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Background: Some gender-related differences have been reported in multiple endocrine neoplasia type 1 (MEN1), although not all reports are conclusive. This systematic review with analysis of the own MEN1 cohort evaluates gender differences and potential consequences for screening. Methods: A systematic review of the literature between 1990 and 2019 with the search terms “MEN1” or “multiple endocrine neoplasia type 1” and “gender” or “sex” was performed. In addition, the prospectively collected data of a genetically confirmed MEN1 cohort of the Philipps University Marburg were retrospectively analyzed. Results: Review of the literature identified five retrospective case series with original data of 1,057 MEN1 patients. One series suggested a higher frequency of pancreatic neuroendocrine neoplasms (NEN), especially gastrinomas, in men (61 vs. 54%) and a higher frequency of pituitary tumors in women (47 vs. 30%), but others did not. Only thymic NEN occurred predominantly in men throughout all studies. Women with MEN1 were found to have an increased risk of breast cancer. In the own series consisting of 116 MEN1 patients (male = 58, female = 58), thymic lesions were also more frequently detected in male patients (male = 5, female = 1). No gender difference was found with regard to the other manifestations. Conclusion: Regarding the typical MEN1 tumor manifestations, gender-adapted diagnostic and therapeutic approaches cannot be recommended. Female MEN1 patients should be encouraged to participate in breast cancer screening programs.

Objectives Pancreatic neuroendocrine neoplasias (pNENs) frequently occur in multiple endocrine neoplasia type 1 (MEN1). Their distribution referring to embryology, that is, the pancreatic anlagen, has not been investigated yet. Methods In the time between 1998 and 2019, we studied the distribution of pNENs in MEN1 concerning the embryologic origin of the pancreas, that is, the dorsal versus ventral anlage using endoscopic ultrasound in 117 MEN1 patients: 56 women, 61 men; aged 40 years (standard deviation, 14 years) at first endoscopic ultrasound. Results In 105 patients, a total of 628 pNENs were detected. They were located in the pancreatic tail: 231; pancreatic body: 177; pancreatic head/uncinate process: 220. Of the latter, 22 were located in the ventral anlage, 176 in the dorsal anlage, and 22 remained undefined. In summary, just 3.5% of all detected pNENs were located in the ventral anlage, 93.0% in the dorsal anlage, and 3.5% could not be assigned. Conclusions Our study indicates that the vast majority of pNENs in MEN1 is located in the dorsal anlage, whereas the ventral anlage of the pancreas seems to be to a large extend spared from pNENs. Implications for new surgical strategies might be considered.

Purpose It is assumed that primary hyperparathyroidism (pHPT) in Multiple Endocrine Neoplasia (MEN) and lithium-associated pHPT (LIHPT) are associated with multiple gland disease (MGD), persistence and recurrence. The studies purpose was to determine frequencies, clinical presentation and outcome of sporadic pHPT (spHPT), LIHPT and pHPT in MEN. Additional main outcome measures were the rates of MGD and persistence/recurrence. Methods Retrospective analysis of medical records of 682 patients with pHPT who had attended the University Hospital of Marburg between 01–01–2004 and 30–06–2013. All patients were sent a questionnaire asking about their history of lithium medication. Results Out of 682 patients, 557 underwent primary surgery (532 spHPT, 5 LIHPT, 20 MEN), 38 redo-surgery (31 spHPT, 7 MEN), 55 were in follow-up due to previous surgery (16 spHPT, 1 LIHPT, 38 MEN) and 37 were not operated (33 spHPT, 1 LIHPT, 3 MEN). Primary surgeries were successful in 97.4%, revealed singular adenomas in 92.4%, double adenomas in 2.9% and MGD in 3.4% of the cases. Rates of MGD in MEN1 (82.35%) were significantly higher than in spHPT (3.8%), while there was no significant difference between LIHPT (20%) and spHPT. Rates of persistence/recurrence did not significantly differ due to type of surgery (bilateral/unilateral) or type of HPT (spHPT/LIHPT/MEN). Conclusions History of lithium medication is rare among pHPT patients. While MGD is common in MEN1, rates of MGD, persistence or recurrence in LIHPT were not significantly higher than in spHPT.

IntroductionDiagnosis and pathological classification of insulinomas are challenging.AimTo characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma.MethodsPatients with surgically resected sporadic insulinoma were included.ResultsEighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a.ConclusionLocalization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.

Obstructive sleep apnea (OSA), independently of obesity (OBS), predisposes to insulin resistance (IR) for largely unknown reasons. Because OSA-related intermittent hypoxia triggers lipolysis, overnight increases in circulating free fatty acids (FFAs) including palmitic acid (PA) may lead to ectopic intramuscular lipid accumulation potentially contributing to IR. Using 3-T-1H-magnetic resonance spectroscopy, we therefore compared intramyocellular and extramyocellular lipid (IMCL and EMCL) in the vastus lateralis muscle at approximately 7 am between 26 male patients with moderate-to-severe OSA (17 obese, 9 nonobese) and 23 healthy male controls (12 obese, 11 nonobese). Fiber type composition was evaluated by muscle biopsies. Moreover, we measured fasted FFAs including PA, glycated hemoglobin A1c, thigh subcutaneous fat volume (ScFAT, 1.5-T magnetic resonance tomography), and maximal oxygen uptake (VO2max). Fourteen patients were reassessed after continuous positive airway pressure (CPAP) therapy. Total FFAs and PA were significantly (by 178% and 166%) higher in OSA patients vs controls and correlated with the apnea-hypopnea index (AHI) (r ≥ 0.45, P

Background Although diabetes is a common complication of acromegaly or Cushing´s disease, there are only few detailed studies with a focus on cardiovascular risk, metabolic control or diabetes therapy. Here, we provide a comprehensive characterization from the longitudinal DPV (Diabetes Patienten Verlaufsdokumentation) registry. Methods Patients from the registry≥18 years of age with diabetes and acromegaly or Cushing´s disease were compared to patients with type 1 diabetes or type 2 diabetes using the statistical software SAS 9.4. Results Patients with diabetes and acromegaly (n=52) or Cushing’s disease (n=15) were significantly younger at diabetes onset (median age 50.1 and 45.0 vs. 59.0 years in type 2 diabetes; both p Conclusion Patients with acromegaly are at a high risk for cardiovascular disease, reflected by dyslipidemia and hypertension. A high proportion of patients with diabetes in acromegaly or Cushing´s disease receives insulin. Based on a multicenter register, a sufficient number of patients with rare forms of diabetes can be analyzed.

