Revascularization with percutaneous coronary intervention does not affect androgen status in males with chronic stable angina pectoris.

There is a clear association between low serum testosterone and coronary artery disease (CAD) in men. Hypotestosteronaemia is associated with accelerated atherosclerosis and a quarter of men with CAD are biochemically hypogonadal. Amongst those with CAD, hypotestosteronaemia is associated with increased mortality. Testosterone vasodilates coronary arteries, and exogenous testosterone reduces ischaemia. Whether hypotestosteronaemia is a cause or a consequence of CAD remains unanswered. The aim of this prospective observational study was to investigate whether coronary revascularization affected androgen status in men with stable angina pectoris. Twenty five men (mean age 62.7, SD 9.18) with angiographically significant CAD and symptomatic angina underwent full coronary revascularization by percutaneous coronary intervention. Androgen status and symptoms of angina, stress, depression and sexual function were assessed before, and at one and 6 months after the coronary revascularization. All patients underwent complete revascularization which was associated with a significant reduction in angina symptoms and ischaemia. No significant difference was seen in total testosterone (11.33 nmol/L baseline; 12.56, 1 month post; 13.04 at 6 months; p = 0.08). A significant and sustained rise in sex hormone-binding globulin was seen (33.99 nm/L baseline; 36.11 nm/L 1 month post PCI; 37.94 nm/L at 6 months; p = 0.03) Overall, there was no significant alteration in any other marker of androgen status including free testosterone or bioavailable testosterone. There was no change in symptoms of anxiety, depression or sexual function. Coronary revascularization has no sustained effect on androgen status. This supports the hypothesis that hypotestosteronaemia is not a consequence of angina pectoris or myocardial ischaemia.

Poverty and suicide research in low- and middle-income countries: systematic mapping of literature published in English and a proposed research agenda.

Approximately 75% of suicides occur in low- and middle-income countries (LMICs) where rates of poverty are high. Evidence suggests a relationship between economic variables and suicidal behaviour. To plan effective suicide prevention interventions in LMICs we need to understand the relationship between poverty and suicidal behaviour and how contextual factors may mediate this relationship. We conducted a systematic mapping of the English literature on poverty and suicidal behaviour in LMICs, to provide an overview of what is known about this topic, highlight gaps in literature, and consider the implications of current knowledge for research and policy. Eleven databases were searched using a combination of key words for suicidal ideation and behaviours, poverty and LMICs to identify articles published in English between January 2004 and April 2014. Narrative analysis was performed for the 84 studies meeting inclusion criteria. Most English studies in this area come from South Asia and Middle, East and North Africa, with a relative dearth of studies from countries in Sub-Saharan Africa. Most of the available evidence comes from upper middle-income countries; only 6% of studies come from low-income countries. Most studies focused on poverty measures such as unemployment and economic status, while neglecting dimensions such as debt, relative and absolute poverty, and support from welfare systems. Most studies are conducted within a risk-factor paradigm and employ descriptive statistics thus providing little insight into the nature of the relationship. More robust evidence is needed in this area, with theory-driven studies focussing on a wider range of poverty dimensions, and employing more sophisticated statistical methods.

The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study.

CONTEXT: The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables. OBJECTIVE: To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study. DESIGN: Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled and parallel group study. SETTING: Outpatient study recruiting from secondary and primary care. PATIENTS: A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study. INTERVENTION: Testosterone 2% transdermal gel vs placebo. MAIN OUTCOME MEASURE: Regression coefficient of AR CAG from linear regression models for each variable. RESULTS: AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR - the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity. CONCLUSION: AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.

Dyslipidaemia is associated with testosterone, oestradiol and androgen receptor CAG repeat polymorphism in men with type 2 diabetes.

