Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03490513
Recruitment Status : Recruiting
First Posted : April 6, 2018
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
Reina, Baylor College of Medicine

Brief 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.


Condition or disease Intervention/treatment Phase
Hypogonadism, Hypogonadotropic Obesity Drug: anastrozole (1 mg/day) Drug: Placebo Phase 4

Detailed Description:

After age of 40, testosterone (T) production in men gradually decreases at a rate of 1.6% per year for total and to 2-3% per year for bioavailable T. This reduction in T production in men parallels the age-associated loss of muscle mass that leads to sarcopenia and impairment of function and the age-associated loss of bone mass that leads to osteopenia and fracture risk.

Hypogonadism is a condition associated with multiple symptom complex including fatigue, depressed mood, osteoporosis, gain of fat mass, loss of libido and reduced muscle strength, all of which deeply affect patient quality of life. The prevalence of hypogonadism among obese men was estimated to be as much as 40% and could as much as 50% if they are also diabetic, with levels of androgens decreasing proportionately to the degree of obesity.

In obese men, the age-related decline in T is exacerbated by the suppression of the hypothalamic-pituitary-gonadal axis by hyperestrogenemia. The high expression of aromatase enzyme in the adipose tissue enhances the conversion of androgens into estrogens which in turn exerts a negative feedback 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 T by the testis resulting in hypogonadotropic hypogonadism (HH). Considering the high aromatase expression in the adipose tissue, the administration of T among obese men with HHG could increase the conversion of the substrate T to estradiol (E2) and fuels the negative feedback on hypothalamus and pituitary, producing a greater suppression of GnRH and gonadotropins. Thus, men with obesity induced HHG may benefit from other treatment strategies that target the pathophysiology of the disease.

Although weight loss intervention improves hormonal and metabolic abnormalities related to obesity, the increase in T levels induced by weight loss are often lost due to weight regain, which is very frequent among patients undergoing massive weight loss. One possible approach is the use of aromatase inhibitors (AI) to stop the conversion of T to E2 thereby interrupting the vicious cycle of E2 inhibition of the hypothalamic-pituitary-gonadal axis and restoring T production to normal levels. Since weight loss remains the standard of care for obese patients, the investigators propose the following OBJECTIVES:

  1. To evaluate the effect of an AI plus WL (AI+WL) compared to WL alone on the changes in hormonal profile in severely obese men with HHG.
  2. To evaluate the effect of an AI+WL compared to WL alone on the changes in muscle strength and muscle mass, and symptoms of hypogonadism in severely obese men with HHG.
  3. To evaluate the effect of an AI+WL compared to WL alone on the changes in body composition and metabolic risk factors in severely obese men with HHG.
  4. To evaluate the effect of an AI+WL compared to WL alone on the changes in bone mineral density (BMD), bone markers, and bone quality in severely obese men with HHG.

As secondary aim, the investigators will elucidate the mechanism for the anticipated positive effects of AI+WL on obesity-associated HHG.

This is a randomized double-blind placebo-controlled study comparing the effect of weight loss + anastrozole to weight loss + placebo for 12 months on the hormonal profile and symptoms associated with hypogonadism in severely obese men with a body mass index (BMI) of more or equal to 35 kg/m2.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Intervention: Subjects will be randomized to 2 groups: 1) placebo+weight loss, and 2) anastrozole+weight loss. Intervention will be conducted for 12 months.

Weight loss + placebo: Subjects will participate in a supervised dietary and exercise program plus a placebo.

Anastrozole + weight loss: Subjects will participate in a supervised dietary and exercise program plus the aromatase inhibitor, anastrozole at 1 mg daily.

All subjects will be provided supplements to ensure an intake of ~1500 mg of calcium/day and ~1000 IU vitamin D/day. We will maintain a serum 25-hydroxyvitamin D level of at least 30 ng/dl. Additional vitamin D supplements will be provided for those with level <30 ng/dl.

Dosage adjustments and monitoring will be done by an unblinded investigator.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: One of the investigators will be unblinded for safety purposes and to adjust the dose of medication
Primary Purpose: Treatment
Official Title: Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
Actual Study Start Date : April 15, 2018
Estimated Primary Completion Date : April 14, 2023
Estimated Study Completion Date : April 14, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Anastrozole

Arm Intervention/treatment
Placebo Comparator: Weight loss plus placebo
Participants will take a placebo every day, attend behavioral classes conducted by a dietitian, receive instruction on how to loss 10% of their body weight and undergo supervised exercise training program.
Drug: Placebo
Participants will take a placebo tablet every day, attend behavioral classes conducted by a dietitian, receive instruction on how to loss 10% of their body weight and participate in a supervised exercise training program.
Other Name: Weight loss

