Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors.

Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown. We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization. Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs. Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.

Long-term Follow-up of 84 Patients With Giant Prolactinomas-A Swedish Nationwide Study.

PURPOSE: To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas. METHODS: Register-based study of patients with giant prolactinomas [serum prolactin (PRL) > 1000 µg/L, tumor diameter ≥40 mm] identified in the Swedish Pituitary Register 1991-2018. RESULTS: Eighty-four patients [mean age 47 (SD ±16) years, 89% men] were included in the study. At diagnosis, the median PRL was 6305 µg/L (range 1450-253 000), the median tumor diameter was 47 mm (range 40-85), 84% of the patients had hypogonadotropic hypogonadism, and 71% visual field defects. All patients were treated with a dopamine agonist (DA) at some point. Twenty-three (27%) received 1 or more additional therapies, including surgery (n = 19), radiotherapy (n = 6), other medical treatments (n = 4), and chemotherapy (n = 2). Ki-67 was ≥10% in 4/14 tumors. At the last follow-up [median 9 years (interquartile range (IQR) 4-15)], the median PRL was 12 µg/L (IQR 4-126), and the median tumor diameter was 22 mm (IQR 3-40). Normalized PRL was achieved in 55%, significant tumor reduction in 69%, and combined response (normalized PRL and significant tumor reduction) in 43%. In the primary DA-treated patients (n = 79), the reduction in PRL or tumor size after the first year predicted the combined response at the last follow-up (P < .001 and P = .012, respectively). CONCLUSION: DAs effectively reduced PRL and tumor size, but approximately 1 patient out of 4 needed multimodal treatment. Our results suggest that the response to DA after 1 year is useful for identifying patients who need more careful monitoring and, in some cases, additional treatment.

Comparison Between Thyroid Stimulating Immunoglobulin and TSH-Receptor Antibodies in the Management of Graves' Orbitopathy.

OBJECTIVES: TSH-receptor antibodies (TRAb) targeting the TSH receptor (TSH-R) induce hyperthyroidism in Graves´ disease (GD). Graves´ orbitopathy (GO) is influenced by stimulation of the TSH-R in the orbita. GO has been, among other factors, linked to high TRAb levels. Thyroid stimulating immunoglobulins (TSI) is a relatively new method for assessing TSH-receptor antibodies. The aim of this study was to investigate the role of TSI in the management of GO. METHODS: Patients with newly diagnosed GD (n=30, median age 55 years (range 35-72), 29 women) received pharmacological therapy (methimazole+++thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. Eleven patients had GO at diagnosis, and another six developed GO during treatment. Blood samples for TSI and other thyroidal biomarkers were obtained at baseline and on five occasions during the 24-month follow-up. Twenty-two subjects completed the drug regimen without surgery or radioiodine treatment. RESULTS: At baseline, TSI was highly correlated with TRAb (r s =0.64, p<0.001), and both assays similarly correlated to fT3 values. TSI and TRAb did not differ significantly between GO and non-GO patients for visit v1 (n=30, 17 GO during the whole study) or at follow-up (n=22, 12 GO during the whole study). During follow-up, levels of TSI and TRAb decreased and normalized in both groups. CONCLUSION: The present study does not support any added benefit of TSI compared to TRAb for the prediction and management of GO.

Prevalence of Nelson's syndrome after bilateral adrenalectomy in patients with cushing's disease: a systematic review and meta-analysis.

PURPOSE: Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson's syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. DATA SOURCES: Systematic literature search in four databases. STUDY SELECTION: Observational studies reporting the prevalence of NS after BA in adult patients with CD. DATA EXTRACTION: Data extraction and risk of bias assessment were performed by three independent investigators. DATA SYNTHESIS: Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22-31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27-50%). The prevalence of treatment for NS was 21% (95% CI 18-26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5-1.6)] or pituitary surgery [0.6 (95% CI 0.4-1.0)]. CONCLUSIONS: Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone.

CONTEXT: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism. OBJECTIVE: This work aimed to study cortisol metabolism during DR-HC and TID-HC. DESIGN: A randomized, 12-week, crossover study was conducted. INTERVENTION AND PARTICIPANTS: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls. MAIN OUTCOME MEASURES: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections. RESULTS: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11ß-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5ß-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5ß-reductase activity. CONCLUSIONS: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11ß-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.

