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The widespread use of diagnostic imaging has led to an increase in the incidence of pituitary tumors. The majority of incidentalomas are hormone-inactive (HI) pituitary microadenomas. The most common clinically relevant pituitary adenomas are prolactin-secreting, followed by HI, and far less common are growth hormone (GH)-, adrenocorticotropic hormone (ACTH)- and thyroid-stimulating hormone (TSH)-secreting adenomas. Pituitary adenomas are usually benign, although aggressive growth and invasion occurs in individual cases. Very rarely, they give rise to metastases and are then termed pituitary carcinomas. All pituitary tumors require endocrine testing for pituitary hormone excess. In addition to the medical history and clinical examination, laboratory diagnostics are very important. Symptoms such as irregular menstruation, loss of libido or galactorrhea often lead to the timely diagnosis of prolactinomas, and hyperprolactinemia can easily confirm the diagnosis (considering the differential diagnoses). Diagnosis is more difficult for all other hormone-secreting pituitary adenomas (acromegaly, Cushing's disease, TSHoma), as the symptoms are often non-specific (i.e., headaches, weight gain, fatigue, joint pain). Furthermore, comorbidities such as hypertension, diabetes, and depression are such widespread diseases that pituitary adenomas are rarely considered as the underlying cause. Timely diagnosis and appropriate treatment have a significant impact on morbidity, mortality, and quality of life. Therefore, the role of primary care physicians is very important for achieving an early diagnosis. In addition, patients with pituitary adenomas should always be referred to endocrinologists to ensure optimal diagnosis as well as treatment., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

While suggested, surgery is not always possible as a first-line treatment of Cushing's Disease (CD). In such cases, patients require medical therapy in order to prevent complications resulting from hypercortisolism. Although there has been a wide expansion in pharmacological options in recent years, mitotane was the agent of choice for treating hypercortisolism decades ago. Due to the introduction of other therapies, long-term experience with mitotane remains limited. Here, we report the case of a woman with CD who was treated with mitotane for 37 years. During the treatment period, biochemical and clinical disease control was achieved and the patient had two uncomplicated pregnancies. Drug-related side effects remained moderate and could be controlled by several dose adjustments. Our case highlights the ability of mitotane to allow an effective control of hypercortisolism and to represent a safe treatment option in special situations where CD requires an alternative therapeutic approach. Furthermore, we provide a literature review of the long-term use of mitotane and reported cases of pregnancy in the context of mitotane therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Seibold, Hönemann, Tönjes and Sandner.)

Background: Cushing Disease (CD) is a rare endocrine disorder associated with impaired growth hormone (GH) and short stature. Insulin-like growth factor-1 (IGF-1) is a marker of GH secretion., Methods: Patients with young onset CD (<21 years old) and available IGF-1 levels at diagnosis and/or follow-up were studied (total = 194, diagnosis = 174, follow-up = 104). IGF-1 was reported as z-score (IGF1z)., Results: IGF1z was lower than expected in the general population (median IGF1z: -0.92 [-1.54, 0.07], p < 0.0001) at diagnosis and remained low at follow-up (median: -1.13 [-1.78, -0.66], p < 0.0001). There was no correlation of IGF1z at diagnosis with BMI; there was a weak correlation with height (r s  = 0.19, p = 0.035). IGF1z was inversely correlated with markers of hypercortisolemia, including morning (r s  = -0.31, p < 0.0001) and midnight cortisol (r s  = -0.30, p < 0.0001), and with insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR, r s  = -0.27, p < 0.01)., Conclusions: IGF-1 levels in CS are on the lower side of the normal range during active disease and remain low at one year after treatment. IGF-1 levels correlated mainly with markers of hypercortisolemia rather than the short stature of patients and should not be used in the assessment of growth in this population., Impact: We report that IGF-1 levels in childhood during active hypercortisolemia and up to 1 year after resolution are on the lower side of the normal range. Our results demonstrate that IGF-1 levels during active hypercortisolemia correlate mainly with markers of Cushing syndrome. This report adds data to the current literature where reports of IGF-1 in Cushing syndrome have shown variable results. Understanding the lack of utility of IGF-1 in assessing growth parameters in the pediatric Cushing syndrome population is important for physicians caring for these patients who should not use IGF-1 for diagnostic or treatment decisions., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: We aimed to evaluate 304 premenopausal women admitted to our clinic for oligomenorrhoea, and to screen for Cushing's syndrome (CS) in this population., Material and Methods: The study included 304 premenopausal women