Testosterone metabolites mediate its effects on myocardial damage induced by ischemia/reperfusion in male Wistar rats

Rubio-Gayosso, Iván; Ramírez-Sánchez, Israel; Ita-Islas, Israel; Ortiz-Vilchis, Pilar; Gutiérrez-Salmeán, Gabriela; Meaney, Alejandra; Palma, Ícela; Olivares, Ivonne; Garcia, Ruben; Meaney, Eduardo; Ceballos, Guillermo

doi:10.1016/j.steroids.2012.12.004

Cited by 20 publications

(24 citation statements)

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“…12,[30][31][32] Furthermore, finasteride exerted protective effects on the myocardium in the setting of ischemia/reperfusion injury. 33 Systemic deletion of the androgen receptor protected male mice from pathological hypertrophy, although, in contradiction to the gonadectomy-based studies, it also triggered cardiac dysfunction and fibrosis. 13 The reason for this discrepancy remains unclear, but could be the consequence of complex secondary effects due to the testicular feminization syndrome observed in these global androgen receptor knockout mice.…”

Section: Discussionmentioning

confidence: 89%

Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction

et al. 2015

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A pproximately 5 million Americans have chronic heart failure. 1 The most common causes for the development of chronic heart failure are chronic arterial hypertension, myocardial hypertrophy, and previous myocardial infarction. 1 The progression of heart failure is driven by pathological ventricular remodeling processes, which mainly involve cardiomyocyte hypertrophy, myocardial fibrosis, and profound changes in gene expression that together lead to left ventricular dilation and systolic, and diastolic dysfunction over time. [2][3][4] Despite recent therapeutic advances, the mortality of chronic heart failure remains high, and, a fact that is somewhat neglected, strikingly different between women and men. Women with heart failure have a lower mortality than men and also a better prognosis when experiencing hypertension, aortic valve stenosis, or hypertrophic cardiomyopathy.1,5 Sex hormones might account for these differences, and, indeed, the expression of androgen, and estrogen receptors was found in male and female hearts, implying that estrogen and androgens could directly act on the myocardium. 6,7 Although, in general, estrogen has been deemed cardioprotective, large randomized and controlled studies have failed to demonstrate the beneficial effects of estrogen therapy in postmenopausal women. 8,9 As a consequence, it is now proposed that the rise in cardiovascular mortality in women after the onset of menopause might be caused by an increased ovarian production of testosterone. 10 Clinical Perspective on p 1081Testosterone and its highly active metabolite dihydrotestosterone (DHT) operate by binding to the androgen receptor, Background-In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure. Methods and Results-We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathic mice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent p...

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Section: Discussionmentioning

confidence: 89%

Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction

et al. 2015

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“…In a mouse model, treatment with finasteride attenuated cardiac hypertrophy and improved left ventricular function. Similarly, Rubio-Gayosso et al (63) reported that T administration protected against cardiac ischemia/reperfusion (I/R) injury in male rats and that inhibition of 5␣-reductase reduced I/R injury in both orchiectomized and intact rats, whereas DHT administration worsened I/R damage. Taken together, this evidence suggests that conversion of T to DHT may underlie CV AEs resulting from TRT.…”

