Hormone Axis Research Articles

Abstract 4141498: Coronary Atherosclerosis and Prostate Cancer: The Impact of Androgen Deprivation Therapy

Background: Men with prostate cancer (PC) who receive androgen-deprivation therapy (ADT), targeting the gonadotropin releasing hormone (GNRH) axis, are at higher risk of cardiovascular disease (CVD). However, the pathophysiology behind ADT cardiotoxicity is unclear. Hypothesis: We hypothesize that ADT is associated with accelerated atherosclerosis due to GNRH-mediated inflammatory cascade. Aims: To prospectively evaluate coronary plaque progression, using coronary computed tomography angiography (CCTA), in a cohort of PC men treated with versus without ADT. Methods: Sixty-eight men with localized PC receiving radiation (XRT) alone (n=17) or XRT+ADT (n=51) were prospectively enrolled. Patients underwent CCTA, as per clinical protocols , at baseline and 12-month follow-up. Plaque quantification was conducted, blinded to therapy and time-point, using semi-automated software (Coronary analysis research prototype, Siemens Healthineers, Forchheim, Germany), with assessment of total plaque volume (TPV) and plaque volume by subtype (calcified, CPV, high-density non-calcified, HD, low-density non-calcified, LD) on a per-patient basis. CAD-RADS was also evaluated. Results: At baseline, median (IQR) TPV, CPV, HD, LD (mm 3 ) and CAD-RADS among patients who received XRT alone versus XRT+ADT were 341.1 (118.5-778.2) vs 717.3 (207-1158.9), 22.2 (4.9-131.9) vs 74.3 (21.3-205.8), 306.6 (102.1-593.6) vs 585.8 (175-895.2), 14 (2.3-47) vs 22.6 (6.2-50.4), 1 (1-2) vs 2 (2-3), respectively. At 12-month follow-up, TPV, CPV, HD, LD, and CAD-RADS between XRT alone versus XRT+ADT were 410.1 (177-941) vs 904.6 (283.7-1402), 21 (12.1-195.1) vs 102.6 (30.5-259.4), 372.6 (157.6-721.6) vs 686.1 (242.7-1062.7), 11.7 (5.6-69.8) vs 34 (10.4-62.1), 2 (1-2) vs 3 (2-3). A statistically significant difference between baseline and follow-up was noted among patients treated with XRT+ADT for TPV, CPV, LD (p<0.001), and HD (p=0.006). A significant difference in CAD-RADS grade was noted in both cohorts (p=0.025 for XRT and p<0.001 for the XRT +ADT). There was no significant difference in any plaque volume between baseline and follow-up in the XRT alone cohort. Conclusion: Addition of ADT to XRT for localized PC treatment was associated with a significant progression of TPV, CPV, HD, LD, and CAD-RADS grade over a 12-month period. Insights on ADT cardiotoxicity may lead to enhanced cardioprotective strategies tailored to patients with PC undergoing combined therapy, potentially improving cardiac outcomes.

Protective Strategies for Pituitary Function During Endoscopic Transnasal Pituitary Adenoma Surgery: A Single-center Experience.

