BACKGROUND: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them.
METHODS: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis.
RESULTS: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001-1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002-1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139-1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165-1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004-1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020-1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029-1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females.
CONCLUSIONS: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.

BACKGROUND: Infection with Angiostrongylus cantonensis (AC) in humans or mice can lead to severe eosinophilic meningitis or encephalitis, resulting in various neurological impairments. Developing effective neuroprotective drugs to improve the quality of life in affected individuals is critical.
METHODS: We conducted a Gene Ontology enrichment analysis on microarray gene expression (GSE159486) in the brains of AC-infected mice. The expression levels of melanin-concentrating hormone (MCH) were confirmed through real-time quantitative PCR (RT-qPCR) and immunofluorescence. Metabolic parameters were assessed using indirect calorimetry, and mice\'s energy metabolism was evaluated via pathological hematoxylin and eosin (H&E) staining, serum biochemical assays, and immunohistochemistry. Behavioral tests assessed cognitive and motor functions. Western blotting was used to measure the expression of synapse-related proteins. Mice were supplemented with MCH via nasal administration.
RESULTS: Postinfection, a marked decrease in Pmch expression and the encoded MCH was observed. Infected mice exhibited significant weight loss, extensive consumption of sugar and white fat tissue, reduced movement distance, and decreased speed, compared with the control group. Notably, nasal administration of MCH countered the energy imbalance and dyskinesia caused by AC infection, enhancing survival rates. MCH treatment also increased the expression level of postsynaptic density protein 95 (PSD95) and microtubule-associated protein-2 (MAP2), as well as upregulated transcription level of B cell leukemia/lymphoma 2 (Bcl2) in the cortex.
CONCLUSIONS: Our findings suggest that MCH improves dyskinesia by reducing loss of synaptic proteins, indicating its potential as a therapeutic agent for AC infection.

BACKGROUND: Irritable bowel syndrome with diarrhea (IBS-D) is frequently accompanied by depression and anxiety, resulting in a reduced quality of life and increased medical expenditures. Although psychological factors are known to play an important role in the genesis and development of IBS-D, an understanding of the central neural control of intestinal dysfunction remains elusive. Melanin-concentrating hormone (MCH) is a gut-brain peptide involved in regulating feeding, sleep-wake rhythms, and emotional states.
METHODS: This study investigated the regulation of the MCHergic neural circuit from the lateral hypothalamic area (LHA) to the dorsal raphe nucleus (DRN) on anxiety- and depression-like behaviors, intestinal motility, and visceral hypersensitivity in a mice model of IBS-D. The models of IBS-D were prepared by inducing chronic unpredictable mild stress.
RESULTS: Chemogenetic activation of the MCH neurons in the LHA could excite serotonin (5-HT) neurons in the DRN and induce anxiety- and depression-like behaviors and IBS-D-like symptoms, which could be recovered by microinjection of the MCH receptor antagonist SNAP94847 into the DRN. The mice model of IBS-D showed a reduction of 5-HT and brain-derived neurotrophic factor (BDNF) expression in the DRN, while an elevation of 5-HT and BDNF was observed in the colon through immunofluorescent staining, ELISA, and Western blot analysis. SNAP94847 treatment in the DRN alleviated anxiety- and depression-like behaviors, improved intestinal motility, and alleviated visceral hypersensitivity responses by normalizing the 5-HT and BDNF expression in the DRN and colon.
CONCLUSIONS: This study suggests that the activation of MCH neurons in the LHA may induce IBS-D symptoms via the DRN and that the MCH receptor antagonist could potentially have therapeutic effects.

BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine.
METHODS: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors.
RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine β hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling.
CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

Corticotropin-releasing hormone (CRH) is known for its crucial role in the stress response system, which could induce pituitary adrenocorticotropic hormone (ACTH) secretion to promote glucocorticoid release in the adrenal gland. However, little is known about other pituitary actions of CRH in teleosts. Somatolactin is a fish-specific hormone released from the neurointermediate lobe (NIL) of the posterior pituitary. A previous study has reported that ACTH was also located in the pituitary NIL region. Interestingly, our present study found that CRH could significantly induce two somatolactin isoforms\' (SLα and SLβ) secretion and synthesis in primary cultured grass carp pituitary cells. Pharmacological analysis further demonstrated that CRH-induced pituitary somatolactin expression was mediated by the AC/cAMP/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, transcriptomic analysis showed that both SLα and SLβ should play an important role in the regulation of lipid metabolism in primary cultured hepatocytes. These results indicate that CRH is a novel stimulator of somatolactins in teleost pituitary cells, and somatolactins may participate in the stress response by regulating energy metabolism.

