Impact of COVID-19 pandemic on psychophysical stress in patients with adrenal insufficiency: the CORTI-COVID study.

PURPOSE: COVID-19 is a novel threat to patients with adrenal insufficiency (AI), whose life expectancy and quality (QoL) are impaired by an increased risk of infections and stress-triggered adrenal crises (AC). If infected, AI patients require prompt replacement tailoring. We assessed, in a cohort of AI patients: prevalence and clinical presentation of COVID-19; prevalence of AC and association with intercurrent COVID-19 or pandemic-related psychophysical stress; lockdown-induced emotional burden, and health-related QoL. METHODS: In this monocentric (Ancona University Hospital, Italy), cross-sectional study covering February-April 2020, 121 (40 primary, 81 secondary) AI patients (59 males, 55 ± 17 years) completed telematically three questionnaires: the purpose-built "CORTI-COVID", assessing medical history and concern for COVID-19-related global health, AI-specific personal health, occupational, economic, and social consequences; the AddiQoL-30; the Short-Form-36 (SF-36) Health Survey. RESULTS: COVID-19 occurred in one (0·8% prevalence) 48-year-old woman with primary AI, who promptly tailored her replacement. Dyspnea lasted three days, without requiring hospitalization. Secondary AI patients were not involved. No AC were experienced, but pandemic-related stress accounted for 6/14 glucocorticoid up-titrations. Mean CORTI-COVID was similar between groups, mainly depending on "personal health" in primary AI (ρ = 0.888, p < 0.0001) and "economy" in secondary AI (ρ = 0.854, p < 0.0001). Working restrictions increased occupational concern. CORTI-COVID correlated inversely with QoL. AddiQoL-30 and SF-36 correlated strongly. Comorbidities worsened patients' QoL. CONCLUSION: If educational efforts are made in preventing acute events, AI patients seem not particularly susceptible to COVID-19. The novel "CORTI-COVID" questionnaire reliably assesses the pandemic-related emotional burden in AI. Even under unconventional stress, educated AI patients preserve a good QoL.

Safety and effectiveness of Omnitrope® in patients with growth hormone deficiency: snapshot analysis of PATRO Adults study in the Italian population.

PURPOSE: PATRO adults is an ongoing, multicenter, observational, post-marketing surveillance study aimed at investigating the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the recombinant human growth hormone (rhGH) Omnitrope® during routine clinical practice. This report describes data from Italian participants in PATRO Adults with growth hormone deficiency (GHD), up to August 2017. METHODS: Participants were adults (aged > 18 years) with GHD requiring rhGH therapy and were prescribed Omnitrope®, including those who had previously received another rhGH product. Adverse events (AEs) were evaluated in all study participants. Data were collected on insulin-like growth factor (IGF)-I levels and cardiovascular risk factors, including blood pressure, lipids, and anthropometric parameters. RESULTS: From September 2007 to August 2017, 88 patients (mean age 48.9 years, 58.0% male) were enrolled at 8 sites in Italy. The mean treatment duration with Omnitrope® was 51.5 ± 37 months. AEs occurred in 54 patients; the most common were asthenia (20.5%), headache (14.8%), and arthralgia (13.6%). Serious AEs occurred in 22 patients (25%), including pneumonia (n = 2) and renal failure (n = 2). Neoplasms (2 benign and 1 malignant) developed in three patients, but none were considered to be drug-related. There were no significant changes in fasting glucose or glycosylated hemoglobin (HbA1c) during the study period. Long-term Omnitrope® therapy showed slight positive effects on lipid profile, while no significant changes were observed in body weight and BMI during the study. CONCLUSION: This snapshot analysis of Italian participants in PATRO Adults confirmed the long-term safety and effectiveness of Omnitrope® in adults with GHD.

Towards the tailoring of glucocorticoid replacement in adrenal insufficiency: the Italian Society of Endocrinology Expert Opinion.

CONTEXT: Glucocorticoid (GC) replacement therapy in patients with adrenal insufficiency (AI) is life saving. After over 50 years of conventional GC treatment, novel formulations are now entering routine clinical practice. METHODS: Given the spectrum of medications currently available and new insights into the understanding of AI, the authors reviewed relevant medical literature with emphasis on original studies, prospective observational data and randomized controlled trials performed in the past 35 years. The Expert Opinion of a panel of selected endocrinologists was sought to answer specific clinical questions. The objective was to provide an evidence-supported guide, for the use of GC in various settings from university hospitals to outpatient clinics, that offers specific advice tailored to the individual patient. RESULTS: The Panel reviewed available GC replacement therapies, comprising short-acting, intermediate and long-acting oral formulations, subcutaneous formulations and the novel modified-release hydrocortisone. Advantages and disadvantages of these formulations were reviewed. CONCLUSIONS: In the Panel's opinion, achieving the optimal GC timing and dosing is needed to improve the outcome of AI. No-single formulation offers the best option for every patients. Recent data suggest that more emphasis should be given to the timing of intake. Tailoring of GS should be attempted in all patients-by experts-on a case-by-case basis. The Panel identified specific subgroups of AI patients that could be help by this process. Long-term studies are needed to confirm the short-term benefits associated with the modified-release GCs. The impact of GC tailoring has yet to be proven in terms of hospitalization rate, morbidity and mortality.

