Pituitary Growth Research Articles

Architects of Pituitary Tumour Growth.

The pituitary is a master gland responsible for the modulation of critical endocrine functions. Pituitary neuroendocrine tumours (PitNETs) display a considerable prevalence of 1/1106, frequently observed as benign solid tumours. PitNETs still represent a cause of important morbidity, due to hormonal systemic deregulation, with surgical, radiological or chronic treatment required for illness management. The apparent scarceness, uncommon behaviour and molecular features of PitNETs have resulted in a relatively slow progress in depicting their pathogenesis. An appropriate interpretation of different phenotypes or cellular outcomes during tumour growth is desirable, since histopathological characterization still remains the main option for prognosis elucidation. Improved knowledge obtained in recent decades about pituitary tumorigenesis has revealed that this process involves several cellular routes in addition to proliferation and death, with its modulation depending on many signalling pathways rather than being the result of abnormalities of a unique proliferation pathway, as sometimes presented. PitNETs can display intrinsic heterogeneity and cell subpopulations with diverse biological, genetic and epigenetic particularities, including tumorigenic potential. Hence, to obtain a better understanding of PitNET growth new approaches are required and the systematization of the available data, with the role of cell death programs, autophagy, stem cells, cellular senescence, mitochondrial function, metabolic reprogramming still being emerging fields in pituitary research. We envisage that through the combination of molecular, genetic and epigenetic data, together with the improved morphological, biochemical, physiological and metabolically knowledge on pituitary neoplastic potential accumulated in recent decades, tumour classification schemes will become more accurate regarding tumour origin, behaviour and plausible clinical results.

Growth hormone secretagogue peptide A233 upregulates Mx expression in teleost fish in vitro and in vivo.

Aquaculture constitutes an alternative source for food production and contributes to a reduction in the indiscriminate catching of aquatic organisms in their natural environment. However, high mortality during the larval state remains a challenge in this sector, mainly because of factors such as diet and diseases caused by pathogens. Therefore, growth and health management is a key strategy for sustainable aquaculture. Synthetic growth hormone secretagogues (GHSs) are a family of ligands that can stimulate pituitary growth hormone release as well as the function of ghrelin, contributing to the immune responses in a variety of vertebrates, including fish. The A233 decapeptide is a GHS with a demonstrated impact on growth, immune system function, and antioxidant defense in tilapia fish, but no antiviral activity has been described for this peptide. Here, using an in vitro model (TRG-2 cells) and two in vivo models (sea bream [Sparus aurata]) and zebrafish [Danio rerio]), we demonstrate for the first time the potential antiviral effect of A233 in teleost fish.

Response of Patients with Acromegaly to Long-acting Octreotide with regard to Regression of Pituitary Adenoma, Growth Hormone and Insulin-like Growth Factor-1

Introduction: Acromegaly is a rare endocrine disease; its treatment is surgical (Hypophysectomy). However, somatostatin analogs represent another modality of therapy in addition to deep X-ray therapy as a third, option. The aim of the study is to find out the response of patients with acromegaly to octreotide as reflected on regression of adenoma size, insulin-like growth factor (IGF), and growth hormone (GH) by studying the medical records of many patients with acromegaly. Method: A total of 80 patients with acromegaly are enrolled in the study from July/2019 to April/2020. Their age range (20–72 years). They are 47 men and 33 women. Their selection was based on their visits to NDC on the basis of prescheduled appointments to be given their monthly injections of long-acting octreotide (LAR) and to be examined clinically plus conducting various types of hormonal studies and biochemical workups to assess their response to treatment on the following parameters: Adenoma size, IGF-1 and GH and its correlation with octreotide dose. Results: It is a cross-sectional comparative clinical trial study of 80 patients with acromegaly. Mean of age was 46.7 ± 12.4 years’, and their age range (20–72 year) minimum and maximum-year-old. Mean duration of taking drug was 8 ± 6.7 years. The mean of total LRA injection was (1073.6 ± 666.2 mg). 58.75% of patients were male while 41.25% were female. 46.25% of patients do not have transsphenoidal direct surgery, but 46.25% undergo one surgery, 7.5% undergo two transsphenoidal hypophysectomies. 87.5% of patients have no gamma knife while 12.5% have gamma knife radiosurgery. Conclusion: Acromegaly is a multi systemic disease that should be diagnosed and treated as early as possible to prevent complications and improve mortality rates.

