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Scientific Reports Jan 2024Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels...
Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects.
Topics: Pregnancy; Humans; Mice; Female; Animals; Polycystic Ovary Syndrome; Androgens; Adiponectin; Anti-Anxiety Agents; Anxiety; Prenatal Exposure Delayed Effects
PubMed: 38177175
DOI: 10.1038/s41598-023-50503-8 -
Neuroscience and Biobehavioral Reviews Feb 2024Circulating testosterone is easily aromatized to estradiol and reduced to dihydrotestosterone in target tissues and elsewhere in the body. Thus, the actions of... (Review)
Review
Circulating testosterone is easily aromatized to estradiol and reduced to dihydrotestosterone in target tissues and elsewhere in the body. Thus, the actions of testosterone can be mediated either by the estrogen receptors, the androgen receptor or by simultaneous action at both receptors. To determine the role of androgens acting at the androgen receptor, we need to eliminate actions at the estrogen receptors. Alternatively, actions at the androgen receptor itself can be eliminated. In the present review, I will analyze the specific role of androgen receptors in male and female sexual behavior as well as in aggression. Some comments about androgen receptors and social recognition are also made. It will be shown that there are important differences between species, even between strains within a species, concerning the actions of the androgen receptor on the behaviors mentioned. This fact makes generalizations from one species to another or from one strain to another very risky. The existence of important species differences is often ignored, leading to many misunderstandings and much confusion.
Topics: Humans; Animals; Male; Female; Receptors, Androgen; Androgens; Testosterone; Estradiol; Receptors, Estrogen; Mammals
PubMed: 38176634
DOI: 10.1016/j.neubiorev.2023.105530 -
Journal of the Endocrine Society Dec 2023Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major...
CONTEXT
Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure.
OBJECTIVE
We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS.
METHODS
In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms.
RESULTS
We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated , which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues.
CONCLUSION
We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice.
PubMed: 38169733
DOI: 10.1210/jendso/bvad162 -
Animals : An Open Access Journal From... Dec 2023BPH is the most prevalent prostatic condition in aging dogs. Nevertheless, clinical diagnosis and management remain inconsistent. This study employed in-solution...
BPH is the most prevalent prostatic condition in aging dogs. Nevertheless, clinical diagnosis and management remain inconsistent. This study employed in-solution digestion coupled with nano-liquid chromatography tandem mass spectrometry to assess serum proteome profiling of dogs with BPH and those dogs after castration. Male dogs were divided into two groups; control and BPH groups. In the BPH group, each dog was evaluated at two time points: Day 0 (BF subgroup) and Day 30 after castration (AT subgroup). In the BF subgroup, three proteins were significantly upregulated and associated with dihydrotestosterone: solute carrier family 5 member 5, tyrosine-protein kinase, and FRAT regulator of WNT signaling pathway 1. Additionally, the overexpression of polymeric immunoglobulin receptors in the BF subgroup hints at its potential as a novel protein linked to the BPH development process. Conversely, alpha-1-B glycoprotein (A1BG) displayed significant downregulation in the BF subgroup, suggesting A1BG's potential as a predictive protein for canine BPH. Finasteride was associated with increased proteins in the AT subgroup, including apolipoprotein C-I, apolipoprotein E, apolipoprotein A-II, TAO kinase 1, DnaJ homolog subfamily C member 16, PH domain and leucine-rich repeat protein phosphatase 1, neuregulin 1, and pseudopodium enriched atypical kinase 1. In conclusion, this pilot study highlighted alterations in various serum proteins in canine BPH, reflecting different pathological changes occurring in this condition. These proteins could be a source of potential non-invasive biomarkers for diagnosing this disease.
PubMed: 38136890
DOI: 10.3390/ani13243853 -
Advanced Science (Weinheim,... Mar 2024Treatment of castration-resistant prostate cancer (CRPC) is a long-standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone...
