ArticleLiterature Review

Testosterone and Coronary Artery Disease

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Abstract

The strongest independent risk factors for coronary artery disease (CAD) are increasing age and male gender. Whilst a wide variation in CAD mortality exists between countries, a male to female ratio of approximately 2:1 is consistently observed. These observations have led to the assumption that testosterone may exert a detrimental influence on the cardiovascular system. Despite this, coronary atherosclerosis increases with age, whilst a marked fall in serum bioavailable testosterone levels is observed. Similarly, low testosterone levels are also associated with other cardiovascular risk factors and increased expression of mediators of the atherosclerotic process. This in itself suggests that testosterone does not promote atheroma formation. Moreover, epidemiological studies show an inverse relationship between testosterone levels and surrogate markers of atherosclerosis, which suggests that it may be a testosterone deficient state, rather than male sex which is associated with CAD. In cholesterol-fed animal models, atherosclerosis is accelerated by castration and reduced after testosterone replacement therapy. Testosterone has also been shown to improve myocardial ischemia in men with angina pectoris. Consequently, increasing evidence suggests that the process of atherosclerosis is beneficially modulated by testosterone. These studies are the focus of this chapter.

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... In cardiovascular pathology, males have a higher risk of developing the disease during the reproductive period in comparison with females of the same age. 1 The sexrelated difference in resistance to cardiovascular disease was hypothesized to be related to the cardioprotective role of estrogen hormones in females and harmful effects of androgen steroids in males. 2 This hypothesis was not initially supported by large-scale follow-up studies. 3 In contrast, many studies indicated the positive role of androgens in cardiovascular protection. 1 Furthermore, follow-up clinical studies showed that plasma concentrations of androgens were associated with various independent cardiovascular risk factors and mortality from cardiovascular pathology. ...
... 3 In contrast, many studies indicated the positive role of androgens in cardiovascular protection. 1 Furthermore, follow-up clinical studies showed that plasma concentrations of androgens were associated with various independent cardiovascular risk factors and mortality from cardiovascular pathology. 1,[4][5][6] For example, decrease in blood testosterone was found to show a positive correlation with the elevation of arterial stiffness (an independent marker of cardiovascular pathology). ...
... 3 In contrast, many studies indicated the positive role of androgens in cardiovascular protection. 1 Furthermore, follow-up clinical studies showed that plasma concentrations of androgens were associated with various independent cardiovascular risk factors and mortality from cardiovascular pathology. 1,[4][5][6] For example, decrease in blood testosterone was found to show a positive correlation with the elevation of arterial stiffness (an independent marker of cardiovascular pathology). 7 In a recent submit your manuscript | www.dovepress.com ...
Article
Full-text available
Cardiovascular effects of android hormones in normal and pathological conditions can lead to either positive or negative effects. The reason for this variation is unknown, but may be influenced by gender-specific effects of androids, heterogeneity of the vascular endothelium, differential expression of the androgen receptor in endothelial cells (ECs) and route of androgen administration. Generally, androgenic hormones are beneficial for ECs because these hormones induce nitric oxide production, proliferation, motility, and growth of ECs and inhibit inflammatory activation and induction of procoagulant, and adhesive properties in ECs. This indeed prevents endothelial dysfunction, an essential initial step in the development of vascular pathologies, including atherosclerosis. However, androgens can also activate endothelial production of some vasoconstrictors, which can have detrimental effects on the vascular endothelium. Androgens also activate proliferation, migration, and recruitment of endothelial progenitor cells (EPCs), thereby contributing to vascular repair and restoration of the endothelial layer. In this paper, we consider effects of androgen hormones on EC and EPC function in physiological and pathological conditions.
... This shows that testosterone is multifunctional hormone. In low (LDL) cholesterol receptor de cient mice, orchiectomy is associated with accelerated formation of atherosclerotic lesions in the aorta, and testosterone supplementation was shown to retard the progression of these lesions(Nettleship et al., 2009). Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). ...
... Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). The LDL cholesterol levels decreases after exogenous testosterone replacement therapy(Nettleship et al., 2009). The significant reduction in LDL levels in Chinese men were seen when testosterone was administered via IM route after four weeks for 3 months. ...
Article
The objective of this study was to assess the testosterone role in modification of ischemic heart disease. All subjects were male aged between 30 to 80 years. At the start of study, blood pressure, serum testosterone, lipid profile and left ventricular function were recorded. Males who were at high risk of cardiovascular disease have low endogenous testosterone level. The testosterone therapy, 250mg/2mlweekly (Intramuscularly) for six months was sufficient to lower the risk of further cardiac complications by decreasing serum total cholesterol, low density lipoprotein and triglycerides levels (p<0.0001) and showed improvement in high density lipoprotein and serum testosterone levels (p<0.02). Moreover it has also ameliorated the Left Ventricular Function. The study concluded that exogenous testosterone may be considered a valuable addition as a regular therapy in Ischemic Heart Disease patients in order to codify their cardiac functions.
... In low (LDL) cholesterol receptor de cient mice, orchiectomy is associated with accelerated formation of atherosclerotic lesions in the aorta, and testosterone supplementation was shown to retard the progression of these lesions (Nettleship et al., 2009). Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). ...
... Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). The LDL cholesterol levels decreases after exogenous testosterone replacement therapy (Nettleship et al., 2009). ...
Article
Full-text available
The objective of this study was to assess the testosterone role in modification of ischemic heart disease. All subjects were male aged between 30 to 80 years. At the start of study, blood pressure, serum testosterone, lipid profile and left ventricular function were recorded. Males who were at high risk of cardiovascular disease have low endogenous testosterone level. The testosterone therapy, 250mg/2mlweekly (Intramuscularly) for six months was sufficient to lower the risk of further cardiac complications by decreasing serum total cholesterol, low density lipoprotein and triglycerides levels (p<0.0001) and showed improvement in high density lipoprotein and serum testosterone levels (p<0.02). Moreover it has also ameliorated the Left Ventricular Function. The study concluded that exogenous testosterone may be considered a valuable addition as a regular therapy in Ischemic Heart Disease patients in order to codify their cardiac functions.
... This shows that testosterone is multifunctional hormone. In low (LDL) cholesterol receptor de cient mice, orchiectomy is associated with accelerated formation of atherosclerotic lesions in the aorta, and testosterone supplementation was shown to retard the progression of these lesions(Nettleship et al., 2009). Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). ...
... Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). The LDL cholesterol levels decreases after exogenous testosterone replacement therapy(Nettleship et al., 2009). The significant reduction in LDL levels in Chinese men were seen when testosterone was administered via IM route after four weeks for 3 months. ...
Article
The objective of this study was to assess the testosterone role in modification of ischemic heart disease. All subjects were male aged between 30 to 80 years. At the start of study, blood pressure, serum testosterone, lipid profile and left ventricular function were recorded. Males who were at high risk of cardiovascular disease have low endogenous testosterone level. The testosterone therapy, 250mg/2mlweekly (Intramuscularly) for six months was sufficient to lower the risk of further cardiac complications by decreasing serum total cholesterol, low density lipoprotein and triglycerides levels (p<0.0001) and showed improvement in high density lipoprotein and serum testosterone levels (p<0.02). Moreover it has also ameliorated the Left Ventricular Function. The study concluded that exogenous testosterone may be considered a valuable addition as a regular therapy in Ischemic Heart Disease patients in order to codify their cardiac functions.
... Epidemiological studies suggest that males are at greater risk for cardiovascular disease when compared to age-matched females during their reproductive years. [1][2][3] In the Framingham cohort, men developed cardiovascular diseases (CVD) at more than twice the rate of women in ages younger than 60-years old. [4] This gender difference has been attributed to an estrogen protective effect in women, and/or an androgen detrimental effect in men. ...
... [5][6][7] More significantly, a growing body of evidence is suggesting the opposite, that androgens exhibit a protective action on the cardiovascular system. [3] Multiple prospective clinical trials and a recent meta-analysis have shown that endogenous ...
Article
Full-text available
The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells (ECs) which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells (EPCs) are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genomic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system.
... Whilst cardiovascular disease mortality rates vary significantly between countries, most evidence has consistently demonstrated that post-myocardial infarction mortality rates are twice as high in males when compared to females [402]. Although TEST has traditionally been implicated in atherosclerosis development [403,404], it is now proposed that the TESTdeficient state in older males may be responsible for worsened outcomes following myocardial ischaemia [405]. This is likely mediated, at least in part, by TD's association with the MetS and its cardiovascular risk factors [406]. ...
... Whilst cardiovascular disease mortality rates vary significantly worldwide, evidence over previous decades has consistently demonstrated that post-myocardial infarction mortality rates are twice as high in males when compared to females [402]. Although TEST was traditionally implicated in the aetiology of atherosclerosis development, it is now proposed that the TEST-deficient state in older males may be responsible for worsened outcomes following myocardial ischaemia [405]. In fact, recent evidence suggests that after adjusting for age and comorbidities, women are more likely than men to experience myocardial infarction, heart failure, stroke and cardiovascular death [407]. ...
Thesis
Full-text available
In males, the widespread prevalence of both obesity-related metabolic syndrome (MetS) and testosterone deficiency (TD) is further exacerbating the socio-economic and health burdens already elicited by the rapidly ageing global population. The strong reciprocal relationship between the MetS and TD in males often results in their shared pathologies presenting together in the clinical setting. Clinical and epidemiological studies have provided convincing evidence that the MetS and TD are highly comorbid [1, 2] and share mutual abnormalities, including visceral obesity, dyslipidaemia and insulin resistance. One or more of these changes associated with the MetS and TD contribute to life-threatening conditions such as cardiovascular disease and increased osteoporotic bone fragility, particularly in the ageing male. Due to limitations of traditional androgen replacement therapy with testosterone (TEST), which is readily converted to active metabolites by enzymes, the therapeutic potential of trenbolone (TREN), a selective androgen receptor modulator (SARM), remains an attractive alternative to TEST. However, TREN’s efficacy has not been investigated in appropriate models representative of obese and TEST-deficient males, especially within the context of cardiometabolic disease and obesity-related osteoporosis/bone strength. In Chapter 3 of this thesis, we investigated the effects of selective androgen receptor (AR) modulation with TREN on: a) cardiometabolic risk factors; b) cardiac remodelling; c) a post-ischaemic myocardial damage marker; and d) prostate and liver morphology, in lean normogonadic male rats. Findings demonstrated that TREN improved body composition, reduced visceral adiposity, increased insulin sensitivity and improved myocardial tolerance to ischaemia/reperfusion (I/R) despite the absence of any underlying pathology. In Chapter 4, we developed and characterised animal models of pathology representative of males with: a) the MetS; b) TD; and c) testosterone-deficient metabolic syndrome (TDMetS). Our novel model of TDMetS demonstrated unique characteristics including: increased total, subcutaneous and visceral fat mass; serum cholesterol, triglycerides and fasting glucose (indicative of diabetes mellitus); reduced serum TEST and left ventricular mass; and impaired myocardial tolerance of I/R. We have confirmed that this novel model is more representative of male patients with TD and the MetS. In Chapter 5, we investigated the effects of selective AR modulation with TREN on: a) cardiometabolic risk factors; b) left ventricular mass and morphology; c) myocardial tolerance to I/R; and d) prostate mass and morphology, and contrasted these effects with those of TEST in our newly characterised male rat model of TDMetS. In this chapter, we demonstrated that both TEST and TREN protected rats against visceral fat accumulation, hypercholesterolaemia and myocardial damage. However, only TREN protected against subcutaneous fat accumulation, hypertriglyceridaemia and hyperinsulinaemia; and also reduced myocardial damage compared to lean, normogonadic untreated controls. We also demonstrated that TEST treatment caused widespread cardiac fibrosis and prostate hyperplasia. These adverse changes were less pronounced with TREN treatment. In light of recent conjecture regarding the implications of visceral obesity and TD on osteoporotic bone fracture risk, in Chapter 6 we investigated the roles of visceral adipose tissue mass and TD on femoral bone mineral composition, structure and strength in appropriate rat models of visceral obesity with and without TD. We demonstrated that visceral obesity decreases femoral bone mineral area (BMA) and content (BMC); and impaired femoral stiffness and strength. We also demonstrated that TD further impairs femoral BMA, BMC and bone mineral density (BMD); and reduced energy to failure in viscerally obese rats. In light of TREN treatment’s reductions in visceral adipose tissue mass (reported in Chapters 3 & 5), we investigated the osteoprotective efficacy of TREN treatment (again compared to that of TEST treatment) in these viscerally obese male rats with TD. Both TEST and TREN treatment restored BMA, BMC and BMD and energy to failure. However, only TREN also reduced visceral adiposity and improved femoral stiffness and strength. This chapter’s findings support a role for visceral adiposity and TD as independent osteoporotic bone fracture risk factors; and provide further evidence of TREN’s improved therapeutic efficacy as an androgen replacement therapy, relative to TEST. In conclusion, we propose that both TD and the MetS may play independently critical roles in the aetiology of both cardiovascular disease and impaired femoral bone structure and strength in males, mediated by one or more of their shared characteristics (i.e. visceral obesity, dyslipidaemia and insulin resistance). Based on our findings, we believe that aged males presenting with the MetS may benefit from evaluation for TD while aged males presenting with TD may benefit from evaluation for the components of the MetS. Our findings demonstrate that TREN treatment reduces visceral adiposity, dyslipidaemia and insulin resistance and is consistently more effective than TEST treatment. We therefore propose that, following pre-clinical and clinical trials, selective androgen receptor modulation with TREN may eventuate as the most appropriate form of androgen replacement therapy for use in these populations, particularly within the contexts of both cardiovascular and bone fracture risk.