SIRT1 suppresses pituitary tumor progression by downregulating PTTG1 expression

Although pituitary tumors are among the most common types of brain tumor, the underlying molecular mechanism of this disease remains obscure. To this end, the role of sirtuin 1 (SIRT1) in pituitary tumors was reported. The results of reverse transcription‑quantitative PCR and immunohistochemistry revealed that sirtuin 1 (SIRT1) expression was downregulated in the tumor tissues of patients with pituitary tumors. Invitro experiments of the present study demonstrated that SIRT1 upregulation suppressed pituitary tumor cell line growth, while SIRT1 downregulation demonstrated the opposite effect. Additionally, it was determined that the enzymatic activity of SIRT1 was required for its cellular function. A mechanistic experiment determined that SIRT1 negatively regulated pituitary tumor‑transforming gene 1 (PTTG1) expression through the deacetylation of histone (H)3 lysine (K)9ac at the promoter region of PTTG1. Moreover, H3K9ac levels at the PTTG1 promoter were determined to be an essential regulatory element for PTTG1 expression. Thus, it was concluded that the SIRT1/H3K9ac/PTTG1 axis contributed to pituitary tumor formation and may represent a potential therapeutic strategy.

Decoding the activated stem cell phenotype of the neonatally maturing pituitary.

The pituitary represents the endocrine master regulator. In mouse, the gland undergoes active maturation immediately after birth. Here, we in detail portrayed the stem cell compartment of neonatal pituitary. Single-cell RNA-sequencing pictured an active gland, revealing proliferative stem as well as hormonal (progenitor) cell populations. The stem cell pool displayed a hybrid epithelial/mesenchymal phenotype, characteristic of development-involved tissue stem cells. Organoid culturing recapitulated the stem cells' phenotype, interestingly also reproducing their paracrine activity. The pituitary stem cell-activating interleukin-6 advanced organoid growth, although the neonatal stem cell compartment was not visibly affected in Il6-/- mice, likely due to cytokine family redundancy. Further transcriptomic analysis exposed a pronounced WNT pathway in the neonatal gland, shown to be involved in stem cell activation and to overlap with the (fetal) human pituitary transcriptome. Following local damage, the neonatal gland efficiently regenerates, despite absence of additional stem cell proliferation, or upregulated IL-6 or WNT expression, all in line with the already high stem cell activation status, thereby exposing striking differences with adult pituitary. Together, our study decodes the stem cell compartment of neonatal pituitary, exposing an activated state in the maturing gland. Understanding stem cell activation is key to potential pituitary regenerative prospects.

Endocrine and osmotic responses to tidally‐changing salinities in Mozambique tilapia, Oreochromis mossambicus

Variations in salinity are among the main physical parameters that drive the capacity of fish to survive and thrive in a range of environments. Acclimation to changes in environmental salinity is regulated by the interplay of local osmotically‐induced cellular responses and the systemic regulation by the neuroendocrine system, which together, direct ion extrusion or uptake responses via the gill and other osmoregulatory tissues. Many euryhaline teleost fish are native to waters in which salinity varies tidally between that of fresh water (FW) and seawater (SW), such as estuaries. The physiology of salinity acclimation of euryhaline teleosts has been studied extensively in steady‐state salinities, and after one‐way transfers between steady‐state salinities. Fewer studies, however, have addressed salinity regimes that reflect or simulate the continuous dynamic changes by which euryhaline fishes may be subject to in a native environment. Experimentally, the simulation of a changing environment was obtained by rearing fish in salinities that changed between those of FW and SW every six hours, in a tidal regime (TR). An overview of the main differences in the regulation of transcripts involved in ion balance between euryhaline Mozambique tilapia, Oreochromis mossambicus, responding to TR and those acclimating to steady‐state salinities is provided. Transcripts analyzed include branchial Na+/K+‐ATPase (nka), Na+, Cl‐ co‐transporter (ncc), Na+/H+ antiporter 3 (nhe3), 2Cl‐ co‐transporter (nkcc), cystic fibrosis transmembrane conductance regulator (cftr), and aquaporin 3 (aqp3). In particular, both cftrand aqp3were highly sensitive to changes in salinity in fish acclimated to a TR, indicating indispensable roles in rapidly maintaining hydromineral balance. The pituitary hormones, prolactin and growth hormone, known to play osmoregulatory roles in Mozambique tilapia, were also compared along with their receptors between TR and steady‐state salinity paradigms. Specifically, through the dynamic changes in hormone receptor transcription observed in the TR rearing paradigm, the endocrine control of osmoregulatory outcomes appears shifted from systemic to local regulation at the level of target tissues. Together, these studies indicate that fish are able to compensate for broad and frequent changes in external salinity while keeping osmoregulatory parameters within a narrow range.

