Outcomes of integrated management versus specialized care for patients with type 2 diabetes: An observational study.

AIMS: To compare type 2 diabetes (T2D) patients included in a Diabetes Integrated Management (DIM) program with those followed in Diabetes Specialized Care (DSC), investigating differences in general characteristics, changes in clinical outcomes, and factors related with the inclusion in the DIM program. METHODS: T2D patients living in the ASLTO3 district and included into the DIM program, a shared disease management between general practitioners and diabetes specialists, from 2008 to 2014 were compared with T2D patients living in the same district and in charge of the local DSC. Demographic, anthropometric and clinical data for both groups of patients were obtained from the electronic records of DSC. RESULTS: 1326 DIM patients were compared with 3494 DSC patients. A higher proportion of females was observed among DIM patients than among DSC patients. DIM patients were older, more frequently in therapy with diet only or with oral hypoglycemic, and had HbA1c and creatinine lower than DSC patients. The analyses of changes in clinical parameters during the study period showed a good and statistically significant improvement of most parameters, independently of the inclusion in DIM or DSC, with the exception of creatinine level. CONCLUSIONS: Integrated Management is an efficient and effective way to achieve good long-term clinical outcomes for patients with diabetes.

Surgical remission of Cushing's syndrome reduces cardiovascular risk.

OBJECTIVE: Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls. DESIGN: A retrospective study of 75 patients with CS followed at an academic center. METHODS: Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population. RESULTS: In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001). CONCLUSIONS: Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission.

Hyperhomocysteinemia in winter elite athletes: a longitudinal study.

Hyperhomocysteinemia is a well-established risk factor for cardiovascular diseases. The aims of this study were to longitudinally investigate, in a group of elite athletes, plasma homocysteine levels and to search for relationships with the muscular workload and the vitamin status. One hundred and three athletes (59 males and 44 females, respectively) were evaluated in different periods: namely the recovery period, the training period, and the competition period; 84 subjects (37 males and 47 females), served as controls. The evaluation sessions consisted in blood sampling and medical examination. The percentages of athletes with normal and elevated homocysteine levels, defined by levels below or above the limit of 15 mumol/l, were 68.0% and 32.0%, respectively, in the recovery period, and these percentages remained unchanged during the following periods. In the control group, relevant percentages were 92.9% and 7.1%, respectively. The comparison between plasma homocysteine of male and female, evaluated in the recovery period, showed significantly higher levels in the former group (18.8+/-18.0 micromol/l vs 10.7+/-5.9 micromol/l, p<0.001 respectively), as well as a higher proportion of individuals with hyperhomocysteinemia (24/59 vs 9/44, p<0.05). The correlation analyses showed a weak but significant negative correlation between homocysteine and folate in the three periods considered, while no significant relationship was observed between homocysteine and creatine-kinase. We found excess prevalence of hyperhomocysteinemia in elite athletes of winter sports. A strategy to understand which mechanisms in these athletes subserve hyperhomocysteinemia is essential in order to reduce the potential risk for future cardio-vascular morbidity and mortality.

Effects of the training status on the hormonal response and recovery from high-intensity isokinetic exercise: comparisons between endurance-trained athletes and sedentary subjects.