This study investigated the impact of endoscopic transnasal pituitary adenoidectomy on function and discussed the factors that contribute to postoperative pituitary function. To provide a foundation for protecting pituitary function and improving the curative effect of pituitary adenoma neuroendoscope resection. From January 2019 to January 2022, in the Neurosurgery Pituitary Tumor Diagnosis and Treatment Research Center, the First Affiliated Hospital of Shenzhen University, the clinical data of 306 patients who underwent endoscopic transnasal pituitary adenoma surgery were analyzed retrospectively. The surgical treatment strategy was discussed and explored, while the factors related to pituitary function were examined based on tumor size and Knosp grade. There were 40 cases (67.8%) of pituitary-thyroid axis, 18 cases (60%) of pituitary-adrenal axis, 25 cases (45.4%) of pituitary-gonad axis, 5 cases (62.5%) of pituitary-growth hormone axis, and 8 cases (72.7%) of diabetes insipidus with postoperative improves of hypopituitarism. Postoperative newly developed hypopituitarism occurred in 20 cases (8.1%) of pituitary-thyroid axis, 15 cases (5.4%) of pituitary-adrenal axis, 10 cases (4.0%) of pituitary-gonad axis, 5 cases (1.7%) of pituitary-growth hormone axis, and 8 cases (2.7%) of new diabetes insipidus. The incidence of pituitary-adrenal axis hypofunction in giant pituitary adenomas was significantly higher than that in microadenomas and macroadenomas (P<0.05). The incidence of hypopituitarism of Knosp grade 4 pituitary adenoma before operation was higher than that of other groups (P<0.05), but there was no significant difference in the incidence of new hypopituitarism after operation (P>0.05). In endoscopic transnasal pituitary adenoma surgery, the incidence of hypothyroidism and adrenal gland dysfunction is higher than in other hormone axes, but the recovery rate is also higher, and the recovery rate of sex hormones is lower. The incidence of postoperative hypothyroidism increases dramatically with tumor size and tumor invasiveness.

Polystyrene microplastics cause reproductive toxicity in male mice

Microplastics are a common environmental pollutant that disrupts the reproductive system of living organisms. We investigated the reproductive toxicity of 2μm polystyrene microplastics (PS-MPs) in mice and treated them with PS-MPs for 6 weeks. We demonstrated that PS-MPs decreased the gonadosomatic index and the serum concentration of pituitary-testicular axis hormones (Follicle-stimulating hormone, Luteinizing hormone, and testosterone). The PS-MPs treatment also reduced viable epididymal sperm number and sperm motility. Our results also demonstrated a marked decrease in tubular differentiation index, spermatogenesis index, repopulation index, and steroidogenic foci. The PS-MPs treated mice demonstrated marketed tissue damage in the testis. We also found that reproductive abnormality in PS-MPs treated mice accompanied by reduced antioxidant capacity elevated oxidative stress, and, elevated apoptotic signaling. It was observed that Endoplasmic reticulum (ER) stress markers, including GRP78 and Chop, were upregulated. Based on these findings, oxidative stress and endoplasmic reticulum stress may contribute to the decline in the steroidogenic function of Leydig cells with PS-MPs treated.

An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells

Insulin is an important regulator of whole-body glucose homeostasis. In insulin sensitive tissues such as muscle and adipose, insulin induces the translocation of glucose transporter 4 (GLUT4) to the cell membrane, thereby increasing glucose uptake. However, insulin also signals in tissues that are not generally associated with glucose homeostasis. In the human reproductive endocrine axis, hyperinsulinemia suppresses the secretion of gonadotropins from gonadotrope cells of the anterior pituitary, thereby linking insulin dysregulation to suboptimal reproductive health. In the mouse, gonadotropes express the insulin receptor which has the canonical signaling response of IRS, AKT, and mTOR activation. However, the functional outcomes of insulin action on gonadotropes are unclear. Here, we demonstrate through use of an optimized cell fractionation protocol that insulin stimulation of the LβT2 gonadotropic cell line results in the unexpected translocation of GLUT1 to the plasma membrane. Using our high purity fractionation protocol, we further demonstrate that though Akt signaling in response to insulin is intact, insulin-induced translocation of GLUT1 occurs independently of Akt activation in LβT2 cells.

Long story from past to present: calcium, phosphorus, and phytase

Abstract Calcium (Ca) and phosphorus (P), two main elements, have vital physiological and metabolic roles in animal bodies. Accurate comprehension of the interaction of these two elements and their value in various resources helps to obtain their optimal formulation in poultry diets. Hence, in previous studies, the hormonal axes controlling Ca and P homeostasis have been primarily investigated. However, to estimate Ca and P requirements in modern broiler chickens, in addition to growth performance, other parameters such as Ca and P digestibility, bone strength, and excretion into the environment should also be considered. Since a large amount of P in poultry feed ingredients is bound to phytate, phytases are added to poultry diets to release the P from phytate. However, many nutritionists need clarification on what dose of dietary phytase is required to release the maximum phytate P and how phytase activity will be optimized. Therefore, the present review study has attempted to explore the factors that affect the digestibility of different resources of Ca and P. In addition, the effect of excess dietary Ca on phytase activity and studies related to super dosing of phytase in broilers are provided. Finally, the values of phytate P in standard poultry feed ingredients and the latest update of the studies on determining Ca and P requirements are summarized.

Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218

Abstract Young children are attracted to flavored foods with enhancers, particularly monosodium glutamate (MSG). Experimental studies have proven that MSG can alter the hypothalamic–pituitary–adrenal (HPA) axis response in neonates. We, therefore, investigated the modulation of microRNAs (miRNAs) by dietary MSG and its association with the stimulation of the HPA axis and inflammatory response in young male rats. One-month-old male rats were fed chow enriched with MSG (3 g/kg) for 16 weeks. Feeding MSG to rats markedly up-regulated hypothalamic miR-218, Toll-like receptors-4, and nuclear factor-kB but down-regulated miR-155 and glucocorticoid receptors (GR). In addition, it triggered a remarkable elevation in adrenocortical lipid peroxidation and depletion of antioxidants. These changes were coupled with increased plasma levels of the HPA axis hormones, comprising corticotropin-releasing hormone, adrenocorticotropic hormone, corticosterone levels, and serum pro-inflammatory cytokines. Taken together, current findings indicated that MSG caused an activation of the HPA axis, a down-regulation of GRs, and a systemic inflammatory response. These disturbances were associated with modulating hypothalamic miRNAs, encompassing miR-218 and 155.

Serum calcium improves the relationship between fluoride exposure and hypothalamic-pituitary-testicular axis hormones levels in males—a cross-sectional study on farmers in the lower reaches of the Yellow River

Numerous studies have reported the toxicity of fluoride to the male reproductive system, but epidemiological evidence is limited. We conducted a cross-sectional study in Kaifeng City, Henan Province in 2011 to explore the association between fluoride exposure and hypothalamic-pituitary-testicular (HPT) axis hormones in men. Morning urinary fluoride (UF), serum HPT axis hormones and serum calcium (SC) concentrations were detected. Percent changes and 95% confidence intervals in HPT axis hormones associated with UF were estimated using adjusted linear regression models, and performed subgroup analysis based on SC levels. The restricted cubic spline model was used to fit nonlinear relationships. For every 10% increase in UF, the concentrations of serum GnRH, T, SHBG and TSI decreased by 2.13%, 2.39%, 2.19% and 1.96%, while E2 and FEI increased by 1.11% and 3.33%. Subgroup analysis showed that for every 10% increase in UF, the levels of GnRH, T, TSI and FTI decreased by approximately 3.15%, 5.49%, 4.47% and 5.14%, while the E2 level increased by 2.92% in low-serum-calcium group (LCG). The levels of GnRH and T decreased by approximately 2.97% and 1.82% in medium-serum-calcium group (MCG). In high-serum-calcium group (HCG), serum SHBG levels decreased by 4.70%, while FTI and FEI levels increased by 4.93% and 4.20% as UF concentration increased (P < 0.05, respectively). The non-linear relationship between serum GnRH and UF concentrations presented an approximately inverted U-shaped curve, with a turning point UF concentration of 1.164 mg/L (P < 0.001), and their nonlinear relationship in LCG and MCG were similar to that in the overall subjects. In conclusion, excessive exposure to fluoride can interfere with male serum HPT axis hormones, and a moderate increase in SC alleviates the effect of fluoride. Prospective cohort studies are essential to confirm the causality.

