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Androgenic deficit and its treatment in stroke male patients with diabetes mellitus type II
Abstract
We have studied 154 men (mean age 61,4+/-4,1 years) with the first hemispheric ischemic stroke. Clinical and laboratory studies have revealed the androgenic deficit in 66,3%, with its frequency higher in patients with diabetes mellitus type II (50 and 26,3%, respectively). Forty-two men with diabetes mellitus type II and acquired androgenic deficit received replacing treatment with testosterone undecanoate in dose 1000 mg intramuscular. The treatment was started one week after the development of stroke, the next injections were given after 6 weeks and then every 12 weeks during 2 years. The control group included 30 males who did not receive androgens. After 2 years from the beginning of treatment, there were the decrease in clinical severity of androgenic deficit, the increase of total and free testosterone levels, and muscle power in the main group compared to the controls. Body mass index, glicated hemoglobin, cholesterol, triglycerides, low density lipoproteins have decreased as well. Secondary stroke has developed in 3 (7,1%) patients of the main group and in 5 (16,6%) controls; 12 (28,6%) patients returned to work in the main group compared to 2 (6,6%) in the control group. The treatment with androgens has a positive effect on risk factors of secondary ischemic stroke. It is an effective method for improvement of social adaptation of men survived after the stroke.
... Although there are ongoing controversies regarding the place of testosterone replacement therapy in men with testosterone deficiency not due to primary testicular or pituitary pathology (91), some experts hold the view that, in subjects with low testosterone who also have metabolic abnormalities including T2DM, testosterone replacement therapy may be indicated. In observational cohorts and small scale trials (90), treatment with testosterone in elderly men and men with T2DM with M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 15 testosterone deficiency have been shown to reduce glycemia (92) and compensatory hyperinsulinemia (93), although larger scale randomized studies are needed to confirm these findings. ...
Diabetes is a chronic disease characterized by its silent and progressive nature. The prevalence of type 2 diabetes (T2DM) increases with age, but there is a worrying trend to an increasingly young age of diagnosis. Compared to their counterparts with late onset of disease, these younger subjects face long disease duration with increased risk of diabetes-related complications. Besides, there is marked phenotypic heterogeneity which can interact with different interventions to give rise to variable clinical outcomes. Thus, early detection and diagnosis of T2DM with risk stratification for personalized care remains the cornerstone for the prevention and control of this global health hazard. Recognized at-risk groups include those with a genetic background (family history and ethnic groups) and phenotypes of insulin resistance (obesity, metabolic syndrome, women with gestational diabetes or polycystic ovarian syndrome, and men with androgen deficiency), specifically those already have “pre-diabetes” (impaired glucose tolerance and impaired fasting glucose). There are also considerable interactions amongst these risk factors which amplify the risk for diabetes, thus calling for the use of risk scores to better identify high risk subjects. Raising awareness and health literacy, regular screening of high risk subjects, structured lifestyle and behavioral modifications including early use of pharmacological agents, individualized therapies to address the predominant pathophysiological defects offers a personalized approach to the prevention and control T2DM and its co-morbidities.
... In the testosterone-treated group, 7% had a recurrence of stroke in 2 years versus 16.6% in the control group, with 28% of the treated men returning to work versus 6% of the control group. There were significant improvements in lipid profile and HbA1c[Morganuv et al. 2011]. ...
While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Some authors blame advertising and the availability of more convenient formulations whilst other have pointed out that the routine testing of men with erectile dysfunction (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous underdiagnosis and undertreatment by adherence to evidence-based guidelines. Urologists and primary care physicians are the most frequent initiators of TRT, usually for erectile dysfunction. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing clearly that therapy associated with clear rise in testosterone levels are associated with reduced mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively they have compared nontreated patients with undertreated or on-compliant subjects involving a range of different therapy regimens. Recent evidence suggests long acting injections may be associated with decreased cardiovascular risk but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5α reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. This paper will attempt to identify who should be treated, and how they should be treated safely to achieve best outcomes, based on a comprehensive MEDLINE and EMBASE and Cochrane searches on hypogonadism, TRT and cardiovascular safety from May 2005 to May 2015. This revealed 1714 papers with 52 clinical trials and 32 placebo-controlled randomized, controlled trials.
... In a recent paper of 145 patients with first ischaemic stroke and diabetes, 66% were found to be hypogonadal, and in the testosterone treated group 7% had a recurrence of stroke in 2 years versus 16.6% in the control group with 28% of the treated men returning to work versus 6% of the control group. There were significant improvements in lipid profile and HbA1c [56]. A recent retrospective US study of 8709 men [57] with baseline TT of 10.4 nmol undergoing coronary angiography involved follow-up for mean 840 days. ...