BACKGROUND: Aging and preoperative sleep disorders are the main risk factors affecting postoperative cognitive outcomes. However, the pathogenesis of delayed neurocognitive recovery after surgery remains ambiguous, and there is still a lack of potential biomarkers for delayed neurocognitive recovery in older adult patients with preoperative sleep disorders. Our study aimed to explore the relationship between melanin-concentrating hormone (MCH) and delayed neurocognitive recovery early after surgery in older adult patients with preoperative sleep disorders.
METHODS: In this monocentric prospective observational study, 156 older adult patients (aged 65 years or older) with preoperative sleep disorders undergoing elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) were included at an academic medical center in Inner Mongolia, China, from October 2021 to November 2022, and all patients underwent spinal anesthesia. The Pittsburgh Sleep Quality Index (PSQI) was applied to assess the preoperative sleep quality of all patients, and preoperative sleep disorders were defined as a score of PSQI >5. We measured the levels of cerebrospinal fluid (CSF) MCH and plasma MCH of all patients. The primary outcome was delayed neurocognitive recovery early after surgery. All patients received cognitive function assessment through the Montreal Cognitive Assessment (MoCA) 1 day before and 7 days after surgery (postoperative day 7 [POD7]). Delayed neurocognitive recovery was defined as a score of POD7 MoCA <26. The potential confounders included variables with P < .2 in the univariate logistic analysis, as well as the important risk factors of delayed neurocognitive recovery reported in the literature. Multivariable logistic regression model based on the Enter method assessed the association of MCH and delayed neurocognitive recovery in older adult patients with preoperative sleep disorders.
RESULTS: Fifty-nine (37.8%) older adult patients with preoperative sleep disorders experienced delayed neurocognitive recovery at POD7. Increase in CSF MCH levels (odds ratio [OR] for an increase of 1 pg/mL = 1.16, 95% confidence interval [CI], 1.09-1.23, P < .001) and decrease in plasma MCH levels (OR for an increase of 1 pg/mL = 0.92, 95% CI, 0.86-0.98, P = .003) were associated with delayed neurocognitive recovery, after adjusting for age, sex, education, baseline MoCA scores, American Society of Anesthesiologists (ASA) grade, and coronary heart disease (CHD).
CONCLUSIONS: In older adult patients with preoperative sleep disorders, MCH is associated with the occurrence of delayed neurocognitive recovery after surgery. Preoperative testing of CSF MCH or plasma MCH may increase the likelihood of identifying the high-risk population for delayed neurocognitive recovery in older adult patients with preoperative sleep disorders.

