Publications by authors named "Sandra Pekic"

63 Publications

EXPRESSION OF KISSPEPTIN AND KISS1 RECEPTOR IN PITUITARY NEUROENDOCRINE TUMORS - AN IMMUNOHISTOCHEMICAL STUDY.

Endokrynol Pol 2021 Feb 23. Epub 2021 Feb 23.

Institute of Pathology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

Introduction: Pituitary neuroendocrine tumors (PitNETs), traditionally designated as pituitary adenomas, show relatively frequent invasive growth with exceptional metastatic potential, causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognized as metastatic suppressors in many malignant tumors. This study aimed to investigate the immunohistochemical expression of Kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray.

Material And Methods: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph and 6 (5.1%) of null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients.

Results: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative Kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%) and moderate in 12 tumors (11.9%); none of the tumors had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumors. Significant statistical difference in terms of Kisspeptin expression between types of PitNET and control group was not observed. Immunohistochemical expression of KISS1R was observed neither in control nor in the experimental group.

Conclusions: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of Kisspeptin in tumorigenesis and aggressiveness of PitNETs. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localization of proteins in the cell.
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http://dx.doi.org/10.5603/EP.a2021.0009DOI Listing
February 2021

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Eur J Endocrinol 2020 Dec 1. Epub 2020 Dec 1.

R Verkauskiene, Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciencies, Kaunas, Lithuania.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform.

Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD.

Design: On-line survey in endocrine centres throughout Europe.

Patients And Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018.

Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved.

Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.
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http://dx.doi.org/10.1530/EJE-20-1180DOI Listing
December 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

Hypopituitarism in five PROP1 mutation siblings: long-lasting natural course and the effects of growth hormone replacement introduction in middle adulthood.

Pituitary 2020 Aug;23(4):400-408

Neuroendocrine Department, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Dr Subotic 13, 11000, Belgrade, Serbia.

Twenty years after the first description of combined hypopituitarism (CPHD) caused by PROP1 mutations, the phenotype of affected subjects is still challenging for clinicians. These patients suffer from pituitary hormone deficits ranging from IGHD to panhypopituitarism. ACTH deficiency usually develops later in life. Pituitary size is variable. PROP1 mutation is the most frequent in familial congenital hypopituitarism (CH). Reports on initiation of hormonal replacement including growth hormone (GH) in adults with CH are scarce. We identified 5 adult siblings with CPHD due to PROP1 mutation (301-302delAG), aged 36-51 years (4 females), never treated for hormone deficiencies. They presented with short stature (SD from - 3.7 to - 4.7), infantile sexual characteristic, moderate abdominal obesity and low bone mineral density in 3 of them. Complete hypopituituitarism was confirmed in three siblings, while two remaining demonstrated GH, TSH, FSH and LH deficiencies. Required hormonal replacement including rhGH was initiated in all patients. After several months necessity for hydrocortisone replacement developed in all patients. After 2 years of continual replacement therapy, BMD and body composition (measured by DXA-dual X-ray absorptiometry) improved in all subjects, most prominently in two younger females and the male sibling. Besides rhGH therapy, these three patients have received sex hormones contributing to the favorable effect. The male sibling was diagnosed with brain glioblastoma two years following complete hormonal replacement. This report provides important experience regarding hormonal replacement, particularly rhGH treatment, in adults with long-term untreated CH. Beneficial effect of such therapy are widely acknowledged, yet these subjects could be susceptible to certain risks of hormonal treatment initiated in adulthood. Careful and continual clinical follow-up is thus strongly advised.
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http://dx.doi.org/10.1007/s11102-020-01049-9DOI Listing
August 2020

Traumatic brain injury: neuropathological, neurocognitive and neurobehavioral sequelae.

Pituitary 2019 Jun;22(3):270-282

Medical Faculty, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia.

Traumatic brain injury (TBI) causes substantial neurological disabilities and mental distress. Annual TBI incidence is in magnitude of millions, making it a global health challenge. Categorization of TBI into severe, moderate and mild by scores on the Glasgow coma scale (GCS) is based on clinical grounds and standard brain imaging (CT). Recent research focused on repeated mild TBI (sport and non-sport concussions) suggests that a considerable number of patients have long-term disabling neurocognitive and neurobehavioral sequelae. These relate to subtle neuronal injury (diffuse axonal injury) visible only by using advanced neuroimaging distinguishing microstructural tissue damage. With advanced MRI protocols better characterization of TBI is achievable. Diffusion tensor imaging (DTI) visualizes white matter pathology, susceptibility weight imaging (SWI) detects microscopic bleeding while functional magnetic resonance imaging (fMRI) provides closer understanding of cognitive disorders etc. However, advanced imaging is still not integrated in the clinical care of patients with TBI. Patients with chronic TBI may experience many somatic disorders, cognitive disturbances and mental complaints. The underlying pathophysiological mechanisms occurring in TBI are complex, brain injuries are highly heterogeneous and include neuroendocrine dysfunctions. Post-traumatic neuroendocrine dysfunctions received attention since the year 2000. Occurrence of TBI-related hypopituitarism does not correlate to severity of the GCS scores. Complete or partial hypopituitarism (isolated growth hormone (GH) deficiency as most frequent) may occur after mild TBI equally as after moderate-to-severe TBI. Many symptoms of hypopituitarism overlap with symptoms occurring in patients with chronic TBI, i.e. they have lower scores on neuropsychological examinations (cognitive disability) and have more symptoms of mental distress (depression and fatigue). The great challenges for the endocrinologist are: (1) detection of hypopituitarism in patients with TBI prospectively (in the acute phase and months to years after TBI), (2) assessment of the extent of cognitive impairment at baseline, and (3) monitoring of treatment effects (alteration of cognitive functioning and mental distress with hormone replacement therapy). Only few studies recently suggest that with growth hormone (rhGH) replacement in patients with chronic TBI and with abnormal GH secretion, cognitive performance may not change while symptoms related to depression and fatigue improve. Stagnation in post-TBI rehabilitation progress is recommended as a signal for clinical suspicion of neuroendocrine dysfunction. This remains a challenging area for more research.
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http://dx.doi.org/10.1007/s11102-019-00957-9DOI Listing
June 2019

