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Urology Practice Nov 2023Hormonal therapy is the standard of care in prostate cancer treatment. The approval of the first oral androgen deprivation therapy, relugolix, to treat prostate cancer... (Review)
Review
INTRODUCTION
Hormonal therapy is the standard of care in prostate cancer treatment. The approval of the first oral androgen deprivation therapy, relugolix, to treat prostate cancer patients provides an opportunity to review adherence to oral and injectable/implantable hormonal therapies to aid patients and physicians in making informed decisions.
METHODS
A PubMed search for available literature on adherence to hormonal therapy in prostate cancer was conducted, including published data on relugolix.
RESULTS
Adherence to oral antiandrogen therapy was above 90% by medication possession ratio in several studies worldwide and from 75% to 91% by proportion of days covered. For injectable/implantable androgen deprivation therapy, adherence to treatment ranged from 71% to 95%. In general, 60% and 29% of injections were reported to be delayed by more than 1 week and 2 weeks, respectively, with some patients experiencing testosterone increases (tests above 50 ng/dL). Although real-world data on adherence to relugolix are currently unavailable, pharmacokinetic/pharmacodynamics models demonstrated that, if necessary, treatment interruption up to 7 days would still maintain testosterone suppression levels.
CONCLUSIONS
In general, adherence to hormonal therapy is high in prostate cancer. Studies revealed that adherence to injectable androgen deprivation therapy dosing schedules is important to maintain castrate levels. Pharmacokinetic/pharmacodynamics models showed that relugolix treatment interruption up to 7 days had minimal impact on testosterone suppression levels.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Prostate-Specific Antigen; Antineoplastic Agents, Hormonal; Testosterone
PubMed: 37647139
DOI: 10.1097/UPJ.0000000000000445 -
Exercise and Sport Sciences Reviews Oct 2023A prominent toxicity of androgen suppression in patients with prostate cancer (PCa) is loss of skeletal muscle. Exercise may induce tumor suppression through the... (Review)
Review
A prominent toxicity of androgen suppression in patients with prostate cancer (PCa) is loss of skeletal muscle. Exercise may induce tumor suppression through the endocrinal function of skeletal muscle; however, this is currently unknown. In this review, we summarize our work demonstrating the acute and chronic myokine response to exercise and the tumor-suppressive effect of circulatory milieu alteration in PCa patients.
Topics: Male; Humans; Androgens; Exercise; Muscle, Skeletal; Prostatic Neoplasms
PubMed: 37288965
DOI: 10.1249/JES.0000000000000323 -
Communications Biology Sep 2023Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy...
Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve radiotherapy response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1α suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with radiotherapy.
Topics: Humans; Male; Canagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Prostatic Neoplasms; Heart Failure; Mitochondria
PubMed: 37684337
DOI: 10.1038/s42003-023-05289-w -
Journal of Cell Communication and... Sep 2023Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is... (Review)
Review
Urological cancers have obtained much attention in recent years due to their mortality and morbidity. The most common and malignant tumor of urological cancers is prostate cancer that imposes high socioeconomic costs on public life and androgen-deprivation therapy, surgery, and combination of chemotherapy and radiotherapy are employed in its treatment. PI3K/Akt signaling is an oncogenic pathway responsible for migration, proliferation and drug resistance in various cancers. In the present review, the role of PI3K/Akt signaling in prostate cancer progression is highlighted. The activation of PI3K/Akt signaling occurs in prostate cancer, while PTEN as inhibitor of PI3K/Akt shows down-regulation. Stimulation of PI3K/Akt signaling promotes survival of prostate tumor cells and prevents apoptosis. The cell cycle progression and proliferation rate of prostate tumor cells increase by PI3K/Akt signaling induction. PI3K/Akt signaling stimulates EMT and enhances metastasis of prostate tumor cells. Silencing PI3K/Akt signaling impairs growth and metastasis of prostate tumor cells. Activation of PI3K/Akt signaling mediates drug resistance and reduces radio-sensitivity of prostate tumor cells. Anti-tumor compounds suppress PI3K/Akt signaling in impairing prostate tumor progression. Furthermore, upstream regulators such as miRNAs, lncRNAs and circRNAs regulate PI3K/Akt signaling and it has clinical implications for prostate cancer patients.
