Sex Hormone Status Research Articles

P21-50 Sex hormone status of male Wistar rat offspring prenatally exposed to pyrethroid insecticide

P21-50 Sex hormone status of male Wistar rat offspring prenatally exposed to pyrethroid insecticide

Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention.A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples.Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group.These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

DIPG-60. OPERATIVE PERFORMANCE OF RAPNO DIPG CRITERIA FOR IMAGING REVIEW- A STUDY FROM THE INTERNATIONAL DIPG/DMG REGISTRY (IDIPGR)

Abstract BACKGROUND The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for diffuse intrinsic pontine glioma (DIPG) recently published its recommendations. Response criteria incorporate radiologic findings, neurologic status, and use of concurrent steroids and antiangiogenic drugs to define response. To test the operative performance of the imaging component, we retrospectively applied RAPNO DIPG recommendations to a convenience sample of 46 patients enrolled in the International DIPG/DMG Registry(IDIPGR). METHODS MRIs were independently reviewed by 2 pediatric neuro-radiologists. These measurements were analyzed utilizing RAPNO DIPG imaging criteria to categorize the response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). For PR evaluation, each MRI was compared to the baseline MRI, and for PD evaluation, each MRI was compared to the MRI with the smallest cross-sectional measurement. The response category for each MRI was compared between 2 neuro-radiologists and was classified as concordant if they agreed, minor discordant if one reported SD and the other reported PR or PD, and major discordant if one reported PR and the other reported PD. RESULTS A total of 276 paired MRIs were analyzed. Sixty-seven percent of the time, the analyzed response assessment was concordant. In 33% discordant reads, 26% were minor discordant, and 7% were major discordant. There were no CRs reported. Further analysis of minor discordant cases showed that 62% of these cases were within 10% of the boundary for PR or PD. The median difference between 2 neuro-radiologists’ long axis measurements was 2 mm (range 0-27mm) and short axis measurements was 2mm (range 0-29mm). These small differences in measurements account for all discordant response categories between 2 neuro-oncologists. CONCLUSION This study demonstrated that RAPNO DIPG imaging criteria can be successfully applied with high concordance between readers. When discordant, measurements were largely at the boundaries of response type.

Anterior Non-Necrotizing Scleritis with Active Uveitis in Cases of Ocular Syphilis

ABSTRACT Purpose To study clinical characteristics and management outcomes of cases of ocular syphilis co-presenting with scleritis and active uveitis. Methods A retrospective analysis of cases diagnosed with ocular syphilis between January 2020 and December 2023 was conducted at a tertiary eye care centre. Clinical records, investigations, and outcomes were reviewed to identify cases with scleritis with active uveitis. Demographic data, clinical features, treatment modalities, and resolution patterns were analyzed. Results Among the 135 eyes of 95 cases of ocular syphilis studied, scleritis with uveitis was observed in 3.70% of eyes (five eyes). All cases with scleritis and uveitis were unilateral and male, with ages ranging from 32 to 61 years. Concurrent features included placoid chorioretinitis, retinal vasculitis, and anterior uveitis. Misdiagnosis with subsequent oral steroid therapy precipitated scleritis as an exacerbation in two cases. Three cases, which were previously undiagnosed, were found to be HIV-positive. Scleritis manifested as anterior, non-necrotizing inflammation, often accompanied by chemosis, and responded rapidly to antibiotic and non-steroidal anti-inflammatory therapy. Scleritis resolution preceded that of chorioretinitis and retinal vasculitis. Conclusions Non-necrotizing anterior scleritis with chemosis can be a rare presentation of active syphilitic uveitis. Large placoid chorioretinitis lesions, preceding inadvertent oral steroid and/or undiagnosed HIV status were the possible risk factors for the development of concurrent scleritis.

