Testosterone Replacement in Metabolic Syndrome and Inflammation

Obesity Clinical Trial

— TERMSINFAT  

Official title:

Testosterone Replacement in Metabolic Syndrome and Inflammation of Fat Tissue

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01123278
• Other study ID #: TestoMet05
• Status: Completed
• Phase: Phase 4
• First received: May 10, 2010
• Last updated: October 25, 2014
• Start date: January 2004
• Est. completion date: October 2014

Study information

• Verified date: October 2014
• Source: University of Roma La Sapienza
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: National Institute of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: October 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 75 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Erectile Dysfunction
• Hypogonadism
• Metabolic Syndrome
• Metabolic Syndrome X
• Obesity
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Italy	Dipartimento di Fisiopatologia Medica - Policlinico Umberto I	Rome
Italy	Policlinico Umberto I Hospital - Sapienza University	Rome

Sponsors (1)

Lead Sponsor	Collaborator
University of Roma La Sapienza

Country where clinical trial is conducted

Italy, 

References & Publications (9)

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. — View 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. Erratum in: Eur Urol. 2005 Apr;47(4):564. — View 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. — View 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. — View 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. Review. — View 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. Review. — View 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. Review. — View Citation

Isidori AM, Greco EA, Aversa A. Androgen deficiency and hormone-replacement therapy. BJU Int. 2005 Aug;96(2):212-6. Review. — View Citation

Isidori AM, Lenzi A. Testosterone replacement therapy: what we know is not yet enough. Mayo Clin Proc. 2007 Jan;82(1):11-3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fat-Free Mass (kg)	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.	3 months	No
Secondary	Fat Mass (kg)	Estimate of within subject absolute change (Kg) in fat mass measured by DEXA at 3 months (90 days) interval during active or placebo treatment.	3 months	No
Secondary	HOMA-IR (homeostasis model assessment)- (insulin resistance)	Estimate of within subject absolute change in measure of insulin resistance homeostatic model HOMA-IR.	3 months	No
Secondary	CRP (C reactive protein)	C reactive protein (High sensitivity).	3 months	Yes
Secondary	Interleukins	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)	3 months	No
Secondary	Adipokines	Estimate of within subject absolute change in serum: ADIPONECTIN, LEPTIN, RESISTIN.	3 months	No
Secondary	Waist circumference	Waist circumference (cm)	3 months	No
Secondary	IIEF	International Index of Erectile Dysfunction	3 months	No
Secondary	Penile CDU (color Doppler ultrasound)	Penile Color-Doppler Ultrasonography of cavernosal arteries before and after active or placebo treatment.	3 months	No
Secondary	PSA (prostatic specific antigen)	PSA	3 months	Yes
Secondary	Hb, Htc	haemoglobin and haematocrit	3 months	Yes
Secondary	Fat-free mass		6 months	No
Secondary	Fat Mass		6 months	No
Secondary	HOMA-IR		6 months	No
Secondary	CRP		6 months	No
Secondary	Interleukins	Serum IL-1, IL-6, IL-10, IL-12, IL-2, IL-8, TNFa	6 months	No
Secondary	Adipokines	Serum ADIPONECTIN, LEPTIN, RESISTIN.	6 months	No