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

Endocr Connect 2019 Apr;8(4):326-337

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background: Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients.

Subjects And Methods: Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP.

Results: Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT.

Conclusions: Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.
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http://dx.doi.org/10.1530/EC-19-0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432870PMC
April 2019

Clinical case seminar: Familial intracranial germinoma.

Endokrynol Pol 2018 ;69(5):612-618

Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Belgrade, Serbia, Serbia and Montenegro; University of Belgrade, School of Medicine, Belgrade, Serbia.

Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurance. Since ICG invades hypothalamus and/or pituitary, the endocrine dysfunction is one of the common determinants of these tumors. We presented two brothers with the history of ICG. Patient 1 is a 25-year-old male who had been suffering from the weakness of the right half of his body at the age of 18. Cranial MRI revealed mass lesion in the left thalamus. He underwent neurosurgery, tumor was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumor after a radiation therapy. At the age of 22 the diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Patient 2 is a 20-year old boy who was presented with diabetes insipidus at the age of 12. MRI detected tumor in the third ventricle and pineal region. After the endoscopic tumor biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy, and treated with GH during childhood. At the age of 18 GH replacement was reintroduced. A six month follow-up during the next two years in both brothers demonstrated the IGF1 normalization with no MRI signs of tumor recurrence.

Conclusion: To the best of our knowledge so far, only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside of Japan. They are treated successfully with GH therapy in adult period. < /p > < p >.
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http://dx.doi.org/10.5603/EP.2018.0060DOI Listing
April 2019

Intracerebral hemorrhage as a first sign of pheochromocytoma: case report and review of the literature.

Endokrynol Pol 2019 23;70(3):298-303. Epub 2018 Oct 23.

Medical Faculty, University of Belgrade, Belgrade, Serbia.

Pheochromocytomas and sympathetic paragangliomas are rare catecholamine-secreting tumours that represent very rare causes of intracerebral haemorrhage in the young, with only a few cases reported. A 32-year-old man presented to our emergency department because of sudden onset of severe headache. He had a six-month history of paroxysmal headache, palpitations, and sweating. During examination he became somnolent and developed left-sided hemiplegia. A computed tomographic (CT) scan of the brain showed a right temporoparietal haematoma. He was admitted to the Clinic for Neurosurgery and the haematoma was evacuated. The patient was comatose, on assisted respiration, with frequent hypertensive crises. An examination for possible secondary causes of hypertension was undertaken. Plasma metanephrine value was elevated (414 pg/mL, reference values < 90 pg/mL). Abdominal CT scans revealed a large mass (6 cm) in the right adrenal gland. After adequate control of the hypertension was achieved with nonselectivealpha- and beta-adrenergic blockers the tumour was excised. The histopathologic findings confirmed the diagnosis of pheochromocytoma. The genetic analysis demonstrated a duplication in exon 1 of the VHL gene. We reported a rare, potentially fatal complication of pheochromocytoma - an intracerebral haemorrhage. This case and review of similar rare cases in the literature illustrate the importance of early recognition of the characteristic symptoms of catecholamine excess in young patients with hypertension.
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http://dx.doi.org/10.5603/EP.a2018.0075DOI Listing
December 2019

Hyperprolactinemia/Prolactinomas in the Postmenopausal Period: Challenges in Diagnosis and Management.

Neuroendocrinology 2019 22;109(1):28-33. Epub 2018 Oct 22.

School of Medicine, University of Belgrade, Belgrade, Serbia,

Hyperprolactinemia is not a common finding in postmenopausal women. Prolactinomas detected after menopause are usually macroadenomas. Due to atypical clinical features they may remain unrecognized for a long period of time. Interestingly the growth potential of prolactinomas remains after menopause. Most tumors are invasive and present with high prolactin levels. They respond to medical treatment with dopamine agonists in terms of prolactin normalization, tumor shrinkage, and improvement in pituitary function. Treatment with dopamine agonists is usually long term. Reducing doses of cabergoline to the lowest that keeps prolactin levels normal prior to withdrawal is proposed to patients with macroprolactinomas who normalize prolactin after > 5 years of treatment and who do not have cavernous sinus invasion. Cabergoline can achieve a high percentage of remission maintenance in the first years after withdrawal. However, the percentage of relapse-free patients 5 years after withdrawal is significantly lower. Besides recurrent hyper-prolactinemia in a subgroup of macroprolactinomas after a long-interval tumor regrowth may be detected. Menopause cannot ensure remission of the tumor so long-term surveillance is suggested. In patients with microadenomas data on long-term remission rates (normalization of prolactin and disappearance of the tumor) after suspension of treatment with dopamine agonists are highly variable. The current strategy for microprolactinomas is not to treat hyperprolactinemia in menopause if it recurrs after discontinuation of dopamine agonists. This is based on: (1) reports that elevated prolactin levels may normalize in some women after menopause, (2) the fact that the association between prolactin levels and breast cancer is inconsistent in postmenopausal women, (3) the lack of clinical evidence that normalization of prolactin levels in postmenopausal women improves bone mineral density or reduces the risk of fracture, and (4) the fact that, concerning the metabolic syndrome, no data are available on metabolic parameters after suspension of treatment with dopamine agonists. For a change in strategy, i.e., for the potential benefits from treatment of hyperprolactinemia in the postmenopausal period with dopamine agonists concerning weight loss, improved insulin sensitivity, decreased fracture risk, and improved sexuality, more evidence is needed.
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http://dx.doi.org/10.1159/000494725DOI Listing
May 2020

