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Journal of Nuclear Medicine : Official... Aug 2022A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited...
A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited efficacy, with about a 19% clinical benefit rate. We investigated the therapeutic enhancement of antiandrogens as radiosensitizers in combination with F-FDG in TNBC. We screened 5 candidate drugs to evaluate shared toxicity when combined with either F-FDG, x-rays, or ultraviolet radiation, at doses below their respective half-maximal inhibitory concentrations. Cytotoxic enhancement of antiandrogen in combination with F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, the therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Bicalutamide, an antiandrogen drug, was found to share similar toxicity in combination with either F-FDG or x-rays, indicating its sensitivity as a radiosensitizer to F-FDG. Cell proliferation assays demonstrated selective toxicity of combination bicalutamide-F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation-induced damage to cells, suggesting the role of bicalutamide as a radiosensitizer to F-FDG-mediated radiation damage. Animal studies in MDA-MB-231, 22RV1, and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of bicalutamide and F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathologic examination corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. These data provide evidence that F-FDG in conjunction with antiandrogens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers.
Topics: Androgen Antagonists; Animals; Cell Line, Tumor; Fluorodeoxyglucose F18; Humans; Mice; Nitriles; Radiation-Sensitizing Agents; Receptors, Androgen; Triple Negative Breast Neoplasms; Ultraviolet Rays
PubMed: 34772792
DOI: 10.2967/jnumed.121.262958 -
Medical Sciences (Basel, Switzerland) Apr 2022Prostate cancer therapy for locally advanced and metastatic diseases includes androgen deprivation therapy (ADT). Second-generation antiandrogens have a role in... (Review)
Review
Prostate cancer therapy for locally advanced and metastatic diseases includes androgen deprivation therapy (ADT). Second-generation antiandrogens have a role in castration-resistant prostate cancer. Nevertheless, some patients do not respond to this therapy, and eventually all the patients became resistant. This is due to modifications to intracellular signaling pathways, genomic alteration, cytokines production, metabolic switches, constitutional receptor activation, overexpression of some proteins, and regulation of gene expression. The aim of this review is to define the most important mechanisms that drive this resistance and the newest discoveries in this field, specifically for enzalutamide and abiraterone, with potential implications for future therapeutic targets. Furthermore, apalutamide and darolutamide share some resistance mechanisms with abiraterone and enzalutamide and could be useful in some resistance settings.
Topics: Androgen Antagonists; Disease Progression; Humans; Male; Prostatic Neoplasms, Castration-Resistant
PubMed: 35645241
DOI: 10.3390/medsci10020025 -
Nature Chemical Biology Dec 2022Patients with castration-resistant prostate cancer inevitably acquire resistance to antiandrogen therapies in part because of androgen receptor (AR) mutations or splice...
Patients with castration-resistant prostate cancer inevitably acquire resistance to antiandrogen therapies in part because of androgen receptor (AR) mutations or splice variants enabling restored AR signaling. Here we show that ligand-activated AR can form transcriptionally active condensates. Both structured and unstructured regions of AR contribute to the effective phase separation of AR and disordered N-terminal domain plays a predominant role. AR liquid-liquid phase separation behaviors faithfully report transcriptional activity and antiandrogen efficacy. Antiandrogens can promote phase separation and transcriptional activity of AR-resistant mutants in a ligand-independent manner. We conducted a phase-separation-based phenotypic screen and identified ET516 that specifically disrupts AR condensates, effectively suppresses AR transcriptional activity and inhibits the proliferation and tumor growth of prostate cancer cells expressing AR-resistant mutants. Our results demonstrate liquid-liquid phase separation as an emerging mechanism underlying drug resistance and show that targeting phase separation may provide a feasible approach for drug discovery.
Topics: Male; Humans; Receptors, Androgen; Androgen Antagonists; Ligands; Drug Resistance, Neoplasm; Prostatic Neoplasms; Cell Line, Tumor; Prostatic Neoplasms, Castration-Resistant
PubMed: 36229685
DOI: 10.1038/s41589-022-01151-y -
International Urology and Nephrology Jun 2022Advanced prostate cancer does not respond to traditional androgen deprivation therapy (ADT) at some point in the treatment. The development of new hormonal agents... (Review)
Review
Evaluation of maintenance of the common androgen deprivation therapy with the new antiandrogen therapy in patients with castration-resistant prostate cancer: a systematic review.
PURPOSE
Advanced prostate cancer does not respond to traditional androgen deprivation therapy (ADT) at some point in the treatment. The development of new hormonal agents demonstrated clear efficacy and changed the treatment scenario.
OBJECTIVES
To evaluate the use of new antiandrogens alone versus their use in combination with maintenance ADT in patients with advanced castration-resistant prostate cancer.
