Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

Alteration of ghrelin/obestatin ratio in adolescence with polycystic ovarian syndrome.

Ghrelin, an endoggenous for the growth hormone secretagogue receptor, has been shown to participate in the regulation of energy homeostasis and pituitary hormone secretion. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. Ghrelin and obestatin are altered in polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and pituitary hormone secretion disorder. The aim of this study was to evaluate ghrelin/obestatin imbalance in relation to insulin resistance and pituitary hormone in adolescence with PCOS. This restrospective case-control study included 33 adolescence with PCOS and 38 control adolescence. Ghrelin and obestatin concentrations in serum were determined by RIA, and the serum fasting glucose and Insulin were determined by the glucose oxidase color method and INS-EASIA. The serum LH and FSH were measured by highly specific hemiluminescence immunoassays. We found that the serum ghrelin levels and ghrelin/obestatin ratio were significant lower in PCOS group than in control group, and the serum obestatin levels were significant higher in PCOS group than in control group. The ghrelin/obestatin ratios were negatively correlation with LH/FSH ratio and insulin resistant index in PCOS group. The findings of this study suggest that ghrelin/obestatin imbalance may play a role in pathogenesis of adolescent PCOS.

Rasd1 is an estrogen-responsive immediate early gene and modulates expression of late genes in rat anterior pituitary cells.

Dexamethasone-induced Ras-related protein 1 (Rasd1) is a member of the Ras superfamily of monomeric G proteins that have a regulatory function in signal transduction. Here we investigated the role of Rasd1 in regulating estrogen-induced gene expression in primary cultures of rat anterior pituitary cells. Rasd1 mRNA expression in anterior pituitary cells decreased after treatment with forskolin or serum and increased after treatment with 17ß-estradiol (E2). Increases in Rasd1 mRNA expression occurred as early as 0.5 h after E2 treatment, peaked at 1 h and were sustained for as long as 96 h. This rapid and profound increase in Rasd1 mRNA expression induced by E2 was also seen in GH4C1 cells, an estrogen receptor-positive somatolactotroph cell line. Among pituitary estrogen-responsive late genes studied, basal mRNA expression of Pim3 and Igf1 genes was decreased by RNA interference-mediated knockdown of Rasd1 expression, whereas basal expression of the Giot1 gene was increased. Moreover, Rasd1 knockdown enhanced stimulation of Pim3 mRNA expression and attenuated inhibition of Fosl1 mRNA expression 24 h after E2 treatment. These changes in mRNA expression were accompanied by enhanced activity of promoters containing CRE, AP-1 and SRE binding sequences. These results suggest that Rasd1 is an estrogen-responsive immediate early gene and modulates E2 induction of at least several late genes in anterior pituitary cells.

Relationship of each anterior pituitary hormone deficiency to the size of non-functioning pituitary adenoma in the hospitalized patients.

Non-functioning pituitary adenoma (NFPA) is often associated with hypopituitarism. Diagnosis of hypopituitarism is important because of its poor prognosis and low quality of life. Among hypopituitarism, it is difficult to diagnose secondary adrenocortical insufficiency and GH deficiency without hormone stimulation test. Therefore, the aim of our study was to identify patients with NFPA who require more careful endocrinological examination. We examined the relationship between NFPA size and the prevalence of each hypopituitarism or the response of each anterior pituitary hormone by insulin tolerance test, LHRH test and TRH test. We studied 63 patients with NFPA admitted for evaluation of pituitary function and surgical indication. They were classified three groups by tumor diameter. The prevalence of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were higher in the group of larger tumor diameter (p<0.0001, p<0.05, p<0.05 and p<0.05, respectively). However, that of secondary adrenocortical insufficiency only tended to be higher (p=0.07). In the group with small NFPA (less than 20 mm), the prevalence of secondary adrenocortical insufficiency was 38% although those of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were 0%, 0% and 8% and 9%, respectively. Anterior pituitary hormone responses except TSH had significantly negative correlation with tumor diameter (ACTH: r=-0.40, GH: r=-0.57, LH: r=-0.69, FSH: r=-0.46, PRL: r=-0.36). The results suggested physicians should proactively suspect GH deficiency, male secondary hypogonadism and secondary hypothyroidism in patients with larger NFPA. On the other hand, adrenocortical function should be examined even in patients with small NFPA.

