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",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8b3c5c4439c736e81433536f7a5447eb",bookSignature:"Prof. Prof Nasser S Awwad and Dr. Ali Abdullah Shati",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9936.jpg",keywords:"Gadolinium Enhancement, Diagnostic Tool, Alloys, Salts, Magnetic Cooling, E. Coli, Bacillus Subtillis, Gadolinium as Burnable, Selective Separation, F-Block Elements, Adsorption, Kinetics",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 16th 2020",dateEndSecondStepPublish:"October 14th 2020",dateEndThirdStepPublish:"December 13th 2020",dateEndFourthStepPublish:"March 3rd 2021",dateEndFifthStepPublish:"May 2nd 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Awwad edited a book for Lanthanides and published more than 25 papers about the elements at f blook, especially Gadolinium. He is a supervisor for 5 Master thesis in the field of Adsorption, removal, purification, kinetics, and modeling of Gadolinium.",coeditorOneBiosketch:"Dr. Shati has a lot of applications about the utilization of gadolinium enhancement. He has published papers about the inhibition of Gadolinium ion for the giant stretch‐activated channels of E. coli and Bacillus subtillis and in use for Kupffer cell depletion ( inactivation).",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"145209",title:"Prof.",name:"Prof Nasser",middleName:"S",surname:"Awwad",slug:"prof-nasser-awwad",fullName:"Prof Nasser Awwad",profilePictureURL:"https://mts.intechopen.com/storage/users/145209/images/system/145209.jpg",biography:"Dr. Nasser S. Awwad has a PhD in inorganic and radiochemistry (2000) from Ain Shams University and a post-doctorate degree at Sandia National Labs, New Mexico, USA, 2004. Nasser Awwad was an Associate Professor of radiochemistry in 2006 and Professor of inorganic and radiochemistry in 2011 at the Egyptian Atomic Energy Authority. He has been a Professor at King Khalid University, Abha, KSA from 2011 to now. He has published two chapters in the following books ”Natural Gas - Extraction to End Use” and 'Advances in Petrochemicals”. He has been the editor for six books about: uranium, new trends in nuclear sciences, dyes in industry and lanthanides, and nuclear power plants. In addition, he has published 94 papers in ISI journals. He supervised 4 PhD and 16 MSc students in the field of radioactive and wastewater treatment. He participated in 25 international conferences in South Korea, USA, Lebanon, KSA, Egypt and India. He participated in 6 large projects with KACST at KSA and Sandia National Labs at USA on the conditioning of radioactive sealed sources and wastewater treatment. He has been the leader of many research groups about the utilization of nanomaterials for treatment of inorganic and organic pollutants and has also been a member of some research groups. He is a member of the Arab Society of Forensic Sciences and Forensic Medicine and is a member of the Egyptian Society for Nuclear Sciences and its applications. He is on the editorial board of the Journal of Energy and Environmental Research and Technology. He is a rapporteur of the Permanent Committee for Nuclear and Radiological Protection at King Khalid University and a member of the Committee for the Development of International Cooperation Management at KKU.",institutionString:"King Khalid University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"King Khalid University",institutionURL:null,country:{name:"Saudi Arabia"}}}],coeditorOne:{id:"330586",title:"Dr.",name:"Ali",middleName:"Abdullah",surname:"Shati",slug:"ali-shati",fullName:"Ali Shati",profilePictureURL:"https://intech-files.s3.amazonaws.com/a043Y00000cA8q1QAC/Co2_Profile_Picture-1599648357298",biography:"Prof. Dr. Ali Abdullah Shati, a Saudi Biologist, graduated with BSc in Biology from King Saud University, Kingdom of Saudi Arabia in 1998, and MSc in Environmental Sciences from Essex University, the United Kingdom in 2004. He received his Ph.D. in Biology of Vertebrates in 2007 from Aberdeen University, United Kingdom. Since 2000, he has been working at King Khalid University in the Kingdom of Saudi Arabia, where he was promoted to Associate Professor in 2013, Professor in 2017 in the major of Vertebrate Physiology and Toxicology. He has held several positions at King Khalid University, including the head of Research Center at College of Science in 2012, Vice Dean of Scientific Research in 2012, Vice Dean of Academic Affairs in the college of science in 2014, and he is currently the Dean of College of Science. His research interests focus on studying the physiological and molecular changes invertebrates as a result of various environmental impacts, in addition to the cytotoxicity of Nano-materials, the therapeutic and protective effect of different bio-extracts, and antioxidant research, He has published more than eighty-seven online papers in international journals indexed in Clarivate Analytics and Scopus, with high impact factor. He has supervised MSc students specialized in the Physiological and Molecular effects of various components on vertebrate's functions. He participated in fourteen international conferences in the United States, United Kingdom, Canada, Australia, New Zealand, and Brazil. In the last ten years, he has awarded several research grants from the deanship of scientific researches at King Khalid University, as a principal investigator. He is also a member of the American Society of Toxicology, the Association of Arab Biologists, and the Saudi Biological Society.",institutionString:"King Khalid University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"King Khalid University",institutionURL:null,country:{name:"Saudi Arabia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"259492",firstName:"Sara",lastName:"Gojević-Zrnić",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/259492/images/7469_n.png",email:"sara.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"44471",title:"Anabolic/Androgenic Steroids in Skeletal Muscle and Cardiovascular Diseases",doi:"10.5772/53080",slug:"anabolic-androgenic-steroids-in-skeletal-muscle-and-cardiovascular-diseases",body:'Testosterone exerts significant effect on muscle cells, and abnormalities of plasma concentrations can cause both skeletal muscle and cardiovascular diseases. Low levels are known to be associated with hypogonadism and have recently been linked to sarcopenia and metabolic syndrome; high levels are associated with hypertrophy. However, most evidence of the link between testosterone and metabolic actions is observational. Studies targeted to establish the mechanisms for such effects at the cell level and their correlation with in vivo models will broaden our understanding of the role played by these male steroid hormones in the pathophysiology of muscular and metabolic diseases.
Anabolic/androgenic steroid hormones are part of the male reproductive endocrine axis. Androgens are the male sex hormones responsible for development of the male reproductive system. Testosterone is the main androgen circulating in the blood and it is secreted from the testes, while other androgens, such as androstenedione and dehydroepiandrostenedione (DHEA) come mainly from the adrenal gland. In some tissues the androgen actions require that testosterone can be converted to dihydrotestosterone by action of 5α-reductase, and in other tissues, including adipose tissue, testosterone can also be converted into estradiol by aromatization of the androgen ring.
Endocrine actions of testosterone are under control of the hypothalamus-pituitary-gonad axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the secretion of luteinizing hormone (LH) from the anterior pituitary (adenohypophysis). In the Leydig cells of the testes, the binding of LH to its receptor activates the uptake of circulating cholesterol, the steroid precursor for biosynthesis of all androgens. In the last step of testosterone biosynthesis, androstenedione is converted to testosterone, which is the main secreted component (95% of circulating androgens). In some cases testosterone acts directly on the cells of the target organ, but in others the active hormone is formed within the cells of the target organ by reduction of testosterone at position 5 of the steroid ring to yield the more active dihydrotestosterone. Androgens are responsible for primary and secondary sexual characteristics in men and also for the development of skeletal muscle mass and strength, erythropoiesis, and bone density, amongst other functions.
The divergent effects that androgens have between the sexes can be explained by differences in concentration, metabolism, and receptor expression. Male sex hormones are also known to fluctuate along the day and throughout life. Testosterone levels are usually low in males before puberty. However, after puberty, the testosterone level increases and reaches its peak around the age of 20–25 in men. As aging occurs, testosterone levels decline.
From total circulating levels of testosterone, only the free fraction of testosterone, the part dissolved in the plasma, is biologically active. In blood, free circulating testosterone is around a 2%, while the rest of the hormone is bound in different proportions to sex hormone binding globulin (SHBG) and albumin. However, the bio-available bound testosterone can be released on demand, as the albumin binding is weak. Thus, a higher apparent concentration of free testosterone is available to act in specific tissues.
The androgens have a variety of peripheral actions. They are anabolic throughout the body. That is, they stimulate protein synthesis. It is for this reason that the male body composition is generally larger and more muscular than the female. Androgen axis alterations are due mainly to deficiency or excess of testosterone, and the final effect will depend on whether the imbalance occurs before or after puberty. Before puberty, it can lead to delayed activation or never reached puberty (hypogonadism). If in excess, the hormone will have the opposite effect promoting early puberty accompanied by growth problems characterized by bone epiphysis alterations. Testosterone deficiency during embryonic development will condition a feminization of the external genitalia in men. After puberty, given the role of the male sex hormone on spermatogenesis, testosterone deficiency can induce infertility. Exogenously induced elevated testosterone concentrations cause hypertrophy in several tissues, with the effects on skeletal and cardiac muscle being critical.
In men, plasma testosterone concentrations range from 300 to 1000 ng/dL, whereas in women circulating levels of testosterone are about 10% of those observed in men [2, 3]. The body composition of men is regulated by testosterone concentrations [4, 5]. Pharmacological suppression of endogenous testosterone levels in healthy young subjects increased fat mass and decreased fat free mass and protein synthesis in muscle, suggesting a direct effect of androgens on body metabolism of lipids and proteins [6]. Healthy young subjects suppressed of endogenous testosterone levels and supplemented with different testosterone doses (from 25 mg to 600 mg testosterone enanthate/week) for 20 weeks increased the volume of the quadriceps muscle in a dose dependent manner, as determined by nuclear magnetic resonance. At the histological level, this increase was explained by an increase in the area of type I and II muscle fibers [7]. In bone tissue, testosterone deficiency is associated with decreased bone density with increasing tissue turnover markers. Thus, hormone replacement therapy in patients with hypogonadism has been established as effective to increase bone density [5]. Although testosterone and its derivatives are well known for their androgenic properties and anabolic effects, so far the effects of androgens on muscle remain incompletely understood.
Androgens exert most of their effects through direct binding to specific intracellular receptors acting as transcriptional activators [8]. Intracellular androgen receptors have been described in skeletal and cardiac muscle cells in addition to other tissues [9, 10]. The intracellular receptor mediates the “classic” genomic response to testosterone and is characterized as a 110-kDa protein with domains for androgen binding, nuclear localization, DNA binding, and transactivation. The conserved domain structure has 3 major functional regions, an NH-terminal transactivation domain, a centrally located DNA binding domain (DBD), and a COOH-terminal hormone-binding domain (HBD). The COOH-terminus contains an additional activation domain and a hinge region connecting the HBD and the DBD. Upon ligand binding, the nuclear receptors translocate to the nucleus, where they dimerize and bind to regulatory DNA sequences on target genes to either activate or repress transcription [11]. These effects are slow, with a latency period before onset, but they are also long lasting, remaining active for several hours after hormone stimulation. Several co-regulatory proteins that bind and regulate the activity of receptors have been identified. These include both co-activators that positively regulate transcriptional effects of intracellular receptors after ligand binding and co-repressors that negatively regulate receptor activity. In addition to this transcriptional or genomic mode of action, increasing evidence suggests that androgens can exert rapid, non-genomic effects. The time course of these responses is not compatible with the classic genomic mechanism for the action of steroids, since they have a rapid onset without an apparent latency period. Common to these early effects is a fast increase in intracellular Ca2+ and activation of Ca2+-dependent pathways and second messenger cascades [12, 13]. Second messenger induction by non-genomic steroid action is insensitive to inhibitors of either transcription or translation. Little is known about these non-genomic effects in cardiac and skeletal muscle cells other than the generation of different patterns of Ca2+ signals and also the activation of complementary Ca2+-dependent pathways involved in these responses. An interesting hypothesis is that these second messenger cascades may ultimately serve to modulate the transcriptional activity of the intracellular androgen receptor and its associated global response [14-16].
