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Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer
ADULT UROLOGY
CHANGES IN FAT AND LEAN BODY MASS DURING ANDROGEN-DEPRIVATION THERAPY FOR PROSTATE CANCER MATTHEW R. SMITH
ABSTRACT Objectives. To assess the effects of androgen deprivation therapy on body composition in men with nonmetastatic prostate cancer. Methods. In a multicenter study, men with Stage M0 prostate cancer were prospectively evaluated during initial androgen deprivation therapy (gonadotropin-releasing hormone agonist or bilateral orchiectomy). The main outcomes were changes in weight, percentage fat mass, and percentage lean mass from baseline to 12 months. Results. Seventy-nine subjects were assessed. Serum testosterone concentrations decreased by 79.7% ⫾ 3.0% (P ⬍0.001). Weight increased by 1.8% ⫾ 0.5% (P ⬍0.001). The percentage fat mass increased by 11.0% ⫾ 1.7%, and the percentage lean mass decreased by 3.8% ⫾ 0.6% (P ⬍0.001 for each comparison). Conclusions. Androgen deprivation therapy increased weight and fat mass and decreased lean mass in men with nonmetastatic prostate cancer. UROLOGY 63: 742–745, 2004. © 2004 Elsevier Inc.
A
ndrogens are important determinants of body composition in men. Serum testosterone concentrations correlate positively with lean mass and negatively with fat mass.1 Testosterone replacement therapy increases lean mass and decreases fat mass in hypogonadal men.2,3 Testosterone supplementation increases lean mass, muscle size, and strength in eugonadal men.4 Less is known about the effects of androgen deprivation therapy on the body composition of men with prostate cancer. We report the results of a multicenter study to evaluate the body composition of men undergoing initial androgen deprivation therapy for prostate cancer. The main outcomes were changes in weight, percentage fat mass, and percentage lean mass from baseline to 12 months.
This study was supported by Novartis Oncology, which also contributed to study conduct and monitoring, data collection, and statistical analysis. From the Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts Reprint requests: Matthew R. Smith, M.D., Ph.D., Division of Hematology-Oncology, Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, MA 02114 Submitted: August 7, 2003, accepted (with revisions): October 28, 2003
742
© 2004 ELSEVIER INC. ALL RIGHTS RESERVED
MATERIALS AND METHODS SUBJECTS All subjects were participants in a randomized controlled study to evaluate the effects of zoledronic acid on bone mineral density in men undergoing initial androgen deprivation therapy for prostate cancer.5 Subjects were accrued at 16 centers in the United States from February 24, 2000 to November 7, 2000. All subjects were initiating androgen deprivation therapy for Stage M0 (no distant metastases) prostate cancer. All men had an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Men with chronic liver disease, serum creatinine concentration of more than 2.0 mg/dL, or other major organ dysfunction were excluded. Men with a lumbar spine bone mineral density more than 3.0 standard deviations below young adult norms (determined by site-specific machine normal values for men) were excluded. Men who had received androgen deprivation therapy, antiandrogens, bisphosphonates, calcitonin, gallium nitrate, or mithramycin within 1 year were also excluded. The institutional review board at each participating institution approved the study. All subjects gave written informed consent.
STUDY DESIGN All subjects received androgen deprivation therapy with a gonadotropin-releasing hormone agonist and an antiandrogen (bicalutamide or flutamide), a gonadotropin-releasing hormone agonist without an antiandrogen, or bilateral orchiectomy. Subjects were randomly assigned to receive either zoledronic acid (Zometa, Novartis Pharmaceuticals, East Hanover, NJ) 4 mg or placebo intravenously every 3 months for 1 year using permuted blocks randomization from a validated automated system. All subjects were instructed to take a 0090-4295/04/$30.00 doi:10.1016/j.urology.2003.10.063
TABLE I. Baseline characteristics Age (yr) Race (%) White Black Asian Other Body mass index (kg/m2) Type of androgen deprivation therapy (%) GnRH agonist GnRH agonist ⫹ antiandrogen Bilateral orchiectomy
71 ⫾ 9 80 6 5 9 28.4 ⫾ 0.5
53 46 1
KEY: GnRH ⫽ gonadotropin-releasing hormone. Data presented as the mean ⫾ standard error, unless otherwise noted.
calcium supplement (500 mg) and multivitamin containing vitamin D (400 IU) daily.
