Line Scan Raman Microspectroscopy for Label-Free Diagnosis of Human Pituitary Biopsies.

Pituitary adenomas are neoplasia of the anterior pituitary gland and can be subdivided into hormone-producing tumors (lactotroph, corticotroph, gonadotroph, somatotroph, thyreotroph or plurihormonal) and hormone-inactive tumors (silent or null cell adenomas) based on their hormonal status. We therefore developed a line scan Raman microspectroscopy (LSRM) system to detect, discriminate and hyperspectrally visualize pituitary gland from pituitary adenomas based on molecular differences. By applying principal component analysis followed by a k-nearest neighbor algorithm, specific hormone states were identified and a clear discrimination between pituitary gland and various adenoma subtypes was achieved. The classifier yielded an accuracy of 95% for gland tissue and 84-99% for adenoma subtypes. With an overall accuracy of 92%, our LSRM system has proven its potential to differentiate pituitary gland from pituitary adenomas. LSRM images based on the presence of specific Raman bands were created, and such images provided additional insight into the spatial distribution of particular molecular compounds. Pathological states could be molecularly differentiated and characterized with texture analysis evaluating Grey Level Cooccurrence Matrices for each LSRM image, as well as correlation coefficients between LSRM images.

MGMT and MSH6 immunoexpression for functioning pituitary macroadenomas.

PURPOSE: Knowledge of biological behavior is crucial for clinical management of functioning pituitary macroadenomas. For recurrent cases unresponsive to standard treatment, temozolomide (TMZ) has been used as a therapeutic alternative. MGMT (O6-methyl-guanine-DNA methyltransferase) and MSH6 (mutS homolog 6) immunoexpression have been linked to the response to TMZ treatment and MGMT immunoexpression has been additionally linked to early recurrence of non-functioning pituitary adenomas. The aim of this study was to assess the prognostic value of MGMT and MSH6 immunoexpression for aggressive functioning pituitary adenomas. METHODS: The study cohort comprised a single center series of 76 patients who underwent an operation for functioning pituitary macroadenoma. We retrospectively compared 38 patients with postoperative persistent or recurrent disease with another set of 38 patients who were in endocrine remission. RESULTS: Low-to-moderate MGMT immunoexpression (<50%) was significantly more frequent in the group with persistent/recurrent disease than in cases of endocrine remission (66 vs. 21%, p < 0.001). Furthermore, adenomas with low-to-moderate MGMT immunoexpression were significantly more often recurrent (76 vs. 30%, p < 0.001) and invasive (64 vs. 28%, p = 0.002). CONCLUSION: In our series, low-to-moderate MGMT immunoexpression was the only marker that significantly correlated with surgical invasiveness and recurrence in functioning pituitary macroadenomas. Therefore, in the future, MGMT status may be considered an additional marker for understanding the biological behavior of pituitary adenomas.

GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

HORMONE SUBSTITUTION AFTER GASTRIC BYPASS SURGERY IN PATIENTS WITH HYPOPITUITARISM SECONDARY TO CRANIOPHARYNGIOMA.