Emerging syndromes and new approaches to classic diseases are now being linked to androgens. The androgen-associated diseases that will be discussed in this section include hypogonadism of the elderly (late onset hypogonadism [LOH]), sarcopenia, and the “metabolic syndrome.” The interrelation between these diseases and decreased androgen levels is complex in the sense that these diseases are not only androgen dependent but that many other factors intervene in their development. Figure 1 shows the relationship between each of these diseases with the others, demonstrating that they are not “pure” androgen-dependent syndromes. With exception of LOH, which has implicit the concept of low androgen levels, neither sarcopenia nor metabolic syndrome are solely androgen-dependent diseases. It is important to bear this characteristic in mind when considering sarcopenia and metabolic syndrome, as there are numerous causes that may be behind the same clinical presentation. Further, the role of each of the hypothesized components may be very different from one patient to the other. The fourth disease that will be discussed here is Kennedy’s disease, a hereditary X-linked neurodegenerative disease that affects mainly the androgen receptor function. In this sense, the pathophysiology of this disease is somewhat different from the 3 previously considered syndromes.
We will review the current definition of each syndrome, the epidemiology, the pathophysiology, and the effects that testosterone supplementation has demonstrated upon the evolution of the disease. After presenting these syndromes, we will highlight the differences observed among clinical studies in relation to age of populations analyzed, type of study, and expected outcome. This issue is important because it may affect the obtained results and therefore the subsequent conclusions.
Clinical expression of 3 syndromes, their relationships, and androgen dependence. Each syndrome has components of “pure” disease. Thus, certain components particular to metabolic syndrome are expressed without muscle mass compromise (sarcopenia) or androgen levels decrease (LOH), although frequently, in association with the common dependence of these diseases upon advanced age, the clinical picture will associate the presence of more than 1 of these syndromes (i.e., metabolic syndrome plus sarcopenia). In another scenario, the expression of a disease, for example, sarcopenia may have decreased androgen levels among its pathophysiologic determinants.
Definition: Hypogonadism in the adult male can be considered as a syndrome, i.e., a constellation of signs and symptoms that collectively characterize a disease/disorder. Currently, there are guidelines to the diagnosis and treatment of this emerging disorder. According to these guidelines [17] the diagnosis of late onset hypogonadism (LOH) should be considered in patients who complain of specific symptoms, mainly in the areas of sexual function (decreased libido, impaired erectile function, shrinking testes), the musculoskeletal system (muscle weakness, increased adiposity, low bone mineral density), and psychological symptoms (depressed mood, decreased vitality, sleep disturbance). In these patients, a low morning serum total testosterone level, measured on 2 different occasions, will confirm the diagnosis of LOH [17, 18]. Wu et al. (2010) [19] conducted a study to establish criteria to more accurately diagnose LOH in the clinical setting. They look for the presence of characteristic symptoms that could help to reach an accurate diagnosis of LOH. After evaluating 3369 men in a cross-sectional study along with data obtained from questionnaires and a single testosterone measurement, the authors came to the conclusion that the combination of at least 3 sexual symptoms and decreased testosterone levels would make the diagnosis of LOH more accurate.
The normal reference levels for total testosterone in adult males vary from 300–1000 ng/dL. Morning levels (before 10 AM) below 250 ng/dL will make the diagnosis highly probable. A second total testosterone measurement is required to confirm the diagnosis. These tests should generally be followed by studies that help in determining the anatomical level of the endocrine failure, in order to confirm the cause of hypogonadism (primary, secondary, or mixed) [19, 20].
Epidemiology: According to the definition of Wu et al. (2010), the actual prevalence of LOH is 2.1% in a random population sample from Europe in men aged 40 to 79 years. The prevalence increased with increasing age of the participants, ranging from 0.1% in men aged 40 to 49 years to 5.1% in men 70 to 79 years of age [19]. Another study carried out in Boston, USA, used slightly different symptoms to define symptomatic hypogonadism. This study indicated an overall prevalence of symptomatic hypogonadism of 5.6%, showing an increased prevalence of 18.4% in men in their 70s [21]. A study performed in Hong Kong established a prevalence of 9.5%. As in the above-cited studies, an increase in the prevalence of hypogonadism was seen with increasing age of patients. Other conclusions that can be obtained from the epidemiological studies are that hypogonadism starts as early as the fourth decade, and that the presence of comorbid conditions (such as type 2 diabetes mellitus and cardiovascular diseases) also increases the prevalence of this syndrome [18].
Pathophysiology: Mean values of testosterone levels have declined in 75 year old men to approximately two-thirds of the values seen in young males [22]. Cross sectional and longitudinal studies have confirmed the observation that testosterone levels decline with age [18, 23-25], and that general health status plays a crucial role in arresting the fall of plasma testosterone. The time of blood sampling also affects the testosterone level, and the slope of the relationship between testosterone and aging [26, 27]. It was shown in healthy North-American men that testosterone decreased progressively at a rate that did not vary significantly with age from the third to the ninth decades. In this study, the magnitude of the decrease in total testosterone was 3.2 ng/dL per year, similar to other studies [23]. Other investigators reported a decrease of 0.8% per year in total testosterone levels (cross-sectionally) in a population of men ranging from 40–70 years [26]. Free and albumin-bound testosterone decreased at 2% per year, whereas SHBG tended to increase at 1.6% per year. These changes tend to include a shift toward inactive bound testosterone vs free bioavailable testosterone [24, 26].
The mechanisms behind this age-associated decline in male hormone levels are still unclear. Various alterations have been described in the elderly men that can lead to LOH. The main points where the physiology of androgens has been found to be affected by age are the testes, the hypothalamus, and the transport protein, SHBG. Primary testicular changes play an important role in age-associated testosterone decline. Leydig cells in the elderly have demonstrated a reduced secretory capacity in response to stimulation with recombinant LH [28]. This decrease has been related to a reduction in the number of Leydig cells. In addition to the decline in testicular reserve seen in the elderly, an altered neuroendocrine regulation, mainly at a hypothalamic level, has been suggested. Moderate increases of basal gonadotropin levels have been observed in response to the decline in testosterone levels, but not all studies agree with this observation [22]. The increases in GnRH as well as LH are thought to be abnormally low in response to the testosterone decline induced by the aforementioned Leydig cell alterations, implying a failure at some point in the neuroendocrine axis. It has been shown that the anterior pituitary has a preserved LH response to exogenous pulsate GnRH stimulation [28], suggesting, in line with other studies, the role played by the hypothalamus and the deficit of GnRH. Finally, increases in SHBG binding capacity have also been related to LOH. This change would result in an even greater decrease of free and bioavailable (albumin-bound) testosterone levels. The cause for this increase in SHBG binding capacity is still unknown.
In conclusion, testosterone decline in the elderly appears to have multiple causes, involving the testicular, hypothalamic, and transport levels. These alterations may be present in different proportions in different patients, making LOH a difficult syndrome both to understand and to treat.
Considerations for testosterone administration: The ability to diagnose hypogonadism with increasing accuracy does not mean that the decision of which patients to treat, how to treat them, and for how long, will be easy. Probably, because of the lack of long-term longitudinal studies that prove the safety of testosterone treatment, there is some degree of agreement not to reach supra-physiological levels with testosterone supplementation. This method of testosterone replacement therapy, in non-pharmacological doses, is presently accepted as a treatment for men diagnosed with LOH. Assuming that a correct diagnosis of hypogonadism has been made, following the above-mentioned guidelines, the choice of whom to treat should be clearer. Next, in the process of treating LOH, it is important to bear in mind the desired outcomes of androgen supplementation, i.e., whether to look only for normalization of plasma testosterone levels or also for prevention or amelioration of generally associated conditions such as osteoporosis and frailty, among others. Testosterone administration to elderly men has been shown to induce beneficial effects on bone, muscle, heart, blood vessels, and mood. The problem is that many of these studies have been unable to demonstrate significant changes in endpoints such as functionality, independence, risk of fractures, etc. Furthermore, in earlier studies about testosterone supplementation, not only “pure” hypo-androgenic men were enrolled to participate, but also men with low-normal testosterone levels, which may have altered the final results. The risks associated with testosterone supplementation are an important issue influencing the decision to treat or not to treat. The development of polycythemia is a common complication of androgen therapy. It has been observed that hematocrit invariably increases with testosterone administration, and that this complication is the most frequent reason for the discontinuation of therapy [24, 29]. Concerning the cardiovascular risks, a recent study conducted in elderly patients with mobility limitations was terminated early because of an increase in the number of adverse cardiovascular events in the testosterone treated group [30]. However, a meta-analysis of randomized controlled trials that included 19 studies showed that there were no statistical differences between placebo and treated groups in relation to cardiovascular events [29]. One of the hypothesis to explain the increased cardiovascular risk is that exogenous testosterone can shift plasma lipids to a pro-atherogenic state [24], and another meta-analysis [4] that examined 29 randomized controlled trials showed a significant decrease in total cholesterol values that was more pronounced in hypogonadal men along with a reduction in HDL-cholesterol (HDL-C) that was detectable only in study populations with higher pretreatment testosterone concentrations. This effect was dependent on the formulation of testosterone used.
Finally, one of the most recognized concerns about testosterone replacement therapy is the risk of developing prostate cancer. It has long been postulated that exogenous androgens can have a causative role in prostate cancer. On the other hand, androgen deprivation therapy has demonstrated a clear role for endogenous androgens in an already settled prostatic cancer. Therefore, the question remains open whether subclinical, “occult,” prostatic lesions could develop into a neoplasia due to exogenous androgen administration. At the level of the prostate tissue, 6 months of testosterone replacement therapy in men with LOH showed no differences with placebo when considering prostate histology, tissue biomarkers, gene expression, and incidence or severity of prostate cancer [31]. Other studies that analyzed the association between testosterone treatment and prostate cancer did not find convincing evidence for this relationship [32, 33]. Nevertheless a meta-analysis [29] has shown a higher risk of detection of prostate events (incidence of prostate cancer, elevated prostatic-specific antigen, prostate biopsies) and increases in International Prostate Symptom Score (IPSS) in treated vs placebo groups.
In conclusion, benefits of testosterone replacement in LOH men have been established, but functional studies that demonstrate a significant improvement in large population samples are scarce and clinical studies of the risks of testosterone replacement therapy are still contradictory. Larger longitudinal, randomized placebo controlled studies are needed to draw definitive conclusions. At present, treatment is recommended for men diagnosed with LOH with appropriate monitoring of the prostate and the cardiovascular and hematological systems.
