The application of the combined corticotropin-releasing hormone plus desmopressin stimulation during petrosal sinus sampling is both sensitive and specific in differentiating patients with Cushing's disease from patients with the occult ectopic adrenocorticotropin syndrome.

CONTEXT: Although bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation is the most accurate procedure for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), 4-15% of patients with Cushing's disease (CD) fail to demonstrate diagnostic gradients. Preliminary data suggest that a more potent stimulation by the combined administration of CRH plus desmopressin during BIPSS may provide some diagnostic advantage. A crucial issue, however, is whether such an amplified stimulation may affect the specificity of the procedure, and this was the main aim of the present study. OBJECTIVE: We investigated the diagnostic accuracy of BIPSS performed by CRH plus desmopressin stimulation. DESIGN AND SETTING: A retrospective analysis was conducted at a single tertiary care center. PARTICIPANTS: Fifty-four patients were admitted for the investigation of ACTH-dependent CS. CD was diagnosed in 47 patients; occult ectopic ACTH syndrome (oEAS) was histologically confirmed in seven patients. INTERVENTION(S): All patients underwent BIPSS with CRH plus desmopressin administration. Additional noninvasive tests included CRH test, high-dose dexamethasone suppression test, desmopressin test, and pituitary magnetic resonance imaging. MAIN OUTCOME MEASURES: Gradients of inferior petrosal sinus (IPS) to peripheral (IPS/P) ACTH were calculated before and after stimulation with CRH plus desmopressin. RESULTS: The sensitivity for a basal IPS/P gradient greater than 2 was 61.7%, with 100% specificity and a diagnostic accuracy of 66.7%. After stimulation with CRH plus desmopressin, receiver operating characteristic (ROC) curve analysis showed that a cutoff gradient of more than 2 offers the best test performance. In total, 46 of 47 patients with CD had an IPS/P gradient greater than 2, but none of the patients with oEAS, resulting in a sensitivity of 97.9%. The specificity was 100%, diagnostic accuracy was 98.2%, and the positive and negative predictive values were 100 and 87.5%, respectively. A subgroup of 18 patients (16 with CD and two with oEAS) had contradictory responses to routine tests with CRH and/or high-dose dexamethasone suppression test; sensitivity, specificity, and accuracy of BIPSS in this subgroup were 100%. CONCLUSIONS: The application of a combined stimulation with CRH plus desmopressin during BIPSS is associated with a high sensitivity but no loss of specificity.

Characterization of patients with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO).

BACKGROUND: Osteoporotic fractures remain a major public health problem. Currently available osteoporosis therapies significantly reduce the risk of fractures, but up to 50% of patients have an inadequate clinical outcome to therapy. AIM: To describe the clinical and quality of life (QOL) of a study population meeting a proposed definition of inadequate clinical outcome to osteoporosis therapy, recruited for the Observational Study of Severe Osteoporosis (OSSO). DESIGN: Cross-sectional, observational study. METHODS: Post-menopausal women with osteoporosis (n = 2314) were divided into Group 1 (those who had previously experienced a fragility fracture despite osteoporosis drug therapy for at least 12 months) (n = 1309, 57%), or Group 2 (those who had previously discontinued osteoporosis drug therapy due to non-compliance or side-effects) (n = 1005; 43%). Baseline clinical characteristics, quality of life (QOL) and osteoporosis/falls risk factors were analysed. RESULTS: The overall population had low BMD (mean +/- SD T-score at lumbar spine -3.1 +/- 1.1), and risk factors for fracture such as previous fractures (67.8%), family history (15.1%), and prolonged glucocorticoid use (17.5%). QOL was poor: total QUALEFFO and EQ-5D scores were 46.8 +/- 18.7, and 0.50 +/- 0.33, respectively. Patients in Group 1 had higher age and body mass index, fewer hours of exercise, more previous fragility fractures and falls, and poorer QOL scores. DISCUSSION: Our definition of inadequate clinical outcome from osteoporosis drug therapy identifies a severe osteoporosis cohort with poor QOL and increased fracture risk. Using such a definition may lead to earlier recognition of inadequate clinical outcome to osteoporosis therapy, and improved interventions and results.

Leptin alterations in the course of sepsis in humans.

