Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin–antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.
Andrea M Isidori, Marianna Minnetti, Emilia Sbardella, Chiara Graziadio, and Ashley B Grossman
Daniele Santi, Elisa Giannetta, Andrea M Isidori, Cristiana Vitale, Antonio Aversa, and Manuela Simoni
Diabetes mellitus (DM) is associated with endothelial dysfunction, reducing nitric oxide-dependent vasodilation, and increasing production of pro-inflammatory factors, leading to an increased risk of long-term cardiovascular disease. As the effects of phosphodiesterase 5 inhibitors (PDE5i) on endothelial function have not been systematically investigated, we conducted a meta-analysis of available randomized clinical trials (RCTs).
A thorough search of the literature was carried out. Relevant studies were considered according to RCT study design, enrollment of men with type 2 DM, chronic administration of PDE5i, and evaluation of endothelial function through both hemodynamic and endothelial inflammation-related parameters.
Fifteen studies fulfilled the eligibility criteria but only six RCTs met the inclusion criteria and were analyzed for 476 diabetic men, 239 randomized to Sildenafil, and 237 to placebo respectively. Four RCTs evaluated flow-mediated dilation (FMD), demonstrating a weighted mean increase of 2.19% (95% CI 0.48 to 3.90). This result showed a high heterogeneity (I 2: 98%). Thus, a further sub-group meta-analysis was performed and this analysis confirmed a significant, Sildenafil-related FMD improvement. Sildenafil improved endothelin 1 and high sensitivity C-reactive protein by ∼−0.94 pg/ml and −0.36 mg/l, respectively, not reaching statistical significance (P=0.69 and P=0.22 respectively). Finally, Sildenafil administration significantly reduced serum levels of interleukin 6 (IL6, −0.82 pg/ml; 95% CI −1.58 to −0.07).
This meta-analysis suggests a beneficial effect of chronic PDE5i administration on endothelial function. Chronic Sildenafil administration seems to improve hemodynamic (FMD) and serum pro-inflammatory makers (IL6) in diabetic men. Larger studies are needed to confirm the effects of chronic PDE5i on endothelial function.
Farid Saad, Antonio Aversa, Andrea M Isidori, Livia Zafalon, Michael Zitzmann, and Louis Gooren
Testosterone has a spectrum of effects on the male organism. This review attempts to determine, from published studies, the time-course of the effects induced by testosterone replacement therapy from their first manifestation until maximum effects are attained.
Literature data on testosterone replacement.
Effects on sexual interest appear after 3 weeks plateauing at 6 weeks, with no further increments expected beyond. Changes in erections/ejaculations may require up to 6 months. Effects on quality of life manifest within 3–4 weeks, but maximum benefits take longer. Effects on depressive mood become detectable after 3–6 weeks with a maximum after 18–30 weeks. Effects on erythropoiesis are evident at 3 months, peaking at 9–12 months. Prostate-specific antigen and volume rise, marginally, plateauing at 12 months; further increase should be related to aging rather than therapy. Effects on lipids appear after 4 weeks, maximal after 6–12 months. Insulin sensitivity may improve within few days, but effects on glycemic control become evident only after 3–12 months. Changes in fat mass, lean body mass, and muscle strength occur within 12–16 weeks, stabilize at 6–12 months, but can marginally continue over years. Effects on inflammation occur within 3–12 weeks. Effects on bone are detectable already after 6 months while continuing at least for 3 years.
The time-course of the spectrum of effects of testosterone shows considerable variation, probably related to pharmacodynamics of the testosterone preparation. Genomic and non-genomic effects, androgen receptor polymorphism and intracellular steroid metabolism further contribute to such diversity.
Emilia Sbardella, Carlotta Pozza, Andrea M Isidori, and Ashley B Grossman
The transition age is the period between childhood to adulthood; it refers to a broad set of physical, cognitive and sociocultural modifications, arbitrarily defined as starting in late puberty and ending with full adult maturation. Pituitary disorders in adolescence represent a challenge that requires careful management during the transition to adult care.