Definition: This term was proposed in 1989 by Irwin Rosenberg to describe a multifactorial syndrome that occurs with age and results in a loss of skeletal muscle mass and function [34]. The Greek word “sarx” means flesh, and “penia” means loss, suggesting with this name the principal organ and function targeted by this syndrome [35]. In 2010, a European Consensus definition and diagnosis of sarcopenia stated that sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, with the risk of adverse outcomes including physical disability, poor quality of life, and death. This working group also recommended criteria for the diagnosis of sarcopenia and highlighted the need to confirm low skeletal muscle mass to make the diagnosis [36].
Epidemiology: Janssen et al. [37] conducted a study to establish reference parameters for total and regional skeletal muscle mass in men and women between 18 and 88 years old. They studied 468 healthy men and women using magnetic resonance imaging, and confirmed previous reports indicating that there are gender differences for regional and whole body muscle mass. Skeletal muscle mass relative to body weight was 38% in men and 31% in women. In relation to muscle distribution, the differences were greater for skeletal muscle mass in the upper body (40% less muscle in women) than in the lower body (33% less muscle). In this population, the loss of muscle mass with age began in the fifth decade (45 years), a finding that agrees with other observations such as fiber cross sectional area and isometric and isokinetic strength, which are reported to change substantially only after 45 years of age. Due to the recent evolution of sarcopenia as a recognizable syndrome, there is still not much agreement in relation to its prevalence in aging populations [38, 39]. Baumgartner et al. [34], based on a definition of sarcopenia as appendicular skeletal muscle mass <2 standard deviations below the sex-specific young-normal mean for estimates of skeletal muscle mass, found a prevalence of sarcopenia of 24.1% in Hispanic women and 23.1% in non-Hispanic white women aged <70 years. The prevalence in men <70 years old was lower, with 16.9% in Hispanic men and 13.5% in non-Hispanic white men. Another study [39], conducted to confirm the sarcopenia rates reported by Baumgartner et al. [34], used body muscle mass measurements and reported a prevalence of sarcopenia of 22.6% in women and 26.8% in men ≥65 years. A more recent study [38] conducted in Spain evaluated healthy elderly participants aged >70 years. The observed prevalence of sarcopenia was 33% in women and 10% in men, differing from those described in the USA and other geographical areas. Ethnicity as well as other characteristics, such as health status and age, could explain these observed differences.
The prevalence of sarcopenia generally increases with age. Baumgartner et al. [34] observed an increase in the prevalence of sarcopenia after 80 years that reached >50% of individuals. Iannuzzi-Sucich et al. [39] also described an increase in the prevalence of sarcopenia in a subgroup of the studied population (80 years or older), reaching 31% in women and 52.9% in men. In reference to the relationship between testosterone levels and physical performance in older men, the Framingham Offspring study [40] described a significant association between serum free testosterone levels, walking speed, and short performance physical battery (SPPB) results. Men with low baseline free testosterone had 57% higher odds of reporting incident mobility limitation and 68% higher odds of worsening mobility limitations. Total testosterone and SHBG were not significantly associated with mobility limitation, subjective health, or physical performance measures.
The prevalence of sarcopenia varies from one study to another and these differences can be explained by different definitions of sarcopenia, differences in the studied populations and their reference (control) populations, sample sizes, and methods used to measure skeletal muscle mass. The unification of criteria to diagnose sarcopenia as well as the methods used to assess it will certainly aid in a better knowledge of the prevalence of this syndrome.
Pathophysiology: Another unresolved issue of sarcopenia is the pathophysiology of this syndrome. Because aging affects multiple organs, sarcopenia has been proposed to be the result of a multifactorial process affecting muscle, motor units, inflammatory cytokines, anabolic hormones, and nutritional intake in the elderly [41, 42].
Muscle mass is determined by a balance between protein synthesis and breakdown. It has been established that with advancing age, there is a decrease in whole body protein turnover [43]. In contrast to what happens in cachexia, where both skeletal muscle mass and fat mass are decreased, in the elderly the loss of muscle mass is accompanied by gains in fat mass [44]. Examination of the synthesis rate of particular proteins in skeletal muscle has shown that there is a particular synthesis rate, at least for each cell compartment in the skeletal muscle. The synthesis rate of mitochondrial and myosin heavy chain (MHC) proteins declines with age, whereas the synthesis rate of the sarcoplasmic protein pool was unchanged [43]. Ferrington et al. (1998) [45] have shown changes in other key skeletal muscle compartments, such as the sarcoplasmic reticulum, in aged rats. The turnover rate of SERCA pumps and ryanodine receptors decreased, whereas calsequestrin showed no changes. Studies about other key contractile elements in aging muscle, such as the α-actin protein, are recently available [46], and it was shown that in the vastus lateralis muscles of middle-aged vs elderly individuals, an isoform switch occurred with a decrease in skeletal muscle α-actin and an increase in the cardiac isoform of α-actin. This change is in accordance with the idea of a fast-to-slow transformation process during aging in the skeletal muscle. In other atrophy models, such as prolonged bed rest, the loss of thin contractile filaments (actin) was larger than that of thick contractile filaments (myosin) [47].
In addition to changes in skeletal muscle mass, there are changes in the motor units innervating the muscles. In humans, there is a decrease in the number of functional motor units with age. These changes have been confirmed in aged rats, where a reduction in the number of muscle fibers innervated per motor axon [41] was evident. These changes will lead to a decreased skeletal muscle fiber/motor neuron interaction that can further explain the decline in coordinated muscle action.
Other elements involved in the development of sarcopenia may be the loss of anabolic factors including neural growth factors, growth hormone, androgens and estrogens, and physical activity. An increase in oxidative stress and inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), and a decrease in food intake with aging have also been implicated [41, 48]. Cross-sectional and longitudinal studies have demonstrated that testosterone levels decrease with normal aging. Serum testosterone levels below the lower limit of normal, has a prevalence of 5% in healthy young men, up to 20% in the sixth decade, and increasing to 40–90% in men over 80 years [49]. Epidemiologic studies have demonstrated a relationship between levels of bioavailable testosterone and fat-free mass as well as muscle strength [49, 50]. These data correlated with physical performance tests. In the Framingham Offspring Study, men with low baseline of free testosterone concentrations showed a higher risk of incident or worsening mobility limitations [40]. In a study conducted in healthy young men to further elucidate the role of testosterone in the maintenance of skeletal muscle mass reported by Mauras et al. [6], a transient pharmacological hypogonadism was induced, decreasing fat-free mass, muscle strength, and fractional muscle protein synthesis in the volunteers. Despite this evidence, there are other studies, mainly that by Travison et al. [51], that have failed to show a clear association between testosterone concentration and physical function. This might be explained by certain aspects of the design of the study, including the selection of a younger population, a basal high physical activity level, mainly normal testosterone concentrations, and minimally demanding physical tests [50].
In short, testosterone has shown a tight association with skeletal muscle mass and a reasonable relationship with muscle strength, but no clear association with physical performance [50, 52]. The pathophysiology of sarcopenia appears, in conclusion, to be explained in part by intrinsic skeletal muscle changes associated with aging, but extrinsic causes also exist, and there are factors that aid in the development of sarcopenia or influence the degree of the attrition in skeletal muscle mass seen in the elderly.
Treatment options and impact of testosterone administration: Considering that protein breakdown and muscle atrophy is the hallmark of sarcopenia, many interventions have aimed to block the increased muscle catabolism seen in this syndrome. Among them, treatment with anabolic hormones, vitamin D, nutrition, and exercise have been studied. Controversial results have been obtained with all of the above-mentioned interventions, but 2 of them, testosterone and exercise, have been more successful. As was the case in relation to testosterone and the pathophysiology of sarcopenia, clinicians must discriminate between the endpoints of the studies that supplement older men with testosterone. In fact, the action of testosterone can be different when looking at muscle mass, strength, power, and whole-body functional probes. The anabolic effect of testosterone in aging men tends to be similar of that observed in young men but in a lesser extent. In general, studies have reported increases in lean body mass and decreases in fat mass, with varying responses concerning strength. Some studies have reported changes in grip strength but no increases in lower body strength [53, 54]. Others do report significant improvements in leg strength [49, 55]. Considering that sarcopenia is a syndrome that affects quality of life and risk of falls, changes in leg strength must be a desirable effect of the selected treatment. The factors that might lead to results showing little improvement in physical function after testosterone treatment in elderly men remains to be investigated. Critical points that should be revisited are basal testosterone levels of the selected population and testosterone concentrations reached during androgen treatment. The rigor of the selected physical probes ideally will present a real challenge in order to avoid an early ceiling effect on the sensitivity of the test.
Physical activity is always associated with a general well being outcome that stimulates cardiovascular, respiratory, and skeletal muscle systems. Endurance and resistance exercise has been shown to improve the rate of decline in muscle mass and strength that occurs with age, although resistance exercise have proven to be more effective increasing muscle mass and strength in older men [54]. There is controversy in the literature regarding the extent of the muscle response induced by exercise in the elderly. Some authors indicate that resistance exercise in older people produces smaller strength increases in absolute terms, but similar in relative terms, to younger people [55]. On the other hand, similar increases in percent muscle strength were found in healthy older individuals and in young people in a prospective investigation that also assessed changes at the satellite cell level following a heavy resistance strength training period [56].
It seems that a key feature of skeletal muscle, its plasticity, is retained even in very old individuals. Muscle cross sectional area, muscle strength, and physical performance have been shown to improve in very old nursing home residents [57] and in community residents [58] engaged in progressive resistance exercise training. The intensity of the resistance exercise required to obtain positive changes is also still under debate. The majority of studies suggest that a high intensity resistance exercise (70–90% of 1 repetition maximum) is needed in order to obtain the desired improvements in muscle mass and strength [59]. As little as 1 resistance training session per week has demonstrated positive strength changes [60]. This recent issue may be an interesting point to explore in order to attract interest of more individuals to participate in strength training programs that will aid in the prevention and treatment of sarcopenia.
In conclusion, understanding sarcopenia as a multifactorial syndrome also involves the potential discovery of a great number of therapeutic targets. So far, testosterone, but more clearly, exercise, have been the more successful therapeutic options. More studies with the newest therapies and/or improved exercise and hormone replacement therapies should be performed in order to gain advances against this quality of life (QOL)-threatening syndrome.
Definition: Metabolic syndrome is the collection of a number of metabolic abnormalities that lead to increased risk of cardiovascular disease and diabetes mellitus (DM) [61]. The definition of metabolic syndrome varies among international consensus groups. Four groups have proposed diagnostic criteria, the World Health Organization (WHO), the Study Group for Insulin Resistance (EGIR), the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and the International Diabetes Federation (IDF). In general, all of these groups maintain similar criteria, but differ in their measurements and cut off points. The IDF and NCEP ATP III are currently the most used. The latter requires the presence of at least 3 of the following 5 criteria for diagnosis: central obesity, elevated triglycerides, low HDL cholesterol (HDL-C), hypertension, and impaired fasting glucose (greater than 110 mg/dL), without categories among the factors. Subsequently, the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) suggested considering 100 mg/dL as the cut off for glucose, while the International Diabetes Federation (IDF) established as a basic requirement the presence of central obesity confirmed by abdominal circumference measurement [62, 63]. Despite the great diversity of clinical criteria for diagnosing metabolic syndrome, the central issue is to recognize that its presence means an increased cardiovascular risk for the diagnosed patient, and to take action to counteract its consequences.
