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Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. Methods: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology(AME) 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 and only those classified as “critical” were considered in the formulation of recommendations. Results: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. Conclusion: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Introduction: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. Methods: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” have been considered in the systematic review of evidence and only those classified as “critical” have been considered in the formulation of recommendations. Results: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the first-choice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. Conclusion: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

IntroductionObesity is a global pandemic and is cause of serious concern in all regions of the world. It is important to raise the attention of health care professionals in order to provide early treatment of patients with obesity. Obesity management, however, varies greatly amongst endocrinologists with respect to attitudes to diagnosis and treatment. Aim of this study was to identify practices and needs of Italian endocrinologists with respect to people with obesity.MethodsIn this study, all members of the Italian Association of Clinical Endocrinologists (AME) were invited to participate in a web-based survey concerning the management of obesity.ResultsThe response rate was 24.1% (542/2248). Nutritional and obesity problems were reported as major areas of interest by 29.4% of the participants. A large proportion of patients seeking an endocrine consultation for other reasons are affected by obesity, but one in five respondents addressed the issue in 25% or less of the cases, while one in three always dealt with the problem. Obesity was managed personally/within a dedicated team by 42.6% of participants, while the remainders referred the patient to a dietician/nutritionist or a 2nd level center for obesity therapy. Metformin was used in a median of 30% of the patients (Interquartile range: 10-50) and liraglutide in 10% of the cases (IQR 0-30), while orlistat (median 0%; IQR 0-10) and naltrexone/bupropion (median 0%; IQR 0-5) were seldom prescribed. Cost of therapy was considered as the major limitation to the use of anti-obesity drugs, affecting adherence to long-term treatment. According to 41.9% of respondents, psychological support should be offered to all patients with obesity. Finally, 56% of participants believe that the availability of new drugs will increase the number of patients candidate to drug therapy.DiscussionIn conclusion, it is of primary importance to raise the awareness of endocrinologists towards the problem of obesity and increase their confidence in managing this pathological condition.

Background: A significant number of patients showed sub-optimal adherence to LT4 therapy, mainly due to the fact that they had to postpone their breakfast of at least 30 minutes. The aim of this observational cross-sectional study was to assess the therapeutic compliance of patients on LT4 treatment and secondly to verify the preference of a lifetime treatment in tablets or liquid formulation. Patients and Methods: To all the participant (ambulatory care patients had to be eighteen or older, affected by hypothyroidism on LT4 substitutive treatment both in tablet or liquid solution) was administered the eight-item Morisky Medication Adherence Scale (MMAS-8). The MMAS-8 questionnaire has been supplemented with other three items in order to specifically evaluate medication preference between tablet and liquid LT4 formulation for long life treating. Results: A total of 320 patients (272 female) with median age of 47.9±15.6 yrs (range 20-78) completed the MMAS-8 questionnaire. We showed a high adherence (87% of the subjects) to therapeutic compliance both for patients on tablets than those on liquid LT4 formulation, although significant difference are emerged. Patients assuming LT4 in tablet forgot more frequently medication(s) (p

The optimal method of assessing GH status in acromegalic patients receiving medical therapy with somatostatin analogs (SSA) has been matter of debate. The aim of the study has been to investigate whether OGTT may add information in patients with discordant random GH (GHr) and IGF values. Moreover, we evaluated the association of GH nadir with the prevalence of co-morbidities observed in acromegalic patients on SSA therapy. We evaluated 130 patients with proven diagnosis of acromegaly on SSA. The patients were subdivided in three groups: patients with controlled disease (both safe random GH and normal IGF-I, group A, 20.0 %), patients with uncontrolled disease (both high random GH and IGF-I, group B, 34.6 %), and patients with discordant random GH and IGF-I values (group C, 35.4 %). A high concordance rate for GH nadir with random GH and IGF-I was observed in group B, while a significant reduced concordance rate has been observed in group A (100 % sensitivity, 64.5 % specificity). By contrast, in group C, we observed concordant results between GH nadir and IGF-I only in 14/59 patients. In group A, the prevalence of diabetes was lower than in group B or C. Safe random GH was the only single criteria associated with a lower prevalence of diabetes. Discrepant IGF-I and either GH nadir or random GH values are frequently observed in acromegalic patients treated with SSA. Concordant IGF-I and random GH may influence the prevalence of metabolic complications. GH nadir measurement may help to interpret discrepancies between random GH and IGF-I data only in few cases.

La prescrizione off-label dei farmaci e un tema di solito trattato da farmacologi o legali. Per recuperare la dovuta attenzione dei medici e invece necessario ricordare che la sicurezza del paziente rappresenta la storica “mission” della professione medica. Solo spronando tale orgoglio culturale si puo pensare di recuperare il senso e l’applicazione della relativa normativa, che solitamente viene considerata come un ennesimo ostacolo burocratico alla nostra pratica clinica quotidiana.

