Giacomo Tirabassi

Testosterone and cardiovascular risk

Cardiovascular (CV) disease is one of the most common causes of death in the western populations and, nowadays, its incidence is increasing even in the developing countries; although CV disease affects both sexes, it is more frequent in males in whom it shortens the average life expectancy. In this regard, this difference has been wrongly attributed for many years to the negative effects of testosterone (T); however, nowadays, a large amount of evidence suggests that this hormone may have protective effects on the CV system and that, indeed, the low levels of T could be associated with an increased CV risk and with an augmentation of morbidity and mortality in males. Such an aspect gains great relevance in light of the consideration that T decrease, besides occurring as a consequence of rare pathological conditions, can often take place with natural aging, causing a state of “male menopause”, also called late-onset hypogonadism. In this review, we aimed to summarize the present state of the art concerning the association between T deficit and CV disease by analyzing the protective role of T on CV system and the relationship of this hormonal lack with metabolic syndrome, CV morbidity and mortality, and with the CV complications, such as ischemic heart disease, heart failure and stroke, that frequently occur in T deficiency.

Use of the desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing's disease.

CONTEXT The desmopressin (DDAVP) test has been proposed to discriminate Cushings disease (CD) from pseudo-Cushing states (PC); however, current information on its value is scarce and contradictory. OBJECTIVE The aim of the study was to assess the ability of the DDAVP test in distinguishing between these conditions, with emphasis on subjects with mild hypercortisolism. DESIGN AND SETTING We conducted a retrospective/prospective study at the Division of Endocrinology, Polytechnic University of Marche, Ancona, Italy. PATIENTS The study included 52 subjects with CD, 28 with PC, and 31 control subjects (CT). INTERVENTION(S) We performed the DDAVP test and standard diagnostic procedures for the diagnosis of Cushings syndrome. MAIN OUTCOME MEASURE(S) The diagnosis/exclusion of CD was measured. RESULTS Interpretation of the DDAVP test based on percentage and absolute increment of cortisol and ACTH did not afford acceptable values of both sensitivity (SE) and specificity (SP). CD diagnosis based on simultaneous positivity for basal serum cortisol greater than 331 nmol/liter and absolute ACTH increment greater than 4 pmol/liter and its exclusion in subjects negative for one or both measures yielded an SE of 90.3% and an SP of 91.5%. The approach was also highly effective in distinguishing PC from: 1) CD with moderate values of urinary free cortisol (SE, 86.9%; SP, 92.8%); 2) CD with moderate values of serum cortisol after dexamethasone suppression (SE, 86.6%; SP, 92.8%); and 3) CD with moderate values of midnight serum cortisol (SE, 100%; SP, 92.8%). CONCLUSIONS Interpretation of the DDAVP test through a combination of parameters allowed effective discrimination of CD from PC, even in subjects with mild hypercortisolism.

Harmful effects of functional hypercortisolism: a working hypothesis

Functional hypercortisolism (FH) is caused by conditions able to chronically activate hypothalamic–pituitary–adrenal axis and usually occurs in cases of major depression, anorexia nervosa, bulimia nervosa, alcoholism, diabetes mellitus, simple obesity, polycystic ovary syndrome, obstructive sleep apnea syndrome, panic disorder, generalized anxiety disorder, shift work, and end-stage renal disease. Most of these states belong to pseudo-Cushing disease, a condition which is difficult to distinguish from Cushing’s syndrome and characterized not only by biochemical findings but also by objective ones that can be attributed to hypercortisolism (e.g., striae rubrae, central obesity, skin atrophy, easy bruising, etc.). This hormonal imbalance, although reversible and generally mild, could mediate some systemic complications, mainly but not only of a metabolic/cardiovascular nature, which are present in these states and are largely the same as those present in Cushing’s syndrome. In this review we aim to discuss the evidence suggesting the emerging negative role for FH.

Corticotrophin-releasing hormone and desmopressin tests in the differential diagnosis between Cushing's disease and pseudo- Cushing state: a comparative study

Background  We recently proposed a new and effective way of interpreting human corticotrophin‐releasing hormone (hCRH) and desmopressin (DDAVP) tests, for the differential diagnosis between Cushing’s disease (CD) and pseudo‐Cushing state (PC), based on the simultaneous analysis of ACTH and cortisol.

