ArticleLiterature Review

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer

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Abstract

This review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer. Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient's quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens, but within the dose range in which expected effects on muscle mass and function are seen androgenic side-effects on prostate, skin, and hair have not been observed. Unlike testosterone, SARMs are orally active, nonaromatizable, nonvirilizing, and tissue-selective anabolic agents. Recent clinical efficacy data for LGD-4033, MK-0773, MK-3984, and enobosarm (GTx-024, ostarine, and S-22) are reviewed. Enobosarm, a nonsteroidal SARM, is the most well characterized clinically, and has consistently demonstrated increases in lean body mass and better physical function across several populations along with a lower hazard ratio for survival in cancer patients. Completed in May 2013, results for the Phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer1 (POWER1) and POWER2 evaluating enobosarm for the prevention and treatment of muscle wasting in patients with nonsmall cell lung cancer will be available soon, and will potentially establish a SARM, enobosarm, as the first drug for the prevention and treatment of muscle wasting in cancer patients.

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... 15 • SARMs with quinolinone core structure, such as LGD-2226, 15,20 LGD-2941, 15 andLGD-3303. 15 • SARMs with tetrahydroquinolinone core structure, such as S-40503, 15 S-101479, 21 and S-49288. 22 • SARMs with indole core structure, such as RAD35010 15 and Ly2452473. ...
... 22 • SARMs with indole core structure, such as RAD35010 15 and Ly2452473. 21 • SARMs with steroidal core structure, such as MK-0773, 15,23 Cl-4-AS-1, TMF-4AS-1, YK-11, and S-42. 15 Despite the evidenced preclinical and clinical studies, 15,21,24 no SARM has yet received full clinical approval. ...
... 19,24 Nutritional supplementation with increased calories, protein, and other supplements has been the most promising. 25 Besides nutrition and exercise-based interventions, pharmacologic agents are being studied for the treatment of cachexia including ghrelin mimetics, 26,27 selective androgen receptor modulators, 28,29 and interleukin-1 targeting therapies. 30 Although cachexia has been traditionally associated with poor response to nutritional interventions, newer data suggest that certain patients may benefit from specific nutritional supplementation, 31 alone or in combination with other agents. ...
... SARMs may represent a promising potential alternative to TTh, which has been the mainstay of the treatment of hypogonadism. While the sexual benefits of TTh are well established, unlike exogenous testosterone, SARMs are orally active, nonaromatizable, non-virilizing, and tissueselective, with a better side effect profile than TTh (66). Previous studies have demonstrated the potential benefit of SARMs for libido in both female and male rats (67,68). ...
Article
Selective androgen receptor modulators (SARMs) are small molecule drugs that function as either androgen receptor (AR) agonists or antagonists. Variability in AR regulatory proteins in target tissues permits SARMs to selectively elicit anabolic benefits while eschewing the pitfalls of traditional androgen therapy. SARMs have few side effects and excellent oral and transdermal bioavailability and may, therefore, represent viable alternatives to current androgen therapies. SARMs have been studied as possible therapies for many conditions, including osteoporosis, Alzheimer's disease, breast cancer, stress urinary incontinence (SUI), prostate cancer (PCa), benign prostatic hyperplasia (BPH), male contraception, hypogonadism, Duchenne muscular dystrophy (DMD), and sarcopenia/muscle wasting/cancer cachexia. While there are no indications for SARMs currently approved by the Food and Drug Administration (FDA), many potential applications are still being explored, and results are promising. In this review, we examine the literature assessing the use of SARMS for a number of indications.
... An added benefit of these synthetic agents is their lack of conversion to other active hormones by aromatase and 5α-reductase. Enobosarm (GTx, Inc.) is the most well studied SARM and has been evaluated in two phase III placebocontrolled clinical trials of men and women with advanced non-small cell lung cancer (NSCLC) at the initiation of chemotherapy to determine its ability to prevent therapyassociated cachexia [70]. These trials showed promising benefits to lean body mass and physical function of enobosarm over placebo in NSCLC and it has since received fast track designation by the FDA for this indication. ...
Article
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Purpose of review: Hypogonadism and the treatment of low testosterone is increasingly a subject of medical inquiry and controversy. The few treatments that are FDA-approved such as testosterone topicals, injections, and pellets create significant demand from patients for treatments with more convenient means of administration, fewer adverse effects, and the ability to maintain male fertility. Off-label drugs are in abundant use for low testosterone, including selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors. Recent findings: In this review, we summarize the evidence in support of commonly used treatments for male hypogonadism, as well as discuss recent updates in the development of novel therapeutics. New therapies include nasal testosterone, new oral testosterone formulations, anabolic-androgenic steroids, and selective androgen receptor modulators.
... 4 steroidal androgens and has likely contributed to observations that the drug has generally been well tolerated in clinical trials. It has selective anabolic effects and is under clinical development for prevention and treatment of muscle wasting (cachexia) in cancer patients (13,14). ...
Article
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Prostate cancer often develops anti-androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst having no effect on the prostate. Here we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis-trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity - by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/AR-Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the AR-Luc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other AR-expressing tissues e.g. testes, seminal vesicles and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen - thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-PTen deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared to enobosarm, and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.
... However, steroid-like side effects such as liver toxicity, increased potential of heart attack and stroke, infertility and mental health problems may also occur with the usage of SARMs. The term "selective" in SARM means they preferentially bind to androgen receptors in muscle tissue without triggering androgenic effects in other tissues such as the prostate (2,4,8). The popularity of SARMs has also increased among athletes seeking anabolic effects while minimizing androgenic side effects. ...
Article
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Performance enhancing substances are becoming increasingly popular amongst bodybuilders and people who want to enhance their physiques. However, due to the rise of the Internet and laws prohibiting sales of these substances without prescription, the route of procurement and administration practices have become more and more dangerous. Prior to the mid-1970’s, anabolic steroids were not regulated and easily available from physicians and pharmacies in several countries. In 1990, the United States enacted the Anabolic Steroid Control Act, leading to the proliferation of black markets and underground laboratories. The shift from pharmacy to underground online sites for the procurement of anabolic steroids led to an increase of fake products with low purity and the ability to potentially endanger the health of anabolic steroid users. Underground laboratories emerged both locally and in countries with lax legal regulations. “Anabolic steroid tourism” and large networks of online resellers emerged, leading to the banalisation of the illegal procurement of anabolic steroids. Furthermore, the increase of anecdotal information spreading on the internet among anabolic steroid user forums nourishes the rampant misinformation and dangerous practices that currently exist. The dosages and ways of administration recommended on these forums can be false and misleading to those who lack a medical background and cannot go to their physician to seek advice because of the fear of repercussions. This review aims to elucidate and describe current practices of the anabolic-androgenic steroids black market and draw attention to potential dangers for users.
... Studies on the role of AR in skeletal muscle conducted using transgenic mouse models have shown it is expressed in multiple cell types in muscle [89,90]. The pharmaceutical industries have developed a number of selective androgen receptor modulators to target AR in muscle as a therapy for age-related or cancer-related loss of muscle function [91,92]. ...
Article
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Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilise inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in the activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium, acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women’s health disorders such as endometriosis and endometrial cancer has prompted renewed interest in the development of drugs targeting these pathways, opening up new opportunities for targeted therapies and precision medicine.
... There was no reduction in free testosterone levels (129). However, two phase III trials involving patients receiving chemotherapy for lung cancer found that enobosarm improved LBM but failed to improve stair climbing power which was a co-primary outcome of the study (178,179). ...
Article
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Clinicians often believe that cachexia is caused by cancer and anorexia as a toxicity of chemotherapy or targeted anti-cancer agents. It is now recognized that chemotherapy and certain targeted agents cause sarcopenia which reduce physical function and quality of life. Pre-treatment sarcopenia predicts chemotherapy toxicity, reduced response, increased disability, poor anti-tumor response and survival. Though bioelectrical impedance and dual energy X-ray absorptiometry (DEXA) scans have been used in the past for body composition measurements, CT scan cuts at the level of the 3rd lumbar vertebral body with measurement of skeletal muscle and visceral and subcutaneous fat areas has become standard. Nonpharmacological approaches to reducing sarcopenia during chemotherapy includes resistance training and dietary counselling. Pharmacologic therapies include vitamin D replacement if depleted, omega-3 fatty acids, testosterone and selective androgen receptor modulators (SARMS) and ghrelin. A comprehensive multimodal and multiple drug approach is likely to be better than single modalities. However, this is yet to be proven. Finally, it is not known if intervening to prevent or reverse sarcopenia will have a clinical benefit in terms of better tolerance to cancer therapy, physical function, well-being, tumor response and survival. Reversing sarcopenia and improving objective outcomes should be the goal of therapy.
... El Enobosarm se encuentra actualmente en estudios de fase II y III en varios subgrupos poblacionales como el cáncer, la insuficiencia renal crónica, la EPOC, y la insuficiencia cardíaca. 137 La grelina es una hormona producida por las células parietales del estómago que tiene propiedades anti-infamatorias y pro-anabólicas. [138][139] Explotando estas propiedades, se ha desarrollado el Anamorelin: un agonista altamente selectivo del receptor de la grelina. ...
