Investigating the KNDy hypothesis in humans by co-administration of kisspeptin, neurokinin B and naltrexone in men

Context: A subpopulation of hypothalamic neurons co-localise three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates and dynorphin (an opioid) inhibits. Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of co-administration of kisspeptin-54, NKB and an opioid receptor antagonist, naltrexone on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release. Design, setting and participants: Ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits. Intervention and main outcome measure: After 1h baseline blood sampling, participants received a different intervention at each visit: oral 50mg naltrexone (NAL), 8h intravenous infusions of vehicle, 2.56nmol/kg/h NKB (NKB), 0.1nmol/kg/h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis. Results: All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (p<0.001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (p<0.01). NAL+KP was the only group to significantly increase LH pulse amplitude (p<0.001 vs vehicle). Conclusions: Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans

The role of genetic biomarkers in the investigation of adenomas and multiple gland disease in sporadic primary hyperparathyroidism: study of miRNAs

Background/aim: Almost 15% of patients with sporadic primary hyperparathyroidism (sPHPT) present with multiple gland disease (MGD). To date, there is no reliable method to diagnose MGD preoperatively. The aim of this study was to investigate the potential role of two polymorphisms of the hsa-miR-30e in sPHPT tumorigenesis and the possible use of hsa-miR-30e as a biomarker for early diagnosis of MGD. Patients and methods: One-hundred twenty sPHPT patients, 77 presenting with a single adenoma and 43 with MGD and 54 healthy controls were genotyped. The SNPs were identified using the allele-specific PCR methodology, while the hsa-miR-30e expression was analyzed by real-time quantitative reverse transcriptase PCR. Results: Hsa-miR-30e expression was found to be significantly higher in patients with MGD compared to patients with single adenomas (p=0.0019), but no differences were found regarding specific genotype carriers. The genotype frequencies for ss178077483 and rs7556088 were significantly different between patients and healthy controls. Conclusion: Although the polymorphisms cannot be used as biomarkers for the differential diagnosis of MGD, hsa-miR-30e expression could potentially serve as a biomarker for this purpose.Σκοπός: Σχεδόν το 15% των ασθενών με σποραδικό πρωτοπαθή υπερπαραθυρεοειδισμό (sPHPT) παρουσιάζουν νόσο πολλαπλών αδένων (MGD). Μέχρι σήμερα, δεν υπάρχει αξιόπιστη μέθοδος γιατη διάγνωση της MGD προεγχειρητικά. Σκοπός αυτής της μελέτης ήταν να διερευνήσει τον πιθανό ρόλο δύο πολυμορφισμών του hsa-miR-30e στην ογκογένεση του sPHPT και την πιθανή χρήση του hsa-miR-30e ως βιοδείκτη για την έγκαιρη διάγνωση της MGD. Ασθενείς και μέθοδοι: Αναλύθηκε το γενετικό υλικό εκατόν είκοσι ασθενών με sPHPT, 77 που παρουσίασαν μονήρες αδένωμα, 43 με MGD και 54 υγιών μαρτύρων. Οι πολυμορφισμοί ταυτοποιήθηκαν χρησιμοποιώντας τη μεθοδολογία της ειδικής για τα αλληλόμορφα-PCR, ενώ η έκφραση του hsa-miR-30e αναλύθηκε με ποσοτική PCR αντίστροφης μεταγραφάσης σε πραγματικό χρόνο. Αποτελέσματα: Η έκφραση του hsa-miR-30e βρέθηκε να είναι σημαντικά υψηλότερη σε ασθενείς με MGD, σε σύγκριση με ασθενείς με μονήρη αδενώματα (p = 0,0019), αλλά δεν βρέθηκαν διαφορές σχετικά με τους φορείς συγκεκριμένου γονοτύπου. Οι συχνότητες των γονοτύπων για τους πολυμορφισμούς ss178077483 και rs7556088 διέφεραν στατιστικά σημαντικά μεταξύ των ασθενών και των υγιών μαρτύρων. Συμπέρασμα: Αν και οι πολυμορφισμοί δεν μπορούν να χρησιμοποιηθούν ως βιοδείκτες για τη διαφορική διάγνωση της MGD από το μονήρες αδένωμα, η έκφραση του hsa-miR-30e θα μπορούσε ενδεχομένως να χρησιμεύσει ως βιοδείκτης για το σκοπό αυτό

