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Purpose: T2 hypointense signal at the posterior edge of the adenohypophysis (T2HSPA) on magnetic resonance imaging (MRI) is incidentally encountered. We aimed to investigate the prevalence and morphology of T2HSPA and their relationship to age., Methods: A total of 212 cases between 3 and 88 years old were examined. Sagittal T2-weighted image (T2WI) was evaluated for the presence of T2HSPA, which classified by its morphology into two types (belt-like or nodal). The Wilcoxon rank sum test and chi-square test were used to evaluate the differences between the groups. The T2HSPA was extracted by ImageJ software and measured as a cross-sectional area (CSA) quantitatively by threshold setting. We examined the relationship between CSA of T2HSPA and age, and Spearman's correlation coefficients were used for statistical analysis., Results: Of the 212 cases, 80 (37.7%) were identified with T2HSPA. The groups with T2HSPA were significantly younger than the groups without it (p = .01). Groups with belt-like T2HSPA were significantly younger than the groups with nodal T2HSPA (p = .01). There was a weak negative correlation between CSA of T2HSPA and age (p = .02)., Conclusion: T2HSPAs were incidentally detected in 37.7% of all cases, tended to be more common in younger cases, and their morphology was related to age. They seem to have little clinical significance as they tend to decrease in size with age., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The biosynthesis of many of the peptides involved in homeostatic control requires peptidylglycine α-amidating monooxygenase (PAM), an ancient, highly conserved copper- and ascorbate-dependent enzyme. Using the production of amidated chromogranin A to monitor PAM function in tumor cells, physiologically relevant levels of hypoxia were shown to inhibit this monooxygenase. The ability of primary pituitary cells exposed to hypoxic conditions for 4 h to produce amidated chromogranin A was similarly inhibited. The affinity of the purified monooxygenase for oxygen (K m  = 99 ± 19 μM) was consistent with this result. The ability of PAM to alter secretory pathway behavior under normoxic conditions required its monooxygenase activity. Under normoxic conditions, hypoxia-inducible factor 1a levels in dense cultures of corticotrope tumor cells expressing high levels of PAM exceeded those in control cells; expression of inactive monooxygenase did not have this effect. The effects of hypoxia on levels of two PAM-regulated genes (activating transcription factor 3 [Atf3] and FK506 binding protein 2 [Fkbp2]) differed in cells expressing high versus low levels of PAM. Putative hypoxia response elements occur in both human and mouse PAM, and hPAM has consistently been identified as one of the genes upregulated in response to hypoxia. Expression of PAM is also known to alter gene expression. A quarter of the genes consistently upregulated in response to hypoxia were downregulated following increased expression of PAM. Taken together, our data suggest roles for PAM and amidated peptide secretion in the coordination of tissue-specific responses to hypoxia., (© 2021 Wiley Periodicals LLC.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CY declared a shared affiliation with the authors to the handling editor at time of review.

Introduction: Worldwide, nanoparticles especially gold-nanoparticles (Au-NPs) are widely used in medicine, cancer treatment and cosmetic industry. They are easily conjugated with different biomedical and biological agents and effortlessly absorbed with few side effects. The pars distalis of the pituitary gland is considered as the maestro of the endocrine peripheral glands since it secrets trophic hormones that controls their functions. 5-10% of the non-granular pars distalis cells are folliculo-stellate cells (FSCs) that support the granular cells' functions. The aim of the study was to explore the histological and the biochemical effects of repeated exposure to Au-NPs on the pars distalis in adult male albino rats with highlighting the impact on FSCs., Material and Methods: Thirty-six adult male albino rats were divided equally into control group and Au-NPs group (received 40 μg/kg/day of 11 ± 2 nm spherical Au-NPs orally for 2 weeks). Then, rats were euthanized and deposition of Au-NPs in pars distalis was investigated. Biochemical investigations and histological studies including hematoxylin and eosin staining, periodic acid Schiff's reaction, immunohistochemistry (IHC) for S-100, connexin 43 (Cx43) and Cytochrome-C (Cyt-C) as well as electron-microscopic and morphometric studies were carried out., Results: The Au-NPs group demonstrated structural disorganization in the pars distalis, inflammation, congestion and increased extracellular PAS-positive colloid deposition due to the accumulation of Au-NPs. A significant increase in the immunoreactivity of S-100, Cx43 and Cyt-c, along with a significant increase in TNF-a, MDA, and bFGF content in the pituitary homogenates, was noted as compared to the control group. Ultrastructurally, degenerative changes were observed in the secretory cells. FSCs showed proliferation and increased phagocytic activity., Conclusions: Repetitive exposure of adult male albino rats to Au-NPs prompted the accumulation of these nanoparticles in the pars distalis that was accompanied by cellular degeneration and dysfunction of the secretory cell and proliferation of FSCs. Thus, monitoring of the pars distalis hormonal levels might be useful for early detection of some hazardous effects possibly associated with the use of gold-nanoparticles.

An acute and prolonged inflammation inhibits the reproduction process by the disruption of the neurohormonal activity of the hypothalamic-pituitary-gonadal axis. It is thought that these changes may be caused by proinflammatory cytokines, i.e., interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) α. The aim of this study was to determine the effect of an acute and prolonged inflammation on the expression of genes encoding cytokine and their receptors, gonadotropin releasing hormone receptor ( GnRHR ), beta subunits of luteinizing hormone ( LHβ ) and follicle-stimulating ( FSHβ ) in the anterior pituitary (AP). Moreover, the circulating concentration of LH and FSH was also assayed. Two experiments were carried out on adult ewes which were divided into two control groups and treated with lipopolysaccharide (LPS; 400 ng / kg). Acute inflammation was caused by a single injection of LPS into the external jugular vein, while the chronic inflammation was induced by seven times LPS injection (one a day). In both experiments, animals were euthanized 3h after the last LPS / NaCl injection and the blood samples collected 15 min before euthanasia. An acute inflammation stimulates the expression of the IL-1β , IL-6 and TNFα genes and their receptors in the AP of sheep. Prolonged inflammation increased TNFα gene expression and both types of TNFα and IL-6 receptors. Both an acute and prolonged inflammation inhibited LHβ gene expression in the AP and reduced LH level in blood. A sevenfold LPS injection raises FSH concentration. The gene expression of GnRHR was reduced in the ovine AP only after a single injection of endotoxin. Our results suggest that there are important differences in the way how an acute and prolonged inflammation influence proinflammatory cytokines and their receptors gene expression in the AP of anestrous ewes, which could be reflected by differences in the AP secretory activity during these states.

