Two Distinctive POMC Promoters Modify Gene Expression in Cushing Disease.

CONTEXT: Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. OBJECTIVE: We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. METHODS: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. RESULTS: We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. CONCLUSION: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

Revalidation of inferior petrosal sinus sampling: the latest results from a single-center experience.

Cushing's disease (CD), which manifests as excess cortisol secretion, is caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas. Such adenomas are occasionally difficult to identify on magnetic resonance imaging (MRI), and thorough endocrinological examination may be required to detect them. Inferior petrosal sinus (IPS) sampling (IPSS) has been the gold standard test for distinguishing CD from ectopic ACTH syndrome (EAS). However, IPSS is an invasive procedure, and proper catheterization is occasionally challenging due to anatomical variations. Thus, there have been ongoing debates regarding the necessity of this procedure. Here, we present our recent IPSS data derived from the analysis of 65 patients who were referred to us for possible CD between April 2018 and December 2020 after undergoing meticulous endocrinological testing. Even with detailed MRI, no obvious lesions were identified in 19 patients. IPSS performed on these 19 individuals identified an IPS-to-peripheral ACTH gradient in 15 of them. The four patients who lacked this gradient were subjected to a classical algorithm using concurrently measured prolactin levels, the results of which were consistent with their ultimately confirmed diagnoses: two true-positive and two true-negative diagnoses. These findings support the validity of the algorithm and demonstrate that the prolactin-adjusted IPS-to-peripheral ACTH ratio can improve the differentiation between CD and EAS. We had no false-negative results, but three patients were false-positive. Consequently, those three patients in which no apparent tumor was clarified during surgery could not have any endocrinological improvement postoperatively.

Pulmonary nocardiosis associated with Cushing's disease: a case report.

Nocardia spp. is a genus of Gram-positive bacteria which can cause cutaneous, pleuropulmonary, or disseminated disease. The latter two forms are encountered in immunocompromised patients, with prolonged usage of corticosteroids being a well-recognized risk factor. However, endogenous Cushing's syndrome is less frequently associated with nocardiosis. We report on a 40-year-old woman who presented for further workup of abnormal findings in the chest computed tomography (three lung nodules, one of which being cavitary). She underwent trans-thoracic fine-needle lung aspiration of the cavitary nodule, which led to the diagnosis of lung nocardiosis. Moreover, the identification of cushingoid features from the history and clinical examination initiated further investigation with hormonal laboratory assessment and bilateral inferior petrosal sinus sampling which established the diagnosis of pituitary adrenocorticotropic hormone (ACTH) hypersecretion (Cushing's disease).  We conclude that pulmonary nocardiosis can be an opportunistic infection as well as a presenting manifestation of Cushing's disease.

Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas.

PURPOSE: somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been described in patients with Cushing's disease (CD). The aim of the study is to verify whether USP8 mutation may predict early and late outcome of pituitary surgery in patients with CD operated at a single institution. METHODS: We performed a retrospective genetic analysis of 92 adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Specimens were screened for USP8 hotspot mutations in the exon 14 with Sanger sequencing. Hormonal and surgical data were compared between USP8 variant carriers and wild-type tumors. RESULTS: USP8 variants were detected in 22 adenomas (23.9%) with higher prevalence in women (28.9% vs. 5.3% in men; p < 0.05). No significant difference in hormonal levels and tumoral features in relation to USP8 status was observed. Interestingly, USP8-variant carriers were more likely to achieve surgical remission than wild-type adenomas (100% vs. 75.7%; p = 0.01). Conversely, recurrence of CD occurred in 23% of USP8-mutated patients and in 13% of patients with wild-type adenoma. The recurrence-free survival did not differ significantly between the two groups (p = 0.42). CONCLUSIONS: ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated by a single neurosurgeon. Recurrence rates are not related with USP8-variant status.

Hormonal aggressiveness according to the expression of cellular markers in corticotroph adenomas.

