Metabolic Perspectives for Non-classical Congenital Adrenal Hyperplasia With Relation to the Classical Form of the Disease

Non-classical congenital adrenal hyperplasia (NC-CAH) represents mild form of CAH with the prevalence of 0. 6 to 9% in women with androgen excess. Clinical and hormonal findings in females with NC-CAH are overlapping with other hyperandrogenic entities such as polycystic ovary syndrome hence causing difficulties in diagnostic approach. Metabolic consequences in subjects with NC-CAH are relatively unknown. We are lacking longitudinal follow of these patients regarding natural course of the disease or the therapeutic effects of the different drug regiments. Patients with NC-CAH similarly to those with classical form are characterized with deteriorated cardiovascular risk factors that are probably translated into cardiometabolic diseases and events. An increased preponderance of obesity and insulin resistance in patients with NC-CAH begin at young age could result in increased rates of metabolic sequelae and cardiovascular disease later during adulthood in both sexes. On the other hand, growth disorder was not proven in patients with NC-CAH in comparison to CAH patients of both gender characterized with reduced final adult height. Similarly, decreased bone mineral density and osteoporosis are not constant findings in patients with NC-CAH and could depend on the sex, and type or dose of corticosteroids applied. It could be concluded that NC-CAH represent a particular form of CAH that is characterized with specificities in clinical presentation, diagnosis, therapeutic approach and metabolic outcomes.This study was funded by the Serbian Ministry of Education, Science and Technological Development (grant numbers 175032 and 41009)

Influence of the change of the hypothalamo-pituitary-adrenal axis reactivity on the outcome in patients with systemic inflammatory response

Uvod: Sindrom sistemskog inflamatornog odgovora (SIRS) predstavlja inflamatorno stanje uzrokovano infekcijom ili sepsom i koje se širi na ceo organizam. SIRS se smatra delom „citokinske oluje“ i manifestuje se disregulacijom različiutih citokina. Ozbiljnost bolesti se najbolje prediktuje korišćenjem APACHE II skora (Acute Physiology and Chronic Health Evaluation II) dok se ishod kod pacijenta, odnosno organska disfunkcija ili insuficijencija prediktuje pomoću SOFA skora (Sequential Organ Failure Assessment). SIRS dovodi do značajnih promena u dinamici kortizola ukazujući na disocijaciju između adrenalnog korteksa i hipotalamo-hipofizne jedinice. Navedena promena se manifestuje visokim koncentracijama kortizola i ACTH odmah nakon početka SIRS-a. Međutim, nekoliko dana kasnije, ACTH se spušta do veoma niskih koncentracija dok koncentracije kortizola ostaju visoke. Navedeno se objašnjava direktnim efektom citokina, kao što je interleukin 6 (IL-6), na koru nadbubrega koji stimulišu oslobađanje glukokortikoida. Odgovor kortizola na stimulaciju sa ACTH predstavlja važan prediktor ishoda kod kritično bolesnih. Bolesnici sa neadekvatnim odgovorom kortizola na stimulaciju sa ACTH imaju visoku stopu mortaliteta. Stimulacija sa 250 μg ACTH se smatra zlatnim standardom u proceni adrenalne funkcije. Međutim, niskodozni test sa 1 μg ACTH (NDT) predstavlja senzitivniji test u detekciji specifičnih formi adrenalne insuficijencije kao što je hipotalamo-hipofizna disfunkcija. Upotreba NDT u kritično obolelih nije jasno definisana jer postoji mali broj podataka za formiranje jasne preporuke...Introduction: Systemic inflammatory response syndrome (SIRS) represens inflamatory condition caused bz infection or sepsis that spreads all over the body. SIRS is considered a part of the „cytokine storm“ and is manifested by dysregulation of different cytokines. The severity of the disease is best predicted using Acute Physiology and Chronic Health Evaluation II (APACHE II) score while the patient’s outcome, namely organ dysfunction/failure during Intensive Care Unit (ICU) monitoring is predicted using Sequential Organ Failure Assessment (SOFA) score. SIRS leads to significant changes in cortisol dynamics indicating on the disociation between adrenal cortex and the hypothalamo-pituitary unit. This is manifested by the very high concentrations of cortisol and ACTH immediatly after commencement of SIRS. However, a few days later ACTH falls to the very low concentration while the concentrations of cortisol remains high. This is explained by direct effect of cytokines, as it is interleukin 6 (IL-6), on the adrenal cortex that is simulating glucocorticoid realease. Cortisol response on the stimulation with ACTH was shown to be important predictor of the outcome in critically ill patients. Patients with inadequate cortisol response on stimulation with ACTH had high mortality rate. Stimulation with 250 μg of ACTH is considered to be gold standard test for the assessment of adrenal function. However, the low-dose (1 μg) test (LDT) represents a more sensitive test for detecting specific forms of adrenal insufficiency as it is hypothalamo-pituitary disfunction. The use of LDT in critically ill patients is not clearly defined as the data on LDT are limited and not sufficient for the clear recommendation..

