Trophic Hormones Research Articles

(299) The Modulating Effects of Follicle Stimulating Hormone and Clomid on Men with Azoospermia or Oligozoospermia Taking Human Chorionic Gonadotropin

Abstract Introduction Depression of spermatogenesis is a significant concern for hypogonadal patients on testosterone therapy. Human chorionic gonadotropin (hCG) is commonly prescribed in these men to prevent testicular atrophy and to maintain some degree of spermatogenesis. Furthermore, hCG dosages are significantly increased when a pregnancy is desired. Historically, we have concomitantly used Clomid to stimulate FSH and testosterone production since both are needed for optimal spermatogenesis. However, with the availability of compounded FSH, we have introduced its usage instead of Clomid to evaluate if it yields superior quantitative sperm production. Objective To investigate which medication pairings yields the greatest improvement in hormone and semen parameters over time. Methods Including men with azoospermia or oligozoospermia who were prescribed hCG, we noted whether the men were additionally taking FSH or Clomid. The patient population of men in the hCG + FSH group had 32, and the hCG + Clomid group totaled 14. Baseline laboratory values were documented for testosterone and total sperm count for each patient prior to being prescribed their combined medications, followed by subsequent values for these variables in the months following this prescription. ANOVAs were employed using SPSS to analyze the change in the two assessed metrics across follow up visits. Results By analyzing increase in testosterone over time, the hCG + FSH cohort experienced the greatest improvement after four follow up visits (600.89 ng/dL after four visits, 150.22 (ng/dL)/visit), outperforming the hCG + Clomid group (505.63 ng/dL after four visits, 126.41 (ng/dL)/visit). The ANOVAs across the subsequent visits for each treatment group are as follows: hCG + FSH: f-ratio = 3.226, p-value = 0.0137; hCG + Clomid: f-ratio = 1.456, p-value = 0.219. Regarding total sperm count, the hCG + FSH group surpassed the HCG + Clomid group across the follow-up visits as well: hCG + FSH: 41.47 million after three follow-up visits; hCG + Clomid: 26.20 million after three follow-up visits. The ANOVAs across the subsequent visits for each treatment group are: hCG + FSH: f-ratio = 3.015, p-value = 0.0339; hCG + Clomid: f-ratio = 1.485, p-value = 0.234. Conclusions Those taking hCG with FSH experienced a greater improvement in both testosterone and total sperm counts compared to men on hCG and Clomid. It would seem that the use of FSH gives a more rapidly successful outcome for hypogonadal patients, since its combination with hCG acts directly to stimulate spermatogenesis, within the testes rather than requiring, as with Clomid, secondary stimulation through the pituitary gland's secretion of LH and FSH. With the relatively recent introduction of FSH as compounded biologics and its reduction in cost compared to brand FSH, the use of this trophic hormone can now be more widely used. Moreover, these data suggest that hCG with FSH results in a more rapid improvement in both spermatogenesis and serum testosterone than historically alternative therapies. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Larry Lipshultz: AbbVie (Consultant) American Medical Systems/Boston Scientific (Speaker) Aytu BioScience (Consultant) Contraline, Inc. (Consultant) Endo Pharmaceuticals (Consultant/Speaker) Inherent Biosciences (Advisor) Lipocine (Consultant).

A cholesterol-centric outlook on steroidogenesis.

