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S Tsagarakis

Publications and source records attributed to S Tsagarakis.

At least 19 recordsLinked to original sources
PubMed2006

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.

Adrenal Gland Neoplasms↗
PubMed2005

Diabetes insipidus, secondary hypoadrenalism and hypothyroidism after traumatic brain injury: clinical implications.

Adequate ADH secretion, adrenal and thyroid functions are vital during the acute and post-acute phases of TBI. Deficiencies of these functions as a result of TBI are increasingly recognized. During the acute phase of TBI the incidence of severe DI is 2.9%; the incidence of less severe forms of DI is 21.6-26%. The development of DI seems to correlate with the severity of trauma. In most occasions DI is transient, but persisting DI may develop with an incidence of 6.9-7.5% amongst TBI victims. The assessment of the adequacy of adrenal function during the acute phase of TBI remains a diagnostic challenge. A few studies demonstrated an incidence of hypoadrenalism of 15-16% during the early phase of TBI. It should be noted that early hypoadrenalism may be due to either a structural damage at the level of the hypothalamo-pituitary unit or it may develop in the context of the so-called "relative adrenal insufficiency", a functional abnormality that is currently increasingly recognized during the course of severe illness. Secondary hypoadrenalism during the late phases of TBI appears with an incidence of 7.1-12.7%. The "low-T3 syndrome" compromises the assessment of thyroid function during the acute phase of TBI; the incidence of TSH insufficiency during the recovery phase varies widely between 1-21%. In summary, diabetes insipidus, secondary hypoadrenalism and hypothyroidism may develop in a small albeit significant proportion of patients during the course of TBI. Therefore, assessment of the integrity of ADH secretion, hypothalamic-pituitary adrenal (HPA) axis and thyroid axis is crucial to ensure survival and optimal rehabilitation of TBI patients.

Adrenal Insufficiency↗
PubMed2005

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.

Adenoma↗
PubMed2005

Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005.

Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction. Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS. Over the last 5 years, we have evaluated six subjects with the clinical diagnosis of AAAS. Three subjects had mutations in the AAAS gene-- including one novel mutation (IVS8+1 G>A)-- and a broad spectrum of clinical presentations. However, three subjects with classic AAAS did not have mutations in the AAAS gene on both alleles. This finding supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded.

Adolescent↗
PubMed2003

Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas?

OBJECTIVE: Subclinical hypercortisolism (SH) is detected increasingly in a substantial proportion of patients with incidentally discovered adrenal adenomas. The clinical implications of SH are currently unclear. Osteoporosis is a well-known complication of glucocorticoid excess. So far, the impact of SH on bone mineral density (BMD) has been studied in a limited number of reports with discordant results. In the present study we evaluated the BMD in a large cohort of post-menopausal women with adrenal incidentalomas. : patients and measurements Forty-two post-menopausal women with incidentally discovered adrenal masses and radiological features highly suggestive of benign adrenal adenomas were investigated. All patients underwent a standard low-dose dexamethasone suppression test (LDDST; 0.5 mg 6-hourly for 2 days). The diagnosis of subclinical hypercortisolism (SH) was based on post-LDDST cortisol concentrations of > 70 nmol/l. According to this criterion patients were subdivided into two groups: with (n = 18; group A) or without (n = 24; group B) SH. There was no significant difference in age, years since menopause and body mass index between these groups. BMD was measured at L2-L4 vertebrae and three sites of the proximal femur by the dual energy X-ray absorptiometry (DEXA) method. RESULTS: Post-menopausal women with SH (group A) exhibited slightly but significantly lower absolute and age-adjusted BMD values compared to group B patients in the femoral neck (BMD g/cm2: 0.72 +/- 0.08 vs. 0.79 +/- 0.09; Z-score: -0.20 +/- 0.82 vs. +0.43 +/- 0.94, P < 0.05) and trochanter (BMD g/cm2: 0.60 +/- 0.09 vs. 0.69 +/- 0.10; Z-score: -0.32 +/- 1.0 vs. +0.30 +/- 1.05, P < 0.01). BMD measurements of the Ward's triangle were also lower in group A patients but the difference did not reach statistical significance (BMD g/cm2: 0.60 +/- 0.10 vs. 0.68 +/- 0.13, P = 0.06). There was no difference in the lumbar vertebrae between the two groups (BMD g/cm2: 0.888 +/- 0.13 vs. 0.90 +/- 0.16, P = 0.78; z-score: +0.50 +/- 1.16 vs. +0.11 +/- 1.5, P = 0.36). The number of patients in the osteoporotic range was minimal with no significant difference between the two groups. However, the frequency of osteopenia in group A was significantly greater than in group B patients in the trochanter and Ward's triangle areas. Serum osteocalcin (BGP) levels were significantly lower in group A compared to group B patients (18.6 +/- 8.6 vs. 26.2 +/- 8.1 ng/ml, P < 0.01); no difference existed regarding parathyroid hormone (PTH) concentrations (43 +/- 15.6 vs. 41.2 +/- 14.8 pg/ml, P = 0.72). CONCLUSIONS: In this series, post-menopausal women with subclinical hypercortisolism had lower absolute and age-adjusted BMD values and a higher rate of osteopaenia in the trabecular loaded and mixed cortical-trabecular bone of proximal femur. These data demonstrate that the subtle hypercortisolism of patients with adrenal incidentalomas may have an adverse effect on the bone mass of these patients.

