A long-term high-fat diet (HFD) leads to excessive lipid deposition, which may cause many diseases, including NAFLD, diabetes, and thyroid dysfunction. In addition, HFD leads to a decrease in serum growth hormone (GH) levels to further increase lipid deposition and obesity. However, the mechanism of such reduction of GH has not been fully elucidated.

Male Sprague-Dawley rats were fed a regular diet (CD) or a high-fat diet (HFD) for 29 weeks. GH synthesis and secretion were evaluated in pituitary and blood samples, respectively. An in vitro model was constructed by treating cultured cells with palmitic acid (PA). Vit D receptor (VDR) plasmids (OE-VDR), paricalcitol and VDR knockdown virus (sh-VDR) were used to overexpress or depress the activation of VDR during PA treatment of GH3 cells. The GH content, lipid content, and relevant expression of different molecules were measured in pituitary and cell samples.

A HFD decreased the levels of circulating GH and the expression of Gh in the anterior pituitary gland tissues of rats. In vitro, PA treatment decreased Pit1 and Gh expression in cultured GH3 cells. VDR expression was reduced in the rat pituitary tissues under HFD conditions and in PA-treated GH3 cells. The overexpression and knockdown of VDR increased and decreased the expression of Pit1 and Gh, respectively. Paricalcitol antagonized the decrease in the expression of Pit1 and Gh caused by PA treatment.

HFD induced lipid deposition in the pituitary may cause GH deficiency, and VDR - Pit1 may be at least partially involved in the process.

Turner syndrome (TS) is characterized by a partial or complete absence of the second X chromosome in female individuals. Here, patients with Xp deletion involving SHOX haploinsufficiency caused by unbalanced X-autosome translocations were discussed and considered as TS variants.

This work aimed to expand the current knowledge of TS and unbalanced X-autosome translocations and to suggest the definition, clinical characteristics, diagnosis workflow, and growth hormone (GH) treatment strategy of TS and its variants.

A 9.0-year-old patient of TS variant with tall target height (+2.03 SD) but low height velocity (3.6 cm/y) and height (-1.33 SD) was evaluated as an example. Reports of patients similar to the index patient were systematically searched for in MEDLINE and EMBASE and summarized. A diagnosis workflow and scores for risk assessment of GH treatment (RiGHT scores) for TS variants were also proposed in this study.

According to the diagnosis workflow, the girl's karyotype was confirmed as 46,X,der(X)t(X;7)(p11.3; p14.1), and was evaluated as low risk using RiGHT scores. After 2-year GH treatment, she had a significantly increased height (-0.94 SD). Additionally, a total of 13 patients from 10 studies were summarized, characterized as short stature, growth retardation, craniofacial abnormalities, disorders of intellectual development, and psychomotor delays. Risk assessment of GH treatment using RiGHT scores was also applied in these 13 patients.

The patients with Xp deletion caused by unbalanced X-autosome translocations should be considered as TS variants. The diagnosis workflow and RiGHT scores is a useful approach for clinicians in addressing complex cases of TS variants with GH treatment in clinical practice.

Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.

The use of blood transfusion in surgery is increasing, and the blood supply is getting tighter. The number of glioma surgeries is increasing year by year, and reports of studies on blood transfusion in glioma surgery are relatively rare.

To investigate the risk factors for intraoperative blood (leukocyte-depleted suspended red blood cells and plasma) transfusion in glioma patients.

We retrospectively analyzed the data of 200 glioma patients who had been operated on in a general teaching hospital in China from January 1, 2018 to March 31, 2022. In terms of whether blood transfusion (leukocyte-depleted suspended red blood cells and plasma) was used intraoperatively, patients were divided into a transfusion group (n=82) and a non-transfusion group (n=118). Multivariate Logistic regression analysis was conducted to identify the risk factors for intraoperative blood transfusion.

The rate of intraoperative transfusion rate in the 200 glioma patients was 41%. Multivariate Logistic regression analysis showed that operation time, intraoperative blood loss ≥500 mL, vascular involvement, and the extent of tumor resection (total resection) were independent risk factors for intraoperative blood transfusion (P<0.05). Patient height was a protective factor against intraoperative blood transfusion (P<0.05).