8015 Growth Hormone Axis Dysfunction in PMM2-CDG: Exploring the Role of Dynamic Tests for the Management of Short Stature in Two Pediatric Cases

Abstract Disclosure: G. Del Medico: None. E. Procopio: None. L. Ferri: None. A. Barbato: None. A. Morrone: None. S. Stagi: None. PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) and is caused by defective phosphomannomutase2 (PMM2) activity. According to the 2019 guidelines, approximately half of PMM2-CDG patients exhibit short stature and low serum levels of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), and acid-labile subunit (ALS). Despite this, there is no expert consensus on the endocrinological management of this condition. We investigated the growth hormone (GH) axis in two 12-year-old female patients with PMM2-CDG. The first patient was compound heterozygote for the most common PMM2 gene variants in Italy, p.(Leu32Arg) and p.(Arg141His). She presented with short stature (&amp;lt; 2 Standard Deviation Score, SDS) and low serum levels of IGF-1 and IGF-BP3 (&amp;lt; 2.5° for age and sex). Bone age was significantly delayed. Tanner stage was prepubertal. Somatotropic response to GH stimulation testing (Levodopa) was normal. After the IGF-1 generation test with recombinant GH, serum IGF-1 increased by 115%. The second patient was compound heterozygote for the known PMM2 pathogenetic variant p.(Ala108Val) and the novel p.(Thr171Asnfs*11) variant (only case described in literature). She presented short stature (&amp;lt; 2 SDS) with near-to-normal IGF-1 and IGF-BP3 serum levels (2.5° for age and sex). Bone age was slightly delayed. Tanner stage was prepubertal. She also exhibited severe obesity, hypertriglyceridemia, and hepatic steatosis. Her somatotropic response to two GH stimulation tests (Levodopa and Arginine) was deficient, probably because of her significant overweight. IGF-1 serum levels didn’t increase after the IGF-1 generation test. Hypoglycosylation in PMM2-CDG impairs the IGF1 system on multiple levels. It destabilizes the ternary complex formed by IGF-1 and glycoproteins IGFBP3 and ALS, therefore reducing the half-life of circulating IGF-1. Hypoglycosylation also reduces IGF1 production by impairing its precursor proIGF-1Ea and its cellular secretion. As a result, PMM2-CDG patients have GH insensitivity, with normal GH production but low levels of IGF-1. However, there is a lack of information in the literature on the use of dynamic tests and hormonal therapies (GH and rhIGF-1) in CDG. The IGF-1 generation test in our patients showed partial GH sensitivity in the first patient and GH insensitivity in the second patient. These observations suggest variability. Some PMM2-CDG patients may benefit from an extended trial with GH therapy, while for GH-insensitive patients a trial with recombinant IGF-1 might be considered. This is one of the first reports that explores the potential role of dynamic tests in PMM2-CDG. As the biochemical effects of hypoglycosylation on the GH-IGF1 pathway are becoming clearer more clinical research is needed to reach a consensus on the management and treatment of short stature in these patients. Presentation: 6/3/2024

The Metabolic Programming of Pubertal Onset.

There is increasing evidence that maternal factors such as nutritional status (both under and over-nutrition) and diabetes, alongside prenatal exposure to endocrine disrupting chemicals (EDCs), are associated with early pubertal onset in offspring. Such children are also at increased risk of the metabolic syndrome during adolescence and young adulthood. This literature review focuses on the role of the prenatal environment in programming pubertal onset, and the impact of prenatal metabolic stressors on the declining average age of puberty. A review of all relevant literature was conducted in PubMed by the authors. The mechanism for this appears to be mediated through metabolic signals, such as leptin and insulin, on the kisspeptin-neuronal nitric oxide-gonadotropin releasing hormone (KiNG) axis. Exposed children have an elevated risk of childhood obesity and display a phenotype of hyperinsunlinaemia and hyperleptinaemia. These metabolic changes permit an earlier attainment of the nutritional "threshold" for puberty. Unfortunately, this cycle may be amplified across subsequent generations, however early intervention may help "rescue" progression of this programming.

Oxidative Stress-induced Hormonal Disruption in Male Reproduction.

