Nuevas perspectivas en el tratamiento farmacológico de la enfermedad de Cushing

Hypercortisolism induced by Cushing disease causes high morbidity and mortality.The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs.The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate).The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported.A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published.The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid.A special review is made of the available clinical trials with pasireotide and cabergoline.     

Successful treatment of Cushing's disease using yttrium-90 rods.

Interstitial irradiation using yttrium-90 (90Y) rods implanted by needle into the pituitary gland was used as primary treatment in 16 patients with pituitary dependent Cushing''s disease. Clinical and biochemical remission was observed within three or six months in 13 and in the remaining three after a supplementary implant. There was no perioperative morbidity. Follow-up from the time of definitive operation ranged from six to 123 months (mean 39). No recurrence has been observed. The return of a normal diurnal cortisol rhythm has been observed in 10/12 patients studied after remission. Some form of long-term pituitary hormone replacement therapy was required in only the six patients who had received the largest irradiation dose. Implantation of 90Y is safe and effective treatment for patients with Cushing''s disease, comparing favourably with selective trans-sphenoidal pituitary surgery.     

Increased MIB-1/Ki-67 labeling index as a predictor of an aggressive course in a case of prolactinoma

Secondary resistance to dopamine agonists is a rare phenomenon in patients with a prolactinoma. We describe a 55-year-old male with a macroprolactinoma initially responding favorably to bromocriptine treatment with normalization of prolactin levels and tumor shrinkage. Two years later, he developed resistance to bromocriptine treatment and subsequently to cabergoline. The aggressive course of the disease necessitated three surgical interventions. Staining of the pituitary tissue revealed a very high MIB/Ki-67 labeling index that increased further in specimens derived from repeated surgery. This case demonstrates that high and increasing levels of the MIB/Ki-67 labeling index may indicate an aggressive course associated with secondary dopamine resistance.     

External irradiation of the hypophysis for Cushing's disease

During the past 12 years 17 patients with Cushing''s disease (bilateral adrenal hyperplasia secondary to excessive pituitary adrenocorticotrophic hormone) have been treated initially with external pituitary irradiation. Of the 15 patients who have had adequate follow-up, nine showed complete biochemical remission, and one showed biochemical improvement. There were no complications. It is therefore recommended that the first mode of therapy for all patients with Cushing''s disease should be pituitary irradiation if the patient''s clinical condition permits.     

The importance of presurgical somatostatin analogue therapy in acromegaly

Different types of treatment, including surgery, medical therapy and radiotherapy, are possible in achieving control of acromegaly. Of the medical therapies available, somatostatin analogues are effective in the majority of patients and can induce pituitary tumour shrinkage. The rationale and outcome of somatostatin analogue treatment before surgery in patients with acromegaly is briefly presented. In summary, the benefits of somatostatin analogues given preoperatively should be considered carefully as optimisation of cardiovascular, respiratory and metabolic functions is clinically relevant for perioperative morbidity. Somatostatin analogues also induce significant shrinkage of GH-secreting pituitary tumours, although this does not seem to be helpful in terms of improved surgical outcome.     

New medical approaches in pituitary adenomas

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5-1.0 microg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D(2) receptors using specific radiotracers such as (123)I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing's disease or Nelson's syndrome.     

Pituitary Adenoma: A Clinician’S Perspective

ObjectiveTo review the underlying causes of pituitary lesions, a rational approach to their diagnosis, and therapeutic options.MethodsThe types of pituitary lesions and their clinical manifestations are reviewed, and treatment strategies and long-term follow-up are discussed.ResultsA pituitary adenoma is quite common and poses a challenge to the clinician to determine the clinical significance, the appropriate diagnosis, the need for treatment, and the appropriate therapy or therapies. The treatment of a pituitary adenoma depends on the type of tumor; a prolactinoma is treated medically with a dopamine agonist drug, and other lesions are usually treated by transsphenoidal surgical removal. Replacement of a deficient hormone or hormones is necessary for optimal functioning. Some patients require more than one treatment, including surgical intervention, replacement of a hormone or hormones, medications to lower hormone hypersecretion to normal (for prolactinoma, acromegaly, or Cushing disease), pituitary radiation therapy (optimally with focused irradiation such as the Gamma Knife or LINEAC), and, in the situation of persistent Cushing disease, bilateral adrenalectomy as a last resort. Lifelong monitoring is necessary for all these patients.ConclusionThe goal is to decrease the mass effect of the adenoma, to restore normal pituitary function, and to suppress hormone hypersecretion. Achievement of this goal necessitates the cooperation and interdisciplinary efforts of several medical specialties. (Endocr Pract. 2008;14:757-763)     

