Anterior Pituitary Cells Research Articles

SAT599 Molecular Analysis Of Pituitary Transdifferentiation In Response To Physiological Cues

Abstract Disclosure: J. Lim: None. In mammals, the control of cell fate is imperative to the development of multicellular organisms as well as tissue homeostasis/regeneration in the adult. The anterior pituitary (AP) controls growth, metabolism, reproduction, and stress responses through the synthesis and secretion of specific hormones by distinct AP cell lineages. Interestingly, the anterior pituitary exhibits a high level of adult cell plasticity that allows committed hormone-producing cells to alter their cell fate and produce different hormones to meet altered organismal demands. The molecular mechanisms underlying this adult cell plasticity have not been fully characterized. To investigate the mechanism(s) of pituitary cell transdifferentiation, our lab has employed a rat GH3 cell culture model that undergoes somatotrope to lactotrope conversion in response to a cocktail of 3 growth factors (EGF, estradiol and insulin). Upon stimulation of lactotrope transdifferentiation, we confirmed a significant reduction of Growth hormone (Gh1) and reciprocal elevation of Prolactin (Prl) protein and transcript levels in the treated group compared to untreated controls. Proteomic and transcriptomic analyses from the same samples detected upregulation of 124 proteins and 553 transcripts and downregulation of 28 proteins and 556 transcripts respectively. Gene ontology analyses identified a number of upregulated proteins involved in autophagy (e.g. autolysosome), MTORC1 signaling, and a number of upregulated transcripts involved in the regulation of cell proliferation and apoptosis. A number of the upregulated proteins and transcripts are involved in Epithelial-to-mesenchymal transition (EMT) and metabolic change (i.e. glycolysis, hypoxia), while downregulated transcripts involved in neurogenesis (i.e. Notch1, Notch2, Sox2, Sox5). Further, differential expression analyses comparing the proteomic and transcriptomic levels of the treated vs. control GH3 cells identified a number of upregulated proteins with no change in their corresponding transcripts related to MTORC1 signaling and glycolysis as well as a number of unchanged proteins with corresponding upregulated transcripts involved in mitochondrial activity suggesting a broad role for post-transcriptional regulation during transdifferentiation. In a complementary in vivo study, we assessed pituitary cell fate changes in response to hypothyroidism, using a similar integrated proteogenomic profiling. Together, we identify a number of altered molecular pathways that underlie distinct pituitary cell plasticity responses to physiological cues. Presentation: Saturday, June 17, 2023

FRI290 Proteomic Identification Of Secretoneurin-Stimulated Proteins In Purified Mouse Gonadotropes

