Globally, cardiovascular disease will continue causing most human deaths for the foreseeable future The consistent gender gap in life span of approximately 56 yr in all advanced economies must derive from gender differences in age-specific cardiovascular death rates, which rise steeply in parallel for both genders but 5-10 yr earlier in men The lack of inflection point at modal age of menopause, contrasting with unequivocally estrogen-dependent biological markers like breast cancer or bone density, makes estrogen protection of premenopausal women an unlikely explanation Limited human data suggest that testosterone exposure does not shorten life span in either gender, and oral estrogen treatment increases risk of cardiovascular death in men as it does in women Alternatively, androgen exposure in early life (perinatal androgen imprinting) may predispose males to earlier onset of atherosclerosis Following the recent reevaluation of the estrogen-protection orthodoxy, empirical research has flourished into the role of androgens in the progression of cardiovascular disease, highlighting the need to better understand androgen receptor (AR) coregulators, nongenomic androgen effects, tissue-specific metabolic activation of androgens, and androgen sensitivity Novel therapeutic targets may arise from understanding how androgens enhance early plaque formation and cause vasodilatation via nongenomic androgen effects on vascular smooth muscle, and how tissue-specific variations in androgen effects are modulated by AR coregulators as well as metabolic activation of testosterone to amplify (via 5alpha-reductase to form dihydrotestosterone acting on AR) or diversify (via aromatization to estradiol acting upon estrogen receptor alpha/beta) the biological effects of testosterone on the vasculature Observational studies show that blood testosterone concentrations are consistently lower among men with cardiovascular disease, suggesting a possible preventive role for testosterone therapy, which requires critical evaluation by further prospective studies Short-term interventional studies show that testosterone produces a modest but consistent improvement in cardiac ischemia over placebo, comparable to the effects of existing antianginal drugs By contrast, testosterone therapy has no beneficial effects in peripheral arterial disease but has not been evaluated in cerebrovascular disease Erectile dysfunction is most frequently caused by pelvic arterial insufficiency due to atherosclerosis, and its sentinel relationship to generalized atherosclerosis is insufficiently appreciated The commonality of risk factor patterns and mechanisms (including endothelial dysfunction) suggests that the efficacy of antiatherogenic therapy is an important challenge with the potential to enhance men's motivation for prevention and treatment of cardiovascular diseases

Androgens and cardiovascular disease.

Introduction to the practice of statistics, (3rd edition), by David S. Moore and George P. McCabe. Pp. 825 (with appendices and CD-ROM). £27.95. 1999. ISBN 0 7167 3502 4 (W. H. Freeman).

Non-genomic Actions of Androgens

Steroid hormone receptors have been traditionally considered to act via the regulation of transcriptional processes, involving nuclear translocation and binding to specific response elements, and ultimately leading to regulation of gene expression. However, novel non-transcriptional mechanisms of signal transduction through steroid hormone receptors have been identified. These so-called ‘nongenomic’ effects do not depend on gene transcription or protein synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane-bound regulatory proteins. Several relevant biological actions of steroids have been associated with this kind of signaling. Ubiquitous regulatory cascades such as mitogen-activated protein kinases, the phosphatidylinositol 3-OH kinase and tyrosine kinases are modulated through non-transcriptional mechanisms by steroid hormones. Furthermore, steroid hormone receptor modulation of cell membrane-associated molecules such as ion channels and Gprotein-coupled receptors has been shown. Tissues traditionally considered as ‘non-targets’ for classical steroid actions are instead found to be vividly regulated by non-genomic mechanisms. To this aim, the cardiovascular and the central nervous system provide excellent examples, where steroid hormones induce rapid vasodilatation and neuronal survival via non-genomic mechanisms, leading to relevant pathophysiological consequences. The evidence collected in the past years indicates that target cells and organs are regulated by a complex interplay of genomic and non-genomic signaling mechanisms of steroid hormones, and the integrated action of these machineries has important functional roles in a variety of pathophysiological processes. The understanding of the molecular basis of the rapid effects of steroids is therefore important, and may in the future turn out to be of relevance for clinical purposes.

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Non-genomic actions of sex steroid hormones

Sex steroid hormones, including estrogen, progesterone, and androgen, mediate their biological effects on cell proliferation, differentiation, and homeostasis through their respective nuclear receptors. In addition to functioning as ligand-activated nuclear transcription factors to regulate gene transcription, these receptors also have been shown to mediate rapid activation of non-genomic signaling pathways independent of their transcriptional activity. Despite the fact that non-genomic effects of sex steroids have been observed since more than three decades ago, the receptor mechanisms mediating these rapid effects still are not well understood. A subpopulation of nuclear steroid receptors localized to the cell membrane or cytoplasm has been proposed to mediate steroid hormone activation of signaling pathways; however, novel membrane receptors unrelated to nuclear receptors have also been implicated. This review focuses on recent advances in our understanding of the nature of the receptors and mechanisms responsible for rapid non-genomic signaling actions of sex steroids, including novel membrane receptors and interactions of nuclear steroid receptors with membrane and cytoplasmic signaling molecules such as adapter proteins, G proteins, ion channels, and protein kinases. A better definition of receptor mechanisms involved in mediating activation of non-genomic signaling pathways is important to our overall understanding of the biology of steroid hormones.

Tomas Morato-Cartagena

Papers

Synthesis and evaluation of the cardiovascular effects of two, membrane impermeant, macromolecular complexes of dextran-testosterone.