PURPOSE: The molecular mechanisms underlying tumor growth in Cushing's disease (CD) still remain a challenge. Moreover, clinical manifestations of CD may vary depending on hormonal activity; however, factors involved in the hormonal aggressiveness of adrenocorticotropic hormone (ACTH)-secreting pituitary tumors have not been fully clarified. We investigated the association between the expression of cellular markers regarding pituitary tumor progression and initial or postoperative hormone levels in patients with CD. METHODS: Tumor tissues from 28 corticotroph adenomas (female 26, male 2, mean age 39.21 ± 10.39 years) were subject to immunohistochemical study using the following antibodies: pituitary tumor-transforming gene 1 (PTTG1), cyclin D1, p16, p27, brahma related-gene 1 (Brg1), and Ki-67. We then analyzed the relationship between each cellular marker expression and hormone levels, including 24 h urinary free cortisol (UFC), plasma ACTH, and serum cortisol. RESULTS: PTTG1 and Ki-67 were expressed in 100% and 50% of patients, respectively. However, the levels did not reflect initial hormonal activity. The cyclin D1-negative group showed higher serum cortisol levels compared to the cyclin D1-positive group (p = 0.01). The 24 h UFC levels were significantly higher in the p27-negative group than in the p27-positive group (p = 0.04), whereas the Brg1-positive group revealed higher serum cortisol levels than in the Brg1-negative group (p = 0.02). CONCLUSIONS: Although PTTG1 and Ki-67 play an essential role in developing ACTH-secreting tumors, cyclin D1, p27, and Brg1 may be better biomarkers to determine hormonal aggressiveness of the tumor. Further research is needed to understand the influence of cellular markers on hormonal activity in CD.

Cushing's syndrome: comparison between Cushing's disease and adrenal Cushing's.

PURPOSE: The most common etiology of Cushing's syndrome (CS) is an ACTH-producing pituitary adenoma (pitCS), reported as 2-3 times more frequent than primary adrenal CS (adrCS). We aimed to analyze and compare features of patients with pitCS and adrCS. METHODS: A retrospective file review of 196 consecutive patients (age 46.8 ± 15.6 years, 76% female) diagnosed with CS in 2000-2017 and followed for 5.2 ± 4.2 years; 109 (55.6%) had pitCS and 76 (38.8%) adrCS. Epidemiologic, clinical and biochemical factors were compared between and within the pitCS and adrCS groups. RESULTS: The relative proportion of pitCS to adrCS (1.4) was lower than previously reported and gradually decreased during the study years to only 1.2 in 2012-2017. The most common reason for CS screening was weight-gain in the pitCS group (48.6%) and adrenal incidentaloma in the adrCS group (39.5%). The pitCS patients were diagnosed at younger age (42.5 ± 15.1 vs. 51.6 ± 15.1 years, p < 0.001) and had lower prevalence of hypertension (51.4 vs. 74%, p = 0.005). There was no between-group difference in severity of hypercortisoluria. Within the adrCS group, patients diagnosed after detection of an adrenal incidentaloma had milder hypercortisoluria than the remaining patients, presented with smaller adrenal lesions (35.9 ± 16.3 vs. 49.1 ± 33.7 cm, p = 0.04), and received post-adrenalectomy glucocorticoid treatment for shorter periods (13 ± 11.6 vs. 31 ± 40 months, p = 0.04). CONCLUSIONS: The relative proportion of adrCS to pitCS is rising, probably because of an increasing detection of cortisol-secreting adrenal incidentalomas associated with milder hypercortisolism. There is no difference between pitCS and adrCS in the severity of hypercortisoluria, although significant clinical differences were found.

Perioperative serum cortisol levels in ACTH sufficient and ACTH deficient patients during transsphenoidal surgery of pituitary adenoma.

PURPOSE: No previous study has analyzed serum cortisol levels during transsphenoidal endoscopic pituitary surgery in patients with and without hydrocortisone (HC) substitution. METHODS: A total of 15 patients undergoing surgery for a pituitary adenoma were studied. Those with normal ACTH function were either not given HC (n = 7) or received 50 mg intravenous HC at the start of surgery (n = 4). Patients with ACTH deficiency received intravenous HC of 100 mg in the morning before surgery (n = 4) with the additional 50 mg for an afternoon operation (n = 2). Propofol and remifentanil were used as anesthetics. Serum cortisol was measured at the start of and every 30 min during surgery. RESULTS: Among 7 patients with normal ACTH function without HC substitution, cortisol levels before surgery were 126-244 nmol/L, among the 4 patients undergoing surgery in the morning, whereas the 3 who underwent surgery in the afternoon had lower levels, 38-76 nmol/L. During nose/sinus surgery cortisol levels decreased to 79-139 and 24-54 nmol/L, respectively. At intrasellar manipulation a distinct rise was noted. Also, in the 4 ACTH sufficient patients receiving HC, cortisol levels decreased during nose/sinus surgery, but only with a slight increase during intrasellar surgery. In the 4 ACTH deficient patients cortisol peaked at 1914-2582 nmol/L. CONCLUSIONS: Patients with normal ACTH function without HC substitution had very low cortisol levels during the first part of surgery, likely suppressed by the anesthetics. After mechanical impact in the sella, a marked increase in cortisol was noted. Supraphysiological cortisol levels were achieved with our routine HC substitution, advising us to reduce the supplementation.

Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review.

PURPOSE: Silent corticotroph adenomas (SCAs) are clinically silent and non-secreting, but exhibit positive adrenocorticotropic hormone (ACTH) immunostaining. We characterized a single center cohort of SCA patients, compared the SCAs to silent gonadotroph adenomas (SGAs), identified predictors of recurrence, and reviewed and compared the cohort to previously published SCAs cases. METHODS: Retrospective review of SCA and SGA surgically resected patients over 10 years and 6 years, respectively. Definitions; SCA-no clinical or biochemical evidence of Cushing's syndrome and ACTH positive immunostaining, and SGA-steroidogenic factor (SF-1) positive immunostaining. A systematic literature search was undertaken using Pubmed and Scopus. RESULTS: Review revealed 814 pituitary surgeries, 39 (4.8%) were SCAs. Mean follow-up was 6.4 years (range 0.5-23.8 years). Pre-operative magnetic resonance imaging demonstrated sphenoid and/or cavernous sinus invasion in 44%, 33% were > 50% cystic, and 28% had high ACTH levels pre-operatively. Compared to SGAs (n = 70), SCAs were of similar size and invasiveness (2.5 vs. 2.9 cm, p = 0.2; 44 vs. 41%, p = 0.8, respectively), but recurrence rate was higher (36 vs. 10%, p = 0.001) and more patients received radiation therapy (18 vs. 3%, p = 0.006). Less cystic tumors (0 vs. 50%, p < 0.001) and higher pre-operative ACTH levels (54 vs. 28 pg/ml, p = 0.04) were predictors of recurrence for SCAs. CONCLUSION: This review is unique; a strict definition of SCA was used, and single center SCAs were compared with SGAs and with SCAs literature reviewed cases. We show that SCAs are aggressive and identify predictors of recurrence. Accurate initial diagnosis, close imaging and biochemical follow up are warranted.

Consensus-driven in-hospital cortisol assessment after ACTH-secreting pituitary adenoma resection.

PURPOSE: Remission from Cushing disease (CD) after pituitary adenoma resection may be predicted by a postoperative reduction in serum cortisol level. A 2008 consensus statement recommends assessing morning cortisol levels during the first postoperative week, and replacing glucocorticoid (GC) if cortisol nadir of < 2 or < 5 µg/dL is achieved. We sought to evaluate adherence to consensus recommendations following adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma resection at our tertiary medical center, and assess time to cortisol nadir to better define the window for assessment and intervention. METHODS: We retrospectively analyzed data extracted from in-hospital electronic medical records for CD surgeries between January 1991 and September 2015. We compared cortisol levels and collection times, ACTH measurement, and postoperative and discharge GC treatment before and after consensus statement publication in July 2008. RESULTS: 107 surgeries were performed in 92 patients with CD. After 2008, more surgeries had at least one cortisol value assessed (67.9% before vs. 91.3% after, p = 0.033), with median initial cortisol measurement at 14 h post-surgery. However, ACTH measurement remained unchanged (42.9% vs. 43.5%; p > 0.99). Cortisol collection during GC treatment tended to increase (32.7% vs. 57.1%; p = 0.068). Of surgeries performed without prior GC treatment, 31.7 and 55.0% had a cortisol nadir of < 2 and < 5 µg/dL, respectively, within 72 h postoperative. CONCLUSIONS: Our physicians were more diligent in measuring in-hospital postoperative cortisol levels consistent with 2008 consensus recommendations. Better management of cortisol measurements and their timing is an opportunity for improvement.