AIM: Aims of the study were: to determine the differences in the mechanical, hormonal and lactate responses to a high-intensity isokinetic exercise in two groups of endurance-trained athletes (EA, n = 11) and sedentary subjects (SED, n = 11); to evaluate the relationships between the hormonal and lactate responses; to evaluate the effects of the training status on the pituitary responsiveness to the exercise. METHODS: EA and SED completed, for each leg, 4 sets of 20 maximal concentric contractions of the knee extensor muscle groups at 180 degrees s-1 angular velocity. Blood and saliva for hormonal and lactate determinations were sampled before, immediately after the test and during the subsequent recovery of 2 hours. RESULTS: The exercise was completed by all subjects and elicited significant mechanical and biochemical responses both in EA and in SED subjects. No differences were found between the two groups both in the mechanical performances and in the increases of lactate and hormones of the pituitary-adrenal axis or in the comparison of the slopes of adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone recovery after the peak. The correlation analyses showed significant positive relationships between lactate peak values and percentages of change for ACTH (r2 = 0.16, P < 0.05), salivary cortisol (r2 = 0.42, P < 0.01), and serum cortisol (r2 = 0.56, P < 0.001). CONCLUSIONS: The adrenocortical activation was found, in this particular setting, at least partly dependent on the muscular lactate production, while no effect of the training status on the pituitary responsiveness to exercise was evident, as it was indirectly confirmed by no abnormalities in the rates of hormonal recovery after the exercise session.

Interleukin-6 response to isokinetic exercise in elite athletes: relationships to adrenocortical function and to mechanical and myoelectric fatigue.

Exercise stimulates the release of interleukin-6 (IL-6). Aims of the study were to: (a) analyse the IL-6 response to exercise in power (n = 7) and endurance athletes (n = 13); (b) determine the effects of the IL-6 production on mechanical and myoelectric fatigue; (c) evaluate the relationship between IL-6 and adrenocortical responses. EMG variables (conduction velocity, mean power frequency, average rectified value), ACTH, cortisol, DHEA, IL-6, myoglobin, and lactate were analysed before and after an isokinetic exercise. The exercise elicited significant mechanical and myoelectric fatigue as well as significant biochemical responses. Power athletes showed IL-6 and lactate responses higher than endurance athletes. The correlation analyses showed that the greater the mechanical fatigue, the greater the increases in lactate and IL-6. No correlations were found between IL-6 and EMG variables. No relationships were found between IL-6 and cortisol, after correction for ACTH levels. In conclusion, the muscular IL-6 production, as inferred by its circulating levels, had no detectable effects on the myoelectric manifestations of fatigue and the cortisol response to exercise was not related to the amount of circulating IL-6, but only to the activation of ACTH secretion.

Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane.

Adreno-cortical carcinoma (ACC) is a rare cancer with poor prognosis. Complete surgical resection of the primary tumor and, when feasible, of the local and distant metastases offers the best prospects for long-term survival; conversely, the role of systemic therapy in patients developing unresectable metastatic disease is unclear. We describe the case of a young female patient (36 yr) who presented with an androgen-releasing metastatic ACC. Treatment consisted of five courses of chemotherapy with etoposide, doxorubicin and cisplatin (EDP scheme) plus oral mitotane, which caused the complete disappearance of distant metastases and reduction of the primary tumor, as documented by serial computed tomography (CT) scans of the chest and the abdomen. Moreover, during treatment, clinical and biochemical resolution of the hypersecretory status occurred. The left adrenal gland was then removed and histopathological examination showed extensive tumor necrosis and the absence of viable cancer cells. The patient is currently alive without evidence of recurrence 3 yr after surgery. This report shows that chemotherapy plus mitotane could result in complete pathological remission, which may be a surrogate for long-term progression- free survival in metastatic ACC patients.

Effects of high-intensity isokinetic exercise on salivary cortisol in athletes with different training schedules: relationships to serum cortisol and lactate.

