Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas.

INTRODUCTION: The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion, and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e., Cushing's disease, a disorder with few medical treatment options. Silibinin, a HSP90 inhibitor, has been studied in tumoral corticotroph cells and its use proposed in Cushing's disease. Aim of the present study was to further investigate the effect of silibinin on human corticotroph adenomas in vitro. METHODS: Seven human ACTH-secreting pituitary adenomas were established in culture and treated with 10-50 µm silibinin with/without dexamethasone for up to 72 h. ACTH medium levels were measured, and POMC and glucocorticoid receptor, i.e., NR3C1, gene expression assessed. RESULTS: Silibinin reduced spontaneous ACTH secretion and restored sensitivity to steroid negative feedback to a different extent in individual adenomas. POMC expression was decreased in both control and dexamethasone-treated wells in specimens sensitive to silibinin. Interestingly, silibinin reduced constitutive NR3C1 expression and reversed the dexamethasone-induced inhibition. CONCLUSIONS: Our findings indicate that silibinin can inhibit ACTH synthesis and secretion in individual human corticotroph adenomas and directly affects NR3C1 gene expression. These results reveal promising effects of this HSP90 inhibitor on human corticotroph adenomas and support an innovative target treatment for patients with Cushing's disease.

Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome.

PURPOSE: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. METHODS: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). RESULTS: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. CONCLUSIONS: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing.

BACKGROUND: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. OBJECTIVES: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. METHODS: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. RESULTS: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. CONCLUSIONS: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more "typical" corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

Early varicocelectomy by percutaneous scleroembolization improves seminiferous tubules spermatozoa release in the adolescent phase of testicular growth.

Varicocele is a rather common andrological condition in adolescents, which can adversely affect testicular growth and seminal parameters, leading to infertility in about 20% of adults. The aim of this study was to investigate if treating varicocele before the age of 18 is a beneficial option to improve testicular hypotrophy and seminal parameters and if minimally invasive techniques could be an appropriate treatment choice for adolescent varicocele associated with spermatic vein reflux. A percutaneous scleroembolization was performed in sixty-four consecutive young patients (13-19 years old) with left varicocele, preceded by a fluoroscopy. In thirty-four of them, semen samples were also collected. We examined semen samples and testicles dimensions before and after percutaneous varicocelectomy, compared to a nonoperated control group, with a six-month follow-up. Total sperm count and sperm morphology were significantly increased in the intervention group. Left testicular volume significantly increased in both groups, while only correction of varicocele improved spermatozoa release per unit of testis volume. We conclude that early varicocelectomy by percutaneous scleroembolization significantly ameliorates seminiferous tubules activity in the critical adolescent phase of testicular growth. It is suggested that adolescents should be; offered varicocele repair as soon as possible in order to improve reproductive potential.

Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells.

An increased rate of acromegaly was reported in industrialized areas, suggesting an involvement of environmental pollutants in the pathogenesis and behavior of GH-secreting pituitary adenomas. Based on these premises, the aim of the study was to evaluate the effects of some widely diffused pollutants (i.e. benzene, BZ; bis(2-ethylhexyl) phthalate, DEHP and polychlorinated biphenyls, PCB) on growth hormone secretion, the somatostatin and estrogenic pathways, viability and proliferation of rat GH-producing pituitary adenoma (GH3) cells. All the pollutants induced a statistically significant increase in GH secretion and interfered with cell signaling. They all modulated the expression of SSTR2 and ZAC1, involved in the somatostatin signaling, and the expression of the transcription factor FOXA1, involved in the estrogen receptor signaling. Moreover, all the pollutants increased the expression of the CYP1A1, suggesting AHR pathway activation. None of the pollutants impacted on cell proliferation or viability. Present data demonstrate that exposure to different pollutants, used at in vivo relevant concentrations, plays an important role in the behavior of GH3 pituitary adenoma cells, by increasing GH secretion and modulating several cellular signaling pathways. These observations support a possible influence of different pollutants in vivo on the GH-adenoma aggressiveness and biological behavior.

