A prospective study of psychiatric and psychological aspects of Cushing's syndrome

OBJECTIVE Cushing's syndrome is associated with psychiatric and psychological disturbances. The aim of this study was to ascertain the extent of mental illness in patients before and after treatment for Cushing's syndrome. DESIGN AND PATIENTS Patients with Cushing's syndrome were identified for a prospective study. Control patients were selected with pituitary adenomas secreting GH or PRL. The aim was to reassess patients after Cushing's syndrome had been treated. MEASUREMENTS Psychiatric symptoms were measured and classified using the Present State Examination (PSE), and analysed on the Catego Programme. The Hamilton Rating Scale (HRS) was used to measure depression. The Crown-Crisp Experiential Index was used to measure common psychoneurotic symptoms (anxiety, phobia, obsession, somatic, depression and hysteria scales). The Eysenck Personality Inventory was used to assess extroversion and neuroticism. Cortisol, ACTH, and other hormones were measured by conventional methods. Parametric and non-parametric tests were used where appropriate. RESULTS Catego analysis of psychiatric ratings showed only 8 patients of 43 with active Cushing's syndrome (19%) were normal. Psychiatric diagnoses were obtained as follows: neurotic depression in 20 (46%), possible neurotic depression in 1 (2%), reactive depression in 6 (14%), and non-specific neurotic symptoms in 8 (19%). Additional Catego ratings of suspected other psychoses were made for 3 patients who were also depressed. None of these 43 patients with active Cushing's syndrome had ratings of schizophrenia or mania, obsessional neurosis or pathological anxiety. In the control group 13 (87%) were normal, 1 patient with acromegaly had an anxiety state and one patient with a prolactinoma had neurotic depression. It was possible to reassess the Present State Examination after treatment in 25 patients, when cortisol levels had been substantially reduced (to normal in 88%), the percentage rated as psychiatrically normal increased from 19 to 68 (χ²=11.7, 1 d.f., P<0.01). Hamilton Rating Scale scores for depression showed significant improvements after treatment for Cushing's syndrome (mean decrease from 9.2 to 2.4, n=36, P<0.001). Crown-Crisp experiential index data showed significant improvements in anxiety, somatic symptoms, and depression (n=25, P<0.05). Eysenck Personality Inventory assessments showed a significant improvement in neuroticism score (n=26 P=0.016), but no significant change in extroversion (P=0.5) or lie score (P=0.6). CONCLUSIONS Most patients with Cushing's syndrome had significant psychiatric pathology, usually depressive illness. As cortisol levels were returned to normal there were significant improvements in scores for depression and anxiety. Management of patients with Cushing's syndrome should include careful assessment of psychological and psychiatric illness.     

Quality of Life in Cushing's disease: A long term issue?

The purpose of this review is to describe how quality of life (QoL) is impaired in patients with hypercortisolism due to Cushing's syndrome of any aetiology, including pituitary-dependent Cushing's disease. It is worse in active disease, but improvement after successful therapy is often incomplete, due to persistent physical and psychological co-morbidities, even years after endocrine “cure”. Physical symptoms like extreme fatigability, central obesity with limb atrophy, hypertension, fractures, and different skin abnormalities severely impair the affected patients’ everyday life. Psychological and cognitive problems like bad memory, difficulties to concentrate and emotional distress, often associated with anxiety and depression, make it difficult for many patients to overcome the aftermath of treated Cushing's syndrome. Recent studies have shown diffuse structural abnormalities in the central nervous system during active hypercortisolism, thought to be related to the wide distribution of glucocorticoid receptors throughout the brain. Even though they improve after treatment, normalization is often not complete. Shortening the exposure to active Cushing's syndrome by reducing the often long delay to diagnosis and promptly receiving effective treatment is highly desirable, together with preparing the patient for the difficult periods, especially after surgery. In this way they are prepared for the impairments they perceive in every day life, and live with the hope of later improvement, which can be therapeutic in many instances.     