Research into the impacts of oxidative stress (OS), and hormonal balance on reproductive potential has increased over the last 40 years possibly due to rising male infertility. Decreased antioxidant levels and increased OS in tissues result from hormonal imbalance, which in turn leads to male infertility. Increased reactive oxygen species (ROS) generation in seminal plasma has been linked to many lifestyle factors such as alcohol and tobacco use, toxicant exposure, obesity, varicocele, stress, and aging. This article provides an overview of the crosslink between OS and gonadal hormone disruption, as well as a potential mode of action in male infertility. Disrupting the equilibrium between ROS generation and the antioxidant defense mechanism in the male reproductive system may affect key hormonal regulators of male reproductive activities. Unchecked ROS production may cause direct injury on reproductive tissues or could disrupt normal regulatory mechanisms of the hypothalamic-pituitary-gonadal (HPG) axis and its interaction with other endocrine axes, both of which have negative effects on male reproductive health and can lead to male infertility.

Lessons from Klotho mouse models to understand mineral homeostasis.

Klotho, a key component of the endocrine fibroblast growth factor receptor-fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism. In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer. In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options. This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular invivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.

Complete remission after glucocorticoid therapy in a patient with primary hypophysitis.

Primary hypophysitis is a rare disease that may have variable clinical presentations. The main treatment options are clinical observation, immunosuppressive drugs, and surgery. Glucocorticoids are used as first-line medical therapy; however, non-responsiveness and recurrences are the major problems. We present a 30-year-old male patient who had an excellent radiologic response to a single course of glucocorticoids. The patient presented with malaise and severe headaches of acute onset. Cranial MRI revealed a pituitary mass compressing the optic chiasm. Hormonal evaluation studies were consistent with anterior pituitary hormone dysfunction except for the growth hormone axis. There was a mild compression on the optic chiasm in the pituitary MRI. The patient was started on methylprednisolone therapy at a dose of 80 mg/day. The pituitary MRI revealed complete regression of the mass after 2 months, and there was a complete recovery of pituitary functions after 6 months. There is no consensus on the optimal dose and duration of glucocorticoid therapy for primary hypophysitis in the literature. We report that steroid therapy, even in lower doses, might be effective in mild-to-moderate cases. Primary hypophysitis is a rare disease with a varied clinical course, and hence the treatment strategies should be individualized. There is no consensus on the optimal dose and duration of glucocorticoid therapy. Glucocorticoid therapy may induce complete remission in some patients, especially with a mild-to-moderate disease course and during the acute phase of the disease.

A metabolomics approach reveals the pharmacological effects and mechanisms of Cistanche tubulosa stems and its combination with fluoxetine on depression in comorbid with sexual dysfunction

Ethnopharmacological relevanceThe dried succulent stems of Cistanche tubulosa (Schenk) Wight are utilized in traditional medicine for tonifying kidney yang, which have shown to be effective in alleviating depression-like behaviors or male sexual dysfunction, respectively. However, the pharmacological effects and mechanisms of C. tubulosa and its combinations in the treatment of depression in comorbid with sexual dysfunction remain unclear. Aim of the studyThis study aims to elucidate the pharmacological effects and mechanisms of C. tubulosa aqueous extract (CTE) and its combination with fluoxetine (FLX) on depression in comorbid with sexual dysfunction. Materials and methodsA mouse model of depression in comorbid with sexual dysfunction was created using the chronic unpredictable mild stress (CUMS) procedure. The therapeutic effects of CTE and its combination with FLX were assessed using depressive-like and mating behavior experiments, histopathological analysis, and hypothalamic-pituitary-gonadal (HPG) axis function evaluation. The mechanisms were explored by integrated serum and testicular metabolomics combined with network correlation analysis. ResultsCTE was confirmed to significantly improve depressive-like behaviors, reduce mating abilities, testicular histopathological damage, and HPG axis hormone secretion disorders in CUMS mice. Subsequently, mechanism exploration findings indicated that CTE might exert its effect by regulating potential efficacy-related biomarkers (isobutyrylglycine, citric acid, D-galactose) to improve certain metabolic pathways centered around steroid hormone biosynthesis and tricarboxylic acid (TCA) cycle. Furthermore, the combination of CTE and FLX exhibited stronger antidepressant effects than FLX alone, and ameliorated the exacerbated sexual dysfunction induced by FLX. These effects were achieved through the regulation of potential efficacy-related biomarkers (17α-hydroxypregnenolone, tetrahydrodeoxy-corticosterone, sphingosine, cortol, thymine, and L-histidine), thereby improving disorders in glycerophospholipid and histidine metabolism. ConclusionIn conclusion, the amelioration effects of CTE and its combination with FLX on depression in comorbid with sexual dysfunction were confirmed for the first time. This key mechanism may be achieved by modulating the levels of potential efficacy-related biomarkers, and then emphatically intervene in steroid hormone biosynthesis, TCA cycle, glycerophospholipid and histidine metabolism. The study offers a new perspective for the development and utilization of C. tubulosa.

