Increased Hormone Secretion Research Articles

Genipin improves reproductive health problems caused by circadian disruption in male mice

BackgroundCircadian rhythm disruption impacts a wide range of physiological processes, including fertility. However, the effect of circadian disruption on male spermatogenesis and fertility, and treatments for these effects have been largely unexplored at the molecular level.MethodsIn this study, we examined the effects of genipin on improving the reproductive health problems caused by circadian disruption. Three groups of animals were fed under different conditions: control group (normal T cycle with saline), group of shortened T cycles (Light/Dark = 4 hours/4 hours) with saline, and a group of shortened T cycles with genipin by oral gavage. The male fertility was evaluated by fertility study and pups parameters analysis after successful sexual behavior and mating with female mice. We sacrificed the treated animals after 5 or 10 weeks and collected the testis, sperm and serum for histological analysis, sperm motility assay, and serum hormone detection, respectively. Furthermore, the effect of genipin was assessed by detection of progesterone secretion and steroidogenic key proteins expression, including StAR and CYP11A1, in mouse Leydig tumor MLTC-1 cells.ResultsMale mice exposed to shortened light-dark cycles, much shorter than 24 hours, had reduced fertility with decreased sperm concentrations and sperm motility. Male mice under circadian disruption have reduced testis size and abnormal morphology, leading to lower fertility rates, reduced litter size and pup body weight. Treatment with exogenous genipin, a natural plant-derived compound, alleviated circadian disruption-induced damage to fertility and spermatogenesis and normalized testosterone, dihydrotestosterone (DHT), and androstenedione (ASD) levels in the male mice. The levels of key proteins involved in steroidogenesis, StAR and CYP11A1, were reduced in mouse testes after the circadian disruption, but genipin treatment restored the reduction. The mRNA expression of SRD5A1, which encodes an androgen synthesis enzyme, was also upregulated by genipin treatment. Furthermore, genipin treatment showed a positive effect on steroidogenesis in MLTC-1 cells, resulting in an increase in hormone secretion and the upregulation of StAR and CYP11A1.ConclusionsOur results showed an association between circadian disruption and reproductive health problems in male mice and indicated that treatments with genipin have positive effects on the reproductive health of male mice with circadian rhythm disorders.

Antiobesity Effects of Adipose-Derived Stromal/Stem Cells in a Naturally Aged Mouse Model.

Adipose-derived stromal/stem cells (ASCs) have multilineage differentiation potential and functional properties, as well as applications for cell-based therapies in tissue repair and regeneration. However, there is a lack of evidence regarding the efficacy of ASCs as an antiobesity agent in aged organisms. This study aimed to clarify the effectiveness of ASCs at treating obesity using a naturally aged mouse model. Old (22 months) C57BL/6J mice with transplanted young-mice (2 months) donor ASCs were measured for weight change, biochemistry, cytokines, hormone secretion, cell senescence, lipid metabolism, and functional changes of ASCs. The results indicated that old mice treated with ASCs showed antiaging and antiobesity effects such as significant loss of body and organ weight, improved stem cell plasticity, increased antioxidant capacity (superoxide dismutase and catalase), improved liver and kidney function, improved lipid metabolism, and increased hormone secretion (sex hormone-binding globulin, thyrotropin, and leptin). Treatment with ASCs decreased cell senescence and suppressed secretion of inflammatory agents (interleukin-6 and tumor necrosis factor alpha). Traditional drugs used in the treatment of obesity have limitations and are unsuitable for the elderly. Based on the results, the future use of ASCs as primary antiaging and antiobesity agents is suggested because of their positive effects on aged animals.

Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

The potential endocrine disruption of pesticide transformation products (TPs): The blind spot of pesticide risk assessment

The ecological and health risk assessment of environmental pesticide residues have attracted ever-growing attention; however, their transformation products (TPs) have seldom been considered. Herein, we examined the endocrine-disrupting effects of 4 widely used pesticides as pyriproxyfen (Pyr), malathion (ML), benalaxyl (BX), and fenoxaprop-ethyl (FE), together with their 21 TPs through in vitro and in silico approaches, and found approximately 50% of the TPs exhibited stronger endocrine-disrupting effects than their corresponding parent compounds. Specifically, Pyr and 9 TPs (five TPs of Pyr, one of ML, one of BX, and two of FE) exhibited estrogen-disrupting effects, which were also confirmed by results of E-screen and pS2 expression assays, and molecular docking showed that certain hydroxylated TPs could well mimic the binding mode of estrogen with ERα. Meanwhile, two TPs of Pyr, ML and its TP demonstrated weak glucocorticoid antagonistic activities partially contributed by hydrogen bonds. We also discovered that in H295R cells, all the endocrine disruptors increased hormone secretion and the related gene expression levels. Conclusively, since an increasing number of pesticide TPs have been being detected in various environmental media, a more comprehensive understanding of the ecological risk of pesticide TPs is imperative for risk assessments more extensively and regulatory policy-making on pesticide restriction in the future.

