Insulin Resistance, Type 2 Diabetes Mellitus, Obesity, Androgen Deficiency, Metabolic Disease
Conditions
Keywords
insulin, androgens, insulin resistance, testosterone, estradiol, obesity
Brief summary
The purpose of this research study is to understand the effects of testosterone and estrogen on the body's response to the hormone insulin.
Detailed description
The investigators will examine the effects of testosterone on insulin sensitivity and body composition in men. This study may lend greater insight into the increased risk of diabetes evident in men with low circulating levels of testosterone. Three drugs will be used in this study: acyline, given by injection; testosterone (T) gel that is applied to the skin; and letrozole, which is an oral drug that blocks the conversion of androgens (male hormones) to estrogens (female hormones). Acyline inhibits the production of luteinizing hormone (LH) and follicle stimulating hormone (FSH). When acyline stops the production of these hormones, it blocks the signal from the brain that stimulates the testicles to make testosterone. Adding testosterone to acyline will restore physiologic levels of testosterone in some study participants. One group of men will receive T gel with letrozole, an aromatase inhibitor; these men will have normal levels of testosterone but low levels of estrogen in the blood. This design will enable determination of the respective metabolic effects of testosterone and estrogen.
Interventions
DRUGAcyline
300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks
DRUGLetrozole
Letrozole oral aromatase inhibitor 5mg daily for 4 weeks
DRUGPlacebo gel (for Testosterone 1.62% gel)
placebo gel manufactured to mimic Testosterone 1.62% gel
DRUGPlacebo pill (for Letrozole)
Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d
Sponsors
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
25 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Prostate-specific antigen (PSA) ≤ 3 ng/mL * Age 25-55 years * Ability to understand the study, study procedures and provide informed consent * Serum total T \> 300 ng/dL * Normal reproductive history and exam * International Prostate Symptom Score (IPSS) \< 11
Exclusion criteria
* A history of prostate cancer including suspicious digital rectal exam (DRE) or history of highgrade prostatic intraepithelial neoplasia (PIN) on prostate biopsy * Invasive therapy for benign prostatic hyperplasia (BPH) in the past * History of acute urinary retention in the previous 3 months * Current or recent past use of androgenic or anti-androgenic drugs, steroids or drugs which interfere with steroid metabolism (within the last 3 months) * Current use of statins or glucocorticoids * Severe systemic illness (renal, liver, cardiac, lung disease, cancer, diabetes mellitus) or skin disease * A history of or current breast cancer * Known, untreated obstructive sleep apnea * Hematocrit \> 50 or \< 34 * Hypersensitivity to any of the drugs used in the study * History of a bleeding disorder or anticoagulation * Participation in any other drug study within past 90 days * History of drug or alcohol abuse within the last 12 months * Weight \> 280 lbs. or BMI ≥ 33 * Desire for fertility in the next 6 months or current pregnant partner * Sperm concentration \<14 million/ml * Significant, uncontrolled hypertension (BP \>160/100 mmHg); subjects with well-controlled BP on medical therapy will be eligible to participate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity Quantified by Matsuda Index | 4 weeks | Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG\*FI)\*(FPG+PG30\*2+PG60\*2+PG90\*2+PG120)/8\*(FPI+PI30\*2+PI60\*2+PI90\*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Body Composition | 4 weeks | Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period |
| Changes in Adipose Tissue Gene Expression | 4 weeks | We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s. |
Countries
United States
Participant flow
Recruitment details
Recruitment period: 06/01/13-11/30/2014 Location: University/Medical Center Flyers, newspaper ads, online postings
Pre-assignment details
116 subjects were screened, 63 subjects didn't meet study inclusion/exclusion criteria or they withdrew consent prior to group assignment, and 3 subjects withdrew prior to the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| Acyline & Placebo Gel & Placebo Pill Acyline (300mcg/kg at Day 0 & week 2, by injections) + placebo transdermal gel + placebo aromatase inhibitor daily for 4 weeks
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Placebo gel (for Testosterone 1.62% gel): placebo gel manufactured to mimic Testosterone 1.62% gel
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d | 13 |
| Acyline & Testosterone Gel 1.25g/d & Placebo Pill Acyline (300mcg/kg at Day 0 & week 2, by injections) + Testosterone 1.62% gel (1.25g) daily + placebo aromatase inhibitor pill daily for 4 weeks
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d | 14 |
| Acyline & Testosterone Gel 5g/d & Placebo Pill Acyline (300mcg/kg every 2 weeks, by injections) + Testosterone 1.62% gel (5g) daily + placebo aromatase inhibitor pill daily for 4 weeks
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks
Placebo pill (for Letrozole): Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d | 13 |
| Acyline & Testosterone Gel & Letrozole Acyline (300mcg/kg at Day 0 & week 2, by injections) + Testosterone transdermal 1.62% gel (5g) daily + letrozole (5mg) aromatase inhibitor pill daily for 4 weeks
Acyline: 300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Testosterone 1.62% gel: Transdermal Testosterone Gel (either 3.75g or 5g/d) for 4 weeks