Memory T-Cells Contribute to Calcium Release from Bones during Lactation in Mice

Objective: Milk production during lactation places a high demand for calcium that is fulfilled both from maternal bone resorption and diet. While it is known that mammary gland-derived PTHrP drives bone resorption during lactation, the impact of postpartum estrogen loss on bone has been unclear. Methods: We used a case-control study design to test the effect of estrogen loss in lactating mice. Results: In the present study, we show for the first time that estrogen loss during lactation activates memory T-cells (TM) to produce TNFα and IL-17A to aid in bone resorption and calcium release. Our studies reveal a new mechanism for the release of calcium from bone postpartum. The findings provide several new insights. First, the immune system plays a critical role in milk production postpartum. Second, evolutionarily, the pathway serves the physiological purpose of increasing bone resorption to release calcium for breastmilk production postpartum but becomes maladaptive postmenopause, leading to osteoporosis. Finally, these results highlight the crosstalk between the brain–bone–breast–endocrine axis and the immune system during lactation.

Gene expression in the hypothalamic-pituitary-thyroid axis in Seriola rivoliana early larvae development at different temperatures

We analyzed the expression of genes involved in the hypothalamic-pituitary-thyroid axis (HPT-axis) in the longfin yellowtail Seriola rivoliana early larva, including temperature effects (22, 26 and 28 °C) and days of development (day one, day two, and day six after hatching). We aimed to determine if egg and larval incubation at different temperatures could disrupt this critical endocrine axis, which, in an aquaculture context, it could provoke mortality during early metamorphosis. There was a significant interaction between temperature and developmental timing on the relative expression of thyrotropin releasing hormone (trh). Larvae at 22 °C was the longest and increased more trh expression than larvae at higher temperatures. Interestingly, thyrotropin stimulating hormone (tsh) was highly expressed after hatching. Subsequently, it was downregulated at any temperature at least until day four, suggesting a temporal inhibition of the HPT axis. Therefore, we suggest that tsh-binding (tshr) to follicles should have occurred from hatching, creating a further “cascade effect” of upregulation of larval thyroglobulin (tg) from day two in a temperature-dependent manner. Consequently, new thyroid hormones should have been produced after yolk sac absorption. The above may indicate a narrow window of larval survival, where the larval transition from endogenous to exogenous feeding would depend on the correct timing to synthesize tg. Temperature significantly affected the expressions of deiodinase 1 (dio1-downregulated) and deiodinase 2 (dio2-upregulated) after hatching. The expressions of thyroid receptors alpha (trα) and beta (trβ) remained constant after hatching without significant effects of temperature and days of development. Then, the differential expression on day six showed that all HPT-axis transcripts increased their expressions as larvae developed, which suggested a functional HPT. Finally, there was no evidence that any temperature would disrupt the endocrine’s larval axis, which indicated that the longfin yellowtail has a wide temperature adaption. Nevertheless, based on tg upregulation, we suggest that larvae should be maintained around 25–26 °C after hatching for a better chance of survival and development.