Abstract Disclosure: A. Herdman: None. A. Lagasse: None. A. Haney: None. S. Byrum: None. U. Boehm: None. M.C. MacNicol: None. A.M. MacNicol: None. G.V. Childs: None. A.K. Odle: None. Secretoneurin (SN) is a proteolytic product of secretogranin II (SCG2), a member of the granin family of proteins. Both SCG2 and SN have been localized in the anterior pituitary (AP), and SCG2 co-localizes to gonadotrope granules containing luteinizing hormone (LH). Preliminary studies from others have shown that exogenous SN is capable of stimulating LH secretion from the mouse LßT2 cell line and goldfish pituitaries, and SN may provide a paracrine signal from other AP cells to support LH production/secretion. Despite the implications for regulatory reproductive signaling, a comprehensive study of the effect of SN on female mammalian gonadotropes has not been conducted. To define the pathways and processes affected by exogenous secretoneurin (SN) on murine gonadotrope protein expression, pituitaries from 18 proestrous female mice expressing Gnrhr-driven Cre and a floxed fluorescent Cre reporter were collected and dispersed. Half of the dispersed pituitaries were stimulated with 1 μM SN, and all cells were incubated for 3 hours. Gonadotropes were purified via fluorescence-activated cell sorting. After pooling to optimize cell counts, control and SN-stimulated gonadotropes were submitted for mass-spectrometry proteomics. A differential expression analysis was performed to determine fold-change (FC) in proteins from SN-stimulated samples over control (unstimulated), and false discovery rate (FDR)-controlled adjusted p values were used to assign significance (Adj p≤0.05). A total of 948 proteins were identified in the purified gonadotrope pools. Of these, 136 proteins were significantly differentially expressed between control and SN-stimulated gonadotrope pools; 53 proteins were upregulated and 83 were downregulated in SN-stimulated gonadotropes. Upregulated targets of particular interest include the SN precursor SCG2 (FC = 12, p<0.05), as well as prohormone convertase 2 (PC2: FC = 8, p<0.05) which can cleave SCG2 to produce SN. Also upregulated is ELAV-like protein 1 (ELAVL1: FC=5, p<0.05), an RNA-binding protein known to regulate gonadotropin-releasing hormone receptor (GnRHR) expression and bind other gonadotrope-critical mRNAs. Although LHß was unchanged, the glycoprotein alpha subunit (CGA) was decreased 4-fold following SN stimulation (p = 0.05). This is consistent with previous reports showing decreased Cga mRNA following SN stimulation. In addition to the expected “cell signaling” and “response to stimulation”, gene ontology analysis showed that the major biological processes altered by SN stimulation include processing of RNA (including RNA binding, translation regulation, etc.) and regulation of cell structure. Indeed, several RNA-binding proteins and actin-related proteins were significantly changed. Our data confirm previous results from LßT2 cells and define new SN targets and pathways that may play a broader role in gonadotrope physiology. Presentation: Friday, June 16, 2023

THU025 Acromegaly And Central Hyperthyroidism

Abstract Disclosure: A. Akhtar: None. M.A. Mahmood: None. Introduction: Pituitary adenomas are usually benign neoplasms that are the third most common type of central nervous system tumors. Although TSH releasing tumor accounts for 1% of pituitary adenomas, about one-third of the time it co-secretes Growth Hormone. Co-secretion of TSH and GH can further promote the prognosis of the tumor, therefore, must be immediately treated medically or surgically. Case Report: The case is of a 42 years old male patient who presented to his orthodontist with the complaint of loosening teeth and was referred to a primary care physician. According to the patient, he has observed an increase in his ring size up to 3 times his usual size, one and a half increase in his shoe size, some degree of joint pain, occasional visual blurriness, no weight loss, and snoring. He has no history of headaches, breast tenderness, or discharge. He works at a farm and has no family history of pituitary tumors. His laboratory findings in May 2021 show IGF-1 1028 ng/mL (normal less than 278 ng/mL), ACTH 72.2 pg/mL (normal <60pg/mL), Prolactin, TSH, LH and FSH levels were normal. These findings suggested an IGF-producing pituitary adenoma. During further workup, he had high levels of free T4 and free T3, 2.7 ng/dL and 8.2pg/mL (Normal 2.3 - 4.2pg/mL), respectively, along with elevated TSH levels, which were 8.1mIU/L (normal 0.27-4.2mIU/L). Magnetic resonance imaging showed a pituitary mass of 1.8cm x 2.0cm x 1.6cm in the suprasellar region, abutting the optic chiasm, and showed heterogeneous enhancement. There were no signs of hemorrhage. His visual field examinations were normal. He was prescribed to take 50mg of octreotide every 8 hours. In six weeks, the patient had improved levels of serum TSH which was lowered to 0.785mIU/L, and free T4 and free T3, which were 1.62pmol/L and 3.45pmol/L, respectively. He had transsphenoidal pituitary surgery. Pathology showed a 2.6 x 2.0 x 0.3 cm tumor of somatotropic type. Post-surgery MRI showed no tumor residues. Discussion: We report a middle-aged man with a rare case of the pituitary tumor with acromegaly and central hyperthyroidism. Thyrotropinomas, also known as TSHomas, are benign pituitary adenoma that produces thyroid stimulating hormones. Although rare, they are macroadenomas 80% of the times and 20-25% of the time co-secrete other pituitary hormones. These tumors may show elevated fT3, fT4, and TSH, and increased alpha-subunit. There is not enough evidence to proof the exact origin of the pathology, however, immunohistologically, the tumor cells arise from PIT1-lineage adenohypophyseal cells and could be associated with MEN 1 mutation on chromosome 11q13. Surgical removal of the tumor is a preferred approach to TSHomas, but recent studies have shown a significant improvement with medial therapy of somatostatin analogs by interacting with somatostatin receptors. Octreotide, a somatostatin analog has been clinically shown to bring the thyroid hormones to a normal level in 80% if cases and shrinkage of tumor size in pituitary adenoma in 60% of cases. It can be used as a pre-operative therapy to reduce the levels of free thyrotropin. It also reduces GH and serum IGF-1 levels. Co-secretion of TSH and GH promotes the prognosis of tumors which may be prevented with early diagnosis and treatment. Presentation: Thursday, June 15, 2023

