The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Susan R Davis - One of the best experts on this subject based on the ideXlab platform.
-
Androgens in postmenopausal women a review
Menopause, 2017Co-Authors: Jan L Shifren, Susan R DavisAbstract:There is significant interest in the use of Androgen Therapy for postmenopausal women. This review provides background on endogenous Androgens in women, describes factors that affect circulating Androgen concentrations, and examines the relationship between low levels of Androgens and sexual problems. Possible effects of Androgens in postmenopausal women beyond sexual function also are discussed. Clinical trials of Androgen Therapy for the treatment of hypoactive sexual desire disorder are reviewed, with a discussion of potential risks. A practical approach to using Androgens to treat low sexual desire with associated distress is presented, accompanied by an illustrative case.
-
Androgen Therapy in women a reappraisal an endocrine society clinical practice guideline
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Margaret E Wierman, Susan R Davis, Rosemary Basson, Karen K Miller, William Rosner, Wiebke Arlt, Mohammad Hassan Murad, Nanette SantoroAbstract:Objective: To update practice guidelines for the therapeutic use of Androgens in women. Participants: A Task Force appointed by the Endocrine Society, American Congress of Obestricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), European Society of Endocrinology (ESE), and International Menopause Society (IMS) consisting of six experts, a methodologist, and a medical writer. Evidence: The Task Force commissioned two systematic reviews of published data and considered several other existing meta-analyses and trials. The GRADE methodology was used; the strength of a recommendation is indicated by a number “1” (strong recommendation, we recommend) or “2” (weak recommendation, we suggest). Consensus Process: Multiple e-mail communications and conference calls determined consensus. Committees of the Endocrine Society, ASRM, ACOG, ESE, and IMS reviewed and commented on the drafts of the guidelines. Conclusions: We continue to recommend against making a diagnosis of Androgen defi...
-
Androgen Therapy in women beyond libido
Climacteric, 2013Co-Authors: Susan R DavisAbstract:AbstractObjective The aim of this review was to summarize the literature regarding the potential role of testosterone Therapy for women.Methods The author conducted a search of the literature using Medline (Ovid, 1946–present) and PubMed (1966–2013) for English-language studies that included the following search terms: ‘testosterone’ or ‘Androgen’ combined with ‘women’, ‘Therapy’ or ‘treatment’.Results Randomized, placebo-controlled trials have consistently shown that transdermal testosterone Therapy improves sexual desire, arousal, orgasm frequency and satisfaction in premenopausal and postmenopausal women presenting with sexual desire/arousal problems. No adverse metabolic effects have been observed in these studies. In postmenopausal women, testosterone Therapy has also been associated with favorable effects on body composition, bone, cardiovascular function and cognitive performance.Conclusions Although Androgens have many varied roles, the focus of testosterone Therapy for women has been on improving...
-
Androgen replacement Therapy in Androgen-deficient women with hypopituitarism.
Drugs, 2008Co-Authors: Hong Zang, Susan R DavisAbstract:Hypopituitarism is a rare disorder, but its prevalence has increased as a result of an increase in secondary causes of hypopituitarism such as traumatic brain injury and cranial irradiation. Estrogen with or without progestogen (progestin) treatment is conventional Therapy in women with hypopituitarism. Recent data demonstrate that women with hypopituitarism may experience marked Androgen deficiency as a consequence of secondary loss of function of the adrenal cortex and/or ovaries. This deficiency is not always considered and therefore Androgen Therapy is not routinely prescribed. Recent clinical trials indicate that testosterone supplementation in physiological doses for Androgen-deficient women with hypopituitarism may improve psychological well-being and sexual function, and increase bone mineral density and lean body mass. Dehydroepiandrosterone (DHEA; prasterone) supplementation may be an option for women with hypopituitarism who have secondary adrenal insufficiency and low levels of DHEA and DHEA sulfate. While short-term treatment with testosterone or DHEA appears to be safe, long-term safety data are lacking. Androgenic adverse effects limit the acceptability of treatment for some women. Further studies to establish the efficacy and safety of Androgen treatment for long-term intervention in a larger group of hypopituitary Androgen-deficient women are needed.
