A National Study of the Associations between Hormonal Modulators in Hydraulic Fracturing Fluid Chemicals and Birth Outcomes in the United States of America: A County-Level Analysis.

BACKGROUND: Risk of preterm birth (PTB) and low birth weight (LBW) due to hydraulic fracturing (HF) exposure is a growing concern. Regional studies have demonstrated links, but results are often contradictory among studies. OBJECTIVES: This is the first US national study to our knowledge linking fracturing fluid ingredients to the human hormone pathways targeted-estrogen, testosterone, or other hormones (e.g., thyroid hormone)-to assess the effect of HF ingredients on rates of PTB and LBW. METHODS: We constructed generalized linear regression models of the impact of HF well density and hormone targeting chemicals in HF fluids (2001-2018) on the county-level average period prevalence rates of PTB and LBW (2015-2018) with each outcome measured in separate models. Our data sources consisted of publicly available datasets, including the WellExplorer database, which uses data from FracFocus, the March of Dimes Peristats, the US Census Bureau, the US Department of Agriculture, and the Centers for Disease Control and Prevention. We conducted additional stratified analyses to address issues of confounding. We used stratification to address issues regarding outcomes in rural vs. urban communities by assessing whether our models achieved similar results in nonmetro counties, as well as farming and mining counties. We also stratified by the year of the HF data to include HF data that was closer to the time of the birth outcomes. We also added covariate adjustment to address other important factors linked to adverse birth outcomes, including the proportion of the population belonging to various racial and ethnic minority populations (each modeled as a separate variable); education (bachelor's degree and high school); use of fertilizers, herbicides, and insecticides, acres of agricultural land per square mile; poverty; insurance status; marital status; population per square mile; maternal care deserts; and drug deaths per 100,000 people. RESULTS: We found that the density of HF wells in a county was significantly associated with both PTB and LBW rates (percentage of live births) in our fully adjusted models. We report the results from our more restrictive stratified analysis with a subset including only the 2014-2018 data, because this resulted in the most meaningful time frame for comparison. Across all models, the magnitude of effect was highest for wells with ingredients that include estrogen targeting chemicals (ETCs), testosterone targeting chemicals (TTCs) and other hormone targeting chemicals (OHTCs), and, finally, all wells grouped regardless of chemical type. For every unit increase in well density per square mile of wells that use chemicals that include an ETC, we observed a 3.789-higher PTB rate (95% CI: 1.83, 5.74) compared with counties with no ETC wells from 2014 to 2018 and likewise, we observed a 1.964-higher LBW rate (95% CI: 0.41, 3.52). Similarly, for every unit increase in well density per square mile of wells that use TTC, we observed a 3.192-higher PTB rate (95% CI: 1.62, 4.77) compared with counties with no TTC wells. Likewise, for LBW, we found a 1.619-higher LBW rate (95% CI: 0.37, 2.87). We also found that an increase in well density per square mile among wells that use chemicals that include an OHTC resulting in a 2.276-higher PTB rate (95% CI: 1.25, 3.30) compared with counties with no OHTC wells, and for LBW, we found a 1.244-higher LBW rate (95% CI: 0.43, 2.06). We also explored the role of HF well exposure in general (regardless of the chemicals used) and found that an increase in total well density (grouped regardless of hormonal targeting status of the chemicals used) resulted in a 1.228-higher PTB rate (95% CI: 0.66, 1.80) compared with counties with no wells, and for LBW, we found a 0.602-higher LBW rate (95% CI: 0.15, 1.05) compared with counties with no wells. We found similar results in our primary analysis that used all data without any exclusions and the statistical significance did not change. DISCUSSION: Our findings reinforce previously identified regional associations between HF and PTB and LBW, but on a national scale. Our findings point to dysregulation of hormonal pathways underpinning HF exposure risk on birth outcomes, which warrants further exploration. Future research must consider the specific ingredients used in HF fluids to properly understand the differential effects of exposure. https://doi.org/10.1289/EHP12628.

The Intersection between Tryptophan-Kynurenine Pathway Metabolites and Immune Inflammation, Hormones, and Gut Microbiota in Perinatal Depression.

Perinatal depression is a prevalent mental disorder among pregnant women, characterized by sleep disturbances, appetite changes, negative emotions, cognitive impairment, and suicidal or homicidal tendencies. These symptoms severely compromise personal well-being, disrupt family life, and burden society. Early detection and intervention are thus crucial. The tryptophan-kynurenine (TRP-KYN) pathway is central to the inflammatory hypothesis of depression and has gained significant attention in perinatal depression research. This pathway encompasses numerous metabolic enzymes and neuroactive metabolites that interact with other physiological systems, influencing neurotransmitter synthesis and neuronal development. Through these interactions, the TRP-KYN pathway exerts psychotropic effects. This article reviews the key metabolites and enzymes of the TRP-KYN pathway and examines its intersection with immune inflammation, hormones, and gut microbiota.

