ORIGINAL RESEARCHEffects 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
Introduction
The acronym “late-onset hypogonadism”[1] is simply a term relating to the increased incidence of testosterone (T) deficiency in many aging men [2] and may affect between 19% and 34% of men over the age of 60 years. Low T levels are recognized as an independent risk factor associated with a number of conditions such as metabolic syndrome (MS) 3, 4, obesity [5], type 2 diabetes mellitus (T2DM) 6, 7, atherosclerosis [8], myocardial infarction [9], chronic heart failure [10] and erectile dysfunction (ED) [11]. The association between low T levels and cardiovascular diseases (CVD) is supported by findings from men undergoing androgen suppression as treatment for prostate cancer that confirm that the hypogonadal state increases body fat mass serum insulin, facilitates the development of insulin resistance and altered glucose metabolism [12], and leads to an increase in cardiovascular events and all-causes mortality [13].
MS is commonly defined as a cluster of risk factors such as central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein (HDL), high blood pressure, increased fasting glucose, and hyperinsulinemia/insulin resistance 14, 15. It is associated with an increased risk for the development of both T2DM and CVD [16]. Interestingly, low T levels can predict the development of insulin resistance [17] and its progression to T2DM [18], and is also associated with an increased cardiovascular risk 19, 20. T has been found to be an important regulator of muscular insulin sensitivity [21] and its administration improves insulin sensitivity in diabetic men with low plasma total T [22].
Section snippets
Aims
The purpose of the present study was to investigate whether long-term T replacement therapy with T undecanoate (TU) may be able to modify cardiovascular risk factors and atherosclerosis progression in a population of hypogonadal men with MS and/or T2DM.
Study Population
Patients were included in the study if they were aging between 45 and 65 years, had MS and/or T2DM defined by the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and by the International Diabetes Federation (IDF) [23] and total T serum level below 3.0 ng/mL (11 nmol/L) or calculated free T levels <250 pmol/L (10 pg/mL) on two early morning separate days (between 8:00 and 11:00 am) at least 1 week apart, and at least two symptoms of hypogonadism as stated by
Results
Baseline characteristics of the study population are shown in Table 1. Biochemical and hormonal changes from baseline are reported in Table 2. After 12 months, a primary analysis, including a total of 50 patients randomized, was performed. Therefore, the study blind was opened because a significant difference (P < 0.01) between the groups in HOMA-IR, CIMT, and hsCRP was found. Subsequently, overall, patient received TU for the remaining 12 months treatment period.
Discussion
The present study shows that in the same patient population, TU treatment for 24 months ameliorates both insulin resistance and visceral adiposity which are factors associated with a higher risk of death [31]. Thus, the presence of MS was reverted because patients no longer had at least three diagnostic criteria after treatment. These effects were robust after 12 months so that the study blinding was opened and all patients were successfully treated with TU without major unwanted effects.
Conclusions
This study demonstrates that TU treatment for 24 months reduced fasting glucose and waist circumference in hypogonadal men with MS. Besides changes in body composition, TU reduced hsCRP and CIMT, which are surrogate markers of endothelial function and atherosclerosis progression. TU should be considered as an adjunctive therapy for the treatment of those men affected by hypogonadism and MS, in whom the correction of lifestyle factors alone, i.e., diet and physical exercise, may not be such
Category 1
- (a)
Conception and Design
Antonio Aversa; Roberto Bruzziches
- (b)
Acquisition of Data
Roberto Bruzziches; Davide Francomano
- (c)
Analysis and Interpretation of Data
Andrea Lenzi; Davide Francomano; Andrea M. Isidori
Category 2
- (a)
Drafting the Article
Antonio Aversa; Roberto Bruzziches; Davide Francomano; Giuseppe Rosano
- (b)
Revising It for Intellectual Content
Giovanni Spera; Andrea Lenzi; Andrea M. Isidori
Category 3
- (a)
Final Approval of the Completed Article
Antonio Aversa; Roberto Bruzziches; Davide Francomano; Andrea Lenzi; Giovanni Spera;
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Conflict of Interest: None.