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Reproductive Sciences (Thousand Oaks,... Jun 2024Atrazine (ATZ, CHClN) is a widely used synthetic herbicide that contaminates drinking water. It is a known endocrine disruptor that disrupts various molecular pathways...
Atrazine (ATZ, CHClN) is a widely used synthetic herbicide that contaminates drinking water. It is a known endocrine disruptor that disrupts various molecular pathways involved in hormone signaling, and DNA damage, and can cause reproductive disorders, including decreased fertility, and abnormal development of reproductive organs, as revealed in animal model studies. However, the effect of ATZ on steroidogenesis in the male reproductive system, especially reduction of ketosteroids to hydroxysteroids, remains unclear. This study investigated the toxicity of ATZ on the male reproductive system in the Wistar rat model, with an emphasis on its adverse effect on aldo-ketoreductase family 1 member C2 (AKR1C2). Male Wistar rats were administered ATZ for 56 days (duration of one spermatogenic cycle) through oral route, at 20, 40 and 60 mg/kg body weight (bw) doses. The results indicate that ATZ exposure affects the body weight, impairs sperm production, and decrease FSH, LH, and testosterone levels. Additionally, the down-regulation of key steroidogenic enzymes by ATZ disrupted the synthesis of testosterone, leading to decreased levels of this essential male hormone. On the other hand, the expression of AKR1C2 (mRNA and protein) in the testis was upregulated. The findings suggest that AKR1C2 plays a role in androgen metabolism. Furthermore, its overexpression may lead to alteration in the expression of genes in the connected pathway, causing an increase in the breakdown or inactivation of androgens, which would result in lower androgen levels and, thereby, lead to hypoandrogenism, as the combined effects of down-regulation of steroidogenic genes and up-regulation of AKR1C2. These findings reveal direct implication of disrupted AKR1C2 in male reproductive health and highlight the need for further research on the impact of environmental toxins on human fertility, ultimately providing for better patient care.
PubMed: 38943029
DOI: 10.1007/s43032-024-01627-3 -
European Journal of Nuclear Medicine... Jun 2024Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal...
Whole pelvis vs. hemi pelvis elective nodal radiotherapy in patients with PSMA-positive nodal recurrence after radical prostatectomy - a retrospective multi-institutional propensity score analysis.
PURPOSE
Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT.
METHODS
A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test.
RESULTS
Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p = .97), MFS (p = .43) and NRFS (p = .43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis.
CONCLUSIONS
Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity.
PubMed: 38940843
DOI: 10.1007/s00259-024-06802-x -
Science China. Life Sciences Jun 2024
PubMed: 38940831
DOI: 10.1007/s11427-024-2652-y -
Clinical Cancer Research : An Official... Jun 2024To assess efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive, unresectable or recurrent/metastatic salivary gland carcinoma (URM-SGC).
PURPOSE
To assess efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive, unresectable or recurrent/metastatic salivary gland carcinoma (URM-SGC).
PATIENTS AND METHODS
This was an open-label, single-arm, multicenter phase II study for patients with AR-positive URM-SGC. The primary endpoint was the overall response rate (ORR) by an independent central radiology review (ICRR) in the first 24 response evaluable patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded.
RESULTS
31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by ICRR was 25.0% (6/24 patients; 95%CI: 9.8%-46.7%; P =0.11 (one-sided)), which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR-positivity ≥ 70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain.
CONCLUSIONS
Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive SGC and safety consistent with prior experience in prostate cancer.
PubMed: 38940667
DOI: 10.1158/1078-0432.CCR-24-0455 -
The European Journal of Contraception &... Jun 2024To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users.
PURPOSE
To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users.
MATERIALS AND METHODS
Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg.
RESULTS
The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment ( < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (-4.45%, < 0.0001) and DHEAS (-19.41%, < 0.0001) serum levels.
CONCLUSIONS
Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels.
PubMed: 38940613
DOI: 10.1080/13625187.2024.2369833 -
BJU International Jun 2024To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the...
Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study: ultralow prostate-specific antigen decline with apalutamide plus androgen-deprivation therapy.