PubMed: 36367667
DOI: 10.1007/s12079-022-00702-1 -
Journal of Ovarian Research Jul 2023Excessive production of androgen drives oxidative stress (OS) and inflammasome activation in ovarian granulosa cells (GCs). Therefore, the induced follicular...
BACKGROUND
Excessive production of androgen drives oxidative stress (OS) and inflammasome activation in ovarian granulosa cells (GCs). Therefore, the induced follicular developmental disorder is the major cause of infertility in women with polycystic ovary syndrome (PCOS). Exercise-induced upregulation of irisin is capable of regulating metabolism by reducing OS and inflammation. Exercise has been shown to alleviate a range of PCOS symptoms, including maintaining a normal menstrual cycle, in several clinical trials.
METHODS
Female Sprague-Dawley (SD) rats and primary ovarian cells were treated with two different androgens, dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), to simulate a hyperandrogenic environment, followed by eight weeks of exercise training and irisin intervention. The levels of reactive oxygen species (ROS), tissue inflammation and fibrosis were examined using hematoxylin and eosin (H&E) staining, western blot, quantitative real-time PCR (qRT-PCR), dichlorofluorescein diacetate (DCF-DA) probe detection, immunofluorescence staining, immunohistochemistry, and Sirius red staining.
RESULTS
Exercise for eight weeks improved polycystic ovarian morphology and decreased the levels of inflammation, OS, and fibrosis in PCOS rats. Hyperandrogen increased ROS production in ovarian cells by inducing endoplasmic reticulum stress (ERS) and activating the inositol-requiring enzyme 1α (IRE1α)-thioredoxin-interacting protein (TXNIP)/ROS-NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway, further enhancing the levels of inflammation. Irisin suppressed the expression of IRE1α and its downstream targets, thus improving the ovarian dysfunction of PCOS rats induced by hyperandrogen.
CONCLUSION
Exercise can alleviate various phenotypes of PCOS rats induced by DHEA, and its therapeutic effect may be mediated by secreting beneficial myokines. IRE1α may be an important target of irisin for reducing OS and inflammation, thereby improving ovarian fibrosis.
Topics: Humans; Rats; Female; Animals; Polycystic Ovary Syndrome; Reactive Oxygen Species; NLR Family, Pyrin Domain-Containing 3 Protein; Endoribonucleases; Fibronectins; Rats, Sprague-Dawley; Protein Serine-Threonine Kinases; Inflammation; Fibrosis; Dehydroepiandrosterone; Carrier Proteins; Cell Cycle Proteins
PubMed: 37525261
DOI: 10.1186/s13048-023-01242-x -
The Journal of Clinical Endocrinology... Oct 2023Serum insulin-like factor 3 (INSL3) is a Leydig cell biomarker, but little is known about the circulating concentration of INSL3 during hypothalamus-pituitary-testicular... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Serum insulin-like factor 3 (INSL3) is a Leydig cell biomarker, but little is known about the circulating concentration of INSL3 during hypothalamus-pituitary-testicular suppression.
AIM
To study the concomitant changes in serum concentrations of INSL3, testosterone, and LH during experimental and therapeutic testicular suppression.
METHODS
We included serum samples from 3 different cohorts comprising subjects before and after testicular suppression: (1) 6 healthy young men who were treated with androgens (Sustanon, Aspen Pharma, Dublin, Ireland); 2) 10 transgender girls (male sex assigned at birth) who were treated with 3-monthly GnRH agonist injections (Leuprorelinacetat, Abacus Medicine, Copenhagen, Denmark); and (3) 55 patients with prostate cancer who were randomized to surgical castration (bilateral subcapsular orchiectomy) or treatment with GnRH agonist (Triptorelin, Ipsen Pharma, Kista, Sweden). Serum INSL3 and testosterone concentrations were quantified in stored serum samples using validated liquid chromatography-tandem mass spectrometry methodologies, and LH was measured by an ultrasensitive immunoassay.
RESULTS
The circulating concentrations of INSL3, testosterone, and LH decreased during experimental testicular suppression in healthy young men by Sustanon injections and subsequently returned to baseline levels after release of suppression. All 3 hormones decreased during therapeutic hormonal hypothalamus-pituitary-testicular suppression in transgender girls and in patients with prostate cancer.
