Feature Papers in Endocrines

Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H₂O₂-induced ROS. Our study supports the anti-oxidative effects of JV-1-36 and contributes in our knowledge towards the in vitro effects of GHRHAnt in cancers. Full article

Background: The American Joint Commission on Cancer on Tumor Node Metastasis (AJCC/TNM) staging system provides adequate information on the risk of differentiated thyroid cancer (DTC)-specific mortality in totally thyroidectomized patients, but its role in predicting persistence and relapse of disease is uncertain. The relatively new 2015 American Thyroid Association (ATA) guidelines recommend stratifying patients at the time of DTC diagnosis with its own risk classification system, in order to identify those at high risk of residual or recurrent morbidity who may benefit from post-operative radioiodine (RAI) administration and/or need additional work-up. Methods: To verify the prevalence proportion of persistence or relapse of disease, a consecutive cohort of 152 patients with a diagnosis of DTC, subjected to total thyroidectomy (+/− post-operative RAI administration as per guidelines indication) and to neck ultrasonography (US), as well as biochemical surveillance for a minimum of 2 years at the Endocrinology Unit of Mater-Domini Hospital (Catanzaro, Italy), was enrolled. The prognostic role of the AJCC/TNM stage and ATA risk classification system was analyzed by logistic regression. Results: At a mean of 9 years after surgical treatment, DTC was found to persist or relapse in 19 (12.5%) participants. The initial risk for these outcomes, based on the ATA classification, was mostly low (53.9%) or intermediate (39.5%). AJCC/TNM stages were predominantly stage I or stage II. Despite a small representation in this cohort, high-risk patients according to the ATA classification had 8-fold higher odds of persistence or relapse of disease than those of low-risk participants, while controlling for potential risk modifiers, including age at DTC diagnosis, male gender, and post-operative RAI administration (p = 0.008). In contrast, the AJCC/TNM stage was not associated with the disease status at the last follow-up visit (p = 0.068 for the 7th Edition; p = 0.165 for the 8th Edition). Furthermore, low-risk participants subjected to post-operative RAI administration had the same probability of persistence or relapse of DTC when compared to those who had undergone total thyroidectomy only. Conclusions: There is a need for the endocrine community to revise the current work-up of DTC. The initial ATA risk classification is a reliable tool for predicting the persistence or relapse of disease in long-term surveillance. Full article

Leydig cells produce androgens which are essential for male sex differentiation and reproductive functions. Steroidogenesis, as well as expression of several genes in Leydig cells, are stimulated by LH/cAMP and repressed by AMP/AMPK. One of those genes is Plau, which codes for the urokinase-type plasminogen activator (uPA), a secreted serine protease. The role of uPA and the regulation of Plau expression in Leydig cells remain unknown. Using siRNA-mediated knockdown, uPA was required for maximal cAMP-induced STAR and steroid hormone production in MA-10 Leydig cells. Analysis of Plau mRNA levels and promoter activity revealed that its expression is strongly induced by cAMP; this induction is blunted by AMPK. The cAMP-responsive region was located, in part, in the proximal Plau promoter that contains a species-conserved GC box at −56 bp. The transcription factor Krüppel-like factor 6 (KLF6) activated the Plau promoter. Mutation of the GC box at −56 bp abolished KLF6-mediated activation and significantly reduced cAMP-induced Plau promoter activity. These data define a role for uPA in Leydig cell steroidogenesis and provide insights into the regulation of Plau gene expression in these cells. Full article

Background: Polycystic ovary syndrome (PCOS) is a frequent reproductive disease characterized by hyperandrogenism, oligo /anovulation, and polycystic aspects at ultrasound. In these last years, a body of evidence disclosed the frequent occurrence in PCOS patients of insulin resistance (IR) and compensatory hyperinsulinemia. Aim: To evaluate whether any relationship exists between IR, compensatory hyperinsulinemia and familial predisposition to diabetes. Methods: A group of overweight/obese PCOS patients (n = 84) was selected from our Clinic database according to the Rotterdam criteria and the following parameters were extracted from the database: insulin, C Peptide, aspartate amino transferase (AST), alanine amino transferase (ALT), HOMA (Homeostasis Model Assessment) index, total cholesterol, LDL (Low Density Lypoprotein), HDL (High Density Lypoprotein), and body mass index (BMI). The presence and absence of diabetes among first grade relatives (parents and/or grandparents) were also considered. The Hepatic Insulin Extraction (HIE) index was computed as a ratio between insulin and C-Peptide plasma levels. Results: PCOS patients with familial diabetes showed higher levels of ALT, AST, HOMA index, and HIE. Baseline insulin levels above 12 μU/mL were more frequently observed in PCOS with familial diabetes. HIE index, ALT, and AST were higher in these latter PCOS patients than in PCOS without diabetic first grade relatives, sustaining the hypothesis of an impaired liver clearance of insulin in the case of familial diabetes. Conclusions: According to our study, the presence of anamnestic evidence of familial diabetes together with baseline levels of insulin higher that 12 µIU/mL and elevated transaminase levels should be considered as a consistent clinical suspect of liver impairment that might trigger compensatory hyperinsulinemia and lead to NAFLD and liver steatosis. Full article

The kisspeptin system includes the cleavage products Kiss1 precursor and kisspeptin receptor (Kiss1R). It was originally discovered and studied in cancer metastasis, but the identification of KISS1/KISS1R gene mutations causing hypogonadotropic hypogonadism (HH) revealed unexpected effects in reproduction. Nowadays, the kisspeptin system is the main central gatekeeper of the reproductive axis at puberty and adulthood, but it also has a widespread functional role in the control of endocrine functions. At the periphery, Kiss1 and Kiss1R are expressed in the testes, but the need for kisspeptin signaling for spermatogenesis and sperm quality is still unclear and debated. This brief manuscript summarizes the main findings on kisspeptin and male reproduction; upcoming data on sperm maturation are also discussed. Full article

