Study of the response of the hormonal replacement therapy of young women with absent or very premature failure of the hypothalamus-pituitary-gonadal axis

Young women with primary or very premature ovarian failure represent a unique category of females who are under estrogen deprivation. In these women, the evaluation of hormone therapy administration is of essential clinical and research interest. The aim of the present study was to evaluate the impact of hormone therapy on several endocrinologic, metabolic and bone parameters in young women with absent or prematurely failed function of the hypothalamic-pituitary-gonadal axis. The study included 40 phenotypically females 14-20 years old with primary or secondary amenorrhea and female external genitalia who presented/referred at the Division of Pediatric-Adolescence Gynecology and Reconstructive Surgery of the 2nd Department of Obstetrics and Gynecology of the University of Athens. The study subjects were divided in three groups: Group A consisted of 12 women with the diagnosis of Turner syndrome, group B consisted of 19 women with the diagnosis of gonadal dysgenesis (Swyer syndrome), and group C consisted of 9 women with the diagnosis of premature ovarian failure. Subjects of groups A and B were given conjugate estrogens in a daily dose of 0.625 mg p.o. for 6 months followed by the cyclic addition of medroxyprogesterone acetate in a daily dose of 5 mg p.o. for the days 17-28 of each cycle for the following 18 months. Subjects of group C were given conjugate estrogens in a daily dose of 0.625 mg p.o. and medroxyprogesterone acetate in a daily dose of 5 mg p.o. for the days 17-28 of each cycle for 24 months. The scheduled clinical and laboratory investigation which was performed before the initiation of hormone therapy, as well as 3, 6, 12 and 24 months afterwards included: development of secondary sexual characteristics, evaluation of serum estradiol, progesterone, free testosterone, androstenedione, DHEA-S, 17-hydroprogesterone, and prolactin levels, evaluation of serum glucose, cholesterol, LDL, HDL, and triglycerides levels, evaluation of platelets, PT, PTT and fibrinogen, and finally evaluation of total femur bone mineral density. In all groups, hormone therapy provided a beneficial hormonal profile and allowed for safe and adequate serum estrogens levels. In group A (Turner syndrome) the hormone therapy resulted in the establishment of puberty, and in the progressive development of breasts and pubic hair which was almost complete at the 24 months of treatment. Hormone therapy had no adverse effects on metabolic and coagulation parameters; on the contrary a positive effect on HDL was noted. Finally, hormone therapy resulted in a progressive, significant increase of BMD which was observed for the whole study period (24 months). Similar positive effects of hormone therapy were noted for group B (Swyer syndrome) subjects, with the exception of a poorer breast development. Finally, in group C (premature ovarian failure) patients, no adverse effects of hormone therapy were noted as well as no favourable effect on HDL; BMD kept significantly increasing until the 12-month evaluation. In conclusion, the administration of hormone therapy is remarkably beneficial for young women with absent or prematurely failed function of the hypothalamic-pituitary-gonadal axis, and should be initiated as soon as possible after the establishment of diagnosis.Οι νεαρές γυναίκες με πρωτογενή ή πολύ πρώϊμη οριστική έκπτωση της ωοθηκικής λειτουργίας αποτελούν μια εξαιρετικά ιδιάζουσα υποκατηγορία γυναικών που βρίσκονται κάτω από συνθήκες ‘έλλειψης’ οιστρογόνων. Στις γυναίκες αυτές, η αξιολόγηση των αποτελεσμάτων της χορήγησης ορμονικής θεραπείας αποκτά σημαντικό κλινικό και ερευνητικό ενδιαφέρον. Σκοπός της παρούσας ερευνητικής μελέτης είναι η αξιολόγηση της επίδρασης της ορμονικής θεραπείας επί πληθώρας παραμέτρων, ορμονολογικών, μεταβολικών και οστικών σε νεαρά κορίτσια με απουσία ή εξαιρετικά πρώϊμη έκπτωση της λειτουργίας του άξονα υποθάλαμος-υπόφυση-γονάδες. Η συλλογή του υλικού πραγματοποιήθηκε εξ’ ολοκλήρου στην Β’ Μαιευτική και Γυναικολογική Κλινική του Πανεπιστημίου