The Effects of Induced Hypogonadism on Arterial Stiffness, Body Composition, and Metabolic Parameters in Males with Prostate Cancer

Abstract

Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.

Glucose intolerance during hormonal therapy for prostate cancer

“…HT (ADT) for PCa causes various metabolic abnormalities. Smith et al 4 described that after 3 months of ADT, the fat mass increased and the lean body mass decreased significantly as compared with baseline measurements, but there were no changes in the blood lipids or glucose during treatment. Alternatively, after 12 months of ADT, the bone mineral density, sexual function and QOL score decreased, 5 whereas the upper body strength, 5 body weight, 6 BMI, 7,9 total cholesterol 7 and triglyceride 7 increased significantly in addition to the changes in the fatty body mass and lean body mass.…”

“…6 With regards to glucose intolerance, after 12-month ADT, the fasting blood glucose and fasting serum insulin levels, in the homeostatic model assessment for insulin resistance (HOMA IR ) were significantly higher than those in the non-ADT or control groups. 4,9 Mechanisms of glucose intolerance after HT for PCa have been suggested based on the previous reports as follows: (1) the increased fat mass after HT influences the insulin concentration and insulin sensitivity, 4,8,9 (2) testosterone has a direct effect on pancreatic islet function by favoring insulin gene expression and release, and the decrease in the testosterone level after HT reduces the pancreatic functions. 8,12 The results of this study were supported by the hypothetical mechanism of glucose intolerance in the previous reports.…”

“…1 Hypogonadism due to HT is manifested by various adverse effects including hot flushes, 3 gynecomastia, metabolic abnormalities and changes of body composition. [4][5][6][7] Although the changes in blood glucose levels in PCa patients receiving androgen deprivation therapy (ADT) has been reportedly associated with insulin resistance, 8,9 to our knowledge, the frequency and background of patients complicated with glucose intolerance has never been reported. In this study, we evaluated the elevation of blood glucose levels and the deterioration of glucosuria in Japanese PCa patients receiving HT.…”

Androgen deprivation therapy for prostate cancer: new concepts and concerns

“…GnRH agonist significantly decrease lean body mass and increase fat mass in men with prostate cancer [27,[63][64][65][66]. In two prospective studies of men with nonmetastatic prostate cancer, for example, we demonstrated that GnRH agonists decreased lean body mass by 2.7 to 3.8% and increase fat mass by 9.4 to 11.0% from baseline to 1 year [65,66].…”

“…In a 3-month study of 22 men with nonmetastatic prostate cancer, GnRH agonist treatment increased mean fat mass by 8.5% (P = 0.008) and decreased lean body mass by 2.6% (P = 0.003) [64]. In another 3-month prospective study of men with nonmetastatic prostate cancer, mean fat mass increased by 4.3% (P = 0.002) and lean body mass decreased by 1.4% (P = 0.006) [67].…”