Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02959853

Enrollment

Registered

2016-11-09

Start date

2016-06-30

Completion date

2018-12-20

Last updated

2020-01-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypogonadism, Severe Obesity

Keywords

Hypogonadism, Severe obesity

Brief summary

After the age of 40, there is a gradual decline in the production of testosterone. Among obese men, the decline in testosterone levels 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 exert a negative feedback on the hypothalamus and pituitary, leading to the inhibition of production of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating hormone (FSH), and as a consequence, of testosterone by the testis resulting in hypogonadotropic hypogonadism (HH). Though bone loss is a well recognized side effect of AI in certain populations, such as women with breast cancer, HH obese men present high levels of circulating estrogens that could potentially prevent them from bone loss, estradiol being the main regulator of the male skeleton. This study is designed to determine if aromatase inhibitors in combination with weight loss, compared to weight loss alone, will have a positive effect on muscle strength, symptoms of hypogonadism, and body composition without negatively impacting bone mineral density and bone quality. Results from this study will help determine if certain groups of obese patients would benefit from therapy with aromatase inhibitors.

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.

Interventions

DRUGAnastrazole

BEHAVIORALweight loss

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

MALE

Age

35 Years to 65 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Percent Change in Muscle Strength as Assessed by Knee Extension and Knee Flexion	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.
Change in Symptoms Score of Hypogonadism	baseline, 3 and 6 months	Symptoms of androgen deficiency were measured with 3 validated questionnaires done at baseline, 3 and 6 months. 1. The Quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire uses questions from a scale of 1-5. The final summation yields a total score between 10 (most symptomatic) and 50 (least symptomatic). 2. The second questionnaire used was the International Index of Erectile Function (IIEF). Total score ranges from 5 to 25, with 5 being severe erectile dysfunction and 25 being no erectile dysfunction. 3. The third questionnaire used was the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-lite). Total score ranges from 31 to 155, with 31 being least symptomatic and 155 being the most symptomatic. 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

Secondary

Measure	Time frame	Description
Change in Fat Mass (in Kilograms)	baseline and 6 months	change in fat was measured by Dual-energy X-ray absorptiometry (DXA) scan at baseline and 6 months only.
Change in Visceral Adipose Tissue (in Grams)	baseline and 6 months	Change in absolute visceral adipose tissue as measured by DXA scan, done at baseline and 6 months.
Percent Change in Bone Mineral Density	baseline and 6 months	Percent change in bone mineral density as measured by DXA scan, done at baseline and 6 months
Percent Change in Bone Quality	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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Placebo Plus Weight Loss Patients given a placebo and counseling on diet and exercise in order to achieve a goal weight loss of 10 percent.	11
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	12
Total	23

Baseline characteristics

Characteristic	Placebo Plus Weight Loss	Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	11 Participants	12 Participants	23 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	7 Participants	5 Participants	12 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	4 Participants	7 Participants	11 Participants
Region of Enrollment United States	11 participants	12 participants	23 participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	11 Participants	12 Participants	23 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 11	0 / 12
other Total, other adverse events	3 / 11	4 / 12
serious Total, serious adverse events	1 / 11	1 / 12

Outcome results

Primary

Change in Symptoms Score of Hypogonadism

Symptoms of androgen deficiency were measured with 3 validated questionnaires done at baseline, 3 and 6 months. 1. The Quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire uses questions from a scale of 1-5. The final summation yields a total score between 10 (most symptomatic) and 50 (least symptomatic). 2. The second questionnaire used was the International Index of Erectile Function (IIEF). Total score ranges from 5 to 25, with 5 being severe erectile dysfunction and 25 being no erectile dysfunction. 3. The third questionnaire used was the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-lite). Total score ranges from 31 to 155, with 31 being least symptomatic and 155 being the most symptomatic. 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

Time frame: baseline, 3 and 6 months

Arm	Measure	Group	Value (MEAN)	Dispersion
Weight Loss	Change in Symptoms Score of Hypogonadism	qADAM score change at 3 months	2.4 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 3.4
Weight Loss	Change in Symptoms Score of Hypogonadism	qADAM score change at 6 months	4.1 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 5.7
Weight Loss	Change in Symptoms Score of Hypogonadism	IIEF score change at 3 monthss	4.3 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 3.8
Weight Loss	Change in Symptoms Score of Hypogonadism	IIEF score change at 6 months	0.9 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 4.11
Weight Loss	Change in Symptoms Score of Hypogonadism	IWQOL-lite score change at 3 month	-12.2 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 23.9
Weight Loss	Change in Symptoms Score of Hypogonadism	IWQOL-lite score change at 6 month	-16.6 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 27.1
Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Change in Symptoms Score of Hypogonadism	IWQOL-lite score change at 3 month	-13.0 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 15.2
Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Change in Symptoms Score of Hypogonadism	IWQOL-lite score change at 6 month	-18.6 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 8.8
Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Change in Symptoms Score of Hypogonadism	qADAM score change at 3 months	5.8 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 6.1
Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Change in Symptoms Score of Hypogonadism	qADAM score change at 6 months	4.4 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 7.2
Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Change in Symptoms Score of Hypogonadism	IIEF score change at 6 months	1.7 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 5.8
Aromatase Inhibitor (Anastrazole) Plus Weight Loss	Change in Symptoms Score of Hypogonadism	IIEF score change at 3 monthss	2.7 score on scale (qADAM, IIEF, IWQOL-lite)	Standard Deviation 4.6

Primary

Percent Change in Muscle Strength as Assessed by Knee Extension and Knee Flexion

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.