Αθηνών στο Τμήμα Παιδικής - Εφηβικής Γυναικολογίας και Επανορθωτικής Χειρουργικής και περιέλαβε 40 φαινοτυπικώς θήλεα άτομα, ηλικίας από 14-20 ετών με πρωτοπαθή ή δευτεροπαθή αμηνόρροια και εξωτερικά γεννητικά όργανα θήλεος τύπου, που διακρίθηκαν σε τρείς ομάδες: Η ομάδα Α περιέλαβε 12 στις οποίες τέθηκε η διάγνωση του συνδρόμου Turner, η ομάδα Β περιέλαβε 19 ασθενείς στις οποίες τέθηκε η διάγνωση της αμιγούς γοναδικής δυσγενεσίας, δηλαδή συνδρόμου Swyer, και η ομάδα Γ περιέλαβε 9 ασθενείς στις οποίες τέθηκε η διάγνωση της πρώϊμης έκπτωσης της ωοθηκικής λειτουργίας. Οι ασθενείς των ομάδων Α (σύνδρομο Turner) και Β (σύνδρομο Swyer) έλαβαν συνεζευγμένα οιστρογόνα από το στόμα σε δόση 0.625 mg ημερησίως σε καθημερινή βάση για 6 μήνες και ακολούθως προστέθηκε οξεική μεδροξυπρογεστερόνη από το στόμα σε δόση 5 mg ημερησίως κατά τις ημέρες 17-28 κάθε 28ημέρου κύκλου θεραπείας για τους υπόλοιπους 18 μήνες. Οι ασθενείς της ομάδας Γ (πρώϊμη έκπτωση ωοθηκικής λειτουργίας) έλαβαν εξ’ αρχής και για 24 μήνες συνεζευγμένα οιστρογόνα από το στόμα σε δόση 0.625 mg ημερησίως σε καθημερινή βάση και οξεική μεδροξυπρογεστερόνη από το στόμα σε δόση 5 mg ημερησίως κατά τις ημέρες 17-28 κάθε 28ημέρου κύκλου θεραπείας. Ο κλινικοεργαστηριακός έλεγχος πραγματοποιήθηκε κατά τις χρονικές στιγμές προ έναρξης της θεραπείας, 3, 6, 12 και 24 μήνες μετά την έναρξη θεραπείας και περιέλαβε την εκτίμηση της ανάπτυξης των δευτερευόντων χαρακτηριστικών φύλου, τους προσδιορισμούς των επιπέδων οιστραδιόλης ορού, προγεστερόνης ορού, ελεύθερης τεστοστερόνης ορού, ανδροστενεδιόνης ορού, θειϊκής δεϋδροεπιανδροστερόνης (DHEA-S) ορού, 17-υδρόξυ προγεστερόνης ορού, προλακτίνης ορού, σακχάρου ορού, χοληστερόλης ορού, χοληστερόλης ορού συνδεδεμένης με λιποπρωτεϊνες χαμηλής πυκνότητας (LDL), χοληστερόλης ορού συνδεδεμένης με λιποπρωτεϊνες χαμηλής πυκνότητας (HDL), τριγλυκεριδίων ορού, αριθμού αιμοπεταλίων, χρόνου προθρομβίνης αίματος, χρόνου μερικής θρομβοπλαστίνης αίματος, ινωδογόνου αίματος και τέλος την μέτρηση οστικής πυκνότητας ολικού ισχίου. Στις γυναίκες και των τριών ομάδων της μελέτης, η χορηγηθείσα ορμονική θεραπεία εξασφάλισε ένα ευεργετικό ορμονικό προφίλ, με ικανοποιητικά, επαρκή και ασφαλή επίπεδα οιστρογόνων στο αίμα. Στις ασθενείς με σύνδρομο Turner, η ορμονική θεραπεία οδήγησε στην επαγωγή της ήβης, με την προοδευτική ανάπτυξη των μαστών και της τρίχωσης του εφηβαίου, που σχεδόν ολοκληρώθηκε μετά την πάροδο των 24 μηνών χορήγησης της θεραπείας. Ουδεμία αρνητική επίδραση της χορηγηθείσας ορμονικής θεραπείας παρατηρήθηκε επί των παραγόντων πηκτικότητας του αίματος ή επί ‘μεταβολικών’ παραμέτρων, όπως επί των επιπέδων γλυκόζης, τριγλυκεριδίων, χοληστερόλης και LDL στον αντίποδα, παρατηρήθηκε μια ευνοϊκή επίδραση της ορμονικής θεραπείας στα επίπεδα της HDL, Τέλος, η επίδραση της ορμονικής θεραπείας στην οστική πυκνότητα των νεαρών ασθενών με σύνδρομο Turner ήταν εντυπωσιακή: η χορήγηση της θεραπείας είχε σαν αποτέλεσμα την σταδιακή, σε στατιστικά σημαντικό βαθμό αύξηση της οστικής πυκνότητας, αύξηση η οποία διατηρήθηκε μέχρι και την μέτρηση των 24 μηνών. Παρόμοια ευεργετικά αποτελέσματα με τα ανωτέρω σημειώθηκαν και για τις ασθενείς με σύνδρομο Swyer, με μόνη διαφορά την πτωχότερη ανάπτυξη των μαστών παρά την χορήγηση της ορμονικής θεραπείας. Τέλος, όσον αφορά τις ασθενείς με πρώϊμη έκπτωση της ωοθηκικής λειτουργίας, ουδεμία αρνητική επίδραση της χορηγηθείσας ορμονικής θεραπείας παρατηρήθηκε στους παράγοντες πηκτικότητας ή σε ‘μεταβολικές’ παραμέτρους, ενώ σε αντίθεση με τα ευρήματα στις ασθενείς με σύνδρομα Turner και Swyer, η χορήγηση ορμονικής θεραπείας δεν συνδυάσθηκε με αύξηση της HDL. Τέλος, παρατηρήθηκε μια σταδιακή αύξηση της οστικής πυκνότητας που αφορούσε όλες τις ασθενείς, και που ήταν στατιστικά σημαντική μέχρι και την μέτρηση των 12 μηνών. Συμπερασματικά, ασθενείς των τριών ανωτέρω κατηγοριών θα πρέπει να αντιμετωπίζονται έγκαιρα και υπεύθυνα από εξειδικευμένους παιδιάτρους, γυναικολόγους, και ενδοκρινολόγους και να τίθενται χωρίς δισταγμό σε ορμονική θεραπεία την οποία και θα πρέπει να ακολουθούν συστηματικά για μεγάλο χρονικό διάστημα, ώστε να αποφευχθούν οι σοβαρές αρνητικές επιπτώσεις της χρόνιας έλλειψης οιστρογόνων

