Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study

Abstract

Summary Objective Ischemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine if testosterone (T) or dihydrotestosterone (DHT) were associated with incident ischemic stroke in elderly men. Design Cohort study Participants Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease, or prostate cancer as of 1994 and were followed until December 2010. Measurements Adjudicated ischemic stroke Results Among 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischemic stroke. Total T and free T were not significantly associated with stroke risk while DHT had a nonlinear association with incident stroke (p=.006) in analyses adjusted for stroke risk factors. The lowest risk for stroke was at DHT levels of 50-75 ng/dL, with greater risk for stroke at DHT levels above 75 ng/dl or below 50ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischemic stroke with HR 0.77 (95% CI, 0.61, 0.98) per standard deviation in analyses adjusted for stroke risk factors. Conclusions DHT had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify if there is an optimal androgen range associated with the least risk for adverse outcomes in elderly men.

Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men

“…As discussed above, the higher circulating DHT levels, obtained with transdermal as opposed to injected T, may be responsible for the trend for increased CV risk with transdermal TRT. In observational studies, Shores et al have shown that shown that high DHT is associated with increased cardiovascular events (66) and increased incident ischemic stroke (65). Interestingly, Zwadlo et al (96) have shown that cardiac expression of 5␣-reductase is markedly increased in humans with heart failure and in a mouse aortic constriction model of heart failure.…”

A Review of the Relationships between Endogenous Sex Steroids and Incident Ischemic Stroke and Coronary Heart Disease Events

“…Five studies reported upon the relationship between T or DHT and incident ischemic stroke, with one report noting a linear relationship [29] and another report noting a Ushaped relationship with DHT but not with T [5]. Three studies reported no significant relationship between total T level and incident stroke events [16,21,30], although the bioavailable fraction of T (the "active" portion not bound to sex hormone binding globulin or SHBG) was associated after but not before adjustment for CVD risk factors in one of these reports [21], and the association between T and incident stroke was of borderline significance in the other two reports [16,30].…”

“…It is therefore possible that more recent studies may have greater power to detect an association between sex steroid levels and ischemic CVD risk. In support of this possibility, more recent prospective cohort studies [5,6,17,19,21,24,28] have tended to report the presence of significant relationships between endogenous sex steroids and ischemic CVD risk.…”

“…These equations incorporate total T and E2 measurements using mass spectrometry or radioimmunoassay, SHBG measurements, and albumin measurements or estimations. In this review, the majority of the studies examining relationships between sex steroids and CVD used indirect radioimmunoassay with the exception of 2 cohorts of elderly men, [5,6,16] and it remains to be seen whether the use of mass spectrometric techniques currently endorsed by medical societies leads to a different pattern of results [78,79].…”

“…where participants are not using exogenous sex steroids, have conflicted with results from randomized trials of sex steroid therapy. Recent reports of endogenous sex steroids suggest that low endogenous testosterone (T) is associated with increased risk of CVD events in men [5][6][7], while randomized trials of T therapy suggest that higher T levels may increase CVD risk [8,9]. Similarly, among women, low endogenous estradiol (E2) associated with the postmenopause has been thought to contribute to increased CVD risk in women [10], but estrogen supplementation trials suggest that higher E2 may be harmful [11].…”