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Development of selective androgen receptor modulators (SARMs)
Abstract
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.
... The AR is a member of the steroid receptor family of ligand-activated transcription factors [12]. The AR is expressed in a diverse range of tissues, and it is involved in various biological processes in bone, muscle, prostate, adipose tissue, as well as the cardiovascular, immune, and reproductive systems [13]. ...
... The AR is expressed in a diverse range of tissues, and it is involved in various biological processes in bone, muscle, prostate, adipose tissue, as well as the cardiovascular, immune, and reproductive systems [13]. This receptor is activated by a wide range of ligands, both exogenous and endogenous, including natural hormones, growth factors, peptides, as well as synthetic molecules, all known as androgens [12]. Endogenous androgens are the primary male sex steroids and are critical for the development of the male phenotype during embryogenesis, the development of sexual maturation during puberty, and maintenance of male reproductive function and behavior [14,15]. ...
... Companies such as Pfizer, Johnson and Johnson, Merck, and Glaxo began developing SARMs in the late 1990s due to preclinical evidence suggesting potent tissue selectivity and anabolic activity [12]. The major goal of the development of SARMs is to increase their tissue selectivity to avoid undesirable side effects [4]. ...
The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological function through complex interactions with the AR. It has been speculated that overexertion of AR signaling cascades as a result of SARM abuse can be a risk factor for the development of various cardiovascular diseases. The present literature review explores the implications of the interaction between SARMs and the AR on cardiovascular health by focusing on the AR structure, function, and mechanisms of action, as well as the current clinical literature on various SARMs. It is shown that SARMs may increase the risk of cardiovascular diseases through implications on the renin–angiotensin system, smooth muscle cells, sympathetic nervous system, lipid profile, inflammation, platelet activity, and various other factors. More research on this topic is necessary as SARM abuse is becoming increasingly common. There is a noticeable lack of clinical trials and literature on the relationship between SARMs, cardiovascular diseases, and the AR. Future in vivo and in vitro studies within this field are vital to understand the mechanisms that underpin these complex interactions and risk factors.
... Dissociating anabolic effects from androgenic activities is one approach to obtaining positive myoanabolic and osteoanabolic outcomes without side effects on the prostate in males or virilization in female patients. Steroidal compounds have failed to obtain desirable result, but some new non-steroidal compounds have shown, in vivo and in clinical trials, promising positive results [15][16][17]. One example is selective androgen receptor modulators (SARMs), which showed strongly dissociating anabolic and androgenic activities following androgen-receptor (AR) activation. ...
... One example is selective androgen receptor modulators (SARMs), which showed strongly dissociating anabolic and androgenic activities following androgen-receptor (AR) activation. These SARMs represent the androgenic counterpart of the selective estrogen receptor modulators (SERMs) in terms of tissue and action specificity [17]. ...
... In contrast, these testosterone treatments had a positive effect on bone healing for osteotomized tibiae, which was stronger than the effect of ostarine treatments [22]. This can be explained by the aromatization of testosterone to estrogen, which is absent in ostarine [17], and testosterone could act not only through ARs but also through ERs [22]. Apparently, the dosage and oral application of testosterone propionate were sufficient to improve bone healing in male rats [22] but failed to affect nonosteotomized femur and vertebral body in the present study. ...
Purpose
The selective androgen receptor modulator ostarine has been shown to have advantageous effects on skeletal tissue properties, reducing muscle wasting and improving physical function in males. However, data on effects in male osteoporosis remain limited. In this study, the effects of ostarine on osteoporotic bone were evaluated in a rat model of male osteoporosis and compared with those of testosterone treatments.
Methods
Eight-month-old male Sprague-Dawley rats were either non-orchiectomized to serve as a healthy control (Non-Orx, Group 1) or orchiectomized (Orx, Groups 2–6) and then grouped (n = 15/group): (1) Non-Orx, (2) Orx, (3) Ostarine Therapy, (4) Testosterone Therapy, (5) Ostarine Prophylaxis and (6) Testosterone Prophylaxis. Prophylaxis treatments started directly after orchiectomy and continued for 18 weeks, whereas Therapy treatments were initiated 12 weeks after Orx. Ostarine and Testosterone were applied orally at daily doses of 0.4 and 50 mg/kg body weight, respectively. The lumbar vertebral bodies and femora were analyzed using biomechanical, micro-CT, ashing, and gene expression analyses.
Results
Ostarine Prophylaxis showed positive effects in preventing osteoporotic changes in cortical and trabecular bone (femoral trabecular density: 26.01 ± 9.1% vs. 20.75 ± 1.2% in Orx and in L4: 16.3 ± 7.3% vs 11.8 ± 2.9% in Orx); biomechanical parameters were not affected; prostate weight was increased (0.62 ± 0.13 g vs 0.18 ± 0.07 g in Orx). Ostarine Therapy increased solely the cortical density of the femur (1.25 ± 0.03 g/cm³ vs. 1.18 ± 0.04 g/cm³ in Orx); other bone parameters remained unaffected. Testosteron Prophylaxis positively influenced cortical density in femur (1.24 ± 0.05 g/cm³ vs. 1.18 ± 0.04 g/cm³ in Orx); Test. Therapy did not change any bony parameters.
Conclusion
Ostarine Prophylaxis could be further investigated as a preventative treatment for male osteoporosis, but an androgenic effect on the prostate should be taken into consideration, and combination therapies with other anti-osteoporosis agents could be considered.
... In one particular study, no dosage of RAD-140 could stimulate the prostate or seminal vesicles to the same extent as testosterone propionate given at a concentration of 1 mg/kg [1]. The primary androgenic activity of endogenous testosterone is increased through its conversion to 5-alphadihydrotestosterone (DHT) by the enzyme 5-alpha reductase in tissues such as the scalp and prostate [3]. This conversion amplifies androgenic effects, leading to side effects like hair loss and prostate enlargement. ...
... However, SARMs are designed to selectively bind to androgen receptors in specific tissues, such as muscle and bone, without undergoing this conversion to DHT. Therefore, SARMs can exhibit greater selectivity for muscles and bones, promoting anabolic effects like increased lean body mass and muscle growth while minimizing androgenic effects in the prostate and other non-target tissues [3]. With increases in muscle growth and a supposed lack of adverse effects, companies such as Sarmscombo are promoting these drugs, with phrases such as "build muscle with little to no side effects." ...
Selective androgen receptor modulators (SARMs) have gained popularity for their alleged ability to selectively target androgen receptors, potentially offering muscle-building benefits with fewer side effects than traditional steroids. However, the safety profile of SARMs, including RAD-140, is not fully understood. This case report presents a 29-year-old male who developed liver injury after taking RAD-140. The patient experienced jaundice and elevated liver enzymes after three months of RAD-140 use. A liver ultrasound revealed hepatic steatosis and a hyperechoic lesion. Symptoms resolved after discontinuing RAD-140. Similar cases of liver injury associated with RAD-140 have been reported, highlighting the potential hepatotoxicity of this SARM. Discontinuation of RAD-140 appears to reverse liver injury, but the long-term effects and risks of SARM use remain unclear. This case highlights the need for caution and monitoring when considering SARMs for performance enhancement.
... Testosterone supplementation can be used as a treatment for this condition, but it has severe negative side effects [4,5]. Therefore, the application of nonsteroidal selective androgen receptor modulators (SARMs) has been proposed for osteoporosis therapy based on their selective anabolic effects on musculoskeletal tissue [6,7]. Ostarine (OST, enobosarm, S-22, MK-2866, or GTx-024) and ligandrol (LIG, LGD-4033, or VK5211) are nonsteroidal SARMs that bind to the androgen receptor (AR) with some tissue selectivity and cannot be converted to dihydrotestosterone and estrogen. ...
... Ostarine (OST, enobosarm, S-22, MK-2866, or GTx-024) and ligandrol (LIG, LGD-4033, or VK5211) are nonsteroidal SARMs that bind to the androgen receptor (AR) with some tissue selectivity and cannot be converted to dihydrotestosterone and estrogen. They are thought to have fewer side effects than testosterone [7][8][9][10]. OST and LIG are still being investigated in clinical trials and are not currently approved for human use in any country [9,[11][12][13][14]. ...
The effects of combination treatments using the selective androgen receptor modulators (SARMs) ostarine (OST) or ligandrol (LIG) with treadmill exercise (TE) were studied in healthy adult rats. Fifteen-week-old male Wistar rats were divided into groups (n = 10/group). Experiment 1 consisted of (1) Control group: sedentary rats receiving vehicle; (2) OST: sedentary rats receiving OST; (3) TE: training rats receiving vehicle; (4) OST + TE: training rats receiving OST. Experiment 2 consisted of (1) LIG: sedentary group receiving LIG; (2) LIG + TE: training group receiving LIG. The TE regime was as follows: 25 m/min, 5° elevation, 40 min, five times/week, and the sedentary regime was 5 min, three times/week. OST and LIG were administered subcutaneously (0.4 mg/kg body weight/day, five times/week). After eight weeks, bone samples underwent microcomputed tomographical, biomechanical, histological, and ashing analyses. All the treatments had weak effects on the bone structure without affecting bone biomechanics. The OST + TE improved bone structure, while the LIG + TE had unfavorable effects. In serum, OST, OST + TE, and LIG + TE altered cholesterol and lipoprotein levels; TE did not change the serum parameters. The SARM treatments had no clear bone benefit, and the serum effects can be considered as side effects. TE represents a safe treatment. Because SARMs are increasingly applied in gyms along with physical activities, attention should be paid to possible side effects.
... It also has important secondary effects via aromatisation to estrogens, impacting on androgenic alopecia, bone re-modelling and by converting to DHT via 5α-reductase, exerting potent stimulatory effects on prostate growth. Since the 1990s, the concept of Selective Androgen Receptor Modulators (SARMs) as molecules that selectively activate ARs in targeted tissues without aromatisation to estrogens or undergoing 5α-reductase conversion to DHT is appealing [64]. SARMs can be engineered to specifically target AR in certain tissues while minimizing off-target effects. ...
... Several experimental SARMs were available since 1998, with pre-clinical studies demonstrating positive effects on osteoporosis, cancer cachexia, and detrusor urinary incontinence. However, to date, they have not demonstrated enough efficacy or safety to pass the clinical trials [64]. Therefore at present, SARMs cannot be a substitute for managing androgen deficiency. ...