Physical exercise is associated with increases of serum and salivary levels of cortisol. The concomitant increase in serum lactate has been implicated as one of the mechanisms responsible for adrenocortical activation. We evaluated the responses of serum lactate and serum and salivary cortisol to an acute bout of high-intensity isokinetic exercise in eleven non-competitive and twenty competitive athletes (NCA and CA, respectively). The latter group was composed of endurance- and power-trained athletes (EA and PA, respectively). Aims of the study were to determine interindividual differences in the lactate and cortisol responses as a function of type and intensity of training and to search for relationships both between lactate and cortisol production and between serum and salivary cortisol levels. The isokinetic exercise test elicited significant cortisol and lactate responses. No difference was evident in the lactate responses between NCA and CA, while the PA showed a higher response during and after the exercise in comparison to EA (peak levels immediately after the exercise: PA 15.0 +/- 1.5 mmol/l vs. EA 11.1 +/- 2.6 mmol/l, p < 0.01). Serum cortisol was higher in the CA in comparison to the NCA group at 30 and 120 minutes after the termination of the exercise, while no differential response was evident between EA and PA groups. Salivary cortisol response was higher in the CA group in comparison to NCA immediately after the exercise and at 90 and 120 minutes after the termination and was higher in PA in comparison to EA at 60, 90, and 120 minutes after the termination (peak levels at 60 minutes: PA 51.2 +/- 18.5 nmol/l vs. EA 27.5 +/- 20.8 nmol/l, p < 0.05). No significant correlations were found between serum or salivary cortisol and lactate levels. The relationship between serum and salivary cortisol was markedly non-linear, the slope of the serum-saliva regression line being lower for serum cortisol concentrations over 500 nmol/l than for concentrations below that value (0.019 and 0.037, respectively, p < 0.01). We have confirmed in this particular setting the existence of an important adrenocortical response that can be reliably and non invasively assessed by a serial saliva sampling and have supported the concept that cortisol and lactate responses to a high-intensity isokinetic exercise are independent. The interindividual differences in cortisol changes are likely to be related to the training status and mode as well as to the correspondence between the evaluation protocol and the discipline individually performed.

Differential responses of serum and salivary interleukin-6 to acute strenuous exercise.

Physical exercise is associated with elevation of serum levels of interleukin-6 (IL-6) because of its production in the muscles. The use of IL-6 measurements in saliva has been proposed in the field of immunopathology, mainly involving salivary gland disease. We evaluated the responses of serum and salivary IL-6 in two different groups of athletes submitted to different types of controlled strenuous exercise (spinning activity and maximal isokinetic test). Serum and salivary samples for IL-6 measurements, and serum samples for lactate and myoglobin determination before and after exercise, were obtained. Salivary IL-6 was measured by ELISA after dilution experiments and compared with results obtained by immunoradiometric assay. Spinning activity elicited significant increases in all the variables, and no correlation was found among the respective variations. A significant response to the isokinetic exercise was observed for serum IL-6, lactate and myoglobin only; no correlation was found between serum and salivary IL-6. Our study demonstrated that serum and salivary IL-6 responses to exercise are dissociated, possibly in relation to the lack of relationships between the systemic/muscular and the salivary routes of IL-6 production. Analytical issues that concern IL-6 measurement in saliva deserve attention, notably regarding the collection method used to absorb saliva. Concomitant monitoring of serum markers of inflammation, muscle metabolism and damage can provide information about muscle function properties and adaptations to physical effort in different types of athletes.

The overtraining syndrome in athletes: a stress-related disorder.

Physical exercise is a type of allostatic load for several endocrine systems, notably the hypothalamic-pituitary-adrenal (HPA) axis. Athletes undergoing a strenuous training schedule can develop a significant decrease in performance associated with systemic symptoms or signs: the overtraining syndrome (OTS). This is a stress-related condition that consists of alteration of physiological functions and adaptation to performance, impairment of psychological processing, immunological dysfunction and biochemical abnormalities. Universally agreed diagnostic criteria for OTS are lacking. The pituitary-adrenal response to a standardized exercise test is usually reduced in overtrained athletes. This HPA dysfunction could reflect the exhaustion stage of Selye's general adaptation syndrome. The most attractive hypothesis that accounts for the observed neuro-endocrine-immune dysregulation is the Smith's cytokine hypothesis of OTS. It assumes that physical training can produce muscle and skeletal trauma, thus generating a local inflammatory reaction. With the excessive repetition of the training stimulus the local inflammation can generate a systemic inflammatory response. The main actors of these processes are the cytokines, polypeptides that modulate HPA function in and outside the brain at nearly every level of activity. It is hoped that future research will focus on endogenous risk factors for morbidities related to the neuro-endocrine-immune adaptation to exercise.

