Robert Krysiak,1 Wojciech Gilowski1,2 & Bogusław Okopien1 1 Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland 2 Cardiology Department, Chrzanow District Hospital, Chrzanow, Poland
Keywords Androgens; Atherogenic dyslipidemia; Fibrates; Hypogonadism; Insulin resistance; Testosterone replacement. Correspondence R. Krysiak, Department of Internal Medicine and Clinical Pharmacology, Medical University w 18, 40-752 Katowice, of Silesia, Medyko Poland. Tel./Fax: +48-32-2523902; E-mail: [email protected]
doi: 10.1111/1755-5922.12139
SUMMARY Introduction: Oral testosterone was found to reduce plasma levels of HDL cholesterol. No previous study has examined the effect of fibrates, known to increase HDL cholesterol, in patients with low testosterone levels requiring testosterone replacement. Aims: The study included three age-, weight-, and lipid-matched groups of older men with atherogenic dyslipidemia and late-onset hypogonadism, treated with oral testosterone undecanoate (120 mg daily, n = 15), micronized fenofibrate (200 mg daily, n = 15), or testosterone plus fenofibrate (n = 18). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, and fibrinogen were assessed before and after 16 weeks of therapy. Results: Apart from an increase in plasma testosterone and a reduction in HDL cholesterol, testosterone undecanoate tended to decrease hsCRP and to improve insulin sensitivity. Fenofibrate administered alone increased HDL cholesterol, reduced triglycerides, decreased insulin resistance, reduced circulating levels of uric acid, hsCRP, and fibrinogen, as well as increased plasma levels of homocysteine. The strongest effect on testosterone, HOMA1-IR, uric acid, hsCRP, and fibrinogen was observed if fenofibrate was administered together with testosterone. Testosterone–fenofibrate combination therapy was also devoid of unfavorable effect on HDL cholesterol and homocysteine. Conclusions: Our study shows that fenofibrate produces a stronger effect on cardiometabolic risk factors in men with late-onset hypogonadism and atherogenic dyslipidemia than oral testosterone undecanoate. The obtained results suggest that this group of patients may benefit the most from the combined treatment with oral testosterone undecanoate and micronized fenofibrate.
Introduction Testosterone levels decline with aging, especially after 40 years of age, because of an age-related attrition in testicular Leydig cells and slowing of the hypothalamic gonadotropin-releasing hormone pulse generator [1]. Because of an increase in sex hormonebinding globulin, the decline is more pronounced for bioavailable testosterone (2–3% per year) than for total testosterone (1.6% per year) [2]. Consequently, a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult men [3]. Moreover, aging in men is often accompanied by a decrease in muscle mass and strength, an increase in abdominal fat (especially visceral fat), insulin resistance, an atherogenic lipid profile, a decrease in libido and pubic hair, osteopenia, decreased cognitive performance, depression, insomnia, perspiration, and a decrease in the general sense of well-being [4,5]. Recent clinical trials have demonstrated that low circulating testosterone levels are associated with increased cardiovascular morbidity and mortality [6,7]. The rate of decline in
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testosterone levels varies in different individuals and some middle-aged and elderly men may develop late-onset hypogonadism (LOH), defined as a clinical and biochemical syndrome associated with advancing age, which is characterized by typical symptoms and deficiency in serum testosterone levels [5]. The prevalence of low testosterone levels and the symptoms of its deficiency is higher in men with comorbidities such as obesity, type 2 diabetes, hypertension, dyslipidemias, cardiovascular disease, asthma, and chronic obstructive pulmonary disease [1,8,9]. Because the symptoms of LOH are similar to those of hypogonadism in young men, testosterone therapy has become a popular option for its therapy [9]. In numerous studies, testosterone replacement was able to improve libido, sexual function, central obesity, glycometabolic control, mood, and muscle strength [8,10,11]. Unfortunately, no previous study has investigated the effect of testosterone therapy on cardiovascular morbidity or mortality, and therefore, the causality of the relationship between low testosterone levels and cardiovascular disease is unclear. Although observational studies show a consistent association of low
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testosterone with adverse lipid profiles [12,13], the question whether testosterone therapy exerts a beneficial effect plasma lipids remains uncertain. Moreover, in some studies, testosterone decreased circulating levels of HDL [14–16], considered to have a protective effect against coronary heart disease [17]. Taking into account the high prevalence of dyslipidemias in the general population [18], many men with LOH require treatment with lipid-lowering agents. However, to the best of our knowledge, no previous study has investigated the impact of concurrent treatment with testosterone and any hypolipidemic agent. The aim of this study was to compare the effect of fenofibrate, known to increase HDL cholesterol [19], administered alone or in combination with testosterone, and the effect of testosterone monotherapy on plasma lipid levels and plasma levels of other cardiometabolic risk factors in nondiabetic patients with LOH and atherogenic dyslipidemia.