Given the complexity of care of pituitary disorders in the transition age, we have reviewed the relevant medical literature focusing on aetiology, clinical manifestations, treatment strategies of GH deficiency (GHD), hypogonadotrophic hypogonadism (HH) in male and female adolescents, central hypothyroidism (CH), central adrenal insufficiency (CAI) and cranial diabetes insipidus (CDI) at this time. The objective of the present review is to provide an up-to-date evaluation of the transition period to evaluate the specific needs of adolescents with chronic pituitary disease in order to optimise their management.
We provide an overview of current clinical management of GHD, HH, CH, CAI and CDI in the transition age.
Specific changes occur in pituitary function during the transition period. A holistic approach including discussion of patients’ concerns and emotional support should constitute a key component of managing pituitary disorders in adolescence. Special transition clinics where paediatric and adult endocrinologists work together, should be increasingly created and strengthened to bridge care, to promote continuity and adherence to treatment and to limit potential negative development, metabolic, skeletal and cardiovascular sequelae of discontinuity of care among adolescents with pituitary disorders.
Emilia Sbardella, Robin N Joseph, Bahram Jafar-Mohammadi, Andrea M Isidori, Simon Cudlip, and Ashley B Grossman
Disease processes that affect the pituitary stalk are broad; the diagnosis and management of these lesions remains unclear.
The aim was to assess the clinical, biochemical and histopathological characteristics of pituitary stalk lesions and their association with specific MRI features in order to provide diagnostic and prognostic guidance.
Design and methods
Retrospective observational study of 36 patients (mean age 37years, range: 4–83) with pituitary stalk thickening evaluated at a university hospital in Oxford, UK, 2007–2015. We reviewed morphology, signal intensity, enhancement and texture appearance at MRI (evaluated with the ImageJ programme), along with clinical, biochemical, histopathological and long-term follow-up data.
Diagnosis was considered certain for 22 patients: 46% neoplastic, 32% inflammatory and 22% congenital lesions. In the remaining 14 patients, a diagnosis of a non-neoplastic disorder was assumed on the basis of long-term follow-up (mean 41.3months, range: 12–84). Diabetes insipidus and headache were common features in 47 and 42% at presentation, with secondary hypogonadism the most frequent anterior pituitary defect. Neoplasia was suggested on size criteria or progression with 30% sensitivity. However, textural analysis of MRI scans revealed a significant correlation between the tumour pathology and pituitary stalk heterogeneity in pre- and post-gadolinium T1-weighted images (sensitivity: 88.9%, specificity: 91.7%).
New techniques of MRI imaging analysis may identify clinically significant neoplastic lesions, thus directing future therapy. We propose possible textural heterogeneity criteria of the pituitary stalk on pre- and post-gadolinium T1 images with the aim of differentiating between neoplastic and non-neoplastic lesions with a high degree of accuracy.
Andrea Salzano, Michele Arcopinto, Alberto M Marra, Emanuele Bobbio, Daniela Esposito, Giacomo Accardo, Francesco Giallauria, Eduardo Bossone, Carlo Vigorito, Andrea Lenzi, Daniela Pasquali, Andrea M Isidori, and Antonio Cittadini
Klinefelter syndrome (KS) is the most frequently occurring sex chromosomal aberration in males, with an incidence of about 1 in 500–700 newborns. Data acquired from large registry-based studies revealed an increase in mortality rates among KS patients when compared with mortality rates among the general population. Among all causes of death, metabolic, cardiovascular, and hemostatic complication seem to play a pivotal role. KS is associated, as are other chromosomal pathologies and genetic diseases, with cardiac congenital anomalies that contribute to the increase in mortality. The aim of the current study was to systematically review the relationships between KS and the cardiovascular system and hemostatic balance. In summary, patients with KS display an increased cardiovascular risk profile, characterized by increased prevalence of metabolic abnormalities including Diabetes mellitus (DM), dyslipidemia, and alterations in biomarkers of cardiovascular disease. KS does not, however, appear to be associated with arterial hypertension. Moreover, KS patients are characterized by subclinical abnormalities in left ventricular (LV) systolic and diastolic function and endothelial function, which, when associated with chronotropic incompetence may led to reduced cardiopulmonary performance. KS patients appear to be at a higher risk for cardiovascular disease, attributing to an increased risk of thromboembolic events with a high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism with higher risk of deep venous thrombosis or pulmonary embolism. It appears that cardiovascular involvement in KS is mainly due to chromosomal abnormalities rather than solely on low serum testosterone levels. On the basis of evidence acquisition and authors’ own experience, a flowchart addressing the management of cardiovascular function and prognosis of KS patients has been developed for clinical use.