Perioperative hypothalamic pituitary adrenal function in patients with silent corticotroph adenomas.

BACKGROUND: Silent corticotroph adenomas (SCAs) are characterized by strong ACTH immunostaining without clinical manifestations of hypercortisolism. Patients with SCAs often present with mechanical symptoms related to tumor growth. This study investigates the hypothalamic pituitary adrenal axis (HPA) characteristics after adenomectomy in patients with SCAs. METHODS: Biochemical parameters of HPA function were monitored frequently after surgical resection of non-functioning macroadenomas. Levels of ACTH, cortisol, DHEA and DHEA-S were measured frequently for 48 h after adenomectomy. HPA data of patients with SCAs (n = 38) were compared to others (Controls) with non-secreting, ACTH-negative immunostaining adenomas of similar age and gender distribution (n = 182) who had adenomectomy. RESULT: Plasma ACTH increased (P < 0.0001) equally in patients with SCA and controls reaching a peak at 3 h (238 ± 123 vs. 233 ± 96 ng/L, respectively) after extubation declining thereafter to baseline values 24-36 h. Similarly, serum cortisol levels increased (P < 0.0001) equally in both groups reaching a maximum at 7 h (36.8 ± 13.9 vs. 39.3 ± 13.3 ug/dL). Serum DHEA also increased (P < 0.001) equally in both groups in parallel to the rise in serum cortisol. Serum DHEA-S levels similarly increased (P < 0.001) from their respective baseline (105.9 ± 67.5 and 106.5 ± 58.7 ug/dL) reaching their peak (154.5 ± 69.5 and 153.5 ± 68.6 ug/dL; respectively) at 15 h after extubation. None of the patients acquired any hormone deficits. CONCLUSIONS: Under the maximal stimulation of the peri-operative stress, HPA function in patients with SCA behaved in an identical manner to others with ACTH-negative macroadenomas. Thus, despite the strong ACTH-positive immunostaining of these tumors, SCAs are truly non- functional.

Circadian Plasma Cortisol Measurements Reflect Severity of Hypercortisolemia in Children with Different Etiologies of Endogenous Cushing Syndrome.

BACKGROUND: The utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet. METHODS: A retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated. RESULTS: Plasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them. CONCLUSION: Our study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.

Efficacy of Microsurgical Sublabial Approach (MSA) Versus Endoscopic Endonasal Approach (EEA) for the Treatment of Pituitary Adenomas Based on Radiological and Hormonal Outcome.

BACKGROUND: The purpose of this study was to compare the surgical efficacy of the microsurgical sublabial approach (MSA) versus the endoscopic endonasal approach (EEA) for the treatment of pituitary adenomas, based on short-term (12 months) radiological and endocrinological follow-up. METHODS: One hundred and fourteen patients affected by pituitary adenoma were enrolled at our Unit between January 2007 and February 2012; 72 were treated with MSA, and 42 with EEA. The preoperative parameters considered were: type of lesion (secreting or nonsecreting), lesion size, presence of intralesional hemorrhage, lesion perimeter (nodular vs. uniform), intrasellar vs. suprasellar, involvement of cavernous sinus, and osteodural infiltration. Hormonal assays and magnetic resonance imaging (MRI) scans were performed at 12 months after the surgical procedure. RESULTS: Univariate analysis of the data documented a statistically significant difference in favor of MSA for the subgroups of secreting adenomas (90.9 % vs. nonsecreting 48.3 %), microadenomas (100 % vs. macroadenomas 57.1 %), adenomas without osteodural infiltration (87.5 % vs. 55.5 % with the infiltration) or those without intralesional hemorrhage (75 % vs. 45.9 % with the hemorrhage), and growth hormone (GH) adenomas (88.8 % vs. 43.7 %). Multivariate analysis confirmed the greater effectiveness of MSA for the treatment of micro-secreting adenomas. CONCLUSIONS: Recent advances in the EEA for treating pituitary adenomas could lead to this modality replacing the microsurgical technique. In our experience the MSA allowed us to achieve better results in the treatment of microadenomas.

The Response of C19 Δ5-steroids to ACTH Stimulation and Hypoglycemia in Insulin Tolerance Test for Adrenal Insufficiency.

