Human Pituitary Gland Research Articles

MEMBRANOUS LAYERS OF THE PITUITARY GLAND

The purpose of this study was to examine the membranous layers of the human pituitary gland and their relationships with invasive adenomas. Histological and microdissection techniques were used to study 8 fetal and 10 adult human cadavers, respectively. The distribution of the membranous layers was observed, and their thickness was measured. The results were analyzed histologically and anatomically. In all specimens, the pituitary glands were found to be coated by 2 membranous layers, the inner layer being referred to here as the lamina propria and the outer as the pituitary capsule. In all specimens, the 2 membranes were intact with no histological defects. An interstice or cavity between the 2 layers was found on the surface of the adenohypophysis. However, as these 2 layers got closer and closer to each other, they began to adhere on the surface of the neurohypophysis. The thickness of the pituitary capsule was not constant like that of the lamina propria: the inferolateral part of the capsule was thicker than the other parts. The medial wall of the cavernous sinus (CS) was also a bilayered membrane just like the other CS walls: the 2 layers of the medial CS wall were composed of the lateral part of the pituitary capsule and the fibrous layer. Many fibrous trabeculae arising from this fibrous layer divided the CS into several small venous spaces and connected the internal carotid arteries with the medial wall. The terminology for the 2 membranous layers, the lamina propria and the pituitary capsule, seemed to be more appropriate and representative of the histological features of the pituitary layers. The lateral part of the capsule and the fibrous layer constituted the medial wall of the CS, which has a superior part that is weaker than the thicker inferior part. It is still difficult to postulate the criteria needed to predict CS invasion. However, the distance between the 2 sides of the internal carotid artery might be another predictive criterion to preoperatively diagnose CS invasion by adenomas. Enhanced knowledge of these membranes may be of assistance in finding a useful criterion.

NOD proteins expression and function in the pituitary folliculostellate cells

Folliculostellate (FS) cells were found to regulate hormonal secretion in pituitary endocrine cells. This cell type share properties with components of the innate immune response such as dendritic cells and macrophages, and it's suggested that they are able to initiate immune responses and act as part of an immunoendocrine regulation system. Members of toll-like receptor (TLR) family recognize bacterial cell wall components and initiate an immune response. Recently, we detected by RT-PCR the TLR4 mRNA expression in FS cell line, TtT/GF. In the present study, we detected the constitutive expression of two members of a novel nucleotide-binding oligomerization domain (NOD) family of proteins that act as cytosolic receptors. We show that NOD1 and NOD2 are expressed in the human and mouse pituitary glands, and in TtT/GF cells. Furthermore, NOD1-agonistic diaminopimelic acid (DAP) and NOD2-agonistic muramyl dipeptide (MDP) induced (NF)-κB activation in TtT/GF cell cultures. Both NOD agonists in combination with TLR4 agonistic, LPS enhanced NF-κB transcriptional activity, and interleukin-6 (IL-6) production in these cells. Knocking-down NOD1 and NOD2 markedly inhibited LPS induced IL-6 production in TtT/GF cells. RNA interference for NOD2, but not NOD1, downregulated NF-κB activity. LPS, MDP and LPS plus MDP increased NF-κB expression and transcriptional activity, in a mechanism involving STAT3, since knocking-down this protein abolished NF-κB activation. All together, we revealed that NOD1 and NOD2 are expressed in the pituitary gland and in TtT/GF cells. In addition our findings suggest that FS cells play a predominant role in the context of imune-endocrine interactions during bacterial infection and inflammation and NOD proteins have a central participation in these processes.

Involvement of pro-apoptotic and anti-apoptotic factors in the early development of the human pituitary gland.

