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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.

Presented in the 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.


(Greek) Time to full effect, following treatment with combined oral contraceptives (cyclic versus continuous administration) in patients with endometriosis after laparoscopic surgery: a prospective cohort study

Olga Triantafyllidou, Georgios Kolovos, Charalambos Voros, Athanasios Vlachos, Panagiotis Vakas, Nikos Vlahos

PMID: 31979988, DOI: 10.1080/14647273.2019.1704451


The risk of recurrence after surgery is a major problem in women who are suffering from endometriosis. The prescription oral contraceptives (OCs) in the treatment of endometriosis-related pain, in women who do not desire fertility, is still controversial. The aim of this prospective cohort study is to evaluate the time until the reduction in the mean intensity of dysmenorrhoea and deep dyspareunia takes effect, for patients who use combined OCs in the accepted cyclic manner, versus in the continuous fashion as after the laparoscopic excision of endometriosis. A total of 28 patients diagnosed with endometriosis who underwent surgical treatment were offered at least a 12 months course of oral contraceptives. The intensity of both symptoms was reduced at the end of observational period in both groups. The use of continuous OCs (11 patients) was associated with a more pronounced reduction in the mean intensity of dyspareunia and dysmenorrhoea at 9 (p = 0.004) and 6 (p = 0.003) months respectively as compared to the cyclic group (17 patients).

Keywords: Oral contraceptives; dysmenorrhoea; dyspareunia; endometriosis; laparoscopy.


Association of endometriosis and breast cancer: mini review of the literature

Foteini Anifantaki, Ioannis Boutas, Theodoros Kalampokas, Emmanouil Kalampokas, Chrisostomos Sofoudis, Nikolaos Salakos

Background Endometriosis is a common, estrogen-dependent, gynecological disease, which is defined as the presence of endometrial tissue outside the uterine cavity. Current data have associated endometriosis with specific malignancies, including ovarian and breast cancer. Purpose The purpose of our study is to summarize and present published literature providing evidence regarding the possible relationship between endometriosis and breast cancer. Methods Pubmed and Scopus databases were searched systematically for studies that sought to identify a potential association of endometriosis and breast cancer. 15 relevant articles were retrieved and included in the present review. Results A small number of observational studies have shown a correlation of endometriosis and breast cancer. Other studies found that the risk of breast cancer increases with age. The scenario of an early interruption of the inflammatory process, derived from endometriosis, by oophorectomy and a possible consequent decrease in the risk of breast cancer has also been proposed. The hypothesis that both conditions could be related through common mutations on BRAC1 and BRAC2 genes has also been investigated. Conclusion The available published evidence is inconclusive. Further studies are needed to evaluate the association of endometriosis and breast cancer and the possible pathogenetic pathways that relate the two disorders.

Keywords: Endometriosis  Breast cancer  Breast neoplasm  Breast malignancies

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Autoimmune Diseases and Male Fertility: A Systematic Review

Evangelos Iliopoulos*

Background: During the last years new targeted regimen for several autoimmune diseases has been developed leading to an ameliorated quality of life for these patients. Nevertheless, their fertility potential seems to be impaired either by the activity of the autoimmune diseases or by the medical treatment used to suppress these conditions. This systematic review intends to reveal how autoimmune diseases and their regimen affect male fertility.
Methods: A search of English-language articles from electronic databases was conducted. The results that were used referred to impaired fertility in male patients with Systemic Lupus Erythematosus, Behcet’s disease, gout, dermatomyositis, celiac disease, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis and sarcoidosis.
Conclusion: Thirty-nine articles were finally included regarding the following diseases: Dermatomyositis, Systemic Lupus Erythematosus, Behcet’s disease, Gout, Celiac disease, Rheumatoid arthritis, Ankylosing spondylitis, Inflammatory bowel disease, Psoriasis, Sarcoidosis as well as two systematic reviews. Cyclophosphamide therapy seems to impair fertility in male patients with Systemic Lupus Erythematosus and Behcet’s disease. Colchicine use may lead to sperm abnormalities in patients with gout whereas anti-TNF treatment in ankylosing spondylitis does not affect the fertility potential. Antisperm antibodies and sulphasalazine treatment in rheumatoid arthritis, as well as mesalazine, infliximab and methotrexate use in inflammatory bowel disease, result in gonadal dysfunction, respectively. More data addressing male fertility are needed for patients with Dermatomyositis, Sarcoidosis, Psoriasis and Celiac disease. Fertility impairment is common in autoimmune diseases. Henceforth, more studies are needed to identify the relationship between fertility and immunity.

