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Oncology Research and Treatment 2020
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins
PubMed: 32428911
DOI: 10.1159/000507053 -
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 -
Drugs of Today (Barcelona, Spain : 1998) Feb 2023Clascoterone is a novel topical antiandrogen medication approved for the treatment of acne. Conventional oral antiandrogen treatments targeting acne such as combined... (Review)
Review
Clascoterone is a novel topical antiandrogen medication approved for the treatment of acne. Conventional oral antiandrogen treatments targeting acne such as combined oral contraceptives and spironolactone exert systemic hormonal effects which commonly preclude their usage in male patients while hampering their application in certain female patients. In contrast, clascoterone is a first-in-class antiandrogen proven to be both safe and effective for female and male patients above the age of 12. Outside of occasional localized skin irritation, clascoterone is usually well tolerated, however, some adolescents in a phase II clinical trial experienced biochemical evidence of HPA suppression, which resolved after discontinuing treatment. In this review, we provide an overview of clascoterone including its preclinical pharmacology, pharmacokinetics and metabolism, safety, clinical studies and indications.
Topics: Adolescent; Humans; Male; Female; Acne Vulgaris; Androgen Antagonists; Propionates; Cortodoxone
PubMed: 36811407
DOI: 10.1358/dot.2023.59.2.3507749 -
JAMA Jan 2024Adverse outcomes associated with treatments for localized prostate cancer remain unclear. (Comparative Study)
Comparative Study Observational Study
IMPORTANCE
Adverse outcomes associated with treatments for localized prostate cancer remain unclear.
OBJECTIVE
To compare rates of adverse functional outcomes between specific treatments for localized prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS
An observational cohort study using data from 5 US Surveillance, Epidemiology, and End Results Program registries. Participants were treated for localized prostate cancer between 2011 and 2012. At baseline, 1877 had favorable-prognosis prostate cancer (defined as cT1-cT2bN0M0, prostate-specific antigen level <20 ng/mL, and grade group 1-2) and 568 had unfavorable-prognosis prostate cancer (defined as cT2cN0M0, prostate-specific antigen level of 20-50 ng/mL, or grade group 3-5). Follow-up data were collected by questionnaire through February 1, 2022.
EXPOSURES
Radical prostatectomy (n = 1043), external beam radiotherapy (n = 359), brachytherapy (n = 96), or active surveillance (n = 379) for favorable-prognosis disease and radical prostatectomy (n = 362) or external beam radiotherapy with androgen deprivation therapy (n = 206) for unfavorable-prognosis disease.
MAIN OUTCOMES AND MEASURES
Outcomes were patient-reported sexual, urinary, bowel, and hormone function measured using the 26-item Expanded Prostate Cancer Index Composite (range, 0-100; 100 = best). Associations of specific therapies with each outcome were estimated and compared at 10 years after treatment, adjusting for corresponding baseline scores, and patient and tumor characteristics. Minimum clinically important differences were 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, and 4 to 6 for bowel and hormone function.
RESULTS
A total of 2445 patients with localized prostate cancer (median age, 64 years; 14% Black, 8% Hispanic) were included and followed up for a median of 9.5 years. Among 1877 patients with favorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -12.1 [95% CI, -16.2 to -8.0]), but not worse sexual function (adjusted mean difference, -7.2 [95% CI, -12.3 to -2.0]), compared with active surveillance. Among 568 patients with unfavorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -26.6 [95% CI, -35.0 to -18.2]), but not worse sexual function (adjusted mean difference, -1.4 [95% CI, -11.1 to 8.3), compared with external beam radiotherapy with androgen deprivation therapy. Among patients with unfavorable prognosis, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel (adjusted mean difference, -4.9 [95% CI, -9.2 to -0.7]) and hormone (adjusted mean difference, -4.9 [95% CI, -9.5 to -0.3]) function compared with radical prostatectomy.
CONCLUSIONS AND RELEVANCE
Among patients treated for localized prostate cancer, radical prostatectomy was associated with worse urinary incontinence but not worse sexual function at 10-year follow-up compared with radiotherapy or surveillance among people with more favorable prognosis and compared with radiotherapy for those with unfavorable prognosis. Among men with unfavorable-prognosis disease, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel and hormone function at 10-year follow-up compared with radical prostatectomy.
Topics: Humans; Male; Middle Aged; Androgen Antagonists; Prostate-Specific Antigen; Prostatic Neoplasms; Urinary Incontinence; United States; SEER Program; Aged; Prostatectomy; Patient Reported Outcome Measures; Prognosis; Watchful Waiting; Radiotherapy
PubMed: 38261043
DOI: 10.1001/jama.2023.26491 -
International Journal of Radiation... Feb 2022
Topics: Androgen Antagonists; Androgens; Hormone Replacement Therapy; Humans; Male; Mythology; Prostatic Neoplasms
PubMed: 34998533
DOI: 10.1016/j.ijrobp.2021.09.032 -
Cancer Research Oct 2023Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression.