Krystallenia I Alexandraki, Gregory A Kaltsas, Andrea M Isidori, Scott A Akker, William M Drake, Shern L Chew, John P Monson, G Michael Besser, and Ashley B Grossman
Cyclical Cushing's syndrome may render the diagnosis and management of Cushing's disease difficult. The aim of the present study was to investigate the prevalence of cyclicity and variability in patients with Cushing's disease, and to identify putative distinctive features.
Retrospective case-note study.
We analysed the case records of 201 patients with Cushing's disease in a retrospective case-note study. Cyclicity was considered as the presence of at least one cycle, defined as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The fluctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, defined the variability.
Thirty (14.9%; 26 females) patients had evidence of cyclicity/variability. ‘Cycling’ patients were older but no difference in sex or paediatric distribution was revealed between ‘cycling’ and ‘non-cycling’ patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identification was observed in ‘cycling’ compared with ‘non-cycling’ patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identification of the adenoma were associated with an increased risk of cyclic disease.
This large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushing's disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specific features can be used as markers.
Emilia Sbardella, Marianna Minnetti, Denise D’Aluisio, Laura Rizza, Maria Rosaria Di Giorgio, Fabio Vinci, Riccardo Pofi, Elisa Giannetta, Mary Anna Venneri, Annarita Vestri, Sergio Morelli, Andrea Lenzi, and Andrea M Isidori
Low-grade incomplete post-dexamethasone cortisol suppression in patients with adrenal incidentalomas – recently defined as possible autonomous cortisol secretion (pACS) – has been associated with increased cardiovascular events and mortality. However, prospective studies documenting cardiac abnormalities in these patients are lacking.
Subjects and methods
Between July 2016 and September 2017, 71 consecutive patients with adrenal lesions were prospectively screened for hypercortisolism by dexamethasone suppression test (NCT 02611258). Complete anthropometric, metabolic and hormonal parameters were recorded along with full cardiac ultrasound assessment and noninvasive measurement of arterial stiffness. All patients underwent chemical-shift magnetic resonance imaging to characterize the lesions. Cardiovascular outcomes were recorded in blind.
According to post-dexamethasone suppression cortisol values (post-DST), 34 patients had pACS and 37 non-functioning adenomas (NFA). The two groups were similar in sex, BMI, age distribution, cardiovascular risk factors and comorbidities. Left ventricular mass index (LVMIBSA) was increased in pACS compared to NFA (P = 0.006) and mildly correlated to the post-DST cortisol level (rho = 0.347; P = 0.004). The post-DST cortisol levels explained up to 13.7% of LVMIBSA variance (P = 0.002). Compared to NFA, patients with pACS had a higher prevalence of diastolic dysfunction (35.1% vs 82.6%; P = 0.001) and worse arterial stiffness assessed by pulse wave velocity (P = 0.033).
In apparently asymptomatic patients, mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling, independently of other risk factors. The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition.
