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Purpose: Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson's syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources: Systematic literature search in four databases. Study Selection: Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction: Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis: Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)]. Conclusions: Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS. [ABSTRACT FROM AUTHOR]

Background: Nelson's syndrome is a rare but challenging sequelae of Cushing's disease (CD) after bilateral adrenalectomy (BLA). We sought to determine if stereotactic radiosurgery (SRS) of residual pituitary adenoma performed before BLA can decrease the risk of Nelson's syndrome. Methods: Consecutive patients with CD who underwent BLA after non-curative resection of ACTH secreting pituitary adenoma and had at least one follow-up visit after BLA were studied. Nelson's syndrome was diagnosed based on the combination of rising ACTH levels, increasing volume of the pituitary adenoma and/or hyperpigmentation. Results: Fifty patients underwent BLA for refractory CD, and 43 patients (7 men and 36 women) had at least one follow-up visit after BAL. Median endocrine, imaging, and clinical follow-up were 66 months, 69 months, and 80 months, respectively. Nine patients (22%) were diagnosed with the Nelson's syndrome at median time after BLA at 24 months (range: 0.6–119.4 months). SRS before BLA was associated with reduced risk of the Nelson's syndrome (HR = 0.126; 95%CI [0.022–0.714], p=0.019), while elevated ACTH level within 6 months after BLA was associated with increased risk for the Nelson's syndrome (HR = 9.053; 95%CI [2.076–39.472], p=0.003). Conclusions: SRS before BLA can reduce the risk for the Nelson's syndrome in refractory CD patients requiring BLA and should be considered before proceeding to BLA. Elevated ACTH concentration within 6 months after BLA is associated with greater risk of the Nelsons' syndrome. When no prior SRS is administered, those with a high ACTH level shortly after BLA may benefit from early SRS. [ABSTRACT FROM AUTHOR]

Purpose: Corticotroph tumor progression (CTP) or Nelson's syndrome (NS) can occur in patients with Cushing's disease (CD) following bilateral adrenalectomy. It has rarely been observed in patients treated with long-term medical therapy for persistent CD. Osilodrostat (LCI699) is a new steroidogenesis inhibitor of 11β-hydroxylase (CYP11β1) that induced remission of hypercortisolism in 86% of patients with refractory CD in the randomized placebo-controlled trial LINC-3 (NCT02180217). Methods: A 40-year-old woman with persistent CD following transsphenoidal surgery was treated with osilodrostat in the LINC-3 trial and was followed with regular hormonal assessments and imaging of residual corticotroph tumor. Results: Under oral therapy with osilodrostat 10 mg twice daily, urinary free cortisol (UFC) normalized and clinical signs of CD regressed during therapy. However after 4 years of treatment, ACTH levels increased from 73 to 500 pmol/L and corticotroph tumor size increased rapidly from 3 to 14 mm, while UFCs remained well controlled. Surgical resection of an atypical tumor with weak ACTH expression and increased proliferative index (Ki-67 ≥ 8%) resulted in current remission but will require close follow-up. Conclusion: This case highlights the importance of monitoring ACTH and corticotroph tumor size in patients with persistent CD, either under effective treatment with steroidogenesis inhibitors or after bilateral adrenalectomy. [ABSTRACT FROM AUTHOR]