A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome

OBJECTIVE The diagnosis of Cushing's syndrome remains a major challenge in clinical endocrinology. Various screening tests are commonly used to support a biochemical diagnosis in the context of clinical suspicion. The aim of this study was to compare the sensitivity in the diagnosis of Cushing's syndrome of a single in-patient sleeping midnight cortisol to a standard 48-hour in-patient low-dose dexamethasone suppression test (LDDST) during the same admission. DESIGN A retrospective analysis was performed on 150 patients Investigated in our department between the years 1970 and 1994 with a confirmed diagnosis of Cushing's syndrome. PATIENTS One hundred and fifty patients with a diagnosis of Cushing's syndrome were analysed: 110 with Cushing's disease; 12 with tumours with ectopic ACTH secretion; 8 with ACTH dependent Cushing's syndrome of so far undetermined origin; 17 with cortisol secreting adrenal tumours; 3 with adrenocortical nodular hyper-plasia. Twenty normal volunteers and nine patients with non-endocrine conditions were also investigated as controls. MEASUREMENTS Plasma cortisol was measured by radioimmunoassay (RIA) in the 122 patients presenting after 1980, and by fluorimetry prlor to this date. RESULTS In all the control subjects the sleeping midnight cortisol was < 50 nmol/l, below the lowest standard of the routine In-house RIA. In every patient with Cushing's syndrome the sleeping midnight cortisol was detectable with a value greater than 50 nmol/l, with a range of 70–2000 nmol/l. In contrast, in three cases, all of whom had proven Cushing's disease on histology, there was uncharacteristic complete suppression of plasma cortisol to < 50 nmol/l following the LDDST. CONCLUSION In this series of 150 cases, a single in-patient sleeping midnight cortisol above 50 nmol/l had a 100% sensitivity for the diagnosis of Cushing's syndrome, clearly different from normal subjects. in contrast, the low-dose dexamethasone suppression test had a sensitivity of 98% even when the drug was administered as an in-patient. We recommend that a low-dose dexamethasone suppression test should not be used alone for confirmation of Cushing's syndrome since it may miss 2% of cases.     

Benzodiazepines attenuate the pituitary-adrenal responses to corticotrophin-releasing hormone in healthy volunteers, but not in patients with Cushing's syndrome

OBJECTIVE The corticotrophin-releasing hormone (CRH) stimulation test has become established as a powerful tool in differentiating the source of ACTH In patients with Cushing's syndrome. Psychiatric symptoms are common In patients with Cushing's syndrome, and many patients with psychiatric illnesses may show disturbances of function of the pituitary-adrenal axis; both of these groups of patients may be receiving benzodiazepine drugs when presenting for evaluation of their possible endocrine problems. Both animal and human studies suggest that Interactions occur between benzodiazepines and the hypothalamopituitary-adrenal axis. We have therefore evaluated the effects of a benzodiazepine drug on the pituitary-adrenal response to CRH. DESIGN We have Investigated the effects of 20 mg oral temazepam or placebo on serum Cortisol and plasma ACTH after the administration of 100μg i.v. human CRH in 12 healthy volunteers and In 9 patients with Cushing's syndrome. RESULTS Temazepam significantly inhibited the peak serum/plasma levels and area under the curve for circulating Cortisol and ACTH in normal subjects after CRH, but there was no such difference after temazepam in patients with Cushing's syndrome. CONCLUSIONS Our results have shown that temazepam Inhibits the pituitary-adrenal responses to human CRH in normal subjects, but not in those with Cushing's syndrome. We believe that Inhibition of endogenous AVP by temazepam is the most likely explanation for our findings in healthy volunteers: the hypercortisolaemia in Cushing's syndrome suppresses the release of both endogenous CRH and AVP In portal blood which then results in abolition of the temazepam induced reduction In the pituitary-adrenal response to exogenous CRH, as seen in our patients. These effects of benzodiazepines should clearly be taken Into account in patients using these compounds while undergoing endocrine assessment.     

Lethal acute demyelinization with encephalo-myelitis as a complication of cured Cushing's disease

Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient.     

