- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02959853
Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
After the 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. Because of the age-related increase in sex hormone binding globulin, the magnitude of the decrease in bioavailable T in men is even greater than the decline in total T levels. 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, increased fat mass, loss of libido and reduced muscle strength, all of which deeply affect patient's quality of life. The prevalence of hypogonadismamong obese men ranges between 29.3% to 78.8%, with levels of androgens decreasing proportionately to the degree of obesity. This decline in T levels is exacerbated among obese patients due 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 (E) 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 HH could increase the conversion of the substrate T to estradiol (E2) and fuels the negative feedback on the hypothalamus and pituitary, producing a greater suppression of GnRH and gonadotropins.
Thus, men with obesity induced HH may benefit from other treatment strategies that target the pathophysiology of the disease. Weight loss intervention which improves hormonal and metabolic abnormalities related to obesity may also be considered a logical approach to improve obesity-induced HH.
One possible approach consists of 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. Increased T and reduced E2 levels have been reported in men with low levels of T after AI administration, even though very few studies investigated clinical outcomes.
We believe that AI use could promote positive changes on hypogonadal symptoms and body composition in HH severely obese patients, acting at the physiopathology of the disease without necessarily causing bone loss.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Texas
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Houston, Texas, United States, 77030
- Michael E. DeBakey Veterans Affairs Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- severely obese (BMI >= 35) male veterans with hypogonadotropic hypogonadism defined as low total testosterone (lower than 300 ng/dl) between 35-65 years of age
- Luteinizing hormone (LH) lower than 9 U/L
- estradiol above 40 pmol/l
- normal Free T4 (FT4), Thyroid Stimulating Hormone (TSH), prolactin, cortisol, Adrenocorticotropic hormone (ACTH), and Insulin-like growth factor-1 (IGF-1) levels.
- Subjects must be ambulatory, willing and able to provide written informed consent
Exclusion Criteria:
- clinical or biochemical evidence of pituitary or hypothalamic disease
- any ongoing illness that, in the opinion of the investigator, could prevent the subject from completing study
any med known to affect gonadal hormones, steroid hormone-binding globulin or bone metabolism, e.g.,
- androgens
- estrogens
- glucocorticoids
- phenytoin
- bisphosphonates
- any medication known to interfere with anastrozole metabolism, e.g. tamoxifen or estrogens
diseases known to interfere with bone metabolism as
- osteoporosis
- hyperparathyroidism
- untreated hyperthyroidism
- osteomalacia
- chronic liver disease
- renal failure
- hypercortisolism
- malabsorption
- immobilization
- patients with a Total T score lower than -2.0 at Lumbar Spine or Left Femur.
- patients with symptomatic prostate disease, prostate carcinoma, or elevated serum Prostate-specific antigen (PSA) >4 ng/ml or >3 for subjects with a family history of prostate cancer among 1st degree relatives needs urologic evaluation before admission into study
- hematocrit greater than 50%
- untreated severe obstructive sleep apnea
- severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) above 19
- documented heart failure
- cardiovascular disease
- liver disease
- excessive alcohol or substance abuse
- unstable weight (changes in weight more than ± 2 kg) during the last 3 months
- history of bariatric surgery
- subjects with elevated liver enzymes as alanine transaminase (ALT), aspartate aminotransferase (AST), Alkaline phosphatase (ALP), and bilirubin at greater than twice the upper limit of normal.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: weight loss
Patients given counseling on diet and exercise in order to achieve a goal weight loss of 10 percent
|
|
Experimental: aromatase inhibitor (anastrazole) plus weight loss
Patient placed on an aromatase inhibitor anastrazole 1 mg daily plus given counseling on diet and exercise in order to achieve a goal weight loss of 10 percent
|
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percent Change in Muscle Strength as Assessed by Knee Extension and Knee Flexion
Time Frame: baseline and 6 months
|
Muscle strength was assessed using Biodex System 4 Isokinetic Dynamometer (Shirley, NY). Peak torque for isokinetic knee extension and flexion was measured at baseline, 6 months on the right leg. During the testing, participants sat with their hips flexed at 120 degrees, secured with thigh and pelvic straps. Testing was performed at an angular velocity of 60 degrees per second. The best result of 3 maximal voluntary efforts for each knee flexion and extension was used as the measure of absolute strength and reported as peak torque at 60 degrees in Newton-meter (N*m) units. The higher the measured Newton-meter (N*m), the greater the measured muscle strength. |
baseline and 6 months
|
Change in Symptoms Score of Hypogonadism
Time Frame: baseline, 3 and 6 months
|
Symptoms of androgen deficiency were measured with 3 validated questionnaires done at baseline, 3 and 6 months.
Score change at 3 months calculated by: total score at 3 months minus total score at baseline Score change at 6 months calculated by: total score at 6 months minus total score at baseline |
baseline, 3 and 6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Fat Mass (in Kilograms)
Time Frame: baseline and 6 months
|
change in fat was measured by Dual-energy X-ray absorptiometry (DXA) scan at baseline and 6 months only.
|
baseline and 6 months
|
Change in Visceral Adipose Tissue (in Grams)
Time Frame: baseline and 6 months
|
Change in absolute visceral adipose tissue as measured by DXA scan, done at baseline and 6 months.
|
baseline and 6 months
|
Percent Change in Bone Mineral Density
Time Frame: baseline and 6 months
|
Percent change in bone mineral density as measured by DXA scan, done at baseline and 6 months
|
baseline and 6 months
|
Percent Change in Bone Quality
Time Frame: baseline and 6 months
|
Percent change in bone quality as measured by high resolution peripheral quantitative computed tomography scan (HR-pQCT), at baseline and 6 months
|
baseline and 6 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Reina Villareal, MD, Baylor College of Medicine
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Endocrine System Diseases
- Gonadal Disorders
- Overnutrition
- Nutrition Disorders
- Overweight
- Body Weight
- Body Weight Changes
- Obesity
- Weight Loss
- Hypogonadism
- Obesity, Morbid
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Hormone Antagonists
- Aromatase Inhibitors
- Steroid Synthesis Inhibitors
- Estrogen Antagonists
- Anastrozole
Other Study ID Numbers
- H-36912
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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