Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism

NCT03490513 | Completed Phase 4 DMC FDA Drug

• 1 other identifier: H-41814
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 1

Brief 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. Although the above original protocol requires the participants to come to our center for dietary and exercise training, since the Covid19 pandemic, study participants were given the following options for lifestyle intervention: 1) in-person visits at our facility for dietary classes and exercise training, 2) to enlist in the gym of their choice with membership paid for by the study, or 3) virtual method of lifestyle intervention. These amendments were put in place due to Covid 19 restrictions; however, we decided to keep these methods because most of our subjects prefer them over coming for in-person visits at our lab even after COVID restrictions were lifted. Since the study had just the first 25 subjects enrolled prior to COVID outbreak, majority of the subject's lifestyle interventions were done by virtual dietary classes every week for the first 3 months and then every 2 weeks thereafter either as a group or by one-on-one sessions. Exercise program was also supervised by exercise physiologist virtually or by phone for subjects who want to exercise at a community gym

Conditions

Hypogonadism, Hypogonadotropic; Obesity

Outcome Measures

Primary Outcomes (4)

• Hormonal Profile Changes

  Assessed by changes in serum testosterone levels.

  12 months

• Changes in muscle strength

  Assessed by changes in knee extension strength using a dynamometer.

  12 months

• Changes in Lean mass

  Assessed by body composition tissue measurement using dual energy x-ray absorptiometry.

  12 months

• Changes in total hip bone mineral density (BMD)

  Assessed by dual energy absorptiometry.

  12 months

Secondary Outcomes (16)

• Other gonadal hormone

  12 months

• Pituitary hormone

  12 months

• Pituitary hormone

  12 months

• Changes in thigh muscle volume

  12 months

• Changes in symptoms of hypogonadism

  12 months

Study Arms (2)

Weight loss plus placebo

PLACEBO COMPARATOR

Participants will take a placebo every day, attend behavioral classes conducted by a dietitian, receive instruction on how to loss 10% of their body weight and undergo supervised exercise training program.

Drug: Placebo

Weight loss plus anastrozole

EXPERIMENTAL

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 undergo supervised exercise training program.

Drug: anastrozole (1 mg/day)

Interventions

anastrozole (1 mg/day) DRUG

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.

Also known as: Weight loss

Weight loss plus anastrozole

Placebo DRUG

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.

Also known as: Weight loss

Weight loss plus placebo

Eligibility Criteria

• Age: 40 Years - 65 Years
• Gender Eligibility Details: The study is investigating obesity induced male hypogonadism
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (1)

Michael E. DeBakey VAMC

Houston, Texas, 77030, United States

Location

Related Publications (12)

• 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.

  PMID: 429508 RESULT

• 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 May 2;168(6):829-43. doi: 10.1530/EJE-12-0955. Print 2013 Jun.

  PMID: 23482592 RESULT

• 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.

  PMID: 26892583 RESULT

• 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 Endocrinol Metab. 2002 Feb;87(2):589-98. doi: 10.1210/jcem.87.2.8201.

  PMID: 11836290 RESULT

• 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.

  PMID: 11502778 RESULT

• 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.

  PMID: 19707253 RESULT

• 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: 10.3109/13685538.2013.844786. Epub 2013 Oct 17.

  PMID: 24134648 RESULT

• 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.

  PMID: 20200299 RESULT

• 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.

  PMID: 7962311 RESULT

• 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.

  PMID: 6811834 RESULT

• Joad S, Ballato E, Deepika F, Gregori G, Fleires-Gutierrez AL, Colleluori G, Aguirre L, Chen R, Russo V, Fuenmayor Lopez VC, Qualls C, Villareal DT, Armamento-Villareal R. Hemoglobin A1c Threshold for Reduction in Bone Turnover in Men With Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne). 2021 Dec 28;12:788107. doi: 10.3389/fendo.2021.788107. eCollection 2021.

  PMID: 35027909 DERIVED

• Vigevano F, Gregori G, Colleluori G, Chen R, Autemrongsawat V, Napoli N, Qualls C, Villareal DT, Armamento-Villareal R. In Men With Obesity, T2DM Is Associated With Poor Trabecular Microarchitecture and Bone Strength and Low Bone Turnover. J Clin Endocrinol Metab. 2021 Apr 23;106(5):1362-1376. doi: 10.1210/clinem/dgab061.

  PMID: 33537757 DERIVED

MeSH Terms

Conditions

Hypogonadism; Obesity

Interventions

Anastrozole

Condition Hierarchy (Ancestors)

Gonadal Disorders; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: One of the investigators will be unblinded for safety purposes and to adjust the dose of medication
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Intervention: Subjects will be randomized to 2 groups: 1) placebo+weight loss, and 2) anastrozole+weight loss. Intervention will be conducted for 12 months. Weight loss + placebo: Subjects will participate in a supervised dietary and exercise program plus a placebo. Anastrozole + weight loss: Subjects will participate in a supervised dietary and exercise program plus the aromatase inhibitor, anastrozole at 1 mg daily. All subjects will be provided supplements to ensure an intake of \~1500 mg of calcium/day and \~1000 IU vitamin D/day. We will maintain a serum 25-hydroxyvitamin D level of at least 30 ng/dl. Additional vitamin D supplements will be provided for those with level \<30 ng/dl. Dosage adjustments and monitoring will be done by an unblinded investigator.

Study Record Dates

• First Submitted: March 22, 2018
• First Posted: April 6, 2018
• Study Start: April 15, 2018
• Primary Completion: May 31, 2025
• Study Completion: May 31, 2025
• Last Updated: August 7, 2025

Record last verified: 2025-08

Locations

US (1)