The risk of intraoperative blood transfusion was higher in glioma patients with longer operation time, more intraoperative blood loss, vascular involvement, and total tumor resection. Clinically, efforts should be made to avoid these transfusion-related risk factors to minimize the risk of blood transfusion in patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD; also known as nonalcoholic fatty liver disease) is a chronic condition associated with metabolic syndrome, a group of conditions that includes obesity, insulin resistance, hyperlipidaemia and cardiovascular disease. Primary growth hormone (GH) deficiency is associated with MASLD, and the decline in circulating levels of GH with weight gain might contribute to the development of MASLD. Raising endogenous GH secretion or administering GH replacement therapy in the context of MASLD enhances insulin-like growth factor 1 (IGF1) production and reduces steatosis and the severity of liver injury. GH and IGF1 indirectly control MASLD progression by regulating systemic metabolic function. Evidence supports the proposal that GH and IGF1 also have a direct role in regulating liver metabolism and health. This Review focuses on how GH acts on the hepatocyte in a sex-dependent manner to limit lipid accumulation, reduce stress, and promote survival and regeneration. In addition, we discuss how GH and IGF1 might regulate non-parenchymal cells of the liver to control inflammation and fibrosis, which have a major effect on hepatocyte survival and regeneration. Development of a better understanding of how GH and IGF1 coordinate the functions of specific, individual liver cell types might provide insight into the aetiology of MASLD initiation and progression and suggest novel approaches for the treatment of MASLD.

Collagenous gastroenteritidesare rare disorders of unknown etiology diagnosed histologically by marked subepithelial deposition of collagen bands thicker than 10µm in the lamina propria with a mononuclear inflammatory infiltrate. Collagenous gastritis (CG) is divided into two phenotypes - pediatric-onset and adult-onset. Up until recently, pediatric-onset CG was thought to be confined to the stomach presenting with abdominal pain and anemia with limited involvement of the colon. Whereas adult-onset CG is often associated with involvement of the small and/or large intestine presenting with chronic non-bloody diarrhea and weight loss. It is now acknowledged that adult-onset and pediatric-onset CG should be considered a similar disease on a continuous spectrum. There are limited case reports of pediatric patients diagnosed as CG with concurrent collagenous duodenitis (CD) and/or collagenous colitis (CC). There are no accepted therapeutic standards for treating these patients. We present a rare case of an adolescent male with selective IgA deficiency and growth hormone deficiency presenting with severe iron deficiency anemia and abdominal pain with an ultimate diagnosis of collagenous gastroduodenitis with suspected jejunal involvement.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (μCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated.

We performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies.

We discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy.

Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

Metabolic syndrome (MetS) is a risk factor for cardiovascular disease (CVD), and CVD is a major challenge for cancer patients. This study aimed to investigate the prevalence and association of MetS and CVD among adult cancer patients.

This cross-sectional study included cancer patients aged > 18 years from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. The prevalence of MetS and CVD was calculated using weighted analysis. Multivariable logistic regression was used to assess the association between MetS and CVD.

The study included 2658 adult cancer patients, of whom 1260 exhibited MetS and 636 had CVD. The weighted prevalence of MetS and CVD in cancer patients was 45.44%, and 19.23%, respectively. Multivariable logistic regression showed a 79% increased risk in higher CVD prevalence in cancer patients with MetS, with the OR (95% CI) of 1.79 (1.31, 2.44). Notably, obesity, elevated blood pressure (BP), high glucose, and low high density lipoprotein cholesterol (HDL-C) in the MetS components were significantly associated with higher CVD prevalence after adjusting for covariates. Moreover, the risk of CVD prevalence in cancer patients increased with more MetS components. Notably, MetS was more strongly linked to CVD in patients aged < 65 and women.

Among adult cancer patients, over two-fifths (45.44%) were estimated to have MetS, while about one-fifth (19.23%) were considered to have CVD. Notably, obesity, elevated BP, high glucose, low HDL-C, and higher number of MetS components were found to be significantly associated with higher CVD prevalence among cancer adults. Cancer patients under 65 and women with MetS may be at increased risk of CVD.

DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.

Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and the GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to the recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin, and MMP2, enhancing drug resistance and migration in the recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights into the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment.

Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.

Partial or complete deficiency of anterior or posterior pituitary hormone production leads to central hypoadrenalism, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, or arginine vasopressin deficiency depending on the hormones affected. Hypopituitarism is rare and likely to be underdiagnosed, with an unknown but rising incidence and prevalence. The most common cause is compressive growth or ablation of a pituitary or hypothalamic mass. Less common causes include genetic mutations, hypophysitis (especially in the context of cancer immunotherapy), infiltrative and infectious disease, and traumatic brain injury. Clinical features vary with timing of onset, cause, and number of pituitary axes disrupted. Diagnosis requires measurement of basal circulating hormone concentrations and confirmatory hormone stimulation testing as needed. Treatment is aimed at replacement of deficient hormones. Increased mortality might persist despite treatment, particularly in younger patients, females, and those with arginine vasopressin deficiency. Patients with complex diagnoses, pregnant patients, and adolescent pituitary-deficient patients transitioning to adulthood should ideally be managed at a pituitary tumour centre of excellence.

This study aimed to assess the long-term outcome of patients with acromegaly.

This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up.

Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population.

A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population.

Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Cardiovascular (CV) diseases and tumors are best known for its high morbidity and mortality worldwide. There is a growing recognition of the association between CV diseases and tumorigenesis. In addition to CV damage caused by anti-tumor drugs and tumor-induced organ dysfunction, CV events themselves and their treatment may also have a role in promoting tumorigenesis. Therefore, Therefore, the diagnosis and treatment of the two kinds of diseases have entered the era of clinical convergence. Emerging evidence indicates significant biologic overlap between cancer and CV diseases, with the recognition of shared biologic mechanisms. Neutrophil extracellular traps (NETs) represent an immune mechanism of neutrophils promoting the development of tumors and their metastasis. It has been recently demonstrated that NETs exist in various stages of hypertension and heart failure, exacerbating disease progression. At present, most studies focus on the biological role of NETs in CV diseases and tumor respectively, and there are relatively few studies on the specific regulatory mechanisms and effects of NETs in cardiovascular diseases associated with tumors. In this narrative review, we summarize some recent basic and clinical findings on how NETs are involved in the pathogenesis of cardiovascular diseases associated with tumors. We also highlight that the development of treatments targeting NETs may be one of the effective ways to prevent and treat cardiovascular diseases associated with tumors.

Nonalcoholic fatty liver disease (NAFLD) is a metabolical disorder and can lead to liver fibrosis. Because it is commonly seen, several noninvasive scores (NS) have been validated to identify high-risk patients. Patients with NAFLD have been shown to have higher serum angiopoietin-like protein-8 (ANGPTL-8) levels.

The risk of NAFLD is known insufficiently in acromegaly. Moreover, the utility of the NS and the link between NAFLD and ANGPTL-8 in acromegaly is unknown.

Thirty-two patients with acromegaly (n = 15, active [AA] and n = 17, controlled acromegaly [CA]) and 19 healthy controls were included. Magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) was used to evaluate hepatic steatosis, and magnetic resonance elastography to evaluate liver stiffness measurement. ANGPTL-8 levels were measured with ELISA.

Median liver MRI-PDFF and NAFLD prevalence in AA were lower than in CA (P = .026 and P < .001, respectively). Median magnetic resonance elastography-liver stiffness measurement were similar across groups. Of the NS, visceral adiposity index, fatty liver index, hepatic steatosis index, and triglyceride-glucose index (TyG) all showed positive correlation with the liver MRI-PDFF in the control group. However, only TyG significantly correlated with liver fat in the AA and CA groups. There was no correlation between traditional NAFLD risk factors (body mass index, waist circumference, C-reactive protein, homeostasis model assessment for insulin resistance, visceral adipose tissue) and liver MRI-PDFF in the AA and CA. Patients with acromegaly with NAFLD had lower GH, IGF-1, and ANGPTL-8 levels than in those without NAFLD (P = .025, P = .011, and P = .036, respectively).