OBJECTIVE: There is a high prevalence of low testosterone and dyslipidaemia in men with type 2 diabetes. The androgen receptor CAG repeat polymorphism (AR CAG) affects receptor transcriptional activity (the shorter repeats the more sensitive AR) and is associated with androgenic parameters and obesity. This study describes the relationships between testosterone, AR CAG and serum lipids in men with type 2 diabetes. DESIGN AND PATIENTS: Cross-sectional study of men with type 2 diabetes in a District General Hospital Diabetes Centre. MEASUREMENTS: Correlation between testosterone, AR CAG and serum lipids. RESULTS: HDL cholesterol (HDL-C) correlated with total testosterone (TT) (r = 0·251, P < 0·001), bioavailable testosterone (BT) (r = 0·19, P = 0·001), free testosterone (FT) (r = 0·165, P = 0·005) and sex hormone-binding globulin (SHBG) (r = 0·147, P = 0·014). HDL-C did not correlate with oestradiol, but men with the lowest quartile of oestradiol had lower HDL-C compared to highest quartile (P = 0·046). Triglycerides correlated negatively with TT (r = -0·195, P = 0·001), BT (r = -0·148, P = 0·013) and SHBG (-0·14, P = 0·019) but not with FT or oestradiol. Total and LDL cholesterol (LDL-C) correlated negatively with oestradiol (r = -0·121, P = 0·05) but not with testosterone or SHBG. One-way anova testing across four quartiles of AR CAG showed a trend to alteration in HDL-C across groups of AR CAG (P = 0·08). HDL-C was significantly higher in men with the longest AR CAG compared with the shortest (1·19 vs 1·08 mmol/l, P = 0·02). CONCLUSIONS: Lower testosterone and oestradiol levels in men with diabetes are associated with an adverse lipid profile. Shorter AR CAG is associated with low HDL-C and testosterone. The paradox that HDL-C is associated with low testosterone levels and a more active AR may suggest divergent effect of testosterone on HDL-C via genomic vs nongenomic mechanisms.

Testosterone acts as an efficacious vasodilator in isolated human pulmonary arteries and veins: evidence for a biphasic effect at physiological and supra-physiological concentrations.

BACKGROUND: Testosterone is recognized to elicit vasodilatation in numerous vascular beds, however to date no study has investigated whether testosterone has this effect in the human pulmonary vasculature. AIM: To determine whether isolated human pulmonary arteries and veins dilate in response to testosterone and whether the response differs in relation to gender, endothelial function or location with the pulmonary vasculature. METHODS: Intralobar pulmonary arteries [no.=44, diameter =581 (349) microm] and veins [no.=27, diameter =573 (302) microm] were dissected from lobectomy samples obtained from male and female patients [no.=40, age =69 (8) yr]. Vessels were mounted in an automated wire myograph, bathed in physiological saline at 37 C and pH 7.4, and loaded to their in vivo pressure. Vessels were preconstricted with noradrenaline (10 microM) and exposed to acetylcholine (1 microM) to assess endothelial function, washed and then preconstricted with potassium chloride (1-100 mM) followed by either cumulative concentrations of testosterone (1 nM-100 microM) or ethanol vehicle (<0.1%). RESULTS: Significant marked vasodilatation was seen in all vessels, irrespective of size, gender and endothelial function at micromolar concentrations. Testosterone triggered significant vasodilatation at concentrations > or = 10 nM in pulmonary arteries obtained from males, a response which was not observed in vessels from females. The maximal response at 100 microM was also significantly greater in male pulmonary arteries. Significant vasodilatation was only observed at physiological (nM) concentrations in pulmonary resistance arteries and pulmonary arteries with good endothelial function. CONCLUSION: Testosterone acts as an efficacious vasodilator in the human pulmonary vasculature, with dilatation observed at physiological concentrations in the male arterial resistance bed, dependent on the presence of an intact endothelium.

Chronic atrial fibrillation: a systematic review of medical heart rate control management.

OBJECTIVE: Recent guidelines by the National Institute for Health and Clinical Excellence (NICE) and the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) on rate control management for chronic atrial fibrillation have relegated digoxin to second line treatment, recommending instead the use of beta-blockers or rate limiting calcium antagonists as first line treatment. The objective of this review is to assess the efficacy of these drugs in controlling heart rate, and in improving symptoms and exercise tolerance. DATA SOURCES: We electronically searched the Medline, Embase and Cochrane databases, hand searched journals and relevant bibliographies for articles. SELECTION OF STUDIES: We included all study designs evaluating or comparing oral digoxin, beta-blockers and calcium antagonists, alone or in combination, for rate control in chronic atrial fibrillation. 46 studies satisfied our inclusion and quality criteria. RESULTS: Published studies are small and too heterogeneous to be quantitatively combined. Descriptive synthesis of the data shows little evidence that monotherapy with beta-blockers or calcium antagonists improves symptoms or exercise capacity in patients with chronic atrial fibrillation. Instead it is associated with dose related side effects. CONCLUSION: Based on the limited data available, we conclude that the combination of digoxin with either a beta-blocker or calcium antagonist should be first line management in patients with chronic atrial fibrillation.