Effective Long-Term Treatment of Cushing’s Disease with Pasireotide: A Case Report

ObjectiveCushing’s disease is a rare, devastating condition associated with high morbidity and increased mortality. Primary treatment for Cushing’s disease is transsphenoidal surgery to remove the pituitary adenoma; however, recurrence can occur in up to 25% of patients. Second-line medical therapies do not directly target the pituitary tumor. Thus, normalization of adrenocorticotropic hormone (ACTH) and inhibition of tumor growth is not usually achieved.MethodsIn this case report, we present a de novo patient with a pituitary macroadenoma who was randomized to receive treatment with subcutaneous twice-daily injections of pasireotide 900 μg as part of the double-blind, Phase III CSOM230B2305 clinical trial.ResultsAround one month after treatment initiation, the patient’s urinary free cortisol (UFC) level showed a dramatic reduction (from 151.1 to 7.4 μg/24h) necessitating a dose reduction to 600 μg to relieve the symptoms of corticosteroid withdrawal. One month after dose reduction, the patient’s UFC levels remained stable and were associated with improvements in clinical signs and symptoms. These improvements continued into the 12-month extension phase following a dose increase to 900 μg and were accompanied by a significant reduction in tumor volume (from 0.797 cm³ at baseline to 0.359 and 0.365 cm³ at months 18 and 24, respectively). UFC remained normalized throughout the extension period. During the study, the patient developed hyperglycemia, which was effectively controlled with diet and then medication.ConclusionIn this case study, long-term pasireotide treatment as first-line therapy led to normalization of UFC, reduction of tumor volume and significant improvement in the clinical signs and symptoms of Cushing’s disease. (Endocr. Pract. 2013;19:e92-e96)     

Substantial Shrinkage of Adenomas Cosecreting Growth Hormone and Prolactin with use of Cabergoline Therapy

ObjectiveTo present 2 cases of patients with acromegaly and severe hyperprolactinemia whose primary therapy with cabergoline resulted in hormonal normalization and a considerable reduction in the size of their somatotroph macroadenomas.MethodsWe summarize the clinical presentation and the pertinent laboratory findings in 2 patients with acromegaly, as well as their clinical response to the therapy with cabergoline. A review of the literature regarding the use of cabergoline in acromegaly is also presented.ResultsA 48-year-old man (case 1) and a 26-year-old woman (case 2) were found to have acromegaly associated with very high levels of serum prolactin (2,700 and 5,250 ng/mL, respectively). These patients received first-line therapy with cabergoline that resulted not only in clinical improvement and normalization of growth hormone, prolactin, and insulin-like growth factor-I levels but also in a substantial reduction in the size of their somatotroph macroadenomas. By 6 months after the patients began to take cabergoline, tumor shrinkage of 94% (in case 1) and of 70% (in case 2) was demonstrated by magnetic resonance imaging.ConclusionOur findings demonstrate that cabergoline should be considered for medical treatment of adenomas cosecreting growth hormone and prolactin, even in the presence of large tumors with appreciable suprasellar extension, because substantial tumor shrinkage is possible with this therapy. (Endocr Pract. 2007;13:396-402)     

Pasireotide and Mifepristone: New Options in the Medical Management of Cushing's Disease

ObjectiveTo review and evaluate medical therapies for Cushing’s disease (CD), with an emphasis on recent clinical trial experience with pasireotide and mifepristone, and to discuss the therapeutic potential and appropriate selection of these compounds in this patient population.MethodsRecently published Phase III trial data for each compound are reviewed and assessed, and relative benefits and risks are examined and compared where possible.ResultsMifepristone and pasireotide are both potentially beneficial for CD patients but have greatly dissimilar mechanisms of action and adverse event (AE) profiles. Pasireotide acts at the level of the pituitary adenoma, reducing cortisol levels through inhibition of adrenocorticotropic hormone (ACTH) release. However, pasireotide reduces insulin secretion and incretin hormone response and is associated with significant risk for new or worsening hyperglycemia. Mifepristone ameliorates the signs and symptoms of hypercortisolemia via glucocorticoid receptor (GR2) blockade, but this approach raises serum cortisol levels and increases risk for adrenal insufficiency (AI), hypokalemia, and endometrial thickening. While response to pasireotide can be monitored via measurements of serum, urine, or late-night salivary cortisol, evaluation of response to mifepristone is solely based on changes in clinical parameters (e.g., hyperglycemia, hypertension, body weight/composition).ConclusionManagement of persistent CD is challenging, and the decision to initiate medical treatment hinges on many factors. Pasireotide may be a more attractive option for most patients due to its action at the underlying tumor and the ability to monitor biochemical responses. However, mifepristone may be more appropriate when it is necessary to avoid or minimize risk for hyperglycemiarelated complications. (Endocr Pract. 2014;20:84-93)     

Pituitary tumors. Current concepts in diagnosis and management.