THU095 Multilineage Plurihormonal (FSH LH TSH PRL ACTH) Pituitary Neuroendocrine Tumour: A Case Report

Abstract Disclosure: U.K. Mahfuza: None. V.A. Preda: None. A. Di Ieva: None. M. Rodiguez: None. Plurihormonal pituitary neuroendocrine tumors (PitNETs) are adenomas that produce more than one hormone. This is an uncommon entity. The 2022 WHO classification has differentiated these pitNETs along histological subtyping based on the tumour cell lineage, cell type, and related characteristics1.We present a case of a 48-year-old gentleman, who initially sought attention for visual symptoms with findings of raised intraocular pressure. His ophthalmologist assessment showed temporal disc pallor. Subsequently, the MRI revealed a 30mm pituitary macroadenoma compressing the optic apparatus. He was referred to our Endocrinology service. He had a low testosterone level. He underwent an endoscopic trans-sphenoidal resection. Post-operatively he remained on testosterone replacement, the rest of the pituitary axes were intact. Pre- and post-operative visual assessment showed retinal ganglion cell loss which has negative prognostic implications. Overall, his eye pressure and visual fields improved following surgery. The histopathology diagnosis was a PitNET/adenoma with predominantly gonadotroph SF1, FSH and LH staining. In addition, there were single cells and nests of strongly TSH and PRL-positive cells scattered through the tumour, but no GH staining. There was specific ACTH staining; also in monophenotypic nests. Pit1 positive nuclei present. The TPit was negative within the tumour. There were some residual adenohypophysis cells which is a rare finding deep within a solid tumour. The tumour extended to the inferior surface of the dura. These unique features lead to uncertainty regarding the potential recurrence rate over time. Conclusion: Multilineage PitNETs are uncommon2. The literature reports that the surgical outcome depends on the histopathology characteristics of the immunohistochemistry and transcription factors. However, PitNETs positive for SF1, FSH, LH, PRL,rl and ACTH staining are not widely reported. With the updated WHO classification and consideration of cell lineage and cell type the knowledge of these tumours will eventually improve. Follow-up and tailored management in this patient’s cohort are needed.

The effect of single-dose radiation on cell survival and growth hormone secretion by rat anterior pituitary cells

The effect of single-dose radiation on cell survival and growth hormone secretion by rat anterior pituitary cells

Neural plate progenitors give rise to both anterior and posterior pituitary cells

The pituitary is the master neuroendocrine gland, which regulates body homeostasis. It consists of the anterior pituitary/adenohypophysis harboring hormones producing cells and the posterior pituitary/neurohypophysis, which relays the passage of hormones from the brain to the periphery. It is accepted that the adenohypophysis originates from the oral ectoderm (Rathke's pouch), whereas the neural ectoderm contributes to the neurohypophysis. Single-cell transcriptomics of the zebrafish pituitary showed that cyp26b1-positive astroglial pituicytes of the neurohypophysis and prop1-positive adenohypophyseal progenitors expressed common markers implying lineage relatedness. Genetic tracing identifies that, in contrast to the prevailing dogma, neural plate precursors of zebrafish (her4.3+) and mouse (Sox1+) contribute to both neurohypophyseal and a subset of adenohypophyseal cells. Pituicyte-derived retinoic-acid-degrading enzyme Cyp26b1 fine-tunes differentiation of prop1+ progenitors into hormone-producing cells. These results challenge the notion that adenohypophyseal cells are exclusively derived from non-neural ectoderm and demonstrate that crosstalk between neuro- and adeno-hypophyseal cells affects differentiation of pituitary cells.