Hormones as a double-edged sword: the role of hormones in cancer progression and the potential of targeted hormone therapies.

Cancer remains a significant cause of mortality in the world, with increasing prevalence worldwide. There are numerous treatments ranging from surgery to chemotherapy and radiotherapy, but since cancer is a heterogeneous disease, only few patients possibly respond to treatments. However, it opens a huge space for the advent of targeted therapies such as hormone therapy, immunotherapy, and target-specific drugs. Hormonal therapy using hormone agonists/antagonists or hormone receptor inhibitors-called the next-generation hormonal agents-hits distinct hormonal pathways that are involved in breast, prostate and ovarian cancer. Preliminary results show that through combination of drugs, it is possible that the synergistic effects may actually lead to better survival than with the use of single drugs. With manageable adverse effects, hormonal therapy offers much hope for treatment of this rather challenging malignancy of the hormone-sensitive cancers, especially in combination with other treatments.

The impact of hormones on lung development and function: an overlooked aspect to consider from early childhood.

The impact of hormones on the respiratory system constitutes a multifaceted and intricate facet of human biology. We propose a comprehensive review of recent advancements in understanding the interactions between hormones and pulmonary development and function, focusing on pediatric populations. We explore how hormones can influence ventilation, perfusion, and pulmonary function, from regulating airway muscle tone to modulating the inflammatory response. Hormones play an important role in the growth and development of lung tissues, influencing them from early stages through infancy, childhood, adolescence, and into adulthood. Glucocorticoids, thyroid hormones, insulin, ghrelin, leptin, glucagon-like peptide 1 (GLP-1), retinoids, cholecalciferol sex steroids, hormones derived from adipose tissue, factors like insulin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and glucagon are key players in modulating respiratory mechanics and inflammation. While ample evidence underscores the impact of hormones on lung development and function, along with sex-related differences in the prevalence of respiratory disorders, further research is needed to clarify their specific roles in these conditions. Further research into the mechanisms underlying hormonal effects is essential for the development of customizing therapeutic approaches for respiratory diseases. Understanding the impact of hormones on lung function could be valuable for developing personalized monitoring approaches in both medical and surgical pediatric settings, in order to improve outcomes and the quality of care for pediatric patients.

Ratiocination of ratios in endocrinology.

Endocrinology is an ever-evolving almanac of science. Precise measurement of hormones and associated analytes are necessary to practice endocrine medicine. As the endocrine system depends upon feedback and crosstalk between various glands and hormones, it makes sense to assess ratios or proportions of related hormones. We review the ratiocination, or rationale, of ratios which have diagnostic and therapeutic utility in endocrine praxis.

Progress in nanoparticle-based electrochemical biosensors for hormone detection.

Hormones are chemical messengers that regulate a wide range of physiological processes including metabolism, development, growth, reproduction and mood. The concentration of hormones that orchestrate the numerous bodily functions is very low (1 nM or less). Efforts have been made to develop highly sensitive tools to detect them. This review represents a critical comparison between different types of nanoparticle-based electrochemical biosensors for the detection of various hormones, namely cortisol, sex hormones (estradiol, progesterone, testosterone), insulin, thyroid-stimulating hormone (TSH) and growth hormone (GH). The electrochemical biosensors investigated for each hormone are first divided on the basis of the biological fluid tested for their detection, and successively on the basis of the electrochemical transducer utilized in the device (voltammetric or impedimetric). Focus is placed on the nanoparticles employed and the successive electrode modification developed in order to improve detection sensitivity and specificity and biosensor stability. Limit of detection (LOD), linear range, reproducibility and possibility of regeneration for continuous reuse are also investigated and compared. The review also addresses the recent trends in the development of wearable biosensors and point-of-care testing for hormone detection in clinical diagnostics useful for endocrinology research, and the future perspectives regarding the integration of nanomaterials, microfluidics, near field communication (NFC) technology and portable devices.

Simulated weightlessness procedure, head-down bed rest has reversible effects on the metabolism of rhesus macaque.