Keywords: Autoimmune diseases; Male fertility; Sperm abnormalities; Semen quality; Fertility impairment

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The intertemporal evolution of contraception. Literature review

Leila Top, Nicolaos Salakos, Michalis Kaloeidas, Georgios Koumantakis, Perilkis Panagopoulos, Efthimios Deligeoroglou

Aim: The aim of this study is to summarize the methods used for contraception from antiquity to nowadays and to highlight the latest ones with their advantages and disadvantages.
Materials and Methods: In order to gather the following data, scientific papers from the PUBMED database, ancient texts, historical data, newer article-searching literature, contraceptive methods and the collection of books of the Family Planning Department of the 2nd Department of Obstetrics & Gynecology of the Aretaieion Hospital.
Results: Contraception is a means of controlling fertility, is an old and sexual function. The history of contraception began with the discovery of the relationship between intercourse and pregnancy. Over the years many contraceptive methods have emerged, involving mechanical components up to the use of pharmaceuticals, and several of them were natural and others were artificial.
Conclusions: Today contraception provides the couples with the opportunity to determine both the time and number of pregnancies. The progress in the decrease of the number of unwanted pregnancies and the provision of contraception with minimal side effects is a collective effort requiring constant collaboration of reliable clinics, scientists and volunteers of clinical trials in combination with the collaboration of the pharmaceutical industry, family planning organizations and the government. The new contraception alternatives are going to improve the opportunities of an appropriate, acceptable contraceptive method by the wider public, eliminating thus birth control failure.

Key Words: Contraception, methods of contraception, history of contraception, new methods of contraception.

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Assisted Reproduction in Congenital Adrenal Hyperplasia

Anastasios Chatziaggelou, Evangelos G. Sakkas , Raffaella Votino, Maria Papagianni , George Mastorakos

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders characterized by defects of adrenal steroidogenesis due to mutations in one of the following enzymes: 21-hydroxylase (21OH), 11b-hydroxylase (11bOH), 17a-hydroxylase (17OH; also known as 17, 20-lyase), 3b hydroxysteroid dehydrogenase type 2 (3bHSD2), steroidogenic acute regulatory protein (StAR), P450 cholesterol side-chain cleavage (P450scc), and P450 oxidoreductase (POR). More than 95% of congenital adrenal hyperplasia cases are due to mutations in CYP21A2, the gene encoding the adrenal steroid 21-hydroxylase enzyme (P450c21). This work focuses on this type of CAH given that it is the most frequent one. This disease is characterized by impaired cortisol and aldosterone production as well as androgen excess. A variant of the CAH is the non-classic type of CAH (NCCAH), usually asymptomatic before the 5th year of age, diagnosed during puberty especially in patients visiting a fertility clinic. NCCAH is characterized mainly by anovulatory cycles and/or high androgen concentrations. Both types of CAH are associated with infertility. Given that the incidence of NCCAH is greater than that of CAH, patients suffering from NCCAH are more often diagnosed for the first time in a fertility clinic. Thus, screening for NCCAH should always be considered. The causes of infertility in CAH patients are multi-factorial including virilization of external genitalia, altered psychosocial development, and hormonal disorders. The main challenges encountered in assisted reproduction are the androgen excess-associated anovulatory cycles as well as the increased circulating progesterone concentrations during the follicular phase which impact endometrial receptivity, tubal motility, and cervical thickness. Administration of sufficient substitution dose of glucocorticoids usually resolves these problems and leads not only to successful assisted reproduction treatment but also to spontaneous pregnancy. Patients with CAH should be followed by a multidisciplinary team including gynecologist, endocrinologist, and pediatrician.

