Effects of Testosterone Gel on Carbohydrate and Lipid Metabolism In Elderly Obese Men

Study Overview
=================
Brief Summary
-----------------
A. HYPOTHESES: In older men low testosterone levels, abdominal obesity and elevated fasting insulin who are at risk for the cardiovascular complications such as heart attack and stroke. Supplemental testosterone will decrease abdominal adipose tissue and hepatic fat) and appendicular fat and intramyocellular lipid in peripheral muscles (IMCL). Supplemental testosterone will improve insulin sensitivity by: Decreasing hepatic glucose output (HGO), a measure of central insulin resistance increasing peipheral glucose disposal (Rd), a measure of periperal insuln sensiivity . Improving peripheral glucose disposal (Rd) by reducing IMCL Increasing appendicular skeletal muscle mass B. OBJECTIVES: Primary Objective: To determine the effects of supplemental testosterone to achieve testosterone levels in the upper normal physiologic range on central adipose tissue (abdominal and hepatic fat) and peripheral skeletal muscle fat (appendicular fat and IMCL). Secondary Objectives: To determine the effects of supplemental testosterone to achieve testosterone levels in the upper normal physiologic range:on central insulin sensitivity ( hepatic glucose output ([HGO]) and peripheral insulin sensitivity (glucose disposal (Rd) Results of this study will provide greater understanding whether androgen therapy enhances insulin sensitivity by decreasing HGO, improving peripheral Rd and if these desired effects are achieved, whether they are due to reductions in abdominal fat or liver lipid, IMCL or effects of augmenting muscle mass per se. Results will generate hypotheses to investigate cellular and molecular mechanisms of androgen effects in persons at risk for the Metabolic Syndrome.

Detailed Description
-----------------
Study Design: This is an investigator-initiated open label, study to investigate the effects of supplemental testosterone (gel formulation) to increase testosterone levels to the upper normal range in 12 older hypogonadal (testosterone levels less than 300 ng/dL) men with abdominal obesity and elevated fasting insulin levels. Subjects will be assigned to receive 10 g of transdermal testosterone (Androgel) every morning to achieve levels in the upper normal physiologic range (similar to men in the 3rd and 4th decades) for 20 weeks. For the primary objective, regional adipose tissue, namely DEXA measures of abdominal and appendicular fat mass and hepatic fat, and IMCL will be quantified by 1H-spectroscopy at baseline (study week 0) and at study week 20 (completion of study therapy). For the secondary objective, insulin sensitivity (peripheral Rd, hepatic glucose output [HGO]) and hepatic gluconeogenesis will be measured directly during a two stage hyperinsulinemic euglycemic clamp at baseline and study week 20. Indirect markers of lipid (adiponectin, ApoB 100) and carbohydrate metabolism (Fasting blood sugar, HOMA-IR) at study week 10, and study week 20. All components of the study will be conducted in the USC NIH-funded (NCRR), General Clinical Research Center.

Official Title
-----------------
Investigator Initiated Study of the Effects of Androgen Therapy on Carbohydrate and Lipid Metabolism In Elderly Men

Conditions
-----------------
Aging, Obesity, Insulin Resistance, Hypogonadism

Intervention / Treatment
-----------------
* Drug: Topical testosterone gel 10 g/day


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Entry Criteria: Men > 60 years of age Total testosterone < 300 ng/dL Waist circumference >102 cm Fasting insulin level > 18 U/L Exclusion Criteria: PSA > 4.1, symptoms of obstructive uropathy (AUA score > 14), unexplained prostate nodule or gland firmness Hematocrit > 50% Malignancy other than cutaneous cancers Sleep apnea requiring CPAP History of myocardial infarction, angina or stroke within the previous 6 months Clinical diagnosis of diabetes or FPG > 126 mg/dL Hypothyroidism not controlled to euthyroid levels with medication for at least 3 months LDL-C >160 mg/dL Transaminases > 1.5X ULN Systemic anticoagulation with warfarin Active progressive resistance training Dieting for weight loss Active inflammatory condition (e.g. rheumatoid arthritis) Use of any anabolic agent (e.g. growth hormone, testosterone precursor, anabolic steroid)or cytokine therapy in the proceeding 12 months

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Open label treatment without masking with each participant serving as his own control. Measurements are compared before and after treatment. | Drug: Topical testosterone gel 10 g/day<br>* Testosterone gel therapy for 20 weeks<br>* Other names: Androgel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Mass and Regional Adipose Adiposiy | Change in total body mass, total fat mass, trunk fat, and extremity fat | Baseline to 20 weeks | 
| Change in Hepatic Lipid | Amount of liver fat is highly predictive of insulin resistance. Hepatic fat is measured by MR spectroscopy and adjusted for H2O and results are reported as ratio of these two. | Baseline to week 20 | 
| Intramyocellular Lipid (IMCL) | IMCL is quantified by MR spectroscopy of the anterior tibialis muscle of the leg. The value is adjusted for creatine and reported as a ratio | Baseline to week 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percentage of Total Body Fat | Percentage of total body fat is quantified by DEXA scanning | Baseline and 20 weeks | 
| Change in Total and Regional Carbohydrate Metabolism During a 2-hr Hyperinsulinemic Euglycemic Clamp and [6,6-2H2] Glucose Studies (Peripheral Glucose Disposal [Rd],Hepatic Glucose Output [HGO]) | In the final analysis, total and regional carbohydrate metabolism during a 2-hr hyperinsulinemic euglycemic clamp (peripheral glucose disposal [Rd],hepatic glucose output [HGO]) were analyzed by mass transfer of glucose during both stages of the clamp relative to insulin levels. | Baseline and 20 weeks | 
| Change in Skeletal Muscle Mass by DEXA | Skeletal muscle mass was assesed by regional DEXA to quantify appendicular lean tissues which is primarily muscle. | Baselne to 20 weeks | 
| Plasma Lipids |  | Baseline to week 20 | 
| Change in HOMA-IR | HOMA-IR is a measure of insulin resistance | Baseline to week 20 | 
| Change in Basal FFAs in Plasma | FFA (plasma free fatty acids) are measure of lipid metabolism | Baseline to week 20 | 
| Change in Plasma Free Fatty Acids During Glucose Clamp |  | Baseline to 20 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Aging, Older men, Abdominal obesity, Central obesity, Insulin resistance, Low testosterone