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Somatic mutations in the PRKACA gene encoding the catalytic α subunit of protein kinase A (PKA-C) are responsible for cortisol-producing adrenocortical adenomas. These benign neoplasms contribute to the development of Cushing's syndrome. The majority of these mutations occur at the interface between the two lobes of PKA-C and interfere with the enzyme's ability to recognize substrates and regulatory (R) subunits, leading to aberrant phosphorylation patterns and activation. Rarely, patients with similar phenotypes carry an allosteric mutation, E31V, located at the C-terminal end of the αA-helix and adjacent to the αC-helix, but structurally distinct from the PKA-C/R subunit interface mutations. Using a combination of solution NMR, thermodynamics, kinetic assays, and molecular dynamics simulations, we show that the E31V allosteric mutation disrupts central communication nodes between the N- and C- lobes of the enzyme as well as nucleotide-substrate binding cooperativity, a hallmark for kinases' substrate fidelity and regulation. For both orthosteric (L205R and W196R) and allosteric (E31V) Cushing's syndrome mutants, the loss of binding cooperativity is proportional to the density of the intramolecular allosteric network. This structure-activity relationship suggests a possible common mechanism for Cushing's syndrome driving mutations in which decreased nucleotide/substrate binding cooperativity is linked to loss in substrate fidelity and dysfunctional regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of interests We declare no competing interests.

