Effects Of Testosterone Replacement Research Articles

The Effect of Testosterone Replacement on Sexual Function in the Elderly: A Systematic Review and Meta-Analysis.

Healthy aging is an important concern in an aging society. Although the causal relationship between hypogonadism and erectile dysfunction in elderly men remains unclear, many physicians have achieved positive results after implementing exogenous testosterone supplementation therapy in patients with normal or slightly low blood testosterone. The purpose of this study was to conduct a systematic review and meta-analysis on whether testosterone replacement therapy (TRT) could improve sexual function in the elderly, as reported recently. As a comprehensive literature search was performed to find articles published in PubMed, Embase, and Cochrane databases by January 2022. The search used keywords of 'aged', 'male', 'sexual behavior', and 'testosterone'. Randomized controlled trials (RCTs) were finally selected. As the main effect variable, results of a questionnaire on sexual function were analyzed and the effects of TRT were compared to those of placebo control. Five RCT studies were included in this meta-analysis. The overall improvement by mean difference of sexual function for testosterone supplementation was 0.082 (95% CI: -0.049 to 0.213). In subgroup analysis, only intramuscular injection of 1,000 mg testosterone significantly improved sexual function of the elderly (0.229, 95% CI: 0.112 to 0.347). There was no significant difference in sexual function according to testosterone dose in meta-ANOVA (p=0.957). The difference was not statistically significant either in the meta-regression test (p=0.310). Egger's regression coefficient test did not indicate a publication bias (p=0.132). Although our overall effect size (that is, sexual function effect of TRT) did not show a significant improvement, the direction of improvement in erection and motivation was clearly shown. The injection formulation resulted in a significant sexual function improvement. Since only a few RCTs were included in the analysis, more well-designed prospective studies are needed to have a definite conclusion.

Testosterone in men with hypogonadism and transgender males: a systematic review comparing three different preparations.

Testosterone therapy is the cornerstone in the care of men with hypogonadism and transgender males. Gel and intramuscular injections are most frequently used and are registered and included in the international guidelines. The specific preparation should be selected according to the patient’s preference, cost, availability, and formulation-specific properties. As the majority of men with hypogonadism and transgender males require lifelong treatment with testosterone, it is important to utilize a regimen that is effective, safe, inexpensive, and convenient to use with optimal mimicking of the physiological situation. This systematic review reviews current literature on differences between the three most used testosterone preparations in adult men with hypogonadism and transgender males. Although it appeared hardly any comparative studies have been carried out, there are indications of differences between the preparations, for example, on the stability of testosterone levels, hematocrit, bone mineral density, and patient satisfaction. However, there are no studies on the effects of testosterone replacement on endpoints such as cardiovascular disease in relation to hematocrit or osteoporotic fractures in relation to bone mineral density. The effect of testosterone therapy on health-related quality of life is strongly underexposed in the reviewed studies, while this is a highly relevant outcome measure from a patient perspective. In conclusion, current recommendations on testosterone treatment appear to be based on data primarily from non-randomized clinical studies and observational studies. The availability of reliable comparative data between the different preparations will assist in the process of individual decision-making to choose the most suitable formula.

The Association between Dietary Inflammatory Index and Sex Hormones among Men in the United States.

This study investigated the association between Dietary Inflammatory Index and sex hormones in a large, nationally representative adult male sample. We utilized data from the 2013-2014 and 2015-2016 National Health and Nutrition Examination Survey. Males aged ≥20 years who provided a 24-hour dietary intake history and underwent serum sex hormone testing were included in analysis. Weighted proportions and multivariable analysis controlling for age, race, energy, smoking status, education level, body mass index and time of venipuncture were used to evaluate the associations between Dietary Inflammatory Index and sex hormones. For 4,151 participants, Dietary Inflammatory Index ranged from -5.05 to 5.48. Mean±SD total testosterone was 419.30±176.27 ng/dl. Mean±SD total testosterone was lower among men in the highest tertile compared with men in the lowest tertile group (410.42±171.97 vs 422.71±175.69, p <0.001). A per unit increase in Dietary Inflammatory Index was related to 4.0% (95% CI 0.5-7.6) higher odds of testosterone deficiency. In the fully adjusted multivariable model, males in Dietary Inflammatory Index tertile 3 (the most pro-inflammatory) had 29.6% (3.1-63.0) higher odds of testosterone deficiency than those in tertile 1 (p trend=0.025). Interaction tests revealed no significant effect of body mass index on the association of Dietary Inflammatory Index with testosterone deficiency and all sex hormone parameters. Men adhering to a more pro-inflammatory diet appear to have a higher risk of testosterone deficiency, indicating the important role of diet in male reproductive health.