METHODS
A literature systematic review of randomized clinical trials, cohorts, and real-life studies including patients who received the new antiandrogens with or without ADT due to histologic confirmed advanced castration-resistant prostate adenocarcinoma was carried out.
RESULTS
2181 articles were identified and three studies were included with a total of 246 patients. Two studies were randomized clinical trials, and the third was a retrospective study, which showed similar results for both arms, in relation to PSA response, radiological progression-free survival, and testosterone levels, in addition to cost analysis with savings avoided in the ADT maintenance-free arm. Despite the positive data, it is still not possible to categorically state whether there is a statistical benefit in suspending the ADT during the use of new antiandrogens, due to the heterogeneity of the studies.
CONCLUSION
The literature is limited on the issue. Available data are still immature with no clear benefit of the use of newer antiandrogens alone in the setting of advanced castration-resistant prostate cancer.
Topics: Androgen Antagonists; Androgens; Humans; Male; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome
PubMed: 35384583
DOI: 10.1007/s11255-022-03201-9 -
Expert Opinion on Drug Safety Nov 2014Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy.... (Review)
Review
INTRODUCTION
Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509).
AREAS COVERED
This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone-naive or in castration-resistant patients.
EXPERT OPINION
Non-steroidal antiandrogens are widely used in the management of hormone-sensitive disease in combination with luteinizing hormone-releasing hormone agonists or in patients failing front-line treatment with androgen-deprivative maneuvers. In selected patients, non-steroidal antiandrogen monotherapy appears to yield comparable results as castration. Novel non-steroidal antiandrogens have been investigated with promising results in castration-resistant prostate cancer. Beyond the safety profile specific to any individual compound, increased testosterone and 17β-estradiol levels are commonly observed during antiandrogen monotherapy, leading to gynecomastia and breast pain. The safety profile of old and novel antiandrogens should be taken into account by clinicians in decision making and in selecting the most suitable patients. Beyond patient selection, full clinical evaluation of patient co-morbidities that might affect the drug tolerability and clinical monitoring are anyway required.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Neoplasm Staging; Neoplasms, Hormone-Dependent; Patient Safety; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 25270521
DOI: 10.1517/14740338.2014.966686 -
Dermatologic Clinics Apr 2006Androgen hormones play an important role in common skin and hair conditions including acne vulgaris, hirsutism, and androgenetic alopecia. Blocking this androgen effect... (Review)
Review
Androgen hormones play an important role in common skin and hair conditions including acne vulgaris, hirsutism, and androgenetic alopecia. Blocking this androgen effect may lead to significant improvements in these conditions. Several medications that work through a variety of different mechanisms may be prescribed safely and effectively as antiandrogen therapies in the dermatology arena.
Topics: Alopecia; Androgen Antagonists; Contraceptives, Oral, Combined; Hair Diseases; Hirsutism; Humans; Skin Diseases
PubMed: 16677962
DOI: 10.1016/j.det.2006.01.002 -
Current Pharmaceutical Design Sep 1999Androgenic manifestations in appearance cause not only social and psychological distress for many women, but serious skin, reproductive and metabolic abnormalities as... (Comparative Study)
Comparative Study Review
Androgenic manifestations in appearance cause not only social and psychological distress for many women, but serious skin, reproductive and metabolic abnormalities as well. Antiandrogen therapy is one of the most promising therapies to treat androgenic disorders. Clinical studies with a variety of agents, including spironolactone, cyproterone acetate, flutamide and finasteride have now proven their utility in the treatment of hirsutism, acne, androgenic alopecia and ovulatory dysfuntion in hyperandrogenic women. Comparative clinical studies, especially with low-dose regimens, suggest that these agents are well tolerated and have the potential for broader clinical utility.
Topics: Androgen Antagonists; Androgens; Clinical Trials as Topic; Female; Hormone Antagonists; Humans
PubMed: 10495361
DOI: No ID Found -
Endocrine Practice : Official Journal... May 2023Gender-affirming hormone therapy guidelines describe the estradiol (E2) doses for intramuscular (IM), but not subcutaneous (SC), routes. The objective was to compare the...
OBJECTIVE
Gender-affirming hormone therapy guidelines describe the estradiol (E2) doses for intramuscular (IM), but not subcutaneous (SC), routes. The objective was to compare the SC and IM E2 doses and hormone levels in transgender and gender diverse individuals.
METHODS
This is a retrospective cohort study at a single-site tertiary care referral center. Patients were transgender and gender diverse individuals who received injectable E2 with at least 2 E2 measurements. The main outcomes were the dose and serum hormone levels between the SC and IM routes.
