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The Influence of Androgen Deprivation Therapy on Metabolism in Patients with Prostate Cancer

Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan

Address all correspondence and requests for reprints to: Dr. Tsutomu Nishiyama, Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi 1-757, Niigata 951-8510, Japan. E-mail: nisiyama{at}med.niigata-u.ac.jp.

	Abstract

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The effects of androgen deprivation therapy (ADT) include not only suppression of tumor growth, but also adverse effects on various bodily functions. The aim of this study was to determine the metabolic effects of ADT in patients with nonmetastatic prostate cancer. Forty-nine men with prostate cancer were treated with ADT before beginning radical therapy for 6 months. Body weight, peripheral red blood cell counts, hemoglobin, hematocrit, fasting blood sugar, serum total cholesterol, blood urea nitrogen, uric acid, compensated calcium, inorganic phosphorus, bone-specific alkaline phosphatase, urinary deoxypyridinoline, and radial bone density determined using dual energy x-ray absorptiometry were examined before and 6 months after ADT treatment. Body weight (P = 0.037) and the levels of fasting blood sugar (P = 0.014), serum total cholesterol (P = 0.017), blood urea nitrogen (P = 0.030), compensated calcium (P < 0.001), inorganic phosphorus (P < 0.001), bone-specific alkaline phosphatase (P < 0.001), and compensated urinary deoxypyridinoline (P < 0.001) increased significantly. Peripheral red blood cell counts (P < 0.001), hemoglobin level (P < 0.001), hematocrit (P < 0.001), uric acid (P < 0.001), and radial bone density (P = 0.023) decreased significantly. These effects of ADT on various bodily functions warrant systematic study in clinical trials. We should be aware of the far-reaching consequences of ADT and incorporate strategies for preventing and managing adverse effects into routine practice.

	Introduction

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SINCE THE OBSERVATION by Huggins and Hodges (1) that disseminated prostate cancer reacts favorably to castration or the administration of estrogenic hormones, first-line hormonal therapy has been used to impair the production or activity of androgens, or both. The mainstay for treatment of men with metastatic prostate cancer is androgen suppression by either orchidectomy or LH-releasing hormone agonists. Recent studies have revealed that androgen deprivation may delay tumor progression and improve survival after radical therapy (2, 3). Consequently, androgen deprivation therapy (ADT) is prescribed to men without evidence of metastatic disease before beginning radical therapy or to men with prostate-specific antigen relapse after local therapy (2, 3).

Androgens play an essential role in men’s health. Testosterone is needed for normal male development, muscle strength, bone mineralization, hemopoietic function, sexual and reproductive functions, etc. (4). Aging is accompanied by important changes in the endocrine system, characterized by decreased testicular function with a decline in plasma testosterone levels. The correlation between age-associated changes in metabolism and decrease in hormone secretion has been investigated (5).

Therefore, the effects of ADT include not only suppression of tumor growth, but also adverse effects on various bodily functions (6). The adverse effects of ADT include vasomotor symptoms, osteoporosis, anemia, sarcopenia, gynecomastia, depression, cognitive decline, sexual dysfunction, etc. (7, 8, 9). These effects negatively affect the quality of life of men (8, 9). The effects of ADT on metabolism, however, are not clearly known.

The aim of this study was to determine the metabolic effects of ADT in patients with nonmetastatic prostate cancer.

	Subjects and Methods

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Patients

Between January 1999 and April 2002, 49 men with histologically proven prostate cancer (T2–3NxM0) were included in this study. To offer ADT, 42 patients were chemically castrated using LH-releasing hormone, and seven patients had bilateral orchidectomy. All patients ingested a nonsteroidal antiandrogen, flutamide (125 mg, every 8 h, orally), to block residual dihydrotestosterone connecting with androgen receptor (10). The patients were treated for prostate cancer with ADT for 6 months before beginning radical therapy. Baseline patient characteristics are listed in Table 1. This research was reviewed and approved by the institutional review board. Informed consent was obtained from all participants.

Body weight, serum prostate-specific antigen, serum testosterone, fasting blood sugar, hematology (peripheral red blood cell counts, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cell counts, and platelet counts), bone metabolism [calcium (Ca), inorganic phosphorus (IP), bone-specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD), and bone mineral density of the radial bone determined using dual energy x-ray absorptiometry (DEXA)], lipid metabolic examination [triglyceride, total cholesterol (TC), and high density lipoprotein cholesterol], and other routine serum parameters [glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase (Alp), lactate dehydrogenase, -glutamyltranspeptitase, cholinesterase, leucine aminopeptidase, total bilirubin, blood urea nitrogen (BUN), creatinine (Cre), uric acid, sodium, potassium, chloride, creatine phosphokinase, total amylase, total protein, albumin-globulin ratio, and C-reactive protein] were examined before and 6 months after ADT treatment. Blood samples were collected from the patients between 0900 and 1200 h. Serum samples were quantified by commercially available assays. All serum samples other than testosterone were quantified by automated fluorescence polarization assays on a TOSOH (TOSOH Corp., Tokyo, Japan). The serum level of testosterone was determined by RIA (BML, Tokyo, Japan). Serum BAP and urinary DPD levels were quantified by Sumitomo Pharmaceuticals Co. Ltd. (Osaka, Japan). The bone mineral density of the radial bone was determined by DEXA using a Hologic QDR 4500 densitometer (Hologic, Inc., Waltham, MA).