referred to our clinic for oligomenorrhoea. Anthropometric measurements and Ferriman-Gallwey score were evaluated, and thyroid hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, prolactin, dehydroepiandrosterone sulphate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) levels were measured in all patients. If basal 17-OHP was > 2 ng/mL, we evaluated adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels. CS was screened by 1 mg-dexamethasone suppression test, and if the cortisol value was > 1.8 μg/dL, we performed additional confirmatory tests, and if necessary, pituitary magnetic resonance imaging (MRI) and inferior petrosal sinus sampling (IPSS) were performed., Results: The most common cause of oligomenorrhoea was polycystic ovary syndrome (PCOS) that was detected in 81.57% of cases, followed by hyperprolactinemia at 7.23% and hypothalamic anovulation at 5.26%. The prevalence of premature ovarian failure (POF) was 1.6%, and non-classical congenital adrenal hyperplasia (NCAH) was 1.97%. CS was detected in 7 (2.30%) patients. All the patients with CS were found to have Cushing's disease (CD). Although 3 patients with CD had classical signs and symptoms, 4 had none. Patients with CD had similar total testosterone values to those in the PCOS and NCAH groups, but they had significantly higher DHEA-S compared to both groups (CD vs. PCOS, p = 0.001 and CD vs. NCAH, p = 0.030)., Conclusions: We found higher prevalence of CS in patients with oligomenorrhoea even in the absence of clinical signs. Therefore, we suggest routine screening for CS during the evaluation of patients with oligomenorrhoea and/or PCOS. The likelihood of CS is greater in patients with high androgen, especially DHEA-S levels.

Aim: To evaluate sleep architecture of patients with Cushing's disease (CD) and to explore whether agouti-related peptide (AgRP) and/or leptin play a permissive role in sleep alterations in patients with active CD., Methods: We performed polysomnography on 26 patients with active CD and age 26 age- and sex-matched control subjects. Blood samples were obtained from all participants for the analyzes of AgRP and leptin. The laboratory and sleep-related parameters were compared., Results: The groups were similar in age, gender, and body mass index. The CD group had reduced sleep efficiency (71.6 ± 12.1% vs. 78.8 ± 12.6%, p = 0.042) and increased wake after sleep onset (WASO%) (24.7 ± 13.1% vs. 17.4 ± 11.6%, p = 0.040) as compared to control group. Seventeen patients with CD (65.4%) and 18 control subjects (69.2%) had obstructive sleep apnea. Serum AgRP (13.2 ± 7.4 pg/ml vs. 9 ± 3.1, p = 0.029), leptin (59.5 mcg/l, [IQR] 32.6-94.6 vs. 25.3 mcg/l, [IQR] 12.9-57.5, p = 0.007) were higher in CD group. AgRP and leptin correlated negatively with total sleep time, sleep efficiency, stage N2 sleep (%), and positively with WASO%. In multiple regression analyses, serum cortisol (ß =  - 0.359, p = 0.042) and AgRP (ß =  - 0.481, p = 0.01) were significant predictor of sleep efficiency. AgRP was also significant predictor of WASO% (ß = 0.452 and p < 0.05)., Conclusions: Active CD carries an increased risk of impaired sleep efficiency and continuity which may worsen health-related quality of life. Elevated circulating AgRP and, to a lesser extent, leptin may be associated with decreased sleep efficiency and continuity in patients with CD. Patients with CD who have subjective sleep symptoms should be screened with polysomnography., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Context: Cushing syndrome (CS) is associated with different hematological abnormalities. Nevertheless, conflicting data about erythropoiesis in CS have been reported. Furthermore, it is unclear whether CS sex and subtype-specific alterations in red blood cells (RBC) parameters are present., Objective: To investigate sex and subtype-specific changes in RBC in patients with CS at initial diagnosis and after remission., Design: Retrospective, monocentric study including 210 patients with CS (women, n = 162) matched 1:1 for sex and age to patients with pituitary microadenomas or adrenal incidentalomas (both hormonally inactive). RBC parameters were evaluated at initial diagnosis and after remission., Results: Women with CS had higher hematocrit (median 42.2 vs 39.7%), hemoglobin (14.1 vs 13.4 g/dl) and mean corpuscular volume (MCV) (91.2 vs 87.9 fl) compared to the controls (all p < 0.0001). Women with Cushing disease (CD) showed higher hematocrit, RBC and hemoglobin levels than those with ectopic Cushing (ECS) (all p < 0.005). Men with CS had lower hematocrit (42.9 vs 44.7%), RBC count (4.8 vs 5.1n*10 6 /µl) and hemoglobin (14.2 vs 15.4 g/dl), but higher MCV (90.8 vs 87.5 fl) than controls (all p < 0.05). In men with CS, no subtype-specific differences were identified. Three months after remission hemoglobin decreased in both sexes., Conclusion: CS is characterized by sexual and subtype-specific differences in RBC parameters. Compared to controls, women with CS showed higher hematocrit/hemoglobin levels, whereas men had lower hematocrit/hemoglobin, which further decreased directly after remission. Therefore, anemia should be considered as complication of CS in men. In women, differences in RBC parameters may help to differentiate CD from ECS., (© 2023. The Author(s).)