Context: Association of central diabetes insipidus (CDI) and pituitary stalk thickening (PST) may have several etiologies (including malignancies) and differential diagnosis remains often difficult., Objective: The purpose of this study was to identify which clinical, biochemical or radiological features could help clinicians to make an etiological diagnosis, especially distinguishing neoplastic from non-neoplastic pituitary stalk lesions., Designs and Methods: We retrospectively analyzed clinical, biochemical, radiological and histological data of 38 adult patients diagnosed with CDI and PST of proven etiology., Results: Of the 38 pituitary stalk lesions included, 11 (29%) were neoplastic. A histopathological diagnosis was obtained in 22/38 (58%) patients. The three most frequently observed etiologies of PST were neuroinfundibulitis (34%), germinoma (21%) and histiocytosis (18%). Pituitary stalk thickness was larger for neoplastic lesions, particularly germinomas. Male gender and a very young age were statistically associated with a risk of germinoma. At least one anterior pituitary deficit was observed in nearly 60% of patients. Patients with neoplastic PST were more affected by multiple anterior pituitary dysfunction than patients with benign PST. A high serum prolactin level was individually the best predictor of a neoplastic origin (90% sensitivity and 60% specificity for a serum prolactin level 1.27-fold above the normal upper limit (ULN))., Conclusion: We confirm a relatively high risk of malignancy in adult patients presenting with the association of CDI and PST. Young age, male gender, a very large thickening of the stalk, multiple anterior pituitary deficits and prolactin above 1.3× ULN increase the likelihood of a neoplastic origin., (© 2020 European Society of Endocrinology.)

Pituitary stalk interruption syndrome (PSIS) is characterized by the association of an absent or thin pituitary stalk, an absent or hypoplastic anterior pituitary lobe and an ectopic posterior pituitary (EPP) lobe. The causes of this anatomical defect include both genetic and environmental factors. Molecular genetic defects have been indentified in a small number of patients with PSIS. A 4-year-old boy presented with hypoglycemia and hyponatremia associated with growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone deficiencies. The patient had right sided strabismus. magnetic resonance imaging images showed pituitary hypoplasia, EPP and absent pituitary stalk. A novel Receptor Roundabout-1 (ROBO1) missense mutation (c.1690C>T, p.Pro564Ser) that may contribute to the disorder was found in this patient and his mother, who also exhibited pituitary abnormalities.

Objective: Human patients with Duchenne muscular dystrophy (DMD) commonly exhibit a short stature, but the pathogenesis of this growth retardation is not completely understood. Due to the suspected involvement of the growth hormone/insulin-like growth factor 1 (GH/IGF1) system, controversial therapeutic approaches have been developed, including both GH- administration, as well as GH-inhibition. In the present study, we examined relevant histomorphological and ultrastructural features of adenohypophyseal GH-producing somatotroph cells in a porcine DMD model., Methods: The numbers and volumes of immunohistochemically labelled somatotroph cells were determined in consecutive semi-thin sections of plastic resin embedded adenohypophyseal tissue samples using unbiased state-of-the-art quantitative stereological analysis methods., Results: DMD pigs displayed a significant growth retardation, accounting for a 55% reduction of body weight, accompanied by a significant 50% reduction of the number of somatotroph cells, as compared to controls. However, the mean volumes of somatotroph cells and the volume of GH-granules per cell were not altered. Western blot analyses of the adenohypophyseal protein samples showed no differences in the relative adenohypophyseal GH-abundance between DMD pigs and controls., Conclusion: The findings of this study do not provide evidence for involvement of somatotroph cells in the pathogenesis of growth retardation of DMD pigs. These results are in contrast with previous findings in other dystrophin-deficient animal models, such as the golden retriever model of Duchenne muscular dystrophy, where increased mean somatotroph cell volumes and elevated volumes of intracellular GH-granules were reported and associated with DMD-related growth retardation. Possible reasons for the differences of somatotroph morphology observed in different DMD models are discussed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Xanthogranuloma is a chronic inflammatory mass characterized by cholesterol crystal deposition, which is rarely seen in the sellar region. The objective of this study is to identify the clinical features and cause of sellar xanthogranulomas., Methods: We retrospectively analyzed manifestation, radiographic, and endocrinologic presentation in 9 patients (7 women and 2 men) whom we had previously treated., Results: The patients were between 26 and 73 years of age (median, 56 years). The chief symptoms were visual symptoms in 3, polyuria in 3, headache in 4, and tiredness in 4 patients. Perimetry found visual field deficit in 6 patients. Anterior pituitary provocation tests disclosed impairment of ≥1 hormone in all patients: growth hormone in 8 patients and adrenocorticotropic hormone-cortisol axis in 8 patients. The lesions were suprasellar in 2 patients, intrasellar in 2 patients, and intrasuprasellar region in 5 patients. Three of the lesions were solid and 6 were single cystic to multicystic. Very low intensity area on T2-weighted magnetic resonance imaging was observed in 4 lesions. Postcontrast study performed in 7 lesions showed enhancement in solid parts or cyst walls. Surgical decompression improved visual disturbance in half of the patients but rarely improved hormonal deficits. Follow-up (median, 47 months) found no recurrence of the lesion. In addition to these 9 cases, we found 2 xanthogranulomatous lesions pathologically associated with ciliated epithelia, which also presented with severe hypopituitarism., Conclusions: Xanthogranuloma seems to be the last stage of the chronic inflammation affecting Rathke cleft cyst or craniopharyngioma presenting with severe anterior pituitary insufficiency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Mutations in the HESX1 gene can give rise to complex phenotypes that involve variable pituitary hormone deficiencies and other developmental defects., Case Description: A 14-year-old boy presented with short stature and delayed puberty and received a diagnosis of GH deficiency, central hypothyroidism, hypogonadotropic hypogonadism, and secondary adrenal insufficiency. He had anterior pituitary hypoplasia, ectopic posterior pituitary, and an interrupted pituitary stalk. Genetic studies uncovered a heterozygous variant in exon 2 of the HESX1 gene (c.219C>T; p.Ser73Ser). This single base change was predicted to be synonymous at the translational level but was shown to cause skipping of exon 2 in the RNA transcript., Conclusions: This study of a patient with combined pituitary hormone deficiency revealed an unusual synonymous mutation of the HESX1 gene leading to abnormal RNA processing and indicates the importance of investigating silent variants that at first glance appear to be benign., (Copyright © 2019 Endocrine Society.)

Context: Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues., Evidence Acquisition: A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized., Evidence Synthesis: The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification., Conclusions: A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients., (Copyright © 2019 Endocrine Society.)

