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Diagnostics (Basel, Switzerland) Aug 2023The aim of this systematic review is to provide a comprehensive overview of the role of fluoro-5α-dihydrotestosterone ([F]-FDHT) for the in vivo imaging of androgen... (Review)
Review
The aim of this systematic review is to provide a comprehensive overview of the role of fluoro-5α-dihydrotestosterone ([F]-FDHT) for the in vivo imaging of androgen receptors (AR) through positron emission tomography (PET) in metastatic breast (mBC) and metastatic castration-resistant prostate cancer (mCRPC). Relevant studies published from 2013 up to May 2023 were selected by searching Scopus, PubMed and Web of Science. The selected imaging studies were analyzed using a modified version of the critical Appraisal Skills Programme (CASP). Eleven studies encompassing 321 patients were selected. Seven of the eleven selected papers included 266 subjects (82.2%) affected by mCRPC, while four encompassed 55 (17.2%) patients affected by mBC. [F]-FDHT PET showed a satisfying test/retest reproducibility, and when compared to a histochemical analysis, it provided encouraging results for in vivo AR quantification both in mCRPC and mBC. [F]-FDHT PET had a prognostic relevance in mCRPC patients submitted to AR-targeted therapy, while a clear association between [F]-FDHT uptake and the bicalutamide response was not observed in women affected by AR-positive mBC. Further studies are needed to better define the role of [F]-FDHT PET, alone or in combination with other tracers (i.e., [F]-FDG/[F]-FES), for patients' selection and monitoring during AR-targeted therapy, especially in the case of mBC.
PubMed: 37568977
DOI: 10.3390/diagnostics13152613 -
Cancer Treatment Reviews Nov 2022The current standard of care for the systemic treatment of metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) with either... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The current standard of care for the systemic treatment of metastatic hormone sensitive prostate cancer (mHSPC) includes androgen deprivation therapy (ADT) with either docetaxel or advanced androgen blockage (AAB). Recently, two studies have tested the combination of ADT, docetaxel and AAB (triplet therapy) relative to docetaxel and ADT in this setting. Herein, we aimed to compare the effect on survival outcomes of available systemic treatments for mHSPC.
METHODS
A comprehensive search for all published phase III randomized control trials on first line mHSPC that evaluated AAB (TITAN, ARCHES, STAMPEDE, LATITUDE, ENZAMET) or docetaxel (GETUG-AFU15, CHAARTED, STAMPEDE) or their combination (ARASENS, PEACE-1) was conducted PubMed, EMBASE, Web of Science, and Scopus databases up to 15/04/2022. We reconstructed survival data from published Kaplan-Meier curves on overall survival (OS) and progression free survival (PFS) and meta-analyzed docetaxel versus AAB versus triplet therapy (grouping together abiraterone/darolutamide and docetaxel). The outcomes of interest were assessed using differences in restricted mean survival time (ΔRMST) at different time points and Cox regression.
RESULTS
Ten trials were included involving 5,544 patients for assessing OS and 5,725 for PFS. Triplet therapy was associated with longer OS when compared to docetaxel (48-month ΔRMST: 2.6; 95 %CI: 1.8,3.4; p < 0.001) but yielded similar OS when compared to AAB (48-month ΔRMST: -0.8; 95 % CI: -1.8, 0.2; p = 0.1). Similarly, triplet therapy was associated with longer PFS when compared to docetaxel (48-month ΔRMST: 10.3; 95 %CI: 9.0,11.6; p < 0.001) but yielded similar PFS when compared to AAB (48-month ΔRMST: 1.1; 95 %CI: -0.2,2.3; p = 0.1).
CONCLUSIONS
Overall, we found no OS nor PFS benefit for patients with mHSPC treated with triplet therapy compared to AAB alone, while an advantage emerged for both AAB or triplet therapy relative to docetaxel.
Topics: Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms
PubMed: 35939976
DOI: 10.1016/j.ctrv.2022.102441 -
Cephalalgia : An International Journal... Nov 2010Data on the association between sex hormone receptor polymorphisms and migraine are conflicting. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Data on the association between sex hormone receptor polymorphisms and migraine are conflicting.