Testosterone substitution and replacement therapy is effective for managing testosterone deficiency. Traditional routes of administration include oral, nasal, transdermal, and intramuscular. Scrotal application of testosterone cream has been made recently available. Physician’s choice of one preparation over another is based on testosterone bioavailability, side effect profile and ability to achieve therapeutic levels. Patient’s choice is influenced by comfort, ease of use and product acceptability. This is important for compliance and achievement of good outcomes. Testosterone substitution can be overused and associated with adverse effects. Individuals at risk are older, obese with chronic cardiorespiratory disorders, and lower urinary tract symptoms. Therapeutic monitoring is vital and is achieved through measuring serum total testosterone levels and clinical follow-up. Decision on therapy outcomes should be individualised, based on symptom control and testosterone effects on organ function. Supra-therapeutic testosterone levels should be avoided as adverse outcomes such as worsening obstructive sleep apnoea, polycythaemia, and prostatic growth stimulation are more likely.
... Esses cofatores ou co-reguladores, além de atuarem por pela 5-redutase, reduzindo assim o risco de efeitos androgênicos. Além disso, os SARMs não são metabolizados em estrogênio pela aromatase, limitando sua ação estrogênica NARAYANAN, et al., 2018;. ...
... Os receptores de hormônios esteróides ou nucleares desempenham papéis importantes na organogênese, fisiologia e patologia de vários tecidos.(SILVA, et al., 2013;NARAYANAN, et al., 2018) Como resultado, 7diidrotestosterona é formado. A testosterona produz 5α-diidrotestosterona (DHT) ou 3α,5αandrostenediol em tecidos periféricos por meio de reações de redução mediadas pelas enzimas 5α-redutasee 3α-redutase (BERNE & LEVY, 2000). ...
Os moduladores seletivos de receptores androgênicos (SARMs) tratam-se de uma classe de ligantes de receptores andrógenos que demonstram efeitos seletivos nos tecidos de sinalizações androgênicos, possuem moléculas quimicamente programadas que possuem o poder de exercer de maneira seletiva efeitos agonistas e antagonistas no receptor de andrógeno em várias escalas, desse modo comprovando a grande diferença entre eles e os anabolizantes esteroidais. Através de pesquisas e estudos randomizados e não randomizados, existe uma preferência de uso dos SARMs para fins estéticos, porém possui efeitos já citados na literatura como eficientes em tratamentos de algumas patologias, o estudo é apresentado como uma revisão bibliográfica de caráter descritivo a respeito do efeito metabólico da utilização dos SARMs e dos esteróides. A maioria dos SARMs detém a capacidade de ativar o receptor de andrógeno nos músculos e ossos, tornando possível uma variedade de ações, principalmente positivas no seu metabolismo. Embora ainda precoce, os dados pré-clínicos se apresentam de forma promissora, os testes que comprovam a eficácia dos SARMs ainda são prematuros. Portanto, mais pesquisas são necessárias para a obtenção
... Theoretical possibilities for more potent androgens include nandrolone derivatives (19)(20)(21) or some non-steroidal synthetic androgens (SARMs) (22,23) though none are yet marketed and their dissociation rates are not well characterized. ...
Objective: Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations create a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it little understood and underdiagnosed.
Design: in silico modelling and in vitro androgen bioassay of the mutated AR to identify its structural and physiological mechanism. Describing clinical features and responses to high dose testosterone treatment of three cases of MAIS cases across a six-generation family pedigree.
Methods: Structural and dynamic in silico molecular modelling and in vitro yeast-based androgen bioassays of the mutant AR. Three cases of MAIS with consistent (gynecomastia, micropenis) and variable (infertility) clinical features across generations and effects of high dose testosterone treatment.
Results: The missense AR exon 8 mutation (nucleotide aga > gga, p.R872G arginine to glycine), known to cause increases ligand dissociation rate from mutant AR in binding assays, modelling shows the mutation weakens the closure energy of the “lid” of the ligand binding pocket allowing for easier ligand dissociation from binding site but with unimpaired in vitro androgen bioactivity. High dose testosterone treatment for 3 years in one young man caused increased virilisation and height growth but was ineffective for micropenis. Genetic counselling allowed effective prediction of MAIS risks in progeny for a carrier and non-carrier sisters.
Conclusions: The differential diagnosis and clinical management of MAIS is reviewed. The novel molecular mechanism of an AR ligand binding domain mutation in MAIS may be present in other case of MAIS.
... Interestingly, nearly all ER-positive XU ET AL. | 7 breast cancer express androgen receptor (AR) (Ricciardelli et al., 2018). This observation has led to the exploration of selective androgen receptor modulators (SARMs) as potential therapeutic agents (Narayanan et al., 2018). However, the precise role of AR in ER-positive breast cancer remains a subject of debate, constraining the implementation of AR-directed therapies. ...
Due to its high heterogeneity and significant impact on women's health globally, breast cancer necessitates robust preclinical models to understand tumor biology and guide personalized treatment strategies. Three‐dimensional (3D) in vitro tumor models hold immense promise in this regard. These tumor models not only mimic the spatial structure and growth environment of tumors in vivo, but also retain the pathological and genetic characteristics of solid tumors. This fidelity makes them powerful tools for accelerating advancements in fundamental research and translational medicine. The diversity, modularity, and efficacy of 3D tumor models are driving a biotechnological revolution. As these technologies become increasingly sophisticated, 3D tumor models are poised to become powerful weapons in the fight against breast cancer. This article expounds on the progress made in utilizing 3D tumor models for breast cancer research.
... In particular, androgen receptor antagonists and degrading agents are currently actively being used for treatment of prostate cancer 42 . Selective androgen receptor modulators (SARMs) are another therapeutically important class of compounds 43 , useful in treatment of certain kinds of muscle dystrophy. Biological membranes are of crucial importance for signal transduction in live cells, and they affect virtually all cellular signaling pathways, either via incorporated receptor proteins or by modulation of lipid bilayer physico-chemical properties. ...
The direct C–H activation of inert C(sp³)–H bonds in a hydrocarbon chain has been a very attractive target in organic synthesis for many decades. Among all the variety of processes, those driven by vinyl carbocations are quite scarce thus far, and it is hard to control for unstabilized vinyl cations. In this study, we designed a double C(sp³)–H functionalization of unactivated alkyl CH2 groups to produce a totally substituted quaternary carbon stereocenter via insertion of vinyl carbocations. These processes represent complicated reaction cascades with high molecular complexity controlled by the cooperative action of Ga(III) salts & GaHal4– anions and allow one-step deep poly-functionalization of simple CH substrates to be performed. In practice, this concept was initially implemented with simple starting compounds such as alkyl acetylenes and activated cyclopropanes, alkenes, or cyclobutanes to construct norbornane, cyclopentatetralin, and other important skeletons.
... AR can positively regulate its own expression as part of a positive feedback regulatory loop 32 . Treatment of CAFs with the AR agonist Ostarine 33 To assess whether nuclear changes are also a feature of CAFs in vivo, we examined the nuclear shape of the fibroblasts within skin SCC lesions compared to fibroblasts from flanking unaffected skin in multiple patient-derived tissues. Double immunofluorescence analysis using antibodies against pan-keratin and vimentin was used to localize cancerous lesions and identify cell types ( Fig. 2E; Supplementary Fig. 2D). ...
Alterations in nuclear structure and function are hallmarks of cancer cells. Little is known about these changes in Cancer-Associated Fibroblasts (CAFs), crucial components of the tumor microenvironment. Loss of the androgen receptor (AR) in human dermal fibroblasts (HDFs), which triggers early steps of CAF activation, leads to nuclear membrane changes and micronuclei formation, independent of cellular senescence. Similar changes occur in established CAFs and are reversed by restoring AR activity. AR associates with nuclear lamin A/C, and its loss causes lamin A/C nucleoplasmic redistribution. AR serves as a bridge between lamin A/C and the protein phosphatase PPP1. Loss of AR decreases lamin-PPP1 association and increases lamin A/C phosphorylation at Ser 301, a characteristic of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the regulatory region of CAF effector genes of the myofibroblast subtype. Expression of a lamin A/C Ser301 phosphomimetic mutant alone can transform normal fibroblasts into tumor-promoting CAFs.
... Studies have shown that AR activation and expression promote the occurrence and development of tumors in the advanced stage and promote malignant behaviors, such as invasion, spread and proliferation, and tumor drug resistance through different mechanisms, such as inhibiting the secretion of relevant immune factors to promote tumor immune escape, inducing angiogenesis, and activating EMT [36][37][38][39][40][41][42] . AR is expressed in both physiological tissues and pathological tissues and plays important roles in various physiological activities of different tissues [43] and in the development of selective androgen receptor modulators (SARMs), which also take advantage of this mechanism [44] . CYP17A1 is one of the key enzymes that affect AR synthesis, and its inhibitor, abiraterone, has been one of the targeted drugs recently implemented by international medical institutions for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [45][46][47] . ...
Objective: To investigate the effects of Lathyrol on the expression of androgen receptor (AR) and sphingosine kinase 2 (SPHK2) in renal cell carcinoma (RCC) mice and to further explore the mechanism by which Lathyrol inhibits the invasion and incidence of epithelial-mesenchymal transition (EMT).
Methods: An RCC xenograft mouse model was constructed, and the mice were randomly divided into a model group, an experiment group and a negative control group. The experiment group was intragastrically gavaged with Lathyrol solution (20 mg/kg), the model group was intragastrically gavaged with 0.9% NaCl (same volume as that used in the experiment group), and the negative control group was injected intraperitoneally with 2 mg/kg cisplatin aqueous solution. Changes in the body weight and tumor volume of the mice were recorded. Western blot (WB) was used to assess the protein expression levels of AR, p-AR, CYP17A1, PARP1, E-cadherin, N-cadherin, vimentin, α-SMA, β-catenin, and ZO-1. Protein expression levels of SPHK2, metal matrix protease 2 (MMP2), MMP9 and urokinase-type plasminogen activator (uPA) in tumor tissues were assessed by immunohistochemistry (IHC). AR expression in tumor tissues was assessed after immunofluorescence (IF) staining.
Results: After 14 days of drug administration, compared with that in the model group, the tumor volumes in the negative control and experiment groups were lower; the difference in tumor volume among the model, control and experiment groups was statistically significant (P<0.05). The differences in body weight among the three groups were not statistically significant (P>0.05). In the model group, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively increased, the protein expression levels of E-cadherin and ZO-1 were relatively reduced (P <0.05), and the protein expression levels of N-cadherin, β-catenin, vimentin, and α-SMA were relatively increased (P<0.05). In the negative control and experiment groups, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively decreased (P<0.05), the protein expression levels of E-cadherin and ZO-1 were relatively increased (P<0.05), and the protein expression levels of N-cadherin, β-catenin, vimentin and α-SMA were relatively decreased (P<0.05).