Suicidal behavior is a complex human behavior and current data suggests that suicide is an increasing cause of death among young people. The neurobiology of suicide is unknown and data investigating the role of the pituitary in suicidal behavior is scarce. Imaging data suggests that this gland increases in size in patients with major depression and recent data implicates hyperactivity of the hypothalamus-pituitary-adrenal axis in suicidal behavior. In this study, we evaluate the size and number of cells as well as markers related to oxidative stress and lipid peroxidation of the anterior and posterior sections of the pituitary gland of male suicide completers. Stereological analysis is used to quantify the total cell number in anterior- and posterior-pituitary regions. We examined nitric oxide (NO) levels, Zinc (Zn) levels, superoxide dismutase (SOD) activity, 4-hydroxy-alkenals (4-HDA), malondialdehyde (MDA) and metallothioneins (MTs). Our results indicate that the anterior-pituitary region of suicide completers exhibits increased weight, likely due to an enhanced number of cells compared to the control group. In addition, we found a reduction of NO levels with higher SOD activity in the anterior-pituitary region of suicide victims. No changes in Zn, MDA, MTs, 4-HDA or MDA were observed in tissue of suicide completers compared to the control group. This study demonstrates that there is an increased number of cells, with an imbalance in oxidative stress without a process of lipid peroxidation in the anterior-pituitary region of young male suicide completers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) plays a key role in GH secretion. In this review, we summarize the current state of knowledge regarding the physiology and molecular machinery of VGCCs in pituitary somatotrophs. We next discuss the possible involvement of Ca2+ channelopathies in pituitary disease and the potential use of Ca2+ channel blockers to treat pituitary disease. Various types of VGCCs exist in pituitary cells. However, because L-type Ca2+ channels (LTCCs) contribute the major component to Ca2+ influx in somatotrophs, lactotrophs, and corticotrophs, we focused on these channels. An increasing number of studies in recent years have linked genetic missense mutations in LTCCs to diseases of the human cardiovascular, nervous, and endocrine systems. These disease-associated genetic mutations occur at homologous functional positions (activation gates) in LTCCs. Thus, it is plausible that similar homologous missense mutations in pituitary LTCCs can cause abnormal hormone secretion and underlying pituitary disorders. The existence of LTCCs in pituitary cells opens questions about their sensitivity to dihydropyridines, a group of selective LTCC blockers. The dihydropyridine sensitivity of pituitary cells, as with any other excitable cell, depends primarily on two parameters: the pattern of their electrical activity and the dihydropyridine sensitivity of their LTCC isoforms. These two parameters are discussed in detail in relation to somatotrophs. These discussions are also relevant to lactotrophs and corticotrophs. High dihydropyridine sensitivity may facilitate their use as drugs to treat pituitary oversecretion disorders such as acromegaly, hyperprolactinemia, and Cushing disease.

To optimize the histologic evaluation of hypophysectomy specimens, sections of 207 canine pituitary glands (196 postmortem, 11 hypophysectomy specimens) were reviewed. Adenohypophyseal proliferation was the most common (n = 79) lesion. Proliferative lesions were sparsely to densely granulated; the granules were usually basophilic to chromophobic and periodic acid-Schiff-positive. Adenohypophyseal proliferation was classified as hyperplasia (n = 40) if ≤2 mm diameter with intact reticulin network, as microadenoma (n = 22) for 1-5 mm homogeneous nodules with lost reticulin network, or as macroadenoma (n = 17) for larger tumors. Craniopharyngeal duct cysts were common incidental lesions and the only lesion in 15 dogs. Uncommon diagnoses included lymphoma (n = 4), hemorrhagic necrosis (n = 4), metastatic carcinoma (n = 3), hypophysitis (n = 3), ependymoma (n = 2), craniopharyngioma (n = 2), and 1 case each of metastatic melanoma, pituicytoma, gliomatosis, germ cell tumor, meningioma, and atrophy. The pituitary histologic diagnosis was associated with hyperadrenocorticism (HAC; P < .001) and adrenocortical histologic diagnosis ( P = .025). Both HAC and adrenocortical hyperplasia showed a positive trend with the degree of adenohypophyseal proliferation. The association of adrenocortical hyperplasia with HAC was not significant ( P = .077). Dogs with adenohypophyseal proliferations were older than dogs with normal pituitary glands ( P < .05). Brachycephalic breeds were overrepresented among dogs with pituitary macroadenoma or craniopharyngeal duct cysts, but the association was not statistically significant ( P = .076). Adenohypophyseal hyperplasia was more common than adenoma among postmortem specimens, but was unexpected in >80% of cases. Pituitary macroadenoma was the most common diagnosis in hypophysectomy specimens.

The process by which the somatotrope lineage emerges in the developing pituitary is regulated by the activity of specific signaling and transcription factors expressed during development. We set out to understand the contribution of FOXO1 to that process by using a mouse model in which FOXO1 is prematurely expressed in the pituitary primordium. Expression of FOXO1 in the oral ectoderm as early as embryonic day (e)9.5 resulted in pituitary gland hypoplasia and reduced expression of anterior lobe hormone transcripts at e18.5. Of note, the relative numbers of somatotropes and thyrotropes were also decreased at e18.5. LHX3 and PITX2, markers of pituitary identity, were present in a reduced number of cells during the formation of the Rathke pouch. Thus, premature expression of FOXO1 may affect adoption of pituitary identity during differentiation. Our results demonstrate that the timing of FOXO1 activation affects its role in pituitary gland organogenesis and somatotrope differentiation.

Introduction: Persistent craniopharyngeal canal (PCC) is a rare anomaly of the base of the skull. PCC is defined as a well-corticated osseous canal, extending from the roof of the nasopharynx to the base of the sella over the course of the sphenoid corpus. We reported a PCC case with unique associations. The magnetic resonance imaging findings are discussed., Case Presentation: We report a case of a 2-year-old boy with persistent craniopharyngeal canal, bilateral microphtalmia with large colobomatous cyst, and ectopic adenohypophysis with Rathke cleft cyst. He also has ectopic neurohypophysis and optic atrophy., Conclusion: The presence of orbital and optic tract malformations, craniofacial and intracranial anomalies, and tumors can accompany craniopharyngeal canals (CCs). MRI is helpful in the evaluation of PCC and associated anomalies in these patients.

Introduction: Ganglioglioma is a generally benign tumor, mostly occurring in patients <30 years old. Temporal lobe is most frequently involved. Up to now, only 3 cases were reported of ganglioglioma in the pituitary gland, all being confined to the neurohypophysis. Here, we are the first to report an adenohypophysis ganglioglioma., Case Presentation: A 43-year-old woman presented with chronic headache was referred to our hospital. Magnetic resonance imaging (MRI) indicated pituitary adenoma. Endoscopic transnasal transsphenoidal surgery was performed. The tumor was rich in blood supply, with tough texture, therefore only subtotal resection was conducted. Pathology analysis revealed an adenohypophysial tumor composed of dysplastic ganglion cells and neoplastic glial cells collided with nonspecific hyperplasia of pituitary cells. Immunohistochemistry revealed positive staining of synaptophysin, glial-fibrillary acidic protein, and CD34. The results were consistent with the diagnosis of ganglioglioma. After the surgery the patient recovered well except developing cerebrospinal fluid rhinorrhea, which was controlled by lumbar drainage. MRI 6 months later did not show any sign of progression., Conclusion: According to the findings of our case, concerns should be raised considering ganglioglioma as a differential diagnosis of mass located in the sellar region. Furthermore, an ideal management strategy for pituitary ganglioglioma is not known; therefore, more cases and long-term follow-up are needed to enrich our knowledge of the diagnosis, treatment, and prognosis of this rare intracranial lesion.

