Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells

Fujimoto, Ryoji; Morimoto, Isao; Morita, Emiko; Sugimoto, Hidekatsu; Ito, Yukio; Eto, Sumiya

doi:10.1016/0960-0760(94)90025-6

Cited by 126 publications

(73 citation statements)

References 18 publications

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“…Endothelial dysfunction in PCOS patients was found to be associated among other factors also to androgens (10,11,13,24). Androgen receptors are present on the vessel wall (25), and testosterone was shown to worsen endothelial function in experimental atherosclerosis (26), suggesting that androgens might operate as proatherogenic factors in PCOS. As expected, there was no significant change in serum androgen levels during spironolactone treatment in our study as spironolactone exerts its antiandrogenic effects primarily through competitive binding to androgen receptor, although it is also a weak inhibitor of testosterone biosynthesis (27).…”

Section: Discussionmentioning

confidence: 99%

Influence of spironolactone treatment on endothelial function in non-obese women with polycystic ovary syndrome

Studen¹,

Šebeštjen²,

Pfeifer³

et al. 2011

European Journal of Endocrinology

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Objective: Accumulating evidence connects polycystic ovary syndrome (PCOS) with increased risk of cardiovascular disease. Endothelial dysfunction is present in PCOS and represents an early, reversible marker of cardiovascular damage. As androgens and renin-angiotensin-aldosterone system are implicated in the atherogenesis process of PCOS, we tested the hypothesis that treatment with spironolactone, an androgen and mineralocorticoid receptor blocking drug, might reverse endothelial dysfunction in PCOS. Patients: A total of 30 non-obese PCOS patients, compared with 20 body mass index matched control subjects, were evaluated. PCOS patients were given spironolactone 100 mg daily in 21-day long intervals followed by a 7-day pause, for 6 months. Measurements: Flow-mediated dilatation (FMD), glyceryl trinitrate-induced dilatation, free testosterone, androstenedione, DHEA-sulfate, total, low-density lipoprotein (LDL)-, high-density lipoproteincholesterol, and triglycerides were determined at baseline and after 6 months. Results: Results are expressed as median (25-75th percentile). At baseline, FMD was significantly lower in PCOS patients than in controls: 6.0 (0.0-11.7) vs 10.2 (6.8-15.9) %, PZ0.018. This difference disappeared after 6 months of spironolactone treatment, as FMD in PCOS patients significantly increased to 8.3 (5.7-10.3) %, PZ0.034, and was no longer different from controls. In PCOS patients, serum androgen levels did not change during treatment, while total and LDL-cholesterol decreased significantly from 4.8 (4.1-5.1) mmol/l to 4.4 (3.9-4.8) mmol/l and from 2.5 (2.1-3.1) to 2.2. (2.1-2.5) mmol/l, P!0.05 and P!0.05 respectively. Conclusion: Treatment with spironolactone normalized endothelial function and improved cholesterol levels in non-obese PCOS patients.

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Section: Discussionmentioning

confidence: 99%

Influence of spironolactone treatment on endothelial function in non-obese women with polycystic ovary syndrome

Studen¹,

Šebeštjen²,

Pfeifer³

et al. 2011

European Journal of Endocrinology

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“…Testosterone is metabolized to estrogen by aromatase (Bulun et al, 2003) or to DHT through 5α-reductase (Fujimoto et al, 1994), and we have recently shown that both of these metabolic enzymes are present in the male cerebral vasculature (Gonzales et al, 2007). Estrogen clearly impacts male reproductive physiology (Hess et al, 1997;Jones and Simpson, 2000), and there is also strong evidence for non-reproductive effects of estrogen in males.…”

Section: Discussionmentioning

confidence: 99%

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

et al. 2007

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Mitochondria are a major source of reactive oxygen species (ROS) and oxidative stress, key contributors to aging and neurodegenerative disorders. We report that gonadal hormones influence brain mitochondrial ROS production in both females and males. Initial experiments showed that estrogen decreases mitochondrial superoxide production in a receptor-mediated manner, as measured by MitoSOX fluorescence in differentiated PC-12 cells. We then assessed in vivo effects of gonadal hormones on brain mitochondrial oxidative stress in female and male rats. Brain mitochondria were isolated to measure a functional indicator of ROS, i.e., activity of the ROS-sensitive mitochondrial enzyme, aconitase. Gonadectomy of both males and females caused a decrease in aconitase activity, suggesting endogenous gonadal hormones influence mitochondrial ROS production in the brain. In vivo treatment of gonadectomized animals with testosterone or dihydrotestosterone (DHT) had no effect, but estrogen replacement significantly increased aconitase activity in brain mitochondria from both female and male rats. This indicates estrogen decreases brain mitochondrial ROS production in vivo. Sex hormone treatments did not affect protein levels of brain mitochondrial uncoupling proteins (UCP-2, 4, and 5). However, estrogen did increase the activity, but not the levels, of manganese superoxide dismutase (MnSOD), the mitochondrial enzyme that catalyzes superoxide radical breakdown, in brain mitochondria from both female and male rats. Thus, in contrast to the lack of effect of androgens on mitochondrial ROS, estrogen suppression of mitochondrial oxidative stress may influence neurological disease incidence and progression in both females and males.

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“…2 These findings indirectly provide support for the hypothesis that arterial sex hormone receptors are probably involved as one part of the genomic actions of sex steroids on the level of the arterial vessel wall. 11 Androgen and estrogen receptors are present in vascular smooth muscle cells, 11,12 human macrophages, human megakaryocytes, and platelets. 13,14 Interestingly, McCrohon et al 15 found sex-specific differences in androgen receptor expression in human macrophages.…”

Section: Discussionmentioning

confidence: 99%

Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

et al. 2001

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Background-Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor. Methods and Results-Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non-hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (Pϭ0.037) and 100 ng/mL (Pϭ0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone. Conclusion-The beneficial effects of testosterone on postinjury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor-dependent pathways in the vascular system. Key Words: testosterone Ⅲ receptors, androgen Ⅲ atherosclerosis T he role of androgens in atherogenesis is controversial 1 ; however, in recent years, several authors have found a number of beneficial effects of testosterone, at least in men. Animal studies have documented an inhibitory effect on plaque development in the cholesterol-fed rabbit model, 2,3 whereas in recent clinical investigations, acute hemodynamic effects of testosterone on coronary vasomotion and stress-test induced ischemia were observed. 4,5 Thus far, only limited information is available regarding the possible involvement of arterial androgen receptors in these processes. Thus, the aim of the present study was to investigate, in an experimental model, (1) the dose-dependent effects of testosterone on plaque development, (2) the expression of the androgen receptor in arteries, and (3) possible dose-dependent changes of androgen receptor expression induced by testosterone. Methods Organ Culture SystemTwelve-week-old male New Zealand White rabbits were used for the present study. The rabbits received standard chow without cholesterol (Altromin Inc) and were housed individually (no female rabbits were present). After sacrifice, the abdomen was opened under sterile conditions, and the connective tissue was removed from the aorta. A 3F-Fogarty catheter (Baxter Inc) was inserted below the iliac bifurcation, and endothelial denudation was performed once with the inflated catheter. The aorta was then comp...

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Androgen receptors, 5 alpha-reductase activity and androgen-dependent proliferation of vascular smooth muscle cells

Cited by 126 publications

References 18 publications

Influence of spironolactone treatment on endothelial function in non-obese women with polycystic ovary syndrome

Influence of spironolactone treatment on endothelial function in non-obese women with polycystic ovary syndrome

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

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