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Traditional textbook physiology has ascribed unitary functions to hormones from the anterior and posterior pituitary gland, mainly in the regulation of effector hormone secretion from endocrine organs. However, the evolutionary biology of pituitary hormones and their receptors provides evidence for a broad range of functions in vertebrate physiology. Over the past decade, we and others have discovered that thyroid-stimulating hormone, follicle-stimulating hormone, adrenocorticotropic hormone, prolactin, oxytocin and arginine vasopressin act directly on somatic organs, including bone, adipose tissue and liver. New evidence also indicates that pituitary hormone receptors are expressed in brain regions, nuclei and subnuclei. These studies have prompted us to attribute the pathophysiology of certain human diseases, including osteoporosis, obesity and neurodegeneration, at least in part, to changes in pituitary hormone levels. This new information has identified actionable therapeutic targets for drug discovery., (© 2023. Springer Nature Limited.)

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed., (© 2015 The authors.)

The human pituitary gland may be the size of a pea, but it punches well above its weight due to secretion of hormones that regulate essential homeostatic processes ranging from growth to stress. Recent advances in imaging and genetics have allowed large-scale interrogation of pituitary structure and function, and in doing so, have revealed that output relies on its organisation into highly plastic networks., (© 2013 British Society for Neuroendocrinology.)

Objectives: Post-traumatic hypopituitarism is well described amongst adult traumatic brain injury (TBI) survivors. We aimed to determine the prevalence and clinical significance of pituitary dysfunction after head injury in childhood., Design: Retrospective exploratory study., Patients: 33 survivors of accidental head injury (27 boys). Mean (range) age at study was 13·4 years (5·4-21·7 years) and median (range) interval since injury 4·3 years (1·4-7·8 years). Functional outcome at study: 15 good recovery, 16 moderate disability, two severe disability., Measurements: Early morning urine osmolality and basal hormone evaluation were followed by the gonadotrophin releasing hormone (GnRH) and insulin tolerance (n = 25) or glucagon tests (if previous seizures, n = 8). Subjects were not primed. Head injury details were extracted from patient records., Results: No subject had short stature (mean height SD score +0·50, range -1·57 to +3·00). Suboptimal GH responses (<5 μg/l) occurred in six peri-pubertal boys (one with slow growth on follow-up) and one postpubertal adolescent (peak GH 3·2 μg/l). Median peak cortisol responses to insulin tolerance or glucagon tests were 538 and 562 nm. Nine of twenty-five and two of eight subjects had suboptimal responses, respectively, two with high basal cortisol levels. None required routine glucocorticoid replacement. In three, steroid cover was recommended for moderate/severe illness or injury. One boy was prolactin deficient. Other basal endocrine results and GnRH-stimulated LH and FSH were appropriate for age, sex and pubertal stage. Abnormal endocrine findings were unrelated to the severity or other characteristics of TBI or functional outcome., Conclusions: No clinically significant endocrinopathy was identified amongst survivors of accidental childhood TBI, although minor pituitary hormone abnormalities were observed., (© 2010 Blackwell Publishing Ltd.)

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke's pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that has been initially characterized from a salmon pituitary extract and subsequently identified in various species from all classes of vertebrates. The present review summarizes the current knowledge regarding the neuroanatomical distribution of MCH-immunoreactive neurons in submammalian vertebrates. In all species examined, MCH-immunoreactive perikarya are confined to the hypothalamus, with the exception of the cyclostome Lampetra fluvialis and the lungfish Protopterus annectens, in which additional populations of MCH-immunoreactive cell bodies occur in the telencephalon, and the frogs Rana ridibunda and Rana esculenta which exhibit MCH-positive perikarya in thalamic nuclei. In teleosts, in the frog R. ridibunda and in the L. fluvialis, MCH is present in the classical hypothalamic-neurohypophysial system indicating that the peptide may play the role of a neurohormone. In other groups, MCH-immunoreactive nerve fibers are widely distributed in various brain regions suggesting that, in these species, MCH in the central nervous system may act as a neurotransmitter or/and a neuromodulator rather than a neurohormone.

The pituitary gland is a complex organ secreting six hormones from five different cell types. It is the end product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism or more complex disorders such as septo-optic dysplasia and holoprosencephaly. However, the overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified; characterization of these will further elucidate the pathogenesis of this complex condition and also shed light on normal pituitary development and function.

