Increased Risk of Metabolic Syndrome, Diabetes Mellitus, and Cardiovascular Disease in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

Polly E. Kintzel, Pharm.D.; Sandra L. Chase, Pharm.D.; Lisa M. Schultz, Pharm.D.; Timothy J. O'Rourke, M.D.

Disclosures

Pharmacotherapy. 2008;28(12):1511-1522. 

In This Article

Abstract and Introduction

Prostate cancer is the leading cancer diagnosis and second leading cause of cancer-related mortality for men in the United States. Due to the increased prevalence of prostate cancer in men older than 50 years, men at risk for prostate cancer represent the same population of men who are at greatest risk for metabolic syndrome, diabetes mellitus, and coronary artery disease (CAD). In addition to risk factors for CAD that are applicable to the general population, men with prostate cancer can be at increased risk for CAD due to long-term androgen deprivation therapy (ADT) administered as treatment for prostate cancer. Men undergo ADT by medical (drug therapy) or surgical (castration) means. Luteinizing hormone–releasing hormone (LHRH) agonists are the primary drug therapies used for ADT. Commercially available LHRH agonists are goserelin, histrelin, leuprolide, and triptorelin. Body composition changes, hyperlipidemia, insulin resistance, metabolic syndrome, and acute coronary syndrome are all reported adverse effects of ADT, which are consequences of reduced levels of circulating testosterone. Metabolic and body composition changes associated with ADT arise within months of beginning medical ADT and persist after discontinuation of therapy. To better understand the increased risk of metabolic syndrome, diabetes, and heart disease in patients undergoing ADT for prostate cancer, we performed a MEDLINE search (1986–2008) to identify pertinent studies and reports. Additional citations were obtained from the articles retrieved from the literature search. We found that the increased risk for serious cardiovascular disease becomes evident within months of beginning ADT. Pharmacists should provide counseling to these patients on primary disease prevention. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome, diabetes, and CAD. Healthy lifestyle practices should be encouraged, and physical therapy should be considered for these patients.

Prostate cancer is the leading cancer diagnosis and second leading cause of cancer-related mortality for men in the United States. In 2007, prostate cancer was diagnosed in approximately 220,000 men, and about 27,000 deaths were attributed to this disease.[1] Increasing age is the greatest risk factor for prostate cancer. The probability of being diagnosed with prostate cancer is 1 in 10,373 for men younger than 40 years. However, this probability increases with age to 1 in 39 at 40–59 years, 1 in 14 at 60–69 years, and 1 in 7 at 70–79 years.[1] Additional risk factors include African-American race, positive family history, and a diet high in animal fat and red meat consumption.[2] The prognosis for men with prostate cancer is quite variable and relates to disease characteristics, such as tumor size, prostate-specific antigen (PSA) level, Gleason score (risk assessment based on histologic findings), malignant extension outside of prostate capsule, seminal vesicle invasion, involvement of regional lymph nodes, and distant sites of metastatic disease.[2] Men with low-risk localized prostate cancer generally live with their tumor and eventually succumb to morbidity and mortality unrelated to malignant disease.[3,4] Fortunately, most cases of prostate cancer are diagnosed when the disease is localized to the prostate. In this group, the 5-year survival rate approaches 100%,[1,2] and the disease is largely asymptomatic except for difficulties from bladder outlet obstruction.[2] Unfortunately, for cases of recurrent or disseminated prostate cancer, the median overall survival time is 12–18 months.[1,2] Complications associated with advanced disease can be debilitating and include hypercalcemia, hypocalcemia, spinal cord compression, osteoblastic bone lesions, and chronic pain.[2] The mean age at death for men with prostate cancer of all prognostic risk levels is 79 years, and the leading cause of death is cardiovascular disease.[4]