The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome.

OBJECTIVE: The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH-dependent Cushing's syndrome and in a group of healthy subjects. DESIGN AND SUBJECTS: We studied 34 patients with Cushing's disease (CD) and nine patients with ectopic ACTH syndrome (EAS). The control group included 30 healthy subjects. Estimates of sensitivity and specificity were determined for a value of ACTH percent increment (Delta%) > 35% and for a Delta % > 50%, following either desmopressin or CRH, to differentiate CD from EAS. The sensitivity and specificity of a composite rule requiring an ACTH net increment (Delta) > 4.5 pmol/l at both values of Delta % was also calculated. When evaluating cortisol responses, the criteria were Delta % > 20% and Delta > 193 nmol/l. Moreover, to allow comparison of individual end points of the desmopressin and CRH tests at multiple levels of Delta % or Delta either for ACTH or cortisol without the bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1 - specificity at each level. RESULTS: In the patients with CD, the frequency of ACTH response was of 90% after both tests while the figures for cortisol were 73% after CRH and 77% after desmopressin, respectively. In the 15 patients who underwent both tests the magnitude of ACTH and cortisol responses induced by the 2 stimuli were fully comparable. In the patients with EAS a (false) positive ACTH response was found in 2/9 cases (22%) after the CRH test and in 2/5 patients (40%) after the desmopressin test. In the healthy subjects the CRH test was performed in 25 cases and the desmopressin test in 15 cases. The frequency of ACTH response was 52% following CRH and 13% following desmopressin. In the 10 healthy subjects who underwent both tests the ACTH response was significantly greater after CRH than desmopressin. The area under the ROC curve for the ACTH Delta % was significantly different than that occurring by chance following CRH but not desmopressin. The point on the ROC curve closest to 1 corresponded to an ACTH Delta % of 47% (sensitivity 87% and specificity 89%). However, a criterion of 100 % specificity would require an increase in the threshold for the ACTH Delta % to 259%. ROC analysis validated also the use of the ACTH Delta as a method to assess the response to CRH, but not after desmopressin. However, the diagnostic performance of this parameter was reduced in comparison to that of the ACTH Delta %, since the best cut-off for the Delta (6.2 pmol/l) had inferior specificity (79%). The operating characteristics of CRH and desmopressin were worse when considering cortisol responses. CONCLUSIONS: The present data suggest that the CRH test is more reliable than the desmopressin test in determining the aetiology of Cushing's syndrome. The desmopressin test resulted in a high frequency of false positive results in patients with ectopic ACTH secondary to carcinoid tumours. This finding may be due to the capability of these tumours to express the V3 vasopressin receptor through which desmopressin acts. However, the clinical endocrinologist may be confronted with some disturbing cases which are misdiagnosed because it is almost impossible to set a diagnostic criterion providing complete specificity in the differentiation of (occult) ectopic Cushing's syndrome using either CRH or desmopressin tests.

The patients with incidentally discovered adrenal adenoma (incidentaloma) are not at increased risk of osteoporosis.