Premenopausal women receiving chemotherapy or endocrine treatment for early breast cancer are at increased risk for cancer treatment induced bone loss (CTIBL). The aim of the randomized, double-blind ProBONE II trial was to investigate whether a 2-year adjuvant treatment with 4 mg intravenous zoledronic acid (ZOL) every 3 months versus placebo would prevent CTIBL after a five-year period.Thirty-one of the 34 participants in the ZOL arm and thirty-four of the 36 participants in the placebo arm were followed-up to the 5-year visit and completed the study as planned. The changes in Bone Mass Density (BMD) were assessed at baseline and each visit after treatment initiation.After 24 months, BMD at the lumbar spine showed a 2.9% increase in patients treated with ZOL vs. a 7.1% decrease in placebo-treated participants compared to baseline (p 0.001). Over the 60-month study period, we found a decrease of 2.2% vs. 7.3% in the BMD at the lumbar spine in patients receiving ZOL and placebo respectively (p 0.001). Over the 60-month study period, BMD in the placebo arm showed a continuous decrease at all sites (p 0001), whereas patients treated with ZOL reached baseline BMD-values at the femoral neck and total hip.In ProBone II, a 2-year treatment with ZOL 4 mg intravenous every 3 months prevented cancer treatment induced bone loss in premenopausal women with breast cancer and maintained the BMD up to 3 years post-treatment.

Aim: Pancreatic neuroendocrine tumors (pNETs) can occur in patients with a familial syndrome either as multiple endocrine neoplasia type 1 (MEN-1) or as sporadic tumors. Endoscopic ultrasound (EUS) has become one of the first-line investigations for pNET characterization. The ultrasonographic features of pNETs may differ depending on the familial versus sporadic pathogenesis of the tumor. Therefore, the EUS findings could help and direct the definition of a pNET with an impact on the most appropriate diagnostic and therapeutic patient management. Methods: In this single-center retrospective study, we reviewed the EUS features of 94 pNETs from 37 MEN-1 patients and 15 pNETs from 11 sporadic disease patients at the time of their first EUS assessment. We analyzed the most relevant morphological and ultrasonographic characteristics of the tumors and compared the findings between the 2 patient groups. Results: Patients with MEN-1 more likely present with multiple pNETs than patients with sporadic disease. Sporadic pNETs are usually much bigger than those due to MEN-1. Moreover, pNETs are more heterogeneous in patients with sporadic disease than in those with MEN-1. No statistical difference with regard to definition of the margins, morphology, and vascularization of the pNETs appears between the 2 groups. Conclusions: Patients with sporadic disease usually present with bigger and more heterogeneous pNETs than patients with MEN-1, who tend to present with a higher number of lesions. EUS can facilitate the precise characterization of a pNET, and the ultrasonographic features of the lesion can help and distinguish MEN-1-related versus sporadic disease.

Little is known regarding the associations between sex-hormone levels, sex, body mass index (BMI), age, other host factors and biomaterial stimulated bone regeneration in the human craniofacial skeleton. The aim of this study was to elucidate the associations between these factors and bone formation after sinus floor augmentation procedures (SFA) utilizing a bioactive tricalcium phosphate (TCP) bone grafting material. We conducted a prospective study in a human population in which 60 male and 60 female participants underwent SFA and dental implant placement using a staged approach. BMI as well as levels of serum estradiol (E2), total testosterone (TT), and the free androgen index (FAI) were measured by radioimmunoassay and electrochemoluminescent-immunoassay. At implant placement, 6 months after SFA, bone biopsy specimens were harvested for hard tissue histology, the amount of bone formation was evaluated by histomorphometry and immunohistochemical analysis of osteogenic marker expression. The Wilcoxon rank-sum U test, Spearman correlations and linear regression analysis were used to explore the association between bone formation and BMI, hormonal and other host factors. BMI and log E2 were significantly positively associated with bone formation in male individuals (p

Use of electronic media is widespread among adolescents. Many male adolescents spend a major part of their evenings playing video games. The increased exposure to artificial light as well as the exciting nature of this pastime is under suspicion to impair sleep. Sleep is considered to be important for memory consolidation, so there is also a potential risk for memory impairment due to video gaming. As learning and gaining knowledge is a very important part of adolescence, we decided to study the effects of prolonged video gaming on sleep and memory. The study was structured in a repeated measures design. Eighteen male participants played either the violent video game “Counter Strike: Global Offensive” or the board game “Monopoly” for five hours each on two Saturday nights. The game evenings were followed by sleep studies. Memory testing and vigilance evaluation was performed the next morning. During the course of the study, saliva samples were taken to determine melatonin and cortisol levels. The results of this crossover study showed slightly reduced sleep efficiency after “Counter Strike: Global Offensive” (-3.5%, p = .017) and impaired declarative memory recall (p = .005) compared to “Monopoly”. Melatonin levels at bedtime were lower after “Counter Strike: Global Offensive” (p = .005), cortisol levels were elevated while playing the video game (p = .031). Negative effects on sleep were not strong but consistent with more wake after sleep onset (+12 min) and a higher arousal index after “Counter Strike: Global Offensive”. We conclude that excessive video gaming in the evening can contribute to worsened sleep and impaired memory in male adolescents.

This study was aimed to investigate the role and relevance of endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of insulinomas. We have analysed the frequency, clinical indications, success rate (obtaining diagnostic tissue), diagnostic accuracy (in comparison to the pathological diagnosis after surgery), complications, and tolerability of endoscopic ultrasound-guided fine-needle aspiration biopsy and the localization and size of the lesions in 47 consecutive patients (29 females, 18 males; 46 ± 15 years) who had surgery for insulinoma following fasting test and were explored by single investigator EUS 1994–2015. Endoscopic ultrasound-guided fine-needle aspiration biopsy was performed in 21 % (10/47) of the patients. The clinical indications for endoscopic ultrasound-guided fine-needle aspiration biopsy were non-conclusive result of fasting test (n = 7), missing toxicology (n = 2), suspected malignancy at EUS (n = 1), suspicious extra-pancreatic localization of the lesion (n = 1). The diagnostic success rate of the procedure was 80 % (8/10 cases), the diagnostic accuracy of the fine-needle aspiration biopsy 70 % (7/10 cases). The lesions undergoing endoscopic ultrasound-guided fine-needle aspiration biopsy were localized in the cauda (n = 5), corpus (n = 2), caput/processus uncinatus (n = 3), the diameter of the tumors was 21 ± 18 (10–70) mm. Only one accidental vascular puncture without any clinical complication occurred and all patients tolerated the procedure well. In the majority of cases, positive fasting test, negative toxicology, and detection of a typical pancreatic lesion at endoscopic ultrasound is sufficient for the diagnosis of insulinoma and the definition of the appropriate surgical strategy. Based on our data, we suggest including endoscopic ultrasound-guided fine-needle aspiration biopsy in the diagnostic work-up of organic hyperinsulinism in selected patients with inconclusive or uncertain diagnosis before surgery.