Benzene and 2-ethyl-phthalate induce proliferation in normal rat pituitary cells.

PURPOSE: Endocrine disruptors are known to modulate a variety of endocrine functions and increase the risk for neoplasia. Epidemiological data reported increased prevalence of pituitary tumors in high industrial areas while genotyping studies showed that mutations in the aryl hydrocarbon receptor (AhR) interacting protein (AIP)-chaperone to the dioxin ligand AhR-gene are linked to predisposition to pituitary tumor development. Aim of the present study was to establish whether endocrine pollutants can induce cell proliferation in normal rat pituitary cells. METHODS: Pituitary primary cultures were incubated with 250, 650 and 1250 pM benzene or 2-ethyl-phthalate for up to 96 h and viability, energy content and cell proliferation assessed. Expression of pituitary tumor transforming gene (PTTG), cyclin D1 (Ccnd1), AhR and AIP was quantified by RT-qPCR. RESULTS: Incubation with benzene or 2-ethyl-phthalate increased viability and energy content in pituitary cells. The endocrine disruptors also increased cell proliferation as well as Ccnd1 and PTTG expression. Increased AhR and AIP expression was observed after incubation with the two pollutants. CONCLUSIONS: Our findings indicate that benzene and 2-ethyl-phthalate activate AhR/AIP expression and stimulate proliferation in normal rat pituitary cells. This study is the first demonstration that pollutants can induce normal pituitary cells to proliferate and provides a link between epidemiological and genomic findings in pituitary tumors.

The role of inferior petrosal sinus sampling in ACTH-dependent Cushing's syndrome: review and joint opinion statement by members of the Italian Society for Endocrinology, Italian Society for Neurosurgery, and Italian Society for Neuroradiology.

In the management of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, inferior petrosal sinus sampling (IPSS) provides information for the endocrinologist, the neurosurgeon, and the neuroradiologist. To the endocrinologist who performs the etiological diagnosis, results of IPSS confirm or exclude the diagnosis of Cushing's disease with 80%-100% sensitivity and over 95% specificity. Baseline central-peripheral gradients have suboptimal accuracy, and stimulation with corticotropin-releasing hormone (CRH), possibly desmopressin, has to be performed. The rationale for the use of IPSS in this context depends on other diagnostic means, taking availability of CRH and reliability of dynamic testing and pituitary imaging into account. As regards the other specialists, the neuroradiologist may collate results of IPSS with findings at imaging, while IPSS may prove useful to the neurosurgeon to chart a surgical course. The present review illustrates the current standpoint of these 3 specialists on the role of IPSS.

AZA-deoxycytidine stimulates proopiomelanocortin gene expression and ACTH secretion in human pituitary ACTH-secreting tumors.

PURPOSE: It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors. METHODS: Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2'-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM-10 µM AZA) and time course (4-96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression. RESULTS: Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 µM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH. CONCLUSIONS: The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing's disease.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

OBJECTIVE: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. DESIGN: Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. METHODS: Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. RESULTS: HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. CONCLUSIONS: This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

Clinical relevance of cardiac structure and function abnormalities in patients with Cushing's syndrome before and after cure.

