DIFFERENTIAL REGULATION OF 11ß-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVITY IN PATIENTS WITH DIFFERING ETIOLOGIES OF HYPOPITUITARISM.

OBJECTIVE: Pituitary patients with different etiologies of hypopituitarism exhibit differing phenotypes, despite similar replacement therapy strategies. We hypothesized that differential regulation of the isoenzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), which mediates the net autocrine conversion of cortisone to cortisol in adipose tissues and liver, may play a role. METHODS: We studied 11ß-HSD1 activity (using urine cortisol/cortisone metabolites ratio) in 36 hypopituitary patients with treated craniopharyngiomas, treated remitted Cushing disease, and treated nonfunctioning pituitary adenomas + prolactinomas on and off growth hormone (GH) replacement. RESULTS: 11ß-HSD1 activity was higher in subjects with craniopharyngioma both on and off GH, as evidenced by increased tetrahydrocortisol to tetrahydrocortisone metabolite ratios compared to other diagnostic groups, but there was no difference in body mass index, insulin levels, serum hormone measurements, or hydrocortisone dose between groups. CONCLUSION: Craniopharyngiomas are associated with enhanced 11ß-HSD1 activity compared to other diagnostic hypopituitary groups, and this may contribute to the adverse phenotypic and metabolic features seen in this condition. ABBREVIATIONS: BMI = body mass index; Em = cortisone metabolites; Fm = cortisol metabolites; GH = growth hormone; 11ß-HSD1 = 11ß-hydroxysteroid dehydrogenase type 1; IGF-1 = insulin-like growth factor 1; NFPA = nonfunctioning pituitary adenoma; THE = tetrahydrocortisone; THF = tetrahydrocortisol.

Long-term outcomes of children treated for Cushing's disease: a single center experience.

PURPOSE: Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients. METHODS: Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2). RESULTS: Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients. CONCLUSIONS: The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.

Investigation for Paediatric Cushing's Syndrome Using Twenty-Four-Hour Urinary Free Cortisol Determination.

OBJECTIVE: Paediatric Cushing's syndrome (CS) remains a challenge to diagnose and exclude. We assessed the accuracy of 24-hour urinary free cortisol (UFC) determination in children referred for suspected CS. DESIGN: We conducted a retrospective study of paediatric patients referred to our centre with suspected CS between 1982 and 2014. PATIENTS: Of 66 subjects (mean age 12.9 years; range 4.4-16.9), there were 47 cases of CS (29 males), which included Cushing's disease (CD; 39 patients, 25 males), primary pigmented nodular adrenocortical disease (8 patients, 4 males) and 19 'controls' (6 males) in whom the diagnosis of CS was excluded. MEASUREMENTS: The subjects had between one and five 24-hour UFC collections analysed by radioimmunoassay, chemiluminescent immunoassay or liquid chromatography-mass spectrometry. The data were normalised, corrected for body surface area (m2) and assessed using receiver operating characteristic analysis and an independent two-tailed t test. RESULTS: The diagnostic accuracy of 24-hour UFC for CS was excellent (area under the curve 0.98, 95% CI 0.946-1.00, sensitivity 89%, specificity 100%). CONCLUSIONS: Twenty-four-hour UFC is a reliable and practical investigation with high diagnostic accuracy for paediatric CS. However, further investigations may be required if the UFC is normal but there is a high diagnostic suspicion of CS.

Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy.

Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50 years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15 years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.

The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients.