Intrasellar pressure in patients with pituitary adenoma \u2013 relation to tumour size and growth pattern

BackgroundOnly a few earlier publications on intrasellar pressure (ISP) have not been able to fully clarify any association between ISP and pituitary adenoma size and growth pattern. The aim of the study was to determine if intrasellar pressure (ISP) is elevated in patients with pituitary adenoma, and if the pressure is associated with tumour size and growth pattern.MethodsThe study included 100 patients operated for suspected pituitary adenoma, who have had their ISP measured intraoperatively. All adenomas were classified on the basis of Knosp and SIPAP, from which further classification of invasiveness was performed. MRT examinations were used to calculate the tumour volume and diameter in three axes.ResultsAfter exclusions, 93 cases were analysed. The mean ISP was 23.0 ± 8.4 mmHg. There were positive correlations between ISP and tumour volume and tumour diameters along all three axes. Coronal tumour diameter showed the strongest correlation with ISP elevation in a multivariate effect test. Adenomas classified as parasellar invasive (Knosp grade 3–4) showed higher mean ISP than adenomas considered as non-invasive (Knosp 0–2).ConclusionsISP is affected by tumour anatomy and correlates positively with tumour volume. Tumour width, i.e. diameter in the coronal plane, appears to be the measure that most strongly affects the ISP. This is confirmed by the association between ISP elevation and parasellar growth.

Research Note: Effects of dietary L-arginine on the production performance and gene expression of reproductive hormones in laying hens fed low crude protein diets

The present study was designed to investigate whether L-arginine (Arg) supplementation would influence the production performance and reproductive traits of laying hens fed low crude protein (LCP) diets. Hy-Line brown laying hens were randomly assigned to dietary treatments of control, LCP, and LCP supplemented with 0.05, 0.10, 0.15, or 0.20% Arg for 7 wk. The results showed no significant variations on the production performance, and relative organ indexes of hens. However, significant transcriptional and structural changes were evident along the HPG axis of hens. Arg supplementation linearly upregulated (P < 0.05) the gonadotropin-releasing hormone 1 (GnRH1), and gonadotropin inhibitory hormone in the hypothalamus. The pituitary growth hormone, GnRH receptor, and follicle-stimulating hormone (FSHβ) were also increased (P < 0.05). In the ovary, GnRH1, and estrogen receptor β were linearly increased by Arg, and the ovarian morphology revealed that LCP induced structural alterations which were minimally recovered by Arg supplementation. Serum insulin-like growth factor 1 (IGF-1) and nitric oxide (NO) were increased (P < 0.05) at higher levels of Arg supplementation. Therefore, supplementing high Arg (0.20%) to LCP hens influenced the ovarian morphology and modulated the gene expression of reproductive hormones in the hypothalamic-pituitary-gonadal axis of laying hens via actions that may be related to NO and IGF-1 activity.

CircVPS13C promotes pituitary adenoma growth by decreasing the stability of IFITM1 mRNA via interacting with RRBP1.