Διερεύνηση γενετικών βιοδεικτών για τη διάκριση αδενώματος και υπερπλασίας στον σποραδικό πρωτοπαθή υπερπαραθυρεοειδισμό: μελέτη πολυμορφισμών microRNAs

Σκοπός: Σχεδόν το 15% των ασθενών με σποραδικό πρωτοπαθή υπερπαραθυρεοειδισμό (sPHPT) παρουσιάζουν νόσο πολλαπλών αδένων (MGD). Μέχρι σήμερα, δεν υπάρχει αξιόπιστη μέθοδος για τη διάγνωση της MGD προεγχειρητικά. Σκοπός αυτής της μελέτης ήταν να διερευνήσει τον πιθανό ρόλο δύο πολυμορφισμών του hsa-miR-30e στην ογκογένεση sPHPT και την πιθανή χρήση του hsa- miR-30e ως βιοδείκτη για την έγκαιρη διάγνωση της MGD. Ασθενείς και μέθοδοι: Αναλύθηκε το γενετικό υλικό εκατόν είκοσι ασθενών με sPHPT, 77 που παρουσίασαν μονήρες αδένωμα και 43 με MGD, και 54 υγιών μαρτύρων. Οι πολυμορφισμοί ταυτοποιήθηκαν χρησιμοποιώντας τη μεθοδολογία της ειδικής για τα αλληλόμορφα-PCR, ενώ η έκφραση του hsa-miR-30e αναλύθηκε με ποσοτική PCR αντίστροφης μεταγραφάσης σε πραγματικό χρόνο. Αποτελέσματα: Η έκφραση του hsa-miR-30e βρέθηκε να είναι σημαντικά υψηλότερη σε ασθενείς με MGD σε σύγκριση με ασθενείς με μονήρη αδενώματα (p = 0,0019), αλλά δεν βρέθηκαν διαφορές σχετικά με τους φορείς συγκεκριμένου γονοτύπου. Οι συχνότητες των γονοτύπων για τα ss178077483 και rs7556088 ήταν σημαντικά διαφορετικές μεταξύ των ασθενών και των υγιών μαρτύρων. Συμπέρασμα: Αν και οι πολυμορφισμοί δεν μπορούν να χρησιμοποιηθούν ως βιοδείκτες για τη διαφορική διάγνωση του MGD από το μονήρες αδένωμα, η έκφραση του hsa-miR-30e θα μπορούσε ενδεχομένως να χρησιμεύσει ως βιοδείκτης για το σκοπό αυτό.Background/aim:Almost 15% of patients with sporadic primary hyperparathyroidism (sPHPT) present with multiple gland disease (MGD). To date, there is no reliable method to diagnose MGD preoperatively. The aim of this study was to investigate the potential role of two polymorphisms of the hsa-miR-30e in sPHPT tumorigenesis and the possible use of hsa- miR-30e as a biomarker for early diagnosis of MGD. Patients and methods: One-hundred twenty sPHPT patients, 77 presenting a single adenoma and 43 with MGD, and 54 healthy controls were genotyped. The SNPs were identified using the allele-specific PCR methodology, while the hsa-miR-30e expression was analyzed by real-time quantitative reverse transcriptase PCR. Results: Hsa-miR-30e expression was found to be significantly higher in patients with MGD compared to patients with single adenomas (p=0.0019), but no differences were found regarding specific genotype carriers. The genotype frequencies for ss178077483 and rs7556088 were significantly different between patients and healthy controls. Conclusion: Although the polymorphisms cannot be used as biomarkers for the differential diagnosis of MGD, hsa-miR-30e expression could potentially serve as a biomarker for this purpose

The menace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development

The delivery of the appropriate thyroid hormones quantity to target tissues in euthyroidism is the result of unopposed synthesis, transport, metabolism, and excretion of these hormones. Thyroid hormones homeostasis depends on the maintenance of the circulating ‘free’ thyroid hormone reserves and on the development of a dynamic balance between the ‘free’ hormones reserves and those of the ‘bound’ hormones with the transport proteins. Disturbance of this hormone system, which is in constant interaction with other hormone systems, leads to an adaptational counter-response targeting to re-establish a new homeostatic equilibrium. An excessive disturbance is likely to result, however, in hypo- or hyper- thyroid clinical states. Endocrine disruptors are chemical substances forming part of ‘natural’ contaminating agents found in most ecosystems. There is abundant evidence that several key components of the thyroid hormones homeostasis are susceptible to the action of endocrine disruptors. These chemicals include some chlorinated organic compounds, polycyclic aromatic hydrocarbons, herbicides, and pharmaceutical agents. Intrauterine exposure to endocrine disruptors that either mimic or antagonize thyroid hormones can produce permanent developmental disorders in the structure and functioning of the brain, leading to behavioral changes. Steroid receptors are important determinants of the consequences of endocrine disruptors. Their interaction with thyroid hormones complicates the effect of endocrine disruptors. The aim of this review is to present the effect of endocrine disruptors on thyroid hormones physiology and their potential impact on intrauterine development

Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks

Primary hyperparathyroidism (pHPT) is a common endocrinopathy resulting from inappropriately high PTH secretion. It usually results from the presence of a single gland adenoma, multiple gland hyperplasia or rarely parathyroid carcinoma. All these conditions require different management and it is important to be able to differentiate the underlined pathology, in order for the clinicians to provide the best therapeutic approach. Elucidation of the genetic background of each of these clinical entities would be of great interest. However, the molecular factors that control parathyroid tumorigenesis are poorly understood. There are data implicating the existence of specific genetic pathways involved in the emergence of parathyroid tumorigenesis. The main focus of the present study is to present the current optimal diagnostic and management protocols for pHPT as well as to review the literature regarding all molecular and genetic pathways that are be involved in the pathophysiology of sporadic pHPT

Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks

Primary hyperparathyroidism (pHPT) is a common endocrinopathy resulting from inappropriately high PTH secretion. It usually results from the presence of a single gland adenoma, multiple gland hyperplasia or rarely parathyroid carcinoma. All these conditions require different management, and it is important to be able to differentiate the underlined pathology, in order for the clinicians to provide the best therapeutic approach. Elucidation of the genetic background of each of these clinical entities would be of great interest. However, the molecular factors that control parathyroid tumorigenesis are poorly understood. There are data implicating the existence of specific genetic pathways involved in the emergence of parathyroid tumorigenesis. The main focus of the present study is to present the current optimal diagnostic and management protocols for pHPT as well as to review the literature regarding all molecular and genetic pathways that are to be involved in the pathophysiology of sporadic pHPT

Sudden ‘cure’ of type two diabetes due to pancreatic insulinoma: A case report

Insulinomas are rare tumors of the islet cells of the pancreas and are the most common cause of endogenous hyperinsulinism. Although they usually present with symptoms of hypoglycemia, sometimes they can have vague symptoms. We present the case of a 62-year-old diabetic female who was diagnosed with a large insulinoma after being investigated for the ‘cure’ of her diabetes. We also review the literature regarding insulinomas in patients with diabetic. A 62-year-old, obese woman with type 2 diabetes mellitus was initially investigated for an unexplained normalization of her blood glucose levels after the cessation of antidiabetic medication due to an episode of severe hypoglycemia. She remained without antidiabetics for three months maintaining normoglycemia, and thereafter, she started experiencing frequent but less severe hypoglycemic episodes. She did not change her diet habits or level of activity and did not lose any weight. The patient underwent further investigation with a supervised 72 h fasting test, which resulted in the biochemical diagnosis of endogenous hyperinsulinism. Imaging studies revealed the presence of a large insulinoma in the head of the pancreas. Finally, the patient underwent a pylorus preserving Whipple procedure, which reversed the aforementioned ‘normalization’ of glucose levels and the underlying diabetes mellitus reappeared. Insulinomas are rare tumors causing hypoglycemia. Even more rarely are found in diabetic patients, making the diagnosis more challenging and probably delayed, as the symptoms are masked by the presence of diabetes, thereby leading to a more advanced disease diagnosis. © 2020, Spandidos Publications. All rights reserved

Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: Old knowledge with new tricks

Primary hyperparathyroidism (pHPT) is a common endocrinopathy resulting from inappropriately high PTH secretion. It usually results from the presence of a single gland adenoma, multiple gland hyperplasia or rarely parathyroid carcinoma. All these conditions require different management, and it is important to be able to differentiate the underlined pathology, in order for the clinicians to provide the best therapeutic approach. Elucidation of the genetic background of each of these clinical entities would be of great interest. However, the molecular factors that control parathyroid tumorigenesis are poorly understood. There are data implicating the existence of specific genetic pathways involved in the emergence of parathyroid tumorigenesis. The main focus of the present study is to present the current optimal diagnostic and management protocols for pHPT as well as to review the literature regarding all molecular and genetic pathways that are to be involved in the pathophysiology of sporadic pHPT. © 2018 The authors