The LHX3 LIM-homeodomain transcription factor is required for correct development of the mammalian pituitary gland and spinal motoneurons. Mutations in the LHX3 gene underlie complex diseases featuring combined anterior pituitary hormone deficiency and, in specific cases, loss of neck rotation considered to result from nervous system abnormalities. The molecular basis for LHX3 protein actions in both normal and aberrant pituitary and nervous system development is poorly understood. In this study, the gene regulatory abilities of mutant LHX3 proteins associated with distinct types of diseases (LHX3a A210V, LHX3a E173Ter, and LHX3a W224Ter) were investigated. The capacity of these proteins to activate pituitary hormone and transcription factor gene promoters, nervous system target genes, and to localize to the nucleus of pituitary cells was measured. Consistent with the symptoms of patients with these mutations, the abnormal proteins displayed diminished capacities to activate the promoters of genes expressed in the pituitary gland. On nervous system promoters, several mutant proteins retained some activity. The ability of the mutant proteins to concentrate in the nucleus of pituitary cells was correlated with the retention of defined nuclear localization signals in the protein sequence, except for the E173Ter protein which unexpectedly localizes to the nucleus, likely due to the insertion of cryptic nuclear localization signals by a frame shift caused by the mutation. This study extends the molecular characterization of the severe neuroendocrine diseases associated with LHX3 gene mutations.

The level of thyrotropin (TSH) secretion is determined by the balance of TSH-releasing hormone (TRH) and thyroid hormones. However, neuromedin B (NB), a bombesin-like peptide, highly concentrated in the pituitary, has been postulated to be a tonic inhibitor of TSH secretion. We studied the pituitary-thyroid axis in adult male mice lacking NB receptor (NBR-KO) and their wild-type (WT) littermates. At basal state, NBR-KO mice presented serum TSH slightly higher than WT (18%, P< 0.05), normal intra-pituitary TSH content, and no significant changes in alpha and beta TSH mRNA levels. Serum thyroxine was normal but serum triiodothyronine (T3) was reduced by 24% (P< 0.01) in NBR-KO mice. Pituitaries of NBR-KO mice exhibited no alteration in prolactin mRNA expression but type I and II deiodinase mRNA levels were reduced by 53 and 42% respectively (P< 0.05), while TRH receptor mRNA levels were importantly increased (78%, P< 0.05). The TSH-releasing effect of TRH was significantly higher in NBR-KO than in WT mice (7.1-and 4.0-fold respectively), but, while WT mice presented a 27% increase in serum T3 (P< 0.05) after TRH, NBR-KO mice showed no change in serum T3 after TRH. NBR-KO mice did not respond to exogenous NB, while WT showed a 30% reduction in serum TSH. No compensatory changes in mRNA expression of NB or other bombesin-related peptides and receptors (gastrin-releasing peptide (GRP), GRP-receptor and bombesin receptor subtype-3) were found in the pituitary of NBR-KO mice. Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH. Therefore, the study highlights the important role of NB as a physiological regulator of pituitary-thyroid axis function and gene expression.

The central control of growth hormone (GH) secretion from the pituitary gland is ultimately achieved by the interaction between two hypothalamic neurohormones, somatostatin which inhibits and growth hormone-releasing hormone (GHRH) which stimulates GH release. The regulation of the somatostatin and GHRH release from the hypothalamus is regulated by a range of other neuropeptides, neurotransmitters, neurohormones. In this mini review we attempt to provide a short summary covering the anatomy and chemical characteristics of the various cell populations regulating GH secretion as a tribute to Miklós Palkovits who pioneered the field of functional neuroanatomy of hypothalamic networks.

The pituitary gland is an important component of the endocrine system, and together with the hypothalamus, exerts considerable influence over the functions of other endocrine glands. The hypothalamus either positively or negatively regulates hormonal productions in the pituitary through its release of various trophic hormones which act on specific cell types in the pituitary to secrete a variety of pituitary hormones that are important for growth and development, metabolism, reproductive and nervous system functions. The pituitary is divided into three sections-the anterior lobe which constitute the majority of the pituitary mass and is composed primarily of five hormone-producing cell types (thyrotropes, lactotropes, corticotropes, somatotropes and gonadotropes) each secreting thyrotropin, prolactin, ACTH, growth hormone and gonadotropins (FSH and LH) respectively. There is also a sixth cell type in the anterior lobe-the non-endocrine, agranular, folliculostellate cells. The intermediate lobe produces melanocyte-stimulating hormone and endorphins, whereas the posterior lobe secretes anti-diuretic hormone (vasopressin) and oxytocin. Representative cell lines of all the six cell types of the anterior pituitary have been established and have provided valuable information on genealogy of the various cell lineages, endocrine feedback control of hormone synthesis and secretions, intrapituitary interactions between the various cell types, as well as the role of specific transcription factors that determine each differentiated cell phenotype. In this review, we will discuss the morphology and function of the cell types that make up the anterior pituitary, and the characteristics of the various functional anterior pituitary cell systems that have been established to be representative of each anterior pituitary cell lineage.