High prevalence of nodular thyroid disease in patients with Cushing's disease

OBJECTIVES In the recent past, we have noted a frequent Occurrence of thyroid nodules in our patients with Cushing's disease. We therefore elected to evaluate thyroid structure and function in these patients and also In patients with Cushing's syndrome of primary adrenal origin. PATIENTS AND METHODS In 33 of the 37 patients (30 women and 3 men aged 19–66 years) with endogenous hypercortisolism referred to our Institution during the last five years, measurement of T4, T3, FT4, FT3, TSH serum levels and thyroid ultrasonography were performed, at first admission in 15 cases and subsequently in the course of follow-up in 18 cases. At the time of the study, 16 of the 33 patients had active Cushing's disease while 9 were in remission after successful surgery, 6 patients had an adrenal tumour and 2 patients had previously undergone unilateral adrenalectomy for an adrenal adenoma. Thyroid function and ultrasonography were also evaluated in 55 normal subjects, 40 women and 15 men aged 20–73 years. RESULTS In 25 patients with Cushing's disease, we found a significantly higher prevalence of thyroid nodular disease than that recorded in 55 control subjects (60.0 vs 20.0%, χ²= 10.779, P < 0.005) and comparable to that in patients with active disease (56.2%) and those in remission (66.6%). Multiple nodules were present in 8 Cushing's patients and in 4 normal subjects while a single nodule was detected in 7 patients and in 7 controls. A markedly lower Occurrence of thyroid abnormality was found in the 8 patients with adrenal tumours (25.0%, NS vs controls). In 9/17 (52.9%) patients with ultrasonographic evidence of thyroid nodules, these were palpable. As expected, serum thyroid hormone and TSH levels were reduced in patients with active Cushing's syndrome compared to normal controls. CONCLUSIONS We found a significantly higher prevalence of nodular thyroid disease in patients with Cushing's disease with respect to a group of controls in whom the prevalence of thyroid nodules was comparable to that reported for the general population in Europe. The possibility that glucocorticoid excess is responsible for the development of thyroid changes does not seem likely since in our small series of patients with adrenal tumours the prevalence was only slightly higher than that observed in control subjects. Other factors related to hyperactivity of the corticotrophic cell, or a growth factor stimulating both corticotroph and thyrocyte proliferation might be involved. Evaluation of a larger series of patients with adrenal tumours may help to distinguish between these possibilities.     

Psychopathology in systemic lupus erythematosus. I. Psychiatric observations

A consecutive series of 17 patients with systemic lupus erythematosus were evaluated psychiatrically. Specific criteria were used for diagnosis. In addition to a systematic retrospective analysis of the past psychiatric complications in these patients, they were also followed personally during the duration of their index admission. Follow-up evaluations were done in some patients. Serious psychiatric syndromes were observed in 41% of the patients. Of 11 episodes observed, a mixed syndrome (characterized by a combination of organic symptoms and either affective or schizophreniform symptoms) was the most common type of psychopathology and occurred in 45% of the episodes. Pure affective syndromes, pure organic brain syndromes, and pure schizophreniform syndromes occurred in 36, 9, and 9% of episodes, respectively. Psychiatric treatment was most frequently required for the mixed syndromes.The findings of this study and those reported in the literature allow some general principles to be formulated concerning the psychiatric syndromes occurring as a complication of SLE: (1) psychiatric episodes do not represent an intensification of psychopathology present before the onset of SLE in most cases; (2) SLE is not merely acting as a nonspecific stress to precipitate psychiatric illness in genetically predisposed individuals; (3) there is considerable variability in both the severity and the symptomatology present at a given time in a given patient; (4) the episodes are totally reversible in the majority of cases; (5) the psychiatric symptoms are frequently severe enough to require psychiatric care; and (6) somatic treatments may give symptomatic relief of the psychiatric disturbances.     