Low levels of testosterone are manifested by erectile dysfunction, reduced sexual desire, and loss of morning erections with increasing numbers of men are being diagnosed and require treatment. The prevalence rates of testosterone deficiency vary according to different studies but may be as high as 40% in populations of patients with type 2 diabetes. There is increasing evidence that testosterone deficiency is associated with increased cardiovascular and all-cause mortality. Screening for low testosterone is recommended in a number of high risk groups including those with type 2 diabetes and metabolic syndrome. There are recent data to suggest that testosterone replacement therapy may reduce cardiovascular mortality as well as improving multiple surrogate markers for cardiovascular events. Specific clinical trials of testosterone replacement therapy are needed in selected populations but in the meantime we must treat patients based on the best current evidence.
... Several parameters were improved by testosterone replacement on those patients, such as body mass index, glycated hemoglobin, cholesterol, triglycerides, and low-density lipoproteins. Furthermore, only 7.1% of the patients receiving testosterone replacement had a secondary stroke compared with 16.6% in the control group (Morgunov et al., 2011). These data indicate that testosterone replacement may be important to reduce cardiovascular risk factors, especially in type 2 diabetes associated with the hypogonadism condition. ...
Androgen receptors are widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Through classic cytosolic androgen receptors or membrane receptors, testosterone induces genomic and non-genomic effects, respectively. Testosterone interferes with the vascular function by increasing the production of pro-inflammatory cytokines and arterial thickness. Experimental evidence indicates that sex steroid hormones, such as testosterone modulate the synthesis and bioavailability of NO and, consequently, endothelial function, which is key for a healthy vasculature. Of interest, aging itself is accompanied by endothelial and vascular smooth muscle dysfunction. Aging-associated decline of testosterone levels is accompanied by age-related diseases, such as metabolic and cardiovascular diseases, indicating that very low levels of androgens may contribute to cardiovascular dysfunction observed in these age-related disorders or, in other words, that testosterone may have beneficial effects in the cardiovascular system. However, testosterone seems to play a negative role in the severity of renal disease. In this mini-review, we briefly comment on the interplay between aging and testosterone levels, the vascular actions of testosterone and its implications for vascular aging. Renal effects of testosterone and the use of testosterone to prevent vascular dysfunction in elderly are also addressed.
Níveis de testosterona sérica já foram relacionados a piora de fatores hematológicos, função e envelhecimento vascular, contribuindo potencialmente para formação de trombos. Com o envelhecimento, dados epidemiológicos mostram declínio dos níveis de testosterona, prejuízo da função vascular e aumento da incidências de doenças vasculares, como o Acidente Vascular Encefálico (AVE).
Níveis de testosterona sérica já foram relacionados a piora de fatores hematológicos, função e envelhecimento vascular, contribuindo potencialmente para formação de trombos. Com o envelhecimento, dados epidemiológicos mostram declínio dos níveis de testosterona, prejuízo da função vascular e aumento das incidências de doenças vasculares, como o AVE. Objetivo: Descrever estudos que abordaram a potencial relação dos níveis de testosterona com a prevenção, apresentação clínica e prognóstico do AVE. Métodos: Uma pesquisa e seleção de artigos foi conduzida em três diferentes bases de dados (MEDLINE, SCIELO, LILACS) utilizando termos relacionados a testosterona e AVE (inglês e português), filtrada para estudos em humanos. Apenas estudos que abordaram algum aspecto da relação entre testosterona e AVE foram incluídos para discussão no presente estudo. Resultados: A busca resultou em 12 estudos relevantes para análise e discussão (7 observacionais, 3 transversais, 2 experimentais). Estudos observacionais verificaram um papel protetor da testosterona na incidência de AVE. Estudos transversais verificaram alterações endocrinológicas, como o hipogonadismo, na fase aguda do AVE, bem como melhor apresentação clínica (gravidade, tamanho da lesão). Estudos experimentais controlados verificaram benefícios clínicos e funcionais da suplementação de testosterona em pacientes em reabilitação. Conclusão: Apesar dos potenciais diversos benefícios destacados de níveis mais altos de testosterona no AVE, mais estudos que abordem de forma sistematizada o papel da testosterona em aspectos preventivos, de apresentação clínica, e de reabilitação e prognóstico serão bem vindos, para melhor manejo e otimização do tratamento do AVE.
Premature mortality in Russia is a major socio-economic problem, especially from acute cerebrovascular diseases which constitute 21.4% of the total mortality and is a considerable contributor to chronic disability. Risk of vascular catastrophe is higher in males than females, thought, in part, due to anti-atherosclerotic effects of oestrogens in females whilst an associated age-related deficiency of testosterone is observed in men. Clinical symptoms such as high blood pressure, changes in lipid profile, insulin resistance, obesity, and blood coagulation factors often accompany declining testosterone in males and reduced total testosterone is considered a cardiovascular risk factor. In the present study, the prevalence of hypogonadism in men who had suffered ischaemic stroke was evaluated along with the efficacy of testosterone undecanoate injections (TU) in patients with testosterone deficiency and type-2 diabetes (T2DM) in the acute phase of hemispheric ischaemic stroke. Hypogonadism was present in 66.3% of patients with ischaemic stroke, 50% with T2DM, and 26.3% without T2DM, respectively. TU treatment, at both the 2 and 5-year observation points, demonstrated significant improvements in biochemical, physical, and mental parameters. This supports that testosterone deficiency is a contributing factor in ischaemic events and that long-term testosterone therapy could play an important role in patient recovery.