The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study.

INTRODUCTION AND AIM: A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS: We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS: LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS: LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm.

Ultrasound-based detection of glucocorticoid-induced impairments of muscle mass and structure in Cushing's disease.

PURPOSE: To investigate the glucocorticoid-induced impairments of muscle mass and structure in patients presenting different stages of steroid myopathy progression. METHODS: Thirty-three patients (28 women) affected by active (N = 20) and remitted (N = 13) Cushing's disease were recruited and the following variables were assessed: walking speed, handgrip strength, total body and appendicular muscle mass by bioelectrical impedance analysis (BIA), thickness and echo intensity of lower limb muscles by ultrasonography. RESULTS: The two groups of patients showed comparable values of both handgrip strength [median (interquartile range) values: active disease: 27.4 (7.5) kg vs. remitted disease: 26.4 (9.4) kg; P = 0.58] and walking speed [active disease: 1.0 (0.2) m/s vs. remitted disease: 1.1 (0.3) m/s; P = 0.43]. Also, the thickness of the four muscles and all BIA-derived sarcopenic indices were comparable (P > 0.05 for all comparisons) between the two groups. On the contrary, the echo intensity of vastus lateralis, tibialis anterior (lower portion), and medial gastrocnemius was significantly (P < 0.05 for all comparisons) higher in patients with active disease compared to patients with remitted disease. Finally, significant negative correlations were found in the whole group of patients between muscle echo intensity and muscle function assessments. CONCLUSIONS: We provided preliminary evidence that the ultrasound-derived measurements of muscle thickness and echo intensity can be useful to detect and track the changes of muscle mass and structure in patients with steroid myopathy and we suggest that the combined assessment of muscle mass, strength, and performance should be systematically applied in the routine examination of steroid myopathy patients.

Pituitary adenomas, stem cells, and cancer stem cells: what's new?

PURPOSE: To clarify the existence of pituitary stem cells (SCs) both in the embryonic and the postnatal gland and the role for SCs in pituitary adenomas. METHODS: This work, which does not address the pathogenesis of pituitary adenomas, reviews the latest research findings and discoveries on SCs in pituitary and cancer SCs (CSCs) in pituitary adenomas and discusses the involvement of the EMT. RESULTS: Several groups using different approaches and techniques have demonstrated the existence of SCs and CSCs and as they are major players in pituitary adenoma onset. CONCLUSIONS: As in other benign and malignant tumors, the hypothesis that CSCs play a pivotal role in pituitary adenoma onset has been confirmed as well as the existence of a link between the epithelial-to-mesenchymal transition (EMT) process and CSC formation in epithelial tumors.

Correction to: Pegvisomant in acromegaly: an update.

Unfortunately, in page 584, second column, the first sentence under the heading "Type of switch" has been published incorrectly. The complete correct sentence is given below.

How to improve effectiveness of pegvisomant treatment in acromegalic patients.

PURPOSE: Pegvisomant (PEGV) treatment in acromegaly patients resistant to somatostatin analogues is less effective in the real life than in clinical trials. This is a multicenter, observational, retrospective, longitudinal study. The aim was to detect characteristics which improve long-term PEGV effectiveness. METHODS: 87 acromegalic patients treated with PEGV have been enrolled in seven referral Italian centres. PEGV was administered for up to 4 years, at doses up titrated until IGF-1 normalization or to ≥ 30 mg/day. The rate of patients who reached IGF-1 normalization at last visit has been calculated. RESULTS: IGF-1 was normalized in 75.9% of patients after 1 year and in 89.6% at last visit. Disease control was associated with lower baseline GH, IGF-1 and IGF-1 xULN and was more frequent when baseline IGF-1 was < 2.7 × ULN (p < 0.02). PEGV dose was dependent on baseline IGF-1 > 2.7 × ULN (p < 0.05) and doses > 1.0 mg/BMI/day were administered more frequently when baseline IGF-1 was > 2.0 × ULN (p = 0.03). PEGV resistance was associated with higher BMI (p = 0.006) and was more frequent when BMI was > 30 kg/m2 (p = 0.07). There were no significant differences between patients treated with monotherapy or combined treatment. IGF-1 normalization, PEGV dose and rate of associated treatment were similar between males and females. PEGV effectiveness was independent from previous management. Diabetic patients needed higher doses of PEGV than non-diabetic ones. CONCLUSIONS: PEGV effectiveness improves when up titration is appropriate. Higher PEGV doses at start and a more rapid up-titration are necessary in patients with obesity and/or IGF-1 > 2.7 × ULN.

