Aromatase Inhibitors and Weight Loss in Severely Obese Hypogonadal Male Veterans (Pilot)
Condition: Hypogonadism; Severe Obesity
MeSH terms: Obesity, Morbid; Hypogonadism; Weight Loss
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Anastrazole; weight loss
Intervention type(s): Drug; Behavioral
Other intervention name(s): Arimidex
Intervention MeSH terms: Anastrozole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hypogonadism; Severe obesity