ORIGINAL RESEARCH
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

https://doi.org/10.1111/j.1743-6109.2010.01931.xGet rights and content

ABSTRACT

Introduction

Longitudinal studies have demonstrated that male hypogonadism could be considered a surrogate marker of incident cardiovascular disease.

Aim

To evaluate the effects of parenteral testosterone undecanoate (TU) in outclinic patients with metabolic syndrome (MS) and late-onset hypogonadism (total testosterone (T) at or below 11 nmol/L or free T at or below 250 pmol/L).

Methods

This is a randomized, double-blind, double-dummy, placebo-controlled, parallel group, single-center study. Fifty patients (mean age 57 ± 8) were randomized (4:1) to receive TU 1,000 mg (every 12 weeks) or placebo (PLB) gel (3–6 g/daily) for 24 months.

Main Outcome Measures

Homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT), and high-sensitivity C-reactive protein (hsCRP).

Results

At baseline, all patients fulfilled the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria for the definition of MS. An interim analysis conducted at 12 months showed that TU markedly improved HOMA-IR (P < 0.001), CIMT (P < 0.0001), and hsCRP (P < 0.001) compared with PLB; thus, all patients were shifted to TU treatment. After 24 months, 35% (P < 0.0001) and 58% (P < 0.001) of patients still presented MS as defined by NCEP-ATPIII and IDF criteria, respectively. Main determinants of changes were reduction in waist circumference (P < 0.0001), visceral fat mass (P < 0.0001), and improvement in HOMA-IR without changes in body mass index (BMI).

Conclusions

TU reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with MS. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in MS without significant hematological and prostate adverse events. Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, and 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.

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;

References (44)

  • G. Caminiti et al.

    Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study

    J Am Coll Cardiol

    (2009)
  • M. Schubert et al.

    Late-onset hypogonadism in the aging male (LOH): Definition, diagnostic and clinical aspects

    J Endocrinol Invest

    (2005)
  • H.A. Feldman et al.

    Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts Male Aging Study

    J Clin Endocrinol Metab

    (2002)
  • A.M. Traish et al.

    The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction

    J Androl

    (2009)
  • J.Y. Oh et al.

    Endogenous sex hormones and development of type 2 diabetes mellitus in older men and women: Rancho-Bernard study

    Diabetes Care

    (2002)
  • A.M. Traish et al.

    The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance

    J Androl

    (2009)
  • M. Fukui et al.

    Role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes

    Curr Diab Rev

    (2007)
  • A.M. Traish et al.

    The dark side of testosterone deficiency: III. Cardiovascular disease

    J Androl

    (2009)
  • C.J. Malkin et al.

    Testosterone therapy in men with moderate severity heart failure: A double-blind randomized placebo controlled trial

    Eur Heart J

    (2006)
  • M.R. Smith et al.

    Insulin sensitivity during combined androgen blockade for prostate cancer

    J Clin Endocrinol Metab

    (2006)
  • M. Maggio et al.

    Relationship between low levels of anabolic hormones and 6-year mortality in older men: The aging in the Chianti Area (InCHIANTI) study

    Arch Intern Med

    (2007)
  • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)

    Adult Treatment Panel III. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults

    Circulation

    (2002)
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