Adrenal Cortex Neoplasms↗
PubMed2003

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.

Adrenocorticotropic Hormone↗
PubMed2002

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.

ACTH Syndrome, Ectopic↗
PubMed2001

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.

17-alpha-Hydroxyprogesterone↗
PubMed2000

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.

Adult↗
PubMed2000

The application of a combined stimulation with CRH and desmopressin during bilateral inferior petrosal sinus sampling in patients with Cushing's syndrome.

BACKGROUND: Bilateral inferior petrosal sinus sampling (BIPSS) is a useful investigative technique in the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). The diagnostic sensitivity of this procedure is improved by the administration of CRH to stimulate ACTH secretion. It has been reported recently that the combined administration of CRH and desmopressin is a more potent stimulus for ACTH release from corticotroph adenomas. We therefore hypothesized that the combined stimulation of ACTH secretion with CRH plus desmopressin may further improve the diagnostic outcome of this procedure. AIMS: To report our experience of the application of combined stimulation with CRH and desmopressin during BIPSS in patients with ACTH-dependent Cushing's syndrome, and to compare these results to those obtained in patients who have undergone BIPSS with CRH stimulation alone. PATIENTS: We studied 34 patients with ACTH-dependent CS: 30 with Cushing's disease (CD) and four with occult ectopic ACTH syndrome (oEAS). A combined stimulation with CRH (100 micrograms i.v.) plus desmopressin (10 micrograms i.v.) during BIPSS was performed in 15 patients with CD, while in a different group of 15 patients with CD, BIPSS was performed with CRH stimulation alone (100 micrograms i.v.). In the patients with oEAS, BIPSS was performed with CRH stimulation in three and CRH plus desmopressin in one patient. RESULTS: In patients with CD the mean peak ACTH levels from the dominant petrosal sinus samples were significantly higher in the group given a combined stimulus than in the group who had only CRH stimulation (mean +/- SD: 1649 +/- 938 vs. 692 +/- 561 ng/l, P < 0. 05). Dominant inferior petrosal sinus/peripheral (IPS/P) ACTH ratios greater than 2 were observed in 15/15 (100%) patients following the combined stimulation with CRH and desmopressin and 13/15 (87%) patients undergoing stimulation with CRH alone. No patient with oEAS had an IPS/P ratio greater than 2. It is of note that the single patient with oEAS studied following a combined stimulation during BIPSS had a IPS/P ratio of less than 2, despite a significant peripheral ACTH and cortisol response. CONCLUSIONS: A combined stimulus using CRH and desmopressin appears to induce a higher ACTH output from pituitary corticotroph adenomas during BIPSS, which may improve the diagnostic sensitivity of this procedure.

Adenoma↗
PubMed1999

Immunocytochemical accumulation of p53 in corticotroph adenomas: relationship with heat shock proteins and apoptosis.