OBJECTIVE
To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC).
PATIENTS AND METHODS
Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used.
RESULTS
By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients.
CONCLUSIONS
In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy.
PATIENT SUMMARY
Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.
PubMed: 38940282
DOI: 10.1111/bju.16449 -
Frontiers in Endocrinology 2024This study aimed to evaluate the relationship between systemic immune-inflammation index (SII) and sex hormones in children and adolescents aged 6-19 years.
OBJECTIVES
This study aimed to evaluate the relationship between systemic immune-inflammation index (SII) and sex hormones in children and adolescents aged 6-19 years.
METHODS
Data were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Inclusion criteria comprised subjects aged 6-19 years with complete data on both SII and sex hormones. We employed weighted multiple regression analysis and subgroup analytical methods to independently estimate the relationship between SII and sex hormones.
RESULTS
In this study, a total of 3767 participants were included, with an average age of 12.32 ± 3.95 years. Males constituted 50.54%, and females 49.46%. Among males, a statistically significant negative correlation emerged between SII and sex hormone-binding globulin (SHBG). Similarly, in the female population, SII exhibited a statistically significant negative correlation with total testosterone (TT), SHBG, and the Ratio of TT to estradiol, while maintaining a positive correlation with free androgen index (FAI). Subgroup analysis underscored variances in the association between sex hormones and SII within cohorts distinguished by pubertal status or different body mass index (BMI). In addition, the relationship between SII and estradiol exhibited nonlinearity. Employing a two-segment linear regression model, we identified an inverted U-shaped association between SII and estradiol, with an inflection point of 748.09 (1000cell/ml).
CONCLUSION
Our findings suggest that SII may be an independent risk factor for changes in sex hormones in both male and female children and adolescents. More prospective and experimental studies should be conducted to validate our results and elucidate the underlying molecular pathways.
Topics: Humans; Adolescent; Female; Male; Child; Gonadal Steroid Hormones; Inflammation; Young Adult; Sex Hormone-Binding Globulin; Nutrition Surveys; Cross-Sectional Studies; Body Mass Index; Testosterone; Estradiol; Immunity
PubMed: 38938517
DOI: 10.3389/fendo.2024.1355738 -
European Journal of Endocrinology Jun 2024Androgen insensitivity syndrome (AIS) manifests itself as variable symptoms of under-virilization in patients with 46, XY disorders caused by androgen receptor (AR) gene...
CONTEXT
Androgen insensitivity syndrome (AIS) manifests itself as variable symptoms of under-virilization in patients with 46, XY disorders caused by androgen receptor (AR) gene variants. This large-sample study aimed to correlate the genotypes and phenotypes to the fertility of individuals.
METHODS
This was a cohort study that analyzed genetic and clinical characteristics of patients with AIS from a single center in China.
RESULTS
The 117 patients were divided into 53 with complete AIS (CAIS) and 64 with partial AIS (PAIS). At their first visit the median age was 1.83 years (0.92-4.17) and the EMS was 3.0 (2.0-6.0). At the last follow-up, 92% (49/53) of patients with CAIS maintained their female gender, and 94% (60/64) of patients with PAIS were raised as males. No gender anxiety was observed in this study. Eighty-eight AR variants were identified, with 31 (35%) being unreported. Moreover, 24% (21/88) occurred more than once. The variants that appeared most frequently were located at amino acid 841, including p.R841H(n=5) and p.R841C(n=2). Variants p.N706S, p.R856H, and p.A871V were each observed 4 times. In terms of inheritance, 83% of patients with parental verification inherited variants from their mothers. We also observed that the variants from one case were inherited from his maternal grandfather who had hypospadias.
CONCLUSION
Most children with PAIS were raised as males. The abundance of maternally inheritable variants and the presence of case of preserved fertility indicate the fertility potential in patients with AIS. Hence, we recommend a careful evaluation of gonadectomy when fertility preservation is being considered.