CircRNAs play important roles in a variety of biological processes by acting as microRNA sponges and protein scaffolds or by encoding functional proteins. However, their functions and underlying mechanisms remain largely unknown. Distinctive circRNA patterns were explored by comparing nonfunctioning pituitary adenomas (NFPAs) and normal pituitary tissues with a circRNA array. The biological functions of selected circRNAs were determined in vitro and in vivo. RNA-seq and circRNA pulldown assays were applied to investigate the underlying mechanisms. The circRNA profile of NFPAs is tremendously different from that of normal pituitary tissues. CircVPS13C is significantly upregulated in NFPA samples and cell lines. Gain- and loss-of-function experiments demonstrate that silencing circVPS13C inhibits the proliferation of pituitary tumor cells in vitro and in vivo. Mechanistically, circVPS13C silencing increases the expression of IFITM1 and subsequently activates its downstream genes involved in MAPK- and apoptosis-associated signaling pathways. Rescue experiments show that IFITM1 overexpression partly reverses the biological effects of circVPS13C. Further studies reveal that circVPS13C inhibits IFITM1 expression through a novel mechanism mainly by competitively interacting with RRBP1, a ribosome-binding protein of the endoplasmic reticulum membrane, and thereby alleviating the stability of IFITM1 mRNA. Clinically, circVPS13C expression is markedly higher in high-risk NFPA samples and is downregulated in patient serum 7 days post-transsphenoidal adenoma resection. Our findings suggest that circVPS13C is a critical regulator in the proliferation and development of NFPAs through a novel mechanism, whereby regulating mRNA stability via interacting with ribosome-binding proteins on the endoplasmic reticulum membrane.

ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway.

ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death(ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.

Rno_circ_0001004 Acts as a miR-709 Molecular Sponge to Regulate the Growth Hormone Synthesis and Cell Proliferation.

(1) Background: As a novel type of non-coding RNA with a stable closed-loop structure, circular RNA (circRNA) can interact with microRNA (miRNA) and influence the expression of miRNA target genes. However, circRNA involved in pituitary growth hormone (GH) regulation is poorly understood. Our previous study revealed protein kinase C alpha (PRKCA) as the target gene of miR-709. Currently, the expression and function of rno_circRNA_0001004 in the rat pituitary gland is not clarified; (2) Methods: In this study, both bioinformatics analysis and dual-luciferase report assays showed a target relationship between rno_circRNA_0001004 and miR-709. Furthermore, the rno_circRNA_0001004 overexpression vector and si-circ_0001004 were constructed and transfected into GH3 cells; (3) Results: We found that rno_circRNA_0001004 expression was positively correlated with the PRKCA gene and GH expression levels, while it was negatively correlated with miR-709. In addition, overexpression of rno-circ_0001004 also promoted proliferation and relieved the inhibition of miR-709 in GH3 cells; (4) Conclusions: Our findings show that rno_circ_0001004 acts as a novel sponge for miR-709 to regulate GH synthesis and cell proliferation, and are the first case of discovery of the regulatory role of circRNA_0001004 in pituitary GH.

Investigation of pituitary functions after acute coronavirus disease 2019.

Although coronavirus disease 2019 (COVID-19) mainly involves the lungs, it also affects many systems. The hypothalamic/pituitary axis is vulnerable to hypoxia, hypercoagulation, endothelial dysfunction and autoimmune changes induced by COVID-19 infection. Given that there is no extensive investigation on this issue, we investigated the pituitary functions three to seven months after acute COVID-19 infection. Forty-three patients after diagnosis of COVID-19 infection and 11 healthy volunteers were included in the study. In addition to the basal pituitary hormone levels, growth hormone (GH) and hypothalamo-pituitary adrenal (HPA) axes were evaluated by glucagon stimulation test (GST) and low-dose adrenocorticotropic hormone (ACTH) stimulation test, respectively. The peak cortisol responses to low-dose ACTH test were insufficient in seven (16.2%) patients. Twenty (46.5%) and four (9.3%) patients had inadequate GH and cortisol responses to GST, respectively. Serum insulin-like growth factor-1 (IGF-1) values were also lower than age and sex-matched references in four (9.3%) patients. The peak GH responses to GST were lower in the patient group when compared to the control group. Other abnormalities were mild thyroid-stimulating hormone elevation in four (9.3%) patients, mild prolactin elevation in two (4.6%) patients and central hypogonadism in four (9.3%) patients. Mean total testosterone values were lower in male patients when compared to male controls; however, the difference was not significant. These findings suggest that COVID-19 infection may affect pituitary functions, particularly the HPA and GH axes. These insufficiencies should be kept in mind in post-COVID follow-up. Long-term data are needed to determine whether these deficiencies are permanent or not.