Neuroendocrine response to sepsis may be divided into acute and prolonged phase. As leptin is implicated in the stress response, leptin's profile during both phases, and the possible relationships between leptin and the neuroendocrine response to sepsis were investigated. Thirty adult patients with sepsis in an intensive care unit were studied. Blood samples were collected at the acute and the prolonged phases. In acute sepsis, leptin levels were higher in patients than in controls (10.2 +/- 2.5 vs. 4.1 +/- 1.2 ng/ml, p =0.01) and correlated positively with insulin levels and insulin resistance. A decline in leptin levels was found during prolonged sepsis (from 10.2 +/- 2.5 to 6.2 +/- 1.7 ng/ml, p=0.001), which was not related to survival (p=0.913). At the onset of sepsis, leptin levels increased in correlation with insulin and insulin resistance, possibly indicating a cause-effect relationship. However, the decline in leptin levels during the prolonged phase of sepsis was not related either to survival or to metabolic and hormonal changes.

High levels of serum soluble interleukin-2 receptors in hyperthyroid patients: correlation with serum thyroid hormones and independence from the etiology of the hyperthyroidism.

The serum levels of soluble interleukin-2 receptors (s-IL-2R) and soluble CD8 antigens (s-CD8) were measured in 33 patients with Graves' disease (GD), 29 with toxic nodular goiter (TNG), 6 with toxic adenoma (TA), and 12 with hypothyroidism, as well as in 11 patients with infectious mononucleosis (known to have high s-IL-2R and s-CD8 levels) and 34 normal controls. Serum levels of T3 and T4, both total and free, and of TSH were simultaneously determined. s-IL-2R levels were significantly higher in all patients with hyperthyroidism (mean +/- SD, 3276 +/- 1273 U/mL for GD, 4183 +/- 1832 for TNG, and 1671 +/- 648 for TA) compared to normal control values (P less than 0.001 for GD and TNG and P less than 0.01 for TA), while in the euthyroid state they were within the normal range (535 +/- 240 U/mL). Hypothyroid patients had significantly lower s-IL-2R levels compared to normal controls (P less than 0.05). A positive correlation (P less than 0.001) between serum s-IL-2R levels and total/free T3-T4 levels was found in these groups of patients, while no correlation between s-CD8 levels and s-IL-2R/T3/T4 was found. These findings suggest an association between hyperthyroxinaemia and activation of human lymphocytes in vivo.

The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing's syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion.

The role of desmopressin, alone or in combination with CRH, in the differential diagnosis between Cushing's disease (CD) and ectopic ACTH secretion (EAS) still remains uncertain. Based on existing data, the desmopressin test is regarded as an alternative to the CRH stimulation test and, when given in combination with CRH, it has been suggested to completely discriminate between patients with CD and EAS. However, assessment of these tests has been limited in only a small number of patients with EAS. Desmopressin is a relatively specific V2 vasopressin receptor (V2R) agonist. Although expression of V3 vasopressin receptor (V3R) is common in tumors with EAS, the expression of V2R has not been extensively investigated. In the present study, we report our findings of the desmopressin and the combined CRH-desmopressin test in a series of patients with CD and EAS; also, the expression of V2R and V3R was investigated in tumors with EAS by a RT-PCR method. We assessed a cohort of 31 patients with ACTH-dependent Cushing's syndrome, including 26 patients with CD and five cases with histologically confirmed EAS. To avoid bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1-specificity at each level of the percent cortisol (F) and ACTH responses to these tests. Following desmopressin administration there was an overlap of the percent F and ACTH responses among patients with CD and EAS, and the area under the ROC curve for both these responses was not significantly different than that occurring by chance. This was also true for the percent F response following the combined CRH-desmopressin test. However, the area under the ROC curve for the percent ACTH rise following the combined test was significantly different; the point of the ROC curve closest to 1 corresponded to a percent ACTH rise of 218% (88% sensitivity and 80% specificity). Expression of V2R and V3R mRNA was investigated in four of the five excised tumors with EAS and revealed the presence of the V2R in all, whereas the V3R mRNA was expressed in three of these cases. In conclusion, in this series the desmopressin test produced a significant overlap of responses between CD and patients with EAS and, therefore, is of limited value in the differential diagnosis of the ACTH-dependent Cushing's syndrome. This is most probably due to the expression of the V2R in tumors with EAS. Moreover, following the combined CRH-desmopressin test only the ACTH but not the F responses were diagnostically useful, but still far from completely discriminating patients with CD and EAS.

Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: in vivo and in vitro studies.

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACTH-dependent Cushing's syndrome. In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-normal baseline cortisol, normal suppression of cortisol after dexamethasone administration, and ACTH levels that were not suppressed and did stimulate after CRH administration. The elevated urinary free cortisol excretion, in conjunction with an atypical cortisol diurnal rhythm, raised the possibility of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which was abolished by prior octreotide administration. Notably, substantial amounts of adrenal androgens were also secreted after food consumption. Removal of the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tumor revealed an adrenocortical adenomatous nodule originating from the inner zona reticularis, consisting mainly of compact cells. A steroidogenic secretory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in vitro from tumor cells cultured in the presence of GIP. The in vitro secretory response to GIP was higher for the adrenal androgen DHEA, compared with cortisol. The expression of the GIP receptor in tumor cells, but not in the adjacent normal adrenal, was demonstrated by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androgen oversecreting adrenocortical nodule with the unusual presentation of hirsutism and not the typical clinical signs of Cushing's syndrome. It is of note that food intake in this patient provoked a substantial increase in both adrenal androgen and cortisol levels that, together with the histological appearance of this nodule, was compatible with a zona reticularis-derived tumor. Thus, aberrant expression of the GIP receptor does not exclusively involve cells of a zona fasciculata phenotype, as previously reported, but may also occur in other types of differentiated adrenocortical cells.

A reappraisal of the utility of somatostatin receptor scintigraphy in patients with ectopic adrenocorticotropin Cushing's syndrome.

Ectopic ACTH hypersecretion is a rare cause of Cushing's syndrome. Bronchial carcinoids are the most common neoplasms causing the occult ectopic ACTH syndrome (EAS). Localization of these tumors is often difficult. The diagnostic utility of somatostatin receptor scintigraphy (SRS) in EAS has been studied in a limited number of patients with conflicting results. Herein we report our experience with 12 consecutive cases. Histological confirmation was obtained in nine patients, the majority being bronchial carcinoids. Among the seven patients with histologically confirmed bronchial carcinoids, SRS was performed in six patients. In three patients SRS correctly localized a bronchial carcinoid tumor at presentation. In the remaining three it became positive after 8, 22, and 27 months during follow-up. In two patients SRS was positive without any finding in the corresponding conventional imaging study. In two patients positive computed tomography/magnetic resonance imaging preceded SRS localization. There was no false positive SRS. Among three patients with highly suspected EAS, SRS was positive in one. Both patients with EAS due to medullary thyroid carcinoma had focal positive uptake. In summary, in this study a substantial number of patients had positive tumor localization by SRS. Therefore, SRS is a useful tool in the evaluation of patients with EAS.

Megavoltage pituitary irradiation lowers but seldom leads to safe GH levels in acromegaly: a long-term follow-up study.

Radiotherapy (RT) has long been used in the treatment of acromegaly, but confusion regarding the definition of biochemical cure has hampered interpretation of previous reports on the outcome of this treatment. In the present study we present additional data using the currently accepted criteria of biochemical cure in a large group of patients followed up by our department. Forty-six acromegalic patients were treated with external beam megavoltage RT and followed up for a mean of 7.6 years (range 2-22 years). Only four patients had had previous surgical treatment by either transsphenoidal or transfrontal routes. Following RT, mean basal GH levels decreased from 30.9 ng/ml (5-96 ng/ml) to 11.5 ng/ml (1-36 ng/ml) at 10 years of follow up with a further fall to 6.1 ng/ml (1-29 ng/ml) in those patients followed up for more than 10 years. As a result, although mean GH levels of less than 5 ng/ml were achieved in 9/28 (30.1%) at 5 years, 6/19 (31.6%) at 10 years, and in 6/11 (54.5%) of those patients followed up for more than 10 years post-RT, only 0/28 (0%), 7/28 (25%), 4/19 (21%) and 1/11 (1%) achieved GH levels of <2.5 ng/ml at 2, 5. 10 and >10 years following RT. Thus, in the whole series only 10/48 (20.8%) patients showed a decrease of GH level to less than 2.5 ng/ml at their latest follow up. Hypopituitarism as a result of RT was only infrequently observed in this series; gonadal deficiency developed in 12 (26.6%) patients, thyrotrophin (TSH) deficiency in 3 (6.6%) and adrenocorticotrophin deficiency in 2 (4.4%). In conclusion, megavoltage RT is an effective treatment for the control of GH hypersecretion in acromegaly, with a continuing lowering effect for several years following RT but seldom leads to safe GH levels.

