Clinical trial NCT02959853: Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)
Official title: Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypogonadism
Severe Obesity
Keywords: Hypogonadism
Severe obesity
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
First posted: 2016-11-09
Enrollment: 23
Sex: MALE
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change in Muscle Strength as Assessed by Knee Extension and Knee Flexion
timeFrame: baseline and 6 months
measure: Change in Symptoms Score of Hypogonadism
timeFrame: baseline, 3 and 6 months
Secondary outcomes:
measure: Change in Fat Mass (in Kilograms)
timeFrame: baseline and 6 months
measure: Change in Visceral Adipose Tissue (in Grams)
timeFrame: baseline and 6 months
measure: Percent Change in Bone Mineral Density
timeFrame: baseline and 6 months
measure: Percent Change in Bone Quality
timeFrame: baseline and 6 months
Other outcomes:
Locations:
city: Houston
country: United States
facility: Michael E. DeBakey Veterans Affairs Medical Center
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Reina Villareal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Colleluori G, Chen R, Turin CG, Vigevano F, Qualls C, Johnson B, Mediwala S, Villareal DT, Armamento-Villareal R. Aromatase Inhibitors Plus Weight Loss Improves the Hormonal Profile of Obese Hypogonadal Men Without Causing Major Side Effects. Front Endocrinol (Lausanne). 2020 May 15;11:277. doi: 10.3389/fendo.2020.00277. eCollection 2020.