STUDY OUTCOMES The percentages fat body mass and lean body mass were determined at baseline and 12 months by dual energy x-ray absorptiometry using a Hologic (DELPHI, QDR 4500 series, or QDR 1000, Hologic, Waltham, Mass) or Lunar (EXPERT, PRODIGY, or DPX series, Lunar, Madison, Wis) densitometer. All dual-energy x-ray absorptiometry scans were reviewed at a central laboratory (Bio-Imaging Technologies, Newtown, Pa). Hemoglobin, prostate-specific antigen, and testosterone concentrations were measured at a central laboratory (Mayo Clinical Laboratories, Rochester, Minn). The coefficient of variation for prostate-specific antigen and testosterone was 2.6% and 6.4%, respectively. For men older than 40 years of age, the normal range for serum testosterone was 240 to 950 ng/dL.
STATISTICAL ANALYSIS Changes in study outcomes (testosterone, prostate-specific antigen, hemoglobin, weight, height, percentage of fat mass, and percentage of lean mass) were compared between the zoledronic acid and placebo groups using analysis of covariance, controlling for baseline. Because no statistically significant differences were noted for any outcomes between the groups, the results for all 79 assessable subjects were combined. The percentage of changes between the baseline and 48-week values for all outcome measures were tested for statistical significance using one-sample t tests. Statistical analyses were performed using Statistical Analysis System, version 6.12 (SAS Institute, Cary, NC). Values are reported as the mean ⫾ standard error. All P values are two sided, and P ⬍0.05 was considered statistically significant.
RESULTS SUBJECT CHARACTERISTICS Seventy-nine assessable subjects were included in the study. The baseline characteristics are summarized in Table I. BIOCHEMICAL OUTCOMES The mean serum testosterone concentration decreased by 79.7% ⫾ 3.0% (P ⬍0.001) from baseline to 48 weeks (Table II). The serum prostateUROLOGY 63 (4), 2004
specific antigen concentrations decreased by 89.4% ⫾ 2.2% (P ⬍0.001). The hemoglobin concentrations decreased by 10.5% ⫾ 0.7% (P ⬍0.001). BODY COMPOSITION The men’s weight increased by 1.8% ⫾ 0.5% (P ⬍0.001) from baseline to 48 weeks (Table II). Their height did not change significantly (P ⫽ 0.35). The percentage fat mass increased by 11.0% ⫾ 1.7%, and the percentage lean mass decreased by 3.8% ⫾ 0.6% from baseline to 48 weeks (P ⬍0.001 for each comparison). COMMENT The results of this multicenter prospective study demonstrated that androgen deprivation therapy markedly alters the body composition of men with prostate cancer. The men’s weight and fat mass increased significantly and their lean mass decreased significantly during androgen deprivation therapy. These changes in body composition may contribute to the adverse effects of androgen deprivation therapy on patients’ quality of life, including fatigue, loss of energy, and emotional distress.6 – 8 Fat mass increased by 11% and lean body mass decreased by 3.8% after 1 year of androgen deprivation therapy. In another study, similar changes in body composition were observed after 3 months of treatment with a gonadotropin-releasing hormone agonist,9 suggesting that body composition changes occur early after initiating androgen deprivation therapy. Additional research is needed to determine the body composition changes during long-term androgen deprivation therapy and after treatment discontinuation. These results are consistent with the results of smaller single-institution studies. In the study by Tayek et al.,10 weight and fat mass increased significantly in 10 men treated with a gonadotropin-releasing hormone agonist for locally advanced or metastatic prostate cancer. Smith et al.11 noted that weight increased by 2.4%, the percentage fat mass increased by 9.4%, and the percentage lean mass decreased by 2.7% after 12 months in 32 asymptomatic men undergoing initial gonadotropin-releasing hormone agonist treatment for nonmetastatic prostate cancer. Similar changes were reported in another 12-month study of 35 men receiving a gonadotropin-releasing hormone agonist.12 Androgen deprivation therapy has been shown to increase the risk of fracture in men with prostate cancer. Gonadotropin-releasing hormone agonists and bilateral orchiectomy decrease bone mineral density, an important determinant of fracture risk. Androgen deprivation therapy decreased lean mass 743
TABLE II. Study outcomes Baseline Testosterone (ng/dL)* Prostate-specific antigen (ng/mL) Hemoglobin (g/dL) Height (cm) Weight (kg) Percentage lean mass Percentage fat mass
332 13.8 14.3 176 87.9 68.7 28.0
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
21 2.5 0.1 0.9 1.7 0.8 0.8
48 wk 47 0.7 12.8 176 89.3 66.0 30.7
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
7 0.2 0.1 1.0 1.6 0.7 0.7