Respiratory muscle strength in hypothyroidism.

To investigate respiratory muscle strength in patients with hypothyroidism, global respiratory muscle strength was assessed by measuring mouth pressure during PImax and PEmax efforts. Maximum pressures, VC, FEV1, FVC, T3, T4, and TSH were measured in 43 hypothyroid patients. Measurements were made before and three months after replacement therapy with thyroxine. The results showed that the mean value of PImax and PEmax increased after treatment. Significant change was found in the mean value of VC, FEV1, and FVC after treatment but not in the FEV1/FVC ratio. A highly statistically significant linear relationship was found between PImax and TSH and between PEmax and TSH as well as between PImax and T3 and PEmax and T3. We conclude that hypothyroidism affects respiratory muscle strength and that this weakness is linearly related to thyroid hormone levels. Respiratory muscle weakness is present in both inspiratory and expiratory muscles and is reversible with treatment.

Comparison of effectiveness between chemotherapy alone versus chemo-radiotherapy in stage III non-small cell lung cancer.

Combined chemotherapy with radiotherapy has been claimed to be superior to radiotherapy alone in stage III non-small cell lung cancer (NSCLC). The present study was designed to give chemo-radiotherapy with 300 cGy only on the day the cytotoxic drugs are administered. The aim was to exploit the cell cycle synergism between the two treatments. Forty-five patients of stage IIIA+B with inoperable NSCLC were randomized in two groups. Group A to be treated with chemotherapy only and group B to be treated with chemotherapy plus radiotherapy. Drugs for group A were: cisplatinum 90 mg/m(2), vindesine 3 mg/m(2) and epirubicin 40 mg/m(2) once every 3 weeks for 8 courses. Group B: cisplatinum 60 mg/m(2), vindesine 3 mg/m(2) and epirubicin 30 mg/m(2) plus 300 cGy radiation, every two weeks for 8 cycles. Then, estimation of response was done. Toxicity was tolerable. In group A the response rate was 52%, in group B 90% (partial and complete). The difference was statistically significant. Additional radiotherapy up to 5,400 cGy was given in patients of group B while patients of group A had palliative radiation on recurrence. Survival rate was significantly longer for patients of group B.

Diurnal changes in glucocorticoid sensitivity in human peripheral blood samples.

The secretion of cortisol, a principle homeostatic regulator in humans, shows a circadian rhythm, with high concentrations in the morning and low levels in the evening and at night. Tissue response to hormones is dependent on hormone concentrations but also on a variety of cellular factors, such as hormone receptors, transcription factors, and activators. In this report, we evaluated whether cell sensitivity to glucocorticoids (GCs) is also subject to diurnal variation using a whole cell system (whole blood samples) stimulated by lipopolysacharide to induce the production of tumor necrosis factor (TNF-alpha); the induction of TNF-alpha is inhibited by dexamethasone. Blood samples obtained in the morning (08.30-09.00 h) and in the evening (22.30-23.00 h) from 37 healthy individuals (18 males, 19 females) aged 29+/-3 years were treated with lipopolysacharide in the presence or absence of 10(-6) M dexamethasone, and the percentage of inhibition of TNF-alpha production was used as an index of sensitivity to GCs. The mean +/- SD in morning samples was 43.5+/-13.8% for the general population, 42.3+/-14.0% for males and 44.6+/-13.8% for females, whereas that in the evening samples was 36.5+/-15.7%, 35.6+/-13.8% and 37.4+/-17.7%, respectively. The results support a significantly increased sensitivity to GCs in the morning hours compared with that in the evening in the general population (P<0.001) as well as in males (P<0.001) and in females (P<0.001). No sex related differences in sensitivity to GCs were observed in the morning or in the evening hours. The sensitive and reproducible assay utilized in this study could also be used to investigate the sensitivity to GCs in various diseases characterized by resistance to GCs and/or alterations in glucocorticoid receptor function.

Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin.

OBJECTIVES: There are numerous indications that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The vitamin D receptor (VDR) gene has been suggested as a possible candidate gene for the regulation of bone mass but the relationship between VDR polymorphisms and bone mineral density (BMD) is controversial and has not been confirmed by all workers in different ethnic groups studied. METHODS: In order to evaluate the contribution of the VDR alleles in bone mass loss, the BsmI, ApaI and TaqI polymorphisms in the VDR gene were studied in 126 postmenopausal women. RESULTS: It was found that the bb, aa and TT genotypes and the bAT and baT haplotypes were associated with a lower BMD measured at the forearm. CONCLUSIONS: Our analysis reveals a significant association between VDR gene alleles and bone mass in the population studied.

Effect of digitalis on diminished baroreceptor sensitivity in diabetics.

The baroreceptor sensitivity was estimated in 50 normal controls (Group A) and in 50 diabetics of comparable age (Group B). The technique used was infusion of angiotensin (0.5 microgram/min) and measurement of the bradycardic response resulting from the increase of blood pressure. The slope was used as an index of baroreceptor sensitivity. Diabetics had significantly lower baroreceptor sensitivity and a higher resting heart rate. Sensitivity decreased with age in both groups. The reproducibility of the method was excellent. Deslanoside-C (0.8 mg) significantly increased the baroreceptor sensitivity in 11 normal controls and 9 diabetics. Very low sensitivity was found in 26 diabetics who had no evidence of orthostatic hypotension, neuropathy, or retinopathy. However all 17 patients with the above findings had very low sensitivity.

Symptomatic pheochromocytoma with normal urinary catecholamine metabolites.

A 61-year old female presented with paroxysmal hypertension and a 4.5cm left adrenal mass on CT scan. Repeated measurements of 24-hour urinary fractionated metanephrines, total catecholamines and vanillylmandelic acid (VMA) were within normal range. A further scintigraphic study with (131)I -metaiodobenzylguanidine ((131)I-MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. After adequate preoperative treatment, successful surgical excision of the tumor was performed and the pathological examination confirmed the diagnosis of a cystic pheochromocytoma with a 2cm solid tumor. On reevaluation three months later using (131)I-MIBG, no evidence of remaining or recurrent disease was found. The patient, off any antihypertensive medication, reported mild recurrent hypertension and panic attacks that were adequately controlled with antidepressants. This is a rare case of a symptomatic pheochromocytoma without elevated urine catecholamines and metanephrines. According to the literature, plasma free metanephrines would be the ideal test for biochemical detection of the tumor. However, in the event that they are not available and there is a high clinical suspicion for the presence of pheochromocytoma, as in our patient, we suggest performance of a functional nuclear medicine study, such as (131)I-MIBG, to confirm the clinical diagnosis.

Fracture incidence and changes in quality of life in women with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO).

UNLABELLED: In this observational study of women with an inadequate clinical outcome to osteoporosis therapy, those with a fracture at baseline were more likely to sustain an incident fracture and have a worse health-related quality of life than those without prior fracture. INTRODUCTION: The Observational Study of Severe Osteoporosis (OSSO) was designed to assess the fracture incidence and health-related quality of life (HRQoL) in women with an inadequate clinical outcome to osteoporosis therapy. METHODS: Post-menopausal women (N=1,885) with established osteoporosis and an inadequate clinical response to osteoporosis drug therapy defined as: a) a fragility fracture despite therapy for one year (index fracture, N=988), or b) discontinued drug therapy due to adverse effects and/or non-compliance (N=897), were assessed during one year for HRQoL using the EQ-5D and the QUALEFFO questionnaires. RESULTS: One hundred and sixty-six (8.8%) women had a total of 209 incident fractures (1,139 fractures/10,000 women-years). Women with an index fracture were more likely to sustain an incident fracture than those without prior fractures (hazard ratio 1.91; 95% CI: 1.37-2.66; p<0.001). Co-morbidities or antidepressant use at baseline also increased the risk of incident fracture. Median total EQ-5D Health State Values and QUALEFFO scores were worse in women with an incident fracture regardless of index fracture status. The worst scores were reported in the EQ-5D sub-domains of self-care, usual activities and pain/discomfort. CONCLUSIONS: Women with an inadequate response to osteoporosis therapy had a high rate of incident fracture which had an adverse impact on HRQoL.