Cholesterol, an essential and versatile lipid, is the precursor substrate for the biosynthesis of steroid hormones, and a key structural and functional component of organelle membranes in eukaryotic cells. Consequently, the framework of steroidogenesis across main steroidogenic cell types is built around cholesterol, including its cellular uptake, mobilization from intracellular storage, and finally, its transport to the mitochondria where steroidogenesis begins. This setup, which is controlled by different trophic hormones in their respective target tissues, allows steroidogenic cells to meet their steroidogenic need of cholesterol effectively without impinging on the basic need for organelle membranes and their functions. However, our understanding of the basal steroidogenesis (i.e., independent of trophic hormone stimulation), which is a cell-intrinsic trait, remains poor. Particularly, the role that cholesterol itself plays in the regulation of steroidogenic factors and events in steroid hormone-producing cells remains largely unexplored. This is likely because of challenges in selectively targeting the steroidogenic intracellular cholesterol pool in studies. New evidence suggests that cholesterol plays a role in steroidogenesis. These new findings have created new opportunities to advance our understanding in this field. In this book chapter, we will provide a cholesterol-centric view on steroidogenesis and emphasize the importance of the interplay between cholesterol and the mitochondria in steroidogenic cells. Moreover, we will discuss a novel mitochondrial player, prohibitin-1, in this context. The overall goal is to provide a stimulating perspective on cholesterol as an important regulator of steroidogenesis (i.e., more than just a substrate for steroid hormones) and present the mitochondria as a potential cell-intrinsic factor in regulating steroidogenic cholesterol homeostasis.

Nutrition care for the adult post-intestinal transplant patient.

Intestinal transplantation has emerged as an accepted treatment choice for individuals experiencing irreversible intestinal failure. This treatment is particularly relevant for those who are not candidates or have poor response to autologous gut reconstruction or trophic hormone therapy, and who can no longer be sustained on parenteral nutrition. One of the main goals of transplant is to eliminate the need for parenteral support and its associated complications, while safely restoring complete nutrition autonomy. An intestinal transplant is a complex process that goes beyond merely replacing the intestines to provide nourishment and ceasing parenteral support. It requires an integrated management approach in the pretransplant and posttransplant setting, and high-quality nutrition treatment is one of the cornerstones leading to favorable outcomes and long-term management. Since the outset of intestinal transplant in the early 2000s, there is observed improvement of achieving nutrition autonomy sooner in the initial posttransplant phase; however, the development of nutrition complications in the chronic posttransplant period remains a long-term risk. This review delineates the decision-making process and clinical protocols used to nutritionally manage and monitor pre- and post-intestine transplant patients.

Prohibitin-1 is an ACTH-Regulated Protein in Human and Mouse Adrenocortical Cells and Plays a Role in Corticosteroid Production

Cell-intrinsic early events involved in different trophic hormone-induced steroidogenesis in their respective steroidogenic cell type are very similar. For example, the activation of the cAMP-PKA signaling pathway in response to trophic hormone stimulation and, subsequently, cholesterol transport to the mitochondria to initiate steroidogenesis is common to them. Recently, we have found that an evolutionarily conserved protein, prohibitin-1 (PHB1), is regulated by Luteinizing Hormone (LH) in murine Leydig cells and plays a role in interconnected cell signaling and mitochondrial steps pertaining to testosterone production. Among the primary steroidogenic tissues, PHB1 expression levels are highest in the adrenal cortex (The Human Protein Atlas); however, its regulation and role in adrenocortical cells are virtually unknown. We investigated the regulation and the role of PHB1 in adrenocortical cells in vitro using human HAC15 and mouse Y-1 cell culture models. It was found that Adrenocorticotrophic Hormone (ACTH) stimulation upregulates PHB1 levels in adrenocortical cells in a time-dependent manner. A similar effect on PHB1 levels was also observed in response to dibutyryl-cAMP stimulation, a cell-permeable analogue of cAMP (the second messenger for ACTH action). Moreover, manipulating PHB1 levels in adrenocortical cells affected mitochondria, lysosomes, and lipid droplet characteristics, modulated phospho-PKA and phospho-ERK1/2 levels, and altered corticosteroid production. This finding suggests that ACTH regulates PHB1 in adrenocortical cells and plays a role in corticosteroid production, which was previously unknown.