Conclusion: Lathyrol and cisplatin inhibit the proliferation of RCC xenografts, reduce the protein expression levels of AR, CYP17A1, SPHK2, PARP1, E-cadherin, and ZO-1 in tumor tissues (P<0.05), and promote the protein expression levels of N-cadherin, β-catenin, vimentin and α-SMA (P<0.05). Therefore, Lathyrol reduces RCC invasion and EMT by affecting the expression of AR and SPHK2 in RCC mice.
... This creates a receptor-ligand complex that translocate to the nucleus where it binds to DNA and acts as a transcriptional regulator of androgen genes response. Unlike natural ligands of this receptor, SARMs have a tissueselective effect, which gives them a significant advantage over other steroidal anabolic substances [1]. Currently, only SARMs antagonists, such as flutamide, nilutamide, bicalutamide, and enzalutamide, have been introduced to pharmacotherapy as nonsteroidal antiandrogen drugs for the treatment of prostate cancer. ...
Purpose: Selective androgen receptor modulators (SARMs) have demonstrated agonist activity on the androgen receptor in various tissues, stimulating muscle mass growth and improving bone reconstruction. Despite being in clinical trials, none has been approved by the Food and Drug Administration (FDA) or European Medicines Agency for pharmacotherapy. Still, SARMs are very popular as performance-enhancing drugs. The FDA has issued warnings about the health risks associated with SARMs, but the long-term exposure and possible adverse events still need to be fully understood. This review aims to evaluate the adverse events associated with using SARMs by humans.
Methods: PubMed database was searched from September 16, 2022, to October 2, 2023. In total, 20 records were included in the final review. Data from preclinical and clinical studies supported the review.
Results: Since 2020, 20 reports of adverse events, most described as drug-induced liver injury associated with the use of SARM agonists, have been published. The main symptoms mentioned were cholestatic or hepatocellular liver injury and jaundice. Limited data are related to the dosages and purity of SARM supplements.
Conclusion: Promoting SARMs as an anabolic agent in combination with other performance-enhancing drugs poses a risk to users not only due to doping controls but also to health safety. The lack of quality control of consumed supplements makes it very difficult to assess the direct impact of SARMs on the liver and their potential hepatotoxic effects. Therefore, more detailed analyses are needed to determine the safety of using SARMs.
... Selective androgen receptor modulators (SARMs) might also be considered in combating muscle dysfunction in SMA. These agents, which mimic the muscle-building anabolic effects of androgens without their pronounced adverse effects -including virilization in women and cardiac and prostatic hypertrophy -were initially developed for the treatment of sarcopenia but have also produced benefit in a rodent DMD model (74)(75)(76). The adjunct therapy that has perhaps garnered the greatest interest as a means to combat primary muscle disease involves interfering with myostatin signaling. ...
Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.
... Jednak powszechna ekspresja receptora androgenowego, jego metabolizm oraz krzyżowa reaktywność z innymi receptorami ograniczają szerokie wykorzystanie terapeutyczne androgenów. Niemniej jednak, odkrycie SARMs oraz innych tkankowo-selektywnych modulatorów jądrowych receptorów hormonalnych, daje możliwość promowania korzystnych efektów androgenów w tkankach docelowych przy minimalizacji niepożądanych skutków ubocznych [7]. SARMs aktywują odpowiednie receptory w sposób specyficzny dla danej tkanki, co niweluje w znacznym stopniu ograniczenia występujące przy stosowaniu androgenów steroidowych. ...
Introduction: Selective Androgen Receptor Modulators (SARMs) are a group of chemical compounds capable of selectively activating androgen receptors (ARs) in the body. These substances can play a significant role in a new therapeutic approach in various fields of medicine, limiting the side effects associated with traditional anabolic steroids. In this article, we will focus on an overview of the current scientific knowledge on SARMs, their mechanisms of action, potential therapeutic applications, risks and challenges related to their use. Aim of the study: The primary aim of this study was to to present potential use of selective androgen receptor modulators in sport and treatment focusing on its benefits and limitations as well as side effects aspects. State of Knowledge: SARMs in research show therapeutic benefits in the treatment of diseases such as osteoporosis, benign prostatic hyperplasia, muscle diseases and some types of cancer. Some studies suggest that few SARMs may be hepatotoxic. Most research on SARMs has been short-term, so the long-term effects of their use remain poorly understood. Conclusion: The popularity of SARMs is constantly growing, and research on their use in medicine and sports provides more and more new ways to use them. Despite promising results, these compounds still pose many scientific challenges and raise legitimate concerns about their long-term effects on human health.
... SARMs promote anabolic androgenic actions while avoiding undesirable effects such as prostate cancer growth. SARMs have the potential use in osteoporosis, Alzheimer's Disease, stress urinary incontinence (SUI), cachexia, and breast cancer (Christiansen, Lipshultz, Hotaling, & Pastuszak, 2020;Narayanan, Coss, & Dalton, 2018). ...
The nuclear receptor (NR) superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiological processes. In this review, we will summarize and discuss recent progress in NR biology and drug development derived from the integration of various approaches, including biophysical techniques, structural studies, and translational investigations. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. Significance Statement Nuclear receptors are ligand regulated transcription factors that function as key regulators of a wide range of physiological functions. NRs also serve as receptors for myriad drugs and in this review we provide an update of recent research into the function of this family of drug targets.
... The tissue-selective model of SARM action proposed by Narayanan et al. is related to a different pattern of AR co-regulators in different tissues. Perhaps the effect of ostarine may also differ between the male and female, due to sex differences in AR coregulators (Narayanan et al., 2018). Further experiments will be necessary to resolve this issue. ...
Ostarine is the most popular compound in the selective androgen receptor modulator group (SARMs). Ostarine is used as a physical performance-enhancing agent. The abuse of this agent in higher doses may lead to severe side effects. Here, we evaluate the effects of ostarine on the heart. We utilized a cardiomyocyte H9C2 cell line, isolated primary female and male cardiac fibroblast cells, as well as hearts obtained from rats. Ostarine increased the accumulation of two fibrosis protein markers, αSMA and fibronectin (p < 00.1) in male, but not in female fibroblast cells. Ostarine increased the expression of the cardiomyopathy marker βMhc in the H9C2 cell line (p < 0.05) and in the heart in rats (p < 0.01). The unfavorable changes were observed at high ostarine doses. Moreover, a decrease in viability and an increase in cytotoxicity marker LDH were observed already at lowest dose (1 nmoL/l). Taken together, our results suggest that ostarine is cardiotoxic which may be more relevant in males than in females.
... 143 Transdermal testosterone gel increases the blood concentration of androgens, which has a favorable anabolic effect on skeletal muscle. 144 However, adverse side effects exist, such as dyslipidemia, benign prostatic hypertrophy and uterine hyper-proliferation. 145 Androgens are important for building and maintaining skeletal muscle, and due to their anabolic effects on muscle, they are considered superior in the potential treatment of sarcopenia. 146 SARMs have an acceptable safety profile and positive effects on body composition and function in clinical trials. ...
Diabetes and sarcopenia are emerging as serious public health issues. Sarcopenia, an age-related disorder characterized by loss of skeletal muscle mass and function, is recognized as a new complication in elderly patients with type 2 diabetes mellitus (T2DM). Type 2 diabetes is characterized by insulin resistance, chronic inflammation, accumulation of advanced glycation products and increased oxidative stress, which can negatively affect skeletal muscle mass, strength and function leading to sarcopenia. There is a mutual interrelationship between T2DM and sarcopenia in light of pathophysiology mechanism and long-term outcome. T2DM will accelerate the decline of muscle mass and function, which will in turn lead to glucose metabolism disorders, reduced physical activity and the risk of diabetes. However, the specific mechanism involved has not been thoroughly studied. Therefore, this review aims to explore the pathophysiology and therapeutic strategy related to sarcopenia and diabetes and provide insight for future investigations, which is of great significance for improving the quality of life in the elderly with diabetes and concurrently reducing the incidence of related complications.
... Overall, this indicates AR activation may be a valid preventive or therapeutic strategy for ER + breast cancer, and, in accordance, clinical trials testing AR activation in this subtype have been implemented. 116,117 Global transcriptional, translational, and chromatin silencing by androgen therapy may also have an oncoprotective effect. However, this observation seems to misalign with increased nucleus sizes observed in luminal epithelial cells after androgen sequence motif (CisBP PPARG_676) match. ...
Estrogen and progesterone have been extensively studied in the mammary gland, but the molecular effects of androgen remain largely unexplored. Transgender men are recorded as female at birth but identify as male and may undergo gender-affirming androgen therapy to align their physical characteristics and gender identity. Here we perform single-cell-resolution transcriptome, chromatin, and spatial profiling of breast tissues from transgender men following androgen therapy. We find canonical androgen receptor gene targets are upregulated in cells expressing the androgen receptor and that paracrine signaling likely drives sex-relevant androgenic effects in other cell types. We also observe involution of the epithelium and a spatial reconfiguration of immune, fibroblast, and vascular cells, and identify a gene regulatory network associated with androgen-induced fat loss. This work elucidates the molecular consequences of androgen activity in the human breast at single-cell resolution.
... Some of the oral SARMs have been associated with elevations of liver enzymes. 23 The most common adverse events associated with an activin receptor blocker, bimagrumab, included muscle spasms, diarrhea, and skin rash. 24 Studies of GH and GH secretagogs have reported a higher frequency of side effects including edema, arthralgias, myalgias, carpal tunnel syndrome, insulin resistance, and increased blood glucose levels, and increased blood pressure. ...
... The selective androgen receptor modulator (SARM) compounds have diverse chemical structures and are categorized into steroidal or nonsteroidal. 5 SARMs bind to the androgen receptor and exhibit tissue-selective activity. 6 They have agonistic effects on anabolic target tissues (muscle and bone) while showing weak agonistic or antagonistic effects on reproductive organs (prostate). ...