The prohormone convertase PC2 requires the aid of a helper protein, known as 7B2, for production of active enzyme. Deletion of 7B2 results in a lethal phenotype resembling Cushing's disease. In this study, we have investigated the effect of a single low dose of recombinant adenovirus vector encoding 7B2 and delivered directly to the pituitary of 7B2 nulls on pituitary ACTH, plasma ACTH, corticosterone, alpha MSH and glucose, and survival time. We show that after injection of recombinant adenovirus encoding 27-kDa 7B2 into 7B2 nulls, transgene expression, as measured by RIA for 7B2, exhibits a transient elevation in the pituitary and blood, with a slight but significant elevation of PC2 activity in pituitaries of 7B2 nulls and a drop in the level of circulating ACTH concomitant with a small increase in circulating alpha MSH. The level of circulating blood glucose was increased, and that of corticosterone was decreased. Lastly, slight but significantly prolonged survival times were observed. These data showing partial rescue of 7B2 nulls support the idea that adenoviral administration of 7B2 will represent an effective means to study the role of this interesting neuroendocrine protein on endocrine function in vivo.

The different members of the endothelin peptide family exhibit potent, long-lasting vasoconstrictive effects and thus play a central role in blood pressure regulation. However, endothelins have also been shown to modulate renal, cardiac and immune functions under physiological and pathophysiological conditions. In addition, endothelins are thought to be involved in the progression of some types of tumours. Soon after their discovery in 1988, it was shown that endothelins affect hormone release in the pituitary. Moreover, the intrapituitary production and expression of both endothelins and endothelin receptors have been described. This review summarises the present day knowledge concerning the expression and regulation of intrapituitary endothelins and their receptors. In addition, the effects of endothelins on hormone production by anterior, intermediate and posterior pituitary cell types are reviewed and their importance for pituitary physiology and pathophysiology is discussed.

Pituitary somatotropes and melanotropes have enabled us to investigate the molecular basis and functional dynamics underlying secretory plasticity, an ability of endocrine cells to adapt their activity to the changing physiologic requirements, which generates discrete cell subpopulations within each cell hormonal type. Porcine somatotropes comprise two morphologically distinct subpopulations of low- (LD) and high-density (HD) cells, separable by Percoll gradient, that respond differently to hypothalamic regulators. In LD somatotropes, somatostatin (SRIF) inhibits growth hormone (GH)-releasing hormone (GHRH)-induced GH secretion. Conversely, SRIF alone stimulates GH release from HD somatotropes. These disparate SRIF actions entail a molecular signaling heterogeneity, in that SRIF increases cAMP levels in HD but not in LD cells as a requisite to stimulate GH release. GHRH-stimulated GH release also involves differential signaling in LD and HD cells: although it acts primarily through the cAMP/extracellular Ca2+ route in both somatotrope subsets, full response of LD somatotropes also requires the inositol phosphate/intracellular Ca2+ pathway. Amphibian melanotropes, which regulate skin adaptation to background color by secreting POMC-derived alpha-melanocyte-stimulating hormone (alphaMSH), also comprise two subpopulations with divergent secretory phenotypes. LD melanotropes show high biosynthetic and secretory activities and high responsiveness to multiple hypothalamic factors. Conversely, HD melanotropes constitute a hormone-storage subset poorly responsive to regulatory inputs. Interestingly, in black-adapted animals most melanotropes acquire the highly-secretory LD phenotype, whereas white-background adaptation, which requires less alphaMSH, converts melanotropes to the storage HD phenotype. These same interconversions can be reproduced in vitro using appropriate hypothalamic factors, thus revealing the pivotal role of the hypothalamus in regulating the functional dynamics of the secretory plasticity. Furthermore, this regulation likely involves a precise control of the secretory pathway, as suggested by the differential distribution in LD and HD melanotropes of key components of the intracellular transport, processing, and storage of secretory proteins. Hence, molecular signaling heterogeneity and unique secretory pathway components seem to relevantly contribute to the control of secretory plasticity, thereby enabling endocrine cells to finely adjust their dynamic response to the specific hormonal requirements.

