-
Frontiers in Endocrinology 2024Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by... (Review)
Review
Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in , resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the ; copy number variants in , , , , , and , and sequence variants in , , , , , , and . Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.
Topics: Humans; Adrenal Hyperplasia, Congenital; 46, XX Disorders of Sex Development; Female; Male; Disorders of Sex Development
PubMed: 38812815
DOI: 10.3389/fendo.2024.1354759 -
Turkish Journal of Medical Sciences 2024Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune...
BACKGROUND/AIM
Atopic dermatitis (AD) is an inflammatory, pruritic, noncontagious, chronic relapsing skin disease. Skin barrier abnormalities, excessive T helper 2 activity, and immune dysregulation are held responsible. Androgens have a negative effect on the integrity of the epidermal skin barrier, while estrogen has a positive effect. We aimed to investigate whether hormones make a difference between healthy children and children with AD during minipuberty.
MATERIALS AND METHODS
A total of 96 infants (postnatal 4-13 weeks), 48 diagnosed with AD and 48 controls, were included. Each group consisted of 23 girls (47.9%) and 25 boys (52.1%). Anthropometric examinations and hormone measurements were compared.
RESULTS
The two groups, having similar age, sex, body mass index, and weight-for-length standard deviation scores, were compared. Serum free thyroxine (FT4) levels were found to be lower and insulin-like growth factor binding protein-3 (IGFBP3) levels were found to be higher in children with AD (p < 0.001 and p = 0.038, respectively). In girls with AD, estradiol, FT4, and insulin-like growth factor-1 (IGF-1) levels were found to be lower, but thyroid-stimulating hormone (TSH) levels were found to be higher (p = 0.023, p < 0.001, p = 0.038, and p = 0.034, respectively). In boys with AD, the FT4 level was found to be lower (p = 0.023). Serum FT4 and TSH levels were within normal reference ranges in all comparisons.
CONCLUSION
Especially in girls with AD, decreased estradiol and IGF-1 levels were observed compared to the controls during minipuberty. In the logistic regression model, decreased levels of serum estradiol, dehydroepiandrosterone sulfate, FT4, and IGF-1, and increased levels of IGFBP3 were associated with an increased likelihood of exhibiting atopic dermatitis.
Topics: Humans; Dermatitis, Atopic; Female; Male; Insulin-Like Growth Factor Binding Protein 3; Infant; Insulin-Like Growth Factor I; Case-Control Studies; Estradiol; Thyroxine; Puberty; Thyrotropin
PubMed: 38812645
DOI: 10.55730/1300-0144.5795 -
Acta Biochimica Polonica 2024To evaluate the clinical efficacy of different androgen deprivation therapies for prostate cancer (PCa) based on dynamic-contrast enhanced magnetic resonance imaging...
OBJECTIVE
To evaluate the clinical efficacy of different androgen deprivation therapies for prostate cancer (PCa) based on dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI).
METHODS
104 patients with PCa were studied, all of whom were treated with androgen deprivation therapy. The patients were divided into a continuous group (continuous androgen deprivation therapy) and an intermittent group (intermittent androgen deprivation therapy) by random number table method, 52 cases/group. The therapeutic effect and DCE-MRI indices were compared and the relationship between DCE-MRI indices and clinical efficacy and the evaluation value of therapeutic efficacy were analyzed.
RESULTS
The objective response rate (ORR) of the intermittent group was higher than that of the continuous group ( < 0.05), and there was no significant difference in disease control rate (DCR) between the two groups ( > 0.05). After treatment, volume transfer coefficient (K), reverse transfer constant (K), volume fraction (Ve), blood volume (BV), and blood flow (BF) in both groups were lowered, and those in the intermittent group were lower than the continuous group ( < 0.05). K, K, Ve, BF, and BV in the ORR group were lower than those in the non-ORR group ( < 0.05). K, K, Ve, BF, and BV were correlated with the therapeutic effect of PCa ( < 0.05). The AUC value of the combined detection of DCE-MRI indices in evaluating the therapeutic effect of PCa was greater than that of each index alone ( < 0.05).
CONCLUSION
Compared with continuous androgen deprivation therapy, intermittent androgen deprivation therapy has better clinical efficacy in the treatment of PCa, and DCE-MRI indices are related to the treatment efficacy of PCa and have an evaluation value.
Topics: Humans; Male; Prostatic Neoplasms; Magnetic Resonance Imaging; Androgen Antagonists; Aged; Middle Aged; Contrast Media; Treatment Outcome
PubMed: 38812492
DOI: 10.3389/abp.2024.12473 -
Scientific Reports May 2024Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate...
Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate classification for the "Fudan University Shanghai Cancer Center (FUSCC) subtyping" has been developed and is considered more suitable for clinical application. Seventy-one paraffin-embedded sections of surgically resected TNBC were classified into four molecular subtypes using the IHC-based surrogate classification. Genomic analysis was performed by targeted next-generation sequencing and the specificity of the subtypes was explored by bioinformatics, including survival analysis, multivariate Cox regression, pathway enrichment, Pyclone analysis, mutational signature analysis and PHIAL analysis. AKT1 and BRCA1 mutations were identified as independent prognostic factors in TNBC. TNBC molecular subtypes encompass distinct genomic landscapes that show specific heterogeneities. The luminal androgen receptor (LAR) subtype was associated with mutations in PIK3CA and PI3K pathways, which are potentially sensitive to PI3K pathway inhibitors. The basal-like immune-suppressed (BLIS) subtype was characterized by high genomic instability and the specific possession of signature 19 while patients in the immunomodulatory (IM) subtype belonged to the PD-L1 ≥ 1% subgroup with enrichment in Notch signaling, suggesting a possible benefit of immune checkpoint inhibitors and Notch inhibitors. Moreover, mesenchymal-like (MES) tumors displayed enrichment in the receptor tyrosine kinase (RTK)-RAS pathway and potential sensitivity to RTK pathway inhibitors. The findings suggest potential treatment targets and prognostic factors, indicating the possibility of TNBC stratified therapy in the future.
Topics: Humans; Triple Negative Breast Neoplasms; Female; Mutation; Middle Aged; Proto-Oncogene Proteins c-akt; Prognosis; Class I Phosphatidylinositol 3-Kinases; Genomics; BRCA1 Protein; Adult; Biomarkers, Tumor; Aged; High-Throughput Nucleotide Sequencing; B7-H1 Antigen
PubMed: 38811720
DOI: 10.1038/s41598-024-62991-3 -
Translational Psychiatry May 2024Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone....
Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone. This study aimed to investigate the associations between testosterone levels, aggressive behavior, and manic symptoms using a network analysis among bipolar disorder (BD) patients in psychiatric emergency departments (PED). Data from January 2021 and March 2022 BD patients in PED were analyzed. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS). Aggression was assessed with subscale of the PANSS scale (PANSS-AG). The undirected network structures of testosterone levels, aggressive behavior, and manic symptoms were estimated, and centrality and bridge centrality indices were examined. Network stability was examined using the case-dropping procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. We recruited a total of 898 BD patients, with the mean YMRS score as 13.30 ± 9.58. The prevalence of level II aggression was 35.6% (95%CI = 32.5%-38.7%), level III aggression was 29.5% (95%CI = 26.3%-32.6%), and level VI aggression was 7.0% (95%CI = 5.4%-8.8%). The male participants had a mean testosterone level of 391.71 (Standard Deviation (SD):223.39) compared to 36.90 (SD:30.50) for female participants in the whole sample. Through network analysis, "Increased motor activity-energy" emerged as the central symptom, with the highest centrality expected influence, followed by "Emotional Instability" and "Disruptive/aggression behavior". Notably, "Emotional Instability" appeared to be the bridge symptom linking manic symptoms to aggressive behavior. Within the flow network model, "Speech rate and amount" exhibited the strongest positive correlation with testosterone levels, followed closely by "Disruptive/aggression behavior". The constructed network model demonstrated robust stability, with gender showing no significant impact on the structure. In this study, "Increased motor activity-energy" stood out as the most influential symptom, and "Speech rate and amount" acted as the main bridge symptom linking testosterone levels, aggressive behavior, and manic symptoms. Targeting the central and bridge symptoms may improve the outcomes of aggression interventions implemented among BD patients in psychiatric emergency care.
Topics: Humans; Bipolar Disorder; Aggression; Testosterone; Male; Female; Adult; Cross-Sectional Studies; Middle Aged; Comorbidity; Mania; Psychiatric Status Rating Scales; Young Adult
PubMed: 38811572
DOI: 10.1038/s41398-024-02957-1 -
World Journal of Clinical Cases May 2024Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can...
Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer. NEPC may arise or develop following androgen deprivation therapy (ADT). NEPC that arise following ADT has the nomenclature "treatment-emerging/induced NEPC (t-NEPC)". t-NEPC would be anticipated in castration resistant prostate cancer (CRPC) and metastatic PCa. t-NEPC is characterized by low or absent androgen receptor (AR) expression, independence of AR signaling, and gain of neuroendocrine phenotype. t-NEPC is an aggressive metastatic tumor, develops from PCa in response to drug induced ADT, and shows very short response to conventional therapy. t-NEPC occurs in 10%-17% of patients with CRPC. NEPC is rare and is accounting for less than 2% of all PCa. The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated. Sphingosine kinase 1 plays a significant role in t-NEPC development. Although neuroendocrine markers: Synaptophysin, chromogranin A, and insulinoma associated protein 1 () are expressed in t-NEPC, they are non-specific for diagnosis, prognosis, and follow-up of therapy. t-NEPC shows enriched genomic alteration in tumor protein P53 () and retinoblastoma 1 (). There are evidences suggest that t-NEPC might develop through epigenetic evolution. There are genomic, epigenetic, and transcriptional alterations that are reported to be involved in development of t-NEPC. Knock-outs of and were found to contribute in development of t-NEPC. PCa is resistant to immunotherapy, and at present there are running trials to approach immunotherapy for PCa, CRPC, and t-NEPC.
PubMed: 38808339
DOI: 10.12998/wjcc.v12.i13.2143 -
Journal of Contemporary Brachytherapy Apr 2024We report outcomes of high-risk prostate cancer (PCa) patients, initially classified according to a 3-tier NCCN classification system, treated with external beam...
PURPOSE
We report outcomes of high-risk prostate cancer (PCa) patients, initially classified according to a 3-tier NCCN classification system, treated with external beam radiation therapy (EBRT) and high-dose-rate brachytherapy boost (HDR-BT). Patients were analyzed based on a re-stratification of their risk grouping using CAPRA score and a newer 5-tier NCCN classification.
MATERIAL AND METHODS
471 high-risk PCa patients treated with EBRT, HDR-BT, and androgen deprivation therapy (ADT) between 1999 and 2018 were included. Competing risk survival analyses to compare individuals with CAPRA scores < 6 vs. ≥ 6 for biochemical relapse (BCR) and metastasis incidence were conducted. Also, overall survival (OS) for both groups using Kaplan-Meier analysis was assessed. The same analyses were repeated using a 5-tier NCCN stratification comparing those classified as high-risk vs. very high-risk patients.
RESULTS
The median age was 71 years, and the median follow-up period was 72 months. The whole cohort received an EQD of 74 Gy or greater, with a median EQD of 106.89 Gy. Both a CAPRA score ≥ 6 and belonging to the NCCN very high-risk group were associated with BCR, with subdistribution hazard ratios (sHRs) of 3.04 ( = 0.015) and 2.53 ( = 0.013), respectively. For metastasis incidence, both the CAPRA and NCCN groups had similar sHRs of 2.60 ( = 0.094) and 2.71 ( = 0.037), respectively. For 10-year OS, patients with CAPRA score ≥ 6 and belonging to the NCCN very high-risk group presented similar HRs of 2.11 ( = 0.005) and 2.10 ( = 0.002).
CONCLUSIONS
We showed that high-risk PCa patients classified according to the 3-tier NCCN system benefit from further stratification using the CAPRA score or the 5-tier NCCN stratification method. Patients with a CAPRA score ≥ 6 or classified as very high-risk demonstrate a higher hazard of BCR, metastasis, and death. These patients might benefit from further intensification of their investigations and treatment, based on ongoing research.
PubMed: 38808208
DOI: 10.5114/jcb.2024.139277 -
Journal of Xenobiotics May 2024There has been emerging research linking per- and poly-fluoroalkyl substances (PFAS) to gamete viability and fertility. PFAS, prevalent in the environment and water... (Review)
Review
There has been emerging research linking per- and poly-fluoroalkyl substances (PFAS) to gamete viability and fertility. PFAS, prevalent in the environment and water supplies, undergo slow degradation due to their C-F bond and a long half-life (2.3-8.5 years). In females, PFAS inhibit the hypothalamic-pituitary-gonadal (HPG) axis, reducing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, leading to the inhibition of androgen and estradiol production. PFAS have been found to cause detrimental effects on egg quality through impairing folliculogenesis. In males, PFAS can impair sperm motility and morphology: two fundamental qualities of successful fertilization. PFAS exposure has been proven to inhibit testosterone production, sperm capacitation, and acrosomal reaction. After fertilization, the results of PFAS exposure to embryos have also been investigated, showing reduced development to the blastocyst stage. The aim of this review is to report the main findings in the literature on the impact of PFAS exposure to gamete competency and fertilization capability by highlighting key studies on both male and female fertility. We report that there is significant evidence demonstrating the negative impacts on fertility after PFAS exposure. At high doses, these environmentally abundant and widespread compounds can significantly affect human fertility.