METHODS
We performed a systematic review and meta-analysis on this topic searching for studies published until August 2009. For each study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs.
RESULTS AND CONCLUSION
Among the seven genes targeted, four variants were investigated in multiple studies. Effect estimates from an additive model suggest that the ESR-1 594 G>A (pooled OR 1.37; 95% CI 1.02-1.83) and ESR-1 325 C>G (pooled OR 1.16; 95% CI 1.03-1.32) variants are associated with any migraine. This pattern does not differ between migraine with and without aura. In contrast, the ESR-1 Pvu II C>T and PGR PROGINS insert polymorphism do not appear to be associated with migraine. Results were driven by studies among Caucasians and may differ in other ethnic groups.
Topics: Adaptor Proteins, Signal Transducing; Aromatase; Estrogen Receptor alpha; Estrogen Receptor beta; Genetic Predisposition to Disease; Humans; Migraine Disorders; Nuclear Proteins; Nuclear Receptor Interacting Protein 1; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, Androgen; Receptors, FSH; Receptors, Progesterone
PubMed: 20959426
DOI: 10.1177/0333102410364155 -
Journal of Xenobiotics May 2023Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular... (Review)
Review
Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.
PubMed: 37218811
DOI: 10.3390/jox13020017 -
The Journal of Clinical Endocrinology... Dec 2023Despite high abundance of small indels in human genomes, their precise roles and underlying mechanisms of mutagenesis in Mendelian disorders require further...
CONTEXT
Despite high abundance of small indels in human genomes, their precise roles and underlying mechanisms of mutagenesis in Mendelian disorders require further investigation.
OBJECTIVE
To profile the distribution, functional implications, and mechanisms of small indels in the androgen receptor (AR) gene in individuals with androgen insensitivity syndrome (AIS).
METHODS
We conducted a systematic review of previously reported indels within the coding region of the AR gene, including 3 novel indels. Distribution throughout the AR coding region was examined and compared with genomic population data. Additionally, we assessed their impact on the AIS phenotype and investigated potential mechanisms driving their occurrence.
RESULTS
A total of 82 indels in AIS were included. Notably, all frameshift indels exhibited complete AIS. The distribution of indels across the AR gene showed a predominance in the N-terminal domain, most leading to frameshift mutations. Small deletions accounted for 59.7%. Most indels occurred in nonrepetitive sequences, with 15.8% situated within triplet regions. Gene burden analysis demonstrated significant enrichment of frameshift indels in AIS compared with controls (P < .00001), and deletions were overrepresented in AIS (P < .00001).
CONCLUSION
Our findings underscore a robust genotype-phenotype relationship regarding small indels in the AR gene in AIS, with a vast majority presenting complete AIS. Triplet regions and homopolymeric runs emerged as prone loci for small indels within the AR. Most were frameshift indels, with polymerase slippage potentially explaining half of AR indel occurrences. Complex frameshift indels exhibited association with palindromic runs. These discoveries advance understanding of the genetic basis of AIS and shed light on potential mechanisms underlying pathogenic small indel events.
Topics: Humans; Male; Androgen-Insensitivity Syndrome; Genome, Human; Mutagenesis; Mutation; Phenotype; Receptors, Androgen
PubMed: 37572362
DOI: 10.1210/clinem/dgad470 -
Medicine Jun 2017Previous studies have been conducted to reveal the relationship between androgen receptor CAG polymorphism and risk of prostate cancer, yet the results were elusive and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previous studies have been conducted to reveal the relationship between androgen receptor CAG polymorphism and risk of prostate cancer, yet the results were elusive and controversial. Thus, this meta-analysis was performed to clarify this association.
METHODS
To obtain the relevant available studies, online databases PubMed, Embase, and Web of science were searched until September 1st, 2016. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of such association. Subgroup analyses were conducted based on ethnicity and source of controls. Moreover, Begg's funnel plots and Egger's linear regression test were conducted to test the publication bias.