Article
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Loss of skeletal muscle mass (LOSMM) in the critically ill patient is the final expression of pathophysiological events unleashed by trauma and injury, inflammation and hypercatabolia. LOSMM might also follow after insufficient intake of energy and nutrients, accentuating the depletion of lean tissues. If not timely intervened, LOSMM might place the patient at risk of ventilatory failure, and hence, intubation and mechanical ventilation, prolongation of hospital stay, and increased costs of hospital and medical care. LOSMM can be recognized by means of functional exploration, anthropometric assessment, and measurement of muscle contraction force through dynamometry. In addition, size of muscle masses can be reconstructed with imagenological techniques such as nuclear magnetic resonance (NMR), and ultrasound (US). Measurement of urinary urea nitrogen (NUU) allows to assess the intensity of hypercatabolia as well as to trace changes in tissue repletion after initiating nutritional intervention. Attenuation of LOSMM along with tissue repletion can be achieved with multimodal therapies combining nutritional support, use of nutrients and drugs specifically aimed to muscle accretion, and promotion of rehabilitation and physical exercise. Promising clinical trials have been completed with agonists of androgens and ghrelin receptors, and inhibitors of FOX transcription factors. As an increasingly higher number of patients admitted to the critical care units already show aging-associated-LOSMM, fostering of guidelines for assessing the size of skeletal muscle mass and quality of muscle contraction force, quantification of metabolic stress and hypercatabolia, and adoption of an effective multimodal program limiting LOSMM, allows for rehabilitation of the patient, and ensures the success of medical surgical actions is becoming imperative. Chapela S, Martinuzzi A. Loss of skeletal muscle mass in the critically ill patient: Cachexia, sarcopenia and/or atrophy? Impact upon therapeutic response and survival. RCAN Rev Cubana Aliment Nutr 2018;28(2):393-416. RNPS: 2221. ISSN: 1561-2929.
... Therapeutic interest of SARMs is based on the prevention or treatment of muscle wasting conditions (sarcopenia, cachexia) [2,3] as well as the treatment of osteoporosis [4][5][6]. However, no SARM has sustained clinical approval up to now. ...
Article
Selective androgen receptor modulators comprise compounds that bind as ligands to the androgen receptor and possess tissue-selective activities. Ideally, they show agonistic properties in anabolic target tissues, while inducing antagonistic or only weak agonistic effects in reproductive organs. Due to their myoanabolic effects, selective androgen receptor modulators are included in the list of prohibited substances and methods of the World Anti-Doping Agency. In the current investigation, the androgenic potential of RAD-140, GSK-2881078 and GLPG0492 was comparably investigated in two different in vitro bioassays. In the yeast androgen screen, the androgenic effects were lower than in the reporter gene assay in prostate carcinoma cells (e.g. for GSK-2881078, the EC 50 values were 4.44 × 10 ⁻⁶ M in the yeast screen and 3.99 × 10 ⁻⁹ M in the prostate cells respectively). For future investigations, it is of importance whether the yeast androgen screen, which has been proven to detect androgenic compounds in urine, can detect an abuse of the selective androgen receptor modulators. Molecular modeling of the binding to the androgen receptor ligand binding domain suggests slight differences in the binding modes of RAD-140, GSK-2881078 and GLPG0492. In conclusion, androgenic activity of the three non-steroidal compounds in the two different in vitro test systems confirmed the results of the in silico modeling of the androgen receptor binding.
... Merck presented the results of a phase2 clinical trial evaluating Ostarine (MK-2866),an investigational SARM in patients with cancer induced muscle loss,also known as cancer cachexia at the Endocrine Society Annual Meeting in Washington in 2009 [40]. colorectal cancer, non-Hodgkins lymphoma, chronic lymphocytic leukemia or breast cancer were randomized. ...
... [61] Sarcopenia is accompanied by a decreased sensitivity to insulin and steroid hormones with aging, and various studies based on the development of such hormone analogues are under way. Selective Androgen Receptor Modulator has recently been shown to be effective in the prevention and treatment of muscle wasting in clinical trials in cancer patients, [62] and clinical trials are underway for other diseases such as COPD. In addition, metformin, a diabetes drug, is undergoing further studies at the animal testing level to confirm a muscle strengthening effect. ...
Article
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Sarcopenia is frequently associated with chronic diseases such as chronic obstructive pulmonary disease (COPD) and cancer. COPD, which is characterized by an irreversible airflow limitation, exacerbates respiratory distress as the disease progresses. The prevalence of sarcopenia in stable COPD was reported to be 15% to 25% in previous foreign studies and 25% in a Korean study. As the amount of activity decreases, muscle mass decreases and eventually oxygen cannot be used effectively, resulting in a vicious cycle of deterioration of exercise capacity. Deconditioning due to decreased activity is a major cause of limb muscle dysfunction in patients with COPD. In these patients, the factors that decrease muscle strength and endurance include chronic inflammation, oxidative stress, inactivity, hypoxemia, hormone abnormality, deficits of nutrients such as protein and vitamin D, and the use of systemic corticosteroid. Therefore, treatment and management should either inhibit this process or should be directed toward supplementing the deficiency, such as with exercise, nutritional support, and medications and supplements. The relationship between sarcopenia and COPD is increasingly being reported, with some overlap in clinical features and treatments. We are fascinated to be able to diagnose 2 diseases through similar physical performance tests and to improve both diseases using the same treatment such as exercise. Therefore, this review summarizes the clinical relevance and integrative management of the 2 diseases.
... Specifically, we hypothesized that an aryl ring appropriately decorated with a nitrile could replace the dihydroquinolinone ring in quinabactin as nitrile nitrogens are good hydrogen bond acceptors, 24 and similar bioisosteric carbonyl/nitrile replacements have been successfully explored for androgen receptor modulators. 25 Moreover, we anticipated that this modification could increase ligand efficiency, by reducing the number of heavy atoms in the scaffold, and increase aqueous solubility. We appended small hydrophobic substituents ortho to the nitrile on our scaffold in an attempt to form hydrophobic interactions with the 3′ tunnel, which normally interacts with ABA's 7′ methyl group and is important for ligand affinity. ...
Article
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Increasing drought and diminishing freshwater supplies have stimulated interest in developing chemicals that can be used to control transpiration. Receptors for the plant hormone abscisic acid (ABA) have emerged as key targets for this application, because ABA controls the apertures of stomata, which in turn regulate transpiration. Here we describe the rational design of cyanabactin, an ABA receptor agonist that preferentially activates Pyrabactin resistance 1 (PYR1) with low nM potency. A 1.63 Å X-ray crystallographic structure of cyanabactin in complex with PYR1 illustrates that cyanabactin’s arylnitrile mimics ABA’s cyclohexenone oxygen and engages the tryptophan lock, a key component required to stabilize activated receptors. Further, its sulfonamide and 4-methylbenzyl substructures mimic ABA’s carboxylate and C-6 methyl groups respectively. Isothermal titration calorimetry measurements show that cyanabactin’s compact structure provides ready access to high ligand efficiency on a relatively simple scaffold. Cyanabactin treatments reduce Arabidopsis whole-plant stomatal conductance and activate multiple ABA responses, demonstrating that its in vitro potency translates to ABA-like activity in vivo. Genetic analyses show that the effects of cyanabactin, and the previously identified agonist quinabactin, can be abolished by genetic removal of PYR1 and PYL1, which form subclade A within the dimeric subfamily III receptors. Thus, cyanabactin is a potent and selective agonist with wide-spectrum ABA-like activity that defines subfamily IIIA receptors as key target sites for manipulating transpiration.
... However, testosterone supplementation in these populations has shown promise for mitigating this muscle loss in men [119,120]. Hypogonadism also commonly accompanies cancer cachexia [117,118], and recent works have begun to evaluate the sufficiency of drugs with androgen-like binding and testosterone itself as pharmacological agents for the treatment of cancer cachexia in men [123,124]. Finally, testosterone supplementation appears to limit glucocorticoid-induced muscle atrophies in male mice [121]. However, despite these promising findings in other muscle pathologies, testosterone status does not appear to influence muscle mass recovery from hindlimb unloading, in that androgen supplementation in these populations does not mitigate muscle losses [125,126]. ...
Article
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Skeletal muscle health is a strong predictor of overall health and longevity. Pathologies affecting skeletal muscle such as cancer cachexia, intensive care unit treatment, muscular dystrophies, and others are associated with decreased quality of life and increased mortality. Recent research has begun to determine that these muscular pathologies appear to present and develop differently between males and females. However, to our knowledge, there has yet to be a comprehensive review on musculoskeletal differences between males and females and how these differences may contribute to sex differences in muscle pathologies. Herein, we present a review of the current literature on muscle phenotype and physiology between males and females and how these differences may contribute to differential responses to atrophic stimuli. In general, females appear to be more susceptible to disuse induced muscle wasting, yet protected from inflammation induced (such as cancer cachexia) muscle wasting compared to males. These differences may be due in part to differences in muscle protein turnover, satellite cell content and proliferation, hormonal interactions, and mitochondrial differences between males and females. However, more works specifically examining muscle pathologies in females are necessary to more fully understand the inherent sex-based differences in muscle pathologies between the sexes and how they may correspond to different clinical treatments.