Background:Intact proinsulin is a biomarker for pancreatic ß-cell dysfunction. In large prospective studies in nondiabetic subjects, elevated intact proinsulin predicted development of type 2 diabetes and/or macrovascular events up to 7 years in advance. This study was performed to evaluate a new semiquantitative lateral flow-based point-of-care rapid test (POCT) for elevated intact proinsulin (cutoff: 15 pmol/L). The test requires 10 µL of capillary whole blood, with visual readout after 5 minutes. It is best applied at 2 hours after a glucose challenge or a meal.Methods:POCT results were obtained by health care professionals from 60 patients and healthy subject (33 female, 27 male, 28 type 2 diabetes, age: 53.6 ± 12.3 years). An additional venous blood sample was obtained from all participants for measurement of intact proinsulin by means of a quantitative ELISA reference method (TecoMedical, Sissach, Switzerland).Results:Elevated intact proinsulin levels (>15 pmol/L) were determined by the reference method in 26 participants, of whom 22 were also positive with the POCT (sensitivity: 85%). All 34 subjects with low intact proinsulin levels were tested negative by the POCT (specificity: 100%).Conclusions:The test successfully detected elevated postprandial intact proinsulin levels in 85% of the tested subjects and no false positive test result occurred. This POCT can therefore serve as a simple screening tool for identification of patients with prevalent ß-cell dysfunction, who are at high risk for development of type 2 diabetes and/or macrovascular events within the next 5-7 years.

Patients with osteoporosis have a low bone mass resulting in an increased risk for bone fractures, morbidity and mortality. One hundred thirty-one female pre-menopausal participants (98 Turkish immigrants living in Germany in comparison with 33 age-matched healthy Germans) were recruited for this study which explored vitamin D deficiency and specific genetic modifications of bone metabolism. The subjects were investigated for their femoral and lumbar bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) of the right total femur and the lumbar spine. Serum levels of osteologic parameters were determined: parathormone (PTH), calcium (Ca), osteocalcin (OC), phosphate (P), alkaline phosphatase (AP), beta-crossLaps (CL), tartrate-resistant acid phosphatase isoform 5b (TRAP5b), and 25-vitamin D3 (25-OH D3). The Bsml- and Fokl-polymorphisms of the vitamin D receptor (VDR) gene and the collagen type I alpha 1 (COLIA1)-gene polymorphism were also genotyped. An extremely high prevalence of vitamin D deficiency could be found in the immigrant cohort (87.8 %). Osteoporosis but not osteopenia was more prevalent in this group. Among immigrants with osteoporosis, TRAP5b was elevated in 42.9 % and beta-CL in 28.6 %. Only the Fokl FF-genotype of the VDR polymorphism was significantly more prevalent among the Turkish women, Ff-genotyped immigrants showed significantly decreased BMD. A significant correlation between the COLIA1-gene polymorphism and BMD could not be identified in the two groups. Vitamin D deficiency and osteoporosis appear to be dominant and unrecognized problem among female Turkish immigrants in Germany. Therefore, in this population, osteologic parameters and BMD should be routinely analyzed and deficiencies be treated immediately.

ObjectiveThere is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response.DesignThis was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database).MethodsWe included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses.ResultsIn a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815).ConclusionsA simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.

Background The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD. Methods The Growth hormone deficiency and Efficacy of Treatment (GET) score (0–100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD. Results Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145). Conclusions The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score. Trial registration NCT number: NCT00934063. Date of registration: 02 July 2009. Electronic supplementary material The online version of this article (10.1186/s12902-018-0237-3) contains supplementary material, which is available to authorized users.

Purpose Adrenal incidentaloma (AI) and adrenal masses in cases of subclinical Cushing’s syndrome (SCS) initially require follow-up imaging. In this study we used endoscopic ultrasound (EUS) as a method for high-resolution imaging. The aim was to evaluate the growth rate of AI and SCS by EUS. Materials and Methods This retrospective analysis included 93 out of 229 patients with AI or SCS who were investigated longitudinally by EUS in our university hospital between 1997 and 2013. The longitudinal follow-up required at least two investigations by EUS and evaluation of endocrine function. Plasma renin, serum aldosterone, 24 h urinary catecholamines and 2 mg dexamethasone suppression test were performed. EUS was performed at baseline and during follow-up. Each time, the maximum diameter was measured. Three groups were defined: non-functioning adenomas (NFA), non-functioning nodular hyperplasias (NFH) and SCS. Results 86 patients had non-functioning masses [NFM] (59 NFA, 48 NFH) and 7 patients had SCS (10 masses). At baseline the mean diameter was 19.4 (± 9.3) mm (NFM) and 19.6 (± 9.2) mm (SCS). The mean follow-up period was 31.6 ± 28.7 months. The estimated mean growth rates per year were low: They were 0.35 mm/yr [NFA], 0.02 mm/yr [NFH] and 0.53 mm/yr [SCS]. Furthermore, there was no malignant progression of any mass. Conclusion The growth rate as determined by EUS was low for all tumor entities observed in this study. There was no difference in tumor growth between the groups.

Reactive hypoglycemia caused by an insulinoma, pre-diabetic metabolic state, fluctuations in diabetic metabolic situation and antidiabetic medication is commonly known. We report on the case of an unusual multi-factorial occurrence of a woman with recurrent hypoglycemia, which cannot be explained adequately by a single commonly known cause. We refer to a cachectic non-diabetic 52-year-old German woman, admitted to our clinic for clarification of an insulinoma. The possibility of an insulinoma could be excluded as well as co-morbidities linked to non-diabetic hypoglycemia like sepsis, alcohol dependence liver disease, cancer or self-harm with hypoglycaemic agents. However, our diagnostics revealed a corticotrophic insufficiency as a result of longtime cortisol medication. Still, further causes have additionally to be considered, including dysfunctional elimination of glucose, renal and hepatic gluconeogenesis and glucose regulation on dialysis. These reasons are assumed as the pathological factors. Although insulinoma is a possible cause of hypoglycemia, it is not the only pathogenesis. Here, various alternatives factors are defined, examined and in part treated specifically. As therapy, besides nutritional counselling, the patient received cortisol. After a 20 month follow-up symptoms of symptomatic hypoglycemia were absent. Key words: Case report, hypoglycemia, chronic kidney disease, corticotrophic insufficiency, epileptic seizure.

