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Changes in Body Composition during Androgen Deprivation Therapy for Prostate Cancer

Massachusetts General Hospital (M.R.S., J.S.F., F.J.M., A.L.Z., M.A.F., D.A.S.), Boston, Massachusetts 02114; and Dana Farber Cancer Institute (P.W.K.), Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Matthew R. Smith, M.D., Ph.D., Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, Massachusetts 02114.

Abstract

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.

PROSTATE CANCER IS the most common malignancy and second leading cause of cancer death in American men. In 2001, there will be approximately 198,100 new prostate cancer cases and 31,500 prostate cancer deaths in the United States (1).

Androgen deprivation therapy with a GnRH agonist is the mainstay of treatment for metastatic prostate cancer. Recent evidence suggests that early androgen deprivation therapy improves outcomes for men with nonmetastatic prostate cancer. Primary androgen deprivation therapy improves survival for men with locally advanced nonmetastatic prostate cancer (2). Adjuvant androgen deprivation therapy improves survival for men with locally advanced prostate cancer treated with radiation therapy (3) and men with lymph node-positive prostate cancer treated with radical prostatectomy and pelvic lymphadenectomy (4). GnRH agonists are frequently administered to men in whom rising serum prostate-specific antigen concentrations are the only indication of disease recurrence after surgery or radiation therapy for early stage prostate cancer (5). The effects of early androgen deprivation therapy on outcomes for men with "prostate-specific antigen-only" disease are unknown. Routine early use of GnRH agonists increases the importance of understanding and preventing adverse effects of treatment.

Androgens are important determinants of body composition in men. Serum T concentrations correlate positively with muscle mass and negatively with fat mass (6). T replacement therapy increases lean body mass in men with hypogonadism due to aging (7), human immunodeficiency virus infection (8, 9), and other chronic diseases (10). Some but not all studies have reported that T replacement therapy decreases fat mass in hypogonadal men (7, 11, 12).

Changes in body composition are generally recognized as adverse effects of androgen deprivation therapy for prostate cancer although the effects of androgen deprivation therapy on body composition are not well defined. GnRH agonist treatment increased weight and fat mass in 10 men with locally advanced or metastatic prostate cancer (13). Pretreatment weight loss and symptomatic metastatic disease, however, make it difficult to determine whether the reported body composition changes were owing to hypogonadism or treatment-related improvements in cancer symptoms. We now report the results of a prospective study of body composition in asymptomatic men receiving initial GnRH agonist treatment for nonmetastatic prostate cancer.

Materials and Methods

Subjects

All subjects were participants in a randomized, controlled study to evaluate the effects of pamidronate on bone loss in men receiving GnRH agonist treatment for prostate cancer (14). Seven of the 47 subjects who were registered for this randomized, controlled trial were excluded from the current study: Three had received prior androgen deprivation therapy and four withdrew before baseline evaluation. All study participants had locally advanced, lymph node-positive, or recurrent prostate cancer; no evidence of bone metastases by radionucleotide bone scan; no history of orchiectomy; and no prior treatment with an antiandrogen, GnRH agonist, or GnRH antagonist. Men with hyperthyroidism, Cushing’s disease, chronic liver disease, or serum creatinine concentration of more than 2.0 mg/dl were excluded. Men were excluded if they had received glucocorticoids or suppressive doses of thyroxine within 1 yr. Men with history of treatment for osteoporosis, taking medications associated with bone loss, or with other bone disorders or secondary causes of osteoporosis were also excluded.

Study design

Subjects were randomly assigned to receive leuprolide 3-month depot (Lupron depot; TAP Pharmaceuticals, Inc., Deerfield, IL) (22.5 mg im every 12 wk) alone (n = 20) or leuprolide 3-month depot and pamidronate (Aredia, Novartis Oncology, East Hanover, NJ) (60 mg iv over 2 h every 12 wk, n = 20) for 48 wk. All men received bicalutamide (Casodex, AstraZeneca PLC, London, UK) (50 mg by mouth daily) for 4 wk to prevent the potential flare associated with the first administration of leuprolide, calcium carbonate (500 mg daily), and a daily multivitamin containing 400 IU vitamin D.