Due to the increased prevalence of prostate cancer in men older than 50 years, men at risk for prostate cancer represent the same population of men who are at risk for metabolic syndrome, diabetes mellitus, and coronary artery disease (CAD).[5] Of these conditions, CAD is the most immediately life threatening. Approximately 60 million people in the United States have CAD, and every year approximately 42% of all deaths are attributed to CAD.[5] The major risk factors for CAD include age and sex (male > 45 yrs, female > 55 yrs), positive family history, elevated low-density lipoprotein cholesterol (LDL) level, low high-density lipoprotein cholesterol (HDL) level, hypertension, diabetes, and tobacco use.[6] In addition to these risk factors for CAD that are applicable to the general population, men with prostate cancer can be at increased risk for CAD due to use of androgen deprivation therapy (ADT). Hyperlipidemia, insulin resistance, metabolic syndrome, and acute coronary syndrome are all reported consequences of ADT. Body composition changes that yield increased fat content occur with long-term administration of a luteinizing hormone–releasing hormone (LHRH) agonist.[7,8] Additional common adverse effects of ADT include hot flushes, fatigue, decreased libido, decreased quality of life, reduced bone mineral density (BMD), and anemia. Adverse effects caused by ADT administration are consequences of reduced levels of circulating testosterone.[7,9,10]

Nonmalignant prostate tissue requires androgenic stimulation for growth, regular function, and morphologic integrity. This quality persists with the development of most cases of prostate cancer. Subsequently, interruption of androgenic activity is detrimental to the viability of malignant and nonmalignant prostate tissue.[2,11] Androgen deprivation therapy for the treatment of prostate cancer dates back to 1941.[2,11] First-line ADT is accomplished medically by using drug therapies that reduce or antagonize the effects of testosterone. The LHRH agonists are the mainstay of the drugs used to induce medical castration. The LHRH agonists are analogs of endogenous gonadotropin-releasing hormone that induce castration levels of testosterone in men by negative regulation of luteinizing hormone and follicle-stimulating hormone secretion from the anterior pituitary gland. Commercially available LHRH agonists are goserelin, histrelin, leuprolide, and triptorelin.[12] These products are available as depot formula-tions that are administered by intramuscular injection every 3–12 months.[13] Additional methods of ADT include bilateral orchiectomy and androgen-blocking agents. Bilateral orchiectomy provides ADT by removing the source of endogenous testosterone. Bilateral orchiectomy and LHRH agonist therapy are considered to be equally effective; however, most men prefer drug therapy over surgery.[2,12]

Drugs categorized as androgen-blocking agents bind cytosolic androgen receptors and act as competitive inhibitors to prevent the initiation of androgen-mediated biologic activity.[11] Androgen-blocking agents are generally administered in combination with LHRH agonists or as a second-line alternative to them.[14] Commercially available androgen-blocking agents are bicalutamide, flutamide, and nilutamide. These products act as competitive inhibitors of androgen at the androgen receptor.[13] Both androgen-blocking agents and LHRH agonists are normally administered continuously. Intermittent administration of ADT, which is related to serum PSA level results, is undergoing evaluation as a method to delay the development of androgen-refractory prostate cancer and reduce treatment-related adverse effects.[2,14] Clearly there is benefit to ADT for the reduction of morbidity in patients with advanced androgen-sensitive prostate cancer.[12,14] However, ADT is not considered curative therapy for prostate cancer, and its role is less well defined in early stages of the malignancy because of the variable nature of disease progression.[3,12,15]

To better understand the increased risk for metabolic syndrome, diabetes, and heart disease in patients receiving ADT for prostate cancer, we performed a search of the medical literature using MEDLINE (1986–2008). Subject headings and key words used were prostatic neoplasms, prostate cancer, leuprolide, goserelin, histrelin, triptorelin, and androgen deprivation therapy. The search was limited to English-language journals and human studies. Clinical and epidemiologic studies pertaining to metabolic syndrome, diabetes, and heart disease in patients undergoing ADT for prostate cancer were included. Additional citations were identified from the studies retrieved from the literature search. The methods of studies published by the same authors were scrutinized to ensure that duplicated data were not inadvertently presented as additional data.

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