OBJECTIVE: Quality of life (QoL) is impaired in hypopituitary patients and patients with primary adrenal insufficiency. The aim of this study was to analyse the impact of glucocorticoid (GC) replacement on QoL. The main hypothesis was that ACTH-insufficient patients experience a dose-dependent deterioration in QoL. DESIGN, PATIENTS AND METHODS: This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Data from 2737 adult GH-deficient (GHD) hypopituitary patients were eligible for analysis. Thirty-six per cent were ACTH sufficient and 64% ACTH insufficient receiving a mean±s.d. hydrocortisone equivalent (HCeq) dose of 22.3±8.7 mg (median 20.0). QoL at baseline and 1 year after commencement of GH replacement was assessed by the QoL-assessment of GHD in adults. RESULTS: At baseline, no significant difference in QoL was observed between ACTH-sufficient and -insufficient patients. Increasing HCeq dose was associated with worse QoL. Patients on HCeq≤10 mg had the best and patients receiving ≥25 mg demonstrated the poorest QoL. At 1 year of GH replacement, the improvement in QoL did not differ between ACTH-sufficient and -insufficient patients, and no association was observed between HCeq dose and QoL improvement. CONCLUSION: Adult hypopituitary patients with untreated GHD receiving GC replacement have similar QoL as ACTH-sufficient patients. Among ACTH-insufficient patients, there is a dose-dependent association between increasing dose and impaired QoL. This association may be explained by supraphysiological GC exposure although it remains plausible that clinicians may have increased GC doses in order to address otherwise unexplained QoL deficits.

Diagnosing unilateral primary aldosteronism - comparison of a clinical prediction score, computed tomography and adrenal venous sampling.

CONTEXT: In patients with primary aldosteronism (PA), adrenalectomy is potentially curative for those correctly identified as having unilateral excessive aldosterone production. It has been suggested that a recently developed and published clinical prediction score (CPS) may correctly identify some patients as having unilateral disease, without recourse to adrenal venous sampling. OBJECTIVE: We have applied the CPS to a large cohort of PA patients with defined and documented outcomes. We also incorporated a minor modification to the CPS and a radiological grading score (RGS) into our analysis to assess whether its performance could be augmented. RESULTS: A total of 75 patients with a robust diagnosis following bilateral adrenal venous cannulation and/or strictly defined surgical outcome were analysed. Applying the CPS to this group of patients produced a sensitivity of 38·8% and a specificity of 88·5% of correctly identifying unilateral aldosterone production. Using a suggested modification to the CPS, in which different levels of hypokalaemia were given different weightings, the sensitivity rose to 40·8%, with an identical specificity. Using the RGS alone improved sensitivity to 91·7%, but specificity was reduced to 62·5%. CONCLUSION: Applying the recently developed CPS to this cohort of patients, it was not possible to reproduce the 100% specificity reported in the original publication. Using the modified score or incorporating the RGS did not improve its performance. In this cohort, we were unable to show superiority of the CPS over an imaging-based strategy. CPS may have a role in guiding clinical decision-making, especially in those whose adrenal venous sampling (AVS) has been unsuccessful.

Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing's disease.

BACKGROUND: Selective adenomectomy remains the first-line treatment for Cushing's disease (CD), until recently by microscopic transsphenoidal pituitary surgery. Endonasal transsphenoidal endoscopic surgery (ETES) is emerging as a novel, less invasive treatment for pituitary adenomas and has become the optimal surgical approach. OBJECTIVE: There are no published series for the treatment of paediatric CD by ETES, and we report our centre's preliminary results. DESIGN: Retrospective analysis. PATIENTS: Six paediatric patients (median age 15·8 years; range 11·7-17·0 years) fulfilled standard diagnostic criteria for CD. Preoperatively, no abnormality was identified on pituitary MR scanning in 3 (50%) patients, one had a macroadenoma. Bilateral petrosal sinus sampling demonstrated central ACTH secretion (IPS/P ACTH ratio ≥3·0, post-CRH) in 3/6 (50%) patients. The same neurosurgeon and endoscopic nasal surgeon undertook all the operations. OUTCOME MEASURES: Therapeutic outcome and rate of complications. RESULTS: Clinical recovery and biochemical 'cure' were achieved in 5 (83%) patients, and a corticotroph adenoma was confirmed histologically in all cured cases. One case developed post-operative CSF leak requiring lumbar drain insertion and patching. At a mean interval of 4·7 years (0·1-10·8 years) post-operatively, cured patients have shown no recurrence. One patient, with a large diffuse adenoma requiring more extensive surgery, has panhypopituitarism, and another patient has GH and gonadotrophin deficiencies. CONCLUSIONS: Our experience shows that ETES for removing corticotroph adenomas in children, in most cases not visualized on MRI, is minimally invasive and gave excellent post-operative recovery/results. In skilled hands, this technique provides an alternative to conventional transsphenoidal microscopic surgery in managing paediatric CD.