Testosterone and coronary artery disease.

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.

Testosterone in chronic heart failure.

Chronic heart failure is common and can be described as a syndrome characterized by impairment of cardiac function associated with a maladaptive metabolic and neurohormonal axis. The thesis that testosterone replacement therapy may be helpful as a treatment for chronic heart failure may seem at first to be unlikely. Testosterone therapy is widely believed to be deleterious to the cardiovascular system and there is a common misconception that the excess of ischaemic heart disease in young and middle-aged males compared to females is a direct effect of endogenous serum testosterone levels. In this chapter we will present the published evidence of the effects of endogenous and therapeutic testosterone on the heart and the human cardiovascular system with an emphasis on the pathologic syndrome of chronic heart failure. There is developing evidence that of all morbid populations, patients with chronic heart failure in particular are likely to benefit from testosterone treatment since the natural history is that of progressive disordered metabolism with catabolic excess and androgen imbalance.

Androgen receptor CAG repeat polymorphism is associated with serum testosterone levels, obesity and serum leptin in men with type 2 diabetes.

OBJECTIVE: To determine the relationships between androgen receptor CAG repeat polymorphism length (AR CAG), sex hormones and clinical variables in men with type 2 diabetes (DM2). Men with DM2 are known to have a high prevalence of low testosterone levels. Studies suggest that testosterone replacement therapy may improve insulin sensitivity and glycaemic control in men with DM2 and reduces central obesity and serum leptin. AR CAG is known to correlate negatively with AR sensitivity and positively with body fat, insulin levels, and leptin in healthy men. DESIGN: Cross-sectional study set in a district general hospital diabetes centre. METHODS: Sex hormones, AR CAG and symptoms of hypogonadism were assessed in 233 men with DM2. Associations were sought between these variables and others such as obesity, leptin, glycaemic control, and blood pressure. RESULTS: Testosterone was negatively associated and AR CAG positively associated with obesity and leptin. The associations of AR CAG with leptin and obesity were independent of testosterone, estradiol, gonadotropins, and age. AR CAG was also independently associated with total, bioavailable and free testosterone, LH, waist circumference, body mass index, leptin, and systolic blood pressure. There was no association of AR CAG with sex hormone binding globulin, estradiol, HbA(1C) or the symptoms of hypogonadism. CONCLUSIONS: The association of longer AR CAG with obesity and leptin suggests that shorter AR CAG may have an influence in maintaining healthy anthropomorphics and metabolism in men with DM2. Testosterone and LH levels are higher in men with longer AR CAG, probably reflecting reduced negative feedback through a less sensitive receptor.

The triad of erectile dysfunction, hypogonadism and the metabolic syndrome.

AIM: To identify the relationship of erectile dysfunction, hypogonadism and the metabolic syndrome in the context of men's health. METHODS: An Expert Panel Meeting was held in December 2006 in Vienna, Austria. In addition a comprehensive literature search was conducted. RESULTS: Men have a higher incidence of cardiovascular events than women of similar ages which has led to the belief that testosterone is a risk factor for cardiovascular disease in men. The latter hypothesis is no longer tenable. On the contrary, low testosterone levels are associated with (visceral) obesity, the metabolic syndrome, diabetes mellitus, cardiovascular disease and erectile dysfunction (ED). Testosterone therapy does not lead to an increased incidence of cardiovascular disease or events such as myocardial infarction, stroke or angina. Until recently (visceral) obesity, the metabolic syndrome, diabetes mellitus, cardiovascular disease and ED were viewed as more or less independent entities affecting the ageing male. It was not recognised that hypogonadism is a common denominator. With a more integrative approach to the health situation of middle-aged and elderly men, these conditions appear closely interrelated in their manifestations, hypothetically in their aetiology, diagnostic strategy and also their treatment. CONCLUSION: Improving sexual health is a portal to identify health hazards and improving men's health. Appropriate diagnosis and medical work up of men presenting with sexual symptoms may have the benefit of the diagnosing and treating other important conditions, such as obesity, diabetes, hypertension and hyperlipidaemia.

