Testosterone Replacement in Metabolic Syndrome and Inflammation

Overview

Hypogonadism (HG) frequently complicates the Metabolic Syndrome (MetS), whether testosterone replacement (TRT) is beneficial has not been clearly ascertained. This study was designed to address the effects of TRT on insulin resistance, body composition and pro-inflammatory status in naïve patients with MetS and HG.

Full Title of Study: “Testosterone Replacement in Metabolic Syndrome and Inflammation of Fat Tissue”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 2014

Detailed Description

The features of Metabolic Syndrome (MetS) include abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance or glucose intolerance. These symptoms are also frequently found in hypogonadal men. Adipose tissue and androgens in male obesity are reciprocally linked. Total and free testosterone (T) are decreased in proportion to the degree of body fatness while T regulates insulin sensitivity and body composition. As a consequence, hypoandrogenism carries an additional independent risk for cardiovascular and metabolic disorders. Men with type 2 diabetes mellitus (T2D) exhibit lowered T levels that are inversely correlated to HbA1c. In addition, abdominal adiposity causes an impairment of testicular steroidogenesis that is directly linked to circulating adipokines; enhanced cytokine release from macrophage-infiltrated adipose tissue is pivotal to the pathogenesis of insulin resistance and atherosclerosis. Both MetS and T2D share with hypogonadism such a proinflammatory state. For this reason we performed a randomized controlled trial on the effects of TRT on insulin resistance and circulating inflammatory markers in a cohort of middle-aged men with mild hypogonadism and MetS at first diagnosis, that were not taking medications known to influence the investigated outcomes. We established strict criteria for enrollment and used a physiological replacing therapy. Given that testosterone replacement therapy (TRT) determines a reduction of body fat mass paralleled by an increase in fat free mass (6), and that TRT exerts an anti-inflammatory role inhibiting interleukins (IL), in particular the IL-6 gene (14), it remains to be established whether these independent effects also reflect in an improvement in insulin resistance.

Interventions

  • Drug: Testosterone
    • Testosterone transdermal gel 50 mg/day (5 gr)
  • Drug: Placebo
    • Placebo transdermal gel (5 gr)

Arms, Groups and Cohorts

  • Experimental: Testosterone gel
    • Testosterone transdermal gel 50 mg/day
  • Placebo Comparator: Placebo gel
    • Placebo gel

Clinical Trial Outcome Measures

Primary Measures

  • Fat-Free Mass (kg)
    • Time Frame: 3 months
    • Estimate of within subject absolute change in fat-free mass measured by DEXA (dual energy x-ray absorptiometry) at 3 months (90 days) interval during active or placebo treatment.

Secondary Measures

  • Fat Mass (kg)
    • Time Frame: 3 months
    • Estimate of within subject absolute change (Kg) in fat mass measured by DEXA at 3 months (90 days) interval during active or placebo treatment.
  • HOMA-IR (homeostasis model assessment)- (insulin resistance)
    • Time Frame: 3 months
    • Estimate of within subject absolute change in measure of insulin resistance homeostatic model HOMA-IR.
  • CRP (C reactive protein)
    • Time Frame: 3 months
    • C reactive protein (High sensitivity).
  • Interleukins
    • Time Frame: 3 months
    • Within subject absolute and percentage change in serum: IL-1, IL-6, IL-10, IL-12, IL-2, IL-8, TNFa (tumor necrosis factor alpha)
  • Adipokines
    • Time Frame: 3 months
    • Estimate of within subject absolute change in serum: ADIPONECTIN, LEPTIN, RESISTIN.
  • Waist circumference
    • Time Frame: 3 months
    • Waist circumference (cm)
  • IIEF
    • Time Frame: 3 months
    • International Index of Erectile Dysfunction
  • Penile CDU (color Doppler ultrasound)
    • Time Frame: 3 months
    • Penile Color-Doppler Ultrasonography of cavernosal arteries before and after active or placebo treatment.
  • PSA (prostatic specific antigen)
    • Time Frame: 3 months
    • PSA
  • Hb, Htc
    • Time Frame: 3 months
    • haemoglobin and haematocrit
  • Fat-free mass
    • Time Frame: 6 months
  • Fat Mass
    • Time Frame: 6 months
  • HOMA-IR
    • Time Frame: 6 months
  • CRP
    • Time Frame: 6 months
  • Interleukins
    • Time Frame: 6 months
    • Serum IL-1, IL-6, IL-10, IL-12, IL-2, IL-8, TNFa
  • Adipokines
    • Time Frame: 6 months
    • Serum ADIPONECTIN, LEPTIN, RESISTIN.