An effective alternative to testosterone therapy is selective androgen receptor modulators (SARMs), a class of compounds that have a tissue-specific effect on muscle and bone. These drugs, which enhance performance, pose a severe abuse risk in competitive sports. GLPG0492 is one of the SARMs discovered in recent decades. This compound has a unique tissue-specific action for muscle and bone against steroid receptors and acts as a partial agonist for androgen receptors. This study examined GLPG0492 and its metabolites in vitro using equine liver microsomes. Liquid chromatography-high resolution mass spectrometry was utilized to determine the probable structures of detected metabolites. This study identified thirty-nine metabolites of GLPG0492 (twenty-one phase I and eighteen phase II). The hydroxylation of GLPG0492 results in mono- and dihydroxylated metabolites. Additionally, the study detected dissociated side chains (3-methyl and 4-(hydroxymethyl)) and corresponding hydroxylated metabolites. A series of glucuronic acid and sulfonic acid conjugated analogues of GLPG0492 were detected during phase II of the study. The findings might help in the detection of GLPG0492 and the elucidation of its illegal use in equestrian sports.
... 6 Diverse chemical structures are associated with SARM compounds, which are categorized into steroidal and nonsteroidal SARMs. 7,8 Several SARM compounds have been tested for use as human therapeutics, but none have been approved for clinical use. 9 SARMs have powerful anabolic properties, as demonstrated in some preclinical and clinical studies. ...
RATIONALE
Since 2010, there has been an increasing number of adverse analytical findings related to selective androgen receptor modulators (SARMs) in competitive sports. It emphasizes the importance of comprehensive doping control analytical procedures that are capable of detecting SARM misuse.
METHODS
In this study, it is described how LY2452473, a selective androgen receptor modulator (SARM), was metabolized in thoroughbred horses after a single dose oral administration and in vitro with equine liver microsome preparations. An investigation of the metabolism of LY2452473 in horses' urine, plasma, and hair matrices was carried out during the study. The plausible structures of the detected metabolites were postulated using high performance liquid chromatography-high resolution mass spectrometry.
RESULTS
Under the experimental conditions fifteen metabolites (twelve phase I, and three conjugates of phase I metabolites) were detected (M1–M15). The major phase I metabolites identified were formed by hydroxylation. Side chain dissociated and methylated metabolites were also detected. In phase II, the glucuronic acid and sulfonic acid conjugates of hydroxy LY2452473 were detected as the major metabolites. In vitro analysis has confirmed the presence of all metabolites found in vivo except for the methylated analogs M11 and M12. A peak concentration of LY2452473 (0.5 pg/mg) in proximal hair segments was achieved four weeks after administration, according to hair analysis.
CONCLUSIONS
Data obtained will aid in identifying LY2452473 and related substances faster, furthermore, the results will assist in checking for the illegal use of these substances in competitive sports.
... Selective androgen receptor modulators (SARMs) were first developed in the late 1990s as agents that selectively target androgen receptors in muscle rather than those in other regions of the body-such as the prostate or seminal vesicles-to achieve anabolic effects of muscular strength and hypertrophy with minimal undesired androgenic effects such as prostate cancer, hair loss, or acne. Possible clinical uses include treatment of sarcopenia, osteoporosis, and cachexia; however, they are more commonly used without a prescription by weightlifters and athletes, many of whom consider SARMs a safer alternative to anabolic steroids (Narayanan et al. 2018;Machek et al. 2020). Nonetheless, there is limited data on the safety of SARMs. ...
Background
Selective androgen receptor modulators (SARMs) are becoming increasingly common amongst athletes and the general population, but their side effect profile in human subjects at recreational doses is understudied.
Case presentation
A 27-year-old asymptomatic male weightlifter presented for an annual physical exam and was coincidentally found to have an abnormal lipid panel, which the patient believed to be due to recreational SARMs (LGD-4033 and S-23) usage. Further work-up revealed elevated liver enzymes suggestive of hepatocellular injury and suppression of the pituitary–gonadal axis. Lipids, hepatic function, and hormones returned to baseline after cessation of SARMs.
Conclusions
This is the first case report on how SARMs may impact LDL, cause hepatocellular rather than cholestatic liver injury, and alter health markers despite complete lack of symptoms. It is also the first case report on the potential negative effects of the SARM S-23.
... The ubiquitous AR responds to androgenic therapies in a non-specific manner, highlighting the necessity to develop selective androgen modulators (SARMs) that promote only beneficial effects in target tissues. 85 Dalton et al. in their 12-week double-blind placebo-controlled phase II clinical trial evaluated the safety and efficacy of the SARM Enobosarm, in both elderly men and postmenopausal women. The selective anabolic effects on muscle and bone led to a significant improvement in patients' physical function and lean body mass. ...
Osteosarcopenia (OS) is a newly defined condition represented by the simultaneous presence of osteopenia/osteoporosis and sarcopenia, the main age-related diseases. The simultaneous coexistence of the two phenotypes derives from the close connection of the main target tissues involved in their pathogenesis: bone and muscle. These two actors constitute the bone–muscle unit, which communicates through a biochemical and mechanical crosstalk which involves multiple factors. Altered pattern of molecular pathways leads to an impairment of both the functionality of the tissue itself and the communication with the complementary tissue, composing the OS pathogenesis. Recent advances in the genetics field have provided the opportunity to delve deeper into the complex biological and molecular mechanisms underlying OS. Unfortunately, there are still many gaps in our understanding of these pathways, but it has proven essential to apply strategies such as exercise and nutritional intervention to counteract OS. New therapeutic strategies that simultaneously target bone and muscle tissue are limited, but recently new targets for the development of dual-action drug therapies have been identified. This narrative review aims to provide an overview of the latest scientific evidence associated with OS, a complex disorder that will pave the way for future research aimed at understanding the bone–muscle-associated pathogenetic mechanisms.
... AR is a steroid receptor belonging to the nuclear receptor superfamily. The AR gene, located on the X chromosome, is encoded by 8 exons and 7 introns for 90-kb long (8)(9)(10). It can be observed in many tissues, such as skeletal muscle, testes, prostate, and breast and uterus tissues. ...
Background:
Androgen receptor (AR) is becoming an important factor in the pathogenesis of breast cancer. Traditional Chinese medicine (TCM) is widely used in treating breast cancer patients. Triple-negative breast cancer (TNBC) is a subtype of breast cancer, which has worse prognosis than other subtypes. Herein, through this retrospective study, we summarize the therapeutic implications of AR and TCM in TNBC.
Methods:
The clinical and pathological data of TNBC patients who had undergone surgery at The First Affiliated Hospital of Zhejiang Chinese Medical University from 2017 to 2019 were collected and examined. The t-test, chi-square test, logistic regression model, and Kaplan-Meier survival estimates were used to analyze the data.
Results:
We identified 823 early breast cancer patients from January 2017 to December 2019, of whom 92 (11.2%) were pathologically confirmed to have TNBC. We excluded 5 patients according to the inclusion and exclusion criteria. In relation to the remaining 87 patients, 33 (37.9%) were AR positive. In the TNBC patients, positive AR expression was correlated with an older age (P=0.006), a higher weight (P=0.006), and lower Ki-67 expression (P=0.031). After a median follow-up time of 37 months (range, 24-60 months), 13 cases of relapse and metastasis (14.9%) were observed. We found that relapse and metastasis were correlated with being unmarried [P=0.004; hazard ratio (HR) =0.105; 95% confidence interval (95% CI): 0.023-0.487], nonporous (P=0.046; HR =0.209; 95% CI: 0.045-0.971), and negative AR expression (P=0.042; HR =1.223; 95% CI: 0.049-1.012). The AR-positive TNBC patients had better disease-free survival (DFS) than the AR-negative TNBC patients 2-5 years after surgery (P<0.05). TCM was an effective treatment for TNBC (P<0.001; HR =51.682; 95% CI: 6.660-401.025). In the AR-negative group, patients who received the TCM treatment tended to have a better DFS than those who did not receive the TCM treatment (P<0.001; HR =34.832; 95% CI: 4.448-272.756); however, no such difference was found in the AR-positive group.
Conclusions:
The TNBC patients with positive AR tended to have a low expression of Ki-67 and a better prognosis than AR negative TNBC patients. TCM is an effective treatment and has slight side effects.
Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in tumor microenvironment corresponds to better overall patient survival, clinically confirming AR’s role as a tumor suppressor. Ligand activation of AR in ER-positive BC xenografts reprograms cistromes, inhibits oncogenic pathways, and promotes cellular elasticity toward a more differentiated state. Sustained AR activation results in cistrome rearrangement toward transcription factor PROP paired-like homeobox 1, transformation of AR into oncogene, and activation of the Janus kinase/signal transducer (JAK/STAT) pathway, all culminating in lineage plasticity to an aggressive resistant subtype. While the molecular profile of AR agonist–sensitive tumors corresponds to better patient survival, the profile represented in the resistant phenotype corresponds to shorter survival. Inhibition of activated oncogenes in resistant tumors reduces growth and resensitizes them to AR agonists. These findings indicate that persistent activation of a context-dependent tumor suppressor may lead to resistance through lineage plasticity-driven tumor metamorphosis. Our work provides a framework to explore the above phenomenon across multiple cancer types and underscores the importance of factoring sensitization of tumor suppressor targets while developing agonist-like drugs.
Objective
Selective androgen receptor modulators (SARMs) are potential treatments for ameliorating age‐related physical dysfunctions caused by sarcopenia, cachexia and chronic illnesses such as cancer. The purpose of this systematic review is to analyse the effect of SARMs on physical performance and body and evaluate their safety profile.
Methods
A systematic review search criteria following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines was performed in three databases for studies reporting physical parameter outcomes after SARM intervention. Study variables included title, author, publication date, study year, number of patients, dosage, mean age, mean follow‐up time, pre and post‐intervention outcomes and rates of complications.
Results
Nine studies, including 970 patients with a mean age of 57.1 years (35.3−75.9) and a mean follow‐up of 80 days (14−180), were included. Six SARMs were analysed: LGD‐4033, PF‐06260414, GSK2881078, GTx‐024, MK‐0773 and OPK‐88004. Mean pre‐intervention stair climbing power (five studies), one repetition maximum leg press (four studies) and short physical performance battery (SPPB) score (two studies), lean body mass (seven studies) and fat mass (five studies) were 352.24 W (69.79−678.7), 1822.77 N (1176.8−2407.3), 9.15 (7.95−9.9), 49.46 kg (30.94−63.9) and 21.99 kg (13.3−33), respectively. Mean post‐intervention values were 315.16 W (89.46−525.73 W), 2191.27 N (1375.87−2462.9 N), 9.79 (8.88−10.4), 50.86 kg (31.02−67.29) and 21.85 kg (12.54−32.16), respectively.
Conclusion
SARMs have a positive effect on physical performance and body composition and are associated with moderate rates of mild to moderate adverse effects (AEs) and a low rate of severe AEs.