Single center study of 53 consecutive patients with pituitary stalk lesions.

Pituitary 2018 Dec;21(6):605-614

Neuroendocrine Department, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, Belgrade, 11000, Serbia.

Background: The etiological spectrum of pituitary stalk lesions (PSL) is wide and yet specific compared to the other diseases of the sellar and suprasellar region. Because of the pituitary stalk's (PS) critical location and role, biopsies of these lesions are rarely performed, and their underlying pathology is often a conundrum for clinicians. A pituitary MRI in association with a clinical context can facilitate their diagnosis.

Aim: To present the various causes of PSL-their clinical, hormonal, histopathological, and MRI characteristics in order to gain better insight into this pathology.

Method: A retrospective observational study consisting of 53 consecutive patients with PSL of the mean age 32 ± 4.2 years (range 6-67), conducted at the Department for Neuroendocrinology, Clinical Center of Serbia 2010-2018.

Results: Congenital malformations were the most common cause of PSL in 25 of 53 patients (47.1%), followed by inflammatory (9/53; 16.9%) and neoplastic lesions (9/53; 16.9%). The exact cause of PSL was established in 31 (58.4%) patients, of whom 23 were with congenital PS abnormalities and 8 with histopathology of PSL (7 neoplastic and 1 Langerhans Cell Hystiocytosis). A probable diagnosis of PSL was stated in 12 patients (22.6%): 6 with lymphocytic panhypophysitis, while Rathke cleft cyst, tuberculosis, dissemination of malignancy in PS were each diagnosed in 2 patients. In 10 patients (18.8%), the etiology of PSL remained unknown.

Conclusion: Due to the inability of establishing an exact diagnosis, the management and prognosis of PSL are difficult in many patients. By presenting a wide array of causes implicated in this condition, we believe that our study can aid clinicians in the challenging cases of this pathology.
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http://dx.doi.org/10.1007/s11102-018-0914-2DOI Listing
December 2018

Familial Cancer Clustering in Patients with Prolactinoma.

Horm Cancer 2019 02 8;10(1):45-50. Epub 2018 Sep 8.

School of Medicine, University of Belgrade, Dr Subotic 8, Belgrade, 11000, Serbia.

People are at higher risk for malignancy as they get older or have a strong family history of cancer. This study aims to collect family history of cancer in a large cohort of patients with pituitary adenomas (PA) in outpatient clinic from years 2005-2017. Overall, 46.6% of 1062 patients with PA had a family member affected with cancer. Breast cancer in family members was reported in 15.3% of patients with prolactinomas which was significantly higher than in families of patients with non-functioning pituitary adenomas (NFPA) (10.0%) or acromegaly (6.8%) (p = 0.004). Lung cancer in family members was reported in 12.1% of patients with prolactinomas, significantly higher than in families of NFPA patients (7.0%, p = 0.049). Colorectal cancer in relatives of patients with PA was reported with any type of PA. Furthermore, patients with a positive family history of malignancy were diagnosed with PA at an earlier age than patients with a negative family history (43.6 ± 15.9 vs 46.0 ± 16.4 years, p = 0.015). Female patients with prolactinoma are more commonly diagnosed before the age of 25 years. Forty-two percent of patients with PA diagnosed before the age of 25 years had a second- and third-degree relative with cancer, significantly higher than patients with PA diagnosed later in life (25.8%, p < 0.001). Breast, lung, and colon cancers in second- and third-degree relatives were reported in significantly higher proportion of patients with PA diagnosed before the age of 25 years, compared with patients with PA diagnosed later in life (breast cancer: 10.9 vs 6.1%, p = 0.033; lung cancer: 10.9 vs 5.8%, p = 0.02; colon cancer: 9.5 vs 4.0%, p = 0.004). These results suggest familial cancer clustering in patients with prolactinoma and young patients with PA (younger than 25 years at diagnosis of PA). In particular, there is a strong association between prolactinoma and family history of breast and lung cancers. Further research of possible shared genetic susceptibility of prolactinoma and breast and lung cancers is needed.
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http://dx.doi.org/10.1007/s12672-018-0348-3DOI Listing
February 2019

Cognitive functioning and quality of life in patients with Hashimoto thyroiditis on long-term levothyroxine replacement.

Endocrine 2018 10 29;62(1):136-143. Epub 2018 Jun 29.

Clinic for Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Centre of Serbia, University of Belgrade, Belgrade, Serbia.