OBJECTIVE: Craniopharyngiomas (CPs) are benign brain tumors presenting frequently in childhood and are treated by surgery with or without radiotherapy. About 50% of cured patients suffer from eating disorders and obesity due to hypothalamic damage, as well as hypopituitarism, necessitating subsequent hormone substitution therapy. Gastric bypass surgery has been reported to be an efficient treatment strategy for morbid hypothalamic obesity. However, so far it is unknown whether oral hormone substitution is affected by impaired intestinal drug absorption, potentially leading to severe hypopituitarism or pituitary crisis. METHODS: Four morbidly obese CP patients with panhypopituitarism treated by gastric bypass surgery were included in this retrospective analysis. Dosages of hormone substitution therapy, blood concentrations of hormones, potential complications of impaired drug absorption, and anthropometric characteristics were investigated pre- and postoperatively after 6 to 14 months and 13 to 65 months. RESULTS: In all CP patients (3 female/1 male; baseline body mass index, 49 ± 7 kg/m(2)), gastric bypass resulted in distinct weight loss (-35 ± 27 kg). In follow-up examinations, mean daily dosage of thyroid hormone (levothyroxinebaseline 156 ± 44 µg/day versus levothyroxinefollow-up 150 ± 30 µg/day), hydrocortisone (hydrocortisonebaseline 29 ± 12 mg/day versus hydrocortisonefollow-up 26 ± 2 mg/day), growth-hormone (somatotropinbaseline 0.9 ± 0.5 mg/day versus somatotropinfollow-up 1.0 ± 0.4 mg/day), and desmopressin (desmopressinbaseline 222 ± 96 µg/day versus desmopressinfollow-up 222 ± 96 µg/day) substitution was unchanged. No patient developed adrenal insufficiency. Oral thyroid/hydrocortisone absorption testing performed in 1 patient indicated sufficient gastrointestinal drug absorption after bariatric surgery. CONCLUSION: Our preliminary results suggest that oral hormone substitution therapy is not impaired following gastric bypass operation in CP patients with morbid obesity, indicating that it might be a safe and effective treatment strategy.

Lactation and appetite-regulating hormones: increased maternal plasma peptide YY concentrations 3-6 months postpartum.

Breast-feeding is associated with maternal hormonal and metabolic changes ensuring adequate milk production. In this study, we investigate the impact of breast-feeding on the profile of changes in maternal appetite-regulating hormones 3-6 months postpartum. Study participants were age- and BMI-matched lactating mothers (n 10), non-lactating mothers (n 9) and women without any history of pregnancy or breast-feeding in the previous 12 months (control group, n 10). During study sessions, young mothers breast-fed or bottle-fed their babies, and maternal blood samples were collected at five time points during 90 min: before, during and after feeding the babies. Outcome parameters were plasma concentrations of ghrelin, peptide YY (PYY), leptin, adiponectin, prolactin, cortisol, insulin, glucose and lipid values. At baseline, circulating PYY concentrations were significantly increased in lactating mothers (100·3 (se 6·7) pg/ml) v. non-lactating mothers (73·6 (se 4·9) pg/ml, P=0·008) and v. the control group (70·2 (se 9) pg/ml, P=0·021). We found no differences in ghrelin, leptin and adiponectin values. Baseline prolactin concentrations were over 4-fold higher in lactating mothers (P<0·001). Lactating women had reduced TAG levels and LDL-cholesterol:HDL-cholesterol ratio, but increased waist circumference, when compared with non-lactating women. Breast-feeding sessions further elevated circulating prolactin (P<0·001), but induced no acute effects on appetite-regulating hormones. In summary, one single breast-feeding session did not acutely modulate circulating appetite-regulating hormones, but increased baseline PYY concentrations are associated with prolonged lactation. PYY might play a role in the coordination of energy balance during lactation, increasing fat mobilisation from maternal depots and ensuring adequate milk production for the demands of the growing infant.

Ectopic lipid metabolism in anterior pituitary dysfunction.

Over the past decades, adapted lifestyle and dietary habits in industrialized countries have led to a progress of obesity and associated metabolic disorders. Concomitant insulin resistance and derangements in lipid metabolism foster the deposition of excess lipids in organs and tissues with limited capacity of physiologic lipid storage. In organs pivotal for systemic metabolic homeostasis, this ectopic lipid content disturbs metabolic action, thereby promotes the progression of metabolic disease, and inherits a risk for cardiometabolic complications. Pituitary hormone syndromes are commonly associated with metabolic diseases. However, the impact on subcutaneous, visceral, and ectopic fat stores between disorders and their underlying hormonal axes is rather different, and the underlying pathophysiological pathways remain largely unknown. Pituitary disorders might influence ectopic lipid deposition indirectly by modulating lipid metabolism and insulin sensitivity, but also directly by organ specific hormonal effects on energy metabolism. In this review, we aim to I) provide information about the impact of pituitary disorders on ectopic fat stores, II) and to present up-to-date knowledge on potential pathophysiological mechanisms of hormone action in ectopic lipid metabolism.