Active acromegaly may protect from NAFLD because of high GH. In patients with acromegaly, NAFLD risk cannot be explained with classical risk factors; hence, additional risk factors must be identified. TyG is the best score to evaluate NAFLD risk. Lower ANGPTL-8 in patients with acromegaly and NAFLD implies this hormone may be raised because of insulin resistance rather than being a cause for NAFLD.

DNA damage repair (DDR) is mediated by phosphorylating effectors ATM kinase, CHK2, p53, and γH2AX. We showed earlier that GH suppresses DDR by suppressing pATM, resulting in DNA damage accumulation. Here, we show GH acting through GH receptor (GHR) inducing wild-type p53-inducible phosphatase 1 (WIP1), which dephosphorylated ATM and its effectors in normal human colon cells and three-dimensional human intestinal organoids. Mice bearing GH-secreting xenografts exhibited induced colon WIP1 with suppressed pATM and γH2AX. WIP1 was also induced in buffy coats derived from patients with elevated GH from somatotroph adenomas. In contrast, decreased colon WIP1 was observed in GHR-/- mice. WIP1 inhibition restored ATM phosphorylation and reversed GH-induced DNA damage. We elucidated a novel GH signaling pathway activating Src/AMPK to trigger HIPK2 nuclear-cytoplasmic relocation and suppressing WIP1 ubiquitination. Concordantly, blocking either AMPK or Src abolished GH-induced WIP1. We identify WIP1 as a specific target for GH-mediated epithelial DNA damage accumulation.

Colorectal endoscopic resection (C-ER) is spreading due to the increase of colorectal cancer (CRC) in Japan. Gastric cancer (GC) sometimes occurs after C-ER. We aimed to analyze the status of GC after C-ER using large-scale data.

We retrospectively used commercially anonymized health insurance claims data of 5.71 million patients from 2005 to 2018, and extracted 62,392 patients ≥ 50 years old who received C-ER. The incidence and risk factors of GC were analyzed. Additionally, subjects were divided into ≥ 2 cm group and < 2 cm group and risks of GC were analyzed.

The median age (range) was 58 (50-75) years and the overall rate of GC was 0.68% (423/62,392). Multivariate analysis showed that significant risk factors for GC [odds rates (OR), 95% confidence interval (CI)] were colorectal lesion size ≥ 2 cm (1.75, 1.24-2.47, p = 0.002), age ≥ 65 y.o. (1.65, 1.31-2.07, p < 0.001), male (2.35, 1. 76-3.13, p < 0.001), diabetes mellitus (1.40, 1.02-1.92, p = 0.035), liver disease (1.54, 1.06-2.24, p = 0.025), Helicobacter pylori infection (2.10, 1.65-2.67, p < 0.001), chronic atrophic gastritis (1.58, 1.14-2.18, p = 0.006), and CRC (1.72, 1.10-2.68, p = 0.017). The rate of GC in the ≥ 2 cm was significantly higher than that in < 2 cm groups (1.17% and 0.65%, p < 0.001). According to the number of significant risk factors, the rates of GC and the hazard ratios of GC (95%CI) were 0.64% and 3.64 (2.20-6.02) and 1.95% and 11.17 (6.57-19.00) for patient with 1-2 and ≥ 3 risk factors, compared with patients without risk factors.

Using large-scale data, risk factors for GC, including colorecal lesions ≥ 2 cm after C-ER could be investigated.

The growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis plays a crucial role in maintaining the normal function of the cardiovascular system. Results of the last decades demonstrated that GH-IGF-1 takes part in regulating peripheral resistance and contributes to preserving physiological cardiac mass and left ventricular function. Vasculoprotective functions of the GH-IGF-1 axis are believed to counteract atherosclerosis. Unlike in childhood, when GH-deficiency results in growth retardation, GH deficiency does not cause specific symptoms in adults. Adult growth hormone deficiency (AGHD) is characterized by a clustering of cardiometabolic risk factors resulting in a clinical picture similar to the metabolic syndrome. Besides visceral obesity, dyslipidemia and insulin resistance, novel cardiovascular risk factors, such as chronic low-grade inflammation, oxidative stress and prothrombotic state have also been reported in AGHD and may contribute to the increased cardiometabolic risk. Based on a growing body of evidence, long-term GH-replacement improves lipid profile significantly and has a favorable impact on body composition, endothelial function, left ventricular mass as well as the novel, non-traditional cardiometabolic risk factors. Increased mortality associated with the disease is now considered to be multicausal and as such cannot be solely attributed to the GH-deficiency. The etiology of GH-deficiency, treatment of the underlying pathology as well as the inadequate treatment of coexisting hormonal deficiencies might also be responsible for the increased mortality. Nevertheless, in hypopituitarism, adequate replacement therapy including GH-substitution may result in a mortality that is comparable to the general population. Orv Hetil. 2023; 164(41): 1616-1627.

