Prostate Cancer and the Metabolic Syndrome
The metabolic syndrome is defined by a cluster of metabolic risk factors for cardiovascular disease (CVD), including insulin resistance, central obesity, and dyslipidemia. Its prevalence is increasing, coincident with the worldwide epidemics of obesity an
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Prostate Cancer and the Metabolic Syndrome Stephen E.M. Langley and Jenny P. Nobes
Introduction
The Metabolic Syndrome
Men with prostate cancer have higher rates of noncancer mortality than men in the general population, with some of this excess attributed to the adverse effects of treatment [1], and there is evidence for an increased prevalence of metabolic syndrome with the therapeutic use of androgen deprivation therapy (ADT) in prostate cancer [2]. The metabolic syndrome is characterized by a cluster of metabolic risk factors for cardiovascular disease (CVD). Because of the generally favorable prognosis for early prostate cancer, decisions about which treatment is likely to offer the most benefit in the long term are particularly important. ADT may be used to treat men with local and locoregional disease and is the mainstay of treatment for metastatic prostate cancer [3]. ADT may be achieved either through surgical castration (bilateral orchidectomy) or chemical castration with a gonadotropin-releasing hormone (GnRH) agonist, the most common approach in modern clinical practice [4]. Traditionally, the use of ADT was reserved for advanced prostate cancer [5]. There has, however, been a trend toward increasing use of ADT in prostate cancer patients [5–9], both as neoadjuvant and primary therapy, since the advent of PSA testing. A population-based cohort study concluded that widespread detection and aggressive treatment of prostate cancer in the USA has been associated with more, rather than less, use of ADT over time [5].
The metabolic syndrome (also known as syndrome X, Reaven syndrome [10], insulin resistance syndrome) is defined by a cluster of lipid and non-lipid metabolic risk factors for CVD, with insulin resistance (IR) as the central characteristic. In IR, there is an exaggerated insulin response to ingested carbohydrates, especially those with a high glycemic index (GI). Insulin acts on fat cells resulting in hydrolysis of stored triglycerides, which elevates plasma levels of free fatty acids. These free fatty acids are absorbed by the liver, resulting in an increased production of triglycerides and very low-density lipoprotein (VLDL) cholesterol and a decreased production of high-density lipoprotein (HDL) cholesterol. Insulin acts on muscle to reduce glucose uptake, whereas in liver it reduces glucose storage, with both effects serving to elevate blood glucose. High levels of insulin cause increased renal sodium absorption, arterial vasospasm, and consequently hypertension. Endothelial effects of elevated insulin levels are also seen, mediated by nitrous oxide. In addition, impairment of cellular repair is apparent, with increased levels of pro-inflammatory cytokines. Concentrations of bound and free serum testosterone, sex hormone-binding globulin (SHBG), and androgen receptor are reduced [11]. The prevalence of metabolic syndrome has increased markedly over the last two decades, coincident with the global epidemics of obesity [12] and type II diabetes [13]. Studies using data from the Third Nation
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