Temporal relationship of sleep apnea and acromegaly: a nationwide study.

PURPOSE: Patients with acromegaly have an increased risk of sleep apnea, but reported prevalence rates vary largely. Here we aimed to evaluate the sleep apnea prevalence in a large national cohort of patients with acromegaly, to examine possible risk factors, and to assess the proportion of patients diagnosed with sleep apnea prior to acromegaly diagnosis. METHODS: Cross-sectional multicenter study of 259 Swedish patients with acromegaly. At patients' follow-up visits at the endocrine outpatient clinics of all seven university hospitals in Sweden, questionnaires were completed to assess previous sleep apnea diagnosis and treatment, cardiovascular diseases, smoking habits, anthropometric data, and S-IGF-1 levels. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale. Patients suspected to have undiagnosed sleep apnea were referred for sleep apnea investigations. RESULTS: Of the 259 participants, 75 (29%) were diagnosed with sleep apnea before the study start. In 43 (57%) of these patients, sleep apnea had been diagnosed before the diagnosis of acromegaly. After clinical assessment and sleep studies, sleep apnea was diagnosed in an additional 20 patients, yielding a total sleep apnea prevalence of 37%. Higher sleep apnea risk was associated with higher BMI, waist circumference, and index finger circumference. Sleep apnea was more frequent among patients with S-IGF-1 levels in the highest quartile. CONCLUSION: Sleep apnea is common among patients with acromegaly, and is often diagnosed prior to their acromegaly diagnosis. These results support early screening for sleep apnea in patients with acromegaly and awareness for acromegaly in patients with sleep apnea.

Histopathological classification of non-functioning pituitary neuroendocrine tumors.

Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify "high-risk adenomas." A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification.

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

OBJECTIVE: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). CONCLUSIONS: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?

OBJECTIVE: The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia. DESIGN: We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms. RESULTS: Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements. CONCLUSION: These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

Somatotropic and thyroid hormones in the acute phase of subarachnoid haemorrhage.

BACKGROUND: Somatotropic and thyroid hormones are probably important for the recovery after acute brain injury. Still, the dynamics of these hormones after spontaneous subarachnoid haemorrhage (SAH) is not well described. The purpose of this study was to investigate the relation between somatotropic and thyroid hormones and clinical factors after SAH. METHODS: Twenty patients with spontaneous SAH were included prospectively. Serum concentrations of TSH, fT4, T3, IGF-1 and GH were measured once a day for 7 days after SAH. Hormone patterns and serum concentrations were compared to the severity of SAH, neurological condition at admission, clinical course and outcome of the patients. RESULTS: During the first week after SAH, all patients showed increased GH and IGF-1 concentrations. In the whole group, concentrations of TSH increased, whereas T3 and fT4 decreased. There were no relations of serum concentrations of IGF-1 or GH to clinical condition at admission, clinical course or outcome of the patients. Half of the patients showed low T3 serum concentrations. A complicated course was associated with a deeper fall in TSH and T3 concentrations. There were negative correlations for mean concentrations of TSH and T3 versus WFNS grade and a positive correlation for T3 versus GOS after 6 months, indicating that low concentrations of TSH and T3 were connected to worse SAH grade and poor outcome. CONCLUSIONS: All patients showed increased GH and IGF-1 concentrations irrespective of the grade of SAH or clinical course. Patients with a complicated clinical course showed a more pronounced fall in TSH and T3 concentrations and low serum T3 concentrations were related to a more serious SAH and poor patient outcome. These results need to be studied further and they may contribute to the accumulated knowledge needed to understand the complex mechanisms influencing the unpredictable clinical course after SAH.

Gastric bypass surgery elevates NT-ProBNP levels.