Neurodevelopmental outcome of pre-term babies less than 34 weeks of gestation at corrected 2 years of age, with respect to their antenatal steroid status

Objectives: The objective of this study was to determine the neurodevelopmental status of pre-term babies between <34 weeks of gestation and equal to or more than 25 weeks of gestation, at corrected 2 years of age with respect to their antenatal steroid status. Materials and Methods: This population-level prospective study was conducted over a period of 6 years from 2017 to 2023 in middle Kerala. Pre-term babies with gestational age at birth between <34 weeks and equal to or more than 25 completed weeks, presenting for follow-up within 3 months of delivery, were randomly enrolled for the study. A total of 150 children were followed up and neurodevelopmental assessment done using Bayley Scales of Infant and Toddler Development edition-3 at their corrected 2 years of age. Approval for this prospective observational study was obtained from the Institutional Ethics Committee, School of Behavioral Sciences, Mahatma Gandhi University, Kottayam, Kerala, dated September 22, 2017. Results: Eighty-one pre-term <34 weeks babies belonged to the antenatal steroid complete group, 40 pre-term <34 weeks babies belonged to the antenatal steroid partial group, and 29 pre-term <34 weeks babies belonged to the nil steroid group. Total neurodevelopmental status score and domain-wise, cognitive, language, motor, and social-emotional developmental scores show significantly higher scores for pre-term <34 weeks with antenatal history of complete course steroid administered before pre-term delivery compared to partial and nil antenatal steroid group. Conclusions: Antenatal steroids are having a significant impact on the overall neurodevelopmental outcome of pre-term babies equal to or more than 25 weeks of gestation and <34 weeks of gestation, at their corrected 2 years of age, the maximum benefit for complete antenatal steroid group pre-term babies, equal to or more than 25 weeks and <34 completed weeks of gestation when compared with pre-term babies, equal to or more than 25 weeks and <34 completed weeks of gestation without any antenatal steroids.

P096 Pathway directionality across different immune cell lineages contributes to methotrexate response in juvenile idiopathic arthritis

Abstract Background/Aims Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease in children with methotrexate (MTX) as the first line treatment. However, about 50% of JIA patients will not respond well to MTX yet still experience drug side effects. Early prediction to MTX treatment response would be beneficial for patients and families to avoid incurring unnecessary MTX side effects and ongoing uncontrolled inflammation: such validated tools or biomarkers are currently not available. Methods Transcriptional analysis was performed on peripheral blood mononuclear cells (PBMC) from pre-MTX-treated JIA patients (n = 97) of all ILAR JIA subtypes, excluding systemic JIA. RNAseq was performed on total PBMC and sorted immune cell populations: CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD14+ monocytes. Clinical data collected at the time of sampling (baseline) and at the follow-up time (between 3-12 months) were used to define outcomes, measured as change in active joint count (AJC), change in Physician VAS (PhysVAS), and change in cJADAS10. After batch normalisation with ComBat-seq, differential gene expression (DGE) analysis was performed using limma-voom with age, sex, ethnicity, and steroid status included as covariates. Log2 fold changes were utilised to rank genes to implement gene set enrichment analysis (GSEA) by fgsea. Results DGE analysis showed minimal significant differentially expressed (DE) genes that passed 5% false discovery rate (FDR). The greatest number of significant DE genes were observed in CD14+ monocytes, where baseline expression of 13 genes were significantly associated with change in PhysVAS. As alterations of gene expression for a heterogeneous disease such as JIA can be subtle and correlated between genes, GSEA was performed to investigate expression changes at pathway level. Using MSigDb Hallmark pathways, GSEA showed interferon-related and tumor-necrosis-factor pathways as significantly associated with MTX response in all cell types (5% FDR). However, the directionality (up/down regulation) differed between cell lineages, suggesting pathways divergence between T cell and non-T cell lineages. For example, in interferon gamma pathway, up-regulation associated with poor treatment response in T-cells and down-regulation in non-T cells. Preliminary analysis of the leading edge genes of the interferon gamma pathway in the non-T cell lineages showed that many of the genes are driven by interferon alpha, whilst within CD4+ and CD8+ T cells the majority of the leading edge genes are specific to interferon gamma. Conclusion Different directionality of pathways that might be relevant to JIA response to treatment with MTX is observed in different mononuclear cell lineages. This could potentially explain the difficulties of finding biomarkers which correlate with response to treatment from whole blood or PBMC. Shared genes across different interferon-related pathways also suggest that interaction between interferon pathways might be driving the different direction of interferon pathway expression in different cell lineages. Disclosure M. Kartawinata: None. W. Lin: None. B. Jebson: None. K. O'Brien: None. E. Ralph: None. R. Restuadi: None. G.T. Hall: None. S. Castellano: None. C. Wallace: None. L.R. Wedderburn: Grants/research support; LRW Declares in kind contributions to CLUSTER by AbbVie, GSK, UCB, Sobi and Pfizer inc and non renumerated collaborations with Lilly and Novartis.