Change (%)
P Value
⫺79.7 ⫺89.4 ⫺10.5 ⫺0.2 1.8 ⫺3.8 11.0
⬍0.001 ⬍0.001 ⬍0.001 0.35 ⬍0.001 ⬍0.001 ⬍0.001
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
3.0 2.2 0.7 0.2 0.5 0.6 1.7
Data presented as the mean ⫾ standard error. * To convert testosterone from nanograms per deciliter to nanomoles per liter, multiply by 0.0347.
in our subjects. The loss of lean mass may contribute to frailty and increase the risk of falls in older men.13 Accordingly, androgen deprivation therapy may increase fracture risk by decreasing bone mineral density and by increasing the fall risk through the loss of lean body mass. Obesity increases the risk of cardiovascular disease, adult-onset diabetes mellitus, hypertension, stroke, osteoarthritis, and some cancers.14 The marked increases in fat mass observed in our subjects suggest that androgen deprivation therapy may increase risk of a variety of comorbid conditions. Gonadotropin-releasing hormone agonists significantly increase fasting plasma insulin levels,9 a marker of insulin resistance. Additional research is needed to evaluate the effects of androgen deprivation therapy on diabetes and other obesityrelated diseases. Resistance exercise training has been shown to decrease fatigue and improve the quality of life in men receiving androgen deprivation therapy for prostate cancer.15 Resistance exercise training also increased muscle size and strength in men with other chronic diseases and normal or moderately low testosterone levels.16,17 Accordingly, exercise may represent a reasonable strategy to mitigate the adverse body composition effects of androgen deprivation therapy. Other strategies, including dietary intervention, intermittent hormonal therapy, and alternative forms of hormonal therapy, warrant further study. Androgens support erythropoiesis by increasing the production of erythropoieten and by directly activating erythrocyte progenitors.18 Androgen deprivation therapy decreased hemoglobin concentrations by more than 10% and caused anemia (hemoglobin less than 13.5 g/dL) in most of our subjects. Similar results have been reported in other men receiving androgen deprivation therapy for prostate cancer.19,20 The present study had limitations. The study did not have a control group because most men would not have accepted randomization to delayed androgen deprivation therapy. Accordingly, part of 744
the observed changes may have resulted from normal aging rather than androgen deprivation therapy. In a prospective study of healthy older men, however, lean body mass and fat mass had not changed significantly after 3 years,21 suggesting that aging alone cannot account for the marked body composition changes observed in our study. We did not control for physical activity or diet, and additional studies are needed to determine the effects of exercise and diet on body composition in hypogonadal men. CONCLUSIONS The results of the present study demonstrated androgen deprivation therapy increased weight and fat mass and decreased lean mass in men with nonmetastatic prostate cancer. REFERENCES 1. Vermeulen A, Goemaere S, and Kaufman JM: Testosterone, body composition and aging. J Endocrinol Invest 22: 110 –116, 1999. 2. Katznelson L, Finkelstein JS, Schoenfeld DA, et al: Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 81: 4358 –4365, 1996. 3. Bhasin S, Storer TW, Berman N, et al: Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 82: 407–413, 1997. 4. Bhasin S, Storer TW, Berman N, et al: The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335: 1–7, 1996. 5. Smith MR, Eastham J, Gleason D, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169: 2008 –2012, 2003. 6. Stone P, Hardy J, Huddart R, et al: Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 36: 1134 –1141, 2000. 7. Herr HW, and O’Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 163: 1743–1746, 2000. 8. Potosky AL, Knopf K, Clegg LX, et al: Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. J Clin Oncol 19: 3750 –3757, 2001. UROLOGY 63 (4), 2004
9. Smith JC, Bennett S, Evans LM, et al: The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 86: 4261–4267, 2001. 10. Tayek JA, Heber D, Byerley LO, et al: Nutritional and metabolic effects of gonadotropin-releasing hormone agonist treatment for prostate cancer. Metabolism 39: 1314 –1319, 1990. 11. Smith MR, Finkelstein JS, McGovern FJ, et al: Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 87: 599 –603, 2002. 12. Berruti A, Dogliotti L, Terrone C, et al: Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 167: 2361–2367, 2002. 13. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56: M146 –M156, 2001. 14. Burton BT, Foster WR, Hirsch J, et al: Health implications of obesity: an NIH Consensus Development Conference. Int J Obes 9: 155–170, 1985.