OBJECTIVE The objective of this study was to evaluate the feasibility of using confocal reflectance microscopy (CRM) ex vivo to differentiate adenoma from normal pituitary gland in surgical biopsy specimens. CRM allows for rapid, label-free evaluation of biopsy specimens with cellular resolution while avoiding some limitations of frozen section analysis. METHODS Biopsy specimens from 11 patients with suspected pituitary adenomas were transported directly to the pathology department. Samples were immediately positioned and visualized with CRM using a confocal microscope located in the same area of the pathology department where frozen sections are prepared. An H & E-stained slide was subsequently prepared from imaged tissue. A neuropathologist compared the histopathological characteristics of the H & E-stained slide and the matched CRM images. A second neuropathologist reviewed images in a blinded fashion and assigned diagnoses of adenoma or normal gland. RESULTS For all specimens, CRM contrasted cellularity, tissue architecture, nuclear pleomorphism, vascularity, and stroma. Pituitary adenomas demonstrated sheets and large lobules of cells, similar to the matched H & E-stained slides. CRM images of normal tissue showed scattered small lobules of pituitary epithelial cells, consistent with matched H & E-stained images of normal gland. Blinded review by a neuropathologist confirmed the diagnosis in 15 (94%) of 16 images of adenoma versus normal gland. CONCLUSIONS CRM is a simple, reliable approach for rapidly evaluating pituitary adenoma specimens ex vivo. This technique can be used to accurately differentiate between pituitary adenoma and normal gland while preserving biopsy tissue for future permanent analysis, immunohistochemical studies, and molecular studies.

The cyclic 3',5'-adenosine monophosphate (cAMP) was the first among the so-called "second messengers" to be described. It is conserved in most organisms and functions as a signal transducer by mediating the intracellular effects of multiple hormones and neurotransmitters. In this review, we first delineate how different members of the cAMP pathway ensure its correct compartmentalization and activity, mediate the terminal intracellular effects, and allow the crosstalk with other signaling pathways. We then focus on the pituitary gland, where cAMP exerts a crucial function by controlling the responsiveness of the cells to hypothalamic hormones, neurotransmitters and peripheral factors. We discuss the most relevant physiological functions mediated by cAMP in the different pituitary cell types, and summarize the defects affecting this pathway that have been reported in the literature. We finally discuss how a deregulated cAMP pathway is involved in the pathogenesis of pituitary disorders and how it affects the response to therapy., (Copyright © 2017. Published by Elsevier B.V.)

Prostate cancer is the most prevalent type of cancer in men around the world. Due to its high incidence, new therapies have been evaluated, including drugs capable of inhibiting the FGF/VEGF pathways, as Nintedanib. The aim herein was to evaluate the Nintedanib therapeutic effects on morphology and COX-2 and IL-17 levels in the prostate anterior lobe in different grades of the tumor progression in TRAMP mice. Animals were treated with Nintedanib at a dose of 10 mg/kg/day in initial and intermediate grades of tumor development. At the end of treatment, the prostate anterior lobe was collected and submitted to morphological, immunohistochemical and Western Blotting analyses. The results showed that Nintedanib delayed the prostate carcinogenesis progression, with over 20% of reduction in frequency of tissue injuries, particularly in the group treated from 12 to 16 weeks of age. Also, decreased COX-2 and IL-17 levels were observed in both groups treated with Nintedanib in the prostate anterior lobe. Thus, we concluded that Nintedanib was effective in delaying tumor progression and, despite not directly acting on inflammation, Nintedanib may adversely affect inflammatory pathways, favoring prostate cancer delay., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The article presents data relating to structural changes in rat adenohypophysis in experimental burn disease and its treatment. Experimental studies were conducted for defining peculiarities of structural changes in rats' adenohypophisis without and after skin burn injuries (in 7-14 and 21-30 days) alongside its correction with 0.9% NaCl solution. Application of DNA-cytometry allowed defining subtle mechanisms of pathogenic influence of burn injuries on the organism in general and the cells in particular.

IL-6 is a pleiotropic cytokine with multiple pathophysiological functions. As a key factor of the senescence secretome, it can not only promote tumorigenesis and cell proliferation but also exert tumor suppressive functions, depending on the cellular context. IL-6, as do other cytokines, plays important roles in the function, growth and neuroendocrine responses of the anterior pituitary gland. The multiple actions of IL-6 on normal and adenomatous pituitary function, cell proliferation, angiogenesis and extracellular matrix remodeling indicate its importance in the regulation of the anterior pituitary. Pituitary tumors are mostly benign adenomas with low mitotic index and rarely became malignant. Premature senescence occurs in slow-growing benign tumors, like pituitary adenomas. The dual role of IL-6 in senescence and tumorigenesis is well represented in pituitary tumor development, as it has been demonstrated that effects of paracrine IL-6 may allow initial pituitary cell growth, whereas autocrine IL-6 in the same tumor triggers senescence and restrains aggressive growth and malignant transformation. IL-6 is instrumental in promotion and maintenance of the senescence program in pituitary adenomas., (© 2017 Society for Endocrinology.)

Macrophages are present throughout the anterior pituitary gland. However, the features and function of macrophages in the gland are poorly understood. Recent studies have indicated that there are two main macrophage classes: M1 (classically activated) and M2 (alternatively activated). In this study, we examine whether both M1 and M2 macrophages are present in the anterior pituitary gland of rats. Our findings indicate that macrophages that are positive for CD68 (a pan-macrophage marker) were localized near capillaries in rat anterior pituitary gland. These macrophages were positive for iNOS or mannose receptor (MR), which are markers of M1 and M2 macrophages, respectively. To determine the morphological characteristics of M2 macrophages under pathological conditions, diethylstilbestrol (DES)-treated rats were used as an animal model of prolactinoma. After 2 weeks of DES treatment, a number of MR-immunopositive cells were present in the gland. Immunoelectron microscopy revealed that MR-immunopositive M2 macrophages had many small vesicles and moderately large vacuoles in cytoplasm. Phagosomes were sometimes present in cytoplasm. Interestingly, M2 macrophages in prolactinoma tissues did not usually exhibit distinct changes or differences during the normal, hyperplasia and adenoma stages. This study is the first to confirm that both M1 and M2 macrophages are present in the anterior pituitary gland of rats. Moreover, the number of M2 macrophages was greatly increased in rats with DES-induced prolactinoma. Future studies should attempt to characterize the functional role of M2 macrophages in the gland.

