Hypogonadism
Conditions
Keywords
diabetes, hypogonadism, obesity, testosterone, insulin sensitivity, inflammation
Brief summary
The purpose of this study is to examine the effect of having testosterone deficiency in men with diabetes and with obesity. The study will also evaluate the effect of testosterone therapy. This will be done by comparing the changes in several body response indicators following treatment with testosterone in diabetic or obese-non diabetic men with low testosterone levels and comparing them to diabetic or obese-non diabetic men with low testosterone who are not treated with testosterone.
Detailed description
Hypogonadotropic hypogonadism (HH) occurs in approximately one-third of obese and type 2 diabetic men. Considering that there are 24 million diabetic and 100 million obese people, of which half are males, obesity and type 2 diabetes potentially constitute the major cause of hypogonadism in the population. We hypothesize that 1) HH in obese and type 2 diabetic men is associated with decreased insulin sensitivity, increased fat tissue mass, decreased lean body mass, increased inflammatory and oxidative stress, impaired sexual function and depressed mood as compared to diabetic and obese men with normal testosterone concentrations; and that 2) testosterone replacement for 24 weeks in men with HH leads to an improvement in these parameters. Our proposed study would be the first prospective, randomized trial to comprehensively evaluate the effect of HH on insulin sensitivity, body composition, inflammatory and oxidative indices in obese and type 2 diabetic subjects and the effect of six months of T replacement on these parameters. The study will have 2 arms (obese and type 2 diabetic arm) with 120 subjects in Diabetes arm and 80 subjects in obese arm. Half of men in each arm will have HH and half men will have normal testosterone concentrations(eugonadal men). Insulin sensitivity will be assessed by hyperinsulinemic-euglycemic clamps. Subcutaneous fat mass and lean body mass will be measured by DEXA and intra-abdominal (visceral) fat mass by MRI. All subjects will undergo hyperinsulinemic-euglycemic clamp, MRI, DEXA and give blood and urine samples (for measurement of inflammatory and oxidative stress) at baseline. Men with HH will then be randomized to receive testosterone or placebo gel for a total of 24 weeks. These men will undergo hyperinsulinemic-euglycemic clamps and give blood and urine samples for inflammation and oxidative stress at 4 weeks and 24 weeks. MRI and DEXA examinations will be carried out at 24 weeks again in men with HH. The primary endpoint of the study is to define a difference in whole body glucose uptake during hyperinsulinemic-euglycemic clamps between hypogonadal and eugonadal diabetes patients at baseline and an increase in glucose uptake in HH subjects after treatment with testosterone for 24 weeks. 30 subjects per group(testosterone and placebo gel each) will provide adequate power (0.8) to detect a significant difference of 10% in whole body glucose uptake. Therefore there will be 60 men with HH in each arm in diabetes group. For baseline comparisons, 60 men with normal testosterone concentrations will also be needed in each arm. We will recruit 40 obese patients in each arm. Thus there will be 120 diabetic men and 80 obese men in the study.
Interventions
DRUGtestosterone
intramuscular every 2 weeks
DRUGplacebo
saline intramuscular every 2 weeks
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
30 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* T2D arm: Males with age 30-65 years * Obese non-diabetic arm: Obese non-diabetic males with age 30-65 years
Exclusion criteria
1)Coronary event or procedure(myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous twelve weeks; 2) PSA \> 4ng/ml; 3)Hemoglobin A1c \> 8%; 4)h/o prostate carcinoma; 5)Hepatic disease (transaminase \> 3 times normal) or cirrhosis; 6)Renal impairment (defined as GFR\<30); 7)HIV or Hepatitis C positive status; 9)Participation in any other concurrent clinical trial; 10)Any other life-threatening, non-cardiac disease; 11)Use of over the counter health supplements which contain androgens; 12)Use of an investigational agent or therapeutic regimen within 30 days of study; 13)prostate nodule or severe enlargement on digital rectal examination; 14)Use of testosterone currently or in the past 4 months; 15)Hematocrit \> 50%; 16)History of untreated severe obstructive sleep apnea(defined as apnea-hypopnea index ≥30); 17)symptoms suggestive of severe BPH; 18)Congestive heart failure, class III or IV; 20)Known to have anemia secondary to iron, B12 or folic acid deficiency; 21)bone marrow disorder such as myelodysplasia or aplastic anemia; 22) currently suffering from symptomatic depression, with or without treatment; 23) history of severe depression in the past which needed hospitalization; 24)currently suffering from foot ulcer, significant periodontal disease or any other chronic infectious condition; 25)planning to have children. 26) Subjects on testosterone or with testosterone replacement in the past 4 months will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | baseline to 6 months | measured by HE clamps (baseline and 6 mths) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Composition | baseline to 6 months | Body composition using Total body fat mass (kg) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Diabetes With HH: Testosterone active drug diabetes hypogonadal arm
