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Metabolic Toxicity: A Significant Problem

doi: 10.1097/01.COT.0000288346.14295.8f

Androgen-deprivation therapy, with or without radiation therapy, to lower testosterone levels is achieved at high cost: decreased libido, impotence, decreased lean body mass and muscle strength, osteoporosis, and reduced quality of life. But far worse is the significantly increased risk of metabolic syndrome and diabetes with their attendant high incidence of cardiovascular events. In fact, more than half the men with prostate cancer who are on ADT have metabolic syndrome.

Shehzad Basaria, MD, Assistant Professor in the Division of Endocrinology and Metabolism of Johns Hopkins University School of Medicine, notes that major complications of hypogonadism are insulin resistance and Type 2 diabetes. When testosterone levels fall, metabolic syndrome, an independent risk factor for cardiovascular disease, is often the result. Cardiovascular disease is the most common cause of death in men with prostate cancer.



“Actually, male hypogonadism from any source is a risk for metabolic syndrome,” Dr. Basaria said. “And most men over age 65 may already have one or two of its five risk factors—fasting glucose greater than 110, triglyceride greater than 150, HDL less than 40, waist circumference more than 102 cm, and blood pressure over 135/85—so when you begin treatment with ADT, there's a high likelihood that the patient will be tipped over into the full-blown syndrome.”

Therefore a Catch-22: As ADT becomes more common in the treatment of prostate cancer, metabolic and cardiovascular complications may increase.

Dr. Basaria described three relevant studies. The first involved 22 men who had a significant increase in serum insulin levels after three months of ADT but no change in plasma glucose. Another three-month prospective study showed that ADT resulted in a 63% increase in fasting insulin, again without change in fasting glucose. And another three-month study using combined androgen blockade resulted in a 26% rise in insulin. All the studies indicated the development of insulin resistance.

In a study looking at long-term metabolic complications of ADT, 53 men were divided into three groups: 18 received ADT for at least 12 months; 17 were eugonadal with nonmetastatic prostate cancer and had undergone prostatectomy and/or radiation therapy and were not androgen deprived; and a control group of 18 were eugonadal.

The mean duration of ADT was 45 months. The men in the ADT group had significantly higher insulin levels and insulin resistance.

“However,” Dr. Basaria said, the key finding was the prevalence of fasting hyperglycemia in the ADT group—in fact, long-term [more than 12 months] ADT is associated with frank diabetes.”

He also said that a recent observational study found that men undergoing ADT had a higher risk of diabetes, coronary artery disease, myocardial infarction, and sudden death, some of which were seen within a few months of the start of androgen-deprivation therapy.

Low serum testosterone is associated with hyperlipidemia, especially elevated total cholesterol, LDL, and triglycerides, all observed in men on ADT.

How to prevent metabolic syndrome? Dr. Basaria said, “We're starting a prospective study in men with prostate cancer who have no diabetes at baseline, and we'll look at the role of diet, exercise, and insulin sensitizers. It will last at least a year, and by the time we get up to full accrual and analyze the data, we should have results in two to three years.”

© 2007 Lippincott Williams & Wilkins, Inc.
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