Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism

Obesity Clinical Trial

Official title:

Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03490513
• Other study ID #: H-41814
• Status: Recruiting
• Phase: Phase 4
• Start date: April 15, 2018
• Est. completion date: April 14, 2026

Study information

• Verified date: March 2024
• Source: Baylor College of Medicine
• Contact: Reina Villareal, MD
• Phone: 1737947534
• Email: reina.villareal[@]bcm.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: April 14, 2026
• Est. primary completion date: April 14, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 40 Years to 65 Years

Eligibility

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%.

Related Conditions & MeSH terms

• Hypogonadism
• Hypogonadism, Hypogonadotropic
• Obesity
• Weight Loss

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Michael E. DeBakey VAMC	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Baylor College of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (10)

Armamento-Villareal R, Aguirre LE, Qualls C, Villareal DT. Effect of Lifestyle Intervention on the Hormonal Profile of Frail, Obese Older Men. J Nutr Health Aging. 2016 Mar;20(3):334-40. doi: 10.1007/s12603-016-0698-x. — View Citation

Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009 Jun;5(3):427-48. doi: 10.2147/tcrm.s3025. Epub 2009 Jun 22. — View Citation

Corona G, Rastrelli G, Monami M, Saad F, Luconi M, Lucchese M, Facchiano E, Sforza A, Forti G, Mannucci E, Maggi M. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 2013 Ma — View Citation

Dhindsa S, Miller MG, McWhirter CL, Mager DE, Ghanim H, Chaudhuri A, Dandona P. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010 Jun;33(6):1186-92. doi: 10.2337/dc09-1649. Epub 2010 Mar 3. Erratum In: Diabetes Care. 2 — View Citation

Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endoc — View Citation

Giagulli VA, Kaufman JM, Vermeulen A. Pathogenesis of the decreased androgen levels in obese men. J Clin Endocrinol Metab. 1994 Oct;79(4):997-1000. doi: 10.1210/jcem.79.4.7962311. — View Citation

Kaplan SA, Lee JY, O'Neill EA, Meehan AG, Kusek JW. Prevalence of low testosterone and its relationship to body mass index in older men with lower urinary tract symptoms associated with benign prostatic hyperplasia. Aging Male. 2013 Dec;16(4):169-72. doi: — View Citation

Khosla S, Melton LJ 3rd, Atkinson EJ, O'Fallon WM. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab. 2001 Aug;86(8):3555-61. doi: 10.1210/jcem.86.8.7736. — View Citation

Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979 Apr;48(4):633-8. doi: 10.1210/jcem-48-4-633. — View Citation

Strain GW, Zumoff B, Kream J, Strain JJ, Deucher R, Rosenfeld RS, Levin J, Fukushima DK. Mild Hypogonadotropic hypogonadism in obese men. Metabolism. 1982 Sep;31(9):871-5. doi: 10.1016/0026-0495(82)90175-5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hormonal Profile Changes	Assessed by changes in serum testosterone levels.	12 months
Primary	Changes in muscle strength	Assessed by changes in knee extension strength using a dynamometer.	12 months
Primary	Changes in Lean mass	Assessed by body composition tissue measurement using dual energy x-ray absorptiometry.	12 months
Primary	Changes in total hip bone mineral density (BMD)	Assessed by dual energy absorptiometry.	12 months
Secondary	Other gonadal hormone	Assessed by changes in serum estradiol	12 months
Secondary	Pituitary hormone	Assessed by changes in serum luteinizing hormone (LH)	12 months
Secondary	Pituitary hormone	Assessed by changes in serum follicle stimulating hormone (FSH)	12 months
Secondary	Changes in thigh muscle volume	Assessed magnetic resonance imaging of both thighs.	12 months
Secondary	Changes in symptoms of hypogonadism	Assessed by the Androgen Deficiency in Aging Male (ADAM) questionnaire; higher scores indicating worse outcome	12 months
Secondary	Changes in symptoms of hypogonadism	Assessed by the International Index of Erectile Function (IIEF) questionnaire; higher scores indicating better outcome	12 months
Secondary	Changes in symptoms of hypogonadism	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	12 months
Secondary	Changes in visceral adipose tissues	Assessed by dual energy x-ray absorptiometry	12 months
Secondary	Changes in metabolic risk factors	Assessed by hemoglobin A1C	12 months
Secondary	Changes in metabolic risk factors	Assessed by lipid profile	12 months
Secondary	Changes in metabolic risk factors	Assessed by homeostasis model assessment for insulin resistance (HOMA-IR)	12 months
Secondary	Changes in volumetric bone density	Assessed by high-resolution peripheral quantitative computer tomography	12 months
Secondary	Changes in bone quality	Assessed by changes in finite element analysis using high-resolution peripheral quantitative computer tomography	12 months
Secondary	Changes in bone markers	Assessed by serum C-telopeptide	12 months
Secondary	Changes in bone markers	Assessed by serum osteocalcin	12 months
Secondary	Changes in bone markers	Assessed by serum procollagen 1 Intact N-terminal	12 months