testosterone: intramuscular every 2 weeks | 22 |
| Obese With HH: Testosterone active drug obese hypogonadal arm
testosterone: intramuscular every 2 weeks | 12 |
| Obese With HH: Placebo placebo obese hypogonadal arm
placebo: saline intramuscular every 2 weeks | 10 |
| Diabetes With HH: Placebo placebo diabetes hypogonadal arm
placebo: saline intramuscular every 2 weeks | 22 |
| Eugonadal Diabetes diabetic men with normal testosterone | 50 |
| Eugonadal Obese obese non-diabetic men with normal testosterone | 21 |
| Total | 137 |
Baseline characteristics
| Characteristic | Obese With HH: Testosterone | Obese With HH: Placebo | Diabetes With HH: Placebo | Diabetes With HH: Testosterone | Eugonadal Diabetes | Eugonadal Obese | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 10 Participants | 22 Participants | 22 Participants | 50 Participants | 21 Participants | 137 Participants |
| Age, Continuous | 46 years STANDARD_DEVIATION 9 | 53 years STANDARD_DEVIATION 7 | 54 years STANDARD_DEVIATION 9 | 54 years STANDARD_DEVIATION 7 | 52 years STANDARD_DEVIATION 9 | 50 years STANDARD_DEVIATION 8 | 52 years STANDARD_DEVIATION 8 |
| Region of Enrollment United States | 12 participants | 10 participants | 22 participants | 22 participants | 50 participants | 21 participants | 137 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 22 Participants | 22 Participants | 50 Participants | 21 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 22 | 0 / 22 | 0 / 12 | 0 / 10 | 0 / 50 | 0 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 12 | 0 / 10 | 0 / 50 | 0 / 21 |
Outcome results
Primary
Insulin Sensitivity
measured by HE clamps (baseline and 6 mths)
Time frame: baseline to 6 months
Population: Glucose infusion rate in HE clamps was measured
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Diabetes With HH: Testosterone | Insulin Sensitivity | 6 months | 8.73 mg/kg fat free mass/min | Standard Deviation 4.27 |
| Diabetes With HH: Testosterone | Insulin Sensitivity | baseline | 6.66 mg/kg fat free mass/min | Standard Deviation 4.36 |
| Diabetes With HH: Placebo | Insulin Sensitivity | 6 months | 5.06 mg/kg fat free mass/min | Standard Deviation 3.62 |
| Diabetes With HH: Placebo | Insulin Sensitivity | baseline | 5.12 mg/kg fat free mass/min | Standard Deviation 2.79 |
| Obese With HH: Testosterone | Insulin Sensitivity | baseline | 11.37 mg/kg fat free mass/min | Standard Deviation 8.83 |
| Obese With HH: Testosterone | Insulin Sensitivity | 6 months | 12.96 mg/kg fat free mass/min | Standard Deviation 7.11 |
| Obese With HH: Placebo | Insulin Sensitivity | 6 months | 14.57 mg/kg fat free mass/min | Standard Deviation 1.71 |
| Obese With HH: Placebo | Insulin Sensitivity | baseline | 12.93 mg/kg fat free mass/min | Standard Deviation 5.16 |
| Eugonadal Diabetes | Insulin Sensitivity | baseline | 10.29 mg/kg fat free mass/min | Standard Deviation 5.55 |
| Eugonadal Obese | Insulin Sensitivity | baseline | 12.30 mg/kg fat free mass/min | Standard Deviation 5.96 |
Secondary
Body Composition
Body composition using Total body fat mass (kg)
Time frame: baseline to 6 months
Population: Body composition using Total body fat mass (kg)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Diabetes With HH: Testosterone | Body Composition | 24 WEEKS | 42.1 kg | Standard Deviation 12.5 |
| Diabetes With HH: Testosterone | Body Composition | Baseline | 44.5 kg | Standard Deviation 13.7 |
| Diabetes With HH: Placebo | Body Composition | Baseline | 44.5 kg | Standard Deviation 15 |
| Diabetes With HH: Placebo | Body Composition | 24 WEEKS | 45.4 kg | Standard Deviation 14.4 |
| Obese With HH: Testosterone | Body Composition | 24 WEEKS | 46.4 kg | Standard Deviation 11.7 |
| Obese With HH: Testosterone | Body Composition | Baseline | 50.2 kg | Standard Deviation 9.5 |
| Obese With HH: Placebo | Body Composition | Baseline | 48.8 kg | Standard Deviation 10.4 |
| Obese With HH: Placebo | Body Composition | 24 WEEKS | 48.4 kg | Standard Deviation 11.2 |
| Eugonadal Diabetes | Body Composition | Baseline | 34.0 kg | Standard Deviation 12 |
| Eugonadal Obese | Body Composition | Baseline | 40.2 kg | Standard Deviation 12.4 |