Epidemiology: Depending on the criteria used, age, gender, and race, the prevalence of metabolic syndrome varies markedly. However, the prevalence increases with age independently of the other criteria used, and it is higher in males when using the criteria of the WHO and EGIR. With the WHO criteria, the prevalence for men and women under 55 years is 14% and 4%, respectively, and 31% and 20% in the older age [62, 63]. In United States, using NCEP ATP III criteria, the overall prevalence is 24%, and increases directly with age and body mass index. In young Americans ages 12 to 19 years the prevalence is 4.2%, and it exceeds 40% by 65 to 69 years. A meta-analysis encompassing 172,573 patients concluded that there is a risk of cardiovascular death that is significantly higher in people with metabolic syndrome and that this is not only explained by its components separately [64].
Pathophysiology: Body fat is an important component of metabolic syndrome because adipose tissue is insulin-resistant in obesity, which increases free fatty acid (FFA) levels in the plasma. This has a direct effect on insulin target organs including liver and muscle, through specific actions that block the intracellular signaling of the insulin receptor. Moreover, in patients with metabolic syndrome, the adipose tissue was predominantly abdominal and associated with increased visceral fat as compared with peripheral distribution. Adipocytes in visceral fat are more metabolically active, releasing more FFA and inflammatory cytokines that drain directly to the liver via the portal circulation. This phenomenon, known as lipo-toxicity, will be responsible for insulin resistance in these organs and the pancreas and unregulated high blood glucose. Lipo-toxicity also affects the cardiovascular system. In addition, FFA are able to increase oxidative stress, encourage a pro-inflammatory environment, and reduce systemic vascular reactivity, which are all factors negatively affecting cardiac cells. In association with these negative changes in adipose tissue, low testosterone levels worsen the clinical setting in the metabolic syndrome. Decreased androgen levels are associated with obesity, mainly with visceral fat accumulation. Epidemiological studies have demonstrated statistically significant correlations between plasma levels of testosterone and adipose tissue distribution, insulin sensitivity, lipoprotein metabolism, and the hemostatic system, among others. All of these cardiovascular risk factors impact endothelial function. It should be noted that these effects of testosterone vary according to sex and age. In normal men, plasma testosterone levels are correlated directly with HDL-C and inversely with triglycerides, LDL-cholesterol (LDL-C), fibrinogen, and plasminogen activator inhibitor type 1 (PAI-1). In addition, testosterone levels have correlated inversely with body mass index (BMI), waist circumference, visceral fat accumulation, insulin, and FFA. It is postulated that in men, low testosterone becomes a new element of the metabolic syndrome [61, 65].
Testosterone regulates the deposition of triglycerides in the abdominal fat tissue by lipoprotein lipase enzymes and a hormone sensitive lipase. Testosterone has an anticoagulant and profibrinolytic action, and by decreasing fibrinogen and PAI-1, it also has a pro-aggregatory effect through decreased platelet cyclooxygenase activity. During eugonadism, testosterone stimulates hormone-sensitive lipase and lipolysis. Thus, in testosterone deficiency, lipolysis is inhibited, favoring the accumulation of adipose tissue [6], which is reversed by testosterone administration. In addition, it has been reported that in hypogonadal patients, the deposition of visceral adipose tissue leads in turn to a further decrease in testosterone concentrations via conversion to estradiol by the aromatase. This leads to further abdominal fat deposition and a higher testosterone deficiency [4, 66]. In parallel, hyperinsulinemia is associated with decreased SHBG production, which decreases plasma total testosterone [67]. To date, the question of whether hypogonadism influences insulin resistance by increased abdominal obesity or whether obesity favors the reduction of plasma testosterone concentrations is still debated. However, insulin resistance leads to increased risk factors including increased triglycerides, lower HDL, and predominance of LDL-C. To these lipoprotein factors are added intolerance to carbohydrates, high blood pressure, and pro-coagulant and antifibrinolytic states [68]. Clinical studies show that men exhibit higher susceptibility to atherosclerosis than pre-menopausal women. The available data indicate that the evolution of atherosclerosis is more rapid in males, independent of dyslipidemia or evidence of endothelial damage, than in females [69]. The actual evidence indicates that low androgen concentrations are strongly associated with increases in cardiovascular risks including atherogenic lipid profile, insulin resistance, obesity, and metabolic syndrome [70, 71].
Impact of testosterone administration: Clinical studies generally show that the effects of exogenous testosterone on cardiovascular risk factors differ considerably depending on the dose, route of administration, and duration of treatment, as well as by age and condition of the patient. The findings most frequently observed are a decrease in HDL-C, a slight decrease in LDL-C, with sustained stability of the relationship between them, and moderation of insulin resistance leading to a decrease in triglyceride levels and visceral fat mass. Other less marked effects of androgen therapy are reduced levels of atherothrombotic lipoprotein Lp(a) and fibrinogen. According to current evidence, androgen therapy may exert beneficial or deleterious effects on various factors involved in the pathogenesis of atherosclerosis, and therefore further studies are required in order to determine optimal testosterone supplementation.
Figure 2 emphasizes some of the determinants that should be considered when analyzing clinical studies working with androgen replacement therapy in sarcopenia and metabolic syndrome. It is important to bear in mind the level of testosterone that is sought with the proposed treatment and from this starting point, other important considerations must be made, including age of the individuals, in order to place the conclusions in an adequate context according to the population seeking treatment.
Highlight of some key considerations in studies of testosterone supplementation for sarcopenia and metabolic syndrome. The process starts with the diagnosis of the disease. From this point, therapy will be initiated and varying testosterone levels can be reached, normal, sub-, or supra-physiologic. Once in this condition, the type of study and the age of the studied sample will influence the results. Most importantly, the expected outcome should be clearly stressed in order to avoid any ambiguity.
Definition: Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, is an infrequent hereditary X-linked neurodegenerative disease that affects approximately 1/40,000 men, typically from age 30 years [72, 73]. It is characterized by slow degeneration and loss of motor neurons in the medulla and spinal cord [74, 75]. Patients exhibit progressive weakness, atrophy of facial, bulbar, and limb muscles, sensory disturbances, and hyper-creatine kinase (hyperCKemia), together with signs of androgen insensitivity [76]. Heterozygous and homozygous females are asymptomatic [77, 78], and the latter may have a subclinical phenotype [73]. The clinical signs are manifested initially as postural and perioral tremor, and progress to proximal or distal weakness of the limbs, dysarthria, dysphagia, hanging jaw, fasciculations, and muscle cramps [76, 79]. Muscle biopsies show changes associated with denervation, such as increased fiber size variability, atrophic fibers, and clumping of sarcolemmal nuclei and necrotic fibers [80, 81]. Nerve biopsy may show reduction of large myelinated fibers [82]. The disease usually progresses irreversibly and most patients die of pneumonia associated with dysphagia and disorders of the pharyngeal and laryngeal musculature, and some may require mechanical ventilation during the course of the disease [74, 83].
Etiology: The disease is caused by the expansion of a polymorphic tandem repeat sequence of the triplet CAG in exon 1 of the androgen receptor gene (AR) located on the X-chromosome (locus Xq11–12). The normal number of repeats is 9 to 36 [84, 85] and in the case of SBMA the number of repeats identified is 40 to 62 [85, 86]. The CAG encodes the amino acid glutamine (Q), so that the AR is expressed with a polyglutamine (poliQ) sequence in the amino terminal transactivation segment [87]. SBMA is considered 1 of the 9 hereditary polyglutamine neurodegenerative diseases [75]. It has been shown that the greater number of repeats in the polyglutamine sequence, the receptor activity is decreased. Thus, in SBMA the AR has limited or null activity. This AR mutant resides in the cytoplasm as apoAR associated with heat shock proteins (Hsps) and accessory proteins until it binds its ligand (testosterone and dihydrotestosterone). The hormone binding induces the exposure of the bipartite nuclear localization signal [88, 89] and translocation to the nucleus, where it is partially degraded by nuclear proteasome [90]. The AR mutation is not able to bind coactivators and corepressors, and its classical androgenic action is not performed [69]. The patient shows signs of androgen insensitivity such as asymmetric gynecomastia, reduced fertility, testicular atrophy, oligospermia, azoospermia, erectile dysfunction, and reduced libido or diabetes [72]. The poli-Q expanded AR deregulates transcription by interfering with several transcriptional coregulators. The number of the repeats is negatively correlated with age disease onset and directly with the severity and progression of the disease [72, 76].
Pathophysiology: The precise mechanism of the disease is still unknown, but there is growing evidence that the poli-Q-expanded AR is not adequately degraded, resulting in the accumulation of fragments of the poli-Q amino terminal fragment [73, 91]. These are accumulated in the nucleus of motor neurons, dorsal root ganglia, or visceral cells, and exert toxic effects that cause dysfunction and loss of neurons [79, 88, 92]. Aggregation requires the presence of androgens, migration of the mutated AR to the nucleus, and inhibition of gene expression of essential factors for the viability of affected neurons [88]. Once it joins the ligand, either testosterone or dihydrotestosterone (DHT), the poli-Q expanded AR migrates to the nucleus and due to misfolding [84], does not perform its genomic functions in the androgen response elements (ARE), but instead forms nuclear aggregates [92]. The nuclear aggregates (neuronal intranuclear inclusions) contain fragments of mutated AR, ubiquitin proteasome system (UPS) (ubiquitin and 19S and 20S proteasome core components), and heat shock proteins (Hsp40, Hsp70 and Hsp90) [93]. Segments with poli-Q expansions form antiparallel beta strands, and by hydrogen bonds the strands form a beta sheet structure, resulting in aggregation of these misfolded proteins as intranuclear inclusions, either as oligomers or larger aggregates [94]. The mutated ARs in the nucleus undergo partial proteolysis due to misfolding, resulting in the production of truncated forms of the poli-Q-expanded AR oligomers. The accumulation of mutant AR aggregates is regarded as protective [95, 96], while diffuse accumulation in the nucleus is considered toxic [92]. These aggregates are observed at light microscopy as inclusions in the nucleus and cytoplasm of affected motor and sensory neurons and those with no apparent signs of damage [92]. It has been found that the number of aggregates was not correlated with toxicity [88]. In addition, this same type of aggregate is seen in other tissues including scrotal skin and abdominal viscera [73]. There is clear evidence that mutated AR aggregation leads to transcriptional dysregulation in affected neurons [97]. Intermediate gene products have been described that reduce the expression of TFG-β receptor type II (TβRII), dynactin 1, and VEGF. Transgenic mice expressing a mutated AR with 97 glutamine repeats (AR-97Q) exhibited muscle atrophy and neurodegeneration similar to that of SBMA in studies, and this was associated with reduced transcription of TβRII [97]. Moreover, in a similar model of transgenic mice, AR-97Q was associated with early decrease in the expression of the p150 (Glued) subunit of dynactin (dynactin 1), and this was related to inadequate retrograde axonal transport resulting in the distal accumulation of neurofilaments, axonopathy with subsequent degeneration of motor neurons, and the onset of characteristic signs of SBMA, which was partially reversed by castration [98]. Overexpression of C terminus of heat shock cognate protein 70-interacting protein (CHIP) in double-transgenic mice significantly reduced the SBMA phenotype by promoting the degradation of the mutated receptor by way of ubiquitin proteasome system (UPS) and significantly reduced the appearance of nuclear aggregates of mutant AR [93], indicating that proper breakdown of mutated protein reduces the negative effects of poli-Q-expanded AR. Interestingly, over-expression of skeletal muscle tissue-specific normal AR induced a phenotype similar to SBMA in transgenic animals, mimicking the effects of poli-Q-expanded AR [75], which suggest that muscle dysfunction may at least partly be behind the pathology of motor neurons and is due to overexpression of the AR in the presence of androgens inducing decreased expression of VEGF, which is critical in maintaining the neuromuscular junction and the viability of motor neurons [75].