We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003-2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH dose increased more in females than males during treatment; this was statistically significant in years 2-6 (p

Context: Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype. Objective: The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs. Design: This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center. Main Outcome Measures: Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured. Results: Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428–610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs. Conclusions: MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.

Endocrine therapy (ET) is a key treatment modality in hormone receptor positive (HR+) early breast cancer (BC) patients. Although the anticancer activity of adjuvant ET + zoledronic acid (ZOL) has been investigated, the potential effects of ET ± ZOL on endocrine hormones in premenopausal women with HR+ early BC are not well understood. ProBONE II was prospective, double-blind, randomized controlled trial. Premenopausal patients with histologically confirmed invasive BC with no evidence of metastases and a T score >−2.5 received ET ± ZOL 4 mg every 3 months for 2 years. Serum levels of estradiol (E2), follicle-stimulating hormone, anti-muellerian hormone (AMH), inhibins A and B, sex hormone-binding globulin, parathyroid hormone, total testosterone, and vitamin D were evaluated at baseline and at every scheduled visit. Of 71 women enrolled, 70 were evaluable (n = 34, ZOL; n = 36, placebo). No statistically significant differences were observed in hormone levels, except E2 and AMH, which showed minor differences. These included decreases in serum E2 levels, which reached a nadir after 3 and 9 months in placebo and ZOL groups, respectively, and decrease in serum AMH levels throughout the study with ZOL, but remained constant with placebo after 6 months. Adverse events in ZOL-treated group were influenza-like illness (32.4 %), bone pain (32.4 %), chills (20.6 %), and nausea (23.5 %). ET ± ZOL was well tolerated. This study showed no influence of ZOL on hormonal level changes that accompany ET, supporting inclusion of ZOL in adjuvant therapy for premenopausal women with HR + BC.

Background: Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD). Methods: We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients. Results: The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations. Conclusions: Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain–gut axis. © 2012 Movement Disorder Society

Summary We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation. Learning points Our patient presents an extraordinary course of disease. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors. This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

Haemochromatosis may impair the function of endocrine organs, amongst others the pituitary gland. It was the aim of this study to determine pituitary function in adult patients with genetically defined hereditary haemochromatosis in a prospective diagnostic study using a standardised stimulation test. Therefore, 22 patients (7 females, 15 males; age at diagnosis of haemochromatosis 48.1 ± 7.9 years; age at study inclusion 50.7 ± 7.7 years) with genetically defined hereditary haemochromatosis were investigated by a combined pituitary stimulation test (CRH, GHRH/arginine, GnRH, TRH). In 11 patients (50% of the study population; 2 females, 9 males), pituitary insufficiencies were detected [isolated corticotrophic insufficiency (peak cortisol181.25 μg/l/500 nmol/l) n=10 (2 females, 8 males); combined corticotrophic and borderline gonadotrophic insufficiency (basal testosterone 2.4-3.0 μg/l without basal LH-elevation) in 1 male]. Somatotrophic pituitary insufficiencies were not found. IFG-1 concentrations below -2 standard deviations in 7 patients (32%) may be attributed to impaired hepatic IGF-1 synthesis. Hypopituitarism, particularly corticotrophic insufficiency, seems to be prevalent in a considerable number of middle-aged patients with hereditary haemochromatosis. Despite normal somatotrophic function, low IGF-1 serum concentrations may be found in a subgroup of haemochromatosis patients.

Zusammenfassung Einleitung: In der hier beschriebenen ROSEStudie wurde die Behandlung mit Zoledronsäure 5 mg einmal pro Jahr mit der mit Alendronat 70 mg einmal wöchentlich im Hinblick auf den Knochenstoffwechsel und die Lebensqualität verglichen. Dieser Beitrag fasst die Ergebnisse zusammen, die in zwei separaten Manuskripten in Osteoporosis International veröffentlicht wurden. Methoden: Die offene, nationale, multizentrische, randomisierte, kontrollierte Einjahresstudie untersuchte die Wirkung von Zoledronsäure und Alendronat auf Serum-NTx als primärem und Serum-P1NP als sekundärem Zielparameter. Studienziel war die Reduktion von NTx bzw. P1NP nach einem Jahr. An 95 deutschen Zentren wurden ca. 600 bisphoshonatnaive Frauen (Alter: 55 bis 90 Jahre, T-Score ≤−2,0 an Hüfte oder Wirbelsäule) im Verhältnis 2 : 1 randomisiert. Die Basismedikation bestand aus 1200 mg Kalzium und 800 IE Vitamin D pro Tag. Veränderungen von Lebens-qualität (QoL) und Schmerzintensität wurden mittels QUALEFFO-41 und VAS ermittelt. Ergebnisse: Die Reduktion der NTx- und P1NP-Spiegel erfolgte in der Zoledronsäure- Gruppe schneller und stärker als in der Alendronat- Gruppe. Der Gesamt-Score QoL sowie die meisten Domänen des Qualeffo-41 tendierten zu einer größeren Verbesserung unter Zoledronsäure. Schlussfolgerung: Die intensivere Knochendynamik unter Zoledronsäure stellt einen Vorteil für Patientinnen dar, bei denen ein schneller Wirkeintritt wichtig erscheint. Neben der Verbesserung der Gesamt-Lebensqualität hat die Infusion mit Zoledronsäure das Potenzial, die Compliance zu verbessern.

Summary Objective There is growing evidence for an increased cardiovascular (CV) risk in untreated growth hormone deficiency of adults (GHD). We aimed at estimating CV risk with established algorithms before and during GH replacement in GHD and in healthy controls and at identifying predictors of risk reduction. Design A prospective, nested case-control study. Patients We included 344 patients (44AE 7±1 4AE9 years) from the German Pfizer (formerly Kabi) International Metabolic Database (KIMS) cohort and included a healthy sex- and age-matched control group from a primary care cohort. Measurements We calculated Framingham, Prospective Cardio

This study was made to evaluate long-term results of an aggressive surgical approach for pancreaticoduodenal neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1). MEN1 patients with either biochemical evidence of functioning or non-functioning pNENs larger than 1 cm in size on imaging underwent duodenopancreatic surgery. Since 1997, patients were followed annually by biochemical testing and imaging studies. Thirty-eight genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 22) or non-functioning (n = 16) pNENs, nine patients were yet not operated. Malignant disease occurred in 12 (35%) patients defined by either lymph node (12 patients) and/or distant metastases (2 patients). Six patients with Zollinger-Ellison syndrome (ZES) required pylorus-preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure and 32 patients underwent other duodenopancreatic resections. Ten (26%) patients underwent up to four reoperations for either recurrent or metastatic disease that resulted in completion pancreatectomy in four patients. After median 109 months, 44 patients were alive and three patients died, one due to thymic carcinoid and two of unrelated causes. All eight patients with organic hyperinsulinism and 7 of 13 patients with ZES were biochemically cured. However, 24 of 38 (78%) patients developed new pNENs in the pancreatic remnant, but none developed distant metastases. Early resection of pNENs in MEN1 may prevent the development of distant metastases. However, the majority of patients develop new pNENs in the duodenopancreatic remnant which may require completion pancreatectomy in the long term.