Identification of in vitro effect of 4-octylphenol on the basal and human chorionic gonadotropin (hCG) stimulated secretion of androgens and superoxide radicals in mouse Leydig cells

The aim of our in vitro study was to assess the potential effect of 4-octylphenol (4-OP) on the basal and human chorionic gonadotropin (hCG)-stimulated cholesterol levels and biosynthesis of steroid hormones in cultured mouse Leydig cells. In addition, we evaluated the intracellular superoxide production following 4-OP treatment. Isolated mouse Leydig cells were cultured in the presence or absence of 1 IU/mL (hCG) with the addition of 0.04; 0.2; 1.0; 2.5 and 5.0 µg/mL 4-OP during 44 h. The level of cholesterol was determined from the culture medium using photometry. Quantification of steroid hormones was performed by the enzyme linked immunosorbent assay and intracellular generation of superoxide radicals was assessed by the nitroblue-tetrazolium assay. Administered concentrations of 4-OP (0.04-5.0 µg/mL) did not affect basal and hCG-stimulated cholesterol level significantly. However, basal DHEA secretion was increased significantly (P < 0.001) in the highest experimental dose (5 µg/mL) of 4-OP. By hCG-stimulated DHEA secretion, a significant (P < 0.001) decrease was recorded at 5.0 µg/mL 4-OP in comparison to the control group. The stimulatory effect of 4-OP was also confirmed in androstenedione secretion, when 2.5 and 5.0 µg/mL increased hormone secretion significantly (P˂0.05; P˂0.001). Exposure to experimental concentrations (0.04 to 5.0 µg/mL) of tested chemical reduced hCG-stimulated androstenedione formation, but not significantly. Measurements of basal testosterone production have shown significant (P˂0.01; P˂0.001) increase at 1.0; 2.5 and 5.0 µg/mL of 4-OP. Furthermore, 44 h treatment by 4-OP (1.0-5.0 µg/mL) caused significant (P˂0.01; P˂0.001) intracellular accumulation of superoxide radicals in exposed cells. A considerably more detailed and systematic research is required for a better understanding of risks associated with male reproductive system in humans and wildlife.

Incretion of Insulin by Pancreas and Its Inactivation in Women during Long-Term Head-down Tilt Bed Rest

An increase in insular activity in response to hyperglycemia when performing a glucose tolerance test (GTT) during normal physical activity in eight women volunteers was found to be associated with increased blood concentrations of insulin provided by an increase in secretion rate and a decrease in inactivation rate. After 81 days of stay in long-term –6° head-down tilt bed rest (bed rest), flattened glycemic curves (with low hyperglycemic lifting) observed during the GTT, what was indicated high insular activity. An increase in the insular activity was evidencing also by a smaller peak of the blood concentration of glucose from 5 min after intravenous nfusion of 20 mL of 40% glucose solution at 120 minute of the GTT. In bed rest on empty stomach no significant changes in the concentrations of insulin and C-peptide were observed. The dynamics of hormone during the GTT was showed that the appearance of flattened glycemic curves when performing GTT during bed rest was associated with more pronounced, than under the usual conditions, an increase in insulin concentration in response to hyperglycemia. An increase in the blood insulin concentration when performing GTT in bed rest was mainly provided by increased hormone secretion rate in the pancreas, but not by a decrease in its inactivation rate. If you use regular exercises for prevention of hypokinesia under conditions of bed rest, an increase in insulin concentration during GTT was mainly provided by a decrease in its inactivation rate and not by an increase in secretion rate.