UROLOGY 63 (4), 2004
15. Segal RJ, Reid RD, Courneya KS, et al: Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 21: 1653–1659, 2003. 16. Grinspoon S, Corcoran C, Parlman K, et al: Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting: a randomized, controlled trial. Ann Intern Med 133: 348 –355, 2000. 17. Bhasin S, Storer TW, Javanbakht M, et al: Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 283: 763–770, 2000. 18. Shahidi NT: Androgens and erythropoiesis. N Engl J Med 289: 72–80, 1973. 19. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 311: 1281–1286, 1984. 20. Crawford ED, Blumenstein BA, Goodman PJ, et al: Leuprolide with and without flutamide in advanced prostate cancer. Cancer 66: 1039 –1044, 1990. 21. Snyder PJ, Peachey H, Hannoush P, et al: Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 84: 2647–2653, 1999.
745
CHANGES IN FAT AND LEAN BODY MASS DURING ANDROGEN-DEPRIVATION THERAPY FOR PROSTATE CANCER MATTHEW R. SMITH
ABSTRACT Objectives. To assess the effects of androgen deprivation therapy on body composition in men with nonmetastatic prostate cancer. Methods. In a multicenter study, men with Stage M0 prostate cancer were prospectively evaluated during initial androgen deprivation therapy (gonadotropin-releasing hormone agonist or bilateral orchiectomy). The main outcomes were changes in weight, percentage fat mass, and percentage lean mass from baseline to 12 months. Results. Seventy-nine subjects were assessed. Serum testosterone concentrations decreased by 79.7% ⫾ 3.0% (P ⬍0.001). Weight increased by 1.8% ⫾ 0.5% (P ⬍0.001). The percentage fat mass increased by 11.0% ⫾ 1.7%, and the percentage lean mass decreased by 3.8% ⫾ 0.6% (P ⬍0.001 for each comparison). Conclusions. Androgen deprivation therapy increased weight and fat mass and decreased lean mass in men with nonmetastatic prostate cancer. UROLOGY 63: 742–745, 2004. © 2004 Elsevier Inc.
A
ndrogens are important determinants of body composition in men. Serum testosterone concentrations correlate positively with lean mass and negatively with fat mass.1 Testosterone replacement therapy increases lean mass and decreases fat mass in hypogonadal men.2,3 Testosterone supplementation increases lean mass, muscle size, and strength in eugonadal men.4 Less is known about the effects of androgen deprivation therapy on the body composition of men with prostate cancer. We report the results of a multicenter study to evaluate the body composition of men undergoing initial androgen deprivation therapy for prostate cancer. The main outcomes were changes in weight, percentage fat mass, and percentage lean mass from baseline to 12 months.
