Clinical trial NCT01123278: Testosterone Replacement in Metabolic Syndrome and Inflammation
Official title: Testosterone Replacement in Metabolic Syndrome and Inflammation of Fat Tissue
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypogonadism
Metabolic Syndrome
Obesity
Erectile Dysfunction
Keywords: Adiponectin
Resistin
Adipocytes
Testosterone
Aging
HOMA-IR
Insulin
Hypogonadism
Metabolic Syndrome
Obesity
Erectile Dysfunction
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2010-05-14
Enrollment: 82
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Fat-Free Mass (kg)
timeFrame: 3 months
Secondary outcomes:
measure: Fat Mass (kg)
timeFrame: 3 months
measure: HOMA-IR (homeostasis model assessment)- (insulin resistance)
timeFrame: 3 months
measure: CRP (C reactive protein)
timeFrame: 3 months
measure: Interleukins
timeFrame: 3 months
measure: Adipokines
timeFrame: 3 months
measure: Waist circumference
timeFrame: 3 months
measure: IIEF
timeFrame: 3 months
measure: Penile CDU (color Doppler ultrasound)
timeFrame: 3 months
measure: PSA (prostatic specific antigen)
timeFrame: 3 months
measure: Hb, Htc
timeFrame: 3 months
measure: Fat-free mass
timeFrame: 6 months
measure: Fat Mass
timeFrame: 6 months
measure: HOMA-IR
timeFrame: 6 months
measure: CRP
timeFrame: 6 months
measure: Interleukins
timeFrame: 6 months
measure: Adipokines
timeFrame: 6 months
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Dipartimento di Fisiopatologia Medica - Policlinico Umberto I
city: Rome
country: Italy
facility: Policlinico Umberto I Hospital - Sapienza University
Study officials:
affiliation: University of Roma La Sapienza
name: Vincenzo Bonifacio, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Roma La Sapienza
name: Andrea M Isidori, MD, PhD
role: STUDY_DIRECTOR
affiliation: University of Roma La Sapienza
name: Andrea Lenzi, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: Isidori AM, Giannetta E, Pozza C, Bonifacio V, Isidori A. Androgens, cardiovascular disease and osteoporosis. J Endocrinol Invest. 2005;28(10 Suppl):73-9.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.