FOXO Transcription Factors Are Required for Normal Somatotrope Function and Growth.

Understanding the molecular mechanisms underlying pituitary organogenesis and function is essential for improving therapeutics and molecular diagnoses for hypopituitarism. We previously found that deletion of the forkhead factor, Foxo1, in the pituitary gland early in development delays somatotrope differentiation. While these mice grow normally, they have reduced growth hormone expression and free serum insulin-like growth factor-1 (IGF1) levels, suggesting a defect in somatotrope function. FOXO factors show functional redundancy in other tissues, so we deleted both Foxo1 and its closely related family member, Foxo3, from the primordial pituitary. We find that this results in a significant reduction in growth. Consistent with this, male and female mice in which both genes have been deleted in the pituitary gland (dKO) exhibit reduced pituitary growth hormone expression and serum IGF1 levels. Expression of the somatotrope differentiation factor, Neurod4, is reduced in these mice. This suggests a mechanism underlying proper somatotrope function is the regulation of Neurod4 expression by FOXO factors. Additionally, dKO mice have reduced Lhb expression and females also have reduced Fshb and Prl expression. These studies reveal FOXO transcription factors as important regulators of pituitary gland function.

MicroRNA-30d target TIMP3 induces pituitary tumor cell growth and invasion.

As one of the most common intracranial tumors, pituitary adenomas, especially the Cushing's disease subtype, have been studied for many years. However, at present, effective methods for the early diagnosis of pituitary adenomas are very limited, especially for subtypes such as Cushing's disease. Therefore, it is of urgent importance to find effective molecular targets to develop new diagnostic and therapeutic methods for pituitary adenomas. We showed the abnormally high expression of miR-30d in pituitary adenomas by analyzing data in the Gene Expression Omnibus (GEO) database and revealed a novel molecular mechanism of miR-30d in regulating the proliferation and invasion of a pituitary adenoma cell line (AtT-20). Cell culture and transfection, and RNA interference (RNAi) were used to treat AtT-20 cells to test the effects of miR-30d and TIMP3 on cells. Quantitative polymerase chain reaction (qPCR) was used to determine the messenger RNA (mRNA) expressions. We used 3-(4,5-diphenyltetrazolium bromide) (MTT) to determine cell viabilities. An invasion assay was performed using Transwell chambers. Luciferase activity was tested with a dual-luciferase assay. We found that the expression of miR-30d in pituitary adenoma was higher than that in normal pituitary tissues. It was revealed that miR-30d promoted the proliferation and invasion of AtT-20 cells by inhibiting the expression of TIMP3. In the above process, miR-30d could bind to the 3'-untranslated region (3'-UTR) of TIMP3 mRNA. The mir-30d/TIMP3 signaling pathway plays an important regulatory role in pituitary adenomas. These new discoveries may reveal more functions of miR-30d and lay the foundation for future clinical development of new drug targets.

