Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency.

Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.

Effect of DHEA supplementation on serum IGF-1, osteocalcin, and bone mineral density in postmenopausal, glucocorticoid-treated women.

PURPOSE: DHEA therapy increases bone formation in postmenopausal women. We have found only a few reports of dehydroepiandrosterone replacement therapy in women receiving long-term glucocorticoid medication. The purpose of this study was to establish whether DHEA replacement therapy may be useful in the treatment of steroid-induced osteoporosis in postmenopausal women. MATERIALS AND METHODS: Nineteen women, aged 50-78 years, treated at least for three years with average daily doses of more than 7.5 mg prednisone, with T-score L2/L4<-1.5 and bisphosphonates intolerance, were enrolled to the study. For the first year of the study the patients were given calcium, vitamin D3 and thiazide diuretics. For another year the patients received orally micronized DHEA 25-50 mg daily. Before the study, after twelve months of Calcium/D3 therapy, then after six weeks and six months of DHEA therapy, serum concentrations of DHEAS, androstenedione, testosterone, estradiol, FSH, IGF-1 and osteocalcin were assessed. Bone mineral density (BMD) in lumbar spine and femoral neck was measured before the treatment, after a year on Calcium/D3 and after six and twelve months of DHEA replacement therapy. RESULTS: In all treated women, DHEA significantly increased serum DHEAS, androstenedione and testosterone concentrations. A significant elevation of serum IGF-1 and osteocalcin concentrations was found as early as after six weeks of DHEA treatment. A significant increase of bone mineral density in the lumbar spine and femoral neck was observed after six and twelve months of DHEA treatment. CONCLUSION: Our results suggest a beneficial role of DHEA replacement therapy in the treatment of steroid-induced osteoporosis.

Incidentally discovered adrenal tumors: a lesson from observation of 1,444 patients.

This study was aimed at summarizing our experience in the management of 1,444 patients with incidentally found adrenal tumors observed at a single endocrinological centre. Hormonal determinations were performed in all patients at the beginning of the observation period to detect subclinical adrenal hyperfunction. The imaging phenotype on CT and MRI was analyzed for defining the malignant potential of the tumors. Based on the results of these examinations we diagnosed among our cohort probably benign masses in 87%, malignant tumors in 10% (adrenal carcinoma - 9%), and metastases in 3%. Subclinical hyperfunction was diagnosed in 8%; the most frequent was the pre-Cushing's syndrome. A subgroup of 480 patients (33%) was submitted to surgery because of oncological or endocrinological indications. The patients not qualified for surgery were carefully controlled by imaging and hormonal examinations. Malignancy is the most serious risk in the group of patients with incidentally discovered adrenal tumors.

1,161 patients with adrenal incidentalomas: indications for surgery.

BACKGROUND AND AIMS: The aim of this study is to analyze the clinical data and criteria for surgery in a group of over 1,100 patients with adrenal incidentalomas (AI) observed at the Department of Endocrinology. PATIENTS AND METHODS: The material consisted of 1,161 patients (842 women and 319 men, 10-87 years old) with AI ranging in size from 1.0 to 23.0 cm. The methods included clinical examination, imaging studies, hormonal determinations in the blood and in the urine as well as histological and immunocytochemical investigations in 390 patients treated by surgery. RESULTS: Basing on these studies, we diagnosed 112 patients with primary malignant adrenal tumors (100 with carcinoma), 45 with metastatic infiltrations, and 1,004 with probable benign AI. Imaging phenotypes (especially high density on computed tomography, CT) were characteristic of malignant and chromaffin tumors. Subclinical adrenal hyperactivity was found in 8% of the patients with pre-Cushing's syndrome as the most frequent form (6.5%). Chromaffin tumors were detected in 3%. CONCLUSIONS: (1) Indications for surgery include malignant tumors (both primary and metastatic), tumors with subclinical hyperfunction, and chromaffin tumors. High density on CT, >20 HU, appeared to be an important indication for surgery. (2) A slight prevalence of oncological indications over endocrinological indications (14 vs. 11%) was found.

Nelson's syndrome -- 46 years later: clinical experience with 37 patients.