It is a consensus in the international manned space field that factors such as microgravity during the space flight can cause anxiety, depression and other important brain function abnormalities in astronauts. However, the neural mechanism at the molecular level is still unclear. Due to the limitations of research conditions, studies of biological changes in the primate brain have been comparatively few. We took advantage of -6° head-down bed rest (HDBR), one of the most implemented space analogues on the ground, to investigate the effects of simulated weightlessness on non-human primate brain metabolites. The Rhesus Macaque monkeys in the experiment were divided into three groups: the control group, the 42-day simulated weightlessness group with HDBR, and the recovery group, which had 28 days of free activity in the home cage after the HDBR. Liquid chromatography-mass spectrometry (LC-MS) was used to perform metabolomics analysis on specific brain areas of the monkeys under three experimental conditions. Our results show that simulated weightlessness can cause neurotransmitter imbalances, the amino acid and energy metabolism disorders, and hormone disturbances. But these metabolomics changes are reversible after recovery. Our study suggests that long-term brain damage in space flight might be reversible at the metabolic level. This lays a technical foundation for ensuring brain health and enhancing the brain function in future space studies.

Gut-Brain Axis: Role of Microbiome, Metabolomics, Hormones, and Stress in Mental Health Disorders.

The influence of gut microbiome, metabolites, omics, hormones, and stress on general and mental health is increasingly being recognized. Ancient cultures recognized the importance of diet and gut health on the overall health of an individual. Western science and modern scientific methods are beginning to unravel the foundations and mechanisms behind some of the ancient beliefs and customs. The gut microbiome, an organ itself, is now thought to influence almost all other organs, ranging from the brain to the reproductive systems. Gut microbiome, metabolites, hormones, and biological sex also influence a myriad of health conditions that range from mental health disorders, obesity, gastrointestinal disorders, and cardiovascular diseases to reproductive health. Here, we review the history and current understanding of the gut-brain axis bidirectional talk in various mental health disorders with special emphasis on anxiety and depressive disorders, whose prevalence has increased by over 50% in the past three decades with COVID-19 pandemic being the biggest risk factor in the last few years. The vagal nerve is an important contributor to this bidirectional talk, but other pathways also contribute, and most remain understudied. Probiotics containing Lactobacillus and Bifidobacterium species seem to have the most impact on improvement in mental health symptoms, but the challenge appears to be maintaining sustained levels, especially since neither Lactobacillus nor Bifidobacterium can permanently colonize the gut. Ancient endogenous retroviral DNA in the human genome is also linked to several psychiatric disorders, including depression. These discoveries reveal the complex and intricately intertwined nature of gut health with mental health disorders.

A Novel "Endocrine Hormone": The Diverse Role of Extracellular Vesicles in Multiorgan Insulin Resistance.

Insulin resistance is the primary contributor to the disruption in glucose homeostasis in the body, playing a significant causative role in many metabolic diseases. Insulin resistance is characterized by compensatory insulin secretion and reduced insulin responsiveness in target organs. Dysregulation of the interaction between insulin-secreting cells and insulin-responsive target organs is an important factor driving the progression of insulin resistance. Circulating endocrine hormones are important mediators mediating the interaction between insulin-secreting cells and insulin-responsive target organs. In addition to the classical hormones secreted by endocrine glands and organ-specific hormones secreted by metabolism-related organs (adipose tissue, muscle, liver, etc.), extracellular vesicles have been recognized as a novel class of endocrine hormones with a complex composition. Extracellular vesicles can transport signaling molecules, such as miRNAs and LncRNAs, to vital organs related to insulin resistance, in a manner akin to conventional hormones. The significant role in regulating the development of insulin resistance underscores the increasing interest in extracellular vesicles as essential contributors to this process. In this review, we summarize the three types of hormones (classical hormones, organokines and extracellular vesicles) that play a regulatory role in insulin resistance, and focus on the novel endocrine hormones, extracellular vesicles, to elaborate the mechanism of extracellular vesicles' regulation of insulin resistance progress from two aspects: the impact on insulin-secreting cells and the influence on insulin-responsive target organs. In addition, this paper outlines the clinical applications of extracellular vesicles in insulin resistance. A comprehensive understanding of the regulatory mechanisms and diagnostic status of the inter-organ network in insulin resistance has great potential to advance targeted therapeutic interventions and diagnostic markers, thereby benefiting both the prevention and treatment of insulin resistance.

Subchronic toxic effects of bisphenol A on the gut-liver-hormone axis in rats via intestinal flora and metabolism.