CONCLUSION
INSL3 resembles testosterone as a sensitive marker of testicular suppression and reflects Leydig cell function, also during exposure to exogenous testosterone. Serum INSL3 measurements may complement testosterone as a Leydig cell marker in male reproductive disorders, during therapeutic testicular suppression as well as in surveillance of illicit use of androgens.
Topics: Humans; Infant, Newborn; Male; Androgens; Gonadotropin-Releasing Hormone; Insulin; Leydig Cells; Prostatic Neoplasms; Proteins; Testis; Testosterone; Luteinizing Hormone
PubMed: 37235781
DOI: 10.1210/clinem/dgad291 -
Proceedings of the National Academy of... Aug 2023Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in...
Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.
Topics: Male; Humans; Histones; Prostatic Neoplasms, Castration-Resistant; Lysine; Receptors, Androgen; Methyltransferases; Histone Demethylases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase; Hepatocyte Nuclear Factor 3-alpha
PubMed: 37549269
DOI: 10.1073/pnas.2220472120 -
Drug Design, Development and Therapy 2023To investigate the mechanism of minoxidil in treating androgenetic alopecia (AGA).
OBJECTIVE
To investigate the mechanism of minoxidil in treating androgenetic alopecia (AGA).
METHODS
The mechanism of action of minoxidil on AGA was first systematically investigated from the viewpoint of network pharmacology, including minoxidil-AGA target prediction, protein-protein interaction (PPI) network analysis, molecular docking and enrichment analysis of targets related to minoxidil and AGA, and dermal papilla cell assays to confirm the viability of prediction.
RESULTS
The combined analysis revealed that minoxidil treatment of AGA not only acts on androgenic receptors (AR) but also on 2 new targets, steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1) and aromatase (CYP19A1). The biological processes linked to these targets were concentrated on several pathways, including enzymes and hormones. Further experiments have revealed that minoxidil suppresses the expression of AR and CYP17A1, boosts the activity of CYP19A1, decreases the formation and binding of dihydrotestosterone, and enhances the production of estradiol. Through these changes, minoxidil acts as a treatment for AGA.
CONCLUSION
Minoxidil may act by altering hormonal and enzymatic pathways. Our study finds two new targets (CYP17A1, CYP19A1) of minoxidil and demonstrates that minoxidil inhibits AR. These targets may provide new ideas for drug research.
Topics: Humans; Minoxidil; Molecular Docking Simulation; Alopecia; Dietary Supplements; Estradiol
PubMed: 37645625
DOI: 10.2147/DDDT.S427612 -
FP Essentials Aug 2023Approximately 0.6% of adults (1 to 1.4 million adults) in the United States identify as transgender, and 2% of high school-aged individuals (150,000 to 300,000...
Approximately 0.6% of adults (1 to 1.4 million adults) in the United States identify as transgender, and 2% of high school-aged individuals (150,000 to 300,000 individuals). Gender-affirming care for transgender and gender- diverse patients can include support with social transition or physical presentation, legal steps, and medical treatments (eg, hormone therapy) and surgeries. Adolescent and adult patients who request gender-affirming hormone therapy must meet several criteria. One is confirmed persistence of gender dysphoria or gender incongruence. Also, the patient must have reached the age of legal medical consent and be able to consent to therapy. For adolescent patients who are minors, meeting of additional criteria is recommended. In eligible adolescent patients, gender-affirming hormone therapy consists of two phases, pubertal suppression and then feminizing or masculinizing hormone therapy. Before puberty, hormone therapy is not recommended. When puberty begins, patients can receive a gonadotropin-releasing hormone agonist to suppress puberty (ie, puberty blocker). Feminizing or masculinizing hormone therapy, which usually is initiated at age 16 years, consists of estradiol or testosterone, respectively. For adult patients requesting gender-affirming hormone therapy, a thorough evaluation should be performed to assess for contraindications and conditions that may increase therapy-associated risks. Feminizing hormone therapy includes estrogen and an antiandrogen, and masculinizing therapy consists of testosterone. These patients should undergo regular monitoring. Cancer screening is based on risk factors, organ inventory, and screening guidelines.
Topics: Adolescent; Adult; Humans; Child; Testosterone; Physical Examination; Risk Factors; Schools
PubMed: 37603883
DOI: No ID Found