The spatial and temporal pattern of appearance of pro-apoptotic caspase-3 and p53 proteins, and anti-apoptotic bcl-2 protein was investigated in the developing pituitary gland of 6 human embryos 5-8-weeks old, using morphological and immunohistochemical techniques. Their dynamic appearance was analyzed in the Rathke's pouch (future adenohypophysis), mesenchyme, and in the developing neurohypophysis. In the 5th and 6th week, caspase-3 positive cells appeared in the Rathke's pouch (5%) and stalk (11%), in the mesenchyme, but not in the neurohypophysis. In the 6th and 7th week, apoptotic cells were more numerous in the caudal part of the Rathke's pouch due to its separation from the oral epithelium. Pro-apoptotic p53 protein was detected in all parts of the pituitary gland throughout the investigated period. Nuclear condensations characterized cells positive to caspase-3 and p53 proteins. Apoptotic cells displayed condensations of nuclear chromatin on an ultrastructural level as well. While caspase-3 dependent pathway of cell death participated in morphogenesis of the adenohypophysis and associated connective tissue, p53-mediated apoptosis most likely participates in morphogenesis of all parts of the gland, including neurohypophysis. The anti-apoptotic bcl-2 protein was also detected in all parts of the developing gland. With advancing development, the positivity to bcl-2 protein increased in the cells of the adenohypophysis, while it decreased in the neurohypophysis. Bcl-2 protein probably prevented cell death in all parts of the gland and enhanced cell differentiation. The described pattern of appearance of the investigated pro-apoptotic and anti-apoptotic factors might be important for normal morphogenesis and function of the pituitary gland.

Expression of Adiponectin and Adiponectin Receptors in Human Pituitary Gland and Brain

Background/Aims: Adiponectin and its receptors, AdipoR1 and AdipoR2, constitute integral components of energy homeostatic mechanism in peripheral tissues. Recent studies have implicated adiponectin in central neural networks regulating food intake and energy expenditure. The present study aimed at investigating the possible expression and distribution of adiponectin and its receptors in human pituitary gland, hypothalamus and different brain areas. Methods: Sections of the pituitary gland, hypothalamus and adjacent basal forebrain area, cerebrum and cerebellum from 35 autopsy cases, were examined using HE, PAS-Orange G, luxol fast blue/cresyl violet stains and single and double immunohistochemistry using adiponectin, AdipoR1, AdipoR2, choline acetyltransferase, FSH, LH, TSH, GH, ACTH and prolactin-specific antibodies. Age and BMI mean values ± SD of the autopsy cases were 56 ± 18 years and 27 ± 5 kg/m², respectively. Results: Strong adiponectin expression was observed in pituitary gland. In pars distalis (PD), adiponectin localized in GH, FSH, LH and TSH-producing cells and in pars tuberalis (PT) in FSH, LH and TSH-producing cells. Strong to moderate expression of AdipoR1 and AdipoR2 was observed in PD by the same cell types as adiponectin. No immunoreactivity for adiponectin receptors was noted in cells of PT. Intense AdipoR1 immunostaining was observed in neurons of lateral hypothalamic area and of nucleus basalis of Meynert (NBM). Conclusions: Adiponectin and its receptors expression in human pituitary might indicate the existence of a local system, modulating endocrine axes. Furthermore, the presence of AdipoR1 in hypothalamus and NBM suggests that adiponectin may participate in central neural signaling pathways controlling energy homeostasis and higher brain functions.

Characterization of C-Kit (CD117) Expression in Human Normal Pituitary Cells and Pituitary Adenomas

c-kit (CD117) is a tyrosine kinase receptor involved in the proliferation, differentiation, and secretory functions of various cells. In experimental animal models, c-kit has been detected in the pars intermedia of the normal pituitary gland and in alpha-melanocyte-stimulating-hormone-positive adenomas and it has been suggested that it plays a role in regulating adrenocorticotropic hormone (ACTH) secretion. To the best of our knowledge, the expression of c-kit in normal human pituitary cells and in pituitary adenomas has never been reported, so the possible biological role of this receptor in the control of pituitary hormone secretion remains unclear. The aim of this study was to evaluate the immunohistochemical expression of c-kit in normal human pituitary glands and in a series of 62 well-characterized pituitary adenomas. In normal adenohypophyses, several cells, mainly located in the central mucoid wedge, showed a c-kit immunoreactivity (IR). Double label immunostaining procedures showed that the c-kit-IR cells corresponded to ACTH cells. Out of 62 adenomas, 15 (24%) were c-kit-IR, including 7/16 (44%) ACTH cell, 3/7 (42%) null cell, 4/11 (36%) alpha-subunit cell, and 1/11 (10%) follicle-stimulating hormone-luteinizing hormone cell adenomas. By contrast, all ten prolactin cell and seven growth hormone cell adenomas were c-kit negative. These data suggest that, in normal conditions, c-kit may be involved in the pituitary-adrenal axis regulation.