Increased GH/IGF-I Axis Activity Relates to Lower Hepatic Lipids and Phosphor Metabolism.

CONTEXT: Non-alcoholic fatty liver disease (NAFLD) is a leading causes of liver-related morbidity and mortality. While data on acromegaly, a state of chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess, suggest an inverse relationship with intrahepatic lipid (IHL) content, less is known about the impact of the GH/IGF-I axis on IHL, lipid composition, and phosphor metabolites in individuals without disorders of GH secretion. OBJECTIVE: The aim was to investigate the relation between activity of the GH/IGF-I axis and IHL content and phosphor metabolism. METHODS: We performed a cross-sectional study in 59 otherwise metabolically healthy individuals (30 females), of which 16 met the criteria of NAFLD with IHL of ≥5.6%. The GH/IGF-I axis was evaluated in a fasting state and during an oral glucose tolerance test (OGTT). Insulin sensitivity was estimated by validated indices. IHL, lipid composition (unsaturation index), and phosphate metabolites were analyzed by using 1H/31P magnetic resonance spectroscopy. RESULTS: In the overall cohort (40.6 ± 15 years; body mass index: 24.5 ± 3 kg/m2; IGF-I: 68.0 ± 17% upper limit of normal), fasting GH (R = -0.31; P = .02), GH during oral glucose tolerance test (R = -0.51; P < .01), and IGF-I (R = -0.28; P = .03) inversely correlated with IHL. GH levels during OGTT were significantly lower in NAFLD than in controls (47.7 [22; 143] ng/mL/min vs 16.8 [7; 32] ng/mL/min; P = .003). GH/IGF-I axis activity correlated with lipid composition and with phosphor metabolites. In multiple regression analysis, the GH/IGF-I axis activity was a strong predictor for IHL and lipid composition independent from insulin sensitivity. CONCLUSION: GH/IGF-I axis activity impacts hepatic lipid and phosphate metabolism in individuals without disorders in GH secretion. Lower GH axis activity is associated with higher IHL and an unfavorable lipid composition, probably mediated by changes in hepatic energy metabolism.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Perioperative Management of a Patient With Cushing Disease.

Patients with Cushing disease (CD) may present with both chronic and acute perioperative complications that necessitate multidisciplinary care. This review highlights several objectives for these patients before and after transsphenoidal surgery. Preoperative management includes treatment of electrolyte disturbances, cardiovascular comorbidities, prediabetes/diabetes, as well as prophylactic consideration(s) for thromboembolism and infection(s). Preoperative medical therapy (PMT) could prove beneficial in patients with severe hypercortisolism or in cases of delayed surgery. Some centers use PMT routinely, although the clinical benefit for all patients is controversial. In this setting, steroidogenesis inhibitors are preferred because of rapid and potent inhibition of cortisol secretion. If glucocorticoids (GCs) are not used perioperatively, an immediate remission assessment postoperatively is possible. However, perioperative GC replacement is sometimes necessary for clinically unstable or medically pretreated patients and for those patients with surgical complications. A nadir serum cortisol of less than 2 to 5µg/dL during 24 to 74 hours postoperatively is generally accepted as remission; higher values suggest nonremission, while a few patients may display delayed remission. If remission is not achieved, additional treatments are pursued. The early postoperative period necessitates multidisciplinary awareness for early diagnosis of adrenal insufficiency (AI) to avoid adrenal crisis, which may also be potentiated by acute postoperative complications. Preferred GC replacement is hydrocortisone, if available. Assessment of recovery from postoperative AI should be undertaken periodically. Other postoperative targets include decreasing antihypertensive/diabetic therapy if in remission, thromboprophylaxis, infection prevention/treatment, and management of electrolyte disturbances and/or potential pituitary deficiencies. Evaluation of recovery of thyroid, gonadal, and growth hormone deficiencies should also be performed during the following months postoperatively.