Dynamics of anterior pituitary immunoreactive gonadotrophs in moulted hens supplemented with protein, symbiotic and probiotics.

The present work delineates redistribution patterns of the hormone-producing cells of the anterior pituitary, after the phase of moulting. Two hundred single comb White Leghorn hens at the end of their first production cycle (Age = 70 week) were purchased from the commercial poultry farm and were induced to moult by high-dietary zinc (3 g/kg feed/day) after 1 week of acclimatization, at the experimental research station, Department of Physiology and Pharmacology, University of Agriculture, Faisalabad. The moulted birds were equally (n = 50) and randomly allocated to their respective groups as G1 (control; CP (Crude protein) 16%, no supplement), G2 (CP18%, no other supplement), G3 (CP16%, symbiotic at does rate of 85 mg/l in drinking water daily) and G4 (CP16%, probiotic at dose rate of 85 mg/l in drinking water daily). Ten birds were slaughtered in each group at 5% and at peak of post-moult production stage to collect their pituitary glands. An earlier post-moult production recovery, sustained and lengthier production span was seen in the G2 as compared to all other groups. The lowest production and an earlier production decline were seen in G1. The cell diameter and area of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gonadotroph increased (p ≤ 0.01) in G2 and G3 as compared to G1. The FSH gonadotroph nucleus diameter and area did increase (p ≤ 0.01) in G2 and G3, while LH gonadotroph nucleus diameter and area decreased (p ≤ 0.01) in G2 and G3 as compared to G1. The increased FSH and LH gonadotroph diameter in protein and symbiotic supplemented birds is accountable for the increased egg production in these groups.

[Sheehan's syndrome--a forgotten disease with 100 years' history]. / Zespól Sheehana--zapomniana choroba ze stuletnia historia.

Although named after Harold Sheehan, postpartum ischemic pituitary necrosis was reported for the first time 100 years ago in Przeglad Lekarski by Leon Konrad Glinski. In the majority of cases, the syndrome is a consequence of severe postpartum bleeding episode resulting in severe hypotension or hemorrhagic shock. The frequency of Sheehan's syndrome has decreased in developed countries as a result of improved obstetrical care, but this clinical entity remains a common cause of hypopituitarism in developing countries. The syndrome is characterized by varying degrees of anterior pituitary dysfunction resulting from the deficiency of multiple pituitary hormones. The order of frequency of hormone loss has generally been found to be growth hormone and prolactin, gonadotropins, ACTH and thyrotropin. Women with Sheehan's syndrome exhibit a variety of signs and symptoms including failure to lactate or resume menses, loss of genital and axillary hair, and often occurring long after delivery clinical manifestations of central hypothyroidism and secondary adrenal insufficiency. Diagnosis is based on laboratory studies, including hormone levels and hormone stimulation tests. Treatment of Sheehan's syndrome involves hormone replacement therapy. The aim of this study is to review current knowledge on clinically relevant aspects of this clinical entity and to provide the reader with recommendations concerning its diagnosis and treatment.

GFP-expressing S100ß-positive cells of the rat anterior pituitary differentiate into hormone-producing cells.