Long-term safety and efficacy of Omnitrope® in adults with growth hormone deficiency: Italian interim analysis of the PATRO Adults study.

PURPOSE: To report the long-term effectiveness and safety of the recombinant human growth hormone Omnitrope®, a somatropin biosimilar to Genotropin®, in Italian patients with growth hormone deficiency (GHD) enrolled in the PATRO Adults study. METHODS: The PATRO Adults study is an ongoing observational, longitudinal, non-interventional global post-marketing surveillance study, conducted in several European countries. The primary endpoint is long-term safety; secondary endpoints include the effectiveness of Omnitrope®, which was assessed using serum insulin-like growth factor-1 levels, body composition, bone mineral density and lipid levels. Here we report the data from the Italian patients enrolled in the study. RESULTS: Sixty-seven patients (mean age 50.4 years, 61.2% male) have been enrolled and have received a mean 45.4 ± 24.3 months of Omnitrope®. A total of 55.2% of patients were reported to have experienced adverse events (AEs), including arthralgia, myalgia, abdominal distension and hypoaesthesia, and 4.5% had adverse drug reactions. Fourteen serious AEs have been recorded; none of these are considered related to the study drug. The effectiveness of Omnitrope® was similar to other available somatropin preparations. CONCLUSIONS: This study confirms the effectiveness and safety of Omnitrope® in adult patients with GHD in Italy. However, due to the limited size of the study population, these results need to be further confirmed by the global PATRO Adults study.

Pegvisomant in acromegaly: an update.

BACKGROUND: In 2007, we published an opinion document to review the role of pegvisomant (PEG) in the treatment of acromegaly. Since then, new evidence emerged on the biochemical and clinical effects of PEG and on its long-term efficacy and safety. AIM: We here reviewed the emerging aspects of the use of PEG in clinical practice in the light of the most recent literature. RESULTS: The clinical use of PEG is still suboptimal, considering that it remains the most powerful tool to control IGF-I in acromegaly allowing to obtain, with a pharmacological treatment, the most important clinical effects in terms of signs and symptoms, quality of life and comorbidities. The number of patients with acromegaly exposed to PEG worldwide has become quite elevated and the prolonged follow-up allows now to deal quite satisfactorily with many clinical issues including major safety issues, such as the concerns about possible tumour (re)growth under PEG. The positive or neutral impact of PEG on glucose metabolism has been highlighted, and the clinical experience, although limited, with sleep apnoea and pregnancy has been reviewed. Finally, the current concept of somatostatin receptor ligands (SRL) resistance has been addressed, in order to better define the acromegaly patients to whom the PEG option may be offered. CONCLUSIONS: PEG increasingly appears to be an effective and safe medical option for many patients not controlled by SRL but its use still needs to be optimized.

A Single-Center 10-Year Experience with Pasireotide in Cushing's Disease: Patients' Characteristics and Outcome.

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing's disease (CD). Our 10-year experience with pasireotide in CD is reported here. Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor(®); Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months). Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients. Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

Increased frequency of the rs2066853 variant of aryl hydrocarbon receptor gene in patients with acromegaly.

CONTEXT: Aryl hydrocarbon receptor (AHR) pathway has a key role in cellular detoxification mechanisms and seems implicated in tumorigenesis. Moreover, polymorphisms and mutations of AHR gene have been associated with several human and animal tumours. Although AHR has been found differently expressed in pituitary adenomas, AHR gene mutation status has never been investigated in acromegalic patients. DESIGN: In this study, we evaluated patients with apparently sporadic GH-secreting pituitary adenoma for AHR gene variants. PATIENTS AND METHODS: Seventy patients with sporadic GH-secreting pituitary adenoma (M = 27, age 59.1 ± 1.6 years) and 157 sex- and age-matched controls were enrolled in the study. In all patients and controls, the exons 1, 2, 3, 5 and 10 of AHR gene were evaluated for nucleotide variants by sequencing analysis. RESULTS: The rs2066853 polymorphism was identified in the exon 10 of 18/70 acromegalic patients and 9/157 healthy subjects (25.7 vs. 5.7%, χ(2) = 18.98 P < 0.0001), in homozygosis in one patient and in heterozygosis in the other 17 and in the 9 healthy subjects. Moreover, a heterozygous rs4986826 variant in exon 10 was identified in a patient with heterozygous rs2066853 polymorphism, and in the patient with homozygous rs2066853 variant. This second polymorphism was not detected in the control group. Patients with rs2066853 polymorphism showed increased IGF-1 ULN (P < 0.05) and prevalence of cavernous sinus invasion (P = 0.05), thyroid (P = 0.02), bladder (P = 0.0001) or lymphohematopoietic (P < 0.05) tumours. CONCLUSIONS: AHR gene rs2066853 polymorphism is significantly more frequent in acromegalic patients than in healthy subjects and is associated with increased disease aggressivity. Moreover, the rs4986826 variant was detected in few patients with rs2066853 polymorphism, but its role is to be cleared.

