Men who receive hormone therapy for prostate cancer with drugs called gonadotropin-releasing hormone (GnRH) agonists may find themselves at higher risk for diabetes and heart disease. Doctors and patients should take this into account when deciding whether GnRH agonist treatment is appropriate, according to a study by Harvard Medical School researchers published in the Journal of Clinical Oncology.

GnRH agonists are also called LHRH agonists. Common drugs in this class include leuprolide (Lupron, Viadur, Eligard), goserelin (Zoladex), and triptorelin (Trelstar).

The goal of hormone therapy for prostate cancer is to reduce levels of testosterone, the male hormone that is known to fuel the growth of the cancer. Hormone therapy is typically given for prostate cancer when it has spread to other parts of the body or has come back after treatment with surgery or radiation. It is also given before radiation in early stages of the cancer to make the tumor easier to treat. The authors say the use of hormone therapy in men with earlier stage prostate cancer has been increasing in recent years.

"Doctors should think twice about prescribing GnRH agonists in situations for which studies have not demonstrated improved survival until we better understand the risks of treatment," study co-author Matthew R. Smith, MD, PhD, associate professor of medicine, said in a statement.

Smith and his colleagues followed more than 73,000 men on Medicare, age 66 and older, who were diagnosed with local or regional prostate cancer. They analyzed the number of men receiving hormone therapy and the number of cases of diabetes and heart disease that developed in this group.

About 36% of the men received a GnRH agonist; 7% had their testicles surgically removed (bilateral orchiectomy), as a way to permanently lower their testosterone production. In men without preexisting diabetes or heart disease, those treated with a GnRH agonist had a significantly higher risk of developing diabetes, coronary heart disease, heart attack, and sudden cardiac death than men not on hormone therapy. This higher risk began as soon as 1-4 months after treatment started and remained elevated among those who continued treatment for longer periods.

Men treated with orchiectomy had a significantly higher risk of diabetes, but not the other conditions. That came as a bit of a surprise, because the researchers had figured both treatments would have the same effect. They say it's possible there were just too few men in the orchiectomy group to see differences in the other conditions. But it could also mean the hormone drugs have a different effect than physical castration; more studies will be needed to know for sure.

The findings mesh with the known side effects of GnRH agonists: weight gain and insulin resistance, both of which can raise a man's risk of diabetes and heart disease.

However, certain factors could not be accounted for in the study. Participants were not randomly assigned to treatment, which would have given researchers more reliable data; the researchers did not have information on other oral medications the men may have been taking that could have affected heart disease and diabetes risk; and the men in the study were older and so already more prone to develop these diseases. Further trials will be needed to address such issues and help refine the criteria for prescribing androgen deprivation therapy.

Nevertheless, the findings should give doctors who routinely prescribe these treatments pause, other experts agree.

"It should make us more cautious in starting men on this therapy, but not preclude starting those who need it," said David Smith, MD, a professor of internal medicine and urology at the University of Michigan who was not involved in the Harvard study. He said hormone therapy can do a lot to improve prostate cancer survival, but that benefit needs to be weighed against the risk of a man developing other dangerous conditions.

Smith said men with metastatic disease are obvious candidates for hormone therapy, but average patients with newly diagnosed prostate cancer likely are not.

Both he and the study authors said men who are going to begin androgen deprivation therapy should be counseled about strategies like exercise and weight loss to reduce their risk for diabetes and heart disease.

Smith says he tells even his fit patients to begin an exercise routine when he puts them on hormone therapy to counteract the weight gain and slower metabolism the drugs can cause.

Citation: "Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer." Published in the Sep. 20, 2006 Journal of Clinical Oncology (Vol. 24, No. 27: 4448-4454). First author: Nancy L. Keating, MD, MPH, Harvard Medical School.