Some non-endocrine cells in the pituitary anterior lobe are responsible for providing stem/progenitor cells to maintain hormone-producing cells. In particular, cells expressing S100ß protein, a calcium-binding protein, have been hypothesized to be a pituitary cell resource. Accumulating data have revealed that S100ß-positive cells comprise heterogeneous populations and some of them certainly show stem/progenitor characteristics in vivo. Hence, we examine whether S100ß-positive cells have the capacity to differentiate into endocrine cells, by means of in vivo and in vitro experiments on transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of the S100ß promoter. Immunohistochemistry of the pituitary confirmed that some S100ß-positive cells expressed SOX2 (SRY [sex-determining region Y]-box 2) and had proliferative activity. Dispersed anterior lobe cells were observed by time-lapse microscopy, followed by immunostaining for hormone and pituitary-transcription-factor1 (PIT1). First, the dispersed anterior lobe cells were immunostained by an antibody against SOX2. S100ß-protein co-localizes with SOX2 (about 89 %). Although 44 of 134 S100ß-positive cells traced were proliferative but negative to any hormones, 14 cells were positive for one of the pituitary hormones and/or PIT1, confirming the presence of all types of hormone-producing cells. Notably, GFP-fluorescence appeared in two hormone-positive cells during culture. On the other hand, we observed hormone-producing cells that were not positive for S100ß at the end of the time-lapse study, despite being initially positive. These findings suggest that S100ß-positive cells cultured from the anterior lobe are capable of developing into hormone-producing cells, although this happens relatively infrequently.

Dioxin-induced retardation of development through a reduction in the expression of pituitary hormones and possible involvement of an aryl hydrocarbon receptor in this defect: a comparative study using two strains of mice with different sensitivities to dioxin.

We have previously revealed that treating pregnant rats with 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2-20 µg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20 µg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects.

Current knowledge of D-aspartate in glandular tissues.

Free D-aspartate (D-Asp) occurs in substantial amounts in glandular tissues. This paper reviews the existing work on D-Asp in vertebrate exocrine and endocrine glands, with emphasis on functional roles. Endogenous D-Asp was detected in salivary glands. High D-Asp levels in the parotid gland during development suggest an involvement of the amino acid in the regulation of early developmental phases and/or differentiation processes. D-Asp has a prominent role in the Harderian gland, where it elicits exocrine secretion through activation of the ERK1/2 pathway. Interestingly, the increase in NOS activity associated with D-Asp administration in the Harderian gland suggests a potential capability of D-Asp to induce vasodilatation. In mammals, an increase in local concentrations of D-Asp facilitates the secretion of anterior pituitary hormones, i.e., PRL, LH and GH, whereas it inhibits the secretion of POMC/α-MSH from the intermediate pituitary and of oxytocin from the posterior pituitary. D-Asp also acts as a negative regulator for melatonin synthesis in the pineal gland. Further, D-Asp can stereo-specifically modulate the production of sex steroids, thus taking part in the endocrine control of reproductive activity. Although D-Asp receptors remain to be characterized, gene expression of NR1 and NR2 subunits of NMDAr responds to D-Asp in the testis.

Anterior hypopituitarism is rare and autoimmune disease is common in adults with idiopathic central diabetes insipidus.

OBJECTIVE: Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood-onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. DESIGN AND PATIENTS: We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function. RESULTS: One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty-three percent had at least one autoimmune disease in addition to central diabetes insipidus. CONCLUSIONS: Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.

Discontinuous versus continuous drinking of ethanol in peripubertal rats: effect on 24-hour pattern of hypophyseal-gonadal axis activity and anterior pituitary oxidative stress.