The main problem in the management of the patients with incidentally discovered adrenal mass (incidentaloma) is whether and when the incidental mass puts the patient at increased risk for an adverse outcome. As osteoporosis is a well known complication of endogenous and exogenous glucocorticoid excess, it is likely that patients with incidentally discovered adrenocortical adenomas have impaired bone mass due to subclinical hypercortisolism. We measured spinal bone mineral density (BMD) by dual energy x-ray absorptiometry in 27 patients (9 men and 18 women) and 54 healthy subjects (18 men and 36 women) carefully matched for age, sex, body mass index, and menstrual status for a case-control analysis. BMD was also measured at the hip in the group of patients. A multiple regression analysis was performed to determine which biochemical variables might influence BMD values. Lumbar BMD values in patients with adrenal incidentaloma were not significantly different from those in control subjects (BMD, 0.926, 0.604--1.144 vs. 0.936, 0.645--1.268 g/cm(2); P = NS). No significant difference in lumbar and femoral BMD was found between patients with or without subclinical Cushing's syndrome. Among the variables processed, only PTH remained in the final model and was inversely correlated with lumbar spine and femoral neck BMD values (r = -0.5; r(2) = 0.25; P = 0.015 and r = -0.42; r(2) = 0.18; P = 0.03, respectively). In conclusion, our data do not suggest that the slight glucocorticoid excess associated with adrenal incidentaloma increases the risk of osteoporosis. The evaluation of BMD does not seem to be crucial in the management of incidentally discovered adrenal masses.

Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors.

OBJECTIVES: To evaluate the utility of Ki-67 immunohistochemical analysis in the differential diagnosis between benign and malignant adrenocortical neoplasms. METHODS: Tissue specimens were obtained from 37 patients referred to our institute from 1990 to 1999. The indications for adrenalectomy were adrenal-dependent Cushing syndrome (n = 9), hyperandrogenism (n = 1), mineralocorticoid excess (n = 8), and nonfunctioning adrenal masses (n = 19). The histologic diagnosis was cortical adenoma in 26 of 37 patients and cortical carcinoma in the remainder. Normal adrenal glands were obtained from subjects who underwent radical nephrectomy because of initial renal carcinoma. Immunohistochemical analysis was performed using the monoclonal antibody anti-Ki-67 (clone MIB-1). The Ki-67 labeling index was expressed as the number of positive cells per 1000 cells.Results. The average Ki-67 expression was 2.0 per thousand +/- 1.2 per thousand (SD) in normal adrenal glands, 11.3 per thousand +/- 16.0 per thousand in adenomas, and 185.8 per thousand +/- 60.3 per thousand in carcinomas (P <0.0001). A threshold value of the Ki-67 labeling index between 70 per thousand and 90 per thousand reliably separated adenoma from carcinoma. A significant inverse correlation was found between Ki-67 expression and overall survival in patients with adrenal carcinoma (r = -0.74, P = 0.009). CONCLUSIONS: Immunohistochemical assessment of the nuclear antigen Ki-67 can be useful in the differential diagnosis between adrenocortical adenoma and carcinoma. High levels of Ki-67 seem to indicate patients with adrenocortical cancer with a worse prognosis.

Ectopic ACTH syndrome: molecular bases and clinical heterogeneity.

There are roughly two types of ectopic ACTH syndrome (EAS). one associated with overt malignancies and one with occult neoplasms. The prototype of the first condition is Cushing's syndrome sustained by small-cell lung cancer (SCLC), while bronchial carcinoid tumors are the most common occult sources of ACTH. Patients with EAS and SCLC may have an atypical presentation with muscle wasting and weight loss that are more frequently observed than the classic cushingoid features. These patients have a poor prognosis because SCLC associated with the EAS is more resistant to chemotherapy and the severe hypercortisolism is responsible for a high rate of life-threatening complications during treatment. Conversely, the clinical and biochemical features of the EAS associated with carcinoid may overlap those seen in pituitary-dependent Cushing's syndrome. An extensive radiological and hormonal work-up is necessary to detect the extrapituitary source of ACTH. However, the differentiation between the pituitary, or eutopic, from the non-pituitary, or ectopic, source of ACTH secretion may be extremely difficult in some cases despite the wide diagnostic armamentarium available. Molecular biology studies have demonstrated that the carcinoid cells achieve a process of corticotroph differentiation being able to express the proopiomelanocortin (POMC) gene and to process POMC correctly to release large amounts of intact ACTH. Conversely, SCLC processes POMC in an aberrant way releasing high concentrations of ACTH precursors and less intact ACTH in the circulation.

Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin.

Juvenile hemochromatosis is a rare genetic disorder that causes iron overload. Clinical complications, which include liver cirrhosis, heart failure, hypogonadotropic hypogonadism and diabetes, appear earlier and are more severe than in HFE-related hemochromatosis. This disorder, therefore, requires an aggressive therapeutic approach to achieve iron depletion. We report here the case of a young Italian female with juvenile hemochromatosis who was unable to tolerate frequent phlebotomy because of coexistent ss-thalassemia trait. The patient was successfully iron-depleted by combining phlebotomy with recombinant human erythropoietin.

The value of dehydroepiandrosterone sulfate measurement in the differentiation between benign and malignant adrenal masses.

OBJECTIVE: Owing to their increasing rate of discovery as incidental findings, the characterization of adrenal masses is an important diagnostic problem which frequently challenges the clinician's skill. DESIGN: The results of dehydroepiandrosterone sulfate (DHEAS) measurement were evaluated in a consecutive series of 107 patients with an adrenal mass (39 men, 68 women aged 15-81 years, median 56 years). DHEAS levels observed in the patients were categorized as reduced, normal or elevated according to sex- and age-adjusted reference ranges obtained by measuring DHEAS in 214 healthy women and 142 healthy men aged 17-93 years. The working hypothesis was that a low DHEAS level is a marker of benignity. METHODS: In 84 patients, the adrenal mass was discovered serendipitously, while in the remainder the mass was clinically symptomatic. Patients with known extra-adrenal malignancies were excluded. The adrenal masses were categorized as benign or malignant by computerized tomography (CT) criteria. All patients with suspected malignant tumors or with overtly hypersecreting tumors underwent adrenalectomy. The patients with a presumptive benign tumor were followed-up for at least 12 months. RESULTS: In the overall series, the sensitivity and specificity of a low DHEAS level in the identification of a benign lesion were 41% and 100% respectively. Superimposable figures were obtained when considering only adrenal incidentalomas. DHEAS levels in adrenal cancers displayed some overlap with adrenal adenomas, but in only 2/11 adrenal cancers were DHEAS levels normal, while they were elevated in the remainder. CONCLUSIONS: The present data suggest that DHEAS measurement may help to differentiate benign from malignant adrenal masses as a complementary test of CT in a clinical research setting. The value of DHEAS measurement in general practice is limited because it may be difficult to differentiate between low and low-normal values, particularly in the elderly.

Different immunohistochemical patterns of TGF-beta1 expression in benign and malignant adrenocortical tumours.

OBJECTIVE: Transforming growth-factor beta1 (TGF-beta1) influences a number of specific functions of adrenocortical cells in several animal species. The aim of our study was to evaluate by immunohistochemical analysis the presence and distribution of TGF-beta1 in normal adrenal tissue and in different adrenal tumours. PATIENTS: We analysed 8 functioning (5 adenomas and 3 carcinomas) and 15 non functioning (6 adenomas and 9 carcinomas) adrenal tumours and 6 normal adrenal glands. RESULTS: In normal adrenal glands, the glomerulosa and the reticularis zones displayed diffuse cytoplasmic staining, while the fasciculata zone was almost completely negative. Functioning adenomas displayed cytoplasmic staining restricted to compact cells while in nonfunctioning adenomas, prevalently composed by clear cells, no staining was observed. Overall, adrenal carcinomas were characterized by the lack of cytoplasmic positivity and by sporadic positive cells around vessels both in functioning and in nonfunctioning tumours. CONCLUSIONS: TGF-beta1 expression is associated with active steroid secretion in normal adrenal tissue, as well as in benign cortical adenomas, while this relationship is lost in primary adrenal malignancies. These data provide indirect evidence for a regulatory role played by TGF-beta1 on steroid secretory pathways.

Twenty-four hour profile of blood pressure in patients with acromegaly. Correlation with demographic, clinical and hormonal features.