... Furthermore, the incidence of CVD was reported to be 89.3% in males, and 91.8% in females, in adults above 80 years of age [6]. With respect to coronary artery disease (CAD), the strongest risk factors are male gender and age [7]. Overall, sex differences that lead to discrepancies in CVD risk factors and outcomes, between men and women, are largely attributed to sex hormones and ...
... Epidemiological studies report an increased risk for cardiovascular disease in aging adult men that is associated with hypogonadism, including reduced levels of testosterone [138,139]. Low testosterone was also shown to be independently associated with a high risk for acute MI in type 2 diabetic males [140], and a high incidence of coronary artery disease (CAD) in men [7]. In older men, low testosterone levels have been linked to a higher risk for stroke [141]. ...
Article
Full-text available
The aging and elderly population are particularly susceptible to cardiovascular disease. Age is an independent risk factor for cardiovascular disease (CVD) in adults, but these risks are compounded by additional factors, including frailty, obesity, and diabetes. These factors are known to complicate and enhance cardiac risk factors that are associated with the onset of advanced age. Sex is another potential risk factor in aging adults, given that older females are reported to be at a greater risk for CVD than age-matched men. However, in both men and women, the risks associated with CVD increase with age, and these correspond to an overall decline in sex hormones, primarily of estrogen and testosterone. Despite this, hormone replacement therapies are largely shown to not improve outcomes in older patients and may also increase the risks of cardiac events in older adults. This review discusses current findings regarding the impacts of age and gender on heart disease.
... In low (LDL) cholesterol receptor de cient mice, orchiectomy is associated with accelerated formation of atherosclerotic lesions in the aorta, and testosterone supplementation was shown to retard the progression of these lesions (Nettleship et al., 2009). Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). ...
... Administration of an aromatase inhibitor blocked the bene cial effects (Nathan et al., 2001). The LDL cholesterol levels decreases after exogenous testosterone replacement therapy (Nettleship et al., 2009). ...
Article
Full-text available
The objective of this study was to assess the testosterone role in modification of ischemic heart disease. All subjects were male aged between 30 to 80 years. At the start of study, blood pressure, serum testosterone, lipid profile and left ventricular function were recorded. Males who were at high risk of cardiovascular disease have low endogenous testosterone level. The testosterone therapy, 250mg/2mlweekly (Intramuscularly) for six months was sufficient to lower the risk of further cardiac complications by decreasing serum total cholesterol, low density lipoprotein and triglycerides levels (p<0.0001) and showed improvement in high density lipoprotein and serum testosterone levels (p<0.02). Moreover it has also ameliorated the Left Ventricular Function. The study concluded that exogenous testosterone may be considered a valuable addition as a regular therapy in Ischemic Heart Disease patients in order to codify their cardiac functions. Key words: Ischemic Heart Disease, Testosterone, HDL, LDL
... There are observations that suggest both estrogen deficiency in women and androgen deficiency in man might contribute to the development of cardiovascular disease and hypertension [9,10]. Most epidemiological studies have found that there is a high prevalence of low testosterone levels in men with coronary heart disease, and that this association exists regardless of the age of the patient [9]. ...
... Most epidemiological studies have found that there is a high prevalence of low testosterone levels in men with coronary heart disease, and that this association exists regardless of the age of the patient [9]. Additionally, considerable evidence now suggests that testosterone and other androgens have protective effects on cardiovascular and may play important roles in the acute regulation of vascular function [10]. Indeed, studies have demonstrated that testosterone exerts beneficial effects on cardiovascular function by inducing rapid vasorelaxation of vascular smooth muscle [11]. ...
Article
Full-text available
Abstract Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.
... In parallel, accumulating evidence from more recent animal studies employing isolated blood vessels in vitro, reveals that TES and other androgen metabolites exert beneficial effects by inducing acute vasorelaxation through rapid, nongenomic mechanisms in a variety of large arteries, as well as smaller resistance arteries, and at physiological as well as pharmacological concentrations (for reviews, see [31,32]). There is also more limited evidence that TES and other androgens produce coronary or systemic vasodilation in humans [30] and in canine [33], porcine [34,35], and rodent animal models [36]. ...
... In contrast, there is limited evidence that acute intra-arterial infusions of TES and other androgens produce coronary or systemic vasodilation in vivo in humans [30] and in canine [33], porcine [34,35], and rodent [36] animal models. In parallel, accumulating evidence from a number of recent animal studies employing isolated blood vessels in vitro, reveals that TES and other androgen metabolites exert beneficial effects by inducing acute vasorelaxation through rapid, nongenomic estrogen-independent mechanisms in a variety of large arteries as well as smaller resistance arteries and at physiological as well as pharmacological concentrations (for reviews, see [31,32]). Together, these in vitro and in vivo studies reveal that acute androgeninduced vasodilation is a structurally specific, nongenomic effect, with efficacies and potencies fundamentally different than those for the genomic effects of androgens on reproductive targets [31,[37][38][39][40]. An intriguing aspect of the structurally specific nongenomic effects of the androgens on vascular function is the effects of the endogenous TES metabolite, 5β-DHT, the stereoisomer of the highly potent androgenic tissue metabolite of TES, 5α-DHT, which is known to mediate the effects of TES in reproductive target tissues. ...
Article
Full-text available
Background: Acutely, testosterone (TES) and other androgens are efficacious vasodilators, both in vitro and in vivo; however, their long-term effects on arterial blood pressure (BP) remain unclear. It was hypothesized that endogenous androgens exert long-term anti-hypertensive effects on systemic BP through a combination of genomic and nongenomic effects to enhance vasodilation of the systemic vasculature. Methods: The long-term effects of endogenous TES and exogenous TES replacement therapy (TRT) on BP were studied in intact (InT) and castrated (CsX) male Sprague-Dawley (SD) and testicular-feminized male (Tfm, androgen receptor defective) rats (12 weeks old). Systolic BP (tail-cuff plethysmography) was determined weekly for 15 weeks in InT-control and CsX rats. Some CsX-SD rats received androgen replacement therapy at 10-15 weeks with TES-enanthate (TRT; 1.75 mg/kg, 2x/week) or DHT-enanthate (DRT; 1.00 mg/kg. 2x/week) and a separate group of CsX-SD rats received losartan-potassium in drinking water (LST, 250 mg/L) for the entire 15 week period. Expression of renin, angiotensinogen (Agt), angiotensin converting enzyme (ACE), and angiotensin II type I receptor (AT1R) mRNA in kidney and aorta were determined by real-time PCR (rt-PCR) and plasma renin levels were determined by radioimmunoassay. Results: There was a progressive rise in BP over 10 weeks in CsX (109 ± 3.3 vs. 143 ± 3.5 mmHg), while BP remained stable in InT-control (109 ± 3.0 vs. 113 ± 0.3). BP gradually declined to normal in CsX-TRT rats (113 ± 1.3), while BP remained elevated in CsX (140 ± 1.2) and normal in InT-control (113 ± 0.3). LST prevented the development of hypertension in CsX at 10 weeks (100 ± 1.5 in CsX + LST vs. 143 ± 3.5 in CsX). During the next 5 weeks with TES-RT, BP declined in CsX-TRT (113 ± 1.3) and remained lower in CsX + LST (99 ± 0.4). DHT-RT reduced BP in CxS to a similar extent. In Tfm, CsX resulted in a similar rise in BP (109 ± 0.7 vs. 139 ± 0.4 mmHg), but TRT reduced BP more rapidly and to a greater extent (106 ± 2.8). rt-PCR of the kidney revealed that CsX increased expression of mRNA for renin (92%), ACE (58%), and AT1R (80%) compared to InT, while TES RT normalized expression of renin, AT1R, and ACE mRNA to levels of InT rats. Plasma renin levels exhibited changes similar to those observed for renin mRNA expression. Conclusions: This is the first study to examine the long-term effects of endogenous and exogenous androgens on BP in male SD and Tfm rats. These data reveal that endogenous androgens (TES) exert anti-hypertensive effects that appear to involve non-genomic and possibly genomic mechanism(s), resulting in reductions in RAS expression in the kidney and enhanced systemic vasodilation.
... Testosterone, which is the principal male sex hormone, plays an important role in complex mechanisms that determine muscle mass, fertility, glucose metabolism, and visceral adiposity [3]. Low testosterone concentrations have been associated with increased risks of metabolic syndrome and type II diabetes [4], hypertension, and atherosclerosis [5]. In addition, it has been recently demonstrated that low concentrations of total testosterone are associated with increased risk of all-cause and cardiovascular mortality [6]. ...
... Restricted cubic splines [23] were also used to further investigate the relationship between sex hormones or SHBG with IGF-1 or IGFBP-3, where knot positions were specified according to the quintiles of the sex hormone concentrations. The slope of the change in the natural logarithm of IGF-1 and IGFBP-3 with increasing quintiles of sex steroid hormones and SHBG concentrations was estimated by entering into the models an ordinal variable with its values corresponding to the quintiles of each hormone measure (1,2,3,4,5), the coefficients of which were evaluated by the Wald test. We also calculated the percentage difference in the geometric means of the hormones between the fifth and the first quintile by subtracting the geometric mean of the first quintile from the geometric mean of the fifth quintile divided by the geometric mean of the first quintile ((Q5 − Q1)/Q1). ...
Article
Full-text available
Sex steroid hormone concentrations and insulin-like growth factor (IGF) proteins have been independently associated with risk of cancer, chronic diseases, and mortality. However, studies that evaluated the inter-relation between the sex hormones and IGF pathways have provided mixed results. We examined the association between endogenous sex hormones and sex hormone-binding globulin (SHBG) with IGF-1 and IGF-binding protein 3 (IGFBP-3) in a population-based sample of US men. Data from 1,135 men aged 20 years or older participating in the third National Health and Nutrition Examination Survey (NHANES III) were analyzed. Weighted linear regression was used to estimate geometric means and 95 % confidence intervals for IGF-1 and IGFBP-3 concentrations by sex steroid hormones and SHBG after adjusting for age, race/ethnicity, body mass index, waist circumference, alcohol consumption, cigarette smoking, physical activity, diabetes, and mutually adjusting for other sex hormones and SHBG. No significant association was observed between sex steroid hormones, SHBG, and IGF-1 concentrations. Total estradiol (% difference in Q5 - Q1 geometric means -9.7 %; P-trend 0.05) and SHBG (% difference -7.3 %; P-trend 0.02) were modestly inversely associated with IGFBP-3. Total testosterone was modestly inversely associated with IGFBP-3 (% difference -6.2 %; P-trend 0.01), but this association disappeared after adjustment for total estradiol and SHBG (% difference 2.6 %; P-trend 0.23). Androstanediol glucuronide was not associated with IGFBP-3. These findings suggest that there may be inter-relationships between circulating total estradiol, SHBG, and IGFBP-3 concentrations. Future research may consider these inter-relationships when evaluating potential joint effects of the sex hormones and IGF pathways.
... The normal reference range for total serum testosterone levels in adult men is approximately 300e1000 ng/dL [14]. Low testosterone levels are associated with CV risk factors such as dyslipidemia, hypertension, obesity, and diabetes [15,16], and some studies have shown an association with changes in carotid intima-media thickness (IMT) and ankle/brachial index (ABI) as a measure of peripheral atherosclerotic disease [17e19]. Other studies have also reported that low testosterone levels are associated with increased CV and all-causes mortality in older men [12,13,20e22]. ...