Autoimmune form of central diabetes insipidus with antibodies against vasopressin-producing hypothalamic cells

Autoantibodies against vasopressin (AVP)-producing cells of the human pituitary gland as well as conventional antibodies were determined in 67 patients with central diabetes insipidus and in 141 controls without diabetes insipidus using an immunofluorescence technique. Eleven out of 30 patients (37%) with nonfamilial idiopathic diabetes insipidus, two out of 28 patients (7%) with symptomatic diabetes insipidus and none of the control persons had AVP-cell antibodies. Antibody titres were between 1 : 2 and 1 : 32, in 8 of the 13 cases the antibodies were complement-binding. In 9 patients with idiopathic diabetes insipidus and in none of the symptomatic cases one or more autoimmune diseases were demonstrable. Demonstration of autoantibodies against AVP-cells of the pituitary in the serum of patients with so-called idiopathic diabetes insipidus indicates an autoimmune basis of the disease. This interpretation of the new antibody results is supported by a frequent association of idiopathic diabetes insipidus with recognized auto-immune diseases.

Acute in vivo stimulatory effects of human pituitary lipid-mobilizing factor on plasma levels of glucagon and insulin in rabbits.

The lipid-mobilizing factor LMF is prepared from deep-frozen human pituitary glands by alkaline extraction, followed by acetone precipitation at pH 4.8, Sephadex gel filtration and DEAE-cellulose chromatography. In addition to its adipokinetic effect in rabbits, LMF also increased the plasma levels of glucagon and insulin in rabbits in doses of 15 to 100 micrograms. The LMF-induced increases in the plasma levels of glucagon were most pronounced in fasted rabbits, whereas the increases in the plasma levels of insulin were most pronounced in fed rabbits. Glucose infusions decreased the LMF-induced hyperglucagonaemia and increased the LMF-induced hyperinsulinaemia. Somatostatin did not inhibit the LMF-induced hyperglucagonaemia with statistical significance, but inhibited the LMF-induced hyperinsulinaemia. The plasma levels of glucose were slightly decreased by 20 and 40 micrograms LMF in fasted rabbits and were unchanged in fed rabbits. In fasted rabbits, LMF had a toxic effect and 100 micrograms LMF killed one rabbits. Human growth hormone (hGH), prepared from the pituitary glands after removal of LMF, also increased the plasma levels of glucagon and insulin in rabbits. It is possible that the observed effects of LMF and hGH were due to the presence of some biologically active substances from the pituitary gland. These postulated substances could be involved in the pituitary control of the endocrine pancreas, and work is in progress to isolate them from the LMF preparation.

P75NTR and TrkC Neurotrophin Receptors Demonstrate a Different Immunoreactivity Profile in Comparison to TrkA and TrkB Receptors in Human Normal Pituitary Gland and Adenomas