Clinical-morphological and immunohistochemical characteristics of adenomas of the anterior pituitary lobe

Introduction Clinical and morphological characterization of pituitary adenomas remains a topical problem of great importance in view of lesions in persons of working age.Purpose of work was to identify clinically relevant morphological and immunohistochemical features of pituitary adenomas.Material and Methods Sixty-two adenomas were studied: 25 in men and 37 in women. Pituitary adenoma was most frequently diagnosed between 51 and 70 years of age. Adenomas were mostly of small and medium size with predominance of supra- and laterosellar location. There were 41 hormone-positive adenomas and 21 “dumb” neoplasms without signs of trophic hormone synthesis. Gonadotropinomas and corticotropinomas prevailed among hormone-positive adenomas. Ki67 index in our material did not exceed 1−2%, which is a favorable prognostic factor for low recurrence of adenomas.Results 62 adenomas were studied, 25 in men and 37 in women. Vast majority of adenomas were diagnosed at the age of 51 to 70 years. Adenomas mainly had small and medium size, with a predominance of supra- and laterosellar localization. Out of 62 adenomas 41 were hormone-positive, and 21 were “silent” neoplasms without signs of synthesis of trophic hormones. Among hormone-positive adenomas, most were gonadotropinomas and corticotropinomas. The Ki67 index in our material did not exceed 1-2%, which is a favorable prognostic factor for low recurrence of adenomas.Discussion In contrast to previously published works, gonadotropinomas and corticotropinomas prevailed in our material. The most diagnostically important markers were identified and applied for routine morphological verification of pituitary adenomas.Conclusion The predominance of hormone-positive adenomas of small size was a peculiarity of the work. At the same time, hormone-positive tumors had no clinical manifestations for quite a long time and were latent. Low proliferativity of the studied adenomas was a favorable prognostic sign.

Neonatal Leptin Levels Predict the Early Childhood Developmental Assessment Scores of Preterm Infants.

Preterm infants have low circulating levels of leptin, a key trophic hormone that influences growth and development. While the clinical importance of prematurity-associated leptin deficiency is undefined, recent preclinical and clinical investigations have shown that targeted enteral leptin supplementation can normalize neonatal leptin levels. We tested the hypothesis that, independent of growth velocity, prematurity-related neonatal leptin deficiency predicts adverse cardiovascular and neurodevelopmental outcomes. In a planned 2-year longitudinal follow-up of 83 preterm infants born at 22 to 32 weeks' gestation, we obtained blood pressures from 58 children and the Ages & Stages Questionnaire (ASQ-3) for 66 children. Based on univariate analysis, blood pressures correlated with gestational age at birth (R = 0.30, p < 0.05) and weight gain since discharge (R = 0.34, p < 0.01). ASQ-3 scores were significantly higher in female than male children. Utilizing best subset regression with Mallows' Cp as the criterion for model selection, higher systolic blood pressure was predicted by rapid postnatal weight gain, later gestation at delivery and male sex (Cp = 3.0, R = 0.48). Lower ASQ-3 was predicted by lower leptin levels at 35 weeks postmenstrual age, earlier gestation at delivery and male sex (Cp = 2.9, R = 0.45). Children that had leptin levels above 1500 pg/mL at 35 weeks postmenstrual age had the highest ASQ-3 scores at 2 years. In conclusion, independent of growth velocity, higher leptin levels at 35 weeks' gestation are associated with better developmental assessment scores in early childhood. While longer-term follow-up of a larger cohort is needed, these findings support investigations that have suggested that targeted neonatal leptin supplementation could improve the neurodevelopmental outcomes of preterm infants.