RESULTS
Overall, our results enrolled 51 studies indicated that significant increased risk of prostate cancer was associated with androgen receptor CAG polymorphism (OR = 0.77, 95% CI: 0.67-0.89). In addition, compared with CAG repeat <20, 22, carriers of ≧20, 22 repeats had decreased risk of prostate cancer (cut-off point = 20: OR = 0.27, 95% CI: 0.13-0.52; cut-off point = 22: OR = 0.82, 95% CI: 0.70-0.97). However, when cut-off point = 23, no significant result was detected in such association (pooled OR = 0.88, 95% CI: 0.63-1.24). When cut-off point is 22, the results were positive only in Asian population (OR = 0.53, 95% CI: 0.32-0.89) in the subgroup analysis by ethnicity. Besides, when the studies were stratified by source of controls, the results were not significant in both the subgroup of population-based controls and hospital-based controls.
CONCLUSIONS
This meta-analysis suggested the carriers of short polymorphic CAG repeats might increase susceptibility to prostate cancer, which held potential as a detecting marker of the risk of prostate cancer.
Topics: Genetic Predisposition to Disease; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Trinucleotide Repeat Expansion
PubMed: 28640128
DOI: 10.1097/MD.0000000000007258 -
Translational Oncology Sep 2021Studies have shown that AR-V7 may be correlated with the poor prognosis of castration resistant prostate cancer (CRPC), however, clinicopathological characteristics...
Clinicopathological characteristics of androgen receptor splicing variant 7 (AR-V7) expression in patients with castration resistant prostate cancer: A systematic review and meta-analysis.
BACKGROUND
Studies have shown that AR-V7 may be correlated with the poor prognosis of castration resistant prostate cancer (CRPC), however, clinicopathological characteristics of AR-V7 have not been fully elucidated.
OBJECTIVE
This study aimed at evaluating the clinicopathological features of AR-V7 in CRPC patients.
MATERIALS AND METHODS
To evaluate the clinicopathological features of AR-V7 in CRPC patients. A search of PubMed, Embase, and Web of Science was performed using the keywords prostate cancer, prostate tumor, prostate neoplasm, prostate carcinoma, AR-V7, AR3, androgen receptor splicing variant-7, or androgen receptor-3. Twenty-four trials published by February 2020 were included in this study.
RESULTS
The proportion of Gleason score ≥ 8 was found to be significantly higher in AR-V7-positive CRPC (69.5%) than negative (54.9%) (OR 1.68, 95% CI 1.25-2.25, p < 0.001), while the rates of T3/T4 stage (OR 1.16, 95% CI 0.60-2.24, p = 0.65) and N1 stage (OR 0.99, 95% CI 0.65-1.51, p = 0.96) were not statistically correlated with AR-V7 status. The AR-V7-positive patients exhibited a significantly higher proportion of any site metastasis (61.3% versus 35.0%; OR 2.19, 95% CI 1.57-3.05, p < 0.001) and bone metastasis (81.7% versus 69.0%; OR 1.97, 95% CI 1.44-2.69, p < 0.001), and a trend close to significance was expected in visceral metastasis (28.8% versus 22.1%; OR 1.29, 95% CI 0.96-1.74, p = 0.09). Incidences of pain in AR-V7-positive CRPC (54.6%) were significantly higher than in negative CRPC (28.1%; OR 4.23, 95% CI 2.52-7.10, p < 0.001), line with worse ECOG performance status (56.7% versus 35.0%, OR 2.18, 95% CI 1.51-3.16, P < 0.001). Limitations of the study include differences in sample sizes and designs, AR-V7 detection assays, as well as disease characteristics of the included studies.
CONCLUSIONS
AR-V7 positivity is associated with a higher Gleason score, bone or any site metastasis, pain and worse ECOG performance scores in CRPC. However, it is not correlated with tumor stage or lymph node metastasis. More studies are needed to confirm these findings.