... They express anabolic effects in the bone and muscle tissues, without causing androgenic side effects such as acne and prostate enlargement. [1][2][3][4] Therefore, they became popular among athletes. They are under investigation for the treatment of muscle wasting in cancer patients and osteoporosis; however, their use is not approved by the US Food and Drug Administration (FDA) and by the World Anti-Doping Agency. ...
Article
We described a 32-year-old man who developed severe drug-induced liver injury after using Ligandrol (LGD-4033). The diagnosis was confirmed by a liver biopsy that showed cholestatic hepatitis with a mild portal, periportal, and perisinusoidal fibrosis. Ligandrol is a selective androgen receptor modulator that is available over the counter and via the internet.
... This new quest aims to replicate the serendipitous, but still largely unexplained, tissue selectivity of selective estrogen receptor modulators (SERM). So far, no non-steroidal androgens are yet approved for clinical use (462)(463)(464) but although their use in sport was prohibited pre-emptively in 2008, characteristically, they soon began to appear illicitly over the internet for doping or bodybuilding, in breach of law, patents and anti-doping codes. For example, Andarine (S-4), widely advertised on the internet (465), has been identified in urine samples from athletes (466,467). ...
Article
Androgens are potent drugs requiring prescription for valid medical indications but are misused for invalid, unproven, or off-label reasons as well as being abused without prescription for illicit non-medical application for performance or image enhancement. Following discovery and first clinical application of testosterone in the 1930s, commercialisation of testosterone and synthetic androgens proliferated in the decades after World War II. It remains among the oldest marketed drugs in therapeutic use, yet after 8 decades of clinical use the sole unequivocal indication for testosterone remains in replacement therapy for pathological hypogonadism, organic disorders of the male reproductive system. Nevertheless, wider claims assert unproven, unsafe, or implausible benefits for testosterone, mostly representing wishful thinking about rejuvenation. Over recent decades this created an epidemic of testosterone misuse involving prescription as a revitalizing tonic for anti-ageing, sexual dysfunction and/or obesity, where efficacy and safety remains unproven and doubtful. Androgen abuse originated during the Cold War as an epidemic of androgen doping among elite athletes for performance enhancement before the 1980s when it crossed over into the general community to become an endemic variant of drug abuse in sufficiently affluent communities that support an illicit drug industry geared to bodybuilding and aiming to create a hypermasculine body physique and image. This review focuses on the misuse of testosterone, defined as prescribing without valid clinical indications, and abuse of testosterone or synthetic androgens (androgen abuse), defined as the illicit use of androgens without prescription or valid indications, typically by athletes, body-builders and others for image-oriented, cosmetic or occupational reasons.
... SARMs were added to the WADA prohibited list in 2008, as a potential misuse was suspected based on the anabolic properties seen in clinical studies (19,20). Subsequently, all samples obtained from elite athletes are subject to testing of several SARMs in WADA accredited laboratories and atypical analytical findings of SARMs have increased throughout the years (20). ...
Article
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Anabolic Androgenic Steroid (AAS) abuse in the society is considered a health problem and has been associated with cardiovascular toxicity, endocrine disruption, as well as psychiatric symptoms such as aggression and cognitive dysfunction. Men and women abusing AAS, as well as persons in close relationship to AAS abusers, may encounter concerns. Subsequently, the Anti-Doping Hotline was formed 1993 to answers questions about doping in the society. Here we have reviewed 7,123 enquiries posted on the Anti-Doping Hotline website between 2005 and 2018 to see what type of questions were raised. Most questions ( n = 2,924) involved AAS, 60% from abusers themselves, and 17% from a person close to an AAS abusers. Only 2.3% of the questions concerned AAS abusing women. Of the AAS specific questions most were from persons who sought personal advice regarding risks and side effects. Notably, the AAS abusers themselves were concerned about somatic side effects (e.g., gynecomastia) and problems related to the AAS injection. The persons in close relationship to an AAS abusers on the other hand, expressed concerns about psychiatric changes including mood swings and aggressivity. In addition to AAS, 26 and 13% of the questions involved dietary supplements and other doping substances, respectively. A gradual decrease of questions regarding ephedrine was noted, whereas the numbers of SARMs related questions increased during this time. Our results show that there is a continuous need to provide medical, nursing, and social support and counseling to AAS abusers and their next of kin.
... These trials enrolled men ≥30 years of age and postmenopausal women with stage III/IV non-small cell lung cancer (NSCLC) at the initiation of platinum-based chemotherapy to evaluate for its effect on the prevention and treatment of muscle wasting associated with NSCLC. POWER1 evaluated patients with platinum and taxane chemotherapy, while POWER2 evaluated patients with platinum and nontaxane chemotherapy [60]. The co-primary endpoints of this trial were lean body mass (LBM) response and physical function response for enobosarm vs. placebo after 3 months of treatment. ...
Article
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There has recently been renewed interest in novel clinical applications of the anabolic-androgenic steroid (AAS) testosterone and its synthetic derivatives, particularly given with the rising popularity of testosterone supplementation therapy (TST) for the treatment of male hypogonadism. In this manuscript, we provide a brief review of the history of AAS and discuss clinical applications of two of the more well-known AAS: nandrolone and oxandrolone. Both agents exhibit favorable myotrophic/androgenic ratios and have been investigated for effectiveness in numerous disease states. We also provide a brief synopsis of selective androgen receptor modulators (SARMs) and postulate how these orally active, non-aromatizing, tissue-selective agents might be used in contemporary andrology. Currently, the applications of testosterone alternatives in hypogonadism are limited. However, it is tempting to speculate that these agents may one day become accepted as alternatives, or adjuncts, to the treatment of male hypogonadism.
... 4,5 Therefore, SARMs have been investigated for the treatment of osteoporosis, sarcopenia, and cachexia; however, their use in clinical practice remains unapproved by the US Food and Drug Administration (FDA). [6][7][8][9][10][11][12][13] Owing to potential misuse of their anabolic effects, they were added to the World Anti-Doping Agency's Prohibited List. 14 However, they are sold as a dietary supplement over the counter and on the internet, causing a serious threat to public health. ...
Article
We report a 52-year-old man who developed drug-induced liver injury after taking Alpha Bolic (contains RAD-140) and Alpha Elite (contains both RAD-140 and LGD-4033) supplements. Liver biopsy demonstrated diffuse centrilobular canalicular cholestasis, prominent ductular reaction, and mild lobular inflammation with rare non-necrotizing epithelioid granuloma suggestive of drug-induced liver injury. Liver enzymes returned to normal levels approximately 3 months after the patient stopped both supplements. We present the mechanism of drug-induced liver injury associated with 2 selective androgen receptor modulators, including RAD-140 and LGD 4033.
... Selective Androgen Receptor Modulators (SARMs) are a novel class of compounds that are androgen receptor ligands with anabolic properties similar to those of anabolic steroids in muscle and bone, but with a milder profile of adverse effects, since they are more tissue selective [1][2][3]. There have been several clinical trials involving SARMs for treatment of different diseases such as cachexia and sarcopenia, but so far none of them have been approved in a pharmaceutical product [3][4][5]. The pharmacological effects and limited side effects make them tempting to use as doping agents and they have been on the World Anti-Doping Agency's Prohibited List since 2008 [6,7]. ...
Article
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Selective Androgen Receptor Modulators (SARMs) have anabolic properties but less adverse effects than anabolic androgenic steroids. They are prohibited in both equine and human sports and there have been several cases of SARMs findings reported over the last few years. The aim of this study was to investigate the metabolite profile of the SARM ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) in order to find analytical targets for doping control. Oral administration of ACP-105 was performed in horses, where blood and urine samples were collected over a time period of 96 h. The in vivo samples were compared with five in vitro incubation models encompassing Cunninghamella elegans, microsomes and S9 fractions of both human and equine origin. The analyses were performed using ultra-high performance liquid chromatography coupled to high resolution Q ExactiveTM OrbitrapTM mass spectrometry (UHPLC-HRMS). A total of 21 metabolites were tentatively identified from the in vivo experiments, of which several novel glucuronides were detected in plasma and urine. In hydrolyzed urine, hydroxylated metabolites dominated. The in vitro models yielded several biotransformation products, including a number of monohydroxylated metabolites matching the in vivo results. The suggested analytical target for equine doping control in plasma is a dihydroxylated metabolite with a net loss of two hydrogens. In urine, the suggested targets are two monohydroxylated metabolites after hydrolysis with β-glucuronidase, selected both due to prolongation of the detection time and the availability of reference material from the in vitro models.