Regulation of FGF2-induced proliferation by inhibitory GPCR in normal pituitary cells.

Intracellular communication is essential for the maintenance of the anterior pituitary gland plasticity. The aim of this study was to evaluate whether GPCR-Gαi modulates basic fibroblast growth factor (FGF2)-induced proliferative activity in normal pituitary cell populations. Anterior pituitary primary cell cultures from Wistar female rats were treated with FGF2 (10ng/mL) or somatostatin analog (SSTa, 100nM) alone or co-incubated with or without the inhibitors of GPCR-Gαi, pertussis toxin (PTX, 500nM), MEK inhibitor (U0126, 100µM) or PI3K inhibitor (LY 294002, 10 μM). FGF2 increased and SSTa decreased the lactotroph and somatotroph BrdU uptak2e (p<0.05) whereas the FGF2-induced S-phase entry was prevented by SSTa co-incubation in both cell types, with these effects being reverted by PTX, U0126 or LY294002 pre-incubation. The inhibition of lactotroph and somatotroph mitosis was associated with a downregulation of c-Jun expression, a decrease of phosphorylated (p) ERK and pAKT. Furthermore, SSTa was observed to inhibit the S-phase entry induced by FGF2, resulting in a further increase in the number of cells in the G1 phase and a concomitant reduction in the number of cells in the S phases (p< 0.05), effects related to a decrease of cyclin D1 expression and an increase in the expression of the cell cycle inhibitors p27 and p21. In summary, the GPCR-Gαi activated by SSTa blocked the pro-proliferative effect of FGF2 in normal pituitary cells via a MEK-dependent mechanism, which acts as a mediator of both anti and pro-mitogenic signals, that may regulate the principal effectors of the G1 to S-phase transition.

Musashi Exerts Control of Gonadotrope Target mRNA Translation During the Mouse Estrous Cycle.

The anterior pituitary controls key biological processes, including growth, metabolism, reproduction, and stress responses through distinct cell types that each secrete specific hormones. The anterior pituitary cells show a remarkable level of cell type plasticity that mediates the shifts in hormone-producing cell populations that are required to meet organismal needs. The molecular mechanisms underlying pituitary cell plasticity are not well understood. Recent work has implicated the pituitary stem cell populations and specifically, the mRNA binding proteins of the Musashi family in control of pituitary cell type identity. In this study we have identified the target mRNAs that mediate Musashi function in the adult mouse pituitary and demonstrate the requirement for Musashi function in vivo. Using Musashi RNA immunoprecipitation, we identify a cohort of 1184 mRNAs that show specific Musashi binding. Identified Musashi targets include the Gnrhr mRNA, which encodes the gonadotropin-releasing hormone receptor (GnRHR), and the Fshb mRNA, encoding follicle-stimulating hormone (FSH). Reporter assays reveal that Musashi functions to exert repression of translation of the Fshb mRNA, in addition to the previously observed repression of the Gnrhr mRNA. Importantly, mice engineered to lack Musashi in gonadotropes demonstrate a failure to repress translation of the endogenous Gnrhr and Fshb mRNAs during the estrous cycle and display a significant heterogeneity in litter sizes. The range of identified target mRNAs suggests that, in addition to these key gonadotrope proteins, Musashi may exert broad regulatory control over the pituitary proteome in a cell type-specific manner.

Growth hormone proteoformics atlas created to promote predictive, preventive, and personalized approach in overall management of pituitary neuroendocrine tumors.