HLA alleles as predisposal factors for postmenopausal osteoporosis in a Greek population.

It is well established that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The major histocompatibility complex in humans, known as human leukocyte antigen (HLA) region, is the most polymorphic human genetic system and it is known as a cluster of genetic markers, associated with several diseases. In order to evaluate the contribution of HLA alleles in bone mass loss, polymorphisms in the HLA class I (-A, -B and -Cw) and class II (-DR and -DQ) antigens were studied in 126 postmenopausal women of Greek origin. It was found that HLA-B7 (P= 0.069), -DR15 (P= 0.019) and -DQ6 (P= 0.026) were associated with a lower bone mineral density measured at the forearm. This study shows a significant association between HLA alleles and bone mass loss in the population studied.

The aldosterone to renin ratio in the evaluation of patients with incidentally detected adrenal masses.

Incidentally discovered adrenal masses are diagnosed with increasing frequency, especially among patients with hypertension. Thus, a reliable screening test for primary hyperaldosteronism (PA) is essential to avoid unnecessary diagnostic procedures to this population. The aim of the present study is the evaluation of aldosterone to renin ratio (ARR), using plasma renin concentration, in the diagnostic algorithm of patients with adrenal incidentaloma. A total of 123 individuals were studied: 17 patients with proven PA (age 55.5 +/- 1.4 years), 27 patients with nonfunctioning adrenal incidentaloma (age 60.3 +/- 1.8 years, 14 hypertensives and 13 normotensives) and 79 control subjects (age 58.7 +/- 1.4 years, 27 hypertensives and 52 normotensives). A receiver operating characteristic (ROC) analysis disclosed that an ARR > or =32 combines a sensitivity of 100% with a specificity of 96.2% for the diagnosis of PA. No difference in AlphaRR between hypertensive and normotensive individuals harbouring an adrenal incidentaloma and hypertensive and normotensive controls was found. Patients with adrenal incidentalomas with subtle glucocorticoid hypersecretion demonstrated similar ARR compared to patients with normal cortisol secretion. In conclusion, ARR is reliable for the exclusion of PA in patients with adrenal incidentalomas. Furthermore, subtle aldosterone hypersecretion, as indicated by increased ARR, in patients with adrenal incidentalomas is not associated with the presence of hypertension or subtle glucocorticoid hypersecretion.

Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications.

Subclinical hypercortisolism (SH) is a newly characterized hormonal disorder that is almost exclusively detected in the context of incidentally discovered adrenal masses. The diagnostic criteria used for the definition of this condition are at present controversial. Amongst the various tests used for the detection of this abnormality (dexamethasone suppression, urinary free cortisol, ACTH levels, midnight serum or salivary cortisol concentrations, ACTH responses to CRH stimulation), the dexamethasone suppression tests (DST) seem to better accomplish the task of unmasking subtle abnormalities of cortisol secretion. Several versions of DST have been used: the 1-mg overnight, the 3-mg overnight and the classical 2-day low-dose DST. This latter test has the theoretical advantage that, by more efficiently suppressing pituitary ACTH secretion, it may provide a measure of the residual (ie non- ACTH-dependent) cortisol secretion from the adrenal mass. In this way, post-dexamethasone cortisol concentrations may quantify the degree of autonomous cortisol hypersecretion. In fact, post-dexamethasone cortisol concentrations have a negative correlation with basal ACTH levels and a positive correlation with midnight cortisol concentrations as well as the size of the incidentally discovered adrenal mass. Most of the existing data indicate that SH detected in the context of adrenal incidentalomas may have some clinically significant implications. In fact, patients with higher post-dexamethasone cortisol concentrations demonstrate higher lipid levels and lower bone mass densities. It has also been suggested that SH may be responsible for biochemical and phenotypic changes reminiscent of the metabolic syndrome. In summary, SH does exist and is associated with a negative impact in patients' health; however, hormonal cut-off criteria for decision-making remain to be defined.