Subjects were evaluated at the General Clinical Research Center at Massachusetts General Hospital at baseline, 24 wk, and 48 wk. Blood was collected on the morning of each visit after an overnight fast. Complete blood counts and serum T, E2, and prostate-specific antigen concentrations were measured at Massachusetts General Hospital Clinical Laboratories. Additional serum samples were stored at -70 C for subsequent batch measurement of serum SHBG, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations. Percentage fat body mass and percentage lean body mass were measured by dual-energy x-ray absorptiometry at baseline and 48 wk. Cross-sectional areas of the abdomen, abdominal sc fat, intraabdominal fat, and paraspinal muscles were determined by quantitative computed tomography at baseline and 48 wk. A research dietitian performed anthropomorphic measurements and bioelectrical impedance analyses at baseline and 48 wk. Disease response and progression were defined according to recommendations from the Prostate Specific Antigen (PSA) Working Group. (15) The institutional review board of Dana Farber Partners Cancer Care reviewed and approved the study and all subjects gave written informed consent.

Outcome measures

Fasting subjects were weighed wearing a hospital gown and no shoes. Body weight was measured to the nearest 0.1 kg using a digital platform scale (Blue Bell BioMedical model 500, SR Instruments, Tonawanda, NY). Height was measured to the nearest 0.1 cm using a wall-mounted stadiometer. The mean of three height measurements was recorded.

Percentage fat body mass and percentage lean body mass were determined by dual-energy x-ray absorptiometry with a QDR 4500A densitometer, software version 11.1 (Hologic, Inc., Waltham, MA). Percentage fat body mass was also estimated using a monofrequency (50 kHz) bioelectrical impedance analyzer (BIA 101-A, RJL Systems Inc., Clinton Township, MI) using a standard equation for adult men (16). Resistance was determined using standard tetrapolar lead placement with subjects in the supine position.

Cross-sectional areas of the abdomen, abdominal sc fat, intraabdominal fat, and paraspinal muscles at the level of the L4 vertebra were determined by quantitative computed tomography (GE Model I scanner, General Electric Medical Systems, Milwaukee, WI) as described previously (11, 17). Briefly, total abdominal area was determined from an outline of the torso using image analysis software. Two contours were identified: the body perimeter and deep fascia that delineates the back and abdominal wall musculature. The abdominal sc fat area was defined as the area between the two contours. Intraabdominal fat was defined as the area within the inner contour comprising all pixels with attenuation coefficients between -50 and -250 Hounsfield units. Additional contours were identified for the psoas and erector spinae muscles. The total paraspinal area was defined as the sum of the cross-sectional areas for the psoas and erector spinae muscles. The paraspinal fat area was defined as the total paraspinal area comprising all pixels with attenuation coefficients between -50 and -250 Hounsfield units. The paraspinal muscle area was defined as the total paraspinal area minus the paraspinal fat area.

Serum T was measured by RIA with an intraassay coefficient of variation of approximately 5% for values within the normal range and 18% for values in the castrate range, and an interassay coefficient of variation of 7–12% (Diagnostic Products, Los Angeles, CA). Serum E2 was measured by RIA with a sensitivity of 3 pg/ml and intra- and interassay coefficients of variation of 10% and 14%, respectively (Nichols Institute Diagnostics, San Juan Capistrano, CA). SHBG was measured by solid-phase chemiluminescent enzyme immunoassay with a sensitivity of 1 nmol/liter and intra- and interassay coefficients of variation of less than 7% and less than 8%, respectively (Immunolite, DPC Inc.). Prostate-specific antigen was measured using a microparticle enzyme immunoassay with a detection limit is 0.1 ng/ml and intra- and interassay coefficients of variation are 2.9% to 3.7% and 4.5% to 5.9%, respectively (Abbott Laboratories; Abbott Park, IL). Serum cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride concentrations were measured by colorimetric enzymatic assays on an automated clinical chemistry analyzer with intra- and interassay coefficients of variation of 0.8% to 1.5% and 1.7% to 2.6%, respectively (Roche Diagnostics/Roche Molecular Biochemicals, Indianapolis, IN).