AIMS: Discontinuous (weekend) consumption of alcohol is common in adolescents and young adults. This study therefore assesses, in peripubertal male rats, the effect of discontinuous as compared to chronic feeding of ethanol or control liquid diet. METHODS: Animals received an ethanol liquid diet (6.2 % w/v) starting on day 35 of life. Every week for 5 weeks, the discontinuous ethanol group received the ethanol diet for 3 consecutive days and the control liquid diet for 4 days. At the 5th week, 24 h after the last ethanol administration to the discontinuously ethanol-treated animals, rats were killed at 4-hour intervals beginning at 09.00 h. Chronically administered rats received the ethanol diet until immediately before study. RESULTS: Disrupted 24-hour rhythmicity together with a significant nocturnal increase in plasma luteinizing hormone (LH), testosterone and prolactin (PRL) occurred in the discontinuous ethanol group. Plasma ethanol levels were undetectable at 24 h after the last ethanol treatment. In contrast, after chronic ethanol administration, plasma PRL was increased late in scotophase while LH and testosterone decreased; blood ethanol levels were 2-fold greater than those in discontinuously ethanol-administered rats killed immediately after ethanol withdrawal. Circulating testosterone positively correlated with LH levels in control rats only. Chronic administration of ethanol significantly augmented mean expression of pituitary nitric oxide synthase (NOS)-2, heme oxygenase (HO)-1, Per1 and Per2 genes and disrupted their diurnal rhythmicity. Decreased NOS-1 and NOS-2 expression during scotophase, together with suppression of the rhythm in Per1 and Per2 expression, were found in the discontinuous ethanol group. CONCLUSIONS: Abstinence after discontinuous drinking of alcohol in rats, as compared to chronic administration of ethanol, is accompanied by increases of plasma LH and testosterone, a greater PRL response and a less pronounced oxidative damage of the anterior pituitary.

EpCAM Is a Surface Marker for Enriching Anterior Pituitary Cells From Human Hypothalamic-Pituitary Organoids.

Human stem cell-derived organoid culture enables the in vitro analysis of the cellular function in three-dimensional aggregates mimicking native organs, and also provides a valuable source of specific cell types in the human body. We previously established organoid models of the hypothalamic-pituitary (HP) complex using human pluripotent stem cells. Although the models are suitable for investigating developmental and functional HP interactions, we consider that isolated pituitary cells are also useful for basic and translational research on the pituitary gland, such as stem cell biology and regenerative medicine. To develop a method for the purification of pituitary cells in HP organoids, we performed surface marker profiling of organoid cells derived from human induced pluripotent stem cells (iPSCs). Screening of 332 human cell surface markers and a subsequent immunohistochemical analysis identified epithelial cell adhesion molecule (EpCAM) as a surface marker of anterior pituitary cells, as well as their ectodermal precursors. EpCAM was not expressed on hypothalamic lineages; thus, anterior pituitary cells were successfully enriched by magnetic separation of EpCAM+ cells from iPSC-derived HP organoids. The enriched pituitary population contained functional corticotrophs and their progenitors; the former responded normally to a corticotropin-releasing hormone stimulus. Our findings would extend the applicability of organoid culture as a novel source of human anterior pituitary cells, including stem/progenitor cells and their endocrine descendants.

Immunohistochemical localization of anterior pituitary hormones in S-100 protein-positive cells in the rat pituitary gland.

In the anterior and intermediate lobes of the rat pituitary gland, non-hormone-producing cells that express S-100 protein coexist with various types of hormone-producing cells and are believed to function as phagocytes, supporting and paracrine-controlling cells of hormone-producing cells and stem cells, among other functions; however, their cytological characteristics are not yet fully understood. Using a transgenic rat that expresses green fluorescent protein under the promoter of the S100ß protein gene, we immunohistochemically detected expression of the luteinizing hormone, thyroid-stimulating hormone, prolactin, growth hormone and proopiomelanocortin by S-100 protein-positive cells located between clusters of hormone-producing cells in the intermediate lobe. These findings lend support to the hypothesis that S-100 protein-positive cells are capable of differentiating into hormone-producing cells in the adult rat pituitary gland.

Prolactin-releasing peptide mRNA expression in mouse medulla remains relatively stable during pregnancy and lactation.