Primary bilateral adrenocortical hyperplasias are rare forms of pituitary ACTH-independent Cushing's syndrome (CS). They are divided between primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia (MiBAH), which is subdivided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). One of the most debated aspects surrounding these entities is their most appropriate therapy. Although bilateral adrenalectomy (BA) has previously been the most utilized therapy for patients with overt CS, recent studies have indicated that unilateral adrenalectomy (UA) can be effective in patients with PBMAH and some with MiBAH with fewer long-term side effects. Medical therapies can also be used for bridging to surgery or rarely in the long-term for these patients. We review the various degrees of CS resulting from PBMAH and MiBAH, with a special focus on their respective therapies including UA, taking into account the recent pathophysiological and genetics findings., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In this review, we provide a comprehensive overview of the utility of steroid profiling for diagnosis of management of overt Cushing syndrome and mild autonomous cortisol secretion. A diagnosis of Cushing syndrome is made through a multistep process that includes confirmation of endogenous hypercortisolism, followed by determination of its cause. Steroid metabolomic testing applied to serum or urine steroids and their metabolites can provide additional and novel insights into alterations of steroid biosynthesis and metabolism and its causes. In particular, increased availability and advances in mass spectrometry-based steroid analysis, coupled with machine learning-based algorithms, have facilitated the development of tailored diagnostic and subtyping approaches for autonomous cortisol secretion and might be useful for detecting low grade autonomous glucocorticoid secretion and in predicting and monitoring of disease severity and associated comorbidities., Competing Interests: Declaration of competing interest IB reports consulting with Corcept, Strongbridge, HRA Pharma, and Sparrow Pharmaceutics outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pituitary surgery is the first-line treatment for patients with Cushing's disease. For patients who are not considered candidates for pituitary surgery, pituitary radiation and bilateral adrenalectomy are further treatment alternatives. Not all patients are cured with pituitary surgery, and a substantial number of patients develop recurrence, sometimes many years after an apparently successful treatment. The same applies to patients treated with radiotherapy. Far from all patients are cured, and in many cases the disease recurs. Bilateral adrenalectomy, although always curative, causes chronic adrenal insufficiency and the remaining pituitary tumour can continue to grow and cause symptoms due to pressure on adjacent tissues, a phenomenon called Nelson's syndrome. In this paper the rate of recurrence of hypercortisolism, as well as the rate of development of Nelson's syndrome, following treatment of patients with Cushing's syndrome, will be reviewed. The aim of the paper is also to summarize clinical and biochemical factors that are associated with recurrence of hypercortisolism and how the patients should be monitored following treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Adrenocortical tumors range from primary bilateral micronodular or macronodular forms of adrenocortical disease to conventional adrenocortical adenomas and carcinomas. Accurate classification of these neoplasms is critical given the varied pathogenesis, clinical behavior, and outcome of these different lesions. Confirmation of adrenocortical origin, diagnosing malignancy, providing relevant prognostic information in adrenocortical carcinoma, and correlation of laboratory results with clinicopathologic findings are among the important responsibilities of pathologists who evaluate these lesions. This article focuses on a practical approach to the evaluation of adrenocortical tumors with an emphasis on clinical and imaging findings, morphologic characteristics, and multifactorial diagnostic schemes and algorithms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing's disease (CD). However, the reversibility of brain damage after the resolution of hypercortisolism remains unclear. Thus, we studied the potential volumetric reversibility in biochemically remitted CD patients. Cross-sectional analysis demonstrated the active CD patients (n = 61) had the smallest gray matter (GM) volumes (553.33 ± 45.90 CM 3 ) among four groups. While the GM volumes of short-term remitted CD patients (586.62 ± 46.89 CM 3 , n = 28) and long-term remitted CD patients (596.58 ± 45.95 CM 3 , n = 35) were between those of the active CD patients and healthy control subjects (628.14 ± 46.88 CM 3 , n = 74). Moreover, significant positive correlations between remitted time and GM volumes were only found in short-term remitted CD patients. On the contrary, the alterations of white matter (WM) in CD patients seem to be independent of concomitant hypercortisolism, persisting after remission. A preliminary longitude analysis also demonstrated similar results. Volumetric reversibility of GM, but not WM is highly prevalent in short-term after resolution of hypercortisolism in Cushing disease. Our study enhances our understanding of the reversible and the irreversible structural alterations in the human brain due to hypercortisolism., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Late-life Generalized Anxiety Disorder (GAD) is relatively understudied and the underlying structural and functional neuroanatomy has received little attention. In this study, we compare the brain structural characteristics in white and gray matter in 31 non-anxious older adults and 28 late-life GAD participants. Gray matter indices (cortical thickness and volume) were measured using FreeSurfer parcellation and segmentation, and mean diffusivity was obtained through Diffusion Tensor Imaging (DTI). We assessed both macroscopic white matter changes [using white matter hyperintensity (WMH) burden] and microscopic white matter integrity [using fractional anisotropy (FA)]. No differences in macro- or microscopic white matter integrity were found between GAD and non-anxious controls (HC). GAD participants had lower cortical thickness in the orbitofrontal cortex (OFC), inferior frontal gyrus, and pregenual anterior cingulate cortex (ACC). Higher worry severity was associated with gray matter changes in OFC, ACC and the putamen. The results did not survive the multiple comparison correction, but the effect sizes indicate a moderate effect. The study suggests that late-life GAD is associated with gray matter changes in areas involved in emotion regulation, more so than with white matter changes. We conclude that anxiety-related chronic hypercortisolemia may have a dissociative effect on gray and white matter integrity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Adrenocorticotropic hormone production by pancreatic neuroendocrine tumor (PNET) is rare and results in hyperstimulation of the adrenal gland to produce ectopic Cushing syndrome. Our case showcases the safety and effectiveness of percutaneous CT-guided microwave ablation of the adrenal gland in a 49-year-old female with PNET and hepatic metastases who presented with ectopic Cushing syndrome despite surgical resection of the primary pancreatic tumor and left adrenal gland. Prior to ablation, the right adrenal gland measured 4.3×1.6×2.0cm and the patient had malignant hypertension with elevated morning serum cortisol level (1976nmol/L). After microwave ablation of the right adrenal gland, the hypertension resolved and the cortisol level decreased dramatically (74nmol/L). As expected after successful treatment, the patient developed adrenal insufficiency and was placed on glucocorticoid and mineralocorticoid supplementation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Little information is available about the risk of progression of seemingly benign adrenocortical hyperplasias to carcinomatous conditions. Using in silico approaches of digitally archived tissue sections, the nuclear morphometric parameters were compared to assess nuclear asymmetry as an index for nuclear atypia., Methods: Four groups of nuclei were used for the current study: spongiocytes and compact cells obtained from adrenocorticotropic hormone (ACTH)-independent macronodular hyperplasia, which were hypothesized to be high risk for nuclear asymmetry, and primary pigmented nodular adrenocortical disease and micronodular adrenocortical hyperplasia samples were used as internal controls., Results: Analyses reveal high nuclear irregularity index of spongiocytes and shape factor abnormalities of both spongiocytes and compact cells of ACTH-independent macronodular adrenal hyperplasia compared with the other 2 groups (high F values and very low P values after analyses of variances), thus confirming the hypothesis that ACTH-independent macronodular adrenal hyperplasia present with subtle morphometric features of nuclear atypia., Conclusions: This probably puts this class of adrenocortical tumors at risk of dysplastic progression, and more studies are needed to test the hypothesis.

