Category Archives: Δημοσιευμένες εργασίες


The Role of Hypothalamic Inflammation in Diet-Induced Obesity and Its Association with Cognitive and Mood Disorders

Sofia Dionysopoulou, Evangelia Charmandari, Alexandra Bargiota, Nikolaos F Vlahos, George Mastorakos and Georgios Valsamakis

Obesity is often associated with cognitive and mood disorders. Recent evidence suggests that obesity may cause hypothalamic inflammation. Our aim was to investigate the hypothesis that there is a causal link between obesity-induced hypothalamic inflammation and cognitive and mood disorders. Inflammation may influence hypothalamic inter-connections with regions important for cognition and mood, while it may cause dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis and influence monoaminergic systems. Exercise, healthy diet, and glucagon-like peptide receptor agonists, which can reduce hypothalamic inflammation in obese models, could improve the deleterious effects on cognition and mood.

Keywords: diet; obesity; hypothalamic inflammation; cognitive disorders; mood disorders; depression; dementia



Novel Approaches in Addressing Ovarian Insufficiency in 2019: Are We There Yet?

Konstantinos Sfakianoudis, Anna Rapani, Sokratis Grigoriadis, Dimitra Retsina, Evangelos Maziotis, Petroula Tsioulou, Polina Giannelou, Konstantinos Pantos, Michael Koutsilieris, Nikolaos Vlahos, George Mastorakos, and Mara Simopoulou

Ovarian insufficiency is described as a multifaceted issue typically encountered in the field of assisted reproduction. The three main identified diagnoses of ovarian insufficiency include premature ovarian failure (POF), poor ovarian response (POR), and advanced maternal age (AMA). Patient heterogeneity in the era of individualized medicine drives research forward leading to the emergence of novel approaches. This plethora of innovative treatments in the service of adequately managing ovarian insufficiency is called to undertake the challenge of addressing infertile patients exploring their reproductive options. This review provides an all-inclusive presentation and critical analysis on novel treatments that have not achieved routine clinical practice status yet, but have recently emerged as promising. In light of the lack of randomized controlled trials conveying safety and efficiency, clinicians are left puzzled in addressing the “how” and “for whom” these approaches may be beneficial. From ovarian injection employing platelet-rich plasma (PRP) or stem cells to artificial gametes and ovaries, ovarian transplantation, and mitochondrial replacement therapy, this descriptive review provides insight toward assisting the practitioner in decision making regarding these cutting-edge treatments. Biological mechanisms, invasiveness levels, efficiency, as well as possible complications, the current status along with bioethical concerns are discussed in the context of identifying future optimal treatment.

ovarian insufficiency, premature ovarian failure, poor ovarian response, stem cells, platelet rich plasma, mitochondria replacement therapy



Implementation of the Endocrine Society clinical practice guidelines for gestational diabetes mellitus to a knowledge tool

Vasiliki M. Korvesi MD, MSc, Ioanna Chouvarda Prof, George Mastorakos Prof, Dimitrios G. Goulis Prof

Background: Despite the production of clinical practice guidelines (CPGs) in many medical areas, their use is not sufficiently adopted in clinical practice. Incorporation of CPGs in knowledge tools (KnowT) or decision support systems (DSS) for routine use can improve healthcare providers’ compliance to CPGs.
Materials and methods: Clinical practice guidelines for gestational diabetes mellitus (GDM) were searched for, collected and compared. The CPG that met prespecified criteria ([a] published by a European or American organization between 2010 and 2018, [b] being developed a systematic way and [c] having statements of “level of evidence” and “strength of recommendation”) was chosen for implementation (Endocrine Society, 2013). Its recommendations were deconstructed, re-organized and reconstructed as an algorithm (in the form of a flowchart), which was integrated into a KnowT. Content completeness and evaluation of CPG by the Guideline Implementability Appraisal tool (GLIA) were performed as well. The primary objective was the development of a clinical algorithm in the field of GDM and its integration into a KnowT. The secondary objective was to demonstrate the completeness of the CPG content and evaluate its implementability in the KnowT.
Results: Endocrine Society 2013 CPG was restructured as a flowchart, and a KnowT was constructed with the use of the “Openlabyrinth” software. The completeness of the content was confirmed, and GLIA appraisal demonstrated its implementability.
Conclusion: Endocrine Society 2013 CPG for GDM is a complete set of recommendations. Its structure makes possible the design of a clinical algorithm and its implementation into a KnowT.