Effects of Ghrelin on intestinal cell proliferation, the expression of protein absorption and metabolism factors in juvenile grass carp (Ctenopharyngodon idella)

Ghrelin can stimulate pituitary growth hormone (GH) release, and has a key role in the regulation of food intake and adiposity in vertebrates. At present, no relevant studies have reported the effects of Ghrelin on intestinal cell proliferation, protein absorption and metabolism. In this paper, firstly we established the intestinal epithelial cell lines of juvenile grass carp (Ctenopharyngodon idella) that can be passed stably and identified by the intestinal specific expression proteins E-cadherin and ZO-1. And we used this cell line as a model to investigate the effects of Ghrelin, Ala-Gln, Ala-Gln+Ghrelin on the proliferation of juvenile grass carp intestinal cells. We found that the use of Ghrelin, Ala-Gln and Ala-Gln+Ghrelin could promote the proliferation of intestinal cells of juvenile grass carp, but Ala-Gln+Ghrelin had the strongest promoting effect. Further, we investigated the effects of Ghrelin on the expression of cdx2, PepT1 and mTOR which are related to intestinal cell proliferation, protein absorption and metabolism of grass carp in vitro and in vivo experiments. And we studied the effects of different protein sources on the expression of Ghrelin, PepT1 and mTOR in grass carp at individual level. The results suggested that Ghrelin can promote grass carp intestinal cell proliferation, and affect the expression of genes which are related to intestinal peptide absorption and metabolism in juvenile grass carp.

The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver.

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip. for 5 days) decreased the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A, but not that of CYP2C6. The alterations in enzymatic activity were accompanied by changes in the CYP protein and mRNA levels. In parallel, a decrease in the pituitary growth hormone-releasing hormone, and in serum growth hormone and corticosterone (but not T3 and T4) concentration was observed. After a 3-week administration period of CP-101,606 less changes were found. A decrease in the CYP3A enzyme activity and protein level was still maintained, though no change in the mRNA level was found. A slight decrease in the serum concentration of corticosterone was also maintained, while GH level returned to the control value. The obtained results imply engagement of the glutamatergic system in the neuroendocrine regulation of cytochrome P450 and potential involvement of drugs acting on NMDA receptors in metabolic drug–drug interactions.

Improvement of goose embryonic and muscular developments by wider angle egg turning during incubation and the regulatory mechanisms

Egg turning during incubation plays important roles in achieving high hatching performance and gosling quality. The objective of this study was to improve embryonic and muscular developments so to achieve better gosling quality by wider egg turning angles during incubation, and to unravel the associated regulatory molecular mechanisms. In each of three consecutive incubations, 1,728 goose eggs were divided into 3 groups that were set in the same type of commercial incubators with turning angles adjusted differently to 50°, 60°, and 70°, respectively. On average of the 3 tests, incubation with wider 70° turning angle reduced the post-18-day embryo mortality, promoted embryonic growth and development, improved the hatchability and gosling quality. On embryonic day of 29, gene mRNA expression levels of the hypothalamic growth hormone-releasing hormone (GHRH), pituitary growth hormone (GH), and liver insulin-like growth factor 1 (IGF-1) were higher in the 70° turning group than in the 50° or 60° groups. Wider angle turning also increased mRNA expression levels of the muscle development regulatory genes such as MYF5, MyoD, Myogenin (MyoG), and MRF4. Changes in expression of the above genes, together with the upregulation of the Pax3 and Pax7 genes in leg muscles, well explained the enhancement of the muscular growth and development when eggs were incubated by wider turning angles. These results also extended our understanding of the impacts and mechanisms of egg turning during incubation on hatching performance and gosling quality.

Pituitary hormones are specifically expressed in trigeminal sensory neurons and contribute to pain responses in the trigeminal system

Trigeminal (TG), dorsal root (DRG), and nodose/jugular (NG/JG) ganglia each possess specialized and distinct functions. We used RNA sequencing of two-cycle sorted Pirt-positive neurons to identify genes exclusively expressing in L3–L5 DRG, T10-L1 DRG, NG/JG, and TG mouse ganglion neurons. Transcription factor Phox2b and Efcab6 are specifically expressed in NG/JG while Hoxa7 is exclusively present in both T10-L1 and L3–L5 DRG neurons. Cyp2f2, Krt18, and Ptgds, along with pituitary hormone prolactin (Prl), growth hormone (Gh), and proopiomelanocortin (Pomc) encoding genes are almost exclusively in TG neurons. Immunohistochemistry confirmed selective expression of these hormones in TG neurons and dural nerves; and showed GH expression in subsets of TRPV1+ and CGRP+ TG neurons. We next examined GH roles in hypersensitivity in the spinal versus trigeminal systems. Exogenous GH produced mechanical hypersensitivity when injected intrathecally, but not intraplantarly. GH-induced thermal hypersensitivity was not detected in the spinal system. GH dose-dependently generated orofacial and headache-like periorbital mechanical hypersensitivity after administration into masseter muscle and dura, respectively. Periorbital mechanical hypersensitivity was reversed by a GH receptor antagonist, pegvisomant. Overall, pituitary hormone genes are selective for TG versus other ganglia somatotypes; and GH has distinctive functional significance in the trigeminal versus spinal systems.