The pathogenesis of corticotroph adenomas is unknown. In a recent study accumulation of p53 protein was detected by immunohistochemistry in a substantial proportion of pituitary corticotroph adenomas, and it has been suggested that it may be causally related to their development. However, other immunohistochemical studies have not confirmed the high incidence of p53 accumulation in this tumor type. Therefore, in the present study, p53 protein accumulation was re-examined in a series of 31 cases of corticotroph adenomas, using different sets of well validated anti-p53 antibodies. Furthermore, in view of the known association of p53 protein with apoptosis, and the known property of p53 to form complexes with heat shock proteins (HSPs), the relationship of p53 accumulation in corticotroph adenomas with apoptosis and HSP-70 was also investigated. Tumor samples from 31 patients with Cushing's disease or Nelson's syndrome were studied. Accumulation of p53 protein was tested by the standard ABC method using two different sets of clone Pab1801 and DO-7 monoclonal antibodies, applied after incubation of sections in a microwave oven. Using the DO-7 antibody, nuclear accumulation of p53 protein was detected in a total of 15 cases, with cytoplasmic staining observed in only 3 tumors. In contrast, using the Pab1801 antibody nuclear staining was observed in only 5 adenomas, with 11 adenomas demonstrating focal cytoplasmic immunoreactivity. Parallel sections of all corticotroph tumors demonstrating cytoplasmic accumulation of p53 protein were tested for the immunohistochemical presence of heat shock protein HSP-70. A striking similar distribution pattern of these two proteins was observed. Apoptosis, identified by the in situ end labeling technique, was detected in a total of 15 out of 28 corticotroph adenomas tested. Calculation of the apoptotic labeling index (ALI) by image analysis showed a significantly lower ALI in those corticotroph adenomas demonstrating nuclear p53 accumulation compared to those with no nuclear p53 immunostaining (p < 0.05). There was no significant difference in the ALI between cytoplasmic p53 positive and negative tumors. It is concluded that depending on the antibody used there is a significant variation of p53 protein detection in corticotroph adenomas. Overall, a significant proportion of corticotroph adenomas studied expressed the p53 protein, which depending on the antibody used, was located either in the nucleus and/or the cytoplasm of tumorous corticotroph cells. Cytoplasmic accumulation of p53, as shown by our colocalization studies with HSP-70, may be due to p53/HSP-70 complex formation. Although such a complex-mediated cytoplasmic exclusion of p53 has no significant effect on apoptosis, nuclear accumulation of p53 protein is associated with a significantly lower apoptotic index indicating a failure of p53 protein to exert its apoptotic action in at least a subset of this tumor type.

Adenoma↗
PubMed1999

Assessment of cortisol and ACTH responses to the desmopressin test in patients with Cushing's syndrome and simple obesity.

OBJECTIVE: The desmopressin test has recently been introduced in clinical practice as an adjunctive tool in the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). It has been reported that the majority of patients with pituitary-dependent CS (Cushing's disease, CD) respond to desmopressin, while no such response is usually observed in other forms of this syndrome. In the present study, the responsiveness of the HPA axis to desmopressin was studied in a group of obese subjects. In addition, the ability of desmopressin administration to differentiate between patients with obesity and the various forms of Cushing's syndrome was investigated. DESIGN AND SUBJECTS: Cortisol and ACTH responses to the administration of desmopressin (10 microg bolus i.v.) were examined in 20 consecutive patients with obesity (14 women and six men; BMI range: 34.5-66.7 kg/m2). Obese subjects had no clinical stigmata of CS. In all obese patients, either an overnight (dex 1 mg at 2300 h) (n = 8) or a formal low-dose (dex 0.5 mg 6-hourly for 2 days) (n = 12) dexamethasone suppression test was performed for the exclusion of Cushing's syndrome. Three of eight subjects showed failure of cortisol suppression (i.e. F > 28 nmol/l) to the overnight dexamethasone suppression test, but they had undetectable cortisol levels (< 28 nmol/l) on further testing with the formal 2-day test. All but two of the remaining subjects had undetectable cortisol levels (< 28 nmol/l) following the formal 2-day, low-dose, dexamethasone suppression test. For comparison, desmopressin responses were also tested in 33 patients with CS of varied aetiologies (25 patients with pituitary-dependent CS, three patients with occult ectopic ACTH secretion and five patients with primary adrenal CS). A positive response was considered to be an increment greater than 20% and 50% from baseline levels of cortisol and ACTH, respectively. RESULTS: Mean cortisol (F) and ACTH levels did not differ from the baseline at any time point following desmopressin administration in the obese group (basal F: 417 +/- 41, peak F: 389 +/- 32 nmol/l, P > 0.05; basal ACTH: 33.5 +/- 4.3, peak ACTH: 50.6 +/- 16.6 ng/l, P > 0.05), or in patients with occult ectopic or primary adrenal CS. In contrast, in the group of patients with CD, there was a significant rise in the mean ACTH and F levels from baseline (basal F: 725 +/- 50, peak F: 1010 +/- 64 nmol/l, P < 0.01; basal ACTH: 88.6 +/- 11.8, peak ACTH: 351 +/- 64 ng/l, P < 0.01). Cortisol responses greater than 20% from baseline were observed in 21/25 (84%) patients with CD, but in only 3/20 (15%) of the obese patients. With regard to ACTH, increments greater than 50% over baseline were observed in 23/25 (92%) of patients with CD, and in only 3/20 (15%) of the obese patients. As previously reported, none of the patients with occult ectopic ACTH secretion or primary adrenal CS had a positive response. CONCLUSIONS: The prevalence of subjects who met the criteria adopted to define positive cortisol and ACTH responses to the desmopressin test was significantly higher in the group of patients with Cushing's disease than in the group of patients with obesity. It is therefore suggested that this test may be occasionally useful in the differentiation between simple obesity and the pituitary-dependent form (but not other forms) of Cushing's syndrome.