Statistical analyses

Changes in all outcome measures were compared between subjects who received leuprolide and pamidronate and subjects who received leuprolide alone using analysis of covariance controlling for baseline. Because there were no significant differences for any outcome measure between treatment groups, the results for all subjects were combined. Percentage changes between baseline and 48-wk values for all outcome measures were tested for significance using one-sample t tests. Statistical analyses were performed using SAS version 8.1 (SAS Institute, Inc., Cary, NC). Values are reported as means plus or minus SE. All P values are two sided and values less than 0.05 are considered statistically significant.

Results

Subject characteristics

Forty eligible men completed baseline evaluation. Eight men were excluded from the analyses: two men withdrew before any follow-up testing was performed, three men discontinued treatment early because of bothersome hot flashes, and three men developed second malignancies (colon cancer, gastric cancer, and lymphoma). The remaining 32 subjects received their assigned treatment and completed the study. Mean (± SE) age was 66 plus or minus 2 yr. Twenty-nine (91%) men were white and three (9%) men were black.

Gonadal steroids and prostate-specific antigen

Serum T and E2 concentrations decreased by 96.3 plus or minus 0.4% (P < 0.001) and 76.6 plus or minus 2.7% (P < 0.001), respectively, after 48 wk (Table 1). Serum SHBG concentrations did not change significantly. Serum prostate- specific antigen concentrations decreased significantly by 88.4% plus or minus 2.8% (P < 0.001) and all men had prostate specific antigen responses. No subject had disease progression during the study.

Weight and body mass index increased by 2.4 plus or minus 0.8% (P = 0.005 for each comparison) during GnRH agonist treatment (Table 2). Percentage fat body mass measured by bioelectrical impedance analysis and dual-energy x-ray absorptiometry increased by 11.1% plus or minus 5.5% (P = 0.06) and 9.4% plus or minus 1.7% (P < 0.001), respectively. Percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001).

Hemoglobin concentrations decreased by 6.5 plus or minus 1.1% after 48 wk (P < 0.001) (Table 4). Ten (31%) men had anemia (hemoglobin <13.5 g/dl) at baseline. Eighteen of 22 (82%) men with baseline hemoglobin concentrations 13.5 g/dl or greater developed anemia during treatment. Serum total cholesterol, HDL cholesterol, and LDL cholesterol concentrations increased by 9.0% plus or minus 2.1% (P < 0.001), 11.3% plus or minus 2.6% (P < 0.001), and 7.3% plus or minus 3.5% (P = 0.05) respectively (Table 4). Serum triglycerides increased by 26.5% plus or minus 10.0% (P = 0.01).

These results demonstrate that GnRH agonist treatment has marked effects on body composition in men with prostate cancer. GnRH agonist treatment increased weight and percentage fat body mass and decreased percentage lean body mass and muscle size. Increased fatness resulted primarily from the accumulation of sc rather than intraabdominal adipose tissue.

Our study is the first prospective evaluation of body composition in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer. Our results are consistent with prior reports that weight and fat mass increased (13) and midarm muscle circumference decreased (18) in men with locally advanced or metastatic prostate cancer receiving GnRH agonist treatment. Similar changes in body composition have been described in young healthy men treated with a GnRH agonist (19). Our results are also consistent with a recent cross-sectional study of body composition in men with prostate cancer (20).

Obesity is associated with an increased incidence of cardiovascular disease, adult onset diabetes mellitus, hypertension, stroke, dyslipidemia, osteoarthritis, and some cancers (21). Intraabdominal adipose tissue is an important determinant of the association between excess weight and obesity-related disease (22, 23). Our study demonstrated that lowering serum gonadal steroid concentrations to castrate levels with a GnRH agonist increases abdominal sc fat area without significantly changing intraabdominal fat area. In contrast, T replacement therapy decreases intraabdominal fat area in obese men with acquired hypogonadism (11) and obese middle-aged men with low serum T concentrations (24). Differences in baseline body composition, serum gonadal steroid concentrations, and age between the study populations may explain the contradictory changes in fat distribution that result from increasing or decreasing gonadal steroid concentrations. Alternatively, differences between these studies may indicate either that T and intraabdominal obesity are not causally related or that the dose-response relationship between T and intraabdominal fat is nonlinear.

