Female-specific risk factors for cardiovascular disease: an update.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. While it was previously believed that men have greater susceptibility to CVD, recent research suggests that women face an increased risk of CVD after the onset of menopause, primarily due to the loss of the protective effects of estrogens. Premature ovarian insufficiency (POI), polycystic ovarian syndrome (PCOS), and gestational factors, such as gestational diabetes mellitus (GDM), recurrent pregnancy loss, preterm delivery, and preeclampsia, are specific reproductive disorders that may contribute to an elevated risk of CVD at earlier ages, i.e., before the onset of menopause. This suggests that women with these conditions should be closely monitored for CVD risk factors even before reaching menopause. Such early intervention may help reduce the incidence of CVD and improve overall cardiovascular health in this population. The precise pathophysiological mechanism underlying the development of CVD in women with menopause, premature POI, PCOS, and gestational factors remains elusive. This review article seeks to elucidate the latest research on the relationship between these conditions and CVD in women, aiming to explore the underlying pathogenic mechanisms contributing to this association.

Secondary diabetes mellitus in pheochromocytomas and paragangliomas.

Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.

Identification of Patients at High Risk for Postsurgical Hypoparathyroidism.

BACKGROUND/AIM: Postsurgical hypoparathyroidism (PostHypo) is a common complication after total thyroidectomy. We studied the risk factors associated with PostHypo. PATIENTS AND METHODS: The study included 109 women, (mean age: 50.7±10.75 years), who underwent total thyroidectomy for thyroid diseases. RESULTS: Based on the development of biochemical hypocalcemia on the first postoperative day following total thyroidectomy, (cCa<8.4 mg/dl), 37 women developed PostHypo and 72 did not. Younger age, a lower preoperative corrected calcium and the presence of parathyroid glands in the specimens were related to the development of PostHypo. Of all patients, 51.4% had a vitamin D deficiency. A parathyroid hormone (PTH) value ≤9.4 pg/ml was 84.9% sensitive and 71.4% specific to predict PostHypo on the 1st postoperative day. A 50% reduction of the PTH value on the 1st postoperative day from the preoperative level could identify patients who develop PostHypo with 76% sensitivity and 75% specificity. CONCLUSION: PTH postoperative measurement and its alteration from the preoperative level can be used to identify patients who are at increased risk to develop PostHypo.

Gender Predilection in Sporadic Parathyroid Adenomas.

Primary hyperparathyroidism is a common endocrinopathy that is mainly caused by benign parathyroid adenomas. The frequency, clinical presentation and complications of the disease show significant differences between genders, with the majority of cases being reported in postmenopausal women. Due to this gender predilection, several studies have investigated the role of sex hormones in the pathogenesis of the disease and their potential use as targets for optimal and gender-specific management. Epigenetic mechanisms that regulate gene transcription may also contribute to these differences between genders. In this review, we outline what is currently known regarding the role of sex hormones and the recent data on the role of non-coding RNAs in the differences between genders in primary hyperparathyroidism due to sporadic parathyroid adenomas.

Management of parathyroid disorders: recommendations of the working group of the Bone Section of the Hellenic Endocrine Society.

The Bone Section of the Hellenic Endocrine Society has issued the recommendations herein presented with the aim of providing guidance on optimal management of patients with parathyroid disorders in everyday clinical practice within the Greek health care setting. Although the methodology followed to formulate these recommendations was not strictly based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles, they were drawn up after an extensive review of the literature and of the currently available guidelines for the management of parathyroid disorders worldwide. Specifically for primary hyperparathyroidism (PHPT), the 2011 guidelines of the Greek National Organization of Medicines were updated accordingly. In particular, definitions, etiologies, and recommended and optional laboratory and imaging examinations are provided both for PHPT and chronic hypoparathyroidism (HypoPT). Finally, treatment algorithms are provided for the management of both PHPT and HypoPT. Specifically for HypoPT, the treatment algorithm describes the recommended steps that should be followed to achieve optimal management of chronic hypocalcemia and the complications of HypoPT through the conventional treatment available in Greece and the use of recombinant human PTH(1-84).

Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms.

BACKGROUND/AIMS: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters. METHODS: Fluorescent immunostaining for the autophagy markers LC3Β and p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analysed in relation to clinico-pathological parameters. TOMM20/LC3B qualitative assessment of mitophagy levels was undertaken by fluorescent immunostaining. The presence of autophagy/mitophagy was validated by transmission electron microscopy. RESULTS: Autophagy levels (LC3B-positive puncta/cell) were discriminative for normal vs. NEN pancreatic tissue (p = 0.007). A significant association was observed between autophagy levels and tumour grade (Ki67 < 3% vs. Ki67 ≥ 3%; p = 0.021), but not functionality (p = 0.266) size (cut-off of 20 mm; p = 0.808), local invasion (p = 0.481), lymph node- (p = 0.849) and distant metastases (p = 0.699). Qualitative assessment of TOMM20/LC3B demonstrated strong mitophagy levels in PanNENs by fluorescent immunostaining as compared with normal tissue. Transmission electron microscopy revealed enhanced autophagy and mitophagy in PanNEN tissue. Response to molecular targeted therapies in metastatic cases (n = 4) did not reveal any patterns of association to autophagy levels. CONCLUSIONS: Increased autophagy levels are present in primary tumours of patients with PanNENs and are partially attributed to upregulated mitophagy. Grade was the only clinico-pathological parameter associated with autophagy scores.

The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms: a systematic review and meta-analysis of adult and paediatric patients.

BACKGROUND: There are no clear histopathological parameters determining the risk of lymph node (LN) metastases and appropriateness of completion prophylactic right hemicolectomy (RHC) in patients with appendiceal neuroendocrine neoplasms (ANENs). MATERIALS AND METHODS: The PubMed, Cochrane Library, Embase, Web of Science and SCOPUS databases were searched up to November 2018. Quality/risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: A total of 526 articles were screened. In 11 adult and 3 paediatric studies, 602 and 77 unique patients, respectively, with ANEN and undergoing RHC, were included. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions <10 mm) among adult patients, with an odds ratio (OR) of 4.8 (95% CI, 1.5-15.8). For 20 mm size cutoff, these figures were 61% (vs 28.2% for lesions <20 mm) with an OR of 3.2 (95% CI, 1.3-7.8). Vascular-, lymph vessel- and perineural invasions were identified as predictive factors for LN metastases in adult patients. In paediatric patients, there were no strong morphological predictors for LN metastases. The 10-year disease-specific survival (DSS) for adult patients without LN metastases was 99.2% vs 95.6% in patients with LN (OR: 0.2; 95% CI, 0.02-2.4). The complication rate of prophylactic RHC was 11.4%. CONCLUSIONS: This meta-analysis demonstrates that tumour size >20 mm as well as >10 mm and/or vascular-, lymph vessel- and perineural invasions are associated with increased risk for LN metastases in adult patients with ANEN. The prognostic value of LN positivity remains to be determined in further studies with long-term follow-up.

The Impact of Obesity on the Association between Vitamin D Deficiency and Cardiovascular Disease.

The aim of this article is to review the literature regarding the relationship between vitamin D deficiency and cardiovascular disease (CVD) and its modification in the presence of obesity. Despite the strong association between vitamin D status and cardiovascular outcomes, vitamin D supplementation trials in the general population have failed to decrease the incidence of cardiovascular events and mortality. A comprehensive study of the published literature and a comparison with experimental data lead to the conclusion that obesity, due to its high prevalence and strong association with both vitamin D deficiency and CVD, may act as a critical confounder, which is responsible for the different results on this association. Adoption of a vitamin D preventive supplementation strategy for CVD is unlikely to yield any benefit to the general population. However, it might be particularly useful in obese adults with increased risk for CVD.

Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?

Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean±SD: 2 mm/year±3.4 mm vs. 1.9 mm/year±3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.

Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms.

Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1-38.9) vs 9 months (95% CI: 0-18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1-19.9) vs 13 months with sunitinib (95% CI: 9.3-16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5-8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3-31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2-6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.

Postsurgical Hypoparathyroidism: A Systematic Review.

This article reviews epidemiology, risk factors and treatment modalities of postsurgical hypoparathyroidism (PHypo). PHypo occurs after total thyroidectomy due to injury of parathyroid glands and/or their blood supply or after parathyroidectomy. PHypo results in hypocalcemia because parathyroid hormone (PTH) secretion is impaired and cannot mobilize calcium from bone, reabsorb calcium from the distal nephron and stimulate renal 1α-hydroxylase activity. It usually appears in the first days after surgery and it can be symptomatic or asymptomatic. Risk factors are low level of intraoperative PTH and presence of parathyroid gland in the pathological specimen. Patients usually present with paresthesia, cramps or tetany, but the disorder may also manifest acutely with seizures, bronchospasm, laryngospasm or cardiac rhythm disturbances. Standard treatment is vitamin D analogues and calcium supplementation.

Metastatic pheochromocytoma and paraganglioma.

BACKGROUND: Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background. DESIGN: We searched the PubMed database through February 2015 to identify studies characterizing metastatic PCs/PGLs as well as currently established and evolving therapies. RESULTS: Large size tumours (> 5 cm), PASS score > 6 and Ki-67 labelling index > 3% are the most robust indices of metastatic PCs/PGLs albeit with great variability. Germline succinate dehydrogenase complex, subunit B (SDHB) mutation constitutes the main reliable molecular predictor of malignancy. Plasma and urinary methoxytyramine are the biochemical markers characterizing metastatic PCs/PGLs along with evolving molecular markers such as miRNAs and SNAIL. Conventional imaging is used for tumour localization, whereas (18)F-FDG-PET for staging of metastatic PCs/PGLs especially those related to SDHB gene mutations. In addition, (68)Ga-DOTATATE PET/CT is emerging as a highly sensitive alternative. Surgery remains the gold standard treatment in reducing tumour bulk and/or controlling the clinical syndrome. Treatment with (131)I-MIBG or radiolabelled somatostatin analogues is considered for unresectable disease. Conventional chemotherapy is reserved for more advanced and refractory to other therapies disease although new schemes are currently evolving. Recent genetic studies have highlighted a number of pathways involved in PCs/PGLs pathogenesis directing towards the use of targeted therapies which have still to be validated in clinical practice. CONCLUSIONS: Metastatic PCs/PGLs remain an orphan disease that is only curable by surgery. However, advances in genomic analyses have improved the pathogenesis of these tumours and may lead to effective and more personalized treatments in the near future.

Hyperandrogenism after menopause.

Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from either the adrenals and/or the ovaries, clinically manifested as the appearance and/or increase in terminal hair growth or the development of symptoms/signs of virilization. In either settings, physicians need to evaluate such patients and exclude the presence of the relatively rare but potentially life-threatening underlying tumorous causes, particularly adrenal androgen-secreting tumors. It has been suggested that the rapidity of onset along with severity of symptom and the degree of androgen excess followed by relevant imaging studies may suffice to identify the source of excessive androgen secretion. However, up to date, there is no consensus regarding specific clinical and hormonal indices and/or imaging modalities required for diagnostic certainty. This is particularly relevant as the aging population is increasing and more cases of postmenopausal women with clinical/biochemical evidence of hyperandrogenism may become apparent. Furthermore, the long-term sequels of nontumorous hyperandrogenism in postmenopausal women in respect to cardiovascular morbidity and mortality still remain unsettled. This review delineates the etiology and pathophysiology of relative and absolute androgen excess in postmenopausal women. Also, it attempts to unravel distinctive clinical features along with specific hormonal cut-off levels and/or appropriate imaging modalities for the facilitation of the differential diagnosis and the identification of potential long-term sequels.