ObjectiveAcromegaly is associated with increased cardiovascular morbidity and mortality and with specific heart and vascular abnormalities. The aim of our study was to investigate arterial stiffness using the ambulatory arterial stiffness index (AASI) and symmetric AASI (Sym-AASI), two indexes derived from 24-h ambulatory blood pressure monitoring (ABPM), in a group of normotensive and hypertensive patients with active acromegaly, compared with normotensive controls (NOR-CTR) or hypertensive controls (HYP-CTR).Subjects and methodsNinety-six consecutive patients with active acromegaly (46 males, mean age 49±14 years) underwent 24-h ABPM and evaluation of cardiovascular risk factors. Based on ABPM measurement, acromegalic patients were divided into 64 normotensive (normotensive acromegalic patients (NOR-ACRO)) and 32 hypertensive (hypertensive acromegalic patients (HYP-ACRO)) patients, and were compared with 35 normotensive (NOR-CTR) and 34 hypertensive (HYP-CTR) age-, sex,- and ABPM-matched control subjects.ResultsThe AASI and Sym-AASI indexes were significantly higher in acromegalic patients than in controls, either in the normotensive (NOR-ACRO vs NOR-CTR, PP=0.005 for Sym-AASI) or in the hypertensive (HYP-ACRO vs HYP-CTR, P=0.01 for AASI and P=0.01 for Sym-AASI) group. Multiple logistic regression analysis showed a significant association of the highest AASI tertile with serum IGF1 (P=0.034) in the whole acromegalic group.ConclusionAASIs are increased in acromegaly, independent of blood pressure (BP) elevation, and may have an important role in predicting cardiovascular risk in this disease.

Cushing's syndrome is associated with high cardiovascular morbility and mortality. Blood pressure (BP) variability within a 24-h period is increasingly recognized as an independent predictor of cardiovascular risk. The aim of our study was to investigate the short-term BP variability indices in Cushing's syndrome. Twenty-five patients with Cushing's syndrome (mean age 49 ± 13 years, 4 males; 21 Cushing's disease and 4 adrenal adenoma patients) underwent 24-h ambulatory BP monitoring (ABPM) and evaluation of cardiovascular risk factors. Cushing patients were divided into 8 normotensive (NOR-CUSH) and 17 hypertensive (HYP-CUSH) patients and were compared with 20 normotensive (NOR-CTR) and 20 hypertensive (HYP-CTR) age-, sex-, and BMI-matched control subjects. Short-term BP variability was derived from ABPM and calculated as the following: (1) standard deviation (SD) of 24-h, daytime, and nighttime BP; (2) 24-h weighted SD of BP; and (3) average real variability (ARV), i.e., the average of the absolute differences between consecutive BP measurements over 24 h. In comparison with controls, patients with Cushing's syndrome, either normotensive or hypertensive, had higher 24-h and daytime SD of BP, as well as higher 24-h weighted SD and ARV of BP (P = 0.03 to P < 0.0001). No difference in metabolic parameters was observed between NOR-CTR and NOR-CUSH or between HYP-CTR and HYP-CUSH subgroups. ABPM-derived short-term BP variability is increased in Cushing's syndrome, independent of BP elevation. It may represent an additional cardiovascular risk factor in this disease. The role of excess cortisol in BP variability has to be further clarified.

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.

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.

The aim of the study was to evaluate patients with Cushing's syndrome the coronary flow reserve (CFR), an index of coronary microvascular function. Fifteen newly diagnosed patients with Cushing's syndrome (1 male/14 females; mean age 45 ± 11 years), were selected for having no clinical evidence of ischemic heart disease. Twelve patients had pituitary-dependent Cushing's disease and three had an adrenal adenoma. Fifteen subjects matched for age, sex, and major cardiovascular risk factors were used as controls. Coronary flow velocity in the left anterior descending coronary artery was investigated by transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was obtained as the ratio hyperemic/resting diastolic flow velocity. A reduced coronary reserve (hyperemic/resting ratio ≤ 2.5) was found in 5/15 Cushing patients and 4/15 controls. In all patients with abnormal CFR, epicardial coronary stenosis was excluded by multi-slice computed tomographic coronary angiography. CFR was inversely related to urinary cortisol in patients with endogenous hypercortisolism (Spearman's rho = -0.57, P = 0.03), while no correlation was found in controls. Coronary microvascular function, as assessed by CFR, is pathologically reduced in a considerable number of patients with Cushing's syndrome without clinical symptoms of ischemic heart disease and in the absence of epicardial coronary artery lesions, as well as in controls matched for cardiovascular risk factors. The presence of comorbidities can explain this early coronary abnormality in both patients and controls. Whether urinary cortisol may be a predictor of coronary microvascular function in the setting of patients with Cushing's syndrome, needs further investigation.