Human growth hormone (GH) is the indispensable hormone for the maintenance of normal physiological functions of the human body, including the growth, development, metabolism, and even immunoregulation. The GH is synthesized, secreted, and stored by somatotroph cells in adenohypophysis. Abnormal GH is associated with various GH-related diseases, such as acromegaly, dwarfism, diabetes, and cancer. Currently, some studies found there are dozens or even hundreds of GH proteoforms in tissue and serum as well as a series of GH-binding protein (GHBP) proteoforms and GH receptor (GHR) proteoforms were also identified. The structure-function relationship of protein hormone proteoforms is significantly important to reveal their overall physiological and pathophysiological mechanisms. We propose the use of proteoformics to study the relationship between every GH proteoform and different physiological/pathophysiological states to clarify the pathogenic mechanism of GH-related disease such as pituitary neuroendocrine tumor and conduct precise molecular classification to promote predictive preventive personalized medicine (PPPM / 3P medicine). This article reviews GH proteoformics in GH-related disease such as pituitary neuroendocrine tumor, which has the potential role to provide novel insight into pathogenic mechanism, discover novel therapeutic targets, identify effective GH proteoform biomarker for patient stratification, predictive diagnosis, and prognostic assessment, improve therapy method, and further accelerate the development of 3P medicine.

Casein Kinase 1α as a Novel Factor Affects Thyrotropin Synthesis via PKC/ERK/CREB Signaling.

Casein kinase 1α (CK1α) is present in multiple cellular organelles and plays various roles in regulating neuroendocrine metabolism. Herein, we investigated the underlying function and mechanisms of CK1α-regulated thyrotropin (thyroid-stimulating hormone (TSH)) synthesis in a murine model. Immunohistochemistry and immunofluorescence staining were performed to detect CK1α expression in murine pituitary tissue and its localization to specific cell types. Tshb mRNA expression in anterior pituitary was detected using real-time and radioimmunoassay techniques after CK1α activity was promoted and inhibited in vivo and in vitro. Relationships among TRH/L-T4, CK1α, and TSH were analyzed with TRH and L-T4 treatment, as well as thyroidectomy, in vivo. In mice, CK1α was expressed at higher levels in the pituitary gland tissue than in the thyroid, adrenal gland, or liver. However, inhibiting endogenous CK1α activity in the anterior pituitary and primary pituitary cells significantly increased TSH expression and attenuated the inhibitory effect of L-T4 on TSH. In contrast, CK1α activation weakened TSH stimulation by thyrotropin-releasing hormone (TRH) by suppressing protein kinase C (PKC)/extracellular signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling. CK1α, as a negative regulator, mediates TRH and L-T4 upstream signaling by targeting PKC, thus affecting TSH expression and downregulating ERK1/2 phosphorylation and CREB transcriptional activity.

Adaptation of the Porcine Pituitary Transcriptome, Spliceosome and Editome during Early Pregnancy

The physiological mechanisms of the porcine reproduction are relatively well-known. However, transcriptomic changes and the mechanisms accompanying transcription and translation processes in various reproductive organs, as well as their dependence on hormonal status, are still poorly understood. The aim of this study was to gain a principal understanding of alterations within the transcriptome, spliceosome and editome occurring in the pituitary of the domestic pig (Sus scrofa domestica L.), which controls basic physiological processes in the reproductive system. In this investigation, we performed extensive analyses of data obtained by high-throughput sequencing of RNA from the gilts' pituitary anterior lobes during embryo implantation and the mid-luteal phase of the estrous cycle. During analyses, we obtained detailed information on expression changes of 147 genes and 43 long noncoding RNAs, observed 784 alternative splicing events and also found the occurrence of 8729 allele-specific expression sites and 122 RNA editing events. The expression profiles of the selected 16 phenomena were confirmed by PCR or qPCR techniques. As a final result of functional meta-analysis, we acquired knowledge regarding intracellular pathways that induce changes in the processes accompanying transcription and translation regulation, which may induce modifications in the secretory activity of the porcine adenohypophyseal cells.