Treatment options: Clinical deprivation of androgens by various strategies has been tested, including the use of the competitive AR blocker flutamide, which was ineffective in animal models. The efficacy to prevent the peripheral conversion of testosterone to dihydrotestosterone (DHT) by blocking the enzyme 5-α-reductase using dutasteride has also been tested, and proved to be ineffective to prevent the progression of the disease [99]. The most promising strategy has been the use of leuprorelin, which is a LHRH analogue that reduces androgen secretion to undetectable levels in plasma and has proven effective in preventing toxic accumulation of mutated AR and neurodegeneration in human patients [100, 101]. Other experimental strategies are based on preventing the deregulation of transcription induced by the mutated AR, since it has been shown to inhibit the histone acetyltransferase (HAT) activity of nuclear proteins like Sp1 and cAMP response element-binding protein-binding protein (CBP) [102], which has been shown to induce a phenotype of SBMA and which has been prevented by histone-deacetylase inhibitors, such as sodium butyrate, in animal studies [100]. The strategy of increasing the degradation of mutated AR via the UPS or by induction of autophagy to reduce the presence of nuclear and cytoplasmic poli-Q AR has also been explored [88, 93], but to date the most effective mechanism to prevent progression of the disease is to reduce circulating androgen concentrations, thereby preventing migration of the mutated AR to the nucleus and its subsequent toxic effects.
High blood levels of androgens, above the physiological range, are produced by exogenous administration of testosterone or its synthetic derivatives. These hormones have been used by athletes to improve performance by increasing muscle mass and strength. Hypertrophy is the more recognized among the numerous documented hormonal effects of long-term use of androgens.
Muscle mass is regulated by the normal balance between synthesis and degradation of muscle proteins. There is consensus that the use of testosterone leads to hypertrophy by increasing net protein synthesis over protein degradation, however the pathways responsible for this effect, and this dependence of intracellular androgen receptor, have not been fully described to date. Moreover, testosterone activates skeletal muscle satellite cell and mesenchymal stem cell differentiation, which also accounts for the clinical effect of this hormone on body composition [103, 104]. Side effects related to use of anabolic steroids are focused especially on the cardiovascular system [105]. It is known that there are increases in blood pressure and peripheral arterial resistance [105-108], and there are also effects on the heart muscle, primarily left ventricular hypertrophy with restricted diastolic function [109-111]. Severe cardiac complications (heart failure, atrial fibrillation, myocardial infarction or sudden cardiac death) in strength athletes with acute anabolic/androgenic steroid abuse have also been reported [112, 113].
The anabolic actions of androgens enhance muscle strength and increase muscle size clinically [6, 7, 114]. In vivo, androgens increase skeletal muscle mass and induce cardiac hypertrophy [10, 109]. The effect of androgens may occur through either the classically described intracellular androgen receptor pathway (genomic pathway) or via a fast, non-genomic pathway. In contrast to the genomic pathway (minutes to hours), the non-genomic pathway has measurable effects in seconds to minutes. It is elicited by hormones, the effects of which cannot be abrogated by transcriptional inhibitors, and may occur without requiring the hormone to bind the intracellular receptors or the receptor to bind DNA [115].
As noted, hypertrophy processes involve changes in gene expression controlled by intracellular androgen receptor-mediated pathways, and recent studies have demonstrated an alternative rapid intracellular androgen receptor-independent mode of testosterone action. The establishment of the testosterone-androgen receptor complex acts as a transcriptional factor for the expression of different genes and proteins necessary for protein synthesis, energy production, and cell growth, which are also crucial for hypertrophic growth. Now, aside from the classical action mechanism of testosterone, non-classical effects have also been implicated in the growth of the muscle cell. Hypertrophy in both skeletal and cardiac muscle is an adaptive response of the cell to increase force and contractile activity. Although initially beneficial, the prolonged activation of muscle cells by hypertrophic stimuli may produce detrimental effects. Unlike that in cardiac muscle, hypertrophy of skeletal muscle cell is a reversible process.
Several pro-hypertrophic stimuli activate common pathways in the muscle cell [116]. Among pathways activated by these stimuli, key regulators are phosphatidylinositol-3 kinase (PI3K)/Akt and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK/ERK1/2) pathways [117-119]. It has also been proposed that testosterone actions involve membrane receptors that stimulated early intracellular signaling pathways through interaction with G proteins in primary cultures of skeletal muscle cells [12] as well as cardiac myocytes [120]. Common to these early effects are the fast intracellular Ca2+ increase, activation of Ca2+-dependent pathways, and second-messenger cascades. Ca2+ is one of the most diverse and important intracellular second messengers as well as a key element in the excitation-contraction coupling of muscle cells. Ca2+ has been related to hypertrophy because of its ability to promote the activation of the protein phosphatase calcineurin through the establishment of a Ca2+/calmodulin complex [121]. Calcineurin promotes translocation of the nuclear factor of activated T cells (NFAT) from cytoplasm to nucleus. NFAT family proteins are responsible for the expression of the early fetal genes, which are expressed during fetal development. These are silenced in adult stages but are re-expressed during cardiac hypertrophy, and thus are considered as hypertrophic markers [119, 121, 122].
Interlinked signaling pathways are related to hypertrophy of the muscle cells. Moreover, it has been described that testosterone induces intracellular Ca2+ increase through a non-genomic action mechanism in skeletal muscle cells [12, 13] and cardiomyocytes [120]. Studies in cultured muscle cells show that through a nongenomic mechanism, testosterone is implicated in the activation of a membrane receptor coupled to a Gαq protein, thus resulting in the production of IP3 and release of Ca2+ from endoplasmic reticulum [12, 120]. These Ca2+ oscillations induce the activation of ERK 1/2, which in turn phosphorylates mammalian target of rapamycin (mTOR), promoting hypertrophic cardiac growth [15].
The PI3K/Akt pathway has been related to cell survival and proliferation in almost all cell types. However, the up-regulation of the pathway by several stimuli induces cardiac hypertrophy. One of the most common downstream targets of Akt is the protein kinase glycogen synthase kinase 3-β (GSK3-β) [123]. Activated GSK3-β phosphorylates several members of the NFAT family, which promotes their translocation from nucleus to cytoplasm. Akt phosphorylates and inhibits GSK3-β, which increases the residence of NFAT in the nucleus. Moreover, Akt has the ability to phosphorylate mTOR, another downstream target of the PI3K/Akt pathway. In muscle cells, protein synthesis is highly regulated by mTOR, which stimulates protein translation and ribosome biosynthesis [124]. The mTOR lies upstream of critical translation regulators such as the 40S ribosomal protein S6 kinase 1 (S6K1) and the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Activation of the mTOR pathway is a critical step to induce cardiac hypertrophy by testosterone in vitro [15].
Thus, considering the current information available regarding androgen actions on muscle cells, it has been proposed that muscle hypertrophy induced by testosterone requires both androgen receptor activity and signal transduction pathways to control protein synthesis.
The role of androgens in modulating both musculoskeletal and cardiovascular function is of the highest importance, especially considering that androgen deficiency is strongly associated with several medical conditions, including sarcopenia, metabolic syndrome, obesity, diabetes, hypertension and atherosclerosis. Testosterone deficiency, as observed in LOH, further deprives muscle of important anabolic effects of androgens in human males. The action mechanism of androgens involves both androgen receptor and signal transduction pathways, so, essential for the diagnosis, clinical and pharmacological intervention studies, a detailed knowledge of these pathways is required. As cardiovascular side effects of testosterone reduce its actual therapeutic use, research in this field is badly needed to have a detailed knowledge of the effects of androgen alterations in order to elaborate safe therapeutic replacement protocols that appear to have a broad potential for high incidence pathological conditions.
This work was supported by FONDECYT (grant 1120259 to M.E. and grant 1110467 to E.J.) and by ACT 1111 (E.J.). C.B. is a CONICYT doctoral fellow (AT 24091020).
With the rapid development of the global economy and a rising population, the search for efficient and clean energy and energy storage technologies has become a priority worldwide. Because of its exceptionally fast energy conversion rate, long life, and environmental friendliness, dielectric energy storage technology has been used in applications for the electronics and power industries such as wearable electronic devices, hybrid vehicles, and weapon systems [1]. As the trend toward high-performance miniaturized electronic devices continues, the demand for dielectric materials with high energy storage density (Ue) is increasing. Ue is an important parameter to measure the energy storage performance of dielectric materials:
where εr is the permittivity of material and εo is the permittivity of free space (8.85 × 10−12 F m−1) [2]. This requires that the dielectric material has a high εr while having a low dielectric loss and a high breakdown strength.
Commonly known high-energy storage dielectric materials are mainly biaxially oriented polypropylene (BOPP), polyester, polycarbonate (PC), polyphenylene disulfide, polyurea, polyurethane, and polyvinylidene fluoride [3]. Among many polymers, polyimide (PI) is a type of polymer containing an imide ring on the main chain [4]. PI is widely used in packaging materials, insulation layers, circuit boards, and interlayer dielectrics due to its high tensile strength, excellent mechanical properties, high glass transition temperature (Tg), and good solvent resistance and thermal stability [5]. However, the εr of polyimide is not sufficiently high (usually less than 10) to meet the requirements of the applications of high-energy density film capacitors.
The chemical groups of a dielectric medium contribute to its molar polarization; as the molar polarization increases, the εr increases. The dielectric properties (including εr and dielectric loss) of polymers are mainly related to molecular polarization, which includes electron polarization, vibration polarization (or atomic polarization), orientation polarization (or dipole polarization), ion polarization, and interfacial polarization. However, low-quality/purity polar molecules can reduce the dielectric properties of PI materials [6].