RESULTS
There were no statistically significant differences in age, body mass index, or antiandrogen use between patients on SC (n = 74) and those on IM (n = 56). The weekly doses of SC E2, 3.75 mg (IQR, 3-4 mg), were statistically significantly lower than those of IM E2, 4 mg (IQR, 3-5.15 mg) (P =.005); however, the E2 levels achieved were not significantly different (P =.69), and the testosterone levels were in the cisgender female range and not significantly different between routes (P =.92). Subgroup analysis demonstrated significantly higher doses in the IM group when the E2 and testosterone levels were >100 pg/mL and <50 ng/dL, respectively, with the presence of the gonads or use of antiandrogens. Multiple regression analysis demonstrated that the dose was significantly associated with the E2 levels after adjusting for injection route, body mass index, antiandrogen use, and gonadectomy status.
CONCLUSION
Both the SC and IM E2 achieve therapeutic E2 levels without a significant difference in the dose (3.75 vs 4 mg). SC may achieve therapeutic levels at lower doses than IM .
Topics: Humans; Female; Retrospective Studies; Estradiol; Injections, Subcutaneous; Androgen Antagonists; Transgender Persons; Testosterone; Injections, Intramuscular
PubMed: 36868378
DOI: 10.1016/j.eprac.2023.02.006 -
The American Journal of Psychiatry May 1981
Topics: Androgen Antagonists; Behavior Control; Ethics, Medical; Humans; Male; Paraphilic Disorders; Risk Assessment; Sex Offenses
PubMed: 7235060
DOI: 10.1176/ajp.138.5.642 -
The Cochrane Database of Systematic... Nov 2020Gender dysphoria is described as a mismatch between an individual's experienced or expressed gender and their assigned gender, based on primary or secondary sexual...
BACKGROUND
Gender dysphoria is described as a mismatch between an individual's experienced or expressed gender and their assigned gender, based on primary or secondary sexual characteristics. Gender dysphoria can be associated with clinically significant psychological distress and may result in a desire to change sexual characteristics. The process of adapting a person's sexual characteristics to their desired sex is called 'transition.' Current guidelines suggest hormonal and, if needed, surgical intervention to aid transition in transgender women, i.e. persons who aim to transition from male to female. In adults, hormone therapy aims to reverse the body's male attributes and to support the development of female attributes. It usually includes estradiol, antiandrogens, or a combination of both. Many individuals first receive hormone therapy alone, without surgical interventions. However, this is not always sufficient to change such attributes as facial bone structure, breasts, and genitalia, as desired. For these transgender women, surgery may then be used to support transition.
OBJECTIVES
We aimed to assess the efficacy and safety of hormone therapy with antiandrogens, estradiol, or both, compared to each other or placebo, in transgender women in transition.
SEARCH METHODS
We searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Biosis Preview, PsycINFO, and PSYNDEX. We carried out our final searches on 19 December 2019.
SELECTION CRITERIA
We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cohort studies that enrolled transgender women, age 16 years and over, in transition from male to female. Eligible studies investigated antiandrogen and estradiol hormone therapies alone or in combination, in comparison to another form of the active intervention, or placebo control.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane to establish study eligibility.
MAIN RESULTS
Our database searches identified 1057 references, and after removing duplicates we screened 787 of these. We checked 13 studies for eligibility at the full text screening stage. We excluded 12 studies and identified one as an ongoing study. We did not identify any completed studies that met our inclusion criteria. The single ongoing study is an RCT conducted in Thailand, comparing estradiol valerate plus cyproterone treatment with estradiol valerate plus spironolactone treatment. The primary outcome will be testosterone level at three month follow-up.
AUTHORS' CONCLUSIONS
We found insufficient evidence to determine the efficacy or safety of hormonal treatment approaches for transgender women in transition. This lack of studies shows a gap between current clinical practice and clinical research. Robust RCTs and controlled cohort studies are needed to assess the benefits and harms of hormone therapy (used alone or in combination) for transgender women in transition. Studies should specifically focus on short-, medium-, and long-term adverse effects, quality of life, and participant satisfaction with the change in male to female body characteristics of antiandrogen and estradiol therapy alone, and in combination. They should also focus on the relative effects of these hormones when administered orally, transdermally, and intramuscularly. We will include non-controlled cohort studies in the next iteration of this review, as our review has shown that such studies provide the highest quality evidence currently available in the field. We will take into account methodological limitations when doing so.
Topics: Androgen Antagonists; Drug Therapy, Combination; Estradiol; Estrogens; Female; Humans; Male; Placebos; Sex Reassignment Procedures; Transgender Persons
PubMed: 33251587
DOI: 10.1002/14651858.CD013138.pub2