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Guido Di Dalmazi, Renato Pasquali, Felix Beuschlein, and Martin Reincke

Subclinical hypercortisolism (SH), defined as alterations of the hypothalamus–pituitary–adrenal axis in the absence of clinical signs or symptoms related to cortisol secretion, is a common finding in patients with adrenal incidentalomas. The clinical correlates of this pathological condition have become clearer over the last few years. The aim of this review is to summarize the co-morbidities and the clinical outcomes of patients with SH. According to the analysis of the results of the studies published within the last 15 years, hypertension and type 2 diabetes are a common finding in patients with SH, occurring roughly in 2/3 and 1/3 of the patients respectively. Moreover, several additional cardiovascular and metabolic complications, like endothelial damage, increased visceral fat accumulation and impaired lipid metabolism have been shown to increase the cardiovascular risk of those patients. Accordingly, recent independent reports investigating the natural history of the disease in a long-term follow-up setting have shown that patients with SH have a higher incidence of cardiovascular events and related mortality. Moreover, longitudinal studies have also shown increased incidence of osteoporotic vertebral fractures. Future research is needed to improve the diagnostic performance of hormonal tests, by assessment of the complete steroid profile with more accurate assays, and to define the efficacy of surgical vs medical treatment in a randomized-controlled setting.

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Davide Calebiro, Guido Di Dalmazi, Kerstin Bathon, Cristina L Ronchi, and Felix Beuschlein

The cAMP signaling pathway is one of the major players in the regulation of growth and hormonal secretion in adrenocortical cells. Although its role in the pathogenesis of adrenocortical hyperplasia associated with Cushing's syndrome has been clarified, a clear involvement of the cAMP signaling pathway and of one of its major downstream effectors, the protein kinase A (PKA), in sporadic adrenocortical adenomas remained elusive until recently. During the last year, a report by our group and three additional independent groups showed that somatic mutations of PRKACA, the gene coding for the catalytic subunit α of PKA, are a common genetic alteration in patients with Cushing's syndrome due to adrenal adenomas, occurring in 35–65% of the patients. In vitro studies revealed that those mutations are able to disrupt the association between catalytic and regulatory subunits of PKA, leading to a cAMP-independent activity of the enzyme. Despite somatic PRKACA mutations being a common finding in patients with clinically manifest Cushing's syndrome, the pathogenesis of adrenocortical adenomas associated with subclinical hypercortisolism seems to rely on a different molecular background. In this review, the role of cAMP/PKA signaling in the regulation of adrenocortical cell function and its alterations in cortisol-producing adrenocortical adenomas will be summarized, with particular focus on recent developments.

Free access

Guido Di Dalmazi, Valentina Vicennati, Eleonora Rinaldi, Antonio Maria Morselli-Labate, Emanuela Giampalma, Cristina Mosconi, Uberto Pagotto, and Renato Pasquali

Background

Subclinical Cushing's syndrome (SCS) is defined as alterations in hypothalamic–pituitary–adrenal axis without classic signs/symptoms of glucocorticoid excess. Whether SCS leads to metabolic and cardiovascular diseases is still controversial.

Aim

To evaluate the prevalence of hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), ischemic stroke, osteoporosis, and fractures, and their relationship to increasing patterns of subclinical hypercortisolism, in patients with nonsecreting adrenal adenomas (NSA) and SCS.

Methods

Using the 1 mg dexamethasone suppression test (DST), 348 patients were classified as follows: 203 were defined as NSA and 19 SCS, using the most stringent cutoff values (<50 and >138 nmol/l respectively). Patients with cortisol post-DST (50–138 nmol/l) were considered as intermediate phenotypes and classified as minor (n=71) and major (n=55) using plasma ACTH and/or urinary free cortisol as additional diagnostic tools.

Results

SCS patients showed higher prevalence of T2D, CHD, osteoporosis, and fractures with respect to NSA. Intermediate phenotypes also showed higher prevalence of CHD and T2D with respect to NSA. The prevalence of all clinical outcomes was not different between intermediate phenotype patients, which were therefore considered as a single group (IP) for multivariate logistic regression analysis: both IP and SCS-secreting patterns showed a significant association with CHD (odds ratio (OR), 4.09; 95% confidence interval (CI), 1.47–11.38 and OR, 6.10; 95% CI, 1.41–26.49 respectively), independently of other potential risk factors. SCS was also independently associated with osteoporosis (OR, 5.94; 95% CI, 1.79–19.68).