Article
Background: The role erectile dysfunction (ED) coupled with low testosterone levels as early markers of atherosclerosis is not well understood. Objectives: To analyze the relationship between serum testosterone levels with both ED and brachial artery flow-mediated vasodilation (FMD), in a primary prevention sample of men. Methods: We enrolled 802 asymptomatic, intermediate CV risk patients, according to the Framingham Risk Score, aged 40-80 years, who underwent the ultrasound examination of FMD, the evaluation of ED and the assessment of total serum testosterone levels. Results: Testosterone levels correlated both with FMD (r = 0.85; p < 0.0001) and IIEF-5 score (rs = 0.65; p < 0.0001). Multivariable logistic regression analyses revealed that lower serum testosterone levels were strongly associated (p < 0.001) with severe (OR 0.78; 95% CI: 0.62-0.86), and moderate ED (OR 0.85; 95% CI: 0.72-0.97), while impaired FMD percentages were strongly associated (p < 0.001) with severe (OR 0.68; 95% CI: 0.59-0.79), moderate (OR 0.76; 95% CI: 0.63-0.83) and mild to moderate ED (OR 0.8; 95% CI: 0.69-0.94). Mild ED resulted statistically associated with lower FMD (OR 0.94; 95% CI: 0.82 - 1.07; p = 0.03) but not with serum testosterone levels. These relations were not substantially affected by adjustments for further potential confounders including smoking status, hypertension, diabetes mellitus and body mass index. Conclusions: lower total serum testosterone levels are associated with impaired FMD and ED in this sample of intermediate CV risk men according to the Framingham Risk Score. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
... In fact, both clinical (Hu et al., 2012;Papierska et al., 2012;Soisson et al., 2012) and experimental studies (Liu et al., 2003;Wu and von Eckardstein, 2003;Deenadayalu et al., 2012) have demonstrated acute and chronic protective effects of androgens on both cardiovascular and metabolic functions; these include their crucial role in anabolic processes and sexual development, which occur through genome-based mechanisms (Mooradian et al., 1987;Bhasin et al., 1996). Nevertheless, testosterone has also been shown to trigger rapid non-genomic events such as vasodilatation; this has been shown to occur in a variety of large vessels (aorta, coronary arteries) as well as in small resistance arteries (mesenteric, prostatic, pulmonary) both in humans and various animal species (Deenadayalu et al., 2001;Malkin et al., 2006;Perusquia et al., 2007;Yang et al., 2008;Bucci et al., 2009;Nettleship et al., 2009;Traish et al., 2009). We have recently demonstrated that hydrogen sulphide (H 2S) contributes to testosterone-induced vasodilatation in aortic tissue, highlighting a link between H2S release and the non-genomic vasodilator effect of testosterone (Bucci et al., 2009). ...
Article
Background and purpose: Hydrogen sulphide (H2S) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilatation. Having previously shown that H2 S contributes to testosterone-induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect. Experimental approach: H2 S biosynthesis was evaluated in rat isolated aortic rings following androgen receptor (NR3C4) stimulation. Co-immunoprecipitation and surface plasmon resonance analysis were performed to investigate mechanisms involved in NR3C4 activation. Key results: Pretreatment with NR3C4 antagonist nilutamide prevented testosterone-induced increase in H2S and reduced its vasodilator effect. Androgen agonist mesterolone also increased H2S and induced vasodilatation; effects attenuated by the selective cystathionine-γ lyase (CSE) inhibitor propargylglycine. The NR3C4-multicomplex-derived heat shock protein 90 (hsp90) was also involved in this effect; its specific inhibitor geldanamycin strongly reduced testosterone-induced H2S production. Neither progesterone nor 17-β-oestradiol induced H2S release. Furthermore, we demonstrated that CSE, the main vascular H2S-synthesizing enzyme, is physically associated with the NR3C4/hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H2S levels in human blood collected from male healthy volunteers were higher than those in female samples. Conclusions and implications: We demonstrated that selective activation of the NR3C4 is essential for H2S biosynthesis within vascular tissue, and this event is based on the formation of a ternary complex between cystathionine-γ lyase, NR3C4and hsp90. This novel molecular mechanism operating in the vasculature, corroborated by higher H2S levels in males, suggests that the L-cysteine/CSE/H2S pathway may be preferentially activated in males leading to gender-specific H2S biosynthesis.
... Whilst cardiovascular disease mortality rates vary significantly worldwide, evidence over previous decades has consistently demonstrated that post-myocardial infarction mortality rates are twice as high in males when compared to females [85]. Although testosterone was traditionally implicated in the aetiology of atherosclerosis development, it is now proposed that the testosterone-deficient state in older males may be responsible for worsened outcomes following myocardial ischemia [86]. In fact, recent evidence suggests that after adjusting for age and comorbidities, women are more likely than men to experience myocardial infarction, heart failure, stroke and cardiovascular death [87]. ...
Article
Introduction: Current models of obesity utilise normogonadic animals and neglect the strong relationships between obesity-associated metabolic syndrome (MetS) and male testosterone deficiency (TD). The joint presentation of these conditions has complex implications for the cardiovascular system that are not well understood. We have characterised and investigated three models in male rats: one of diet-induced obesity with the MetS; a second using orchiectomised rats mimicking TD; and a third combining MetS with TD which we propose is representative of males with testosterone deficiency and the metabolic syndrome (TDMetS). Methods: Male Wistar rats (n = 24) were randomly assigned to two groups and provided ad libitum access to normal rat chow (CTRL) or a high fat/high sugar/low protein "obesogenic" diet (OGD) for 28 weeks (n = 12/group). These groups were further sub-divided into sham-operated or orchiectomised (ORX) animals to mimic hypogonadism, with and without diet-induced obesity (n = 6/group). Serum lipids, glucose, insulin and sex hormone concentrations were determined. Body composition, cardiovascular structure and function; and myocardial tolerance to ischemia-reperfusion were assessed. Results: OGD-fed animals had 72% greater fat mass; 2.4-fold greater serum cholesterol; 2.3-fold greater serum triglycerides and 3-fold greater fasting glucose (indicative of diabetes mellitus) compared to CTRLs (all p<0.05). The ORX animals had reduced serum testosterone and left ventricle mass (p<0.05). In addition to the combined differences observed in each of the isolated models, the OGD, ORX and OGD+ORX models each had greater CK-MB levels following in vivo cardiac ischemia-reperfusion insult compared to CTRLs (p<0.05). Conclusion: Our findings provide evidence to support that the MetS and TD independently impair myocardial tolerance to ischemia-reperfusion. The combined OGD+ORX phenotype described in this study is a novel animal model with associated cardiovascular risk factors and complex myocardial pathology which may be representative of male patients presenting with TDMetS.
... In the cardiovascular system, testosterone has multifaceted actions, ranging from protective to deleterious effects (39,52). Testosterone induces vasodilatation; decreases total cholesterol, low-density lipoprotein, and triglycerides levels; and inhibits fatty streak formation, indicating that androgens may have protective effects against atherosclerosis (45,46,55). On the other hand, supraphysiological doses of testosterone reduce high-density lipoprotein and promote unfavorable changes in the lipid profile (26). ...
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Testosterone exerts both beneficial and harmful effects on the cardiovascular system. Considering that testosterone induces reactive oxygen species (ROS) generation and ROS activate cell death signaling pathways, we tested the hypothesis that testosterone induces apoptosis in vascular smooth muscle cells (VSMC) via mitochondria-dependent ROS generation. Cultured VSMC were stimulated with testosterone (10(-7) mol/L) or vehicle (2-12h) in the presence of flutamide (10(-5) mol/L), CCCP (10(-6) mol/L), MnTMPyP (3x10(-5) mol/L), Z-IETD-FMK (10(-5) mol/L) or vehicle. ROS were determined with lucigenin and dichlorodihydrofluorescein; apoptosis with annexin V and calcein; O2 consumption with a Clark-type electrode, and procaspases, caspases, cytochrome c, Bax and Bcl-2 levels by immunoblotting. Testosterone induced ROS generation [(rlu/mg protein, 2h), 162.6 ± 16 vs. 100] and procaspase 3 activation [(arbitrary units, au, 6h), 166.2 ± 19 vs. 100]. CCCP, MnTMPyP and flutamide abolished these effects. Testosterone increased annexin V fluorescence [(au) 197.6 ± 21.5 vs. 100] and decreased calcein fluorescence [(au), 34.4 ± 6.4 vs. 100] and O2 consumption [(nmol O2/min) (18.6 ± 2.0 vs. 34.4 ± 3.9). Testosterone also reduced Bax/Bcl-2 ratio, but not cytochrome c release from mitochondria. Moreover, testosterone (6 h) induced cleavage of procaspase 8 [(au) 161.1 ± 13.5 vs. 100) and increased gene expression of FasL [(2(ΔΔCt)) 3.6 ± 1.2 vs. 0.7 ± 0.5] and TNF-alpha (1.7 ± 0.4 vs. 0.3 ± 0.1). CCCP, MnTMPyP and flutamide abolished these effects. These data indicate that testosterone induces apoptosis in VSMC via the extrinsic apoptotic pathway with the involvement of androgen receptor activation and mitochondria-generated ROS.
... Moreover, epidemiologic studies have shown that men are at higher risk of having unfavorable lipid profiles 80 and suffer from cardiovascular disease mortality more frequently when compared with women. 81,82 These observations have prompted some investigators to hypothesize that the difference in incident dyslipidemia and cardiovascular disease between the 2 sexes is related to the different levels of circulating sex hormones. As a result, multiple studies have tried to correlate levels of sex hormones, including testosterone, with lipoprotein subfractions. ...
Article
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Recent data from the Massachusetts Male Aging Study (MMAS) have revealed an increasing incidence of hypogonadism within the aging US population. The Massachusetts Male Aging Study estimates indicate that ≈2.4 million men aged 40 to 69 suffer from hypogonadism in the United States.[1][1] The
... Diferentes investigaciones han indicado que la coadministración de andrógenos atenúa el efecto cardioprotector de los estrógenos sobre la HDL-C sérica; reduce el colesterol total y los triglicéridos 22,23 ; tienen un efecto neutro sobre el flujo sanguíneo 24 , mientras que el tratamiento con testosterona parenteral no produce modificaciones en las concentraciones de lipoproteínas, pero mejora la vasodilatación tanto dependiente como independiente del endotelio asociada a la terapia hormonal de reemplazo en la menopausia 25 . ...
... TT deficiency alters carbohydrate, protein and lipid metabolism, thus contributing to oxidative stress, endothelial dysfunction and increase production of pro-inflammatory factors, which in turn promote the pathogenic process leading to the atherosclerosis (Agledahl et al. 2008;Jones and Saad 2009;Traish and Kypreos 2011). Clinical and epidemiological studies have suggested a strong association between low plasma TT levels and atherosclerosis (Nettleship et al. 2007(Nettleship et al. , 2009). Our observations on association of serum TT, lipid profile and FBG also in agreement with the findings of Zmuda et al. (1997), Makinen et al. (2008), Akishita et al. (2010) and Haring et al. (2011). ...
Article
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Testosterone is commonly known for its role in the regulation of reproductive physiology in men. Epidemiologic studies suggest that endogenous testosterone levels may be implicated in cardiovascular diseases (CVDs). Our study aimed to investigate the relationship between serum total testosterone (TT) levels and lipid profile as well as fasting blood glucose (FBG) levels in male patients ranging from 40 to 70 years old with angiographically proven CVDs from Nadia and Murshidabad district of West Bengal, India. These data were compared with the normal men with no CVD history. We observed a significantly low serum TT levels in CVD patient group compared to the normal group. Among CVD patients, a significant (p < 0.05) negative association was found between serum TT and total cholesterol, triglyceride, low density lipoprotein and very low density lipoprotein, whereas a significant positive correlation (p < 0.05) was found between serum TT and high density lipoprotein. We also observed a highly significant negative correlation between TT and FBG levels in CVD patient group. Thus, in these two densely populated district of West Bengal with poor socio-economic condition, low levels of serum TT in elderly men is associated with CVD that appear together with an atherogenic lipid milieu that may be involved in the pathogenesis of CVD. Results further indicate that low serum TT might have a role in the development of hyperglycemia as evidenced from high FBG level in elderly men.