OBJECTIVE: Pituitary tumours occurring after bilateral adrenalectomy for Cushing's disease (Nelson's syndrome) are frequently aggressive, so an early diagnosis and careful management are of prime importance. For a new insight into this entity it is necessary to analyse the factors predisposing to its development and the course of the disease, as well as the methods of diagnosis and modalities of treatment. PATIENTS AND METHODS: Thirty-seven patients with Nelson's syndrome were observed, 32 women and 5 men, aged 16 to 61 years at the time of pituitary tumour detection (at present, 27 to 82 years old). The diagnostic methods included clinical observation, imaging examinations (X-ray studies, CT, MRI), hormonal evaluation (especially ACTH and cortisol levels during replacement therapy) and ophthalmologic investigations. Neurosurgery was the main method of treatment. RESULTS: The clinical analysis indicated that young age at the time of adrenalectomy, pregnancy, insufficient replacement therapy and fulminant course of Cushing's disease were the main factors predisposing to Nelson's syndrome. MRI appeared to be the most valuable imaging method, as this detected Nelson's tumours in the microadenoma stage in 7 patients. Plasma ACTH levels varied between 32.6 pmol/l in an early phase to 2 000 pmol/l in the full-blown syndrome. Absolute temporal scotomas found in ophthalmologic examinations were an early abnormality. The best results after therapy were obtained in patients treated by neurosurgery using a transsphenoidal approach in an early stage. CONCLUSIONS: MRI, ophthalmologic examination and plasma ACTH determination were the most valuable investigations for early diagnosis of Nelson's syndrome. Early neurosurgery offered the best outcome in our group of patients.

Autoantibodies against pituitary proteins in patients with adrenocorticotropin-deficiency.

BACKGROUND: An autoimmune cause of adrenocorticotropin (ACTH)-deficiency is presented, as it is known to be a characteristic feature of lymphocytic hypophysitis, a disease of the pituitary gland considered to be autoimmune. MATERIALS AND METHODS: The aim of this study was twofold: (1) to evaluate the occurrence of pituitary autoantibodies and (2) to correlate it to clinical and immunological features in a large group of patients with ACTH-deficiency of possible autoimmune aetiology. Sixty-five patients with ACTH-deficiency and 57 healthy subjects participated in the study. Pituitary autoantibodies were measured by an immunoblotting assay with human pituitary cytosol as antigen. RESULTS: Autoantibodies to a novel 36-kDa pituitary autoantigen were seen in sera from 18.5% (12/65) patients and only 3.5% (2/57) of control subjects (P = 0.0214). When taking only those subjects with strong immunoreactivity into account, the significance was lost; P = 0.3642. Immunoreactivity to a 49-kDa pituitary autoantigen was observed in 21.5% (14/65) of ACTH-deficient patients compared with 8.8% (5/57) of control subjects (P = 0.0910). This 49-kDa pituitary autoantigen has recently been identified as neurone-specific enolase and a candidate marker for neuroendocrine autoimmunity. Clinical parameters in patients with positive versus those with negative pituitary immunoreactivity did not differ. However, autoantibodies to thyroglobulin were positively correlated to immunoreactivity against the 36-kDa pituitary autoantigen (P = 0.014). CONCLUSIONS: Our findings of pituitary autoantibodies in patients' sera support the theory that an autoimmune destruction of corticotrophs may be the underlying cause of hormonal deficit in some patients with ACTH-deficiency.

Adrenal ganglioneuroblastoma in pregnant woman: diagnosis with three-dimensional ultrasound.

The diagnostic approach for evaluation of adrenal tumour in pregnant women is a problem. This article presents the multifactorial diagnosis of rare, incidentally detected massive adrenal tumour with 2D and 3D US. Grey-scale 2D and 3D US with tissue harmonic imaging showed inhomogeneous, encapsulated, solid tumour of the right adrenal region. Three-dimensional colour Doppler and power Doppler studies showed ample neovascularization in the tumour and the adrenal vein draining to the inferior vena cava similarly to angiographic studies performed in the past.

Clinical results of the use of mitotane for adrenocortical carcinoma.

