Selective androgen receptor modulators

PURPOSE: Selective androgen receptor modulators (SARMs) have demonstrated agonist activity on the androgen receptor in various tissues, stimulating muscle mass growth and improving bone reconstruction. Despite being in clinical trials, none has been approved by the Food and Drug Administration (FDA) or European Medicines Agency for pharmacotherapy. Still, SARMs are very popular as performance-enhancing drugs. The FDA has issued warnings about the health risks associated with SARMs, but the long-term exposure and possible adverse events still need to be fully understood...

In castrate-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic "bypass" mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic PC patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs)...

Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1...

Selective androgen receptor modulators (SARMs) are prohibited by the World Anti-Doping Agency (WADA) since 2008. Similarly, to anabolic androgenic steroids (AAS), SARMs are detrimental to health not only in athletes but also in the general population. However, studies of the occurrence of SARMs outside of sport are scarce. Swedish healthcare samples from the Drugs of Abuse Laboratory at Karolinska were analyzed using WADA-accredited screening methods at the Doping Control Laboratory in Stockholm to estimate the frequency of SARM use outside of the WADA laboratories...

Selective androgen receptor modulators (SARMs) such as ACP-105 are prohibited in sports due to their anabolic properties. ACP-105 has in previous equine studies shown to undergo extensive metabolism, which makes its metabolite profile important to investigate in humans, since the metabolism is unknown in this species. The aims of the study were to systematically optimize in vitro microsome incubations for improved metabolite yield and to utilize a multivariate data analysis (MVDA) approach to aid the metabolite discovery...

BACKGROUND: Anabolic-androgenic steroids (AAS) mimic the effects of testosterone and may include testosterone itself; they are used for body enhancement within the general population. AAS use has been linked with increased mortality, cardiovascular disease, mental health disorders, and infertility. AAS-induced hypogonadism can persist for an uncertain time period despite cessation, during which men may report physical and neuropsychiatric symptoms. In an attempt to mitigate these symptoms and expedite testicular recovery, many men self-administer post-cycle-therapy (PCT), typically involving human chorionic gonadotrophin (hCG) and selective oestrogen receptor modulators (SERMs), which are known to potently stimulate testicular function...

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INTRODUCTION: The specific role of testosterone (T) replacement therapy in patients with late onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T levels (primary hypogonadism). AREAS COVERED: Advantages and limitations related to available new treatments will be discussed in detail. In addition, possible news related to preparations in the pipeline will be discussed...

UNLABELLED: Lipid droplets (LD) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows that LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer, LD accumulation is associated with cancer aggressiveness, therapy resistance, and poor clinical outcome. Prostate cancer arises as an androgen receptor (AR)-driven disease. Among its myriad roles, AR mediates the biosynthesis of LDs, induces autophagy, and modulates cellular oxidative stress in a tightly regulated cycle that promotes cell proliferation...

Liver injury associated with selective androgen receptor modulators (SARMs) is an issue that has not been reported often. We report a case of a previously healthy 24-year-old male, who was referred to our hospital for severe jaundice with intense pruritus. He had previously taken the SARM Enobosarm (also known as Ostarine) for muscle-building purposes. Blood serum levels of total bilirubin exceeded 30 mg/dL with only a slight elevation of liver enzymes . Liver biopsy revealed isolated hepatocellular cholestasis (bland cholestasis) with limited inflammation or necrosis...

Overweight and obesity are associated with severe metabolic disorders and an increased risk of cardiovascular diseases. It is a known fact that physical activity has a positive effect on metabolic parameters, and also reduces the risk of diseases such as diabetes. Some products can enhance the rate of lipolysis and help in improving fat loss. One of these are selective androgen receptor modulators (SARMs) which act as anabolic agents and are also believed to aid in fat-burning. In this study, we investigated whether 30 days of ostarine administration could potentially improve metabolic parameters using the rat model of obesity combined with exercise...

RATIONALE: The use of selective androgen receptor modulators (SARM) in sports is prohibited by the World Anti-Doping Agency (WADA) due to their potential as performance-enhancing drugs, offering an unfair advantage. LGD-4033 is a SARM known for its similarities to anabolic steroids and can be easily purchased online, leading to increased availability and misuse. Adverse analytical findings have revealed the presence of SARMs in dietary supplements. Although LGD-4033 misuse has been reported in human sports over the years, concerns also arise regarding its illicit use in animal sports, including camel racing...

PURPOSE: To review the impact of testosterone and other androgenic-anabolic steroids (AASs) on male fertility, exploring potential drugs that can be used to preserve or restore male fertility upon AAS use or prior contact. METHODS: A review was performed to provide a unifying clinical link between drugs used to preserve or restore male fertility (ie, clomiphene citrate, human chorionic gonadotropin, selective estrogen receptor modulators, recombinant luteinizing and follicle-stimulating hormones, and human menopausal gonadotrophin) in the context of AAS-induced infertility and related aspects...

It is becoming increasingly more significant to detect and separate hormones from water sources, with the development of synthetic recognition materials becoming an emerging field. The delicate nature of biological recognition materials such as the antibodies means the generation of robust viable synthetic alternatives has become a necessity. Molecularly imprinted nanoparticles (NanoMIPs) are an exciting class that has shown promise due the generation of high-affinity and specific materials. While nanoMIPs offer high affinity, robustness and reusability, their production can be tricky and laborious...

INTRODUCTION: The pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule. METHODS: The suitable in vivo -model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay)...

The effects of combination treatments using the selective androgen receptor modulators (SARMs) ostarine (OST) or ligandrol (LIG) with treadmill exercise (TE) were studied in healthy adult rats. Fifteen-week-old male Wistar rats were divided into groups ( n = 10/group). Experiment 1 consisted of (1) Control group: sedentary rats receiving vehicle; (2) OST: sedentary rats receiving OST; (3) TE: training rats receiving vehicle; (4) OST + TE: training rats receiving OST. Experiment 2 consisted of (1) LIG: sedentary group receiving LIG; (2) LIG + TE: training group receiving LIG...

Ligandrol, also known as LGD-4033, belongs to the group of selective androgen receptor modulators (SARMs). Ligandrol was first included in the WADA Prohibited List in 2018. This work presents a method that allows for the detection and identification of ligandrol and its metabolite in athletes' urine and in dietary supplements by means of ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Samples were prepared according to an approach involving acid hydrolysis and double liquid-liquid extraction (LLE)...

The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer...

RAD140 is a selective androgen receptor modulator that produces anabolic effects within skeletal muscle. Thus, RAD140 may be effective at treating sarcopenia. No long-term studies have investigated how RAD140 influences strength in ageing muscle. This study aimed to determine how 10 weeks of RAD140 supplementation impacts strength, recovery from exercise, and overall health in ageing mice. Young and adult females were assigned to receive RAD140 (5 mg/kg) or a control solution. Dorsiflexor muscles were exposed to repeated bouts of eccentric contractions, and torque was measured before and after each bout...

The Androgen Receptor (AR) is a ligand (androgen) activated transcription factor and a member of the nuclear receptor (NR) superfamily. It is required for male sex hormone function. AR-FL (full-length) has the domain structure of NRs, an N-terminal domain (NTD) required for transactivation, a DNA-binding domain (DBD), a nuclear localization signal (NLS) and a ligand-binding domain (LBD). Paradoxes exist in that endogenous ligands testosterone (T) and 5α-dihydrotestosterone (DHT) have differential effects on male sexual development while binding to the same receptor and transcriptional specificity is achieved even though the androgen response elements (AREs) are identical to those seen for the progesterone, glucocorticoid and mineralocorticoid receptors...