Can dysglycemia in OGTT be predicted by baseline parameters in patients with PCOS?

BackgroundPolycystic ovary syndrome (PCOS) is considered a risk factor for the development of type 2 diabetes mellitus (T2DM). However, which is the most appropriate way to evaluate dysglycemia in women with PCOS and who are at increased risk are as yet unclear. Aim of the studyTo determine the prevalence of T2DM, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in PCOS women and potential factors to identify those at risk. Subjects and methodsThe oral glucose tolerance test (OGTT), biochemical/hormonal profile, and ovarian ultrasound data from 1614 Caucasian women with PCOS and 362 controls were analyzed in this cross-sectional multicenter study. The data were categorized according to age and BMI. ResultsDysglycemia (T2DM, IGT, and IFG according to World Health Organization criteria) was more frequent in the PCOS group compared to controls: 2.2% vs 0.8%, P = 0.04; 9.5% vs 7.4%, P = 0.038; 14.2% vs 9.1%, P = 0.002, respectively. OGTT was essential for T2DM diagnosis, since in 88% of them basal glucose values were inconclusive for diagnosis. The presence of either T2DM or IFG was irrespective of age (P = 0.54) and BMI (P = 0.32), although the latter was associated with IGT (P = 0.021). There was no impact of age and BMI status on the prevalence of T2DM or IFG. Regression analysis revealed a role for age, BMI, fat deposition, androgens, and insulin resistance for dysglycemia. However, none of the factors prevailed as a useful marker employed in clinical practice. ConclusionsOne-third of our cohort of PCOS women with either T2DM or IGT displayed normal fasting glucose values but without confirming any specific predictor for dysglycemic condition. Hence, the evaluation of glycemic status using OGTT in all women with PCOS is strongly supported

The effect of subchronic supplementation with folic acid on homocysteine induced seizures

Influence of folic acid on the CNS is still unclear. Folate has a neuroprotective effect, while on the other hand excess folate can exacerbate seizures in epileptics. The aim of the present study was to examine the effect of subchronic administration of folic acid on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone induced seizures in adult rats. The activity of Na+/K+-ATPase and Mg2+-ATPase in different brain regions was investigated. Adult male Wistar rats were divided into groups: 1. Controls (C, 0.9% NaCl); 2. DL homocysteine-thiolactone 8.0 mmol/kg (H); 3. Subchronic supplementation with folic acid 5 mg/kg for 7 days (F) and 4. Subchronic supplementation with F + single dose of H (FH). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0–4. For EEG recordings, three gold-plated recording electrodes were implanted into the skull. Subchronic supplementation with folic acid did not affect seizure incidence, median number of seizure episodes and severity in FH, comparison with H (p > 0.05). The majority of seizure episodes in all groups were of grade 2. There were no significant differences in lethal outcomes at 24 h upon H injection in the FH vs. H group. The activity of Na+/K+-ATPase and Mg2+-ATPase was significantly increased in almost all examined structures in the FH vs. H group. Subchronic folic acid administration did not exacerbate H induced seizures and completely recovered the activity of ATPases

