Review about “Androgen-Induced Vasorelaxation: A Potential Vascular Protective Effect” by M. Perusquía

The author reviews the case of androgen effects on vascular functions and points out correctly that arterial tone is determined by smooth muscle cells and vascular endothelium and comes to the conclusion that testosterone (T) has a vasodilating and potentially vascular protective effect. In fact, the conclusion is already reached in the third paragraph of the article and sustained further on by a significant and obviously deliberate omission of relevant literature concerning studies in humans. The discussion of studies with findings contradicting the author's opinion is restricted to mentioning experimental flaws in ex-vivo animal studies.

There is a significant amount of information on vascular function and T contradicting the author's opinion which is not discussed, starting with cross-sectional observations: vascular reactivity was found to be increased in androgen-deprived men vs. controls ([Herman et al., 1997]) and deleterious effects on vascular reactivity were seen in female-to-male transsexuals ([McCredie et al., 1998]) as well as in male bodybuilders using anabolic steroids ([Ebenbichler et al., 2001]). Likewise, as androgen effects are negatively associated with the length of CAG repeats within the androgen receptor gene, vascular reactivity was found to be increased in healthy men with longer triplet residues, hence mitigated T effects ([Zitzmann et al., 2001]).

The author mentions two interventional studies in humans demonstrating a vasodilating effect of T ([Webb et al., 1999]; [Ong et al., 2000]). When discussing the effect, it should be mentioned that T was given intravascularly, reaching concentrations of about the 20 fold of the upper normal limit. When Ong et al. used a dose to increase T levels within the normal range, no effect was observed. The results involving high-dosed intravascular T are not consistent, as a similar approach could not demonstrate any effect on myocardial perfusion ([Thompson et al., 2002]). Conflicting results are reported on the use of androgens in women, showing either a deleterious ([Penotti et al., 2001]) or beneficial effect ([Worboys et al., 2001]). The administration of dihydro-T or the elevation of endogenous T by human chorion gonadotropin in men with androgen levels within the low normal range had no effect on vascular functions ([Ly et al., 2001]; [Liu et al., 2002]). Another group using a transdermal T preparation in men with androgen levels at the lower limit of normal found corresponding results ([Kenny et al., 2002]). The only study in clearly hypogonadal men receiving treatment regimens of either external or endogenous T elevation and comparing them to a control group could demonstrate that vascular reactivity was reduced into the normal range of healthy men upon elevation of androgen levels. Within the normal range of T, no association to vessel relaxation was observed ([Zitzmann et al., 2002]).

Finally, the author should refer to a major review on vascular reactivity and gender differences ([Sader and Celermajer, 2001]). Interestingly, as erly as 1992 the latter investigator had shown that vascular reactivity is lower in men compared to women ([Celermajer et al., 1992]).

Regarding these findings and those discussed by M. Perusquía, we come to a different conclusion: the effects of T on vascular function are depend strongly on T concentrations.

Within the hypogonadal range, a decrement of endothelium-mediated vasodilatation occurs with increasing T levels. The effect plateaus within the normal range. Within the normal range, androgen receptors are more or less saturated and androgen effects are modulated by the CAG repeat polymorphism of the AR in the sense of the first statement: androgens reduce vascular reactivity. Within the high supraphysiological range, non-genomic action of T on the endothelium as well as directly on smooth muscle cells takes place, possibly leading to vasodilatation. Androgens and vessel functions should not be regarded as isolated from other (protective and adverse) effects of androgens on cardiovascular risk, such as lipid metabolism, platelet aggregation, fibrinolysis, macrophage function, insulin resistance and inflammatory cytokines (a review: Wu and von Eckardstein, 2003).

We recognize that Perusquía's review was written before some of the articles that we cite were published, but the observed bias can, unfortunately, not be fully explained by this.

References

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