Background/Aims: Recent knowledge indicates that neurotrophins play a significant role in neuroendocrine systems through their specific receptors TrkA, TrkB, TrkC and low-affinity p75^NTR receptor. TrkA and TrkB receptors have been previously detected in numerous endocrine cells in human anterior pituitary and adenomas. In the present study, the localization of p75^NTR and TrkC along with TrkA and TrkB receptors was investigated. Methods: Semi-serial paraffin-embedded sections of 5 human normal pituitaries and 30 adenomas were immunostained using specific antibodies. Results: Expression of p75^NTR receptor was demonstrated in the intricate capillary and reticulin network in the anterior pituitary and in the pericapillary tissue and pituicytes in the posterior lobe. p75^NTR immunoreactivity was absent from all adenomas. In normal anterior pituitary, a few scattered cells showed weak TrkC immunoreactivity in contrast to a high percentage of endocrine cells distributed throughout the pars distalis and pars intermedia which exhibited strong TrkA and/or intermediate TrkB immunoreactivity. Double immunohistochemistry demonstrated TrkA immunoreactivity in more than 80% of lactotropes and 70% of corticotropes and to a lesser extent in other cell types. Furthermore, in the majority of adenomas, independently of type, sex and age, a high percentage of TrkA- and/or TrkB-positive cells was detected. Interestingly, TrkC expression appeared to be increased in some adenomas compared to normal pituitary. Endothelial cells and perivascular connective tissue were always TrkB-immunostained. Conclusion: The above findings support a potential role of all neurotrophins, through their different receptors, in pituitary functions.

Immunohistochemical Analysis of VEGF-C/VEGFR-3 System and Lymphatic Vessel Extent in Normal and Adenomatous Human Pituitary Tissues

The angiogenic growth factor Vascular Endothelial Growth Factor-C (VEGF-C) and its receptor VEGFR-3 are also known to be implicated in the development of lymphatic vessels. We assessed the expression of VEGF-C and VEGFR-3, together with blood and lymphatic vessel extents and proliferation index (PI) values, by immunohistochemistry (IHC) in 6 normal human pituitary glands and 53 pituitary adenomas of different tumour grade, on consecutive tissue sections. VEGF-C was detected in around 10% of the endocrine cells in normal pituitary tissue, while this gland was devoid of lymphatic vascularization and showed very few vessels positive for VEGFR-3. Concerning tumour tissue, most of the adenomas showing VEGF-C immunoreactivity (21/47) were positive in 60% of the tumour cells and the ones positive for VEGFR-3 showed a number of immunostained vessels higher than those observed in the normal pituitary. Most of the tumours positive for VEGFR-3 did not show any LYVE-1 positive vessels (18/53), suggesting that at least in these cases, VEGFR-3 is expressed on blood vessels. Nevertheless, we observed a significant association between low expression of VEGFR-3 and low lymphatic vessel number, suggesting that VEGFR-3 might be involved in the starting of DE NOVO lymphangiogenesis in this tumour type. Moreover, tumours bearing lymphatic vessels showed the tendency to shift towards a more aggressive behaviour (high tumour grade and high PI). In conclusion, the VEGF-C/VEGFR-3 system might be involved in controlling tumour angiogenesis in the pituitary adenomas lacking lymphatic vessels, but may also play a role in starting the process of tumour lymphangiogenesis.

The clinical neurology and epidemiology of Creutzfeldt-Jakob disease, with special reference to iatrogenic cases.

The clinical characteristics of Creutzfeldt-Jakob disease (CJD) in a newly analysed group of 223 cases transmitted to primates at the NIH are compared to a recent large series of neuropathologically verified cases in France, and the limited conclusions from worldwide epidemiological studies are briefly summarized. Discussion then focuses on iatrogenic CJD, with special attention to the interplay of clinical, laboratory and epidemiological features of the current outbreak of CJD in hypopituitary dwarfs treated with growth hormone extracted from pools of human pituitary glands.

Involvement of the calcium-binding protein secretagogin in pituitary adenoma hormone production