Mouse models have been used to study various aspects of pituitary development, function and disease. Transgenic or knockout technology has been applied to examine the regulation of hormone gene expression and the pathophysiology of its alterations, to ascertain the factors that determine cell differentiation, and to manipulate oncogenesis. Transgenic mice have elucidated the necessary elements required for the tissue- and cell-specific expression of pituitary hormones. Transgenic and knockout technologies have derived mice with hormone overexpression or abrogation of hormone action, and have identified novel hormones. The role of precursor cells in cell differentiation has been confirmed by genetic ablation of cell lineages. Inactivation of transcription factors implicated in pituitary organogenesis and cytogenesis has proven their critical roles in pituitary development. Pituitary oncogenesis has been studied by promoter-directed oncogene expression or tumor suppressor gene ablation, by adenohypophysiotropic hormone overexpression, or by growth factor or receptor overexpression. The tumors have provided a number of cell lines for use in the continuing study of pituitary physiology and pathology. These models may also be used in the future to examine novel therapeutic strategies for the management of patients with pituitary disorders.

Objective: Several genes encoding homeobox transcription factors are important for normal pituitary gland development and eventually for hormone production., Methods and Results: By interacting with each other on the basis of a distinct temporal and spatial expression pattern, as well as with other extrinsic and intrinsic signals, they control cell determination, cell differentiation and eventually maintenance of cell function which is most important for the lifelong secretion of the pituitary-derived hormones in an appropriate manner. The different phenotypes, as mainly studied in the mouse, may help to analyze the consequences of disruption of a known or yet unknown individual transcription factor in humans., Conclusion: Therefore, to study the different steps in morphogenesis will shed light onto developmental processes which will open a most fascinating time not only for basic scientists and biologists, but also for clinicians seeing all these patients., (Copyright 2001 S. Karger AG, Basel)

The objectives of the present work were to determine the influence of hypophysectomy and/or peroxisome proliferators (PP) on certain xenobiotic-metabolizing enzyme activities, i.e. glutathione transferases (GST), glutathione peroxidase (GPX), phenol sulphotransferases (pSULT), phenol UDP-glucuronosyl transferases (pUGT), catalase, NADP(H) quinone oxidoreductase (QR) and epoxide hydrolases (EH) in the rat testes. Adult male rats, hypophysectomized and their sham-operated controls, were treated for 10 days with clofibrate (0.5%), perfluorooctanoic acid (0.05%, PFOA), acetylsalicylic acid (1%, ASA) and di(2-ethylhexyl)phthalate (2%, DEHP) in their diet. The results show that, in addition to both body and testis weight, hypophysectomy caused dramatic changes in most of the xenobiotic-metabolizing enzyme activities, which have been measured here. The most pronounced effects were seen in cytosolic QR (2.2-fold increase), pUGT (95% reduction), pSULT (75% reduction), mitochondrial catalase (75% reduction), microsomal EH (70% reduction) and microsomal GST (55% reduction). Treatment with PP, i.e. perfluorooctanoic acid (PFOA), clofibrate, acetyl salicylic acid (ASA) and di(2-ethylhexyl)phthalate (DEHP) showed varied effects on the xenobiotic-metabolizing enzyme activities, the highest effects (10-60% reduction) were seen in sham-operated animals. These effects were not so pronounced or were not seen in hypophysectomized rats except for the case of PFOA treatment, which caused increases of enzyme activities. The highest increases were seen with microsomal GST (70%), GPX (75%) and cytosolic EH (75%). It is concluded from these experiments that the regulation of several xenobiotic-metabolizing enzymes in the rat testis is affected by the pituitary and/or pituitary hormones and that different peroxisome proliferators have variable effects on the levels of these xenobiotic-metabolizing enzymes. The general trend of reduction in enzyme activities implies that the testis is less protected under conditions that can perturb hormonal status.

Using specific antibody for chum salmon somatolactin (SL), immunocytochemical studies were employed to determine the distribution of this hormone in the pituitary gland and the brain of Orechromis niloticus. The results indicated that the SL-immunoreactive (ir) cells are found in the pars intermedia (PI) of the pituitary gland. The SL-ir cells showed strong and specific immunoreactivity to anti-chum salmon SL. Moreover, SL-ir cells were found to be widely distributed in most brain regions. Most of the SL-ir cell bodies were scattered along a nearly continuous line extending posteriorly from the olfactory bulb to the medulla oblongata through the nucleus preopticus periventricularis, habenula, and midbrain tegmentum and ventral to the nucleus lateralis tuberis pars posterior through the nucleus preopticus basalis lateralis and organum vasculosum luminae terminalis. Also SL-ir cells were observed in the cerebellum. The synthetic and secretory activity of the SL-ir cells, in the pituitary and the brain, showed an increase during sexual maturation and spawning. The highly organized SL-containing system and the gradual stimulation of SL synthesis and release during sexual maturation and spawning of O. nilotcus suggest that SL may be involved in the control of some steps of reproductive processes., (Copyright 1999 Academic Press.)

