Dose-Response of Gonadal Steroids and Bone Turnover in Older Men

The purpose of this study is to determine the levels of testosterone and/or estradiol at which changes in bone turnover, body composition, strength, sexual function etc. begin to occur in older men. This information may help determine when to intervene with hormone replacement therapy in aging men.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Testosterone; Drug: Goserelin acetate

Detailed Description

In this protocol, men age 60-75 will be randomized to one of 6 groups. Groups 1-5 will receive goserelin acetate (Zoladex) plus 0 (placebo gel), 1.25, 2.5, 5, or 10* g/day of testosterone gel (Androgel). Group 6 will receive placebos for both goserelin acetate and testosterone gel. (*Note that the 10 g/day dose was reduced to 7.5 g/day part-way through the trial due to reports of possible increased risk of cardiovascular events with testosterone administration).

Subjects will be blinded with respect to group assignment. Dietary calcium intake will be assessed by a research dietitian and adjustments made through diet or supplements so that calcium intake is between 1000 and 1200 mg/day.

Subjects will be seen on the Clinical Research Center at 4 week intervals for 16 weeks (0, 4, 8, 12, and 16 weeks). At each visit, compliance with Androgel will be assessed by reviewing a medication diary. A standardized series of questions will be posed to each subject to assess potential side effects of the study drugs. Subjects receiving Androgel' will be given a new 4 week supply of medication (except at week 16). A fasting blood and second voided urine sample will be collected. After the blood and urine samples have been obtained, subjects will be given their goserelin injection. The blood and urine tests listed below as well as anthropometric measures, and questionnaires will be performed at each visit. Dual-energy x-ray absorptiometry (DXA), quantitate computed tomography (QCT) scans, and strength assessments will be performed at 0 and 16 weeks only. Subjects who discontinue participation at or after week 8 will be asked if they are willing to have an early discontinuation visit in which all procedures normally done at week 16 will be performed.

The following measures will be assessed:

• Routine chemistries and prostate specific antigen, PSA (for safety assessment)
• Bone turnover using blood and urine tests
• Hormones
• Lipids
• Body composition
• Strength
• Sexual desire and erectile function
• Bone mineral density and bone microarchitecture

• Study Type: Interventional
• Enrollment (Actual): 177
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy men age 60 to 75

Exclusion Criteria:

• History of significant cardiac, renal, pulmonary, hepatic, benign prostatic hyperplasia, or malignant disease, current alcohol or illicit drug abuse, or major psychiatric disorders.
• Current diagnoses of disorders known to affect bone metabolism including hyperthyroidism, hyperparathyroidism, osteomalacia, or Paget's disease.
• Current use of medications known to affect bone metabolism including estrogens, androgens, anti-estrogens, bisphosphonates, calcitonin, fluoride, oral or inhaled glucocorticoids, suppressive doses of thyroxine, lithium, pharmacological doses of vitamin D (greater than 2000 IU/day), or anti-convulsants.
• Cognitive or intellectual impairment that precludes complete understanding of the study protocol.
• History of deep vein thrombosis, pulmonary embolism, or clotting disorders.
• Serum 25-hydroxyvitamin D < 15 ng/mL
• Serum parathyroid hormone (PTH) < 10 or > 65 pg/mL
• Serum thyroid stimulating hormone (TSH) < 0.5 or > 5.0 U/L
• Serum calcium > 10.6 mg/dL
• Serum creatinine > 2 mg/dL
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2x the upper limit of normal
• Serum bilirubin > 2 mg/dL
• Serum alkaline phosphatase > 150 U/L
• Plasma hemoglobin < 11 gm/dL
• Hematocrit > 50
• Fracture within the last 6 months.
• Serum testosterone level < 270 or > 1070 ng/dL
• Serum prostate specific antigen (PSA) level > 4 ug/L.
• International Prostate Symptom Score (IPSS) > 19
• Systolic blood pressure > 160 or diastolic blood pressure > 95
• Framingham risk score greater than or equal to 20
• Difficulty walking 2 blocks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: 0 g/day; Zoladex plus Placebo Testosterone (T) gel	Drug: Testosterone; Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day; Other Names: Androgel; Drug: Goserelin acetate; 3.6 gms sc every 4 weeks; Other Names: Zoladex
Experimental: Group 2: 1.25 g/day; Zoladex plus 1.25 g/day T gel	Drug: Testosterone; Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day; Other Names: Androgel; Drug: Goserelin acetate; 3.6 gms sc every 4 weeks; Other Names: Zoladex
Experimental: Group 3: 2.5 g/day; Zoladex plus 2.5 g/day T gel	Drug: Testosterone; Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day; Other Names: Androgel; Drug: Goserelin acetate; 3.6 gms sc every 4 weeks; Other Names: Zoladex
Experimental: Group 4: 5 g/day; Zoladex plus 5 g/day T gel	Drug: Testosterone; Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day; Other Names: Androgel; Drug: Goserelin acetate; 3.6 gms sc every 4 weeks; Other Names: Zoladex
Experimental: Group 5: 10* g/day; Zoladex plus 10* g/day T gel. *Note that the 10 g/day dose was reduced to 7.5 g/day part-way through the trial	Drug: Testosterone; Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day; Other Names: Androgel; Drug: Goserelin acetate; 3.6 gms sc every 4 weeks; Other Names: Zoladex
Experimental: Group 6: Placebo/Placebo (PBO/PBO); Placebo Zoladex plus Placebo T gel (controls)	Drug: Testosterone; Androgel placebo or 1.25, 2.5, 5. or 10* gms topically each day; Other Names: Androgel; Drug: Goserelin acetate; 3.6 gms sc every 4 weeks; Other Names: Zoladex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Bone Turnover Marker (Serum C-telopeptide, CTX)	Baseline and 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Body Composition: Fat Mass		Baseline and 16 weeks
Percentage Change in Thigh Muscle Area	Assessed by quantitative computed tomography (QCT)	Baseline and 16 weeks
Change in Erectile Function Symptoms	Based on International Index of Erectile Function (IIEF) scale, question #15, which asked subjects to rate their confidence that they could achieve and maintain an erection. Scores range from 1 to 5, with higher scores being better.	Baseline and 16 weeks
Change in Libido / Sexual Desire	Change in libido from baseline (scale ranges from -2 to +2), with -2 being much less, -1 somewhat less, 0 same, +1 somewhat more, +2 much more	16 weeks

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: AbbVie; AstraZeneca; National Institute on Aging (NIA); Solvay Pharmaceuticals
• Investigators: Principal Investigator: Ben Z Leder, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Finkelstein JS, Lee H, Burnett-Bowie SM, Darakananda K, Gentile EC, Goldstein DW, Prizand SH, Krivicich LM, Taylor AP, Wulczyn KE, Leder BZ, Yu EW. Dose-Response Relationships Between Gonadal Steroids and Bone, Body Composition, and Sexual Function in Aging Men. J Clin Endocrinol Metab. 2020 Aug 1;105(8):2779-88. doi: 10.1210/clinem/dgaa318.
• Bachmann KN, Huang S, Lee H, Dichtel LE, Gupta DK, Burnett JC Jr, Miller KK, Wang TJ, Finkelstein JS. Effect of Testosterone on Natriuretic Peptide Levels. J Am Coll Cardiol. 2019 Mar 26;73(11):1288-1296. doi: 10.1016/j.jacc.2018.12.062.
• Finkelstein JS, Lee H, Leder BZ, Burnett-Bowie SA, Goldstein DW, Hahn CW, Hirsch SC, Linker A, Perros N, Servais AB, Taylor AP, Webb ML, Youngner JM, Yu EW. Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J Clin Invest. 2016 Mar 1;126(3):1114-25. doi: 10.1172/JCI84137. Epub 2016 Feb 22.
• Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF, Jones BF, Barry CV, Wulczyn KE, Thomas BJ, Leder BZ. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013 Sep 12;369(11):1011-22. doi: 10.1056/NEJMoa1206168.

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: June 13, 2005
• First Submitted That Met QC Criteria: June 13, 2005
• First Posted (Estimate): June 14, 2005

Study Record Updates

• Last Update Posted (Actual): October 8, 2019
• Last Update Submitted That Met QC Criteria: September 27, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Body composition; Aging; Hypogonadism; Testosterone; Sexual function; Bone turnover
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Androgens; Goserelin; Testosterone
• Other Study ID Numbers: 2003-P-001868; R01AG030545 (U.S. NIH Grant/Contract)