-
Androgen Therapy in women an endocrine society clinical practice guideline
The Journal of Clinical Endocrinology and Metabolism, 2006Co-Authors: Margaret E Wierman, Susan R Davis, Rosemary Basson, Sundeep Khosla, Karen K Miller, William Rosner, Nanette SantoroAbstract:Objective: The objective was to provide guidelines for the therapeutic use of Androgens in women. Participants: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Evidence: The Task Force used systematic reviews of available evidence to inform its key recommendations. The Task Force used consistent language and graphical descriptions of both the strength of recommendation and the quality of evidence, using the recommendations of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group. The strength of a recommendation is indicated by the number 1 (strong recommendation, associated with the phrase “we recommend”) or 2 (weak recommendation, associated with the phrase “we suggest”). The quality of the evidence is indicated by cross-filled circles, such that QEEE denotes very-low-quality evidence, QQEE low quality, QQQE moderate quality, and QQQQ high quality. Each recommendation is followed by a description of the evidence. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and e-mail communications. The drafts prepared by the taskforcewiththehelpofamedicalwriterwerereviewedsuccessively by The Endocrine Society’s CGS, Clinical Affairs Committee (CAC), andExecutiveCommittee.TheversionapprovedbytheCGSandCAC was placed on The Endocrine Society’s web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. Conclusions: We recommend against making a diagnosis of Androgen deficiency in women at present because of the lack of a welldefined clinical syndrome and normative data on total or free testosterone levels across the lifespan that can be used to define the disorder. Although there is evidence for short-term efficacy of testosteroneinselectedpopulations,suchassurgicallymenopausalwomen, we recommend against the generalized use of testosterone by women because the indications are inadequate and evidence of safety in long-term studies is lacking. A review of the data currently available is presented, and areas of future research are outlined. To formulate clinical guidelines for use of testosterone in women, additional informationwillbenecessary.Thisincludesdefiningconditionsthat,when not treated with Androgens, have adverse health consequences to women; defining clinical and laboratory parameters that distinguish those with these conditions; and assessing the efficacy and long-term safety of Androgen administration on outcomes that are important to women diagnosed with these conditions. This necessary clinical research cannot occur until the biological, physiological, and psychological underpinnings of the role of Androgens in women and candidatedisordersarefurtherelucidated.(JClinEndocrinolMetab91: 3697–3710, 2006)
James T Dalton - One of the best experts on this subject based on the ideXlab platform.
-
nonsteroidal selective Androgen receptor modulators sarms dissociating the anabolic and Androgenic activities of the Androgen receptor for therapeutic benefit
Journal of Medicinal Chemistry, 2009Co-Authors: Michael L Mohler, James T Dalton, Casey E Bohl, Amanda Jones, Christopher C Coss, Ramesh Narayanan, Dong Jin Hwang, Duane D MillerAbstract:Interest in the development and therapeutic potential of nonsteroidal tissue-selective Androgen receptor modulators (SARMs) has increased dramatically within the past decade. Rapidly expanding knowledge of nuclear hormone receptor structure and function and successful proof-of-principle clinical trials with SARMs have revived an almost dormant search for improved Androgens. This Award Address attempts to chronicle the landmark discoveries (with emphasis on our work), organize the SARM landscape into clinically relevant bins, and provide insight into the clinical prospects for SARMs. 1.1. Origins of Androgen Use. An early (1889) and unusual experiment in Androgen Therapy was performed by Charles Edouard Brown-Sequard, age 72. He administered a testicular extract to himself and reported that he felt “increased vigor and capacity for work”. Despite retrospective suggestions that any effect was purely placebo, this report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. Attempts to isolate the active components of testicular extract failed until 1935 when testosterone (17 hydroxy-4-andosten-3-one) was isolated from bull testes. Shortly thereafter, its synthesis was reported. In the same year, extracts of urine from males were shown to cause nitrogen retention, an indicator of anabolic metabolism. Testosterone was the first anabolic Androgen to be used clinically, but its use is limited by its Androgenicity and pharmacokinetic (PK) issues. 1 In the latter half of the 20th century, the chemical scaffold of testosterone was modified extensively, producing many
-
expanding the therapeutic use of Androgens via selective Androgen receptor modulators sarms
Drug Discovery Today, 2007Co-Authors: Wenqing Gao, James T DaltonAbstract:Selective Androgen receptor modulators (SARMs) are a novel class of Androgen receptor (AR) ligands that might change the future of Androgen Therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of Androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contributions of differential tissue distribution, tissue-specific expression of 5α-reductase, ligand-specific regulation of gene expression and AR interactions with tissue-specific coactivators to their observed tissue selectivity, and lead to even greater expansion of selective anabolic therapies.
-
key structural features of nonsteroidal ligands for binding and activation of the Androgen receptor
Molecular Pharmacology, 2003Co-Authors: Donghua Yin, Duane D Miller, Minoli A Perera, Seoung Soo Hong, Craig A Marhefka, Nina Stourman, Leonid Kirkovsky, James T DaltonAbstract:The purposes of the present studies were to examine the Androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiAndrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective Androgen receptor modulators (SARMs) for Androgen Therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.
Duane D Miller - One of the best experts on this subject based on the ideXlab platform.
