Stelios Fountoulakis

The protective role of exercise on stress system dysregulation and comorbidities.

Abstract:  The human body, when under threat, elicits a set of neuroendocrine responses, including an increased secretion of glucocorticoids (GCs) and catecholamines from the adrenal gland and the activation of the sympathetic nervous system. These hormonal secretions allow a “fight or flight” response by mobilizing endogenous substrate and inducing a state of insulin resistance in the liver and skeletal muscles. Although the stress response was essential in ancient times to survive physical aggression, this threat has disappeared in our industrialized societies. However, in todays environment, the same stress responses can be elicited by emotional stimuli or professional and social stress. Such psychological stress may be protracted and unrelated to an increased metabolic demand. Thus, the energy mobilized is not used but is stored in visceral fat depots by the combined action of hypercortisolism and hyperinsulinemia. In addition, chronic activation of the stress system causes suppression of the gonadal, growth hormone (GH), and thyroid axes. These metabolic disturbances, in concert, lead to the clinical expression of a number of comorbidities including central obesity, hypertension, dyslipidemia, and endothelial dysfunction, all components of the metabolic syndrome and cardiometabolic risk factors. Moreover, chronic stress has deleterious effects on the brain and, in particular, affects hippocampal structure and function leading to cognitive and mood disturbances. Importantly, this stress‐induced clinical phenotype is likely to be exaggerated in the presence of physical inactivity, resulting in a “stress‐induced/exercise deficient” phenotype. Assuming that the stress response is a neuroendocrine mechanism that occurs in anticipation of physical action, then physical activity should be the natural means to prevent the consequences of stress. Indeed, accumulating evidence documents the beneficial effects of regular exercise in preventing or ameliorating the metabolic and psychological comorbidities induced by chronic stress. These benefits are thought to derive from a central effect of exercise to reduce the sensitivity to stress and also peripheral actions influencing metabolic functions and, in particular, insulin sensitivity and the partitioning of fuels toward oxidation rather than storage. It is concluded that chronic psychosocial stress, in the presence of physical inactivity, is likely to contribute to the epidemic of cardiometabolic and emotional disease of our current society. The way to prevent and combat this burden is by regular exercise.

On the pathogenesis of autoimmune thyroid disease: a unifying hypothesis.

Autoimmune thyroid disease (AITD) is the most common organspecific autoimmune disorder resulting in dysfunction (hyperfunction, hypofunction or both) of the thyroid gland. The presently accepted classification of AITD, listed in Table 1, includes chronic autoimmune thyroiditis or Hashimoto’s thyroiditis (HT) and its variants (painless postpartum and sporadic thyroiditis), autoimmune atrophic thyroiditis or primary myxoedema and Graves’ disease (GD). Investigation of the AITDs has focussed on determining their pathogenesis and origin in order to develop specific aetiologically based therapeutic measures. Genetic and environmental factors appear to interact leading to appearance of autoantigens and accumulation of professional antigenpresenting cells (APCs) in the thyroid. Consequently, due to loss of immune tolerance, autoreactive immune cells activated by APCs, invade the thyroid gland interacting with thyroid cells in a battle for survival. The activation of apoptotic pathways through surface receptors and ligands is of great significance for the outcome of this battle and thus the clinical expression of AITD. The apoptotic pathways are regulated at several levels and normally remain inactive but blocking can be overcome after cell exposure to certain cytokines produced locally by the activated T lymphocytes. It is likely that the regulation of apoptosis during this interaction between the invading lymphocytes and the defending thyroid cells, may play an important role for the clinical expression of AITD. In this article, current evidence regarding the mechanisms underlying the pathogenesis of AITD is reviewed. Particular emphasis is given to the role of iodine in inducing thyroid autoimmunity and, more importantly, to the role of apoptosis in determining the diverse clinical outcome following the disturbance in immune tolerance and the inappropriate activation of the immune system against the thyroid gland. An overview of the immune regulation

Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension

CONTEXT Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA). OBJECTIVE We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT). PATIENTS AND METHODS One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs. RESULTS Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group. CONCLUSIONS A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