Chapter
Introduction Polycystic ovary syndrome (PCOS) is one of the most common causes of ovulatory dysfunction and identifiable causes of infertility. Clomiphene citrate, aromatase inhibitors such as letrozole, metformin, the combination of metformin and clomiphene citrate, and gonadotropins are the most commonly used medications for ovulation induction in patients with PCOS. The following chapter discusses the background and indications for use of each of these medications. Clomiphene citrate Clomiphene citrate, a selective estrogen receptor modulator, has been used as a first-line medical ovulation induction agent since 1967. Clomiphene citrate is administered for 5 days beginning on any spontaneous or progestin-induced menstrual cycle day from 2 to 5, starting with 50 mg/day and increasing to 150 mg/day if anovulatory. If ovulation cannot be achieved at doses of 150 mg/day, the patient is deemed to have clomiphene citrate resistance. The dose of clomiphene citrate can be increased up to 250 mg. If pregnancy cannot be achieved after six ovulatory cycles, then the patient is deemed a clomiphene citrate failure. Most conceptions occur within the first six ovulatory cycles and at doses of less than 150 mg a day, but the fecundity rate decreases dramatically with age (<4% at >41 years of age) [1 – 3]. Studies with clomiphene citrate have shown an ovulation rate of 60–85% and a pregnancy rate of 30–50% after six ovulatory cycles, with an increased risk of multiple pregnancy of 5–7% [4]. A Cochrane systematic review and meta-analysis of three randomized controlled trials comparing clomiphene citrate with placebo demonstrated that clomiphene citrate improves both ovulation and pregnancy rate [5] The addition of an ovulatory trigger dose of human chorionic gonadotropin (hCG) to clomiphene citrate ovulation induction therapy does not improve ovulation, pregnancy, or miscarriage rates [6]. Aromatase inhibitors Aromatase inhibitors were first proposed as ovulation-inducing drugs in anovulatory women in 2001 [7].
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Introduction The less we know about something, the greater the need to constantly redefine it. (P. G. McDonough [1]) Polycystic ovary syndrome (PCOS) affects 6-10% of reproductive age females, making it the most common metabolic endocrine condition in this population [2]. PCOS was first officially described in 1935 by Drs. Stein and Leventhal, resulting in its eponymous name, the Stein-Leventhal syndrome. The syndrome they described were patients who presented with amenorrhea, hirsutism, polycystic-appearing ovaries, and oft en obesity. They described the operation known as a "wedge resection," which was oft en followed by regular menses and sometimes pregnancy. On pathological examination of tissue from the ovarian "wedge resection," they noted multiple subcapsular cysts associated with a thickening of the tunica [3]. Later, this constellation of signs and symptoms became known as PCOS, which reflected the multiple subcapsular follicular cysts. Since 1935, our understanding of this syndrome has expanded and in 2012 an evidence-based methodology workshop was sponsored by the National Institutes of Health. At this workshop one recommendation was to change the name from PCOS to more closely reflect the complex pathophysiology of this condition, which would improve accurate communication and progress in both the clinical and research arenas [4]. Nature vs. nurture PCOS is a complex condition characterized by anovulation and androgen overproduction affecting reproductive age women. Th is phenotype can result in infertility due to ovulatory dysfunction, irregular menses, endometrial hyperplasia, endometrial carcinoma, iron deficiency anemia due to heavy menses, hirsutism, virilization, miscarriage, insulin resistance, glucose intolerance, gestational and type 2 diabetes mellitus, hyperlipidemia, and the potential for increased risk of cardiovascular disease. Other conditions associated with PCOS include obesity, sleep apnea, anxiety, depression, and possible reduction in quality of life. Studies have demonstrated a strong genetic component, supported by family and twin studies, with an important environmental contribution.
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Androgens exert specific effects on the development and function of the female reproductive organs and secondary sexual characteristics and the external genitalia. These include effects on the uterus, vagina, oviduct, preputial gland, clitoris, and the mammary glands [1]. The normal physiology of the female genital tract encompasses complex processes, which are highly dependent on the structural and functional integrity of the genital tissues, involving complex neurovascular mechanisms modulated by numerous local neurotransmitters, vasoactive agents, sex steroid hormones, and growth factors. Regulation of vaginal and clitoral physiology by androgens is an area of great interest, not only in terms of basic understanding of the molecular and cellular bases of vaginal and clitoral function, but also because of clinical implications for use of androgen therapy in women. However, this area of investigation remains, at best, rudimentary and poorly studied. Clinically, testosterone is implicated in maintaining female genital sexual arousal response and sexual desire. Androgens play a key role in maintaining vaginal nerve network fibers and sexual arousal responses and facilitate genital hemodynamics and vaginal lubrication, thus preventing dyspareunia. Androgens in the development and differentiation of female genitalia Sexual development is a function of two processes: sex determination and differentiation. Sex determination is the initial decision to direct the development of the bipotential gonadal ridges into either testes or ovaries [2]. This decision of gonadal sex is governed by genetic sex, and is dependent on the integration of a host of molecular pathways that direct and dictate the development of germ cells and their migration to the urogenital ridge. Determination of whether testes or ovaries will develop is dependent on the presence or absence of the Y chromosome. Sex determination sets the conditions for the un differentiated embryo to develop in a sexually dimorphic manner [3].
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The polycystic ovary syndrome (PCOS) was first coined as a term in 1935 by Stein and Leventhal, who identified a series of patients with the combination of oligo-ovulation and hyperandrogenism [1]. Since that time, diagnosis of this syndrome has undergone multiple iterations of application of diagnostic criteria. Abnormal uterine bleeding was the most common symptom associated with the condition in the late 1800s, but over time, new and better evidence has become available to inform the diagnosis. As recognition of this entity as a complex constellation of symptoms and metabolic derangements expanded, multiple professional groups have attempted to better and more precisely characterize this common syndrome. In the past 25 years, three major sets of diagnostic criteria have emerged to defi ne PCOS (Table 7.1) [2 – 4]. The first set of criteria, outlined at the National Institutes of Health (NIH) in Bethesda, Maryland, in 1990, is the most stringent. It has largely been replaced in clinical practice by the more inclusive Rotterdam criteria. In Rotterdam, The Netherlands, in 2003, a task force sponsored by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) met to review the available data and to propose a revision of the 1990 NIH diagnostic paradigm. More recently, in 2009, the Androgen Excess Society (AES) outlined its own set of criteria for PCOS. Due to the subtle heterogeneities between the various diagnostic criteria, the reported prevalence of PCOS can vary depending on which definition is used by investigators. The discriminating reader should take note of the specific criteria utilized in the reporting. The NIH meeting in 1990 was the first international conference on PCOS. The information available to attendees at the time was based largely on expert opinion [2].
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Androgens are potent pharmacological drugs requiring legal prescription for valid medical indications but are also misused for invalid or unproven off-label medical reasons as well as used illicitly as a form of drug abuse. Understanding these distinctions and applications requires a knowledge of androgen physiology, pharmacology, and toxicology which is discussed in historical as well as present clinical practice terms. The present epidemic of testosterone misuse mainly involves using testosterone as an antiaging and/or sexual dysfunction tonic for middle-aged or older men for which the efficacy and safety are unproven, and there is concern that such treatment may be unsafe. Androgen abuse originated during the Cold War as an epidemic among elite athletes as ergogenic agents but in the 1980s transitioned to become an endemic in most communities with sufficient affluence to support an illicit drug industry geared toward body sculpting of hypermasculine body image for occupational or recreational reasons.
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Beyond prescribing testosterone for its only valid indication, testosterone replacement therapy for pathological hypogonadism, there increasing prevalence of testosterone misuse and abuse in most countries. Testosterone misuse is when testosterone is prescribed for non-valid medical indications such as male infertility, sexual dysfunction (in men without pathological hypogonadism), but most commonly for anti-aging. Androgen abuse is the non-prescription use of testosterone or a synthetic androgen unrelated to medical indications but rather for doping, body building, or other recreational, cosmetic, or occupational reasons.
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Introduction Magnetic resonance imaging (MRI) is an extremely powerful tool for evaluating the adrenal glands. MRI has the unique ability to characterize soft tissues. Th is ability allows for specific pathologic diagnoses to be made in a large number of adrenal lesions. Th is is accomplished without the use of ionizing radiation and, oft entimes, without the need for intravenous contrast material. However, certain lesions may remain indeterminate on MRI findings alone. In these cases, correlation with the overall clinical picture will aid in diagnosis. Rarely, biopsy may be required for definitive diagnosis. MRI utilizes the property of proton nuclear magnetic resonance coupled with robust spatial localization techniques to generate images. Various pulse sequences can be performed in the course of an MRI study. A pulse sequence is a series of radiofrequency electromagnetic wave excitations, magnetic gradients, and resulting radio frequency signals (echoes), which can be arranged in a variety of ways. The arrangement determines which tissue property is emphasized. Pulse sequences can be formulated to highlight certain aspects of the tissues being imaged. For example, the sequence can highlight tissue water content (e.g., T2-weighted) or fat content (e.g., Dixon fat-only images). Lipid detection techniques In fact, fat or lipid detection turns out to be very important in imaging of the adrenal glands. Several lipid-sensitive sequences exist. The two major categories that are utilized in adrenal imaging are chemical shift selective suppression (CHESS) and chemical shift imaging (CSI). Both of these techniques harness the property that water protons and fat protons resonate (precess, spin) at slightly different frequencies (rates) when placed in a strong external magnetic field. This difference in rate of precession is also called the chemical shift. The way these two sequences utilize this property differs such that the resulting images give complementary information. Chemical shift imaging Since there is a precessional (resonance, spin) frequency difference between water and fat protons, only at specific interval periods during nuclear spin precession will a lipid proton and a water proton be in sync, i.e., “in phase.”