Sex-Related Differences in Self-Reported Symptoms at Diagnosis in Pheochromocytomas and Paragangliomas.

Biological sex can play a role in the severity of certain diseases. Our objective was to evaluate whether sex-related differences affect the signs and symptoms of pheochromocytomas and paragangliomas (PPGLs) at presentation. We reviewed the records of patients with PPGLs at our center from 1995 to 2022. Our study included 385 patients with PPGLs: 118 (30.6%) head and neck paragangliomas (HNPGLs), 58 (15.1%) thoracoabdominal paragangliomas (TAPGLs) and 209 (54.3%) pheochromocytomas (PHEOs). The cohort consisted of 234 (60.8%) women and 151 (39.2%) men. At diagnosis, more women than men presented with headaches (47.5% vs 32.4%; P = .007); however, more men presented with diabetes (21.1% vs 12.5%; P = .039). When subdivided by tumor location, headaches occurred more often in women with HNPGLs and TAPGLs (31.0% vs 11.4%; P = .0499 and 60.0% vs 21.7%; P = .0167). More men presented with diabetes among patients with PHEOs (28.2% vs 11.2%; P = .0038). In regard to nonsecretory PPGLs, women presented with a higher prevalence of headaches (46.9% vs 3.6%; P = .0002), diaphoresis (16.3% vs 0.0%; P = .0454), and palpitations (22.4% vs 0.0%; P = .0057). In patients with secretory tumors, women presented with more headaches (58.9% vs 42.7%; P = .0282) and men with more diabetes (29.3% vs 12.5%; P = .0035). In our cohort, more women presented with headaches across all tumor types and secretory statuses. More men presented with diabetes among patients with PHEOs and secretory tumors. In nonsecretory PPGLs, women had more adrenergic symptoms. These findings can be explained by differences in adrenergic receptor sensitivity, self-reported symptoms, and possibly other vasoactive peptides and sex-hormone status.

Daily supplement of sesame oil prevents postmenopausal osteoporosis via maintaining serum estrogen and aromatase levels in rats

Estrogen deficiency is one of the main causes of postmenopausal osteoporosis in elderly women. Hormone replacement therapy has been employed to manage postmenopausal osteoporosis; however, it has raised concerns related to heart attacks and breast cancer. Sesame oil has been reported to affect sex hormone status. The aim of the present study is to evaluate the effect of sesame oil supplement on postmenopausal osteoporosis in rats. We used female Sprague Dawley rats that underwent bilaterally ovariectomy (OVX) as an experimental postmenopausal osteoporosis animal model. These rats were orally administrated sesame oil (0.25 or 0.5 mL/kg/day) for four months as the therapeutic group. We assessed bone mineral density (BMD) and the levels of osteocalcin, procollagen-I C-terminal propeptide (PICP), collagen cross-linked N-telopeptide (NTx), estradiol, and aromatase in the sera. The daily supplementation of sesame oil significantly increased BMD, serum osteocalcin levels, and trabecular areas in the OVX-treated rats. Sesame oil also elevated serum PICP levels and decreased NTx levels in these rats. Furthermore, sesame oil effectively maintained serum estradiol and aromatase levels in the OVX-induced osteoporosis rats. In conclusion, daily supplementation of sesame oil prevents postmenopausal osteoporosis by maintaining serum estrogen and aromatase levels, while also modulating the imbalance between bone formation and resorption in osteoporosis rats.

Gut microbiome responds to alteration in female sex hormone status and exacerbates metabolic dysfunction

ABSTRACT Women are at significantly greater risk of metabolic dysfunction after menopause, which subsequently leads to numerous chronic illnesses. The gut microbiome is associated with obesity and metabolic dysfunction, but its interaction with female sex hormone status and the resulting impact on host metabolism remains unclear. Herein, we characterized inflammatory and metabolic phenotypes as well as the gut microbiome associated with ovariectomy and high-fat diet feeding, compared to gonadal intact and low-fat diet controls. We then performed fecal microbiota transplantation (FMT) using gnotobiotic mice to identify the impact of ovariectomy-associated gut microbiome on inflammatory and metabolic outcomes. We demonstrated that ovariectomy led to greater gastrointestinal permeability and inflammation of the gut and metabolic organs, and that a high-fat diet exacerbated these phenotypes. Ovariectomy also led to alteration of the gut microbiome, including greater fecal β-glucuronidase activity. However, differential changes in the gut microbiome only occurred when fed a low-fat diet, not the high-fat diet. Gnotobiotic mice that received the gut microbiome from ovariectomized mice fed the low-fat diet had greater weight gain and hepatic gene expression related to metabolic dysfunction and inflammation than those that received intact sham control-associated microbiome. These results indicate that the gut microbiome responds to alterations in female sex hormone status and contributes to metabolic dysfunction. Identifying and developing gut microbiome-targeted modulators to regulate sex hormones may be useful therapeutically in remediating menopause-related diseases.