Letrozole: Letrozole oral aromatase inhibitor 5mg daily for 4 weeks | 13 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | New Job | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Weight Loss | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Acyline & Placebo Gel & Placebo Pill | Total | Acyline & Testosterone Gel & Letrozole | Acyline & Testosterone Gel 5g/d & Placebo Pill | Acyline & Testosterone Gel 1.25g/d & Placebo Pill |
|---|---|---|---|---|---|
| Age, Continuous | 37 years | 36 years | 34 years | 42 years | 35 years |
| Body Mass Index (BMI) | 26 kg/m2 STANDARD_DEVIATION 4 | 25 kg/m2 STANDARD_DEVIATION 3 | 25 kg/m2 STANDARD_DEVIATION 4 | 25 kg/m2 STANDARD_DEVIATION 2 | 26 kg/m2 STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 44 Participants | 13 Participants | 11 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 8 Participants | 0 Participants | 2 Participants | 3 Participants |
| Fasting Glucose | 97 mg/dL STANDARD_DEVIATION 6 | 98 mg/dL STANDARD_DEVIATION 9 | 98 mg/dL STANDARD_DEVIATION 9 | 101 mg/dL STANDARD_DEVIATION 7 | 97 mg/dL STANDARD_DEVIATION 13 |
| Percentage Body Fat | 28 %total body mass STANDARD_DEVIATION 7 | 24 %total body mass STANDARD_DEVIATION 6 | 23 %total body mass STANDARD_DEVIATION 7 | 24 %total body mass STANDARD_DEVIATION 4 | 23 %total body mass STANDARD_DEVIATION 6 |
| Percentage Lean Mass | 68 %total body mass STANDARD_DEVIATION 7 | 72 %total body mass STANDARD_DEVIATION 6 | 73 %total body mass STANDARD_DEVIATION 7 | 72 %total body mass STANDARD_DEVIATION 4 | 73 %total body mass STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 9 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 7 Participants | 37 Participants | 11 Participants | 11 Participants | 8 Participants |
| Region of Enrollment United States | 13 participants | 53 participants | 13 participants | 13 participants | 14 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 53 Participants | 13 Participants | 13 Participants | 14 Participants |
| Weight | 82 kg STANDARD_DEVIATION 14 | 81 kg STANDARD_DEVIATION 12 | 82 kg STANDARD_DEVIATION 11 | 78 kg STANDARD_DEVIATION 8 | 81 kg STANDARD_DEVIATION 15 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 13 | 9 / 14 | 7 / 13 | 10 / 13 |
| serious Total, serious adverse events | 2 / 13 | 1 / 14 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Insulin Sensitivity Quantified by Matsuda Index
Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG\*FI)\*(FPG+PG30\*2+PG60\*2+PG90\*2+PG120)/8\*(FPI+PI30\*2+PI60\*2+PI90\*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load
Time frame: 4 weeks
Population: Of the 53 subjects who attended the baseline study visit, 2 withdrew from the study and 1 was discontinued due to a protocol violation. 50 subjects completed the week 10 study visit. Of these, 5 subjects were excluded from the final analyses; 1 was found to have undiagnosed diabetes, and 4 subjects were excluded due to study drug non-adherence.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyline & Placebo Gel & Placebo Pill | Insulin Sensitivity Quantified by Matsuda Index | 5.0 units on a scale |
| Acyline & Testosterone Gel 1.25g/d & Placebo Pill | Insulin Sensitivity Quantified by Matsuda Index | 9.4 units on a scale |
| Acyline & Testosterone Gel 5g/d & Placebo Pill | Insulin Sensitivity Quantified by Matsuda Index | 7.2 units on a scale |
| Acyline & Testosterone Gel & Letrozole | Insulin Sensitivity Quantified by Matsuda Index | 7.3 units on a scale |
p-value: 0.164RM-ANOVA
Secondary
Changes in Adipose Tissue Gene Expression
We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s.
Time frame: 4 weeks
Population: Subjects were included who had adipose tissue samples available from both baseline and week 4 (end-of-treatment) visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acyline & Placebo Gel & Placebo Pill | Changes in Adipose Tissue Gene Expression | 7493 gene copy number per ng RNA | Standard Deviation 1293 |
| Acyline & Testosterone Gel 1.25g/d & Placebo Pill | Changes in Adipose Tissue Gene Expression | 8224 gene copy number per ng RNA | Standard Deviation 3485 |
| Acyline & Testosterone Gel 5g/d & Placebo Pill | Changes in Adipose Tissue Gene Expression | 7885 gene copy number per ng RNA | Standard Deviation 2736 |
| Acyline & Testosterone Gel & Letrozole | Changes in Adipose Tissue Gene Expression | 8320 gene copy number per ng RNA | Standard Deviation 3133 |
Comparison: The null hypothesis was that short-term testosterone deprivation would not affect lipoprotein lipase expression in adipose tissue. Repeated measures ANOVA was used to determine if a time-by-group effect was apparent for lipoprotein lipase expression.p-value: >0.1ANOVA
Secondary
Changes in Body Composition
Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period
Time frame: 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acyline & Placebo Gel & Placebo Pill | Changes in Body Composition | Change in fat mass | 1.1 kg | Standard Deviation 0.8 |
| Acyline & Placebo Gel & Placebo Pill | Changes in Body Composition | Change in lean mass | -1.2 kg | Standard Deviation 1 |
| Acyline & Testosterone Gel 1.25g/d & Placebo Pill | Changes in Body Composition | Change in lean mass | -1.4 kg | Standard Deviation 1.5 |
| Acyline & Testosterone Gel 1.25g/d & Placebo Pill | Changes in Body Composition | Change in fat mass | 0.7 kg | Standard Deviation 0.5 |
| Acyline & Testosterone Gel 5g/d & Placebo Pill | Changes in Body Composition | Change in fat mass | -0.4 kg | Standard Deviation 1 |
| Acyline & Testosterone Gel 5g/d & Placebo Pill | Changes in Body Composition | Change in lean mass | 0.0 kg | Standard Deviation 1 |
| Acyline & Testosterone Gel & Letrozole | Changes in Body Composition | Change in fat mass | 0.5 kg | Standard Deviation 0.8 |
| Acyline & Testosterone Gel & Letrozole | Changes in Body Composition | Change in lean mass | -0.3 kg | Standard Deviation 1.3 |
Comparison: Time-by-group interaction for fat massp-value: 0.003RM-ANOVA
p-value: 0.03RM-ANOVA