Purpose: Nelson's syndrome (NS) is regarded as an aggressive complication of total bilateral adrenalectomy (TBA) for Cushing's disease (CD). This challenge may be addressed by using clinical criteria to guide frequency of neuroimaging to enable timely management of NS and also avoid unnecessary frequent imaging. Methods: All patients (n = 43) with CD subjected to TBA over 35 years at a tertiary care centre were included. NS was defined as a newly appearing or expanding (> 2 mm) pituitary adenoma with or without ACTH levels exceeding 500 pg/ml. Pre-and post-TBA parameters like clinical symptomatology, cortisol, ACTH and radiology were analysed for the prediction of NS. Results: NS developed in 39.5% (n = 17) patients with a median follow-up of 7 years. Half of them had new appearance, while rest had an expansion of pre-existing pituitary tumour. Majority (90%) had ACTH above 500 pg/ml. On Cox proportional hazards analysis, frequent discriminatory features of protein catabolism (≥ 4) (HR 1.15, CI 0.18, 7.06), proximal myopathy (HR 8.82, CI 1.12, 69.58) and annual ACTH increment of 113 pg/ml (HR 12.56, CI 1.88, 88.76) predicted NS. First post-operative year ACTH indices predicting NS included ACTH rise of 116 pg/ml and absolute ACTH of 142 pg/ml (sensitivity, specificity exceeding 90%). Annual ACTH increment exceeding 113 pg/ml, ≥ 4 discriminatory features and uncontrolled hypertension had the best overall prediction. Conclusion: Patients who developed NS had higher rebound rise of ACTH following TBA and a more severe disease phenotype at baseline. Consistent ACTH increment can be used as a marker for predicting the development of NS. [ABSTRACT FROM AUTHOR]

Purpose: This paper presents our 18 years of experience in treating ACTH secreting adenomas (Cushing's disease and Nelson's syndrome) using the Leksell gamma knife (LGK) irradiation. Methods: Twenty-six patients with Cushing's disease were followed-up after LGK irradiation for 48-216 months (median 78 months). Seventeen patients had undergone previous surgery, in nine patients LGK irradiation was the primary therapy. Furthermore, 14 patients with Nelson's syndrome were followed-up for 30-204 months (median 144 months). Results: LGK treatment resulted in hormonal normalization in 80.7 % of patients with Cushing's disease. Time to normalization was 6-54 months (median 30 months). The volume of the adenoma decreased in 92.3 % (in 30.7 % disappeared completely). There was no recurrence of the disease. In all 14 patients with Nelson's syndrome ACTH levels decreased (in two patients fully normalized) their ACTH levels. When checked up 5-10 years after irradiation regrowth of the adenoma was only detected in one patient (9.1 %), in 27.3 % adenoma volume remained unchanged, in 45.4 % adenoma volume decreased and in 18.2 % adenoma completely disappeared. Hypopituitarism did not develop in any patient where the critical dose to the pituitary and distal infundibulum was respected. Conclusion: LGK radiation represents an effective and well-tolerated option for the treatment of patients with Cushing's disease after unsuccessful surgery and may be valuable even as a primary treatment in patients who are not suitable for, or refuse, surgery. In the case of Nelson's syndrome it is possible to impede tumorous growth and control the size of the adenoma in almost all patients. [ABSTRACT FROM AUTHOR]

Introduction: Radiation therapy is an important therapy for patients with Cushing's disease who are not in remission or relapse after transsphenoidal pituitary surgery and are not considered surgical candidates. The development of stereotactic radiation therapy, using gamma knife, linear accelerators or proton beam based methods, has enabled selective radiation delivery to the target while minimizing exposure of healthy tissues. In patients whose tumors are sufficiently distant from the optic apparatus, stereotactic radiation therapy can be delivered in a single session, a procedure termed radiosurgery, which significantly improves patient convenience. Methods: Original articles on radiation therapy in Cushing's disease, published during the past 12 months (2013-2014), were identified and pertinent data extracted. Results: Recent studies have reported on the outcomes of patients with Cushing's disease who received mostly stereotactic radiation therapy. While tumor control has been excellent, biochemical remission was less consistently achieved. Some studies suggested that stereotactic radiation may lead to biochemical remission faster than conventional radiation therapy. In addition, retrospective data have suggested that withdrawing medical therapy around the time stereotactic radiation therapy is administered might lead to a faster biochemical response. Regardless of the radiation therapy method, biochemical recurrences may develop and these patients are at long-term risk of developing anterior hypopituitarism and require lifelong periodic endocrine follow-up. Other, less frequent complications may include cranial neuropathies, secondary tumor formation or temporal lobe necrosis. It is plausible that complications may be less frequent after stereotactic radiation therapy, but this requires confirmation. Conclusions: Radiation therapy is an effective second line therapy in patients with Cushing's disease. Ongoing refinements in delivery of radiation therapy are anticipated to lead to improved patient outcomes, but long-term follow-up data, including adequate control groups, are needed to fully investigate this possibility. [ABSTRACT FROM AUTHOR]