The synthetic 20‐keto‐steroid S42 ( 1 ) demonstrated selective androgen receptor modulator (SARM) properties in preclinical studies and, consequently, received growing attention also in the context of sports drug testing programs. Fundamental understanding of the behavior of S42 ( 1 ) and of relevant derivatives in gas chromatography‐electron ionization MS experiments at high resolution (GC‐EI‐HRMS) is indispensable to develop a reliable qualitative and quantitative doping control method for S42 ( 1 ) and its metabolites in body fluid matrices. We present important fundamental mechanistic data on the EI fragmentation behavior of S42 ( 1 ) and of silyl ether derivatives as well as of stable isotope‐labelled reference material.
Sarcopenia is a condition marked by a significant reduction in muscle mass and strength, primarily due to the aging process, which critically impacts muscle protein dynamics, metabolic functions, and overall physical functionality. This condition leads to increased body fat and reduced daily activity, contributing to severe health issues and a lower quality of life among the elderly. Recognized in the ICD-10-CM only in 2016, sarcopenia lacks definitive treatment options despite its growing prevalence and substantial social and economic implications. Given the aging global population, addressing sarcopenia has become increasingly relevant and necessary. The primary causes include aging, cachexia, diabetes, and nutritional deficiencies, leading to imbalances in protein synthesis and degradation, mitochondrial dysfunction, and hormonal changes. Exercise remains the most effective intervention, but it is often impractical for individuals with limited mobility, and pharmacological options such as anabolic steroids and myostatin inhibitors are not FDA-approved and are still under investigation. This review is crucial as it examines the potential of natural products as a novel treatment strategy for sarcopenia, targeting multiple mechanisms involved in its pathogenesis. By exploring natural products' multi-targeted effects, this study aims to provide innovative and practical solutions for sarcopenia management. Therefore, this review indicates significant improvements in muscle mass and function with the use of specific natural compounds, suggesting promising alternatives for those unable to engage in regular physical activity.
S‐23 is an arylpropionamide selective androgen receptor modulator that has been investigated in animal models for use as a male hormonal contraceptive but is not yet available therapeutically. S‐23 is available alongside other selective androgen receptor modulators (SARMs) to purchase online via uncontrolled sites, sold as supplement products. It has been detected in several human doping cases, highlighting the importance of identifying the best analytical targets for equine doping control. The purpose of this study was to investigate the detection of S‐23 and its phase I metabolites in equine urine and plasma following a multiple dose oral administration to two Thoroughbred racehorses. Liquid chromatography‐high resolution mass spectrometry was used for metabolite identification, and liquid chromatography–tandem mass spectrometry was used for full sample analysis and generation of urine and plasma profiles. S‐23 and seven phase I metabolites were observed in urine following enzyme hydrolysis and solvolysis. The most abundant analyte detected was the hydroxylated 4‐amino‐2‐(trifluoromethyl)benzonitrile metabolite, which also allowed the longest duration of detection in urine from both horses, for up to 360 h following administration. The data suggest that this metabolite was likely to be highly conjugated with both sulphate and glucuronide moieties. In plasma, S‐23 and two phase I metabolites were observed. S‐23 was the most abundant analyte detected for both horses, allowing detection for up to 143 h post‐administration. To the best of the authors' knowledge, this is the first report of S‐23 and metabolites in equine urine and plasma samples.
Background
Selective androgen receptor modulators (SARMs) are small synthetic drug molecules that are still not approved as medicine in Europe or the United States but are sold on illegal websites to improve sport performance, particularly bodybuilding.
Aim
To address the quality issues of illegal SARM products and their increasing diffusion in Italy with their potential health risks for consumers.
Methods
Web-based tools were used to investigate retail websites, trending searches, and information exchange via social media. Thirteen SARM products, purchased on retail websites accessible from Italy, were subject to visual inspection and chemical analysis by mass spectrometry and quantitative nuclear magnetic resonance.
Outcomes
The primary outcome was demonstration of additional health risks due to the illicit presence of other active ingredients, contamination, and misdosage in SARM products sold on the internet. The secondary outcome was to show the increasing trend of interest in Italy for these products.
Results
Most websites reported misleading information; specifically, the statement “for research only” was reported notwithstanding indications on dosage and training phases. The trending search showed that interest toward SARMs increased in Italy in the last years. The use of these products is clearly encouraged by the emerging phenomenon of “broscience” as revealed in socials. Visual inspection evidenced nonconform labeling. Qualitative analysis confirmed the presence of the stated SARM in about 70% of samples. In 23% of samples, the expected SARM was not detected but a different one instead, and in 1 sample, no SARMs were detected. Other undeclared pharmaceutical substances (tamoxifen, clomifene, testosterone, epimethandienone, tadalafil) were measured in 30% of samples. The copresence of >1 active substance was observed in >60% of samples. Quantitative nuclear magnetic resonance data showed nonuniform content ranging from 30% to 90% of the label claim.
Clinical Implications
The use of SARMs, in the presence of unexpected life-threatening reactions in persons using the products to increase sport performance, should be assessed.
Strengths and Limitations
This investigation involved an integrated approach to study SARM products and related sociologic aspects. The main shortcomings are the limited number of samples and retail websites in the clear web investigated.
Conclusion
SARMs sold online as food supplement–like products represent a health hazard due to the presence of unapproved and undeclared active substances. The presence of contaminants clearly indicates the absence of good manufacturing practices in the production, which increases the health risks.
Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular treatment and result in resistant and aggressive disease. These breast cancers usually have fewer treatment options. Targeted therapies for cancer patients may offer fewer adverse side effects because of specificity compared to conventional chemotherapy. Signaling pathways of nuclear receptors, such as the estrogen receptor (ER), have been intensively studied and used as therapeutic targets. Recently, the role of the androgen receptor (AR) in breast cancer is gaining greater attention as a therapeutic target and as a prognostic biomarker. The expression of constitutively active truncated AR splice variants in breast cancer is a possible mechanism contributing to treatment resistance. Therefore, targeting both the full-length AR and AR variants, either through the activation or suppression of AR function, depending on the status of the ER, progesterone receptor, or human epidermal growth factor receptor 2, may provide additional treatment options. Studies targeting AR in combination with other treatment strategies are ongoing in clinical trials. The determination of the status of nuclear receptors to classify and identify patient subgroups will facilitate optimized and targeted combination therapies.
Approximately one in twenty men have sperm counts low enough to impair fertility but little progress has been made in answering fundamental questions in andrology or in developing new diagnostic tools or management strategies in infertile men. Many of these problems increase with age, leading to a growing population of men seeking help. To address this, there is a strong movement towards integrating male reproductive and sexual healthcare involving clinicians such as andrologists, urologists, endocrinologists and counselors. This book will emphasize this integrated approach to male reproductive and sexual health throughout the lifespan. Practical advice on how to perform both clinical and laboratory evaluations of infertile men is given, as well as a variety of methods for medically and surgically managing common issues. This text ties together the three major pillars of clinical andrology: clinical care, the andrology laboratory, and translational research.
Selective androgen receptor modulators (SARMs) are prohibited by the World Anti‐Doping Agency (WADA) since 2008. Similarly, to anabolic androgenic steroids (AAS), SARMs are detrimental to health not only in athletes but also in the general population. However, studies of the occurrence of SARMs outside of sport are scarce. Swedish healthcare samples from the Drugs of Abuse Laboratory at Karolinska were analyzed using WADA‐accredited screening methods at the Doping Control Laboratory in Stockholm to estimate the frequency of SARM use outside of the WADA laboratories. Twenty (4%) of the male urine samples ( n = 542) were positive for SARMs, whereas none of the analyzed female samples ( n = 100) contained any SARMs. The top three SARMs found were LGD‐4033 followed by RAD140 and ostarine. Two or more SARMs were found in >50% of the SARM‐positive samples. AASs were identified in 40% of samples containing SARMs. A difference between genders was observed where 34% male and 7% female samples contained AAS. Many samples displayed testosterone/epitestosterone values indicative of testosterone intake, without presence of other AAS, and hence, there is a risk that these samples are being falsely reported as negative. Our results indicate that SARM use might be a concern outside of sport. Subsequently, in addition to AAS, the healthcare system should also be informed about SARM abuse and the associated adverse side effects.
Liver injury associated with selective androgen receptor modulators (SARMs) is an issue that has not been reported often. We report a case of a previously healthy 24-year-old male, who was referred to our hospital for severe jaundice with intense pruritus. He had previously taken the SARM Enobosarm (also known as Ostarine) for muscle-building purposes. Blood serum levels of total bilirubin exceeded 30 mg/dL with only a slight elevation of liver enzymes. Liver biopsy revealed isolated hepatocellular cholestasis (bland cholestasis) with limited inflammation or necrosis. Supportive treatment was begun in our hospital with molecular adsorbent recirculation system (MARS) albumin dialysis, as well as cholestyramine for pruritus relief. During therapy, bilirubin levels and symptoms regressed, and after five sessions of dialysis, the patient could be released from our clinic in a markedly improved clinical and laboratory condition. However, bilirubin parameters regressed slowly after this, reaching normal levels as late as six months after first intake of the compound. Exome-based genetic testing brought about no pathogenic variants for cholestatic liver disease in our patient. Nevertheless, three common heterozygous polymorphisms associated with an increased risk for intrahepatic cholestasis could be identified. Our case demonstrates that SARMs can cause severe liver injuries not prominently mentioned in safety data sheets. Therefore, these compounds constitute a potential danger to the user’s health. This holds especially true when taking SARMs without supervision by a medical professional, which should consist of a thorough monitoring of liver enzyme and bilirubin levels.
Objective
Aging male syndrome is a clinical biochemical syndrome characterized by typical aging symptoms and serum testosterone deficiency. Although it is accompanied by various health problems, directly affects life satisfaction, and requires proper management, no clear prevention or treatment other than hormone replacement therapy is currently available for this syndrome. Here, we aimed to determine the efficacy and safety of the Lespedeza cuneata extract in the management of the aging male syndrome.
Methods
Males aged 43-70 years who provided consent for participation and had a total Aging Males’ Symptom questionnaire score ≥ 37 and testosterone level ≤ 500 ng/dL were enrolled in this study. This study was conducted in a randomized, double-blind manner. Participants were randomly assigned to either the experimental or control groups and orally administered the assigned product twice a day. Efficacy was evaluated by measuring changes in Aging Males’ Symptom score, Androgen Deficiency in the Aging Male questionnaire score, International Index of Erectile Function score, International Prostatic Symptom Score, blood test results, and body mass index at 8 weeks.