Introduction: Paraneoplastic Cushing's syndrome (CushingPS) in small-cell lung cancer is rare but severe., Methods: We studied 383 patients with small-cell lung cancer diagnosed between 1998 and 2012. Among them, 23 patients had CushingPS, 56 had other paraneoplastic syndrome (OtherPS), and 304 had no paraneoplastic syndrome (NoPS)., Results: After comparison of the three groups, we observed that CushingPS patients had more extensive disease: 82.6% versus 67.8% versus 53.3% (p = 0.005), respectively, with more than two metastatic sites: 63.2% versus 15.8% and 24.1% (p ≤ 0.001), a higher World Health Organization performance status (2-4): 73.9% versus 57.1% versus 43.7% (p = 0.006), greater weight loss (≥10%): 47.8% versus 33.9% versus 16.4% (p ≤ 0.001), reduced objective response to first-line treatment: 47.6% versus 74.1% versus 71.1% (p = 0.04), and poorer sensitivity to first-line treatment: 19% versus 38.9% versus 48.6% (p = 0.01). NoPS patients, with World Health Organization performance status of 3-4, had extensive disease at diagnosis, with response, sensitivity to first-line treatment, and survival similar to the CushingPS group. At relapse, the CushingPS group had no objective response to second-line treatment versus 25% versus 42.8% in OtherPS and NoPS groups, respectively (p = 0.005). The median survival of CushingPS patients was 6.6 months versus 9.2 months for OtherPS and 13.1 months for NoPS patients (p ≤ 0.001). CushingPS is a prognostic factor of death (hazard ratio, 2.31; p ≤ 0.001)., Conclusion: CushingPS is the worst form of the paraneoplastic syndromes with particularly extensive tumors. Reduced objective response and sensitivity to first-line treatment and no response to second-line treatment suggest starting palliative care early at first line and exclusively at relapse.

Background: Hypercortisolism leads to various physical, psychological and cognitive symptoms, which may partly persist after the treatment of Cushing's disease. The aim of the present study was to investigate abnormalities in white matter integrity in patients with long-term remission of Cushing's disease, and their relation with psychological symptoms, cognitive impairment and clinical characteristics., Methods: In patients with long-term remission of Cushing's disease (n = 22) and matched healthy controls (n = 22) we examined fractional anisotropy (FA) values of white matter in a region-of-interest (ROI; bilateral cingulate cingulum, bilateral hippocampal cingulum, bilateral uncinate fasciculus and corpus callosum) and the whole brain, using 3 T diffusion tensor imaging (DTI) and a tract-based spatial statistics (TBSS) approach. Psychological and cognitive functioning were assessed with validated questionnaires and clinical severity was assessed using the Cushing's syndrome Severity Index., Results: The ROI analysis showed FA reductions in all of the hypothesized regions, with the exception of the bilateral hippocampal cingulum, in patients when compared to controls. The exploratory whole brain analysis showed multiple regions with lower FA values throughout the brain. Patients reported more apathy (p = .003) and more depressive symptoms (p < .001), whereas depression symptom severity in the patient group was negatively associated with FA in the left uncinate fasciculus (p < 0.05). Post-hoc analyses showed increased radial and mean diffusivity in the patient group., Conclusion: Patients with a history of endogenous hypercortisolism in present remission show widespread changes of white matter integrity in the brain, with abnormalities in the integrity of the uncinate fasciculus being related to the severity of depressive symptoms, suggesting persistent structural effects of hypercortisolism.