... This sex difference has been attributed to estrogen's protective effect in females and/or a detrimental androgen effect in males (Thompson and Khalil, 2003). However, a growing body of evidence suggests that androgens exhibit protective actions on the cardiovascular system (Nettleship et al., 2009). Administration of testosterone has been shown to induce both endothelium-dependent and independent vasorelaxation in rabbit aorta (Yue et al., 1995), FIGURE 7 | Western blot analysis of eNOS and peNOS expression in control and UCD-T2DM rat aorta. ...
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Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. The objectives of this study were to examine whether there were (1) sex differences in aortic function and (2) alterations in the relative contribution of endothelium-derived relaxing factors in modulating aortic reactivity in UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine (ACh) was measured in aortic rings before and after exposure to pharmacological inhibitors. Relaxation responses to sodium nitroprusside were assessed in endothelium-denuded rings. Moreover, contractile responses to phenylephrine (PE) were measured before and after incubation of aortic rings with a nitric oxide synthase (NOS) inhibitor in the presence of indomethacin. Metabolic parameters and expression of molecules associated with vascular and insulin signaling as well as reactive oxygen species generation were determined. Diabetes slightly but significantly impaired EDV in response to ACh in aortas from females but potentiated the relaxation response in males. The potentiation of EDV in diabetic male aortas was accompanied by a traces of nitric oxide (NO)-and prostanoid-independent relaxation and elevated aortic expression of small-and intermediate conductance Ca 2+-activated K + channels in this group. The smooth muscle sensitivity to NO was not altered, whereas the responsiveness to PE was significantly enhanced in aortas of diabetic groups in both sexes. Endothelium-derived NO during smooth muscle contraction, as assessed by the potentiation of the response to PE after NOS inhibition, was reduced in aortas of diabetic rats regardless of sex. Accordingly, decreases in pAkt and peNOS were Frontiers in Physiology | www.frontiersin.org 1 July 2021 | Volume 12 | Article 616317 Akther et al. Aortic Function in UCD-T2DM Rats observed in aortas from diabetic rats in both sexes compared with controls. Our data suggest that a decrease in insulin sensitivity via pAkt-peNOS-dependent signaling and an increase in oxidative stress may contribute to the elevated contractile responses observed in diabetic aortas in both sexes. This study demonstrates that aortic function in UCD-T2DM rats is altered in both sexes. Here, we provide the first evidence of sexual dimorphism in aortic relaxation in UCD-T2DM rats.
... These effects, like those observed in a variety of arterial vessels in vitro, are structurally specific and AR-independent. The abundance of previous in vitro studies of TES-induced vasorelaxation (6,26,31,46,47,49,50), together with more limited in vivo studies of TES-induced regional vasodilation (3,23,48), provides clear and consistent support for the idea that the hypotensive effects of TES on systemic BP observed in vivo in the present study result from a systemic vasodilatory action, which is nongenomic and independent of the AR. ...
Article
The effects of i.v. androgen infusions on mean arterial blood pressure (BP) and heart rate (HR) were determined in conscious, ganglionic-blocked (hexamethonium, HEX, 30 mg/kg, i.p.) male Sprague-Dawley (SD) and Testicular-feminized male (Tfm; androgen receptor(AR)-deficient) rats. BP and HR were recorded with increasing doses of androgens (0.375-6.00 μmol/kg/min, i.v.; 10 min/dose). Data are means ± S.E. (n = 5-8 rats/group). In SD, baseline BP and HR averaged 103 ± 4 mmHg and 353 ± 12 beats/min (BPM). Testosterone (TES)produced a dose-dependent reduction in BP to a low of 87 ± 4 mmHg (Δ16%), HR was unchanged. Neither BP (109 ± 3 mmHg) nor HR (395 ± 13 BPM) were altered by vehicle (10% EtOH in 0.9% saline; 0.15 ml/kg/min, i.v.). In Tfm, TES produced a similar reduction in BP (Δ13%); HR was unchanged. In SD, 5β-dihydrotestosterone (genomically-inactive metabolite) produced a greater reduction in BP than TES (102 ± 2 to 79 ± 2 mmHg, Δ23%); HR was unchanged. A 20 μg i.v. bolus of Na-nitroprusside in both SD and Tfm rats reduced BP 30-40 mmHg while HR was unchanged, confirming blockade by HEX. Pretreatment of SD with nNOS inhibitor (S-methyl-thiocitrulline, 20 μg/kg/min x 30 min) abolished hypotensive effects of TES on BP (104 ± 2 vs. 101 ± 2 mmHg) and HR. These data suggest the systemic hypotensive effect of TES and other androgens involves a direct vasodilatory action on the peripheral vasculature which, like the effect observed in isolated arteries, is structurally-specific and AR-independent, and involves activation of nNOS. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
... In accordance with this finding, in our population subjects with a diagnosis of CAD were older than those in the no-CAD group. Alongside age, male gender is considered the other major contributor in increasing CAD risk development [50,52]. For this reason, both these confounders were considered in the analysis of results. ...
Article
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Clinical data indicate that low circulating l-homoarginine (HArg) concentrations are associated with cardiovascular (CV) disease, CV mortality, and all-cause mortality. A high number of LC-based analytical methods for the quantification of HArg, in combination with the l-arginine (Arg)-related pathway metabolites, have been reported. However, these methods usually consider a limited panel of analytes. Thus, in order to achieve a comprehensive picture of the Arg metabolism, we described an improved targeted metabolomic approach based on a multiple reaction monitoring (MRM) mass spectrometry method for the simultaneous quantification of the Arg/nitric oxide (NO) pathway metabolites. This methodology was then employed to quantify the plasma concentrations of these analytes in a cohort of individuals with different grades/types of coronary artery disease (CAD) in order to increase knowledge about the role of HArg and its associated metabolites in the CV field. Our results showed that the MRM method here implemented is suitable for the simultaneous assessment of a wide panel of amino acids involved in the Arg/NO metabolic pathway in plasma samples from patients with CV disease. Further, our findings highlighted an impairment of the Arg/NO metabolic pathway, and suggest a sex-dependent regulation of this metabolic route.
... 57 Both the incidence and prevalence of CVD are more frequently reported in men than women, leading to concerns about possible detrimental cardiovascular effects of T. 58,59 In fact, CVD remain the main causes of mortality in men, even if low rather than normal or elevated levels of serum T are frequently observed in patients with underlying CVD. [60][61][62][63][64] Elderly men, who often display hypogonadism, are more prone to the progression of atherosclerosis. 65 Indeed, normal levels of T are necessary for maintaining an optimal lipid metabolism and glucose control, as well as for reducing blood pressure, left ventricle mass, waist circumference, and circulating concentration of inflammatory cytokines. ...
Article
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Background: The novel Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) disease 2019 (COVID-19) seems to have a worse clinical course among infected men compared to women, thus, highlighting concerns about gender predisposition to serious prognosis. Therefore, androgens, particularly testosterone (T), could be suspected as playing a critical role in driving this excess of risk. However, gonadal function in critically ill men is actually unknown, mainly because serum T concentration is not routinely measured in clinical practice, even more in this clinical context. Objective: To overview on possible mechanisms by which serum T levels could affect the progression of COVID-19 in men. Methods: Authors searched PubMed/Medline, Web of Science, EMBASE, Cochrane Library, Google, and Institutional websites for medical subject headings terms and free text words referred to "SARS-CoV-2", "COVID-19", "testosterone", "male hypogonadism", "gender" "immune system", "obesity", "thrombosis" until May 19th 2020. Results: T, co-regulating the expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2 in host cells, may facilitate SARS-CoV-2 internalization. Instead, low serum T levels may predispose to endothelial dysfunction, thrombosis and defective immune response, leading to both impaired viral clearance and systemic inflammation. Obesity, one of the leading causes of severe prognosis in infected patients, is strictly associated with functional hypogonadism, and may consistently strengthen the aforementioned alterations, ultimately predisposing to serious respiratory and systemic consequences. Discussion and conclusion: T in comparison to estrogen may predispose men to a widespread COVID-19 infection. Low serum levels of T, which should be supposed to characterize the hormonal milieu in seriously ill individuals, may predispose men, especially aged men, to poor prognosis or death. Further studies are needed to confirm these pathophysiological assumptions and to promptly identify adequate therapeutic strategies.
... Men have been shown to be exposed to a higher risk of CV disease during the reproductive period compared to age-matched women. 1 This was generally explained by the cardioprotective effects of oestrogens in women and the assumed deleterious effects of androgens in men. However, the effects of sex hormones on CV health are complex and the results from the considerable amount of literature remain conflicting. ...
... Low-density lipoprotein, total cholesterol and triglycerides are reduced by testosterone therapy; in addition, testosterone replacement increases high-density lipoprotein (HDL) and inhibits fatty streak formation, suggesting a protective effect against atherosclerosis [113][114][115]. Similarly, some studies including 4-year follow-up study found that the degree of atherosclerosis progression is inversely associated with testosterone levels [116,117]. ...
Article
The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca²⁺ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.
... But a change in testosterone can be affecting the amount of blood glucose, cholesterol, and triglyceride (6). Theoretically, Low amount of Testosterone can cause changing to increase cholesterol and decrease arteries' elasticity which in turn can be leads coronary artery atherosclerotic (7,8). In any case, the effect of resistance training on cardiovascular disease factor is not clear (1,9). ...
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Background. The impact of movement pattern of resistance training on some factors related to cardiovascular diseases is not clear. Objectives. Therefore, the purpose of this study was to investigate the effects of 8 week different resistance training patterns on lipid profile and hormonal responses in young males. Methods. Forty untrained students in 23.8±2.66 average years old and weight of 67.43±4.96 kg were randomly selected, who participated volunteering in this investigation. They were randomly divided into practice groups including upper-body, lower-body, and compound for 3 sessions during 8 weeks (%60 to %80 of a maximum repetition) (control n=10). In order to assess lipid profile and hormone concentration, body composition and blood samples of subjects were measured in similar conditions in three stages: pre-test, end of the 4th week, and end of the 8th week. Results. fat percentage (P
... Extensive epidemiological data have revealed the existence of a prominent sexual dimorphism in the incidences of primary vascular diseases that involve excessive vasoconstriction. Thus, among the strongest independent risk factors for coronary artery disease is male sex and a male to female ratio of approximately 2:1 is consistently observed (Nettleship et al. 2009). In contrast, migraine headache ( Bartelink et al. 1993) and Raynaud's Disease (Voulgari et al. 2000) all occur in premenopausal women at rates as much as fourfold higher than in men. ...
Article
Key points: The fat surrounding blood vessels (perivascular adipose tissue or PVAT) releases vasoactive compounds that regulate vascular smooth muscle tone. There are sex differences in the regulation of vascular tone, but, to date, no study has investigated whether there are sex differences in the regulation of blood vessel tone by PVAT. This study has identified that the cyclooxygenase products thromboxane and PGF2α are released from coronary artery PVAT from pigs. Thromboxane appears to mediate the PVAT-induced contraction in arteries from females, whereas PGF2α appears to mediate the contraction in arteries from males. These sex differences in the role of these prostanoids in the PVAT-induced contraction can be explained by a greater release of thromboxane from PVAT from female animals and greater sensitivity to PGF2α in the porcine coronary artery from males. Abstract: Previous studies have demonstrated that perivascular adipose tissue (PVAT) causes vasoconstriction. In this present study, we determined the role of cyclooxygenase-derived prostanoids in this contractile response and determined whether there were any sex differences in the regulation of vascular tone by PVAT. Contractions in isolated segments of coronary arteries were determined using isolated tissue baths and isometric tension recording. Segments were initially cleaned of PVAT, which was then re-added to the tissue bath and changes in tone measured over 1 h. Levels of PGF2α and thromboxane B2 (TXB2 ) were quantified by ELISA, and PGF2α (FP) and thromboxane A2 (TP) receptor expression determined by Western blotting. In arteries from both male and female pigs, re-addition of PVAT caused a contraction, which was partially inhibited by the cyclooxygenase inhibitors indomethacin and flurbiprofen. The FP receptor antagonist AL8810 attenuated the PVAT-induced contraction in arteries from males, whereas the TP receptor antagonist GR32191B inhibited the PVAT-induced contraction in arteries from females. Although there was no difference in PGF2α levels in PVAT between females and males, PGF2α produced a larger contraction in arteries from males, correlating with a higher FP receptor expression. In contrast, release of TXB2 from PVAT from females was greater than from males, but there was no difference in the contraction by the TXA2 agonist U46619, or TP receptor expression in arteries from different sexes. These findings demonstrate clear sex differences in PVAT function in which PGF2α and TXA2 antagonists can inhibit the PVAT-induced vasoconstriction in male and female PCAs, respectively.