Conclusions

Patterns of increasing subclinical hypercortisolism in adrenal adenomas are associated with increased prevalence of adverse metabolic and cardiovascular outcomes, independently of other potential risk factors.

Free access

Guido Di Dalmazi, Marcus Quinkler, Timo Deutschbein, Cornelia Prehn, Nada Rayes, Matthias Kroiss, Christina M Berr, Günter Stalla, Martin Fassnacht, Jerzy Adamski, Martin Reincke, and Felix Beuschlein

Objective

Endogenous hypercortisolism is a chronic condition associated with severe metabolic disturbances and cardiovascular sequela. The aim of this study was to characterize metabolic alterations in patients with different degrees of hypercortisolism by mass-spectrometry-based targeted plasma metabolomic profiling and correlate the metabolomic profile with clinical and hormonal data.

Design

Cross-sectional study.

Methods

Subjects (n = 149) were classified according to clinical and hormonal characteristics: Cushing’s syndrome (n = 46), adrenocortical adenomas with autonomous cortisol secretion (n = 31) or without hypercortisolism (n = 27). Subjects with suspicion of hypercortisolism, but normal hormonal/imaging testing, served as controls (n = 42). Clinical and hormonal data were retrieved for all patients and targeted metabolomic profiling was performed.

Results

Patients with hypercortisolism showed lower levels of short-/medium-chain acylcarnitines and branched-chain and aromatic amino acids, but higher polyamines levels, in comparison to controls. These alterations were confirmed after excluding diabetic patients. Regression models showed significant correlation between cortisol after dexamethasone suppression test (DST) and 31 metabolites, independently of confounding/contributing factors. Among those, histidine and spermidine were also significantly associated with catabolic signs and symptoms of hypercortisolism. According to an discriminant analysis, the panel of metabolites was able to correctly classify subjects into the main diagnostic categories and to distinguish between subjects with/without altered post-DST cortisol and with/without diabetes in >80% of the cases.

Conclusions

Metabolomic profiling revealed alterations of intermediate metabolism independently associated with the severity of hypercortisolism, consistent with disturbed protein synthesis/catabolism and incomplete β-oxidation, providing evidence for the occurrence of metabolic inflexibility in hypercortisolism.

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Marco Mezzullo, Alessandra Gambineri, Guido Di Dalmazi, Alessia Fazzini, Matteo Magagnoli, Margherita Baccini, Valentina Vicennati, Carla Pelusi, Uberto Pagotto, and Flaminia Fanelli

Objective. To investigate the impact of age, obesity and metabolic parameters on thirteen circulating steroids in reproductive and menopausal age. To define reference intervals (RI).

Design. Cross-sectional.

Methods. 325 drug-free, healthy and eumenorrheic women were selected from the general population. Independent relationships of LC-MS/MS-determined steroid levels with age, body mass index (BMI) and metabolic parameters were estimated. Reference sub-cohorts were defined for calculating upper and lower limits in reproductive age, menstrual phases and menopause, and these were compared with limits in dysmetabolic sub-cohorts.

Results. Lower androgens, pro-androgens and estrogens, but higher cortisol and metabolites were found in menopausal compared to reproductive age women. Androgens and precursors decreased during reproductive age (P<0.001–P=0.002) but not after menopause. 17OH-progesterone decreased with BMI (P=0.006) and glucocorticoids with waist circumference (P<0.001–P=0.002) in reproductive age, but increased with triglycerides (P=0.011-P=0.038) after menopause. Inverse associations of dihydrotestosterone with BMI (P=0.004) and HDL-cholesterol (P=0.010), estrone with total cholesterol (P=0.033) and estradiol with triglycerides (P=0.011) were found in reproductive age. After menopause, estrone increased with waist circumference (P<0.001) and decreased with insulin resistance (P=0.012). Ovarian steroid RI were estimated in menstrual phases and menopause. Age- and reproductive status-specific RI were generated for androgens, precursors and corticosteroids. Lower limits for reproductive age cortisol (P=0.020) and menopausal 11-deoxycortisol (P=0.003) in dysmetabolic sub-cohorts were reduced and increased, respectively, compared to reference limits.