Insulin-Induced Copeptin Response in Children and Adolescents to Diagnose Arginine Vasopressin Deficiency

Introduction: The diagnosis of arginine vasopressin deficiency (AVD, formerly central diabetes insipidus) remains a challenge. In recent years, stimulated copeptin has emerged as a promising tool to diagnose AVD. Methods: In this single centre retrospective study, we identified paediatric patients with suspected pituitary insufficiency who underwent standard insulin tolerance testing (ITT) previously. Patients with AVD and non-matched controls without polyuria-polydipsia syndrome were identified. Diagnosis of AVD was confirmed retrospectively using comprehensive clinical and diagnostic characteristics. Serum copeptin concentrations were measured using a commercially available automated immunofluorescence assay (B.R.A.H.M.S Copeptin-proAVP KRYPTOR®) in −20°C stored samples collected before and 30, 45, and 60 min after insulin injection. Cut-off analyses were performed using ROC curves. Results: Twenty-five patients with AVD and 43 non-matched controls were available for analysis. Median basal copeptin concentrations of 1.51 pmol/L (IQR: 0.91–1.95; serum osmolarity: 288.5 mmol/L, IQR: 282.3–293.5) increased at a median of 30 min to a maximum of 1.95 pmol/L (IQR: 1.31–2.39) in AVD patients (p = 0.113) and from 4.41 pmol/L (IQR: 3.36–6.68; serum osmolarity: 281.0 mmol/L, IQR: 274.0–286.0, p < 0.001) to a maximum of 8.39 pmol/L (IQR: 4.95–19.72, p < 0.001) in controls. ROC analysis resulted in a cut-off of 3.0 pmol/L for maximum copeptin (91.7% sensitivity, 94.1% specificity) for the diagnosis of AVD. Conclusion: Our results suggest that insulin-stimulated serum copeptin concentrations are a sensitive and specific diagnostic tool for AVD in paediatric patients, which allows us to test multiple pituitary hormone axes simultaneously in a single test.

Bidirectional Mendelian randomization highlights causal relationships between circulating INHBC and multiple cardiometabolic diseases and traits.

Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined if Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidaemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD.

Anterior pituitary hormone dysfunction among individuals with complete heart block requiring pacemaker.

Background & objectives Neuronal hypoxia associated with conditions like traumatic brain injury and cardiac tachyarrhythmia has been implicated in causing hypopituitarism. Individuals with complete heart block (CHB) may be predisposed to develop anterior pituitary hormone dysfunction in the long term. The objective of this study was to investigate anterior pituitary hormone functions in individuals after CHB. Methods This prospective cohort study included 30 individuals (21 men and 9 women) with CHB requiring pacemaker implantation, who were evaluated at admission and then at a mean follow up of 12.4 ± 2.2 months to look for development of any degree of hypopituitarism. In addition to the measurement of hormones like follicle-stimulating hormone (FSH), luteinising hormone (LH), thyroid stimulating hormone (TSH), total tetra iodothyronines (TT4), free tetraiodothyronines (FT4), cortisol, insulin-like growth factor-1 (IGF-1), testosterone and estradiol, a fixed-dose glucagon stimulation test (GST) was performed to assess growth hormone (GH) and adrenocorticotrophic hormone (ACTH) axis. Results The mean age of the participants was 64.9 ± 11.3 yr. At follow up evaluation, 17 (56.7%) had low serum IGF-1, and among them, seven (23%) had growth hormone deficiency (GHD) (peak GH <1.0 ng/ml after GST). Six participants (20%) had ACTH deficiency (peak cortisol <9 ug/dl after GST) and one had TSH deficiency. None had prolactin (PRL) or gonadotropin deficiency. Overall, hormone deficiencies were observed in nine patients (30%). Interpretation & conclusions This pilot study detected loss of anterior pituitary hormones in a significant number of individuals of CHB at 12 months follow up. Unrecognised hypopituitarism may have resulted in significant morbidity and mortality in these individuals.