Statistical analysis

Statistical comparison of the influence on metabolism was analyzed using the Wilcoxon signed-rank test. The test was two-sided, and P < 0.05 was considered statistically significant. The correlation between the metabolisms before ADT and those after ADT treatment was analyzed using the Spearman rank correlation coefficient analysis (rs). The test was two-sided, and P < 0.05 was considered statistically significant. Statistical analyses were calculated and tested using SPSS software version 11.0 for the personal computer (SPSS, Inc., Chicago, IL).

	Results

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Influence of ADT on metabolism

The patient characteristics are listed in Table 1. Testosterone levels fell to the castration level after ADT (Table 2). Eight of the 49 patients were withdrawn from flutamide treatment because of adverse effects. Five of these withdrawals were due to liver dysfunction, and three to diarrhea.

Serum Ca (P = 0.007), compensated Ca (P < 0.001), IP (P < 0.001), Alp (P < 0.001), BAP (P < 0.001), and compensated urinary DPD (DPD/Cre; P < 0.001) increased significantly after ADT treatment (Table 2). The bone mineral density of the radial bone decreased significantly (P = 0.023) after ADT.

Body weight (P = 0. 037) and the levels of fasting blood sugar (P = 0.014) and serum TC (P = 0.017) decreased significantly after ADT (Table 2). The serum triglyceride level did not change during ADT (P = 0.460). Although Cre did not change during ADT (P = 0.763), BUN increased significantly after ADT (P = 0.030). Serum uric acid decreased significantly after ADT (P < 0.001).

Correlations between metabolisms before and after ADT

High correlations were found between the metabolisms before ADT and those after ADT; these changes were statistically significant, except for DPD/Cre (rs = 0.122; P = 0.519; Table 3).

	Discussion

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Androgens act on the hemopoietic system in a variety of ways (11). Weber et al. (11) revealed that reversible androgen deprivation leads to lowering of hemoglobin levels. However, there was no associated increase in the serum erythropoietin level. ADT is associated with a significant decrease in the hemoglobin concentration, and red blood cell counts revealed normocytic and normochromic reduction of about 10% after 6 months of ADT in our data. Strum et al. (12) showed that significant symptoms related to anemia due to ADT occurred in 13% of patients with ADT and anemia, and the symptoms in the patients were easily corrected with sc administration of recombinant human erythropoietin. We recommend that patients receiving ADT be monitored for hemoglobin levels and symptoms that may indicate significant anemia associated with ADT.

Osteoporosis is a complication of ADT (13). Several noninvasive methods can be used to measure bone mineral density. Changes in bone mineral density, as shown by DEXA, were small during the 6-month observation period. The hip and lumbar spine are considered the preferred sites for assessment of bone mineral density. However, we measured bone mineral density of the radial bone to avoid the influences of bone metastasis, coexisting facet joint disease, and extravertebral calcification. Changes in the serum concentrations of Ca, IP, and Alp were small. Measurements of biochemical markers of bone resorption, such as DPD, and of bone formation, such as BAP, complemented the measurement of bone mineral density. No correlation between the DPD/Cre before ADT and that after ADT (the changes in which were statistically significant) was found (rs = 0.122; P = 0.519). One of the reasons a correlation was not found between DPD/Cre before ADT and that after ADT may be the analysis of DPD in urine. Recently, serum biochemical markers of bone resorption, such as type I collagen cross-linked N-terminal telopeptide, have become available. In Japan, the Japan Osteoporosis Society provides a guideline for the adequate use of bone markers in medical care for osteoporosis (14). Bone markers may provide early detection of loss of bone mineral density during ADT (15).

It is well known that androgens modulate body composition (16, 17). Therefore, androgens work on lipid and protein metabolisms. However, it is not well known whether ADT affects lipid and protein metabolisms. The results of the influence of ADT on serum concentrations of lipids have been different in previous reports (16, 17). ADT did not change blood glucose levels in previous reports (18). Our finding, however, revealed that the fasting blood sugar level increased slightly, but statistically significantly. The influence of ADT on protein metabolisms has not been clarified. Darlington et al. (19) revealed that serum uric acid, BUN, and creatinine fell significantly 1 month after castration. In our results, ADT produced increases in body weight, fasting blood sugar, and serum concentrations of TC and BUN. ADT also caused a decrease in serum uric acid. We did not measure the insulin concentration. Smith et al. (18) revealed that insulin concentrations are elevated during ADT treatment, and adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. There is a correlation between the changes in fat mass and insulin concentration during ADT (18). Additional studies are needed to evaluate the clinical significance of treatment-related changes in lipid and protein metabolisms (20, 21, 22).

The adverse effects of ADT may affect physical function and quality of life (8, 9). Testosterone replacement is contraindicated in men with prostate cancer; therefore, nonhormonal therapies or other hormones have been examined for potentially improving the adverse effects of ADT (9, 23). Intermittent androgen blockade, antiandrogen monotherapy, or antiandrogen with 5-reductase inhibitor therapy appears to be a promising treatment for prostate cancer that may limit the side-effects of hormonal ablation (24, 25, 26).

ADT not only acts on prostate cancer, but also affects various metabolisms, including hematogenesis, bone, fat, protein, nucleic acid, and saccharometabolism. These effects of ADT on various bodily functions warrant systematic study in clinical trials. We should be aware of the far-reaching consequences of ADT and incorporate strategies for preventing and managing adverse effects into routine practice.

	Footnotes

 
First Published Online November 23, 2004

Abbreviations: ADT, Androgen deprivation therapy; Alp, alkaline phosphatase; BAP, bone-specific alkaline phosphatase; BUN, blood urea nitrogen; Cre, creatinine; DEXA, dual energy x-ray absorptiometry; DPD, deoxypyridinoline; IP, inorganic phosphorus; TC, total cholesterol.

Received August 12, 2004.

Accepted November 12, 2004.

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