Context: In Cushing disease, the association between the rate of serum cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized., Objective: To analyze postoperative serum cortisol and recurrence rates in Cushing disease., Methods: Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables., Results: A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P < .0001)., Conclusion: Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: a very low-calorie ketogenic diet (VLCKD) is associated with improvement of metabolic and cardiovascular disorders. We aimed to evaluate the effects of a VLCKD in patients with Cushing's disease (CD) as adjunctive therapy to treatment for the primary disease., Methods: we evaluated clinical, hormonal and metabolic parameters in 15 patients with CD and 15 controls at baseline after 1 week and 3 weeks of VLCKD and, further, after 2 weeks of a low-carbohydrate ketogenic diet (LCKD)., Results: after 5 weeks of diet, a significant decrease in BMI ( p = 0.002), waist circumference (WC) ( p = 0.024), systolic blood pressure ( p = 0.015), diastolic blood pressure ( p = 0.005), ACTH ( p = 0.026), cortisone ( p = 0.025), total cholesterol ( p = 0.006), LDL cholesterol ( p = 0.017), triglycerides ( p = 0.016) and alkaline phosphatase ( p = 0.008) and a significant increase in HDL cholesterol ( p = 0.017), vitamin D ( p = 0.015) and oral disposition index (oDI) ( p = 0.004) was observed in the CD patients. A significant decrease in BMI ( p = 0.003), WC ( p = 0.002), systolic blood pressure ( p = 0.025), diastolic ( p = 0.007) blood pressure and total cholesterol ( p = 0.026) and an increase in HDL cholesterol ( p = 0.001) and oDI ( p < 0.001) was observed in controls., Conclusions: the current study confirms that a ketogenic diet is effective in improving metabolic disorders in CD and shows that a nutritional approach may be combined with conventional CD therapy in order to improve metabolic and cardiovascular comorbidities.

Background: Cushing disease (CD) may lead to accelerated cardiovascular remodeling and increased mortality. There are suspected differences in the mechanism of cardiovascular dysfunction between males and females with CD. The purpose of this study was to assess the effect of patient sex on the hemodynamic profile assessed via impedance cardiography and echocardiography in patients newly diagnosed with CD., Material and Methods: The 54 patients newly diagnosed with CD (mean age 41 years; 77.8% of females) who were included in this prospective clinical study underwent impedance cardiography to assess specific parameters (including systemic vascular resistance index [SVRI], total arterial compliance index [TACI], Heather index [HI], stroke index [SI], cardiac index [CI], velocity index [VI], and acceleration index [ACI]) and transthoracic echocardiography to assess heart chamber diameters and left ventricular systolic and diastolic function., Results: Males with CD exhibited higher afterload, with higher SVRI (3,169.3 ± 731.8 vs. 2,339.3 ± 640.8 dyn*s*cm -5 *m² in males and females, respectively; p=0.002), lower TACI (0.80 ± 0.30 vs. 1.09 ± 0.30 mL/mmHg*m 2 ; p=0.008), and lower hemodynamic parameters of left ventricular function, with lower HI (9.46 ± 2.86 vs. 14.1 ± 5.06 Ohm/s 2 ; p=0.0007), lower VI (35.1 ± 11.9 vs. 44.9 ± 13.1 1*1000 -1 *s -1 ; p=0.009), lower SI (36.5 ± 11.7 vs. 43.6 ± 9.57 mL/m 2 ; p=0.04), lower CI (2.36 ± 0.46 vs. 3.17 ± 0.76 mL*m -2 *min -1 ; p=0.0009), and lower ACI (50.4 ± 19.8 vs. 73.6 ± 25.0 1/100/s 2 ; p=0.006). There were no significant differences between the sexes in left ventricular systolic or diastolic function assessed by echocardiography., Conclusion: In comparison with females with CD, males with CD have a less favorable hemodynamic profile, with higher afterload and worse left ventricular function. Sex differences in cardiovascular system function should be taken into consideration in designing personalized diagnostic and therapeutic management of patients with CD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jurek, Krzesiński, Uziębło-Życzkowska, Witek, Zieliński, Kazimierczak, Wierzbowski, Banak and Gielerak.)