Results
After 8 weeks, the experimental group had significantly improved symptom scores compared to the control group on the Aging Males’ Symptom and Androgen Deficiency in the Aging Male questionnaires. However, no significant differences in the International Index of Erectile Function score, International Prostatic Symptom Score score, blood test results, and body mass index were observed between the experimental and control groups.
Conclusion
Lespedeza cuneata extract safely alleviates andropause symptoms without any significant side effects, suggesting its potential for the treatment of the aging male syndrome.
RAD140 is a selective androgen receptor modulator that produces anabolic effects within skeletal muscle. Thus, RAD140 may be effective at treating sarcopenia. No long‐term studies have investigated how RAD140 influences strength in ageing muscle. This study aimed to determine how 10 weeks of RAD140 supplementation impacts strength, recovery from exercise, and overall health in ageing mice. Young and adult females were assigned to receive RAD140 (5 mg/kg) or a control solution. Dorsiflexor muscles were exposed to repeated bouts of eccentric contractions, and torque was measured before and after each bout. Adaptive potential and strength gains were calculated to assess the efficacy of RAD140 in muscle, while frailty status and mortality risk were used to measure health span. Supplementation of RAD140 increased frailty status and mortality risk in the young and adult treated groups compared to the controls ( p ≤ 0.042). RAD140 decreased adaptive potential in young ( p = 0.040) but not adult mice ( p = 0.688). Torque did not differ between groups after 2–3 weeks of recovery ( p ≥ 0.135). In conclusion, long‐term RAD140 supplementation reduced indices of overall health and failed to improve strength in female mice, suggesting that RAD140 (at a 5mg/kg dosage) may be more detrimental than beneficial in delaying or preventing sarcopenia.
Type 2 diabetes mellitus (T2DM) and sarcopenia (low skeletal muscle mass and function) share a bidirectional relationship. The prevalence of these diseases increases with age and they share common risk factors. Skeletal muscle fat infiltration, commonly referred to as myosteatosis, may be a major contributor to both T2DM and sarcopenia in older adults via independent effects on insulin resistance and muscle health. Many strategies to manage T2DM result in energy restriction and subsequent weight loss, and this can lead to significant declines in muscle mass in the absence of resistance exercise, which is also a first-line treatment for sarcopenia. In this review, we highlight recent evidence on established treatments and emerging therapies targeting weight loss and muscle mass and function improvements in older adults with, or at risk of, T2DM and/or sarcopenia. This includes dietary, physical activity and exercise interventions, new generation incretin-based agonists and myostatin-based antagonists, and endoscopic bariatric therapies. We also highlight how digital health technologies and health literacy interventions can increase uptake of, and adherence to, established and emerging treatments and therapies in older adults with T2DM and/or sarcopenia.
Our study investigates potential neurochemical effects of (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), a selective androgen receptor modulator (SARM), in the rat hippocampus, with a particular focus on oxidative stress and mitochondrial function, as well as its potential effect when combined with exercise (EXE). To validate YK11's anabolic potential, we performed a molecular docking analysis with the androgen receptor (AR), which showed high affinity with YK11, highlighting hydrogen interactions in Arg752. During the five-week protocol, we divided male Wistar rats into the following groups: Control, YK11 (0.35g/kg), EXE (swimming protocol), and EXE+YK11. The administration of YK11 resulted in alterations in the endogenous antioxidant system, promoting increased oxidative stress and proteotoxic effects, impairing all mitochondrial function markers in the hippocampus. In contrast, EXE alone had a neuroprotective effect, increasing antioxidant defenses and improving mitochondrial metabolism. When combined, EXE+YK11 prevented alterations in some mitochondrial toxicity markers, including MnSOD/SOD2 and MTT reduction capacity, but did not reverse YK11's neurochemical impairments regarding increased oxidative stress and dysfunction of the mitochondrial respiratory chain and mitochondrial dynamics regulatory proteins in the hippocampus. In summary, our study identifies important pathways of YK11's hippocampal effects, revealing its potential to promote oxidative stress and mitochondrial dysfunction, suggesting that the administration of YK11 may pose potential neurological risks for athletes and bodybuilders seeking to enhance performance. These findings highlight the need for further research to assess the safety and efficacy of YK11 and SARM use in humans.
Contraception, or the purposeful temporary inhibition of one’s own fertility, is a vital additional level of control over family planning. Though many potent and reversible contraceptives are on the market, most of these contraceptives are for women – leaving a disproportionate burden of the responsibility for contraception and family planning on women. Reversible forms of contraception available for men are limited to the use of condoms and withdrawal. The only other form of male contraception that approaches the same efficacy as some available options for women is vasectomy, which is not always reversible and often has lasting effects on fertility [1]. To meet the unmet need of potent and reversible male contraception, research and clinical trials for hormonal male contraceptives have been ongoing for nearly the past 50 years; yet roadblocks, such as unfavorable injections and undesirable side effects, have slowed the emergence of this option on the market [2, 3]. New research is now under way for optimized hormonal contraceptives and a myriad of nonhormonal contraceptive options. Early preclinical tests of nonhormonal contraceptive compounds in animal models and in small clinical studies have successfully demonstrated that pharmacological compounds targeting specific proteins can result in complete and reversible contraceptive efficacy. However, since many compounds used in early studies were not specifically tailored for their use as contraceptives in some cases, or due to the potential for off-target effects identified from preclinical testing, more work is needed to improve these compounds for selectivity and to identify novel protein targets [4–6]. Nonetheless, the plethora of research and clinical advances made in this field in recent years has done much to make a male contraceptive pill closer to reality. In this chapter, we discuss the history and recent advances in novel hormonal and nonhormonal contraceptive development and provide a brief overview of how contraceptive compounds modulate the dynamics of sperm production and transport.
https://www.cambridge.org/core/books/abs/infertility-in-the-male/male-contraception/AC6B8BD4454E6B5B539A86D4C86242EC
Testosterone, many steroidal androgens, and nonsteroidal ligands that bind to androgen receptor and exert tissue-specific transcriptional activity (selective androgen receptor modulators [SARMs]) are being developed as function-promoting therapies to treat functional limitations associated with aging and chronic diseases. This narrative review describes preclinical studies, mechanisms, and randomized trials of testosterone, other androgens, and nonsteroidal SARMs. Sex differences in muscle mass and strength and empiric use of anabolic steroids by athletes to increase muscularity and athletic performance provide supportive evidence of testosterone's anabolic effects. In randomized trials, testosterone treatment increases lean body mass, muscle strength, leg power, aerobic capacity, and self-reported mobility. These anabolic effects have been reported in healthy men, hypogonadal men, older men with mobility limitation and chronic diseases, menopausal women, and HIV-infected women with weight loss. Testosterone has not consistently improved walking speed. Testosterone treatment increases volumetric and areal bone mineral density, and estimated bone strength; improves sexual desire, erectile function, and sexual activity; modestly improves depressive symptoms; and corrects unexplained anemia in older men with low testosterone levels. Prior studies have not been of sufficient size or duration to determine testosterone's cardiovascular and prostate safety. The efficacy of testosterone in reducing physical limitations, fractures, falls, progression to diabetes, and correcting late-onset persistent depressive disorder remains to be established. Strategies to translate androgen-induced muscle mass and strength gains into functional improvements are needed. Future studies should evaluate the efficacy of combined administration of testosterone (or a SARM) plus multidimensional functional exercise to induce neuromuscular adaptations required for meaningful functional improvements.
Wasting in cancer patients has long been recognized as a condition that adversely affects cancer patients' quality of life, treatment tolerance, and oncological outcomes. Historically, this condition was mainly evaluated by changes in body weight. However, this approach is not quite accurate because body weight is the overall change of all body compartments. Conditions such as edema and ascites can mask the severity of muscle and adipose tissue depletion. Changes in body composition assessment in cancer patients have historically been underappreciated because of the limited availability of measurement tools. As more evidence highlighting the importance of body composition has emerged, it is imperative to apply a more precise evaluation of nutritional status and a more targeted approach to provide nutritional support for cancer patients. In this review, we will discuss the modalities for evaluating body composition and how to manage body composition changes in cancer patients.
Background:
As people age, physical impairments may have a deleterious role in skeletal muscles. Sarcopenia Clinical Practice Guidelines 2017 and the European Working Group on Sarcopenia in older people are two organizations that have published essential guidelines on the definition of "sarcopenia". Sarcopenia is a geriatric syndrome, characterized by skeletal muscle mass degeneration brought on by ageing, which lowers muscular function and quality. Moreover, sarcopenia can be classified as primary or age-associated sarcopenia and secondary sarcopenia. Also, secondary sarcopenia occurs when other diseases such as diabetes, obesity, cancer, cirrhosis, myocardial failure, chronic obstructive pulmonary disease, and inflammatory bowel disease also contribute to muscle loss. Furthermore, sarcopenia is linked with a high risk of negative outcomes, considering a gradual reduction in physical mobility, poor balance, and increased fracture risks which ultimately leads to poor quality of life.
Objective:
In this comprehensive review, we have elaborated on the pathophysiology, and various signaling pathways linked with sarcopenia. Also, discussed are the preclinical models and current interventional therapeutics to treat muscle wasting in older patients.
Conclusion:
In a nutshell, a comprehensive description of the pathophysiology, mechanisms, animal models, and interventions of sarcopenia. We also shed light on pharmacotherapeutics present in clinical trials which are being developed as potential therapeutic options for wasting diseases. Thus, this review could fill in the knowledge gaps regarding sarcopenia-related muscle loss and muscle quality for both researchers and clinicians.
Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500–5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by loss-of-function mutations in the DMD gene coding for dystrophin, a cytoskeletal protein that stabilizes the plasma membrane of muscle fibers. In September 2016, the US Food and Drug Administration granted accelerated approval for eteplirsen (or Exondys 51), a drug that acts to promote dystrophin production by restoring the translational reading frame of DMD through specific skipping of exon 51 in defective gene variants. Eteplirsen is applicable for approximately 14% of patients with DMD mutations. This article extensively reviews and discusses the available information on eteplirsen to date, focusing on pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials. Issues faced by eteplirsen, particularly those relating to its efficacy, will be identified. Finally, the place of eteplirsen and exon skipping as a general therapeutic strategy in Duchenne muscular dystrophy treatment will be discussed.
Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer.
