T-IR- Study to Understand the Effects of Testosterone and Estrogen on the Body's Response to the Hormone Insulin

Study Overview
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Brief Summary
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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
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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.

Official Title
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Androgen-mediated Pathways in the Regulation of Insulin Sensitivity in Men

Conditions
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Insulin Resistance, Type 2 Diabetes Mellitus, Obesity, Androgen Deficiency, Metabolic Disease

Intervention / Treatment
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* Drug: Acyline
* Drug: Testosterone 1.62% gel
* Drug: Letrozole
* Drug: Placebo gel (for Testosterone 1.62% gel)
* Drug: Placebo pill (for Letrozole)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acyline & placebo gel & placebo pill<br>Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily | Drug: Acyline<br>* 300 mcg/mL administered subcutaneously (at Day 0, Week 2)<br>Drug: Placebo gel (for Testosterone 1.62% gel)<br>* placebo gel manufactured to mimic Testosterone 1.62% gel<br>Drug: Placebo pill (for Letrozole)<br>* Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d<br>|
| Experimental: Acyline & Testosterone 1.25g & placebo pill<br>Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily | Drug: Acyline<br>* 300 mcg/mL administered subcutaneously (at Day 0, Week 2)<br>Drug: Testosterone 1.62% gel<br>* Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks<br>* Other names: Androgel;Drug: Placebo pill (for Letrozole)<br>* Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d<br>|
| Experimental: Acyline & Testosterone 5g & placebo pill<br>Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily | Drug: Acyline<br>* 300 mcg/mL administered subcutaneously (at Day 0, Week 2)<br>Drug: Testosterone 1.62% gel<br>* Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks<br>* Other names: Androgel;Drug: Placebo pill (for Letrozole)<br>* Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d<br>|
| Experimental: Acyline & Testosterone & Letrozole<br>Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily | Drug: Acyline<br>* 300 mcg/mL administered subcutaneously (at Day 0, Week 2)<br>Drug: Testosterone 1.62% gel<br>* Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks<br>* Other names: Androgel;Drug: Letrozole<br>* Letrozole oral aromatase inhibitor 5mg daily for 4 weeks<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 4 weeks | 
| 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. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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obesity, insulin, androgens, insulin resistance, testosterone, estradiol