Osilodrostat (LCI699) is a potent inhibitor of the human steroidogenic cytochromes P450 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2). LCI699 is FDA-approved for the treatment of Cushing disease, which is characterized by chronic overproduction of cortisol. While phase II and III clinical studies have proven the clinical efficacy and tolerability of LCI699 for treating Cushing disease, few studies have attempted to fully assess the effects of LCI699 on adrenal steroidogenesis. To this end, we first comprehensively analyzed LCI699-mediated inhibition of steroid synthesis in the NCI-H295R human adrenocortical cancer cell line. We then studied LCI699 inhibition using HEK-293 or V79 cells stably expressing individual human steroidogenic P450 enzymes. Our studies using intact cells confirm the potent inhibition of CYP11B1 and CYP11B2 with negligible inhibition of 17-hydroxylase/17,20-lyase (CYP17A1) and 21-hydroxylase (CYP21A2). Furthermore, partial inhibition of the cholesterol side-chain cleavage enzyme (CYP11A1) was observed. To calculate the dissociation constant (K d ) of LCI699 with the adrenal mitochondrial P450 enzymes, we successfully incorporated P450s into lipid nanodiscs and carried out spectrophotometric equilibrium and competition binding assays. Our binding experiments confirm the high affinity of LCI699 to CYP11B1 and CYP11B2 (K d ≈ 1 nM or less) and much weaker binding for CYP11A1 (K d = 18.8 μM). Our results confirm the selectivity of LCI699 for CYP11B1 and CYP11B2 and demonstrate partial inhibition of CYP11A1 but not CYP17A1 and CYP21A2., Competing Interests: Declaration of interest RJA has received consulting fees from Recordati Rare Diseases and Novartis Pharmaceuticals, contracted research support from Novartis Pharmaceuticals, and a sample of osilodrostat solid used for the experiments described in this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Patients with Cushing's disease (CD) in remission maintain an increased cardiovascular risk. Impaired characteristics of gut microbiome (dysbiosis) have been associated with several cardiometabolic risk factors., Methods: Twenty-eight female non-diabetic patients with CD in remission with a mean ± SD) age of 51 ± 9 years, mean ( ± SD) BMI, 26 ± 4, median (IQR) duration of remission, 11(4) years and 24 gender-, age, BMI-matched controls were included. The V4 region of the bacterial 16S rDNA was PCR amplified and sequenced to analyse microbial alpha diversity (Chao 1 index, observed number of species, Shannon index) and beta diversity analysis through the Principal Coordinates Analysis (PCoA) of weighted and unweighted UniFrac distances. Inter-group difference in microbiome composition was analysed using MaAsLin2., Results: The Chao 1 index was lower in CD as compared with controls (Kruskal-Wallis test, q = 0.002), indicating lower microbial richness in the former. Beta diversity analysis showed that faecal samples from CS patients clustered together and separated from the controls (Adonis test, p<0.05). Collinsella , a genus form of the Actinobacteria phylum was present in CD patients only, whereas Sutterella , a genus from Proteobacteria phylum , was scarcely detectable/undetectable in CD patients as well as Lachnospira , a genus of the Lachnospiraceae family of the Firmicutes phylum. In CS, the Chao 1 index was associated with fibrinogen levels and inversely correlated with both triglyceride concentrations and the HOMA-IR index (p<0.05)., Conclusions: Patients with CS in remission have gut microbial dysbiosis which may be one of the mechanisms whereby cardiometabolic dysfunctions persist after "cure"., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Valassi, Manichanh, Amodru, Fernández, Gaztambide, Yañez, Martel-Duguech, Puig-Domingo and Webb.)