There has been considerable speculation that hormones produced in the anterior pituitary gland act as positive regulators of primary B cell development in the bone marrow. In order to identify endocrine factors that have such a role, B cell differentiation was examined in a panel of mice with genetic mutations that result in compromised production of one or more anterior pituitary hormones. This analysis demonstrated that the frequency of B lineage cells is significantly reduced in the dwarf and hypothyroid strains of mice, which have defects in the pituitary/thyroid axis, and that the production of normal numbers of pre-B cells is particularly dependent upon thyroid hormones. B cell development was normal in Little and IGF-I knockout animals, which have defects in the production of growth hormone and/or insulin-like growth factor I. The dependence of B lymphopoiesis on thyroid hormones appeared to be specific for that lineage, as myelopoiesis and thymopoiesis were normal in dwarf and hypothyroid mice. In addition to describing a specific endocrine hormone involved in the regulation of B cell development, these data provide evidence that normal production of bone marrow B lineage cells is dependent on extramedullary signals.

The products of the cAMP response element modulator (CREM) gene play an important role in the transcriptional response to cAMP in endocrine cells. By virtue of an alternative, intronic promoter within the gene, the inducible cAMP early repressor (ICER) isoform is generated. ICER was shown to act as a dominant negative regulator and to be cAMP-inducible in various neuroendocrine cells and tissues. ICER negatively autoregulates its own expression and has been postulated to participate in the molecular events governing oscillatory hormonal regulations. To elucidate ICER function in pituitary physiology, we have generated AtT20 corticotroph cell lines expressing the sense or antisense ICER transcript under the control of the cadmium-inducible human methallothionein IIA promoter. Here we demonstrate that changes in the regulated levels of ICER have drastic consequences on the physiology of the corticotrophs. Ectopic ICER expression induces remarkable modifications in AtT20 morphology. Cells with persistent, nonregulated high levels of ICER are blocked in the G2/M phase of the cell cycle, while the opposite effect is obtained in cells expressing an antisense ICER transcript. We show that the effect of ICER on the AtT20 cell cycle is correlated to a direct down-regulation of the cyclin A gene promoter by ICER. Finally, we show that ACTH hormonal secretion from the corticotrophs is completely blocked by ICER ectopic expression. Interestingly, this effect is not due to a direct regulation of the POMC gene, but is mediated by a transcriptional control of the prohormone convertase 1 gene. These results point to a key regulatory function of CREM in pituitary physiology.

The data reviewed establish the presence and important role in body fluid homeostasis of brain atrial natriuretic peptide (ANP) in all vertebrate-species examined. The peptide is localized in neurons in hypothalamic and brain stem areas involved in body fluid volume and blood pressure regulation, and its receptors are located in regions that contain the peptide. Most, if not all, of the actions of ANP are mediated by activation of particulate guanylyl cyclase with generation of guanosine 3',5'-cyclic monophosphate, which mediates its actions in brain as in the periphery. Although atrial stretch releases ANP from cardiac myocytes, the experiments indicate that the response to acute blood volume expansion is markedly reduced after elimination of neural control. Volume expansion distends baroreceptors in the right atria, carotid-aortic sinuses, and kidney, altering afferent input to the brain stem and hence the hypothalamus, resulting in stimulation via ANPergic neurons in the hypothalamus of oxytocin release from the neurohypophysis that circulates to the right atrium to stimulate ANP release. The ANP circulates to the kidney and induces natriuresis. Atrial natriuretic peptide also induces vasodilation compensating rapidly for increased blood volume by increased vascular capacity. Atrial natriuretic peptide released into hypophysial portal blood vessels inhibits release of adrenocorticotropic hormone (ACTH), thereby decreasing aldosterone release and enhancing natriuresis. Furthermore, the ANP neurons inhibit AVP release leading to diuresis and decreased ACTH release. Activation of hypothalamic ANPergic neurons via volume expansion also inhibits water and salt intake. These inhibitory actions may be partially mediated via ANP neurons in the olfactory system altering salt taste. Atrial natriuretic peptide neurons probably also alter fluid movement in the choroid plexus and in other brain vascular beds. Therefore, brain ANP neurons play an important role in modulating not only intake of body fluids, but their excretion to maintain body fluid homeostasis.