Purpose: Review the indications, outcomes, and consequences of bilateral adrenalectomy (BLA) in patients with Cushing's disease. Methods: A literature review was performed. Results: The primary therapy for Cushing's disease is surgery, with medical therapy and radiation therapy relegated to an adjuvant role. BLA is indicated in cases of persistent disease following pituitary surgery or in situations where rapid normalization of hypercortisolism is required. When performed via the laparoscopic approach, BLA is associated with a significantly reduced morbidity compared to the traditional, open approach. Following BLA, patients are at risk for adrenal crisis and the concern of Nelson's syndrome. However, BLA leads to a rapid resolution of the signs and symptoms of CS and leads to an improved long-term quality of life. Conclusion: BLA should be considered in the treatment algorithm for patients with persistent CD after failed pituitary surgery, especially in patients who have severe consequences of hypercortisolism or desire pregnancy. [ABSTRACT FROM AUTHOR]

Purpose: We report the first case of an Ectopic adrenocorticotrophin (ACTH)-secreting pituitary adenoma (EAPA) located within the posterior nasal septum associated with Nelson's syndrome, which eluded diagnosis for over a decade. In this report, we explore the reasons for such diagnostic difficulty and suggest ways in which an earlier diagnosis may be made. Methods and results: A 19 years old Lebanese man presented in 2000, with overt Cushing's syndrome confirmed with markedly elevated urine free cortisols and failed dexamethasone suppression tests. An unsuppressed ACTH and a possible 5 mm adenoma on MRI (Magnetic Resonance Imaging) pituitary suggested Cushing's disease. The patient underwent trans-sphenoidal surgery (TSS), but histology revealed normal pituitary tissue and Cushing's syndrome persisted. A repeat MRI pituitary showed no anomaly, and extensive investigations failed to locate an ectopic lesion. Subsequently a bilateral adrenalectomy was performed. Over the ensuing years, the patient developed Nelson's syndrome with hyperpigmentation and markedly elevated ACTH levels. Repeated high dose dexamethasone suppression tests, corticotrophin releasing hormone (CRH) tests, and CRH stimulated inferior petrosal sinus samplings (IPSS) suggested a pituitary origin of the ACTH. Two further TSS were unsuccessful. The pituitary was irradiated. Subsequent review of his previous MRIs revealed an enlarging mass within the posterior nasal septum, which was excised in 2011. The histology confirmed the diagnosis of an EAPA within the nasal septum. Conclusion: Ectopic ACTH-secreting pituitary adenomas can occur not only along the developmental route of Rathke's pouch, but other aberrant locations giving a clinical and biochemical picture identical to Cushing's disease or Nelson's syndrome. Clinicians should suspect an EAPA, when a central ACTH source seems to be apparent with no obvious pituitary adenoma. A detailed MRI involving possible EAPA sites aids in locating these unusual lesions. [ABSTRACT FROM AUTHOR]