We compared levels of prolactin-releasing peptide (PrRP) mRNA expression in mouse medulla at different stages of pregnancy and lactation. Mouse medulla samples were collected on days 6, 12 and 18 of pregnancy and lactation, respectively (six per group), for mRNA. Expression levels of PrRP mRNA in the medulla were measured by semi-quantitative RT-PCR, with glyceraldehyde 3-phosphate dehydrogenase as a control. PrRP mRNA was highly expressed in mouse medulla oblongata on day 6 of pregnancy (0.53), followed by 0.43 at lactation day 6, and 0.42 at lactation day 12. The expression level of PrRP mRNA on days 12 and 18 of pregnancy and day 18 of lactation shared the same value of 0.36. PrRP mRNA levels during lactation decreased slightly compared with that during pregnancy, but the differences between them were not significant. In summary, PrRP mRNA levels in the medulla oblongata remain relatively stable during pregnancy and lactation. This is evidence that medulla PrRP is not involved in the regulation of prolactin secretion.

Renewing an old interest: Pituitary folliculostellate cells.

Anterior pituitary folliculostellate (FS) cells, first described almost 50 years ago, have a wide range of functions with respect to supporting and coordinating endocrine cell function, in particular through paracrine and gap junction-mediated signalling. Our previous studies identified the morphological organisation of FS cells, which mediates coordinated calcium activity throughout the homotypic FS network and allows signalling across the whole pituitary gland. It is also clear that FS cells can modify endocrine output and feedback on pituitary axes over a range of timescales. Recently, several studies have defined FS cells as a source of anterior pituitary endocrine cell renewal, which has resulted in a renaming of FS cells as "Sox2+ve stem cells". Here, we highlight the broader potential of the FS cell population in fine-tuning and coordinating pituitary axes function. In addition, we identify a need for: the definition of the possible subtypes of FS cell and their relationship with the stem cell population; the potential role of FS cells in pulsatile hormone secretion and coordination of heterotypic cell networks; and the roles that FS cells may play in both early-life programming of pituitary axes and in memory, or anticipation, of demand. Further studies of FS cells may demonstrate the fundamental importance of this cell type and its potential as a therapeutic target to correct pituitary gland dysfunction, one of which is stem cell therapy. Clearly, a thorough understanding of all of these interactions and relationships of FS and endocrine cells is required whatever therapeutic use is suggested by their various roles.

Annotation of pituitary neuroendocrine tumors with genome-wide expression analysis.

Pituitary neuroendocrine tumors (PitNETs) are common, generally benign tumors with complex clinical characteristics related to hormone hypersecretion and/or growing sellar tumor mass. PitNETs can be classified based on the expression pattern of anterior pituitary hormones and three main transcriptions factors (TF), SF1, PIT1 and TPIT that regulate differentiation of adenohypophysial cells. Here, we have extended this classification based on the global transcriptomics landscape using tumor tissue from a well-defined cohort comprising 51 PitNETs of different clinical and histological types. The molecular profiles were compared with current classification schemes based on immunohistochemistry. Our results identified three main clusters of PitNETs that were aligned with the main pituitary TFs expression patterns. Our analyses enabled further identification of specific genes and expression patterns, including both known and unknown genes, that could distinguish the three different classes of PitNETs. We conclude that the current classification of PitNETs based on the expression of SF1, PIT1 and TPIT reflects three distinct subtypes of PitNETs with different underlying biology and partly independent from the expression of corresponding hormones. The transcriptomic analysis reveals several potentially targetable tumor-driving genes with previously unknown role in pituitary tumorigenesis.

Functional importance of blood flow dynamics and partial oxygen pressure in the anterior pituitary.

The pulsatile release of hormone is obligatory for the control of a range of important body homeostatic functions. To generate these pulses, endocrine organs have developed finely regulated mechanisms to modulate blood flow both to meet the metabolic demand associated with intense endocrine cell activity and to ensure the temporally precise uptake of secreted hormone into the bloodstream. With a particular focus on the pituitary gland as a model system, we review here the importance of the interplay between blood flow regulation and oxygen tensions in the functioning of endocrine systems, and the known regulatory signals involved in the modification of flow patterns under both normal physiological and pathological conditions.