Sonohysterography is superior to transvaginal sonography for the diagnostic approach of irregular uterine bleeding in women of reproductive age

Purpose. To evaluate and compare the accuracy of transvaginal sonography (TVS) and sonohysterography (SHG) in the investigation of women of reproductive age presenting with irregular uterine bleeding (IUB). Methods. This prospective study included 104 women presenting with IUB. All patients underwent TVS, SHG, and hysteroscopy, during which endometrial biopsies were obtained and any endometrial mass was treated with hysteroscopic surgery. Statistical analysis was performed by calculating the sensitivity, specificity, and positive and negative predictive values of TVS and SHG in diagnosing endometrial polyp, submucous myoma and all endometrial pathologies (polyp, submucous myoma, endometrial hyperplasia, and endometrial carcinoma) with the histopathological report of the tissues obtained by hysteroscopy serving as the end point for the analysis. Results. The sensitivity, specificity, and positive and negative predictive values, respectively of TVS were 61.2%, 90.9%, 85.7%, and 72.5% for diagnosing endometrial polyps; 75.0%, 92.0%, 63.1%, and 95.3% for diagnosing submucous myomas; and 75.0%, 80.6%, 87.9%, and 63.0% for diagnosing any kind of pathology. The corresponding diagnostic values of SHG were 83.7%, 96.4%, 95.3%, and 86.9% for polyps; 87.5%, 98.9%, 93.3%, and 97.8% for submucous myomas; and 88.2%, 91.7%, 95.2%, and 80.5% for any kind of pathology. Conclusions. SHG showed superior sensitivity, specificity, and positive and negative predictive values compared with TVS in diagnosing intrauterine lesions in women of reproductive age with IUB. (c) 2006 Wiley Periodicals, Inc

Home-Based Exercise Training and Cardiac Autonomic Neuropathy in Kidney Transplant Recipients with Type-II Diabetes Mellitus

This randomized clinical trial aimed to examine the effects of a 6-month home-based, combined exercise training program on Cardiac Autonomic Neuropathy (CAN) in kidney transplant recipients (KTRs) with diabetes. Twenty-five KTRs (19 men (76.0%), with a mean age of 54.4 ± 11.3 years old, CAN and type II Diabetes Mellitus (DM-II)), were randomly assigned into two groups: A (n1 = 13 KTRs), who underwent a home-based exercise training program for 6 months, and B (n2 = 12 KTRs), who were assessed at the end of the study. A cardiopulmonary exercise testing (CPET), sit-to-stand test in 30 s (30-s STS), isokinetic muscle strength dynamometry, and 24-h electrocardiographic monitoring were applied to all participants, both at the baseline and at the end of the clinical trial. At first, there were no statistically significant differences between groups. After 6 months, group A showed higher values in exercise time by 8.7% (p = 0.02), VO2peak by 7.3% (p p p p = 0.02), respectively, compared to the B group. Furthermore, inter-group changes at the end of the 6-month study indicated that group A statistically increased the standard deviation of R-R intervals (SDNN) by 30.3% (p = 0.01), root mean square of successive differences between normal heartbeats (rMSSD) by 32.0% (p = 0.03), number of pairs of successive NN (R-R) intervals that differ by more than 50 ms (pNN50) by 29.0% (p = 0.04), high frequency (HF (ms2)) by 21.6% (p p = 0.01), and turbulence slope (TS) by 22.5% (p = 0.02), and decreased the low frequency (LF (ms2)) by 13.2% (p = 0.01), LF (n.u.) by 24.9% (p = 0.04), and LF/HF ratio by 24% (p = 0.01), compared to group B. Linear regression analysis after the 6-month study showed that there was a strong positive correlation between VO2peak and SDNN (r = 0.701, p < 0.05) in group A. Moreover, multiple regression analysis showed that KTRs’ participation in the exercise program showed favorable modifications to sympathovagal balance and aerobic capacity, as measured with SDNN and VO2peak, respectively. To summarize, diabetic KTRs’ cardiac autonomic function and functional capacity can be improved after a home-based long-term exercise training program