Studies on the time course of ACTH- or insulin-induced hypoglycemia stimulating adrenal androgens are usually limited to dehydroepiandrosterone and/or its sulphate. Our data on dehydroepiandrosterone (DHEA) and its hydroxylated metabolites clearly show that measurements of DHEA and its sulphate (DHEAS) are valuable markers of the integrity of the HPA (hypothalamus-pituitary-adrenal) axis. Assessments of HPA function should rely on measurements of baseline and/or stimulated serum cortisol concentrations, and C19 Δ5-steroids may provide additional information. The art of stimulation of 7- and 16-hydroxylated metabolites of DHEA can help our understanding of the formation sequence of these compounds.

VENOUS SAMPLING FOR CUSHING DISEASE: COMPARISON OF INTERNAL JUGULAR VEIN AND INFERIOR PETROSAL SINUS SAMPLING.

OBJECTIVE: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS. METHODS: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus. RESULTS: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity). CONCLUSION: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotrophin-releasing hormone CS = Cushing syndrome DDAVP = desmopressin EAS = ectopic ACTH secretion IJVS = internal jugular vein sampling IPSS = inferior petrosal sinus sampling JVS = jugular venous sampling MRI = magnetic resonance imaging.

Clinical significance of screening for subclinical Cushing's disease in patients with pituitary tumors.

Cushing's syndrome (CS) is a clinical state caused by chronic excess of glucocorticoid, and results in hypertension, impaired glucose tolerance, and dyslipidemia. Recently, a mild state of pituitary CS without typical Cushingoid appearance (subclinical Cushing's disease; SCD) has been identified. However, the true prevalence of SCD and its effect on metabolic disorders remain obscure. The aim of this prospective study was to determine the prevalence of SCD according to the guideline proposed by the working group of the Japanese Ministry of Health, Welfare and Labor, and to assess the outcome of surgery on metabolic disorders. The prevalence of SCD was investigated in 105 consecutive patients diagnosed with pituitary adenomas by MRI. ACTH-dependent hypercortisolism was diagnosed based on the results of the 0.5 mg dexamethasone suppression test (serum cortisol >3.0 µg/dL) plus one positive finding of the following two tests: midnight serum cortisol level >5.0 µg/dL or ACTH increase >50% after 1-deamino-5-D-arginine vasopressin (DDAVP) challenge. The final diagnosis of SCD was established by positive staining for ACTH in surgically-excised pituitary adenoma. Three patients (4.8%) were diagnosed with SCD among 62 patients with pituitary adenoma. Transsphenoidal adenomectomy partially resulted in improvement of blood pressure and glucose metabolism in SCD patients. Our results emphasize the importance of SCD screening in patients with pituitary tumors, especially in those patients with metabolic disorders.

Diagnosis of Cushing's disease.

Diagnosis of Cushing's disease frequently remains a challenge. In this review we critically appraise the clinical features, biochemical tests, and imaging modalities used for this purpose. We outline recommendations for approaches to clinical investigation, with a particular focus on developments made within the last two years.

Medical combination therapies in Cushing's disease.

INTRODUCTION: There has been growing interest on medical therapy for the management of Cushing's disease (CD), particularly in cases of persistent or recurrent hypercortisolism. Ketoconazole, an inhibitor of adrenal steroidogenesis, is the most widely used drug, whereas cabergoline and pasireotide are the most promising centrally acting agents. The main purpose of this review article is to highlight the options of medical treatment for CD, with a special emphasis on combination therapies, a topic that has only been addressed by a limited number of studies. CONCLUSIONS: According to the results of these studies, combination therapies involving medications with additive or synergistic effects on ACTH and cortisol secretion seem quite attractive as they yield higher probability of longterm control of the hypercortisolism at lower doses, a lower incidence of side-effects, and possibly a lower rate of treatment escapes. Currently, ketoconazole, cabergoline, and pasireotide are the best drugs to be prescribed in combination.

ACTH adenomas transforming their clinical expression: report of 5 cases.