A role for life events in the pathogenesis of Cushing's disease

OBJECTIVE We have previously reported on 30 patients with Cushing's syndrome suggesting an aetiological role for stressful life events. The investigation about life events in the year before the first signs of disease onset was extended to a larger population of patients with Cushing's syndrome, allowing us to differentiate patients with pituitary-dependent and pituitary-independent forms. DESIGN Case-control study. PATIENTS Sixty-six consecutive patients with Cushing's syndrome of various aetiologies (46 with pituitary-dependent forms and 20 with primary adrenal hyperfunction or ectopic ACTH production) and a control group of 66 healthy subjects, matched for sociodemographic variables, were studied. MEASUREMENTS Paykel's Interview for Recent Life Events (a semistructured research interview covering 64 life events) was administered after the acute phase of illness while in remission. RESULTS Patients with Cushing's syndrome reported significantly more stressful life events (P < 0.001), both events that had an objective negative impact (P < 0.001) and independent events (P < 0.001), than controls, confirming previous findings. Patients with pituitary-dependent Cushing's disease were compared with their matched controls and reported significantly more total events, events with an objective negative impact and independent events (all at P < 0.001). There were no significant differences between patients with pituitary-independent forms and their matched controls. CONCLUSIONS These findings indicate a causal role for stressful life events exclusively in pituitary-dependent Cushing's disease, and suggest a limbic-hypothalamic involvement in the pathogenesis of this condition. The results are similar to those obtained in major depression, and add to other analogies between the two disorders.     

Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing's syndrome

OBJECTIVE Cushing's syndrome In childhood and adolescence Is rare. We analysed the clinical presentation, Investigation, management and therapeutic outcome In 12 paediatric patients with Cushing's syndrome. DESIGN Retrospective review of case notes. PATIENTS Twelve patients, 7 males and 5 females, aged 7.6-17.8 years with Cushing's syndrome who were admitted to St Bartholomew's Hospital between 1978 and 1993, were studied. Aetiologies of the Cushing's syndrome patients were: Cushing's disease (9), adrenal adenoma (1), nodular adrenocortical dysplasia (1) and ectopic ACTH syndrome (1). One further male patient, aged 17.8 years who presented with Nelson's syndrome after bilateral adrenalectomy for Cushing's disease In 1978, Is described. MEASUREMENTS Presenting symptoms, endocrine tests for hypercortlsolism, Imaging studies, simultaneous bilateral Inferior petrosal sinus sampling and therapeutic strategies are discussed. RESULTS The dominant clinical features were obesity, short stature, virillzation, headaches, fatigue and emotional lability. Investigations confirmed Cushing's syndrome by demonstrating absent Cortisol clrcadlan rhythm and Impaired suppression on low dose dexa-methasone test and differentiated Cushing's disease from other aetiologies by high dose dexamethasone and hCRH tests. In Cushing's disease, pituitary CT scan Identified a microadenoma In 4 out of 9 subjects. In 5 of the 9 patients (3 with a normal pituitary CT, 2 with a suggested microadenoma), a pituitary MRI scan was performed and confirmed the CT findings. Inferior petrosal sinus catheterization for ACTH In 4 patients confirmed excess pituitary ACTH secretion, correctly lateralizing the tumour In all cases. Cushing's disease was treated by transsphenoidal surgery alone In 6 patients and combined with pituitary Irradiation In 3 patients. Of these 9 patients, 7 are cured and 2 are in remission. The patient with Nelson's syndrome Is cured after total hypophysectomy. CONCLUSIONS This series describes the clinical features, aetiologies and management of juvenile Cushing's syndrome. Investigation with low and high-dose dexamethasone suppression tests and hCRH test identified the aetiology In each case. Collaboration between paediatric and adult endocrine units together with an experienced neurosurgeon and a radiotherapist contributed to the successful therapeutic outcome of these patients     

The desmopressin stimulation test in the differential diagnosis of Cushing's syndrome

objective We assessed the ability of desmopressin to stimulate the pituitary-adrenal axis in patients with Cushing's syndrome. DESIGN AND SUBJECTS The Cortisol response to 5 or 10 fig of intravenous desmopressin was evaluated in 31 patients with Cushing's syndrome of several aetiologies and in 15 normal subjects. RESULTS Cortisol responses were observed in 15 out of 16 patients with pituitary dependence and in two patients with adrenal nodular hyperplasia, the increase above baseline ranging from 61 to 379% in the responders. Eight patients with adrenal tumours and one with the ectopic ACTH syndrome did not respond to desmopressin, having shown changes In their Cortisol levels from -5 to 42% above baseline. Responses occurred in two out of the 15 normal Individuals, whose Cortisol increased 58 and 69% above baseline, respectively. Stimulation tests with standard agents as lysine vasopressin or ovine corticotrophin-releasing hormone were performed in the same patients and there was a high degree of concordance. No serious adverse reactions were observed in the tests with desmopressin. CONCLUSIONS Desmopressin was able to stimulate the pituitary-adrenal axis in patients with Cushing's disease and, like corticotrophin releasing hormone, it may prove useful in the differential diagnosis of Cushing's syndrome.     