Evaluation of GH reserve in patients with adrenal incidentalomas and biochemical evidence of subclinical autonomous glucocorticoid hypersecretion.

OBJECTIVE: Although it is well established that overt hypercortisolism in patients with active Cushing's syndrome leads to a profound suppression of stimulated GH secretion, the role of subclinical autonomous glucocorticoid hypersecretion (SAGH), currently detected with increasing frequency in patients with adrenal incidentalomas, on GH secretory reserve has received little attention. The aim of the present study was to evaluate whether SAGH in patients presented with adrenal incidentalomas has a negative effect on GH secretory reserve. DESIGN AND PATIENTS: Sixteen patients with overt Cushing's syndrome (CS) and 36 patients with adrenal incidentalomas were investigated. The latter group was further divided in 23 patients who demonstrated an adequate suppression of cortisol levels (of < 70 nmol/l) following the low-dose dexamethasone suppression test (LDDST) and in 13 patients, who failed to suppress (cortisol levels post-LDDST > 70 nmol/l). The former group was defined as normocortisolaemic (NC) and the latter group as representing patients with SAGH. The combined pyridostigmine + GHRH test (PD + GHRH) was used to assess the GH secretory reserve of these patients. RESULTS: Peak GH levels following PD + GHRH administration were significantly lower in CS patients compared to both the NC and SAGH group of patients with adrenal incidentalomas (2.2 +/- 0.7 vs. 18.9 +/- 2.6 and 21.5 +/- 3.6 microg/l, respectively, P < 0.05); no difference was observed in peak GH responses between the NC and SAGH group of patients. A subnormal GH response (defined as GH(max) < 12.8 microg/l) was observed in all 16 patients with CS. However, only seven NC and three SAGH patients failed to respond adequately. Correlation analysis revealed a negative correlation between peak GH response to PD + GHRH and plasma cortisol concentrations in CS patients (R =-0.6, P = 0.012), while in patients with adrenal incidentalomas such a correlation was absent. Contrary to patients with CS in whom body mass index (BMI) was not correlated to peak GH, a significant negative correlation between peak GH response to PD + GHRH and BMI was disclosed in patients with adrenal incidentalomas (R =-0.49, P = 0.003). In these patients, again contrary to CS patients, a significant negative correlation was also found between peak GH post PD + GHRH and age (R = -0.46, P = 0.002). CONCLUSIONS: In conclusion, our results provide evidence that, contrary to patients with overt CS, SAGH does not affect the GH secretory response to provocative stimulation.

Serum soluble interleukin-2 receptors as an index of the biological activity of thyroid hormones in hyperthyroidism.

In order to examine whether serum soluble Interleukin-2 Receptors (sIL-2R) could be used as a marker of the biological effects of the thyroid hormones, we measured the sIL-2R, sex hormone binding globulin and beta-2 microglobulin levels in thirty-three hyperthyroid patients (14 with Graves' disease, 17 with Toxic Nodular Goiter and 2 with toxic adenoma) before and during treatment with antithyroid drugs. We found that serum sIL-2R concentrations of the patients, at diagnosis, were significantly higher compared with normal controls (2424 +/- 1447 vs 459 +/- 184 U/ml). All hyperthyroid patients had sIL-2R levels > mean + 2SD of normal controls, with 28 of the 33 patients having sIL-2R concentrations higher than 1011 U/ml (mean + 3SD of normal controls). Only 15 patients had SHBG levels higher than 3SD above the mean for the normal controls and 28 had SHBG levels 2SD above the mean for the normal controls. Three of the 5 hyperthyroid patients with normal SHBG levels at presentation had abnormally high sIL-2R levels. In all patients sIL-2R levels decreased gradually during therapy down to normal levels when euthyroidism was achieved. A strong positive correlation was found between sIL-2R, SHBG and T3 and T4 concentrations. Serum B2-microglobulin (B2-m) levels were higher than the upper normal limit only in 9 patients, but a significant decrement was observed in all patients when euthyroidism was achieved. The above results indicate that serum sIL-2R levels could be a useful marker of the in vivo biological effects of the thyroid hormones on lymphocytes in hyperthyroid patients.