**9. ADT, metabolic syndrome and cardiovascular disease**

Metabolic syndrome (MS) is a known risk factor for cardiovascular disease (CVD) (120). According to the Adult Treatment Panel III guidelines (121), a man is considered to have MS if he meets 3 of the following 5 criteria: fasting plasma glucose level >110 mg/dL, serum triglyceride level 150 mg/dL, serum high-density lipoprotein level <40 mg/dL, waist circumference >102 cm, and blood pressure ≥ 130/85 mmHg. Subjects on antihypertensive and antilipid medications are also considered positive for the respective criteria. Recently, male hypogonadism has surfaced as an independent risk factor for MS. Cross-sectional studies have shown that men with hypotestosteronemia have a higher prevalence of MS (122). Longitudinal studies also show that lower androgen levels in men independently predict the development of MS (105).

These observations suggest that profound hypogonadism due to ADT imparts increased metabolic burden. Long-term prospective studies are needed to determine the time of onset of various metabolic alterations in these men.

Since MS is associated with CVD, large studies were conducted to assed the CV risk and ADT. A large SEER-Medicare–based analysis of 73,196 men aged 66 years and older with PCa identified significant GnRH agonist-associated elevations in risk for myocardial infarction (HR, 1.11; p= .03), sudden cardiac death (HR, 1.16; p = .004), and new diagnosis of coronary heart disease (HR, 1.16; p< .001) (123). Similarly, a second SEER-Medicare–based study of 23,000 men with PCa found a 20% ADT-attributable rise in CV morbidity at 1 year (124).

In contrast, a recently reported matched cohort analysis of approximately 20,000 men in an On-tario database found no association between ADT and acute myocardial infarction (HR, 0.91; 95% CI, 0.84–1.00) (125).

A smaller population-based observational study of 3262 men who had undergone prostatectomy for PCa found that ADT was significantly associated with CV mortality, although only in the subset of men aged 65 years and older (126). This analysis failed to validate baseline coronary artery disease and diabetes as risk factors for CV mortality. Finally, combined analysis of 3 randomized trials involving men with localized PCa found that in the subset of men aged 65 years and older, 6 months of treatment with a GnRH agonist led to earlier onset of fatal myocardial infarction (127).

Three large randomized, controlled trials by the Radiation Therapy Oncology Group (RTOG) have been retrospectively analyzed for an association between neoadjuvant/ concomitant/adjuvant ADT and CV mortality. These analyses have not found convincing evidence of an association (128-130). Secondary analyses of a randomized controlled trial from the EORTC found no association between ADT and CV mortality. The RTOG and EORTC trials were randomized, featured large enrollments, and had long-term follow-up.

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Table 2. Summary of main organ systems affected by severe hypogonadism (by ADT)