Calcium is a potent intracellular signal transducer whose fluctuations control numerous cellular processes among them hormone production. Secretagogin (SCGN) is an intracytoplasmatic protein belonging to the EF-hand calcium binding protein superfamily, which was initially isolated from a human pancreatic cDNA library and was shown to be involved in the regulation of insulin synthesis and secretion. Since SCGN was also detected in neuroendocrine cells in the anterior pituitary, we have studied the expression of SCGN both in normal and tumoral pituitary and have started to elucidate its role in pituitary cells. Our preliminary results obtained by Real time PCR analysis showed the expression of SCGN in a group of 4 normal human anterior pituitary glands and in 26 different pituitary adenomas. In the tumours, SCGN mRNA was downregulated in 2/4 somatotrophinomas, 6/7 nonfunctioning pituitary adenomas, 4/6 prolactinomas, 3/6 corticotrophinomas and 2/2 thyrotrophinomas when compared to the expression in normal pituitary tissue. The co-transfection of a rat SCGN expression plasmid with prolactin-luc reporter plasmid, GH-luc plasmid and POMC-luc reporter plasmid, respectively in mammosomatotroph GH3 cells and in corticotroph AtT-20 cells, showed that SCGN overexpression was able to induce a 46% increase in the activity of the prolactin gene promoter and a 60% increase in the activity of the GH gene promoter, while in AtT-20 cells the activity of POMC gene promoter showed an increase of 66%. The analysis of the different promoter elements showed an activation of CRE element in GH3 cells after SCGN plasmid co-transfection and an increase in cAMP production. In AtT-20 cells SCGN plasmid co-transfection was able to induce an increase in the activities of AP-1, Nbr-E and NurrRE elements, which was also accompanied by an increase in cAMP production. These preliminary findings suggest the involvement of SCGN in controlling the synthesis of pituitary hormones, therefore constituting a potential target for inhibiting the hormone production.

Aromatase cytochrome P450 enzyme expression in human pituitary

Aromatase (P450AROM) converts testosterone to estrogen. This conversion could be important in normal physiology and estradiol-induced tumorigenesis in human pituitary. The objective of this study was to examine the expression of P450AROM in normal human pituitary and determine the gender difference. We examined aromatase expression in 19 normal human pituitary glands [13 males, 6 females, median age: 30 years (interquartile ranges, IQR: 23-63)] obtained from autopsy. We demonstrated aromatase gene expression levels by quantitative RT-PCR and aromatase protein with immunohistochemical staining in normal male and female human pituitary. Although median relative expression level of aromatase mRNA of male individuals [median DeltaCt = 42.6 (IQR: 7.6-93.9)] was higher than the female individuals [median DeltaCt = 3.9 (IQR:0-44.8)], we could not determine a significant gender difference in aromatase mRNA levels (p = 0.2). The difference between the aromatase protein density by immunohistochemistry was not significant between genders (p = 0.78). The aromatase levels were also not correlated with the age of the study subjects (p = 0.42 r = -0.21). The results indicate that aromatase enzyme is present in human pituitary. The amount and the density of the enzyme show a large variance among different individuals. Although higher mRNA expression was observed in male pituitary compared to female pituitary, there was no statistically significant difference for gender or age.

Increased Incidence of Pituitary Microadenomas in Suicide Victims

Background: Current data suggest an influence of the hypothalamic-pituitary-adrenal axis on suicidal behavior. The frequency of pituitary adenomas in suicide victims has not yet been investigated. Objectives: The aim of this study was to assess whether the incidence of pituitary adenomas is correlated with suicide. Methods: Serial sections of 151 human pituitary glands obtained upon autopsy were examined microscopically. The glands were collected from 70 suicide victims and 81 subjects whose deaths were classified as unexpected or accidental (nonsuicidal group). The sections were stained with hematoxylin-eosin and the presence of adenoma was confirmed by immunostaining for collagen III. Results: In the suicidal group, pituitary microadenomas were found in 32 cases (47.7%), while in the nonsuicidal group microadenomas were detected in 15 cases (18.3%). The observed difference was statistically significant (p = 0.0003). The relative risk ratio of suicide in persons with pituitary adenomas was estimated at 1.9. Logistic regression analysis in a model controlled for age and sex showed that microadenomas constituted a unique risk factor in this model. The immunohistochemical phenotyping revealed a higher percentage of immunopositive (secreting) microadenomas in the nonsuicidal group as compared to the suicidal group (80.0 vs. 59.38%) and a predominance of growth hormone-secreting microadenomas in both groups. However, these differences as well as differences in the hormonal profiles of microadenomas between the groups were not significant. Conclusions: These results suggest that pituitary adenomas belong to suicide risk factors.

