Study documents health risks of GnRH therapy

Boston-Gonadotropin-releasing hormone (GnRH) agonist therapy for locoregional prostate cancer is associated with significantly increased risks of diabetes as well as cardiovascular disease morbidity and mortality, according to the results of a population-based, observational cohort study.

The investigation was undertaken by researchers at Harvard Medical School here and was recently published in the Journal of Clinical Oncology (2006; 24:4448-56). It identified men who were fee-for-service Medicare enrollees (age 66 years and older) with locoregional cancer diagnosed between 1992 and 1999 using the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Cox proportional hazards models adjusting for patient and tumor characteristics were used to compare rates of incident diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death among subgroups treated with a GnRH agonist or orchiectomy relative to those receiving no androgen deprivation therapy (ADT).

The analyses were based on a total of 73,196 men who had a mean age of 74.2 years at diagnosis and a median follow-up of 4.55 years. Of those men, about 36% received GnRH agonist therapy and about 7% underwent bilateral orchiectomy. Rates of development of incident diabetes, MI, sudden cardiac death, and CHD were 10.9%, 5.4%, 4.5%, and 25.3%, respectively.

"It will be important to see if these findings will be replicated in future studies in other populations. However, given the underlying physiologic plausibility for the risks observed and considering that GnRH agonists are associated with other adverse effects, we believe our study should raise caution in the minds of clinicians who prescribe these agents," said Nancy L. Keating, MD, assistant professor of medicine and health care policy at Harvard.

"Information about the potential risks and benefits should be thoroughly reviewed with the patient, but if there is not good evidence that GnRH agonist treatment is likely to improve cancer-specific outcomes, we believe it might be prudent to withhold their use until we better understand the potential risks."

Influence of previous studies

The investigators were prompted to undertake this study based on some previous research, including studies led by co-author Matthew R. Smith, MD, that identified a variety of adverse physiologic effects associated with GnRH agonist therapy. Those investigations showed that men developed significant increases in fat mass and insulin resistance as soon as within 12 weeks after treatment initiation. The GnRH agonists have also been reported to prolong the QT interval and alter serum lipoproteins.

"Those findings led us to wonder whether there could be even greater deleterious health implications associated with these treatments. Given that use of GnRH agonists has been increasing over the last decade, including among men whose prostate cancer generally has a favorable prognosis, the investigation of such risks is an important issue," Dr. Keating explained.

The researchers were surprised to find that orchiectomy did not significantly increase the risk of any of the cardiovascular events investigated.