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AIMS - Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).
MATERIALS AND METHODS - We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg min ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp.
RESULTS - Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion.
CONCLUSIONS - These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.
© 2017 John Wiley & Sons Ltd.
After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Pituitary blastoma, a recently described tumor of the neonatal pituitary, exhibits differentiation to Rathke epithelium and adenohypophysial cells of folliculostellate and secretory type, a reflection of arrested pituitary development and unchecked proliferation (Scheithauer et al. in Acta Neuropathol 116(6):657-666, 2008). Herein, we report the pathologic features of three additional cases, all ACTH-producing. One involved a 9-month-old male presenting with progressive right ophthalmoplegia, MRI findings of a large suprasellar mass with cavernous sinus invasion, and elevated plasma ACTH levels. The second was nonfunctioning and occurred in a 13-month-old female with right third nerve palsy. The third had been previously published as a "pituitary adenoma" in a 2-year-old female (Min et al. in Pathol Int 57(9):600-605, 2007). The subtotally resected tumors were subject to histochemical, immunohistochemical and, in two cases, ultrastructural study. Histologically, the complex tumors consisted of glands of varying from rosettes to glandular structures resembling Rathke epithelium, small undifferentiated-appearing cells (blastema), and large secretory cells. Mucin-producing goblet cells were noted in case 3. Cell proliferation was high in two cases and low in case 3. Immunoreactivity of the secretory cells included synaptophysin, chromogranin, various keratins and, to a lesser extent, ACTH and beta endorphin. MGMT immunolabeling was 40-60%. Mitotic activity was moderate to high in cases 1 and 2 and was low in case 3. The same was true for MIB-1 labeling. Germ cell markers were lacking in all cases. One tumor ultrastructurally consisted of three cell populations including (a) small, polyhedral, primitive-appearing cells (blastema) with scant cytoplasm, abundant glycogen and few organelles, (b) folliculostellate cells and (c) large corticotroph cells containing rough endoplasmic reticulum, golgi membranes, spherical, 150-400 nm secretory granules and occasional perinuclear, intermediate filament bundles. A second example (case 3) lacked a blastema and glandular component. The clinical and morphologic features of our three cases were those of pituitary blastoma. The finding of cellular elements of adenohypophysial development is consistent with a diagnosis of pituitary blastoma and aligns it with blastomas of other organs. It also suggests an underlying specific genetic abnormality. Marked variations in cellular proliferative activity suggest blastomas occur in low- and higher-grade form. Variable MGMT reactivity suggests an incomplete response to temozolomide therapy. Literature regarding similar morphologically complex, infantile, Cushing disease-associated lesions is briefly reviewed.
OBJECTIVE - To determine whether a random postoperative day-3 cortisol value of 10 μg/dL or greater is predictive of adrenal sufficiency 3 to 10 weeks after transsphenoidal surgery (TSS) and during long-term clinical follow-up.
METHODS - We retrospectively reviewed the case records of patients who underwent TSS at our institution between 1991 and 2008. Inclusion criteria were as follows: random cortisol measured on the morning of postoperative day 3, adrenal dynamic testing performed 3 to 10 weeks after TSS, and clinical assessment of the hypothalamic-pituitary-adrenal (HPA) axis at least 6 months after TSS.
RESULTS - A total of 466 patients underwent TSS at our institution during the study period. Eighty-three patients met study inclusion criteria. Sensitivity of a random postoperative day-3 serum cortisol value of 10 μg/dL or greater for the prediction of adrenal sufficiency at a median follow-up of 42 days was 64.81% (95% confidence interval, 50.6%-77.32%), with an odds ratio of 3.1 (95% confidence interval, 1.08-8.58). Specificity was 62.1% (95% confidence interval, 42.3%-79.3%). At a median follow-up of 500 days, only 2 patients with a postoperative day-3 cortisol value of 10 μg/dL or greater required hydrocortisone replacement, both of whom had multiple anterior pituitary hormone deficiencies and evidence of pituitary dysfunction during the perioperative period.