Case report: schwannoma arising from the unilateral adrenal area with bilateral hyperaldosteronism

BackgroundWe report a rare case of a juxta-adrenal schwannoma that could not be discriminated from an adrenal tumor before surgical resection and was complicated by bilateral hyperaldosteronism. To the best of our knowledge, this is first case in which both a juxta-adrenal schwannoma and hyperaldosteronism co-existed.Case presentationA 69-year-old male treated for hypertension was found to have a left supra-renal mass (5.8 × 5.2 cm) by abdominal computed tomography. His laboratory data showed that his plasma aldosterone concentration (PAC) was within the normal range, but his plasma renin activity (PRA) was reduced, resulting in an increased aldosterone/renin ratio (ARR). Load tests of captopril or furosemide in the standing position demonstrated autonomous aldosterone secretion and renin suppression. Adrenal venous sampling (AVS) with ACTH stimulation indicated bilateral hypersecretion of aldosterone. A left supra-renal tumor was resected because of the possibility of malignancy and was found to be a benign schwannoma arising from the juxta-adrenal region together with an adrenal gland. The dissected left adrenal gland was morphologically hyperplastic in the zona glomerulosa, but was immunohistochemically negative for CYP11B2 (aldosterone synthase). Multiple CYP11B2-positive adrenocortical micronodules were detected in the adrenal gland, indicating micronodular hyperplasia. Although bilateral aldosteronism was indicated by AVS before the operation, the PRA, PAC and ARR values were within their respective reference ranges after resection of the unilateral tumor, suggesting that the slight increase in hormone secretion from the remaining right-sided lesion could not be detected after resection.ConclusionA clinical and morphologic diagnosis of juxta-adrenal schwannoma is difficult, particularly in a case of hyperaldosteronism, as shown in this case. These data suggest the complexity and difficulty diagnosing adrenal incidentaloma.

Enhanced oxygen permeability in membrane-bottomed concave microwells for the formation of pancreatic islet spheroids.

In this study, we present a noble design to control the oxygen distribution in concave microwell arrays for the formation of highly functional pancreatic islet spheroids by engineering the bottom of the microwells. Our new platform significantly enhanced oxygen permeability that turned out to improve cell viability and spheroidal functionality compared to the conventional thick-bottomed 3-D culture system. Therefore, we believe that this could be a promising medical biotechnology platform to further develop high-throughput tissue screening system as well as in vivo-mimicking customised 3-D tissue culture systems.

Protective effects and mechanisms investigation of Kuntai capsule on the ovarian function of a novel model with accelerated aging ovaries

Ethnopharmacological relevanceKuntai capsule, a traditional Chinese medicine, has been widely used for the clinical treatment of menopausal syndrome. However, its mechanisms remain poorly understood. Considering that aging ovaries are the primary cause of menopause, this study was designed to investigate the effects and mechanisms of Kuntai capsule on ovarian function in a novel mice model with accelerated aging ovaries. Materials and methodsSeventy-five female C57BL/6 mice were chosen for this study. Fifteen of the mice were separated into the normal control group (NC). The remaining sixty were used to establish the novel accelerated aging ovary model by superovulation and oxidative stress and then by randomly dividing the mice into four equal groups. One group was considered the model group (Mod). The other three groups were treated with low (0.4g/kg), middle (0.8g/kg) and high (1.6g/kg) doses of Kuntai capsule intragastrically every day for 4 weeks. During the treatment, the body weight and fur condition of all mice were recorded. All the mice were forced to swim to record their exhaustive swimming time (EST), which measures their strength. Mice were then sacrificed for sampling. Ovarian reserve was evaluated using follicle counts and AMH expression. Ovarian function was evaluated using estrous cycle, sex hormone level and litter experiments. Ovarian follicles were categorized and counted to estimate ovarian reserve, and ovarian histologic sections were stained for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) to detect apoptotic cells. The ultrastructure of ovarian cells was observed using transmission electron microscopy. Western blotting was used to measure expression of Bax, Bcl2, AMH and SOD2 protein. ResultsCompared with the NC GROUP, the Mod group clearly displayed worse fur condition and ovarian function. These situations showed some improvement after Kuntai capsule treatment. Specifically, the fur condition and the EST of the Kuntai capsule groups were superior to the fur condition and EST of the Mod group. In cases of damaged ovarian function, Kuntai capsule can regulate the estrous cycles, increase hormone secretion and fertility and significantly decrease atretic follicles. The transmission electron microscopy results revealed that Kuntai capsule rescued the ovarian ultrastructure of mice. TUNEL staining confirmed that the apoptotic cells were reduced after Kuntai capsule treatment. Western blotting revealed that Kuntai capsule can increase AMH, SOD2, and Bcl2 protein expression and decrease Bax expression. ConclusionsKuntai capsule may improve damaged ovarian function, which may be related to its antioxidant and anti-apoptosis effects.