Materials and Methods The participants of the study were recruited among men (55– 79 years old) with atherogenic dyslipidemia, defined as plasma HDL cholesterol less than 40 mg/dL and triglycerides at least 150 mg/dL), complying with lifestyle intervention for at least 3 months before the beginning of the study. To be admitted to the study, they had to meet the criteria of LOH: total testosterone level below 3.0 ng/mL on two different occasions combined with the presence of the following symptoms: decreased frequency of morning erection, erectile dysfunction, and decreased frequency of sexual thoughts. The exclusion criteria were as follows: prostate cancer, severe lower urinary tract symptoms (the American Urological Association International Prostate Symptom Score exceeding 19), baseline prostate-specific antigen greater than 4 ng/mL (or prostate-specific antigen above 3 ng/ mL in men at high risk of prostate cancer), breast cancer, myocardial infarction, acute coronary event, unstable angina, stroke or coronary revascularization procedure within 6 months preceding the study, severe heart failure (classes II–IV according to the New York Heart Association Functional Classification), uncontrolled arterial hypertension, hematocrit exceeding 50%, untreated obstructive sleep aspnea, diabetes mellitus or treatment with any hypolipemic agents within 3 months, concomitant treatment with other drugs known either to affect plasma lipid levels or to interact with testosterone and fibrates, and poor patient compliance. The Bioethical Committee of the Medical University of Silesia approved the study protocol. All enrolled patients provided their written informed consent for the investigation, and the study was performed according to the Declaration of Helsinki. The study population was divided into three age-, weight-, and lipid-matched groups, treated with testosterone and fenofibrate (group 1, n = 15), testosterone alone (group 2, n = 15), or fenofibrate alone (group 3, n = 18). Both testosterone undecanoate (120 mg daily) and micronized fenofibrate (200 mg daily) were administered orally for 16 weeks without any changes in dosage throughout the study. Testosterone undecanoate was given in three equal doses, while fenofibrate once daily. Moreover, throughout the study, the participants continued to comply with lifestyle modifications. Compliance, investigated during each visit,
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was regarded as satisfactory if the number of tablets taken by a patient ranged from 90% to 110%. Venous blood samples were drawn from the antecubital vein, after a 12-h overnight fast, in a quiet temperature controlled room (24–25°C) between 8.00 and 9.00 a.m. (to avoid possible circadian fluctuations in the parameters studied) before and after 16 weeks of treatment. Plasma lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), fasting glucose, and plasma uric acid were assayed by routine laboratory techniques (Roche Diagnostics, Basel, Switzerland). LDL-cholesterol levels were measured directly. Plasma insulin, total testosterone, and dehydroepiandrosterone sulfate (DHEA-S) were determined by enzyme-linked immunosorbent assay (DRG Instruments GmbH, Marburg, Germany). To calculate the homeostasis model assessment 1 of insulin resistance ratio (HOMA1-IR), the following equation was used: (fasting serum glucose [mg/dL] 9 fasting insulin level [lU/mL])/405. Circulating levels of CRP were assessed using a high-sensitivity monoclonal antibody assay (hsCRP) (MP Biomedicals, Orangeburg, New York, United States). Plasma homocysteine levels were determined with the use of enzyme immunoassay (Diazyme, San Diego, CA, USA). Plasma fibrinogen levels were determined with a semi-automated blood coagulation analyzer OPTION 2 Plus using reagents obtained from bioMerieux (Marcy l’Etoile, France). The intraand interassay coefficients of variation for the assessed variables were less than 6.2 and 8.7%, respectively. The distribution of the variables was analyzed using the Kolmogorov–Smirnov test. Outcomes for triglycerides, HOMA1-IR, hsCRP homocysteine, fibrinogen, and hormones were natural-log transformed to meet the assumptions of normality and equal variance. Between-group comparisons were performed using oneway ANOVA followed by the post hoc Bonferroni test. The differences between the means of variables within the same treatment group were analyzed with Student’s paired t-test. Chi-squared test was used to compare associations between categorical variables. Correlations were calculated using Kendall’s tau test. Values of P < 0.05 were considered statistically significant.