Anterior pituitary dysfunction in moderate-to-severe chronic traumatic brain injury patients and the influence on functional outcome.

OBJECTIVE: The objective of this study is to determine the prevalence of anterior pituitary dysfunction in moderate-to-severe chronic traumatic brain injury (TBI) patients. The investigation of a relationship between pituitary hormonal status and body mass index (BMI) in TBI patients by observing changes in BMI was conducted as well as an assessment of whether there is a difference in functional outcome related to anterior pituitary dysfunction in TBI patients. METHODS: Forty-five TBI patients and 30 normal controls underwent a series of standard endocrine tests for anterior pituitary hormone function. It was studied whether changes in BMI correlated with anterior pituitary hormone levels. This study also compared changes in mini-mental state examination (K-MMSE) and functional independence measure (FIM) scores between patients in the hormone-sufficient and -deficient groups. RESULTS: Anterior pituitary dysfunction was found in 31.1% of TBI patients. Changes in BMI statistically correlated with IGF-1 and basal cortisol levels. A meaningful difference was found between the hormone-sufficient and -deficient groups in light of the K-MMSE and FIM score gains. CONCLUSIONS: These findings strongly suggest that patients who suffer head trauma should be routinely tested for anterior pituitary hormone deficiency.

Effects of Melatonin on Anterior Pituitary Plasticity: A Comparison Between Mammals and Teleosts.

Melatonin is a key hormone involved in the photoperiodic signaling pathway. In both teleosts and mammals, melatonin produced in the pineal gland at night is released into the blood and cerebrospinal fluid, providing rhythmic information to the whole organism. Melatonin acts via specific receptors, allowing the synchronization of daily and annual physiological rhythms to environmental conditions. The pituitary gland, which produces several hormones involved in a variety of physiological processes such as growth, metabolism, stress and reproduction, is an important target of melatonin. Melatonin modulates pituitary cellular activities, adjusting the synthesis and release of the different pituitary hormones to the functional demands, which changes during the day, seasons and life stages. It is, however, not always clear whether melatonin acts directly or indirectly on the pituitary. Indeed, melatonin also acts both upstream, on brain centers that control the pituitary hormone production and release, as well as downstream, on the tissues targeted by the pituitary hormones, which provide positive and negative feedback to the pituitary gland. In this review, we describe the known pathways through which melatonin modulates anterior pituitary hormonal production, distinguishing indirect effects mediated by brain centers from direct effects on the anterior pituitary. We also highlight similarities and differences between teleosts and mammals, drawing attention to knowledge gaps, and suggesting aims for future research.

The major tyrosine-sulfated protein of the bovine anterior pituitary is a secretory protein present in gonadotrophs, thyrotrophs, mammotrophs, and corticotrophs.

The anterior pituitary is a complex secretory tissue known to contain several sulfated macromolecules. In the present study, we identified the major tyrosine-sulfated protein of the bovine anterior pituitary and investigated its cellular and subcellular localization. This protein consisted of two tyrosine-sulfated polypeptides of molecular weight 86,000 and 84,000 that were highly homologous to each other. In agreement with previous biochemical studies, the tyrosine-sulfated protein of Mr 86,000/84,000 was found to be secretory, as it was observed in the matrix of secretory granules by immunoelectron microscopy. Immunofluorescence studies indicated that the tyrosine-sulfated, secretory protein of Mr 86,000/84,000, referred to as TSP 86/84, was present in all endocrine cells except for some somatotrophic cells. Higher levels of immunoreactivity for TSP 86/84 were observed in gonadotrophic and thyrotrophic than in mammotrophic and corticotrophic cells. This appeared to result from the occurrence of TSP 86/84 in all secretory granules of the former cells and in only some secretory granules of the latter cells. We discuss the possibility that TSP 86/84 may have a role in the packaging of several distinct peptides hormones into secretory granules. One, though not the only, possible function of tyrosine sulfation may concern the sorting of this protein in the Golgi complex.