Effects of testosterone replacement on serotonin levels in the prostate and plasma in a murine model of hypogonadism

Benign prostate hyperplasia is a dysfunctional disease with an elevated prevalence. Despite the accepted impact of aging and testosterone (TES) in its pathophysiology, its aetiology remains unknown. Recent studies described that serotonin (5-HT) inhibits benign prostate growth through the modulation of the androgen receptor, in the presence of TES. Accordingly, this work aimed to determine the impact of castration and TES replacement in plasmatic and prostatic 5-HT regulation. C57BL/6 mice were submitted to surgical castration and divided into three groups, continually exposed to either vehicle or different TES doses for 14 days. Plasmatic 5-HT concentration was measured before and after castration, and after TES reintroduction. Finally, total prostatic weight and intra-prostatic 5-HT were determined in the different groups. Our results demonstrate that mice prostate exhibits high 5-HT tissue levels and that intra-prostatic total 5-HT was independent of castration or TES reintroduction, in all studied groups. Also, 5-HT plasmatic concentration significantly increased after castration and then normalized after TES administration. Our findings revealed that mice prostate has a high 5-HT content and that total prostatic 5-HT levels do not depend on androgens’ action. On the other hand, castration induced a significant increase in plasmatic 5-HT concentration, raising the hypothesis that androgens might be regulating the production of extra-prostatic 5-HT.

The Effect of Testosterone Replacement on Intramedullary, Inguinal and Visceral Fat in Ovariectomized Rats.

The present article aims to evaluate the impact of testosterone treatment on the expansion of visceral, subcutaneous and intramedullary adipose tissue of ovariectomized rats and the visceral and subcutaneous fat expression of peroxisome proliferator-activated receptors (PPARs) gamma. METHODS: In total 48 female Wistar rats were castrated and randomly divided into 6 treatment groups: group E2 was submitted to estradiol 5 μg/day; group T, to testosterone 5 μg/day; group E2 + T, to estradiol 5 μg/day + testosterone 5 μg/day; group TT, to testosterone 30 μg/day; group E2 + TT, to estradiol 5 μg/day + testosterone 30 μg/day; and placebo was administered to group P. After 5 weeks, the rats were euthanized, the inguinal and visceral adipose tissues were harvested, weighted, and had their PPAR gamma expression evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The right femurs were harvested and histologically prepared to perform the number count of the intramedullary adipocytes. The expansion of visceral fat tissue was much higher in the TT group when compared with other treated groups (p < 0.001). The TT group also showed a higher expansion of inguinal fat (p < 0.01), and groups E2 + T and E2 + TT presented lower growth compared to the P group (p < 0.01). The number of femur intramedullary adipocytes only showed significant differences between groups TT and E2 + TT (p < 0.05). The expression of PPAR gamma showed no differences among the groups. The use of testosterone in high doses leads to an important expansion in both visceral and inguinal adipose tissues. Association with estradiol exerts an expansion-repressive effect on the visceral and inguinal adipose tissues.

Increase in Osteocalcin Following Testosterone Therapy in Men With Type 2 Diabetes and Subnormal Free Testosterone.