Recently, correlations between corticotroph tumor dedifferentiation and both E-cadherin immunostaining and reduced mRNA expression of the E-cadherin gene ( CDH1) have been demonstrated. The purpose of this study was to explore whether tumor dedifferentiation correlated with glucocorticoid resistance and whether the resistance was associated with both positively and negatively regulated genes. Tumor material from 20 patients with verified Cushing's disease or Nelson's syndrome operated on at Rikshospitalet, Oslo. Reverse transcription polymerase chain reaction analysis of genes such as E-cadherin ( CDH1), proopiomelanocortin ( POMC), glucocorticoid-induced leucine zipper ( GILZ), and thioredoxin-interacting protein ( TXNIP) was performed. The correlations between the expression of the GILZ, TXNIP, and POMC genes in different stages of corticotroph adenomas, the E-cadherin mRNA expression and staining pattern, and the preoperative 24-h cortisol excretion were examined. The GILZ and TXNIP expression levels were positively correlated to the CDH1 expression and were highest in microadenomas and in tumors with a high membranous E-cadherin reactivity. In contrast, the POMC expression was not significantly different between the groups. This divergence between the genes that were positively and negatively regulated by glucocorticoids could not be supported by other gene expression analyses. No correlations to urinary cortisol were found. The expression of the glucocorticoid-responsive genes POMC, GILZ, and TXNIP in corticotroph adenomas showed a remarkable variation. The pattern and variability of glucocorticoid resistance in corticotroph adenomas seem to correlate with a loss of the epithelial phenotype associated with corticotroph tumor dedifferentiation. [ABSTRACT FROM AUTHOR]

Nelson's syndrome (NS) is characterized by the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for the treatment of Cushing's disease. Such corticotroph macroadenomas respond poorly to currently available therapeutic options which include surgery, radiotherapy and chemotherapy. P53 protein accumulation may be detected by immunohistochemistry in pituitary corticotroph adenomas and it has been suggested that it might be causally related to tumor development. Wild type P53 protein plays an important role in the cellular response to ionizing radiation and other DNA damaging agents and is mutated in many human tumors. In this study we report an adult male patient with NS who underwent both transsphenoidal and transcranial pituitary surgeries, conventional and stereotaxic radiotherapy and brachytherapy. Despite of the efforts to control tumor mass and growth, this macroadenoma displayed relentless growth and aggressive behavior. DNA extracted from the first two surgical samples, as well as DNA from peripheral blood leukocytes disclosed normal p53 sequence. DNA extracted from tumor samples obtained at surgeries performed after pituitary irradiation carried a somatic heterozygous mutation, consisting of a deletion of four cytosines between nucleotides 12,144-12,149 in exon 4 of the p53 gene. This frameshift mutation creates a stop codon in exon 4 excluding the expression of a functional protein from the defective allele. These data demonstrate a possible association between the P53 protein loss of function induced by radiotherapy and the aggressive course of the disease in this patient. [ABSTRACT FROM AUTHOR]

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We report the results of long-term (6-year) treatment of Nelson’s syndrome with the long-acting dopamine agonist, cabergoline, in a 55-year-old woman. The disease presented 26 years after bilateral adrenalectomy and radiation treatment for Cushing’s disease, followed by glucocorticoid and mineralocorticoid replacement therapy. Signs of Nelson’s syndrome included skin and mucosal hyperpigmentation accompanied by elevated plasma levels of adrenocorticotropic hormone (ACTH) (984 pmol/l; normal, 2.0–11.5 pmol/l). Magnetic resonance imaging of the pituitary demonstrated sellar enlargement with a 15 mm macroadenoma. The patient was initially treated with bromocriptine (10 mg/d) which had no effect on either ACTH level or tumor mass. Because of visual loss, transsphenoidal surgery was performed, with partial excision of the adenoma and chiasmal decompression, followed by radiosurgery. However, ACTH levels improved only temporarily, and then increased to previous levels. Therefore, cabergoline treatment (1.5 mg/week) was initiated. ACTH levels decreased dramatically from 1050 to 132 pmol/l, accompanied by clinical improvement. Repeated imaging studies demonstrated a stable residual pituitary tumor. This case demonstrates that long-term cabergoline treatment may be efficient in patients with Nelson’s syndrome. [ABSTRACT FROM AUTHOR]