Mitotane (o,p'-DDD) acts mainly as an inhibitor of intramitochondrial pregnenolone and cortisol synthesis. Its adrenolytic effect depends on metabolic activation due to conversion to o,p'-DDA and o,p'-DDE. The drug has been used for 40 years in the treatment of adrenocortical carcinoma, mainly its regional and metastatic stage, as an adjuvant to surgical resection of the tumor. In the medical literature there are controversial opinions about its efficacy for the treatment of adrenocortical carcinoma. In our experience, mitotane administered immediately after surgery appeared to be much more efficient than when administered later. We have administered this drug in all cases of microscopically confirmed adrenocortical carcinoma, irrespectively of stage at the time of surgery, for fear of a false too optimistic classification. In our series of 82 patients with adrenocortical carcinoma, 59 patients have been treated with mitotane, 32 of them immediately after surgery, and 27 with a delay of 2 to 24 months. Today there are 18 survivors in the group of patients treated with mitotane soon after the operation and only 6 survivors in the group receiving mitotane with a delay. All patients were simultaneously given replacement therapy. Undesired effects of mitotane administration included increased aminotransferase and alkaline phosphatase activity, decreased white cell, platelet or red cell number, and myasthenia. Furthermore, we used mitotane with good results in Cushing's syndrome of non-malignant origin as pre-treatment before surgery or in long-term treatment for patients with poor tolerance of other adrenal inhibitors.

Discriminatory power of MRI for differentiation of adrenal non-adenomas vs adenomas evaluated by means of ROC analysis: can biopsy be obviated?

The purpose of our study was to evaluate the discriminatory power of MRI in high-field magnet (1.5 T) for differentiation of adrenal non-adenomas vs adenomas assessing the following parameters separately and in combination: mean diameter of adrenal mass; previously described and new ratios as well as index calculated from signal intensity (SI) on SE T2-weighted images, chemical shift imaging (CSI), and Gd-DTPA-enhanced dynamic studies. One hundred eight adrenal masses (36 non-hyperfunctioning adenomas, 27 pheochromocytomas, 23 aldosterone-secreting adenomas, 20 malignant masses and 2 cortisol-secreting adenomas) in 95 patients were evaluated with SE sequences, CSI and Gd-DTPA dynamic studies. Indices and ratios of SI for all examined MRI methods were calculated and examined retrospectively for significance of differences between the groups with calculation of sensitivity and specificity. Receiver operating characteristics (ROC) analysis of calculated parameters in combination was performed. The multifactorial analysis of all four parameters, including size of the tumor, T2(liver) index, CSI ratio reflecting lipid content in the tumor and Wo(max/last) ratio reflecting maximal washout of contrast agent from the tumor had 100 % sensitivity and 100 % specificity in characterization of adrenal non-adenoma. The best performance of combination of mean tumor diameter with single MRI SI parameter was achieved in combination with T2(liver) index for all adrenal masses (area under ROC 0.987) and CSI ratio for non-hyperfunctioning adrenal masses (area under ROC 0.991). Magnetic resonance imaging enables sensitive and specific diagnosis of adrenal non-adenoma.

Determination of mitotane (o,p-DDD) and its metabolites o,p-DDA and o,p-DDE in plasma by high-performance liquid chromatography.

The adrenolytic agent mitotane (o,p'-DDD or 1,1-(o,p'-dichlorodiphenyl)-2,2-dichoroethane) is believed to be metabolically activated, resulting in the generation of reactive intermediates or the formation of o,p'-DDA. A new high-performance liquid chromatographic (HPLC) method for measurement of mitotane and two of its metabolites, o,p'-DDA (1,1-(o,p'-dichlorodiphenyl) acetic acid) and o,p'-DDE (1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene), in plasma has been developed. Sample preparation involves precipitation of plasma proteins with acetone before chromatographic separation under isocratic conditions on a silica-based diphenyl column. Mitotane and metabolites are quantified by ultraviolet detection at 218 nm. Recoveries for the three compounds range between 99% and 110%, with between-day and within-day coefficients of variation <6% within the therapeutic range. Limits of detection are 0.5 microM and the assay is linear up to at least 800 microM for o,p'-DDA and 100 microM for mitotane and o,p'-DDE. The method has been evaluated using samples from three patients on mitotane therapy, revealing o,p'-DDA levels in plasma 3 to 10 times higher than the levels of the parent compound.