Evaluation of therapeutic effects of aqueous cinnamon extract against obesity associated dysregulation of pituitary-adrenal axis

Obesity is distinguished by unwanted and surplus accumulation of lipids in body principally in adipocytes. Inactive lifestyle and dietary irregularities are considered as premiers among a variety of obesogenic risk factors. Obesity is associated with variations in the concentration of trophic and tropic hormones from pituitary gland affecting different body parts and other endocrine glands including adrenal gland. Current study was design to explore the anti-obesity potential of cinnamon (Cinnamomum verum) against high sugar and high fat induced hyper-activity of pituitary-adrenal (PA) axis and obesity. Twenty-five healthy Wistar albino female rats were selected as model animal. Body weight, oral glucose tolerance test, serum cortisol, hematology and histopathological analysis were performed. The high sugar and high fat induced increase in body eight was decline by cinnamon administration. Hematological analysis revealed a significant decreased concentration of RBCs and hemoglobin and increased WBCs and platelet count following sub-acute exposure of high sugar and high fat changes were attenuated by cinnamon. High sugar and fat associated elevated serum cortisol was normalized after cinnamon exposure. Moreover, cinnamon protected the histopathological alterations following high sugar and fat administration, showed protective effects of Cinnamon against obesity associated dysregulation of PA axis and metabolic impairment.

Preterm rat survival is enhanced by gestational environmental enrichment

Throughout the last decade, the estimated global human preterm birth rate was 10.6 %, with higher rates in Asia, South America, and Africa. Preterm individuals, even in adulthood, are more likely to develop cardiorespiratory, renal, and metabolic disorders. On the other hand, when experimental animals are housed in an enriched environment during gestation, the development of the progeny in utero is accelerated, compared to standard housing conditions. By terminating gestation one and a half days before parturition, we investigated whether environmental enrichment restricted to gestation may have an impact on progeny survival. Our results demonstrate that the gestational enriched environment tripled the rat´s offspring survival, which was associated with decreased expression of anxiety-like behaviors in the pregnant mother. Sex of the offspring was not a factor in determining survival. We discuss the effect of increased secretion of various trophic factors and hormones induced by the enriched environment on progeny survival.

Angiotensin II Regulates Mitochondrial mTOR Pathway Activity Dependent on Acyl-CoA Synthetase 4 in Adrenocortical Cells.

Two well-known protein complexes in mammalian cells, mTOR type 1 and type 2 (mTORC1/2) are involved in several cellular processes such as protein synthesis, cell proliferation, and commonly dysregulated in cancer. An acyl-CoA synthetase type 4 (ACSL4) is one of the most recently mTORC1/2 regulators described, in breast cancer cells. The expression of ACSL4 is hormone-regulated in adrenocortical cells and required for steroid biosynthesis. mTORC1/2 have been reported to be crucial in the proliferation of human adrenocortical tumor cells H295R and interestingly reported at several subcellular locations, which has brought cell biology to the vanguard of the mTOR signaling field. In the present work, we study the regulation of mTORC1/2 activation by angiotensin II (Ang II)-the trophic hormone for adrenocortical cells-the subcellular localization of mTORC1/2 signaling proteins and the role of ACSL4 in the regulation of this pathway, in H295R cells. Ang II promotes activation by phosphorylation of mTORC1/2 pathway proteins in a time-dependent manner. Mitochondrial pools of ribosomal protein S6, protein kinase B (Akt) in threonine 308, and serine 473 and Rictor are phosphorylated and activated. Glycogen synthase kinase type 3 (GSK3) is phosphorylated and inactivated in mitochondria, favoring mTORC1 activation. Epidermal growth factor, a classic mTORC1/2 activator, promoted unique activation kinetics of mTORC1/2 pathway, except for Akt phosphorylation. Here, we demonstrate that ACSL4 is necessary for mTORC1/2 effectors phosphorylation and H295R proliferation, triggered by Ang II. Ang II promotes activation of mitochondrial mTORC1/2 signaling proteins, through ACSL4, with a direct effect on adrenocortical cellular proliferation.

A randomized clinical trial demonstrating cell type specific effects of hyperlipidemia and hyperinsulinemia on pituitary function.

