Hypogonadism, HypogonadotropicPhase 4NCT03490513
Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
A Phase 4 study testing anastrozole (1 mg/day) in people with Hypogonadism, Hypogonadotropic and Obesity, run by Baylor College of Medicine at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 40 to 65 years, men only
- Conditions the study is for
- Hypogonadism, Hypogonadotropic, Obesity
- What is being tested?
- anastrozole (1 mg/day)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 121 participants
- Where
- 1 siteUnited States
- Study dates
- 1 May 2018to 30 Jun 2026
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 65 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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,
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- 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%.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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
Read the detailed 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:
- 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.
- 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.
- 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.
- 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.
- Conditions
- Hypogonadism, Hypogonadotropic, Obesity
- Being tested
- anastrozole (1 mg/day), Placebo
- Keywords
- obesity, hypogonadism, testosterone, aromatase inhibitors, weight loss
- Medical subject headings
- Hypogonadism, Obesity, Weight Loss
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
anastrozole (1 mg/day)Drug
Also called Weight loss
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.
PlaceboDrug
Also called Weight loss
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.
| Study group | Role | What they receive |
|---|---|---|
| placebo | Placebo comparator | Participants will take a placebo every day Receives: Drug: Placebo |
| anastrozole | Experimental | Participants will take Anastrozole 1mg per day Receives: Drug: anastrozole (1 mg/day) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Serum Testosterone From Baseline to 12 Months
Change in serum testosterone levels from baseline to 12 months. An increase in testosterone levels suggests in improvement in hormonal profile in men with hypogonadism or low testosterone.
Measured: 12 months
Percent Change in Muscle Strength From Baseline to 12 Months
Percent change in muscle strength (in Newton-meters) as assessed by knee extension strength using a Biodex machine from baseline to 12 months. An increase in knee extension indicates an improvement in muscle strength of the lower extremity.
Measured: 12 months
Percent Change in Total Lean Mass From Baseline to 12 Months.
Percent change in total lean mass (in kilograms) as measured by dual energy x-ray absorptiometry from baseline to 12 months. An increase in lean mass suggests an increase in muscle mass while a reduction implies the opposite.
Measured: 12 months
Percent Change in Total Hip Areal Bone Mineral Density From Baseline to 12 Months.
Precent change in total hip areal bone mineral density (aBMD) in g/cm2 as assessed by dual energy absorptiometry of the proximal left femur (right if left had surgery) from baseline to 12 months. An increase in hip aBMD indicates improvement in hip bone mass while a reduction suggests the opposite.
Measured: 12 months
Secondary outcomes (16)
Change in Estradiol From Baseline to 12 Months.
Change in serum estradiol levels from baseline to 12 months. Men with obesity have high estradiol levels due to increase conversion of testosterone to estradiol in the abundant fat tissues. A reduction in estradiol in men with obesity from weight loss, with or without anastrozole, suggests an improvement in hormonal profile.
Measured: 12 months
Change in Luteinizing Hormone Levels From Baseline to 12 Months.
Change in serum luteinizing hormone (LH) levels from baseline to 12 months. In men with obesity, LH level is suppressed due to high estradiol level. An increase in LH from weight loss, with or without anastrozole, indicates improvement in hormonal profile.
Measured: 12 months
Change in Follicle Stimulating Hormone Levels From Baseline to 12 Months
Change in serum follicle stimulating hormone (FSH) from baseline to 12 months. In men with obesity, FSH level is suppressed due to high estradiol level. An increase in FSH from weight loss, with or without anastrozole, indicates improvement in hormonal profile.
Measured: 12 months
Changes in Thigh Muscle Volume
Assessed magnetic resonance imaging of both thighs.
Measured: 12 months
Percent Change in Symptoms of Hypogonadism Using the Androgen Deficiency in Aging Male (ADAM) Questionnaire From Baseline to 12 Months.
Percent change in symptoms of hypogonadism from baseline to 12 months as assessed by the quantitative Androgen Deficiency in Aging Male (qADAM) questionnaire; higher scores indicate better outcome. Minimum score is 10 (poorest, i.e. most symptomatic) and the highest score is 50 (excellent, i.e. least symptomatic). Percent changes in scores from baseline to 12 months were calculated. An increase in scores from baseline indicates improvement in symptoms of low testosterone or hypogonadism.
