Please select the eligibility criteria that correspond to the clinical trial below.
Title: Testosterone Replacement Therapy in Men With Type 2 Diabetes Mellitus and Low Testosterone Levels
Brief Summary: In men with type 2 diabetes, low testosterone levels have been associated with insulin resistance, truncal obesity and symptoms such as fatigue and erectile dysfunction. Low testosterone may impair cardiac function and increase cardiovascular risk and cause osteoporosis. The goal of this project is to assess prospectively whether, in men with type 2 diabetes mellitus and low testosterone levels, testosterone replacement improves insulin resistance, body composition, bone density, cardiac function symptoms associated with low testosterone level.

The investigators will recruit 140 ambulatory men with type 2 diabetes and a low serum testosterone level (\<10 nmol/L) from Austin Health Endocrine clinics, General Practise surgeries, and from the general public by direct consumer advertising via newspaper and other local media. Men will be randomised to either intramuscular testosterone undecanoate (Reandron 1000, Bayer Schering Pharma) or placebo. Men with contraindications to testosterone replacement or to intramuscular injections will be excluded from the study. All men will receive intramuscular testosterone or placebo injections at 0, 6, 18 and 30 weeks (a total of four injections).

All 140 study subjects will have a clinical and laboratory assessment at baseline, 18 weeks and at study end (40 weeks). All 140 subjects will also have imaging studies at baseline and at study end (40 weeks). The study protocol is outlined in more detail below:

Clinical and laboratory assessment (Baseline and repeated 18 weeks, 40 weeks) A full medical history and physical examination will be performed. Symptoms will be assessed by the following standardised questionnaires: 1) Androgen Deficiency in the Aging Male (ADAM); 2) Aging Male Symptom scale (AMS); 3) International Index of Erectile Dysfunction (IIED); 4) International Prostate Symptom Score (IPSS); 5) SF-36 (all five questionnaires are attached to Module 1).

Laboratory studies will consist of blood tests to measure total testosterone, fasting glucose, C-peptide, HBA1c and other routine parameters.

Imaging studies (Baseline and repeated at 40 weeks)

1. Body composition and bone mineral density by DEXA
2. Body composition by magnetic resonance imaging
3. Bony micro-architecture by high resolution quantitative computed tomography \[HR-pQCT\]),
4. Cardiac dimensions and function by transthoracic doppler echocardiography


Options:
A: Inclusion Criteria:

* Men, 40-70 years of age, in a stable relationship, with mild to moderate erectile dysfunction for at least 6 months; defined as an IIEF-EF domain score between 11 and 25 (mild to moderate ED)
* Neutral or extremely dissatisfied with one's sex life
* Presence of androgen deficiency defined as serum total testosterone level less than 300 ng/dL (measured by LC-MS/MS) and/or free testosterone level (measured by equilibrium dialysis) less than 50 pg/ml.
* Able to understand the nature of the study and provide written, informed consent

Exclusion Criteria:

* Contraindication for use of testosterone, e.g., history of prostate or breast cancer
* benign prostatic hyperplasia with AUA/IPSS symptom scores of 21 or greater
* erythrocytosis (hematocrit \>50% at baseline)
* untreated, severe sleep apnea
* serum PSA levels \>4 ug/L will be excluded unless they have had a urologic evaluation in the past three months to exclude prostate cancer.
* Contraindication for use of sildenafil, e.g., symptomatic coronary artery disease taking long-acting or short-acting nitrate drugs on a regular basis.
* Symptomatic postural hypotension
* Congestive heart failure with class III or IV symptoms
* History of myocardial infarction or stroke within the past six months
* Primary diagnosis of another sexual disorder such as premature ejaculation
* AST, ALT, alkaline phosphatase elevation greater than three times the upper limit of normal, creatinine greater than 2 mg/dL.
* Currently taking testosterone or oral androgen precursors; unless willing to discontinue their use for 4 weeks (oral precursors or transdermal testosterone patch or gel) or 6 weeks (if injectable testosterone) before the initial screen visit.
* Currently taking medications that affect androgen metabolism, action, or clearance (dilantin, phenobarbital, aldactone, flutamide, finasteride).
* Uncontrolled diabetes mellitus or diabetes mellitus, e.g., if their baseline hemoglobin A1C is less than 8.5%.
* Structural abnormalities of the penis, including Peyronie's disease, will be excluded.
* Men who are taking medications for erectile dysfunction, including sildenafil, must stop using these medications for at least 4 weeks before starting Visit 2.
* DSM-IV criteria for an Axis I psychiatric disorder within the past year, including depression; use of psychotropic medication for at least six months, or dementia is also an exclusion.
B: Inclusion Criteria:

* Type 2 diabetes
* Testosterone less than 10 nmol/L

Exclusion Criteria:

* Contraindication to
* Testosterone or
* IM injection
C: Inclusion Criteria:

* Total testosterone level \<300 nanogram per deciliter (ng/dL) \[10.4 nanomole per Liter (nmol/L)\] at each of 2 screening visits
* At least 1 symptom of testosterone deficiency, which must include decreased energy or decreased sexual drive
* Prostate Specific Antigen (PSA) \<4 nanogram per milliliter (ng/ml) at screening

Exclusion Criteria:

* Sexual partner who is or becomes pregnant at any time during the study
* Use of long-acting intramuscular (IM) testosterone undecanoate or testosterone pellets in the 6-month period prior to screening
* Body Mass Index (BMI) \>37 kilogram per square meter (kg/m\^2) at screening
* Severe lower urinary tract symptoms and/or significant prostate enlargement
* Prolactin lab test result of \>30 ng/mL at screening
* Hemoglobin A1c (HbA1c) \>11% at screening
* Hematocrit ≥50% (\>54% at elevated altitude) at screening
* Current use of any medications, herbal, and/or nutritional supplements that can interfere with testosterone
* Dermatologic condition in underarm area that might interfere with testosterone absorption (for example, eczema) or be exacerbated by topical testosterone replacement therapy
* Currently receiving treatment with cancer chemotherapy or antiandrogens
* Chronic use of systemic glucocorticoids (use for \>14 days within the 3 months prior to screening); use of non-testosterone anabolic steroids within 12 months prior to screening
* Competitive athletes involved in a sport in which they may be screened for anabolic steroids
* History of use of estrogenizing agents within 12 months prior to screening
* History of luteinizing hormone-releasing hormone antagonist or agonist treatment in the last 6 months prior to screening
* History of clomiphene or other anti-estrogen treatment in the 3 months prior to screening
* Use of finasteride within 3 months prior to screening, or use of dutasteride within 6 months prior to screening
* Current use of warfarin or phenprocoumon
* History of frequent opioid use: \>1 time/week during any week within 30 days prior to screening
* Current use of dopamine receptor agonists (cabergoline, pergolide, bromocriptine)
* Have a history of significant central nervous system injuries or disease (including stroke, spinal cord injury, or multiple sclerosis) within 6 months prior to screening
* Systolic blood pressure \>170 or \<90 millimeter of mercury (mm Hg) or diastolic blood pressure \>100 or \<50 mm Hg at screening or a history of malignant hypertension
* History of unstable angina as defined by Braunwald Classification of Unstable Angina or angina occurring during sexual intercourse in the last 6 months
* History of any of the following coronary conditions within 90 days of screening: myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention (angioplasty or stent placement)
* Have any supraventricular arrhythmia with an uncontrolled ventricular response \[mean heart rate \>100 beats per minute (bpm)\] at rest, or have any history of spontaneous or induced sustained ventricular tachycardia (heart rate \>100 bpm for ≥30 seconds), or use of an automatic internal cardioverter-defibrillator
* Have a history of sudden cardiac arrest
* Exhibit any evidence of congestive heart failure \[New York Heart Association (NYHA) Class 2 or above\], within 6 months prior to screening
* Have had a new, significant cardiac conduction defect within 90 days prior to screening
* Clinical suspicion (or history) of prostate cancer during digital rectal examination at screening
* Known or suspected breast cancer (or history of breast cancer) or other active cancer (with the exception of nonmelanotic skin cancer)
* Exhibit evidence of severe renal impairment \[creatinine clearance \<30 milliliter per minute (mL/min) as determined by the Cockcroft-Gault formula\] at screening
* Exhibit a history of severe liver disease or clinical evidence of hepatic impairment at screening
* Have a history of human immunodeficiency virus (HIV) infection
* Severe sleep apnea
* Untreated hypothyroidism, hypercortisolism or other significant endocrinopathy (other than hypogonadism) that contributes to symptoms of low energy or fatigue
D: Inclusion Criteria:

* Physically active (at least 2 days per week aerobic and/or resistance exercise)
* Not taking any prescription medications and/or willing to refrain from all medication use prior to and throughout the entire study period, unless provided/approved by the study physician
* Willing to refrain from alcohol, smoking, e-cigarettes, or use of any nicotine product, caffeine, and dietary supplement use throughout the entire study period

  * At the discretion of the study physician, wash-out period for medications, supplements, and over-the-counter medications is ≥ 1 to 4 weeks
  * Wash-out period for caffeine and alcohol is ≥ 7 days
* Willing to live on the Pennington Biomedical Research Center inpatient unit for 28 consecutive days
* Willing to have a urine drug screening
* Meets age-specific U.S. Army body composition standards according to Army Regulation 600-9, which includes estimates of percent body fat based on height, weight, and circumference measures (neck and waist)
* Total testosterone concentration is within the normal physiological range, total testosterone (300-1,000 ng/dL).

Exclusion Criteria:

* Musculoskeletal injuries that compromise exercise capability
* Diagnosed cardiometabolic disorders (i.e., hypertension, hyperlipidemia, kidney disease, diabetes, etc.)
* Allergies or intolerance to foods, vegetarian practices, or history of complications with lidocaine
* Anabolic steroid, human growth hormone, or nutritional testosterone precursor-like supplement use within the past 6 months
* Will not refrain from smoking (any nicotine product), alcohol, caffeine, or any other dietary supplement during the study
* Any use of antibiotics, except topical antibiotics, within 3 months of study participation
* Colonoscopy within 3 months of study participation
* Chronic use of laxatives, stool softeners, antacids, or anti-diarrheal medications (≥ once a week)
* History of gastrointestinal disease (e.g., celiac, irritable bowel syndrome, colitis, Crohn's disease)
* Restrained eater (the Three-Factor Eating Questionnaire) as assessed by the study's psychological and behavioral assessment staff
* Adults unable to consent
* Women
* Prisoners
* Metal implants, claustrophobia, head size incompatible with MRI equipment, etc.
* Sedentary or engages in \<2 days of physical activity per week (aerobic and/or resistance training)
* Exceeds age-specific U.S. Army body composition standards according to Army Regulation 600-9
* Previous history of kidney stones unless otherwise approved by the medical investigator
* Systolic blood pressure \> 150 or diastolic blood pressure \> 95 mmHg
* Previous history of breast or prostate cancer
* Previous history of Chronic Obstructive Pulmonary Disease or Obstructive Sleep Apnea
* Findings of lab results of prostate-specific antigen \> 3ng/ml, Hematocrit \> 50%, or positive urine drug screening
* Based on the investigative team's clinical judgment, a subject may not be appropriate for participation in the study

Answer: B