Long-term remission and recurrence rates in Cushing's disease: predictive factors in a single-centre study.

OBJECTIVE: To investigate the early and late outcomes of patients with Cushing's disease (CD) submitted to a neurosurgical procedure as first-line treatment. DESIGN: In this single-centre retrospective case notes study, 131 patients with CD with a minimum follow-up period of 6 years (124 operated by transsphenoidal surgery (TSS) and seven by the transcranial approach) were studied. Apparent immediate cure: post-operative 0900 h serum cortisol level <50 nmol/l; remission: cortisol insufficiency or restoration of 'normal' cortisol levels with resolution of clinical features; and recurrence: dexamethasone resistance and relapse of hypercortisolaemic features. RESULTS: In patients operated by TSS, remission of hypercortisolaemia was found in 72.8% of 103 microadenomas and 42.9% of 21 macroadenomas, with recurrence rates 22.7 and 33.3% respectively with a 15-year mean follow-up (range, 6-29 years). Of 27 patients with microadenomas operated after 1991, with positive imaging and pathology, 93% obtained remission with 12% recurrence. In multivariate analysis, the time needed to achieve recovery of hypothalamo-pituitaryadrenal axis was the only significant predictor of recurrence; all patients who recurred showed recovery within 3 years from surgery: 31.3% of patients had total hypophysectomy with no recurrence; 42% of patients with selective adenomectomy and 26.5% with hemi-hypophysectomy showed recurrence rates of 31 and 13% respectively (χ(2)=6.275, P=0.03). Strict remission criteria were not superior in terms of the probability of recurrence compared with post-operative normocortisolaemia. CONCLUSIONS: Lifelong follow-up for patients with CD appears essential, particularly for patients who have shown rapid recovery of their axis. The strict criteria previously used for 'apparent cure' do not appear to necessarily predict a lower recurrence rate.

Overall and cause-specific mortality in GH-deficient adults on GH replacement.

OBJECTIVE: Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. DESIGN: In KIMS (Pfizer International Metabolic Database) 13,983 GH-deficient patients with 69,056 patient-years of follow-up were available. METHODS: This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. RESULTS: All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). CONCLUSIONS: GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

A prospective evaluation of postural stimulation testing, computed tomography and adrenal vein sampling in the differential diagnosis of primary aldosteronism.

CONTEXT: In primary aldosteronism (PA), discriminating unilateral from bilateral disease is crucial because adrenalectomy is frequently curative in the former case but rarely helps in the latter. Various series have reported the utility of postural stimulation testing (PST), cross-sectional imaging and adrenal vein sampling (AVS) in the assessment of PA, but most of these studies were retrospective. OBJECTIVE: To prospectively determine the diagnostic utility of PST, AVS and computed tomography (CT) using a radiological scoring system in the assessment of PA in a tertiary centre, as well as to document the incidence of autonomous cortisol cosecretion. DESIGN AND SETTING: Fifty consecutive patients with PA underwent PST, CT, AVS and a low-dose dexamethasone suppression test with measurement of serum cortisol at 48 h. For patients who underwent surgery, histological confirmation, and a normal postoperative serum aldosterone concentration and plasma renin activity were taken as evidence for unilateral disease. For other patients, results from successful adrenal vein sampling were the diagnostic evidence against which CT and PST were assessed. RESULTS: Postural stimulation testing had a sensitivity and specificity of 44-56% and 71-75%, respectively. CT had an overall sensitivity and specificity of 77% and 80%, respectively, rising to 100% sensitivity and specificity if there was a single, discrete macronodule with an unequivocally normal contralateral gland. Evidence of cosecretion of cortisol occurred in 14% of patients. CONCLUSIONS: Preliminary experience is presented of an objective radiological scoring system for selecting patients with PA for AVS. PST provides little, if any, useful additional information. A significant minority of patients with PA exhibit evidence of cortisol cosecretion, which may have implications for perioperative management.

The interaction between growth hormone and the thyroid axis in hypopituitary patients.