Human corticotropin releasing hormone test performance in the differential diagnosis between Cushing's disease and pseudo-Cushing state is enhanced by combined ACTH and cortisol analysis

OBJECTIVE Corticotropin releasing hormone (CRH) test does not reliably distinguish Cushings disease (CD) from normality or pseudo-Cushing state (PC). We assessed whether this could be achieved with a novel approach while preserving the ability of the test to distinguish CD from ectopic ACTH syndrome (EAS). Design Retrospective/prospective study. SUBJECTS AND METHODS We studied 51 subjects with CD, 7 with EAS, 26 with PC, and 31 controls (CT). Human CRH (hCRH) test was performed at 0830 h by measuring plasma ACTH and serum cortisol at -15, 0, 15, 30, 45, 60, 90, and 120 min. RESULTS The area under the curve-ACTH exhibited a significant negative correlation with baseline serum cortisol in CT and PC, but not in CD or EAS patients. ACTH response to hCRH was blunted in PC compared with CT, whereas peak serum cortisol was higher in PC than in CT subjects. These findings suggested that ACTH-dependent Cushings syndrome can be diagnosed by the presence of two hCRH test parameters and excluded if either or both are absent. Application of i) basal serum cortisol >12 microg/dl and peak plasma ACTH >54 pg/ml, or ii) peak serum cortisol >21 microg/dl and peak plasma ACTH >45 pg/ml, had 91.3% (95% confidence intervals (CI) 81-97.1) and 94.8% (CI 85.6-98.9) sensitivity and 98.2% (CI 90.6-99.9) and 91.2% (CI 80.7-97) specificity respectively, in diagnosing ACTH-dependent Cushings syndrome. The >14% serum cortisol increase from mean baseline values to the mean of 15 and 30 min values in patients who were positive for the test completely discriminated between CD and EAS. CONCLUSIONS Simultaneous plasma ACTH and serum cortisol analysis enables the hCRH test to distinguish CD from PC and from normality, while preserving its ability to discriminate CD from EAS.

Protective effect of leg fat against cardiovascular risk factors in obese premenopausal women.

BACKGROUND AND AIMS While the relationship between abdominal fat and cardiovascular risk (CVR) factors is well established, the possible protective role of peripheral fat against these factors has received less attention, particularly in severely obese individuals. The principal aim of this study was to analyse the relationship, if any, among amount of leg fat, CVR factors and body mass index (BMI) in obese premenopausal women. METHODS AND RESULTS Subjects were 80 obese premenopausal women. Body composition was measured by dual energy X-ray absorptiometry (DEXA); CVR factors (blood pressure, plasma lipids, glucose) were determined and anthropometric measurements (waist and hip circumferences) taken. In severely obese women (BMI>40 kg/m(2)) leg fat correlated negatively with CVR factors, whereas metabolic parameters were not significantly different from those of subjects with BMI<40 kg/m(2). CONCLUSIONS Leg fat seems to play a protective role against CVR factors in severely obese premenopausal women.

Vascular Endothelial Growth Factor and Microvessel Density in Periodontitis Patients With and Without Diabetes

BACKGROUND Periodontal disease is one of the major problems encountered in patients with diabetes mellitus (DM), and vascular changes may contribute to periodontitis. Our aim was to investigate vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in patients with periodontitis with and without DM. METHODS Immunohistochemical detection of VEGF and MVD analysis, evaluated by CD34+ endothelial cell counts, were performed in 66 gingival samples from patients with generalized, severe, chronic periodontitis who were divided into three groups: 22 participants without systemic diseases (controls), 22 participants with type 1 DM (T1DM), and 22 participants with type 2 DM (T2DM). RESULTS In patients with T1DM or T2DM, positive VEGF cells were found to be significantly increased in the epithelium compared to controls. In patients with T1DM, endothelial VEGF expression and MVD were significantly greater than in patients with T2DM and controls. CONCLUSIONS In patients with diabetes, VEGF overexpression plays a primary role in promoting the extravasation of inflammatory cells, suggesting a useful antiangiogenic strategy for periodontitis treatment. The decreased endothelial VEGF expression and MVD found in patients with T2DM may be caused by insulin resistance and endothelial dysfunction, which are often present in patients with T2DM.