Adrenocorticotropic Hormone↗
PubMed1998

The low-dose dexamethasone suppression test in patients with adrenal incidentalomas: comparisons with clinically euadrenal subjects and patients with Cushing's syndrome.

OBJECTIVE: Increasing evidence favours subtle glucocorticoid excess in many patients with adrenal incidentalomas. However, existing evidence is based mainly on the overnight dexamethasone suppression test, a test that is commonly abnormal even among clinically euadrenal subjects. The aim of the present study was to evaluate patients with adrenal incidentalomas for subtle glucocorticoid excess by the more specific low-dose dexamethasone test (LDDST). Moreover, since the criteria of what constitutes an abnormal cortisol response following this test have been largely anecdotal, we report our results in comparison with those obtained in clinically euadrenal subjects, and patients with Cushing's syndrome. DESIGN: A prospective study of 57 patients with adrenal incidentalomas with CT characteristics highly suggestive of benign adrenocortical adenomas and 85 clinically euadrenal subjects consisting of 54 obese women with BMI > 30 kg/m2 (range 30-54.7), 13 women with BMI < 30 kg/m2 (range 20.3-29.6) and 18 healthy volunteers (10 women and eight men) over 40 years of age (mean age 51.7 +/- 9.9, range 40-74; mean BMI 30 +/- 6.6, range 20.3-47.5 kg/m2). A retrospective analysis was performed on 60 patients with a confirmed diagnosis of Cushing's syndrome. MEASUREMENTS: All subjects were admitted to the endocrine ward and underwent a standard LDDST, as follows: after a 48-h stabilization period, a 24-h urine collection for basal urinary free cortisol was performed. Basal serum cortisol and plasma ACTH were measured at 0800 h the following day, and subjects were started on dexamethasone 0.5 mg 6-hourly for 2 days. Post-dexamethasone cortisol and ACTH levels were measured at 0800 h, 6 h after the last dose of dexamethasone. RESULTS: Following dexamethasone suppression serum cortisol concentrations became undetectable (< 28 nmol/l) in all clinically euadrenal subjects. In patients with incidentally discovered adrenal masses, post-LDDST cortisol concentrations were undetectable in 12 (21%), between 28-140 nmol/l in 38 (67%), and 140-216 nmol/l in seven (12%) patients; post-LDDST cortisol values correlated positively with the size of the adenoma (r = +0.482, P < 0.001). Post-LDDST cortisol concentrations in patients with Cushing's syndrome ranged from 85 to 1786 nmol/l; in 3/42 (7%) patients with ACTH-dependent Cushing's syndrome cortisol concentrations were < 140 nmol/l. CONCLUSIONS: On the basis of our data in a large group of clinically euadrenal subjects, we suggest that following LDDST cortisol concentrations should become undetectable with the currently used radioimmunoassays. In patients with adrenal incidentalomas, application of the LDDST confirmed the presence of incomplete suppression of cortisol in the majority of patients. We suggest that the LDDST is a sensitive index of autonomous cortisol production in patients with adrenal incidentalomas; following this test a grading of subtle glucocorticoid excess may be obtained but future studies correlating biochemical, clinical and epidemiological data are required, in order to develop widely agreed cut-off levels of clinically significant glucocorticoid excess in these patients.

Adrenal Cortex Function Tests↗
PubMed1998

Elevated post-dexamethasone suppression cortisol concentrations correlate with hormonal alterations of the hypothalamo-pituitary adrenal axis in patients with adrenal incidentalomas.