The aim of this research was to quantify the changes in the morphology and density of the anterior pituitary folliculostellate (FS) and luteinizing hormone (LH) cells. Material was tissue of the pituitary gland of the 14 male cadavers. Tissue slices were immunohistochemically stained with monoclonal anti-LH antibody and polyclonal anti-S100 antibody for the detection of LH and FS cells, respectively. Digital images of the stained slices were afterwards morphometrically analyzed by ImageJ. Results of the morphometric analysis showed significant increase of the FS cells volume density in cases older than 70 years. Volume density of the LH cells did not significantly change, whereas their area significantly increased with age. Nucleocytoplasmic ratio of the LH cells gradually decreased and became significant after the age of 70. Finally, volume density of the FS cell significantly correlated with LH cells area and nucleocytoplasmic ratio. From all above cited, we concluded that in men, density and size of the FS cells increase with age. Long-term hypertrophy of the LH cells results in their functional decline after the age of 70. Strong correlation between FS cells and LH cells morphometric parameters might point to age-related interaction between these two cell groups., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Adenohypophysis spindle cell oncocytoma (ASCO) is a rare tumor recently reported by Roncaroli et al in 2002. This tumor is considered a grade I tumor by the World Health Organization.We report a rare case of malignant ASCO with repeating recurrences and a high Ki-67 index-a challenging diagnosis guided by clinical presentations, radiological signs, and postoperative pathological tests.We represent a 30-year-old man who had suffered from headaches, diplopia, and impaired visual field and acuity. His magnetic resonance imaging revealed an abnormal sellar mass and was originally misdiagnosed as a pituitary macroadenoma. We present detailed analysis of the patient's disease course and review relevant literature.When surgically treated, the specimen revealed a typical histopathology pattern of ASCO. The tumor recurred for several times and the patient underwent 3 surgeries and 1 γ-knife treatment, which was accompanied by a continuously increasing Ki-67 index.This is the first reported case of malignant ASCO (WHO III-IV grade). Despite its rarity, ASCO should be considered in the differential diagnosis of sellar lesions that mimic pituitary adenomas., Competing Interests: The authors have no conflicts of interest to disclose.

Treating pituitary adenomas in the infundibulum with stereotactic radiosurgery (SRS), achieving tumor volume control while preserving pituitary endocrine function and visual function, is challenging. We present a case of a recurrent remnant infundibular lesion treated with Gamma Knife surgery (GKS). The mass was treated with microsurgical resection twice, and the residual stalk lesion was treated with single-session SRS employing a margin dose of 15 Gy to the infundibulum. Five years after GKS, tumor regression persists without visual dysfunction or hypopituitarism. Radiosurgical doses of 30 Gy to the pituitary stalk may be tolerated by patients while maintaining endocrine function.

We present a case of spindle cell oncocytoma (SCO) of the adenohypophysis in a 70-year-old Vietnamese male. The patient was admitted to Cho Ray Hospital after suffering from headache and visual disturbance for 6 months. Clinicians detected a 60×55×45 mm(3) mass located in the suprasellar-sellar region. Histopathologically, the resected tumor was composed of spindle cells with oncocytic appearance. Immunohistochemical examination revealed expression of anti-mitochondria antibody (AMA), vimentin, thyroid transcription factor 1 (TTF-1), epithelial membrane antigen (EMA) and galectin-3. These histologic and immunohistochemical findings are suggestive of SCO., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Pituitary stalk transection syndrome (PSTS) is a rare complication that can accompany breech delivery. Early diagnosis of this syndrome is difficult, and it may cause a serious delay in the diagnosis. We present a case of PSTS ascertained after breech delivery. A 20-year-old woman presented with primary amenorrhea. The patient was born by breech delivery and had a history of treatment for pituitary dwarfism. Her laboratory findings showed pituitary hypothyroidism, and hormone replacement therapy was initiated. At 28 years old, she became pregnant and had a normal delivery at 38 weeks' gestation. One year after delivery, her thyroid hormone level changed. Laboratory test showed adrenocortical insufficiency, and magnetic resonance imaging of the pituitary gland showed transection of the pituitary stalk and development of an ectopic posterior lobe. These findings were compatible with PSTS. When a patient who has been born by breech delivery presents with symptoms of pituitary deficiency, PSTS should be considered in the differential diagnosis., (© 2015 Japan Society of Obstetrics and Gynecology.)

Cadmium (Cd) is one of the most dangerous occupational and environmental toxins. The objective of the present study is to examine the potential prophylactic effects of phytic acid (PA) on thyroid hormones of male rats intoxicated with Cd. The male albino rats were divided into five groups: group I (control) was fed with the basal diet, group II was intoxicated with Cd in drinking water, groups III, IV, and V were intoxicated with Cd in drinking water and fed with the diet containing 3.5, 7, and 10 g of PA/kg, respectively. The results indicated that the serum calcium, iron (Fe), and total Fe binding capacity levels and serum T3 and T4 in Cd-treated rats of group II were decreased when compared with the control group, while PA-administered groups with Cd showed a significant improvement when compared with the Cd-treated rats only. Serum thyroid stimulating hormone (TSH) level was significantly increased in Cd-treated rats compared with the control group, while the addition of PA in diet decreased the high levels of TSH. These results indicated a prophylactic effect of PA against Cd-induced toxicity in rats., (© The Author(s) 2013.)

A 50-year-old male immigrant from Ethiopia presented for consultation after 3 years of hematochezia/melena requiring > 25 units of blood transfusions. Physical examination revealed severe proximal muscle wasting and weakness, central obesity, proptosis, and abdominal striae, accompanied by eosinophilia, elevated hemoglobin A1c, elevated 24-hour urinary cortisol, lack of suppression of 8 am cortisol levels by 1 mg dexamethasone, and inappropriately elevated random adrenocorticotropic hormone (ACTH) level. Histopathological examination of gastrointestinal biopsies showed large numbers of Strongyloides stercoralis, indicating Strongyloides hyperinfection. Treatment with 2 days of ivermectin led to resolution of gastrointestinal bleeding. This syndrome was due to chronic immunosuppression from a pituitary ACTH (corticotroph) microadenoma, of which resection led to gradual normalization of urine cortisol, improved glycemic control, resolution of eosinophilia, and no recurrence of infection., (© The American Society of Tropical Medicine and Hygiene.)

Introduction: Pituicytoma is a rare tumor arising from the neurohypophysis or pars intermedia of the adenohypophysis., Case Report: A 36 year old male came to our observation presenting polydipsia, polyuria, polyphagia, decreased libido and altered sleep-wake rhythm. The biochemical tests showed hypotonic urine, mild hyperprolactinemia, hypogonadotropic hypogonadism, central hypothyroidism. Magnetic resonance revealed an expansive lesion of the suprasellar region (slightly isointense on T1, hyperintense on T2, impregnating contrast medium), that was partially removed by trans-cranial neurosurgical approach. The histopathological diagnosis was pituicytoma. After surgery, in addition to endocrine disorders, the patient presented severe neurological sequelae and hyperthermia, likely due to damage of the hypothalamus, followed by a progressive metabolic syndrome. The residual tumor was monitored by MRI, and, due to the early gradual increase in volume, was treated by stereotactic radiosurgery., Discussion/conclusions: Pituicytomas are often difficult to distinguish from other hypothalamic or pituitary lesions. However, their identification would be preferable in a pre-operative setting in order to optimize the work-up and to initiate a proactive management of the expected complications.