TO THE MEMORY OF PROFESSOR RAFAIL BOYKO - TO 90 YEARS ANNIVERSARY

The article is devoted to the biography of professor Rafail Boyko, Doctor of medical sciences, histologist, endocrinologist, Learner of Professor Boris Alyoshin, who made a significant contribution to the teaching of histology, embryology and cytology in soviet medical schools in the second half of the 20th century. He headed the Department of Histology and Embryology of the Izhevsk State Medical Institute (1972-1977), the Department of Histology and Embryology of the Kursk State Medical Institute (1977-1980), the Department of Physiology of the Kherson State University (1981-1995). Professor Rafail Boyko had a significant impact on the development of scientific morphological research and the formation of the scientific community in Russia and Ukraine. The purpose of the study is to restore the history of the formation of Russian science and the scientific morphological school of the outstanding Russian histologists Boris Lavrentiev - Boris Alyoshin, analysis of the scientific works of Professor Rafail Boyko, determination of his contribution to the development of the scientific community of morphologists and endocrinologists in Russia and Ukraine and to the system of higher medical education. The subject of the research in the article was the scientific biography of the scientist, histologist, physiologist and endocrinologist Rafail Boyko, one of the representatives of the famous scientific morphological school of histology. The object of the study was the scientific work of Rafail Boyko in 60th - 70th of 20th century. The research methods are based on comparative-historical, biographical, historical-scientific and documentary-retrospective research methods. The authors of the article prove the contribution of Professor Rafail Boyko in the development of the scientific community of morphologists and endocrinologists in Russia and Ukraine, in the structure and function of the hypothalamic-pituitary system and peripheral endocrine glands, in the development of histochemical and immunochemical research methods. He became one of the first researchers who stained and described the structure of adenohypophysis cells synthesizing adrenocorticotropic hormone. Authors show the contribution of Rafail Boyko in the development of the system of higher medical education in Russia and research centers in Ukraine and that the results of published scientific research by Professor Rafail Boyko are relevant at the present time.

Use of rapid immunochromatographic tests and PCR for the detection of vaccine viruses (CPV, CDV CAV) in faeces and conjunctival sac swabs of vaccinated dogs

The pathologically changed pattern of gonadotropin secretion, responsible for ovulation disorders in fatty ewes, may result from the prolonged increase in leptin concentration as well as from diminution of leptin receptors expression in anterior pituitary cells. Leptin acting peripherally reduces the secretion of insulin – the potent inhibitor of lipolysis. Consequently, an increment in plasma fatty acids level is observed. It was also found that in ewe lambs born to obese sheep carrying twins or triplets, a high plasma level of saturated fatty acids (SFA) is in positive correlation with the delay in puberty. However, the relationship between SFA and gonadotropin secretion from the ovine pituitary cells in pubescent ewe lambs is not clear. Therefore, the aim of the study was to establish the effect of SFA on GnRH-induced secretion of FSH and LH. Pituitary glands were isolated from 7 month old ewe lambs. Pituitary cells were cultured in McCoy 5A medium without GnRH and SFA (negative control), with GnRH only (positive control), with GnRH and 10–9-10–3 M/l of the butyric (C4:0), caprylic (C8:0), lauric (C12:0), palmitic (C16:0) or stearic acid (C18:0). After 2 or 6 h of exposure to SFA followed by 2, 6, 12, 18, 24 or 30 h incubation, the media for LH and FSH analysis were collected. It was found that all used SFA reduce GnRH-induced LH and FSH secretion from pituitary cells in vitro. The most significant (P ≤ 0.05) suppressive effect was observed after 6 h exposure of cells to 10–3 M/l of caprylic acid, 10–4 M/l of palmitic acid and 10–4 M/l of stearic acid compared to the positive control.

Effects of different coating materials on the morphological characteristics of chicken adenohypophyseal folliculo-stellate cells in vitro.