Objective: Intrinsic imperfections of thyroid hormone replacement therapy may affect long-term general well-being. In patients with Hashimoto thyroiditis (HT), cognitive functioning may be affected via altered thyroid hormones action as well as by the autoimmune process. The aim of this study was to evaluate cognitive function and quality of life (QoL) in patients on long-term levothyroxine replacement for HT in relation to thyroid function tests and TPO (thyroid-peroxidase) antibody (TPOAb) status.

Design: Retrospective cross-sectional study.

Patients And Measurements: One-hundred-and thirty patients with HT on long-term levothyroxine replacement and 111 euthyroid control subjects. Both groups were divided into two age subgroups, 20-49 years (N = 59 vs N = 79) and > 50 years (N = 71 vs N = 32). Evaluation included biochemical and neuropsychological tests, evaluating attention, global cognitive status, verbal and working memory, executive function, depression and anxiety, and quality of life. We used ANOVA and partial correlations to test for significant associations.

Results: FT4 (free-thyroxine), FT3 (free-triiodothyronine) levels and FT3/FT4 ratio were not different between patients and controls. Mean TSH (thyroid-stimulating hormone) was normal in all subjects but significantly higher in the patients (20-49 yrs:3.64 ± 2.74 vs 1.93 ± 1.10, >50 yrs:3.93 ± 2.84 vs 1.91 ± 0.90). Antibodies (TgAb,TPOAb) were higher in patients. Global cognitive function (MMSE-Mini mental state examination), conceptual tracking (TMT-Trail Making Test:A/B), verbal divergent thinking (like Phonemic fluency test), and anxiety and depression scores were significantly worse in patients vs controls. QoL was impaired in patients. there was a significant negative correlation between antibodies (TPOAb, TgAb) and quality in life (total SF36 score).

Conclusion: Patients on long-term levothyroxine replacement show persistent impairments in both cognitive functioning and general well-being.
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http://dx.doi.org/10.1007/s12020-018-1649-6DOI Listing
October 2018

Macimorelin as a Diagnostic Test for Adult GH Deficiency.

J Clin Endocrinol Metab 2018 08;103(8):3083-3093

Swedish Neuroscience Institute, Seattle, Washington.

Purpose: The diagnosis of adult GH deficiency (AGHD) is challenging and often requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is considered the reference standard GHST but is labor intensive, can cause severe hypoglycemia, and is contraindicated for certain patients. Macimorelin, an orally active GH secretagogue, could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose.

Materials And Methods: The present multicenter, open-label, randomized, two-way crossover trial was designed to validate the efficacy and safety of single-dose oral macimorelin for AGHD diagnosis compared with the ITT. Subjects with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for AGHD and healthy, matched controls (n = 25) were included in the efficacy analysis.

Results: After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Using GH cutoff levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for ITTs, the negative agreement was 95.38% (95% CI, 87% to 99%), the positive agreement was 74.32% (95% CI, 63% to 84%), sensitivity was 87%, and specificity was 96%. On retesting, the reproducibility was 97% for macimorelin (n = 33). In post hoc analyses, a GH cutoff of 5.1 ng/mL for both tests resulted in 94% (95% CI, 85% to 98%) negative agreement, 82% (95% CI, 72% to 90%) positive agreement, 92% sensitivity, and 96% specificity. No serious adverse events were reported for macimorelin.

Conclusions: Oral macimorelin is a simple, well-tolerated, reproducible, and safe diagnostic test for AGHD with accuracy comparable to that of the ITT. A GH cutoff of 5.1 ng/mL for the macimorelin test provides an excellent balance between sensitivity and specificity.
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http://dx.doi.org/10.1210/jc.2018-00665DOI Listing
August 2018

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.

Eur J Endocrinol 2018 Apr 1;178(4):377-388. Epub 2018 Feb 1.

Service of EndocrinologyDiabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland

Objective: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.

Design: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders.

Methods: Exome sequencing data were used to identify rare variants in known genes in CHH ( = 116), CDGP ( = 72) and control cohorts ( = 36 874 ExAC and  = 405 CoLaus).

Results: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%,  = 7.6 × 10) or controls (18%,  = 5.5 × 10). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%,  = 0.002) and controls (2%,  = 6.4 × 10).

Conclusions: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.
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http://dx.doi.org/10.1530/EJE-17-0568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863472PMC
April 2018

Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unit.

Endocrine 2017 Nov 14;58(2):312-319. Epub 2017 Sep 14.

Department of Neuroendocrinology, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia.

Background: Hyponatremia can unmask hypopituitarism and secondary adrenal insufficiency. This is important, since the need to screen for steroid deficiency, in patients with hyponatremia is often neglected.

Patients And Methods: In a retrospective study, twenty-five patients (13f/12m, age 58.9 ± 18.6 years) with hyponatremia (119.7 ± 10.5 mmol/L) were identified among 260 in-patients treated for hypopituitarism in our specialized endocrine unit, over the last decade. We analyzed clinical characteristics, etiology, and severity of hypopituitarism in patients who presented with hyponatremia.