THU579 Severe Hypokalemia: Is It Mineralocorticoid Excess Induced By Abiraterone Or Exogenous Hypercortisolism?

Abstract Disclosure: D. Katwal: None. B.C. Barreto: None. J. Turner: None. D. James: Research Investigator; Self; Sanofi, Abbvie, Regeneron Pharmaceuticals. Introduction: Abiraterone is a CYP171A1 inhibitor used to treat metastatic, castration-resistant prostate cancer (CRPC). We report a case of severe hypokalemia in a patient with prostate cancer treated with abiraterone and prednisone, refractory after cessation of abiraterone, raising the concern for exogenous hypercortisolism. Case: A 69-year-old male with a history of locally advanced prostate cancer on Abiraterone 1 gm daily and prednisone 5 mg BID for a year presented to the local hospital ER with generalized weakness, diffuse paresthesia, and frequent falls. He was diagnosed with severe hypokalemia, renal wasting, metabolic alkalosis, and severe hypocalcemia. The patient's serum aldosterone was undetectable. CT scan of the pelvis was unremarkable for adrenal adenoma. Despite the undetectable aldosterone level, the patient's hypokalemia was initially attributed to an adverse effect of abiraterone, which was discontinued. He was discharged on potassium supplementation and eplerenone. However, he noted worsening symptoms, prompting him to visit our hospital the next day. On arrival, he was hypertensive. Lab showed potassium 2.9 mEq/L(3.6-5.0), bicarbonate 34mEq/L (21-31), creatinine 0.4 mg/dl (0.5-1.2), corrected calcium 6 mg/dl (8.4-10.2), ical 0.66 mmol/L (1.12-1.32), PTH 168 pg/ml (15-65) and vitamin D 25 OH 33 ng/ml (30-100). Oncology and nephrology were consulted to evaluate for abiraterone-causing hypokalemia. Nephrology suspected exogenous hypercortisolism, given his persistent electrolyte abnormalities off abiraterone for a week. He required aggressive potassium replacement of 240-360 mEq/day. Endocrinology was consulted to assist in tapering steroids, given the suspected exogenous hypercortisolism and risk of glucocorticoid-induced adrenal insufficiency. His biochemical profile improved over a week as we tapered his steroid to a maintenance dose of hydrocortisone. He was discharged with a plan to perform a cosyntropin test as an outpatient. Discussion: Abiraterone selectively and irreversibly inhibits CYP17A1 and subsequently inhibits androgen biosynthesis. Abiraterone treatment results in cortisol deficiency, with the compensatory elevation of ACTH level leading to hypokalemia, fluid retention, and hypertension due to excess mineralocorticoid. Steroids are co-administered with abiraterone to suppress ACTH and mineralocorticoid overproduction preventing adverse events. Our patient's persistent hypokalemia resulted from two distinct mechanisms of medical therapies used for his prostate cancer. Given his variable steroid status, a dexamethasone suppression test (DST) to establish biochemical hypercortisolism was not performed. This case highlights the importance of swiftly identifying endocrinopathies that may develop due to treatment from hormonal therapies that have become widespread in various fields of medicine. Presentation Date: Thursday, June 15, 2023

Steroid metabolites as overlooked emerging contaminants: Insights from multimedia partitioning and source–sink simulation in an estuarine environment