The aim of the present study was to investigate the ultrastructural damage and the expression of heat shock protein 70 (HSP70) in the rat adenohypophysis following pulsed electromagnetic wave (PEMW) exposure. The rats were randomly divided into four groups: Sham PEMW exposure, 1 x 10(4) pulses of PEMW exposure, 1 x 10(5) pulses of PEMW exposure and 3 x 10(5) pulses of PEMW exposure. Whole body radiation of 1 x 10(4) pulses, 1 x 10(5) pulses and 3 x 10(5) pulses of PEMW were delivered with a field strength of 100 kV/m. The rats in each group (n=6 in each) were sacrificed 12, 24, 48 and 96 h after PEMW exposure. Transmission electron microscopy was then used to detect the ultrastructural changes and immunocytochemistry was used to examine the expression of HSP70. Cellular damage, including mitochondrial vacuolation occurred as early as 12 h after PEMW exposure.More severe cellular damages, including cell degeneration and necrosis, occurred 24 and 48 h after PEMW exposure. The PEMW-induced cellular damage increased as the number of PEMW pulses increased. In addition, the expression of HSP70 significantly increased following PEMW exposure and peaked after 12 h. These findings suggested that PEMW induced ultrastructural damages in the rat adenohypophysis and that HSP70 may have contributed to the PEMW-induced adenohypophyseal damage.

Human kallikrein 10 (hk10), a secreted serine protease, was reported to function as a tumor suppressor. hK10 immunoexpression has been demonstrated in lactrotrophs and corticotrophs of the nontumorous human adenohypophysis. In the present study, for the first time we report hK10 immunoexpression in various surgically removed corticotroph adenoma subtypes. Specimens were fixed in formalin and embedded in paraffin. Immunostaining was performed using the streptavidin-biotin-peroxidase complex method with an hK10-specific rabbit polyclonal antibody. Results showed that the endocrinologically active adrenocorticotropic hormone (ACTH)-producing pituitary tumors and the silent subtypes were immunopositve for hK10. Intensity of staining varied between the different subtypes. Intensity was lowest in the silent subtypes (silent corticotroph subtypes 1 and 2) compared with nontumorous human adenohypophysial corticotrophs, whereas the endocrinologically active subtypes (ACTH-secreting adenomas, corticotroph carcinomas, Crooke cell adenomas, Crooke cell carcinomas), showed the highest hK10 immunoexpression. Immunopositivity in the nuclei of the ACTH-secreting adenomas and carcinomas, as well as dual cytoplasmic and nuclear localization of hK10 in some of the secreting tumor types was an intriguing finding. Immunoexpression of hK10 in the ACTH-secreting tumors as well as in the Crooke cell tumors was significantly increased when compared with the nonfunctioning tumors and in the corticotrophs of nontumorous pituitaries.

Spindle cell oncocytoma (SCO) of the adenohypophysis is a rare tumor in the sellar region. Due to its rarity, little information is available regarding SCO. It is often misdiagnosed as another type of sellar tumor. In the present study, two cases of SCO were reported. One patient was a 35-year-old female presenting with decreased visual acuity, amenorrhea and lactation. The other patient was a 62-year-old female with no clear symptoms or signs. Cranial magnetic resonance imaging (MRI) revealed a suprasellar mass with marked homogeneous enhancement in the two cases. A craniotomy was performed to completely resect the tumors. The tumors were immunopositive for vimentin, epithelial membrane antigen (EMA), S-100 and thyroid transcription factor-1 (TTF-1). The tumors were pathologically diagnosed as SCO. No recurrence occurred during the follow-up period of 15-21 months. In the present study, the literature was reviewed and the clinical data, imaging features, intraoperative findings and recurrence of 24 cases were analyzed in the literature as well as the present two cases. The average age of the SCO patients was 58.5 years and no gender preference was observed for the disease. The tumor exhibited homogeneous enhancement on the MRI. The intraoperative assessment revealed that the tumor had a rich blood supply and the SCO tumors were immunopositive for vimentin, S-100, EMA and TTF-1. These findings provided valuable clinical data for the preoperative diagnosis and surgical removal of SCO tumors.

Background: Anasarca in patients with lymphoma is a rare symptom. We report a patient with DLBCL associated with pituitary gland infiltration that was diagnosed based on significant anasarca., Case Presentation: A 72-year-old woman with a 10-year history of hypertension visited a local hospital presenting with anasarca and 15-kg weight gain in the past 3 months. we clinically diagnosed central hypothyroidism caused by pituitary gland infiltration of diffuse large B-cell lymphoma (DLBCL) (clinical stage IV in the Ann Arbor staging classification). The first course of chemotherapy improved anasarca remarkably and the patient's body weight returned to what it was 3 months before., Conclusions: We experienced a patient with remarkable anasarca caused by DLBCL infiltration of the pituitary gland. A pituitary gland lesion with central hypothyroidism should be considered as one of the differential diagnoses of edema. This case was very valuable because we could assess it by following the time course of symptoms (edema and delayed relaxation time of the Achilles tendon reflex), laboratory data, and imaging findings (swelling anterior pituitary lobe).