Is bursting more effective than spiking in evoking pituitary hormone secretion? A spatiotemporal simulation study of calcium and granule dynamics.

Endocrine cells of the pituitary gland secrete a number of hormones, and the amount of hormone released by a cell is controlled in large part by the cell's electrical activity and subsequent Ca(2+) influx. Typical electrical behaviors of pituitary cells include continuous spiking and so-called pseudo-plateau bursting. It has been shown that the amplitude of Ca(2+) fluctuations is greater in bursting cells, leading to the hypothesis that bursting cells release more hormone than spiking cells. In this work, we apply computer simulations to test this hypothesis. We use experimental recordings of electrical activity as input to mathematical models of Ca(2+) channel activity, buffered Ca(2+) diffusion, and Ca(2+)-driven exocytosis. To compare the efficacy of spiking and bursting on the same cell, we pharmacologically block the large-conductance potassium (BK) current from a bursting cell or add a BK current to a spiking cell via dynamic clamp. We find that bursting is generally at least as effective as spiking at evoking hormone release and is often considerably more effective, even when normalizing to Ca(2+) influx. Our hybrid experimental/modeling approach confirms that adding a BK-type K(+) current, which is typically associated with decreased cell activity and reduced secretion, can actually produce an increase in hormone secretion, as suggested earlier.

Is There a Testosterone Awakening Response in Humans?

Circulating testosterone (T) follows a diurnal pattern with high waking levels that decline across the day. The hypothalamic-pituitary-adrenal axis produces cortisol in a similar manner but also undergoes an abrupt increase in hormone secretion immediately upon waking (a cortisol awakening response, CAR). Whether the hypothalamic-pituitary-gonadal axis, and circulating T levels, exhibit a similar post-waking response is unclear. Here we describe post-waking T changes in a sample of 108 young adult males from metropolitan Cebu City, the Philippines. As expected, salivary T was higher at waking than in the evening but, remarkably, 60 % of this diurnal decline occurred within 30 min of awakening. There was a strong inverse linear relationship between waking T and the post-waking T decline, such that men with higher waking T experienced a more rapid decline in the hormone. Even though fathers had lower waking T, they experienced a greater post-waking decline than non-fathers. Men with a larger positive CAR had modestly attenuated post-waking T declines. We speculate that these findings reflect a testosterone awakening response (TAR) that helps partition the target tissue effects of T by time of day. T rises overnight to facilitate muscle anabolism at a time when the hormone’s impacts on social behavior are limited. Upon waking, the rapid drop in T helps shift from anabolic to catabolic processes in support of physical activity, while also calibrating T levels in line with the competing social priorities of the individual, as determined by the current balance of behavioral investment towards mating and parental effort.

Effects of dietary omega-3/omega-6 fatty acid ratios on reproduction in the young breeder rooster.

BackgroundPolyunsaturated fatty acids (PUFAs) are necessary for the body's metabolism, growth and development. Although PUFAs play an important role in the regulation of reproduction, their role in testis development in the rooster is unknown. The present study was conducted to investigate the effects of omega-3/omega-6 (n-3/n-6, PUFAs) ratios on reproductive performance in young breeder roosters. Plasma levels of reproductive hormones, testis development, and reproductive hormone receptor and StAR mRNA expression were also assessed.ResultsAlthough PUFAs (n-3/n-6: 1/4.15) had no significant effect on the testis index (P > 0.05), the spermatogonial development and germ cell layers were increased. Moreover, serum levels of hormones (GnRH, FSH, LH and T) on day 35 were also significantly increased by PUFAs (n-3/n-6: 1/4.15). To investigate whether PUFAs regulate the expression of hormone receptors and StAR, real time-PCR was used to measure GnRHR, FSHR, LHR and StAR mRNA levels. PUFAs significantly increased the mRNA levels of all of these genes.ConclusionsThese results indicate that PUFAs enhance the reproductive performance of young roosters by increasing hormone secretion and function, the latter by up-regulating receptor expression. These findings provide a sound basis for a balanced n-3/n-6 PUFA ratio being beneficial to young rooster reproduction.

Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression

Abnormal serotonin type 1A (5-HT1A) receptor function and binding have been implicated in the pathophysiology of mood disorders. Preclinical studies have consistently shown that stress decreases the gene expression of 5-HT1A receptors in experimental animals, and that the associated increase in hormone secretion plays a crucial role in mediating this effect. Chronic administration of the mood stabilizers lithium and divalproex (valproate semisodium) reduces glucocorticoid signaling and function in the hippocampus. Lithium has further been shown to enhance 5-HT1A receptor function. To assess whether these effects translate to human subject with bipolar disorder (BD), positron emission tomography (PET) and [18F]trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N-(2-pyridyl) cyclohexanecarboxamide ([(18)F]FCWAY) were used to acquire PET images of 5-HT1A receptor binding in 10 subjects with BD, before and after treatment with lithium or divalproex. Mean 5-HT1A binding potential (BPP) significantly increased following mood stabilizer treatment, most prominently in the mesiotemporal cortex (hippocampus plus amygdala). When mood state was also controlled for, treatment was associated with increases in BPP in widespread cortical areas. These preliminary findings are consistent with the hypothesis that these mood stabilizers enhance 5-HT1A receptor expression in BD, which may underscore an important component of these agents' mechanism of action.

P02-30 Estrogen regulates exercise-induced pituitary type 1 deiodinase increase and growth hormone secretion

P02-30 Estrogen regulates exercise-induced pituitary type 1 deiodinase increase and growth hormone secretion

Diurnal patterns of salivary cortisol and DHEA in adolescent anorexia nervosa

Although there is well-documented evidence for hyperactivity of hypothalamic–pituitary–adrenal (HPA) axis function in anorexia nervosa (AN), there has been little research into secretory patterns of salivary cortisol and dehydroepiandrosterone (DHEA) in this condition. The cortisol awakening response (CAR), a prominent and discrete feature of the cortisol cycle, has not been extensively explored in adolescent AN. Saliva samples were collected at awakening, 30 min and 12 h post-awakening on two consecutive weekdays from eight female adolescents with clinically diagnosed AN and 41 healthy control (HC) age-matched females. Adolescent AN patients had greater salivary cortisol and DHEA concentrations than HC girls at all points. Increased hormone secretion was unrelated to body mass index. However, despite hypersecretion of both hormones, the circadian pattern including the CAR paralleled that of the HC group. Findings from this preliminary study confirm dysregulation of HPA axis function in adolescent AN as evidenced by hypersecretion of both cortisol and DHEA, which share the common secretagogue adrenocorticotropic hormone. However, the parallel diurnal profiles for AN and HC participants, including the CAR, may indicate hypersecretion per se rather than differential regulation of the diurnal pattern of these two adrenal steroids in AN.

The secretory response of parathyroid hormone to acute hypocalcemia in vivo is independent of parathyroid glandular sodium/potassium-ATPase activity

The involvement of sodium/potassium-ATPase in regulating parathyroid hormone (PTH) secretion is inferred from in vitro studies. Recently, the α-klotho-dependent rapid recruitment of this ATPase to the parathyroid cell plasma membrane in response to low extracellular calcium ion was suggested to be linked to increased hormone secretion. In this study, we used an in vivo rat model to determine the importance of sodium/potassium-ATPase in PTH secretion. Glands were exposed and treated in situ with vehicle or ouabain, a specific inhibitor of sodium/potassium-ATPase. PTH secretion was significantly increased in response to ethylene glycol tetraacetic acid-induced acute hypocalcemia and to the same extent in both vehicle and ouabain groups. The glands were removed, and inhibition of the ATPase was measured by (86)rubidium uptake, which was found to be significantly decreased in ouabain-treated parathyroid glands, indicating inhibition of the ATPase. As ouabain induced systemic hyperkalemia, the effect of high potassium on hormone secretion was also examined but was found to have no effect. Thus, inhibition of the parathyroid gland sodium/potassium-ATPase activity in vivo had no effect on the secretory response to acute hypocalcemia. Hence, the suggested importance of this ATPase in the regulation of PTH secretion could not be confirmed in this in vivo model.

Expression and Function of Sonic Hedgehog Pathway Components in Pituitary Adenomas: Evidence for a Direct Role in Hormone Secretion and Cell Proliferation