Vitamin D and cardiovascular disease: From atherosclerosis to myocardial infarction and stroke

There continues to be interest in understanding the role of vitamin D in the pathogenesis, epidemiology and prevention of cardiovascular disease (CVD). In fact vitamin D deficiency has been associated to an increased risk of developing CVD given to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which vitamin D deficiency leads from endothelial dysfunction to myocardial infarction and stroke are not fully understood. Thus, the goal of this review is to provide an updated review of the literature on the basic science of how vitamin D may affect the cardiovascular system and in particular to analyze the role that vitamin D may have in the whole dynamic process from the initiation of endothelial dysfunction to the development of myocardial infarction and stroke.

Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept

In the last few years, more attention has been given to the “non-calcemic” effect of vitamin D. Several observational studies and meta-analyses demonstrated an association between circulating levels of vitamin D and outcome of many common diseases, including endocrine diseases, chronic diseases, cancer progression, and autoimmune diseases. In particular, cells of the immune system (B cells, T cells, and antigen presenting cells), due to the expression of 1α-hydroxylase (CYP27B1), are able to synthesize the active metabolite of vitamin D, which shows immunomodulatory properties. Moreover, the expression of the vitamin D receptor (VDR) in these cells suggests a local action of vitamin D in the immune response. These findings are supported by the correlation between the polymorphisms of the VDR or the CYP27B1 gene and the pathogenesis of several autoimmune diseases. Currently, the optimal plasma 25-hydroxyvitamin D concentration that is necessary to prevent or treat autoimmune diseases is still under debate. However, experimental studies in humans have suggested beneficial effects of vitamin D supplementation in reducing the severity of disease activity. In this review, we summarize the evidence regarding the role of vitamin D in the pathogenesis of autoimmune endocrine diseases, including type 1 diabetes mellitus, Addison’s disease, Hashimoto’s thyroiditis, Graves’ disease and autoimmune polyendocrine syndromes. Furthermore, we discuss the supplementation with vitamin D to prevent or treat autoimmune diseases.

Sexual dysfunctions in men affected by autoimmune Addison's disease before and after short-term gluco- and mineralocorticoid replacement therapy.

INTRODUCTION There is evidence suggesting that autoimmune Addisons disease (AD) could be associated with sexual dysfunctions probably caused by gluco- and mineralocorticoid deficiency; however, no study has yet treated this subject in males. AIM To evaluate male sexuality and psychological correlates in autoimmune AD before and after gluco- and mineralocorticoid replacement therapy. METHODS Twelve subjects with a first diagnosis of autoimmune AD were studied before (baseline) and 2 months after (recovery phase) initiating hormone replacement therapy. MAIN OUTCOME MEASURES Erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), overall satisfaction (OS), depression, and anxiety were studied using a number of questionnaires (International Index of Erectile Function, Beck Depression Inventory, and Spielberger State-Trait Anxiety Inventory); clinical, biochemical, and hormone data were included in the analysis. RESULTS At baseline, low values were found for EF, OF, SD, IS, and OS and high values for depression and anxiety; all of these parameters improved significantly in the recovery phase compared with baseline. EF variation between the two phases correlated significantly and positively with the variation of serum cortisol, urinary free cortisol, systolic blood pressure, and diastolic blood pressure and inversely with that of upright plasma renin activity. Multiple linear regression analysis using EF variation as dependent variable confirmed the relationship of the latter with variation of serum cortisol, urinary free cortisol, and upright plasma renin activity but not with variation of systolic and diastolic blood pressure. CONCLUSIONS Our study showed that onset of autoimmune AD in males is associated with a number of sexual dysfunctions, all reversible after initiating replacement hormone therapy; cortisol and aldosterone deficiency seems to play an important role in the genesis of erectile dysfunction although the mechanism of their activity is not clear.