Ma et al. [7] used high-throughput density functional theory (DFT) to rationally design high εr and band gaps and linked experimental and theoretical results to changes in PI to demonstrate the relationship between chemical functionality and dielectric properties. Currently, researchers usually use two methods to prepare polyimide film capacitors with high εr, low dielectric loss, and high breakdown strength. One method is directly based on the molecular design of polyimide: Polar groups, conjugated components, or electron-rich groups are introduced into the main polymer chain to increase molecular polarizability, thereby increasing the εr [8]. The other method, which is currently the most studied, prepares a composite material by introducing high-εr ferroelectric materials such as TiO2, BaTiO3 (BT), Pb (Zr, Ti)O3, etc. into the polymer matrix to significantly improve the dielectric properties [5].
Kapton PI is an aromatic PI film that has been commercially available since the mid-1960s. Due to its continuous operating temperature of 300–350°C, it is widely used as a high-temperature wire and cable insulation material. At 25°C and 1 kHz, Kapton’s εr is 3.1, but it drops to 2.8 at 300°C. Despite its good thermal stability, Kapton PI cannot be applied to capacitor films because it is difficult to manufacture films with a thickness of <12 μm, and problems of carbonization during breakdown. Consequently, research is required to find other PIs with superior dielectric properties. SIXEF-44 is a fluorinated PI (from Hoechst Celanese) prepared from 2,2-bis(3,4-dicarboxyphenyl)-1,1,1,3,3,3-hexafluoropropane dianhydride (6FDA) and 2,2-bis(4-aminophenyl)hexafluoropropane (4,4′-6F diamine). This fluorinated PI has a εr of 2.8 at 1 kHz, Tg of 323°C, and a change in εr of less than 10% over a temperature range of −55 to 300°C. Other aromatic PIs include: perfluoropolyimide (PFPI; developed by TRW), prepared from the perfluoroisopropylidene diamine of 2,2-bis[4-(4-aminophenoxy)phenyl]hexafluoropropane (4-BDAF) and pyromellitic dianhydride (PMDA); and Upilex-S (from ICI), prepared from 3,3′,4,4′-biphenyltetracarboxylic dianhydride (BPDA) and p-phenylenediamine (p-PDA). The Tg of PFPI is >300°C, the εr is 3.1 at 25°C, and decreases to 2.9 at 300°C; Upilex-S has a Tg of 355°C, εr of 3.3 at 25°C and 1 kHz, and remains stable at 300°C. Most of these aromatic PIs affect practical applications due to processing difficulties. A polyetherimide (PEI) called Ultem is modified by the addition of flexible moieties such as ether bonds and alkyl groups in the polymer backbone; it is synthesized from the disodium salt of bisphenol A and 1,3-bis(4-nitrophthalimido)benzene. After development, the PEI film can attain a thickness of 5 μm by melt extrusion and stretching. In order to give PEI flexibility, ether bonds and alkyl groups are added, which results in the following changes (compared to PI): the Tg reduces to circa 215°C; the εr increases to 25 at 200°C, and the εr over 100 Hz–10 kHz is 3.1 [9]. Some of the heat-resistant PI polymers used as capacitor dielectrics are shown in Figure 1.
Heat-resistant PI polymers used as capacitor dielectrics [9].
The relationship between the dielectric properties of PI and molecular structure can be studied by changing the structure of the aromatic tetracarboxylic dianhydride and diamine monomers used to prepare PI. However, the preparation of the aromatic tetracarboxylic dianhydride is often complex and the yield is low while the synthetic method for phenyl-substituted aromatic diamine is relatively simple, diverse, and high yield. Consequently, modifying the structure of the aromatic diamine monomers has become the primary choice to improve the properties of PIs [10].
Peng et al. [3] used 5,5′-bis[(4-amino)phenoxy]-2,2′-bipyridine (BPBPA) diamine monomer (as shown in Figure 2) and different dianhydrides [BPDA, PMDA, 3,3′,4,4′-Benzophenonetetracarboxylic dianhydride (BTDA), 4,4′-Oxydiphthalic anhydride (OPDA)] to give a series of bispyridyl-containing PIs using a two-step synthesis. The bipyridyl unit enhanced the electronic polarization and coupling: The polarized PI had a εr of ≤7.2, the dielectric loss was ≥0.04, and the energy density was ≤2.77 J cm−3. At the same time, it demonstrated good thermal and mechanical properties.
Dipyridyl-containing diamine monomer [3].
Tong et al. [4] studied the relationship between molecular structure and properties using a range of modified PIs. In this study, the εr was increased by introducing sulfonyl groups, the loss factor was reduced by introducing flexible bonds, and the Tg was increased by retaining the aromatic structure. The resulting sulfonyl-containing PI with different flexible connections gave high εr (4.50–5.98), low loss coefficients (0.00298–0.00426), high breakdown strength (mostly at 500 MV m−1 or more) and high heat resistance (Tg: 244–304°C) (Figure 3).
Synthesis of sulfo-containing PI [4].
For the anhydride 3,3′,4,4′-diphenylsulfonetetracarboxylic dianhydride (DSDA-mDS, each repeat unit contains two -SO2-, which has the highest dipole density), the εr was not as high as expected but it can be seen that the two -SO2- units improved the stiffness of the overall chain, hindering the rotation of the dipole. Therefore, in addition to the dipole moment and dipole density, the “effective” dipole is another important factor affecting the value of the εr. Compared to ortho-symmetric OPDA-mDS, para-symmetric PI (OPDA-pDS) was more effective for PI with sulfonyl group (OPDA-pDS) in the diamine moiety (para-para bond). The symmetric structure and low free rotation energy barrier facilitate the alignment of the excimer: The εr increased to 5.98; the dielectric properties were stable at 150°C; the discharge energy density and charge and discharge efficiency increased to 7.04 J cm−3 and 91.3% at 500 MV m−1 respectively [4].
Due to the high polarity of nitrile groups, special classes of PIs containing nitrile units for piezoelectric and other dielectric applications have previously been studied [11]. Kakimoto et al. [12] reported that attaching a polar -CN side group to a PI could increase its εr. Treufeld et al. [11] found that adding a CN dipole to the PI main chain had two main effects: Firstly, because the -CN group is directly connected to the main chain in a 90° configuration, the motion is hindered and generates significant friction with randomly stacked adjacent chains, so dipole motion (such as wobble) is introduced into the PI sample; secondly, by adding the -CN group, the PI becomes more polar, easily contaminated by impurity ions, thereby improving ion mobility. Furthermore, it has been shown that the presence of three nitrile groups on the diamine unit is more effective in improving the εr than one nitrile group. Wang et al. [13] studied and synthesized a series of PIs from a diamine synthesized with three nitrile groups (as shown in Figure 4) and four commercial dianhydride starting materials. All PIs showed a high Tg, thermal stability and excellent mechanical properties; the PI had a εr of 4.7 resulting from the introduction of three highly polar nitrile groups.
Diamine monomer containing three nitrile groups [13].
Unlike ordinary composite materials, graft polymers, with good properties, were synthesized by Chen et al. [7]. The copper phthalocyanine oligomer (o-CuPc, shown in Figure 5) is a semiconductor material with unique electrical properties (εr > 103) and good thermal stability, used widely in organic optoelectronics, the dye industry, catalysis, electrochromism, and electroluminescence display and other fields. The design and synthesis resulted in a high-εr all-organic polymer material, that is, a CuPc-PI homogeneous block copolymer was prepared (see Figure 6). The CuPc-PI also showed low dielectric loss, high breakdown strength, high Ue, high thermal stability, and good mechanical properties; its overall performance was higher than the direct use of o-CuPc/PI composites obtained using CuPc as the conductive filler [7].
Synthetic copper phthalocyanine oligomer [7].
Schematic diagram of graft reaction [7].
Modification of the molecular structure of the polymer can improve its dielectric properties although the effect can be small. Using a simple compounding method with a high εr filler (e.g., ceramic filler, conductive filler), a polymer with a high breakdown field strength can be obtained. This procedure has gained acceptance due to its simple preparation method.
The conductive filler polymer-based composite material can attain a high εr for relatively small additions of filler, and the large increase in εr can be explained by the percolation theory. Adding filler at the percolation threshold will greatly increase the electrical conductivity and εr of the composite material, thereby improving the transition layer between the filler and the matrix. Carbon materials such as carbon nanofibers (CNFs), carbon black, carbon nanotubes (CNTs), graphene, and graphite flakes are most commonly used in recent research. Among these conductive fillers, CNTs are a good choice due to their high electrical and thermal conductivity and high aspect ratios. Wu et al. [14] functionalized multi-walled carbon nanotubes (MWCNTs) with carboxyl groups prior to dispersing into PI nanofibers using electrospinning technology. Hot pressing was then performed to produce high-performance PI/MWCNT composites with a high εr, good mechanical flexibility, and excellent thermal stability. When the concentration of MWCNT was close to the percolation threshold of 12–14 vol%, the material showed a high εr, low breakdown strength, and maximum Ue. When the MWCNT content was 12 vol%, the maximum Ue was 1.957 J cm−3, which was 4.8 times that of pure PI (0.404 J cm−3), and the dielectric loss was less than 0.1. As a two-dimensional nanomaterial, graphene has great potential in the future because it can improve the mechanical, thermal, and electrical properties of polymers. Among these materials, graphene oxide (GO) has also been reported in some articles to improve the mechanical properties and thermal stability of polymer-based composites. Chen et al. [15] prepared pure PI, PI/GO, and PI/reduced GO (rGO) films by in situ polymerization, as shown in Figure 7. Among them, PI/GO and PI/rGO films both demonstrated improved thermal stability compared to pure PI films. Furthermore, at 100 Hz, when the mass fractions of GO and rGO were 2 wt%, εr were also improved (4.9 and 5.8, respectively).
Schematic illustration of the film preparation procedure for GO and PI/GO composites [15].
Adding conductive particles as a filler to the polymer matrix can improve the εr of the polymer composite. When the added amount is close to the percolation threshold, the εr can be significantly increased. However, as the amount of addition increases, a conductive network is formed, and their dielectric loss will increase sharply. In general, nanostructured BT fillers and BT-based nanocrystals are the more promising materials due to their excellent dielectric and ferroelectric properties [16].
Fan et al. [17] studied the relationship between the εr and the temperature for thermosetting PI matrix nanocomposite films containing BT nanoparticles at 103 Hz. Two temperature changes were reported, namely heating from 50 to 150°C and cooling from 150 to 50°C to investigate the effects of the transition of the BT crystal phase and the free volume change in PI on the εr for BT/PI nanocomposite membranes. Theoretical models were also used to predict the εr of composite materials to study the role of the diameter and shape of the nanoparticles. Rajib et al. [18] prepared BT/PI nanocomposites and increased their energy density at high temperatures using different volume fractions to analyze their effect on the dielectric properties. All samples were tested at high temperatures to evaluate their energy storage capacity. The highest Ue was found when the volume fraction of BT was 20% reaching 9.63 J cm−3 at 20°C and 6.79 J cm−3 at 120°C. As a dielectric material, it is expected to maintain a high energy density value at a temperature of 120°C. A pure PI film prepared by Sun et al. [19] showed high breakdown strength (451 kV mm−1) and high energy density (5.2 J cm−3). The introduction of BT nanoparticles increased the εr of the nanocomposite to 6.8, while the dielectric loss was still relatively low (0.012 at 104 Hz). However, a small amount of (3 vol%) BT nanoparticles also caused a significant decrease in the breakdown field strength (275 kV mm−1), which greatly reduced the energy density (1.7 J cm−3) of the BT/PI nanocomposite.