ContextOne-third of men with type 2 diabetes have subnormal free testosterone concentrations. We evaluated the following: (i) whether bone mineral density (BMD) and bone strength are affected by gonadal status in type 2 diabetes and (ii) the effect of testosterone replacement on markers of osteoblast and osteoclast activity.DesignThis is a secondary analysis of a previously completed, randomized, placebo-controlled trial. Ninety-four men with type 2 diabetes were recruited; 44 had subnormal free testosterone concentrations. Men with subnormal free testosterone concentrations were randomized to receive intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Dual energy X-ray absorptiometry scans were performed at baseline and at 23 weeks.ResultsMen with subnormal free testosterone had similar BMD compared with men with normal free testosterone. However, bone strength indices were lower in men with subnormal free testosterone. BMD was related to free estradiol concentrations (r = 0.37, P = 0.004 at hip), whereas bone strength was related to free testosterone concentrations (r = 0.41, P < 0.001). Testosterone replacement increased osteocalcin concentrations [mean change (95% CI), 3.52 (0.45, 6.59), P = 0.008]. C-Terminal telopeptide (CTx) concentrations also increased at 15 weeks but reverted to baseline following that. There were no changes in other bone turnover markers or BMD.ConclusionWe conclude that testosterone replacement resulted in an increase in osteocalcin and a transient increase in CTx, indicating an increase in osteoblastic activity and transient increase in bone breakdown. Therefore, a major action of testosterone is to increase bone turnover in men with type 2 diabetes.

Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials

The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov, number NCT00799617. The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2-15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5-6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5-21·9; p=0·0004) and PF10 (4·9, 2·2-7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0-14·1; p=0·0237) and PF10 (3·6, 1·3-5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35-3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61-5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall). Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations. US National Institute on Aging and AbbVie.

Androgen replacement therapy in men: current evidence and controversy

The decline in Testosterone (T) levels in the ageing male - known as andropause or late-onset hypogonadism - may be responsible for several aspects of quality of life decline in older men: erectile dysfunction, impaired libido, decreased strength and energy, sarcopenia, osteopenia, fatigue and even depression in some cases. Many of these signs and symptoms represent the same alterations that are usually attributed to the process of ageing. When some individual presents with such symptoms, hypogonadism should be suspected, and serum T level should be evaluated. Men who are symptomatic and present low levels of serum Testosterone (generally below 300 ng/ml) are candidates for T replacement therapy. Current evidence shows that, when correctly selected, patients receiving T replacement may benefit from improvement in libido, erectile function, overall and sexual related quality of life, bone density and muscle mass. Conversely, patients with physiological circulating levels of T who receive hormone, aiming at supraphysiologic levels, may face severe side effects, including testicular atrophy and behavioral changes. Of note, T replacement, regardless of age and pre-therapy levels, leads to fertility impairment which can be transient or persistent. Direct testosterone replacement should not be indicated in men who wish to conceive children, although other options are available. The effect of Testosterone replacement on prostate cancer and on cardiovascular risk is still controversial; hypogonadal men known to have prostate cancer or high cardiovascular risk should be examined individually to have their risks stratified and mitigated.

Hypogonadotropic Hypogonadism in Men With Diabesity.

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA1c in men with diabetes. The effect of testosterone replacement on cardiovascular events or mortality in men with diabesity is not known and remains to be studied in prospective trials.

The effects of testosterone replacement on penile structure and erectile function after long-term castration in adult male rats.

Short periods of testosterone suppression have been shown to reduce trabecular smooth muscle content and increase interstitial connective tissue accumulation in animal models. However, the long-term effects of testosterone suppression remain unclear. The aim of this study was to evaluate the long-term effects of testosterone suppression on penile structure and erectile function in rats. Subjects were divided into two groups by observation period (short-period group (group I), 12 weeks; long-period group (group II), 20 weeks). Each group comprised three different subgroups (10 rats each): sham-operated control, surgical castration, and testosterone replacement (4 weeks after an 8-week castration period). Group II subgroups included a sham control, surgical castration, and testosterone replacement (4 weeks after a 16-week castration period). Erectile function was assessed by measuring intracavernosal pressure in response to cavernous nerve stimulation, and expression of the endothelial nitric oxide synthase (eNOS) protein was determined by western blot analysis. Serum testosterone values were measured via radioimmunoassay. The results indicated that serum testosterone level, penile length and girth, cavernosal smooth muscle content, and eNOS activity decreased significantly in castrated animals. These effects were rescued by testosterone undecanoate injection. Erectile function was normalized over 4 weeks in rats that received androgen replacement. Expression of eNOS was decreased in the corpus cavernosum of castrated animals compared with controls, while androgen replacement normalized the expression of eNOS. These results were consistently observed regardless of the duration of androgen deprivation. Thus, these data suggest that androgen regulates the expression of eNOS in the rat penile corpus cavernosum and confirm the importance of androgens in the maintenance of erectile function. Additionally, long-term androgen deprivation does not induce irreversible structural or erectile functional changes in sexually mature adult male rats.