A large body of in vitro evidence shows that cytokines influence the hypothalamic–pituitary–adrenal axis both in physiological conditions and in Cushing’s disease (CD). In order to study in vivo the role of intrapituitary cytokines in CD, we assayed two cytokines known for their action on the pituitary, i.e. interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), and also soluble interleukin-6 receptor (sIL-6R), important for the neural activities of IL-6, in a carefully selected sample of subjects affected by CD undergoing bilateral inferior petrosal sinus sampling. Similarly to ACTH, all cytokines basally showed a higher concentration in the ipsilateral sinus compared to the controlateral one and to that of peripheral blood; after CRH infusion, both ipsilaterally and controlaterally, IL-6 and sIL-6R values increased compared to basal ones, while IL-1β increased significantly up to 5 min after CRH and then decreased significantly compared to basal values in subsequent measurements; peripherically no significant variations in the cytokines were observed after CRH. Again similarly to ACTH, the three cytokines presented a higher increase ipsilaterally than controlaterally; moreover all three interleukins in the ipsilateral sinuses showed positive and significant correlations between their basal value and that of basal ACTH. These findings allow us to hypothesize that the central production of IL-1β and IL-6 could be involved in ACTH hypersecretion which occurs in CD: more specifically, we hypothesize that these cytokines are produced directly by the corticotroph adenoma and have the task of enhancing tumoral secretion of ACTH with an autocrine-paracrine mechanism.

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.

Summary Objective To verify whether patients with pituitary disorders in remission and on appropriate treatment display significant differences in psychological distress compared to healthy controls and other patients treated for nonpituitary endocrine disorders. Design A single-centred, controlled study. Patients Eighty-six outpatients cured or in remission for at least 9 months following appropriate treatment by surgery, irradiation and/or pharmacological interventions for pituitary disease were compared with 86 healthy subjects. A sample comprising 60 outpatients cured or in remission from nonpituitary endocrine disorders was also compared. Measurements (1) A modified version of the Structural Clinical Interview for DSM-IV; (2) a shortened version of the structured interview for the Diagnostic Criteria for Psychosomatic Research (DCPR); (3) the Psychosocial Index (PSI); and (4) the Medical Outcomes Study (MOS) short form General Health Survey (SF-20) were employed. Results Patients with pituitary disease displayed a higher prevalence of psychiatric disease (P

OBJECTIVE: Glucocorticoids were found to inhibit adiponectin gene expression and secretion both in vitro and in animal models. We evaluated first the acute effect of i.v. glucocorticoids on adiponectin in normal subjects and secondly plasma adiponectin levels in a series of patients with Cushing's syndrome compared with controls. DESIGN AND METHODS: Hydrocortisone (25 mg) was administered i.v. to five healthy volunteers, with blood samples taken at -15, 0, 30, 60, 120 and 180 min. Twenty-one patients with Cushing's syndrome were divided in two groups: one with 11 obese and the other with 10 non-obese Cushing's patients. Each group was compared with controls that were matched for sex, age, body mass index, waist circumference, glucose, insulin, lipid levels and blood pressure. RESULTS: In normal subjects, hydrocortisone produced a decrease in adiponectin at 30 and 60 min, compared with placebo (P

Background: The purpose of the study was to assess the frequency and characteristics of psychological distress, even after adequate treatment, in the heterogeneous population of an endocrine outpatient clinic. Methods: 146 endocrine patients (31 males/115 females; age 39.4 ± 12.5 years), who were cured or in remission, were studied in a university endocrine outpatient clinic. Semistructured clinical interviews to assess psychiatric (Structured Clinical Interview for DSM-IV) and psychological (Diagnostic Criteria for Psychosomatic Research, DCPR) diagnoses were employed and were supplemented by self-rated instruments (the Psychosocial Index and the Medical Outcome Study short form General Health Survey) which could provide the patients’ perception of their own quality of life. Results: There were 118 patients (81%) who presented with at least 1 psychiatric (DSM-IV) or psychological (DCPR) diagnosis. The most frequent diagnostic findings were generalized anxiety disorder (29%), major depression (26%), irritable mood (46%), demoralization (34%) and persistent somatization (21%). By self-rated instruments, patients with at least 1 DSM-IV or DCPR diagnosis reported significantly more stressful life circumstances, psychological distress and an impaired quality of life compared to those who had none. Conclusions: A high prevalence of psychological distress may be encountered in the long-term follow-up of endocrine patients. A biopsychosocial consideration of the person and his/her quality of life appears to be mandatory for improving therapeutic effectiveness in endocrine disorders.

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.

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 (p0.01), 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.

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.

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)

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.

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.