Cardiovascular disease associated with androgen-deprivation therapy: time to give it due respect.

Abstract

It all began in 1941 when Huggins and Hodges first described the androgen dependence of prostate cancer (PCa) by demonstrating regression of metastases by androgen deprivation. PCa is now the most common cancer in men in the United States, and androgendeprivation therapy (ADT) is the mainstay of treatment for locally advanced and metastatic PCa. Testosterone, the main male androgen, is secreted by testicular Leydig cells under the influence of gonadotropins and possesses both androgenic and anabolic functions. Testosterone is metabolized into two biologically active hormones: dihydrotestosterone and estradiol. Androgen deprivation can be achieved surgically (orchiectomy), medically (gonadotropin-releasing hormone [GnRH] agonists and antagonists, and estrogens), and by inducing androgen resistance (androgen receptor antagonists). Orchiectomy and treatment with GnRH agonists and antagonists decreases serum testosterone and its metabolites, whereas monotherapy with antiandrogens results in an increase in gonadal hormones. Treatment with GnRH agonists has become the most common form of ADT. Indeed, these drugs are relatively easy to administer, allow the psychological harm associated with orchiectomy to be avoided, and testosterone suppression is reversible on their discontinuation. In clinical practice, a symptomatic man is generally considered androgen deficient if his serum total testosterone level is less than 300 ng/dL. The goal of ADT is to suppress the serum testosterone level to at least below 50 ng/dL, inducing a state of profound androgen deficiency. Recent estimates suggest that more than half a million men in the United States are receiving ADT. Although ADT improves quality of life and survival in a subset of patients, its role in patients with earlystage PCa and those experiencing biochemical recurrence after local treatment remains unclear. Sexual dysfunction, low bone mass, reduced muscle strength, and decreased energy are well-established symptoms of androgen deficiency. Recent population studies have shown that low testosterone is also associated with increased fat mass, diabetes, atherosclerosis, and cardiovascular (CV) disease. Laboratory investigations have shown that testosterone acts on pluripotent mesenchymal stem cells and promotes their differentiation toward myogenic lineage while inhibiting their differentiation into adipocytes. Hence, it is not surprising that androgen deficiency results in an increase in fat mass (rich source of inflammatory cytokines that promote insulin resistance) and a reduction in skeletal muscle (the largest source of glucose disposal), leading to metabolic dysregulation. Data from preclinical models also show that orchiectomy in low-density lipoprotein receptor–deficient mice promotes atherosclerosis, and testosterone supplementation (and its aromatization to estradiol) attenuates this process. These data support the biologic plausibility that testosterone deficiency may be a risk factor for CV disease. Orchiectomy and GnRH agonists decrease testosterone and estradiol levels, whereas monotherapy with antiandrogens increases both hormones. Hence, the CV disease risk in patients undergoing monotherapy with antiandrogens may be different from that of men receiving other forms of ADT. Adverse effects of ADT have become better appreciated during the last 15 years. Sexual dysfunction, vasomotor symptoms, osteoporosis, and reduced quality of life are well-known consequences of ADT. In 2001, a Welsh study first reported an increase in fat mass and associated insulin resistance (a precursor to diabetes) after 3 months of ADT. Later reports showed that patients undergoing long-term ADT have a higher prevalence of metabolic syndrome and diabetes, with the duration of ADT directly associated with the degree of metabolic perturbations. These cohort studies were followed by population-based reports showing an association between GnRH agonist use and an increased risk of incident coronary heart disease, myocardial infarction, and sudden cardiac death. Interestingly, this increased risk was evident within 1 to 4 months of starting ADT. Subsequent population studies confirmed these findings. One interesting report evaluating the neoadjuvant role of ADT showed that ADT increases the risk of all-cause mortality in men with a previous history of myocardial infarction or coronary artery disease–related heart failure, suggesting that men with known CV disease might be at a higher risk. An increased risk of stroke, venous thromboembolism, and peripheral arterial disease have also been reported in patients undergoing both surgical and medical ADT. All of these reports prompted the US Food and Drug Administration to issue a safety warning in October 2010, requiring GnRH agonist labeling to disclose an “increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death and stroke) in men receiving these medications for the treatment of prostate cancer.” Unlike population studies, postrandomization analyses from clinical trials have yielded conflicting data. In a pooled analysis from three randomized trials of patients receiving radiation therapy and ADT for localized PCa, older ( 65 years) patients receiving 6 months of ADT had shorter times to fatal myocardial infarction compared with men not receiving ADT. In contrast, post hoc analyses from JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 11 APRIL 1