Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome.

CONTEXT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized. OBJECTIVE: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients. METHODS: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated. RESULTS: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients). CONCLUSION: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Treating type 2 diabetes in COVID-19 patients: the potential benefits of injective therapies.

The coronavirus disease 2019 (COVID-19) has been declared as pandemic by the World Health Organization and is causing substantial morbidity and mortality all over the world. Type 2 diabetes, hypertension, and cardiovascular disease significantly increase the risk for hospitalization and death in COVID-19 patients. Hypoglycemia and hyperglycemia are both predictors for adverse outcomes in hospitalized patients. An optimized glycemic control should be pursued in patients with diabetes and SARS-CoV-2 infection in order to reduce the risk of severe COVID-19 course. Both insulin and GLP-1RAs have shown optimal glucose-lowering and anti-inflammatory effects in type 2 diabetic patients and may represent a valid therapeutic option to treat asymptomatic and non-critically ill COVID-19 diabetic patients.

The role of autoimmunity in pituitary dysfunction due to traumatic brain injury.

PURPOSE: Traumatic brain injury (TBI) is one of the most common causes of mortality and long-term disability and it is associated with an increased prevalence of neuroendocrine dysfunctions. Post-traumatic hypopituitarism (PTHP) results in major physical, psychological and social consequences leading to impaired quality of life. PTHP can occur at any time after traumatic event, evolving through various ways and degrees of deficit, requiring appropriate screening for early detection and treatment. Although the PTHP pathophysiology remains to be elucitated, on the basis of proposed hypotheses it seems to be the result of combined pathological processes, with a possible role played by hypothalamic-pituitary autoimmunity (HPA). This review is aimed at focusing on this possible role in the development of PTHP and its potential clinical consequences, on the basis of the data so far appeared in the literature and of some results of personal studies on this issue. METHODS: Scrutinizing the data so far appeared in literature on this topic, we have found only few studies evaluating the autoimmune pattern in affected patients, searching in particular for antipituitary and antihypothalamus autoantibodies (APA and AHA, respectively) by simple indirect immunofluorescence. RESULTS: The presence of APA and/or AHA at high titers was associated with an increased risk of onset/persistence of PTHP. CONCLUSIONS: HPA seems to contribute to TBI-induced pituitary damage and related PTHP. However, further prospective studies in a larger cohort of patients are needed to define etiopathogenic and diagnostic role of APA/AHA in development of post-traumatic hypothalamic/pituitary dysfunctions after a TBI.

Erectile hydraulics: maximizing inflow while minimizing outflow.

INTRODUCTION: Penile rigidity depends on maximizing inflow while minimizing outflow. AIM: The aim of this review is to describe the principal factors and mechanisms involved. MAIN OUTCOME MEASURE: Erectile quality is the main outcome measure. METHODS: Data from the pertinent literature were examined to inform our conclusions. RESULTS: Nitric oxide (NO) is the principal factor increasing blood flow into the penis. Penile engorgement and the pelvic floor muscles maintain an adequate erection by impeding outflow of blood by exerting pressure on the penile veins from within and from outside of the penile tunica. Extrinsic pressure by the pelvic floor muscles further raises intracavernosal pressure above maximum inflow pressure to achieve full penile rigidity. Aging and poor lifestyle choices are associated with metabolic impediments to NO production. Aging is also associated with fewer smooth muscle cells and increased fibrosis within the corpora cavernosa, preventing adequate penile engorgement and pressure on the penile veins. Those same penile structural changes occur rapidly following the penile nerve injury that accompanies even "nerve-sparing" radical prostatectomy and are largely prevented in animal models by early chronic use of a phosphodiesterase type 5 (PDE5) inhibitor. Pelvic floor muscles may also decrease in tone and bulk with age, and pelvic floor muscle exercises have been shown to improve erectile function to a similar degree compared with a PDE5 inhibitor in men with erectile dysfunction (ED). CONCLUSIONS: Because NO is critical for vascular health and ED is strongly associated with cardiovascular disease, maximal attention should be focused on measures known to increase vascular NO production, including the use of PDE5 inhibitors. Attention should also be paid to early, regular use of PDE5 inhibition to reduce the incidence of ED following penile nerve injury and to assuring normal function of the pelvic floor muscles. These approaches to maximizing erectile function are complementary rather than competitive, as they operate on entirely different aspects of erectile hydraulics.

Metabolic syndrome and cancer: holistic or reductionist?

Metabolic syndrome has become a major public health problem worldwide and represents a common clinical condition in countries with a high incidence of obesity and western dietary patterns. Metabolic syndrome associates with common cancers at many sites, including liver, colorectal, and bladder cancers in men, and endometrial, pancreatic, breast post-menopausal, and colorectal cancers in women. However, the role played by each single component of the syndrome on cancer risk is still unclear. For endometrial cancer, obesity and/or high circumference waist explain all the risk associated with the full metabolic syndrome, while for post-menopausal breast cancer, the risk conveyed by metabolic syndrome appears to be greater than its parts, as no single component explains the full risk associated with the syndrome. Future research should cover other avenues in order to elucidate the complexity of biological processes linking metabolic syndrome and cancer.