Alessia Cozzolino, Tiziana Feola, Ilaria Simonelli, Giulia Puliani, Valeria Hasenmajer, Marianna Minnetti, Elisa Giannetta, Daniele Gianfrilli, Patrizio Pasqualetti, Andrea Lenzi, and Andrea M Isidori
Neurosurgery is the first-line treatment for acromegaly. Whether metabolic disorders are reversible after neurosurgery is still debated. The meta-analysis aimed to address the following questions: (i) Does neurosurgery affect glycolipid metabolism? (ii) Are these effects related to disease control or follow-up length?
A meta-analysis and systematic review of the literature.
Three reviewers searched databases until August 2019 for prospective trials reporting glycometabolic outcomes after neurosurgery. Three other extracted outcomes, all assessed the risk of bias.
Twenty studies were included. Neurosurgery significantly reduced fasting plasma glucose (FPG) (effect size (ES): −0.57 mmol/L, 95% CI: −0.82 to −0.31; P < 0.001), glucose load (ES: −1.10 mmol/L, 95% CI: −1.66 to −0.53; P < 0.001), glycosylated haemoglobin (HbA1c) (ES: −0.28%, 95% CI: −0.42 to −0.14; P < 0.001), fasting plasma insulin (FPI) (ES: −10.53 mU/L, 95% CI: −14.54 to −6.51; P < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (ES: −1.98, 95% CI: −3.24 to −0.72; P = 0.002), triglycerides (TGDs) (ES: −0.28 mmol/L, 95% CI: −0.36 to −0.20; P < 0.001) and LDL-cholesterol (LDLC) (ES: −0.23 mmol/L, 95% CI: −0.45 to −0.02 mmol/L); P = 0.030) and increased HDL-cholesterol (HDLC) (ES: 0.21 mmol/L, 95% CI: 0.14 to 0.28; P < 0.001). Meta-regression analysis showed that follow-up length – not disease control – had a significant effect on FPG, with the greatest reduction in the shortest follow-up (beta = 0.012, s.e. = 0.003; P = 0.001).
Neurosurgery improves metabolism with a significant decrease in FPG, glucose load, HbA1c, FPI, HOMA-IR, TGDs, and LDLC and increase in HDLC. The effect on FPG seems to be more related to follow-up length than to disease control.
Krystallenia I Alexandraki, Gregory A Kaltsas, Andrea M Isidori, Helen L Storr, Farhad Afshar, Ian Sabin, Scott A Akker, Shern L Chew, William M Drake, John P Monson, G Michael Besser, and Ashley B Grossman
To investigate the early and late outcomes of patients with Cushing's disease (CD) submitted to a neurosurgical procedure as first-line treatment.
In this single-centre retrospective case notes study, 131 patients with CD with a minimum follow-up period of 6 years (124 operated by transsphenoidal surgery (TSS) and seven by the transcranial approach) were studied. Apparent immediate cure: post-operative 0900 h serum cortisol level <50 nmol/l; remission: cortisol insufficiency or restoration of ‘normal’ cortisol levels with resolution of clinical features; and recurrence: dexamethasone resistance and relapse of hypercortisolaemic features.
In patients operated by TSS, remission of hypercortisolaemia was found in 72.8% of 103 microadenomas and 42.9% of 21 macroadenomas, with recurrence rates 22.7 and 33.3% respectively with a 15-year mean follow-up (range, 6–29 years). Of 27 patients with microadenomas operated after 1991, with positive imaging and pathology, 93% obtained remission with 12% recurrence. In multivariate analysis, the time needed to achieve recovery of hypothalamo-pituitary–adrenal axis was the only significant predictor of recurrence; all patients who recurred showed recovery within 3 years from surgery: 31.3% of patients had total hypophysectomy with no recurrence; 42% of patients with selective adenomectomy and 26.5% with hemi–hypophysectomy showed recurrence rates of 31 and 13% respectively (χ 2=6.275, P=0.03). Strict remission criteria were not superior in terms of the probability of recurrence compared with post-operative normocortisolaemia.
Lifelong follow-up for patients with CD appears essential, particularly for patients who have shown rapid recovery of their axis. The strict criteria previously used for ‘apparent cure’ do not appear to necessarily predict a lower recurrence rate.