A thirty-eight year-old lady with a history of bilateral adrenalectomy for Cushing's disease seven years previously, presented with sudden onset of severe headache, nausea, vomiting and loss of consciousness. She was somnolent and confused. She had neck stiffness, sixth nerve palsy and mydriasis on the left side. Computerized tomography (CT) and magnetic resonance imaging (MRI) studies revealed a non-homogeneous, grade IV D pituitary mass lesion associated with hemorrhage in the chiasmatic, interhemispheric, cerebellopontine, perimesencephalic cisterns and a hematoma within the frontal lobe. Angiography showed only bilateral elevation of horizontal segments of the anterior cerebral arteries. According to this angiographic evidence, it was presumed that the subarachnoid hemorrhage and the intracerebral hematoma were linked to pituitary adenoma apoplexy. ACTH level was 450 pg/ml. The hemorrhagic lesion with suprasellar extension was totally removed by left pterional craniotomy. Histological examination revealed a necrotic, ACTH-secreting pituitary adenoma. Even though apoplexy is a well known complication of pituitary adenomas, to our knowledge subarachnoid hemorrhage and intracerebral hematoma as a result of pituitary apoplexy in the context of Nelson's syndrome has not previously been reported. [ABSTRACT FROM AUTHOR]

We investigated the molecular size of circulating immunoreactive ACTH by gel chromatography in patients with ACTH hypersecretion due to various disorders of the hypothalamic-pituitary-adrenal axis. 4 patients with Addison's disease, 2 with Nelson's syndrome, 4 with Cushing's disease, 6 with the ectopic ACTH syndrome (2 bronchial carcinoma, 1 medullary carcinoma, 1 metastatic islett cell carcinoma, 1 benign bronchial carcinoid and 1 patient with occult ectopic Cushing's syndrome) and 1 patient with hypersecretion of ACTH from a clinically nonfunctioning pituitary adenoma were studied. Analysis of the molecular size of immunoreactive ACTH was performed by gel chromatography on a Sephadex G-75 column (superfine, 100×1.5 cm) equilibrated with 1% formic acid. 2 ml fractions were collected and evaporated to dryness. The ACTH content of the recovered samples was determined by RIA. In Addison's disease, Nelson's syndrome and Cushing's disease the plasma showed a single peak of ACTH immunoreactivity at the expected position of 1-39 ACTH. In the ectopic ACTH syndrome the plasma of 4 patients revealed at chromatography at least one other peak eluting between the void volume and 1-39 ACTH suggestive of a high molecular weight form of ACTH whereas plasma of 2 patients showed only a single ACTH peak at the position of labeled 1-39 ACTH. The patient with a clinically non-functioning pituitary adenoma revealed a gel filtration pattern similar to the patients with ectopic ACTH syndrom and secretion of high molecular weight ACTH. We conclude that secretion of high molecular weight forms of ACTH is not a unique feature of the ectopic ACTH syndrome. It may therefore not serve as a marker of the ectopic Cushing's syndrome in the differential diagnosis of the ACTH dependent Cushing's syndrome. Vice versa, lack of high molecular weight ACTH does not exclude an ectopic source of ACTH secretion as cause of Cushing's syndrome. [ABSTRACT FROM AUTHOR]

We investigated the effect of sodium valproate on plasma ACTH and serum cortisol concentrations in different pathological states of ACTH hypersecretion. Five patients with pituitary dependent Cushing's syndrome, two patients with Nelson's syndrome and five patients with Addison's disease were studied. Neither a single dose nor long term administration of sodium valproate resulted in a significant decrease of plasma ACTH levels in patients with Cushing's disease and Nelson's syndrome. Furthermore, the response of ACTH and cortisol to stimulation with lysine-vasopressin was unaffected during acute and chronic treatment. Patients with Addison's disease showed a slight attenuation of the ACTH response to lysine-vasopressin as compared to placebo but the difference was not statistically significant. In conclusion: sodium valproate does not appear to be effective in controlling ACTH hypersecretion in pituitary dependent Cushing's syndrome. [ABSTRACT FROM AUTHOR]