Keywords: infertility, IVF (in vitro fertilization), congenital adrenal hyperplasia (CAH), pregnancy, assisted reproduction (ART)

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Demographic, clinical and hormonal characteristics of patients with premature ovarian insufficiency and those of early menopause: data from two tertiary premature ovarian insufficiency centers in Greece


The aim of the study was to compare demographic, hormonal and clinical parameters in patients with premature ovarian insufficiency (POI) and women with early menopause in Greece. One hundred thirty-nine women of Greek origin, aged 14–45 years, referring for oligomenorrhea and having elevated FSH concentrations were divided into three groups regarding the age of menstrual disturbances onset [POI1: </=30 years (n = 42); POI2: 31–39 years (n = 36); early menopause: 40–45 years (n = 61)].

The mean age of menstrual disturbances onset and that of diagnosis in all POI and early menopause patients were 28.7 years (28.7 ± 7.7) versus 42.1 years (42.1 ± 1.5) and 33.8 years (33.8 ± 7.2) versus 43.3 years (43.3 ± 1.4), respectively. POI patients and women with early menopause were diagnosed, respectively, five years and approximately four to six months later than the age of menstrual disturbances onset. Moreover, FSH2 (second confirmatory FSH measurement at 4-to-6-weeks interval) was greater in all POI patients than in early menopause women (55.4 ± 33.9 vs. 32.4 ± 19.4; p < .05) whereas mean age of menarche was greater in early menopause women than in POI patients (13 ± 1.3 vs. 12 ± 2.2; p < .05). Furthermore, FSH2 was increased in all POI and decreased in early menopause patients.

Keywords: Premature ovarian insufficiency, premature ovarian failure, hypoestrogenism, subfertility, early menopause

ΕΠΕΙΓΟΥΣΑ ΑΝΑΚΟΙΝΩΣΗ σχετικά με την αναστολή των πάσης φύσεως εκπαιδευτικών λειτουργιών από 11.3.2020 έως και 24.3.2020

Αναφορικά με την ανακοίνωση περί αναστολής των πάσης φύσεως εκπαιδευτικών λειτουργιών από 11 Μαρτίου 2020 και για 14 ημέρες, και σε εφαρμογή απόφασης της διεύθυνσης του ΠΜΣ, σας ενημερώνουμε ότι τα μαθήματα από 11.3.2020 έως και 9.4.2020 θα πραγματοποιηθούν αποκλειστικά διαδικτυακά, χωρίς να απαιτείται η φυσική παρουσία των φοιτητών στο Αρεταίειο Νοσοκομείο. Το διδακτικό προσωπικό που έχει προγραμματισμένες διαλέξεις στο πλαίσιο του εν λόγω χρονικού διαστήματος μπορεί να απευθύνεται στη γραμματεία του ΠΜΣ για σχετικές οδηγίες, σε περίπτωση αδυναμίας πραγματοποίησης διάλεξης από απόσταση.


The effects of autoimmune disorders on mental health of women in reproductive age.

Hell Iatr 2018; 84: 15-22.

Salioni A-M, Christopoulos P, Zervas I, Mastorakos G.

Nowadays, we know how important is to understand being healthy. Contrary to this, we have to investigate more and more the hidden faces of longterm illnesses and find the reasons of morbidity. The activation of autoimmunity inclines to be increased in contemporary time, not only in Greece, but also globally, without understanding the causes. The systematic erythematosus lupus (SEL) and rheumatoid arthritis (RA) are, probably, two of the most characteristic examples of up to date chronic autoimmunity diseases. Women are more frequent affected than men in proportion of 3:1, a fact that create changes not only physical and organic, but also psychological. Additionally, there are a lot of chances either in childhood or in reproductive and old one. The psychological morbidity is taking place in most of these diseases, affecting the patients’ behavior and their position against them. Multiple factors are incriminated for their appearance, as fatigue, stress, anxiety, etc. In addition a lot of causes affect their development both at their remission and at their relapse. The depression dominate and is promptly correlated both with the systematic erythematosus lupus and rheumatoid arthritis.

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