Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Heart rate variability is reduced in acromegaly patients and improved by treatment with somatostatin analogues.

BACKGROUND: Cardiovascular complications, including arrhythmias and cardiac sudden death, are the most common causes of enhanced mortality in acromegaly. However, few data are available on cardiac autonomic functions and sympathovagal balance in acromegalic patients. OBJECTIVE: The aim of this study was to investigate both the time and frequency domain parameters of Heart Rate Variability (HRV), in order to characterize the cardiac autonomic functions in patients affected by acromegaly. This study correlated anthropometric, metabolic, echocardiographic parameters and blood pressure with those relating to HRV, to identify the main factors responsible for the HRV related alterations possibly present. We also aimed to analyze the effects of the treatment with somatostatin analogues (SSAs) on HRV. MATERIALS AND METHODS: This study enrolled 47 acromegalic patients (23 males, age 49.1 ± 13.5 years) and 37 (13 males) age matched (52.3 ± 13.3 years) healthy subjects. All participants underwent 12-lead 24 h ECG Holter recordings and a HRV analysis of the ECG tracings was performed. The parameters obtained from the time domain analysis of HRV included pNN50, SDNN, SDNN index, SDANN and RMSSD. The power spectral analysis of HRV was obtained by summing powers of the LF (low frequency) and the HF (high frequency) band. Sympathovagal balance was estimated by calculating the LF/HF ratio during 24 h and 15 min of clinostatism. The HRV of 28 acromegalic patients was studied before and after SSAs treatment. RESULTS: Acromegalic patients showed significantly lower SDNN and SDANN compared to controls. Diabetic and non-diabetic acromegalic patients showed decreased SDNN and SDANN, when compared to healthy subjects. Diabetic acromegalic patients had a lower LF/HF ratio during 24 h when compared to non-diabetic acromegalic patients. Similar results were obtained analyzing patients affected by acromegaly and impaired glucose tolerance. SDNN and SDANN were lowered by hypertension in the acromegalic population, when compared to controls, and hypertensive acromegalic patients also displayed a decreased LF/HF ratio during 24 h when compared to normotensive acromegalic subjects. Patients with ventricular arrhythmias in Lown classes 3-5 showed a decreased SDANN compared to patients in Lown class 0-2. The treatment with SSAs was able to ameliorate all the time domain parameters of HRV, without altering the 24 h LF/HF ratio. CONCLUSION: Cardiac autonomic functions and sympathovagal balance are altered in patients affected by acromegaly and could be ameliorated by SSAs therapy. HRV analysis allows an estimation of the autonomic sympathovagal balance and may be a useful clinical tool for the cardiac risk stratification in acromegalic patients.

Evidence for ultra-short loop autoregulation of adrenocorticotropin secretion in man.

The existence of feedback inhibition of ACTH on its own secretion has been postulated. To investigate its existence in man, the effects of synthetic ACTH 1-24 on endogenous ACTH secretion were tested in 13 patients with Addison's disease. Plasma ACTH was measured using an immunoradiometric assay, specific for endogenous ACTH 1-39. Ten patients were given 50 micrograms ACTH 1-24 as a bolus iv dose followed by a 50-microgram infusion in 90 min. Blood samples for ACTH and cortisol assay were obtained at 0, 15, 30, 60, 90, and 120 min. As a control, a saline infusion was given 2 days earlier. Three other patients were given 100 micrograms ovine corticotropin-releasing hormone (oCRH) iv and ACTH 1-24 as described above. Blood samples for ACTH and cortisol assay were drawn every 15 min for 2 hours. A CRH test was performed during saline infusion as a control 2 days earlier. In all patients steroid replacement therapy was maintained during the studies. ACTH 1-24 caused a significant decrease (P less than 0.01) in endogenous plasma ACTH at 15 min compared to saline. oCHR administration markedly stimulated ACTH release in the three patients tested, and the ACTH response to oCRH was completely inhibited by the simultaneous administration of ACTH 1-24. These findings strongly support the presence of ACTH autoregulation in man. The complete inhibition of the ACTH response to oCRH by exogenous ACTH 1-24 provides evidence for ultra-short feed-back inhibition at the pituitary level.