Background: Bisphenol A (BPA), a characteristic endocrine disruptor, is a substance that seriously interferes with the human endocrine system and causes reproductive disorders and developmental abnormalities. However, its toxic effects on the gut-liver-hormone axis are still unclear. Method: Male and female rats were exposed to BPA (300 mg/kg) by oral gavage for 60 consecutive days. H&E staining was used for histopathological evaluation, and the serum biochemical indexes were determined using an automatic analyzer. The 16S rRNA gene sequencing was used to detect the intestinal microbial diversity, and the GC-MS was used to analyze the contents of short-chain fatty acids (SCFAs) in colon contents. UPLC-QTOF MS was used to analyze the related metabolites. The ELISA method was used to assess the levels of serum inflammatory factors. Results: Histopathological analysis indicated that the liver, heart, and testis were affected by BPA. There was a significant effect on alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) in the male-BPA group (P < 0.05), and globulin (GLB), indirect bilirubin (IBIL), alkaline phosphatase (ALP), ALT, TG, TC, high-density lipoprotein (HDL), and creatinine (Cr) in the female-BPA group (P < 0.05). Metagenomics (16S rRNA gene sequencing) analysis indicated that BPA reduced the diversity and changed the composition of gut microbiota in rats significantly. Compared with the control and blank groups, the contents of caproic acid, isobutyric acid, isovaleric acid, and propanoic acid in the colon contents decreased in the male-BPA group (P < 0.05), and caproic acid, isobutyric acid, isovaleric acid, and valeric acid in the colon contents decreased in the female-BPA group (P < 0.05). Metabolomic analysis of the serum indicated that BPA could regulate bile acid levels, especially ursodeoxycholic acid (UDCA) and its conjugated forms. The contents of amino acids, hormones, and lipids were also significantly affected after exposure to BPA. The increase in interleukin-6 (IL-6), interleukin-23 (IL-23), and transforming growth factor-ß (TGF-ß) in the serum of the male-BPA group suggests that BPA exposure affects the immune system. Conclusion: BPA exposure will cause toxicity to rats via disrupting the gut-liver-hormone axis.

A study on the mediating role of serum hormones in the effects of heavy metals on preeclampsia.

Exposure to environmental heavy metals may pose a risk factor for developing preeclampsia (PE) modified through intervention. This case-control study aimed to investigate the association between serum heavy metal concentrations and PE in pregnant women and whether hormones served as mediating factors in the impact of heavy metals on PE. From October 2020 to 2022, 160 patients with PE and 160 pregnant women with normal deliveries were recruited at Dongguan Songshan Lake Central Hospital. Serum concentrations of manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd), lead (Pb), ß-human chorionic gonadotropin (ß-hCG), progesterone (P), estradiol (E2), testosterone (T), cortisol (Cort), and cortisone (Cor) were measured. Logistic, restricted cubic splines, weighted quantile sum and multivariate linear regression models were employed to account for different aspects and explore the relationships among heavy metals, hormones, and PE. Mediation model analysis was performed to assess the role of hormones in mediation. The median concentrations of Mn, E2, and Cort were lower in the PE group than in the control group. The median concentrations of Cu, Zn, ß-hCG, and T were higher in the PE than in the control. Mn, E2, and Cort showed negative associations with PE, while Cu, Zn, ß-hCG, and T demonstrated positive associations, as determined through logistic regression. Mn, Cu, and Zn displayed linear dose-response relationships with PE. Zn and Cu had high weights in the positive association model of mixed heavy metal exposure with PE. The mediation analysis revealed that serum E2, P, T, Cort, and Cort/Cor might be potential mediators of the association between heavy metals (Mn, Cu, and Zn) and PE.

[Simultaneous determination of 61 hormones in water by solid phase extraction-ultra performance liquid chromatography-tandem mass spectrometry].