HLA-DR Expressing Peripheral T Regulatory Cells in Newly Diagnosed Patients with Different Forms of Autoimmune Thyroid Disease

BACKGROUND Several reports have claimed a role for T regulatory cells (Tregs) in the pathogenesis of various autoimmune diseases, including autoimmune thyroid disease (AITD). The aim of the present study was to examine whether changes in the number of peripheral CD4 + CD25highHLA-DR + lymphocytes, a subpopulation of Tregs, occur in patients with AITD. METHODS Three-color flow cytometry was used to detect the proportion of CD4 cells expressing CD25, CD25high, and HLA-DR in 70 newly diagnosed and untreated AITD patients and 20 controls. The intensity of CD25 expression on these cells was also examined. RESULTS The proportion of CD4 + CD25 + cells as well as the proportion of CD4 + CD25high cells among the population of CD4 lymphocytes was not different in AITD patients relative to controls. However, a significant increase in the proportion of CD4 + CD25highHLA-DR + cells among the population of CD4 lymphocytes was found in patients with Hashimotos thyroiditis (HT) compared to controls. CONCLUSIONS In HT patients there is a quantitative increase of CD4 + CD25highHLA-DR + cells that may indicate a compensatory expansion of this subpopulation of Tregs in an attempt to suppress the immune response.

Primary aldosteronism in hypertensive patients: clinical implications and target therapy

The prevalence of primary aldosteronism (PA) in hypertensive patients varies according to diagnostic testing and ascertained normal cut‐offs. The aim of this case–control study was to confirm the high prevalence of PA in a large hypertensive population and evaluate the antihypertensive effect of mineralocorticoid receptor antagonists (MRA) treatment.

Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow‐up

Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR) and ACS after prolonged follow‐up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow‐up.

Brain and optic chiasmal herniation following cabergoline treatment for a giant prolactinoma: wait or intervene?

OBJECTIVEDopamine agonists (DA) are the treatment of choice in patients with macroprolactinomas. Brain and optic chiasm herniation are unusual complications following treatment with DA.REPORTWe present a case of a giant prolactinoma complicated by visual deterioration following cabergoline treatment. A 42-year-old man was admitted with seizures, right visual loss and visual defect in the upper left temporal quadrant. Magnetic resonance imaging (MRI) identified a giant adenoma, which proved to be a prolactinoma, compressing the optic chiasm and extending into the suprasellar region. Treatment with cabergoline was initiated resulting in improvement in visual fields, tumor shrinkage and prolactin level decrease. Five months later and despite tumor reduction, a deterioration of his visual fields was observed. The second MRI revealed brain and optic chiasmal herniation into the pituitary sella. Cabergoline dose was reduced and surgical resection of the adenoma along with untethering of the optic nerve was performed leading to improvement of the visual defects.CONCLUSIONSThis report describes a rare case of brain and optic chiasmal herniation attributed to DA therapy for a macroprolactinoma. It is important for clinicians to examine visual fields and promptly identify any visual deterioration in patients with macroprolactinomas receiving DA treatment.

Impact and duration effect of telemonitoring on ΗbA1c, BMI and cost in insulin-treated Diabetes Mellitus patients with inadequate glycemic control: A randomized controlled study.

OBJECTIVE: To monitor and control the blood glucose levels in inefficiently insulin-treated patients with type 1 and 2 diabetes mellitus (DM) using a telemonitoring system and determine whether the improvement of HbA1c has a lasting effect following its discontinuation. DESIGN: Seventy inefficiently controlled insulin-treated DM patients using telemonitoring (telemonitoring group-TG) [HbA1c 9.9±2.3% (85±24.9mmol/mol)] and 35 age-, body mass index (BMI)- and Hba1c-matched insulin-treated patients receiving outpatient care (control group-CG) [HbA1c 9.7±2.1% (82±23.4mmol/mol)] were enrolled. Data of TG were transmitted from the glucose-meters to our computers via modem. Communication was achieved via e-mails and mobile phone text-messages through integrated software. HbA1c and BMI were evaluated at enrollment, 3 and 6 months, and 6 months after telemonitoring discontinuation. Frequency of hypo- and hyperglycemias and cost were also analyzed. RESULTS: Significant reduction in HbA1c was observed in TG both at 3 [7.1±1.0% (54±10.5mmol/mol) p<0.001] and 6 months [6.9±0.9% (52±9.5mmol/mol) p<0.001], compared to the CG group at the same timepoints. Significant reduction was also observed in the TG subgroups with HbA1c≥10% and 10>HbA1c≥7.5% at 3 and 6 months, compared to CG. No statistically significant differences in BMI were observed between TG and CG. Six months after telemonitoring discontinuation, HbA1c in TG was slightly increased [7.3±1.0% (56±10.4mol/mol)]. Attenuation was also observed in both TG subgroups. Compared to CG, the number of monthly hypo- and hyperglycemias was reduced in TG. The intervention had a financial benefit for patients living more than 100 km from the health care provider. CONCLUSIONS: Telemonitoring can result in reduction of HbA1c and frequency of hypo- and hyperglycemias. This beneficial effect is slightly attenuated 6 months after terminating telemonitoring.