Outbreak of exogenous Cushing's syndrome due to unlicensed medications

Objective Despite the widespread medical use of glucocorticoids, reports of factitious administration of these hormones have been uncommon. We herein report an outbreak of Cushing's syndrome in Tehran among the addicts using Tamgesic (a brand of Buprenorphine) to help them through the narcotic withdrawal stage, without knowledge of the glucocorticoid content of the black‐market drug. Design and measurements Case histories of 19 patients with a final diagnosis of iatrogenic Cushing's syndrome were reviewed. Liquid chromatography/mass spectrometry (LC–Mass) method was used to evaluate glucocorticoid existence in the brand. High performance liquid chromatography was used to determine plasma dexamethasone level. Results No buprenorphine was present in the vials. Each Tamgesic vial contained 0·4 mg of Dexamethasone disodium phosphate; Heroin was also found in them. The duration of injection abuse and the total dexamethasone intake was 4·5 (1–18) months and 2·6 (0·8–8) mg/day, respectively. Median plasma dexamethasone concentration was 5·8 nmol/l, with a range of 5–8·7. Physical findings of the cases were not different from those of the classic endogenous Cushing's syndrome but their serum cortisol and urinary free cortisol were suppressed. Severe life‐threatening complications were demonstrated in five cases. Conclusion Surreptitious use of steroids resulting in Cushing's syndrome may be more common in opium addicts; a high degree of suspicion is needed to uncover this disorder. Whenever facing a cushingoid appearance in addicts, the possibility of using black market drugs with corticosteroid contents should be kept in mind.     

Impact of Cushing's syndrome on fertility and pregnancy

Cushing's syndrome is defined by an endogenous or exogenous hypercortisolism. Increased cortisol, as well as increased androgens will have a negative impact on the pulsatile secretion of GnRH, thus leading to an increased risk of infertility. However, pregnancy can occur in a woman with Cushing's syndrome: it is a challenging situation, because of the numerous consequences which can be observed in the mother (increased risk of gestational diabetes, hypertension, eclampsia… in addition to the specific complications of hypercortisolism) and in the fetus (intrauterine growth retardation, prematurity). In contrast, Cushing's syndrome can also appear during pregnancy. It is a very rare situation: the diagnosis is challenging because of the numerous hormonal changes induced by pregnancy on cortisol levels. The objective of this brief review will be to detail the mechanisms of infertility due to hypercortisolism, the diagnostic methods of Cushing's syndrome during pregnancy, the maternal and fetal consequences of hypercortisolism during pregnancy, and finally the potential means of contraception that can be proposed.     

THE DIAGNOSIS OF CUSHING'S SYNDROME USING 131I-19-IODOCHOLESTEROL UPTAKE AND ADRENAL IMAGING

Uptake measurements and visualization of the adrenal glands were performed using ¹³¹I-19-iodocholesterol in ten healthy subjects and fourteen patient suffering from Cushing's syndrome (nine hyperplasias and five adenomas). The normal range in healthy subjects (average uptake value ± 2 SD) is 0·12–0·27% for both adrenals. In patients with Cushing's syndrome the uptake values ranged from 0·321 to 1·497 %. Normal bilateral images were obtained in all the healthy subjects as well as in eight of the patients with hyperplasia, whilst the remaining patient with hyperplasia showed distinctly enlarged glands. In contrast, an image of the diseased side only was obtained in patients with adrenal adenomas. We conclude that radiocholesterol studies in Cushing's syndrome allow confirmation of the diagnosis, definition of the pathophysiologic type of disease and lateralization of adrenal adenomas.     