PubMed: 38938059
DOI: 10.1093/ejendo/lvae082 -
Journal of Nuclear Medicine : Official... Jun 2024Homeobox 13 (HOXB13) is an oncogenic transcription factor that directly regulates expression of folate hydrolase 1, which encodes prostate-specific membrane antigen...
Homeobox 13 (HOXB13) is an oncogenic transcription factor that directly regulates expression of folate hydrolase 1, which encodes prostate-specific membrane antigen (PSMA). HOXB13 is expressed in primary and metastatic prostate cancers (PCs) and promotes androgen-independent PC growth. Since HOXB13 promotes resistance to androgen receptor (AR)-targeted therapies and regulates the expression of folate hydrolase 1, we investigated whether SUVs on PSMA PET would correlate with HOXB13 expression. We analyzed 2 independent PC patient cohorts who underwent PSMA PET/CT for initial staging or for biochemical recurrence. In the discovery cohort, we examined the relationship between HOXB13, PSMA, and AR messenger RNA (mRNA) expression in prostate biopsy specimens from 179 patients who underwent PSMA PET/CT with F-piflufolastat. In the validation cohort, we confirmed the relationship between HOXB13, PSMA, and AR by comparing protein expression in prostatectomy and lymph node (LN) sections from 19 patients enrolled in F-rhPSMA-7.3 PET clinical trials. Correlation and association analyses were also used to confirm the relationship between the markers, LN positivity, and PSMA PET SUVs. We observed a significant correlation between PSMA and HOXB13 mRNA ( < 0.01). The association between HOXB13 and F-piflufolastat SUVs was also significant (SUV, = 0.0005; SUV, = 0.0006). Likewise, the PSMA SUV was significantly associated with the expression of HOXB13 protein in the F-rhPSMA-7.3 PET cohort ( = 0.008). Treatment-naïve patients with LN metastases demonstrated elevated HOXB13 and PSMA levels in their tumors as well as higher PSMA tracer uptake and low AR expression. Our findings demonstrate that HOXB13 correlates with PSMA expression and PSMA PET SUVs at the mRNA and protein levels. Our study suggests that the PSMA PET findings may reflect oncogenic HOXB13 transcriptional activity in PC, thus potentially serving as an imaging biomarker for more aggressive disease.
PubMed: 38936974
DOI: 10.2967/jnumed.123.267301 -
In Vivo (Athens, Greece) 2024When hormone therapy (HT) is combined with radiotherapy, understanding the recovery of testosterone levels after the end of HT becomes crucial for considering subsequent...
BACKGROUND/AIM
When hormone therapy (HT) is combined with radiotherapy, understanding the recovery of testosterone levels after the end of HT becomes crucial for considering subsequent therapy. The aim of this study was to determine the factors influencing the time to recovery of testosterone levels after discontinuation of HT and the likelihood of recovery.
PATIENTS AND METHODS
The study included a total of 108 patients with prostate cancer who were treated with GnRH agonist in combination with radiotherapy and followed up for at least 12 months after discontinuation of the GnRH agonist. The presence of recovery of testosterone levels and the time to recovery were investigated. Univariate and multivariate analyses were performed on several factors contributing to testosterone recovery, including age at initiation of HT, and the duration of HT.
RESULTS
Testosterone levels recovered in 61 cases (56.5%). The median time to recovery was 14.8 months. There was a significant difference in the recovery of testosterone levels between patients aged ≥71 years and those aged <71 years at the start of HT (p=0.002), and between those who had been on HT for ≥34 months and those for <34 months (p=0.031). In both univariate and multivariate analyses, age at initiation of HT and duration of HT contributed to the recovery of testosterone levels.
CONCLUSION
The rate of recovery of testosterone levels after long-term (median 34.3 months) HT was lower in patients who were older than 71 years at the start of HT.
Topics: Humans; Testosterone; Male; Aged; Prostatic Neoplasms; Middle Aged; Aged, 80 and over; Gonadotropin-Releasing Hormone; Combined Modality Therapy; Treatment Outcome; Antineoplastic Agents, Hormonal
PubMed: 38936898
DOI: 10.21873/invivo.13666