Assessment of endothelial dysfunction by flow‐mediated dilatation in men on long‐term androgen deprivation therapy for prostate cancer

Abstract

New FindingsAndrogen deprivation therapy (ADT) in men with prostate cancer has been linked to an increased incidence of cardiovascular events and mortality, but the underpinning mechanisms are unclear. Endothelial dysfunction is considered a precursor for cardiovascular disease. Previous studies have reported variably on the association between ADT and endothelial function. This blinded case-control study examined endothelial function, using high-resolution ultrasound to measure flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-mediateddilatation in the brachial artery, in 20 men with prostate cancer (69 ± 7 years old) treated by ADT (median duration 22 months, range 6-133 months) and 20 men without prostate cancer (69 ± 5 years old) matched for age, physical activity, coexistent cardiovascular disease and body mass index. The magnitude of dilatation was calculated traditionally and allometrically scaled, adjusting for baseline diameter. There were no differences between groups for resting vascular measures (means ± SD). Flow-mediated dilatation was lower in men on ADT than in control subjects (3.9 ± 2.1 versus 5.9 ± 3.8% for traditional, P = 0.047; 3.7 ± 2.7 versus 6.0 ± 2.7% for allometrically scaled, P = 0.023). Response to GTN was similar in both groups (12.2 ± 4.2 versus 14.8 ± 5.7% for traditional, P = 0.113; 12.3 ± 4.6 versus 14.4 ± 4.6% for allometrically scaled, P = 0.163). The magnitude of difference in mean FMD between groups was marginally altered to 2.4% (95% confidence interval 0.3-4.5) after adjustment for the difference in body fat mass and concomitant cardiovascular medication, with the difference in FMD remaining significant (P = 0.029). There is evidence of endothelial dysfunction in men with prostate cancer on long-term ADT. Although a causal relationship is unproven, the findings are consistent with

Androgen Deprivation Therapy Reversibly Increases Endothelium‐Dependent Vasodilation in Men With Prostate Cancer

“…In contrast, Gilbert and colleagues studied men with prostate cancer treated with ADT and controls matched for sex, age, and body mass index. 22 Similarly, the ADT‐treated men had significantly lower testosterone levels compared with controls (12 versus 533 ng/dL). In this study, however, brachial artery endothelium‐dependent vasodilation was lower in men with prostate cancer treated with ADT (3.9%) compared with matched controls (5.9%).…”

Sex differences in vascular aging in response to testosterone

“…Similarly, endothelial function improved in older men following 3 months of ADT [76]. However, these data are inconsistent with a case-control study that showed that brachial artery FMD was reduced in older men with prostate cancer treated with ADT compared to men without prostate cancer that were matched for age, physical activity, and comorbid CVD and body composition [77]. Discrepancies in the literature could be explained by differences in participant characteristics (age, presence/absence of comorbidities), length of androgen deficiency, and/or in the methodological assessment of FMD, including occlusion placement (upper arm vs lower arm occlusion), and in the analysis of the peak FMD response post cuff deflation (i.e., pre-determined time point vs. continuous).…”

Current and future strategies for the nutritional management of cardiometabolic complications of androgen deprivation therapy for prostate cancer

“…However, the high incidence of premature cardiac events on ADT suggests that any cardioprotective effects of HDL may be offset by the adverse effects of ADT on other CVD risk factors. Evidence for the effects of ADT on vascular function in humans has been mixed, with reports of increased arterial stiffness and loss of endothelial cell function in some studies (13)(14)(15) , but not in others (35,41) . There is evidence, exclusively from animal models, (96) Messing et al (2006) (ECOG/EST 3886) (97) Bolla et al (2010) (EORTC 22863) (98) Schröder et al (2009) (EORTC 30846) (99) Studer et al (2006) (EORTC 30891) (100) Efstathiou et al (2009) (RTOG 85-31) (39) Roach et al (2008) (RTOG 86-10) (17) Denham et al (2011) (TROG 96.01) (101) Overall Test for heterogeneity: Q = 5 .…”

“…These findings were soon corroborated by further primary studies, and a highly publicised metaanalysis of observational prospective cohort studies that showed GnRH agonists to be associated, unequivocally, with an increased risk of fatal and non-fatal CVD (12) . These associations have been linked to the adverse effects of ADT on body composition, insulin sensitivity and other cardiometabolic risk factors described below (6) , and also to the specific effects of GnRH agonists in precipitating cardiac events by promoting vascular dysfunction (13)(14)(15) and destabilising atherosclerotic plaque (16) . Nevertheless, RCT have generally failed to substantiate a direct, and thus causal, link between ADT/GnRH agonists and cardiac mortality (17)(18)(19)(20)(21) (Fig.…”