Steroids have been attracting global attention given potential carcinogenic and endocrine-disrupting effects, yet the environmental status of steroids, especially their metabolites, in estuarine environment remain largely unexplored. This study investigated 31 steroids and metabolites in suspended particulate matter (SPM), water phase and sediments of the Pearl River Estuary (PRE) during the dry and wet seasons to elucidate their spatiotemporal patterning, partitioning behavior, and environmental fate. The results showed that natural steroids predominated in SPM and sediments while the metabolites predominated in water. The spatial distribution of steroids and metabolites varied seasonally, with hydrophobicity and environmental factors influencing phase partitioning in the estuary. Furthermore, a natural steroid, progesterone (P) could serve as a trustworthy chemical indicator to estimate the concentrations of steroids and metabolites in the PRE. Importantly, the mass budget of P was estimated using an improved multi-box mass balance model, revealing that outflow to the South China Sea was the primary sink of P in water (∼87%) and degradation was the primary sink of P in sediments (∼68%) of the PRE. Overall, this study offers insightful information about the distribution and environmental fate of steroids and metabolites in estuarine environment, with implications for future management strategies.

Disruption of Vitamin D Signaling Impairs Adaptation of Cerebrocortical Microcirculation to Carotid Artery Occlusion in Hyperandrogenic Female Mice.

Vitamin D deficiency contributes to the pathogenesis of age-related cerebrovascular diseases, including ischemic stroke. Sex hormonal status may also influence the prevalence of these disorders, indicated by a heightened vulnerability among postmenopausal and hyperandrogenic women. To investigate the potential interaction between sex steroids and disrupted vitamin D signaling in the cerebral microcirculation, we examined the cerebrovascular adaptation to unilateral carotid artery occlusion (CAO) in intact, ovariectomized, and hyperandrogenic female mice with normal or functionally inactive vitamin D receptor (VDR). We also analyzed the morphology of leptomeningeal anastomoses, which play a significant role in the compensation. Ablation of VDR by itself did not impact the cerebrocortical adaptation to CAO despite the reduced number of pial collaterals. While ovariectomy did not undermine compensatory mechanisms following CAO, androgen excess combined with VDR inactivity resulted in prolonged hypoperfusion in the cerebral cortex ipsilateral to the occlusion. These findings suggest that the cerebrovascular consequences of disrupted VDR signaling are less pronounced in females, providing a level of protection even after ovariectomy. Conversely, even short-term androgen excess with lacking VDR signaling may lead to unfavorable outcomes of ischemic stroke, highlighting the complex interplay between sex steroids and vitamin D in terms of cerebrovascular diseases.

Estrous cycle dependent expression of oxycodone conditioned reward in rats

Oxycodone is one of the most widely prescribed and misused opioid painkillers in the United States. Evidence suggests that biological sex and hormonal status can impact drug reward in humans and rodents, but the extent to which these factors can influence the rewarding effects of oxycodone is unclear. The purpose of this study was to utilize place conditioning to determine the effects of sex and female hormonal status on the expression of oxycodone conditioned reward in rats. Gonadally intact adult Sprague-Dawley male and female rats were used to test: (1) whether both sexes express conditioned reward to oxycodone at similar doses, (2) the impact of conditioning session length on oxycodone conditioned reward expression in both sexes, and (3) the influence of female estrous cycle stage on oxycodone conditioned reward expression. Both sexes expressed conditioned reward at the same doses of oxycodone. Increasing the length of conditioning sessions did not reveal an effect of sex and resulted in lower magnitude conditioned reward expression. Importantly however, female stage of estrous cycle significantly influenced oxycodone conditioned reward expression. These results suggest that female hormonal status can impact the rewarding effects of opioids and thus have important implications for prescription opioid treatment practices.

Five-year survival outcomes in patients with melanoma with complete response to immunotherapy who discontinue therapy.