Results At the start of the study, there was no difference between the treatment groups in terms of age, weight, medical background, and laboratory characteristics. Demographic data and baseline results are shown in Tables 1 and 2. Two patients treated with testosterone undecanoate and fenofibrate stopped participating in the study because of increased transaminase activity and increased hematocrit. One subject receiving fenofibrate was withdrawn from the study because of noncompliance with the study protocol. Another patient (treated with testosterone) withdrew his content and therefore did not complete the study. Neither significant adverse effects nor any complications were reported throughout the entire study period in the remaining participants. Testosterone undecanoate administered alone increased plasma testosterone levels by 65% (P < 0.001), reduced plasma HDL cholesterol by 12% (P < 0.05), as well as insignificantly reduced plasma levels of hsCRP ( 14%, P = 0.086) and HOMA1-IR ( 11%, P = 0.098). Testosterone undecanoate produced no effect
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Table 1 Baseline characteristics of participantsa
Variable
Testosterone
Fenofibrate
Combined therapy
Number of patients Age [years; mean (SD)] Body mass index [kg/m2; mean (SD)] Waist circumference [cm; mean (SD)] Smokers [n (%)] Metabolic syndrome [n (%)] Treated hypertension [n (%)] Systolic blood pressure [mmHg; mean (SD)] Diastolic blood pressure [mmHg; mean (SD)]
14 67 (4) 28.8 (2.6)
14 68 (5) 29.1 (2.4)
16 68 (5) 28.3 (2.2)
98 (5)
99 (5)
97 (4)
5 (36) 12 (86)
4 (29) 12 (86)
5 (31) 14 (88)
10 (71)
10 (71)
11 (69)
127 (7)
128 (7)
125 (8)
83 (4)
82 (4)
81 (4)
a
Only data of patients who completed the study were included in the final analyses.
on plasma levels of DHEA-S, total and LDL cholesterol, triglycerides, glucose, uric acid, fibrinogen, and homocysteine (Table 2). Fenofibrate administered alone increased plasma levels of HDL cholesterol by 22% (P < 0.01), decreased plasma levels of triglycerides by 42% (P < 0.001), as well as insignificantly reduced plasma levels of total ( 13%, P = 0.056) and LDL ( 10%, P = 0.083) cholesterol. Moreover, fenofibrate reduced circulating levels of uric acid by 19% (P < 0.05), hsCRP by 29% (P < 0.001), and fibrinogen by 16% (P < 0.05), decreased HOMA1-IR by 20% (P < 0.01), as well as increased plasma homocysteine by 24% (P < 0.05). The drug did not affect plasma testosterone, DHEA-S, and glucose (Table 2). Testosterone–fenofibrate combination reduced plasma levels of LDL cholesterol by 19% (P < 0.01), total cholesterol by 21% (P < 0.01), and triglycerides by 44% (P < 0.001). Moreover, 16 weeks of testosterone–fenofibrate combination therapy increased plasma testosterone by 94% (P < 0.001), reduced HOMA1-IR by 38% (P < 0.001), as well as decreased circulating levels of uric acid by 40% (P < 0.001), hsCRP by 45% (P < 0.001), and fibrinogen by 28% (P < 0.01). No changes in DHEA-S, HDL cholesterol, fasting glucose, and homocysteine were observed (Table 2). The combination therapy was superior to (1) testosterone undecanoate alone and fenofibrate alone with regard to circulating levels of testosterone, uric acid, hsCRP, and fibrinogen as well as HOMA1-IR; (2) testosterone undecanoate alone in affecting total cholesterol, LDL cholesterol, HDL testosterone, and triglycerides; (3) fenofibrate alone in affecting plasma homocysteine. Fenofibrate alone was superior to testosterone undecanoate alone in affecting HDL cholesterol, triglycerides, hsCRP, uric acid, and fibrinogen, as well as inferior to testosterone undecanoate in affecting plasma testosterone (Table 2). At entry, there was a correlation between plasma levels of uric acid, hsCRP, homocysteine, fibrinogen, and plasma levels of total cholesterol (r values between 0.31 [P < 0.05] and 0.41