Bei organischen Erkrankungen der Hypophyse, die einen Wachstumshormonmangel verursachen, ist die Substitution mit Wachstumshormon eine sehr sinnvolle Masnahme. Eine gunstige Beeinflussung verschiedener wichtiger Zielparameter ist in hochwertigen Studien untersucht und belegt. Diese Therapie ist wissenschaftlich gut begrundet, eine entsprechende Zulassung durch die Zulassungsbehorde liegt vor. Andere sinnvolle Indikationen gibt es im Erwachsenenalter nicht.

The ROSE study compared a once-yearly intravenous dose of zoledronic acid with a once-weekly oral dose of alendronate in postmenopausal women. Once-yearly zoledronic acid showed a greater and faster reduction in the levels of two markers of bone turnover and may be an effective option for the treatment of osteoporosis.The open-label Rapid Onset and Sustained Efficacy (ROSE) study was designed to compare a once-yearly intravenous (iv) dose of zoledronic acid with a once-weekly oral dose of alendronate with respect to markers of bone turnover in approximately 600 postmenopausal women in Germany.Levels of N-telopeptide of collagen type I (NTx) and procollagen 1 C terminal extension peptide (P1NP) were assessed during the study. The primary objective was to assess if zoledronic acid was superior to alendronate in reducing serum NTx levels after 12 months' treatment.A significantly greater reduction in NTx levels from baseline to month 12 (as determined by the area under the curve) was observed in patients treated with zoledronic acid (n = 408) versus those receiving alendronate (n = 196; 0.282 ng/mL vs. 0.270 ng/mL; P = 0.012). The reduction in levels of P1NP after 1 year was also significantly greater in patients treated with zoledronic acid compared with those receiving alendronate (28.21 vs. 25.53 ng/mL; P = 0.0024). The overall incidence of adverse events was similar between groups; both treatments were generally well tolerated. Although post-dose symptoms, including the incidence of influenza-like symptoms, were higher with zoledronic acid than alendronate initially, the incidence was similar between groups from days 4-360. Gastrointestinal symptoms were more frequent with alendronate than zoledronic acid throughout the study.In this study, once-yearly iv zoledronic acid provided a greater and faster reduction in the levels of NTx and P1NP versus once-weekly oral alendronate.

Prolactinomas and hyperprolactinaemia cause hypogonadism and impairment of sexual and reproductive function. In this transcultural study, clinical characteristics of prolactinoma/hyperprolactinaemia were compared between a liberal, western, industrialised country and a more traditional, Islamic, oriental society.Sixty-two Syrian patients with hyperprolactinaemia were compared to 62 German patients with hyperprolactinaemia.In Syria and Germany, prolactinoma and hyperprolactinaemia were more frequent in females than in males (Syria 87% females; Germany 63% females). Prolactinomas were larger in males, males were older at diagnosis in both countries. Recorded clinical symptoms were comparable, even if culturally determined differences in spontaneous reporting of and asking for symptoms might be considered. The average age of the Syrian patients at diagnosis of hyperprolactinaemia was more than 6 years lower than in the German cohort (33.4 ± 10.4 vs. 39.7 ± 17.6 years). In Germany, a variety of therapeutic regimens were applied. In Syria, bromocriptine was prescribed exclusively.The differences may be attributed to culturally determined differences in sexual and reproductive behaviour, i.e. sexual intercourses of young, unmarried girls and women in association to the use of oral contraceptives regulating the menstrual cycle, maternal age at first delivery and birth frequency. Exclusive prescription of bromocriptine in Syria may be associated to limited resources and the safety of bromocriptine during pregnancy.

Cushing's syndrome is characterized by excessive elevation of glucocorticoid concentrations. In rare cases, the treatment of Cushing's syndrome may result in unmasking or aggravation of diseases responsive to glucocorticoid medication. We report two cases of sarcoidosis following Cushing's syndrome. A 43 year-old male developed cutaneous sarcoidosis and mediastinal lymphadenopathy after resection of an ACTH-secreting pituitary microadenoma. A 32 year-old female showed cutaneous sarcoidosis, arthralgia, mediastinal lymphadenopathy and elevation of angiotensin-converting enzyme and interleukin 2-receptor concentrations after traumatic adrenal bleeding, which ceased formerly undiagnosed hypercortisolism caused by an adrenal adenoma. Sarcoidosis seems to be a rare sequel following the treatment of hypercortisolism. Skin affections were present and suggestive for the diagnosis in all reported cases. As some cases are probably missed when skin affections are lacking, a more frequent evaluation of patients after Cushing's syndrome for the possible diagnosis of sarcoidosis might be necessary.

Aims: Contradictory reports exist regarding the influence of the exon 3 deleted (d3)/full-length (fl) growth hormone receptor (GHR) polymorphism on responsiveness to recombinant human growth-hormone therapy in idiopathic short stature, small for gestational age and GH-deficient children, Turner syndrome patients and GH-deficient adults. In some of these studies, the d3 allele was associated with increased responsiveness to GH. The aim of this study was to test this association in a group of GH-deficient adult patients receiving recombinant GH treatment. Materials & methods: Patients were derived from the prospective German Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. The GHRd3/fl polymorphism was determined in 133 German adult patients (66 men and 67 women; mean age: 45.4 years ± 13.1 standard deviation; majority Caucasian) with a GH-deficiency of different origin. Patients received GH treatment for 12 months with a finished dose-titration of GH and standardized insulin-like growth factor (IGF)-1 measurements in one central laboratory. GH dose after 1 year of treatment, IGF-1 serum concentrations, IGF-1 standard deviation score (SDS) values and anthropometric data were analyzed by GHRd3/fl genotypes. Results: After 1 year of GH treatment, the individually required GH dose was significantly lower in GH-deficient patients carrying one or two d3 alleles, compared with patients with the full-length receptor (p = 0.04). Genotype groups (d3-allele carriers vs noncarriers) showed no significant differences in IGF-1 serum concentrations (p = 0.51), IGF-1 SDS (p = 0.36) nor in gender (p = 0.53), age (p = 0.28), weight (p = 0.13), height (p = 0.53) or BMI (p = 0.15). Conclusion: The d3-allele carriers required approximately 25% less exogenous GH compared with the homozygous fl-allele carriers, which may express an increased responsiveness to exogenous GH. Variability of the individually required GH dose in adult GH-deficient patients may therefore be partly due to the GHRd3/fl polymorphism. Further studies are required to confirm these results.