Results: Hyponatremia was recorded in 9.6% of our patients with hypopituitarism. In 80.7% it was the key to diagnosis of hypopituitarism. All patients with hyponatremia were steroid deficient with complete hypopituitarism compared to 75% (steroid deficient) and 60% (complete hypopituitarism) of the patients in the cohort. The most common etiology of hypopituitarism was non-functioning pituitary macro adenoma (NFPA) (n = 128, 49.2%). Patients with hyponatremia were divided into two groups, based on the etiology of hypopituitarism: Group 1. with NFPA n = 15 (5F/10M), mean age 71.47 ± 4.8 years, who were significantly older compared to patients with hyponatremia from other rare causes of hypopituitarism in Group 2. n = 10 (8F/2M), mean age 40.2 ± 15.3 years (p < 0.01), such as: congenital hypopituitarism(n = 2), Sheehan's syndrome (n = 2), intracranial aneurysm (n = 2), lymphocytic hypophysitis (n = 1), traumatic brain injury (n = 1), surgery and radiotherapy for astrocytoma (n = 1), pituitary metastasis from bronchial carcinoma (n = 1). Hyponatremia was more severe in Group 2. compared to Group 1. (113.5 ± 10.9 mmol/L vs. 124.3 ± 8.1 mmol/L, p < 0.01). Older age (p = 0.0001) and number of endocrine deficiencies (p < 0.05) were identified as predictive factors for hyponatremia by multivariate analysis in patients with hypopituitarism.

Conclusion: Hyponatremia is an important presenting feature of pituitary disease and a strong indicator of life-threatening steroid deficiency. Old age and severity of hypopituitarism are major risk factors for hyponatremia. In older patients NFPA is the most common etiology, while other rare causes of hypopituitarism are more prevalent in younger patients with hyponatremia.
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http://dx.doi.org/10.1007/s12020-017-1415-1DOI Listing
November 2017

Lymphocytic Hypophysitis Successfully Treated with Stereotactic Radiosurgery: Case Report and Review of the Literature.

J Neurol Surg A Cent Eur Neurosurg 2018 Jan 25;79(1):77-85. Epub 2017 Jul 25.

Department of Neuroendocrinology, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia.

Lymphocytic hypophysitis (LH) is an autoimmune inflammatory infiltration of the pituitary gland, usually with a benign evolution. In rare circumstances the inflammatory process may extend beyond the pituitary and infiltrate the surrounding structures. We present a 42-year-old woman affected by an aggressive form of LH with extension to the cavernous sinus causing internal carotid artery occlusion and right sixth cranial nerve palsy. Prednisone therapy caused severe iatrogenic Cushing's syndrome, and the patient underwent transsphenoidal decompression. The histopathology report was consistent with LH. The patient was symptom free for a short period with reappearance of severe headache, diplopia, and hearing loss (middle ear inflammation) 3 months after surgery. Corticosteroids were reintroduced with the addition of azathioprine, but there was no regression of the pituitary mass. The patient was referred for stereotactic radiosurgery (SRS) using Gamma Knife (15 Gy to the margin). After 26 months, azathioprine was stopped, and the dose of prednisone was gradually tapered to 7.5 mg/day. Sellar magnetic resonance imaging showed regression of the pituitary mass. After follow-up for > 3 years after SRS, there was no clinical or radiologic evidence of the disease, but carotid arteries remained occluded. The patient developed secondary hypothyroidism and hypogonadism as consequences of SRS. An aggressive form of LH extending beyond the pituitary gland infiltrating surrounding structures is described. It was successfully treated with SRS after failure of transsphenoidal surgery and combined immunosuppressive therapy (prednisone, azathioprine). The review of the literature presents timely information concerning treatment with azathioprine and SRS of patients with an aggressive form of LH.
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http://dx.doi.org/10.1055/s-0037-1604079DOI Listing
January 2018

All that glitters on PET is not cancer! 18F-deoxy-glucose avidity versus tumor biology: pituitary incidentaloma in a survivor of two previous unrelated malignancies.

Endokrynol Pol 2017 ;68(3):352-359

Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Belgrade, Serbia, Serbia and Montenegro; University of Belgrade, School of Medicine, Belgrade, Serbia.

Introduction: 18F-deoxy-glucose positron emission tomography combined with computed tomography (18F-FDG PET/CT) is routinely used in the detection of malignant disease based on the property of malignant cells to fuel their growth and replication by increased glucose uptake. Malignant lesions are rare in the sellar region, while pituitary adenomas are the most common pathology. These are benign neoplasms with insidious onset and low proliferation activity, and therefore are only exceptionally detected by 18F-FDG PET/CT. Studies that compare the biology of pituitary adenomas and their radiological properties using PET/CT are still lacking.

Case Report: We investigate and discuss tumour biology in light of increased 18F-FDG avidity in a symptom-free, 70-year-old male patient, previously treated for two different malignancies (lung and rectal). Increased tracer accumulation in the sellar region was incidentally detected on a follow-up 18F-FDG PET/CT scan. Additional MRI disclosed pituitary adenoma. Normal hormonal status was found, consistent with the diagnosis of non-functioning pituitary adenoma. Analysis of tumour tissue after pituitary surgery confirmed a silent gonadotroph adenoma with low proliferation index. Low expression of oncogene-induced senescence markers did not support senescence as the explanation for the tumour's low proliferative activity although it was in consonance with the hormonal activity.