... On the other hand, epidemiologic studies have shown that men are at higher risk of having unfavourable lipid profiles (Nettleship et al. 2009). The evidence available in the literature regarding the effect of testosterone on serum lipids is conflicting and until now a clear consensus has not been established yet. ...
Article
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This study investigated the effects of chronic supraphysiological dose of testosterone propionate administration cardiovascular function in rats from the perspective of haemostatic function including platelet functions, coagulation, and fibrinolysis. Testosterone significantly enhanced cardiac contractility by enhancing LVSP (10%), dp/dtmax(36.7%), dp/dtmin(14.6%) without altering heart rate, diastolic function, and serum lipid profile. While it has no effect on platelets count, thromboxane B2 levels, and platelet aggregation, testosterone significantly enhanced bleeding time and increased circulatory and thoracic aorta mRNA and protein levels of tPA (46.5%, 58.2%, and 74.3%, respectively) and significantly decreased those of PAI-1 (29.3%, 26.4%, and 32.8%, respectively). While there were no significant changes in PT and aPTT, mRNA and protein levels of prothrombin and factor VII were downregulated in the livers of the testosterone-treated rats (57.7% and 64.9%, respectively). Overall, chronic testosterone administration in rats may act as a cardio-protective agent by modulating haemostasis in rats.
... The risk of cardiovascular events increases with age, and this is paralleled by the declined levels of circulating T in aging men. However, this decline is observed only in the part of the elderly male population and is not as common as widely believed [3]. ...
Article
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The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no ex vivo studies suggest that circulating androgen levels influence the activation and reactivity of blood platelets - one of the main components of the haemostasis system directly involved in atherosclerosis. The levels of testosterone, dihydrotestosterone and oestradiol in plasma from men and women aged from 60 to 65 years were measured by LC-MS; the aim was to identify any potential relationships between sex steroid levels and the markers of platelet activation (surface membrane expression of GPII/IIIa complex and P-selectin) and platelet reactivity in response to arachidonate, collagen or ADP, monitored with whole blood aggregometry and flow cytometry. The results of the ex vivo part of the study indicate that the concentrations of testosterone and its reduced form, dihydrotestosterone are significantly negatively associated with platelet activation and reactivity. These observations were confirmed in an in vitro model: testosterone and dihydrotestosterone significantly inhibited platelet aggregation triggered by arachidonate or collagen. Our findings indicate that testosterone and dihydrotestosterone are significant haemostatic steroids with inhibitory action on blood platelets in older people.
... Higher inflammatory and oxidative stress levels are known risk factors for the onset of CVD, 79 and people with endocrine abnormalities often have slow gait speed. 80 Some researchers have reported that slow gait speed is associated also with subclinical atherosclerotic lesions. 81 This may explain the higher incidence of CVD in people with slow gait speed. ...
Article
Objectives: Slow gait speed may be associated with premature mortality, cardiovascular disease (CVD), and cancer, although a comprehensive meta-analysis is lacking. In this systematic review and meta-analysis, we explored potential associations between gait speed and mortality, incident CVD, and cancer. Design: A systematic search in major databases was undertaken from inception until March 15, 2018 for prospective cohort studies reporting data on gait speed and mortality, incident CVD, and cancer. Setting and participants: All available. Measures: The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), based on the model with the maximum number of covariates for each study between gait speed (categorized as decrease in 0.1 m/s) and mortality, incident CVD, and cancer, were meta-analyzed with a random effects model. Results: Among 7026 articles, 44 articles corresponding to 48 independent cohorts were eligible. The studies followed up on a total of 101,945 participants (mean age 72.2 years; 55% women) for a median of 5.4 years. After adjusting for a median of 9 potential confounders and the presence of publication bias, each reduction of 0.1 m/s in gait speed was associated with a 14% increased risk of earlier mortality (45 studies; HR = 1.12, 95% CI: 1.09-1.14; I2 = 90%) and 8% increased risk of CVD (13 studies; HR = 1.08, 95% CI: 1.03-1.13; I2 = 81%), but no relationship with cancer was observed (HR = 1.00, 95% CI: 0.97-1.04; I2 = 15%). Conclusion/implications: Slow gait speed may be a predictor of mortality and CVD in older adults. Because gait speed is a quick and inexpensive measure to obtain, our study suggests that it should be routinely used and may help identify people at risk of premature mortality and CVD.
... It is also possible that heart failure or peripheral artery diseases are linked to slower walking speed [11]. Other possible explanations of the link between slow walking speed and cardiovascular mortality include risk factors for CVD, such as higher inflammatory and oxidative stress levels, and it has been observed that people with endocrine abnormalities often have slow gait speed [12,13]. Nevertheless, little is known about whether a link between walking speed and mortality exists when also other causes of death are considered, such as respiratory and cancer mortality. ...
Article
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Objective: To explore over trajectories of terminal decline and terminal drop in a large nationally representative sample of older adults aged 60 and over living in England. We further explore whether trajectories in terminal decline differed according to the cause of death. Methods: Data are from participants aged 60 and over of the English Longitudinal Study of Ageing (ELSA) from 2002 to 2018. Repeated measures of walking speed were used, which was assessed objectively over a distance of 8ft (2.4m). Mortality by cause was ascertained up to 2018. Mixed effects models were used to estimate growth curve models of walking speed by cause of death, adjusted for confounders. Results: Compared to survivors, respondents who died of cancer (b=-0.034m/s; 95% CI: -0.05; -0.01), cardiovascular diseases (b=-0.082m/s; 95% CI: -0.13; -0.06), and respiratory diseases (b=-0.137m/s; 95% CI: -0.24; -0.10) reported significant lower walking speed. Also, declines in walking speed accelerate closer to death particularly for those who died of cardiovascular (b=-0.003m/s) and respiratory diseases (b=-0.005m/s). Conclusion: We observed both terminal decline and terminal drop in walking speed in the years preceding death. Participants aged 70 who died of cardiovascular and respiratory conditions had steeper decline of walking speed than those who stayed alive.
... Intriguingly, Sertoli cells show higher heritability enrichment for CAD phenotypes, which leads us to hypothesize that where CAD-associated variants can act in Sertoli cells. The risk of CAD has been linked to testosterone level, increasing age and male gender (Nettleship et al. 2009) . Our hypothesis can be supported by the role of Sertoli cells in testosterone level regulation through influencing the Leydig cell function and testicular vasculature (Rebourcet et al. 2016(Rebourcet et al. , 2017 . ...
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Spermatogenesis depends on an orchestrated series of developing events in germ cells and full maturation of the somatic microenvironment. To date, the majority of efforts to study cellular heterogeneity in testis has been focused on single-cell gene expression rather than the chromatin landscape shaping gene expression. To advance our understanding of the regulatory programs underlying testicular cell types, we analyzed single-cell chromatin accessibility profiles in more than 25,000 cells from mouse developing testis. We showed that scATAC-Seq allowed us to deconvolve distinct cell populations and identify cis-regulatory elements (CREs) underlying cell type specification. We identified sets of transcription factors associated with cell type-specific accessibility, revealing novel regulators of cell fate specification and maintenance. Pseudotime reconstruction revealed detailed regulatory dynamics coordinating the sequential developmental progressions of germ cells and somatic cells. This high-resolution data also revealed putative stem cells within the Sertoli and Leydig cell populations. Further, we defined candidate target cell types and genes of several GWAS signals, including those associated with testosterone levels and coronary artery disease. Collectively, our data provide a blueprint of the 'regulon' of the mouse male germline and supporting somatic cells.
... In addition to the evidence of female sex hormones, many recent studies indicated the positive role of male sex hormones (androgens) in cardiovascular protection [81,[110][111][112][113][114]. Preclinical studies showed that testosterone induces endothelium-independent relaxation in isolated coronary artery and aorta, and also contributes to the vagal outflow, but not to the sympathetic outflow to the heart of male rats [111,113,115]. ...
Article
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Background Ethanol use is related to a wide variety of negative health outcomes, including cardiovascular diseases. Stress is also involved in numerous pathologies, such as cardiovascular diseases and psychiatric disorders. Sexual dimorphism is an important factor affecting cardiovascular response and has been proposed as a potential risk factor for sex-specific health problems in humans. Here, we evaluated the effect of prolonged ethanol vapor inhalation on arterial pressure, heart rate, and tail skin temperature responses to acute restraint stress, investigating differences between male and female rats. Methods We exposed male and female Long-Evans rats to ethanol vapor for 14 h, followed by ethanol withdrawal for 10 h, for 30 consecutive days, or to room air (control groups). The animals underwent surgical implantation of a cannula into the femoral artery for assessment of arterial pressure and heart rate values. The tail skin temperature was measured as an indirect measurement of sympathetic vasomotor response. Results Chronic ethanol vapor inhalation reduced basal heart rate in both female and male rats. Sex-related difference was observed in the decrease of tail cutaneous temperature evoked by stress, but not in the pressor and tachycardiac responses. Furthermore, prolonged ethanol inhalation enhanced the blood pressure and heart rate increase caused by acute restraint stress in male, but not in female rats. However, no effect of chronic ethanol vapor was observed in the tail cutaneous temperature response to restraint in either sex. Conclusion Chronic ethanol vapor exposure increased the cardiovascular reactivity to stress in male, but not in female rats.
... In addition to the evidence of female sex hormones, many recently studies indicated the positive role of male sex hormones (androgens) in cardiovascular protection [81,[110][111][112][113][114][115]. Preclinical studies showed that testosterone induces endothelium-independent relaxation in isolated coronary artery and aorta, and also contributes to the vagal out ow, but not to the sympathetic out ow to the heart of male rats [111,113,116]. ...
Preprint
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Background: Ethanol use is related to a wide variety of negative health outcomes, including cardiovascular diseases. Stress is also involved in numerous pathologies such as cardiovascular diseases and psychiatric disorders. Sexual dimorphism is an important factor affecting cardiovascular response and has been proposed as a potential risk factor for sex-specific health problems in humans. Here, we evaluated the effect of prolonged ethanol vapor inhalation on arterial pressure, heart rate and tail skin temperature responses to acute restraint stress, investigating differences between male and female rats. Methods: We exposed male and female Long-Evans rats to ethanol vapor for 14 hours, followed by ethanol withdrawal for 10 hours, for 30 consecutive days, or to room air (control groups). The animals underwent surgical implantation of a cannula into the femoral artery for assessment of arterial pressure and heart rate values. The tail skin temperature was measured as an indirect measurement of sympathetic vasomotor response. Results: Chronic ethanol vapor inhalation reduced basal heart rate in both female and male rats. Sex-related difference was observed in the decrease of tail cutaneous temperature evoked by stress, but not in the pressor and tachycardiac responses. Furthermore, prolonged ethanol inhalation enhanced the blood pressure and heart rate increase caused by acute restraint stress in male, but not in female rats. However, no effect of chronic ethanol vapor was observed in the tail cutaneous temperature response to restraint in either sex. Conclusion: Chronic ethanol vapor exposure increased the cardiovascular reactivity to stress in male, but not in female rats.
... Both the conditions present with a high prevalence of multihormonal deficiencies [13,14]. e impairment of major anabolic systems (somatotropic, adrenal, and gonadal) does not appear to represent a mere epiphenomenon but is involved in the CHF pathophysiology; especially low serum testosterone (T), dehydroepiandrosterone-sulfate (DHEA-S), and insulin-like growth factor (IGF)-1 levels have been correlated to the symptoms severity and the adverse outcomes in men suffering from CHF [15][16][17][18][19]. On the contrary, T, DHEA-S, and IGF-1 are known to regulate oxidative stress in different manners [20], exerting pro-oxidative effects or exhibiting an antioxidant power. ...
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Background: While anabolic hormone deficit is a common finding in heart failure with reduced ejection fraction (HFrEF), few data are available in heart failure with preserved ejection fraction (HFpEF). Methods: Blood samples were collected for metabolic (total cholesterol, HDL cholesterol, LDL cholesterol, creatinine, and glucose) and hormonal (IGF-1, DHEA-S, TSH, fT3, fT4, and T) determination, comparing 30 patients with HFpEF and 20 patients with HFrEF. Total antioxidant capacity was evaluated by using the spectrophotometric method using the latency time in the appearance of the radical species of a chromogen (LAG, sec) as a parameter proportional to antioxidant content of the sample. Echocardiographic parameters were also assessed in the two groups. Results: A high prevalence of testosterone (32% in HFrEF and 72% in HFpEF, p < 0.05) and DHEA-S deficiencies was observed in HFpEF patients. Echocardiographic parameters did not correlate with hormone values. A significant direct correlation between T (r2 = 0.25, p < 0.05) and DHEA-S (r2 = 0.19, p < 0.05) with LAG was observed only in HFpEF. Conclusion: Anabolic hormone deficiency is clearly shown in HFpEF, as already known in HFrEF. Although longitudinal studies are required to confirm the prognostic value of this observation, our data suggest different mechanisms in modulating antioxidants in the two conditions, with possible therapeutic implications.