Reduced serum levels of dehydroepiandrosterone sulphate in adrenal incidentalomas: a marker of adrenocortical tumour

BACKGROUND AND OBJECTIVE Reduced serum levels of dehydroeplandrosterone sulphate (DHEAS) have been shown In patients with Cushing's syndrome resulting from adrenocortical adenoma, In contrast with normal DHEAS levels In patients with Cushing's disease. The elm of this study was to verify whether patients with incidentally discovered adrenocortical adenomas also have reduced levels of DHEAS. DESIGN Evaluation of serum DHEAS, serum and urinary cortisol, plasma ACTH and low dose dexamethasone suppression test In patients with adrenal Incidentaloma and Cushing's syndrome. PATIENTS Thirty-two patients with adrenal Incidentaloma and, as controls, 17 patients with overt Cushing's syndrome, were studied. RESULTS Serum DHEAS levels lower than normal were found In 21/24 (81.5 %) patients with adrenocortical Incidentaloma, but In only 1/8 patients with a mass of non-adrenocortical origin. This patient had massive bilateral metastatic infiltration of both adrenal glands and primary adrenal failure. The prevalence of low DHEAS levels in the two groups was significantly different (P= 00001). In patients with adrenocortical Incidentaloma, the prevalence of low DHEAS levels was significantly higher (P= 00001) than that found for some hormonal alterations Indicating pre-clinical hypercortlsoilsm (high urinary cortisol, unsuppressed serum cortisol after low dose dexamethasone administration and low plasma ACTH). Low DHEAS levels were found in all patients with Cushing's syndrome due to adrenocortical adenoma but in none of those with Cushing's disease. CONCLUSIONS Our results Indicate that the finding of low DHEAS levels can be considered a marker of the adrenocortical origin of an adrenal Incidentaloma, provided adrenal failure has been excluded.     

Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience

Background There has been a rapid shift from open to laparoscopic approaches in adrenal surgery, but the safety and efficacy of bilateral laparoscopic adrenalectomy (BLA) in patients with corticotrophin (ACTH)‐dependent Cushing's syndrome continues to be defined. Objective Review outcomes in the largest series of patients reported to date undergoing BLA for ACTH‐dependent Cushing's syndrome. Design Retrospective review study. Patients Between January of 1995 and October of 2006, BLA was attempted in 68 patients with ACTH‐dependent Cushing's syndrome (26 ectopic ACTH syndrome; 42 persistent pituitary‐dependent Cushing's syndrome following pituitary surgery). Measurements Review of peri‐operative morbidity and mortality, biochemical parameters and patient‐reported symptom response from chart review and mailed questionnaire. Results BLA was successfully completed in 59 of 68 patients (87%); nine (13%) required conversion to open adrenalectomy (OA). Intra‐operative complications occurred in three patients (4·4%) (two BLA, one OA), and non‐operative complications occurred in 11 (16%) patients (eight BLA, three OA). There were no peri‐operative deaths. Median hospitalization was 5·5 days (range, 3–28) and 11·9 days (range, 4–29) for the BLA and OA groups, respectively. In patients with follow‐up data available, all achieved biochemical resolution and at least partial clinical resolution of signs and symptoms associated with hypercortisolism. Resolution of hypertension, diabetes and obesity was achieved in 64%, 29% and 35% of patients carrying those diagnoses prior to surgery, respectively. Conclusions This study further supports the role of BLA as an effective treatment option for patients with ACTH‐dependent Cushing's syndrome.     

