Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism

• Status: Recruiting
• Trial end date: 2024-04-14
• Target enrollment: 0
• Participant gender: Male

Summary

The investigators have preliminary data suggesting that obese patients with hypogonadotropic hypogonadism (HHG) have minimal benefit from testosterone therapy likely because of its conversion to estradiol by the abundant aromatase enzyme in the adipocytes. The increased conversion of androgens into estrogens in obese men results in a negative feedback of high estradiol levels on hypothalamus and pituitary, inhibiting the production of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) and, as a consequence, of testosterone by the testis. Testosterone administration could increase estradiol production, further promoting the inhibitory feedback to the hypothalamic-pituitary-gonadal axis. Although weight loss from lifestyle modification has been shown to reduce estradiol and increase testosterone levels, the effect is at best modest and weight regain results in recurrence of hypogonadism. The use of aromatase inhibitors, in combination with weight loss, could be an effective alternative strategy due to its action at the pathophysiology of the disease.

Intervention Subjects (body mass index of ≥35, testosterone <300 ng/dl) will be randomized to the active (anastrozole) or control (placebo) group. Anastrozole 1 mg tablet / day will be self-administered with or without food, at around the same time every day (active group); placebo 1 tablet/day with or without food to take at around the same time every day (control group). The study duration will be 12 months.

Both groups will undergo lifestyle intervention consisting of diet and supervised exercise program. Target weight loss will be at least 10% of baseline body weight during the intervention. Subjects will attend weekly group behavior modification sessions which will last ~75-90 min for the first 3 months and decreased to every two weeks from 3 to 12 months. Subjects will attend supervised research center-based exercise sessions during the first 6 months followed by community fitness center-based sessions during the next 6 months for at least 2 d/wk, with recording of home-based exercises for the other 2-4 days/week.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Baylor College of Medicine
• Treatments: Anastrozole; Aromatase Inhibitors

Criteria

Inclusion Criteria:

• obese men with body mass index (BMI) of ≥35 kg/m2

• age between 40 to 65 years old

• average fasting testosterone level from 2 measurements taken between 8 to 10 AM on 2 separate days of <300 ng/dl

• Luteinizing Hormone (LH) of <9.0 mIU/L

• Estradiol of ≥17 pg/ml

• Symptoms consistent with androgen deficiency as assessed by Androgen Deficiency in Aging Male (ADAM) questionnaire

Exclusion criteria:

• pituitary or hypothalamic disease,

• drugs affecting gonadal hormone levels, production and action or bone metabolism (bisphosphonates, teriparatide, denosumab, glucocorticoids, phenytoin)

• diseases affecting bone metabolism (e.g. hyperparathyroidism, untreated hyperthyroidism, osteomalacia, chronic liver disease, significant renal failure, hypercortisolism, malabsorption, immobilization, Paget's disease),

• prostate carcinoma or elevated serum prostate specific antigen (PSA)> 4 ng/ml,

• Hematocrit > 50%,

• untreated severe obstructive sleep apnea,

• Cardiopulmonary disease (e.g. recent myocardial infarction, unstable angina, stroke) or unstable disease (e.g., New York Heart Association Class III or IV congestive heart failure

• severe pulmonary disease requiring steroid pills or the use of supplemental oxygen (that would contraindicate exercise or dietary restriction)

• History of deep vein thrombosis or pulmonary embolism

• severe lower urinary tract or prostate symptoms with International Prostate Symptom Score (IPSS) above 19

• excessive alcohol or substance abuse

• unstable weight (i.e. >±2 kg) in the last 3 months

• condition that could prevent from completing the study

• screening bone mineral density (BMD) T-score of <-2.0 at the spine, femoral neck or total femur

• history of osteoporosis or fragility fracture

• Diabetes mellitus with a fasting blood glucose of >140 mg/dl, and/or Hemoglobin A1C (A1C) >8.5%.