Sonic hedgehog signaling pathway in normal and adenomatous pituitary

This work investigates for the first time the expression and the role of Sonic hedgehog signaling pathway in adult pituitary and in pituitary tumors. Shh is a signaling protein, important in regulating patterning and proliferation in the embryo and the adult. It has a crucial role in pituitary development and Shh deficient mice do not even have a rudimentary Rathke's pouch (the development structure that gives rise to anterior pituitary). This study reveals the presence of an active Shh pathway in the post-developmental pituitary gland, with major impacts on hormone secretion and cell proliferation. After embryonic development, Shh continues to be expressed in the normal adult pituitary, being mainly co-localized in corticotrophs. These cells express also the receptor Ptc2 and the Shh induced transcription factor Gli1, being so Shh-producing and Shh-responsive cells. Shh acts in an autocrine way inside corticotrophs, inducing a major stimulation of ACTH secretion in the normal rat pituitary and in the AtT-20 cell line. The Shh induced ACTH secretion effect is synergistic with CRH. Shh stimulation increases CRH-R1 levels, up-regulating so the response of corticotrophs to CRH. At the same time, Gli1 is not only activated by Shh, but also by CRH and PKA. Gli1 itself activates POMC-transcription and acts in parallel upstream to CREB and AP-1. A major increase in Shh protein levels is seen as a result of CRH stimulation. All these results put in evidence a multiple cross-talk between these two important pathways acting at different levels to insure the final ACTH stimulation. Other types of hormone-secreting adenohypophysial cells possess one of Shh receptors (Ptc1 or Ptc2) and the transcription factor Gli1, so they have an active Shh pathway. Shh produced in the corticotrophs is a signaling protein, so it diffuses and acts also in distance. Shh increases GH secretion from the rat pituitary somatotrophs and from the GH3 cell line, while the effect on Prolactin is not statistically significant. The Sonic hedgehog pathway is downregulated in pituitary adenomas. Screening of 55 pituitary tumors reveals that they have a significantly reduced expression of Shh and Gli1. Although Shh in the normal pituitary is secreted by corticotroph cells, all the Cushing tumors screened had no Shh expression at all. Cell culture experiments performed in the AtT-20 corticotroph cell line in vitro show that Shh reduces cell proliferation by 50% and this effect is partially reducible by Cyclopamine. So Shh maintains the low proliferative capacity of corticotrophs in the normal pituitary gland and its loss may be one of the factors leading to tumor progression. It is concluded that Shh is produced in the anterior pituitary gland, is a major stimulant of ACTH and GH secretion, acts synergistically with CRH, opposes corticotroph cell proliferation and is downregulated in pituitary adenomas.In der vorliegenden Arbeit wurde erstmals die Expression und die Rolle des Sonic Hedgehog (Shh) Signalweges in adulten Hypophysen und Hypophysentumoren untersucht. Shh ist ein Signalprotein, das im Embryo und beim Erwachsenen wichtig fuer die Regulation der Zelldifferenzierung und -proliferation ist. Es ist fuer die Entwicklung der Hypophyse von herausragender Bedeutung, da Shh-defiziente Maeuse noch nicht einmal eine rudimentaere Rathkesche Tasche (aus der sich der Hypophysenvorderlappen entwickelt) bilden koennen. Die hier praesentierte Untersuchung zeigt, dass es in der voll entwickelten Hypophyse einen aktiven Shh-Signaltransduktionsweg gibt, der von betraechtlicher Bedeutung fuer die Hormonsekretion und Zellproliferation ist. Nach der Embryonalentwicklung wird Shh weiter in der normalen, erwachsenen Hypophyse exprimiert, wobei es vorwiegend in kortikotropen Zellen lokalisiert ist. Diese Zellen exprimieren auch den Shh-Rezeptor Ptc2 und den Shh-induzierten Transkriptionsfaktor Gli1 und sind somit sowohl Shh-produzierende als auch Shh-responsive Zellen. Shh wirkt auf autokrine Weise in den kortikotropen Zellen, indem es eine erhebliche Stimulation der ACTH Sekretion in der normalen Hypophyse und in der kortikotropen AtT20 Zelllinie induziert. Shh wirkt synergistisch mit CRH auf die Induktion der ACTH Freisetzung. Die Stimulation mit Shh erhoeht die Expression des CRH-Typ 1 Rezeptors (CRH-R1) und erhoeht so die Empfindlichkeit kortikotroper Zellen auf CRH. Gleichzeitig wird Gli1 nicht nur durch Shh, sondern auch durch CRH und PKA erhoeht. Gli1 selbst aktiviert die POMC Transkription parallel zu CREB und AP-1. Ein erheblicher Anstieg der Shh-Proteinspiegel wird nach CRH-Stimulation beobachtet. In ihrer Gesamtheit weisen diese Ergebnisse auf vielfaeltige Interaktonen auf unterschiedlichen Ebenen zwischen diesen zwei wichtigen Signalwegen hin, um letztlich die ACTH Stimulation zu gewaehrleisten. Auch andere hormonsezernierende Hypophysenzellen besitzen einen der Shh-Rezeptoren (Ptc1 oder Ptc2) und den Transkriptionsfaktor Gli1 und haben daher ein aktives Shh-System. Shh, das in kortikotropen Zellen gebildet wird, ist ein Signalprotein, das nach Diffusion auch in einiger Entfernung in benachbarten Zellen wirksam ist. Shh steigert die GH Sekretion in somatotropen Zellen und in laktosomatotropen GH3 Zellen, waehrend sein Effekt auf Prolaktin statistisch nicht signifikant ist. Der Shh-Signaltransduktionsweg ist in Hypophysenadenomen herunterreguliert. Die Untersuchung von 55 Hypophysenadenomen ergab, daaa in den Tumoren die Expression von Shh und Gli1 signifikant reduziert ist. Obwohl in der normalen Hypophyse Shh von kortikotropen Zellen sezerniert wird, exprimierten alle untersuchten kortikotropen Adenome ueberhaupt kein Shh. Zellkulturexperimente mit AtT20 Zellen zeigten, dass Shh die Zellproliferation um 50 % reduzierte und dass dieser Effekt teilweise durch Cyclopamine, einem Inhibitor des Shh-Signaltransduktionsweges, aufgehoben werden kann. Das weist darauf hin, dass Shh fuer die geringe proliferative Kapazitaet von kortikotropen Zellen in der normalen Hypophyse verantwortlich ist, und dass sein Verlust einer der Gruende ist, die zur Progression von Hypophysentumoren fuehren. Zusammenfassend kann man feststellen, dass Shh im Hypophysenvorderlappen produziert wird, dass es ein bedeutender Stimulator der ACTH und GH Sekretion ist, dass es syergistisch mit CRH wirkt, dass es der Proliferation von kortikotropen Zellen entgegenwirkt und dass es in Hypophysenadenomen herunterreguliert ist