Pheochromocytoma (PCC) is a challenging and life-threatening neoplasm. Herein, the authors report an interesting and unexpected solution for a clinical case concerning a patient with a PCC, who developed delayed ectopic adrenocorticotropic hormone Cushing syndrome originating from the PCC. In addition, after a misleading I-labeled metaiodobenzylguanidine single-photon emission computed tomography/computed tomography, an F-fluorodeoxyglucose positron emission tomography/computed tomography, executed to confirm the diagnosis of PCC, showed a silent pulmonary nodule that unexpectedly turned out to be a lung nocardiasis.

Commonly used dermatologic eponyms and characteristic skin signs are enormously helpful in guiding a diagnosis, even though they may not be pathonemonic. They include, on the nails, Aldrich-Mees' lines (syn.: Mees' lines), Beau's lines, Muehrcke's lines, Terry's nails, and half and half nails, often associated, respectively, with arsenic poisoning, acute stress or systemic illness, severe hypertension, liver disease and uremia, and, around the nails, Braverman's sign, associated with collagen-vascular disease. Elsewhere, one may see the Asboe-Hansen and Nikolsky's signs, indicative of the pemphigus group of diseases, Auspitz's sign, a classic finding in psoriasis, Borsieri's and Pasita's signs, seen in early scarlet fever, the butterfly rash, indicative of systemic lupus erythematosus, and the buffalo hump, seen in Cushing's disease and also in the more common corticosteroid toxicity. Gottron's papules and the heliotrope rash are signs of dermatomyositis. Janeway's lesions and Osler's nodes are seen in bacterial endocarditis. A Dennie-Morgan fold under the eye is seen in association with atopic disease. Koplik's spots are an early sign of rubeola. Fitzpatrick's sign is indicative of a benign lesion (dermatofibroma), whereas Hutchinson's sign is indicative of a malignant one (subungual melanoma). Petechiae are seen in many diseases, including fat embolization, particularly from a large bone fracture following trauma. Palpable purpura is indicative of leukocytoclastic vasculitis, and is an early, critical sign in Rickettsial diseases, including Rocky Mountain Spotted Fever, which must be diagnosed and treated early. Hyperpigmentation of areolae and scars is seen in Addison's disease. Acanthosis nigricans may indicate internal cancer, especially stomach cancer, whereas Bazex's syndrome occurs in synchrony with primary, usually squamous cancer, in the upper aerodigestive tract or metastatic cancer in cervical lymph nodes. Perioral pigmented macules or one or more cutaneous sebaceous neoplasms may be a sign of the Peutz-Jeghers or Muir-Torre syndrome, respectively, both associated also with intestinal polyps that have a malignant potential. Telangiectasiae in the perioral region may be associated with similar lesions internally in Osler-Weber-Rendu disease. Kerr's sign is indicative of spinal cord injury and Darier's sign of mastocytosis. Post proctoscopic periobital purpura (PPPP) is a phenomenon observed in some patients with systemic amyloidosis. Koebner's isomorphic response refers to the tendency of an established dermatosis, such as psoriasis, to arise in (a) site(s) of trauma, whereas Wolf's isotrophic response refers to a new dermatosis, such as tinea, not yet seen in the patient, arising in (a) site(s) of a former but different dermatosis, such as zoster., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Although numerous studies have shown that transsphenoidal surgery is the best initial treatment for Cushing disease offering 59-95% of success, fewer information is available on the long-term outcome in the subgroup of patients harboring ACTH-secreting macroadenomas. The aims of this study were to analyze our 10-year experience with transsphenoidal surgery in Cushing's disease and to examine whether remission rates were different between micro- and macroadenomas., Patients and Methods: Forty consecutive patients with proven Cushing's disease (28 microadenomas, 12 macroadenomas [diameter: 10-25 mm], 3 patients with no visible adenoma at MRI) underwent transsphenoidal surgery (TSS) assisted by neuronavigation in our center between 1996 and 2007. The diagnosis was made using standard endocrinological criteria including bilateral inferior petrosal sinus sampling (BIPSS) with CRH stimulation in all patients with discordant or equivocal biochemical and radiological testing. Morning serum cortisol was measured during the first week postoperatively, and a complete endocrine evaluation was made in all patients at 6-8 weeks. Remission at follow-up was defined as a normal postoperative 24-h urinary free cortisol (UFC) or continued need for glucocorticoid hormone replacement after TSS., Results: Overall, 32/40 patients (80%) were in remission after one or more TSS. Interestingly, a very good remission rate (92%) was observed in the subset of macroadenomas, similar to that found in the group of microadenomas (84%, NS), while no post-surgical remission was observed in the 3 patients with no visible adenoma at MRI (p<0.01). Of the 8 patients not in remission after repeated TSS surgery, 3 underwent radiation therapy and three had bilateral adrenalectomy, allowing remission of their hypercortisolism. There was minor morbidity and no death., Conclusion: While our overall results are in accordance with other published series, we show here that ACTH-secreting pituitary macroadenomas are usually not associated with a bad outcome, in contrast with patients with no visible adenoma at preoperative MRI.