BACKGROUND: Brain natriuretic peptide (BNP) is produced in the heart in response to stretching of the myocardium. BNP levels are negatively correlated to obesity, and in obese subjects, a reduced BNP responsiveness has been described. Diet-induced weight loss has been found to lower or to have no effect on BNP levels, whereas gastric banding and gastric bypass have reported divergent results. We studied obese patients undergoing gastric bypass (GBP) surgery during follow-up of 1 year. METHODS: Twenty patients, 18 women, mean 41 (SD 9.5) years old, with a mean preoperative BMI of 44.6 (SD 5.5) kg/m(2) were examined. N-terminal pro-brain natriuretic peptide (NT-ProBNP), glucose and insulin were measured preoperatively, at day 6 and months 1, 6 and 12. In 14 of the patients, samples were also taken at days 1, 2 and 4. RESULTS: The NT-ProBNP levels showed a marked increase during the postoperative week (from 54 pg/mL preop to 359 pg/mL on day 2 and fell to 155 on day 6). At 1 year, NT-ProBNP was 122 pg/mL (125 % increase, p = 0.01). Glucose, insulin and HOMA indices decreased shortly after surgery without correlation to NT-ProBNP change. Mean BMI was reduced from 44.6 to 30.5 kg/m(2) at 1 year and was not related to NT-ProBNP change. CONCLUSIONS: The data indicate that GBP surgery rapidly alters the tone of BNP release, by a mechanism not related to weight loss or to changes in glucometabolic parameters. The GBP-induced conversion of obese subjects, from low to high NT-ProBNP responders, is likely to influence the evaluation of cardiac function in GBP operated individuals.

National incidence and prevalence of TSH-secreting pituitary adenomas in Sweden.

CONTEXT: TSH-secreting pituitary adenomas (TSHomas) are rare. Epidemiological data are scant and there are no reports on national incidence. OBJECTIVE: The objective of the study was to estimate the national Swedish incidence and prevalence of TSHomas. DESIGN: This was an observational study. SETTING: The study was conducted at tertiary referral centers. PATIENTS: The Swedish Pituitary Registry and World Health Organization International Statistical Classification of Diseases and Related Health Problems coding at all university hospitals were used to identify patients diagnosed with TSHomas 1990-2010. The identified patients' medical records were studied until the latest follow-up [median 5.0 years (range < 1-20 years)]. MAIN OUTCOME MEASUREMENTS: Incidence, prevalence, demographics, tumor characteristics, treatment outcome, and thyroid hormone level at diagnosis were measured. RESULTS: The age-standardized national incidence of 28 TSHoma patients was 0.15 per 1 million inhabitants per year, with an increasing incidence over time (0.05 per 1 million per year in 1990-1994 to 0.26 per 1 million per year in 2005-2009). The national prevalence in 2010 was 2.8 per 1 million inhabitants, in which 0.85 per 1 million had active disease. Most patients (n = 22) underwent pituitary surgery, 5 had radiotherapy, and 6 had somatostatin analogues. Eighteen patients were considered cured at the latest follow-up; 25% remained uncontrolled. Subjects treated for putative primary hyperthyroidism prior to diagnosis had TSH levels more than double those with intact thyroid at diagnosis (P = .013). The median time to diagnosis was longer for women than men (4 vs < 1 year, P = .026). More women than men were treated surgically (94.1% vs 54.5%, P = .022). CONCLUSION: This is the first estimate of a national incidence of TSHoma. Additional epidemiological studies are needed to compare these results with other geographical areas. This study suggests an increased incidence of TSHomas, in agreement with reports on other pituitary adenomas.

Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy.

CONTEXT: The psychosocial health and working capacity in hypopituitary patients receiving long-term growth hormone (GH) therapy are unknown. OBJECTIVE: Psychosocial health and levels of employment were compared between GH deficient (GHD) patients on long-term replacement and the general population. DESIGN AND PARTICIPANTS: In a Swedish nationwide study, 851 GHD patients [101 childhood onset (CO) and 750 adult onset (AO)] and 2622 population controls answered a questionnaire regarding current living, employment and educational level, alcohol consumption and smoking habits. The median time on GH therapy for both men and women with CO GHD was 9 years and for AO GHD 6 years, respectively. RESULTS: As compared to the controls, the GHD patients were less often working full time, more often on sick leave/disability pension, and to a larger extent alcohol abstainers and never smokers (all; P<0.05). Predominantly CO GHD women and men, but to some extent also AO GHD women and men, lived less frequently with a partner and more often with their parents. Particularly AO GHD craniopharyngioma women used more antidepressants, while AO GHD men with a craniopharyngioma used more analgesics. CONCLUSIONS: A working capacity to the level of the general population was not achieved among hypopituitary patients, although receiving long-term GH therapy. Patients were less likely to use alcohol and tobacco. The CO GHD population lived a less independent life.