Erectile dysfunction is associated with low bioactive testosterone levels and visceral adiposity in men with type 2 diabetes.

Low testosterone levels in men are associated with type 2 diabetes mellitus. Erectile dysfunction (ED) is a frequent complication of type 2 diabetes. The aim of our cross-sectional study was to investigate the relationship between ED and total, bioavailable and free testosterone levels in 198 men with type 2 diabetes. In addition, we examined the associations of various cardiovascular risk factors involved in the development of ED in type 2 diabetic men. We found that bioavailable and free testosterone levels were significantly lower in men with ED (p = 0.006 and 0.027 respectively) than those without ED. Sex hormone-binding globulin levels were also reduced, but there was no significant difference in total testosterone (TT) levels between men with and without ED. The severity of ED as assessed by International Index of Erectile Function scores was significantly associated with TT (r = 0.32; p < 0.001), bioavailable testosterone (r = 0.32; p < 0.001) and calculated free testosterone (r = 0.35; p < 0.001) levels. ED was more frequently observed in men with hypertension and a higher waist circumference (p = 0.03). There was also a higher prevalence of ED among smokers (p = 0.06), but there were no significant associations between ED and alcohol consumption or with BMI > 30. This study has shown that ED is associated with low bioavailable and free testosterone levels, age, visceral adiposity and hypertension in type 2 diabetic men.

An evaluation of the effects of Tai Chi Chuan and Chi Kung training in patients with symptomatic heart failure: a randomised controlled pilot study.

OBJECTIVE: To study the effect of Tai Chi on exercise tolerance in patients with moderate heart failure. DESIGN: Randomised parallel group study balanced for baseline variables. SETTING: Cardiology Department, Royal Hallamshire Hospital. PATIENTS AND METHODS: 52 patients (42 men, mean age (68.9 years), range (46-90 years), and 10 women, mean age (70.0 years), range (58-82)) with chronic heart failure (New York Heart Association symptom class II-III) were studied. Patients were randomised to Tai Chi Chuan twice a week for 16 weeks or to standard medical care without exercise rehabilitation. MAIN OUTCOME MEASURES: The primary outcome measure was the change in the distance walked in the shuttle walk test. Secondary outcome measures were changes in symptom scores and quality of life indices. RESULTS: Objective measures of exercise tolerance did not improve significantly with Tai Chi, but patients having Tai Chi exercise had an improvement in symptom scores of heart failure measured by the Minnesota Living with Heart Failure Questionnaire (comparison of deltas, -2.4 control vs -14.9; p = 0.01), and depression scores measured by the SCL-90-R questionnaire (-2.9 vs -6.8; p = 0.12) compared with those patients in the control group. CONCLUSION: In patients with chronic heart failure, 16 weeks of Tai Chi training was safe, with no adverse exercise related problems. It was enjoyed by all taking part and led to significant improvements in symptoms and quality of life.

The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes.

OBJECTIVE: Serum testosterone levels are known to inversely correlate with insulin sensitivity and obesity in men. Furthermore, there is evidence to suggest that testosterone replacement therapy reduces insulin resistance and visceral adiposity in type 2 diabetic men. Adipocytokines are hormones secreted by adipose tissue and contribute to insulin resistance. We examined the effects of testosterone replacement treatment on various adipocytokines and C-reactive protein (CRP) in type 2 diabetic men. DESIGN: Double-blinded placebo-controlled crossover study in 20 hypogonadal type 2 diabetic men. Patients were treated with testosterone (sustanon 200 mg) or placebo intramuscularly every 2 weeks for 3 months in random order followed by a washout period of 1 month before the alternate treatment phase. METHODS: Leptin, adiponectin, resistin, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and CRP levels were measured before and after each treatment phase. Body mass index (BMI) and waist circumference were also recorded. RESULTS: At baseline, leptin levels significantly correlated with BMI and waist circumference. There was a significant inverse correlation between baseline IL-6 and total testosterone (r=-0.68; P=0.002) and bioavailable testosterone levels (r=-0.73; P=0.007). CRP levels also correlated significantly with total testosterone levels (r=-0.59; P=0.01). Testosterone treatment reduced leptin (-7141.9 +/- 1461.8 pg/ml; P=0.0001) and adiponectin levels (-2075.8 +/- 852.3 ng/ml; P=0.02). There was a significant reduction in waist circumference. No significant effects of testosterone therapy on resistin, TNF-alpha, IL-6 or CRP levels were observed. CONCLUSION: Testosterone replacement treatment decreases leptin and adiponectin levels in type 2 diabetic men. Moreover, low levels of testosterone in men are associated with pro-inflammatory profile, though testosterone treatment over 3 months had no effect on inflammatory markers.