Diagnostic criteria of small sellar lesions with hyperprolactinemia: Prolactinoma or else.

Objective: To evaluate the combined predictive value of MRI criteria with the prolactin-volume-ratio (PVR) to differentiate prolactinoma from non-prolactinoma, in small sellar lesions with hyperprolactinemia. Methods: Retrospective analysis of 55 patients with sellar lesions of ≤15 mm diameter on MRI and hyperprolactinemia of ≤150 ng/mL, surgically treated between 2003 and 2020 at the Medical University of Vienna, with a conclusive histopathological report. Serum prolactin levels, extent of pituitary stalk deviation, size and volume of the lesion were assessed. The PVR was calculated by dividing the preoperative prolactin level by tumor volume. Results: Our study population consisted of 39 patients (71%) with a prolactin-producing pituitary adenoma (group A), while 16 patients (29%) had another type of sellar lesion (group B). Patients in group A were significantly younger (p=0.012), had significantly higher prolactin levels at diagnosis (p<0.001) as well as smaller tumor volume (p=0.036) and lower degree of pituitary stalk deviation (p=0.009). The median PVR was significantly higher in group A (243 ng/mL per cm3) than in group B (83 ng/mL per cm3; p=0.002). Furthermore, the regression operating characteristics analysis revealed a PVR >100 ng/mL per cm3 to be predictive for distinguishing prolactin-producing lesions from other small sellar lesions. Conclusion: In patients with small sellar lesions, Prolactin-Volume-Ratios >100 represents a possible predictive marker for the diagnosis of prolactin-producing pituitary adenomas.

Impact of Tafamidis and Optimal Background Treatment on Physical Performance in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET). METHODS: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4-16 months). Improvement in peak VO2 at follow-up was defined as ∆peak VO2≥1.0 mL/(kg·min), stable peak VO2 was defined as 0≤∆peak VO2<1.0 mL/(kg·min), and decline in peak VO2 was defined by ∆peak VO2<0 mL/(kg·min). RESULTS: Baseline peak VO2>14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization (P=0.002, P=0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance (P=0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO2 (P<0.0001), an improvement of peak VO2 (P<0.0001), and better physical performance at follow-up (P<0.0001). Patients with stable or improved peak VO2 had less advanced heart disease at baseline (P=0.046). CONCLUSIONS: Our findings demonstrate that baseline peak VO2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

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.

Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing's syndrome.

Objective: To evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Methods: Retrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference. Results: 469 patients were analyzed [78% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94%); ECS, n=26 (6%)] and 237 patients [228 CD (96%), 9 ECS (4%)]. Both tests were performed in 205 patients (44%). The post-CRH %-increase at 30 minutes of both ACTH (cut-off ≥31%, sensitivity 83%, specificity 85%, AUC 0.81) and cortisol (cut-off ≥12%, sensitivity 82%, specificity 89%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the %-suppression during the 8 mg DST was ≥55% (sensitivity 80%, specificity 78%, AUC 0.75). Conclusion: The CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.

Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension.

Objective: To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11ß-hydroxylase inhibitor, for treating Cushing's disease (CD). Design/methods: A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline. Results: Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1-245) and median average dose was 7.4 mg/day (range 0.8-46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension. Conclusions: Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.

[Emergency card, emergency medication, and information leaflet for the prevention and treatment of adrenal crisis (Addison crisis): an Austrian consensus document]. / Notfallausweis, Notfallmedikation und Informationsmaterial zur Prävention und Therapie der Nebennierenkrise (Addison-Krise): Ein österreichisches Konsensusdokument.