Cortisol and adrenocorticotropic hormone dynamics in the acute phase of subarachnoid haemorrhage.

OBJECTIVE: An adequate response of hypothalamic-pituitary-adrenal (HPA) axis is important for survival and recovery after a severe disease. The hypothalamus and the pituitary glands are at risk of damage after subarachnoid haemorrhage (SAH). A better understanding of the hormonal changes would be valuable for optimising care in the acute phase of SAH. PATIENTS: Fifty-five patients with spontaneous SAH were evaluated regarding morning concentrations of serum (S)-cortisol and P-adrenocorticotropic hormone (ACTH) 7 days after the bleeding. In a subgroup of 20 patients, the diurnal changes of S-cortisol and P-ACTH were studied and urine (U)-cortisol was measured. The relationships of hormone concentrations to clinical and radiological parameters and to outcome were assessed. RESULTS: S-cortisol and P-ACTH were elevated the day of SAH. S-cortisol concentrations below reference range were uncommon. Early global cerebral oedema was associated with higher S-cortisol concentrations at admission and a worse World Federation of Neurological Surgeons (WFNS) and Reaction Level Scale 85 grade. Global cerebral oedema was shown to be a predictor of S-cortisol at admittance. Patients in better WFNS grade displayed higher U-cortisol. All patients showed diurnal variations of S-cortisol and P-ACTH. A reversed diurnal variation of S-cortisol was more frequently found in mechanically ventilated patients. Periods of suppressed P-ACTH associated with S-cortisol peaks occurred especially in periods of secondary brain ischaemia. CONCLUSION: There was an HPA response acutely after SAH with an increase in P-ACTH and S-cortisol. Higher U-cortisol in patients in a better clinical grade may indicate a more robust response of the HPA system. Global cerebral oedema was associated with higher S-cortisol at admission and was a predictor of S-cortisol concentrations. Global cerebral oedema may be the result of the stress response initiated by the brain injury. Periods of suppressed P-ACTH occurred particularly in periods of brain ischaemia, indicating a possible connection between brain ischaemia and ACTH suppression.

Fracture incidence in GH-deficient patients on complete hormone replacement including GH.

UNLABELLED: Fracture risk in GHD patients is not definitely established. Studying fracture incidence in 832 patients on GH therapy and 2581 matched population controls, we recorded a doubled fracture risk in CO GHD women, but a significantly lower fracture risk in AO GHD men. INTRODUCTION: The objective of this study was to evaluate fracture incidence in patients with confirmed growth hormone deficiency (GHD) on replacement therapy (including growth hormone [GH]) compared with population controls, while also taking potential confounders and effect modifiers into account. MATERIALS AND METHODS: Eight hundred thirty-two patients with GHD and 2581 matched population controls answered a questionnaire about fractures and other background information. Incidence rate ratio (IRR) and 95% CI for first fracture were estimated. The median time on GH therapy for childhood onset (CO) GHD men and women was 15 and 12 yr, respectively, and 6 and 5 yr for adult onset (AO) GHD men and women, respectively. RESULTS: A more than doubled risk (IRR, 2.29; 95% CI, 1.23-4.28) for nonosteoporotic fractures was recorded in women with CO GHD, whereas no risk increase was observed among CO GHD men (IRR, 0.61) and AO GHD women (IRR, 1.08). A significantly decreased incidence of fractures (IRR, 0.54; 95% CI, 0.34-0.86) was recorded in AO GHD men. CONCLUSIONS: Increased fracture risk in CO GHD women can most likely be explained by interaction between oral estrogen and the GH-IGF-I axis. The adequate substitution rate of testosterone (90%) and GH (94%) may have resulted in significantly lower fracture risk in AO GHD men.

Early changes in ghrelin following Roux-en-Y gastric bypass: influence of vagal nerve functionality?