OBJECTIVES: Sustained hypercortisolism impacts cardiac function, and, indeed, cardiac disease is one of the major determinants of mortality in patients with Cushing's syndrome. The aim of this study was to assess the clinical relevance of cardiac structure and function alterations by echocardiography in patients with active Cushing's syndrome and after disease remission. STUDY DESIGN: Seventy-one patients (61 women, 10 men) with Cushing's syndrome and 70 age-, sex- and blood pressure-matched controls were enrolled. Echocardiography was performed in 49 patients with active disease and at several time points after remission in 44 patients (median follow-up 46.4 months), and prevalence of abnormal left ventricular mass measurements and systolic and diastolic functions indices was compared between patients with active disease, after remission and controls. Twenty-two patients were evaluated both before and after remission. RESULTS: Up to 70% of patients with active Cushing's syndrome presented abnormal left ventricular mass parameters; 42% presented concentric hypertrophy and 23% concentric remodelling. Major indices of systolic and diastolic functions, i.e. ejection fraction and E/A ratio, respectively, were normal. Upon remission of hypercortisolism, left ventricular mass parameters ameliorated considerably, although abnormal values were still more frequent than in controls. Both cortisol excess and hypertension contribute to cardiac mass alterations and increase the prevalence of target organ damage. CONCLUSIONS: Cushing's syndrome is associated with an increased risk for abnormalities of cardiac mass, which ameliorates, but does not fully disappear after remission. Systolic and diastolic functions are largely within the normal range in these patients.

Von Willebrand factor and fibrinolytic parameters during the desmopressin test in patients with Cushing's disease.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Desmopressin is a known haemostatic agent and is also being used, albeit at lower doses, during the diagnostic work-up of Cushing's syndrome, a condition characterized by excess cortisol concentrations and frequent thromboembolic events. No study has yet evaluated whether administration of desmopressin for diagnostic purposes induces significant, adverse changes in endothelial cell markers in these patients. WHAT THIS STUDY ADDS: Administration of desmopressin to patients with Cushing's disease induces changes in endothelial cell markers comparable with those observed in obese and normal weight subjects. It follows, that desmopressin testing does not induce disease-specific untoward changes in coagulatory markers in patients with endogenous hypercortisolism and its use in this context appears safe. AIMS: Desmopressin, a vasopressin analogue, is used for various clinical purposes, including haemostasis and, in recent times, the diagnostic work-up of patients with Cushing's syndrome, a condition associated with a known prothrombotic profile. We decided to evaluate whether and to what extent a diagnostic dose of desmopressin induces significant changes in endothelial parameters in patients with Cushing's disease (CD) and obese and normal weight controls. METHODS: Twelve patients with CD, 10 obese and five normal weight controls were studied. Von Willebrand antigen (VWF:Ag), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were measured at baseline and up to 4 h after 10 µg desmopressin i.v. RESULTS: Desmopressin 10 µg transiently increased VWF:Ag and t-PA and decreased PAI-1 in all subjects. The magnitude of the VWF:Ag and t-PA increases after desmopressin was comparable in the three groups (VWF:Ag peak-to-basal ratio 1.9 ± 0.17, 1.5 ± 0.11 and 1.8 ± 0.13 and t-PA peak-to-basal ratio 1.6 ± 0.18, 1.6 ± 0.20 and 1.8 ± 0.24 for CD, obese and controls, respectively, all NS). The PAI-1 decrease observed in patients with CD was comparable with obese (0.7 ± 0.07 and 0.6 ± 0.09, NS) and controls (0.7 ± 0.07 vs. 0.4 ± 0.09, P= 0.08). CONCLUSIONS: Administration of desmopressin to patients with CD for diagnostic purposes induces a transitory increase in VWF:Ag counterbalanced by a decrease in PAI-1 and increase in t-PA. The magnitude of these changes is largely comparable with that observed in obese and normal weight controls. Our data show that testing with desmopressin does not induce disease-specific changes in endothelial markers in patients with CD.

Dual effects of 9-cis retinoic acid on ACTH-dependent hyperplastic adrenal tissues.

Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid in patients with cortisol excess due to a pituitary ACTH-secreting adenoma and indicated that retinoids might act also on the adrenal. Aim of the present study was to evaluate the effect of 9-cis retinoic acid on adrenals from patients with ACTH-dependent Cushing's syndrome. Adrenal specimens from six patients with Cushing's disease were incubated with 10 nM-1 µM 9-cis retinoic acid with and without 10 nM ACTH. Cortisol secretion was measured by immunoassay and expression of genes involved in steroidogenesis as well as retinoic acid action were evaluated by real-time RT-PCR. Incubation with 10-100 nM 9-cis retinoic acid increased spontaneous cortisol secretion and expression of STAR and CYP17A. On the other hand, in wells treated with ACTH, 9-cis retinoic acid markedly diminished ACTH receptor upregulation and no stimulatory effect on cortisol secretion or steroidogenic enzyme synthesis was observed. ACTH itself increased ligand-induced retinoic acid receptor expression, possibly enhancing sensitivity to retinoic acid. Our findings indicate that the effect of 9-cis retinoic acid in presence of ACTH is distinct from unchallenged wells and support the hypothesis of a direct adrenal action in patients with Cushing's disease.

Obesity Is Strongly Associated With Low Testosterone and Reduced Penis Growth During Development.

CONTEXT: Growth of male genitalia represents an important marker of sexual development. Testicle size is the primary measure and little is known regards penile length changes during puberty. OBJECTIVE: This work aims to assess penis growth and testosterone levels in obese vs normal-weight children and adolescents, to evaluate a possible influence of obesity on genital development in boys, and to establish a new method for measuring penis length that allows comparison of normal-weight and overweight boys. METHODS: We assessed anthropometric and genital development in 1130 boys from birth to age 20 years. Testosterone levels were also measured. A new method for penile length measurement was employed to minimize errors when comparing obese and nonobese children. Penis length was measured with a gentle, painless, straight positioning on a centimetric ruler without stretching, which is doable from the first years of life until the end of adolescence. RESULTS: Penis length and testosterone are strongly related in children during puberty. Penile length growth is significantly decreased (by about 10%) in obese boys when compared to normal-weight boys, with concomitantly reduced testosterone levels, across puberal phases. CONCLUSION: Childhood obesity represents an important determinant of lower testosterone level and reduced penis development. A new method should be employed to improve penis measurement in normal-weight and overweight/obese boys. The possible significance of these observations for adult genital development and reproductive potential will require large longitudinal studies.

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. RESULTS: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.

Cushing's disease due to double pituitary ACTH-secreting adenomas: the first case report.

Double pituitary adenomas are rare occurrences in autoptical, surgical and neuroradiological series and are mostly due to non-functioning pituitary adenomas, GH-secreting and prolactin-secreting adenomas. ACTH secreting tumours are more rare and, to our knowledge, two distinct ACTH-producing adenomas within the same pituitary have never been reported. We herewith describe a 56 year old woman with Cushing' s disease due to two clearly distinct ACTH-secreting pituitary adenomas. She presented with signs and symptoms of hypercortisolism and hormonal testing was indicative for pituitary-dependent Cushing' s syndrome. Sellar MRI visualized an asymmetric pituitary gland with suspect lesions in both the right and the left pituitary lobes. Both lesions were removed during transsphenoidal surgery and remission of hypercortisolism ensued. Pathology confirmed the existence of two distinct adenomas located in different sites in the gland. Both presented ACTH immunoreactivity but displayed distinct morphological features. Our case indicates that double ACTH-secreting pituitary adenomas may occur in patients with Cushing' s disease. Careful radiological, surgical and pathological examination is necessary to recognize this condition and avoid surgical failure.

Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas.

(1) Background. Cushing's disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing's disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy.

Recent challenges in the diagnosis of Cushing's syndrome.

