Testosterone Replacement in Metabolic Syndrome and Inflammation

Phase 4

Completed

• Conditions: Obesity; Hypogonadism; Metabolic Syndrome; Erectile Dysfunction
• Interventions: Drug: Placebo; Drug: Testosterone

• Registration Number: NCT01123278
• Lead Sponsor: University of Roma La Sapienza

Brief Summary

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.

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.

Study Timeline

• Study Start: 2004-01
• Study First Submitted: 2010-05-10
• Study First Submitted QC: 2010-05-11
• Study First Posted: 2010-05-14
• Status Verified: 2014-10
• Primary Completion: 2014-10
• Study Completion: 2014-10
• Last Update Submitted: 2014-10-25
• Last Update Posted: 2014-10-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 82

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo gel	Placebo	Placebo gel
Testosterone gel	Testosterone	Testosterone transdermal gel 50 mg/day

Primary Outcome Measures

Name	Time	Method
Fat-Free Mass (kg)	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 Outcome Measures

Name	Time	Method
PSA (prostatic specific antigen)	3 months	PSA
Hb, Htc	3 months	haemoglobin and haematocrit
Fat-free mass	6 months
Fat Mass (kg)	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)	3 months	Estimate of within subject absolute change in measure of insulin resistance homeostatic model HOMA-IR.
CRP (C reactive protein)	3 months	C reactive protein (High sensitivity).
Interleukins	6 months	Serum IL-1, IL-6, IL-10, IL-12, IL-2, IL-8, TNFa
Adipokines	6 months	Serum ADIPONECTIN, LEPTIN, RESISTIN.
Waist circumference	3 months	Waist circumference (cm)
IIEF	3 months	International Index of Erectile Dysfunction
Penile CDU (color Doppler ultrasound)	3 months	Penile Color-Doppler Ultrasonography of cavernosal arteries before and after active or placebo treatment.
Fat Mass	6 months
HOMA-IR	6 months
CRP	6 months

Trial Locations

Locations (2)

Dipartimento di Fisiopatologia Medica - Policlinico Umberto I; 🇮🇹 Rome, Italy

Policlinico Umberto I Hospital - Sapienza University; 🇮🇹 Rome, Italy