Early adrenal hypofunction in patients with organ-specific autoantibodies and no clinical adrenal insufficiency.

Idiopathic Addison's disease occurs frequently in association with other organ-specific autoimmune diseases, and autoantibodies to adrenal cortex are markers of this condition. A variable asymptomatic period with subtle adrenal dysfunction may precede the onset of clinical manifestations. We studied the pituitary-adrenal axis by measuring plasma ACTH, cortisol, and 17 alpha-hydroxyprogesterone after ovine CRH (100 micrograms as an iv bolus) stimulation in 19 patients with organ-specific autoimmune disease and adrenal autoantibodies, in whom adrenal steroids were normal under baseline conditions and normally responsive to a standard ACTH stimulation test (250 micrograms). In all subjects, oCRH produced a normal increase in plasma ACTH. Plasma cortisol, which was normoresponsive in 11 subjects, showed little or no increase in 8 subjects. Two of these patients developed overt adrenal failure after 1 yr. The 17 alpha-hydroxyprogesterone response to oCRH, tested in 10 of 19 patients, paralleled that of plasma cortisol, excluding a steroidogenic block at the 21-hydroxylase site. Our data demonstrate the existence of a very early phase of Addison's disease in which adrenal function shows an impaired response to ovine CRH-stimulated ACTH.

Risk factors and long-term follow-up of adrenal incidentalomas.

The natural course of adrenal incidentalomas and the risk that such lesions evolve toward hormonal hypersecretion or malignancy are still under evaluation. Of 246 consecutive patients with adrenal incidentaloma studied at our institution in the last 15 yr, 91 underwent surgery. Of the remaining patients, a group of 75 (52 females and 23 males; median age, 56 yr; range, 19-77 yr) with incidentally discovered asymptomatic adrenal masses (60 unilateral and 15 bilateral; median diameter, 2.5 cm; range, 1.0-5.6) was enrolled in an endocrine and morphological follow-up of at least 2 yr after diagnosis (median, 4 yr; range, 2-10). During follow-up, no patients developed malignancy; 9 showed mass enlargement, with appearance of a new mass in the contralateral gland in 2; 3 developed adrenal hyperfunction (overt Cushing's syndrome in 2, nonclinical hypercortisolism in 1); and 3 showed adrenal mass enlargement associated with adrenal hyperfunction (nonclinical hypercortisolism in 2, pheochromocytoma in 1). The estimated cumulative risks to develop mass enlargement and hyperfunction were 8% and 4%, respectively, after 1 yr, 18% and 9.5% after 5 yr, and 22.8% and 9.5% after 10 yr. Nine risk factors for adrenal mass enlargement or hyperfunction were arbitrarily selected and evaluated: sex, age, presence of obesity, hypertension, diabetes, abnormal endocrine tests, mass size, mass location, and scintigraphic uptake pattern. Three of them attained statistical significance: mass size of 3 cm or more at diagnosis and exclusive radiocholesterol uptake by the mass at scintigraphy had relevance for the occurrence of adrenal hyperfunction, whereas the presence of endocrine test abnormalities at diagnosis had predictive value for mass enlargement. It is concluded that subtle hormonal abnormalities are risk factors for mass size increase, which is not a sign of malignant transformation. Both mass size of 3 cm or more at diagnosis and exclusive radiocholesterol uptake, indicating higher risks of hyperfunction, should be considered to plan a more thorough endocrine follow-up.

Age-related changes in glucocorticoid fast feedback inhibition of adrenocorticotropin in man.