CONCLUSIONS - In the appropriate clinical context, a postoperative day-3 cortisol value of 10 μg/dL or greater accurately predicts the integrity of the HPA axis. The final decision regarding corticosteroid replacement should be personalized, considering the postoperative day-3 cortisol level, the clinical context in which the measurement was obtained, and any evidence of concomitant pituitary dysfunction in the perioperative period.
Fasting-induced suppression of thyroid hormone levels is an adaptive response to reduce energy expenditure in both humans and mice. This suppression is mediated by the hypothalamic-pituitary-thyroid axis through a reduction in TRH levels expressed in neurons of the paraventricular nucleus of the hypothalamus (PVN). TRH gene expression is positively regulated by leptin. Whereas decreased leptin levels during fasting lead to a reduction in TRH gene expression, the mechanisms underlying this process are still unclear. Indeed, evidence exists that TRH neurons in the PVN are targeted by leptin indirectly via the arcuate nucleus, whereas correlative evidence for a direct action exists as well. Here we provide both in vivo and in vitro evidence that the activity of hypothalamic-pituitary-thyroid axis is regulated by both direct and indirect leptin regulation. We show that both leptin and α-MSH induce significant neuronal activity mediated through a postsynaptic mechanism in TRH-expressing neurons of PVN. Furthermore, we provide in vivo evidence indicating the contribution of each pathway in maintaining serum levels of thyroid hormone.
BACKGROUND - Several investigators have recommended serial measurements of serum cortisol in the days following pituitary surgery to identify patients at risk of recurrence.
OBJECTIVE - We systematically reviewed the literature on this topic and analyzed the usefulness of this test in our own patient population.
METHODS - We identified studies publishing data regarding recurrence rates after transsphenoidal surgery for Cushing's disease, focusing on studies with data regarding patients with early postoperative cortisol levels. We determined a cumulative relative risk of having a subnormal vs normal cortisol level postoperatively using a fixed-effects meta-analysis model. Additionally, we analyzed our own patients with Cushing's disease undergoing transsphenoidal surgery and performed Kaplan-Meier analysis of recurrence-free survival for patients with undetectable, subnormal but detectable, and normal immediate 8 AM serum cortisol levels.
RESULTS - Fourteen studies met inclusion criteria. The length of follow-up varied between 32 and 115 months. The cumulative rate of recurrence in the group of patients with subnormal cortisol levels was 9% (95% confidence interval: 6%-12%). The cumulative rate of recurrence in the group with normal cortisol levels was 24% (95% confidence interval: 17%-31%). We analyzed 73 of our own patients and found similar recurrence rates in patients with subnormal vs normal early postoperative cortisol levels (4% vs 22%, chi2 test, P < .05).
CONCLUSION - Although a subnormal early postoperative cortisol level is predictive of improved outcome after transsphenoidal surgery for Cushing's disease, it is not analogous with cure, nor is a normal level completely predictive of future failure.
CONTEXT - Dominant-negative GH1 mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. The basis of the variable expression and progression of IGHD II among relatives who share the same GH1 mutation is poorly understood.
OBJECTIVE - We hypothesized that the cellular ratios of mutant/normal GH1 transcripts would correlate with the severity of the IGHD II phenotype. We determined the relative amounts of mutant and normal GH1 transcripts in cell lines and correlated transcript ratios with severity.
DESIGN AND PATIENTS - Members of the same IGHD II kindred were genotyped for the GH1 E3+1 G/A mutation by DNA sequencing. Ratios of their 17.5-kDa (mutant)/22-kDa (normal) GH1 transcripts were determined in cultured lymphocytes (CLs), and these ratios were correlated with height sd scores obtained before GH replacement therapy.
RESULTS - Ratios of 17.5-/22-kDa GH1 transcripts in CLs from family members with the same IGHD II mutation correlated with differences in their height SD scores.