Conclusions: Pituitary adenomas can manifest as hypermetabolic foci on 18F-FDG PET/CT imaging with increased tracer uptake even in indolent, clinically silent pituitary adenomas with low mitotic activity. Special attention should be paid to evaluation of 18F-FDG avid pituitary adenomas in patients with multiple malignancies, bearing in mind that avidity does not always mirror its biological behaviour.
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http://dx.doi.org/10.5603/EP.2017.0027DOI Listing
December 2017

Controversies in the risk of neoplasia in GH deficiency.

Best Pract Res Clin Endocrinol Metab 2017 02 22;31(1):35-47. Epub 2017 Feb 22.

University of Belgrade, School of Medicine, Dr Subotica 8, 11000 Belgrade, Serbia. Electronic address:

Growth hormone (GH) replacement in GH deficient (GHD) children secures normal linear growth, while in GHD adults it improves metabolic status, body composition and quality of life. Safety of GH treatment is an important issue in particular concerning the controversy of potential cancer risk. Unlike in congenital IGF-1 deficiency, there is no complete protection against cancer in GHD patients. Important modifiable risk factors in GHD patients are obesity, insulin resistance, sedentary behavior, circadian rhythm disruption, chronic low grade inflammation and concomitant sex hormone replacement. Age, family history, hereditary cancer predisposition syndromes or cranial irradiation may present non-modifiable risk factors. Quantifying the risk of cancer in relation to GH therapy in adult GHD patients is complex. There is evidence that links GH to cancer occurrence or promotion, but the evidence is progressively weaker when moving from in vitro studies to in vivo animal studies to epidemiological studies and finally to studies on GH treated patients. GH-IGF inhibition in experimental animals leads to decreased cancer incidence and progression. Epidemiological studies suggest an association of high normal circulating IGF-1 or GH to cancer incidence in general population. Data regarding cancer incidence in acromegaly are inconsistent but thyroid and colorectal neoplasias are the main source of concern. Replacement therapy with rhGH for GHD is generally safe. Overall the rate of de novo cancers was not increased in studies of GH-treated GHD patients. Additional caution is mandated in patients with history of cancer, strong family history of cancer and with advancing age. Childhood cancer survivors may be at increased risk for secondary neoplasms compared with general population. In this subgroup GH therapy should be used cautiously and with respect to other risk factors (cranial irradiation etc). We believe that the benefits of GH therapy against the morbidity of untreated GH deficiency outweigh the theoretical cancer risk. Proper monitoring of GH treatment with diligent cancer surveillance remains essential.
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http://dx.doi.org/10.1016/j.beem.2017.02.004DOI Listing
February 2017

DIAGNOSIS OF ENDOCRINE DISEASE: Expanding the cause of hypopituitarism.

Eur J Endocrinol 2017 Jun 3;176(6):R269-R282. Epub 2017 Mar 3.

School of MedicineUniversity of Belgrade, Belgrade, Serbia.

Hypopituitarism is defined as one or more pituitary hormone deficits due to a lesion in the hypothalamic-pituitary region. By far, the most common cause of hypopituitarism associated with a sellar mass is a pituitary adenoma. A high index of suspicion is required for diagnosing hypopituitarism in several other conditions such as other massess in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain injury, vascular lesions, infiltrative/immunological/inflammatory diseases (lymphocytic hypophysitis, sarcoidosis and hemochromatosis), infectious diseases and genetic disorders. Hypopituitarism may be permanent and progressive with sequential pattern of hormone deficiencies (radiation-induced hypopituitarism) or transient after traumatic brain injury with possible recovery occurring years from the initial event. In recent years, there is increased reporting of less common and less reported causes of hypopituitarism with its delayed diagnosis. The aim of this review is to summarize the published data and to allow earlier identification of populations at risk of hypopituitarism as optimal hormonal replacement may significantly improve their quality of life and life expectancy.
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http://dx.doi.org/10.1530/EJE-16-1065DOI Listing
June 2017

Combined Administration of Ghrelin and Corticotropin-Releasing Hormone in the Diagnosis of Cushing's Disease.

Neuroendocrinology 2017 2;104(1):33-39. Epub 2016 Feb 2.

Department of Neuroendocrinology, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia.

Background/aims: Exaggerated adrenocorticotropic hormone (ACTH) and cortisol responses to ghrelin in Cushing's disease (CD) have previously been reported, similarly to responses to corticotropin-releasing hormone (CRH). We assessed the ability of ghrelin to enhance ACTH and cortisol responses when added to CRH stimulation in CD patients.

Methods: In 21 CD patients (18 females, 3 males; age 49.8 ± 10.2 years; BMI 29.8 ± 0.8) and 8 healthy subjects (7 females, 1 male; age 40.6 ± 5.3 years; BMI 29.9 ± 1.2), we administered (1) ghrelin 100 µg i.v. bolus, (2) CRH 100 µg i.v. bolus, and (3) ghrelin + CRH combination. ACTH and cortisol were analyzed by commercially available kits from samples taken at 0, 15, 30, 45, 60, 90 and 120 min. ACTH and cortisol responses were calculated as peak and area under the curve (AUC0-120 min).

Results: ACTH and cortisol at baseline and stimulated with ghrelin and/or CRH (peak and AUC0-120 min) were significantly higher in CD patients compared to controls (p < 0.01). ACTH and cortisol responses to ghrelin or CRH were similar in CD patients. Combined ghrelin + CRH administration in CD patients produced the highest ACTH response (peak and AUC0-120 min) compared to ghrelin or CRH alone (p < 0.01). Cortisol responses after ghrelin + CRH were uncoupled with ACTH responses and similar to the response to ghrelin or CRH alone in both groups. ACTH and cortisol responses, during all three tests, were similar in CD patients with micro- or macroadenomas.