Background:
While much cancer research focuses on tumours and their microenvironment, malignancies cause widespread physiologic changes. Cancer and treatment-related sarcopenia, measured with quantitative imaging or as a decrease in overall body mass, are indicative of poor prognosis in elderly diffuse large B-cell lymphoma (DLBCL) patients, skeletal muscle radiodensity (SMD) may be a better prognostic marker. SMD, a measure of muscle radiation attenuation on CT imaging, is more prognostic than sarcopenia or International Prognostic Index (IPI) scores in follicular lymphoma and multiple solid organ malignancies. Low SMD appears to correlate with fat accumulation in muscle and is associated with inflammation. This study set out to examine SMD's prognostic ability in DLBCL.
Methods:
All DLBCL patients treated with rituximab-containing therapy between 2004 and 2009 were compared to determine SMD's prognostic ability in this single centre, retrospective study. Pre-treatment CT scans were used to measure SMD and muscle cross-sectional area. Primary endpoints included progression free (PFS) and overall survival (OS) while objective response rates (ORR) were secondary.
Results:
Of 224 evaluable patients, 116 were identified as having low SMD. Low SMD predicted poorer 5 year PFS, 60 vs. 81% (p = 0.001) and OS, 58 vs. 86% (p < 0.0001). SMD's prognostic ability retained significance in multivariate analysis taking into consideration the Revised International Prognostic Index (R-IPI) and sex. Although high SMD was not predictive of ORR (95.4 vs. 91.4%, p = 0.17), it was strongly associated with radiographic complete response (85 vs. 66%, p = 0.0007). Contrary to previous findings, sarcopenia did not predict for poorer OS but suggested improved OS in elderly DLBCL patients (HR 0.38, p = 0.01).
Conclusions:
SMD is a novel prognostic (and potentially treatment predictive) marker independent of R-IPI in DLBCL. It presents an inexpensive yet complementary assessment to R-IPI for prognosticating DLBCL outcomes.
Objectives:
To evaluate two selective androgen receptor modulators (SARMs) (GTx-024 and GTx-027) in a post-menopausal animal model in order to determine their effect on pelvic floor muscles. Stress urinary incontinence (SUI), a prevalent condition, is represented by an involuntary leakage of urine that results, at least in part, from weakened or damaged pelvic floor muscles and is triggered by physical stress. Current treatment options are limited with no oral therapies available. The pelvic floor is rich in androgen receptor and molecules with anabolic activity including (SARMs) may serve as therapeutic options for individuals with SUI.
Methods:
Female C57BL/6 mice were ovariectomized and their pelvic muscles allowed to regress. The animals were then treated with vehicle or doses of GTx-024 or GTx-027. Animal total body weight, lean body mass and pelvic floor muscle weights were measured along with the expression of genes associated with muscle catabolism.
Results:
Treatment with the SARMs resulted in a restoration of the pelvic muscles to the sham-operated weight. Coordinately, the induction of genes associated with muscle catabolism was inhibited. Although a trend was observed towards an increase in total lean body mass in the SARM- treated groups, no significant differences were detected.
Conclusions:
Treatment of an ovariectomized mouse model with SARMs resulted in an increase in pelvic floor muscles, which may translate to an improvement of symptoms associated with SUI and serves as the basis for evaluating their clinical use. This article is protected by copyright. All rights reserved.
Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm's effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484 , NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1 .
Androgens increase skeletal muscle mass, but their clinical use is hampered by lack of tissue selectivity and subsequent side-effects. Selective androgen receptor modulators (SARMs) elicit muscle-anabolic effects while only sparingly affecting reproductive tissues. The SARM GTx-024 (enobosarm) is being investigated for cancer cachexia, sarcopenia, and muscle wasting diseases. Here, we investigate the role of muscle androgen receptor (AR) in the anabolic effect of GTx-024. In mice lacking AR in the satellite cell lineage (satARKO), the weight of the androgen-sensitive levator ani muscle was lower, but decreased further upon orchidectomy. GTx-024 was as effective as dihydrotestosterone (DHT) in restoring levator ani weights to sham levels. Expression of the muscle-specific androgen-responsive genes S-adenosylmethionine decarboxylase and myostatin was decreased by orchidectomy and restored by GTx-024 and DHT in control mice, while expression was low and unaffected by androgen status in satARKO. In contrast, insulin-like growth factor IEa expression was not different between satARKO and control muscle, decreased upon castration, and was restored by DHT and GTx-024 in both genotypes. These data indicate that GTx-024 does not selectively modulate AR in the satellite cell lineage and that cells outside this lineage remain androgen-responsive in satARKO muscle. Indeed, residual AR positive cells were present in satARKO muscle, coexpressing the fibroblast-lineage marker vimentin. AR positive, muscle-resident fibroblasts could therefore be involved in the indirect effects of androgens on muscle. In conclusion, both DHT and GTx-024 target AR pathways in the satellite cell lineage, but cells outside this lineage also contribute to the anabolic effects of androgens.
The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
Importance of androgen receptor (AR) as an independent prognostic marker in Pakistani women with breast cancer (BCa) remains unexplored. Our aim was to identify the expression and potential prognostic value of AR, its upstream regulator (pAkt) and target gene (pPTEN) in invasive BCa.
This study used a cohort of 200 Pakistani women with invasive BCa diagnosed during 2002-2011. Expression of AR, pAkt and pPTEN was determined on formalin fixed paraffin embedded tissue sections by immunohistochemistry. The association of AR, pAkt and pPTEN with clinicopathological parameters was determined. Survival analyses were undertaken on patients with ≥5years of follow-up (n=82).
Expression of AR, pAkt and pPTEN was observed in 47.5%, 81.3% and 50.6% of patients, respectively. AR-expressing tumors were low or intermediate in grade (P<.001) and expressed ER (P=.002) and PR (P=.001). Patients with AR(+) tumors had significantly higher OS (Mean OS=10.2±0.465years) compared to patients with AR(-) tumors (Mean OS=5.8±0.348years) (P=.047). Furthermore, AR-positivity was associated with improved OS in patients receiving endocrine therapy (P=.020). Patients with AR(+) /pAkt(+) /pPTEN(-) tumors, had increased OS (Mean OS=7.1±0.535years) compared to patients with AR(-)/pAkt(+)/pPTEN(-) tumors (Mean OS=5.1±0.738years).
AR-expressing tumors are frequently characterized by low or intermediate grade tumors, expressing ER and PR. In addition, expression of AR, pAkt and pPTEN, could be considered in prognostication of patients with invasive BCa.
More than 50% of prostate cancers have undergone a genomic reorganization that juxtaposes the androgen-regulated promoter of TMPRSS2 and the protein coding parts of several ETS oncogenes. These gene fusions lead to prostate-specific and androgen-induced ETS expression and are associated with aggressive lesions, poor prognosis and early-onset prostate cancer. In this study, we showed that an enhancer at 13 kb upstream of the TMPRSS2 transcription start site is crucial for the androgen regulation of the TMPRSS2 gene when tested in bacterial artificial chromosomal vectors. Within this enhancer, we identified the exact androgen receptor binding sequence. This newly identified androgen response element is situated next to two binding sites for the pioneer factor GATA2, which were identified by DNase I footprinting. Both the androgen response element and the GATA-2 binding sites are involved in the enhancer activity. Importantly, a single nucleotide polymorphism (rs8134378) within this androgen response element reduces binding and transactivation by the androgen receptor. The presence of this SNP might have implications on the expression and/or formation levels of TMPRSS2 fusions, since both have been shown to be influenced by androgens.
The role of estrogen receptor beta (ER-beta) in breast cancer (BC) remains unclear. Some studies have suggested that ER-beta may oppose the actions of estrogen receptor alpha (ER-alpha), and clinical evidence has indicated that the loss of ER-beta expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-beta and the ER-alpha/ER-beta ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-beta expression levels.
Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-beta, ER-alpha and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred's method. Statistical analyses were performed using an ANOVA and Spearman's correlation coefficient tests, with significance at p <= 0.05.
The frequency of ER-beta expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-beta-negative cases (p = 0.45), but in the ER-beta-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-alpha and ER-beta expression levels. Only patients with an ER-alpha/ER-beta expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026).
Our results provide additional data that indicate that the measurement of ER-beta in BC patients may help predict tamoxifen and anastrozole responsiveness in the neoadjuvant setting. These effects of hormonal treatment appear to be dependent on the ratio of ER-alpha/ER-beta expression.Trial registration: Current Controlled Trials ISRCTN89801719.
The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3 alpha-HSD (AKRIC4), type 2 3 alpha(17 beta)-HSD (AKR1C3), type 3 3 alpha-HSD (AKR1C2) and 20 alpha(3 alpha)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3 alpha-, 17 beta- and 20 alpha-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with k(cat)/K-m values for substrates that exceeded those obtained with other isoforms by 10-30-fold. In the reduction direction, all isoforms inactivated 5 alpha-dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one; 5 alpha-DHT) to yield 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-androstanediol). However, only AKR1C3 reduced Delta(4)-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17 beta-oestradiol, and progesterone to 20 alpha-hydroxy-pregn-4-ene-3,20-dione (20 alpha-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3a-androstanediol to the active hormone 5 alpha-DHT. AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione. All isoforms oxid ized 17 beta-oestradiol to oestrone, and 20 alpha-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high k(cat)/K-m allows this enzyme to form 5 alpha/5 beta-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with Delta(4)-androstene-3,17-dione, but to inactivate 5 alpha-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert Delta(4)-androstene-3,17-dione to testosterone (a substrate aromatizable to 17 beta-oestradiol), oestrone to 17 beta-oestradiol, and progesterone to 20 alpha-hydroxyprogesterone, and this concerted reductive activity may yield a. pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3 alpha-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 sand AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereospecificity for 3 alpha-hydroxysteroids exists.
The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.
Background:
Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer.
Methods:
We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844.
Findings:
Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range -2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, -4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range -5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug.
Interpretation:
Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents.
Funding:
GTx.
Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.
A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561-570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen's action, through one of or both of the ERs, mediates the aforementioned human disease states.
Background
Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation.
Methods
A 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60 years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety.
Results
GTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (P < 0.001, 3 mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (P = 0.013, 3 mg vs. placebo) and insulin resistance (P = 0.013, 3 mg vs. placebo). The incidence of adverse events was similar between treatment groups.
Conclusion
GTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.
Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced
effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize
the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function
using >1000 synthetic AR ligands. These compounds produced a spectrum of activities in each assay ranging from 0 to 100% of
maximal response. By testing different classes of compounds in ovariectomized rats, we established that ligands that transactivated
a model promoter 40–80% of an agonist, recruited the coactivator GRIP-1 <15%, and stabilized the N-/C-terminal interdomain
interaction <7% induced bone formation with reduced effects in the uterus and in sebaceous glands. Using these criteria, multiple
SARMs were synthesized including MK-0773, a 4-aza-steroid that exhibited tissue selectivity in humans. Thus, AR activated
to moderate levels due to reduced cofactor recruitment, and N-/C-terminal interactions produce a fully anabolic response,
whereas more complete receptor activation is required for reproductive effects. This bimodal activation provides a molecular
basis for the development of SARMs.