OTX2 is a homeodomain transcription factor that is necessary for normal head development in mouse and man. Heterozygosity for loss-of-function alleles causes an incompletely penetrant, haploinsufficiency disorder. Affected individuals exhibit a spectrum of features that range from developmental defects in eye and/or pituitary development to acephaly. To investigate the mechanism underlying the pituitary defects, we used different cre lines to inactivate Otx2 in early head development and in the prospective anterior and posterior lobes. Mice homozygous for Otx2 deficiency in early head development and pituitary oral ectoderm exhibit craniofacial defects and pituitary gland dysmorphology, but normal pituitary cell specification. The morphological defects mimic those observed in humans and mice with OTX2 heterozygous mutations. Mice homozygous for Otx2 deficiency in the pituitary neural ectoderm exhibited altered patterning of gene expression and ablation of FGF signaling. The posterior pituitary lobe and stalk, which normally arise from neural ectoderm, were extremely hypoplastic. Otx2 expression was intact in Rathke's pouch, the precursor to the anterior lobe, but the anterior lobe was hypoplastic. The lack of FGF signaling from the neural ectoderm was sufficient to impair anterior lobe growth, but not the differentiation of hormone-producing cells. This study demonstrates that Otx2 expression in the neural ectoderm is important intrinsically for the development of the posterior lobe and pituitary stalk, and it has significant extrinsic effects on anterior pituitary growth. Otx2 expression early in head development is important for establishing normal craniofacial features including development of the brain, eyes and pituitary gland., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Mutations in the growth hormone releasing hormone receptor (GHRHR) gene are a relatively rare cause of isolated growth hormone deficiency (IGHD)., Objective: This study aimed to understand the biochemical basis of hypoglycemia in the index case and the molecular basis of severe short stature in a large consanguineous family with IGHD., Patients and Methods: The index case presented with a hypoglycemic convulsion, following which eight members in two related consanguineous Turkish families were identified with IGHD. Homozygosity mapping identified the homozygous regions shared only among the affected individuals. Sanger sequencing of GHRHR, which resided in the shared homozygous region, was performed. In silico analysis of the pathogenic GHRHR variant was performed., Results: The clinical presentation and hormonal analysis confirmed GH deficiency in all affected individuals. Magnetic resonance imaging scan of the pituitary gland showed anterior pituitary hypoplasia in five affected individuals in which the youngest was only 0.4 years old, but with normal pituitary size in three affected individuals. Homozygosity mapping showed two large homozygous regions on chromosome 7 shared only among affected individuals. Sanger sequencing of GHRHR gene present in one of these shared regions identified a novel homozygous missense mutation (p.C64G) segregating with the disease phenotype. In silico analysis predicted the mutation to be deleterious and disease causing., Conclusions: We describe a large consanguineous Turkish kindred with IGHD due to a novel homozygous missense GHRHR mutation. This is the first description of presentation with hypoglycemia and the earliest reported occurrence of anterior pituitary hypoplasia in patients with GHRHR mutation.

Humanin (HN) is a 24-amino acid peptide with cytoprotective action in several cell types such as neurons and testicular germ cells. Rattin (HNr), a homologous peptide of HN expressed in several adult rat tissues, also has antiapoptotic action. In the present work, we demonstrated by immunocytochemical analysis and flow cytometry the expression of HNr in the anterior pituitary of female and male adult rats as well as in pituitary tumor GH3 cells. HNr was localized in lactotropes and somatotropes. The expression of HNr was lower in females than in males, and was inhibited by estrogens in pituitary cells from both ovariectomized female and orquidectomized male rats. However, the expression of HNr in pituitary tumor cells was not regulated by estrogens. We also evaluated HN action on the proapoptotic effect of TNF-α in anterior pituitary cells assessed by the TUNEL method. HN (0.5 µM) per se did not modify basal apoptosis of anterior pituitary cells but completely blocked the proapoptotic effect of TNF-α in total anterior pituitary cells, lactotropes and somatotropes from both female and male rats [corrected]. Also, HN inhibited the apoptotic effect of TNF-α on pituitary tumor cells. In summary, our results demonstrate that HNr is present in the anterior pituitary gland, its expression showing sexual dimorphism, which suggests that gonadal steroids may be involved in the regulation of HNr expression in this gland. Antiapoptotic action of HN in anterior pituitary cells suggests that this peptide could be involved in the homeostasis of this gland. HNr is present and functional in GH3 cells, but it lacks regulation by estrogens, suggesting that HN could participate in the pathogenesis of pituitary tumors.

The most common presentation of metastases to the pituitary gland in systemic lymphoma is diabetes insipidus resulting from infiltration of the infundibulum/posterior lobe. We describe a 69-year-old man with diffuse large B-cell stage IV lymphoma who presented with anterior pituitary hypofunction, without features of posterior pituitary involvement. He presented with a few months of postural dizziness and hypotension, weight loss, fever, strabismus of right eye and a superficial abdominal wall mass. At this time he had no history of malignancy. Biochemically he had hypovolemic hyponatremia, secondary hypothyroidism and adrenal insufficiency. Further hormonal work-up revealed panhypopituitarism but no diabetes insipidus. Imaging of the brain, thorax and abdomen demonstrated diffuse intracranial pachymeningeal thickening and enhancement, multiple lymphadenopathies, a bulky right adrenal gland and a large left suprarenal mass, which were indicative of an infiltrative disease. Imaging of the pituitary showed heterogeneous enhancement of the anterior lobe with an unremarkable pituitary stalk and posterior lobe. Biopsy of the superficial abdominal wall mass revealed diffuse large B-cell lymphoma confirmed by bone marrow aspiration biopsy. Positron emission tomography (PET) scan confirmed diffuse systemic disease involving the right orbital apex, bilateral adrenal glands, bone and bone marrow, retroperitoneum and subcutaneous tissues; however, the pituitary gland, infundibulum and hypothalamus did not show any lesions on the PET scan. The patient was commenced on two cycles of chemotherapy but unfortunately died, thus recovery of pituitary function was not tested. Pure anterior pituitary hypofunction can uncommonly present in individuals with metastases to the pituitary gland, in contrast to the more common posterior pituitary/infundibulum involvement., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In humans, alcoholism is associated with a decrease in basal ACTH and cortisol levels, and blunted pituitary ACTH responses to administered corticotropin-releasing hormone (CRH) during active drinking and after long-term abstinence. Preclinical studies indicate that a persistent decrease in pituitary activation after chronic exposure to ethanol is due to a direct effect of ethanol on the corticotrope of the anterior pituitary. The present studies were undertaken to determine if ethanol has effects on proopiomelanocortin (POMC) gene transcription activity in mouse anterior pituitary corticotrope tumor cell AtT20. We measured the levels of the POMC primary nuclear RNA transcript (PT), processing intermediate, and mature mRNA in the nucleus and the levels of the POMC mRNA in the cytoplasm after treatment of AtT20 cells with 5-15 mM concentrations of ethanol. After 15 mM ethanol for 60 to 120 min, the POMC PT levels were significantly decreased. This decreased POMC gene transcription activity was coupled with a significant reduction of the POMC cytoplasmic mRNA levels. After ethanol for 4h, however, both the decreases were no longer observed. After 8h, a decrease in the ACTH secretion in the medium was found. We further investigated if CRH or glutamate modulates the effects of ethanol on the POMC gene transcription activity. CRH at 10nM after 60 min increased the POMC PT levels, and 15mM ethanol attenuated the effect of CRH on the nuclear transcription activity. Glutamate receptor proteins, including NMDA receptor subtype NR1 (but not NR2A or NR2B) and GluR2, were identified by Western immunoblot analysis in AtT20 cells, with similar sizes to those in mouse hypothalamus. The inhibitory effect of 60 min ethanol at 5 to 15 mM on the POMC PT levels was attenuated by 50 μM L-glutamate. Together, our data showed that: (1) ethanol treatment in intoxicate doses significantly inhibited POMC gene transcription activity in a dose- and time-dependent manner in AtT20 cells, and (2) the POMC gene transcription activity in response to CRH or glutamate was altered by ethanol. Our results suggest that ethanol has an inhibitory effect on the POMC gene transcription activity in the anterior pituitary corticotrope, which may contribute to the persistent decrease in pituitary activation after chronic ethanol exposure., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: The VE1 monoclonal antibody was developed to recognize the V600E mutation in BRAF, which is found in various tumors., Methods: We report that the VE1 antibody stains normal anterior pituitary gland and adrenal cortex, which lack detectable BRAF V600E mutations., Results: Staining with the VE1 antibody was seen in the adenohypophysis and correlated well with adrenocorticotropic hormone (ACTH)-positive cells. ACTH-positive cells were typically most concentrated in the central mucoid wedge and pars intermedia, and VE1 staining was strong in these regions. Moreover, VE1 staining was seen in ACTH-expressing pituitary adenomas without detectable BRAF mutations. VE1 staining of the adrenal cortex was also significant, with the strongest staining seen in the inner segment of the zona fasciculata. Parathyroid glands, pancreatic islets, or parafollicular C cells in the thyroid showed no VE1 staining., Conclusions: Overall, VE1 staining of endocrine tissues strongly suggests limitations on the use of this antibody for the detection of BRAF mutations., (Copyright© by the American Society for Clinical Pathology.)