Inverse relationship between serum levels of interleukin-1beta and testosterone in men with stable coronary artery disease.

OBJECTIVES: To examine the relationship between serum levels of inflammatory cytokines and testosterone in men with stable coronary artery disease (CAD). Evidence supports a beneficial effect of testosterone upon objective measures of myocardial ischaemia in men with CAD, and in animal models of atherosclerosis. Inflammatory cytokines are involved in many stages of the atherosclerotic process, however, the effect of testosterone upon inflammatory cytokines within the cardiovascular system is largely unknown. METHODS: Serum was collected from 69 men (59+/-1 years) having >75% occlusion of 1, 2, or 3 coronary arteries. Levels of total testosterone (TT), bioavailable testosterone (BT), tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1-beta (IL-1beta), IL-6 and IL-10 were measured and analysis made between men with 1, 2, or 3 vessel CAD, and between men with hypogonadal, borderline hypogonadal and eugonadal serum levels of testosterone. RESULTS: In patients with 1, 2, or 3 vessel CAD, significant stepwise increases were observed in levels of IL-1beta: 0.16+/-0.03, 0.22+/-0.06, and 0.41+/-0.08 pg/ml (p=0.035), and IL-10: 0.93+/-0.11, 1.17+/-0.14, and 2.94+/-0.65 pg/ml (p=0.008). A significant stepwise increase in levels of IL-1beta was also observed in eugonadal, borderline hypogonadal, and hypogonadal men: 0.19+/-0.05, 0.29+/-0.05, and 0.46+/-0.13 pg/ml (p=0.047). CONCLUSION: Consequently this data implicates IL-1beta and IL-10 in the pathogenesis of CAD and suggests that testosterone may regulate IL-1beta activity in men with CAD.

Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.

OBJECTIVE: Low levels of testosterone in men have been shown to be associated with type 2 diabetes, visceral adiposity, dyslipidaemia and metabolic syndrome. We investigated the effect of testosterone treatment on insulin resistance and glycaemic control in hypogonadal men with type 2 diabetes. DESIGN: This was a double-blind placebo-controlled crossover study in 24 hypogonadal men (10 treated with insulin) over the age of 30 years with type 2 diabetes. METHODS: Patients were treated with i.m. testosterone 200 mg every 2 weeks or placebo for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostatic model index (HOMA) in those not on insulin), fasting blood glucose and glycated haemoglobin. The secondary outcomes were changes in body composition, fasting lipids and blood pressure. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared against the treatment effect of testosterone. RESULTS: Testosterone therapy reduced the HOMA index (-1.73 +/- 0.67, P = 0.02, n = 14), indicating an improved fasting insulin sensitivity. Glycated haemoglobin was also reduced (-0.37 +/- 0.17%, P = 0.03), as was the fasting blood glucose (-1.58 +/- 0.68 mmol/l, P = 0.03). Testosterone treatment resulted in a reduction in visceral adiposity as assessed by waist circumference (-1.63 +/- 0.71 cm, P = 0.03) and waist/hip ratio (-0.03 +/- 0.01, P = 0.01). Total cholesterol decreased with testosterone therapy (-0.4 +/- 0.17 mmol/l, P = 0.03) but no effect on blood pressure was observed. CONCLUSIONS: Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes. Improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk.

Junior doctors and the full shift rota--psychological and hormonal changes: a comparative cross-sectional study.

We studied the hormonal and psychological effect of the full shift rota on junior doctors after implementation of the European Working Time Directive, using a comparative, cross-sectional study design of male doctors in South Yorkshire. Cortisol and testosterone levels were measured and subjects completed the general health questionnaire (GHQ-12) and the androgen deficiency in the aging male screening questionnaire (ADAM), after a week of holiday (baseline), a week of nights, and a normal working week. The results showed that cortisol levels decreased from 480.6 +/- 33.1 nmol/l at baseline (after a week of holiday), to 355.7 +/- 29.1 nmol/l post normal working week (p = 0.003); to 396.7 +/- 32.5 nmol/l post nights (p = 0.03). GHQ-12 scores increased from 0.5 +/- 0.3 at baseline, to 1.8 +/- 0.5 post normal working week (p = 0.02) and to 2.3 +/- 0.5 post nights (p = 0.005). These results suggest that there are still appreciable physiological consequences with new work patterns.