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Table 2 The effect of testosterone undecanoate and fenofibrate treatment on steroid hormones, plasma lipids, glucose homeostasis markers, and the investigated cardiometabolic risk factors in men with late-onset hypogonadism and atherogenic dyslipidemiai Variable
Testosterone
Total testosterone [ng/mL; mean (SD)] Baseline 1.7 (0.4) After 16 weeks 2.8 (0.5)c,h DHEA-S [lg/dL; mean (SD)] Baseline 130 (35) After 16 weeks 142 (49) Total cholesterol [mg/dL; mean (SD)] Baseline 236 (25) After 16 weeks 228 (30) LDL-cholesterol [mg/dL; mean (SD)] Baseline 144 (14) After 16 weeks 142 (16) HDL cholesterol [mg/dL; mean (SD)] Baseline 34 (3) After 16 weeks 30 (3)a Triglycerides [mg/dL; mean (SD)] Baseline 259 (41) After 16 weeks 249 (37) Glucose [mg/dL; mean (SD)] Baseline 99 (5) After 16 weeks 99 (6) HOMA1-IR Baseline 3.8 (0.7) After 16 weeks 3.4 (0.6) Uric acid [lmol/L; mean (SD)] Baseline 395 (58) After 16 weeks 383 (60) hsCRP [mg/L; mean (SD)] Baseline 3.7 (0.8) After 16 weeks 3.2 (0.5) Homocysteine [lmol/L; mean (SD)] Baseline 38 (8) After 16 weeks 37 (11) Fibrinogen [mg/dL; mean (SD)] Baseline 407 (60) After 16 weeks 412 (60)
Fenofibrate
Combined therapy
1.6 (0.4) 1.9 (0.4)
1.8 (0.3) 3.5 (0.6)c,d,h
120 (29) 140 (41)
116 (37) 129 (29)
240 (31) 210 (29)
243 (36) 193 (28)b,d
149 (17) 134 (18)
155 (19) 126 (16)b,d
32 (4) 39 (5)b,f
32 (3) 35 (4)a,d
267 (43) 159 (35)c,f
249 (39) 140 (35)c,f
100 (6) 96 (5)
97 (5) 93 (5)
3.5 (0.6) 2.8 (0.4)b
3.7 (0.8) 2.3 (0.4)c,f,g
378 (70) 308 (52)a,d
411 (68) 247 (55)c,f,g
3.8 (0.6) 2.7 (0.5)c,d
4.0 (0.8) 2.2 (0.4)c,f,g
34 (8) 42 (6)a
40 (11) 36 (5)g
420 (58) 351 (61)a,d
396 (62) 285 (69)b,e,g
P < 0.05, bP < 0.01, cP < 0.001 vs. baseline value; dP < 0.05, P < 0.01, fP < 0.001 vs. testosterone-treated patients; gP < 0.05, h P < 0.001 vs. fenofibrate-treated patients. iOnly data of patients who completed the study were included in the final analyses. a
e
[P < 0.001]), LDL cholesterol (r values between 0.32 [P < 0.05] and 0.40 [P < 0.001]), HDL cholesterol (r values between 0.35 [P < 0.01] and 0.49 [P < 0.001]), and triglycerides (r values between 0.37 [P < 0.01] and 0.51 [P < 0.001]). There were also correlations between circulating levels of uric acid, hsCRP, homocysteine and fibrinogen, and HOMA1-IR (r values between 0.38 [P < 0.01] and 0.56 [P < 0.001]), as well as between levels of uric acid, hsCRP, homocysteine and fibrinogen, and testosterone (r values between 0.34 [P < 0.01] and 0.51 [P < 0.001]). The effect of fenofibrate administered alone or in combination with testosterone on uric acid, hsCRP, and fibrinogen correlated
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weakly with the effect of this drug on HOMA1-IR (fenofibrate: r values between 0.40 [P < 0.01] and 0.58 [P < 0.001]; combination therapy: r values between 0.37 [P < 0.01] and 0.59 [P < 0.001]) but not with the effect on plasma lipids. Treatmentinduced changes in uric acid, hsCRP, and fibrinogen inversely correlated with baseline testosterone levels (testosterone: r values between 0.30 [P < 0.05] and 0.48 [P < 0.001]; fenofibrate: r values between 0.42 [P < 0.001] and 0.53 [P < 0.001]; combination therapy: r values between 0.37 [P < 0.01] and 0.50 [P < 0.001]).