As sexual dysfunction is closely related to metabolic processes and treatments associated with diabetes. Aging men also develop delayed or unsatisfactory ejaculation or penile numbness, which is often associated with peripheral neuropathic changes and the use of drugs such as a-blockers, to treat associated benign prostatic hypertrophy (BPH). In the case of women, the problem is often the complex issue of hypoactive sexual desire (HSDD) or low sexual desire, and assessment tools such as the Female Sexual Function Index (FSFI) are highly subjective, leading to great difficulty in establishing true efficacy. There is increasing evidence that testosterone deficiency syndrome (TDS) and erectile dysfunction (ED) independently predict increased cardiovascular and all-cause mortality. Studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels. Both hyperinsulinemia and low testosterone have been shown to predict the development of type 2 diabetes.
Objectives:
In the absence of large, prospective, placebo-controlled studies of longer duration, substantial evidence regarding the safety and risk of testosterone (T) therapy (TTh) with regard to cardiovascular (CV) outcomes can only be gleaned from observational studies. To date, there are limited studies comparing the effects of long-term TTh in men with hypogonadism who were treated or remained untreated with T, for obvious reasons. We have established a registry to assess the long-term effectiveness and safety of T in men in a urological setting. Here, we sought to compare the effects of T on a host of parameters considered to contribute to CV risk in treated and untreated men with hypogonadism (control group).
Patients and methods:
Observational, prospective, cumulative registry study in 656 men (age: 60.7 ± 7.2 years) with total T levels ≤12.1 nmol/L and symptoms of hypogonadism. In the treatment group, men (n = 360) received parenteral T undecanoate (TU) 1000 mg/12 weeks following an initial 6-week interval for up to 10 years. Men (n = 296) who had opted against TTh served as controls. Median follow-up in both groups was 7 years. Measurements were taken at least twice a year, and 8-year data were analyzed. Mean changes over time between the 2 groups were compared by means of a mixed-effects model for repeated measures, with a random effect for intercept and fixed effects for time, group, and their interaction. To account for baseline differences between the 2 groups, changes were adjusted for age, weight, waist circumference, fasting glucose, blood pressure, and lipids.
Results:
There were 2 deaths in the T-treated group, none was related to CV events. There were 21 deaths in the untreated (control) group, 19 of which were related to CV events. The incidence of death in 10 patient-years was 0.1145 in the control group (95% confidence interval [CI]: 0.0746-0.1756; P < .000) and 0.0092 in the T-treated group (95% CI: 0.0023-0.0368; P < .000); the estimated difference between groups was 0.0804 (95% CI: 0.0189-0.3431; P < .001). The estimated reduction in mortality for the T-group was between 66% and 92%. There were also 30 nonfatal strokes and 26 nonfatal myocardial infarctions in the control group and none in the T-treated group.
Conclusion:
Long-term TU was well tolerated with excellent adherence suggesting a high level of patient satisfaction. Mortality related to CV disease was significantly reduced in the T-group.
Background/objectives
Long-term testosterone therapy (TTh) in men with hypogonadism has been shown to improve all components of the metabolic syndrome. In this study, we investigated the effects of long-term TTh up to 8 years in hypogonadal men with a history of cardiovascular disease (CVD).
Patients and methods
In two urological clinics observational registries, we identified 77 hypogonadal men receiving TTh who also had a history of CVD. The effects of TTh on anthropometric and metabolic parameters were investigated for a maximum duration of 8 years. Any occurrence of major adverse cardiovascular events was reported. All men received long-acting injections of testosterone undecanoate at 3-monthly intervals.
Results
In 77 hypogonadal men with a history of CVD who received TTh, we observed a significant weight loss and a decrease in waist circumference and body mass index. Mean weight decreased from 114±13 kg to 91±9 kg, change from baseline: −24±1 kg and −20.2%±0.5%. Waist circumference decreased from 112±8 cm to 99±6 cm, change from baseline: −13±0.3 cm. Body mass index decreased from 37±4 to 29±3, change from baseline: −8±0.2 kg/m². Cardio-metabolic parameters such as lipid pattern, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably. No patient suffered a major adverse cardiovascular event during the full observation time.