Alterations in the hypothalamo-pituitary-thyroid axis have been reported following growth hormone (GH) administration in both adults and children with and without growth hormone deficiency. Reductions in serum free thyroxine (T4), increased tri-iodothyronine (T3) with or without a reduction in serum thyroid-stimulating hormone secretion have been reported following GH replacement, but there are wide inconsistencies in the literature about these perturbations. The clinical significance of these changes in thyroid function remains uncertain. Some authors report the changes are transient and revert to normal after a few months or longer. However, in adult hypopituitary patients, GH replacement has been reported to unmask central hypothyroidism biochemically in 36-47% of apparently euthyroid patients, necessitating thyroxine replacement and resulting in an attenuation of the benefit of GH replacement on quality of life in those who became biochemically hypothyroid after GH replacement. The group at highest risk are those with organic pituitary disease or multiple pituitary hormone deficiencies. It is therefore prudent to monitor thyroid function in hypopituitary patients starting GH therapy to identify those who will develop clinical and biochemical features of central hypothyroidism, thus facilitating optimal and timely replacement.

Erdheim-Chester disease mimicking multiple meningiomas.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis with systemic manifestations. We present a case report of a patient initially diagnosed with multiple meningiomas, wherein an orbital biopsy disclosed the true nature of the disease.

Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation.

CONTEXT: Preoperative localisation of insulinoma improves cure rate and reduces complications, but may be challenging. OBJECTIVE: To review diagnostic features and localisation accuracy for insulinomas. DESIGN: Cross-sectional, retrospective analysis. SETTING: A single tertiary referral centre. PATIENTS: Patients with insulinoma in the years 1990-2009, including sporadic tumours and those in patients with multiple endocrine neoplasia syndromes. INTERVENTIONS: Patients were identified from a database, and case notes and investigation results were reviewed. Tumour localisation by computed tomography (CT), magnetic resonance imaging (MRI), octreotide scanning, endoscopic ultrasound (EUS) and calcium stimulation was evaluated. MAIN OUTCOME MEASURE(S): Insulinoma localisation was compared to histologically confirmed location following surgical excision. RESULTS: Thirty-seven instances of biochemically and/or histologically proven insulinoma were identified in 36 patients, of which seven were managed medically. Of the 30 treated surgically, 25 had CT (83.3%) and 28 had MRI (90.3%), with successful localisation in 16 (64%) by CT and 21 (75%) by MRI respectively. Considered together, such imaging correctly localised 80% of lesions. Radiolabelled octreotide scanning was positive in 10 out of 20 cases (50%); EUS correctly identified 17 lesions in 26 patients (65.4%). Twenty-seven patients had calcium stimulation testing, of which 6 (22%) did not localise, 17 (63%) were correctly localised, and 4 (15%) gave discordant or confusing results. CONCLUSIONS: Preoperative localisation of insulinomas remains challenging. A pragmatic combination of CT and especially MRI predicts tumour localisation with high accuracy. Radionuclide imaging and EUS were less helpful but may be valuable in selected cases. Calcium stimulation currently remains useful in providing an additional functional perspective.

Discontinuation of growth hormone (GH) treatment during the transition phase is an important factor determining the phenotype of young adults with nonidiopathic childhood-onset GH deficiency.

CONTEXT: Little is known about the impact of childhood-onset GH deficiency (GHD), in particular the duration of GH cessation during the transition phase, on adult phenotype. OBJECTIVE: We investigated the association between the manifestations and management of GHD during childhood/adolescence and the clinical features of GHD in adulthood. DESIGN/SETTING/PATIENTS/INTERVENTION: Patients with reconfirmed childhood-onset GHD who resumed GH treatment as adults were identified from two sequential databases (n = 313). The cohort was followed up longitudinally from GH start in childhood to reinitiation of treatment in adulthood and 1 yr beyond. Analyses were performed in the total cohort and in subgroups of patients with idiopathic GHD (IGHD) and non-IGHD. The cohorts were stratified based on duration of GH cessation (short, < or = 2 yr; long, > 2 yr). MAIN OUTCOME MEASURES: Regimen of pediatric GH administration, duration of GH interruption, IGF-I sd score, lipid concentrations, and quality of life were measured. RESULTS: Mean duration of GH interruption was 4.4 yr. IGF-I sd score in adulthood was related to severity of childhood GHD. In non-IGHD patients, a longer duration of GH interruption was associated with a worse lipid profile (P < 0.0001). Non-IGHD patients who gained more height during childhood GH treatment reported better quality of life than those who gained less height (P < 0.05). CONCLUSIONS: Pediatricians should tailor GH treatment, not only for its beneficial effect on growth but also for future health in adulthood. In adults with reconfirmed GHD, particularly those with non-IGHD, early recommencement of GH should be considered.