Vitamin D and critical illness:what endocrinology can learn from intensive care and vice versa.

The prevalence of vitamin D deficiency in intensive care units ranges typically between 40 and 70%. There are many reasons for being or becoming deficient in the ICU. Hepatic, parathyroid and renal dysfunction additionally increases the risk for developing vitamin D deficiency. Moreover, therapeutic interventions like fluid resuscitation, dialysis, surgery, extracorporeal membrane oxygenation, cardiopulmonary bypass and plasma exchange may significantly reduce vitamin D levels. Many observational studies have consistently shown an association between low vitamin D levels and poor clinical outcomes in critically ill adults and children, including excess mortality and morbidity such as acute kidney injury, acute respiratory failure, duration of mechanical ventilation and sepsis. It is biologically plausible that vitamin D deficiency is an important and modifiable contributor to poor prognosis during and after critical illness. Although vitamin D supplementation is inexpensive, simple and has an excellent safety profile, testing for and treating vitamin D deficiency is currently not routinely performed. Overall, less than 800 patients have been included in RCTs worldwide, but the available data suggest that high-dose vitamin D supplementation could be beneficial. Two large RCTs in Europe and the United States, together aiming to recruit >5000 patients, have started in 2017, and will greatly improve our knowledge in this field. This review aims to summarize current knowledge in this interdisciplinary topic and give an outlook on its highly dynamic future

Long-Term Safety of Growth Hormone in Adults With Growth Hormone Deficiency:Overview of 15 809 GH-Treated Patients

Context Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. Objective We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. Methods The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. Results A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. Conclusion These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice

Hypertension in Acromegaly in Relationship to Biochemical Control and Mortality: Global ACROSTUDY Outcomes