Bone complications in patients with Cushing's syndrome: looking for clinical, biochemical, and genetic determinants.

SUMMARY: This is the first study examining the impact of both clinical, biochemical, and genetic determinants in the occurrence of bone complications in patients with overt Cushing's syndrome (CS). It demonstrates that the degree and duration of hypercortisolism seem to play a major role in bone loss and fractures development in these patients. INTRODUCTION: Bone loss and fractures are a common complication of CS. We investigate the role of gender, disease etiology, duration, and degree of hypercortisolism as well as the impact of glucocorticoid receptor (GR) polymorphisms on the development of bone complications in CS. METHODS: Fifty-two patients with active CS (38 Cushing's disease and 14 with cortisol-secreting adrenal adenoma) were genotyped for GR polymorphisms (BclI, N363S, ER22/23EK, and A3669G). In all patients, clinical, hormonal, and biochemical markers of bone turnover, densitometric parameters [lumbar spine and left femur bone mineral density (BMD), T-score, Z-score] as well as the prevalence of bone demineralization and both vertebral and peripheral fractures were assessed. RESULTS: No differences were found in bone complications according to gender, disease etiology, and genetic variants distribution. Fractured patients compared to non-fractured ones showed increased levels of urinary free cortisol (UFC) and a more compromised densitometric profile. UFC levels correlated with the occurrence of vertebral fractures (r = 0.43, p = 0.009) while midnight serum cortisol correlated with L1-L4 BMD values (r = -0.35, p = 0.04). Disease duration correlated with the presence of peripheral fractures (r = 0.36, p = 0.04). CONCLUSIONS: While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism.

Advances in the epidemiology, pathogenesis, and management of Cushing's syndrome complications.

Cushing's syndrome (CS) is a clinical condition resulting from chronic exposure to glucocorticoid excess. As a consequence, hypercortisolism contributes significantly to the early development of systemic disorders by direct and/or indirect effects. Complications such as obesity, hypertension, diabetes, dyslipidemia, and hypercoagulability cause premature atherosclerosis and increase cardiovascular mortality. Impairment of the skeletal system is a relevant cause of morbidity and disability in these patients especially due to the high prevalence of vertebral fractures. In addition, muscle weakness, emotional lability, depression, and impairment of quality of life are very common. Clinical management of these patients is complex and should be particularly careful in identifying global cardiovascular risks and aim at controlling all complications. Although the primary goal in the prevention and treatment of complications is the correction of hypercortisolism, treatment does not completely eliminate these comorbidities. Given that cardiovascular risk and fracture risk can persist after cure, early detection of each morbidity could prevent the development of irreversible damage. In this review we present the various complications of CS and their pathogenetic mechanisms. We also suggest the clinical management of these patients based on our extensive clinical experience and on the available literature.

Fine-needle aspiration cytology of adrenal masses: a re-assessment with histological confirmation.

BACKGROUND: Fine-needle aspiration (FNA) of adrenal masses is a method currently indicated in lesions suspected of being extra-adrenal in origin; even though its diagnostic reliability has already been determined in many studies, few have used histological examination obtained after adrenalectomy for diagnostic confirmation. AIM: To analyze the diagnostic performance of adrenal FNA in subjects with an available histological confirmation. SUBJECTS AND METHODS: Fifty subjects (26 benign adrenal lesions, 9 primary malignant lesions, and 15 metastatic lesions) who had undergone ultrasound (US)-guided adrenal FNA and then adrenalectomy were re-analyzed retrospectively. RESULTS: FNA guaranteed a sensitivity of 85.7% and a specificity of 100% in all subjects; after having divided the subjects into oncologic and non-oncologic groups, the sensitivity of the test in oncologic patients (100%) increased significantly compared to non-oncologic (57.1%) with no difference in specificity (100% in both groups). Considering also non-diagnostic samples in our analysis (no.=11; 22% of all samples studied), FNA correctly diagnosed malignancy only in 75% of the cases and benignancy only in 66.6%; however, even after including non-diagnostic samples, the percentage of correct malignancy diagnosis remained significantly higher in oncologic (93.3%) than in non-oncologic patients (44.4%) without significant statistical difference between the 2 groups regarding the percentage of correct benignancy diagnosis (respectively 100% and 63.6%). CONCLUSIONS: Our study, based on histological confirmation, underlines the low discriminant value of US-guided adrenal FNA, though the method may have value in oncologic patients.

Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.