A single-center open-label study to investigate the efficacy and safety of repeated subcutaneous injections of lanreotide Autogel in patients with acromegaly previously treated with octreotide.

OBJECTIVE: To evaluate the efficacy of lanreotide Autogel, a depot preparation of a long-acting somatostatin analogue, in patients with acromegaly who were previously treated with octreotide. METHODS: In a prospective single-center, open-label, comparative study, 13 patients were switched from octreotide treatment (baseline) to lanreotide Autogel therapy at a fixed dosage of 90 mg/4 wk. After 6 injections, the dosage was titrated to 60, 90, or 120 mg/4 wk, on the basis of growth hormone (GH) levels, for a further 6 injections. Mean GH and insulinlike growth factor-I (IGF-I) levels were determined at baseline, during treatment (to 48 weeks), and up to 8 weeks after the last injection. RESULTS: There was no significant change in the proportion of patients with GH and IGF-I control from baseline to week 48 (GH, 85% to 89%; IGF-I, 46% to 62%). Mean GH levels changed little from baseline, but mean IGF-I levels were significantly lower after 32 weeks (P<.05) and 48 weeks (P<.02). Data collected at 6 and 8 weeks after the last injection suggested that the efficacy of lanreotide Autogel can persist for longer than 4 weeks. CONCLUSION: This small study suggests that lanreotide Autogel is at least as effective as octreotide in the control of acromegaly and may last for longer than the recommended 4 weeks. It appears to be a useful alternative to long-acting octreotide in the treatment of acromegaly.

Positron emission tomography in the diagnosis and management of intracranial germ cell tumours.

Positron emission tomography (PET) with (18)F-fluorodeoxy-glucose indicates metabolically active tissue. When investigating enhancing intracranial tumours, we have suggested that PET positivity might suggest an intracranial germ cell tumour (IGCT). Here, we present a case with dicentric IGCT where PET was initially discordant between the lesions and where PET then became negative despite clearly aggressive clinical behaviour. A cautionary note is introduced with respect to the interpretation of negative (18)F-FDG PET when investigating enhancing intracranial lesions.

Adult GH deficiency throughout lifetime.

It is now accepted that adults with severe GH deficiency (GHD) demonstrate impaired physical and psychological well-being and may benefit from replacement with recombinant human GH. Post-marketing surveillance surveys, such as the Pfizer International Metabolic Database (KIMS), were initially set-up to provide safety data on long-term treatment but have the added benefit of providing ongoing observational data on the effect of GH replacement on body composition, lipid and glucose status, hypertension, bone density and quality of life. These data demonstrate that although GHD has clinical impact at all ages, the individual consequences of this condition may take on greater significance at different stages in life. At all ages, accurate, safe diagnosis and appropriate GH dosing are necessary to provide the individual with the best possible outcome.

The prevalence and characteristic features of cyclicity and variability in Cushing's disease.

OBJECTIVE: Cyclical Cushing's syndrome may render the diagnosis and management of Cushing's disease difficult. The aim of the present study was to investigate the prevalence of cyclicity and variability in patients with Cushing's disease, and to identify putative distinctive features. DESIGN: Retrospective case-note study. METHODS: We analysed the case records of 201 patients with Cushing's disease in a retrospective case-note study. Cyclicity was considered as the presence of at least one cycle, defined as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The fluctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, defined the variability. RESULTS: Thirty (14.9%; 26 females) patients had evidence of cyclicity/variability. 'Cycling' patients were older but no difference in sex or paediatric distribution was revealed between 'cycling' and 'non-cycling' patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identification was observed in 'cycling' compared with 'non-cycling' patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identification of the adenoma were associated with an increased risk of cyclic disease. CONCLUSIONS: This large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushing's disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specific features can be used as markers.