BACKGROUND: Roux-en-Y gastric bypass (RYGBP) effectively produces massive weight reduction, improving health in morbidly obese patients. The mechanisms for the weight loss, and the fate of the excluded gastric mucosa, are not fully clarified. To what extent the appetite-stimulating gastric peptide ghrelin is affected remains controversial. METHODS: Circulating concentrations of ghrelin, pancreatic polypeptide (PP), pepsinogen I (PGI) and gastrin were examined in 15 morbidly obese patients (median BMI 45 kg/m2) preoperatively, and on days 1, 2, 4, 6 and at months 1, 6 and 12 after RYGBP. RESULTS: Ghrelin levels fell on postoperative day 1 and increased after 1 month to preoperative levels, and rose further at 6 and 12 months. PP concentrations decreased on day 1 and subsequently returned to preoperative levels. PGI levels peaked transiently the first days after surgery and subsequently declined to lower than preoperative levels. Gastrin levels were gradually reduced postoperatively. CONCLUSION: Ghrelin and PP fall transiently after surgery, possibly due to vagal dysfunction, and ultimately, as weight loss ensues, ghrelin secretion increases to higher than preoperative levels. The RYBGP procedure affects the gastric mucosa, as reflected by a transient increase in circulating PGI, and subsequently, the mucosa in the excluded stomach is at rest, as shown by low levels of PGI and gastrin.

Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans.

Presently surgery is the most effective way to obtain a controlled weight reduction in morbidly obese patients. Roux-en-Y gastric bypass (RYGBP) surgery is effective and used worldwide, but the exact mechanism of action is unknown. The effect of RYGBP on ghrelin, insulin, adiponectin, and leptin levels was investigated in 66 obese subjects; mean weight 127 kg (range, 96-195 kg) and mean body mass index (BMI) 45 kg/m(2) (range, 33-64) before and after surgery. Ghrelin levels were also compared in 10 nonoperated and 10 operated obese, BMI-matched women. RYGBP resulted in 22% and 30% weight loss at 6 and 12 months, respectively. Ghrelin increased by 44% and 62% and adiponectin by 36% and 98%, but insulin declined by 57% and 62% and leptin by 60% and 64%. The changes were all related to the reduction in BMI. In addition, ghrelin and insulin were inversely correlated at all time points as were changes of the peptides at 12 months (F = 4.9, P = 0.031), independent of the change in BMI. No evidence for RYGBP surgery per se having an effect on ghrelin levels, independent of weight loss, was obtained. The profound changes in the regulatory peptides are likely to reflect the new state of energy balance achieved. A close inverse association between ghrelin and insulin was observed, supporting an important role for ghrelin in glucose homeostasis.

Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial.

Thirty-eight women, aged 25-65 yr, with androgen deficiency due to hypopituitarism were treated with oral dehydroepiandrosterone (DHEA; 30 mg/d if <45 yr of age and 20 mg if > or =45 yr of age) for 6 months in a randomized, placebo-controlled, double blind study, followed by a 6-month open treatment period. The administration of DHEA raised the serum levels of DHEAS to normal age-related reference ranges and increased androstenedione and T to subnormal levels. Androgen effects on skin and/or pubic and/or axillary hair were observed in 84% (32 of 38) of the women after all received 6 months of DHEA treatment. No such effects were observed after the placebo treatment. These effects after 6 months were correlated with the serum levels of DHEAS (r = 0.37; P = 0.03), androstenedione (r = 0.42; P = 0.01), and T (r = 0.37; P = 0.03). The percentages of partners who reported improved alertness, stamina, and initiative by their spouses were 70%, 64%, and 55%, respectively, in the DHEA group and 11%, 6%, and 11%, respectively, in the placebo group (P < 0.05). According to the partners, sexual relations tended to improve compared with placebo (P = 0.06). After 6 months of treatment, increased sexual interest or activity was reported by 50% of the women taking 30 mg DHEA, by none taking 20 mg DHEA, and by two women taking placebo (P = NS). Compared with levels after placebo administration, high density lipoprotein cholesterol and apolipoprotein A-1 levels decreased after DHEA. Serum concentrations of IGF-I, serum markers of bone metabolism, and bone density did not change. In conclusion, oral administration of a low dose of DHEA to adult hypopituitary women induced androgen effects on skin and axillary and pubic hair as well as changes in behavior, with only minor effects on metabolism.