DEXAMETHASONE SUPPRESSION TESTS: USEFULNESS OF SIMULTANEOUS MEASUREMENT OF PLASMA CORTISOL AND DEXAMETHASONE

The effect of oral dexamethasone on the plasma content of cortisol and dexa-methasone was investigated in 175 patients suspected of having Cushing's syndrome. Plasma concentrations of cortisol and dexamethasone were measured by specific radioimmunoassays at 08.00 h following administration of either a low-low (0·5 mg), low (1·0 mg), high (4·0 mg) or high-high (8·0 or more mg) dose of dexamethasone at midnight. All seventeen patients with documented Cushing's syndrome exhibited resistance to the action of low-low and/or low dose dexamethasone on suppression of 08.00 h plasma cortisol content. Nine of twelve patients with pituitary dependent Cushing's syndrome had plasma cortisol values of less than 166 nmol/l following high-high dose testing. In 157 patients with suspected Cushing's syndrome, standard dexamethasone testing was considered unsatisfactory in at least 20%. After low-low or low dose tests 11% had supranormal cortisol values, but plasma cortisol content overlapped with values observed in patients with Cushing's syndrome only when plasma dexamethasone content was less than 5·6 nmol/l. Twelve per cent of patients suspected of having Cushing's syndrome had sufficient elevation of plasma dexamethasone values after low dose testing so that marked reduction of plasma cortisol might be expected even in patients with pituitary dependent Cushing's syndrome. Four patients receiving anticonvulsants had subnormal plasma levels of dexamethasone for the dose administered, but all exhibited normal suppression when plasma levels of dexamethasone and cortisol were correlated simultaneously. In summary, there is considerable variation in the plasma content of dexamethasone following oral doses. Simultaneous measurement of both plasma levels of dexamethasone and cortisol has proved most useful in identifying patients with unsatisfactory dexamethasone suppression tests.     

OVERNIGHT DEXAMETHASONE PRE-TREATMENT IMPROVES THE PERFORMANCE OF THE LYSINE-VASOPRESSIN TEST IN THE DIAGNOSIS OF CUSHING'S SYNDROME

OBJECTIVE There is no endocrine test which is completely reliable for the confirmation of Cushing's syndrome and in separation of the various aetiologies. We have tested the hypothesis that overnight dexamethasone pre-treatment should result in a better performance of the lysine-vasopressin (LVP) test in the diagnosis of Cushing's syndrome. STUDY DESIGN AND PATIENTS We studied 61 subjects, including 25 pituitary-dependent and 9 pituitary independent Cushing's (7 adrenal tumours and 2 ectopic ACTH syndromes), 18 euadrenal controls, 4 depressed subjects, and 5 cushingoid patients. The subjects received 1 mg of dexamethasone orally at 2300 h and the following morning they were given 10 IU of lysine-vasopressin im. MEASUREMENTS Plasma cortisol (RIA) was measured at times ?15, 0, 15, 30, 45, 60, 75, 90 and 120 minutes. RESULTS The dexamethasone-modified LVP (Dx/LVP) test resulted in four patterns of cortisol response. The dexa sensitive pattern (positive suppression and negative response to LVP) was found in euadrenal subjects; the dexa insensitive pattern (negative suppression and positive response to LVP) was seen in Cushing’s disease; a non-responsive pattern (negative suppression and negative response to LVP) was observed only in pituitary independent Cushing's; and an indeterminate pattern (positive suppression and positive response to LVP) was equivocal, being observed in 2 control subjects, 1 patient with Cushing’s disease and 1 depressed patient. In separating control subjects from Cushing's syndromes the Dx/LVP test had 88.9% sensitivity, 100% specificity and 96.2% diagnostic accuracy; when the test was used to segregate Cushing's disease from control subjects we found 96.0% sensitivity, 100% specificity and 97.7% diagnostic accuracy. The performance variables for the Dx/LVP test in separating pituitary dependent from pituitary independent Cushing's were uniformly 100%. Depressed and cushingoid subjects did not differ from control subjects in their cortisol patterns during the test. Successful removal of the pituitary microadenoma in Cushing's disease was invariably followed by a reversal of the abnormal cortisol pattern (dexa insensitive) during the test to a dexa sensitive pattern indistinguishable from that of control subjects. CONCLUSION These results confirm our hypothesis and suggest that an improved performance of any corticotroph stimulus (oCRH, LVP, AVP or desmopressin) in the diagnosis of Cushing's syndrome should result from pre-treatment with dexamethasone.     