Purpose: To investigate changes in the size, shape, and signal intensity of the pituitary gland during the first 2 years of life., Methods: One hundred consecutive MR studies, spin-echo T1- and T2-weighted sequences, of children 0 to 2 years of age were analyzed. Signal intensity and shape of the gland were graded and its signal intensity measured., Results: There was a statistically significant difference in the signal intensity of both the anterior and posterior pituitary gland and in the shape between children younger than and older than 6 weeks of age and younger than and older than 27 weeks of age. There were definite trends in the size of the gland with age (decrease in height and increase in anteroposterior diameter and width)., Conclusions: There are changes in the pituitary gland in the newborn period that may reflect the ongoing changes in pituitary hormones reported to occur during this time.

To investigate whether pituitary-dependent hormones may regulate galanin (GAL) content, synthesis and distribution in the hypothalamus, female hypophysectomized Wistar rats were treated for 2 weeks with subcutaneous injections of thyroxine (T4, 2 x 1 microgram), bovine growth hormone (GH, 2 x 125 micrograms), cortisol (C, 50 micrograms), subcutaneous implants of beta-estradiol (E2, 5-mm implant, dilution 1:1), or with the combinations [T4+GH], [T4+GH+C+E2] or [T4+GH+C+E2 + rat PRL, 2 x 125 micrograms] (doses/100 g BW/day). Concentrations of GAL in the hypothalamus were measured by radioimmunoassay (RIA) and GAL mRNA abundance was quantified by Northern blot (6 rats/group); 2 rats/group were used for immunohistochemistry. Hypophysectomy caused decreases of hypothalamic GAL peptide and mRNA concentrations (by 70 and 50%, respectively; p < 0.05 vs. intact rats). GAL immunoreactivity disappeared in the median eminence (ME), but increased in the neurohypophyseal magnocellular neurons of hypophysectomized rats. Substitution with T4, GH, [T4+GH], C or E2 had no significant effect on total hypothalamic GAL peptide and GAL mRNA concentrations. A treatment combining [T4+GH+C+E2] increased hypothalamic GAL (1.9 +/- 0.1 vs. 1.2 +/- 0.1 ng/mg protein in untreated hypophysectomized rats; p < 0.01) and GAL mRNA concentrations (127 +/- 19 vs. 59 +/- 2 densitometric units in untreated rats, p < 0.001). Addition of PRL to this combined treatment had no further effect. Treatment with T4, GH, [T4+GH] or E2 enhanced GAL labeling in the ME of hypophysectomized rats. The effect of estrogens was restricted to the GnRH-rich lateral regions of the ME. The combined treatment with [T4+GH+C+E2] restored the ME GAL immunoreactivity to levels observed in intact rats. In contrast, the increased GAL labeling observed in magnocellular neurons after hypophysectomy was not influenced by any hormonal treatment. In conclusion, hypophysectomy leads to marked reductions of hypothalamic GAL and GAL mRNA concentrations, and of GAL immunoreactivity in the ME. These reductions are prevented in part by a combined hormonal treatment associating T4, GH, C and E2, but not by any hormone given alone. This suggests specific pituitary hormone-dependent regulation of the hypophysiotropic GAL neurons. In contrast, the increased GAL labeling in magnocellular neurons of hypophysectomized rats persists despite hormonal treatment and likely represents a lesional effect on the neurohypophyseal GAL system.

The present study demonstrates cell-specific distribution and describes distinct functional regulation of different adenylyl cyclases (AC, types I-VI) in rat pituitary cell tumor cell lines (GH12C1, GH3 and GH4C1 cells) and pituitary tissue. Northern-blot analysis revealed a distinct pattern of cell-specific expression of the different AC types; Ca2+/calmodulin (CaM)-insensitive AC type II was found in all cell lines tested except GH(1)2C1 cells. The Ca(2+)-inhibitable AC type VI was found in all cell types tested. We observed a lack of the Ca2+/CaM-sensitive AC type I in GH3 and GH4C1 cells. GH(1)2C1 cells exclusively contained both Ca2+/CaM-sensitive AC types I and III, the latter previously believed to be specific for olfactory tissue. An additional transcript of AC type III was found in rat brain and rat liver tissue. AC type IV, which is Ca2+/CaM insensitive, could be detected in the prolactin-producing GH3 and GH4C1 cells and pituitary tissue but not in growth-hormone-producing GH(1)2C1 cells. Basal and vasoactive-intestinal-peptide-(VIP)-releasing-hormone, somatostatin (SRIF) and thyrotropin-releasing-hormone (TRH)-modulation of AC activity was measured in the presence of 100 microM EGTA, anti-CaM serum (dilution 1:2000) or 10 microM trifluoroperazine. Antisera against guanine-nucleotide-binding protein (G-protein) alpha subunits (G(i)-2 alpha, Gs alpha) and beta subunits (G beta 35/36) and CaM were added for functional studies of the SRIF and VIP-modulated AC in GH(1)2C1 and GH3 cells. These experiments indicate that the VIP and the SRIF receptors are coupled to a Ca2+/CaM-sensitive AC in GH(1)2C1 cells, different from the AC involved in the regulation of cAMP levels in GH3 and GH4C1 cells. In addition, the beta gamma-complex is possibly able to modulate SRIF-inhibited AC activity by potentiating the inhibitory effect. The TRH receptor in GH3 and GH4C1 cells is coupled to a Ca2+/CaM-sensitive AC which is different from the already cloned forms of AC types I and III. We, therefore, conclude that hormone regulation of pituitary tumour cell functions differs between the GH cell lines, due to specific utilisation of AC types.