Diagnostic advances have resulted in earlier and more frequent recognition of pituitary tumors. Pituitary tumors cause problems owing to the hormones they secrete or the effects of an expanding sellar mass--hypopituitarism, visual field abnormalities, and neurologic deficits. Prolactin-secreting tumors (prolactinomas), which cause amenorrhea, galactorrhea, and hypogonadism, constitute the most common type of primary pituitary tumors, followed by growth hormone-secreting tumors, which cause acromegaly, and corticotropin-secreting tumors, which cause Cushing''s syndrome. Hypersecretion of thyroid-stimulating hormone, the gonadotrophins, or alpha-subunits is unusual. Nonfunctional tumors currently represent only 10% of all clinically diagnosed pituitary adenomas, and some of these are alpha-subunit-secreting adenomas. Insights into the pathogenesis and biologic behavior of these usually benign tumors have been gained from genetic studies. We review some of the recent advances and salient features of the diagnosis and management of pituitary tumors, including biochemical and radiologic diagnosis, transsphenoidal surgery, radiation therapy, and medical therapy. Each type of lesion requires a comprehensive but individualized treatment approach, and regardless of the mode of therapy, careful follow-up is essential.     

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.     

Plasma Levels of Immunoreactive Corticotrophin in Patients with Cushing's Syndrome

Plasma levels of immunoreactive corticotrophin (A.C.T.H.) have been determined in 56 patients with Cushing''s syndrome by means of a homologous radioimmunoassay. In untreated Cushing''s disease (bilateral adrenal hyperplasia due to excessive A.C.T.H. secretion from the pituitary) plasma values ranged from 40 to 200 μμg./ml., between 8 and 10 a.m., compared with a range in normal subjects of 12 to 60 μμg./ml. Considerably raised levels, often above 2,000 μμg./ml., were found in patients with Cushing''s disease after bilateral adrenalectomy. A.C.T.H. concentrations were usually higher in patients with bilateral adrenal hyperplasia associated with ectopic A.C.T.H. production than in patients with untreated Cushing''s disease; whereas plasma A.C.T.H. was undetectable in the presence of an adrenocortical tumour. All patients with Cushing''s syndrome failed to show the normal circadian rhythm of circulating A.C.T.H. levels.     

American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: Management of Acromegaly Patients: What is the Role of Pre-Operative Medical Therapy?

Objective: Acromegaly is a complex disease characterized by growth hormone (GH) excess originating in most cases from a pituitary tumor. The goals of treatment include removing the tumor or reducing tumor burden, normalizing GH secretion and insulin-like growth factor 1 levels, and preserving normal pituitary function if possible. Surgery by an experienced neurosurgeon is still considered first-line therapy, especially in cases with small tumors. In the last few decades, significant progress in the development of selective pharmacologic agents has greatly facilitated the management of active acromegaly, with agents such as somatostatin-receptor ligands (SRLs), GH-receptor antagonists, and dopamine agonists. In addition to adjuvant treatment, pre-operative medical therapy and primary therapy in de novo patients are increasingly employed.Methods: A United States National Library of Medicine PubMed search (through July 2014) was conducted for the following terms: acromegaly, pre-operative medical therapy, somatostatin-receptor ligands, and somatostatin analogs. Articles not in English and those not in peer-reviewed journals were excluded. In reviewing pertinent articles, focus was placed on biochemical and other postoperative outcomes of medical therapy.Results: An analysis of the full effect of pre-operative use of SRLs on surgical outcomes (remission rates and peri-operative complications) is limited by heterogeneity of methodology, low overall surgical cure rates, and different study designs. The assumption that SRL use prior to surgery reduces peri-operative surgical risk has yet to be proven. A variable degree of tumor shrinkage with preoperative SRLs is observed. Likewise, SRL treatment 3 months before surgery may improve surgical remission rates in the short term; however, positive results do not persist in the long term.Conclusion: We consider that medical therapy before surgery could play a role in carefully selected patients, but treatment should be individualized. Primary medical therapy with a SRL may be considered in patients with macroadenomas without local mass effects on the optic chiasm, as SRLs have been shown to reduce tumor size and control GH hypersecretion. However, the data are insufficient to support general use of a SRL prior to surgery in order to improve post-surgery biochemical outcomes. Theoretically, patients with severe cardiac and respiratory complications due to acromegaly could potentially benefit from pre-operative SRLs in order to reduce peri-operative morbidity. Further investigation and investment in large randomized long-term clinical trials are needed to define the precise role and duration of pre-surgical medical treatment in acromegaly patients.Abbreviations: GH = growth hormone IGF-1 = insulin-like growth factor 1 MRI = magnetic resonance imaging SRL = somatostatin-receptor ligand     