Comparison of Cranial Cruciate Ligament Rupture Incidence among Parous and Nulliparous Rottweiler Bitches: Evidence from a Lifetime Cohort Study Supporting a Paradigm of Pregnancy-Associated Protection against Subsequent Non-Reproductive Disease Outcomes.

Emerging evidence in women supports the notion that pregnancy may reset disease resistance, thereby providing protection against subsequent adverse health outcomes, but this hypothesis has not been adequately explored in domestic dogs. Cranial cruciate ligament (CCL) rupture is a degenerative orthopedic disease that frequently affects pet dogs, and its risk has been associated with disruption of the reproductive hormone axis. Our research team is conducting a lifetime cohort study of purebred Rottweilers in North America that have lived 30% longer than breed-average. Detailed medical and reproductive histories of 33 nulliparous and 32 parous Rottweilers were generated from questionnaires and review of medical records. Interviews with owners of bitches in the nulliparous group served to limit selection bias, confirming that in no instance was the reason for nulliparity based upon the owner's suspicion that a bitch had a heightened risk for CCL rupture. The risk of CCL rupture associated with parity and other exposure variables was estimated using multivariate logistic regression. Overall, CCL rupture was diagnosed in 17 of 65 (26%) bitches. Median age at first litter and CCL rupture were 3.6 and 6.5 years, respectively. Compared to nulliparous, parous bitches had a significant 94% reduction in CCL rupture risk adjusted for duration of ovary exposure, overweight body condition, dietary pattern, habitual physical activity, and work/sport activity [ORadjusted (95% CI) = 0.06 (0.01-0.46); (p = 0.006)]. The observed parity-associated CCL rupture risk reduction remained robust in sensitivity analysis excluding six nulliparous bitches for which decision not to breed was based on diagnosis of hip or elbow dysplasia, conditions which may be genetically linked to CCL rupture [ORadjusted (95% CI) = 0.08 (0.01-0.58); (p = 0.01)]. This work sets the stage for replication studies in other canine populations that should begin to explore the mechanistic basis for parity-associated CCL rupture risk reduction and to pursue other non-reproductive health outcomes in bitches whose incidence or severity may be parity-sensitive.

Early Surgical Intervention in Nonfunctioning Pituitary Macroadenomas in Adult Patients without Optic Apparatus Compression—Should We Consider It? A Matched Case-Control Study

BackgroundSurgical decompression is the recommended treatment for patients with non-functioning pituitary macroadenomas (NFPMAs) with associated visual impairment. Other relative indications for surgery include endocrinopathies, craniopathies, and headaches. Nevertheless, patients without those 'classical indications' who would otherwise be considered asymptomatic with regards to the NFPMAs, and treated conservatively with clinical radiological surveillance, may suffer higher rates of other morbidities related to the NFPMAs. We aimed to evaluate the prevalence of newly diagnosed comorbidities in conservatively treated patients with NFPMAs. MethodsWe reviewed the medical records of 55 patients with NFPMAs from 2012-2022 who lacked classical indications for surgery at diagnosis. During the follow-up period we searched for any of the following potentially associated newly reported symptoms and signs: headache, dizziness, syncope, GI symptoms, hyponatremia, falls, weakness and general deterioration, CVA related, and endocrine-related including DM-2. Patients were compared to a matched control group. Cohort patients were further analyzed to discover specific endocrine axes deficiencies, and tumor volumes were measured using MRI scans at diagnosis. Results55 patients were included in the final cohort. NFPMAs were associated with the development of newly diagnosed headaches, hypertension and Hypopituitarism. Other symptoms associated with NFPMAs included – dizziness, syncope/pre-syncope, GI-related symptoms, hyponatremia, general weakness and falls, infectious-related symptoms. Average associated ER visits in this group were higher compared to the control group. ConclusionsThese results may suggest the advantages of early surgical intervention for NFPMAs to mitigate comorbidities and improve health-related quality of life.