Section: E1038 Safety and Effectiveness Of Injected Testosteronementioning

confidence: 94%

Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men

Borst

Yarrow

2015

American Journal of Physiology-Endocrinology and Metabolism

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Borst SE, Yarrow JF. Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men. Am J Physiol Endocrinol Metab 308: E1035-E1042, 2015. First published April 21, 2015; doi:10.1152/ajpendo.00111.2015.-The value of testosterone replacement therapy (TRT) for older men is currently a topic of intense debate. While US testosterone prescriptions have tripled in the past decade (9), debate continues over the risks and benefits of TRT. TRT is currently prescribed for older men with either low serum testosterone (T) or low T plus accompanying symptoms of hypogonadism. The normal range for serum testosterone is 300 to 1,000 ng/dl. Serum T Յ 300 ng/dl is considered to be low, and T Յ 250 is considered to be frank hypogonadism. Most experts support TRT for older men with frank hypogonadism and symptoms. Treatment for men who simply have low T remains somewhat controversial. TRT is most frequently administered by intramuscular (im) injection of long-acting T esters or transdermally via patch or gel preparations and infrequently via oral administration. TRT produces a number of established benefits in hypogonadal men, including increased muscle mass and strength, decreased fat mass, increased bone mineral density, and improved sexual function, and in some cases those benefits are dose dependent. For example, doses of TRT administered by im injection are typically higher than those administered transdermally, which results in greater musculoskeletal benefits. TRT also produces known risks including development of polycythemia (Hct Ͼ50) in 6% of those treated, decrease in HDL, breast tenderness and enlargement, prostate enlargement, increases in serum PSA, and prostate-related events and may cause suppression of the hypothalamic-pituitary-gonadal axis. Importantly, TRT does not increase the risk of prostate cancer. Putative risks include edema and worsening of sleep apnea. Several recent reports have also indicated that TRT may produce cardiovascular (CV) risks, while others report no risk or even benefit. To address the potential CV risks of TRT, we have recently reported via meta-analysis that oral TRT increases CV risk and suggested that the CV risk profile for im TRT may be better than that for oral or transdermal TRT. testosterone; muscle; bone; cardiovascular risk HEREIN, WE REVIEW THE LITERATURE, which indicates that intramuscularly injected testosterone replacement therapy (TRT) produces greater musculoskeletal benefits and lower cardiovascular risk compared with transdermal TRT. TRT also produces risks of polycythemia, prostate enlargement, and suppression of the hypothalamic-pituitary-gonadal axis. The effects of injection vs. transdermal administration on these risks are unknown. We also review the literature discussing the use of 5␣-reductase inhibitors as a promising means of improving the safety profile of TRT. Definition of HypogonadismThe Endocrine Society recommends TRT for men with androgen deficiency, defined as low serum T with ...

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“…Enzymatic inhibition of aromatase however significantly 481 increases myocardial damage induced by I/R insult[74]. In con-482 trast, enzymatic inhibition of 5a-R significantly reduces myocar-483 dial damage while treatment with DHT increases myocardial 484 damage[74], conclusively implicating DHT as the metabolite 485 responsible for myocardial damage elicited by exogenous testos-486 terone treatment.…”

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confidence: 96%

“…73 1.1. Androgenic-anabolic steroids 74 Androgenic-anabolic steroid (AAS) misuse is an ever-growing 75 public health concern, particularly in developed countries 76 [15][16][17][18][19]. With the emergence of predominantly biased, non-scien- 77 tific recommendations for AAS misuse published on the internet 78 [20], misinformation regarding AAS safety is no longer isolated 79 within the gymnasiums of the Western world [21,22] (Table 1).…”

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confidence: 99%

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Improvements in body composition, cardiometabolic risk factors and insulin sensitivity with trenbolone in normogonadic rats

et al. 2015

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Trenbolone (TREN) is used for anabolic growth-promotion in over 20 million cattle annually and continues to be misused for aesthetic purposes in humans. The current study investigated TREN's effects on body composition and cardiometabolic risk factors; and its tissue-selective effects on the cardiovascular system, liver and prostate. Male rats (n=12) were implanted with osmotic infusion pumps delivering either cyclodextrin vehicle (CTRL) or 2mg/kg/day TREN for 6 weeks. Dual-energy X-ray Absorptiometry assessment of body composition; organ wet weights and serum lipid profiles; and insulin sensitivity were assessed. Cardiac ultrasound examinations were performed before in vivo studies assessed myocardial susceptibility to ischemia-reperfusion (I/R) injury. Circulating sex hormones and liver enzyme activities; and prostate and liver histology were examined. In 6 weeks, fat mass increased by 34±7% in CTRLs (p<0.01). Fat mass decreased by 37±6% and lean mass increased by 11±4% with TREN (p<0.05). Serum triglycerides, HDL and LDL were reduced by 62%, 57% and 78% (p<0.05) respectively in TREN rats. Histological examination of the prostates from TREN-treated rats indicated benign hyperplasia associated with an increased prostate mass (149% compared to CTRLs, p<0.01). No evidence of adverse cardiac or hepatic effects was observed. In conclusion, improvements in body composition, lipid profile and insulin sensitivity (key risk factors for cardiometabolic disease) were achieved with six-week TREN treatment without evidence of adverse cardiovascular or hepatic effects that are commonly associated with traditional anabolic steroid misuse. Sex hormone suppression and benign prostate hyperplasia were confirmed as adverse effects of the treatment.

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Testosterone metabolites mediate its effects on myocardial damage induced by ischemia/reperfusion in male Wistar rats

Cited by 20 publications

References 36 publications

Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction

Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction

Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men

Improvements in body composition, cardiometabolic risk factors and insulin sensitivity with trenbolone in normogonadic rats

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