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Energy deficiency, menstrual disorders and low bone mineral density in female athletes: a systematic review

Nikitas S Skarakis, George Mastorakos, Neoklis Georgopoulos & Dimitrios G Goulis

* Poster Presentation in 7th ESE Young Endocrinologists and Scientists (EYES) Meeting

Background and aim: Low energy availability (LEA) may lead to menstrual disorders and low bone mineral density, predisposing to the female athlete triad (FAT) syndrome. The primary aim of this review was to systematically investigate the impact of sports on the energy status of professional female athletes compared to sedentary, recreationally active controls, with regard to their menstrual status and bone mineral density (BMD). A secondary aim was the estimation of the combined prevalence of the components of FAT in athletes as compared with non-athletes.
Materials and methods: A systematic review was conducted from 2007 to February 2018. Inclusion and exclusion criteria of studies were established in advance of the literature search, according to the clinical inquiry and the study design.
Results: Four studies were included in this systematic review. The FAT syndrome was more prevalent in professional athletes compared with non-athletes. The same results occurred for both LEA and menstrual disorders. However, BMD and Z-scores showed high heterogeneity among the studies.
Conclusions: Both professional athletes and sedentary women are prone to LEA and subsequent menstrual disorders and low BMD or osteoporosis. Future studies are needed to examine the energy availability in elite female athletes, as well as in non-athletes.


Μελέτη της διαφορικής έκφρασης των ισομορφών του IGF-I στο ανθρώπινο σπέρμα

Μ. Καρβούνη, Ε. Μαζιώτης, Π. Γιαννέλου, Α. Παπαδοπετράκη, Ν. Νίτσος, Κ. Πάντος, Α. Φιλίππου, Μ. Κουτσιλιέρης, Μ. Σιμοπούλου

*Ανακοίνωση στο 46ο Πανελλήνιο Ιατρικό Συνέδριο

ΣΚΟΠΟΣ: H διερεύνηση της έκφρασης των ισομορφών του ινσουλινο-μιμητικού αυξητικού παράγοντα IGF-I (IGF-1Ea, IGF-1Eb, IGF-1Ec) στο σπέρμα μεταξύ νορμοζωοσπερμικών ανδρών και εκείνων με μη φυσιολογικές παραμέτρους σπέρματος.
ΥΛΙΚΟ: Στη μελέτη συμμετείχαν 40 άνδρες ηλικίας 32-54 ετών (43,9±4,6 έτη), οι οποίοι υποβλήθηκαν σε σπερμοδιάγραμμα και κατηγοριοποιήθηκαν σε 4 ομάδες μελέτης, σύμφωνα με τη διάγνωση του σπερμοδιαγράμματος: «Νορμοζωοσπερμικούς», «Μία μη-φυσιολογική παράμετρος», «Δύο μη-φυσιολογικές παραμέτρους» και «Ολιγοασθενοτερατοζωοσπερμικούς (ΟΑΤ)». Τα δείγματα υποβλήθηκαν σε διαδικασία απομόνωσης RNA, σύνθεση cDNA και ποσοτικοποίησή του μέσω Real-time PCR, χρησιμοποιώντας ειδικούς εκκινητές για τις τρεις ισομορφές. Ταυτόχρονα, απομονώθηκε σπερματικό πλάσμα και πρωτεΐνες από τα σπερματοζωάρια και ελέγχθηκε η πρωτεϊνική έκφραση των τριών ισομορφών μέσω Western Blot. Η στατιστική ανάλυση διεξήχθη στo υπολογιστικό περιβάλλον της R.
ΑΠΟΤΕΛΕΣΜΑΤΑ: Η ανίχνευση των ισομορφών IGF-IEa και IGF-IEb δεν ήταν δυνατή σε επίπεδο mRNA και πρωτεϊνης. Αντίθετα, η ισομορφή IGF-IEc ανιχνεύθηκε σε επίπεδο mRNA και στις 4 ομάδες μελέτης, ωστόσο, τα επίπεδα ήταν χαμηλότερα στους «Νορμοζωοσπερμικούς» από τους άνδρες με «Δύο μη-φυσιολογικές παραμέτρους» (5,1±8,5, p-value=0.0117*) και τους «OAT» (2,9±2,3, p-value=0.0072*). Επιπλέον, βρέθηκε αρνητική συσχέτιση μεταξύ των επιπέδων του IGF-IEc και του ολικού αριθμού σπερματοζωαρίων (ρ=-0.3895225, p-value=0.01298), της προωθητικής (ρ=-0.4505146, pvalue=0.003532) και της ολικής κινητικότητας (ρ =-0.3790446, p-value=0.01586).
ΣΥΜΠΕΡΑΣΜΑΤΑ: Τα αποτελέσματα της μελέτης υποδηλώνουν ότι στα σπερματοζωάρια οι δράσεις του ΙGF-I εκπροσωπούνται κυρίως από την ισομορφή Ec και υπάρχει πιθανή συσχέτιση των επιπέδων της με την ανδρική υπογονιμότητα οφειλόμενη σε 2 ή περισσότερες ανωμαλίες σπερμοδιαγράμματος. Τα υψηλά επίπεδα της Ec πιθανώς επηρεάζουν αρνητικά τη σπερματογένεση και τη διαδικασία ωρίμανσης των σπερματοζωαρίων.