e21503 Background: Immune checkpoint inhibitor (ICI) therapy for advanced melanoma in the first-line setting often results in durable responses and prolonged overall survival (OS) after achieving a complete response (CR). While generally well-tolerated, there are financial toxicities and treatment related adverse events (TRAEs) associated with ICI use. There are limited data to inform the optimal duration of therapy after CR, and how specific patient factors may lead to variable OS in patients (pts) with CR. Methods: Pts with locally advanced stage III or stage IV melanoma who started first-line ICI therapy with pembrolizumab, nivolumab, or ipilimumab/nivolumab (ipi/nivo) and achieved CR were identified at a single institution under an Institutional Review Board approved protocol. Pts were only included in the sample if they had initiated treatment by 2013 and discontinued therapy by February of 2021 and had documented follow-up at least 1 year after discontinuing ICI therapy. Recurrence rates were determined by the presence of any recurrence after CR. Pts were analyzed by baseline stage (III vs IV), BRAF status, use of steroids for TRAEs, time from treatment start to CR, and total duration of therapy. OS was determined by time from treatment start to death or date of last follow-up. Results: 78 Pts with CRs from ICI therapy who discontinued treatment were identified at the University of Pennsylvania. Median follow-up time was 63 months from ICI treatment start. Median age at treatment start was 65 years (range 33-94). 51 Pts (68%) had an ECOG performance status (PS) of 0 vs 24 (32%) with ECOG PS of 1-2. 21 Pts (27%) had locally advanced stage III and 57 (73%) had stage IV disease. Of stage IV pts, 8 were M1a, 16 M1b, 22 M1c, and 11 M1d. 61 (78%) pts were treated with pembrolizumab, 5 (6%) nivolumab, 12 (15%) ipi/nivo. 34 pts (44%) were treated with steroids for TRAEs. Of the 78 total pts, 13 (16.7%) developed a recurrence after stopping treatment. The median time to recurrence was 57 months (range 9-110). Melanoma specific survival was 96%. Of the pts with recurrence, 3 died of melanoma, 9 are disease free after additional local and/or systemic treatment and one patient is alive with disease. There was no significant difference ( p < 0.05) in OS based on baseline stage, BRAF status, or use of steroids for TRAEs. Pts were treated for a median of 6 months (range 1 day to 24 months). Conclusions: With over 5 years median follow-up time, the majority of pts with advanced melanoma who attain a CR from first-line ICI therapy remain disease free after treatment discontinuation. Patient factors including stage at treatment initiation, BRAF status, and steroid usage during treatment were not associated with significant variation in OS in this cohort. Most pts with recurrences remain disease free after additional local and/or systemic treatment. Few melanoma specific deaths occurred in pts with a CR to ICI who discontinued treatment.

Comparison of Characteristics of Methotrexate Tolerant and Intolerant Patients Having Rheumatoid Arthritis

Objectives: To compare the characteristics of methotrexate-tolerant and intolerant patients having rheumatoid arthritis. To determine the association of methotrexate intolerance with the patient and disease-related factors. Method: This cross-sectional study was carried out at the rheumatology department of Combined Military Hospital Lahore from 31st April to 30th June 2022. It included 181 rheumatoid arthritis (RA) patients using methotrexate (MTX) for > 3 months. Patient demographic variables, disease duration and activity, and information regarding MTX intake were recorded. English methotrexate intolerance severity score (MISS) questionnaire was used to calculate MTX intolerance. Different variables were compared between methotrexate-tolerant and intolerant patients. Association of age, disease duration, and activity, MTX route/dose with MTX intolerance was determined. Results: The majority of patients were females 140(77%). The median disease duration was 6(1-40) years. MTX intolerance was found in 48(26.5%) of RA patients. Intolerant patients had a higher disease activity score (DAS 28>5.1 in 20.8 vs 3.8%; P = 0.002) and longer duration of MTX intake in months (23.5 vs 12; p=0.018) compared to tolerant patients. Additionally, MTX intolerance was associated with younger age, longer disease duration and higher MTX dose>10mg/wk (P=0.007, P=0.025, P=0.050). There was no significant difference between the two groups in gender, marital status, education, and use of other DMARDs or steroids. (P >0.05). Conclusion: There was a significant association between age, disease duration, and MTX dose with MTX intolerance. We also noted a significant association between disease activity and route of intake with MTX intolerance but this was lost when adjusted for multiple confounders.

Neuronostatin accts as a counterregulatory factor to protect against hypoglycemia