Nelson's syndrome is rare and difficult to cure. The tumours in this condition may behave invasively and require multiple interventions. Two patients who had been followed up for nearly 20 years developed signs of cavernous sinus involvement, one with an empty sella. Long term follow-up for such patients is emphasized. [ABSTRACT FROM AUTHOR]

In 17 primary transnasal operations on Nelson tumours long-term results are assessed measuring ACTH plasma levels and performing regular neuroradiological controls. In small intrasellar adenomas only one recurrent ACTH elevation near to pretreatment levels without symptoms from tumour growth was observed after 10 years. ACTH normalization was rarely achieved in large tumours, but only in one patient was a relapse visible in CT scan after three years. Thus selective tumour removal seems to be advisable at an early stage when sellar enlargement occurs. Interpretation of ACTH plasma levels has to include completeness of adrenalectomy, cystic tumour necrosis, and corticoid replacement which reduces ACTH levels. Elevation of ACTH plasma levels over 5,000 pg/ml has been regularly accompanied by extrasellar tumour extension. In large adenomas with definitely elevated ACTH levels, additional radiation therapy should be considered. [ABSTRACT FROM AUTHOR]

Cell suspensions of ACTH cell adenomas of 10 patients with Nelson's syndrome were investigated for in-vitro secretion of ACTH. Two incubation systems, one using incubation beakers and the other a superfusion system, were employed. The cells were tested for their reactivity to lysine-vasopressin (LVP), cortisol, and combinations of both. LVP regularly provoked a rapid significant increase of ACTH secretion. The effect of cortisol was heterogeneous. Paradoxical initial stimulatory effects of cortisol were observed. There was a suppressive effect in some patients, which correlates to low proliferative activity in histological evaluation. In both systems a low secretory activity coincided with high proliferative activity in vivo. [ABSTRACT FROM AUTHOR]

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Adrenocorticotrophic hormone (ACTH)-secreting adenomas of patients with Cushing's disease (undifferentiated and well-differentiated ACTH-cell adenomas) were studied ultrastructurally and analysed morphometrically by a computer-supported quantitative image-analysing system. They were compared with identically prepared ACTH tumours (undifferentiated and well-differentiated ACTH-cell adenomas) of pituitaries from bilateral adrenalectomised patients with Nelson's syndrome. The aim of our study was to look for significant differences in ultrastructure and to evaluate these findings statistically regarding adenoma types and clinical syndromes. Clinical syndromes aside, more secretory granules and larger-sized prosecretory granules were measured in the well-differentiated ACTH-cell adenomas. The undifferentiated adenomas showed a greater content of nucleoli and prosecretory granules. Within the adenoma types, comparison of well-differentiated ACTH-cell adenomas showed that the clinical group of Cushing's disease contained larger areas of cytofilaments, whereas the clinical group of Nelson's syndrome had a larger tumour size and more lysosomes. Comparing the undifferentiated adenomas of both clinical groups the adenomas in Cushing's disease contained larger nuclei and more lysosomes, whereas the adenomas in Nelson's syndrome were larger in tumour size and contained larger prosecretory granules. Comparison of well-differentiated and undifferentiated adenomas in Cushing's disease showed more secretory granules and bigger prosecretory granules in well-differentiated adenomas whereas in undifferentiated adenomas the total area of the nuclei is larger, the nucleoli increase in number and size and the lysosomes are more frequent. Comparison of well-differentiated and undifferentiated adenomas in Nelson's syndrome demonstrated more lysosomes in well-differentiated adenomas and a larger total area of the nuclei in undifferentiated adenomas. The differences between the well-differentiated adenomas (mainly more secretory granules and larger prosecretory granules) and undifferentiated adenomas (mainly more and larger nuclei and nucleoli and more prosecretory granules) prove the clear separability between the adenoma types, not demonstrated in the literature up to now. The significant differences between adenomas in Cushing's disease (mainly more cytofilaments) and Nelson's syndrome (mainly more ribosomes and larger prosecretory granules) may be interpreted as different cell reactions due to the hypercortisolism present in Cushing's disease and lacking in Nelson's syndrome following adrenalectomy. Despite the fact that both clinical syndromes are based on the same adenoma types, indistinguishable by light microscopy, significant morphometrical findings in ultrastructure allow a clear discrimination of both clinical types. [ABSTRACT FROM AUTHOR]