Recombinant human growth hormone (rhGH) and GH receptor antagonists (GHAs) are used clinically to treat a range of disorders associated with GH deficiency or hypersecretion, respectively. However, these biotherapeutics can be difficult and expensive to manufacture with multiple challenges from recombinant protein generation through to the development of long-acting formulations required to improve the circulating half-life of the drug. In this review, we summarize methodologies and approaches used for making and purifying recombinant GH and GHA proteins, and strategies to improve pharmacokinetic and pharmacodynamic properties, including PEGylation and fusion proteins. Therapeutics that are in clinical use or are currently under development are also discussed.

Human growth hormone (hGH) is a pituitary-derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development, and metabolism. Following adulthood, GH is also a regulator of multiple pathologies like fibrosis, cancer, and diabetes. Therefore, there is a significant pharmaceutical interest in developing antagonists of hGH action. Currently, there is a single FDA-approved antagonist of the hGH receptor (hGHR) prescribed for treating patients with acromegaly and discovered in our laboratory almost 3 decades ago. Here, we present the first data on the structure and function of a new set of protein antagonists with the full range of hGH actions-dual antagonists of hGH binding to the GHR as well as that of hGH binding to the prolactin receptor. We describe the site-specific PEG conjugation, purification, and subsequent characterization using MALDI-TOF, size-exclusion chromatography, thermostability, and biochemical activity in terms of ELISA-based binding affinities with GHR and prolactin receptor. Moreover, these novel hGHR antagonists display distinct antagonism of GH-induced GHR intracellular signaling in vitro and marked reduction in hepatic insulin-like growth factor 1 output in vivo. Lastly, we observed potent anticancer biological efficacies of these novel hGHR antagonists against human cancer cell lines. In conclusion, we propose that these new GHR antagonists have potential for development towards multiple clinical applications related to GH-associated pathologies.

Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins in a tissue. Male bovine growth hormone (bGH) transgenic mice experience metabolic dysfunction with a marked decrease in lifespan and with increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these initial findings to evaluate WAT fibrosis in female bGH mice and the role of transforming growth factor (TGF)-β in the development of WAT fibrosis. Our findings established that female bGH mice, like males, experience a depot-dependent increase in WAT fibrosis, and bGH mice of both sexes have elevated circulating levels of several markers of collagen turnover. Using various methods, TGF-β signaling was found unchanged or decreased-as opposed to an expected increase-despite the marked fibrosis in WAT of bGH mice. However, acute GH treatments in vivo, in vitro, or ex vivo did elicit a modest increase in TGF-β signaling in some experimental systems. Finally, single nucleus RNA sequencing confirmed no perturbation in TGF-β or its receptor gene expression in any WAT cell subpopulations of Sc bGH WAT; however, a striking increase in B lymphocyte infiltration in bGH WAT was observed. Overall, these data suggest that bGH WAT fibrosis is independent of the action of TGF-β and reveals an intriguing shift in immune cells in bGH WAT that should be further explored considering the increasing importance of B cell-mediated WAT fibrosis and pathology.

Active acromegaly is characterized by lipolysis-induced insulin resistance, which suggests adipose tissue (AT) as a primary driver of metabolic aberrations.

To study the gene expression landscape in AT in patients with acromegaly before and after disease control in order to understand the changes and to identify disease-specific biomarkers.