Factores pronósticos de remisión a largo plazo tras cirugía transesfenoidal en la enfermedad de Cushing

There is no consensus on the remission criteria for Cushing's disease or on the definition of disease recurrence after transsphenoidal surgery, and comparison of the different published series is therefore difficult. A long-term recurrence rate of Cushing's disease ranging from 2%-25% has been reported. Predictors of long-term remission reported include: 1) adenoma–related factors (aggressiveness, size, preoperative identification in MRI), 2) surgery-related factors, mainly neurosurgeon experience, 3) clinical factors, of which dependence on and duration of glucocorticoid treatment are most important, and 4) biochemical factors. Among the latter, low postoperative cortisol levels, less than 2 mcg/dL predict for disease remission. However, even when undetectable plasma cortisol levels are present, long-term recurrence may still occur and lifetime follow-up is required. We report the preliminary results of the first 20 patients with Cushing's disease operated on at our hospital using nadir cortisol levels less than 2 mcg/dl as remission criterion.     

Five cases of cyclical Cushing's syndrome.

Reported cases of cyclical Cushing''s syndrome are rare. Of 14 successive patients with Cushing''s syndrome nine collected sequential urine samples for the estimation of cortisol:creatinine ratio. Five had cyclical Cushing''s syndrome while two had considerable variation in urinary cortisol excretion without a cyclical pattern being established. Two of the five patients with a cyclical syndrome had paradoxical responses to dexamethasone. In only one patient with a cyclical pattern did the cortisol:creatinine ratio fall after treatment with bromocriptine or cyproheptadine, or both. The high incidence of the cyclical form of Cushing''s syndrome has important clinical implications. A high index of suspicion of the syndrome is required in patients with symptoms or signs of Cushing''s syndrome but with normal cortisol values, in patients with fluctuating cortisol values, and in patients with anomalous responses to dexamethasone. Because of possible variations in steroidogenesis the results of drug studies in Cushing''s syndrome must be interpreted cautiously.     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

Overnight Dexamethasone Suppression Test: A Reliable Screen for Cushing's Syndrome in the Obese

Objective: Reevaluation of the validity of the 1-mg overnight dexamethasone suppression test (ODST) as a screening test for Cushing's syndrome in obese patients. Research Methods and Procedures: Eighty-six obese patients (body mass index, 30 to 53 kg/m²) that were referred to a general endocrine outpatient clinic for evaluation of simple obesity, diabetes mellitus, hypertension, polycystic ovary disease, or pituitary tumor. One milligram dexamethasone was administered orally at 11:00 pm , and serum cortisol levels were measured the following morning between 8:00 am and 9:00 am . Suppression of serum cortisol to <80 nM (3 μg/dL) was chosen as the cut-off point for normal suppression. Patients with serum cortisol levels ≥80 nM were evaluated for Cushing's syndrome. Results: Suppression of morning cortisol levels to <80 nM occurred in 79 of the 86 obese patients. Seven patients had serum cortisol levels higher than 80 nM; five were eventually diagnosed with Cushing's syndrome and two were considered false positive results in view of normal 24-hour free urinary cortisol and normal suppression on a low dose dexamethasone suppression test (0.5 mg of dexamethasone every 6 hours for 2 days). We found a false positive rate of 2.3% for the ODST using a cut-off serum cortisol of 80 nM. Discussion: The ODST is a valid screening test for Cushing's syndrome in the obese population. The false positive rate was 2.3%, even when using a strict cut-off serum cortisol of 80 nM. Abnormal cortisol suppression in obese patients should be investigated and not be considered false positive results.     

Pregnancy,prolactin, and pituitary tumours

Nine pregnancies are described in patients with pituitary tumours. All patients had definite radiological evidence of a pituitary tumour and no evidence of acromegaly or Cushing''s disease. In seven patients serum prolactin levels were estimated before pregnancy and found to be raised.Seven patients had been treated with pituitary implantation of yttrium-90. The remaining two developed complications of the tumour during pregnancy. One developed a bitemporal visual field defect in the second trimester which was successfully treated by emergency yttrium-90 implantation. The other developed diabetes insipidus in the third trimester which resolved spontaneously after delivery.Six patients were treated with drugs to achieve pregnancy. Four took bromocriptine to suppress raised prolactin levels, one was treated with human menopausal gonadotrophin, and one was treated with clomiphene.     

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease

ObjectiveTo assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case.Material and methodsLaboratory tests included morning and midnight serum cortisol levels, 24 h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques.ResultsA patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results.ConclusionsOur case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.