Context: Hypertension is a major cardiovascular risk factor related to increased mortality in acromegaly. Surgical cure of acromegaly is associated with improvement in blood pressure levels, however little is known about the effect of pegvisomant (PEGV) treatment in patients with hypertension. This analysis evaluates outcomes in patients with hypertension and acromegaly included in ACROSTUDY. Methods: ACROSTUDY is a global non-interventional surveillance study of long-term treatment with PEGV, monitoring its safety and efficacy. The cohort was retrospectively divided in two subgroups: patients with and without hypertension. Stepwise logistic regression and Kaplan-Meyer analyses were performed for testing predictors of mortality. Results: The tota

Andere spezifische Diabetesformen

Zahlreiche endokrine Erkrankungen können Störungen des Kohlenhydratstoffwechsels bewirken und zur Manifestation eines Diabetes mellitus führen bzw. diese begünstigen. Mit Ausnahme der Hyperthyreose, bei der dies nur in Ausnahmefällen zu beobachten ist, sind diese Erkrankungen selten. Akromegalie und Cushing-Syndrom sind besonders häufig mit gestörter Glukosetoleranz oder Diabetes assoziiert, bei Phäochromozytom und Conn-Syndrom stellt dies die Ausnahme dar. Bei Medikamenten, die zur Manifestation eines Diabetes führen können, sind in erster Linie Hormone, atypische Antipsychotika und Immunsuppressiva anzuführen. Weiters kommen Pankreaserkrankungen wie Pankreatitis, Pankreaskarzinom, zystische Fibrose und Hämochromatose als sekundäre Diabetesursachen in Frage, ebenso wie das Down-Syndrom, das Klinefelter-Syndrom, das Turner-Syndrom und das Prader-Willi-Syndrom sowie andere seltenere immunmediierte oder genetische Syndrome.Numerous endocrine diseases are associated with impaired glucose metabolism and can induce diabetes mellitus. With the exception of hyperthyroidism, where this is uncommon, these diseases are rare. Acromegaly and Cushing syndrome are frequently associated with impaired glucose tolerance and diabetes. In contrast, this is a rare finding in pheochromocytoma and Conn syndrome. Among the many drugs that can induce diabetes this can be observed most frequently with hormones, atypic antipsychotic drugs and immunosuppressives. In addition, diseases of the pancreas such as pancreatitis, pancreatic carcinoma, cystic fibrosis and hemochromatosis can cause diabetes as well as Down syndrome, Klinefelter syndrome, Turner syndrome and Prader Willi syndrome and rare immunmediated or genetic syndromes.(VLID)346207

Differential Regulation of Plasma Obestatin and Ghrelin by Meal Intake and the Cholinergic System in Lean, But Not Obese Individuals

Context: Obestatin is cosecreted with and stemming from the same precursor as ghrelin and is apparently involved in energy metabolism. Relatively little is known about the regulation of obestatin release. Objective: The regulation of obestatin release and obestatin-to-ghrelin ratios by meal intake and the cholinergic system were studied in lean and obese subjects. Design, Participants, and Setting: We conducted a randomized, double-blind, placebo-controlled, crossover study with 4 study days in eight obese (body mass index Ͼ30 kg/m 2 ) and eight matched lean (body mass index Ͻ25 kg/m 2 ) healthy subjects (two males and six females per group) at a University Clinical Research Unit. Interventions: Atropine (1 mg iv) was administered alone and in combination with breakfast (550 kcal) intake, or placebo (isotonic saline) alone and in combination with breakfast. Main Outcome Measures: We measured plasma obestatin and obestatin/ghrelin ratios. Results: Both obestatin and ghrelin/obestatin ratios decreased significantly from baseline by either atropine or meal intake in lean individuals, with the two effects adding up on the combined atropine/breakfast day. In contrast, there were no statistically significant differences in obese subjects, who also showed significantly greater association between ghrelin and obestatin values than their lean counterparts. Conclusions: Obestatin and ghrelin release is differentially regulated by meal intake and the cholinergic system in lean individuals. This regulation is impaired in obesity. (J Clin Endocrinol Metab 95: 0000 -0000, 2010) G hrelin, the octanoylated peptide produced mainly by the stomach and natural ligand to the GH secretagogue-receptor, is now well established as an orexigenic hormone mediating increased food intake resulting in a positive energy balance (1). Obestatin, an amidated cleavage product of the preproghrelin gene, was initially described as opposing the functions of ghrelin on appetite, resulting in decreased gastric food intake and weight gain in rodents, by binding to its cognate receptor, an (until then) orphan receptor termed g protein coupled receptor 39 (2). These results have been partially confirmed, but also called into question (see Ref. 3 and the references therein). Obestatin does bind to membranes of pancreatic cells and cell lines with high affinity and promotes survival o