Growth hormone releasing hormone priming increases growth hormone secretion in patients with Cushing's syndrome

OBJECTIVE In patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed though the basic mechanism is unknown. In states of chronic deficiency of hypothalamic growth hormone releasing hormone (GHRH) release, a blunted GH response to exogenous GHRH has been reported; such impairment can be partially normalized by repetitive GHRH administration (priming). In order to clarify whether a deficit in hypothalamic release of GHRH is the basis of the decreased GH secretion in patients with Cushing's syndrome, GHRH plus pyridostigmine tests were undertaken, both before and after GHRH priming. DESIGN GHRH (200 μg/day as a single s.c. injection) was given daily over 7 days. Two pyridostigmine (120 mg p.o.) plus GHRH (100 μg i.v.) tests were performed before and after priming to assess GH response. PATIENTS Eight patients (seven women, one man), with untreated Cushing's syndrome (six Cushing's disease, one autonomous bilateral adrenal hyperplasia, one adrenal adenoma), were studied. MEASUREMENTS Plasma GH levels were measured by immunoradiometric assay. RESULTS GHRH plus pyridostigmine-induced GH release was impaired in patients with untreated Cushing's syndrome (mean peak 52 ± 14 mU/l, area under the curve (AUC) 472 ± 96). Repetitive administration of GHRH over 7 days partially restored the GH response to the second pyridostigmine-GHRH test (mean peak 150±21 mU/l. AUC 1016±104), both P < 005. All of the eight Cushing's syndrome patients studied presented a higher GHRH plus pyridostigmine-induced GH secretion after priming. CONCLUSIONS Repetitive administration of GHRH increases the pyridostigmine-GHRH-induced GH secretion in patients with Cushing's syndrome. This suggests that impaired hypothalamic release of GHRH is a contributing factor to the decreased GH secretion observed in chronic hypercortisolism.     

The role of minor salivary glands’ biopsy in the diagnosis of Sjögren's syndrome and other systemic diseases

BackgroundThe minor salivary glands’ biopsy is a minimally invasive procedure used for the diagnosis of Sjögren's syndrome. Its significance has also been reported in other inflammatory/infiltrative diseases. The objectives are to investigate its use in the diagnosis of Sjögren's syndrome, as well as to evaluate its role in the diagnosis of amyloidosis and sarcoidosis.MethodsA retrospective analysis was carried out on patients who underwent minor salivary glands’ biopsies between April of 2014 and December of 2017.ResultsA total of 173 patients were identified. Of the patients with suspected Sjögren's syndrome, in 40% of the cases there was evidence of lymphocytic sialadenitis. The antibodies against SSA, antinuclear antibodies and the Rheumatoid Factor correlated significantly with the presence of lymphocytic sialadenitis. The result of the minor salivary glands’ biopsies allowed an increase of 12.4% of patients who met the criteria defined by the American – European Consensus Group. Of the patients with suspected amyloidosis (25%), the biopsies were positive in 4 patients.ConclusionThe minor salivary glands’ biopsy is a simple procedure with effectiveness in the diagnosis of Sjögren's syndrome and amyloidosis. In this study, its use increased the number of patients who met the Sjögren's syndrome classification criteria. It also appears to be useful in the diagnosis of amyloidosis.     

THROMBOEMBOLIC COMPLICATIONS IN CUSHING'S SYNDROME

Thromboembolic events are thought to occur with increased frequency in Cushing's syndrome due to the predisposing factors, obesity, hypertension, a raised haematocrit and major surgery plus a ‘hypercoagulable state’. To examine this postulate further we have studied 43 patients with Cushing's syndrome retrospectively and 10 patients prospectively to determine the incidence of arterial and venous thrombosis, both spontaneous and post-operative. Arterial events were noted in four cases (9%) and deep vein thrombosis or pulmonary thromboembolism (PTE) occurred in six cases (11%). Post-operative PTE occurred in 2-7% of all operations. These vascular complications tended to occur in the older patients with Cushing's syndrome. In our series, clinically significant thromboembolic episodes appear no more common than expected and the indications for prophylactic anticoagulation (the older and more obese patients) may not be different from other patients undergoing major surgery. An incidental finding was of a greater frequency of hypertension in Cushing's patients due to an adrenal adenoma.