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Metabolic Syndrome After Hormone-Modifying Therapy: Risks Associated With Antineoplastic Therapy

Metabolic Syndrome After Hormone-Modifying Therapy: Risks Associated With Antineoplastic Therapy

ABSTRACT: The incidence of metabolic syndrome is rapidly increasing. Metabolic syndrome is associated with elevated morbidity and mortality secondary to cardiovascular disease, insulin resistance, and hepatic dysfunction. A body of evidence has already implicated metabolic syndrome as a cancer risk factor; emerging evidence now suggests that cancer survivors themselves may be at risk for developing metabolic syndrome as a result of their anti-cancer therapy. Treatment of both breast cancer and prostate cancer often involves hormone-modifying agents that have been linked to features of metabolic syndrome. Androgen suppression in men with prostate cancer is associated with dyslipidemia, increasing risk of cardiovascular disease, and insulin resistance. Anti-estrogen therapy in women with breast cancer can affect lipid profiles, cardiovascular risk, and liver function. Similar findings have been noted in men with testicular cancer treated with chemotherapy. In addition, several emerging therapies, including mammalian target of rapamycin (mTOR) inhibitors and targeted kinase inhibitors, are increasingly associated with some features of metabolic syndrome. As the number of cancer survivors continues to grow, consideration of these factors and of the risk of metabolic syndrome will become increasingly important when choosing between therapy options and managing long-term follow-up.

The last 3 decades have seen a steady increase in the prevalence of obesity, diabetes, dyslipidemia, and hypertension, most notably in the American population but also on a global scale.[1,2] These trends have resulted in a marked increase in the prevalence of metabolic syndrome; this term is used to describe a specific constellation of findings, defined by the American Heart Association and the National Heart, Lung, and Blood Institute as including the following: elevated waist circumference (>102 cm in men or >88 cm in women), elevated triglyceride level (>150 mg/dL or the use of specific treatment for elevated triglycerides), reduced high-density lipoprotein (HDL) cholesterol level (<40 mg/dL in men or <50 mg/dL in women), elevated blood pressure (>130/85 mm Hg or the use of medication for hypertension), and elevated fasting glucose level (>100 mg/dL or the use of medication for hyperglycemia). Recent studies estimate that one in five Americans, or nearly 50 million people, suffer from metabolic syndrome.[3]

Understanding, treating, and preventing metabolic syndrome has become a priority because of the tremendous health burden faced by individuals in whom the syndrome is diagnosed. Not only are patients with metabolic syndrome at a substantially elevated risk for cardiovascular disease and the development of cancer,[4] but the combined metabolic irregularities of the syndrome are also directly linked to greatly elevated morbidity and mortality associated with other conditions that arise from metabolic derangement. In addition to increasing the morbidity associated with cardiovascular disease,[5] metabolic syndrome leads to an elevated incidence of type 2 diabetes and is increasingly associated with nonalcoholic steatohepatitis, a rising cause of liver transplantation, even in children.[6,7] For the individual patient and for society, the potential long-term consequences of untreated metabolic syndrome are immense.

Accumulating evidence suggests that cancer survivors may be at particular risk for developing metabolic syndrome secondary to their anti-cancer therapy.[8,9] Because both estrogen and testosterone have been implicated in driving malignant cell growth, hormone-modifying agents are currently used to treat several different cancers, including breast and prostate tumors. Multiple studies indicate that changes in sex hormone levels modify metabolism,[10-12] and relative hormone levels may help explain the marked differences observed between the incidence of metabolic syndrome in men and the incidence in women.[13] Metabolic changes associated with modification of either estrogen or androgen levels are consequently of direct relevance to the large and ever-growing number of cancer survivors who have received hormone-modifying agents.

In addition, the newest classes of anti-cancer drugs include multiple compounds with potentially far-reaching effects on intracellular signaling pathways. A number of these agents, including kinase inhibitors, angiogenesis inhibitors, and mammalian target of rapamycin (mTOR) inhibitors, have the potential to affect not only cellular proliferation but also critical growth and energy-sensing mechanisms that may have profound effects on metabolism.

There are a myriad of ways in which cancer survivors can be affected by antineoplastic therapy. It is thus the aim of this review to synthesize the available data in order to assess the risk of metabolic syndrome associated with selected antineoplastic therapies.

Metabolic Syndrome in Patients With Prostate Cancer

Treatment for prostate cancer includes surgery, radiation, and androgen suppression therapy.[14,15] Androgen suppression is highly successful at treating the disease, but accumulating evidence suggests that this therapy may lead to metabolic syndrome. Studies in a cohort of Medicare enrollees demonstrate that androgen suppression is linked to an increased risk of coronary artery disease, myocardial infarction (MI), and sudden cardiac death.[8] Tsai and colleagues[16] demonstrated that, even after controlling for age and pre-existing cardiovascular risk factors by regression analysis, patients who underwent androgen ablation still had a nearly three-fold increase in risk of death from cardiovascular causes. Of particular interest, when the incidence of fatal MI in a group of patients treated with androgen suppression was compared with the incidence in a group not treated with androgen suppression, the patients who received androgen suppression were found to be more likely to have a fatal MI at an earlier age.[17] In fact, the cardiovascular risk associated with androgen suppression therapy is so substantial that increased cardiovascular morbidity may even contribute to lower disease survival in men with low-risk prostate cancer.[17] When compared with age-matched controls, patients who undergo androgen suppression have higher levels of central obesity and greater elevations of blood triglyceride levels.[18] Also, the low testosterone levels associated with either gonadal dysfunction or androgen suppression therapy are also thought to raise total cholesterol levels, low-density lipoprotein (LDL) cholesterol levels, and triglyceride levels—all factors associated with increased risk of cardiovascular disease.[19]

In addition to its effect on cardiovascular risk factors, androgen suppression is also known to affect insulin resistance, another characteristic of metabolic syndrome.[20] Several studies demonstrating the link between androgen suppression and adverse changes in patients’ cardiac risk profiles also note an increased risk of incident diabetes or hyperglycemia in patients who receive androgen suppression, in some cases with a calculated risk that exceeds the risk of cardiovascular disease.[8,18] Importantly, changes in the risk of hyperglycemia and diabetes develop independently of patient age and body mass index (BMI) at time of diagnosis, suggesting that androgen suppression therapy itself can contribute to the development of glycemic irregularities.[21] In fact, in a population of men with low testosterone levels, a decreased testosterone level preceded detectable elevations in fasting glucose, insulin, and hemoglobin A1c levels, suggesting that a low testosterone level may serve as a marker for the development of incident diabetes.[22] Even short-term androgen suppression therapy has been shown to influence both abdominal obesity and insulin sensitivity.[23] Finally, in a cohort of men with pre-existing diabetes, glycemic control as measured by serum glucose levels and hemoglobin A1c levels markedly worsened in up to 22% of the cohort following initiation of androgen suppression.[24]

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