Neuronostatin (NST) is a 13-amino acid hormone derived from the somatostatin (SST) preprohormone that exerts metabolic and cardiovascular actions in many tissue types. In transformed alpha cell lines and isolated rat islets neuronostatin enhanced low glucose-stimulated proglucagon transcription and glucagon secretion1. Additionally, neuronostatin inhibited high glucose-stimulated insulin secretion from isolated rat islets, which was mirrored in vivo in rats subjected to an intra-arterial glucose tolerance test. Rats that received a bolus injection of neuronostatin followed by infusion glucose exhibited delayed glucose disposal and impaired insulin release, causing an increased peak blood glucose1. We, therefore hypothesized the ability of neuronostatin to act as a counterregularoty factor to protect against hypoglycemia. We found that Neuronostatin administered prior to an insulin tolerance test significantly reduced hypoglycemia compared to the saline control. In addition, we found that administration of exogenous Insulin significantly reduced Neuronostatin plasma levels. These data suggest Neuronostatin may act as a counterregulatory factor in adult, male rats to prevent hypoglycemia. However, after menopause or OVX, a precipitous decline in insulin sensitivity parallels an increase in fat mass, suggesting estrogens at physiological concentrations may maintain insulin action and glucose tolerance. We therefore investigated the neuronostatin-induced blood glucose changes in conscious, cycling females. We found blood glucose levels following neuronostatin administration decreased on diestrus, when both estrogen and progesterone levels are low, but not on proestrus or estrus. From these data we conclude that the metabolic actions of Neuronostatin are modulated by sex hormone status. Further studies are required to determine the contributions of chromosomal sex and individual sex hormones to these metabolic effects of Neuronostatin.1. Salvatori AS, Elrick MM, Samson WK, Corbett JA, Yosten GL. Neuronostatin inhibits glucose-stimulated insulin secretion via direct action on the pancreatic alpha-cell. Am J Physiol Endocrinol Metab. 2014;306:E1257–E1263. Saint Louis University Internal Funds This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 5287: Is testosterone the male sex hormone responsible for increased male mortality in melanoma? In-vitro studies based on human melanoma (BLM) cell model

Abstract Clinical studies showed that menstruating females were better protected in melanoma than post-menopausal women and men of any age. But, these studies did not correlate with the steroid status of females. Our in-vitro study with progesterone (P), a female sex hormone showed significant inhibition of human melanoma cell growth. A literature survey showed that progesterone levels ranged between 1000-1500 ng/dl in menstruating females compared to post-menopausal women (20-100 ng/dl) and men (27-90 ng/dl), suggesting increased progesterone levels could offer protection to the menstruating females. Moreover, Elisarray showed that progesterone action was mediated by specific suppression of proinflammatory cytokine IL-8. So, it was proposed that a low level of progesterone in males leading to non-suppression of IL-8 in melanoma, could be responsible for increased melanoma cell growth and male mortality. This hypothesis prompted us to check the effect of male sex hormones androstenedione (AD) and testosterone (T) on melanoma cell growth and IL-8 secretion. Both AD and T decreased IL-8 secretion along with a decrease in cell growth. However, when progesterone was added along with androgens, there was a significant decrease in cell growth and in IL-8 secretion. This raised the question of why male mortality was high when androgens also decreased cell growth and IL-8 secretion. In order to address this question, it was decided to induce endogenous IL-8 in melanoma cells by pre-incubating with endothelin (50ng/ml) and then add steroids. AD and P individually decreased IL-8 secretion and in combination significantly decreased IL-8 secretion and cell growth even in endothelin pretreated cells when compared to their respective control cells. But, T was not able to suppress endogenous IL-8 induced by endothelin and in fact, cell growth also was slightly increased compared to straight T-treated cells. Conclusion: So, in males 2 reasons 1) a deficiency of progesterone and 2) inefficiency of T to suppress endogenous IL-8 could possibly result in increased IL-8 levels. This increased IL-8 level in males could lead to increased cell growth and metastasis in melanoma (IL-8 had already been shown to stimulate melanoma cell growth and metastasis by us and others) leading to death. So, a situation arising out of male reproductive endocrine physiology could probably be responsible for increased male mortality in melanoma. Citation Format: Pandurangan Ramaraj. Is testosterone the male sex hormone responsible for increased male mortality in melanoma? In-vitro studies based on human melanoma (BLM) cell model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5287.

An effective tool for tracking steroids and their metabolites at the watershed level: Combining fugacity modeling and a chemical indicator

Steroids have attracted concern worldwide because of their potential carcinogenicity and severe adverse effects on aquatic organisms. However, the contamination status of various steroids, particularly their metabolites, at the watershed level remains unknown. This was the first study to employ field investigations to elucidate the spatiotemporal patterns, riverine fluxes, and mass inventories, and conduct a risk assessment of 22 steroids and their metabolites. This study also developed an effective tool for predicting the target steroids and their metabolites in a typical watershed based on the fugacity model combined with a chemical indicator. Thirteen steroids in the river water and seven steroids in sediments were identified with total concentrations of 1.0–76 ng/L and <LOQ–121 ng/g, respectively. In water, the levels of steroids were higher in the dry season, but the opposite trend was observed in sediments. Approximately 89 kg/a flux of steroids were transported from the river to the estuary. Mass inventories indicated that sediments acted as crucial sinks for steroids. Steroids in rivers might pose low to medium risks to aquatic organisms. Importantly, the fugacity model combined with a chemical indicator effectively simulated the steroid monitoring results within an order of magnitude at the watershed level, and various key sensitivity parameter settings provided reliable steroid concentration predictions under different circumstances. Our results should benefit environmental management and pollution control of steroids and their metabolites at the watershed level.