Chicken adenohypophyseal cells were cultured in plates coated with different materials, and their morphologies were examined to confirm the characteristics of chicken folliculo-stellate (FS) cells in vitro. The adenohypophyseal cells were dispersed with a collagenase/trypsin mixture in media and seeded in plates coated in either poly L-lysine (PLL), collagen, or laminin. After 7days of culture, the cells were fixed and immunocytochemistry was performed. 5-Bromo-2'-deoxyuridine incorporation test indicated that the proliferation activity of the culture cells was different based on the coating materials, and it was higher in the collagen-coated plate than two other coating materials. Fluorescence immunocytochemistry was also performed using mixed antibodies against growth hormone, prolactin, luteinizing hormone β-subunit, basic cytokeratin (bCK), and S100B. The culture cells on the PLL- and laminin-coated surfaces were round or oval in shape, and bCK-immunopositive FS cells were morphologically indistinguishable from endocrine cells. In the collagen-coated plate, many endocrine cells were round or oval in shape, but FS cells displayed a larger and flattened morphology. S100B-immunoreactions were localized in the nuclei of bCK-immunopositive FS cells. These results suggest that culturing the chicken adenohypophyseal cells in the collagen-coated plate enables the distinction of FS cells from endocrine cells.

Fluctuation of CD9/SOX2-positive cell populations during the turnover of GH- and TSH-producing cells in the adult anterior pituitary gland.

The adenohypophysis is comprised of the anterior and intermediate lobes (AL and IL, respectively). Cluster of differentiation 9 (CD9)- and sex-determining region Y-box 2 (SOX2)-positive cells are stem/progenitor hormone-producing cells in the AL. They are located in the marginal cell layer (MCL) facing Rathke's cleft between the AL and IL (primary niche) and the parenchyma of the AL (secondary niche). We previously showed that, in rats, CD9/SOX2-positive cells in the IL side of the MCL (IL-side MCL) migrate to the AL side (AL-side MCL) and differentiate into prolactin-producing cells (PRL cells) in the AL parenchyma during pregnancy, lactation, and diethylstilbestrol treatment, all of which increase PRL cell turnover. This study examined the changes in CD9/SOX2-positive stem/progenitor cell niches and their proportions by manipulating the turnover of growth hormone (GH)- and thyroid-stimulating hormone (TSH)-producing cells (GH and TSH cells, respectively), which are Pit1 lineage cells, as well as PRL cells. After induction, the isolated CD9/SOX2-positive cells from the IL-side MCL formed spheres and differentiated into GH and TSH cells. We also observed an increased GH cell proportion upon treatment with GH-releasing hormone and recovery from continuous stress and an increased TSH cell proportion upon propylthiouracil treatment, concomitant with alterations in the proportion of CD9/SOX2-positive cells in the primary and secondary niches. These findings suggest that CD9/SOX2-positive cells have the potential to supply GH and TSH when an increase in GH and TSH cell populations is required in the adult pituitary gland.

Paraneoplastic autoimmune hypophysitis: a novel form of paraneoplastic endocrine syndrome.

Paraneoplastic syndromes are defined by symptoms or signs resulting from damage to organs or tissues that are remote from the site of malignant neoplasms or its metastasis. They are due to tumor secretion of functional hormones or peptides or are related to immune cross-reactivity with the host tissue. In particular, paraneoplastic endocrine syndromes are mainly caused by ectopic hormone production by the tumor such as PTHrP in humoral hypercalcemia in malignancy and ACTH in ectopic ACTH syndrome. Recently, it has been reported that a specific form of hypophysitis is caused as an immune-mediated paraneoplastic syndrome; paraneoplastic autoimmune hypophysitis, in which an ectopic pituitary antigen expression in the tumor evoked autoimmunity against pituitary-specific antigens, resulting in hypophysitis and exhibiting the injury of specific anterior pituitary cells by cytotoxic T cells. This novel clinical entity, paraneoplastic autoimmune hypophysitis consists of several conditions such as anti-PIT-1 hypophysitis and a part of isolated ACTH deficiency and immune checkpoint inhibitor-related hypophysitis with common mechanisms. These conditions can explain at least in part, the underlying mechanisms of acquired specific pituitary hormone deficiencies. In addition, it is important to apply a comprehensive discipline of onco-immuno-endocrinology to understand the pathophysiology and this approach; the expansion and application of immune-mediated paraneoplastic syndrome to endocrine diseases may give a new clue to understand pathophysiology of the autoimmunity against endocrine organs.