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Introduction The steady decline of serum androgen levels across the lifespan of an adult woman has been well documented. Comparisons between early reproductive age women and women aged 65-75 show mean total testosterone (T) serum levels decreased by 55% and similar reductions are seen for mean values of free T (49%), dehydroepiandrosterone sulfate (DHEA-S) (77%), and androstenedione (A) (77%) [1]. While ovarian aging and the complete cessation of ovarian estradiol (E 2) synthesis produces the dramatic fall in E 2 levels that defines menopause, there is no evidence that the onset of natural menopause influences androgen levels. Rather, the postmenopausal ovarian hilar and stromal cells continue to respond to luteinizing hormone and secrete androgens. A 15-fold difference for T and a fourfold difference for A were noted between ovarian and peripheral veins in postmenopausal women [2], and in four out of five women a gradient for T still appeared more than 10 years aft er onset of menopause [3]. Additionally, women who underwent surgical menopause with hysterectomy and bilateral oophorectomy had a 40-50% lower serum level of total T and free T than those women with intact ovaries [4]. Other cross-sectional studies have added to the observation that women who had bilateral oophorectomies have significantly lower free T levels [1]. The mechanism of adrenal aging is less well understood, but the age-associated gradual, but marked decline in circulating dehydroepiandrosterone (DHEA) and androgen metabolites has been confirmed by Labrie et al. [5]. DHEA combined with its sulfated conjugate, DHEA-S, is present in the highest amount of all synthesized steroids and is almost totally supplied from the adrenals. While no specific action of its own has been proven, in peripheral tissue DHEA can be converted into active forms of both estrogens and androgens.
Article
Rationale: Selective androgen receptor modulators (SARMs) represent an emerging class of therapeutics targeting inter alia conditions referred to as cachexia and sarcopenia. Due to their anabolic properties, the use of SARMs is prohibited in sports as regulated by the World Anti-Doping Agency (WADA), and doping control laboratories test for these anabolic agents in blood and urine. In order to accomplish and maintain comprehensive test methods, the characterization of new drug candidates is critical for efficient sports drug testing. Hence, in the present study the mass spectrometric properties of the SARM YK-11 were investigated. Methods: YK-11 was synthesized according to literature data and three different stable-isotope-labeled analogs were prepared to support the mass spectrometric studies. Using high-resolution/high-accuracy mass spectrometry following electrospray ionization as well as electron ionization, the dissociation pathways of YK-11 were investigated, and characteristic features of its (product ion) mass spectra were elucidated. These studies were flanked by density functional theory (DFT) computation providing information on proton affinities of selected functional groups of the analyte. Results and conclusions: The steroidal SARM YK-11 was found to readily protonate under ESI conditions followed by substantial in-source dissociation processes eliminating methanol, acetic acid methyl ester, and/or ketene. DFT computation yielded energetically favored structures of the protonated species resulting from the aforementioned elimination processes particularly following protonation of the steroidal D-ring substituent. Underlying dissociation pathways were suggested, supported by stable-isotope labeling of the analyte, and diagnostic product ions for the steroidal nucleus and the D-ring substituent were identified. Further, trimethylsilylated YK-11 and its deuterated analogs were subjected to electron ionization high-resolution/high-accuracy mass spectrometry, complementing the dataset characterizing this new SARM. The obtained fragment ions resulted primarily from A/B- and C/D-ring structures of the steroidal nucleus, thus supporting future studies e.g. concerning metabolic pathways of the substance. Copyright © 2017 John Wiley & Sons, Ltd.
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Introduction Androgens play an important role in the normal development and functioning of human skin and its accompanying structures. They are necessary for a wide variety of cutaneous processes, ranging from sweat production to hair growth. However, when their careful regulation goes awry, androgens can contribute to the pathogenesis of multiple dermatoses. A deeper understanding of androgens and their impact on human skin allows us to work towards more effective therapeutic options for these skin disorders. Role of androgens in normal human skin. Skin-related androgens The adrenal cortex is largely responsible for synthesizing the circulating hormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S). Both the adrenal cortex and the ovaries contribute equally to the production of androstenedione in women [1]. DHEA, DHEA-S, and androstenedione are weak prohormones, which exert their effects after their conversion to their more potent counterparts, testosterone and 5 α-dihydrotestosterone (DHT). In females of reproductive age, androstenedione is secreted by the ovary and adrenal cortex and converted into testosterone in the peripheral organs, including the skin [2] (Figure 8.1). Because of its concentration and potency, testosterone is the main circulating androgen [3]. In both genders, peripheral organs are the main synthesizers of DHT, the most potent tissue androgen produced from the metabolism of testosterone by 5 α-reductases (Figures 8.1 and 8.2) [4]. Although the skin is not the major site of androgen production, the circulating prohormones DHEA and androstenedione can be converted into testoster-one and DHT in sebocytes, sweat glands, and dermal papilla cells [4]. Consequently, these potent androgens can impact dermal functioning. Sweat glands and sebaceous glands account for the vast majority of androgen metabolism in the skin [5]. The peripheral organs produce 100% of the active sex steroids in postmenopausal women [6] (Figure 8.1).
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Introduction Aging in men leads to decline in multiple physiologic and psychological parameters. The physical effects of aging broadly recognized include weight gain, loss of muscle mass, and skin changes. The decline is a universal event for men as they age and is due in part to decreasing androgen production. The reduction of serum levels of total, free, and bioavailable testosterone throughout aging has been well documented [1-3]. While the majority of men remain asymptomatic, some complain of symptoms that are attributed to this drop in androgens. The symptoms are oft en vague and nonspecific like depression, loss of energy, and sexual dysfunction. The symptoms secondary to decreased androgen production are so common that some would say that they are not reflective of a medical condition, but rather the normal consequence of aging. Th is perspective may cause clinicians to question the wisdom of androgen replacement therapy in aging men, even in men suffering a significant decrease in quality of life [2]. Occasionally, skeptics of androgen replacement therapy point to the surprising results of the Women’s Health Initiative (WHI) studies to warn of similar, possibly unrecognized risks associated with hormone replacement therapy (HRT) in aging men. One may ask whether such comparison is appropriate. To address this question, a brief review of HRT in women and the WHI studies is necessary [4]. Menopause, women, and hormone replacement therapy Menopause is the permanent cessation of the menstrual cycle. Menopause is tied to a specific date, defined as the day after the final menstrual period, and determined retrospectively once 12 months have gone by with no menstrual flow at all. In the United States, the average age of a woman having her last period, menopause, is 51; however, some women have their last period in their forties, though most have it later in their fifties.
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Androgen replacement therapy should be considered for all hypogonadal men with persistent low serum testosterone levels and symptoms of testosterone deficiency. Before commencement of replacement, contraindications to androgen treatment should be identified. In hypogonadal men, androgens improve sexual function, energy and mood, increase muscle mass and strength, as well as bone mineral density. Androgen therapy can be tailored to each patient’s needs and preferences. There are many new androgen delivery systems introduced in the past few years and many more are in development. Selective androgen receptor modulators may have the potential of optimizing beneficial effects while minimizing potential adverse effects. In older men, monitoring of prostate dysfunction and red cell indexes is necessary and important. With care, androgens can be used efficaciously and with minimal potential side effects.
Chapter
Androgens are potent pharmacological drugs requiring legal prescription for valid medical indications but are also misused for invalid or unproven off-label medical reasons as well as used illicitly as a form of drug abuse. Understanding these distinctions and applications requires a knowledge of androgen physiology, pharmacology, and toxicology which is discussed in historical as well as present clinical practice terms. The present epidemic of testosterone misuse mainly involves using testosterone as an antiaging and/or sexual dysfunction tonic for middle-aged or older men for which the efficacy and safety are unproven, and there is concern that such treatment may be unsafe. Androgen abuse originated during the Cold War as an epidemic among elite athletes as ergogenic agents but in the 1980s transitioned to become an endemic in most communities with sufficient affluence to support an illicit drug industry geared toward body sculpting of hypermasculine body image for occupational or recreational reasons.
Cachexia is a state of increased metabolism associated with high morbidity and mortality. Dysregulation of cytokines and hormone activity causes reduced protein synthesis and excessive protein breakdown. various treatments are available, depending on the primary disease and the patient's state. Besides pharmacological treatment, crucial is nutritional support as well as increasing physical activity. The main purpose of pharmacological treatment is to diminish inflammation, improve appetite and decrease muscle wasting. Therefore a lot of medications aim at proinflammatory cytokines such as Interferon-α or Tumor Necrosis Factor-β, but because of the complicated mechanism of cachexia, the range of targets is very wide. in cachexia treatment, use of corticosteroids is common, which improve appetite, diminish inflammation, inhibit prostaglandin metabolism, Interleukin-1 activity. They can also decrease protein synthesis and increase protein degradation, which can be prevented by resveratrol. Estrogen analogs, progesterone analogs, testosterone analogs, Selective Androgen Receptor Modulators (SARM), Angiotensin-Converting-Enzyme Inhibitors (ACEI), Nonsteroidal anti-inflammatory drugs (NSAIDs), thalidomide, melatonin, Growth Hormone Releasing Peptide-2 (GHRP-2) may play important role in wasting syndrome treatment as well. However, for the usage of some of them, evidence-based recommendations are not available. This review highlights current therapeutic options for cachexia with a specific focus on steroid therapy.