High-density lipoprotein cholesterol levels is negatively associated with intertrochanter bone mineral density in adults aged 50 years and older.

High-density lipoprotein cholesterol (HDL-C) has long been viewed as a protective factor for cardiovascular health. Yet, higher HDL-C was not necessarily beneficial. The purpose of this study was to investigate the relationship between HDL-C levels and intertrochanter bone mineral density. The study collected the most recent data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Weighted multiple regression analysis was used to evaluate the relationship between HDL-C and intertrochanter BMD, and further subgroup analysis and threshold effect analysis were conducted. Finally, the relationship between HDL-C and intertrochanter BMD was analyzed by fitting smooth curves. The study included 3,345 people ranging in age from 50 to 80. HDL-C was discovered to be negatively correlated with intertrochanter BMD (β = -0.03, 95%CI: -0.04, -0.01, P = 0.0002). In subgroup analysis, the negative correlation was found among 60-70-year-olds (β = -0.04, 95%CI: -0.06, -0.02, P = 0.0010), additionally, non-Hispanic whites (β = -0.03, 95%CI: -0.05, -0.01, P = 0.0140), and obese individuals (β = -0.03, 95%CI: -0.05, -0.01, P = 0.0146). The negative correlation, on the other hand, remained significant and consistent across genders, menstruation status, hormone usage, and long-term use of steroids. The relationship between HDL-C and intertrochanter BMD was an inverted U-shaped curve in men and hormone users, with inflection points of 1.01 mmol/L and 1.71 mmol/L, and an U-shaped curve in other Hispanic and premenopausal individuals, with inflection points of 0.96 mmol/L and 1.89 mmol/L. HDL-C was negatively associated with intertrochanter BMD in people over 50 years of age, non-Hispanic whites, and obesity.

Predictors of steroid dependence and resistance in patients with ulcerative colitis

AIM: detection of steroid dependence and steroid resistance predictors in patients with ulcerative colitis (UC).PATIENTS AND METHODS: a retrospective study was conducted. The medical documentation of 1105 patients, who underwent inpatient treatment in Ryzhikh National Medical Research Center of Coloproctology from 2018 to 2021, were analyzed. 69% of patients (n=762) received systemic steroid therapy for UC. In accordance with inclusion and non-inclusion criteria, the medical documentation of 170 patients was selected for statistical analysis. Depending on the steroid status of patients, three groups were identified: group 1 (n=56) with steroid dependence, group 2 (n=56) with steroid resistance and group 3 - control (n=58), who were prescribed systemic GCS without the further development of steroid dependence and resistance.RESULTS: the incidence of steroid dependence was 23.4% (n=259), and steroid resistance was 15.2% (n=168). We identified the following predictors and risk factors of steroid dependence: age of the disease onset &lt;30 y.o. (AOR=0,960, 95%CI= 0,928-0,993, p=0,019), start dose of prednisolone &lt;60 mg (AOR=2,369, 95%ДИ= 1,030-5,441, p=0,042), prescription of systemic GCS ≥2 courses per year (AOR=2,988, 95%ДИ= 1,349-6,619, p=0,007), Mayo Index Score &lt;10 (AOR=0,631, 95%ДИ=0,492-0,809, p&lt;0,001). The risk of steroid resistance statistically significant when Mayo Index Score ≥10 (AOR=2,573, 95%ДИ=1,094-6,050, p=0,030), albumin level &lt;37,1 g/l (AOR=4,571, 95%ДИ=1,567-13,330, p=0,005), CRP ≥47,1 mg/l (AOR=2,641, 95%ДИ=1,102-6,328, p=0,029).CONCLUSION: it is rational to predict an individual response to GCS in patients with UC. With a high risk of developing steroid dependence and steroid resistance, it is advisable to consider early appointment of biological and target therapy, avoiding represcription of GCS.