Effect of testosterone replacement on feeding behaviors after acute and chronic stress in gonadectomized male NMRI mice

We study the role of gonadectomy on the response to unavoidable stress and the role of testosterone replacement on gonadectomy in the male Naval Medical Research Institute mice (30±5 g) were studied. For this purpose, the hormonal and metabolic changes were investigated. In the experimental group, the gonads were surgically removed, and a cannula was inserted into the left lateral ventricle. For acute and chronic stress induction, animals were placed in the communication box for 30 min for one day and four consecutive days, respectively. The animals received different doses of intraventricular (ICV) testosterone (0.01, 0.05, 0.1 μg/mouse) 5 minutes or intraperitoneal (IP) testosterone (0.05, 0.01, 0.1 mg/kg) 30 minutes before the stress induction. The results showed that acute and chronic stress increases plasma cortisol concentration. IP testosterone injections of testosterone did not decrease cortisol concentrations in response to acute stress, whereas ICV injections did reduce cortisol concentrations. The stress reduced anorexia time, while the administration of testosterone increased anorexia time. In addition, acute stress reduced food intake in the gonadectomized mice. IP testosterone at 0.01 and 0.05 mg/kg increased food intake. Additionally, stress in gonadectomized mice reduced water intake, while the IP injection of testosterone in chronic stress further reduced water intake. Also, stress reduced the animals’ brain/adrenal volumes, while the IP and ICVinjection of testosterone at 0.01 mg/kg inhibited this effect. The results showed that the IP (0.05, 0.01, 0.1 mg/kg) and ICV (0.01, 0.05, 0.1 μg/mouse) administration of testosterone in the gonadectomized mice can modulate hormonal and metabolic changes induced by stress.

Effects of Testosterone Replacement on Insulin Sensitivity, Blood Glucose, Serum Lipids and Vitamin D Concentration in a Rat Model of Andropause

Background: Testosterone facilitates various metabolic processes in the bones, muscles, bone marrow, brain and immune system. Testosterone deficiency may contribute to cardiovascular diseases, central obesity and metabolic dysfunction. Aim: to investigate the effects of testosterone deficiency on blood glucose levels, insulin sensitivity, vitamin D, Homeostatic model assessment of insulin resistance (HOMA-IR), Homeostatic model assessment for beta function (HOMA-IR) and serum lipids in rat models of andropause. Methods, 48 male rats divided into 4 equal groups (n=12/group); a) Control (C) group. b) Orchiectomy (O) group underwent bilateral removal of the testicles. c) Orchiectomy and treated (O+T) group given daily IM testosterone replacement therapy for 7 days, d) Sham and treated (Sh+T) group in which sham operated rats were given the same daily dose of T as O+T group for 7 days. Results: we found that plasma glucose concentration increased significantly (P<0.001) in O group. This increase was corrected by testosterone injection in O+T group. In (Sh+T) group, there is a significant reduction in serum glucose (P<0.001). We also found that insulin level reduced significantly (P<0.001) in O group. This reduction in insulin level was corrected by testosterone. In (Sh+T) group, insulin level increased significantly. 25-OHVD3 was reduced significantly (P<0.05) in O group and increased significantly in O+T group. HOMA-IR level decreased significantly (P<0.001) and this reduction was corrected by Testosterone. HOMA-β reduced significantly (P<0.001) and this reduction was corrected by Testosterone in O+T group. In SH group, there is a marked increase in HOMA-β. We also found insignificant differences between the four groups in serum triglycerides. However, we found very highly significant differences in total cholesterol, LDL and VLDL between C group and O group and very highly significant differences between O+T group and Sh+T group in comparison with O group. We also found significant differences in serum HDL-c in (O) group in comparison with (C) group and between O+T and Sh+T groups in comparison with O group. In conclusion, we found significant reduction in 25-OH(VD), Testosterone, Insulin, HOMA-IR and HOMA-B and significant increase in glucose serum levels in O group and these changes were corrected by Testosterone injection in O+T group. We also found insignificant differences between the four groups in serum triglycerides. However, we found highly significant differences in total cholesterol, LDL, HDL-c and VLDL between C group and O group and very highly significant differences between O+T group and Sh+T group in comparison with O group.