Participating in This Clinical Trial

Inclusion Criteria

  • patients with Metabolic Syndrome according to ATPIII – patients with mild hypogonadism (both testosterone evaluations between 6 and 11 nmol/L) – patients naïve to hypoglycemic therapies Exclusion Criteria:

  • patients on hypoglycemic medications – patients with severe hypogonadism (<5 nmol/L) – patients with borderline T values hypogonadism (>11 nmol/L) – patients with contraindication to testosterone therapy: prostate cancer, PSA>4 ng/ml, severe hepatic or renal insufficiency, Hb>17, Htc>52%, severe urinary retention

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Roma La Sapienza
  • Provider of Information About this Clinical Study
    • Principal Investigator: Andrea M. Isidori, Professor of Endocrinology – University of Roma La Sapienza
  • Overall Official(s)
    • Vincenzo Bonifacio, MD, PhD, Principal Investigator, University of Roma La Sapienza
    • Andrea M Isidori, MD, PhD, Study Director, University of Roma La Sapienza
    • Andrea Lenzi, MD, PhD, Study Chair, University of Roma La Sapienza

References

Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, Fabbri A. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999 Oct;84(10):3673-80. doi: 10.1210/jcem.84.10.6082.

Aversa A, Isidori AM, Greco EA, Giannetta E, Gianfrilli D, Spera E, Fabbri A. Hormonal supplementation and erectile dysfunction. Eur Urol. 2004 May;45(5):535-8. doi: 10.1016/j.eururo.2004.01.005. Erratum In: Eur Urol. 2005 Apr;47(4):564.

Isidori AM, Giannetta E, Pozza C, Bonifacio V, Isidori A. Androgens, cardiovascular disease and osteoporosis. J Endocrinol Invest. 2005;28(10 Suppl):73-9.

Isidori AM, Greco EA, Aversa A. Androgen deficiency and hormone-replacement therapy. BJU Int. 2005 Aug;96(2):212-6. doi: 10.1111/j.1464-410X.2005.05603.x. No abstract available.

Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005 Sep;63(3):280-93. doi: 10.1111/j.1365-2265.2005.02339.x.

Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, Isidori A, Fabbri A, Lenzi A. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf). 2005 Oct;63(4):381-94. doi: 10.1111/j.1365-2265.2005.02350.x.

Isidori AM, Lenzi A. Testosterone replacement therapy: what we know is not yet enough. Mayo Clin Proc. 2007 Jan;82(1):11-3. doi: 10.4065/82.1.11. No abstract available.

Aversa A, Isidori AM, Spera G, Lenzi A, Fabbri A. Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction. Clin Endocrinol (Oxf). 2003 May;58(5):632-8. doi: 10.1046/j.1365-2265.2003.01764.x.

Aversa A, Isidori AM, De Martino MU, Caprio M, Fabbrini E, Rocchietti-March M, Frajese G, Fabbri A. Androgens and penile erection: evidence for a direct relationship between free testosterone and cavernous vasodilation in men with erectile dysfunction. Clin Endocrinol (Oxf). 2000 Oct;53(4):517-22. doi: 10.1046/j.1365-2265.2000.01118.x.

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