Pituitary tumors develop in about one-quarter of the population, and most arise from the anterior lobe (AL). The pituitary gland is particularly sensitive to genetic alteration of genes involved in the cyclin-dependent kinase (CDK) inhibitor (CKI)-CDK-retinoblastoma protein (Rb) pathway. Mice heterozygous for the Rb mutation develop pituitary tumors, with about 20% arising from the AL. Perplexingly, none of the CKI-deficient mice reported thus far develop pituitary AL tumors. In this study, we show that deletion of p19(Ink4d) (p19), a CKI gene, in mice results in spontaneous development of tumors in multiple organs and tissues. Specifically, more than one-half of the mutant mice developed pituitary hyperplasia or tumors predominantly in the AL. Tumor development is associated with increased cell proliferation and enhanced activity of Cdk4 and Cdk6 and phosphorylation of Rb protein. Though Cdk4 is indispensable for postnatal pituitary cell proliferation, it is not required for the hyperproliferative pituitary phenotype caused by p19 loss. Loss of p19 phosphorylates Rb in Cdk4(-/-) pituitary AL cells and mouse embryonic fibroblasts (MEFs) and rescues their proliferation defects, at least partially, through the activation of Cdk6. These results provide the first genetic evidence that p19 is a tumor suppressor and the major CKI gene that controls pituitary AL cell proliferation., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Gonadotrophs in the anterior pituitary secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Neonatal diethylstilbestrol (neoDES) treatment affects reproductive function of male and female mice, but the effect of this treatment on the development as well as direct effects on pituitary gonadotrophs have not been ascertained. We investigated LH-secreting gonadotropes and the expression of genes involved in the synthesis and secretion of gonadotropins in the anterior pituitary of neoDES mice using immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR). The percentage of LH-secreting gonadotropes in 90-day-old female mice treated neonatally with an oil vehicle (neoOil) was significantly lower than in 30-day-old neoOil females but not in males, indicating a significant reduction after reproductive maturation in females. The percentage of LH-secreting gonadotropes in the medial area of 90-day-old neoDES females was significantly lower than that of 90-day-old neoOil females, ovariectomized neoOil females, and neoOil and neoDES males. The expression of the LH beta (Lhb) subunit in the anterior pituitary of 90-day-old neoDES females was similar to that in neoOil females, but it was significantly lower than that observed in 90-day-old males. Ovariectomy increased the expression of the alpha subunit of glycoprotein hormones, FSH beta (Fshb) subunit and Lhb subunit both in neoOil and neoDES females, suggesting that the anterior pituitary of neoDES female mice is regulated by ovarian hormones via negative feedback. In organ-cultured, anterior pituitaries exposed to DES exhibited no change in the number of LH-secreting gonadotropes but did reduced gene expression. These results suggest that LH-secreting gonadotropes in the female mice are not only directly affected by neoDES but also are influenced by the masculinization of the hypothalamus. That is, neonatal DES exposure can masculinize or defeminize the hypothalamus of female mice. However, the regulation of the pituitary gonadotropins by the hypothalamus could be different from that in intact male mice.

An early thirties man diagnosed with Erdheim-Chester disease (ECD) was simultaneously disclosed to have hypogonadotropic hypogonadism, central adrenal insufficiency, and GH deficiency in addition to central diabetes insipidus (CDI). Pituitary magnetic resonance imaging (MRI) showed swelling in the stalk, enlargement of the anterior lobe with delayed enhancement, and loss of high intensity of the posterior lobe on T1-weighted images, suggesting of pituitary involvement of ECD. Three months after starting treatment with interferon α and zoledronic acid, polyuria and polydipsia were ameliorated without DDAVP, accompanied with improvement of MRI. Simultaneously technetium-99m bone scintigraphy showed improvement, accompanied with a relief of bone pain and high fever. In contrast, he developed secondary hypothyroidism with slight enlargement of anterior pituitary gland without relapse of CDI, suggesting of different responses to treatment with interferon α between anterior pituitary lobe and posterior one. So far he continues to be replaced with deficient hormone replacement therapy. As for bone pain, it remains to be controlled with the decreased levels of bone resorption marker with decreased abnormal uptake in bone scintigraphy although zoledronic acid was discontinued for osteonecrosis of the jaw. For four years, he has not showed new involvement at other organs besides bones and the pituitary. While CDI is known to be very common in ECD, improvement of CDI has been reported in a few cases. Other endocrine manifestations, especially with detailed endocrine status, have been also reported in limited cases. Thus we report this case and review the literature.

We report characteristic magnetic resonance (MR) image findings in a case of Sheehan's syndrome. A 37-year-old woman experienced complications of retained placenta and massive bleeding (3600 g) during delivery of a full-term baby. A pituitary function test demonstrated panhypopituitarism. MR image of the pituitary gland on postpartum day 10 revealed swelling of the anterior lobe. A hook-shaped enhancement was demonstrated on a sagittal image. The pituitary stalk, majority of the marginal zone of the anterior lobe, the anterior lobe just in front of the posterior lobe, and posterior lobe were well enhanced. In contrast, the central portion and the superior margin, just in front of the stalk insertion of the anterior lobe, were not enhanced. Anatomically, blood supply to these unenhanced portions of the anterior lobe was via the hypophyseal long portal vein and trabecular artery, which are tributaries of the superior hypophyseal artery that originate far from the internal carotid artery. Based on clinical history and MR image findings, the patient was diagnosed with Sheehan's syndrome and treated with hydrocortisone and levothyroxine. Follow-up MR image revealed marked atrophy of the anterior lobe. The characteristic hook-shaped enhancement in Sheehan's syndrome well reflected the vulnerability to massive bleeding based on the complex pituitary vasculature, which has not been reported previously. MR image with contrast enhancement is useful in the diagnosis of the acute phase of Sheehan's syndrome and in evaluating infarction of the anterior lobe.