Reversal of impaired counterregulatory cortisol response following diazoxide treatment in a patient with non insulinoma pancreatogenous hypoglycemia syndrome: Case report and overview of pathogenetic mechanisms

OBJECTIVENon-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is one of the rare causes of endogenous hyperinsulinism. Its diagnosis is challenging and may require selective intraarterial calcium stimulation and concomitant hepatic vein sampling (SACVS). Impaired counterregulatory hormones’ production in response to hypoglycemia has been previously described in patients with diabetes, insulinoma and infancy hypoglycemia. We present a case of endogenous hyperinsulinism, secondary to NIPHS, with deficient Cortisol response to hypoglycemia which resolved after diazoxide treatment.DESIGN-RESULTSA 43-year-old woman was admitted with recurrent episodes of registered fasting and postprandial hypoglycemia. Abdominal computed tomography, magnetic resonance imaging and endoscopic ultrasonography of the pancreas failed to reveal any lesion while SACVS sampling demonstrated a 5- to 8-fold increase in insulin levels in diverse parts of the pancreas. Counterregulatory hormones’ measurement revealed an attenuated Cortisol response. Treatment with diazoxide resulted in disappearance of hypoglycemic episodes. Twelve months later, an insulin tolerance test was performed which revealed a normal Cortisol response.CONCLUSIONSThis report describes the first, to our knowledge, reported case in the literature of NIPHS with deficient Cortisol response to hypoglycemia which resolved after diazoxide treatment. It is important for clinicians to include NIPHS in the differential diagnosis of hypoglycemia and identify possible impairment of counterregulatory hormones’ production.

Identification of a novel mutation of the PRKAR1A gene in a patient with Carney complex with significant osteoporosis and recurrent fractures

OBJECTIVE Carney complex (CNC) is a rare autosomal dominant multiple neoplasia syndrome characterized by the presence of endocrine and non-endocrine tumors. More than 125 different germline mutations of the protein Kinase A type 1-α regulatory subunit (PRKAR1A) gene have been reported. We present a novel PRKAR1A gene germline mutation in a patient with severe osteoporosis and recurrent vertebral fractures. DESIGN Clinical case report. CASE REPORT A 53-year-old male with a medical history of surgically removed recurrent cardiac myxomas was evaluated for repeated low-pressure vertebral fractures and severe osteoporosis. Physical examination revealed spotty skin pigmentation of the lower extremities and papules in the nuchal and thoracic region. The presence of hypercortisolism due to micronodular adrenal disease and the history of cardiac myxomas suggested the diagnosis of CNC; the patient underwent detailed imaging investigation and genetic testing. METHODS Standard imaging and clinical testing; DNA was sequenced by the Sanger method. RESULTS Sequence analysis from peripheral lymphocytes DNA revealed a novel heterozygous point mutation at codon 172 of exon 2 (c.172G>T) of the PRKAR1A gene, resulting in early termination of the PRKAR1A transcript [p.Glu58Ter (E58X)]. CONCLUSION We report a novel point mutation of the PRKAR1A gene in a patient with CNC who presented with significant osteoporosis and fractures. Low bone mineral density along with recurrent myxomas should point to the diagnosis of CNC.