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Advanced Practice Providers (APP) working in urology clinical environments will have the opportunity to screen for and manage men with testosterone deficiency. APPs must be able to accurately diagnose, treat, and manage hypogonadal men effectively while monitoring for side effects. Hypogonadism has been associated with several common diseases that are factors in male morbidity and mortality, and providers have many options for treating low levels. The increased prevalence of hypogonadism and subsequent surge in treatment resulted in the creation of effective guidelines for the evaluation and management of hypogonadism.
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Although estrogen and testosterone deficiency have often been associated with the development of cardiac diseases in postmenopausal women, the benefits of estrogen or testosterone therapy are controversial. Supplementation high dose of estrogen or testosterone alone has been associated with many side-effects, especially estrogen. This study was aimed to investigate whether supplementation of testosterone in combination with low-dose estrogen conferred stronger cardioprotective effects on ovariectomized rats subjected to ischemia/reperfusion (I/R) injury. Female Sprague- Dawley rats were subjected to sham operation (Sham) or bilateral ovariectomy (OVX). Two weeks after ovariectomy, OVX rats were treated with one of the following: (1) vehicle (OVX),(2) testosterone (100μg/kg/day) (OVX+T), (3) estrogen (20μg/kg/day) (OVX+E), (4) testosterone (100μg/kg/day) + estrogen (20μg/kg/day) (OVX+T+E) for four weeks.The hearts were mounted on Langendorff apparatus and subjected to ischemia/reperfusion (I/R) injury subsequent to the determination of hemodynamic parameters. We examined the release of lactate dehydrogenase, serum estrogen and testosterone levels and the expression of pAkt/Akt, bax/bcl-2. Testosterone supplementation alone improved the heart function, increased p-Akt/Akt and bcl-2 expression, decreased the release of lactate dehydrogenase. Accordingly, these effects of testosterone were more pronounced when low-dose estrogen was administered simultaneously, while estrogen alone at the dose of the experiment had no significant effects. These effects might be partially orchestrated by the Akt signaling pathway.
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Introduction: Clomiphene citrate (CC) is as an effective treatment for men with hypogonadism (HG). Identifying the ideal candidate for this strategy has to date largely relied upon a patient's interest in preservation of testicular volume and spermatogenesis. Aim: This analysis was undertaken to define if predictors existed of robust elevation in serum testosterone (T) levels in response to CC. Methods: Seventy-six men with a diagnosis of HG (two separate early morning total T levels <300 ng/dL) opting for CC therapy constituted the study population. Demographic, comorbidity data, and physical and laboratory characteristics were recorded. Laboratory tests were conducted 4 weeks after commencement and every 6 months thereafter. Multivariable analysis was conducted to define if predictors of biochemical response could be identified. Parameters included in the model were patient age, mean testicular volume, varicocele presence, and baseline total T, free T, and luteinizing hormone (LH) levels. Main outcome measure: Successful biochemical response to CC, defined as an increase of ≥200 ng/dL in total T level at ≥6 months after commencing CC, was the main outcome measure. Results: Mean age was 46 ± 22 years. Mean pretreatment testicular volume was 16 ± 8 mL. Mean baseline T and LH levels were 179 ± 72 ng/dL and 7.2 ± 5.6 IU/mL, respectively. Mean total T on CC was 467 ± 190 ng/dL. Forty-seven patients (62%) met the responder definition, with a mean increase in total T levels of 302 ± 76 (204-464) ng/dL. In CC responders, the mean LH rise was 5.6 ± 3.1 IU/mL. On multivariable analysis, factors predictive of CC response included: mean testicular volume (adjusted [adj.] r = 0.32, P < 0.01), mean testicular volume ≥14 mL (hazard ratio [HR] 2.2, P < 0.01), LH level (adj. r = 0.48, P < 0.001), and LH level ≤6 IU/mL (HR 3.5, P < 0.001). Conclusion: These data indicate that two thirds of men with HG meet a robust responder definition and that pretreatment testicular volume and LH levels (in continuous and dichotomized fashions) are predictors of response.
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Testosterone deficiency syndrome (TDS) presents several sequences that generally involve different organs such as testis, bone, skeletal muscle, and heart, inducing osteoporosis, strongly reducing muscle mass, facilitating heart insufficiency and decreasing exercise capacity and strength. Approximately 25% of patients affected by chronic heart failure (CHF) are characterized by plasma Testosterone (T) levels below normal ranges also related to disease progression. In addition, reduction of testosterone concentration may contribute to some specific features of TDS syndrome such as abnormal energy handling, weakness, dyspnoea and cachexia in particular. According to some recent evidence it has emerged that testosterone replacement therapy (TRT) may be able to improve muscle strength and functional pulmonary capacity in CHF men with TDS. This review will place emphasis either on the pathophysiologic role of testosterone deficiency in CHF men or on the effects of testosterone replacement therapy.
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Objective and methods: The correlation between total testosterone levels, exercise capacity, and metabolic and echocardiographic parameters was studied in 1097 male subjects with coronary artery disease (CAD) and different stages of glucose tolerance. Results: Testosterone level was the lowest among diabetics as compared to prediabetics or controls (P < 0.001). Total and abdominal adiposity were the highest in the subjects with the lowest testosterone. Independent of adiposity, fasting glucose, insulin, and leptin were higher (P < 0.03 to < 0.001) among diabetic and control groups in the lowest, and HbA1c values (P < 0.001) higher among diabetics in the lowest, than in the highest testosterone tertile. Controls and prediabetic subjects with the lowest testosterone levels had the lowest HDL-cholesterol levels, and controls also the highest triglycerides. An association between low testosterone level and low maximal exercise capacity was observed in diabetics (P < 0.001) and controls (P < 0.03). Independent of adiposity and metabolic parameters, low testosterone levels were associated with the highest septal wall thickness (P < 0.03) among diabetics. Conclusion: A negative correlation between low testosterone and dysmetabolic features was observed. Independent of metabolic status, low plasma testosterone seems to be an indicator of impaired maximal exercise capacity and cardiac hypertrophy among CAD patients with type II diabetes.
The vulnerable health status usually preceding the onset of overt disability is often referred to as frailty. A stringent definition is elusive but it can be viewed as a physiological syndrome, characterized by decreased reserve and diminished resistance to stressors, resulting from a cumulative decline across multiple physiological systems and causing vulnerability to adverse outcomes. Elements of frailty are related to the neurological system, metabolism, joints, bones, and muscles. Sarcopenia seems to be the major determinant of frailty. Several components of the frailty syndrome are related to loss of physiological actions of testosterone (T). T and/or its aromatized metabolite, estradiol, are necessary for maintenance of bone mineral density. Furthermore, T stimulates erythrocyte formation. T has a profound effect on body composition. Androgens promote differentiation of mesenchymal pluripotent cells into the myogenic lineage and inhibit differentiation into the adipogenic lineage. Skeletal muscles of older men are as responsive to the anabolic effects of T as of younger men. Thus, although frailty is obviously a complex syndrome, some elements are androgen-associated and these can improve in men with subnormal T levels when treated with T. Evidence suggests that T treatment in frail elderly men with low T improves body composition, quality of life, and physical function, including increased axial bone mineral density and body composition. The data available to date strongly suggest a relationship between T-deficiency and frailty and warrant further basic and clinical investigations to extend these observations to the management of elderly men with frailty.
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Sex hormones are steroids derived from cholesterol, which have numerous biological functions on reproductive organs, glands from these organs and on important systems of our organism controlling or modulating various functions such as reproduction, growth and metabolism. Moreover, the sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal and neural. These hormones can have either complementary or antagonistic actions. Indeed, it has been described in the technical literature that the actions of testosterone are contrary to the estrogen in the regulation of blood pressure. Estrogen alone or combined with progesterone has been associated with decreased blood pressure, whereas testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system. The effects of testosterone in the development of cardiovascular disease (CVD) are contradictory. While some researchers suggest positive effect, others indicate negative actions of testosterone. It has been reported that androgen deprivation in adult men impaired endothelium-dependent relaxation and promoted the progression of atherosclerosis. Nevertheless, many other clinical and epidemiological studies have also reported that testosterone inhibits CVD development. Another evidence about the benefits of the male sex hormone is laid down when we assess the effects of induced hypogonadism on hypertension by analyzing large artery stiffening in men. Studies have shown that after three months of induced hypogonadism diastolic pressure is elevated, along with mean pulse pressure. Similarly, estrogen showed protective effects on vascular function and heart failure, which are related to the prevention of arterial hypertension. Estrogens can promote vasodilation and lower BP by different mechanisms as their direct actions on blood vessels, which physiologically stimulate the release of endothelium-derived vasodilator factors as well as modification of vasoconstrictor factors and inhibition of the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy (HRT). Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature depending on location of the vessel and level of exposure. Indeed, progesterone at physiological levels can inhibit the production of endothelin-1, but at supraphysiological levels, it inhibits endothelium-independent relaxation. Despite the alleged benefits of estrogen and progesterone on cardiovascular disease, the use of these hormones to postmenopausal women for HRT are still controversial. In addition, the negative findings of Heart and Estrogen/progestin Replacement Study (HERS) I and II and Women's Health Initiative (WHI) studies on HRT in postmenopausal women, such as stroke, venous thromboembolic disease and deep vein thrombosis have shaken our previous ideas that HRT was protective. Thus, other therapies being tested in hormone replacement as the selective estrogen receptor modulator (SERMs) that, like estrogen, may induce endothelium-dependent acute vasodilation resulting in lowering of blood pressure. However, the mechanisms through which sex hormones modulate the blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men, and perhaps to improved forms of therapy. In this chapter we will be a discussing the potential mechanisms through which male and female sex hormones may regulate the blood pressure as well as the cellular, biochemical and molecular pathways by which sex hormones may modify the effects of hypertension on the cardiovascular system.
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Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents.
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Low male testosterone levels impact multiple organ systems. Low testosterone impacts men's health with physiologic effects on cognition, muscle mass and strength, bone density, metabolic function, and mood. Differential diagnosis is based on history, physical exam, clinical symptoms, and testosterone levels. The medical management of low testosterone consists of replacement therapy and associated symptom management.
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Vascular complications are a leading cause of morbidity and mortality in both men and women with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus, however the prevalence, progression and pathophysiology of both microvascular (nephropathy, neuropathy and retinopathy) and macrovascular [coronary heart disease (CHD), myocardial infarction, peripheral arterial disease (PAD) and stroke] disease are different in the two sexes. In general, men appear to be at a higher risk for diabetic microvascular complications, while the consequences of macrovascular complications may be greater in women. Interestingly, in the absence of diabetes, women have a far lower risk of either micro- or macro-vascular disease compared with men for much of their lifespan. Thus, the presence of diabetes confers greater risk for vascular complications in women compared with men and some of the potential reasons, including contribution of sex hormones and sex-specific risk factors are discussed in this review. There is a growing body of evidence that sex hormones play an important role in the regulation of cardiovascular function. While estrogens are generally considered to be cardioprotective and androgens detrimental to cardiovascular health, recent findings challenge these assumptions and demonstrate diversity and complexity of sex hormone action on target tissues, especially in the setting of diabetes. While some progress has been made toward understanding the underlying mechanisms of sex differences in the pathophysiology of diabetic vascular complications, many questions and controversies remain. Future research leading to understanding of these mechanisms may contribute to personalized- and sex-specific treatment for diabetic micro- and macro-vascular disease. © 2017. Portland Press Limited on behalf of the Biochemical Society.