Cardiovascular events are frequently reported in patients with acromegaly and they are usually related to arterial hypertension. Aim of the present study was to assess the 24-hour profile of blood pressure (BP) and heart rate (HR) in patients with active acromegaly and to correlate them with clinical and hormonal data. Sixteen patients and 16 healthy, age and sex matched subjects underwent ambulatory blood pressure monitoring by means of a portable automatic device (SpaceLabs monitor 90207, Kontron) with measurements every 20 minutes for 24 hours. The presence of the nocturnal fall was assessed by the calculation of the night-day systolic and diastolic ratio. The mean 24-hour diastolic BP was significantly higher in acromegalic patients than in controls (79.1+/-11.5 mmHg vs 70.8+/-5.3 mmHg, p<0.05) and the circadian diastolic profile was flatten. In fact, 10/16 patients were defined as nondippers while this figure was 2/16 in the control group (62% vs 12%, p<0.01). Also the mean 24-hour systolic BP was higher in acromegalic patients than in controls (124.8+/-17.2 mmHg vs 114.1+/-8.6 mmHg, p<0.05). The circadian systolic profile paralleled that of diastolic and was flatten, without a significant nocturnal fall. Ten out of 16 patients were nondippers compared to 2/16 controls (62 vs 12%, p<0.01). No significant correlation was found between mean 24-hour BP, either diastolic or systolic, and demographic or hormonal characteristics of the patients. HR patterns did not differ between patients and controls and were characterized by a prominent nocturnal fall.

Subclinical Cushing's syndrome in adrenal incidentaloma.

OBJECTIVE: Some patients with incidentally discovered adrenal adenomas display autonomous cortisol secretion not fully restrained by pituitary feedback, a condition that may be defined as subclinical Cushing's syndrome. We have evaluated the presence of subclinical Cushing's syndrome and its natural history in a cohort of patients with incidentally discovered adrenal adenomas. PATIENTS: Fifty-three consecutive patients (30 women and 23 men; median age 58 years, range 18-81 years) were studied. Diagnostic procedures were initiated for extra-adrenal complaints. Patients with known extra-adrenal malignancies or patients with hypertension of possible endocrine origin were excluded. MEASUREMENTS: All patients underwent the following endocrine evaluation: (1) measurement of DHEA-S at 0800 h, (2) measurement of serum cortisol at 0800 and 2400 h, (3) measurement of the 24-h excretion of urinary free cortisol (UFC), (4) overnight low-dose dexamethasone suppression test, (5) measurement of plasma ACTH at 0800 h (mean of at least two samples on different days), (6) oCRH stimulation test. Different groups of healthy subjects recruited from the hospital medical staff and their relatives served as controls for the various tests. The same endocrine work-up was repeated after 12 months in 25 patients. All patients were followed up at regular intervals for at least 12 months with clinical examination and abdominal computed tomography. Subclinical hypercortisolism was arbitrarily defined as definitive, probable or possible, according to the degree of endocrine abnormalities. RESULTS: UFC was significantly higher in patients with incidentaloma than in controls (262, 25-690 nmol/24 h versus 165, 25-772 nmol/24 h; P = 0.012). The percentage of subjects who did not suppress on dexamethasone was greater among patients than among healthy subjects (9/53 (17%) versus 5/103 (5%), P = 0.026). Plasma ACTH concentrations were lower in patients with adrenal incidentaloma than in controls (3, 1-9 pmol/l versus 5, 1-14 pmol/l; P = 0.014). These findings consistently point toward a functional autonomy of the adrenal adenomas even if the degree of cortisol excess is mild. Three patients fulfilled the criteria for definitive subclinical hypercortisolism, five for probable and two possible, but none of them experienced clinical and/or biochemical progression to overt hypercortisolism after 12 months. During follow-up, no signs of extra-adrenal malignancy became manifest and the size of the mass did not increase significantly in any patient. CONCLUSIONS: This study provides a clear demonstration of the current opinion that some patients with incidentally discovered adrenal adenomas may be exposed to a subtle, silent hypercortisolism. In some patients, in whom the clustering of more abnormalities in the hypothalamo-pituitary-adrenal axis occurs, subclinical Cushing's syndrome could be assumed. This term should be preferred to that of pre-clinical Cushing's syndrome since the biochemical abnormalities do not become clinically manifest, at least in the short term.