Sonic hedgehog (Shh) belongs to a family of signaling proteins involved in development and has been recently implicated in cancer. Shh signaling is active in the corticotrophs of the adult pituitary gland, where it cross-talks with the CRH pathway and regulates ACTH secretion. Because developmental pathways are involved in pituitary tumorigenesis, we hypothesized that Shh may be important in pituitary tumors. The objective of this study was to examine the expression and function of Shh-pathway components in pituitary adenomas. Using immunohistochemistry, we determined the expression of Shh and its receptors Patched 1 (Ptc1) and Patched 2 (Ptc2) in 55 human pituitary adenomas compared with the normal pituitary gland. The AtT-20 and GH3 pituitary tumor cell lines were used as models for studying the role of Shh on cell proliferation and hormone secretion. The effect of Shh on hormone secretion was confirmed in primary cultures of normal rat pituitaries and human pituitary tumors. Ptc1 and Ptc2 were present, whereas Shh was down-regulated in pituitary adenomas and completely absent in Cushing tumors. Shh inhibited cell proliferation in AtT-20 corticotrophinoma cells and the Shh-specific inhibitor cyclopamine increased proliferation in GH3 mammosomatotrophinoma cells. On the other hand, exogenous administration of Shh increased hormone secretion from normal rat pituitaries, pituitary cell lines, and 10 different pituitary tumors. Our results suggest that Shh might maintain pituitary cells in a nonproliferative state. We conclude that Shh is a newly described hypophysiotropic cytokine and its down-regulation may be involved in the pathogenesis of pituitary adenomas.

GPR54 and puberty

At puberty, pulsatile secretion of hormones initiates sexual maturation of the gonads. The G-protein-coupled receptor GPR54 is crucially involved in the initiation of puberty, along with its ligand metastin. Mice lacking GPR54 fail to undergo puberty and have immature reproductive organs and low levels of sex steroids and gonadotrophic hormones, but have normal levels of gonadotrophin-releasing hormone in the hypothalamus. In humans, several cases of hypogonadism have been ascribed to mutations in GPR54. Production of metastin and, to a lesser extent, GPR54 are negatively regulated by testosterone and oestrogen, and injecting GPR54 ligands can increase hormone secretion in rodents. Thus, GPR54 is required for normal functioning of the hypothalamic–pituitary–gonadal axis, probably at the level of gonadotrophin-releasing-hormone secretion. At puberty, pulsatile secretion of hormones initiates sexual maturation of the gonads. The G-protein-coupled receptor GPR54 is crucially involved in the initiation of puberty, along with its ligand metastin. Mice lacking GPR54 fail to undergo puberty and have immature reproductive organs and low levels of sex steroids and gonadotrophic hormones, but have normal levels of gonadotrophin-releasing hormone in the hypothalamus. In humans, several cases of hypogonadism have been ascribed to mutations in GPR54. Production of metastin and, to a lesser extent, GPR54 are negatively regulated by testosterone and oestrogen, and injecting GPR54 ligands can increase hormone secretion in rodents. Thus, GPR54 is required for normal functioning of the hypothalamic–pituitary–gonadal axis, probably at the level of gonadotrophin-releasing-hormone secretion.

Functions of erg K+ channels in excitable cells.

Ether-à-go-go-related gene (erg) channels are voltage-dependent K+ channels mediating inward-rectifying K+ currents because of their peculiar gating kinetics. These characteristics are essential for repolarization of the cardiac action potential. Inherited and acquired malfunctioning of erg channels may lead to the long QT-syndrome. However, erg currents have also been recorded in many other excitable cells, like smooth muscle fibres of the gastrointestinal tract, neuroblastoma cells or neuroendocrine cells. In these cells erg currents contribute to the maintenance of the resting potential. Changes in the resting potential are related to cell-specific functions like increase in hormone secretion, frequency adaptation or increase in contractility.

Expression of Nerve Growth Factor in Human Pancreatic β Cells

Nerve growth factor (NGF) is an important modulator of rat pancreatic β-cell physiology in vitro. In this study, we analysed the expression of NGF, TrkA and insulin in human pancreatic islets from normal, ductal adenocarcinoma and insulinoma-afflicted samples, using double immunofluorescent labelling and confocal microscopy.We found that in normal human pancreas, insulin and NGF are co-expressed in β cells. Moreover, similar to previous observations in rat, the high affinity NGF receptor TrkA is also expressed in β cells.Pancreatic β cells in normal islets from adenocarcinoma and mucinous cystadenocarcinoma patients also expressed NGF. In 2 out of 15 exocrine tumour samples, NGF was detected also in the tissue surrounding the islets, while 2 out of 13 adenocarcinoma tumours expressed this growth factor.In five insulinoma samples, we observed weaker immunofluorescent labelling of insulin and NGF in the neoplastic tissue, compared to the islets not afflicted by the tumour, which may be a consequence of increased hormone secretion rate.We demonstrate that human β cells express TrkA and NGF. These findings are consistent with the hypothesis that NGF modulates insulin secretion through a paracrine/autocrine loop, similar to the one observed in cultured rat β cells.