Concerns over the emergence of steroid hormones as pollutants in water have grown. Steroid hormone compounds present challenges in the simultaneous detection of total residual hormones owing to their analogous structures and diverse types. In this study, we established a rapid and high-throughput continuous online method based on solid phase extraction (SPE) coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the simultaneous determination of 61 hormone components, including 48 glucocorticoids, 1 mineralocorticoid, 4 androgens, and 8 progesterones, in water. Various SPE columns were investigated to assess their extraction efficiency for enriching and purifying target compounds in a large sample volume (1 L). An HC-C18 SPE column was selected because of its superior performance. Acetonitrile was used as a washing solution during SPE to ensure that the majority of the tested substances achieved recoveries exceeding 70% and effectively avoid interferences from water-soluble components. Various C8 and C18 columns were tested, and the optimal HPLC conditions for hormone retention were established. We systematically evaluated different UPLC columns and mobile phases, including methanol-water and acetonitrile-water systems with 0.1% formic acid added to the aqueous phase. The optimized UPLC conditions were as follows: BEH C18 column (100 mm×2.1 mm, 1.7 µm); column temperature, 40 ℃; flow rate, 0.3 mL/min; injection volume, 5 µL; mobile phase A: 0.1% formic acid aqueous phase; mobile phase B: acetonitrile. Gradient elution was performed as follows: 0-0.5 min, 30%B; 0.5-15.0 min, 30%B-75%B; 15.0-18.0 min, 75%B-98%B; 18.0-19.0 min, 98%B; 19.0-19.1 min, 98%B-30%B; 19.1-20.0 min, 30%B. Both positive- and negative-ion modes were explored in the UPLC-MS/MS experiment to obtain the full scan of the parent ions, and positive mode was finally selected for electrospray ionization (ESI). Two product ions exhibiting strong signals and minimal interference were selected for quantitative and qualitative ion analyses, using an external standard method for quantification. MS/MS was performed in positive-ion (ESI+) mode with multiple reaction monitoring (MRM) scanning. The MS/MS parameters were as follows: atomizing gas pressure, 379 kPa; curtain air pressure, 241 kPa; spray voltage, 5500 V; desolvation temperature, 550 ℃; collision exit voltage (CXP), 13 V; intake voltage (EP), 10 V; and residence time of each ion pair, 0.5 ms. Other instrument settings, such as the collision energy and declustering voltage, were also optimized. The 61 hormones exhibited excellent linear relationships within their corresponding concentration ranges, with correlation coefficients greater than 0.99. The method detection limits (MDLs) were in the range of 0.05-1.50 ng/L. The average recoveries of the 61 hormones across three spiked levels ranged from 62.3% to 125.2%, with relative standard deviations (RSDs, n=6) of 1.1%-10.5%. Using this method, we successfully detected 10 hormone components (cortisone, fluticasone propionate, ciclesonide, betamethasone dipropionate, clobetasone butyrate, diflucortolone valerate, halobetasol propionate, isoflupredone, difluprednate, and hydroxyprogesterone caproate) in various surface water and groundwater samples collected from the Taihu Basin region. The SPE-UPLC-MS/MS method presented in this paper is simple, highly sensitivity, and exceptionally accurate. Thus, it exhibits promising potential for tracing targeted hormone residues in water and will be of great value in monitoring and ensuring water safety. Finally, a regional analysis was conducted on the hormone levels in water, and suggestions were made for the targeted treatment of hormone residues in future sewage treatment processes.

Extended Chemical and Microbial Stability of Various Hormones in Phytobase and HRT Heavy Cream Bases.

The release of USP chapter <800> Hazardous Drugs -Handling in Healthcare Settings and the major revisions to USP <795> Pharmaceutical Compounding -Nonsterile Preparations in 2023 rendered many studies previously used to justify extended beyond use date (BUD) no longer sufficient. To provide compounders with high quality evidence to support physical, chemical, and microbial stability of hormone preparations in two aqueous cream vehicles, Phytobase™ and HRT Heavy™, we set out to perform stability indicating testing and antimicrobial effectiveness testing (AET) per USP <51> on 12 different combinations bracketed in high and low concentrations (for a total of 24 tested formulas) of common topical and transdermal hormones. In this study we discuss the suitability of Phytobase™ and HRT Heavy™ for compounded hormone therapy (CHT) and the compatibility of these vehicles with hormones including estriol, estradiol, testosterone, progesterone, and dehydroepiandrosterone both alone and in combination.

Consideration of hormonal changes for orthodontic treatment during pregnancy and lactation - a review.

Hormonal changes in pregnant and lactating women significantly affect bone metabolism and overall stress levels, positioning them as a unique group within the orthodontic population. Fluctuations in estrogen, progesterone, prolactin, and other hormones are closely linked to bone remodeling and the periodontal tissue's response to inflammation caused by dental plaque. Hormones such as thyrotropin, leptin, and melatonin also play crucial roles in pregnancy and bone remodeling, with potential implications for orthodontic tooth movement. Additionally, adverse personal behaviors and changes in dietary habits worsen periodontal conditions and complicate periodontal maintenance during orthodontic treatment. Notably, applying orthodontic force during pregnancy and lactation may trigger stress responses in the endocrine system, altering hormone levels. However, these changes do not appear to adversely affect the mother or fetus. This review comprehensively examines the interaction between hormone levels and orthodontic tooth movement in pregnant and lactating women, offering insights to guide clinical practice.

Clinical Evaluation of Response to Octreotide and Chemotherapy in High-Grade Malignant Neuroendocrine Tumors and Promising In Vitro Preclinical Results with Pasireotide.

Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.