Cushing's syndrome is a rare endocrine disease characterized by cortisol hypersecretion, induced mainly by a pituitary tumor (Cushing's disease) or, rarely, by an adrenal or an ectopic neuroendocine tumor. Cushing's syndrome is associated with severe morbidities and an increased mortality. The major systemic complications and the main cause of death are represented by cardiovascular disease. The prognosis of the disease is mainly affected by the difficulties in the diagnosis and treatment of the disease, which remain a considerable challenge.

Cushing's syndrome results from prolonged exposure to excess glucocorticoids. Patients with Cushing's syndrome may develop multiple metabolic problems including obesity, hyperglycemia, hypertension, depression, low bone mass, muscle atrophy, and hypogonadism. Cutaneous manifestations of hypercortisolism include skin atrophy, excessive bruising, purple striations, poor wound healing, facial plethora, vellous hypertrichosis and hirsutism. Diagnostic tests used to screen for Cushing's syndrome include 24-hour urine cortisol, the 1 mg dexamethasone suppresion test, and late night salivary cortisol. A normal screening test excludes the diagnosis of Cushing's. Patients with an abnormal screening test should be referred to an endocrinologist for complete evaluation of the pituitary-adrenal axis.

Corticotropin (ACTH)-independent bilateral macronodular adrenal hyperplasia (AIMAH) and primary pigmented nodular adrenocortical disease (PPNAD) are responsible for approximately 10% of adrenal Cushing's syndrome. AIMAH also can be present as subclinical bilateral incidentalomas in sporadic or familial forms. Diverse aberrant hormone receptors have been found to be implicated in the regulation of steroidogenesis and pathophysiology of AIMAH. PPNAD can be found alone or in the context of Carney complex, a multiple endocrine neoplasia syndrome. Additionally, it can be secondary to mutations of type 1 alpha-regulatory subunit of cAMP-dependent protein kinase A (PRKARIA). Strategies for the investigation and treatment of AIMAH and PPNAD are discussed.