PubMed: 34130051
DOI: 10.1016/j.tranon.2021.101145 -
Frontiers in Oncology 2020The prognostic value of androgen receptor splice variant 7 (AR-V7) for the treatment response of metastatic castration-resistant prostate cancer (mCRPC) remains unclear....
BACKGROUND
The prognostic value of androgen receptor splice variant 7 (AR-V7) for the treatment response of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we aimed to synthesize relevant studies that assessed the prognostic value of AR-V7 status for the treatment response of mCRPC patients treated with androgen receptor signalling inhibitors (ARSis) and chemotherapy.
METHODS
We searched the PubMed, Embase, and MEDLINE databases by using the keywords and to identify relevant studies published before 25 September 2019. The main outcomes were prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS). Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.
RESULTS
A total of 1,545 patients from 21 studies were included. For the mCRPC patients treated with ARSis, AR-V7-positive patients had a lower PSA response rate (OR 6.01, 95% CI 2.88-12.51; < 0.001), shorter PFS (HR 2.56, 95% CI 1.80-3.64; < 0.001) and shorter OS (HR 4.28, 95% CI 2.92-6.27; < 0.001) than AR-V7-negative patients. Although AR-V7-positive patients treated with chemotherapy also had a lower PSA response rate (OR 2.23, 95% CI 1.38-3.62; = 0.001) and shorter OS than AR-V7-negative patients (HR 1.60, 95% CI 1.02-2.53; = 0.043), there was no significant difference in PFS (HR 1.05, 95% CI 0.74-1.49; = 0.796) between these groups. Furthermore, AR-V7-positive patients receiving ARSis had a shorter median OS than those receiving chemotherapy (HR 3.50, 95% CI 1.98-6.20; < 0.001); There was no significant difference among AR-V7-negative patients (HR 1.30, 95% CI 0.64-2.62; = 0.47).
CONCLUSIONS
AR-V7 is a potential biomarker of treatment resistance in mCRPC patients. AR-V7-positive mCRPC patients had poorer treatment outcomes than AR-V7-nagetive patients when treated with ARSis. AR-V7-positive patients have better outcomes when treated with taxane than ARSis. Furthermore, the ability of AR-V7 status to predict treatment outcomes varies from different detection methods. The detection of AR-V7 before treatment is important for the selection of treatment modalities for mCRPC patients.
PubMed: 33330031
DOI: 10.3389/fonc.2020.562504 -
Frontiers in Oncology 2020This study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival...
The Prognostic Value of Androgen Receptor Splice Variant 7 in Castration-Resistant Prostate Cancer Treated With Novel Hormonal Therapy or Chemotherapy: A Systematic Review and Meta-analysis.
PURPOSE
This study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) in CRPC patients treated with novel hormonal therapy (NHT) (Abiraterone and Enzalutamide) or taxane-based chemotherapy (Docetaxel and Cabazitaxel).
METHODS
A comprehensive literature search was conducted on PubMed, Embase, and the Web of Science from inception to February 2020. Studies focusing on the prognostic values of AR-V7 in CRPC patients treated with NHT or chemotherapy were included in our meta-analysis. The OS and PFS were analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for the AR-V7 conversion after treatment and the PSA response.
RESULTS
The AR-V7 positive proportion increased significantly after NHT treatment (OR 2.56, 95% CI 1.51-4.32, P<0.001), however, it declined after chemotherapy (OR 0.51, 95% CI 0.28-0.93, P=0.003). AR-V7-positive patients showed a significantly decreased PSA response rate after NHT (OR 0.13, 95% CI 0.09-0.19, P<0.001) but not statistically significant for chemotherapy (OR 0.63, 95% CI 0.40-1.01, P=0.06). Notably, PFS (HR 3.56, 95% CI 2.53-5.01, P<0.001) and OS (HR 4.47, 95% CI 3.03-6.59, P<0.001) were worse in AR-V7-positive ttreated with NHT. Similarly, AR-V7 positivity correlated with poor prognosis after chemotherapy as evidenced by shorter OS (HR 1.98, 95% CI 1.48-2.66, P<0.001) and a significantly shorter PFS (HR 1.35, 95% CI 0.97-1.87, P=0.07).