RNA sequencing was performed on paired subcutaneous adipose tissue (SAT) biopsies from six patients with acromegaly at time of diagnosis and after curative surgery. Clustering and pathway analyses were performed in order to identify disease activity-dependent genes. In a larger patient cohort (n = 23), the corresponding proteins were measured in serum by immunoassay. Correlations between growth hormone (GH), insulin-like growth factor I (IGF-I), visceral AT (VAT), SAT, total AT, and serum proteins were analyzed.

743 genes were significantly differentially expressed (P-adjusted < .05) in SAT before and after disease control. The patients clustered according to disease activity. Pathways related to inflammation, cell adhesion and extracellular matrix, GH and insulin signaling, and fatty acid oxidation were differentially expressed.Serum levels of HTRA1, METRNL, S100A8/A9, and PDGFD significantly increased after disease control (P < .05). VAT correlated with HTRA1 (R = 0.73) and S100A8/A9 (R = 0.55) (P < .05 for both).

AT in active acromegaly is associated with a gene expression profile of fibrosis and inflammation, which may corroborate the hyper-metabolic state and provide a means for identifying novel biomarkers.

Growth hormone (GH) has established effects on protein metabolism, such as increasing protein synthesis and decreasing amino acid degradation, but its effects on circulating amino acid levels are less studied. To investigate this relationship, metabolomic analyses were used to measure amino acid concentrations in plasma and feces of mice with alterations to the GH axis, namely bovine GH transgenic (bGH; increased GH action) and GH receptor knockout (GHRKO; GH resistant) mice. To determine the effects of acute GH treatment, GH-injected GH knockout (GHKO) mice were used to measure serum glycine. Furthermore, liver gene expression of glycine metabolism genes was assessed in bGH, GHRKO, and GH-injected GHKO mice. bGH mice had significantly decreased plasma glycine and increased hydroxyproline in both sexes, while GHRKO mice had increased plasma glycine in both sexes and decreased hydroxyproline in males. Glycine synthesis gene expression was decreased in bGH mice (Shmt1 in females and Shmt2 in males) and increased in GHRKO mice (Shmt2 in males). Acute GH treatment of GHKO mice caused decreased liver Shmt1 and Shmt2 expression and decreased serum glycine. In conclusion, GH alters circulating glycine and hydroxyproline levels in opposing directions, with the glycine changes at least partially driven by decreased glycine synthesis.

Hormones have attracted considerable interest in recent years due to their potential use in treatment of many diseases. Their ability to have a multidirectional effect leads to searching for new and increasingly effective drugs and therapies. Limitations in formulating drug forms containing hormones are mainly due to their low enzymatic stability, short half-life and limited bioavailability. One of the solutions may be to develop a hydrogel as a potential hormone carrier, for epidermal and transdermal application. This review discusses the main research directions in developing this drug formulation. The factors determining the action of hormones as drugs are presented. An analysis of hydrogel substrates and permeation enhancers that have the potential to enhance the efficacy of hormones applied to the skin is reviewed.

Pituitary adenomas (PAs) have been shown to cause excess cardiovascular disease comorbidity and mortality. Cerebrovascular disease (CeVD) is a small subset of cardiovascular disease with high morbidity, and its risk in patients with pituitary adenomas has been sparingly explored. In this review, we examine what is known about the prevalence of cerebrovascular disease in patients with PAs, from its initial discovery in 1970 to present. An abundance of literature describes increased cerebrovascular mortality in patients with acromegaly, while research on other PA subtypes is less frequent but shows a similarly elevated CeVD mortality relative to healthy populations. We also review how cerebrovascular risk changes after PAs are treated, with PA treatment appearing to prevent further accumulation of cerebrovascular risk without reversing prior elevations. While acromegaly-associated CeVD appears to be caused by elevated growth hormone (GH) levels and Cushing disease's elevated glucocorticoids similarly cause durable alterations in cerebrovascular structure and function, less is known about the mechanisms behind CeVD in other PA subpopulations. Proposed pathophysiologies include growth hormone deficiency inducing vessel wall damage or other hormone deficits causing increased atherosclerotic disease. Early diagnosis and treatment of PAs may be the key to minimizing lifetime CeVD risk elevations. More research is needed to better understand the mechanisms behind the increased CeVD seen in patients with PAs. Physicians caring for PA patients must remain vigilant for signs and symptoms of cerebrovascular disease in this patient population.