Objective: To investigate the clinicopathological characteristics of plurihormonal PIT1-lineage pituitary neuroendocrine tumors. Methods: Forty-eight plurihormonal PIT1-lineage tumors were collected between January 2018 and April 2022 from the pathological database of Sanbo Brain Hospital, Capital Medical University. The related clinical and imaging data were retrieved. H&E, immunohistochemical and special stains were performed. Results: Out of the 48 plurihormonal PIT1-lineage tumors included, 13 cases were mature PIT1-lineage tumors and 35 cases were immature PIT1-lineage tumors. There were some obvious clinicopathological differences between the two groups. Clinically, the mature plurihormonal PIT1-lineage tumor mostly had endocrine symptoms due to increased hormone production, while a small number of immature PIT1-lineage tumors had endocrine symptoms accompanied by low-level increased serum pituitary hormone; patients with the immature PIT1-lineage tumors were younger than the mature PIT1-lineage tumors; the immature PIT1-lineage tumors were larger in size and more likely invasive in imaging. Histopathologically, the mature PIT1-lineage tumors were composed of large eosinophilic cells with high proportion of growth hormone expression, while the immature PIT1-lineage tumors consisted of chromophobe cells with a relatively higher expression of prolactin; the mature PIT1-lineage tumors had consistently diffuse cytoplasmic positive staining for keratin, while the immature PIT1-lineage tumors had various expression for keratin; the immature PIT1-lineage tumors showed more mitotic figures and higher Ki-67 proliferation index; in addition, 25.0% (12/48) of PIT1-positive plurihormonal tumors showed abnormal positive staining for gonadotropin hormones. There was no significant difference in the progression-free survival between the two groups (P=0.648) by Kaplan-Meier analysis. Conclusions: Plurihormonal PIT1-lineage tumor belongs to a rare type of PIT1-lineage pituitary neuroendocrine tumors, most of which are of immature lineage. Clinically increased symptoms owing to pituitary hormone secretion, histopathologically increased number of eosinophilic tumor cells with high proportion of growth hormone expression, diffusely cytoplasmic keratin staining and low proliferative activity can help differentiate the mature plurihormonal PIT1-lineage tumors from the immature PIT1-lineage tumors. The immature PIT1-lineage tumors have more complicated clinicopathological characteristics.
目的： 探讨垂体多激素PIT1谱系神经内分泌肿瘤的临床病理学特点。 方法： 收集首都医科大学三博脑科医院2018年1月至2022年4月病理数据库中诊断为多激素PIT1谱系肿瘤的垂体神经内分泌肿瘤病例，整理相关临床及影像学资料，进行HE、免疫组织化学及特殊染色。 结果： 48例多激素PIT1谱系肿瘤纳入研究，成熟性多激素PIT1谱系肿瘤13例，不成熟性PIT1谱系肿瘤35例，研究显示两组肿瘤的临床及病理学特征均存在明显差异。临床特征：（1）成熟性多激素PIT1谱系肿瘤几乎均有垂体激素分泌增多的临床症状，而不成熟性PIT1谱系肿瘤少见，但有62.9%（22/35）的患者存在血清垂体激素低水平升高；（2）不成熟性PIT1谱系肿瘤患者偏年轻化，肿瘤体积更大，影像学易见侵袭周围组织。病理学特征：（1）成熟性多激素PIT1谱系肿瘤由大的嗜酸性细胞组成，生长激素表达比例高，而不成熟性PIT1谱系肿瘤由嫌色性细胞组成，催乳素表达比例更高；（2）成熟性多激素PIT1谱系肿瘤表现为一致性、弥漫性胞质广谱细胞角蛋白阳性，而不成熟性PIT1谱系肿瘤细胞角蛋白表达则具多样性；（3）不成熟性PIT1谱系肿瘤增殖明显活跃；（4）25.0%（12/48）多激素PIT1谱系肿瘤存在性激素的异常表达。使用Kaplan-Meier法进行肿瘤无进展时间分析，两组肿瘤间差异无统计学意义（P=0.648）。 结论： 多激素PIT1谱系肿瘤属于少见的PIT1谱系垂体神经内分泌肿瘤类型，以不成熟性PIT1谱系肿瘤多见。依据垂体激素分泌增多的临床症状、嗜酸性肿瘤细胞、高比例生长激素表达、细胞角蛋白弥漫性胞质阳性和低增殖活性，可以协助成熟性多激素PIT1谱系肿瘤与不成熟性PIT1谱系肿瘤的鉴别。不成熟性PIT1谱系肿瘤临床病理学比较复杂。.

OBJECTIVE: Currently, endoscopic transsphenoidal surgery is the main treatment for pituitary neuroendocrine tumors (PitNETs). Excision of the tumor may have positive or negative effects on pituitary endocrine function, and the pituitary function of somatotroph tumors is a point of particular concern after the operation. This study aimed to conduct a meta-analysis on the effect of endoscopic transsphenoidal somatotroph tumor resection on pituitary function.
METHODS: A systematic literature search was conducted for articles that included the evaluation of pituitary target gland before and after endoscopic transsphenoidal pituitary tumor resection and were published between 1992 and 2022 in PubMed, Cochrane, and Ovid MEDLINE.
RESULTS: Sixty-eight studies that included biochemical remission rates in 4524 somatotroph tumors were concluded. According to the 2000 consensus, the biochemical remission rate after transsphenoidal endoscopic surgery was 66.4% (95% CI, 0.622-0.703; P = 0.000), the biochemical remission rate was 56.2% according to the 2010 consensus (95% CI, 0.503-0.620; P = 0.041), and with the rate of biochemical remission ranging from 30.0 to 91.7% with investigator\'s definition. After endoscopic resection, adrenal axis dysfunction was slightly higher than that before surgery, but the difference was not statistically significant. Hypothyroidism was 0.712 times higher risk than that before surgery (OR = 0.712; 95% CI, 0.527-0.961; P = 0.027). Hypogonadism was 0.541 times higher risk than that before surgery (OR = 0.541; 95% CI, 0.393-0.746; P = 0.000). Hyperprolactinemia was 0.131 times higher risk than that before surgery (OR = 0.131; 95% CI, 0.022-0.783; P = 0.026). The incidence of pituitary insufficiency was 1.344 times the risk before surgery after endoscopic resection of somatotroph tumors, but the difference was not statistically significant.
CONCLUSIONS: In patients with somatotroph tumors after undergoing endoscopic surgery, the risk of dysfunction and pituitary insufficiency tend to increase, while preoperative thyroid insufficiency, gonadal insufficiency, and hyperprolactinemia will be partially relieved.