Conclusion: Ghrelin administration causes exaggerated ACTH and cortisol responses in CD patients compared to healthy controls. In combination with CRH, it additionally enhances ACTH secretion without further additive effect on cortisol output.
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http://dx.doi.org/10.1159/000444281DOI Listing
May 2017

Oncogene-Induced Senescence in Pituitary Adenomas--an Immunohistochemical Study.

Endocr Pathol 2016 Mar;27(1):1-11

Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, Sweden.

Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.
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http://dx.doi.org/10.1007/s12022-015-9405-4DOI Listing
March 2016

Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy.

BMC Neurol 2015 Mar 4;15:22. Epub 2015 Mar 4.

Background: Pol III-related leukodystrophies, including 4H leukodystrophy, are recently recognized disorders that comprise hypomyelination and various neurologic and non-neurologic clinical manifestations. We report the unique neurologic presentation of the micturition dysfunction in Pol III-related leukodystrophy and describe the novel endocrine abnormalities in this entity.

Case Presentation: A 32-year-old Caucasian female exhibited chronic urinary incontinence that commenced at the age of 7 years and remained the unexplained symptom more than two decades before the onset of progressive neurologic decline. A transient growth failure and absent sexual development with hypoprolactinemia appeared in the meanwhile. Neurologic, endocrine, neuroradiologic, and genetic evaluation performed only in the patient's thirties, confirmed the diagnosis of 4H leukodystrophy as the only cause of the micturition disturbance.

Conclusion: The report shows for the first time that an unexplained chronic bladder dysfunction should be evaluated also as a possible 4H leukodystrophy, thus alerting to the unexpected neurologic and endocrine features in 4H leukodystrophy.
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http://dx.doi.org/10.1186/s12883-015-0283-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351912PMC
March 2015

Chronic rhinosinusitis: association of recalcitrant nasal polyposis and fungal finding in polyp's single-cell suspension.

Eur Arch Otorhinolaryngol 2015 Dec 29;272(12):3727-34. Epub 2015 Jan 29.

Faculty of Medicine, Institute of Microbiology and Immunology, University of Belgrade, Dr Subotica 1, Belgrade, Serbia.

In recent years fungi are favoured as origin of chronic rhinosinusitis (CRS), especially with nasal polyps (wNP). Sensitive methods for fungal detection are still absent, therefore we used NP tissue single-cell suspension for mycology investigations in patients with recalcitrant NP (rNP) that underwent functional endoscopic sinus surgery (FESS). A prospective case-series study and culture-based mycological examination were conducted in patients who underwent FESS for the first time (ft-FESS) and those with repeated FESS (re-FESS). The study was conducted in a tertiary Otorhinolaryngology Unit of Clinical Centre of Serbia. A total of 43 consecutive patients with CRSwNP underwent FESS. Culture-based mycological examination of single-cell suspension was done on 55 NPs samples. Patient's co-morbidity data were collected. Repeated FESS was observed in 19/43 (44 %) patients (re-FESS group). Asthma and aspirin intolerance were more frequent in re-FESS than in ft-FESS group (p = 0.000, p = 0.002; respectively). Fungi were detected (wF) in 10/43 (23.3 %) patients (FESSwF group), representing 13/55 culture positive NP tissue (23.6 %). Fungal presence was higher in re-FESS than in ft-FESS group (42 and 8 %, respectively; p = 0.01). Significantly longer duration of CRS was observed in FESSwF than in fungal negative patients (p = 0.033). Predominate strain was Aspergillus flavus detected in 6/10 patients. This is the first study which analysed association of fungi in single-cell suspension of NP tissue and rNP. We demonstrate significantly higher percentage of positive fungal finding in re-FESSwF than in ft-FESSwF group. The most commonly isolated species in our patients was A. flavus.
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http://dx.doi.org/10.1007/s00405-015-3511-2DOI Listing
December 2015

Alternative causes of hypopituitarism: traumatic brain injury, cranial irradiation, and infections.

Handb Clin Neurol 2014 ;124:271-90

Faculty of Medicine, University of Belgrade, and Clinic of Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center Belgrade, Belgrade, Serbia. Electronic address:

Hypopituitarism often remains unrecognized due to subtle clinical manifestations. Anterior pituitary hormone deficiencies may present as isolated or multiple and may be transient or permanent. Traumatic brain injury (TBI) is recognized as a risk factor for hypopituitarism, most frequently presenting with isolated growth hormone deficiency (GHD). Data analysis shows that about 15% of patients with TBI have some degree of hypopituitarism which if not recognized may be mistakenly ascribed to persistent neurologic injury and cognitive impairment. Identification of predictors for hypopituitarism after TBI is important, one of them being the severity of TBI. The mechanisms involve lesions in the hypothalamic-pituitary axis and inflammatory changes in the central nervous system (CNS). With time, hypopituitarism after TBI may progress or reverse. Cranial irradiation is another important risk factor for hypopituitarism. Deficiencies in anterior pituitary hormone secretion (partial or complete) occur following radiation damage to the hypothalamic-pituitary region, the severity and frequency of which correlate with the total radiation dose delivered to the region and the length of follow-up. These radiation-induced hormone deficiencies are irreversible and progressive. Despite numerous case reports, the incidence of hypothalamic-pituitary dysfunction following infectious diseases of the CNS has been underestimated. Hypopituitarism usually relates to the severity of the disease, type of causative agent (bacterial, TBC, fungal, or viral) and primary localization of the infection. Unrecognized hypopituitarism may be misdiagnosed as postencephalitic syndrome, while the presence of a sellar mass with suprasellar extension may be misdiagnosed as pituitary macroadenoma in a patient with pituitary abscess which is potentially a life-threatening disease.
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http://dx.doi.org/10.1016/B978-0-444-59602-4.00018-6DOI Listing
July 2016

Adipsic diabetes insipidus and venous thromboembolism (VTE): recommendations for addressing its hypercoagulability.