This study was supported by Novartis Oncology, which also contributed to study conduct and monitoring, data collection, and statistical analysis. From the Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts Reprint requests: Matthew R. Smith, M.D., Ph.D., Division of Hematology-Oncology, Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, MA 02114 Submitted: August 7, 2003, accepted (with revisions): October 28, 2003
742
© 2004 ELSEVIER INC. ALL RIGHTS RESERVED
MATERIALS AND METHODS SUBJECTS All subjects were participants in a randomized controlled study to evaluate the effects of zoledronic acid on bone mineral density in men undergoing initial androgen deprivation therapy for prostate cancer.5 Subjects were accrued at 16 centers in the United States from February 24, 2000 to November 7, 2000. All subjects were initiating androgen deprivation therapy for Stage M0 (no distant metastases) prostate cancer. All men had an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Men with chronic liver disease, serum creatinine concentration of more than 2.0 mg/dL, or other major organ dysfunction were excluded. Men with a lumbar spine bone mineral density more than 3.0 standard deviations below young adult norms (determined by site-specific machine normal values for men) were excluded. Men who had received androgen deprivation therapy, antiandrogens, bisphosphonates, calcitonin, gallium nitrate, or mithramycin within 1 year were also excluded. The institutional review board at each participating institution approved the study. All subjects gave written informed consent.
STUDY DESIGN All subjects received androgen deprivation therapy with a gonadotropin-releasing hormone agonist and an antiandrogen (bicalutamide or flutamide), a gonadotropin-releasing hormone agonist without an antiandrogen, or bilateral orchiectomy. Subjects were randomly assigned to receive either zoledronic acid (Zometa, Novartis Pharmaceuticals, East Hanover, NJ) 4 mg or placebo intravenously every 3 months for 1 year using permuted blocks randomization from a validated automated system. All subjects were instructed to take a 0090-4295/04/$30.00 doi:10.1016/j.urology.2003.10.063
TABLE I. Baseline characteristics Age (yr) Race (%) White Black Asian Other Body mass index (kg/m2) Type of androgen deprivation therapy (%) GnRH agonist GnRH agonist ⫹ antiandrogen Bilateral orchiectomy
71 ⫾ 9 80 6 5 9 28.4 ⫾ 0.5
53 46 1
KEY: GnRH ⫽ gonadotropin-releasing hormone. Data presented as the mean ⫾ standard error, unless otherwise noted.
calcium supplement (500 mg) and multivitamin containing vitamin D (400 IU) daily.
STUDY OUTCOMES The percentages fat body mass and lean body mass were determined at baseline and 12 months by dual energy x-ray absorptiometry using a Hologic (DELPHI, QDR 4500 series, or QDR 1000, Hologic, Waltham, Mass) or Lunar (EXPERT, PRODIGY, or DPX series, Lunar, Madison, Wis) densitometer. All dual-energy x-ray absorptiometry scans were reviewed at a central laboratory (Bio-Imaging Technologies, Newtown, Pa). Hemoglobin, prostate-specific antigen, and testosterone concentrations were measured at a central laboratory (Mayo Clinical Laboratories, Rochester, Minn). The coefficient of variation for prostate-specific antigen and testosterone was 2.6% and 6.4%, respectively. For men older than 40 years of age, the normal range for serum testosterone was 240 to 950 ng/dL.
STATISTICAL ANALYSIS Changes in study outcomes (testosterone, prostate-specific antigen, hemoglobin, weight, height, percentage of fat mass, and percentage of lean mass) were compared between the zoledronic acid and placebo groups using analysis of covariance, controlling for baseline. Because no statistically significant differences were noted for any outcomes between the groups, the results for all 79 assessable subjects were combined. The percentage of changes between the baseline and 48-week values for all outcome measures were tested for statistical significance using one-sample t tests. Statistical analyses were performed using Statistical Analysis System, version 6.12 (SAS Institute, Cary, NC). Values are reported as the mean ⫾ standard error. All P values are two sided, and P ⬍0.05 was considered statistically significant.