Effect of testosterone replacement in hypogonadal men with type 2 diabetes in routine clinical practice

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Effects of Testosterone Replacement on Pain Catastrophizing and Sleep Quality in Men with Opioid-Induced Androgen Deficiency

The objective of this investigation was to determine the effects of testosterone administration on pain catastrophizing and sleep quality in adult men with opioid-induced androgen deficiency. Sixty-two men aged 18-64 years using opioid analgesics for chronic non-cancer pain with total testosterone levels < 350 ng/dl were randomized to 14 weeks of transdermal testosterone gel or placebo gel daily. Total testosterone levels were measured by liquid chromatography mass spectrometry and free testosterone was calculated using the law of mass action equation. Outcomes were assessed by administering validated instruments such as Pain Catastrophizing Scale (PCS) and Insomnia Severity Index (ISI) at baseline and 14 weeks. Baseline characteristics were similar between the two groups. Mean (SD) total testosterone concentrations increased from 223 ± 86 to 775 ± 555 ng/dl in the testosterone group, but did not meaningfully change in placebo group. Mean changes in PCS and ISI scores during intervention did not differ significantly between groups and were not related to changes in on-treatment serum testosterone concentrations. In this 14-week trial, testosterone administration in men with opioid-induced androgen deficiency was not associated with improvements in pain catastrophizing or sleep quality.

Effects of testosterone replacement on metabolic and inflammatory markers in men with opioid-induced androgen deficiency.

Symptomatic androgen deficiency is common in patients taking opioid analgesics, and testosterone replacement in these men improves libido, quality of life and body composition. However, the effects of testosterone replacement on metabolic and inflammatory markers in this setting have not been evaluated. This is important as opiate use itself has been associated with metabolic abnormalities. The objective of this investigation was to determine the effects of testosterone administration on metabolic and inflammatory markers in adult men with opioid-induced androgen deficiency. Sixty-four nondiabetic men aged 18 to 64 years using opioid analgesics for chronic noncancer pain with total testosterone levels <12 nmol/l were randomized to 14 weeks of transdermal testosterone gel or placebo gel daily. Total testosterone levels were measured by liquid chromatography mass spectrometry, and free testosterone was calculated using the law-of-mass-action equation. Metabolic parameters, inflammatory markers and oral glucose tolerance test (OGTT) were evaluated at baseline and 14 weeks. Baseline characteristics were similar between the two groups. Testosterone concentrations increased from 7·7 ± 3·0 to 27 ± 19 nmol/l in the testosterone group, but did not meaningfully change in placebo group. Mean changes in metabolic and inflammatory markers during intervention did not differ significantly between groups and were not related to changes in on-treatment serum testosterone concentrations. Glucose and insulin response to the 75 g OGTT also did not differ between groups. In this 14-week trial, testosterone administration in men with opioid-induced androgen deficiency was not associated with worsening of metabolic and inflammatory markers.

Metabolic syndrome and hypogonadism--two peas in a pod.