Serum markers of bone and collagen turnover in patients with Cushing's syndrome and in subjects with adrenal incidentalomas.

The aim of this study was to assess serum levels of some markers of bone turnover and collagen synthesis in 22 patients with adrenal incidentalomas (AI), a model of silent glucocorticoid excess, and to compare the results with those obtained in 18 patients with Cushing's syndrome (CS). Osteocalcin (BGP), bone isoenzyme of alkaline phsophatase, carboxy-terminal propeptide of type I procollagen, and carboxy-terminal cross-linked telopeptide of type I collagen were measured as biochemical indexes of bone turnover, and amino-terminal propeptide of type III procollagen was determined as an index of collagen synthesis. Two groups of healthy volunteers evenly matched for sex, age, and menstrual status were used for a case-control analysis of AI and CS groups, respectively. Patients with AI showed a slight, albeit significant, reduction in serum BGP and a mild increase in carboxy-terminal cross-linked telopeptide of type I collagen levels compared with controls [median, 6.6 vs. 7.8 ng/mL (P < 0.05) and 4.2 vs. 3.1 micrograms/L (P < 0.01), respectively]. No significant differences were found when comparing the other markers. Patients with CS had BGP, bone isoenzyme of alkaline phosphatase, and amino-terminal propeptide of type III procollagen levels significantly lower than control values [median, 3.0 vs. 7.3 ng/mL (P < 0.0001); 4.4 vs. 11.5 micrograms/L (P < 0.01); 2.2 vs. 4.3 micrograms/L (P < 0.0001), respectively], but no significant difference in the other markers. These results confirm a clear inhibition of osteoblastic activity in CS and could suggest an enhanced bone metabolism in patients with AI. The degree of impairment of bone turnover in patients with AI does not seem enough to recommend surgery (removal of the adrenal adenoma) in the absence of other indications.

Cushing's syndrome due to ACTH-independent bilateral adrenocortical macronodular hyperplasia.

ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is a rare cause of Cushing's syndrome in which adrenal glands become very enlarged, occupied and distorted by multiple cortical nodules. We report on such two patients, a 44-year-old man and a 40-year-old woman. Physical examination revealed in both cases a classic cushingoid habit. Laboratory studies showed overt hypercortisolism with high urinary free cortisol excretion and elevated serum cortisol with loss of the circadian rhythm. Serum cortisol levels were not modified after high dose dexamethasone. ACTH levels were undetectable both in baseline conditions and following CRH or metyrapone. In both cases, abdominal CT demonstrated bilaterally enlarged adrenal glands which were distorted by multiple bumps. 131I-Norcholesterol scintiscan showed bilateral uptake of the radionuclide. Pituitary region was normal at neuroradiologic imaging. Bilateral adrenalectomy was performed in both cases. In patient I, adrenal glands weighted 77 and 90 g, respectively, while in patient II they were of 90 and 55 g, respectively. At histological examination, the adrenal cortex was occupied by multiple nodular lesions composed mostly of clear cells. In the internodular regions, no evidence of cortical architecture was observed. At the immunohistochemical evaluation, both cases displayed KI-67 staining comparable with that of ACTH-dependent diffuse hyperplasia. Postoperative course was uneventful and signs of Cushing's syndrome resolved in about three months. At the last follow up, the patients are going well on glucocorticoid and mineralocorticoid supplementation. Plasma ACTH levels are 65 and 107 pg/ml, respectively.