-
nonsteroidal selective Androgen receptor modulators sarms dissociating the anabolic and Androgenic activities of the Androgen receptor for therapeutic benefit
Journal of Medicinal Chemistry, 2009Co-Authors: Michael L Mohler, James T Dalton, Casey E Bohl, Amanda Jones, Christopher C Coss, Ramesh Narayanan, Dong Jin Hwang, Duane D MillerAbstract:Interest in the development and therapeutic potential of nonsteroidal tissue-selective Androgen receptor modulators (SARMs) has increased dramatically within the past decade. Rapidly expanding knowledge of nuclear hormone receptor structure and function and successful proof-of-principle clinical trials with SARMs have revived an almost dormant search for improved Androgens. This Award Address attempts to chronicle the landmark discoveries (with emphasis on our work), organize the SARM landscape into clinically relevant bins, and provide insight into the clinical prospects for SARMs. 1.1. Origins of Androgen Use. An early (1889) and unusual experiment in Androgen Therapy was performed by Charles Edouard Brown-Sequard, age 72. He administered a testicular extract to himself and reported that he felt “increased vigor and capacity for work”. Despite retrospective suggestions that any effect was purely placebo, this report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. Attempts to isolate the active components of testicular extract failed until 1935 when testosterone (17 hydroxy-4-andosten-3-one) was isolated from bull testes. Shortly thereafter, its synthesis was reported. In the same year, extracts of urine from males were shown to cause nitrogen retention, an indicator of anabolic metabolism. Testosterone was the first anabolic Androgen to be used clinically, but its use is limited by its Androgenicity and pharmacokinetic (PK) issues. 1 In the latter half of the 20th century, the chemical scaffold of testosterone was modified extensively, producing many
-
key structural features of nonsteroidal ligands for binding and activation of the Androgen receptor
Molecular Pharmacology, 2003Co-Authors: Donghua Yin, Duane D Miller, Minoli A Perera, Seoung Soo Hong, Craig A Marhefka, Nina Stourman, Leonid Kirkovsky, James T DaltonAbstract:The purposes of the present studies were to examine the Androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiAndrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective Androgen receptor modulators (SARMs) for Androgen Therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.
Hao Wang - One of the best experts on this subject based on the ideXlab platform.
-
transformer a randomized phase ii study comparing bipolar Androgen Therapy versus enzalutamide in asymptomatic men with castration resistant metastatic prostate cancer
Journal of Clinical Oncology, 2021Co-Authors: Samuel R Denmeade, Hao Wang, Michael T Schweizer, Neeraj Agarwal, David C Smith, Mark N Stein, Vasileios J Assikis, Przemyslaw Twardowski, Thomas W Flaig, Russell Z SzmulewitzAbstract:PURPOSEProstate cancer (PCa) becomes resistant to Androgen ablation through adaptive upregulation of the Androgen receptor in response to the low-testosterone microenvironment. Bipolar Androgen the...
-
transformer bipolar Androgen Therapy bat versus enzalutamide e for castration resistant metastatic prostate cancer mcrpc
Journal of Clinical Oncology, 2020Co-Authors: Samuel R Denmeade, Hao Wang, Michael T Schweizer, Harry Cao, Ting Wang, Rehab Abdallah, Vanessa Bolejack, Neeraj Agarwal, David C Smith, Mark N SteinAbstract:5517Background: Rapid cycling between high and low testosterone (T) (i.e BAT) produces tumor response in mCRPC, and may overcome resistance to newer AR therapies. Here we report a randomized study ...
-
bipolar Androgen Therapy in men with metastatic castration resistant prostate cancer after progression on enzalutamide an open label phase 2 multicohort study
Lancet Oncology, 2018Co-Authors: Benjamin A Teply, Hao Wang, Brandon Luber, Rana Sullivan, Irina Rifkind, Ashley Bruns, Avery Spitz, Morgan Decarli, V SinibaldiAbstract:Summary Background Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiAndrogen Therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar Androgen Therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide. Methods We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0–2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist Therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA 50 ) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114. Findings Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15–49; p 50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33–71; p 50 response. During BAT, the only grade 3–4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3–4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. Interpretation BAT is a safe Therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between Androgen and antiAndrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients. Funding National Institutes of Health and National Cancer Institute.
-
effect of bipolar Androgen Therapy for asymptomatic men with castration resistant prostate cancer results from a pilot clinical study
Science Translational Medicine, 2015Co-Authors: Michael T Schweizer, Hao Wang, Avery Spitz, Emmanuel S Antonarakis, Seun A Ajiboye, Michael C Haffner, Srinivasan Yegnasubramanian, Michael A Carducci, Mario A Eisenberger, John T IsaacsAbstract:Targeting Androgen receptor (AR) axis signaling by disrupting Androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating Therapy and secondary Androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone Therapy monoTherapy. Castrating Therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar Androgen Therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving Androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.
Filippo Spriano - One of the best experts on this subject based on the ideXlab platform.
-
dual functions of spop and erg dictate Androgen Therapy responses in prostate cancer
Nature Communications, 2021Co-Authors: Geniver El Tekle, Tiziano Bernasocchi, Marco Bolis, Azzurra Mutti, Arianna Vallerga, Laura P Brandt, Filippo SprianoAbstract:Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen Androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic Androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to Androgen deprivation therapies, ERG promotes sensitivity to high-dose Androgen Therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.