The link between erectile and cardiovascular health: the canary in the coal mine.

Lifestyle and nutrition have been increasingly recognized as central factors influencing vascular nitric oxide (NO) production and erectile function. This review underscores the importance of NO as the principal mediator influencing cardiovascular health and erectile function. Erectile dysfunction (ED) is associated with smoking, excessive alcohol intake, physical inactivity, abdominal obesity, diabetes, hypertension, and decreased antioxidant defenses, all of which reduce NO production. Better lifestyle choices; physical exercise; improved nutrition and weight control; adequate intake of or supplementation with omega-3 fatty acids, antioxidants, calcium, and folic acid; and replacement of any testosterone deficiency will all improve vascular and erectile function and the response to phosphodiesterase-5 inhibitors, which also increase vascular NO production. More frequent penile-specific exercise improves local endothelial NO production. Excessive intake of vitamin E, calcium, l-arginine, or l-citrulline may impart significant cardiovascular risks. Interventions discussed also lower blood pressure or prevent hypertension. Certain angiotensin II receptor blockers improve erectile function and reduce oxidative stress. In men aged <60 years and in men with diabetes or hypertension, erectile dysfunction can be a critical warning sign for existing or impending cardiovascular disease and risk for death. The antiarrhythmic effect of omega-3 fatty acids may be particularly crucial for these men at greatest risk for sudden death. In conclusion, by better understanding the complex factors influencing erectile and overall vascular health, physicians can help their patients prevent vascular disease and improve erectile function, which provides more immediate motivation for men to improve their lifestyle habits and cardiovascular health.

The effects of diet on inflammation: emphasis on the metabolic syndrome.

Reducing the incidence of coronary heart disease with diet is possible. The main dietary strategies include adequate omega-3 fatty acids intake, reduction of saturated and trans-fats, and consumption of a diet high in fruits, vegetables, nuts, and whole grains and low in refined grains. Each of these strategies may be associated with lower generation of inflammation. This review examines the epidemiologic and clinical evidence concerning diet and inflammation. Dietary patterns high in refined starches, sugar, and saturated and trans-fatty acids, poor in natural antioxidants and fiber from fruits, vegetables, and whole grains, and poor in omega-3 fatty acids may cause an activation of the innate immune system, most likely by an excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. The whole diet approach seems particularly promising to reduce the inflammation associated with the metabolic syndrome. The choice of healthy sources of carbohydrate, fat, and protein, associated with regular physical activity and avoidance of smoking, is critical to fighting the war against chronic disease. Western dietary patterns warm up inflammation, while prudent dietary patterns cool it down.

Mediterranean diet and cardiovascular health.

Diets that are high in fruits, vegetables, legumes, and whole grains and include fish, nuts, and low-fat dairy products have protective health effects. The traditional Mediterranean diet encompasses these dietary characteristics. Other compounds of the Mediterranean diet, the antioxidants, which exist in abundance in vegetables, fruit, beverages, and also virgin olive oil, may contribute to the prevention of coronary heart disease and possibly several forms of cancer and other diseases, thus providing a plausible explanation for its apparent benefits. It may be misleading to focus on a single element of the diet; this may explain, at least in part, the disappointing and frustrating results obtained in trials with vitamin supplementation, prematurely thought to be "the magic bullet" for preventing a myriad of chronic diseases. The results of intervention studies aimed at evaluating whether Mediterranean-type diets are superior to classic diets in the secondary prevention of coronary heart disease have all been encouraging. The biologic mechanisms by which these compounds might exert their effects include, among others, antioxidant functions and induction of detoxification enzymes. However, from a public health perspective it is not essential to wait for elucidation of every mechanism underlying health promotion activities and interventions; given the simplicity of the diet quality score, increasing the intake of recommended foods represents a practical recommendation for improving health.

Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial.