ACTH-producing pituitary adenomas obtained from two patients with Cushing's disease were maintained in organ culture for 2 weeks. After 4-6 days of incubation, hydrocortisone (0.1, 1, and 5 mg/ ml) was added to the culture medium. Addition of cortisol to the media in concentrations which generally inhibit the ACTH secretion in vivo in patients with Cushing's disease (1 mg/ml) failed to affect the ACTH secretion in vitro. A decrease of ACTH secretion occurred only with 5 mg/ml after 5 days of incubation. A similar effect on growth hormone (GH) release was seen when cortisol (10 mg/ml) was added to cultures from GH-producing pituitary adenoma. No ultrastructural changes were found in cultured cells that could be attributed to the addition of 0.1 mg/ml cortisol in the culture medium. With higher concentrations, (1 mg/ml and 5 mg/ml) minor ultrastructural changes were suspected. Our present findings implicate the hypothalamus as the target area for the feedback control of ACTH in Cushing's disease but could not reveal whether or not the primary lesion (i.e. the tumor) was of pituitary or hypothalamic origin. Our organ culture system appears to be a suitable model for investigating possible ACTH-regulating factors. [ABSTRACT FROM AUTHOR]

Nelson's syndrome is a specific form of Cushing's disease treated by bilateral adrenalectomy, presenting with a deep hyperpigmentation caused by a pituitary adenoma (corticotropinoma). These ACTH-secreting tumors are frequently aggressive, so early diagnosis is of prime importance. We have studied 33 patients with Nelson's syndrome, 28 women and 5 men, aged 14-56 yr at the time of adrenalectomy and 16-58 yr at the time of Nelson's syndrome diagnosis (observed for 5-32 yr). Methods of examination included simultaneous adrenocorticotropic hormone (ACTH) and cortisol measurements during routine hydrocortisone replacement therapy, computed tomography (CT), pituitary magnetic resonance imaging (MRI), and visual field examination. The results obtained in a group of six patients diagnosed in the last 3 yr were compared with those obtained in a group of 27 patients examined before 1992. High plasma ACTH levels accompanied by normal serum cortisol concentration were characteristic for a late stage of the disease. Absolute temporal scotomas were an early finding. MRI, especially with the gadolinium enhancement, was superior to CT in demonstrating pituitary microadenomas in Nelson's syndrome. Thus, MRI diagnosis allowed for an early neurosurgical treatment of the patients with Nelson's tumors. [ABSTRACT FROM AUTHOR]

Clinical features and the operative results in the author's personal series of ten cases with Nelson's syndrome are presented. There were nine females and one male patient with ages ranging from 20 to 44 years (mean 36 y). All patients presented with typical hyperpigmentation of the skin and had abnormally raised plasma ACTH levels. X-ray polytomography detected sellar abnormalities in 80% of the cases. Computerized tomography was positive for pituitary tumour in three patients. Trans-sphenoidal microsurgical removal of Nelson's ACTH adenomas were successful in seven of ten patients. The operative technique of radical-selective resection to achieve endocrinological cure is described. Pertinent literature is reviewed and the incidence of Nelson's syndrome, an issue of controversies regarding the pathogenesis, and the management of Nelson's adenomas are discussed. [ABSTRACT FROM AUTHOR]

We report the MRI appearances of an infarcted cavernous sinus tumor in a patient with Nelson's syndrome. Invasive tumors of the pituitary extending to the cavernous sinus are discussed and the role of MRI in preoperative investigation is highlighted. [ABSTRACT FROM AUTHOR]