Hormones (Athens) 2014 Jul-Sep;13(3):420-3

Clinic of Endocrinology, Medical Faculty, Belgrade University, Clinical Center of Serbia, Belgrade, Serbia.

Adipsic diabetes insipidus (ADI) is a rare disorder. It can occur after transcranial surgery for craniopharyngeoma, suprasellar pituitary adenoma and anterior communicating artery aneurysm but also with head injury, toluene exposure and developmental disorders. It is often associated with significant hypothalamic dysfunction and complications like obesity, sleep apnea, thermoregulatory disorders, seizures and venous thromboembolism (VTE). Morbidity and mortality data have been reported as single case reports with only one large series suggesting increased risk for VTE in patients with ADI. Here we report a mini-series of four patients with ADI and VTE. Post-surgery immobilization, obesity, infection, with prolonged hospitalization, hemoconcentration and changes in coagulation which might be induced by inadequate hormone treatment in the postoperative period (high doses of glucocorticoids, sex steroids and DDAVP replacement) may all contribute to the pathogenesis of VTE. Thromboprophylactic treatment after pituitary surgery and during episodes of hypernatremia is therefore warranted.
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http://dx.doi.org/10.14310/horm.2002.1496DOI Listing
October 2015

The influence of hyperprolactinemia on coagulation parameters in females with prolactinomas.

Srp Arh Celok Lek 2014 May-Jun;142(5-6):314-9

Introduction: Currently there is little information on the effects of prolactin (PRL) on the coagulation and fibrinolytic systems.

Objective: The aim of this study was to evaluate the effects of hypeprolactinemia on the parameters of the hemostatic system and activation of the coagulation system.

Methods: We studied PRL levels, body mass index (BMI), values of activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), D-dimer level, von Willebrand factor antigen (vWFAg) and fibrinogen in 15 young female patients with microprolactinomas before and after therapy and in 15 healthy female controls.

Results: As expected, pretreatment PRL levels were significantly higher in patients than in controls (140.90 +/- 42.87 vs. 12.53 +/- 4.05 ng/ml; p < 0.001). PT, although still in the normal range, was prolonged in patients with hyperprolactinemia as compared to the control group (13.53 +/- 1.39 vs. 12.65 +/- 0.53 s; p = 0.03) and normalized after therapy (12.69 +/- 0.65 vs. 12.65 +/- 0.53 s; p = 0.88). TT, although in normal range, was significantly shorter in the hypeprolactinemic patients than in the controls (14.34 +/- 4.52 vs. 17.21 +/- 1.35 s; p < 0.025) and after treatment remained significantly shorter than in the controls (15.17 +/- 1.55 vs. 17.21 +/- 1.35 s; p < 0.0001). D-dimer values before treatment in the patients with hyperproplactinemia were above the normal range (239.47 +/- 107.93 vs. 131.27 +/- 50.64 ng/ml, p = 0.002) and decreased to normal values after therapy (239.47 +/- 107.93 vs. 146.60 +/- 39.15 ng/ml; p < 0.001). D-dimer levels correlated with PRL (r = 0.30) and the change in serum D-dimer values significantly correlated with the change in PRL levels during therapy (r = 0.62). aPTT, vWFAg and fibrinogen were similar in patients and controls.

Conclusion: In our study, increased thrombin generation that resulted in elevated D-dimer levels may be one of the contributing factors to the prethrombotic state in patients with hyperprolactinemia.
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http://dx.doi.org/10.2298/sarh1406314mDOI Listing
October 2015

Metabolic issues in psychotic disorders with the focus on first-episode patients: a review.

Psychiatr Danub 2013 Dec;25(4):410-5

Clinic for Psychiatry, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia.

Before the onset of the illness, future schizophrenia patients do not weigh more comparing to their peers. However, during the later course of the illness, obesity is twice as prevalent as in general public, afflicting the half of schizophrenia patient population. There is a list of potential factors that contribute to this, including lifestyle, dietary habits, unsatisfactory monitoring of physical health etc, but nowadays side effects of antipsychotic medication become the most prominent concern when weight gain and metabolic issues in psychosis are addressed. The fact is that second generation antipsychotics (SGA) are associated with weight gain and metabolic syndrome, but that might be the case with the first generation antipsychotics (FGA) too. Besides, obesity might be evident in patients before any exposure to medications, and all that bring lot of dilemmas into the field. This paper critically reviews available data on metabolic problems in patients with psychotic disorders, raging from genetic to molecular and environmental factors, and highlights the necessity of screening for the early signs of metabolic disturbances, as well as of multidisciplinary assessment of psychiatric and medical conditions from the first psychotic episode.
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December 2013