Effects of Home-Based Exercise Training on Cardiac Autonomic Neuropathy and Metabolic Profile in Diabetic Hemodialysis Patients

Background: This study aimed to investigate the effects of a home-based exercise training program on Cardiac Autonomic Neuropathy (CAN) and metabolic profile in Diabetic Kidney Disease (DKD) patients undergoing maintenance hemodialysis (HD). Method: Twenty-eight DKD patients undergoing hemodialysis were randomly assigned into two groups. The exercise (EX) group followed a 6-month combined exercise training program at home, while the control (CO) group remained untrained. All participants at baseline and the end of the study underwent cardiopulmonary exercise testing (CPET), biochemical tests for glucose and lipid profile, and 24-h electrocardiographic monitoring for heart rate variability (HRV) analysis and heart rate turbulence (HRT). Results: At the end of the study, compared to the CO, the EX group showed a significant increase in serum high-density lipoprotein (HDL) by 27.7% (p = 0.01), peak oxygen uptake (VO2peak) by 9.3% (p p = 0.03), percentage of successive RR intervals higher than 50ms (pNN50) by 51.1% (p = 0.02), turbulence slope (TS) index by 18.4% (p = 0.01), and decrease in (glycated hemoglobin) HbA1c by 12.5% (p = 0.04) and low-frequency power LF (ms2) by 29.7% (p = 0.01). Linear regression analysis after training showed that VO2peak was correlated with SDNN (r = 0.55, p = 0.03) and HF (r = 0.72, p = 0.02). Multiple regression analysis indicated that the improvement of sympathovagal balance and aerobic capacity depended on patients’ participation in exercise training. Conclusion: In conclusion, a 6-month home-based mixed-type exercise program can improve cardiac autonomic function and metabolic profile in DKD patients on HD

Inactivation of mgrB gene regulator and resistance to colistin is becoming endemic in carbapenem-resistant Klebsiella pneumoniae in Greece: A nationwide study from 2014 to 2017

Introduction: In Greece, the spread of carbapenem-resistant Enterobacteriaceae in humans has led to the reintroduction of colistin as a therapeutic agent. Unfortunately, colistin resistance with different mechanisms has emerged. The present work aims to determine the prevalence of carbapenem and colistin resistance and the corresponding mechanisms in Klebsiella pneumoniae clinical isolates from Greece. Methods: From 2014 to 2017, 288 carbapenem-resistant K. pneumoniae clinical strains were gathered from a collection of 973 isolates from eight different hospitals in Greece. Antibiotic susceptibility testing was performed using three different methods. Screening of carbapenem and colistin resistance genes was conducted using polymerase chain reaction (PCR) amplification and sequencing. Results: Among the 288 (29.6 %) carbapenem-resistant isolates, 213 (73.9%) were colistin-resistant (minimum inhibitory concentration [MIC] >2 mg/L). The KPC type was the most common carbapenemase gene (116; 40.3%), followed by VIM (41; 14.2%), NDM (33; 11.5%) and OXA-48 (22; 7.6%). Moreover, 44 (15.3%) strains co-produced two types of carbapenemases. No mcr genes were detected for colistin resistance but mutations in chromosomal genes were found. These included inactivation of the mgrB gene for 148 (69.5%) strains, including insertion sequences for 94 (44.1%), nonsense mutations for 4 (1.9%) and missense mutations for 24 (11.3%). Moreover, PCR amplification of mgrB gene was negative for 26 (12.2%) strains. Finally, 65 (30.5%) colistin-resistant strains exhibited a wild-type mgrB, the mechanisms of which remain to be elucidated. Conclusion: This study shows that K. pneumoniae clinical strains in Greece are resistant to both carbapenems and colistin and this is endemic and is likely chromosomally encoded. (C) 2020 Published by Elsevier B.V