The role of peripheral autonomic nerve failure in the development of medial arterial calcification is discussed controversially in the literature. In addition, the influence of medial wall calcification in the development of trophic foot lesions is still not fully understood. We have compared 28 diabetic patients with cardiac autonomic failure and/or decreased acetylcholine-induced sweat response with 22 diabetic patients without evidence of diabetic neuropathy and 27 healthy control subjects. A strong association was found between medial wall calcification and diminished heart rate variation (p.001) or diminished peripheral sweat response (p < 0.001). Only one subject in the control group exhibited a calcification of the tunica media in the lower limb. Medial calcinosis was accompanied by a significant rise of systolic ankle blood pressure (p < 0.05). In addition, there was a strong relationship between medial wall calcification and trophic foot lesions (p < 0.0001). Our results demonstrate a strong association between sympathetic C-fibre neuropathy and the development of medial wall calcification, as well as between calcification of the tunica media and trophic foot ulceration. Further investigation is necessary to determine whether there is a causal connection between medial arterial sclerosis and diabetic foot ulceration, or whether both are independent consequences of diabetic neuropathy.

Growth hormone stimulates collagen type I synthesis. Collagen type I is a common matrix compound in a large number of connective tissues. The aim of our study was to prove whether a stimulation of collagen type I synthesis might be accompanied by a deposition of collagen type I in the skin (cutis). Twenty growth hormone-deficient hypopituitary patients were included in a randomised, double-blind, placebo controlled, prospective, twelve-month study (eighteen patients assessable at the end of the study). The patients were treated with recombinant human growth hormone 0.25 U/kg/week subdivided in daily subcutaneous injections beginning with half the dosage during the first four weeks. During the first six months half of the patients were treated with placebo. PICP, the indicator of collagen type I synthesis, was increased after six months of therapy when compared to placebo. Skin thickness measured by ultrasound at the forearm and mechanically at the dorsum of the hand with strong compression of the skin both increased significantly following growth hormone substitution. Our data indicate that the stimulation of collagen type I synthesis by growth hormone substitution is followed by a deposition of collagen type I in the skin.

Transabdominal sonography of the adrenal glands frequently is non-successful. It was the aim of this project to improve the imaging of the adrenal glands using high resolution sonography in order to obtain information about even small changes in these organs. Therefore, endosonographic imaging was investigated using an endosonoscope PENTAX FG32UA. The correct identification of the adrenal glands was examined in five human cadavers. A total of 58 patients with 113 adrenal glands (in 3 cases history of unilateral adrenalectomy) were investigated. 109 adrenal glands (97%) were identified and evaluated. Healthy adrenal glands are slightly hyperechoich and regarding their echogeneity comparable to other endocrine organs such as the testes or the thyroid. Adrenal size can be determined as largest cross sectional area and was found to be 216 +/- 93 mm2 right and 231 +/- 98 mm2 left. In the adrenal glands which could be imaged by endosonography, all findings detected by CT (n = 33) or MRI (n = 19) could also be demonstrated endosonographically. Additional information as compared to CT/MRI was obtained in 7 out of 33 and in 6 out of 19 patients. This concerns in particular differentiation between tumor and hyperplasia and detection of small adrenal adenomas. High resolution endosonography of the adrenal glands can provide information about adrenal gland morphology which cannot be obtained by any other diagnostic approach.

Retinol binding protein 4 (RBP4) has recently been suggested as a good biomarker for insulin resistance and the metabolic syndrome. With this study, we wanted to investigate the effect of pioglitazone (PIO) and simvastatin (SIMVA) on insulin resistance and RBP4 plasma concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications. The prospective, parallel, randomized, double-blind clinical trial was performed with 125 nondiabetic patients with increased cardiovascular risk (78 females, 47 males, age (mean+/-STD): 58.6+/-7.8 years, BMI: 30.8+/-4.2 kg/m (2)). They were randomized to either receive PIO (45 mg)+placebo, SIMVA (40 mg)+placebo, or PIO+SIMVA for 3 months. Key outcome measures were the HOMA (IR)-Score, an oral glucose tolerance test, adiponectin, hsCRP, and RBP4 at baseline and endpoint. No correlation could be detected between the HOMA (IR) values or the impaired fasting glucose tolerance status and RBP-4. Treatment with PIO alone or in combination with SIMVA resulted in a significant improvement of the HOMA (IR)-Score and the adiponectin values, while no change in HOMA (IR) and a decrease in adiponectin (p

For the insertion of dental implants, mechanical bone properties at the implantation site have great impact both for therapeutic regimes as well as for the overall long-term success, making a reliable method for the preoperative assessment of the bone quality desirable. Ultrasound transmission velocity (UTV) has been introduced as a noninvasive method to analyze mechanical properties of bone. The aim of this study was the first intra-oral in vivo assessment of alveolar crest UTV values of edentulous jaws. Partly or fully edentulous patients ( n = 108) were enrolled in this study, taking into account possible influence factors that affect bone quality (osteoporosis, radiation therapy). Six intra-oral measurement points were used: left side region, right side region and frontal region, for upper and lower jaw, respectively. Ultrasound transmission velocity values were measured bicortically (in bucco-oral direction) and correlated to sex, age, measurement site and history of osteoporosis or radiation therapy. We found a minimum mouth opening of 30 mm, as well as a residual alveolar ridge height of 8 mm as thresholds for a reliable intra-oral placement of the device. Xerostomia was no contraindication. Assessment of intra-oral UTV showed significantly higher values both for mandibular side regions (female 1713 ± 153 m/s, male 1734 ± 221 m/s) and the maxillary frontal region (female 1665 ± 189 m/s, male 1648 ± 82 m/s) than for maxillary side regions (female 1538 ± 177 m/s, male 1583 ± 90 m/s). These data were even more clarified by intra-individual correlation of upper and lower jaw side region UTV values. We found no correlation between assessed UTV values and the variables sex, age, osteoporosis or radiation therapy. The use of a small UTV device in this study allowed the recording of intra-oral UTV values in a large and heterogeneous patient collective for the first time. Assessment of alveolar-ridge UTV might offer the possibility to identify critical bone quality before implantation or to monitor bone healing (mineralization) after augmentation procedures. (E-mail: klein@mkg.klinik.uni-mainz.de)