CONCLUSION
NHT treatment increased AR-V7 positive proportion whereas chemotherapy decreased it. Moreover, AR-V7 positivity correlated with lower PSA response, poorer PFS, and OS in CRPC treated with NHT, and shorter OS in patients receiving chemotherapy.
PubMed: 33425724
DOI: 10.3389/fonc.2020.572590 -
The Journal of Sexual Medicine Mar 2020It has been hypothesized that gender incongruence in transgender women could result from an antenatal impaired androgen activity on the developing brain. As the length... (Meta-Analysis)
Meta-Analysis
Polymorphic Cytosine-Adenine-Guanine Repeat Length of Androgen Receptor Gene and Gender Incongruence in Trans Women: A Systematic Review and Meta-Analysis of Case-Control Studies.
INTRODUCTION
It has been hypothesized that gender incongruence in transgender women could result from an antenatal impaired androgen activity on the developing brain. As the length of polymorphic cytosine-adenine-guanine (CAG) repeat sequences in the androgen receptor (AR) gene is inversely correlated with AR transcriptional activity, some studies explored a possible association between long CAG repeats and gender incongruence in trangender women. Yet results remain inconclusive.
AIM
To systematically evaluate whether a difference exists in the length of AR CAG repeat sequences between trans women and men without gender incongruence.
METHODS
A thorough search of Medline, Scopus, Cochrane Library, Web of Science, and CINAHL databases was carried out to identify suitable case-control studies. Methodological quality of the included articles was assessed using the Newcastle-Ottawa Scale. In the absence of between-studies heterogeneity, as assessed by the Cochrane's Q and I tests, standardized mean differences (SMDs) in the length of AR CAG repeats were combined using a fixed effect model. Funnel plot and trim-and-fill analysis were used to assess publication bias.
MAIN OUTCOME MEASURE
The association of gender incongruence in transgender women with longer length of AR CAG repeat sequences was evaluated by calculating pooled standardized mean difference with 95% confidence interval (CI).
RESULTS
5 studies included in the quantitative analysis collectively provided information on 795 trans women and 1,355 control men. At the overall estimate, the MtF group exhibited a significantly longer length of AR CAG repeat sequences (pooled standardized mean difference: 0.13, 95% CI: 0.04 to 0.22; P = 0.005; I = 0%, P = 0.51). Sensitivity analysis demonstrated the high stability of the result. Funnel plot revealed a possible publication bias, and the trim-and-fill test detected 2 putative missing studies. Nevertheless, the significant association persisted even when pooled estimate was adjusted for publication bias.
CLINICAL IMPLICATIONS
These findings could suggest a contribution of a genetically mediated impairment in androgen signaling in development of gender incongruence for transgender women.
STRENGTH & LIMITATIONS
This is the first meta-analysis exploring the relationship between AR CAG repeat polymorphism and gender incongruence. However, interactions with other functional genetic variants were not explored, and caution should be exercised when generalizing these results because of the possible variability in the distribution of CAG repeats among different populations and ethnic groups.
CONCLUSION
Trans woman population exhibits significantly longer polymorphic CAG repeat sequences in the AR gene. Further studies are warranted to elucidate whether, how and to what extent multiple functional variants in sex hormone signaling genes could be associated with gender incongruence/dysphoria. D'Andrea S, Pallotti F, Senofonte G, et al. Polymorphic Cytosine-Adenine-Guanine Repeat Length of Androgen Receptor Gene and Gender Incongruence in Trans Women: A Systematic Review and Meta-Analysis of Case-Control Studies. J Sex Med 2020;17:543-550.
Topics: Adenine; Case-Control Studies; Cytosine; Female; Guanine; Humans; Male; Polymorphism, Genetic; Pregnancy; Receptors, Androgen; Signal Transduction; Transgender Persons; Trinucleotide Repeats
PubMed: 31926901
DOI: 10.1016/j.jsxm.2019.12.010