A decrease in hypothalamic-pituitary-adrenal axis sensitivity to glucocorticoid feedback suppression seems to occur with aging. To investigate possible abnormalities in the inhibitory effect of glucocorticoids on ACTH secretion in the elderly, we evaluated the endogenous ACTH response to hydrocortisone (25 mg as an i.v. bolus) in 15 healthy aged (65-88 yr) and 15 healthy young (18-26 yr) men. Blood samples for ACTH and cortisol determinations were collected at -15, 0, 2, 5, 10, 15, 30, 45, 60, 90, 120, and 180 min. Hydrocortisone injection produced a rapid increase in plasma cortisol levels within the first 2 min in both groups. In old men, in concomitance with the cortisol increase, ACTH levels showed only a slight and nonsignificant decrease within the first 15 min, followed by a pronounced and significant decline thereafter. In young subjects, in concomitance with the plasma cortisol increase, a marked decrease in ACTH levels was observed within the first 15 min, followed by a less pronounced decline thereafter. The response curve of ACTH inhibition could be arbitrarily divided in two parts. The first part (from 0-60 min) showed a significant difference between old and young men, whereas the remaining part of the curve (from 60-180 min) showed no differences between the two groups. The slower response in glucocorticoid feedback inhibition of ACTH in old men supports the concept of some alteration in the central regulation by steroids in aging. Age-related vascular factors affecting cortisol penetration through the blood-brain barrier more than hippocampus-hypothalamus receptor abnormalities could be involved in the fast component of hypothalamic-pituitary-adrenal axis feedback regulation.

Effect of surgical treatment on hypertension in Cushing's syndrome.

The effect of a surgical cure of hypercortisolism on hypertension in 54 patients with Cushing's syndrome was assessed. The correlation between preoperative duration of hypertension and posttreatment blood pressure was significant (P < .01). Restoration of normal cortisol was associated with blood pressure normalization in 39 out of 54 cases. Duration of hypertension of patients with normalized blood pressure was significantly shorter than that of patients with persistent hypertension postoperatively (P < .0001). Duration of hypertension, ie, long-lasting exposure to increased cortisol, appears to be the determinant of persistent hypertension following successful surgery in Cushing's syndrome.

[Use of catheterization of the inferior petrosal sinus in the diagnosis of Cushing's disease]. / Impiego del cateterismo dei seni petrosi inferiori nella diagnostica della malattia di Cushing.

Previous reports have emphasized the value of bilateral and simultaneous catheterization of the inferior petrosal sinus for the measurement of both basal and oCRH (ovine Corticotropin Releasing Hormone) stimulated ACTH levels to determine the site of the microadenoma in the pituitary and for the differential diagnosis of Cushing's disease. This method is mainly employed in those patients whose hormonal studies are ambiguous and whose CT-scans and NMR (Nuclear-Magnetic-Resonance) results yield inconclusive or negative findings. Ten patients were studied: 9 were under evaluation for Cushing's disease and one was a "relapse" (4 yrs after transsphenoidal microadenomectomy). In all patients, except two who are awaiting surgery and one who was a "relapse", surgical findings were consistent with the ipsilateral hypersecretion (one had a central microadenoma). These results confirm that bilateral and simultaneous catheterization of the inferior petrosal sinus associated with a oCRH stimulus could be of great help in localizing the site of the adenoma and therefore improve the results of surgery. Moreover, this methodology may be of great value in diagnosing ectopic secretion.

Patterns of ACTH response to oCRH in Cushing's disease: correlation with histological/immunocytochemical findings.

The most common lesion in Cushing's disease is an anterior pituitary adenoma. However, normal or hyperplastic corticotropic pituitary tissue has also been found in some cases. In an attempt to distinguish the patterns of ACTH response to oCRH in different forms of anterior pituitary hypersecretion, 17 patients with pituitary adenoma and 17 without pathological evidence of adenoma were studied. These patients underwent transsphenoidal pituitary surgery by the same surgeon and were retrospectively evaluated. The diagnosis of pituitary lesions was confirmed by microscopical and immunohistochemical studies. Patients without pituitary adenoma showed a higher and more prolonged mean plasma ACTH response than that observed in patients with pituitary tumors. In patients with pituitary adenoma, the peak ACTH response was observed within 30 min after oCRH administration, and was followed by a gradual decrease to basal levels in the following 30 min. In those cases in whom no pituitary adenoma was found, oCRH injection produced a marked increase in plasma ACTH levels during the first 60 min with a slower decline at the subsequent time points. The mean response curves of the two groups, analyzed by Beherens-Fischer nonparametric ANOVA, showed significant differences, either when they were compared globally (p < 0.01), or at single time points. Differences in ACTH response to oCRH stimulation support the hypothesis of different pathogenetic mechanisms leading to ACTH hypersecretion in Cushing's disease with and without pituitary adenoma.

Response of hypertension to conventional antihypertensive treatment and/or steroidogenesis inhibitors in Cushing's syndrome.