Peroxisome Proliferator‐Activated Receptor γ in the Human Pituitary Gland: Expression and Splicing Pattern in Adenomas Versus Normal Pituitary

Pituitary adenomas are slow-growing tumours arising within the pituitary gland. If secreting, they give rise to well-known syndromes such as Cushing's disease or acromegaly; when hormonally inactive, they come to clinical attention often with local mass effects or pituitary deficiency. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor with a key role in fat and glucose metabolism, but also involved in several neoplasia, has recently been detected in pituitary adenomas. In the present study, we evaluated the occurrence and splicing profile of PPARgamma in 43 cases of pituitary adenoma of different subtypes and compared it to 12 normal pituitary glands. By real-time polymerase chain reaction, PPARgamma was expressed as much in adrenocorticotrophic hormone (ACTH)-secreting and ACTH-silent adenomas as in controls, with a moderate underexpression in somatotrophinomas and prolactinomas and overexpression in 54% of nonfunctioning pituitary adenomas (NFPA). There was no apparent qualitative change in the splicing profile of pathological pituitary glands, nor was the presence of specific isoforms with dominant negative effects against PPARgamma detected. Western blotting revealed similar expression levels in the different subgroups of pituitary adenomas and normal glands. Immunohistochemistry confirmed PPARgamma expression in approximately one-half of analysed samples. The intra- and intergroup differences observed in pituitary adenomas may represent new elements in the process of understanding the different clinical responses of Cushing's and Nelson patients to PPARgamma-ligand treatment. Moreover, the higher level of PPARgamma expression detected in the NFPA subgroup may suggest its possible role as a molecular target in these pituitary adenomas, paving the way for investigations on the effectiveness of treatment with thiazolidinediones in such patients.

Ultrastructural and immunohistochemical characteristics of developing human pituitary gland

The development and differentiation of the human pituitary gland and its relationship to other structures of the head were analysed in nine human embryos and fetuses aged 5-10 weeks old using morphological and immunohistochemical methods. In the 5th developmental week, the primordium of Rathke's pouch was closely associated with the cranial tip of the notochord, head mesenchyme and diencephalon. Cells of the Rathke's pouch displayed typical epithelial features that transformed into gland-like structures during development. Numerous Ki-67 positive cells characterised the Rathke's pouch, the diencephalon (neurohypophysis) and the associated mesenchyme. The highest proliferation rate was noticed in the earliest developmental stage, while it significantly decreased in the 7th week of development. The first intermediate filaments to appear in the Rathke's pouch showed cytokeratin 8 immunolabelling which decreased with advanced maturation. The diencephalon and infundibulum displayed parallel immunolabelling of vimentin, glial fibrillary acidic protein (GFAP) and neurofilament protein (NF), while the surrounding mesenchyme showed only vimentin labelling. Changes in the labelling of Ki-67 proliferation marker and intermediate filament proteins in the developing human pituitary gland coincided with separation of the Rathke's pouch from the pharyngeal epithelium and subsequent differentiation of different parts of the gland.

The NAD-dependent protein deacetylase Sirt1 is present in the human anterior pituitary gland where it plays a role in GH transcription

One of the best known experimental procedures that extend lifespan and resistance to aging-related diseases is caloric restriction. In yeast, C. elegans and Drosophila, Sir2 was shown to mediate the lifespan extending effect of caloric restriction. Sir2 and its mammalian homologue Sirt1 are NAD-dependent protein deacetylases that are sensitive to changes in cellular energy levels. Caloric restriction was shown to decrease plasma GH and IGF-I in rats, but the mechanism has never been understood. In the present study Sirt1 transcript was detected in the human anterior pituitary gland, and Sirt1 protein was found to be widely present in all endocrine cell types, as determined by immunohistochemistry. In order to investigate the effect of Sirt1 on GH expression, the rat mammosomatotrophinoma GH3 cells were transfected with a reporter vector bearing the GH promoter upstream the luciferase gene and Sirt1 was knocked down by RNA interference. Knocking down Sirt1 increased GH relative luciferase activity. GH transcription is under the control of the cAMP pathway. Sirt1 immunoprecipitated with Creb-binding protein (CBP), and was found to block CBP activity. It is possible that this is the mechanism mediating the inhibitory action of Sirt1 on GH transcription. These preliminary data show that Sirt1 is expressed in the anterior pituitary gland, where it can regulate GH synthesis in response to metabolic changes.