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Sarcopenia is the degenerative loss of muscle mass and function with aging. Recently sarcopenia was recognized as a clinical disease by the International Classification of Disease, 10th revision, Clinical Modification. An imbalance between protein synthesis and degradation causes a gradual loss of muscle mass, resulting in a decline of muscle function as a progress of sarcopenia. Many mechanisms involved in the onset of sarcopenia include age-related factors as well as activity-, disease-, and nutrition-related factors. The stage of sarcopenia reflecting the severity of conditions assists clinical management of sarcopenia. It is important that systemic descriptions of the disease conditions include age, sex, and other environmental risk factors as well as levels of physical function. To develop a new therapeutic intervention needed is the detailed understanding of molecular and cellular mechanisms by which apoptosis, autophagy, atrophy, and hypertrophy occur in the muscle stem cells, myotubes, and/or neuromuscular junction. The new strategy to managing sarcopenia will be signal-modulating small molecules, natural compounds, repurposing of old drugs, and muscle-specific microRNAs.
Article
Analytical chemistry represents a central aspect of doping controls. Routine sports drug testing approaches are primarily designed to address the question whether a prohibited substance is present in a doping control sample and whether prohibited methods (for example, blood transfusion or sample manipulation) have been conducted by an athlete. As some athletes have availed themselves of the substantial breadth of research and development in the pharmaceutical arena, proactive and preventive measures are required such as the early implementation of new drug candidates and corresponding metabolites into routine doping control assays, even though these drug candidates are to date not approved for human use. Beyond this, analytical data are also cornerstones of investigations into atypical or adverse analytical findings, where the overall picture provides ample reason for follow-up studies. Such studies have been of most diverse nature, and tailored approaches have been required to probe hypotheses and scenarios reported by the involved parties concerning the plausibility and consistency of statements and (analytical) facts. In order to outline the variety of challenges that doping control laboratories are facing besides providing optimal detection capabilities and analytical comprehensiveness, selected case vignettes involving the follow-up of unconventional adverse analytical findings, urine sample manipulation, drug/food contamination issues, and unexpected biotransformation reactions are thematized.
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Yusuke Ito, Marianne D Sadar Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada Abstract: Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information. Steady-state concentration minimums (Cmin or trough) in the range of ~1–13 μg/mL are measured in patients at therapeutic doses. Interestingly, enzalutamide which is considered to have strong affinity for the androgen receptor (AR) requires Cmin levels >10 μg/mL. The sequence of antiandrogens and the clinical order of application in regard to other drugs that target the androgen axis remain of high interest. One novel first-in-class drug, called ralaniten, which binds to a unique region in the N-terminus domain of both the full-length and the truncated constitutively active splice variants of the AR, is currently in clinical trials for patients who previously received abiraterone, enzalutamide, or both. This highlights the trend to develop drugs with novel mechanisms of action and potentially differing mechanisms of resistance compared with antiandrogens. Better and more complete inhibition of the transcriptional activity of the AR appears to continue to provide improvements in the clinical management of mCRPC. Keywords: prostate cancer, enzalutamide, antiandrogens, Cmin, trough, pharmacology, cross-resistance, clinical trials, PSA response, ralaniten, EPI-002
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Physical demands from activity take a toll on the body, especially as the athlete ages. Abilities and routines that seemed second nature become more difficult to perform. Therefore, a variety of antiaging and performance drugs have “hit the market” with promises to recapture the sense of youth and ease performance at high level activities, or slow the aging process. Many drugs have been shown to improve cognition, physical function, physiologic parameters, and performance. In this chapter, we will discuss the more common supplements as well as what is new on the horizon.
Article
The selective androgen receptor modulators are a recent class of anabolic agents, used to improve athletic performance. Among these molecules, there is (2 S)-N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluoro-4-chlorophenoxyl)2-hydroxy-2-methyl-propanamide, commonly known as S-23. This molecule appeared very recently on the doping market. As a result, very few data are available in the literature, and nothing has been published about long-term effects of S-23. The authors focused on the detection of S-23 and its metabolites in human urine, following a single oral administration of approx. 8 mg to a volunteer, using standard ultra-performance liquid chromatography-triple quadrupole-mass spectrometry (UPLC-MS/MS), and ultra-performance liquid chromatography-quadrupole time of flight-mass spectrometry (UPLC-Q-TOF-MS). To the best of the authors knowledge, this seems to be the first study ever achieved on S-23. In vitro experiment was performed, using human liver microsomes, in order to investigate the potential CYP- and UGT-dependent S-23 metabolites. Four metabolites were produced, which were identified as hydroxy-S-23 (C18H12O4N2ClF4: m/z [M-H⁻] 431.0423); O-dephenylate-S-23 (C12H10O3N2F3: m/z [M-H⁻] 287.0647); S-23-glucuronide (C24H20O9N2ClF4: m/z [M-H⁻] 591.0794) and hydroxy-S-23-glucuronide (C24H20O10N2ClF4: m/z [M-H⁻] 607.0743). After consumption of S-23, the parent drug was detectable in hydrolyzed urine from 2 hours post administration up to 28 days, with concentrations ranging between 0.5 and 93 ng/mL. In the urine, only one of the four metabolites identified in vitro was detected, hydroxy-S-23. This metabolite was detected up to 28 days. It does not seem to increase the window of detection of S-23 as the ratio between hydroxy-S-23 and the parent drug was always lower than 1. Another metabolite, dihydroxy-S-23, not identified in vitro, was identified in the urine of the volunteer. Hair sample, collected one month after the consumption of a single tablet, was negative for S-23 and hydroxy-S-23, with a LOQ at 0.1 pg/mg.
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Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilize inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women’s health disorders such as endometriosis and endometrial cancer has prompted renewed interest in development of drugs targeting these pathways opening up new opportunities for targeted therapies and precision medicine.
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In recent years, an increasing focus has been given to the study of selective androgen receptor modulators (SARMS) due to the fewer side effects they exhibit compared to anabolic androgenic steroids. The crystal structure of ostarine (Os) and andarine (AND) has been determined by X-ray single crystal diffraction. It was found that ostarine crystallizes in the monoclinic system, P21 space group with Z = 2 and one molecule in the asymmetric unit, while andarine crystallizes in the tetragonal system, P42212 space group with Z = 8 and one molecule per asymmetric unit. A polymorph of ostarine (Os–P1) has been identified as being monoclinic, space group P21, Z = 2 with two molecules in the asymmetric unit and has been solved by X-ray powder diffraction using Parallel tempering Monte Carlo technique and refined by Rietveld method. This polymorph has been obtained by phase change as a result of heating. All studied compounds were further characterized by IR spectroscopy, differential thermal analysis (DTA) and thermogravimetric analysis (TGA). The molecular self-assembly architectures are built by hydrogen bonds as O–H⋯N and N–H⋯O in ostarine, respectively O–H⋯O, N–H⋯O in andarine. Crystal packing energies were calculated using atom-atom force field method (London-Coulomb-Pauli, CLP) which involves the evaluation of Coulombic, polarization, dispersion and repulsion terms. Furthermore, Hirshfeld surface and fingerprint plot analysis was carried out in order to understand the presence of different intermolecular interactions and how hydrogen bonding holds the stability of the crystal structure.
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The history of the appearance and development of selective androgen receptor modulators (SARMs) is described. The main classes of SARMs and various approaches to their determination are considered. The use of chromatography-mass spectrometry is shown to be promising for the reliable determination of SARM traces in various samples. Well-known sample preparation and determination methods in biological materials are considered, and the metabolic pathways the best studied SARM (andarine) using cell cultures (in vitro) and laboratory animals and humans (in vivo) are compared.
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This paper describes the studies of the in vitro biotransformation of two selective androgen receptor modulators (SARMs), namely RAD140 and S‐23, and the in vivo metabolism of RAD140 in horses using ultra‐high performance liquid chromatography‐high resolution mass spectrometry (UPLC‐HRMS). In vitro metabolic studies of RAD140 and S‐23 were performed using homogenised horse liver. The more prominent in vitro biotransformation pathways for RAD140 included hydrolysis, hydroxylation, glucuronidation and sulfation. Metabolic pathways for S‐23 were similar to those for other arylpropionamide‐based SARMs. The administration study of RAD140 was carried out using three retired thoroughbred geldings. RAD140 and the majority of the identified in vitro metabolites were detected in post‐administration urine samples. For controlling the misuse of RAD140 in horses, RAD140 and its metabolite in sulfate form gave the longest detection time in hydrolysed urine, and could be detected for up to 6 days post‐administration. In plasma, RAD140 itself gave the longest detection time of up to 13 days. Apart from RAD140 glucuronide, the metabolites of RAD140 described herein have never been reported before.