METTL3-mediated RNA m6A Hypermethylation Promotes Tumorigenesis and GH Secretion of Pituitary Somatotroph Adenomas.

Pituitary growth hormone-secreting (GH) pituitary adenomas (PAs) cause mass effects and dysregulated hypersecretion of GH. However, somatic mutation burden is low in PAs. While progress has been made in identifying the epigenetic changes involved in GH-PA initiation, the precise details of its tumorigenesis in GH-PA patients remains to be elucidated. As N6-methyladenosine (m6A) has been shown to often play a critical role in various tumors, it represents a possible initiation point for the tumorigenesis of pituitary adenomas. However, the role of RNA methylation in GH adenomas remains unclear. Protein expression of m6A regulators was measured by immunohistochemistry. Global levels and distribution of m6A methylation were separately analyzed by m6A enzyme-linked immunosorbent assay and m6A sequencing (m6A-seq). RNA interference and lentivirus knockdown system were used to investigate the role of methyltransferase-like 3 (METTL3) and its m6A- dependent regulatory mechanism in tumor progression and GH secretion. We show that both METTL3 messenger RNA and protein expression are elevated in GH-PA samples when compared with both normal pituitary tissue specimens and nonsecreting pituitary adenomas. Levels of m6A modification increased in GH-PAs, and hypermethylated RNAs are involved in hormone secretion and cell development. Knockdown of METTL3 in GH3 cell line resulted in decreased cell growth and GH secretion. Importantly, we found that GNAS and GADD45γ act as the downstream targets in this process. Our findings strongly suggest that m6A methyltransferase METTL3 promotes tumor growth and hormone secretion by increasing expression of GNAS and GADD45γ in a m6A-dependent manner. Thus, METTL3 and the methylated RNAs constitute suitable targets for clinical treatment of GH-PAs.

Клинико-гормональная характеристика больных с гигантскими образованиями хиазмально-селлярной области

Цель исследования: изучить клинико-гормональную характеристику пациентов с гигантскими образованиями хиазмально-селлярной области. Материал и методы. За период с 2015 по 2016 г. обследовано 35 взрослых больных с макроаденомами гипофиза, из них 48,6 % мужчин. Средний возраст мужчин составил 37,12 года, женщин — 38,15 года. Давность заболевания колебалась в пределах от 2 месяцев до 25 лет. Результаты. Распределение больных по топографо-анатомической классификации стороны роста аденомы гипофиза показало, что наиболее часто наблюдались аденомы гипофиза с тотальным вариантом роста (51,4 %). У больных с гигантскими аденомами гипофиза наиболее часто встречались пангипопитуитаризм (44,4 %), а также битемпоральная гемианопсия (61,1 %) и вторичная аменорея (33,3 %). Такие нарушения, как вторичная остеопения, эндокринная энцефалопатия, задержка физического и полового развития, были выявлены только в этой группе больных. Кроме того, достоверное снижение средних значений базальных уровней тропных гормонов гипофиза (соматотропный гормон (СТГ), лютеинизирующий гормон (ЛГ), фолликулостимулирующий гормон (ФСГ), адренокортикотропный гормон) было зафиксировано у пациентов с гигантскими аденомами гипофиза. Выводы. У больных с гигантскими аденомами гипофиза в первую очередь отмечается снижение уровня СТГ, ФСГ, ЛГ. Наиболее выраженные нейроэндокринные и офтальмологические нарушения встречаются у больных с гигантскими аденомами гипофиза.