SIGNIFICANCE
Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.
Topics: Male; Humans; Receptors, Androgen; Androgen Antagonists; Androgens; Prostatic Neoplasms, Castration-Resistant; Ferroptosis; Nitriles; Castration; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 37527336
DOI: 10.1158/0008-5472.CAN-23-0285 -
Endocrinology Sep 2021In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through... (Review)
Review
In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through the androgen receptor (AR), the primary driver of prostate cancer, some malignancies are able take advantage of the closely related glucocorticoid receptor (GR). Escape from AR dependency often involves a simple functional switch from 1 steroid receptor to another. Recent research efforts have outlined the mechanism enabling this switch, which involves alterations in glucocorticoid metabolism that occur with antiandrogen therapy to increase tumor tissue glucocorticoids and enable GR signaling. Targeting this mechanism pharmacologically by blocking hexose-6-phosphate dehydrogenase shows promise in normalizing glucocorticoid metabolism and restoring responsiveness to antiandrogen therapy. This perspective reviews what we have learned about this resistance mechanism, examines potential implications, and considers how this knowledge might be harnessed for therapeutic benefit.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Glucocorticoids; Humans; Male; Metabolic Networks and Pathways; Molecular Targeted Therapy; Prostatic Neoplasms
PubMed: 34180973
DOI: 10.1210/endocr/bqab132 -
JAMA Oncology Jul 2023The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed.
OBJECTIVE
To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects.
DATA SOURCES
PubMed, EMBASE, and Scopus (inception to September 12, 2022).
STUDY SELECTION
Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, fatigue, weakness), or falls were evaluated.
DATA EXTRACTION AND SYNTHESIS
Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Enhancing the Quality and Transparency of Health Research reporting guidelines. Tabular counts for all-grade toxic effects were determined to test the hypothesis formulated before data collection.
MAIN OUTCOMES AND MEASURES
Risk ratios (RRs) and SEs were calculated for cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the asthenic toxic effect extracted from all studies, data on fatigue are specified in the results. Meta-analysis and meta-regression were used to generate summary statistics.
RESULTS
The systematic review included 12 studies comprising 13 524 participants. Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR, 2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001) was noted among individuals treated with second-generation AAs vs those in the control arms. The findings were consistent in studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79; P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression supported that, across studies, increased age was associated with a greater risk of fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In addition, the use of second-generation AAs was associated with an increased risk of falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001).
CONCLUSIONS AND RELEVANCE
The findings of this systematic review and meta-analysis suggest that second-generation AAs carry an increased risk of cognitive and functional toxic effects, including when added to traditional forms of hormone therapy.
Topics: Humans; Male; Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Cognition; Fatigue; Prospective Studies; Prostatic Neoplasms; Quality of Life; Retrospective Studies
PubMed: 37227736
DOI: 10.1001/jamaoncol.2023.0998 -
Revue Medicale de Liege Oct 2022Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of...
Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of treatment for advanced prostate cancer. In the metastatic setting, although ADT is initially effective, castration-resistant disease eventually develops in almost all men with prostate cancer. Since 2015, the addition of docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide with docetaxel to ADT has been shown to improve overall survival (OS) of patients starting ADT for metastatic disease. Castration resistance occurs when disease progresses despite testosterone in the castrate range most commonly with or, more rarely, without detectable metastases. The addition of next-generation antiandrogens to ADT has been shown to improve OS in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) identified by a PSA doubling time (DT) ? 10 months. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor without agonist activity. When added to ADT apalutamide has been shown to improve OS by 35 % in patients starting ADT for metastatic prostate cancer both in patients with upfront metastatic disease or after previous treatment with curative intent. Similarly apalutamide has been shown to provide a 14-month OS improvement in patients with nmCRPC and short PSA DT. These OS benefits were obtained at no cost in terms of quality of life. Apalutamide is given orally once a day and is well tolerated. The most common side effects are fatigue, rash, hypertension and hot flushes. Potential interactions with concomitant medication should be taken into account.
Topics: Androgen Antagonists; Androgens; Docetaxel; Gonadotropin-Releasing Hormone; Humans; Ligands; Male; Nonsteroidal Anti-Androgens; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Receptors, Androgen; Testosterone; Thiohydantoins
PubMed: 36226398
DOI: No ID Found -
International Journal of Molecular... Jul 2023Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis... (Review)
Review
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Receptors, Androgen; Signal Transduction; Orchiectomy; Protein Serine-Threonine Kinases
PubMed: 37446279
DOI: 10.3390/ijms241311100