Conclusions: Obesity and dysmetabolism differently influence circulating steroids in reproductive and menopausal status. Age, menstrual and menopausal status-specific RI were provided by LC-MS/MS for a broad steroid panel.

Free access

Alessandra Gambineri, Valentina Vicennati, Guido Di Dalmazi, Carla Pelusi, Paola Altieri, Flaminia Fanelli, Andrea Repaci, Silvia Garelli, Danilo Ribichini, and Uberto Pagotto

Restricted access

Marco Mezzullo, Guido Di Dalmazi, Alessia Fazzini, Margherita Baccini, Andrea Repaci, Alessandra Gambineri, Valentina Vicennati, Carla Pelusi, Uberto Pagotto, and Flaminia Fanelli

Objective

To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men.

Design

Cross-sectional study.

Methods

Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts.

Results

We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (−0.34 nmol/L, P = 0.045), cortisol (−87 nmol/L, P = 0.045–0.002) and corticosterone (−10.1 nmol/L, P = 0.048–0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively.

Conclusions

Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.

Free access

Marco Mezzullo, Guido Di Dalmazi, Alessia Fazzini, Margherita Baccini, Andrea Repaci, Alessandra Gambineri, Valentina Vicennati, Carla Pelusi, Uberto Pagotto, and Flaminia Fanelli

Restricted access

Srdjan Pandurevic, Luca Bergamaschi, Carmine Pizzi, Laura Patton, Paola Rucci, Francesca Corzani, Carolina Cecchetti, Carla Pelusi, Paola Altieri, Valentina Vicennati, Guido Di Dalmazi, Flaminia Fanelli, Djuro Macut, Uberto Pagotto, and Alessandra Gambineri

Objective

Research into cardiovascular disease (CV) prevention has demonstrated a variety of ultrasound (US) markers predicting risk in the general population but which have been scarcely used for polycystic ovary syndrome (PCOS). Obesity is a major factor contributing to CV disease in the general population, and it is highly prevalent in PCOS. However, it is still unclear how much risk is attributable to hyperandrogenism. This study evaluates the most promising US CV risk markers in PCOS and compares them between different PCOS phenotypes and BMI values.

Design

Women fulfilling the Rotterdam criteria for PCOS were recruited from our outpatient clinic for this cross-sectional study.

Methods

Participants (n = 102) aged 38.9 ± 7.4 years were stratified into the four PCOS phenotypes and the three BMI classes (normal-weight, overweight, obese). They were assessed for clinical and biochemical parameters together with the following US markers: coronary intima-media thickness (cIMT), flow-mediated vascular dilation (FMD), nitroglycerine-induced dilation (NTG), and epicardial fat thickness (EFT).

Results

There was no statistical difference among the four phenotypes in terms of cIMT, FMD, NTG or EFT, however all the US parameters except NTG showed significant differences among the three BMI classes. Adjusting for confounding factors in multiple regression analyses, EFT retained the greatest direct correlation with BMI and cIMT remained directly correlated but to a lesser degree.

Conclusions

This study showed that obesity rather than the hyperandrogenic phenotype negatively impacts precocious US CV risk markers in PCOS. In addition, EFT showed the strongest association with BMI, highlighting its potential for estimating CV risk in PCOS.

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Martin Reincke, Adriana Albani, Guillaume Assie, Irina Bancos, Thierry Brue, Michael Buchfelder, Olivier Chabre, Filippo Ceccato, Andrea Daniele, Mario Detomas, Guido Di Dalmazi, Atanaska Elenkova, James Findling, Ashley B. Grossman, Celso E Gomez-Sanchez, Anthony P Heaney, Juergen Honegger, Niki Karavitaki, Andre Lacroix, Edward R Laws, Marco Losa, Masanori Murakami, John Newell-Price, Francesca Pecori Giraldi, Luis G. Pérez‐Rivas, Rosario Pivonello, William E Rainey, Silviu Sbiera, Jochen Schopohl, Constantine A Stratakis, Marily Theodoropoulou, Elisabeth F.C. van Rossum, Elena Valassi, Sabina Zacharieva, German Rubinstein, and Katrin Ritzel

BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson’s syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing’s disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28th, 2018.

RESULTS: Data covered definition and incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.