GnRH agonist treatment increased serum concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in our subjects. In another study of elderly men with prostate cancer, GnRH agonist treatment did not change any lipoprotein parameter significantly (25). In two studies of young healthy men, short-term treatment with a GnRH agonist increased HDL cholesterol significantly but did not change total or LDL cholesterol (26, 27). Additional studies are needed to evaluate the clinical significance of treatment-related changes in lipoproteins and triglycerides.

Androgens promote erythropoiesis by increasing erythropoietin production and direct activation of erythrocyte progenitors (28). GnRH agonist treatment decreased hemoglobin concentrations significantly and caused anemia in most of our subjects. Similar results have been reported in other men treated with GnRH agonists for prostate cancer (29, 30, 31).

Our study has limitations. The study did not have a control group because most patients would not have accepted randomization to no treatment. Accordingly, part of the observed changes may have resulted from normal aging rather than GnRH agonist treatment. We did not control for physical activity or diet. Additional studies are needed to determine the effects of exercise and diet on body composition changes in hypogonadal men. Finally, most of the study participants were white, and body composition changes may differ in other racial groups.

Androgen deprivation therapy increases fracture risk in men with prostate cancer (32, 33, 34). GnRH agonist treatment decreases bone mineral density (14, 35, 36, 37, 38), an important determinant of fracture risk. Our study demonstrates that GnRH agonist treatment also decreases percentage lean body mass and muscle size in men with prostate cancer. These body composition changes may results in frailty and increased the risk of falls in older men (39). Thus, androgen deprivation therapy may increase fracture risk by decreasing both bone mineral density and lean body mass.

Androgen deprivation therapy is associated with fatigue, loss of energy, emotional distress, and lower overall quality of life (18, 40, 41). Changes in body composition may contribute to the adverse effects of androgen deprivation therapy on physical function and quality of life. The potential impact of body composition changes on overall physical and emotional health may influence individual decision about the timing and duration of androgen deprivation therapy for asymptomatic men with nonmetastatic prostate cancer.

Acknowledgments

We thank the dedicated nursing and nutrition staffs of Mallinckrodt General Clinical Research Center; Ellen Anderson for performing dietary assessments; Denise Keefe for supervising performance of the study protocol on the General Clinical Research Center; Molly Sweep, Robin Cleary, Sarah Zhang, and Irene Lehrman for performing dual-energy x-ray absorptiometry scans; and Brian Capell for analyzing quantitative computed tomography scans.

Footnotes

This work was supported by NIH Grants K24-DK02759 (to J.S.F.) and RR-1066, NIH Clinical Associate Physician Award (to M.R.S.), Doris Duke Charitable Foundation Clinical Scientist Development Award (to M.R.S.), and an award from CaP CURE (to M.R.S., J.S.F., and P.W.K.).

Abbreviations: HDL, High-density lipoprotein; LDL, low-density lipoprotein.

Received October 31, 2001.

Accepted November 20, 2001.

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				H. K. Tsai, A. V. D'Amico, N. Sadetsky, M.-H. Chen, and P. R. Carroll Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality J Natl Cancer Inst, October 17, 2007; 99(20): 1516 - 1524. [Abstract] [Full Text] [PDF]

				C. A Clay, S. Perera, J. M Wagner, M. E Miller, J. B Nelson, and S. L Greenspan Physical Function in Men With Prostate Cancer on Androgen Deprivation Therapy Physical Therapy, October 1, 2007; 87(10): 1325 - 1333. [Abstract] [Full Text] [PDF]

				M. D. Michaelson and M. R. Smith In Reply J. Clin. Oncol., August 1, 2007; 25(22): 3385 - 3386. [Full Text] [PDF]

				M. R. Smith Obesity and Sex Steroids during Gonadotropin-Releasing Hormone Agonist Treatment for Prostate Cancer Clin. Cancer Res., January 1, 2007; 13(1): 241 - 245. [Abstract] [Full Text] [PDF]