Histologic study of the human pituitary gland in acute traumatic brain injury

Purpose: Approximately 25% of patients with traumatic brain injury (TBI) may develop partial or complete hypopituitarism. The causative mechanisms involved in its development are not clear. To the authors’ knowledge, there have been no recent morphologic studies of the pituitary following TBI.Methods: To characterize the resultant histologic changes, this study investigated the pituitaries of 42 patients who died following a motor vehicle accident, all from the Mayo Tissue Registry. Twelve patients died instantly at the scene of the accident (Group I) whereas 30 survived between 3 hours and 7 days (Group II). All pituitary specimens were obtained at autopsy, formalin-fixed and paraffin-embedded. Hematoxylin-eosin sections cut in horizontal or sagittal plane were examined light-microscopically.Results: No infarction was noted in the pituitary specimens from group I. In group II, 13 of 30 (43%) showed acute infarcts of varying size. The extent of infarction in group II ranged from focal to sub-total necrosis involving 90% of the adenohypophysis.Conclusions: Underlying adenohypophysial pathology in patients dying after TBI is acute infarction. Loss of large numbers of adenohypophysial cells causes reduced secretion of adenohypophysial hormones and may contribute to post-traumatic hypopituitarism.

Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: Colocalization of MT1 with vasopressin, oxytocin, and corticotropin‐releasing hormone

Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. We here describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin-releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and anterior pituitary. These findings provide a neurobiological basis for the participation of melatonin in the regulation of various hypothalamic and pituitary functions. The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for stress conditions such as depression.

The NAD-dependent protein deacetylase Sirt1 is expressed in the human anterior pituitary gland and it regulates GH transcription

The NAD-dependent protein deacetylase Sirt1 is expressed in the human anterior pituitary gland and it regulates GH transcription

Gonadotrope and thyrotrope development in the human and mouse anterior pituitary gland

Genes and orthologous intrinsic and extrinsic factors critical for embryonic pituitary gonadotrope and thyrotrope cell differentiation have been identified mainly in rodents, but data on the human are very limited. In human fetal pituitaries examined between 14 and 19 weeks of gestation using immunofluorescent confocal microscopy, we found that most fetal gonadotropes expressed α-GSU, LHβ, and FSHβ gonadotropin subunits while almost no cells expressed α-GSU and LHβ alone. Gonadotropes expressing α-GSU and FSHβ only were detected in both male and female pituitaries, increasing in proportion to total gonadotropes in both males and females from 14 (approximately 4.5%) to 19 weeks (approximately 16.5%) with a peak in males of 45.5% compared with females of 16.5% at 17 weeks of gestation. When FSHβ or LHβ genes were expressed, gonadotropes were non-dividing. This profile of human fetal gonadotrope development differs from the current mouse model. Furthermore, while expression of α-GSU appears to be the lead protein in gonadotropes, in thyrotropes which ultimately express α-GSU with TSHβ, we observed that most if not all thyrotropes were TSHβ-positive but α-GSU-negative until around 19 weeks in human, and e15 in mouse, fetal pituitaries. Furthermore, the TSHβ-only thyrotropes were dividing, and TSHβ rather than α-GSU was the lead protein in thyrotrope development. Thus, while biologically active dimeric FSH and LH can be produced by the human fetal pituitary by 14 weeks, dimeric biologically active TSH will only be produced from around 17 weeks of gestation. The mechanism(s) responsible for the different molecular regulation of α-GSU gene expression in gonadotropes and thyrotropes in the developing human fetal pituitary now requires investigation.