We had previously shown that homoeostatic thymus hormone (HTH), an H2A-H2B histone dimer, possesses an age-dependent adrenostimulatory activity in vivo. It was therefore of interest to investigate the adrenocorticotropin (ACTH)-releasing activity of histones and other related preparations on perifused pituitary cells from young (2-4 months) and mature (16-18 months) rats. Histones and protamines gave a positive interference with the immunoradiometric assays (IRMA) for ACTH and corticotropin releasing hormone (CRH) whereas the histone fragment MB35, as well as nucleohistone and nucleoprotamine complexes did not. The latter three substances induced a significant ACTH response in pituitary cells from young and, to a lesser extent, mature rats. Our results suggest that nucleoprotein complexes released into the extracellular milieu may act as hypophysiotropic signals. On the other hand, the responsiveness of pituitary cells to these signals seems to decrease with the age of the donor.

The intermediate lobe of the pituitary is composed of a homogeneous population of endocrine cells, the melanotrophs, which secrete several bioactive peptides including alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin. In contrast to most endocrine glands which are richly vascularized, the intermediate lobe of the pituitary contains very few blood vessels; in some species, the pars intermedia is virtually totally avascular. In contrast, pituitary melanotrophs are richly supplied by nerve fibers originating from the hypothalamus. The pars intermedia thus appears as a pure model of neuroendocrine communication, i.e. it is an archetype of the mode of transducing interface between the central nervous system and endocrine effectors. In mammalian species, different types of nerve terminals containing dopamine, norepinephrine, gamma-aminobutyric acid (GABA) and serotonin have been identified. In lower vertebrates, particularly in fish and amphibians, the pars intermedia is also innervated by peptidergic fibers which are though to take part in regulation of the secretory activity of the melanotroph. In these animals, the pars intermedia is regarded as a major center of neuroendocrine integration and an exceptional model to investigate the process of communication between the brain and the endocrine glands. The purpose of the present review is to summarize our current knowledge on the synthesis, processing and release of peptide hormones from pars intermedia cells and to survey the multiple regulatory mechanisms which are involved in the control of the activity of pituitary melanotrophs. Proopiomelanocortin, a multifunctional precursor. Pituitary melanotrophs synthetise a major precursor protein called proopiomelanocortin (POMC) which generates through proteolytic cleavage several biologically active peptides including adrenocorticotropic hormone (ACTH), endorphins and MSHs. In lower vertebrates, alpha-MSH is generally considered as the major hormone secreted by melanotrophs, in that it is involved in the process of skin colour adaptation. The post-translational processing of POMC, which yields to the mature hormones released by melanotrophs, includes a number of steps: glycosylation, phosphorylation, tissue-specific proteolytic cleavage, amidation and acetylation. Some of these posttranslational modifications can be regulated by neuroendocrine factors. For instance, in frogs, it has been shown that dopamine inhibits acetylation of alpha-MSH and thus reduces the secretion of the biologically active form of the peptide. The intermediate lobe of the pituitary: a model of neuroendocrine integration. In most vertebrate species, the intermediate lobe of the pituitary is innervated by catecholamine-containing fibers. In particular, the presence of dopaminergic nerve fibers has been observed in the pars intermedia of mammals and poikilotherms.(ABSTRACT TRUNCATED AT 400 WORDS)

The increased production of cortisol by the fetal adrenal gland at term acts as the trigger for parturition in some species. The fetal pituitary controls fetal adrenal function. However, ACTH is only one of a family of closely related peptides which derive from a common precursor and we have shown that although ACTH is the dominant form in the adult pituitary, the expression of the "family trees' is altered in the fetus. In the sheep, it is large-molecular-weight precursors and, in the primate, the smaller peptides such as alpha-MSH, CLIP, beta-MSH and beta-endorphin that predominate in fetal life and which may be responsible for fetal adrenal function. It is still unclear what causes the developmental change in the ACTH "family tree'. Since it may result from a change in pituitary function - from the peptides of the pars intermedia, in the fetus, to those of pars anterior, in the adult - we have studied these two lobes separately in pituitaries taken from adult and fetal sheep and monkeys. Our preliminary results suggest that the change may occur in the neurointermediate lobe in the primate, but that in the sheep the developmental changes occur in the anterior lobe.