				T. Kvorning, M. Andersen, K. Brixen, and K. Madsen Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo-controlled, and blinded intervention study Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1325 - E1332. [Abstract] [Full Text] [PDF]

				M. Maggio, A. Blackford, D. Taub, M. Carducci, A. Ble, E. J. Metter, M. Braga-Basaria, A. Dobs, and S. Basaria Circulating Inflammatory Cytokine Expression in Men With Prostate Cancer Undergoing Androgen Deprivation Therapy J Androl, November 1, 2006; 27(6): 725 - 728. [Abstract] [Full Text] [PDF]

				N. L. Keating, A. J. O'Malley, and M. R. Smith Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer J. Clin. Oncol., September 20, 2006; 24(27): 4448 - 4456. [Abstract] [Full Text] [PDF]

				M. R. Smith, H. Lee, and D. M. Nathan Insulin Sensitivity during Combined Androgen Blockade for Prostate Cancer J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1305 - 1308. [Abstract] [Full Text] [PDF]

				V. B. Shahinian, Y.-F. Kuo, J. L. Freeman, and J. S. Goodwin Risk of the "androgen deprivation syndrome" in men receiving androgen deprivation for prostate cancer. Arch Intern Med, February 27, 2006; 166(4): 465 - 471. [Abstract] [Full Text] [PDF]

				J. Q. Purnell, L. B. Bland, M. Garzotto, D. Lemmon, E. M. Wersinger, C. W. Ryan, J. D. Brunzell, and T. M. Beer Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer J. Lipid Res., February 1, 2006; 47(2): 349 - 355. [Abstract] [Full Text] [PDF]

				S. L. Greenspan, P. Coates, S. M. Sereika, J. B. Nelson, D. L. Trump, and N. M. Resnick Bone Loss after Initiation of Androgen Deprivation Therapy in Patients with Prostate Cancer J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6410 - 6417. [Abstract] [Full Text] [PDF]

				C. J. Ryan and E. J. Small Early Versus Delayed Androgen Deprivation for Prostate Cancer: New Fuel for an Old Debate J. Clin. Oncol., November 10, 2005; 23(32): 8225 - 8231. [Abstract] [Full Text] [PDF]

				N. Sharifi, J. L. Gulley, and W. L. Dahut Androgen Deprivation Therapy for Prostate Cancer JAMA, July 13, 2005; 294(2): 238 - 244. [Abstract] [Full Text] [PDF]

				T. Nishiyama, F. Ishizaki, T. Anraku, H. Shimura, and K. Takahashi The Influence of Androgen Deprivation Therapy on Metabolism in Patients with Prostate Cancer J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 657 - 660. [Abstract] [Full Text] [PDF]

				M. R. Smith, M. Goode, A. L. Zietman, F. J. McGovern, H. Lee, and J. S. Finkelstein Bicalutamide Monotherapy Versus Leuprolide Monotherapy for Prostate Cancer: Effects on Bone Mineral Density and Body Composition J. Clin. Oncol., July 1, 2004; 22(13): 2546 - 2553. [Abstract] [Full Text] [PDF]

				D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson Androgens and Bone Endocr. Rev., June 1, 2004; 25(3): 389 - 425. [Abstract] [Full Text] [PDF]

				M. Leblanc, M.-C. Belanger, P. Julien, A. Tchernof, C. Labrie, A. Belanger, and F. Labrie Plasma Lipoprotein Profile in the Male Cynomolgus Monkey under Normal, Hypogonadal, and Combined Androgen Blockade Conditions J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1849 - 1857. [Abstract] [Full Text] [PDF]

				P. Szulc, B. Claustrat, F. Marchand, and P. D. Delmas Increased Risk of Falls and Increased Bone Resorption in Elderly Men with Partial Androgen Deficiency: The MINOS Study J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5240 - 5247. [Abstract] [Full Text] [PDF]

				J. A. Talcott Androgen Deprivation as Primary Treatment for Early Prostate Cancer: Should We "Just Do Something"? J Natl Cancer Inst, March 20, 2002; 94(6): 407 - 409. [Full Text] [PDF]

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