CONTEXT: The metabolic syndrome has been identified as a target for dietary therapies to reduce risk of cardiovascular disease; however, the role of diet in the etiology of the metabolic syndrome is poorly understood. OBJECTIVE: To assess the effect of a Mediterranean-style diet on endothelial function and vascular inflammatory markers in patients with the metabolic syndrome. DESIGN, SETTING, AND PATIENTS: Randomized, single-blind trial conducted from June 2001 to January 2004 at a university hospital in Italy among 180 patients (99 men and 81 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III. INTERVENTIONS: Patients in the intervention group (n = 90) were instructed to follow a Mediterranean-style diet and received detailed advice about how to increase daily consumption of whole grains, fruits, vegetables, nuts, and olive oil; patients in the control group (n = 90) followed a prudent diet (carbohydrates, 50%-60%; proteins, 15%-20%; total fat, <30%). MAIN OUTCOME MEASURES: Nutrient intake; endothelial function score as a measure of blood pressure and platelet aggregation response to l-arginine; lipid and glucose parameters; insulin sensitivity; and circulating levels of high-sensitivity C-reactive protein (hs-CRP) and interleukins 6 (IL-6), 7 (IL-7), and 18 (IL-18). RESULTS: After 2 years, patients following the Mediterranean-style diet consumed more foods rich in monounsaturated fat, polyunsaturated fat, and fiber and had a lower ratio of omega-6 to omega-3 fatty acids. Total fruit, vegetable, and nuts intake (274 g/d), whole grain intake (103 g/d), and olive oil consumption (8 g/d) were also significantly higher in the intervention group (P<.001). The level of physical activity increased in both groups by approximately 60%, without difference between groups (P =.22). Mean (SD) body weight decreased more in patients in the intervention group (-4.0 [1.1] kg) than in those in the control group (-1.2 [0.6] kg) (P<.001). Compared with patients consuming the control diet, patients consuming the intervention diet had significantly reduced serum concentrations of hs-CRP (P =.01), IL-6 (P =.04), IL-7 (P = 0.4), and IL-18 (P = 0.3), as well as decreased insulin resistance (P<.001). Endothelial function score improved in the intervention group (mean [SD] change, +1.9 [0.6]; P<.001) but remained stable in the control group (+0.2 [0.2]; P =.33). At 2 years of follow-up, 40 patients in the intervention group still had features of the metabolic syndrome, compared with 78 patients in the control group (P<.001). CONCLUSION: A Mediterranean-style diet might be effective in reducing the prevalence of the metabolic syndrome and its associated cardiovascular risk.

Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.

CONTEXT: Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue. OBJECTIVE: To determine the effect of a program of changes in lifestyle designed to obtain a sustained reduction of body weight on markers of systemic vascular inflammation and insulin resistance. DESIGN AND SETTING: Randomized single-blind trial conducted from February 1999 to February 2002 at a university hospital in Italy. PATIENTS: One hundred twenty premenopausal obese women (body mass index > or =30) aged 20 to 46 years without diabetes, hypertension, or hyperlipidemia. INTERVENTIONS: The 60 women randomly assigned to the intervention group received detailed advice about how to achieve a reduction of weight of 10% or more through a low-energy Mediterranean-style diet and increased physical activity. The control group (n = 60) was given general information about healthy food choices and exercise. MAIN OUTCOME MEASURES: Lipid and glucose intake; blood pressure; homeostatic model assessment of insulin sensitivity; and circulating levels of interleukin 6 (IL-6), interleukin 18 (IL-18), C-reactive protein (CRP), and adiponectin. RESULTS: After 2 years, women in the intervention group consumed more foods rich in complex carbohydrates (9% corrected difference; P<.001), monounsaturated fat (2%; P =.009), and fiber (7 g/d; P<.001); had a lower ratio of omega-6 to omega-3 fatty acids (-5; P<.001); and had lower energy (-310 kcal/d; P<.001), saturated fat (-3.5%; P =.007), and cholesterol intake (-92 mg/d; P<.001) than controls. Body mass index decreased more in the intervention group than in controls (-4.2; P<.001), as did serum concentrations of IL-6 (-1.1 pg/mL; P =.009), IL-18 (-57 pg/mL; P =.02), and CRP (-1.6 mg/L; P =.008), while adiponectin levels increased significantly (2.2 microg/mL; P =.01). In multivariate analyses, changes in free fatty acids (P =.008), IL-6 (P =.02), and adiponectin (P =.007) levels were independently associated with changes in insulin sensitivity. CONCLUSION: In this study, a multidisciplinary program aimed to reduce body weight in obese women through lifestyle changes was associated with a reduction in markers of vascular inflammation and insulin resistance.

Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals.

OBJECTIVES: To compare the effect of a high-fat meal and a high-carbohydrate meal (pizza), with and without antioxidant vitamins, on endothelial activation in healthy subjects and in patients with type 2 diabetes mellitus. BACKGROUND: The postprandial state is becoming increasingly acknowledged to affect some early events of atherogenesis. METHODS: In a randomized, observer-blinded, crossover study, 20 newly diagnosed type 2 diabetic patients and 20 age- and gender-matched healthy subjects received two meals at one-week intervals: a high-fat meal (760 calories) and an isoenergetic high-carbohydrate meal (non-cheese pizza). In all subjects, the same meals were repeated immediately following ingestion of vitamin E, 800 IU, and ascorbic acid, 1,000 mg. RESULTS: In normal subjects, the high-fat meal increased the plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which were prevented by vitamins. No change in these parameters occurred after pizza ingestion or pizza ingestion with vitamins. In diabetic patients, basal concentrations of glucose, cytokines and adhesion molecules were significantly higher than in nondiabetic controls. Both meals significantly increased cytokine and adhesion molecule levels, but the increase was more sustained following the high-fat meal. There was no significant change from baseline when vitamin supplementation accompanied each meal. There was a relationship between changes in serum triglycerides and changes in TNF-alpha (r = 0.39, p < 0.01), IL-6 (r = 0.28, p < 0.05) and VCAM-1 (r = 0.25, p < 0.05), and between changes in plasma glucose and changes in IL-6 (r = 0.36, p < 0.01) and ICAM-1 (r = 0.31, p < 0.02). CONCLUSIONS: An oxidative mechanism mediates endothelial activation induced by post-meal hyperlipidemia and hyperglycemia.