Swiss Webster mice were hypophysectomized on Day 10 of pregnancy and the effect of the ablation on mammary gland development was estimated by measuring the total weight and the DNA, RNA, and alpha-lactalbumin contents and concentrations of the mammary gland on Days 14 and 18 of gestation. Although a significant increase in mammary gland weight occurred in the hypophysectomized animals between Days 10 and 18 of pregnancy, the mammary gland weight of the hypophysectomized mice was significantly reduced when compared with intact and sham-operated mice on both Days 14 and 18 of pregnancy. The total RNA content of the mammary gland was also reduced in the hypophysectomized mice, although it increased significantly from Day 10 to Day 18. The alpha-lactalbumin content of the mammary gland increased only slightly between Days 10 and 14 of gestation in the intact and sham-operated mice, but a large increase was found on Day 18 in both groups. There was, on the other hand, no increment in the alpha-lactalbumin content of the mammary gland in the hypophysectomized mice either on Day 14 or 18 of gestation. The DNA content of the mammary gland was not affected by hypophysectomy when estimated on Days 14 and 18 of pregnancy. The effects of hypophysectomy on the concentrations of mouse placental lactogen II (mPL-II), progesterone, corticosterone, and thyroxine in the maternal serum were also assessed. The concentration of mPL-II was significantly elevated in the hypophysectomized mice, whereas the circulating concentrations of both corticosterone and thyroxine were greatly reduced. The serum progesterone concentration was not significantly altered by hypophysectomy. (ABSTRACT TRUNCATED AT 250 WORDS)

A gonadotropin-receptor preparation from trout during full spermatogenesis known to bind 125I-hCG was used to test the ability of trout pituitary proteins to dislocate hCG from the receptors. From the proteins of male trout pituitaries chromatographed on immobilized concanavalin A, only the glycoprotein fraction was able to compete with hCG for the receptors. Unabsorbed proteins eluting in three fractions were radioiodinated and used as ligands. The fact that they were not taken up specifically by the receptor preparation, and the competition of the glycoproteins with 125I-hCG, is discussed in the context of the vertebrate's gonadotropic hormone system.

Eels were adapted to black- or white-coloured backgrounds and the pituitary glands were prepared for light and electron microscopy. Immunocytochemical staining was used to study the distribution of the neurohypophysial melanin-concentrating hormone in the neurointermediate lobe. The hormone was located in small, elliptical, electron-opaque neurosecretory granules, measuring approximately 120 x 90 nm. The neurones terminated on blood vessels in the centre of the neurohypophysis and on the basement membrane separating neural and intermediate lobe tissues. The results of both light and electron immunocytochemistry and of radioimmunoassay are consistent with a higher rate of hormone release from eels adapted to white backgrounds than from those adapted to black backgrounds. In addition to this, when fish that had been adapted to white tanks were transferred to black tanks, there was an accumulation of irMCH in the gland and an increased numerical density of secretory granules at nerve terminals. These results reinforce the proposal that MCH is released during adaptation to a white background, to cause melanin concentration and to inhibit MSH release, and that its release is halted in black-adapted fish.

The hypothesis that pituitary hormones are required for increased fibrinogen synthesis after inflammation or endotoxin was tested by measuring plasma fibrinogen concentrations after inflammation or endotoxin in normal and hypophysectomized rats. Animals were divide into groups receiving no exogenous adrenal steroids, low-dose adrenal steroids, or high-dose adrenal steroids. Hypophysectomy failed to prevent fibrinogen levels from rising after intramuscular turpentine (mean 240 mg/100 ml prior to and 556 mg/100 ml 24 h after turpentine). Steroids did not suppress this rise. Endotoxin, 5 mug/100 g, caused a marked rise in fibrinogen in normal rats at 24 h (mean 296 mg/100 ml before endotoxin and 554 mg/100 ml after endotoxin). This dose of endotoxin killed hypophysectomized rats within 12 h. Hoevr, if hypophysectomized rats were protected with high-dose adrenal steroids, then 5 mug of endotoxin per 100 g caused the same fibrinogen rise as in normal rats (mean 299 mg/100 ml before endotoxin and 587 mg/100 ml after endotoxin). Aparently, pituitary hormones are not necessay for increased fibrinogen synthesis after either inflammation or endotoxin in the rat.