Conclusion
In men with hypogonadism, TTh appears to be effective in achieving sustained improvements in all cardiometabolic risk factors and may be effective as an add-on measure in the secondary prevention of cardiovascular events in hypogonadal men with a history of CVD.
While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Several authors blame advertising and the availability of more convenient formulations, whilst others have pointed out that the routine testing of men with erectile dysfunction (ED) (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous under-diagnosis and under-treatment in line with evidence based guidelines. It is unlikely that persuasive advertising or convenient formulations could grow a market over such a sustained period if the treatment was not effective. Urologists and primary care physicians are the most frequent initiators of TRT usually for ED. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with a possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing that therapy associated with clear increases in serum testosterone levels to the normal range is associated with reduced all-cause mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively, they have compared non-treated patients with under-treated or non-compliant subjects involving a range of different therapy regimes. Recent evidence suggests long-acting injections may be associated with decreased cardiovascular risk, but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5-alpha reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. In a response to concerns about the possible risks associated with inappropriate prescribing expressed by Public Citizen, the Food and Drug Administration (FDA) published a complete refutation of all the concerns, only to issue a subsequent bulletin of concern over inappropriate use, whilst confirming the benefits in treating men with established testosterone deficiency. No additional evidence was provided for this apparent change of opinion, but longer term safety data on testosterone products were strongly suggested. In contrast, the European Medicines Agency (EMA), in November 2014, concluded that "there is no consistent evidence of increased cardiovascular risk with testosterone products". This paper explores the most recent evidence surrounding the benefits and risks associated with TRT.
To study whether lifestyle factors and/or chronic disease are associated with the age-related decline of total and free testosterone in men, or if these factors might be associated with the variation of total and free testosterone but not with their age-related decline.
A population-based, cross-sectional study was used.
Total testosterone and sex hormone binding globulin (SHBG) levels were analyzed and free testosterone levels were calculated in 1563 men participating in the Tromsø study in 1994/1995. Anthropometric characteristics were also measured and two standardized questionnaires completed, including lifestyle factors and medical history. The data were analyzed with multiple linear regression analysis of covariance, and logistic regression.
Total and free testosterone were inversely associated (P=0.001 and P<0.001), while SHBG was positively associated (P<0.001) with age. Body mass index (BMI) was inversely associated with total (P<0.001) and free (P=0.016) testosterone and SHBG (P<0.001). Both total and free testosterone were positively associated with tobacco consumption (P<0.001 and P=0.004) and total testosterone was positively associated with coffee consumption (P<0.001). SHBG was positively associated with smoking (P=0.004) and coffee consumption (P<0.001). Men who reported having had a stroke or having a cancer diagnosis had lower levels of total testosterone (P<0.001 and P<0.01) and free testosterone (P<0.01).
BMI and smoking are independent contributors to the variation of total and free testosterone and SHBG levels, and coffee consumption to the variation of total testosterone and SHBG. Thus, lifestyle factors can have a direct effect on circulating levels of free endogenous sex hormones and to total levels due to the effect on SHBG levels.
Increased plasma oestrogen levels have been reported in men with myocardial infarction. To establish whether similar findings occur in stroke, plasma oestradiol and testosterone levels were measured in 26 male survivors of stroke and 27 healthy male controls. There was no difference in oestradiol or testosterone levels between the two groups and the oestradiol : testosterone ratio was also identical. The result of this study does not support the suggestion that hyperoestrogenaemia is a risk factor for atherosclerosis in general.
To assess the relationship between endogenous androgen levels and arterial stiffness in older men.
A retrospective, cross-sectional study.
A London hospital-based, clinical research unit for the elderly.
Fifty-five men (mean age+/-standard deviation=71.1+/-8.0).
Sex hormone-binding globulin (SHBG), testosterone, and dehydroepiandrosterone sulfate (DHEAS) were measured in all subjects who had a stored serum sample drawn the same day as arterial stiffness measures were performed. Free testosterone index (FTI) was calculated ((total testosterone/SHBG) x 100 (%)). The measures of arterial stiffness used were pulse wave velocity (PWV) using the Complior system and systemic arterial compliance (SAC) using the area method.
Relationship between arterial stiffness and serum androgens.
: FTI showed a strong positive relationship with SAC (r=0.507, P<.001) and, correspondingly, an inverse relationship with carotid-femoral (C-F) and carotid-radial (C-R) PWV (r=-0.427 and -0.402, respectively, P<or=.002). With multiple regression, including age, blood pressure, cholesterol, body mass index, and waist/hip ratio, FTI remained a significant determinant of SAC and C-R PWV but not C-F PWV. In the subgroup of men without cardiovascular disease or vasoactive medication use (n=37), all three relationships remained significant. DHEAS was inversely related to C-F PWV only (r=-0.304, P=.041).
The known association between lower androgenicity and increased cardiovascular risk in men might be explained by altered vascular stiffness.