Therefore, for BT/PI nanocomposites, future research may concern improvements in the thermal conductivity of nanocomposites and the formation of interpenetrating networks throughout the polymer matrix. Improvements in this area will make nanocomposites less susceptible to breakdown [19]. Wang et al. [20] successfully prepared BT nanowire/PI (BT-NW/PI) and BT nanoparticle/PI (BT-NP/PI) composites with low volume fractions. Due to strong interfacial polarization, the εr of BT-NW filled composites was greater than that of BT-NP/PI. The εr of the composite containing 5 vol% BT-NW was 6.6 at 100 Hz, which was 94% higher than pure PI (εr = 3.4 at 100 Hz) and 22% higher than that of composite containing 10 vol% BT-NP (εr = 5.4 at 100 Hz). In addition, BT-NW also significantly improved the Ue of the composite. When the content of BT-NW was 2 vol%, the Ue obtained at 2200 kV cm−1 was 1.06 J cm−3, which was 37% greater than pure PI. Therefore, it could be shown that the introduced linear ceramic filler had a positive effect on the dielectric properties and Ue of the composite material [20]. Hu et al. [1] prepared and studied the dielectric properties of a BT nanofiber/PI (BT-NF/PI) composite membrane over the temperature range 20–200°C. The introduction of BT-NF at 9 vol% increased the εr for BT-NF/PI to 8.3 while the dielectric loss increased only slightly; these effects could be attributed to dipolar polarization and interfacial displacement of the nanocomposites. The breakdown strength of BT/PI composites containing 1 vol% BT-NF reached 550 kV mm−1, and the discharge energy density reached 5.82 J cm−3. Additionally, the introduction of BT-NF reduced the leakage current and improved the heat conduction. At 1 vol% BT-NF, the PI nanocomposites also exhibited high energy utilization efficiency and good thermal stability. At 150 and 100°C, when the efficiency was greater than 90%, the discharge energy density values were >2.1 J cm−3 and ≈4 J cm−3, respectively [1]. The authors used electrospinning to prepare BT-NF while the PI composite membranes were prepared by in situ dispersion polymerization. The dielectric properties of BT-NF/PI composite films in the frequency range of 102–106 Hz at a temperature of 20–150°C were studied. The results showed that the εr of the PI nanocomposite film with 30 vol% BT-NF at 100 Hz increased to ≈27 while the dielectric loss was only 0.015.
Furthermore, the calcination temperature of BT has a significant influence on the εr of the PI/BT-nanocomposite film as shown in Figure 8. The εr of the PI composite film calcined at 1000°C was higher than the PI composite films calcined at 600 and 800°C; when the BT-NF content was 30 vol%, the εr of the BT-NF/PI composite film increased to 26.6 [16]. Beier et al. [21] added Ba0.7Sr0.3TiO3 (BST) nanocrystals to the PMDA-1,3-bis(4-aminophenoxy)benzene (BAPB) PI system to generate nanocomposites. Compared with the εr (2.8) of pure PMDA-BAPB PI, the εr of composites containing 18 vol% BST increased to 6.2; below 1 MHz, the dielectric loss of composite materials with different contents of BST was less than 0.04. At an addition level of 10 vol% BST, the breakdown strength of PMDA-BAPB/BST nanocomposites increased, to reach a maximum value 296 V μm−1, while the energy density of the composite was twice that of pure PMDA-BAPB PI. The observed relative increases in εr and breakdown strength together with the reduction in dielectric loss for the nanocomposite with 10 vol% BST are desirable characteristics for practical applications [21]. Wang et al. [22] prepared PI-based composites with good dielectric properties using CaCu3Ti4O12 (CCTO) and Zr-modified CaCu3Ti3.95Zr0.05O12 (CCTZO) particles as fillers. The results showed that at a filling content of 40 vol%, the εr of the CCTZO/PI composite film could reach a value of 70 at 10 Hz, and this was higher than that of the CCTO/PI composite film under the same conditions; at 150°C, the εr of the CCTZO/PI composite material reached ≈260 [22].
Frequency dependence of dielectric property of 30 vol% BT nanoparticles (a) dielectric permittivity and (b) dielectric loss measured at room temperature [16].
By changing the design of the inorganic filler, interface problems between the filler and the polymer can be improved, such as poor flake/fiber morphology. The nanosheets can increase the breakdown strength of composites because they provide a uniform insulating center and a curved path for the electrons. Boron nitride nanosheets (BNNSs) have a layered structure like graphene and are wide band gap (6 eV) insulators. Unlike traditional dielectric materials (high-εr ceramics and conductive fillers), polymer/BNNS nanocomposites may provide higher breakdown field strengths. Wan et al. [23] prepared three-phase composites of BNN, BT-fibers, and PI (BNNS@BT-fiber/PI) using in situ polymerization. The combination of BNNS and BT fibers can facilitate the dispersion of BNNS nanosheets in BT fibers, thereby improving energy storage performance. When the content of BNNS@BT-fiber was 20% by weight, the εr of the composite material was 47.57 at room temperature and 43.03 at 200°C at 100 kHz, demonstrating a reasonable thermal stability. At a BNNS@BT-fiber content of 1 wt%, the maximum Ue of the composite at 3438 kV cm−1 was 7.1 J cm−3, that is, about three times that of pure PI [23].
In order to achieve better dispersion and alignment of the filler in the PI matrix, Gu et al. [24] prepared micron boron nitride (mBN)/PI composites by in situ polymerization and electrostatic spinning technology. At 30 wt% mBN, the mBN/PI composite material exhibited a high εr (3.77) and low dielectric loss (0.007); the material also showed good thermal stability (λ = 0.696 W m−1 K−1), a high temperature index (279°C), and Tg was 240°C [24]. Cheng et al. [25] considered that molybdenum disulfide (MoS2) had an appreciable band gap and excellent heat resistance, and prepared MoS2/PI nanocomposite films. Compared with the pure PI film, the εr of the composite film was significantly increased, while the dielectric loss remained relatively low. At a filler content of 1 vol%, the breakdown field strength reached 395 MV m−1, while Ue increased to ≈3.35 J cm−3. Furthermore, at 395 MV m−1, the charge and discharge efficiency could still be maintained above 80% [25]. Alumina (Al2O3) filler has good insulation performance, high thermal conductivity, and is relatively inexpensive. Therefore, it can be added to the polymer matrix as a filler to improve thermal performance. Choi et al. [26] used 6FDA, 4,4′-methylenedianiline, and bis(3-aminopropyl)-terminated polydimethylsiloxane to prepare PI films with different siloxane content. Since PI-3, PI-4 and PI-5 films were independent and flexible, PI/Al2O3 composite films were prepared at different concentrations of Al2O3 using these three PIs. The results showed that the thermal conductivity of the composite film increased with increasing Al2O3 content. The composite film containing 75% by weight of Al2O3 was flexible. The composite film containing 80 wt% Al2O3 showed improved thermal conductivity (>1.3 W m−1 K−1). Compared with traditional polysiloxane/Al2O3 composite materials, PI/Al2O3 composite films demonstrated improved thermal properties [26].
Because of its simple method, the compounding of fillers and polymers to produce composite materials has become accepted. However, preparation methods, external conditions, and other complications can give rise to many structural defects and electric field concentrations between the two phases of the filler and the polymer matrix. Therefore, surface treatment of the filler using a coupling agent, or decorative insulating, or conductive particles has become a key area of research [27, 28].
Halloysite (Al2Si2O5(OH)4·2H2O) is an aluminosilicate clay, which has a unique tubular structure. It has a high εr (6–8), but extremely low dielectric loss (10−3). Because there are moderate hydroxyl groups on the surface that can be chemically modified, and suitable surface modification can be performed, halloysite nanotubes (HNTs) may be an ideal filler for the preparation of dielectric polymer-based composites with high εr and low dielectric loss characteristics. Zhu et al. [29] used KH550 (3-aminopropyltriethoxysilane) and polyaniline (PANI) to modify the surface of HNT, and prepared HNT/PI, KH550 modified HNT/PI and PANI-HNT/PI nanocomposite membranes. Among these, at 100 Hz, the PANI-HNT/PI films attained a maximum εr of 17.3, while the dielectric loss was only 0.2. Notably, the prepared composite has high breakdown strength (>110.4 kV mm−1), and a maximum discharge energy density of 0.93 J cm−3; these properties could still be maintained at temperatures ≤300°C [29]. Wang et al. [30] prepared a nanocomposite with high thermal conductivity by introducing amide-functionalized MWCNT [MWCNT@p-phenylenediamine (PPD)] into a PEI matrix, as shown in Figure 9. Compared with unmodified MWCNT, MWCNT@PPD could participate in the in situ polymerization of PEI to form covalent bonds in the matrix, thereby improving the dispersibility of the filler. This method solved the disadvantages of the traditional CNT acid treatment that can destroy their conjugate structure and greatly affect the aspect ratio. The results showed that the thermal conductivity of nanocomposites containing 4.0 wt% MWCNT@ PPD ≤0.43 W m−1 K−1 [30].
Schematic for the preparation of multi-walled carbon nanotubes@azide polyacrylic acid (MWCNT@PPD) [30].
Yang et al. [27] investigated the dielectric properties of PI incorporating CCTO/Ag nanoparticles (CCTO@Ag). The use of Ag coating to modify the surface of CCTO nanoparticles increased the conductivity of the intermediate layer, thereby enhancing the space charge polarization and Maxwell-Wagner-Sillars effect, improving the electric field distortion. The results showed that when the content of CCTO@Ag was 3 vol%, the εr of PI/CCTO@Ag composites was significantly increased to 103, which was about 30 times the εr of pure PI. At the same time, the dielectric loss was very low at 0.018 [27]. Wang et al. [31] used 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTCA) and TH-615 acrylic-acrylate-amide copolymers to modify BT nanoparticles, and then prepared a BT/PI composite film by in situ polymerization. The results showed that this surface modification method could improve the dispersion uniformity of filler particles in the matrix and improve the interfacial compatibility between the two phases. At 103 Hz, a BT/PI film modified with 8% PBTCA had a εr of 23.5, a dielectric loss of 0.00942, a breakdown strength of 80 MV m−1, and a Ue of 0.67 J cm−3. At the same frequency, the composite modified with 6% TH-615 had a εr of 20.3, a dielectric loss of 0.00571, a breakdown strength of 73 MV m−1, and a Ue of 0.68 J cm−3 [31]. Due to its unique chemical structure, GO shows great potential in the field of capacitors. The graphene oxide sheet has many hydroxyl groups and epoxy groups on the surface while carboxyl groups are mainly located on the edges. However, most studies involving graphene-based composites have used only marginal carboxyl groups, so the polymer chains were attached to the edges only. Fang et al. [32] made full use of oxygen functional groups to prepare PPD-carboxyl-functionalized graphene oxide (CFGO)/PI composites. The polymer chain was fixed on the base surface, and the graphene oxide sheet was effectively separated. Thermogravimetric analysis (TGA) tests showed that PPD-CFGO/PI composites had good thermal stability below 500°C. When the content of PPD-CFGO was 4 wt%, the εr increased to 36.9, which was 12.5 times higher than that of pure PI polymer (≈3.0), the dielectric loss was only 0.0075, and the breakdown strength remained at a high level [32].