IntroductionObesity is characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism, reducing fertility and increasing risk of pregnancy complications and birth defects. We termed this phenotype ‘Reprometabolic Syndrome’ and showed that it can be recapitulated by acute infusions of lipid/insulin into healthy, normal weight, eumenorrheic women. Herein, we examined the broader impact of hyperlipidemia and euglycemic hyperinsulinemia on anterior pituitary trophic hormones and their targets.MethodsSerum FSH, LH, TSH, growth hormone (GH), prolactin (PRL), thyroid hormones (free T4, total T3), cortisol, IGF-1, adiponectin, leptin and creatinine were measured in a secondary analysis of an interventional crossover study of 12 normal weight cycling women who underwent saline and heparin (control) infusion, or a euglycemic insulin infusion with heparin and Intralipid® (lipid/insulin), between days 2–5 in sequential menstrual cycles.ResultsIn contrast to the decrease in gonadotropins, FSH and LH, infusion of lipid/insulin had no significant effects on other trophic hormones; TSH, PRL or GH. Thyroid hormones (fT4 and total T3), cortisol, IGF-1, adiponectin and creatinine also did not differ between saline or lipid/insulin infusion conditions. Leptin increased in response to lipid/insulin (p<0.02).ConclusionAcute hyperlipidemia and hyperinsulinemia exerted differential, cell type specific effects on the hypothalamic-pituitary-gonadal, adrenal and thyroid axes. Elucidation of mechanisms underlying the selective modulation of pituitary trophic hormones, in response to changes in diet and metabolism, may facilitate therapeutic intervention in obesity-related neuroendocrine and reproductive dysfunction.

Oral Intake of Slowly Digestible α-Glucan Such as Resistant Maltodextrin Leads to Increased Secretion of Glucagon-Like Peptide-2 in Rats and Helps Thicken Their Ileal Mucosae.

To investigate whether the oral intake of slowly digestible α-glucan (SDG) could have a trophic (i.e., thickening) effect on their ileal mucosae, for 10 d, rats were given control (non-SDG), 10% isomaltodextrin (IMD) or 10% resistant maltodextrin (RMD) diets. In addition, experimental rat groups were further divided into two groups each and their diets either had or had not 1% sodium carboxymethylcellulose (CMC) added as a thickening agent. In the jejuna and the ilea, compared with control rats, the villus length and the mucosal thickness, but not the crypt depth, were significantly greater in the RMD-fed rats, with the trophic effect being weaker in the IMD-fed rats than in the RMD-fed rats. The colonic crypt depth was significantly greater in SDG groups than in the control group. The concentration of plasma glucagon-like peptide (GLP)-2 in the portal veins of the RMD group but not the IMD group was significantly higher than in the control group, with no effect of CMC supplementation on its concentration. The concentrations of cecal short-chain fatty acids did not significantly increase with SDG supplementation except for propionate concentration of the IMD-supplemented rats, compared with those in the control rats. We concluded that SDGs, especially RMD, thickened the mucosae of the rat distal small intestines. In particular, this effect of RMD but not IMD could have resulted from increased glucose available as a secretagogue of the trophic hormone GLP-2, in the ileum.

Identification of severity and passive measurement of oxidative stress biomarkers for β–thalassemia patients: K-means, random forest, XGBoost, decision tree, neural network based novel framework

Iron-overload induced oxidative stress in β–thalassemia patients is one of the major challenges in the associated treatment protocol. The severity and accurate prognosis of the disease is largely dependent on several clinical parameters, and different hormones also provide passive indication in this context. The present study focused on clinical implication of iron overload, tropic hormones, and oxidative stress biomarkers on severity of β–thalassemia patients as well as understating their interactive effects. Extensive blood serum samples were collected from group of case and control and statistical analysis was performed on the analyzed study parameters from the serum samples. The oxidative stress biomarkers, Malondialdehyde (MDA) and protein carbonyl level showed significant positive correlation with ferritin levels in case. A novel framework was developed to categorize the severity of the disease through K-means clustering and several classification algorithms, such as XGBoost, random forest, and decision tree. Furthermore, a neural network model was used for predicting the oxidative stress biomarker, MDA and protein carbonyl from measured value of ferritin and trophic hormones. The results of clustering depicted that ferritin and the oxidative stress biomarkers were conclusive parameters in determining the severity of the disease. Among the classifiers, XGBoost showed the highest accuracy after k-cross validation (100%). The neural network model exhibited high accuracy in predicting MDA and protein carbonyl. The proposed technique can be chosen as a real life decision tool for medical professionals in the diagnosis and treatment of β–thalassemia. Furthermore, the approach of passive determination of some critical blood parameters may be attributed from the developed prediction model, which can also be instrumental in the similar area of medical research.