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Hair and urine concentrations of the non‐steroidal selective androgen receptor modulator GSK2881078 were examined following single oral administration to investigate its hair incorporation and estimate the general suitability of hair testing for selected androgen‐receptor modulators. Hair segments were collected following a single dose of 1.5 mg GSK2881078 by repeated shaving of scalp hair at week 0 (blank), week 1 (representing the pre‐application period), week 3 (ideally focusing the time of incorporation), weeks 5 and 9 (post‐administration period). The intact compound and various (at least 4) hydroxy‐metabolites exhibited similar elimination profiles. The peak urinary concentration (approx. 920 pg/mL) was observed after 8 hours, and is reduced to the detection limit (2 pg/mL) on day 42 following administration of 760 μg GSK2881078. Correspondingly, hair concentrations of GSK2881078 (intact compound only) following a single oral dose of 1.5 mg GSK2881078 reached a peak concentration of 1.7 pg/mg in the segments collected 3 weeks post administration, representing the time of ingestion. The concentration rapidly declined to trace amounts of 0.7 pg/mg (week 5) and 0.2 pg/mg (week 9), respectively. In conclusion, measurement of the intact compound GSK2881078 is feasible for both urine and hair analysis. However, concentrations in hair after single oral administration are in the low pg/mg‐range and can only be detected, if the segments cover the administration period.
Purpose of review: In this review, we outline the most recent advances in the development of Leydig stem cells (LSCs) and summarize the current and upcoming treatments for hypogonadism. Recent findings: In-vitro and in-vivo studies show that inducing stem cells to differentiate into testosterone-producing adult Leydig cells is possible. In addition, LSCs can be grafted with Sertoli cells to increase testosterone levels in vivo. This therapy causes minimal effects on luteinizing hormone and follicle stimulating hormone levels. Novel therapies for hypogonadism include varying methods of testosterone delivery such as intranasal and oral agents, as well as novel selective estrogen and androgen receptor modulators. Summary: LSC therapies provide an effective way of increasing testosterone levels without detrimentally affecting gonadotropin levels. Next steps in developing viable Leydig cell grafting options for the treatment of hypogonadism should include the assessment of efficacy and potency of current animal models in human trials. Recently, both intranasal and oral testosterone have been made available and shown promising results in treating hypogonadism while maintaining fertility. Enclomiphene citrate and selective androgen receptor modulators have been suggested as future therapies for hypogonadism; however, further studies assessing efficacy and adverse effects are needed.
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Chronic obstructive pulmonary disease (COPD) represents a complex respiratory disorder characterized by persistent respiratory symptoms due to chronic airflow limitation caused by exposure to noxious particles/gases with an increased inflammatory response of the airways. COPD is common in older people, with an estimated prevalence of 10% in the US population aged > 75 years and is often accompanied by other concomitant chronic conditions that negatively impact prognosis and health status. The aim of this paper is to highlight the relationship between COPD and other comorbidities in elderly population. We focus our attention on the relationship existing between COPD and cardiovascular diseases, lung cancer, obstructive sleep apnoea syndrome, malnutrition/sarcopenia and osteoporosis with particular attention to adipokines, considering that adipose tissue plays a relevant role in the cross-talk between organs.
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The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.
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Cancer cachexia often occurs in malignant tumors and is a multifactorial and complex symptom characterized by wasting of skeletal muscle and adipose tissue, resulting in weight loss, poor life quality and shorter survival. The pathogenic mechanism of cancer cachexia is complex, involving a variety of molecular substrates and signal pathways. Advancements in understanding the molecular mechanisms of cancer cachexia have provided a platform for the development of new targeted therapies. Although recent outcomes of early-phase trials have showed that several drugs presented an ideal curative effect, monotherapy cannot be entirely satisfactory in the treatment of cachexia-associated symptoms due to its complex and multifactorial pathogenesis. Therefore, the lack of definitive therapeutic strategies for cancer cachexia emphasizes the need to develop a better understanding of the underlying mechanisms. Increasing evidences show that the progression of cachexia is associated with metabolic alternations, which mainly include excessive energy expenditure, increased proteolysis and mitochondrial dysfunction. In this review, we provided an overview of the key mechanisms of cancer cachexia, with a major focus on muscle atrophy, adipose tissue wasting, anorexia and fatigue and updated the latest progress of pharmacological management of cancer cachexia, thereby further advancing the interventions that can counteract cancer cachexia.
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Cachexia is one of the most devastating conditions associated to cancer. Severe wasting produces both a high symptomatic burden and secondary psychological distress, and it is estimated to directly cause 20% of cancer deaths. Its pathophysiology is characterized by tumor-host interactions that, mediated mainly by tumor- and host-derived molecules, lead to profound metabolic changes that predominantly affect the central nervous system, the gastrointestinal tract, the adipose and the skeletal muscle tissue, and the immune system. Due to its clinical variability, consensus definitions were established, which defined cancer cachexia as the consequence of a variable combination of decreased oral intake and impaired metabolism that is refractory to conventional nutritional support. The establishment of clinical stages in which lean body mass evaluations were progressively incorporated to improve tissue wasting detection has increasingly stressed the early detection of the syndrome. Although cancer cachexia treatment has been an active research field in the last decades, no single drug has clinically demonstrated a robust benefit, and progestogens remain the only drugs specifically approved for this condition. Ongoing research is being conducted to elucidate whether intervening earlier in the natural history of the syndrome or combining drugs, nutritional interventions, and/or physical activity programs is able to improve outcomes. Additionally, the bottleneck-shaped pathophysiology of cancer cachexia, which begins within tumor cells, raises hope that better oncologic treatments will decisively contribute to decrease the dramatic impact of this condition.
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A procedure for the determination of several selective androgen receptor modulators in human urine, namely, Andarine (S-4, GTx-007), Ostarine (S-22, GTx-024, MK-2866) and Ligandrol (LGD-4033, VK-5211), as well as a phytosteroid Laxogenin and Ibutamoren (MK-677), related to non-peptide growth hormone secretagogues, has been developed. Most of these are prohibited by the World Anti-Doping Agency due to their anabolic effects. With the aim of the analytes purification and concentration, a procedure for solid-phase extraction with the use of Varian Bond Elut C8 (100 mg, 1 mL), Biotage Isolute C18 (EC) (100 mg, 1 mL) and Waters Oasis HLB (30 mg, 1 mL) cartridges was applied. To achieve good resolution of the analytes, reversed-phase ultra-high-performance liquid chromatography coupled with the triple quadrupole mass spectrometer as a detector in positive and negative ion detection modes was used. The limits of detection were in the range of 0.1-0.5 ng/mL, limits of quantification were between 0.25-0.5 ng/mL. Calibration curves were examined to be linear in the wide range of concentrations. Matrix effects were also evaluated and were found not to influence the results of the analytes quantification. The proposed method was applied for the analysis of real samples after single 15 mg oral administration of the analytes. All the analytes were positively detected in the human urine samples in 12h, thus, proving the applicability of the procedure for the analytes quantification in the urine.
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PURPOSEEmerging evidence suggests muscle depletion predicts survival of patients with cancer. PATIENTS AND METHODS At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models.ResultsBody mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001). CONCLUSIONCT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.
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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.
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Cancer cachexia is a metabolic syndrome that can be present even in the absence of weight loss ('precachexia'). Cachexia is often compounded by pre-existing muscle loss, and is exacerbated by cancer therapy. Furthermore, cachexia is frequently obscured by obesity, leading to under-diagnosis and excess mortality. Muscle wasting (the signal event in cachexia) is associated not only with reduced quality of life, but also markedly increased toxicity from chemotherapy. Many of the primary events driving cachexia are likely mediated via the central nervous system and include inflammation-related anorexia and hypoanabolism or hypercatabolism. Treatment of cachexia should be initiated early. In addition to active management of secondary causes of anorexia (such as pain and nausea), therapy should target reduced food intake (nutritional support), inflammation-related metabolic change (anti-inflammatory drugs or nutrients) and reduced physical activity (resistance exercise). Advances in the understanding of the molecular biology of the brain, immune system and skeletal muscle have provided novel targets for the treatment of cachexia. The combination of therapies into a standard multimodal package coupled with the development of novel therapeutics promises a new era in supportive oncology whereby quality of life and tolerance to cancer therapy could be improved considerably.
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Objective: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment. Design and methods: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition. Results: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency. Conclusion: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.
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A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A(50) = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.
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Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity.
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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.
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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.
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Context and objective: GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. Design and participants: A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m(2) . d) from baseline, combined with placebo (Pl) or Ox in low (0.03 mg/kg . d) or conventional (0.06 mg/kg . d) dose from the age of 8 yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. Results: Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean +/- sd, 9.5 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.02) and per-protocol analysis (9.8 +/- 4.9 vs. 6.8 +/- 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl (8.3 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P < 0.001). Conclusions: In GH-treated girls with TS, we discourage the use of the conventional Ox dosage (0.06 mg/kg . d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development.