OBJECTIVE: Ischemia and hemorrhage of pituitary adenomas (PA) caused important clinical syndrome. However, the differences on clinical characteristics and surgical outcomes between these two kinds apoplexy were less reported.
METHODS: A retrospective analysis was made of patients with pituitary apoplexy between January 2013 and June 2018. Baseline and clinical characteristics before surgery were reviewed. All patients underwent transsphenoidal surgery and were followed up at least 1 year.
RESULTS: Total 67 cases (5.8%) among 1147 pituitary tumor patients were enrolled, which consisted of 28 (~2.4%) ischemic PA and 39 (~3.4%) hemorrhagic PA. There were more male patients in the ischemic group compared with hemorrhagic group (78.6% vs 53.8%, p=0.043). However, the mean age, tumor size and functional tumor ratio were significant higher in the hemorrhagic group. Headache was more common in ischemic PA (82.1%) than that of hemorrhagic PA (51.3%, p=0.011). Magnetic resonance imaging findings found that mucosal thickening and enhancement of the sphenoid sinus was observed in 15 ischemic PA patients (n=27, 55.6%), but none in patients with hemorrhagic PA (n=38, p<0.0001). It was worth noting that the rate of pre-surgical hypopituitarism in ischemic PA patients were seemed higher than that in hemorrhagic PA patients, but not significant. The two groups got a total tumor resection rate at 94.1% and 92.9%, independently. No significant difference on the operative time, blood loss in operation and complications in perioperative period was observed in two groups. After operation, cranial nerve symptoms recovered to normal at 81.8% of ischemic PA patients and 82.6% of hemorrhagic PA patients. Importantly, the incidence of postoperative hypopituitarism partially decreased in both groups, among which the rate of hypothyroidism in ischemic PA patients significantly decreased from 46.4% to 18.5% (p=0.044).
CONCLUSIONS: Patients with ischemic PA presented different clinical characteristics to the hemorrhagic ones. Transsphenoidal surgery should be considered for the patients with neuro-ophthalmic deficits and might benefit for pituitary function recovery of the apoplectic adenoma patients, especially pituitary thyroid axis in ischemic PA patients.

Prolactin (PRL) is an important hormone that is secreted by the pituitary gland and plays an important role in the growth, development and reproduction of organisms. Thyrotropin-releasing hormone (TRH) is a common prolactin-releasing factor that regulates the synthesis and secretion of prolactin. In recent studies, microRNAs (miRNAs) have been found to play a key role in the regulation of pituitary hormones. However, there is a lack of systematic studies on the regulatory role that TRH plays on the pituitary transcriptome, and the role of miRNAs in the regulation of PRL synthesis and secretion by TRH lacks experimental evidence. In this study, we first investigated the changes in PRL synthesis and secretion in the rat pituitary gland after TRH administration. The results of transcriptomic analysis after TRH treatment showed that 102 genes, including those that encode Nppc, Fgf1, PRL, Cd63, Npw, and Il23a, were upregulated, and 488 genes, including those that encode Lats1, Cacna2d1, Top2a, and Tfap2a, were downregulated. These genes are all involved in the regulation of prolactin expression. The gene expression of miR-126a-5p, which regulates the level of PRL in the pituitary gland, was screened by analysis prediction software and by a dual luciferase reporter system. The data presented in this study demonstrate that TRH can regulate prolactin synthesis and secretion through miR-126a-5p, thereby improving our understanding of the molecular mechanism of TRH-mediated PRL secretion and providing a theoretical basis for the role of miRNAs in regulating the secretion of pituitary hormones.