OBJECTIVES: To evaluate the effect of conventional antihypertensive drugs and/or inhibitors of steroid production in the management of hypertension in Cushing's syndrome. DESIGN: A retrospective open clinical study with pre- and post-treatment assessment. SETTING: A university hospital, where patients were initially admitted and then followed-up in an ambulatory clinic over a period of 6 years. SUBJECTS: Forty consecutive hypertensive patients with Cushing's syndrome. INTERVENTIONS: Patients were divided into two groups according to the different management of hypertension. The first group (group 1) of 28 patients included those treated with antihypertensive drugs at full dose (diuretics, calcium antagonists, angiotensin converting enzyme [ACE] inhibitors, as single agents or in combination). The second group (group 2) of 12 patients received ketoconazole alone. MAIN OUTCOME MEASURES: Blood pressure variations compared to pre-treatment levels. RESULTS: Blood pressure normalization was obtained in four of the 28 patients of group 1. In 12 of the remaining patients, ketoconazole, an inhibitor of steroid production, was subsequently added and this normalized blood pressure in all but the one in whom cortisol was not decreased. In the 12 patients of group 2, ketoconazole alone lowered blood pressure within normal limits in all but one who had long-standing hypertension. CONCLUSIONS: In hypertensive patients with Cushing's syndrome, conventional antihypertensive therapy is mostly ineffective. Blood pressure response is satisfactory only after the restoration of normal cortisol levels, indicating the need for a specific treatment for hypertension in this disorder.

Selective venous sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome.

Bilateral simultaneous inferior petrosal sinus sampling, associated with the oCRH stimulation test (100 micrograms i.v. as a bolus) was performed in 22 patients with Cushing's syndrome and no signs of pituitary abnormalities. Catheters were inserted into both femoral veins. More than one site in the superior and inferior vena cava was sampled before reaching the inferior petrosal sinuses. Blood samples for ACTH and beta-endorphin were gently aspirated from both petrosal sinuses and from a peripheral vein simultaneously. Blood was drawn at 0, 5, 10 and 15 min after oCRH injection. Seventeen of 22 patients showed an ipsilateral to peripheral vein ratio higher than 1.5, and 12 patients showed a lateralization of ACTH levels after oCRH stimulation. Seventeen patients underwent transsphenoidal pituitary surgery. Nine patients had a pituitary adenoma at the expected side; 1 at the contralateral side, while in 2 it was central. Three of 4 patients in whom the ipsilateral/peripheral ratio was less than 1.5 had the highest ACTH levels at the superior or inferior vena cava, not responsive to oCRH stimulation. One of these had a mediastinal and one a pulmonary mass. The third one, with an occult ectopic source, is still under investigation. At immunohistochemical and biological in vitro studies, both tumors were shown to secrete ACTH. In 13 patients in whom both beta-endorphin and ACTH measurements were performed, these hormones showed similar patterns of response. In conclusion, simultaneous bilateral petrosal sinus catheterization is a useful tool in the differential diagnosis of Cushing's syndrome as concerning pituitary and ectopic forms.(ABSTRACT TRUNCATED AT 250 WORDS)

Slow-release lanreotide treatment in acromegaly: effects on quality of life.

BACKGROUND: It is not known whether medical treatment to lower growth hormone (GH) and insulin-like growth factor (IGF)-1 levels may improve the compromised quality of life of patients with acromegaly. METHODS: We studied the effects on quality of life of the slow-release somatostatin analogue lanreotide, 30 mg i.m., every 14 days for 2 months in 10 patients with active acromegaly (8 females/2 males, mean age 57.3 +/- 11.4). Hormone measurements and psychometric evaluation by means of self-rating scales were carried out in baseline conditions and after 1 and 2 months. The Symptom Questionnaire (SQ), the Cognitive Scale of the Screening List for Psychosocial Problems by Kellner and the Social Situation Questionnaire by Marks were employed. RESULTS: Together with a significant decrease in GH and IGF-1, treatment with lanreotide significantly improved SQ psychological distress, SQ well-being and Social Situation Questionnaire social fears. CONCLUSION: Medical treatment with lanreotide may improve the quality of life of patients with acromegaly. Being an open trial, changes could be due to nonspecific effects. However, they did not fade at 2 months. Improvement involved fears of social situations that have been linked to GH abnormalities.