Background: Peroxiredoxin 4 (PRDX4), a secreted antioxidant enzyme, can protect against hepatocellular carcinoma and lung adenocarcinoma, but its role in papillary thyroid carcinoma (PTC) is still unclear. In this study, we investigated the association of the PRDX4 expression with the prognosis of patients with advanced PTC. Methods: We conducted a retrospective case-control study at Kanazawa Medical University Hospital. We selected PTC patients over 55 years of age who received surgery from 2006 to 2014. The PRDX4 expression was immunohistochemically analyzed in paraffin-embedded tumor specimens of 70 patients with stages Ⅱ–Ⅳ advanced PTC. We also investigated the key roles of PRDX4 in a human PTC cell line (K-1) in vitro. Result: The weak expression of PRDX4 was found to be significantly associated with recurrence. In a multivariate analysis, the weak expression of PRDX4—rather than other pathological features of high invasiveness—predicted a poor prognosis. In vitro, the viability of human PTC cells was significantly suppressed after PRXD4 plasmid transfection. Conclusion: The weak expression of PRDX4 can predict recurrence with a potential poor prognosis in advanced PTC. Full article

Moxonidine is a centrally acting, anti-hypertensive medication that exerts additional metabolic properties. It is unknown whether its effects are mediated by neurotransmitters or sympathetic tone regulators, including Neuropeptide Y (NPY). In this study, we evaluated the effects of moxonidine administration on serum NPY in humans. Methods: Ninety individuals with mild or moderate arterial hypertension that required monotherapy were categorized in three age and gender-matched groups according to their Body Mass Index (BMI) as normal weight (n = 30), overweight (n = 30), and obese (n = 30). Moxonidine was administered in therapeutic doses of up to 0.6 mg daily for 12 weeks, and clinical, biochemical and hormonal parameters were recorded. Results: In all three groups, a decrease in systolic and diastolic blood pressure and heart rate was shown. After treatment, BMI, 24 h urine catecholamines and catecholamines’ metabolites, and serum total cholesterol were also reduced. Most importantly, we found a decrease in serum NPY levels in all study groups, with the largest mean decrease in the group of obese and overweight participants compared to normal weight. Conclusions: Moxonidine administration results in improvement in cardio-metabolic parameters, as well as a decrease in serum NPY levels, which therefore represents it being a potent agent against obesity-associated hypertension. Its involvement in energy balance regulation warrants further investigation. Full article

Dysmetabolic iron overload syndrome (DIOS) corresponds to the increase in iron stores associated with components of metabolic syndrome (MtS) and in the absence of an identifiable cause of iron excess. The objective of this work was to review the main aspects of DIOS. PUBMED and EMBASE were consulted, and PRISMA guidelines were followed. DIOS is usually asymptomatic and can be diagnosed by investigating MtS and steatosis. About 50% of the patients present altered hepatic biochemical tests (increased levels of γ-glutamyl transpeptidase itself or associated with increased levels of alanine aminotransferase). The liver may present parenchymal and mesenchymal iron overload, but the excess of iron is commonly mild. Steatosis or steatohepatitis is observed in half of the patients. Fibrosis is observed in about 15% of patients. Hyperferritinemia may damage the myocardium, liver, and several other tissues, increasing morbidity and mortality. Furthermore, DIOS is closely related to oxidative stress, which is closely associated with several pathological conditions such as inflammatory diseases, hypertension, diabetes, heart failure, and cancer. DIOS is becoming a relevant finding in the general population and can be associated with high morbidity/mortality. For these reasons, investigation of this condition could be an additional requirement for the early prevention of cardiovascular diseases. Full article

The transgender concept is described as a clinically significant distress due to the incongruity between the experienced gender and assigned gender. A transgender person carries a gender identity that is different from their assigned sex at birth. Transgender people may be binary: male to female (transgender women) or female to male (transgender men) or genderqueer (non-binary, fluid or variable gender expression). The binary concept has been described in transgender population, where the term transwomen is used to describe people assigned male at birth (AMAB) who are recognized as females during gender transition; with the term transmen where they are assigned female at birth (AFAB) and are then recognized as males in gender transition. According to the DSM-5 classification, gender dysphoria is described when a transgender person develops clinically relevant bio-psychosocial suffering. Currently, the transgender population has gained massive public awareness through social media and gained a considerable level of attention globally. Several studies on transgender populations from different parts of the world have shown real discrimination and stigma towards transgender people, which sometimes acts as a barrier to the provision of the required care for them. Lack of access to the required information, legal issues, lack of solutions to fertility problems, financial constraints, and psychological and emotional obstacles, together with risk of sexually transmitted infections, including human immunodeficiency virus (HIV), all make the life of a transgender person more complicated. Testosterone therapy is a hormone-based therapy for transgender men that provides a body image tallying with the favored gender identification, whereas estrogen and androgen-suppressing agents are used in transgender females to produce changes compatible with their required gender identity. Gender affirmation surgery is a broad term, under which the genital reconstruction is described as a major component. Psychological conditions such as depression, substance abuse, suicidal deaths, and sexually transmitted infections, particularly among males having sex with males, are reported at a significantly higher rate among transgender populations. Cardiovascular morbidity is higher among this population, and continuous medical surveillance is warranted. Medical care provision to transgender populations should be handled with great care, while attending to the unmet needs of this population, as this care should extend beyond routine hormonal therapy and gender reassignment surgery. Full article

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most children diagnosed with isolated GHD present with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, and a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature. Full article