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The role of testosterone in the pathophysiology of inflammation is of critical clinical importance; however, no universal mechanism(s) has been advanced to explain the complex and interwoven pathways of androgens in the attenuation of the inflammatory processes. PubMed and EMBASE searches were performed, including the following key words: “testosterone”, “androgens”, “inflammatory cytokines”, “inflammatory biomarkers” with focus on clinical studies as well as basic scientific studies in human and animal models. Significant benefits of testosterone therapy in ameliorating or attenuating the symptoms of several chronic inflammatory diseases were reported. Because anti–tumor necrosis factor therapy is the mainstay for the treatment of moderate-to-severe inflammatory bowel disease; including Crohn’s disease and ulcerative colitis, and because testosterone therapy in hypogonadal men with chronic inflammatory conditions reduce tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6, we suggest that testosterone therapy attenuates the inflammatory process and reduces the burden of disease by mechanisms inhibiting inflammatory cytokine expression and function. Mechanistically, androgens regulate the expression and function of inflammatory cytokines, including TNF-α, IL-1β, IL-6, and CRP (C-reactive protein). Here, we suggest that testosterone regulates multiple and overlapping cellular and molecular pathways involving a host of immune cells and biochemical factors that converge to contribute to attenuation of the inflammatory process.
Article
Late-onset hypogonadism: Review of the problem The study investigates late-onset hypogonadism (LOH), its influence on male joint system, build, cardiovascular system, haematopoesis, cognitive functions, and sexual function. LOH is a clinical and biochemical syndrome, which is related to aging and characterised by typical symptoms and a decreased serum testosterone level. It causes a worsened life quality, and the functions of various organs are badly affected. LOH is diagnosed when the testosterone level is below 8 nmol/l (230 ng/dl) or it is at the border-line (from 8 and 12 nmol/l) and there are LOH clinical symptoms such as a decreased libido, erectile dysfunction, reduced muscular mass and strength, increased obesity, reduced bone mineral density, osteoporosis, and depression. All patients with LOH are indicated testosterone replacement therapy (TRT). TRT is contra-indicated to patients suffering from prostate or thoracic gland carcinoma. In case of erythrocytosis (haematocrit > 52%), severe heart failure, marked prostate benign hyperplasia with the obstruction of urine pathways, and obstructive sleep apnoe syndrome, TRT is relatively contra-indicated and should not be started unless these dysfunctions are cured. The treatment of LOH requires thorough patient monitoring, which includes digital rectal examination and Prostate Specific Antigen conducted after 3-6 months and 12 months in the first treatment year. It is necessary to determine the total blood count after 3-4 and 12 months in the first treatment year and afterwards once a year.
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Atherosclerosis is a multifactorial disease that is strongly influenced by endocrine pathways. One obvious player is estrogen that has been thought to be responsible for the lower risk of premenopausal women for cardiovascular events as compared to age matched men [1, 2]. In general, the mechanisms how the endocrine system affects atherosclerosis are very complex and specific for each hormone. First of all major risk factors of atherosclerosis, such as hyperlipidemia, diabetes, hypertension and obesity are strongly affected by the endocrine system. Prominent examples are the major impact of the renin angiotensin aldosterone system (RAAS) and the sympathetic nerve system on blood pressure [3-5], the effect of thyroid hormones [6, 7], sex hormones [8-12] and insulin [13] on plasma lipids and glucose concentrations or the effect on body weight of leptin [14, 15]. Furthermore, very specific molecular effects such as the generation of reactive oxygen species (ROS) or modulation of inflammatory pathways e.g. by RAAS or glucocorticoids [5, 16, 17] contribute to endocrine effects on atherosclerosis. In addition, an extensive cross talk exists between the endocrine pathways. Therefore, the net effect of a given endocrine player is a composite of the specific systemic actions, cross talk and additional specific local actions that interfere with the pathophysiology of atherosclerosis on the molecular level.
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BACKGROUND: Studies have shown that adenosine triphosphate-binding cassette transporter 1 (ABCA1) gene influences atherosclerosis. Studies have also demonstrated that cerebral infarction does not occur often in pre-menopausal women. It has been, therefore, assumed that sex plays a role in R219K polymorphism of ABCA1 gene and cerebral infarction. OBJECTIVE: To explore the relationship between lipid metabolism-correlated R219K polymorphism of ABCA1 gene, risk factors of cerebral infarction and lipid level, and to determine whether there were significant differences in gender between R219K polymorphism of ABCA1 gene and cerebral infarction. DESIGN, TIME AND SETTING: A multicentral and non-randomized, controlled study based on gene polymorphism was performed at the Chinese National Human Genome Center, and lipid concentrations were measured at Beijing Xuanwu Hospital. Patients with cerebral infarction and healthy subjects were enrolled from eight hospitals of six provinces of China between October 2002 and December 2004. PARTICIPANTS: There were 177 patients in the cerebral infarction group, including 119 males and 58 females, with a mean age of (60 ± 13) years, and 234 healthy subjects in the normal control group, including 79 males and 155 females, with a mean age of (58 ± 12) years. METHODS: R219K polymorphism of the ABCA1 gene was detected using polymerase chain reaction-restriction fragment length polymorphism, and blood lipid concentrations were simultaneously measured. MAIN OUTCOME MEASURES: Genotype and allele frequency of R219K polymorphic site, and blood lipid concentrations. RESULTS: RR genotype and R allele frequency of males in the cerebral infarction were significantly greater than males in the normal control group [RR genotype: x2 = 5.305, OR (95% CI), 2.326 (1.120-4.828), P < 0.05; R allele: x2 = 4.219, OR (95% CI), 1.528 (1.019-2.292), P < 0.05]. In addition, RR genotype and R allele frequency of males were significantly greater than females in the cerebral infarction group [RR genotype: x2 = 5.172, OR (95% CI), 2.604 (1.120-6.057), P < 0.05; R allele: x2 = 4.818, OR (95% CI), 1.652 (1.053-2.589), P < 0.05]. There were no significant differences between genotype and lipid concentrations between the two groups (P > 0.05). CONCLUSION: The RR genotype of ABCA1 R219K might be associated with onset of cerebral infarction in males, but blood lipid concentrations do not relate to R219K polymorphism.
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Physical demands from activity take a toll on the body, especially as the athlete ages. Abilities and routines that seemed second nature become more difficult to perform. Therefore, a variety of antiaging and performance drugs have “hit the market” with promises to recapture the sense of youth and ease performance at high level activities, or slow the aging process. Many drugs have been shown to improve cognition, physical function, physiologic parameters, and performance. In this chapter, we will discuss the more common supplements as well as what is new on the horizon.
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Introduction. Testosterone deficiency (TD) imposes a substantial public health burden in the U.S. We modeled the costs associated with TD-related sequelae including cardiovascular disease (CVD), diabetes mellitus (DM), and osteoporosis-related fractures (ORFs). Aim. To quantify the incremental cost burden imposed by TD's cardiometabolic sequelae. Method. Incidence, prevalence, and mortality of these conditions were collected for men ages 45–74 from six national databases and large cross-sectional studies. Relative risk (RR) rates were determined for these sequelae in patients with T < 300 ng/dL. The prevalence of TD was determined for this cohort of men. Main Outcome Measures. Adjusted incidence and prevalence were determined. Annual costs for the three TD-related sequelae were inflated at a real rate of 3% for 20 years. Results. Actual and adjusted (normalized for T deficiency) rates of CVD, DM, and ORFs in U.S. men aged 45–74 assuming a TD prevalence of 13.4% were calculated. We determined that, over a 20-year period, T deficiency is projected to be involved in the development of approximately 1.3 million new cases of CVD, 1.1 million new cases of DM, and over 600,000 ORFs. In year 1, the attributed cost burden of these diseases was approximately $8.4 billion. Over the entire 20-year period, T deficiency may be directly responsible for approximately $190–$525 billion in inflation-adjusted U.S. health care expenditures. Conclusion. TD may be a significant contributor to adverse public health. Further study is needed to definitively describe the whether TD is a modifiable risk factor for CVD, DM, and ORFs. This may represent an opportunity for nationwide public health initiatives aimed at preventive care. Moskovic DJ, Araujo AB, Lipshultz LI, and Khera M. The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. J Sex Med **;**:**–**.
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Excess androgen secretion and exogenous androgen administration may decrease insulin sensitivity and impair glucose tolerance. We examined the responses to an oral glucose tolerance test in 30 normal men before and after 6 weekly injections of androgen administered in a double-blinded study design. The men were randomly assigned to 1 of 4 treatment groups: testosterone enanthate (TE), 100 or 300 mg/week, or 19-nortestosterone decanoate (ND), 100 or 300 mg/week. Serum testosterone levels, measured 2-3 days after the last dose, did not change in the men given 100 mg TE/week, increased 3-fold in those given 300 mg TE/week, and decreased in both ND groups. All four groups had comparable reductions in serum LH levels. Weight increased significantly in all except the 100 mg TE/week group, but there was no change in waist to hip ratio in any group. In spite of the demonstrated biological effects of the doses of steroid administered, androgen administration for 6 weeks did not increase fasting serum glucose or insulin concentrations. There was also no increase in peak serum insulin levels and areas under the insulin and glucose response curves after a 100-g oral glucose load. However, the mean serum insulin area under the curve decreased significantly in the men given 300 mg ND/week. In contrast to the results of studies of 17-alkylated androgens, our results demonstrate that pharmacological doses of testosterone and the administration of 19-nortestosterone for 6 weeks do not impair glucose tolerance or alter insulin secretion in normal men.
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Serum sex hormone levels were measured preoperatively in 57 morbidly obese patients (19 men and 38 premenopausal women) and 12 months after vertical banded gastroplasty. In the male group, there was a significant decrease in estradiol and an increase in follicle-stimulating hormone (FSH), total testosterone and sex-hormone-binding globulin (SHBG). Among female patients, a significant decrease in estradiol, total and free testosterone and an increase in FSH and SHBG was found. Irregular menses present preoperatively in 5 women were corrected after successful weight loss. In conclusion, altered sex hormonal levels and gynecologic abnormalities associated with morbid obesity are corrected with adequate weight loss following vertical banded gastroplasty.
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The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription-PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.
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The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction. Therefore, the effects of dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, dihydrotestosterone had significant effects on circulating hormones (increased dihydrotestosterone; decreased total and free testosterone, LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols; unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass; unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.
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In men, an association between lower plasma total testosterone (PTT) and insulin resistance has been found in cross-sectional studies (1,2) and in one nested case-control study (3) without any possible conclusion in terms of causality or direction of the relationship. Indeed, to obtain such information, randomized controlled trials are needed. Until now, only one clinical trial has suggested that testosterone therapy improves insulin sensitivity in obese men (4). Cross-sectional studies concerning leptin regulation by androgens have provided no definitive conclusions as to whether the negative association between androgens and leptin level is independent (5) or dependent (6). This randomized controlled trial was designed to assess the role of androgens on insulin sensitivity and leptin regulation in healthy adult men. This study was a randomized, double-blind, unicentric, controlled, clinical trial. Three treatments (testosterone, dihydrotestosterone [DHT], and placebo) were compared in parallel groups during a 3-month period. All of the examinations were performed by only two physicians, using a standardized protocol. Blood was drawn between 8:00 a.m. and 9:30 a.m. after an overnight fast to determine fasting plasma glucose, insulin, leptin, sex hormones, lipids, coagulation and fibrinolysis parameters, hepatic enzymes, and prostate-specific antigen (PSA) and blood cell count. Then, a standard 75-g oral glucose tolerance test and a digital rectal examination were performed. In addition, between days 10 and 20, all of the subjects were monitored to measure sex hormones in order to adapt the treatment dose. The study protocol was approved by the Henri Mondor Hospital Ethics Committee. All of the included subjects gave written informed consent. Men with low levels of PTT (confirmed by two measurements) were selected from a large occupation-based population. The inclusion criteria were as follows: 1 ) either PTT ≤3.4 ng/ml [5th percentile value of PTT distribution in the 1,718 men of the TELECOM …
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The effects of T supplementation on insulin sensitivity, inflammation-sensitive markers, and apolipoproteins remain poorly understood. We do not know whether T's effects on plasma lipids, apolipoproteins, and insulin sensitivity are dose dependent, or whether significant anabolic effects can be achieved at T doses that do not adversely affect these cardiovascular risk factors. To determine the effects of different doses of T, 61 eugonadal men, 18-35 yr of age, were randomly assigned to 1 of 5 groups to receive monthly injections of long-acting GnRH agonist to suppress endogenous T secretion and weekly injections of 25, 50, 125, 300, or 600 mg T enanthate for 20 wk. Dietary energy and protein intakes were standardized. Combined administration of GnRH agonist and graded doses of T enanthate resulted in nadir T concentrations of 253, 306, 542, 1345, and 2370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Plasma high density lipoprotein cholesterol and apolipoprotein A-I concentrations were inversely correlated with total and free T concentrations and were significantly decreased only in the 600 mg/wk group (change in high density lipoprotein cholesterol: -8 +/- 2 mg/dl; P = 0.0005; change in apolipoprotein A-I: -16 +/- 2 mg/dl; P = 0.0001). Serum total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, and apolipoprotein C-III were not significantly correlated with T dose or concentration. There was no significant change in total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, or apolipoprotein C-III levels at any dose. The insulin sensitivity index, glucose effectiveness, and acute insulin response to glucose, derived from the insulin-modified, frequently sampled, iv glucose tolerance test using the Bergman minimal model, did not change significantly at any dose. Circulating levels of C-reactive protein were not correlated with T concentrations and did not change with treatment in any group. Significant increments in fat-free mass, muscle size, and strength were observed at doses that did not affect cardiovascular risk factors. Over a wide range of doses, including those associated with significant gains in fat-free mass and muscle size, T had no adverse effect on insulin sensitivity, plasma lipids, apolipoproteins, or C-reactive protein. Only the highest dose of T (600 mg/wk) was associated with a reduction in plasma high density lipoprotein cholesterol and apolipoprotein A-I. Long-term studies are needed to determine whether T supplementation of older men with low T levels affects atherosclerosis progression.