Background and Aims: Skin microvascular assessment has progressed to an important evaluation in patients with diabetes mellitus. This study was done to evaluate a new device using micro-lightguide spectrophotometry in the assessment of skin microvascular function. Material and Methods: Twenty nondiabetic subjects (age 46.6 ± 14.8 years; mean ± SD) and 20 diabetic patients (age 59.4 ± 8.4 years) participated in repeated microvascular measurements using micro-lightguide spectrophotometry. This technique allows simultaneous, noninvasive measurement of microvascular blood flow and hemoglobin oxygenation (SO 2) at the same anatomical area in different tissue layers. A skin probe was placed on nonhairy skin at the thenar eminence of the left hand for the measurement of SO2, and the postischemic reactive hyperemia response (PRH) was measured in skin and underlying muscle tissue. Results: Repeated measurements in PRH revealed a good correlation at the superficial skin layer ( r = 0.97, p < 0.0001) with a coefficient of variation at 9.2 ± 1.7% and at the superficial muscle layer ( r = 0.80, p < 0.0002) with a coefficient of variation at 9.7 ± 1.5%. A slightly weaker correlation was observed for the SO 2 measurement at the skin layer (r = 0.69 ± p < 0.0001) with a coefficient of variation at 17.5 ± 3.8% and at the muscle layer ( r = 0.48; p = 0.0016) with a coefficient of variation at 18.1 ± 10.5%. Conclusions: Lightguide spectrophotometry is an easy, noninvasive, and reliable method for simultaneous measurement of superficial microvascular blood flow by laser Doppler fluxmetry and skin oxygenation by spectrophotometry. Further studies are required to clarify the validity of these measures in special patient populations such as diabetes mellitus with specified microvascular complications.

Objective: Collagen type I is a common structural protein in bone and skin. Similar to its association with the mechanical properties of the skeleton and, thus, bone-fracture risk, the collagen type I α (COLIA)-1 specific protein (Sp)-1 polymorphism may be related to variations in the collagen type I-containing subcutaneous tissue and its biological properties. In this study, we analyzed a possible influence of the COLIA1 Sp1 polymorphism on the effect of subcutaneously injected recombinant human growth hormone (hGH) in GH-deficient adults. Materials & methods: We determined the COLIA1 Sp1 polymorphism in 122 adults with GH deficiency of different origin, who were derived from the prospective Pfizer International Growth Database (KIMS) Pharmacogenetics Study. Inclusion criteria were subcutaneous applied treatment with hGH for over 12 months, finished dose titration of hGH by following serum IGF-1 concentrations until desired levels were achieved, and centralized, standardized IGF-1 measurements. The genotypes (GG/GT/TT) were statistically related to clinical data from the KIMS database. Results: The dose of injected hGH was significantly related to the COLIA1 Sp1 genotypes (p = 0.049), whereby the GG homozygotes were treated with a significantly higher dose of hGH than TT homozygotes (p = 0.03). Accordingly, the IGF-1:GH ratios were significantly lower in GG compared with TT homozygotes (p = 0.04). Both groups showed no significant differences in their IGF-1 serum concentrations (p = 0.98) and IGF-1 SDS (p = 0.79). Conclusion: The COLIA1 Sp1 polymorphism is related to the dose of individually required, subcutaneous injected hGH in GH-deficient adults, probably because of an alteration of the subcutaneous collagen type I structure, content and/or biological/biomechanical properties. GG homozygotism, which is related to a more stable bone structure and decreased fracture risk, may impact skin resistance to subcutaneous injected protein-based drugs, as shown for hGH in this study.

UNLABELLED In contrast to the reliable imaging of the adrenal gland in infants and children, transabdominal sonography of the adrenal glands is often unsuccessful. AIM To improve the imaging of the adrenal glands with high resolution in order to obtain information on even small changes in these organs. METHOD Adrenal glands taken from human cadavers were investigated using a 7.5 MHz transducer. Thereafter, endosonographic imaging was investigated in 5 human cadavers using an endosonoscope PENTAX FG32 UA (longitudinal sector scanning. 7.5 MHz). Furthermore, the adrenal glands were imaged in a total of 30 patients with different indications for endosonography. RESULTS The adrenal glands in 5 human cadavers could be identified in each case. This was proved in one human cadaver by endosonographically guided fine needle puncture with consecutive preparation of the tissue damage caused by the needle. In a total of 30 patients with 56 adrenal glands (in 4 cases preview history of unilateral adrenalectomy), 55 adrenal glands were correctly identified and evaluated. The only exception was the left adrenal gland of a patient with Billroth-II-stomach, which was slightly pulled to the right and very small. Healthy adrenal glands are slightly hyperechoic as compared to the parenchyma of the kidney and have echogeneity comparable to other endocrinal organs such as the testicles or the thyroid. Endosonographic imaging of the adrenal glands is far superior in resolution and determination to transabdominal sonography. In 18 of 30 patients (60%) endosonography provided additional diagnostic information compared to conventional sonography. CONCLUSION Endosonography of the adrenal glands enables imaging of these organs with high resolution using a 7.5 MHz transducer from a distance of 1-2 cm.

BACKGROUND AND OBJECTIVE Diabetics with abnormal hypoglycaemia awareness cannot recognize hypoglycaemic symptoms early and adequately enough to respond, thus endangering in everyday life not only themselves but also others. Thus it is important to diagnose such symptoms early and assess the extent to which the diabetic is at risk of severe hypoglycaemia. This study was designed to contribute to the evaluation of hypoglycaemia awareness in type 1 (IDDM) diabetics. PATIENTS AND METHODS In 57 diabetics (IDDM) awareness of typical hypoglycaemic warning symptoms and of hormonal counterregulation were tested during controlled induced hypoglycaemia. A questionnaire was used to measure at fixed time intervals, along a four-point scale, the severity of 6 autonomic and 6 cerebral warning symptoms, and compare them with synchronously obtained plasma levels of glucagon and epinephrine. RESULTS The cohort was divided into three groups according to the rise of epinephrine levels induced by the hypoglycaemia. Group A (n = 22) showed a significant rise in epinephrine level at the onset of hypoglycaemia; group B (n = 22): significantly increased epinephrine only after 30 min of hypoglycaemia; group C (n = 15): no epinephrine rise at any time during hypoglycaemia. None of the patients had a significant rise in glucagon levels. There were significant differences between the three groups regarding HbA1c levels and the duration of diabetes. Low levels of HbA1c and duration of diabetes were commonly associated with a loss of hormonal counterregulation. In only 40% of patients was it possible to draw any conclusion about epinephrine-induced hypoglycaemia from symptoms revealed in the past history. CONCLUSIONS The past history of hypoglycaemic symptoms is an unreliable and inadequate guide for objectively assessing the actual risk of hypoglycaemia in type 1 diabetics. The results of this study indicate that when severe hypoglycaemic attacks (requiring outside help etc.) are suspected, standardized diagnostic tests of hypoglycaemia awareness should be performed in specialized centres, particularly if an official medical report ist required.