The Natural History of Neuroendocrine Changes in Pediatric Posttraumatic Stress Disorder (PTSD) After Motor Vehicle Accidents: Progressive Divergence of Noradrenaline and Cortisol Concentrations Over Time

Panagiota Pervanidou, Gerasimos Kolaitis, Stella Charitaki, Christina Lazaropoulou, Ioannis Papassotiriou, Peter Hindmarsh, Chrysa Bakoula, John Tsiantis, and George P. Chrousos

Background: The hypothalamic-pituitary-adrenal axis and the catecholaminergic system are involved in the pathophysiology of posttraumatic stress disorder (PTSD). This was a prospective and longitudinal study of neuroendocrine physiology in children with PTSD following a motor vehicle accident (MVA).
Methods: Sixty children aged 7–18 were studied immediately after an MVA and 1 and 6 months later. Fasting morning plasma catecholamine and serum cortisol concentrations were measured. Salivary cortisol concentrations were measured serially five times daily to examine circadian variation in all three assessments. Values were compared between those who did (PTSD) or did not develop PTSD (non-PTSD) after the trauma and a control group at months 1 and 6.
Results: Twenty-three of the children had PTSD at the 1-month and 9 children at the 6-month evaluations. 1) Plasma noradrenaline concentrations were higher in the PTSD group than in the other two groups at both months 1 and 6 (p = .001 and p = .001, respectively). Additionally, the PTSD patients presented with significantly higher salivary cortisol concentrations at 18.00 (p = .03) and 21.00 (p = .04) at month 1.2) Eight children suffering from PTSD at both months 1 and 6 had significantly elevated plasma noradrenaline concentrations at month 6 compared with those at month 1 and at baseline and to the other two groups (within subjects: p<.001; between subjects: p=.005). The initially elevated evening salivary cortisol concentrations in this group normalized at month 6.
Conclusions: This progressive divergence of noradrenaline and cortisol concentrations over time might underlie the natural history and pathophysiology of PTSD.

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Morning Preprandial Plasma Ghrelin and Catecholamine Concentrations in Patients with Phenylketonuria and Normal Controls: Evidence for Catecholamine-Mediated Ghrelin Regulation

Kleopatra H. Schulpis, Ioannis Papassotiriou, Maria Vounatsou, George A. Karikas, Stylianos Tsakiris, and George P. Chrousos

Patients with phenylketonuria (PKU) have a diet-controlled deficiency in the conversion of  henylalanine (Phe) to tyrosine (Tyr), leading to decreased production of noradrenaline, adrenaline, and dopamine. Poor diet control results in high plasma Phe and low plasma Tyr and catecholamine concentrations. Ghrelin, a recently described gastrointestinal hormone that is elevated in the fasting state and low in the fed state, is considered a major appetite-stimulating hormone, possibly involved in the generation of obesity and insulin resistance. We evaluated morning preprandial plasma ghrelin levels in 14 diet-controlled and 15 poorly controlled PKU patients and 20 age- and body mass index (BMI)-matched healthy children (controls) and correlated its concentrations with those of Phe and catecholamines as well as with their BMI and 24-h nutrient intake. Plasma ghrelin levels were measured by RIA, plasma catecholamine concentrations were determined by HPLC with electrochemical detection, and Phe and Tyr levels were measured in an amino acid analyzer. The ghrelin concentration (744 _ 25 ng/liter) in diet-controlled patients did not differ from that in controls (802 _ 26 ng/liter; P > 0.05). On the contrary, the ghrelin concentration was significantly reduced in poorly controlled patients (353 _ 23 ng/liter; P < 0.0001). Ghrelin correlated negatively with Phe in all three groups, whereas it correlated positively with catecholamine levels and energy intake and negatively with BMI only in diet-controlled patients and controls. We conclude that ghrelin secretion may receive positive direct or indirect input from catecholamines. The absence of a correlation between ghrelin and catecholamines, energy intake, or BMI in PKU patients on an inadequate diet may be due to dysregulation of their neuroendocrine system and might be affected by high Phe levels in the stomach and/or central nervous system. (J Clin Endocrinol Metab 89: 3983–3987, 2004)

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Investigating apoptotic, inflammatory, and growth markers in poor responders undergoing natural in vitro fertilization cycles: a pilot study

Konstantinos Sfakianoudis,, Petroula Tsioulou, Evangelos Maziotis, Sokratis Grigoriadis, Argyro Glava, Nikolaos Nitsos, Polina Giannelou, Evangelos Makrakis, Agni Pantou, Anna Rapani, Michael Koutsilieris, George Mastorakos, Konstantinos Pantos and Mara Simopoulou