Incidentally found adrenocortical carcinoma. A study of 21 patients.

The frequency of adrenocortical carcinoma was studied in a group of 311 incidentally discovered adrenal tumours. Clinical characteristics were also analysed. Ultrasound scan and computed tomography were the main imaging techniques used. Hormonal examinations were also carried out. The patients with an adrenal tumour diameter greater than or equal to 4.0 cm, and those with excess steroid production were recommended for surgery. Of 131 patients treated with surgery, adrenocortical carcinoma was diagnosed in 21 cases. The diameter of these tumours ranged between 3.2 and 20.0 cm. The majority of these were hormonally inactive, but, in some cases increased corticosteroid secretion was noted. In 17/21 patients, mitotane was administered following surgery, with a good response in 13 cases. These 21 cases were compared with a group of 51 patients with clinically overt adrenocortical carcinoma.

Secondary adrenal insufficiency associated with autoimmune disorders: a report of twenty-five cases.

OBJECTIVE: Addison's disease is frequently a component of autoimmune polyendocrinopathies while secondary adrenal insufficiency associated with autoimmune disorders is believed to be a rare event. We present a series of patients with secondary adrenal insufficiency coexisting with autoimmune diseases and/or antithyroid autoantibodies. DESIGN AND PATIENTS: Among a group of 102 patients with secondary adrenal failure of unknown origin diagnosed at the Department of Endocrinology of the Centre for Postgraduate Medical Education (Warsaw, Poland) we have identified a group with associated autoimmune disorders. Thyroid abnormalities occurred most frequently. Other diseases included insulin-dependent diabetes mellitus, pernicious anaemia, vitiligo, premature ovarian failure and autoimmune thrombocytopaenia. There were 23 women and one man aged 17-72 years at the time of investigation. Additionally, we included a woman with Addison's disease in whom the ACTH deficiency appeared 18 years after the onset of primary adrenal hypofunction. MEASUREMENTS: Pituitary-adrenal function tests comprised urinary excretion of 17-hydroxycorticosteroids in basal conditions and during a 2-day tetracosactrin test, plasma concentrations of ACTH and cortisol, and a 2-day metyrapone test (in eight cases). Thyroid function and immunity tests were: TSH, thyroxine, the antithyroglobulin, antimicrosomal and anti-peroxidase autoantibodies. Other endocrine studies included: serum LH, FSH and PRL. RESULTS: The 17-hydroxycorticosteroid values, both basally and during stimulation tests were consistent with a diagnosis of secondary adrenal insufficiency. Serum cortisol and plasma ACTH concentrations were low. In 14 patients primary hypothyroidism was confirmed by low T4 levels. In three patients subclinical primary hypothyroidism was revealed (elevated TSH levels). Three patients who had a past history of Graves' disease were euthyroid at the time of investigation. Twenty-three patients had antibodies against peroxidase. Most patients had gonadotrophins and PRL values within normal limits. CONCLUSIONS: The co-existence of autoimmune disorders with secondary adrenal insufficiency suggests an autoimmune aetiology for the ACTH deficiency.

MRI versus CT in the diagnosis of Nelson's syndrome.

The purpose of the study was to evaluate the utility of MRI and CT in the diagnosis of Nelson's syndrome, i. e. pituitary tumours in patients bilaterally adrenalectomized for Cushing's disease. Thirteen patients, followed up for 5-29 years after adrenalectomy, were studied. In 6 of them CT and MRI revealed no changes in the pituitary gland. In the remaining 7 patients only three CT scans were suggestive of a pituitary adenoma. MRI studies with administration of gadodiamide confirmed the CT diagnosis of Nelson's tumour in 3 patients and disclosed microadenomas in a further 4 patients. Neurosurgical treatment in 4 patients confirmed the MRI findings. Additionally CT and MRI examinations were performed in 5 patients suspected of a recurrent Nelson's tumour 3-11 years after neurosurgery. MRI visualized recurrent adenomas in 3 patients that were not well seen by CT scans. In our experience MRI was more effective than CT in the diagnosis of Nelson's syndrome.