ObjectiveHypothalamic–pituitary insufficiency may have diverse causes. The aim of this study was to determine the incidence of hypothalamic–pituitary insufficiency in patients with previous infectious diseases of the central nervous system (CNS) of different etiologies and mild-to-moderate clinical course.DesignPatient series. Basal and stimulated (insulin tolerance test) pituitary function testing was performed in 19 patients with previous neuroborreliosis, encephalitis, or meningitis following an interval of between 10 and 56 months (mean 26.1±13.1 months) after the acute event.ResultsFour patients (21%; two males, two females) showed an isolated corticotropic insufficiency (peak cortisol ConclusionsHypothalamic–pituitary dysfunction and especially isolated corticotropic insufficiency may develop in a relevant proportion of patients after infectious diseases of the CNS.

Background: The management of incidentalomas with tumor size 3 cm and larger is still under controversial discussion. Study Design: Clinical charts of 65 patients who underwent adrenalectomy for an incidentaloma were reviewed. Results: Sixty-five patients were operated. There were 28 men and 37 women with a median age of 56.9 years. Median size of all resected lesions was 4.1 cm. Indications for surgery were tumor size equal and larger than 3 cm, recurrent pain, hormone status and patients’ fear of malignancy. In 45 patients, the adenomas did not meet the defined criteria of malignancy. There were 9 cases of adrenal hyperplasia, and two cysts and two hematomas were found in 4 patients. Moreover, 1 schwannoma and 1 myelolipoma were removed. In 3 patients, a primary adrenocortical carcinoma of 3.4, 4.0, and 5.0 cm in diameter, respectively, was identified. In 1 patient, an adrenal cortical carcinoma of 10.0 cm in diameter was operated. In 1 patient, the status (size: 4.5 cm) could not be determined conclusively. Conclusion: Hormonal activity should be determined independent of the size, and lesions with hormonal activity should be resected; in the presence of hormonally inactive masses, removal of tumors of 3 cm and larger in size is recommended.

Objective Genetic factors play an expanding role in understanding growth hormone (GH) disorders, therefore the German KIMS Pharmacogenetics Study was initiated with the aim of genotyping various GH-/IGF-I-axis-related genes of GH-deficient adult patients to investigate genotype:phenotype relationships and response to GH therapy. Patients and methods 129 consecutively enrolled GH-deficient adult patients were genotyped for variant 1 (V1) of the alternatively spliced noncoding exons in the 5′-untranslated region and for the nine coding exons of the GH receptor (GHR) gene, which obviously play a striking role in the function of the GH-IGF-I-axis. After detection of a heterozygous, non-synonymous mutation R179C in exon 6 in one single patient with acquired GH-deficiency (GHD) in late adulthood, analysis of her clinical data followed, leading to the diagnosis of mild short stature (−1.5 SD). For further endocrine evaluation, five pituitary stimulation tests (arginine) of this patient were statistically compared to stimulation tests (arginine) of ten GH-deficient control patients, retrospectively. Results The formerly in patients with Laron syndrome and idiopathic short stature reported mutation R179C leads to an amino acid change from an arginine residue (codon CGC) to a cysteine residue (codon TGC) in position 179 of the extracellular domain of the GHR. Statistical analysis revealed significant decreased IGF-I/GH 0 ratio ( p = 0.004) and IGF-I/GH max ratio ( p = 0.001) of the index patient compared to the control patients, implying growth hormone resistance of the index patient at the level of the GHR, according to the detected R179C mutation. Conclusions This study reports on the unusual case of a patient with mild short stature, who acquired GHD in late adulthood due to a non-secreting pituitary adenoma and get additionally diagnosed for pre-existing growth hormone insensitivity due to a formerly in two short statured patients described, single, heterozygous, non-synonymous mutation in the GHR. Our findings support the theory that heterozygous mutations in the GHR gene can have mild phenotypical consequences.

BACKGROUND In addition to its role in glucose metabolism, insulin has shown to exert numerous vascular effects, and an impaired vascular function of insulin is assumed to be a major contributor in the development of vascular complications. Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to investigate the effect of insulin on arterial stiffness and parameters of endothelial function in patients with type 1 diabetes and healthy control subjects. METHODS Fourteen patients with type 1 diabetes (six male, eight female) with a mean age of 36.6 +/- 11.8 years and 14 healthy subjects (seven male, seven female) with a mean age of 27.3 +/- 5.5 years were randomized to an euglygemic clamp with either a low (0.25 mU/kg/min) or a high (1.0 mU/kg/min) insulin dose on two different days. The mean HbA1c in the diabetic subjects was 7.3 +/- 0.7%. In these subjects, arterial stiffness was measured by pulse wave analysis (SphygmoCor, AtCor Medical, Australia). AP was calculated as the difference between the second and the first systolic shoulders of the central pressure wave curve, and the Aix was expressed as the percentage of AP from total pulse pressure. As parameters of endothelial function, cyclic guanosine monophosphate, nitrotyrosine, and asymmetric dimethylarginine were determined at baseline and after 120 minutes. RESULTS Patients with type 1 diabetes showed increased values for AP with 3.5 +/- 3.1 mm Hg and Aix with 12.5 +/- 12.5% compared to healthy controls with -0.7 +/- 2.6 mm Hg for AP and -4.2 +/- 10.6% for Aix. This difference was statistically significant (p < 0.01). During the euglycemic clamp, insulin improved, but did not normalize the increased values for AP and Aix in patients with type 1 diabetes. Concerning parameters of endothelial function, patients with type 1 diabetes showed statistically significant increased values for nitrotyrosine compared to healthy controls at baseline [low insulin: diabetes mellitus (DM) 1993.12 +/- 1330.85 nmol/liter vs healthy controls 803.7 +/- 726.91; high insulin DM: 2208.02 +/- 1736.57 nmol/liter vs healthy controls: 750.83 +/- 426.03 nmol/liter] (p < 0.05). CONCLUSION Patients with type 1 diabetes mellitus revealed an increased arterial stiffness measured as augmentation and augmentation index and increased nitrotyrosine levels as a marker of oxidative stress compared to healthy control subjects at baseline. Application of insulin improves the arterial elastic properties, but was not able to normalize the vascular function in patients with type 1 diabetes.