Treatment of castration-resistant prostate cancer (CRPC) is a long-standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone biosynthesis or blocking androgen receptor (AR) signaling. Here it is demonstrated that AR inhibitor treatment gives rise to a drug-tolerant persister (DTP) state. The thioredoxin/peroxiredoxin pathway is up-regulated in DTP cells. Peroxiredoxin 5 (PRDX5) promotes AR inhibitor resistance and CRPC development. Inhibition of PRDX5 suppresses DTP cell proliferation in culture, dampens CRPC development in animal models, and stabilizes PSA progression and metastatic lesions in patients. Therefore, the study provides a novel mechanism and potential target for the management of castration-resistant prostate cancer.
Topics: Male; Animals; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Peroxiredoxins; Signal Transduction
PubMed: 38115765
DOI: 10.1002/advs.202304939 -
The Journal of Steroid Biochemistry and... Feb 2024Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and...
Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and activation despite systemic androgen deprivation therapy underlies the development of castration-resistant PC (CRPC), but the precise pathways involved remain controversial. Here we investigated the differential contributions of de novo androgen biosynthesis and androgen precursor conversion to androgen accumulation. Steroid flux analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on (CR)PC cell lines and fresh patient PC tissue slices after incubation with classic and alternative biosynthesis intermediates, alongside quantitative PCR analysis for steroidogenic enzyme expression. Activity of CYP17A1 was undetectable in all PC cell lines and patient PC tissue slices. Instead, steroid flux analysis confirmed the generation of testosterone and DHT from adrenal precursors and reactivation of androgen metabolites. Precursor steroids upstream of DHEA were converted down the first steps of the alternative DHT biosynthesis pathway, but did not proceed through to active androgen generation. Comprehensive steroid flux analysis of (CR)PC cells provides strong evidence against intratumoral de novo androgen biosynthesis and demonstrates that androgen precursor steroids downstream of CYP17A1 activities constitute the major source of intracrine androgen generation.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Androgen Antagonists; Chromatography, Liquid; Tandem Mass Spectrometry; Testosterone; Dihydrotestosterone; Receptors, Androgen; Steroids; Cell Line, Tumor; Steroid 17-alpha-Hydroxylase
PubMed: 38104728
DOI: 10.1016/j.jsbmb.2023.106446 -
Trials Dec 2023Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen...
Induction of double-strand breaks with the non-steroidal androgen receptor ligand flutamide in patients on androgen suppression: a study protocol for a randomized, double-blind prospective trial.
BACKGROUND
Prostate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans.
METHODS
Patients with newly diagnosed, biopsy-confirmed localized prostatic adenocarcinoma will be recruited. Flutamide, an oral non-steroidal androgen receptor ligand, will be administered orally 6-12 h prior to prostate biopsy (performed under anesthesia prior to brachytherapy seed implantation). Key study parameters will include the assessment of DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either flutamide intervention or placebo standard-of-care (with all patients receiving definitive brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of cancer cells positive and number of foci per cancer cell) is greater in patients receiving flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe cancer-specific methylation patterns of cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as a DNA-based biomarker for tracking therapeutic response.
DISCUSSION
This study will confirm in humans the pharmacodynamic effect of AR ligands to induce transient double-strand breaks when administered in the context of androgen deprivation as a novel therapy for prostate cancer. The findings of this study will permit the development of a larger trial evaluating flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/- brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018.
Topics: Male; Humans; Flutamide; Androgens; Prostatic Neoplasms; Androgen Antagonists; Receptors, Androgen; Ligands; Prospective Studies; Treatment Outcome; DNA; Randomized Controlled Trials as Topic
PubMed: 38104131
DOI: 10.1186/s13063-023-07838-4 -
Frontiers in Endocrinology 2023We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable...
BACKGROUND
We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets.
METHODOLOGY
Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).
RESULTS
Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that (l2fc<-1.5) and related genes - (l2fc<-5.5), (l2fc<-4.1) and (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively.