OBJECT Adrenocorticotropic hormone (ACTH) adenomas have been recognized as a more aggressive and invasive subtype of pituitary adenomas. An additional and clinically relevant peculiarity of these tumors is their ability to modify their clinical expression from a silent form to Cushing disease or vice versa. The aim of this study was to review a series of patients with pituitary adenomas and analyze the clinical implications of the transformation of clinical expression in 5 cases that showed this phenomenon. METHODS The authors retrospectively reviewed a series of patients with pituitary adenoma and collected clinical, biohumoral, and neuroradiological data of those who presented with a transformation from silent ACTH adenomas to functioning tumors or vice versa. In all the cases, preoperative assessment consisted of brain MRI, ophthalmological examination, and complete baseline endocrinological investigation. In patients with clinical and/or biochemical findings suspicious for Cushing syndrome, a low-dose dexamethasone suppression test was performed to rule in or out this diagnosis. Endocrinological evaluations were repeated 1 month after surgery, 3 months after surgery, and every 6 months or annually thereafter. Ophthalmological evaluations and brain MRIs were repeated after 3 months and then every 6 or 12 months thereafter. RESULTS Five patients (2 men and 3 women) included in this series had corticotropic tumors that showed transformation from an endocrinologically silent form to manifest Cushing disease and vice versa. The mean age at presentation was 40 years (range 18-51 years). In 3 of these patients, a transformation from silent to functioning ACTH adenoma with manifest Cushing disease occurred. In 1 patient, the authors observed the transition from a functioning to a silent adenoma with spontaneous resolution of hypercortisolism. Another patient's silent adenoma "shifted" to a functioning adenoma and then regressed back to a silent form with spontaneous resolution of Cushing disease. This patient again developed hypercortisolism, which finally resolved spontaneously. In this series, the transformation occurred after a mean of 3.5 years (range 6 months to 7 years). The shift from an ACTH-silent to a functioning adenoma was observed in 9% of the ACTH-silent adenomas in this series (4 of 44 cases), and the spontaneous remission of Cushing disease to a silent corticotroph cell adenoma occurred in 1.5% of cases of this series (2 of 132 functioning ACTH adenomas). At follow-up (mean 107 months; range 60-177 months), cortisol levels were within normal limits in all 5 cases. However, 1 patient required Gamma Knife radiosurgery and eventually adrenalectomy for disease control to be achieved. CONCLUSIONS The ability of silent ACTH adenomas to transform their secretion pattern poses a challenge for neurosurgeons and endocrinologists. Because the transformation is often unexpected, the clinical and biochemical data can be underestimated. Furthermore, this bizarre and unpredictable postoperative tumor behavior can lead to misinterpretation of clinical and endocrinological outcomes. Even if these cases are very rare, they are not anecdotal in large series. Thus, ACTH adenomas require careful biohumoral and neuroradiological follow-up to detect possible transformations.

Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers.

Morbidity and mortality in Cushing's disease (CD) patients are increased if patients are not appropriately treated. Surgery remains the first line therapy, however the role of medical therapy has become more prominent in patients when biochemical remission is not achieved/or recurs after surgery, while waiting effects of radiation therapy or when surgery is contraindicated. Furthermore, use of preoperative medical therapy has been also recognized. In addition to centrally acting therapies (reviewed elsewhere in this special issue), adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are frequently used. A PubMed search of all original articles or abstracts detailing medical therapy in CD, published within 12 months (2013-2014), were identified and pertinent data extracted. Although not prospectively studied, ketoconazole and metyrapone have been the most frequently used medical therapies. A large retrospective ketoconazole study showed that almost half of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement; however almost 20% discontinued ketoconazole due to poor tolerability. Notably, hepatotoxicity was usually mild and resolved after drug withdrawal. Etomidate remains the only drug available for intravenous use. A new potent inhibitor of both aldosterone synthase and 11ß-hydroxylase, following the completion of a phase II study LCI699 is being studied in a large phase III with promising results. Mifepristone, a glucocorticoid receptor antagonist, has been approved for hyperglycemia associated with Cushing's syndrome based on the results of a prospective study where it produced in the majority of patients' significant clinical and metabolic improvement. Absence of both a biochemical marker for remission and/or diagnosis of adrenal insufficiency remain, however, a limiting factor. Patient characteristics and preference should guide the choice between different medications in the absence of clinical trials comparing any of these therapies. Despite significant progress, there is still a need for a medical therapy that is more effective and with less adverse effects for patients with CD.

Bilateral adrenalectomy for Cushing's disease.

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