RESULTS SUBJECT CHARACTERISTICS Seventy-nine assessable subjects were included in the study. The baseline characteristics are summarized in Table I. BIOCHEMICAL OUTCOMES The mean serum testosterone concentration decreased by 79.7% ⫾ 3.0% (P ⬍0.001) from baseline to 48 weeks (Table II). The serum prostateUROLOGY 63 (4), 2004
specific antigen concentrations decreased by 89.4% ⫾ 2.2% (P ⬍0.001). The hemoglobin concentrations decreased by 10.5% ⫾ 0.7% (P ⬍0.001). BODY COMPOSITION The men’s weight increased by 1.8% ⫾ 0.5% (P ⬍0.001) from baseline to 48 weeks (Table II). Their height did not change significantly (P ⫽ 0.35). The percentage fat mass increased by 11.0% ⫾ 1.7%, and the percentage lean mass decreased by 3.8% ⫾ 0.6% from baseline to 48 weeks (P ⬍0.001 for each comparison). COMMENT The results of this multicenter prospective study demonstrated that androgen deprivation therapy markedly alters the body composition of men with prostate cancer. The men’s weight and fat mass increased significantly and their lean mass decreased significantly during androgen deprivation therapy. These changes in body composition may contribute to the adverse effects of androgen deprivation therapy on patients’ quality of life, including fatigue, loss of energy, and emotional distress.6 – 8 Fat mass increased by 11% and lean body mass decreased by 3.8% after 1 year of androgen deprivation therapy. In another study, similar changes in body composition were observed after 3 months of treatment with a gonadotropin-releasing hormone agonist,9 suggesting that body composition changes occur early after initiating androgen deprivation therapy. Additional research is needed to determine the body composition changes during long-term androgen deprivation therapy and after treatment discontinuation. These results are consistent with the results of smaller single-institution studies. In the study by Tayek et al.,10 weight and fat mass increased significantly in 10 men treated with a gonadotropin-releasing hormone agonist for locally advanced or metastatic prostate cancer. Smith et al.11 noted that weight increased by 2.4%, the percentage fat mass increased by 9.4%, and the percentage lean mass decreased by 2.7% after 12 months in 32 asymptomatic men undergoing initial gonadotropin-releasing hormone agonist treatment for nonmetastatic prostate cancer. Similar changes were reported in another 12-month study of 35 men receiving a gonadotropin-releasing hormone agonist.12 Androgen deprivation therapy has been shown to increase the risk of fracture in men with prostate cancer. Gonadotropin-releasing hormone agonists and bilateral orchiectomy decrease bone mineral density, an important determinant of fracture risk. Androgen deprivation therapy decreased lean mass 743
TABLE II. Study outcomes Baseline Testosterone (ng/dL)* Prostate-specific antigen (ng/mL) Hemoglobin (g/dL) Height (cm) Weight (kg) Percentage lean mass Percentage fat mass
332 13.8 14.3 176 87.9 68.7 28.0
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
21 2.5 0.1 0.9 1.7 0.8 0.8
48 wk 47 0.7 12.8 176 89.3 66.0 30.7
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
7 0.2 0.1 1.0 1.6 0.7 0.7
Change (%)
P Value
⫺79.7 ⫺89.4 ⫺10.5 ⫺0.2 1.8 ⫺3.8 11.0
⬍0.001 ⬍0.001 ⬍0.001 0.35 ⬍0.001 ⬍0.001 ⬍0.001
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
3.0 2.2 0.7 0.2 0.5 0.6 1.7
Data presented as the mean ⫾ standard error. * To convert testosterone from nanograms per deciliter to nanomoles per liter, multiply by 0.0347.