Anatomical and histological characteristics of pituitary gland in domestic animals

As it regulates important physical functions and general wellbeing, the hypophysis plays a major role in responding to the increased demand for different hormones. In the current review, we described the anatomical and the histological structures of the pituitary glands in different domestic animals. Unlike other glands, the pituitary gland has two main parts; the adenohypophysis (anterior lobe), which contains multiple populations of endocrine cells and is responsible for producing each of the pituitary trophic hormones. Another part of the pituitary gland is that the neurohypophysis (posterior lobe) secretes granules that contain certain neurohypophyseal hormones, like antidiuretic hormone and oxytocin, which are synthesized in the hypothalamus.

A short note on oxytocin and stress attenuation.

Stress is integral part of life and it initiates appropriate response at times of adversities to promise survival. Stress could be either physiological or psychogenic. Stress is often psychogenic in nature and it induces the release of cortisol from adrenal cortex into circulation by activating Hypo thalamo-pituitary-adrenal axis (HPA). Cortisol thus released mediates the stress response by its catabolic effects to enhance the activity of vital organs during emergency. However, prolonged activation of the HPA axis can lead to physical and mental illness as an outcome of persistent stress. Nature has bestowed the biological system with an array of endogenous mechanisms to buffer stress. Oxytocin, a nano-peptide released by the magno-cellular neurons of hypothalamic paraventricular nucleus (PVN) is an efficient stress buffering neuro-peptide. This hormone mediates many physiological and behavioural functions get released during stress. It attenuates the stress axis initiated by the release of corticotropin releasing hormone (CRH) from the parvocellular neurons of the same hypothalamic nucleus. Oxytocin released by PVN exerts an inhibitory effect on the release of CRH by down-regulating the expression of the gene that transcribes for this hypothalamic hormone. Thus, it inhibits the release of adreno cotico trophic hormone (ACTH) and cortisol, exerting an overall suppressive modulation of the stress axis and attenuates stress.

257 Awardee Talk: Pursuit of Novel Factors that Regulate Ovarian Follicular Function

Abstract As follicles grow, theca cells (TC) and granulosa cells (GC) must proliferate with minimal differentiation while thecal vascularization increases so that follicles do not prematurely ovulate or luteinize before the oocyte is fully mature. In the early 2000s we used Affymetrix microarrays to discover several unique genes involved in ovarian follicular development. Thrombospondin and fibroblast growth factor (FGF) 2 receptor genes were stimulated by IGF1 in porcine GC. We compared GC gene expression in bovine cystic versus normal follicles and discovered several novel genes including Indian hedgehog protein (IHH), FGF9, brain ribonuclease (BRB), and G protein-coupled receptor 34 (GPR34), leading to identification of roles for these proteins in ovarian follicular development. During the past 10 years, follow-up TC microarray and mechanistic studies have identified FGF9 control of cell cycle proteins, tight junction proteins, and microRNA 221 (MIR221), and that the mitogenic and steroidogenic responses to the major trophic hormones of the ovary (including IGF1, LH and FSH) are altered by overexpression of MIR221 in GC. In addition, we discovered that: 1) FGF9 stimulates GC and TC mitosis while inhibiting steroidogenesis; 2) FGF9 induces E2 transcription factor (E2F)-1, E2F-8 and cyclin D1 (CCND1), and that both IGF1 and vascular endothelial growth factor-A (VEGFA) synergize with FGF9 to further induce E2F8 and CCND1 mRNA; 3) FGF9 induces the nuclear protein UHRF1; and 4) an E2F inhibitor blocks the stimulatory and inhibitory effects of FGF9 on GC proliferation and steroidogenesis, respectively, and down-regulates UHRF1 mRNA and up-regulates VEGFA mRNA. Thus, aberrant production of FGF9 and the factors it induces/inhibits may lead to vascular dysfunction and ovarian disorders such as ovarian cysts. With additional research, knowledge about these newly identified factors may be used to help the livestock industry improve reproductive efficiency via new treatments for estrous synchronization, superovulation and cystic ovaries.