Experimental: Weight loss plus anastrozole
Participants will take Anastrozole 1mg per day, attend behavioral classes conducted by a dietitian, receive instruction on how to loss 10% of their body weight and undergo supervised exercise training program.
Drug: anastrozole (1 mg/day)
Participants will take Anastrozole 1mg per day, attend behavioral classes conducted by a dietitian, receive instruction on how to loss 10% of their body weight and participate in a supervised exercise training program.
Other Name: Weight loss




Primary Outcome Measures :
  1. Hormonal Profile Changes [ Time Frame: 12 months ]
    Assessed by changes in serum testosterone levels.

  2. Changes in muscle strength [ Time Frame: 12 months ]
    Assessed by changes in knee extension strength using a dynamometer.

  3. Changes in Lean mass [ Time Frame: 12 months ]
    Assessed by body composition tissue measurement using dual energy x-ray absorptiometry.

  4. Changes in total hip bone mineral density (BMD) [ Time Frame: 12 months ]
    Assessed by dual energy absorptiometry.


Secondary Outcome Measures :
  1. Other gonadal hormone [ Time Frame: 12 months ]
    Assessed by changes in serum estradiol

  2. Pituitary hormone [ Time Frame: 12 months ]
    Assessed by changes in serum luteinizing hormone (LH)

  3. Pituitary hormone [ Time Frame: 12 months ]
    Assessed by changes in serum follicle stimulating hormone (FSH)

  4. Changes in thigh muscle volume [ Time Frame: 12 months ]
    Assessed magnetic resonance imaging of both thighs.

  5. Changes in symptoms of hypogonadism [ Time Frame: 12 months ]
    Assessed by the Androgen Deficiency in Aging Male (ADAM) questionnaire; higher scores indicating worse outcome

  6. Changes in symptoms of hypogonadism [ Time Frame: 12 months ]
    Assessed by the International Index of Erectile Function (IIEF) questionnaire; higher scores indicating better outcome

  7. Changes in symptoms of hypogonadism [ Time Frame: 12 months ]
    Assessed by the 36-Item Short-Form Health Survey (SF-36) questionnaire; scores on the physical and mental component subscales of the SF-36 range from 0 to 100, with higher scores indicating better health status

  8. Changes in visceral adipose tissues [ Time Frame: 12 months ]
    Assessed by dual energy x-ray absorptiometry

  9. Changes in metabolic risk factors [ Time Frame: 12 months ]
    Assessed by hemoglobin A1C

  10. Changes in metabolic risk factors [ Time Frame: 12 months ]
    Assessed by lipid profile

  11. Changes in metabolic risk factors [ Time Frame: 12 months ]
    Assessed by homeostasis model assessment for insulin resistance (HOMA-IR)

  12. Changes in volumetric bone density [ Time Frame: 12 months ]
    Assessed by high-resolution peripheral quantitative computer tomography

  13. Changes in bone quality [ Time Frame: 12 months ]
    Assessed by changes in finite element analysis using high-resolution peripheral quantitative computer tomography

  14. Changes in bone markers [ Time Frame: 12 months ]
    Assessed by serum C-telopeptide

  15. Changes in bone markers [ Time Frame: 12 months ]
    Assessed by serum osteocalcin

  16. Changes in bone markers [ Time Frame: 12 months ]
    Assessed by serum procollagen 1 Intact N-terminal



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   The study is investigating obesity induced male hypogonadism
Accepts Healthy Volunteers:   No
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%.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03490513


Contacts
Layout table for location contacts
Contact: Reina Villareal, MD 1737947534 reina.villareal@bcm.edu
Contact: Dennis T Villareal, MD 7137947156 dennis.villareal@bcm.edu

Locations
Layout table for location information
United States, Texas
Michael E. DeBakey VAMC Recruiting
Houston, Texas, United States, 77030
Contact: Reina Armamento-Villareal, MD    713-794-7534 ext 27534    reina.villareal@bcm.edu   
Contact: Dennis T Villareal, MD    7137947156 ext 27156    dennis.villareal@bcm.edu   
Sponsors and Collaborators
Baylor College of Medicine

Publications of Results:

Layout table for additonal information
Responsible Party: Reina, Associate Professor of Medicine, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT03490513     History of Changes
Other Study ID Numbers: H-41814
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Hypogonadism
Weight Loss
Body Weight Changes
Body Weight
Signs and Symptoms
Gonadal Disorders
Endocrine System Diseases
Anastrozole
Aromatase Inhibitors
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs