Standards of care for medical management of acromegaly in pituitary tumor centers of excellence (PTCOE).

PURPOSE: A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE). METHODS: Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options. RESULTS: Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively. CONCLUSIONS: Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.

Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

Serum Insulin-Like Growth Factor-1 (IGF-1) Age-Specific Reference Values for Healthy Adult Population of Serbia.

Context: Insulin-like growth factor-1 (IGF-1) is main serum surrogate marker of growth hormone (GH) secretion, used in diagnostics and treatment of GH deficiency (GHD) and acromegaly. Regional, ethnic, racial or nutritional factors obscure cross-population applicability of IGF-1 reference values. Establishment of population- and assay-specific reference values requires sizable representative cohort of healthy subjects. Subjects and Methods: In representative sample of healthy adult population of Serbia (N=1200, 21-80 years, 1:1 male:female) serum IGF-1 was analyzed by Siemens Immulite 2000 assay under uniform laboratory conditions. Upper and lower limit of reference range (5th - 95th percentile) were calculated for each of the 12 quinquennial age intervals. IGF-1 distribution was normalized and standard deviation score (SDS) calculated by Logarithmic and LMS methods. Results: IGF-1 and age correlated significantly, with most prominent decline at 21-50 years, followed by a plateau up to age of 70. Gender differences were not significant overall. Plateau in age-related IGF-1 decline was less prominent in women. Correlations of IGF-1 with body mass index (BMI) or waist to hip ratio (WHR) were insignificant. Superior IGF-1 SDS transformation was achieved with LMS method, while logarithmic method was simpler to use. Conclusions: Normative age-specific serum IGF-1 reference values were established on a representative cohort of healthy adults in Serbia. Our results support recommendations against necessity for gender-specific or BMI- and WHR-specific reference ranges. Population-based data serve to generate IGF-1 SDS, which is valuable in rational application of consensus guidelines, proper longitudinal follow-up, advancement in efficacy and safety and personalization of treatment targets.

Secondary hyperparathyroidism prevalence and prognostic role in elderly males with heart failure.

AIM: Evaluation of secondary hyperparathyroidism (SHPT) and its prognostic impact on all-cause mortality in elderly males with heart failure (HF). METHODS: Seventy three males (67 ± 7 years old) with systolic HF were included. Baseline PTH was measured. Patients were grouped according to PTH cut-off levels of 65 pg/ml (>65 pg/ml = SHPT vs. normal PTH). All-cause mortality was evaluated at 6-year follow-up. RESULTS: SHPT was diagnosed in 43 (59 %) patients. They were more severe compared to the patients with normal PTH regarding NYHA functional class (2.4 ± 0.5 vs. 2.1 ± 0.2, p = 0.001), quality of life score (34 ± 14 vs. 24 ± 12, p = 0.005), 6-min walking distance (378 ± 79 vs. 446 ± 73 m, p < 0.0001), left ventricular ejection fraction (27 ± 8 vs. 31 ± 7 %, p = 0.019), and NT-proBNP [2452 (3399) vs. 918 (1372) pg/ml, p < 0.0001]. No differences in age, vitamin D status, and renal function were noted between studied groups. A total of 41 (56 %) patients died within 6 years of follow-up. Kaplan-Meier survival analysis showed impaired long-term survival in patients with SHPT versus patients with normal PTH (p = 0.009). The rate of death was highest (75 %) in the group of patients with SHPT and NT-proBNP levels above median value (p = 0.003). Cox regression analysis demonstrated that NT-proBNP was the single independent predictor of all-cause mortality at 6-year follow-up [HR 3.698 (1.927-7.095), p < 0.0001]. CONCLUSION: SHPT was highly prevalent in elderly males with HF and was associated with impaired survival. HF patients with SHPT had more severe disease compared to the patients with normal serum PTH. Determination of serum PTH levels provided additional value to NT-proBNP for risk stratification in these patients.

First Report of Soybean Cyst Nematode (Heterodera glycines Ichinohe) on Soybean in the Province of Quebec, Canada.

In eastern Canada, soybean, Glycine max (L.) Merr., is the most important legume, and its cultivation is expanding to new regions as cultivars for the short growing season are developed. The soybean cyst nematode (SCN), Heterodera glycines Ichinohe, is among the most destructive pests of soybean in the world. This nematode is also under quarantine regulations in many countries, including Canada. Until now, in Canada, SCN was only reported in the province of Ontario. Since its first detection in 1988 in the southwestern part of the province (1), SCN has been found in 12 other counties. It appears that SCN has been spreading in a north and northeast direction along the St. Lawrence River. We report here the first detection of SCN in the province of Quebec. Second stage juveniles (J2) and cysts were found in St. Anicet, Quebec, Canada, in a 10-ha soybean field. Light textured soil is a characteristic of the field, the same site where Pratylenchus alleni was recently discovered (2) and where irregular patches of stunted soybean plants were observed. Morphological and molecular studies of J2 and cysts confirmed the identification of this nematode population as SCN. The J2 were typical for SCN with a body length of 393 to 428 µm, lateral fields harboring four straight lines, a well-developed stylet 23 to 25 µm long, sub-ventral base knobs with posterior slops, a tail length of 43 to 50 µm, and a hyaline part of 23 to 29 µm. Cysts were brown and lemon-shaped with a posterior protuberance, ambifenestrated, underbridged, and had a strongly developed bullae. Key morphometrics were: a cyst fenestra 40 to 57 µm long and 28 to 44 µm wide, and a vulval slit 39 to 53 µm long. All of these are coincident with those of SCN (3). Ribosomal DNA of the ITS, 18S, and D2/D3 regions, and mitochondrial COX1 gene were PCR amplified from cysts and J2s gDNA using primers ITS-F (5'-TTGATTACGTCCCTGCCCTTT-3') and ITS-R (5'-ACGAGCCGAGTGATCCACCG-3'); 18S-F (5'-TTGGATAACTGTGGTTTAACTAG-3') and 18S-R (5'-ATTTCACCTCTCACGCAACA-3'); D2A (5'-ACAAGTACCGTGAGGGAAAGT-3') and D3B (5'-GACCCGTCTTGAAACACGGA-3'); and COXI-F (5'-CCTACTATGATTGGTGGTTTTGGTAATTG-3') and COX1-R (5'-GTAGCAGCAGTAAAATAAGCACG-3'), respectively, and sequenced. The nucleotide sequences were 98 to 100% similar to those of SCN found in NCBI nr database (July 2013). All the sequences have been submitted to GenBank with the following accession numbers: ITS (KF453621); 18S (KF453622); D2/D3 (KF453623); and COX1 (KF453624). Using species specific sequence characterized amplified region (SCAR) primers (4) also confirmed this was H. glycines. This is the first reported case of SCN in Quebec, Canada. The proximity of St. Anicet to the Ontario border is in accordance with the North/Northeastern dispersal hypothesis. The HG type of the SCN population will have to be determined before any resistant cultivars are deployed for the management of this pathogen in the province. References: (1) T. R. Anderson et al. Plant Dis. 72:453, 1988. (2) G. Bélair et al. Plant Dis. 97:292, 2013. (3) R. H. Mulvey. Can. J. Zool. 50:1277, 1972. (4) S. Ou et al. Nematology 10:397, 2008.

Role of plasma exchange in autoimmune hyperthyroidism complicated by severe tiamazol-induced cholestatic jaundice.

Therapeutic plasma exchange (TPE) is an alternative treatment for hyperthyroidism, resulting in a rapid decline in plasma thyroid hormones and anti-thyroid antibodies. TPE has also been used both in primary liver disease and in drug-induced cholestasis. Data on thyrotoxic patients with severe hepatic complications are scarce. Cholestasis induced by imidazol-derived anti-thyroid drugs is extremely rare. The use of TPE for treating this complication was not previously reported. We report the experience of one such patient with a favorable response to TPE. A 45-year-old male patient with Graves' disease, presented with severe jaundice and extremely high serum bilirubin levels due to hepatotoxicity induced by tiamazol. Through extensive investigation primary liver disease, including viral, metabolic, neoplastic and autoimmune disease, as a cause of cholestasis were all ruled out. The patient underwent total of 6 TPEs which in combination with low dose of glucocorticoids and standard supportive measures, resulted in normalization of thyroid hormones and normal liver function tests. TPE provided a safe, rapid and effective treatment of severe drug-induced cholestasis and auto immune hyperthyroidism. From this case we conclude that TPE should be considered as a valuable alternative therapeutic option in thyrotoxic patients with severe complications. Guidelines and indication criteria for TPE treatment in patients with hyperthyroidism are still lacking.

The persistence of seroprotective levels of antibodies after vaccination with PreHevbrio, a 3-antigen hepatitis B vaccine.

Prevention of hepatitis B virus (HBV) infection by vaccination can potentially eliminate HBV-related diseases. PreHevbrio™/PreHevbri® is a 3-antigen (S, preS1, preS2) HBV vaccine (3A-HBV) recently licensed for adults in the US, EU and Canada. This study evaluated antibody persistence in a subset of fully vaccinated and seroprotected (anti-HBs ≥ 10 mIU/mL) Finnish participants from the phase 3 trial (PROTECT) of 3A-HBV versus single-antigen HBV vaccine (1A-HBV). 465/528 eligible subjects were enrolled (3A-HBV: 244; 1A-HBV: 221). Baseline characteristics were balanced. After 2.5 years, more 3A-HBV subjects remained seroprotected (88.1 % [95 %CI: 84.1,92.2]) versus 1A-HBV (72.4 % [95 %CI: 66.6,78.3)], p < 0.0001) and had higher mean anti-HBs [1382.9 mIU/mL (95 %CI: 1013.8,1751.9) versus 252.6 mIU/mL (95 %CI: 127.5,377.6), p < 0.0001]. In multiple variable logistic regression analysis including age, vaccine, initial vaccine response, sex and BMI, only higher post dose 3 (Day 196) antibody titers significantly reduced the odds of losing seroprotection.

The importance of timing in surgical treatment of unruptured symptomatic aneurysm of abdominal aorta.

AIM OF STUDY: Aim of this study is to define an entity of unruptured symptomatic AAA, to examine the influence of timing of the surgical treatment and to analyze the results of the treatment of unruptured symptomatic AAA in acute expansion. MATERIALS AND METHOD: The study is designed as retrospective analysis of 390 operatively treated patients in the last five years at the Clinics of Vascular Surgery in Novi Sad. All patients were grouped into four categories: elective operative surgical treatment, surgical treatment 24 hours after the admission through the Department of Urgent Surgery with an urgent CT diagnosis (in first 2 hours), surgical treatment within 24 hours since the admission through the Department of Urgent Surgery with an urgent CT diagnosis (in first 2 hours) and immediate surgical treatment of ruptured AAA. RESULTS: In the period from Jan 1, 2005 to Dec 31, 2009, 390 patients with AAA were operatively treated. 89 patients had ruptured AAA, 52 were operated 24 hours after the urgent admission, 18 patients were operated in the first 24 hours after the urgent admission and 231 patients were planned for elective surgery. Mortality rates between the groups were as follows: elective surgery-5.1 %, patients operated 24 hours after the urgent admission 7.2 %, patients operated in the first 24 hours after the urgent admission 23 %, and patients who had ruptured AAA 34 %. CONCLUSION: Considering the obtained data, it can be concluded that the treatment of unruptured symptomatic AAA is related to a higher risk of postoperative mortality in relation to an elective surgery. Moreover, surgical treatment in the first 24 hours after the urgent admission of unruptured symptomatic AAA has higher rate of mortality and morbidity compared to surgical treatment 24 hours after the urgent admission of the patients, so we can conclude that the early (semi) elective surgery is a method of choice for the treatment of unruptured symptomatic AAA in acute expansion (Tab. 2, Fig. 2, Ref. 21).

Effects of conventional versus biocompatible peritoneal dialysis solutions on peritoneal and systemic inflammation, malnutrition and atherosclerosis in CAPD patients.

BACKGROUND: Chronic inflammation, malnutrition and atherosclerosis (MIA syndrome) are important predictors of high mortality in continuous ambulatory peritoneal dialysis (CAPD) patients. We aimed to evaluate the effects of PD solutions (standard vs. biocompatible) on some parameters of MIA syndrome in patients undergoing CAPD. METHODS: 42 stable patients who were on CAPD at least 2.5 years participated in this cross-sectional study. Patients who had severe anemia (Hb < 10 g/l), immunomodulatory therapy, peritonitis or any inflammatory conditions for at least 3 months before the analysis, malignant disease and acute exacerbation of heart failure, were excluded. 21 (50%) patients were treated with standard PD solutions (CAPDP-1), while the remaining 21 (50% of patients) were treated with biocompatible PD solutions (neutral solutions with lower level of glucose degradation products and lower concentration of calcium, CAPDP-2). All patients underwent echocardiography and B-mode ultrasonography of common carotid arteries together with assessments of nutrition status and parameters of systemic and local inflammation. RESULTS: There were no significant differences between the groups concerning age, gender, underlying disease, residual renal function, peritoneal transport characteristics, comorbidity or therapy applied. Patients from group CAPDP-2 had a significantly lower serum level of hs-CRP (3.7 ± 2.6 mg/l vs. 6.3 ± 4.5 mg/l; p = 0.023) and significantly better nutritional status confirmed by mid-arm circumference (p = 0.015), mid-arm muscle circumference (p = 0.002) and subjective global assessment (14.28% of patients in CAPDP-2 vs. 71% of patients in CAPDP-1 were malnourished; p = 0.000). Group CAPD-2 had less frequent left ventricular hypertrophy (p = 0.039), thinner intima-media thickness (p = 0.005), smaller carotid narrowing (p = 0.000) and fewer calcified plaques of common carotide arteries (p = 0.003). No significant difference between the CAPDP groups was observed in serum and effluent levels of inflammatory cytokines (IL-1, IL-6 and TNF-α) and CA-125 effluent level. Logistic regression analysis did not confirm that biocompatibility of PD solutions was an independent predictor of any parameter of MIA syndrome. CONCLUSIONS: According to the present study and logistic regression analysis, the effect of biocompatible CAPD solutions on parameters of malnutrition, inflammation and atherosclerosis have to be confirmed by well-designed and controlled studies in a higher number of patients.

Association of increased parathyroid hormone with neuroendocrine activation and endothelial dysfunction in elderly men with heart failure.

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged ≥ 55 yr were recruited. PTH, 25-hydroxyvitamin D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77 ± 33 vs 40 ± 11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17 ± 9 vs 10 ± 2 µg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NTpro- BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Manifesto for the current understanding and management of traumatic brain injury-induced hypopituitarism.

Traumatic brain injury (TBI)-induced hypopituitarism remains a relevant medical problem, because it may affect a significant proportion of the population. In the last decade important studies have been published investigating pituitary dysfunction after TBI. Recently, a group of experts gathered and revisited the topic of TBI-induced hypopituitarism. During the 2-day meeting, the main issues of this topic were presented and discussed, and current understanding and management of TBI-induced hypopituitarism are summarized here.

Chronic cognitive sequelae after traumatic brain injury are not related to growth hormone deficiency in adults.

OBJECTIVE: The objective of the study was to asses the possible influence of hypothalamo-pituitary deficiencies, and growth hormone (GH) deficiency in particular, on cognition in adult patients with traumatic brain injury (TBI). TBI is a recently identified risk factor for cognitive deficits and hypopituitarism. Even the patients with favorable outcome after TBI may present with persistent bodily, psychosocial, and cognitive impairments, resembling patients with untreated partial or complete pituitary insufficiency. DESIGN: We performed retrospective and cross-sectional study of endocrine and cognitive function in TBI in 61 patients (aged 37.7 +/- 1.7 years) of both sexes (44 m,17 f), at least 1 year after TBI (3.9 +/- 0.6 years). Serum insulin-like growth factor 1 (IGF-I), thyroxin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in men), prolactin, and cortisol were measured, and GH secretion was assessed by growth hormone releasing hormone (GHRH) + growth hormone releasing peptide-6 (GHRP-6) test. Cognitive function was assessed by using a standard neuropsychological battery. RESULTS: GH deficiency (GHD) and GH insufficiency (GHI) were found in 20 patients (32.8%). After adjustment for confounders [age, body mass index (BMI), education level, time elapsed from TBI], there were no significant differences in results of neuropsychological tests between patients with TBI with GHD, GHI, and normal GH secretion. There were no correlations of neuropsychological variables with stimulated peak GH secretion or IGF-I level. CONCLUSIONS: GHD persists long after the TBI, independently of trauma severity and age at traumatic event. GH secretion is more sensitive to TBI than other pituitary hormones. No evidence is found for an association of cognitive function impairment and somatotropic axis impairment in adult patients tested more than 1 year after the TBI.

Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy.

OBJECTIVE: Traumatic brain injury (TBI) has been recently recognized as a risk factor for cognitive impairment and hypopituitarism, presented most frequently with GH deficiency (GHD). GHD is associated not only with changes in body composition, but also with impaired quality of life, cognitive dysfunctions and some psychiatric sequelae, usually classified as "depression" or "atypical depression". The impact of GH therapy on mental status in TBI patients is still unknown. DESIGN: Psychiatric and cognitive functions were tested in 6 GHD patients at baseline (minimum 3 yr after TBI), reassessed after 6 months of GH therapy as well as 12 months after discontinuation of GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and 3 instruments: Symptom-checklist (SCL-90-R), Zung Depression Inventory, and standard composite neuropsychological battery. RESULTS: Six months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and non-verbal memory) and significantly improved psychiatric functioning. Severity of depression decreased, as well as intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety, and psychoticism. Somatization, obsessive-compulsive symptoms and phobic anxiety decreased in all except in one patient. In 3 GHD patients who stopped GH therapy for 12 months we registered worsening of the verbal and non-verbal memory, as well symptoms in 3 SCL dimensions: inter-personal sensitivity, anxiety, and paranoid ideation. CONCLUSION: GH-deficient TBI patients are depressed and have cognitive impairment. GH therapy induced reduction of depression, social dysfunction, and certain cognitive domains. Our preliminary data support the necessity of conducting randomized placebo-controlled trials on the effects of GH therapy on neuropsychological and psychiatric status in GHD TBI patients.

ACTH and cortisol responses to ghrelin and desmopressin in patients with Cushing's disease and adrenal enlargement.

BACKGROUND: Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing's disease (CD). AIM: In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargement. SUBJECTS AND METHODS: Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 age and sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin. RESULTS: Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin. CONCLUSION: Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview.

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

Triple-way therapeutic approach for paraganglioma-dependent erythrocytosis: drugs and surgery plus "multi-manner" apheresis.

Paragangliomas are tumors arising from the extra-adrenal paragangliar neural crest cells. The sympathoadrenal neuroendocrine system consists of extra-adrenal paragangliar cellular layer along the paravertebral and para-aortic axis, and the adrenal medullae. Paraganglioma should be included in the differential diagnosis of secondary erythrocytosis due to its possible ectopic erythropoietin (EPO) secretion. Thus, in this report we present a 24-year-old female patient with onset of unregulated ectopic EPO secretion, and consecutive erythrocytosis followed by hypertension, secondary to paraganglioma of multifocal retroperitoneal localization. Clinical, laboratory, and radiological investigations confirmed both an elevated EPO level and the presence of multiple paraganglioma. This paraneoplastic-mediated medical condition with high risk of cellular hyperviscosity syndrome (CHVS) requires prompt diagnosis and rapid therapeutic interventions. Initially, simple phlebotomy procedures were used; following that, tumors were surgically removed. In the course of the disease, this tumor relapsed, and urgent apheresis, as a treatment of life-threatening state, was used. The therapy performed resulted in a rapid blood viscosity depletion and a significant (P < 0.01) serum EPO reduction, as well as the general clinical benefit. Therefore, we conclude that the use of our own "multi-manner" apheresis (erythrocythapheresis plus plasma exchange), for long-time interval (until further causative therapy), effectively cross-bridged the possible hazards of EPO-dependent CHVS.

Incidence of cervical cancer in Montenegro.

OBJECTIVE AND METHOD: To analyze the development of the number of cervical cancer cases and those who died of the disease in Montenegro. We used data on the number of cases and deaths over a eight-year period (2000-2007). RESULTS: In Montenegro 550 women developed cervical cancer in that period, which is 45% of all cancers affecting the female genital organs. In the first five years, the average disease rate was 19.52/100,000, but in the last three years it amounted to 25,61/100,000 (around 24% higher). The trend suggests significant growth. The average mortality rate was 4.2/100,000. The trend suggests very slight growth. The majority of cases were aged between 40 and 49 years (196 cases out of 550 or 35.64%). CONCLUSION: Almost 2/3 of the cases (64.19%) were aged between 40 and 59 years. There is a need to organize screening of the entire female population aged between 20 and 65-70 years. There is also a need to establish a central registry for malignant diseases in Montenegro.

Glucose metabolism during ghrelin infusion in patients with anorexia nervosa.

Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation due to fear of adiposity. Ghrelin, gastric peptide with potent orexigenic, adipogenic, GH-releasing and metabolic properties, is elevated in AN. We have previously shown that intervention with exogenous ghrelin is not effective in terms of inducing neuroendocrine and appetite responses in AN. In this arm of the same study protocol we investigated glucose metabolism responses to 5 h i.v. infusion of active ghrelin in a) 9 severely malnourished AN patients, b) 6 AN patients who partially recovered body weight (PRAN), c) 10 constitutionally thin female subjects with regular menstrual cycles. At baseline, no significant differences were observed in blood glucose, insulin, c-peptide, adiponectin, and homeostasis model assessment index values, between the studied groups. During ghrelin infusions, blood glucose levels significantly increased in all groups although significantly less in low-weight AN; insulin levels were not significantly affected, while c-peptide levels were significantly suppressed only in the constitutionally thin and PRAN subjects. In addition to our previous findings of impaired neuroendocrine and appetite responses in patients with AN, we conclude that metabolic responses to ghrelin are attenuated in these patients, which tend to recover with weight gain.

Etiology of Hypopituitarism in Adult Patients: The Experience of a Single Center Database in the Serbian Population.

There are only a few published studies related to the population-based etiology of hypopituitarism. New risks for developing hypopituitarism have been recognized in the last 10 years. Aim. To present data regarding the etiology of hypopituitarism collected in a tertiary center over the last decade. This is a cross-sectional database study. Patients and Methods. We included 512 patients (pts) with hypopituitarism, with a mean age of 45.9 ± 1.7 yrs (range: 18-82; male: 57.9%). Results. Nonfunctional pituitary adenomas were presented in 205 pts (40.5%), congenital causes in 74 pts (14.6%), while acromegaly and prolactinomas were presented in 37 (7.2%) and 36 (7.0%) patients, respectively. Craniopharyngiomas were detected in 30 pts (5.9%), and head trauma due to trauma brain injury-TBI and subarachnoid hemorrhage-SAH in 27 pts (5.4%). Survivors of hemorrhagic fever with renal syndrome (HFRS) and those with previous cranial irradiation were presented in the same frequency (18 pts, 3.5% each). Conclusion. The most common causes of hypopituitarism in our database are pituitary adenomas. Increased awareness of the other causes of pituitary dysfunction, such as congenital, head trauma, extrapituitary cranial irradiation, and infections, is the reason for a higher frequency of these etiologies of hypopituitarism in the presented database.

Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa.

CONTEXT: Anorexia nervosa (AN) is an eating disorder characterized by self-induced starvation. Gastric hormone ghrelin, potent orexigen, and natural GH secretagogue are increased in AN. Although exogenous ghrelin stimulates appetite, GH, prolactin, and cortisol release in humans, its effects have not been studied, during infusions, in AN patients. OBJECTIVE: The objective of the study was to determine the effects of ghrelin on appetite, sleepiness, and neuroendocrine responses in AN patients. DESIGN: This was an acute interventional study. SETTING: The study was based at a hospital. Investigated SUBJECTS: Twenty-five young women, including nine patients diagnosed with AN with very low body weight, six AN patients who partially recovered their body weight but were still amenorrheic, and 10 constitutionally thin female subjects, without history of eating disorder, weight loss, with regular menstrual cycles, were included in the study. INTERVENTION: Each patient received 300-min iv infusion of ghrelin 5 pmol/kg.min and was asked to complete Visual Analog Scale questionnaires hourly. MAIN OUTCOME MEASURES: Visual Analog Scale scores for appetite and sleepiness, GH, prolactin, and cortisol responses were measured. RESULTS: At baseline, AN patients had significantly higher ghrelin, GH, and cortisol levels and significantly lower leptin than constitutionally thin subjects. GH responses to ghrelin infusion were blunted in patients with AN. Ghrelin administration did not significantly affect appetite but tended to increase sleepiness in AN patients. CONCLUSIONS: Ghrelin is unlikely to be effective as a single appetite stimulatory treatment for patients with AN. Our results suggest that AN patients are less sensitive to ghrelin in terms of GH response and appetite than healthy controls. Ghrelin effects on sleep need further studies.