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Serum androgen levels decline with aging in normal males, such that a significant number of men over 60 yr of age will have a mean serum total testosterone (T) level near the low end of the normal adult range. It is not known whether lower T levels in older men have an effect on androgen-responsive organ systems, such as muscle, bone, bone marrow, and prostate, nor are there data to evaluate the relative benefits and risks of T supplementation in older men. We assessed the physiological and biochemical effects of T therapy in 13 healthy men, 57-76 yr old, who had low or borderline low serum T levels (< or = 13.9 nmol/L). Intramuscular testosterone enanthate (TE; 100 mg weekly) and placebo injections were given for 3 months each. Before treatment and at the end of both 3-month treatment regimens, lean body mass, body fat, biochemical parameters of bone turnover, hematological parameters, lipoprotein profiles, and prostate parameters [such as prostate-specific antigen (PSA)] were evaluated. Serum T levels rose in all subjects with TE treatment, such that the lowest level of T during a week's period was 19.7 +/- 0.7 nmol/L (mean +/- SE). After 3 months of TE treatment, lean body mass was significantly increased, and urinary hydroxyproline excretion was significantly depressed. With TE treatment, there was a significant increase in hematocrit, a decline in total cholesterol and low density lipoprotein cholesterol, and a sustained increase in serum PSA levels. Placebo treatment led to no significant changes in any of these parameters. We conclude that short term (3 months) TE supplementation to healthy older men who have serum T levels near or below the lower limit of normal for young adult men results in an increase in lean body mass and possibly a decline in bone resorption, as assessed by urinary hydroxyproline excretion, with some effect on serum lipoproteins, hematological parameters, and PSA. The sustained stimulation of PSA and the increase in hematocrit that occur with physiological TE supplementation suggest that older men should be screened carefully and followed periodically throughout T therapy.
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Plasma insulin is a risk factor for diabetes mellitus and cardiovascular disease in men. We investigated the association between plasma testosterone and plasma insulin in an occupational sample of 1292 healthy adult men. Total plasma testosterone decreased with each decade of age and insulin increased with each decade of age. In these cross-sectional data, this significant graded inverse association between testosterone and insulin was independent of age. The association was reduced but not explained by the addition of obesity and subscapular skinfold to the model. Adjustment for alcohol consumption, cigarette smoking and plasma glucose did not materially alter the association. These results are the reverse of the positive association of androgens with insulin in women and suggest alternative possible explanations for the effect of hyperinsulinaemia on cardiovascular disease risk. Prospective studies will be necessary to determine the direction and causal nature of this association.
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Studied relationship in serum concentration of testosterone and lipids in 35 men with a positive coronarographic finding and 30 sterile men, in comparison with a control group. From lipid parameters we determined serum concentration of cholesterol, triacylglycerols and apolipoprotein B, and lipid distribution in lipoprotein fractions. Serum testosterone concentration was found decreased in both the group as against the controls. As to lipid parameters, cholesterol concentration was depressed in the high-density lipoprotein (HDL) fraction of both the clinical groups. As increased apolipoprotein B level was seen in men with the positive coronarographic finding. The results point to a negative effect of lowered testosterone concentrations on lipid metabolism.
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Twenty-three healthy men (age 25 to 50 years), covering a wide range of fatness and body fat distribution, were studied. An oral glucose tolerance test was performed and adipose tissue areas were calculated from computed tomography (CT) scans made at the level of L4/L5. Visceral fat area was associated with elevated concentrations of insulin and C-peptide and with glucose intolerance before and after the oral glucose load. Concentrations of sex-hormone-binding globulin (SHBG), as well as total and free testosterone, were negatively correlated with waist/hip circumference ratio and visceral fat area and also negatively associated with increased glucose, insulin, and C-peptide concentrations. In multiple linear regression, adjusting for age, body mass index, and visceral fat area, serum concentrations of free testosterone were still negatively correlated with glucose, insulin, and C-peptide levels. Without claiming any causality in the observed associations, we conclude that, unlike in women, abdominal fat distribution, insulin, glucose, and C-peptide levels are negatively associated with serum testosterone levels in men.
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Low plasma testosterone and high levels of the rapid inhibitor of plasminogen activator (PA-I) have been proposed as risk factors for myocardial infarction. In this study, the relationship between testosterone and PA-I activity levels in middle-aged men without thrombotic antecedent was investigated. In 54 normogonadic men (testosterone, 7.3 to 29.1 nmol/L), PA-I was related positively to body mass index (BMI) and triglycerides and negatively to testosterone. When these variables were controlled, the relation between PA-I and testosterone remained significant (P less than .01). In the 41 normogonadic men with BMI less than 25, testosterone was the only variable to influence PA-I. Fibrinolytic activity was evaluated by the euglobulin lysis plate method and the specific measurement of functional tissue plasminogen activator. The basal fibrinolytic activity and the response to venous occlusion were essentially controlled by PA-I but were not significantly related to testosterone. In 17 men with severe hypogonadotrophinic hypogonadism (testosterone less than 3 nmol/L), PA-I was significantly increased (18.5 +/- 1.8 AU/mL, mean +/- SE) compared with 9.5 +/- 0.8 AU/mL in 41 normogonadic men of normal weight (P less than .001). However, 14 hypogonadic men had a hypertriglyceridemia or a BMI greater than 25, which could explain high PA-I levels. This study shows that the level of the inhibitor of plasminogen activator is partly dependent on hormonal status in men and provides a link between independently established epidemiologic data.
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A cross-sectional study was performed to see if the previously described association between high density lipoprotein (HDL) cholesterol and plasma total testosterone concentration reflected a relationship with free testosterone or with sex hormone binding globulin (SHBG). In 295 employed middle-aged men, measurements were made of total testosterone and SHBG in serum and of testosterone in saliva, and also of plasma total and HDL cholesterol, plasma triglycerides and other factors which might influence HDL cholesterol levels such as body mass index, alcohol and smoking habits and thyroid hormone levels. In a multiple regression analysis using the GLIM package programme total testosterone concentrations had a persistent positive association with HDL cholesterol (t = 3.5, P less than 0.001) - this association was independent of SHBG (which had a negative association with HDL: t = -1.8, P less than 0.07. The association of HDL cholesterol with testosterone was independent of and stronger than the association of HDL cholesterol with body mass index, alcohol intake and cigarette smoking. Salivary testosterone (a measure of the circulating free hormone) also had a positive independent association with HDL cholesterol. The relationship between HDL cholesterol and testosterone thus appears to reflect an association with circulating hormone levels rather than with the hormone binding globulin.
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High-density lipoprotein (HDL) cholesterol is inversely associated with risk of heart attack. Sex hormones have been suggested as possible factors contributing to the gender difference of coronary heart disease risk. Little is known about how endogenous sex hormone concentration might be related to HDL cholesterol. The relation was examined in 225 men participating in the Multiple Risk Factor Intervention Trial. Plasma testosterone concentration was positively correlated with HDL cholesterol and the change in testosterone concentration was also positively correlated with change in HDL cholesterol. The relation between testosterone and HDL cholesterol could not be fully explained by age, relative weight, alcohol consumption and cigarette smoking in the cross-sectional study. However, when this relation was examined longitudinally, the partial correlation between changes in testosterone and HDL cholesterol did not quite achieve statistical significance (0.05 less than p less than 0.10). The biologic process that relates HDL cholesterol to testosterone is not known. The results suggest an inverse relation between plasma estradiol concentration and low-density lipoprotein cholesterol, but no statistical significant correlation with HDL cholesterol. In addition, there was no association noted in the current research between estradiol concentrations and the known determinants of HDL cholesterol.
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Objectives: The relation between endothelium-dependent vasodilator function in the brachial and coronary arteries was determined in the same subjects. Background: Coronary artery endothelial dysfunction precedes the development of overt atherosclerosis and is important in its pathogenesis. A noninvasive assessment of endothelial function in a peripheral conduit vessel, the brachial artery, was recently described, but the relation between brachial artery function and coronary artery vasodilator function has not been explored. Methods: In 50 patients referred to the catheterization laboratory for the evaluation of coronary artery disease (mean age +/- SD 56 +/- 10 years), the coronary vasomotor response to serial intracoronary infusions of the endothelium-dependent agonist acetylcholine (10(-8) to 10(-6) mol/liter), was studied. Endothelium-dependent vasodilation was also assessed in the brachial artery by measuring the change in brachial artery diameter in response to reactive hyperemia. Results: Patients with coronary artery endothelial dysfunction manifested as vasoconstriction in response to acetylcholine had significantly impaired flow-mediated vasodilation in the brachial artery compared with that of patients with normal coronary endothelial function (4.8 +/- 5.5% vs. 10.8 +/- 7.6%, p < 0.01). Patients with coronary artery disease also had an attenuated brachial artery vasodilator response compared with that of patients with angiographically smooth coronary arteries (4.5 +/- 4.6% vs. 9.7 +/- 8.1%, p < 0.02). By multivariate analysis, the strongest predictors of reduced brachial dilator responses to flow were baseline brachial artery diameter (p < 0.001), coronary endothelial dysfunction (p = 0.003), the presence of coronary artery disease (p = 0.007) and cigarette smoking (p = 0.016). The brachial artery vasodilator response to sublingual nitroglycerin was independent of coronary endothelial responses or the presence of coronary artery disease. The positive predictive value of abnormal brachial dilation ( < 3%) in predicting coronary endothelial dysfunction is 95%. Conclusions: This study demonstrated a close relation between coronary artery endothelium-dependent vasomotor responses to acetylcholine and flow-mediated vasodilation in the brachial artery. This noninvasive method may become a useful surrogate in assessing the predisposition to atherosclerosis in patients with cardiac risk factors.
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Studies on regional differences of adipose tissue metabolism have mainly been performed in vitro. To allow measurements of lipid uptake in vivo in man, radioactive label from [9,10-3H]oleic acid in 80 g orally administered milk fat was measured after 4 h in abdominal and femoral sc adipose tissues in 28 middle-aged, abdominally obese men. Radioactivity was measured in adipose tissue triglycerides extracted from needle biopsies. Lipoprotein lipase (LPL) activity was also measured. Uptake of label in triglycerides and LPL activity were higher (20% and 15%, respectively; P < 0.05) in the abdominal compared to the femoral adipose tissue region. The men were then randomly assigned to three groups, receiving testosterone (T), dihydrotestosterone, or placebo, for 9 months. After 2 months of treatment, the procedure of administration of label was repeated, this time using [U-14C]oleic acid as a marker. Measurements of radioactive label was then performed after 4 h and monthly up to 7 months. Supplementation with T was followed by an inhibited uptake of label in triglycerides (34%; P < 0.05), lower LPL activity (48%; P < 0.05), and a shorter t1/2 (30%; P < 0.05) in the abdominal adipose tissue region compared with the dihydrotestosterone and placebo groups. No significant effect of T on triglyceride uptake, LPL activity, or t1/2 was found in sc femoral adipose tissue. It was concluded that the turnover rate of depot triglycerides is more rapid in abdominal compared to femoral sc adipose tissue in men. Furthermore, T supplementation inhibits triglyceride uptake and LPL activity and causes a more rapid turnover of triglycerides only in the sc abdominal adipose tissue region. These results demonstrate the marked effects of T on adipose tissue metabolism in vivo and suggest that T is an important regulator of the proportion of depot fat mass in central and peripheral adipose tissue in men.