Tuning PFKFB3 Bisphosphatase Activity Through Allosteric Interference

The human inducible phospho-fructokinase bisphosphatase isoform 3, PFKFB3, is a crucial regulatory node in the cellular metabolism. The enzyme is an important modulator regulating the intracellular fructose-2,6-bisphosphate level. PFKFB3 is a bifunctional enzyme with an exceptionally high kinase to phosphatase ratio around 740:1. Its kinase activity can be directly inhibited by small molecules acting directly on the kinase active site. On the other hand, here we propose an innovative and indirect strategy for the modulation of PFKFB3 activity, achieved through allosteric bisphosphatase activation. A library of small peptides targeting an allosteric site was discovered and synthesized. The binding affinity was evaluated by microscale thermophoresis (MST). Furthermore, a LC-MS/MS analytical method for assessing the bisphosphatase activity of PFKFB3 was developed. The new method was applied for measuring the activation on bisphosphatase activity with the PFKFB3-binding peptides. The molecular mechanical connection between the newly discovered allosteric site to the bisphosphatase activity was also investigated using both experimental and computational methods

Computer aided design and NMR characterization of an oligopeptide targeting the Ebola virus VP24 protein

The Ebola viral Protein 24 (VP24) inhibits interferon signaling through its interaction with the human protein Karyopherin, thus impairing the immune response of the host against the infection and increasing its rate of diffusion into the organism and its lethality. This makes VP24 a potential pharmacological target, as the inhibition of its interaction with Karyopherin could reduce Ebola virulence. In this work, we carried out an atomic level study of the network of interactions between VP24 and Karyopherin using molecular dynamics and computational alanine scanning. Modeling the VP24-Karyopherin complex allowed us to identify the amino acid residues responsible for protein-protein binding and led to the identification of a nonapeptide with VP24 binding potential. Subsequently, the ability of this peptide to actually bind VP24 in solution has been assayed using Saturation Transfer Difference NMR and Circular Dichroism. Experimental and molecular modeling data concerning the VP24-peptide complex have been compared and putative peptide binding sites and modes are discussed

Metabolomics Reveals Reduction of Metabolic Oxidation in Women with Polycystic Ovary Syndrome after Pioglitazone-Flutamide-Metformin Polytherapy

Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients

MPOWERED trial open-label extension: long-term efficacy and safety data for oral octreotide capsules in acromegaly

Context The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated long-term efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly. Core trial primary endpoint data demonstrated noninferiority to injectable somatostatin receptor ligands (iSRLs). Core trial completers were invited to participate in the OLE phase. Objective To assess long-term efficacy and safety of OOC in patients with acromegaly who previously responded to and tolerated both OOC and injectable octreotide/lanreotide and completed the core phase. Methods The unique study design of transitioning between OOC and iSRLs allowed within-patient evaluations. The proportion of biochemical responders (insulin-like growth factor I < 1.3 x upper limit of normal) at end of each extension year who entered that year as responders was the main outcome measure. Results At year 1 extension end, 52/58 patients from both the monotherapy and the combination therapy groups were responders (89.7%; 95% CI 78.8-96.1), 36/41 (87.8%; 95% CI 73.8-95.9) in year 2, and 29/31 (93.5%; 95% CI 78.6-99.2) in year 3. No new or unexpected safety signals were detected; 1 patient withdrew owing to treatment failure. Patients who transitioned from iSRLs in the core trial to OOC in the OLE phase reported improved treatment convenience/satisfaction and symptom control. Conclusion Patient-reported outcome data support for the first time that transitioning patients randomized to iSRL (who previously responded to both OOC and iSRLs) back to OOC had a significant effect on patients' symptoms score in a prospective cohort. The MPOWERED OLE showed long-term maintenance of response and sustained safety with OOC.Metabolic health: pathophysiological trajectories and therap

Oxidative stress in pregnancy and fertility pathologies

Oxidative stress designates the state of imbalance between reactive oxygen species (ROS) production and antioxidant levels. In a healthy placenta, there is an increase in ROS production, due to formation of new tissues and inherent metabolism, but this is balanced by higher levels of antioxidants. However, this balance is lost in some situations, with a consequent increase in oxidative stress levels. Oxidative stress has been implicated in several placental disorders and pregnancy pathologies. The present review intends to summarize what is known about the relationship between oxidative stress and well-known pregnancy disorders