OBJECTIVE: It has recently been suggested that autonomous cortisol production may lead to subclinical glucocorticoid excess in a substantial number of patients with incidentally discovered adrenocortical adenomas. Following a standard low-dose dexamethasone suppression test (LDDST) cortisol concentrations are frequently incompletely suppressed in patients with adrenal incidentalomas, due to an ACTH-independent secretion of cortisol by the adrenal mass. Thus, post LDDST cortisol concentrations may provide a measure of the degree of autonomous glucocorticoid secretion, but hormonal alterations in relation to post-LDDST cortisol concentrations have not been thoroughly investigated. PATIENTS AND MEASUREMENTS: 61 patients with radiological features highly suggestive of adrenal adenomas were studied. These included 43 women, 18 men; mean age 59 +/- 1.4, range: 25-76 years; BMI 30.9 +/- 0.8 kg/m2 and waist:hip ratio 0.90 +/- 0.016. All subjects underwent a standard LDDST, as follows: after a 48-hr stabilisation period, 24-hr urine collections for basal urinary free cortisol (UFC) were performed. Basal serum cortisol and plasma ACTH were measured at 8 AM and at midnight the following day, and subjects started dexamethasone 0.5 mg 6 hourly for 2 days. Post-dexamethasone cortisol and ACTH levels were measured at 8 AM, 6-hrs after the last dose of dexamethasone. Blood samples for dehydroepiandrosterone sulphate (DHEAS) and serum lipids were obtained on the morning preceding dexamethasone administration. RESULTS: Post-LDDST cortisol concentrations correlated positively with the size of the adenoma (r = +0.527, P < 0.001). There was a negative rank correlation of post-LDDST cortisol concentrations and basal ACTH levels at 0900 h (rs = -0.426, P < 0.001) and DHEAS (rs = -0.380, P = 0.006). Moreover, there was a good rank correlation between DHEAS and basal ACTH levels (rs = +0.456, P < 0.001). A positive rank correlation was observed between post-LDDST cortisol concentrations and midnight cortisol concentrations (rs = +0.317, P = 0.020). As recent studies have suggested that post-LDDST cortisol levels higher than 70 nmol/l may indicate significant hypercortisolism comparisons were also performed between patients divided according to post-LDDST cortisol values into 3 groups: Group A, > 70 nmol/l (19 pts); Group B, 30-70 nmol/l (27 pts); Group C, < 30 nmol/l (15 pts). Although there was no difference in basal cortisol and UFC values between these groups, ACTH and DHEAS levels were significantly lower, and midnight cortisol significantly higher in group A compared to group C patients (P = 0.030, P = 0.017 and P = 0.001 respectively). Cholesterol and triglyceride levels were slightly albeit significantly higher in group A compared to group C patients (P < 0.05). CONCLUSIONS: It is concluded that higher post-low dose dexamethasone cortisol concentrations are associated with lower ACTH and dehydroepiandrosterone sulphate, higher midnight cortisol concentrations and larger adenomas. These findings are consistent with the hypothesis that post-low dose dexamethasone cortisol concentrations represent a useful index in assessing subtle glucocorticoid autonomy in patients with adrenal adenomas.

Adenoma↗
PubMed1998

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.

Acromegaly↗
PubMed1997

Regionalization of occult pancreatic insulinomas with the arterial stimulation venous sampling (ASVS) technique.

Non-invasive modalities (ultrasound, computerized tomography, MRI and somatostatin receptor scintigraphy) often fail to localize insulinomas smaller than 1.5 cm in diameter. Recently, regionalization of such occult insulinomas was facilitated by the arterial stimulation and venous sampling (ASVS) technique, using calcium as the insulin secretagogue. However, so far experience with this technique has been limited to a few tertiary referrals centres worldwide. In these case studies we report our experience in three consecutive patients with occult insulinomas. Three consecutive patients (all men 34, 51 and 56 years of age) with insulin-mediated hypoglycaemia were studied. Diagnosis of insulin hypersection was established by the finding of a high amended insulin: blood sugar ratio during fasting. Localization of a pancreatic mass lesion was unsuccessful by ultrasound, CT and/or MRI in all patients. Two patients had negative octreotide scans. In all patients after the infusion of calcium sequentially into the gastroduodenal, splenic and the superior mesenteric arteries, insulin levels rose significantly in right hepatic vein samples giving rise to diagnostic gradients from the splenic artery (in 2 patients) and gastroduodenal artery (in 1 patient), regionalizing insulinomas in the tail and head or neck of the pancreas respectively. The simultaneously obtained angiogram was positive in only 1 patient, in whom it corresponded to the insulin gradient. Regionalization of these occult tumours was subsequently confirmed at laparoscopy in the 2 patients operated. It is concluded, that the arterial stimulation venous sampling technique is an effective method in regionalizing occult insulinomas and should complement invasive angiography whenever the latter procedure is performed.

Adult↗