Prostate and breast cancer are hormone-dependent malignancies of the aging male and female and require the local production of androgens and estrogens to stimulate cell proliferation. Aldo-keto reductases (AKR) play key roles in this process. In the prostate, AKR1C3 (type 5 17beta-HSD) reduces Delta(4)-androstene-3,17-dione to yield testosterone while AKR1C2 (type 3 3alpha-HSD) eliminates 5alpha-dihydrotestosterone (5alpha-DHT), and AKR1C1 forms 3beta-androstanediol (a ligand for ERbeta). In the breast, AKR1C3 forms testosterone, which is converted to 17beta-estradiol by aromatase or reduces estrone to 17beta-estradiol directly. AKR1C3 also acts as a prostaglandin (PG) F synthase and forms PGF(2alpha) and 11beta-PGF(2alpha), which stimulate the FP receptor and prevent the activation of PPARgamma by PGJ(2) ligands. This proproliferative signaling may stimulate the growth of hormone-dependent and -independent prostate and breast cancer.
Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.
Multiple proto-signals (p-NLSs) for nuclear targeting, none of which suffices on its own, cooperate in the estrogen (ER) and progesterone (PR) receptors. In the ER, an estrogen-inducible p-NLS was found in the hormone binding domain (HBD), in addition to three lysine/arginine-rich motifs resembling prototype constitutive nuclear localization signals (NLSs). The inducible and the constitutive ER p-NLSs cooperate in the presence of estrogen and hydroxy-tamoxifen, but not in the presence of ICI 164,384. In the PR, three p-NLSs, two of which are located within and directly adjacent to the second zinc finger, cooperate with each other and a weak hormone-inducible p-NLS in the PR HBD. No 'masking' of p-NLSs by the HBD was observed for ER and PR, while the ligand-free glucocorticoid receptor HBD inhibited the activity of both homologous and heterologous NLSs. Nuclear co-translocation experiments indicated that in vivo the stability of ER and PR dimers is hormonally controlled, but that, in the absence of the cognate ligand, ER dimers are more stable than PR dimers. This is likely to account for the differential hormone requirement of ER and PR DNA binding in vitro.
A series of human androgen receptor (AR) deletion mutants was constructed to study the relationship between the structural domains and their different functions in the AR protein. Human AR mutants were expressed in COS-1 and HeLa cells to investigate hormone binding, transcriptional activation, and subcellular localization. The wild-type human AR (AR 1-910) was expressed as a 110- to 112-kDa doublet, as revealed on immunoblots. All mutant AR proteins also migrated as doublets, except for one. This AR has a deletion from amino acid residues 51-211 and migrated as a single protein band, possibly due to altered posttranslational modification. The AR steroid-binding domain is encoded by approximately 250 amino acid residues in the C-terminal end. Deletions in this domain as well as truncation of the last 12 C-terminal amino acid residues abolished hormone binding. Cotransfection studies in HeLa cells showed that transcriptional activation of an androgen-regulated reporter gene construct was induced by the wild-type human AR. Mutational analysis revealed two regions in the N-terminal part, encoded by amino acid residues 51-211 and 244-360, to be essential for this transcriptional activation. Deletion of the hormone-binding domain yielded a constitutively active AR protein, indicating that in the absence of hormone this domain displays an inhibitory function. In the presence of its ligand, the wild-type AR was located in the cell nucleus. In the absence of androgens the receptor was mainly nuclear, but cytoplasmic localization was observed as well.(ABSTRACT TRUNCATED AT 250 WORDS)
Purpose:
Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ETs). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.
Experimental design:
Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER+/PgR+) breast cancer.
Results:
Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by ≈90% and exemestane by ≈50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.
Conclusions:
These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer.
Background:
Loss of skeletal muscle is predictive of a poor prognosis in patients with various malignant lesions. Our aim was to determine whether changes in skeletal muscle after neo-adjuvant therapy (NAT) predict prognosis in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophagectomy.
Patients and methods:
The cross-sectional areas of the psoas muscles were measured on computed tomographic images collected at the initial visit, preoperatively and postoperatively in 84 patients. The psoas muscle index (PMI) was calculated by normalizing the cross-sectional areas to the patients' heights.
Results:
Low PMI at the initial visit was not associated with a poor prognosis. The majority of patients showed decreased PMI after NAT and surgery. The group in which the post-NAT PMI decreased had poorer overall survival than group without PMI decrease (p=0.025).
Conclusion:
Decreased PMI correlates well with a poor prognosis in patients with ESCC. Changes in PMI over a period of time may have greater sensitivity when evaluating prognosis than the PMI at any single time point.
In the adult male testosterone (T) deficiency (TD) is a well-established medical condition, which has been recognized for more than a century. T therapy in men with TD was introduced as early as 1940s and was reported to improve overall health with no concomitant serious adverse effects. A wealth of recent studies demonstrated that T therapy in men with TD is associated with increased lean body mass, reduced fat mass and waist circumference, improvement in glycemic control and reduced obesity. T therapy is also associated with improvements in lipid profiles, amelioration of metabolic syndrome (Met S) components, reduced inflammatory biomarkers, reduced systolic and diastolic blood pressure and improvements in sexual function. T therapy is associated with amelioration of diabetes and reduced mortality. However, few studies, marred with serious methodological and analytical flaws reported between 2010 and 2014, suggested that T therapy is associated with increased cardiovascular (CV) risk. As summarized in this review, a thorough and critical analysis of these studies showed that the risks purported are unsubstantiated and such studies lacked credible scientific and clinical evidence. Moreover, recent observational, registry studies, clinical trials and meta-analyses, all revealed no increase in CV risks in men receiving T therapy. In this review, the benefits of T therapy in men with TD and the lack of credible evidence suggesting that T therapy is linked to increased CV risks are discussed. It should be noted that the literature is replete with studies demonstrating beneficial effects of T therapy on CV and overall health.
Introduction:
The long-term effects of long-acting testosterone undecanoate (TU) and androgen receptor CAG repeat lengths in Thai men with late-onset hypogonadism (LOH) have not been reported.
Aim:
To analyze the 8-year follow-up effects of intramuscular TU therapy on metabolic parameters, urinary symptoms, bone mineral density, and sexual function and investigate CAG repeat lengths in men with LOH.
Methods:
We reviewed the medical records of 428 men with LOH who had been treated with TU and 5 patients were diagnosed with prostate cancer during TU therapy. There were 120 patients (mean age = 65.6 ± 8.9 years) who had 5 to 8 years of continuous TU supplementation and sufficiently completed records for analysis. Genomic DNA was extracted from peripheral blood and the CAG repeat region was amplified by polymerase chain reaction. Fragment analysis, sequencing, electropherography, and chromatography were performed.
Main outcome measures:
The main outcome measure was dynamic parameter changes during testosterone supplementation.
Results:
TU did not improve all obesity parameters. A statistically significant decrease was found in waist circumference, percentage of body fat, glycated hemoglobin, cholesterol, low-density lipoprotein, and International Prostate Symptom Score (P < .05). TU did not produce differences in body mass index, high-density lipoprotein, triglyceride, or the Aging Male Symptoms score from baseline. However, a statistically significant increase was found in the level of testosterone, prostate-specific antigen, hematocrit, International Index of Erectile Function score, and vertebral and femoral bone mineral density (P < .05). No major adverse cardiovascular events or prostate cancer occurred during this study. The CAG repeat length was 14 to 28 and the median CAG length was 22. There was no association between CAG repeat length and any of the anthropometric measurements.
Conclusion:
Long-term TU treatment in men with LOH for up to 8 years appears to be safe, tolerable, and effective in correcting obesity parameters.
To locate in detail the regions in the human androgen receptor (AR) involved in transcription activation, a series of N-terminal deletions was introduced in the wild type AR and in a constitutively active AR. The different constructs were tested for their capacity to activate transcription. Almost the entire N-terminal domain (residues 1-485) was necessary for full wild type AR activity when cotransfected with the (GRE)(2)tkCAT reporter in HeLa cells. In contrast, a smaller part of the N-terminal domain (amino acids 360-528) was sufficient for the constitutively active AR to induce transcription of the same (GRE)(2)tkCAT reporter in HeLa cells. This demonstrates the capacity of the AR to use different regions in the N-terminal domain as transcription activation units (TAUs). To obtain additional information of AR N-terminal TAUs, the GAL4 DNA binding domain was linked to either the entire or parts of the AR N-terminal domain and cotransfected with the (UAS)(2)tkCAT reporter in HeLa cells. The results confirmed that the first 485 amino acid residues accommodate a transcription activation function. When the chimeric AR-GAL4 constructs were tested on a different reporter ((UAS)(5)E1bCAT), a small shift in position of the TAU, responsible for full transcription activation, was observed. The data presented show that the size and location of the active TAU in the human AR is variable, being dependent on the promoter context and the presence or absence of the ligand binding domain.
Background:
Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia.
Methods:
ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index <20 kg/m(2)) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282.
Findings:
From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs -0·47 kg [-1·00 to 0·21], p<0·0001) and ROMANA 2 (0·65 kg [0·38 to 0·91] vs -0·98 kg [-1·49 to -0·41], p<0·0001). We noted no difference in handgrip strength in ROMANA 1 (-1·10 kg [-1·69 to -0·40] vs -1·58 kg [-2·99 to -1·14], p=0·15) or ROMANA 2 (-1·49 kg [-2·06 to -0·58] vs -0·95 kg [-1·56 to 0·04], p=0·65). There were no differences in grade 3-4 treatment-related adverse events between study groups; the most common grade 3-4 adverse event was hyperglycaemia, occurring in one (<1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2.
Interpretation:
Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia.
Funding:
Helsinn Therapeutics.
Purpose
Muscle mass depletion is associated with adverse outcomes in cancer patients. There is limited information on the impact of age, sex, tumor type, and inflammation on muscle loss in the end of life of cancer patients.
Methods
Muscle depletion and loss of muscle in the last 2 years of life was estimated in 471 cancer patients from 779 dual-energy X-ray absorptiometry scans. A linear mixed model was used to estimate the impact of age, sex, tumor type, and inflammation.
Results
Patients above median age (>71 y