Commentary on "Classifications of Anterior Pituitary Cell Types With Immunoenzyme Histochemistry": Dr. Paul Nakane Blazed the Trail to Modern Technology.

Commentary on "Classifications of Anterior Pituitary Cell Types With Immunoenzyme Histochemistry": Dr. Paul Nakane Blazed the Trail to Modern Technology.

Current Approaches to Craniopharyngioma Management.

Craniopharyngiomas (CP) are rare noncancerous brain tumors located in the skull base. To date, CP remain challenging-to-resect tumors, owing to their difficult location and invasive potential, with profound adverse effects for the patient if left to grow. Indeed, gross total resection may also be accompanied by unwelcome sequalae, underscoring the need for continued investigation. In the present work, we provide a scoping review of current CP management, with emphasis on our knowledge of their genesis, available treatment options, post-intervention clinical outcomes. Leading theories of CP development are (1) the embryonic theory, explaining the development of adamantinomatous CP from epithelial remnants of Rathke's pouch and (2) the metaplastic theory, which describes papillary CP development as a result of adenohypophyseal cell metaplasia. Treatment may include surgery, intracystic therapy, or irradiation depending on tumor size, history and location. However, whether a single ideal approach and timing for CP intervention exists remains debated. We appraise and critique these areas with priority for emerging basic results and innovation.

IFN-γ differential expression in the hypothalamus-pituitary-ovary axis of thyroidectomized rats

IFN-γ is critical for both thyroid and ovarian function, while thyroxine, secreted from the thyroid gland, regulates the ovarian function via the hypothalamus-pituitary -ovary axis. However, the effect of thyroxine on INF-γ involved in the regulation of hypothalamic pituitary ovarian axis ovarian function is hitherto unknown. Therefore, we set up three groups including a sham-operated group, an experimental thyroidectomized group, and an experimental thyroidectomized group treated with T4 to reveal the IFN-γ expression levels in the in the hypothalamus, pituitary gland, and ovary by immunohistochemical staining, RT-PCR, and Western blotting. IFN-γ-like immunoreactive-positive substances were visualized in the hypothalamus, pituitary gland, and ovary, which were located mainly in the cytoplasm of the hypothalamic neurons anterior pituitary cells, luteal cells, and theca cells in the ovary of hypothyroidism rats, respectively. RT-PCR and Western blotting showed that the rats in the experimental thyroidectomized group treated with T4 had significantly elevated expression of IFN-γ at both the mRNA and protein levels. Thyroxine affects the expression of IFN-γ in the thalamus-pituitary-ovarian axis, which may influence the secretion of IFN-γ to regulate ovarian function during hypothyroidism. This work highlights the potential effect of thyroxine on the involvement of INF-γ in the modulation of the ovarian function in the hypothalamic-pituitary-ovarian axis.

Corticotropin-Releasing Hormone: Biology and Therapeutic Opportunities.

In 1981, Wylie Vale, Joachim Spiess, Catherine Rivier, and Jean Rivier reported on the characterization of a 41-amino-acid peptide from ovine hypothalamic extracts with high potency and intrinsic activity stimulating the secretion of adrenocorticotropic hormone and β-endorphin by cultured anterior pituitary cells. With its sequence known, this neuropeptide was determined to be a hormone and consequently named corticotropin-releasing hormone (CRH), although the term corticotropin-releasing factor (CRF) is still used and preferred in some circumstances. Several decades have passed since this seminal contribution that opened a new research era, expanding the understanding of the coding of stress-related processes. The characterization of CRH receptors, the availability of CRH agonists and antagonists, and advanced immunocytochemical staining techniques have provided evidence that CRH plays a role in the regulation of several biological systems. The purpose of this review is to summarize the present knowledge of this 41-amino-acid peptide.