This study investigates follicular fluid (FF) from patients with poor and normal ovarian response undergoing natural assisted reproductive technology cycles.We report about (1) cell-free DNA (cfDNA), which reflects apoptosis; (2) corticotropin-releasing hormone (CRH); (3) interleukin (IL)-15, which reflects inflammation; (4) granulocyte colony–stimulating factor (G-CSF); (5) vascular endothelial growth factor (VEGF); and (6) insulin-like growth factor I (IGF-I), which reflects follicular growth. Forty-four poor responders and 44 normal responders—according to the Bologna criteria—were recruited. FF samples were prepared for cfDNA quantification employing Q-PCR and for CRH, IL-15, G-CSF, VEGF, and IGF-I quantification employing ELISA. Statistically nonsignificant different levels of FF cfDNA, CRH, IL-15, VEGF, and IGF-I were observed. Interestingly, statistically significant higher G-CSF levels were observed in normal responders (302.48 ± 474.36 versus 200.10 ± 426.79 pg/mL, P = 0.003). Lower cfDNA integrity was observed in cycles resulting in clinical pregnancy for both groups (normal: 0.07 ± 0.04 versus 0.25 ± 0.17 ng/µL, P < 0.001; poor: 0.10 ± 0.06 versus 0.26 ± 0.12 ng/µL, P < 0.001). The results predominantly showcase similarities between normal and poor responders pertaining to inflammatory, apoptotic, and growth factors. This may be attributed to the employment of natural cycles in order to exclude controlled ovarian stimulation as a factor—indicating its detrimental effect. As G-CSF levels presented significantly higher in normal responders, its vital role in understanding a compromised ovarian response is highlighted.

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Study of the associations between polymorphisms in genes related to the Thyroid hormone metabolic pathways and clinical outcome in hypothyroid children.

Αποτελέσματα της εργασίας παρουσιάστηκαν στο 4th ISNS Middle East-North Africa Regional Meeting, Limassol, Cyprus, March 8-11, 2020, “Introducing and expanding Newborn Screening in the MENA region”.

Gkika Anna1, Papathanasiou Mando1, Platis Dimitrios1, Voutetakis Antonis2, Mastorakos George3, Kanaka-Gantenbein Christina2, Girginoudis Panagiotis1, Joanne Traeger-Synodinos4 and Iliadi Alexandra1

1Institute of Child Health, Hellenic Newborn Screening Laboratory, Athens, Greece
3Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital
3Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION Hospital, Faculty of Medicine, National and Kapodistrian University of Athens
4Laboratory of Medical Genetics, National and Kapodistrian University of Athens

Introduction: Congenital hypothyroidism (CH) is the most frequently encountered Congenital Endocrinopathy, with a prevalence of 1:1500-3000 births, and may lead to mental subnormality if not diagnosed and treated promptly. Implementation of Neonatal Screening Programs for Congenital Hypothyroidism (CH) have reduced related nosologies and eradicated CH-associated mental impairment. The Hellenic Newborn Screening Program is carried out by the Institute of Child Health (ICH) which is also responsible for final diagnosis, treatment initiation and clinical and hormonal follow-up of CH patients. 

Objectives: The identification of biomarker-polymorphisms (SNPs) in genes associated with Thyroid hormones metabolic pathways that can be correlated with clinical features of CH, such as L-T4 replacement therapy response, would be an extremely valuable tool for the prognosis of the disease at a very early stage. Genetic analysis was focused on the detection of 6 single nucleotide polymorphisms (SNPs), rs1991517, rs225014, rs939348, rs4704397, rs12095080, rs11206244 in TSHR, DIO1, DIO2, THRa, PDE8B genes. The present study is the first attempt to correlate specific polymorphisms with clinical features in CH children with a known pathoetiology of the disease.

Methods: Laboratory, clinical and ultrasonographic data were recorded from the medical records of children diagnosed with CH by the Hellenic Neonatal CH Screening Program. Patients with specific inclusion criteria (n= 400): CH dyshormonogenesis/transient CH, age >3 years old, natural conception, monocytic pregnancy, non- syndromic, non- low birth-weight were selected.  DNA was isolated and genotyped with RE-PCR. Statistical analysis was performed to compare clinical features such as birth weight, gestational age, TSH and FT4 before LT-4 substitution, Guthrie TSH level, dose at 1 and 3 years and BMI at 3 and 5 years with different genotypes.

Results/Discussion: CH is a multifactorial and polygenetic disease with a variety of features and phenotypes. Identifying genetic biomarkers that might help us predict LT-4 substitution dose, clinical outcome/severity of disease is of paramount importance.