Cushing's syndrome (CS) is a relevant model to better understand the effects of glucocorticoid (GC) excess on the human brain. The importance of GC excess on the central nervous system is highlighted by the high prevalence of neuropsychiatric disorders such as depression and cognitive impairment in patients who have CS. In addition, there is a high incidence of apparent diffuse loss of brain volume in patients who have CS. Recent studies indicate at least partial reversibility of these abnormalities following correction of hypercortisolism.

Background: Patients with spontaneous Cushing's syndrome are exposed to elevated levels of endogenous cortisol for months to years. We previously reported that hippocampal formation volume (HFV) increased in such patients after treatment lowered cortisol to normal concentrations. In the present study, we examined whether the structural increase was associated with improvement in cognition., Methods: Twenty-four patients with Cushing's disease were studied before treatment and following treatment. Magnetic resonance imaging was used to measure HFV and caudate head volume. Neuropsychologic tests of verbal cognition, learning, and memory were also administered., Results: Patients showed variability in improvement on neuropsychologic test performance. After partialing out age, education, duration of illness, and time since surgical treatment, greater improvement in word list learning, as measured by the Selective Reminding Test was associated with greater increase in HFV (r =.59, p <.02). There were no significant associations between improvement in paragraph or paired-word learning or memory tasks and increase in HFV. Improvement in other verbal tasks not strongly dependent on the hippocampus were not significantly associated with increase in HFV., Conclusions: After cortisol levels decline to normal concentrations, structural volumetric increase in HFV is accompanied by functional improvement in learning of unrelated words.

Intraoperative bilateral cavernous sinus sampling combined with rapid ACTH measurement was performed in a pilot study in seven patients with Cushing's disease during transsphenoidal pituitary surgery before and immediately after removal of the ACTH-producing pituitary microadenoma. Before tumor removal a gradient in ACTH concentrations greater than 1.5:1 toward the side of the tumor was found in six patients whereas ACTH concentrations in the right and left cavernous sinuses were similar in one patient with a midline tumor. Immediately after tumor removal, six of seven patients showed variable decreases in ACTH levels in the ipsilateral and/or contralateral side, whereas in one patient the ACTH levels in cavernous sinuses failed to reflect successful tumor removal. These results indicate that intraoperative bilateral cavernous sinus sampling combined with rapid ACTH measurement may be useful to confirm and lateralize ACTH-producing pituitary microadenomas during surgery, but ACTH levels measured immediately after tumor removal do not always predict surgical cure.

Multihormonal bilateral petrosal sinus sampling (BPSS) has been proposed to improve corticotroph microadenomas prediction of lateralisation. Few series have simultaneously compared data of pituitary MRI, surgical findings and multihormonal BPSS. Seven patients (6F/1M) with Cushing's disease, mean age at diagnosis of 35 years (range 24-55) were prospectively studied to compare radiological and multihormonal BPSS data with surgical and pathological findings. In untreated patients, simultaneous measures of ACTH, TSH and prolactine (PRL) were done at time 0, 7, 15, 22 minutes after CRH (500 microgram) and TRH (200 microgram) stimulation. An intersinus gradient of 1.4 was considered as a lateralisation. All microadenomas were identified during surgery, diameters ranged from 2 to 7 mm. All patients were in long-term surgical remission. Pathological studies confirmed a tumoral tissue with ACTH immunostaining in 6/7 cases and PRL in 3/7 cases. Pituitary MRI correctly identified tumors in 4 cases, the remaining tumors were not seen. Basal and stimulated intersinus gradients of ACTH, TSH and PRL were homolateral in 6/7 cases and were coincident with surgical findings in 4/7 cases. The other three cases were contralateral to MRI and surgical data. In conclusion, simultaneous gradient of ACTH, PRL and TSH did not improve lateralisation prediction in this series. Hormonal hypersecretion was homolateral in six cases whereas pathological studies demonstrated a mixed secretion in only three cases. A preferential pituitary draining could explain these discordances. Data from our series and from others (done with CRH stimulation and ACTH-PRL measures) strongly suggest a paracrine interaction between tumoral and normal pituitary tissue.

Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome is a rare disease. Recent evidence suggests that these tumors form part of a continuous spectrum ranging from well-differentiated carcinomas to small cell carcinomas. We report two new cases and review the 23 cases reported in the literature since 1972. The different diagnostic modalities are discussed, and an algorithm for the diagnosis of ectopic secretion of adrenocorticotropin (ACTH) is presented. In the future, the advent of radiologic and nuclear imaging as well as more accurate workup should help to diagnose these tumors at an earlier stage and improve the long-term outcome.

The clinical recognition of Cushing's syndrome and its biochemical confirmation is a challenging problem. The best diagnostic approach to patients with suspected Cushing's syndrome is still evolving. The traditional diagnostic approach of urine free cortisol and low-dose dexamethasone suppression testing may be inadequate when the degree of hypercortisolism is mild. Late-night salivary cortisol determinations may evolve as the simplest means of screening patients for suspected hypercortisolism. Repeated measurements of cortisol secretion (urine free cortisol or late-night salivary cortisol) over an extended period of time may be necessary to provide diagnostic certainty. The dexamethasone-CRH test is a reasonable approach in patients with equivocal data. The introduction of reliable, sensitive, and specific plasma ACTH measurements, the use of IPSS for ACTH with CRH stimulation, and the improved techniques of pituitary and adrenal imaging have made the differential diagnosis of Cushing's syndrome relatively straightforward (see Fig. 2). Clinicians who have never missed the diagnosis of Cushing's syndrome or have never been fooled by attempting to establish its cause should refer their patients with suspected hypercortisolism to someone who has.

Introduction: Disturbances of the sense of smell have been documented in many general pathologies. The actual etiology of such impairments is often difficult to determine. The aim of the authors is to review the literature on olfactory disorders in general diseases., Current Knowledge and Key Points: Acute and chronic liver disorders are frequently associated with hyposmia, which can be improved by vitamin A intake. Renal insufficiency could induce hyposmia according to the severity of the renal disease. Olfactory disorders seem to regress after transplantation but not after dialysis. Patients with AIDS--especially neurological forms--often present with taste and smell impairments. Smell alteration can also be noted in hypothyroidism and pseudohypoparathyroidism. In addition, taste and smell impairments have been described in patients with adrenal insufficiency or Cushing's disease. Subsequent to glucocorticoid therapy, adrenal insufficiency can induce regressive olfactory hypersensitivity. Olfactory impairments in diabetic patients can be associated with diabetic macrovascular manifestations due to ischemic alterations in the olfactory neuroepithelium. Impairment of the sense of smell has been described in many systemic diseases such as Horton's arteritis and Sjögren's syndrome., Future Prospects and Projects: Olfactory disorders should be investigated in patients presenting one of the above-mentioned diseases.

Background: Central obesity results in a cluster of metabolic abnormalities contributing to premature death. Glucocorticoids regulate adipose-tissue differentiation, function, and distribution, and in excess, cause central obesity. Glucocorticoid hormone action is, in part, controlled by two isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which interconverts hormonally active cortisol to inactive cortisone. We studied cortisol metabolism within different adipose tissue depots., Methods: We analysed expression and activity of the two isoforms (1 and 2) of 11 beta-HSD in cultured omental and subcutaneous adipose stromal cells from 16 patients undergoing elective abdominal surgery., Findings: Only the type 1 isoform (11 beta-HSD1) was expressed in adipose stromal cells. The predominant activity was oxo-reductase (conversion of cortisone to cortisol greater than cortisol to cortisone) and was higher in omental than subcutaneous fat (cortisone to cortisol, median 57.6 pmol mg-1 h-1 [95% CI 25.8-112.9] vs 0 pmol mg-1 h-1 [0-0.6], p < 0.001). 11 beta-HSD1 oxo-reductase activity was further increased (127.5 pmol mg-1 h-1 [82.1-209], p < 0.05) when omental adipose stromal cells were treated with cortisol and insulin., Interpretation: Adipose stromal cells from omental fat, but not subcutaneous fat, can generate active cortisol from inactive cortisone through the expression of 11 beta-HSD1. The expression of this enzyme is increased further after exposure to cortisol and insulin. In vivo, such a mechanism would ensure a constant exposure of glucocorticoid specifically to omental adipose tissue, suggesting that central obesity may reflect "Cushing's disease of the omentum".