Does repeated gold-nanoparticles administration affect pars distalis hormonal and folliculo-stellate cells in adult male albino rats?

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

Feline Pituitary Adenomas: Correlation of Histologic and Immunohistochemical Characteristics With Clinical Findings and Case Outcome.

Pituitary glands from 141 feline autopsy cases were reviewed histologically. Adenoma and hyperplasia were the most common lesions at 13 cases each. Pituitary adenoma was more likely than hyperplasia to be associated with clinical evidence of endocrinopathy or an intracranial mass (P < .001). A histochemical and immunohistochemical panel was applied to 44 autopsy- or hypophysectomy-derived pituitary adenomas in 43 cats from 2 diagnostic laboratories. Adenomas were differentiated from hyperplasia by the presence of disrupted reticulin fibers. One cat had a double (somatotroph and melanotroph) adenoma. Twenty somatotroph adenomas consisted of periodic acid-Schiff (PAS)-negative acidophils that expressed growth hormone; 16/20 had hypersomatotropism; 17/20 had diabetes mellitus. Eleven melanotroph adenomas consisted of PAS-positive basophils or chromophobes that expressed melanocyte-stimulating and adrenocorticotrophic hormones; 5/11 had hypercortisolism; 6/11 had diabetes mellitus. Eleven gonadotroph adenomas consisted of PAS-negative chromophobes that expressed follicle-stimulating and/or luteinizing hormones. Two thyrotroph adenomas consisted of PAS-negative basophils or chromophobes that expressed thyroid-stimulating hormone. Pituitary-dependent disease was not recognized in cats with gonadotroph or thyrotroph adenomas. The Ki-67 proliferation index in hypophysectomy specimens was lower in somatotroph than in melanotroph adenomas. Fourteen cats with hypophysectomy-treated somatotroph or melanotroph adenoma had an 899-day median survival time versus 173 days in 17 nonsurgical cases. After adjusting for age, adenoma size and type, hypophysectomized cats had an overall better survival time than nonsurgical cases (P = .029). The study results underscore the value of hypophysectomy and trophic hormone immunohistochemistry in the treatment and classification of feline pituitary adenomas.