Measured: 12 months
Changes in Symptoms of Hypogonadism Using International Index of Erectile Function (IIEF) Questionnaire
Assessed by the International Index of Erectile Function (IIEF) questionnaire; higher scores indicating better outcome. Minimum score is 0 (poorest or most symptomatic) and maximum score is 75 (excellent or least symptomatic). Percent change in scores from baseline to 12 months were calculated. An increase in scores from baseline indicates an improvement in erectile symptoms.
Measured: 12 months
Changes in Symptoms of Hypogonadism and Obesity
Evaluated by the Impact of Weight on Quality of Life questionnaire which assesses weight-related quality of life and include 5 domains as: Physical Function (11 items), Self-Esteem (7 items), Sexual Life (4 items), Public Distress (5 items), Work (4 items)
Measured: 12 months
Percent Change in Visceral Adipose Tissue Volume From Baseline to 12 Months.
Percent change in visceral adipose tissue (VAT) volume (in cubic centimeter) measured by dual energy X-ray absorptiometry from baseline to 12 months. High VAT volume is associated with increased metabolic dysfunction and inflammation. A reduction in VAT from weight loss is usually associated with improvement in metabolic and inflammatory profile.
Measured: 12 months
Percent Change in Hemoglobin A1C From Baseline to 12 Months.
Percent change in hemoglobin A1C (A1C, unit in %)) in the blood from baseline to 12 months. A reduction in A1C indicates an improvement in glucometabolic homeostasis.
Measured: 12 months
Percent Change in Low Density Cholesterol Levels From Baseline to 12 Months.
Percent change in serum low density cholesterol (LDL, unit in mg/dl) levels from baseline to 12 months. A reduction in LDL cholesterol indicates in improvement lipid metabolism.
Measured: 12 months
Percent Change in Homeostatic Model Assessment for Insulin Resistance From Baseline to 12 Months.
Percent change in serum homeostatic model assessment for insulin resistance (HOMA-IR, unitless as it is an index) calculated as (insulin [microU/L] x glucose [mg/dl])/405, from baseline to 12 months. A reduction in HOMA-IR indicates improvement in insulin resistance.
Measured: 12 months
Percent Change in Total Volumetric Bone Density of the Radius
Percent change in total volumetric bone mineral density (vBMD, unit in milligrams per cubic centimeter) of the radius by high-resolution peripheral quantitative computer tomography from baseline to 12 months. An increase in vBMD indicates bone gain while a reduction suggests bone loss.
Measured: 12 months
Percent Change in Failure Load at the Radius From Baseline to 12 Months,
Percent change in failure load (unit in kilo-Newtons or Kn), a measure of bone strength, assessed by high-resolution peripheral quantitative computer tomography of the radius from baseline to 12 months. An increase in failure load indicates increase in bone strength while the reduction suggests the opposite
Measured: 12 months
Percent Change in C-terminal Telopeptide of Type I Collagen (CTX)
Percent change in serum C-terminal telopeptide of type I collagen (CTX) (unit in ng/ml), a marker of bone resorption, from baseline to 12 months. An increase in CTX indicates increased bone resorption which contributes to bone loss, while a reduction suggests decreased bone resorption.
Measured: 12 months
Percent Change in Osteocalcin From Baseline to 12 Months.
Percent change in serum osteocalcin (unit in ng/ml), a marker of bone formation, from baseline to 12 months. An increase in osteocalcin suggests an increase in bone formation.
Measured: 12 months
Percent Change in Procollagen Type 1 N-terminal Propeptide (P1NP) From Baseline to 12 Months
Percent change in serum N-terminal propeptide (P1NP) (unit in ng/ml), a marker of bone formation, from baseline to 12 months. An increase in P1NP suggests an increase in bone formation.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Apr 2018
- Study start1 May 2018
- Primary completion30 Jun 2025
- Study completion30 Jun 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Hypogonadism, HypogonadotropicStudies of the same condition, open and under way.
- More trials run by Baylor College of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 121 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baylor College of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Reina Villareal MD, Baylor College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03490513
- Sponsor's protocol ID
- H-41814
- Other IDs
- 5R01HD093047-05
- Status last verified
- Aug 2026
- First submitted
- 22 Mar 2018
- Last updated
- 19 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 429508Corona 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.
PubMed 23482592Armamento-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.
PubMed 26892583Feldman 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.
PubMed 11836290Khosla 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.
PubMed 11502778Bassil 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.
PubMed 19707253Kaplan 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.
PubMed 24134648Dhindsa 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.
PubMed 20200299Giagulli 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.
PubMed 7962311Strain 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.
PubMed 6811834Joad 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.
PubMed 35027909Vigevano 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.
PubMed 33537757