A central goal of the adrenal insufficiency management is the prevention of acute adrenal insufficiency (also known as adrenal crisis or Addison crisis). This consensus document was generated in order to achieve better implementation and harmonization of measures for the prevention and treatment of acute adrenal insufficiency in Austria. The following measures are generally recommended for all patients with adrenal insufficiency and are outlined in this manuscript: (1) Provision of a "steroid emergency card" and possibly also a medical alert bracelet or necklace (or similar identification). (2) Provision of a hydrocortisone injection kit (or alternative glucocorticoid preparations) for emergency use plus sufficient oral glucocorticoid doses for stress situations/illness. (3) Education of patients and relatives on glucocorticoid stress dosing and "sick day rules" as well as on self-injection of hydrocortisone. (4) Provision of a treatment guideline (information leaflet) for the prevention and therapy of the adrenal crisis, which should also be shown to healthcare staff if necessary. (5) Provision of an emergency phone number (contact details) of the responsible endocrine specialist team or other trained staff. (6) Reinforcement of patient education on a regular basis (preferably yearly). This consensus document also includes recommendations for glucocorticoid dosing in the perioperative setting as well as in various other stress situations.

Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release.

Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early-response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects.

The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS: We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS: Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A(1c), and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS: The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

MANAGEMENT OF ENDOCRINE DISEASE: Cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing's syndrome: a practical approach.

Cushing's syndrome (CS) is associated with increased mortality that is driven by cardiovascular, thromboembolic, and infection complications. Although these events are expected to decrease during disease remission, incidence often transiently increases postoperatively and is not completely normalized in the long-term. It is important to diagnose and treat cardiovascular, thromboembolic, and infection complications concomitantly with CS treatment. Management of hyperglycemia/diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with clinical care standards. Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism, and treatment adjustments can be made based on disease pathophysiology and drug-drug interactions. Thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding. Pneumocystis jiroveci pneumonia prophylaxis should be considered for patients with high urinary free cortisol at the initiation of hypercortisolism treatment.

The Interaction of Insulin and Pituitary Hormone Syndromes.

Pituitary hormone axes modulate glucose metabolism and exert direct or indirect effects on insulin secretion and function. Cortisol and growth hormone are potent insulin-antagonistic hormones. Therefore impaired glucose tolerance, elevated fasting glucose concentrations and diabetes mellitus are frequent in Cushing's disease and acromegaly. Also prolactinomas, growth hormone (GH) deficiency, hypogonadism and hypothyroidism might be associated with impaired glucose homeostasis but usually to a lesser extent. Therefore glucose metabolism needs to be closely monitored and treated in patients with pituitary adenomas. Correction of the pituitary dysfunction is frequently followed by improvement of glucose homeostasis.

Morpho-Molecular Metabolic Analysis and Classification of Human Pituitary Gland and Adenoma Biopsies Based on Multimodal Optical Imaging.

Pituitary adenomas count among the most common intracranial tumors. During pituitary oncogenesis structural, textural, metabolic and molecular changes occur which can be revealed with our integrated ultrahigh-resolution multimodal imaging approach including optical coherence tomography (OCT), multiphoton microscopy (MPM) and line scan Raman microspectroscopy (LSRM) on an unprecedented cellular level in a label-free manner. We investigated 5 pituitary gland and 25 adenoma biopsies, including lactotroph, null cell, gonadotroph, somatotroph and mammosomatotroph as well as corticotroph. First-level binary classification for discrimination of pituitary gland and adenomas was performed by feature extraction via radiomic analysis on OCT and MPM images and achieved an accuracy of 88%. Second-level multi-class classification was performed based on molecular analysis of the specimen via LSRM to discriminate pituitary adenomas subtypes with accuracies of up to 99%. Chemical compounds such as lipids, proteins, collagen, DNA and carotenoids and their relation could be identified as relevant biomarkers, and their spatial distribution visualized to provide deeper insight into the chemical properties of pituitary adenomas. Thereby, the aim of the current work was to assess a unique label-free and non-invasive multimodal optical imaging platform for pituitary tissue imaging and to perform a multiparametric morpho-molecular metabolic analysis and classification.