Ketoconazole treatment in Cushing's syndrome: experience in 34 patients.

OBJECTIVE: Ketoconazole treatment of Cushing's syndrome has been reported in single cases and a few small groups of 5-8 patients. We report our experience in 34 patients. DESIGN: Clinical study, with pretreatment and post-treatment evaluations. PATIENTS: Out of 67 patients with Cushing's syndrome admitted during the last 6 years, 34 (28 females/six males; age range 14-67 years) received ketoconazole as a palliative treatment due to severe clinical conditions or management of the disease while awaiting results of definitive therapy. MEASUREMENTS: Urinary cortisol, plasma cortisol and ACTH, and routine chemistry were measured every week for 4 weeks, and then once a month. RESULTS: Comparing the last values (mean +/- SEM) during treatment with baseline, urinary cortisol decreased from 1296 +/- 176 to 270 +/- 69 nmol/d (n = 34; P less than 0.001); plasma cortisol decreased from 672 +/- 31 to 549 +/- 35 nmol/l (n = 34; P less than 0.001). For patients with pituitary-dependent Cushing's syndrome, urinary cortisol decreased from 1073 +/- 126 to 200 +/- 21 nmol/d (n = 28; P less than 0.001) while plasma ACTH changed from 12.5 +/- 1.3 to 11.3 +/- 0.8 pmol/l (n = 26; not significant). Twelve patients were treated for more than 6 months, and those with pituitary-dependent disease all received pituitary radiation therapy, except the two who eventually escaped pharmacological control. One additional patient with adrenal carcinoma and one with ectopic ACTH syndrome showed lack of control of urinary cortisol levels. Ketoconazole was withdrawn within the first week in two patients for allergic reaction and acute liver toxicity. Other side-effects included: asymptomatic liver function abnormalities in three patients; gastrointestinal symptoms in four; worsening of gynaecomastia in one. Rapid clinical improvement was observed together with the normalization of urinary cortisol levels, with regression of symptoms such as diabetes mellitus, hypertension, hypokalaemia, and restoration of well being. CONCLUSIONS: These data confirm that ketoconazole is valuable in the management of hypercortisolism, provided that patients are closely watched to exclude those who may develop liver toxicity and to prevent the occurrence of adrenal insufficiency.

Inhibition of pituitary beta-endorphin by ACTH and glucocorticoids.

beta-Endorphin and ACTH are secreted concomitantly in baseline conditions and in response to physiological and pharmacological stimuli. However, few and contradictory data are available on their feedback inhibition mechanisms. To investigate this aspect, the effects of exogenous ACTH1-24 and glucocorticoids on endogenous ACTH1-39 and beta-endorphin were tested in 18 patients with Addison's disease. Two main experimental protocols were employed: (1) 7 patients were given ACTH1-24 50 micrograms as an intravenous bolus followed by a 50-micrograms infusion in 90 min. Blood samples for beta-endorphin, ACTH and cortisol were obtained at 0, 15, 30, 45, 60, 90, 120 min. Six other patients were given oCRH 100 micrograms i.v. plus ACTH1-24, as described above. (2) In 5 other patients, hydrocortisone 37.5 mg was administered i.v. in 90 min. Blood samples for beta-endorphin, ACTH and cortisol were drawn at 0, 15, 30, 45, 60, 90, 120 min. One week later, the same patients were given oCRH 100 micrograms i.v. and hydrocortisone 37.5 mg, as described above. ACTH1-24 administration caused a significant (p less than 0.01) decrease in endogenous ACTH but not in beta-endorphin. oCRH injection significantly stimulated both ACTH and beta-endorphin. The response of both ACTH and beta-endorphin was inhibited by exogenous ACTH1-24. There was a potent inhibition by hydrocortisone on both basal and stimulated beta-endorphin, confirming that the feedback mechanism of glucocorticoids concomitantly inhibits ACTH and beta-endorphin. On the other hand, only CRH-stimulated but not basal secretion of beta-endorphin seems affected by ACTH ultrashort feedback, suggesting an intrapituitary regulation.