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Prostate cancer drugs' safety in question: links with heart disease and diabetes have resulted in FDA review of the drugs' safety.

The Food and Drug Administration (FDA) has announced that it is investigating the safety of a widely-used class of prostate cancer drugs, gonadotropin-releasing hormone (GnRH) agonists, in the wake of reports linking them with a rise in the risk of heart disease and diabetes.

The drugs work by suppressing the production of the hormone testosterone. It's not the first time concerns have been raised about the drugs--a 2009 study suggested that overall anti-hormone therapies raised the risk of heart disease by as much as 25 percent in men taking them, while other research suggests that men who take the drugs have double the risk of developing metabolic syndrome, a cluster of risk factors that has been linked to the development of heart disease.



While it isn't clear what triggers prostate cancer, the disease relies on testosterone to grow. This means that cutting off the hormone may cause prostate cancer cells to die or grow less rapidly. GnRHs, which include Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, Zoladex and several generic options, block testosterone production by the testicles, with the result that almost no testosterone circulates in the body. The drugs may be used both before radiation therapy, in order to shrink tumors, and after radiation or surgery, to slow the growth of any cancer cells that might remain.


GnRHs aren't a cure for prostate cancer--tumors can eventually become resistant--but can prolong survival, and as such they play a vital role in treating the disease. However, while cutting out testosterone prevents the growth of prostate cancer, previous studies have linked low testosterone with a higher risk of cardiac events. Although a direct association between testosterone and heart disease hasn't been found, men's increasing risk for heart disease as they age parallels a simultaneous natural decline in testosterone production.

Testosterone benefits heart health by increasing production of nitric oxide, which dilates the arteries, and inhibiting plaque (the waxy cholesterol deposits that can build up and block arteries). The hormone also is thought to help prevent the insulin resistance that underlies pre-diabetes and metabolic syndrome (men with pre-diabetes and diabetes are more likely to have low testosterone), and may help limit the systemic inflammation that underlies heart disease. Men with low testosterone also have more body fat--particularly the more harmful abdominal fat--which increases the risk of heart disease and diabetes.

FINDING A BALANCE. The FDA hasn't reached any conclusions about whether GnRH agonists cause an increase in the risk of diabetes and heart disease, but has advised that health care professionals should be aware of the potential risks and carefully weigh the benefits and risks of GnRH agonists when determining a treatment for patients with prostate cancer.

"While our review of these prostate cancer treatments is ongoing and there are some limitations to the data, the FDA believes it is important to tell patients and health care professionals that there may be an increased risk of serious side effects," says Robert Justice, MD, director of the Division of Drug Oncology Products in the FDA's Center for Drug Evaluation and Research.

Based on its initial findings, the FDA advises that patients receiving a GnRH agonist should be monitored for the development of diabetes and cardiovascular disease, and that cardiovascular risk factors such as smoking and increases in blood pressure, cholesterol, blood sugar and weight should be carefully managed. Patients shouldn't stop treatment with a GnRH agonist unless instructed to do so by their doctor. These recommendations are consistent with a Science Advisory issued by the American Heart Association, American Cancer Society, and American Urological Association, in the February 2010 issue of the journal Circulation.


Professor of Medicine,

Duke Medicine Signature Care, Duke



Quality of Life Can Still Be Enhanced and Enjoyed

"For the majority of men whose disease recurs there is no curative treatment option. It is for these individuals that systemic therapy is of value. The objective of systemic therapy is to control the disease (usually metastases to bone) while maintaining quality of life. GnRH agonists remain the best tolerated and among the most effective of the options for systemic therapy for metastatic prostate cancer. They are not perfect: Long-term use may lead to loss of testosterone sensitivity of the tumor, hence to lack of effect. Other options, however, including surgical castration and estrogen therapy are less well accepted; the latter is associated with increased cardiovascular risk as well. We physicians should be fully aware of the potential for adverse outcomes that GnRH agonists confer. If we are careful to diagnose these problems--diabetes, hyperlipidemia, metabolic syndrome--early, and treat appropriately, we can continue to use this valuable resource for men who have so few acceptable treatment options."

Androgen deprivation therapy (ADT), or hormone therapy, is linked to an array of cardiovascular, metabolic and musculo-skeletal side effects, including: Decline in muscle mass; cognitive problems; decreased mental sharpness; cardiovascular disease; increased risk of heart attack; blood sugar abnormalities; increased risk of diabetes; loss of male hormones; decline in libido and sexual function; loss of bone density; increased risk of osteoporosis and fractures.

The hypothalamus signals the pituitary gland to release hormones. These hormones travel through the bloodstream to the testicles which turn the hormones into testosterone. When the testosterone travels to the prostate it stimulates the growth of new prostate cells. Androgen deprivation therapy interrupts the cycle by slowing growth of prostatic cells and limiting new cell growth.


Prostate cancer is the second-most common type of cancer in men (behind skin cancer). Initially, it may not cause any harm, since it typically grows at a slow rate--so slow in fact that the disease can be present for 15 to 20 years before the person with it experiences symptoms. Men over age 75 are more likely to die with prostate cancer than from it (the prostates of most elderly men are found to contain prostate cancer cells at autopsy even though they may never have had any signs or symptoms of the disease). However, some prostate cancers are aggressive and do require treatment.
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Title Annotation:CANCER
Author:Kelly, James R.
Publication:Duke Medicine Health News
Date:Aug 1, 2010
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