BACKGROUND: The diagnosis of Cushing's syndrome still represents a challenge for the endocrinologist. Correct implementation and interpretation of diagnostic procedures require expertise and a high degree of clinical knowledge. The diagnosis should be established based on results of two or more concordant first-line tests (e.g., urinary free cortisol, midnight serum cortisol and low-dose dexamethasone testing); otherwise, second-line tests such as the dexamethasone-suppressed corticotrophin-releasing hormone (CRH) test, desmopressin stimulation or later reevaluation can confirm/exclude the diagnosis. Aetiological diagnosis requires measurement of plasma corticotrophin (ACTH) to distinguish between ACTH-dependent (pituitary or extrapituitary ACTH-secreting tumors) and ACTH-independent Cushing's syndrome (adrenal cortisol-secreting lesions), and the possible detection of normal ACTH levels in patients with adrenal Cushing's syndrome must be kept in mind. Lastly, the differential diagnosis between pituitary and ectopic ACTH secretion can be performed using CRH testing, high-dose dexamethasone suppression and inferior petrosal sinus sampling. CONCLUSIONS: The different epidemiology of the two entities and the incomplete diagnostic accuracy of diagnostic procedures mandate careful evaluation of test results.

Differential diagnosis of ACTH-dependent hypercortisolism: imaging versus laboratory.

Differential diagnosis of ACTH-dependent Cushing's syndrome often presents major difficulties. Diagnostic troubles are increased by suboptimal specificity of endocrine tests, the rarity of ectopic ACTH secretion and the frequent incidental discovery of pituitary adenomas. A 43-year-old female reported with mild signs and symptoms of hypercortisolism, and initial hormonal tests and results of pituitary imaging (7-mm adenoma) were suggestive for Cushing's disease. However, inadequate response to corticotrophin-releasing hormone and failure to suppress after 8 mg dexamethasone pointed towards an ectopic source. Total body CT scan visualized only a small, non-specific nodule in the right posterior costophrenic excavation. Inferior petrosal sinus sampling revealed an absent center:periphery ACTH gradient but octreoscan and (18)F-FDG-PET-CT failed to detect abnormal tracer accumulation. We weighed results of the laboratory with those of imaging and decided to remove the lung nodule. Pathology identified a typical, ACTH-staining carcinoid and the diagnosis was confirmed by postsurgical hypoadrenalism. In conclusion, imaging may prove unsatisfactory or even misleading for the etiologial diagnosis of ACTH-dependent Cushing's syndrome and should therefore be interpreted only in context with results of hormonal dynamic testing.

[Are teachers at risk for psychiatric disorders? Stereotypes, physiology and perspectives of a job prevalently done by women]. / Professione docente: un mestiere a rischio di disagio psichico? Indagine su stereotipi, vissuti, biologia e prospettive di un lavoro al femminile.

BACKGROUND: Teachers are one of the so-called helping professions which are strongly exposed to the "Burnout syndrome". Nonetheless, public opinion is still convinced teachers enjoy a privileged status and physicians most often ignore psychiatric disorders following burnout due to teaching-related stress. Indeed, although France recently issued a suicide warning among teachers, and psychiatric diagnosis among this profession almost doubled in Japan in ten years, only few studies have been published on the subject in peer-reviewed journals. OBJECTIVE AND METHODS: The present study was carried out by administering a questionnaire to 1295 teachers from ten different Italian regions aimed at evaluating teachers' conditions as well as their perception of work-related health risks. RESULTS AND CONCLUSIONS: The outcome showed that teachers are mostly unaware of work-related health risks, they are discouraged by their employers, perceive union support as highly insufficient and feel under attack by the mass media as well as by the public. Further, any attempt by the head teacher to protect teacher's health--mandatory according to recent Italian legislation--is frequently misinterpreted as mobbing, due to the lack of appropriate legal knowledge. Interestingly, the study population believed that investigating the link between menopause and depressive disorders among teachers was extremely useful. In fact, over 82% of teachers are women with a median age of approximately 50. Social stress among women has in fact increased greatly given the triple role played by fifty-year-old teachers (mother of adolescents, care-giver for elderly parents and teacher). Lastly, general practitioners and psychiatrists need to be educated on psychiatric disorders due to teaching-related stress in order to achieve a correct diagnosis and treatment.