Testosterone deficiency is highly prevalent in up to 50% of men with the metabolic syndrome and type 2 diabetes mellitus. Low testosterone levels in men appear to be an independent cardiovascular risk factor and predictor of subsequent development of the metabolic syndrome. Reciprocally, the metabolic syndrome leads to a decrease in testosterone levels. This review provides an account of the pathophysiological mechanisms in the bidirectional relationship between hypogonadism and body composition, inflammation and insulin sensitivity as well as the effects of testosterone replacement on diverse metabolic parameters.

1008 The effect of testosterone replacement in men with testosterone deficiency syndrome on cognitive performance and depression

1008 The effect of testosterone replacement in men with testosterone deficiency syndrome on cognitive performance and depression

Gonadal function in male patients with metastatic renal cell cancer treated with sunitinib: Effects of testosterone replacement on quality of life.

525 Background: Sunitinib (S) is a standard first line treatment of metastatic renal cell carcinoma (mRCC). Asthenia and fatigue are the most prevalent toxicities but the relevant causes are not fully elucidated. Since endocrine glands are highly vascularized, the potent antiangiogenic effect of S can potentially impair their function. With the exception of hypothyroidism, the endocrine-related side-effects of S have not been extensively explored. Methods: We performed a cross-sectional study in which pituitary, thyroid, parathyroid, adrenal and gonadal functions were assessed in 25 mRCC patients who received 9 months of S therapy. Since a high prevalence of hypogonadism was observed, we subsequently enrolled 16 mRCC male patients in a prospective cohort study in which serum testosterone (T) serum free T, serum FSH and LH were evaluated at baseline and after 6 weeks (1 cycle) of S therapy. In patients eligible for testosterone replacement after andrologic evaluation, a FACT-G questionnaire for quality of life (QoL) assessment was prospectively administered at baseline and after 3 months. Results: In the cross sectional study 15/22 S treated male patients (68%) had serum T below the normal range and 13 of them (87%) presented with low/normal levels of LH. In the prospective study mean T levels (95% CI) were 5.04 ng/ml (3.4 - 6.7) at baseline and 4.1 ng/ml (3 - 5.3) after 6 weeks (p 0.05). The corresponding free T were 91.4 pg/ml (66 – 116.8) and 80.2 pg/ml (65 – 95.3) (p 0.24), respectively. Hypogonadism was observed in 5 (31%) patients at baseline and 10 (63%) patients after 6 weeks of S therapy. In the 5 patients becoming hypogonadic after S therapy, LH was 11.4 mU/ml (3.2 - 19.5) at baseline and 11.5 mUI/ml (0 – 23.5) after 6 weeks. Four patients were addressed to testosterone replacement. QoL significantly improved in 3 of them, with the strongest advantage in the physical comfort area. Conclusions: S therapy induces hypogonadism in a high proportion of male patients with mRCC. Low or inappropriately normal LH levels are consistent with a pituitary origin of the endocrine disorder. Testosterone replacement may improve the QoL and treatment tolerance.

Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα.

Despite the importance of testosterone as a metabolic hormone, its effects on myocardial metabolism in the ischemic heart remain unclear. Myocardial ischemia leads to metabolic remodeling, ultimately resulting in ATP deficiency and cardiac dysfunction. In the present study, the effects of testosterone replacement on the ischemic heart were assessed in a castrated rat myocardial infarction model established by ligating the left anterior descending coronary artery 2 weeks after castration. The results of real-time PCR and Western blot analyses showed that peroxisome proliferator-activated receptor α (PPARα) decreased in the ischemic myocardium of castrated rats, compared with the sham-castration group, and the mRNA expression of genes involved in fatty acid metabolism (the fatty acid translocase CD36, carnitine palmitoyltransferase I, and medium-chain acyl-CoA dehydrogenase) and glucose transporter-4 also decreased. A decline in ATP levels in the castrated rats was accompanied by increased cardiomyocyte apoptosis and fibrosis and impaired cardiac function, compared with the sham-castration group, and these detrimental effects were reversed by testosterone replacement. Taken together, our findings suggest that testosterone can modulate myocardial metabolic remodeling by upregulating PPARα after myocardial infarction, exerting a protective effect on cardiac function.