1894-P: Interruption of Glucagon Signaling Increases Pancreas Mass

Interruption of glucagon signaling by glucagon receptor gene inactivation or treatment with a glucagon receptor blocking monoclonal antibody (GCGR-Ab) stimulates alpha cell proliferation and expansion. Surprisingly, pancreas weight is also increased in mice with GCG gene inactivation. To investigate mechanisms linking glucagon signaling and pancreas size, we treated C57BL/6J mice with GCGR-Ab or a control IgG. Eight weeks of treatment (N=4-15 mice/treatment) increased absolute pancreas weight (0.42±0.013 vs. 0.32±0.008; p&amp;lt;0.0001), pancreas weight normalized to body weight (1.39±0.03% vs. 1.11±0.02%; p&amp;lt;0.0001), and serum levels of 15 amino acids (AA), including glutamine (1.7-4.67 fold, p&amp;lt;0.0001). GCGR-Ab treatment promoted acinar cell proliferation (Ki67+, 0.65±0.14% vs. 0.20±0.03%; p=0.0058), increased acinar cell size (peri-islet region: 438.4±12.77 vs. 341.7±22.05μm2; p=0.0045; peripheral region: 431.1±9.34 vs. 334.2±25μm2, p=0.0055; central region: 437.0±10.45 vs. 338.7±13.6 μm2, p=0.0006), and increased pancreas protein content (248.3±9.84 vs. 194±8.67μg/mg tissue; p=0.0003). By electron microscopy, GCGR-Ab treatment increased acinar cell zymogen granule number (129±9 vs. 49±6; p&amp;lt;0.0001; n=28-37 cells/treatment) and led to acinar cell ER dilatation, but did not induce pancreatitis or alter acinar cell apoptosis or pancreatic macrophage number. Serum cholecystokinin and total glucagon-like peptide-1, trophic hormones linked to exocrine growth, were not changed by GCGR-Ab treatment. GCGR-Ab treatment upregulated mRNA and protein levels of the glutamine transporter, Slc38a3, and increased mTOR-related ribosomal protein S6 phosphorylation in acinar cells. Together, these data indicate that interruption of glucagon signaling increases pancreas mass by inducing acinar cell hyperplasia and hypertrophy and activates protein synthesis and mTOR signaling; whether this is mediated by elevated glutamine or AA levels is not known. Disclosure C. Dai: None. A. Bradley: None. K.C. Coate: None. G. Poffenberger: None. E. Spears: None. J.J. Wright: None. S. Shrestha: None. D. Dean: None. M. Brissova: None. A.C. Powers: None. Funding National Institutes of Health (DK117147)

Potential applications for rhIGF-I: Bone disease and IGF[sbnd

Growth hormone (GH) and insulin like growth factor-I (IGFI) are key bone trophic hormones, whose rising levels during puberty are critical for pubertal bone accrual. Conditions of GH deficiency and genetic resistance impact cortical and trabecular bone deleteriously with reduced estimates of bone strength. In humans, conditions of undernutrition (as in anorexia nervosa (AN), or subsequent to chronic illnesses) are associated with low IGF-I levels, which correlate with disease severity, and also with lower bone mineral density (BMD), impaired bone structure and lower strength estimates. In adolescents and adults with AN, studies have demonstrated a nutritionally acquired GH resistance with low IGF-I levels despite high concentrations of GH. IGF-I levels go up with increasing body weight, and are associated with rising levels of bone turnover markers. In short-term studies lasting 6–10 days, recombinant human IGF-I (rhIGF-I) administration in physiologic replacement doses normalized IGF-I levels and increased levels of bone formation markers in both adults and adolescents with AN. In a randomized controlled trial in adults with AN in which participants were randomized to one of four arms: (i) rhIGF-I with oral estrogen-progesterone (EP), (ii) rhIGF-I alone, (iii) EP alone, or (iv) neither for 9 months, a significant increase in bone formation markers was noted in the groups that received rhIGF-I, and a significant decrease in bone resorption markers in the groups that received EP. The group that received both rhIGF-I and EP had a significant increase in bone density at the spine and hip compared to the group that received neither. Side effects were minimal, with no documented fingerstick glucose of <50 mg/dl. These data thus suggest a potential role for rhIGF-I administration in optimizing bone accrual in states of undernutrition associated with low IGF-I.

Proton Pump Inhibitor Use and Risk of Gastric, Colorectal, Liver, and Pancreatic Cancers in a Community-Based Population.

Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the association between PPI use and gastrointestinal cancers. We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.81-1.42), colorectal (OR: 1.05, 95% CI: 0.99-1.12), liver (OR: 1.14, 95% CI: 0.91-1.43), or pancreatic cancers (OR: 1.22, 95% CI: 0.89-1.67), compared to non-users. In exploratory analyses, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use, but no consistent associations were found for increasing PPI dose and/or duration of use. PPI use of ≥2 years was not associated with increased risks of gastrointestinal cancers. The cancer risks associated with PPI use of ≥10 years requires further study.