However, the covalent functionalization method adopted by Fang et al. [32] reduced the conductivity of graphene by destroying the π-π conjugate structure of graphene. In order to overcome this shortcoming, Feng et al. decorated the surface of rGO with a solid π-π stack by insulating reduced polyaniline (R-PANI) to introduce a space effect and effectively prevent the irreversible agglomeration of rGO. At 1 kHz, the highest εr (25.84) was observed in nanocomposite films containing 20 wt% rGO@R-PANI, and the dielectric loss was 0.11. The εr and dielectric loss of rGO/PI nanocomposite films were 8.23 and 56.4, respectively. Furthermore, the 5 wt% weight loss temperature for 20 wt% rGO@ R-PANI/PI nanocomposite film was 480°C, indicating that the nanocomposite film has great potential in the field of high-temperature dielectric materials [5]. Yue et al. [5] introduced reduced barium titanate (rBT), sintered in a reducing atmosphere (95N2/5H2), to PI without using any modifier or surfactant ingredients in the matrix. Surface defects of rBT and interface interactions between two phases caused by the reducing atmosphere lead to an increase in εr and Ue. Compared with pure PI, the rBT/PI composite with 30 wt% rBT exhibited the following characteristics: The εr at 1000 kHz was ≤31.6 (pure PI = 4.1), the material maintained a low dielectric loss (0.031), the Ue of 9.7 J cm−3 at 2628 kV cm−1 represented an increase of >400% (for pure PI Ue = 1.9 J cm−3 at 3251 kV cm−1) [5].
Recently, much work has focused on introducing an intermediate layer or an insulating shell on the surface of the filler to prevent them from directly connecting to each other. Fillers in composite materials can increase electrical conductivity and cause excessive polarization interfaces. Researchers are also attempting to introduce intermediate layers or oxide shells between fillers to reduce dielectric loss. Studies have also shown that the core-shell structure can achieve a high εr, low dielectric loss, and high energy density [28, 33].
Liu et al. [34] synthesized a sandwich-shaped core-shell SiO2@GO hybrid to prepare a novel SiO2@GO/PI flexible composite film using in situ polymerization. The dense SiO2 layer grafted onto the GO surface can effectively suppress leakage current. The results showed that at 40 Hz, the εr of the composite material containing 20 wt% SiO2@GO was as high as 73, which was 21 times that of pure PI (3.0), and the dielectric loss was only 0.39. In order to improve interfacial compatibility, two coupling agents, 3-aminopropyl triethoxysilane and 3-glycidoxypropyltrimethoxysilane (GPTS), were used to modify the surface of SiO2@GO: At 40 Hz, the εr of the GPTS-SiO2@GO/PI composite increased to 79 and the loss decreased to 0.25. This significant improvement in the dielectric properties was due to the improved dispersibility of the filler following GPTS modification. Wang et al. [28] prepared a core-shell structure of BT@SiO2 nanofibers by electrospinning, and successfully prepared a nanocomposite membrane composed of core-shell BT@SiO2 nanofibers and PI. Because SiO2 has very low dielectric loss (0.00002) and moderate εr, using a thin layer of SiO2 to isolate PI from BT nanofibers can alleviate the local field concentration. The latter is caused by the large difference in εr between the concentrations of the two phases, thereby enhancing the breakdown strength of the PI nanocomposite film. Compared with pure PI, the composite film filled with 3 vol% BT@SiO2 nanofibers had a maximum Ue of 2.31 J cm−3 at 346 kV mm−1 (pure PI Ue = 1.42 J cm−3 at 308 kV mm−1). TGA also showed that below 500°C, BT@SiO2/PI nanocomposite films had good thermal stability [28]. Wang et al. [35] prepared a core-shell AgNW/PI composite film with high εr and low loss (see Figure 10). The insulating shell could protect the silver cores from being directly connected to each other, so that when the εr of the composite film reached its maximum value (126), the dielectric loss remained at a low level [35].
(a) TEM image of core-shell structured AgNW. (b) TEM image of an individual AgNW. (c) SEM image of core-shell structured AgNW. (d) SEM image of AgNW/PI hybrid film [35].
Weng et al. [33] synthesized a novel core-shell of Ag@Al2O3 nanoparticles as conductive fillers and doped them into PI to prepare Ag@Al2O3/PI composite films. The composite film containing 10% by weight of Ag@Al2O3 had a εr of 21, which was seven times higher than that of pure PI (3.1). This increase in εr may be due to the high electrical conductivity of the Ag@Al2O3 filler, which caused interfacial polarization inside the composite in the applied electric field. Hence, when the mass fraction of Ag@Al2O3 was increased to 30%, the maximum value of εr was 124 [33].
Most polymer nanocomposites are expected to achieve high energy density by combining the high breakdown strength of the polymer matrix with the high εr of the filler. In fact, when the filler is introduced into the polymer matrix, the breakdown strength often decreases, especially when the volume fraction of the composite filler is high, which does not improve the energy density of the nanocomposite. Therefore, there is a need to expand nanocomposites into multilayer structures to compensate for the reduced breakdown strength [36].
Chen et al. [36] designed a three-layer PI composite membrane by combining KTa0.5Nb0.5O3 (KTN) nanoparticles with PI. Pure PI (with high breakdown field strength) was used as the middle layer with KTN/PI nanocomposite as the two outer layers to improve the energy storage performance of the entire composite film. The results showed that the maximum discharge energy density of the triple-layer composite film (t-KPI) was 3.0 J cm−3 at 300 kV mm−1, which was much larger than the maximum discharge energy density of the equivalent single-layer composite film (1.5 J cm−3, at 210 kV mm−1); at a high electric field of 300 kV mm−1, the t-KPI composite film could still maintain 88% charge and discharge efficiency [36]. Amin Azizi et al. [37] prepared large-scale high-quality hexagonal boron nitride (h-BN) films using vapor deposition technology (CVD) and transferred them to PEI films to synthesize h-BN/PEI/h-BN composite film. As shown in Figure 11, this composite film exhibits excellent charge-discharge efficiency and dielectric stability at high temperatures. At 100°C, the discharge energy density of h-BN-coated PEI reached 2.93 J cm−3, and its charge-discharge efficiency was >90%. As the operating temperature increased, its advantages become more obvious. At 200°C, the energy density of h-BN-coated PEI film was 1.19 J cm−3. Rapid cyclic discharge experiments were performed at 150°C and 200 MV m−1 to test the stability of h-BN/PEI/h-BN composite films under electric fields and high temperature. The results demonstrated that the h-BN/PEI/h-BN film coated with 19 layers of h-BN did not show any reduction in discharge energy density and charge-discharge efficiency over 55,000 charge-discharge cycles [37].
Charge-discharge efficiency of the dielectrics as a function of temperatures measured at an applied field of (a) 200, (b) 300, and (c) 400 MVm−1. (d) Discharged energy density achieved at above 90% charge-discharge efficiency at varied temperatures [37].
Chen et al. [38] prepared an amino-modified CNT/PI (NH2-MWCNT/PI) flexible composite film with a three-layer structure in which a high-dielectric NH2-MWCNT was inserted between pure PI layers (serving as the bottom and top layers) of the complex. Since the conductive paths of the insulating layer could be effectively isolated, the three-layer composite film showed high εr and low dielectric loss. It is worth noting that at 1 kHz, when the NH2-MWCNT content of the intermediate layer was 10 wt%, the multilayer composite film (P-10-P) gave the highest εr of 31.3, while the dielectric loss was 0.0016. In addition, the maximum energy density of the composite membrane containing 5 wt% NH2-MWCNT in the intermediate layer (P-5-P) was as high as 1.95 J cm−3, which is more than 50% higher than that of pure PI (1.41 J cm−3). The maximum energy density of the composite film P-10-P also remained at 1.31 J cm−3 [38]. Among the various films, h-BN/PI composite film filled with 5 vol% h-BN as the outer layer could improve the heat dissipation ability of the three-layer composite material, thereby maintaining the dielectric strength and suppressing leakage current at high temperatures. Hence, this sandwich structure composite material had excellent energy storage properties and high temperature stability. At 25 and 150°C, the maximum field strengths of the composite film with a Zr and Ca modified BT (BZT-BCT) content of 1 vol% in the intermediate layer were 360 and 350 kV mm−1 respectively, while the storage densities were 2.3 and 1.83 J cm−3, respectively [39]. Zhou et al. [40] proposed a method for preparing high-performance polymer dielectrics at high temperatures (designed roll-to-roll plasma enhanced CVD), which was easily adapted to large-scale production of various surface-functionalized polymer films. In this experiment, they uniformly deposited wide-band gap SiO2 on the dielectric polymer film at ambient temperature and atmospheric pressure, and their productivity was comparable to that of melt extrusion. The results showed that the introduced SiO2 layer increased the potential barrier at the electrode/dielectric interface, resulting in a significant decrease in conductivity. Therefore, compared with the pure polymer (see Figure 12), the SiO2-coated film exhibited good high-temperature capacitance performance and had a higher energy storage efficiency (η) value. For example, at 150°C, when η > 90%, the maximum Ue values of PEI-SiO2, PEN-SiO2, PI-SiO2, PC-SiO2, and FPE-SiO2 composite films were 2.12, 1.75, 1.24, 1.79, and 2.06 J cm−3, which were respectively 236, 672, 510, 1279, and 644% greater than the corresponding pure films. At 100°C, when η > 90%, Ue for PEI-SiO2 was 3.0 J cm−3 [40].
(a) Charge-discharge efficiency and discharged energy density of BOPP and BOPP-SiO2 films with 180 nm coating layer on each side of the polymer measured at 120°C. (b) Charge-discharge efficiency of the various dielectric films before and after coating measured at 150°C. (c) Maximum discharged energy density of the various dielectric films before and after coating achieved at above 90% charge-discharge efficiency measured at 150°C. (d) Discharged energy density obtained from cyclic fast discharge tests of pristine BOPP and BOPP-SiO2 films [40].
In conclusion, the high-temperature polyimide dielectric materials used in energy storage application have been summarized, including pure PI, structure modification of PI, PI-based nanocomposites, etc. Many methods for micro molecule dimension and macrostructure design have been analyzed. The reviewed research studies encompassed commercial products progress, material design, and specification, the fundamental theory such as dielectric properties, energy density, and thermal properties. However, the current research for available high-temperature dielectric materials still falls short of industrial application, especially operating under extreme environment conditions, due to the relatively low dielectric permittivity and higher dielectric loss, which severely limit the energy storage density. Moreover, the thermal conductivity is also a limiting factor for high-temperature polymer dielectric materials. Therefore, more fundamental research on developing high-performance intrinsic polymer and high-temperature dielectric phenomena should be focused for future application.
This work was financially supported by National Nature Science Foundation of China (No. 51977114).
The authors declare no conflict of interest.
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