PPAR in Cardiovascular Disorders.

Peroxisome proliferation-activated receptors (PPARs) are ligand-inducible transcription factors that, upon binding their ligands, translocate into the nucleus, where they regulate transcription of numerous genes that have the peroxisome proliferator response element (PPRE) in the promoter region [1]. In humans, there are 3 PPAR isoforms: PPAR-α, PPAR-β/δ, and PPAR-γ. The isoforms have partially overlapping spectra of activity and are differently expressed in organs and tissues [2]. PPAR-α is expressed mostly in tissues characterized by high catabolic activity, including skeletal muscle, liver, proximal tubular cells in kidneys, and brown fat. This PPAR isoform regulates components of β-oxidation pathway, enzymes, and transporters involved in fatty acid metabolism and promotes lipolysis and fatty acid oxidation. PPAR-α can be activated by fatty acids, prostaglandins, fibric acid derivatives (fibrates), and a number of recently developed specific agonists. Activation of PPAR-α has a beneficial effect on processes involved in the development of atherosclerosis, as it decreases plasma triglyceride levels, increases high density lipoprotein cholesterol, and reduces inflammatory response. Therefore, PPAR-α agonists gain attention as potential components of antiatherosclerotic therapy [3, 4]. PPAR-β/δ is expressed in many organs and tissues, with relatively high levels present in skeletal muscle, liver, kidney, and macrophages. It is activated by fatty acids and carbaprostacyclin, stimulates fatty acid oxidation, and improves insulin sensitivity in insulin-resistant animal models. This isoform is also known to have potential antiatherosclerotic properties and is considered for treatment of cardiovascular disorders [5, 6]. PPAR-γ is mainly expressed in white and brown fat and can also be found in other organs and tissues, including liver, kidney, and immune cells. It is activated by fatty acids implicated in regulation of glucose homeostasis, lipid metabolism, and adipogenesis. Synthetic PPAR-γ agonists, thiazolidinediones, such as pioglitazone and rosiglitazone, are currently used as insulin sensitizers but can have a broader therapeutic potential for treatment of conditions associated with increased cardiovascular risk [7]. Therefore, PPARs have a wide spectrum of biological activities relevant to prevention and treatment of cardiovascular diseases. Moreover, the availability of natural and synthetic small molecule agonists, many of them being relatively well studied by now, makes PPARs attractive therapeutic targets. To date, PubMed literature database delivers more than 3300 articles found by key words “PPAR” + “cardiovascular”. In this special issue, we are happy to present several important works revealing various aspects of PPAR involvement in cardiovascular conditions. The importance of PPAR-α signalling for regulation of cardiomyocyte metabolism is highlighted by the research articles of E. Czarnowska with coauthors, who studied the correlation of PPAR-α activity and cardiomyocyte function during heart failure, and J. Yang with coauthors, who demonstrated that PPAR-α upregulation mediated the effect of testosterone replacement on cardiac metabolic remodelling after myocardial infarction. G. Barreto-Torres with S. Javadov and W.-Y. Wei with coauthors presented the links between PPAR activation and the key cellular signalling network, which includes the AMPK and AKT pathways and regulates cellular metabolism, growth, and response to stress. Another evidence of anti-inflammatory properties of pioglitazone in patients with drug eluting stents is presented by Z. Wang and coauthors. H.-J. Liu and coauthors provide evidence for the critical role of PPAR-γ in cardiac fibrosis, and A. Pleskovic with coauthors reported that PPAR-γ polymorphisms have a minor effect on atherosclerosis markers in diabetic patients. K.-D. Wagner with coauthors demonstrates that inducible vascular-specific overexpression of PPAR-β/δ causes cardiac hypertrophy. Finally, a review article of W.-S. Lee and J. Kim provides an overview of the roles of PPARs in the heart. Together, the works collected in this special issue add to our growing knowledge on the PPARs and their activators in the context of cardiovascular disorders. Alexander N. Orekhov Nigora Mukhamedova Ekaterina A. Ivanova Manfredi Rizzo