CONCLUSIONS - Our findings suggest that expression levels of both the mutant and normal GH1 allele are important in the pathogenesis of IGHD II, that the ratio of mutant/normal transcripts may be a predictive marker of the penetrance and severity of IGHD II, and that CLs may be useful as surrogates to study GH1 transcript expression of subjects whose anterior pituitary cells are not available.
The evaluation and management of patients with residual Cushing's disease is one of the more complex issues facing neurosurgeons and neuroendocrinologists in clinical practice. There is considerable controversy over several relevant issues such as the timing of the assessment of whether a patient is in remission, what biochemical parameters define remission, the most appropriate course of action to take after residual disease has been defined, etc. As a consequence of the controversies, treating physicians develop notions and fall into certain practice patterns based on evidence of varying levels, their anecdotal experiences, and information gleaned from scientific meetings. This practice pattern, we believe, constitutes the "art of medicine." We conducted a PubMed literature search to identify manuscripts containing data relevant to Cushing's disease, outcomes of various therapeutic modalities, and recurrences. Reference lists were used to identify additional relevant manuscripts. We focused our review on manuscripts that included reasonably large series of patients, those reflecting the experience of pituitary centers and physicians recognized as experts in the field, and those papers felt to represent seminal contributions to the literature. Furthermore, trends in the evaluation and management of relevant patients have been incorporated by the senior author who has seen and evaluated over 750 patients with documented Cushing's syndrome over the past 18 years in clinical practice. An analysis of current evidence indicated that, despite advances in neurosurgical techniques and recent developments in adjuvant therapies, patients with residual Cushing's disease present significant management challenges to treating physicians. In this era, however, it is indeed possible to gain control of the hypercortisolism in most patients. Despite the wide variability in research methodology designed to collect relevant data, a step-wise approach to the management of these patients can be achieved. A logical step-wise approach to the evaluation of postoperative patients with Cushing's disease is essential. Patients with residual disease require the development of an individualized plan of management that takes into account numerous factors pertaining to status of disease, the experience of treating physicians, and available therapeutic modalities.
A family of single-stranded DNA-binding proteins (or SSBPs) has been shown to augment the function of LIM-homeodomain (LIM-HD) transcription factors in embryogenesis by interaction with LIM domain-binding protein-1 (LDB1). No DNA-binding complex has been described, however, containing a LIM-HD protein, LDB1, and SSBP, and the mechanism by which SSBPs affect LIM-HD function had not been elucidated. Through use of electrophoretic mobility shift, antibody supershift, and ChIP analyses, we show that an Lhx2-Ldb1-Ssbp3 complex binds a specific element in the Lhx2 target gene Cga (encoding the alpha subunit of glycoprotein hormones) in the alphaT3-1 pituitary cell line. Using overexpression and knockdown approaches, we demonstrate that SSBP3 inhibits Lhx2 and Ldb1 turnover, stimulates assembly of this DNA-binding complex, promotes its recruitment to the Cga promoter, and enhances Cga transcription. These studies provide novel insights into the regulation of pituitary gene expression and LIM-HD function more generally.
Recent studies revealed that the Wnt receptor Frizzled-5 (Fzd5) is required for eye and retina development in zebrafish and Xenopus, however, its role during mammalian eye development is unknown. In the mouse embryo, Fzd5 is prominently expressed in the pituitary, distal optic vesicle, and optic stalk, then later in the progenitor zone of the developing retina. To elucidate the role of Fzd5 during eye development, we analyzed embryos with a germline disruption of the Fzd5 gene at E10.25, just before embryos die due to defects in yolk sac angiogenesis. We observed severe defects in optic cup morphogenesis and lens development. However, in embryos with conditional inactivation of Fzd5 using Six3-Cre, we observed no obvious early eye defects. Analysis of Axin2 mRNA expression and TCF/LEF-responsive reporter activation demonstrate that Fzd5 does not regulate the Wnt/beta-catenin pathway in the eye. Thus, the function of Fzd5 during eye development appears to be species-dependent.