in our subjects. The loss of lean mass may contribute to frailty and increase the risk of falls in older men.13 Accordingly, androgen deprivation therapy may increase fracture risk by decreasing bone mineral density and by increasing the fall risk through the loss of lean body mass. Obesity increases the risk of cardiovascular disease, adult-onset diabetes mellitus, hypertension, stroke, osteoarthritis, and some cancers.14 The marked increases in fat mass observed in our subjects suggest that androgen deprivation therapy may increase risk of a variety of comorbid conditions. Gonadotropin-releasing hormone agonists significantly increase fasting plasma insulin levels,9 a marker of insulin resistance. Additional research is needed to evaluate the effects of androgen deprivation therapy on diabetes and other obesityrelated diseases. Resistance exercise training has been shown to decrease fatigue and improve the quality of life in men receiving androgen deprivation therapy for prostate cancer.15 Resistance exercise training also increased muscle size and strength in men with other chronic diseases and normal or moderately low testosterone levels.16,17 Accordingly, exercise may represent a reasonable strategy to mitigate the adverse body composition effects of androgen deprivation therapy. Other strategies, including dietary intervention, intermittent hormonal therapy, and alternative forms of hormonal therapy, warrant further study. Androgens support erythropoiesis by increasing the production of erythropoieten and by directly activating erythrocyte progenitors.18 Androgen deprivation therapy decreased hemoglobin concentrations by more than 10% and caused anemia (hemoglobin less than 13.5 g/dL) in most of our subjects. Similar results have been reported in other men receiving androgen deprivation therapy for prostate cancer.19,20 The present study had limitations. The study did not have a control group because most men would not have accepted randomization to delayed androgen deprivation therapy. Accordingly, part of 744
the observed changes may have resulted from normal aging rather than androgen deprivation therapy. In a prospective study of healthy older men, however, lean body mass and fat mass had not changed significantly after 3 years,21 suggesting that aging alone cannot account for the marked body composition changes observed in our study. We did not control for physical activity or diet, and additional studies are needed to determine the effects of exercise and diet on body composition in hypogonadal men. CONCLUSIONS The results of the present study demonstrated androgen deprivation therapy increased weight and fat mass and decreased lean mass in men with nonmetastatic prostate cancer. REFERENCES 1. Vermeulen A, Goemaere S, and Kaufman JM: Testosterone, body composition and aging. J Endocrinol Invest 22: 110 –116, 1999. 2. Katznelson L, Finkelstein JS, Schoenfeld DA, et al: Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 81: 4358 –4365, 1996. 3. Bhasin S, Storer TW, Berman N, et al: Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 82: 407–413, 1997. 4. Bhasin S, Storer TW, Berman N, et al: The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335: 1–7, 1996. 5. Smith MR, Eastham J, Gleason D, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169: 2008 –2012, 2003. 6. Stone P, Hardy J, Huddart R, et al: Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 36: 1134 –1141, 2000. 7. Herr HW, and O’Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 163: 1743–1746, 2000. 8. Potosky AL, Knopf K, Clegg LX, et al: Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study. J Clin Oncol 19: 3750 –3757, 2001. UROLOGY 63 (4), 2004
9. Smith JC, Bennett S, Evans LM, et al: The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 86: 4261–4267, 2001. 10. Tayek JA, Heber D, Byerley LO, et al: Nutritional and metabolic effects of gonadotropin-releasing hormone agonist treatment for prostate cancer. Metabolism 39: 1314 –1319, 1990. 11. Smith MR, Finkelstein JS, McGovern FJ, et al: Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 87: 599 –603, 2002. 12. Berruti A, Dogliotti L, Terrone C, et al: Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 167: 2361–2367, 2002. 13. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56: M146 –M156, 2001. 14. Burton BT, Foster WR, Hirsch J, et al: Health implications of obesity: an NIH Consensus Development Conference. Int J Obes 9: 155–170, 1985.
UROLOGY 63 (4), 2004
15. Segal RJ, Reid RD, Courneya KS, et al: Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 21: 1653–1659, 2003. 16. Grinspoon S, Corcoran C, Parlman K, et al: Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting: a randomized, controlled trial. Ann Intern Med 133: 348 –355, 2000. 17. Bhasin S, Storer TW, Javanbakht M, et al: Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 283: 763–770, 2000. 18. Shahidi NT: Androgens and erythropoiesis. N Engl J Med 289: 72–80, 1973. 19. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 311: 1281–1286, 1984. 20. Crawford ED, Blumenstein BA, Goodman PJ, et al: Leuprolide with and without flutamide in advanced prostate cancer. Cancer 66: 1039 –1044, 1990. 21. Snyder PJ, Peachey H, Hannoush P, et al: Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 84: 2647–2653, 1999.
745