Selective inhibition of L-type Ca2+ channels in A7r5 cells by physiological levels of testosterone.

Testosterone has marked beneficial cardiovascular effects, many of which have been attributed to a vasodilatory action. However, the molecular target of testosterone underlying this effect is subject to debate. In this study, we have used microfluorimetry as a noninvasive means of examining whether testosterone could exert dilatory effects via inhibition of voltage-gated Ca2+ entry in the model vascular smooth muscle cell line, A7r5. Rises of [Ca2+]i evoked by 50 mm K+ -containing solution were suppressed in a concentration-dependent manner by testosterone (IC50, 3.1 nm) and by the nonaromatizable analog, 5beta-dihydrotestosterone (IC50, 6.9 nm). The effects of testosterone were apparent in the presence of pimozide (to block T-type Ca2+ channels) but not nifedipine (to block L-type Ca2+ channels). Testosterone did not alter Ca2+ mobilization from intracellular stores by the prostaglandin analog U46619 or capacitative Ca2+ entry in cells pretreated with thapsigargin. Our results indicate that testosterone, at physiological concentrations, can selectively suppress Ca2+ entry into A7r5 cells via L-type Ca2+ channels. We suggest this effect is a likely mechanism underlying its vasodilatory actions and beneficial cardiovascular effects.

The influence of sex hormones on pulmonary vascular reactivity: possible vasodilator therapies for the treatment of pulmonary hypertension.

Pulmonary hypertension is a rare disease of the pulmonary vasculature defined as a mean pulmonary artery pressure >25 mmHg at rest or 30 mmHg with exercise. Recent therapies such as epoprostenol, bosentan and sildenafil are directed at the arterial vascular bed, causing vasodilatation and reducing pulmonary vascular resistance. However idiopathic pulmonary artery hypertension (IPAH) occurs predominantly in women, with three times the incidence compared to men and this suggests that sex hormones may be involved in the pathogenesis. 17beta -oestradiol is a pulmonary vasodilator, proposed to act via an endothelium-dependant pathway, involving nitric oxide (NO) and has also been shown to alter responses to hypoxia. Progesterone is also a pulmonary vasodilator but differs from 17beta-oestradiol in having endothelial-dependant and independent processes implicated. Interestingly testosterone has been shown to be a vasodilator in both the coronary and pulmonary circulation with a mechanism of action involving calcium channel blockade of the vascular smooth muscle and without endothelial involvement. In clinical trials testosterone confers symptomatic benefits in patients with coronary heart disease and heart failure, acting as a vasodilator. These observations lend support to the notion that testosterone could be a potential treatment for patients with PAH as vasodilator therapy remains the mainstay of treatment. Other potential beneficial effects of testosterone in the pulmonary circulation include immuno-modulation, altering expression of cytokines and an anti-thrombotic action. In this review the influence of sex hormones on the pulmonary vasculature will be discussed, with specific focus on pulmonary hypertension and the potential treatment of this condition.

The role of vasopressin in cardiorespiratory arrest and pulmonary hypertension.

Vasopressin is a peptide synthesized in the hypothalamus whose primary role is in fluid homeostasis. It has recently gained interest as a potential agent in the treatment of cardiorespiratory arrest. Initial human studies have shown benefits with vasopressin in patients with out of hospital ventricular fibrillation and asystolic cardiac arrest. One subgroup of patients not included in these trials is patients with pulmonary hypertension, who have a five-year mortality rate of 50%. Animal studies have shown vasopressin to be a vasodilator in the pulmonary vascular system of rats, under normoxic and hypoxic conditions, with conflicting results in canines. Human studies have shown conflicting results with increases, decreases and no changes seen in pulmonary artery pressures of patients with a variety of clinical conditions. Research needs to be done in patients with pulmonary hypertension regarding the potential role of vasopressin during cardiac arrest in this subgroup.