This article examines Cushing's syndrome in four main categories as associated with nodular adrenal glands: adrenal adenoma, adrenal carcinoma, primary pigmented nodular adrenal dysplasia, and macronodular adrenal hyperplasia. A summary of clinical features of these four categories is presented.

Knowledge of clinico-pathological correlations in canine Cushing's disease is rather poor. Therefore we describe, clinically and pathologically, a case of pituitary tumour-dependent Cushing's disease in an 8-year old female cocker spaniel. Based on our results, the tumour was defined as a non-dexamethasone-suppressive, corticotrophic adenocarcinoma characterized by some new findings such as intracerebral metastases of anti-ACTH-labelled tumour cells and combined alpha-, beta- and gamma 3-MSH immunoreactivity in the tumour.

Transsphenoidally removed samples of pituitary adenomas from 14 patients with Cushing's disease and 5 patients with Nelson's syndrome always contained groups of uniform small ACTH-cells. Antibodies against the pro-opiocortin precursor fragments beta-endorphin, ACTH, and 16k-peptide recognized material in typical adenoma cells. A subpopulation of these cells, varying in number from sample to sample, specifically exhibited alpha-melanotropin immunoreactivity. Most periadenomatous samples showed signs of severe degeneration. Typical Crooke cells only occurred in samples from patients with Cushing's syndrome, but, with this exception, no clear differences between pituitaries of patients with Cushing's and Nelson's syndromes could be discerned. Two other forms of ACTH-immunoreactive cells were observed: rare, single, highly immunoreactive cells, with characteristics of both normal and Crooke cells, and numerous syncytial groups of cells in an advanced state of disintegration, presumably the remnants of hyperplastic follicles. The four different corticotrophs are characterized according to their fine structure and immunoreactivity in this study.

The ultrastructural findings in a muscle biopsy of a patient with Cushing's disease associated with severe myopathy are described. They included pronounced mitochondrial damage, thickening and deep invaginations of the sarcolemmal basement membrane, and thickening of the basement membrane of the capillaries. In addition, the muscle fibers showed a marked degree of disarray and wide interfibrillar spaces, containing large numbers of vacuoles, which presented degenerated mitochondria. The similarity between these findings and the ultrastructural features of corticosteroid-induced myopathy is discussed.

Neurophysins have been recognized as the carrier proteins of vasopressin and oxytocin. The distribution of neurophysins is immunohistochemically confirmed in the hypothalamus, median eminence, and posterior lobe of the pituitary gland. The authors detected neurophysins in the human corticotrophs and pituitary adenomas with the use of the immunohistochemical method with antiserum to human neurophysins, which did not cross-react with adrenocorticotropic hormone (ACTH), beta-endorphin, and corticotropin-releasing factor. All of ten pituitary glands obtained by autopsy revealed the presence of neurophysin-positive cells in the anterior, intermediate, and the posterior lobes. The neurophysin-positive cells were similar to the corticotrophs in shape and distribution. Simultaneous staining for ACTH and neurophysins in the serial sections revealed that neurophysin-positive cells were also ACTH-positive. One hundred twenty-four cases of pituitary adenoma operated upon were investigated. All of 7 Cushing's adenomas were composed of neurophysin-positive cells. Six tumors with giantism showed sparsely distributed neurophysin-positive cells. No neurophysin-positive cells were observed in any other cases. This study is the first reported evidence of the presence of neurophysins in the human corticotrophs and pituitary adenomas.