Discussion The major finding of our prospective study is that fenofibrate produced a stronger effect on cardiometabolic risk factors in men with LOH and atherogenic dyslipidemia than oral testosterone undecanoate did. Previously, we observed a multidirectional action of fenofibrate including an improvement in glucose metabolism and the inhibitory action on plasma lipids and other risk factors in various metabolic disturbances, including prediabetes, overt diabetes, and mixed dyslipidemia [20–24]. However, the present study is the first which has shown a beneficial effect of any fibrate in patients with hypogonadism. The fact that the strength with which fenofibrate altered uric acid, hsCRP, and fibrinogen inversely correlated with baseline testosterone levels indicates that the obtained results are in part a consequence of the effect of testosterone on LOH itself. The impact of fenofibrate on uric acid, hsCRP, and fibrinogen cannot be explained by the lipid-lowering potential of this drug. However, the presence of a correlation between the strength of this action and the treatment-induced changes in HOMA1-IR suggests that the pleiotropic effects are, in part, associated with an improvement in insulin sensitivity and may be mediated by free fatty acids. As our previous results show, fenofibrate reduced plasma levels of these acids [21,24] being endogenous ligands for PPAR-a receptors [19]. This association may explain why in the Veterans Affairs High-Density Lipoprotein Intervention Trial, a large clinical study including men with low HDL cholesterol levels and the average age of 64 years, the reduction in coronary heart disease events and related mortality was achieved mainly in individuals with insulin resistance [25]. In comparison with fenofibrate, the effect of testosterone was less pronounced. It should be stressed that when administered orally, testosterone undecanoate is absorbed into the lymphatic system with newly formed chylomicrons, then gets to the systematic circulation, and is rapidly converted into dihydrotestosterone [26]. Although, as recommended, testosterone undecanoate was taken with meals, its absorption in our patients might have been reduced because the participants were required to comply with lifestyle modifications and their fat intake was low. However, the fact that oral testosterone increased plasma testosterone levels as well as slightly reduced HDL cholesterol, which is in line with the observations of other research groups [14–16], based on populations not having to limit their lipid intake, indicates that impaired absorption cannot solely explain a relatively weak effect of testosterone in our study.
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Another interesting finding of our study was that the treatment-induced changes in plasma lipids, insulin sensitivity, and cardiovascular risk factors were strongest in patients receiving the combination therapy. Fenofibrate prevented a testosteroneinduced decrease in HDL cholesterol, while testosterone prevented an unfavorable effect of fenofibrate on plasma homocysteine, attributed to an alteration in creatine-creatinine metabolism and/or changes in methyl transfer [27,28]. Taking into account that increased levels of the investigated variables are associated with the earlier development and accelerated progression of atherosclerosis-related disorders [29–32], men with LOH and atherogenic dyslipidemia may benefit the most from the combined treatment with oral testosterone undecanoate and micronized fenofibrate. It seems that this combined treatment is an interesting therapeutic option particularly in symptomatic males with metabolic syndrome and very low testosterone levels. This study has some limitations. The most important of them is a small number of men participating in the study, its short duration and nonrandomized nature. Moreover, our study measured only surrogates, and its results cannot be easily translated to hard points. Because the study included only nondiabetic subjects, it remains unanswered whether oral testosterone, fenofibrate, and the combined treatment bring any benefits to males with LOH and diabetes. Finally, because testosterone was administered orally, the question of whether route of administration may affect the obtained results requires further studies. In conclusion, fenofibrate was superior to testosterone in improving plasma lipids and insulin sensitivity, and with exception of homocysteine, in reducing the remaining cardiometabolic risk factors. These effects, which are lipid-independent and more potent if both agents are administered together, may delay the onset and progression of atherosclerosis and related disorders.
Acknowledgments This work was supported by the statutory grant of the Medical University of Silesia (grant number NN-1-038/10).
Conflict of Interest The authors declare no conflict of interests.
Author Contributions Robert Krysiak conceived the study, participated in its design, as well as drafted and edited the manuscript. Wojciech Gilowski conducted the literature search, carried out the immunoassays, and performed the statistical analysis. Boguslaw Okopien participated in its design and coordination and provided critical input during manuscript preparations. All authors read and approved the final manuscript.
Institutional Approval The study was approved by the Bioethical Committee of the Medical University of Silesia.
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