OUTCOME
This therapeutic effect was independent of the actions of ACTH, postulating a promising application of activation in endogenous hypercortisolism.
Topics: Humans; Adrenalectomy; Cushing Syndrome; Hydrocortisone; Hyperplasia; PPAR gamma
PubMed: 38098864
DOI: 10.3389/fendo.2023.1265794 -
ACS Omega Dec 2023The enzyme steroid type II 5-alpha-reductase (SRD5α2) is responsible for the conversion of testosterone to dihydrotestosterone (DHT), which is involved in prostate...
The enzyme steroid type II 5-alpha-reductase (SRD5α2) is responsible for the conversion of testosterone to dihydrotestosterone (DHT), which is involved in prostate cancer, benign prostatic hyperplasia, and androgenic alopecia. Inhibition of SRD5α2 activity has been explored and presented as a potential treatment for these conditions, but current drugs have side effects and alternative treatment approaches are needed. The CRISPR/Cas9 system, an innovative gene-editing tool, shows potential for targeting the SRD5α2 gene knockout as a therapeutic approach. Liposomes have been used for the immobilization and delivery of different proteins, and studies have shown that liposomes can enhance the stability and activity of enzymes. In this study, we provided the immobilization of Cas9 protein by encapsulating it in a novel cationic liposome formulation that carries sgRNA on its outer surface for gene delivery approaches. This novel delivery system has shown promising results in terms of physicochemical properties, stability, cytotoxicity, cellular uptake, and gene knockout efficiency, together with providing flexibility in sgRNA selection. The optimized final formulations showed an average diameter of 229.1 ± 3.66 nm, a polydispersity index of 0.089 ± 0.013, and a zeta potential value of 25.7 ± 0.87 mV. The encapsulation efficiency of the developed formulations has been revealed as 80.60%. The cellular uptake efficiency was evaluated and measured as 45.6% for the final formulation. Furthermore, the Lipo/Cas9:sgRNA (1.5:1) formulation decreased the relative SRD5α2 mRNA expression by 29.7% compared to the control group. The results of this study reveal that the liposomal formulation based on enzyme immobilization of Cas9 protein using CRISPR technology, an innovative gene-editing tool for SRD5α2 suppression, might be an alternative treatment option for prostate cancer or BPH treatment without current drug side effects.
PubMed: 38075788
DOI: 10.1021/acsomega.3c07138 -
Cureus Nov 2023Prostate cancer is the second most frequently diagnosed cancer among men worldwide, and it represents a substantial worldwide health issue, primarily impacting men as... (Review)
Review
Prostate cancer is the second most frequently diagnosed cancer among men worldwide, and it represents a substantial worldwide health issue, primarily impacting men as they grow older. Understanding its epidemiology and etiology is crucial for crafting efficient preventive measures and enhancing treatment results. The epidemiology of this disease provides valuable insights into its prevalence and distribution. Age is a critical factor, with the risk of prostate cancer increasing with advancing years. Incidence rates are notably higher in developed countries, suggesting a role for lifestyle and environmental factors. Furthermore, there are significant racial and geographical disparities in prostate cancer incidence, with African-American men experiencing both a higher incidence and more aggressive forms of the disease. On the other hand, hormones, especially testosterone and its conversion to dihydrotestosterone (DHT), contribute to prostate cell growth and, potentially, cancer. Genetics also plays a pivotal role, with certain gene mutations, like Breast Cancer gene 1 & 2 (BRCA1 and BRCA2), elevating risk. Dietary habits and lifestyle choices influence susceptibility, with diets low in fruits and vegetables and high in saturated fats linked to higher risk. Chronic inflammation, often tied to prostatitis, may further increase susceptibility to prostate cancer. This review article explores the complex realm of prostate cancer, providing insights into its occurrence, factors that elevate risks, and the fundamental factors that play a role in its emergence and how we can prevent it.
PubMed: 38054148
DOI: 10.7759/cureus.48252