Androgens and the cerebrovasculature: modulation of vascular function during normal and pathophysiological conditions

Abstract

Sex steroids are commonly known for their contribution to phenotypic as well as biological reproductive sex differences mediated through classical regulation of neuroendocrine loops. However, sex steroids also have considerable impact on physiological function of non-reproductive tissues including the cerebrovasculature. Preclinical studies have shown that endogenous and exogenous administration of sex steroids significantly influences both cerebrovascular tone and brain function under normal conditions and following a pathological insult (e.g., middle cerebral artery occlusion). However, the precise mechanism(s) of how sex steroids modulate vasomotor responses and/or neurological outcomes in vivo is difficult to define since evidence based on both clinical and experimental studies has been shown to be dependent upon several variables including dose, duration of administration, presence of underlying pathologies, species, and sex. While progesterone, testosterone (TEST), and dihydrotestosterone (DHT) have all been investigated for their impact on the cerebral circulation, the effects of 17β-estradiol (E2) have been best characterized. Since recent reviews have highlighted studies reporting the actions of E2 on cerebral vascular function and health, only key points are included in this review. Conversely, less is known about the effect of androgens on the blood vessel wall, particularly in the cerebral circulation. The few studies that do address a role for androgen's modulation of cerebrovascular function under normal and pathophysiological conditions provide confounding evidence for either beneficial or detrimental effects. Therefore, the focus of this review is to highlight mechanisms associated with TEST, DHT, and its recently recognized androgen metabolite (3β-diol) on cerebrovascular function during healthy and diseased states.

New steps forward in the neuroactive steroid field

“…In agreement, the metabolite of T, DHT, exacerbates ischemic damage [122]. As recently reviewed by Gonzales, few studies have been so far devoted to evaluate androgen effects in the cerebrovascular function, and the results of these studies are controversial (i.e., both beneficial and detrimental effects have been reported) [123]. In transgenic mice expressing mutant AR, an experimental model for spinal and bulbar muscular atrophy, only males are fully affected by the disease and T treatment in females induces clinical manifestation [124].…”

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

“…Generally, animal and in-vitro studies suggest that androgens might be pro-inflammatory, thrombotic, and atherogenic while estrogens attenuate inflammation [46]. Potential mechanisms have been summarized in several recent reviews [42][43][44][45]. Briefly, in vascular endothelial cells, estrogens increase synthesis of nitric oxide synthase (NOS) and also increase NOS activity through phosphorylation, thus enabling NO-induced vasodilation.…”

“…Sex steroids have genomic and non-genomic effects, [42][43][44] i.e. sex steroids affect gene transcription but also can have effects that are mediated through pathways other than protein or RNA synthesis (Fig.…”

The Impact of Gonadal Hormones on the Expression of Human Neurological Disorders

“…Estrogens also increase dendritic cell differentiation and production of the anti-inflammatory molecules, Treg, IL-4, IL-10 and TGFβ by M2 macrophages, and decrease deposition of atherogenic oxidized low-density lipoprotein within the vascular wall. Androgens, on the other hand, may accelerate atherosclerosis by facilitating innate immune cell activation and the elaboration of proinflammatory cytokines [31,33]. Progestins may contribute to the danger of cerebral infarction by promoting dyslipidemia, hypercoagulability and hypertension [34,35].…”