PubMed: 38804291
DOI: 10.3390/jox14020038 -
Frontiers in Physiology 2024In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are...
In addition to loss of sensory and motor function below the level of the lesion, traumatic spinal cord injury (SCI) may reduce circulating steroid hormones that are necessary for maintaining normal physiological function for extended time periods. For men, who comprise nearly 80% of new SCI cases each year, testosterone is the most abundant circulating sex steroid. SCI often results in significantly reduced testosterone production and may result in chronic low testosterone levels. Testosterone plays a role in respiratory function and the expression of respiratory neuroplasticity. When testosterone levels are low, young adult male rats are unable to express phrenic long-term facilitation (pLTF), an inducible form of respiratory neuroplasticity invoked by acute, intermittent hypoxia (AIH). However, testosterone replacement can restore this respiratory neuroplasticity. Complicating the interpretation of this finding is that testosterone may exert its influence in three possible ways: 1) directly through androgen receptor (AR) activation, 2) through conversion to dihydrotestosterone (DHT) by way of the enzyme 5α-reductase, or 3) through conversion to 17β-estradiol (E2) by way of the enzyme aromatase. DHT signals via AR activation similar to testosterone, but with higher affinity, while E2 activates local estrogen receptors. Evidence to date supports the idea that exogenous testosterone supplementation exerts its influence through estrogen receptor signaling under conditions of low circulating testosterone. Here we explored both recovery of breathing function (measured with whole body barometric plethysmography) and the expression of AIH-induced pLTF in male rats following C2-hemisection SCI. One week post injury, rats were supplemented with either E2 or DHT for 7 days. We hypothesized that E2 would enhance ventilation and reveal pLTF following AIH in SCI rats. To our surprise, though E2 did beneficially impact overall breathing recovery following C2-hemisection, both E2 supplementation and DHT restored the expression of AIH-induced pLTF 2 weeks post-SCI.
PubMed: 38803364
DOI: 10.3389/fphys.2024.1390777 -
Cureus Apr 2024Introduction Androgens play a key role in modulating periurethral and preputial vascularity, cavernosal smooth muscle integrity, and penile growth. As a result, low...
Introduction Androgens play a key role in modulating periurethral and preputial vascularity, cavernosal smooth muscle integrity, and penile growth. As a result, low testosterone may adversely affect the severity and outcome of urethral stricture patients. So, to find out the hormonal influence on the clinical outcome of urethral stricture we conducted a prospective longitudinal study at our institute. Methods The study was conducted at the Department of Urology, Institute of Post Graduate Medical Education & Research (IPGMER), Kolkata, India, from February 2023 to September 2023. This study was approved by the Institutional Ethics Committee at IPGMER, Kolkata with the approval number IPGMER/IEC/2023/436. Hormonal levels in patients with diagnosed non-traumatic urethral stricture were compared with patients without stricture. Patients with any overt hormonal abnormality or androgen-secreting tumor were excluded. A morning 10 cc blood sample was collected for testosterone, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone. The association of hormonal levels was measured in both groups and compared statistically. Any association of hypogonadism (testosterone <300 ng/dL) with respect to length, severity, and recurrence of urethral stricture was also studied. Results Forty patients with urethral stricture and same number of patients without stricture were included in the study. The mean testosterone level was found to be significantly low in patients with stricture (386 ng/dL vs 660 ng/dL). The age-wise distribution also showed low mean testosterone compared to patients without stricture. The incidence of hypogonadism is also found to be higher in stricture patients (47.5% vs 27.5%). It was also observed low testosterone is more prevalent in pan-anterior stricture (10/40) and long-segment stricture(>2 cm). Patients with stricture were also followed up for 6 months for recurrence of symptoms. Thirteen patients had recurrence. Patients with recurrence had significantly low serum testosterone (272 ng/dL vs 440 ng/dL). Conclusion Our study documented stricture patients with low serum testosterone have poor outcomes. Low testosterone level is strongly associated with longer stricture and increased risk of stricture recurrence.
PubMed: 38800237
DOI: 10.7759/cureus.58895