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

Phase 1

Completed

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

Interventions: Drug: Acyline
Drug: Testosterone 1.62% gel
Drug: Placebo gel (for Testosterone 1.62% gel)
Drug: Placebo pill (for Letrozole)
Drug: Letrozole

Registration Number: NCT01686828

Lead Sponsor: University of Washington

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 53

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Acyline & Testosterone 1.25g & placebo pill	Testosterone 1.62% gel	Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily
Acyline & placebo gel & placebo pill	Placebo gel (for Testosterone 1.62% gel)	Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily
Acyline & placebo gel & placebo pill	Placebo pill (for Letrozole)	Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily
Acyline & Testosterone 1.25g & placebo pill	Placebo pill (for Letrozole)	Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily
Acyline & Testosterone 5g & placebo pill	Testosterone 1.62% gel	Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily
Acyline & Testosterone 5g & placebo pill	Placebo pill (for Letrozole)	Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily
Acyline & Testosterone & Letrozole	Acyline	Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily
Acyline & Testosterone & Letrozole	Testosterone 1.62% gel	Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily
Acyline & Testosterone & Letrozole	Letrozole	Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily
Acyline & placebo gel & placebo pill	Acyline	Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily
Acyline & Testosterone 1.25g & placebo pill	Acyline	Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily
Acyline & Testosterone 5g & placebo pill	Acyline	Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.