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The average weight-losing pancreatic cancer patient undergoing palliative therapy is frequently overweight rather than underweight, and this can confound conventional measures used for risk stratification. The aim of this study was to evaluate if weight and body composition, specifically sarcopenia, assessed from diagnostic computed tomography (CT) scans, is of prognostic value in patients with pancreatic cancer. The nature and extent of tissue loss over subsequent months was also evaluated. A total of 111 patients entering a palliative therapy program, who had CT images and had undergone nutritional screening, were studied. In patients for whom follow-up scans were available (n = 44), longitudinal changes in body composition were studied at a mean of 230 +/- 62 and 95 +/- 60 days prior to demise. Sixty-two patients (55.9%) were sarcopenic, 44 (39.6%) were overweight/obese, and 18 (16.2%) were both. Age > or =59 years (hazard ratio, 1.71; 95% confidence interval, 1.10-2.66; P = 0.018), and overweight/obese sarcopenia (hazard ratio, 2.07; 95% confidence interval, 1.23-3.50; P = 0.006) were identified as independent predictors of survival on multivariate analysis. Longitudinal analysis revealed that total fat-free mass index decreased from 15.5 +/- 2.5 kg/m(2) to 14.5 +/- 2.0 kg/m2 (P = 0.002), and total fat mass index decreased from 7.5 +/- 2.0kg/m2 to 6.0 +/- 1.5kg/m2 (P < 0.0001) over 135 days. Sarcopenia in overweight/obese patients with advanced pancreatic cancer is an occult condition but can be identified using CT scans. This condition is an independent adverse prognostic indicator that should be considered for stratification of patients' entering clinical trials, systemic therapy, or support care programs.
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Body composition has emerged as an important prognostic factor in cancer patients. Severe depletion of skeletal muscle (sarcopenia) and, hence, of overall lean body mass may represent an occult condition in individuals with normal or even high body weight. Sarcopenia has been associated with poor performance status, 5-fluorouracil toxicity, and shortened survival in cancer patients. Here, we prospectively studied patients with metastatic breast cancer receiving capecitabine treatment in order to determine if sarcopenia was associated with a higher incidence of toxicity and a shorter time to tumor progression (TTP). Fifty-five women with metastatic breast cancer resistant to anthracycline and/or taxane treatment were included. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment, and TTP was determined prospectively. Approximately 25% of patients were classified as sarcopenic, and this feature was seen in normal weight, overweight, and obese individuals. Toxicity was present in 50% of sarcopenic patients, compared with only 20% of nonsarcopenic patients (P = 0.03), and TTP was shorter in sarcopenic patients (101.4 days; confidence interval, 59.8-142.9) versus nonsarcopenic patients (173.3 days; confidence interval, 126.1-220.5; P = 0.05). Sarcopenia is a significant predictor of toxicity and TTP in metastatic breast cancer patients treated with capecitabine. Our results raise the potential use of body composition assessment to predict toxicity and individualize chemotherapy dosing.
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Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.
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A novel nonsteroidal androgen receptor (AR) binder, S-40503, was successfully generated in order to develop selective androgen receptor modulators (SARMs). We evaluated the binding specificity for nuclear receptors (NRs) and osteoanabolic activities of S-40503 in comparison with a natural nonaromatizable steroid, 5alpha-dihydrotestosterone (DHT). The compound preferentially bound to AR with nanomolar affinity among NRs. When S-40503 was administrated into orchiectomized (ORX) rats for 4 weeks, bone mineral density (BMD) of femur and muscle weight of levator ani were increased as markedly as DHT, but prostate weight was not elevated over the normal at any doses tested. In contrast, DHT administration caused about 1.5-fold increase in prostate weight. The reduced virilizing activity was clearly evident from the result that 4-week treatment of normal rats with S-40503 showed no enlargement of prostate. To confirm the bone anabolic effect, S-40503 was given to ovariectomized (OVX) rats for 2 months. The compound significantly increased the BMD and biomechanical strength of femoral cortical bone, whereas estrogen, anti-bone resorptive hormone, did not. The increase in periosteal mineral apposition rate (MAR) of the femur revealed direct bone formation activity of S-40503. It was unlikely that the osteoanabolic effect of the compound was attribute to the enhancement of muscle mass, because immobilized ORX rats treated with S-40503 showed a marked increase in BMD of tibial cortical bone without any actions on the surrounding muscle tissue. Collectively, our novel compound served as a prototype for SARMs, which had unique tissue selectivity with high potency for bone formation and lower impact upon sex accessory tissues.
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The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.
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Carcinoma of the prostate is the most commonly diagnosed cancer in men. The current pharmacological treatment of choice for progressive androgen-dependent prostate cancer is the nonsteroidal antiandrogen, bicalutamide, either as monotherapy or with adjuvant castration or luteinizing hormone-releasing hormone superagonists to block the synthesis of endogenous testosterone. To date, no nonsteroidal or antagonist-bound androgen receptor (AR) structure is available. We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalutamide at 1.8-A resolution. This mutation confers agonist activity to bicalutamide and is likely involved in bicalutamide withdrawal syndrome. The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone. Knowledge of the binding mechanism for R-bicalutamide will provide molecular rationale for the development of new antiandrogens and selective AR modulators.
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Selective androgen receptor modulators (SARMs) have many potential therapeutic applications, including male hypogonadism, osteoporosis, muscle-wasting diseases, sexual libido, and contraception. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides bearing a four-halogen substituent in the B-ring that displayed in vivo activity were identified in our previous study. Interestingly, in vivo pharmacological activity was not correlated with in vitro androgen receptor (AR) binding affinity. In this study, analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological activity. Studies also suggested that two simple criteria (i.e., Ki < 10 nM and lower in vivo clearance) could be used to identify efficacious and potent SARMs. We tested this hypothesis using a series of four compounds incorporating either a nitro or cyano substituent at the para-position of the A- and B-aromatic rings. The S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-nitro-3-trifluromethylphenyl) propionamides (S-19 and S-20, respectively) and S-3-(4-nitrophenoxy) and S-3-(4-cyanophenoxy) 2-hydroxy-2-methyl-N-(4-cyano-3-trifluromethylphenyl) propionamides (S-21 and S-22, respectively) demonstrated high AR binding affinity, with Ki values ranging from 2.0 to 3.8 nM. Pharmacokinetic studies of selected compounds showed that the in vivo clearance of S-22 was the slowest followed sequentially by S-20, S-21, and S-19. The dose-response relationships for S-22 showed that S-22 exerted efficacious and selective activity in anabolic tissues at dose rates as low as 0.03 mg/day, indicative of the high potency of this compound in anabolic tissue (relative potency 4.41) and its potential for clinical use in androgen deficiency-related disorders.
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The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights more than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.
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The mechanism by which the androgen receptor (AR) distinguishes between agonist and antagonist ligands is poorly understood. AR antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal AR ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type AR. We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the AR binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists.
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We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.
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Alanine amino-transferases (ALTs) play a crucial role in drug development as a surrogate marker of liver injury where elevations in serum ALT activity are used to diagnose drug-induced liver damage. Two ALT isoforms have been characterized with disparate but overlapping tissue expression. ALT1 is primarily expressed in live; ALT2 is found in muscle and prostate tissues. We investigate ALT gene expression in diverse rodent tissues following administration of the steroidal androgen receptor (AR) agonist dihydrotestosterone and a novel tissue selective nonsteroidal agonist S-23. Putative AR regulation of ALT expression was determined in silico by an orthologous promoter androgen response element (ARE) search. Regulation was evaluated by transient transfection of ALT promoter region constructs and qRT-PCR experiments in cultured cells and in tissues following androgen administration. Several putative AREs were found in the proximal promoter regions of ALT1 and ALT2. AREs in ALT2 but not ALT1 were capable of AR-mediated transcription. ALT2 expression was affected by castration and androgen administration in muscle and prostate but not liver tissues. Androgen action in non-hepatic tissues, as opposed to xenobiotic toxicity alone, may contribute to increases in serum ALT activity following androgen administration.
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Although androgens are known to protect bone, side effects and poor oral bioavailability have limited their use. We previously reported that S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S-4) is a potent and tissue-selective androgen receptor modulator (SARM). This study was designed to evaluate the skeletal effects of S-4 in an osteopenic model. Aged female rats were gonadectomized or sham operated on day 1 and assigned to treatment groups. Dosing was initiated on day 90 and continued daily until day 210. Whole animal bone mineral density (BMD), body weight, and fat mass were determined by dual energy x-ray absorptiometry (DEXA). Regional analysis of excised bones was performed using DEXA or computed tomography. Femur strength was evaluated by 3-point bending. S-4 restored whole body and lumbar vertebrae (L5-L6) BMD to the level of intact controls. Significant increases in cortical bone quality were observed at the femoral midshaft, resulting in increased load bearing capacity. S-4 demonstrated partial/complete recovery of bone parameters to age-matched intact levels. Increased efficacy observed in cortical bone sites is consistent with reported androgen action in bone. The ability of S-4 to promote bone anabolism, prevent bone resorption, and increase skeletal muscle mass/strength positions these drugs as promising new alternatives for the treatment of osteoporosis.