Objective: To evaluate whether age-related differences exist in clinical characteristics, diagnostic approach, and management strategies in patients with Cushing's syndrome (CS) included in the European Registry on Cushing's Syndrome (ERCUSYN)., Design: Cohort study., Methods: We analyzed 1791 patients with CS, of whom 1234 (69%) had pituitary-dependent CS (PIT-CS), 450 (25%) adrenal-dependent CS (ADR-CS), and 107 (6%) had an ectopic source (ECT-CS). According to the WHO criteria, 1616 patients (90.2%) were classified as younger (<65 years old) and 175 (9.8%) as older (≥65 years old)., Results: Older patients were more frequently males and had a lower Body Mass Index (BMI) and waist circumference when compared with the younger. Older patients also had a lower prevalence of skin alterations, depression, hair loss, hirsutism, and reduced libido, but a higher prevalence of muscle weakness, diabetes, hypertension, cardiovascular disease, venous thromboembolism, and bone fractures than younger patients, regardless of sex (P < .01 for all comparisons). Measurement of urinary free cortisol supported the diagnosis of CS less frequently in older patients when compared with the younger (P < .05). An extrasellar macroadenoma (macrocorticotropinoma with extrasellar extension) was more common in older PIT-CS patients than in the younger (P < .01). Older PIT-CS patients more frequently received cortisol-lowering medications and radiotherapy as a first-line treatment, whereas surgery was the preferred approach in the younger (P < .01 for all comparisons). When transsphenoidal surgery was performed, the remission rate was lower in the elderly when compared with their younger counterpart (P < .05)., Conclusions: Older CS patients lack several typical symptoms of hypercortisolism, present with more comorbidities regardless of sex, and are more often conservatively treated., Competing Interests: Conflicts of interest: M.R. received consulting fees from Novartis, Recordati, Crinetics, HRA Pharma, and Ipsen during the past 5 years. D.K. received consulting fees from Recordati Rare Disease and HRA Pharma Rare Diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although human cell cultures stimulated with dexamethasone suggest that the glucocorticoid receptor (GR) activates stress erythropoiesis, the effects of GR activation on erythropoiesis in vivo remain poorly understood. We characterized the phenotype of a large cohort of patients with Cushing disease, a rare condition associated with elevated cortisol levels. Results from hypercortisolemic patients with active Cushing disease were compared with those obtained from eucortisolemic patients after remission and from volunteers without the disease. Patients with active Cushing disease exhibited erythrocytosis associated with normal hemoglobin F levels. In addition, their blood contained elevated numbers of GR-induced CD163+ monocytes and a unique class of CD34+ cells expressing CD110, CD36, CD133 and the GR-target gene CXCR4. When cultured, these CD34+ cells generated similarly large numbers of immature erythroid cells in the presence and absence of dexamethasone, with raised expression of the GR-target gene GILZ. Of interest, blood from patients with Cushing disease in remission maintained high numbers of CD163+ monocytes and, although their CD34+ cells had a normal phenotype, these cells were unresponsive to added dexamethasone. Collectively, these results indicate that chronic exposure to excess glucocorticoids in vivo leads to erythrocytosis by generating erythroid progenitor cells with a constitutively active GR. Although remission rescues the erythrocytosis and the phenotype of the circulating CD34+ cells, a memory of other prior changes is maintained in remission.

Introducción: La enfermedad de Cushing (EC) es rara durante el embarazo y se asocia con complicaciones maternas y fetales significativas. El objetivo fue reportar el caso de una paciente con EC que logró embarazo y parto sin complicaciones tras el tratamiento con dosis bajas de cabergolina. Métodos: Mujer de 29 años con diagnóstico de EC (macroadenoma secretor de ACTH que produce desplazamiento del quiasma óptico, infiltra el seno cavernoso derecho y engloba la arteria carótida interna). Se somete a cirugía transesfenoidal con resección tumoral incompleta. Luego de un año de estabilidad clínica, reaparecen los síntomas por lo que se instaura tratamiento médico con cabergolina. Durante el tratamiento la paciente concibe embarazo y se suspende la medicación. Resultados: En el primer trimestre, los parámetros clínicos y bioquímicos indican EC activa, por lo que se decide reinstaurar Cabergolina a dosis bajas durante el resto de la gestación. Con el agonista dopaminérgico se alcanza normalizar parámetros clínicos y de laboratorio y la paciente dio a luz una niña sana a las 38 semanas, dentro de percentiles normales y sin complicaciones. Conclusión: El embarazo es un evento raro en pacientes con EC. Sin embargo, las consecuencias de la exposición materno-fetal al hipercortisolismo pueden ser graves. Nuestra experiencia con el uso de cabergolina a dosis bajas en una embarazada con EC, aporta datos favorables a los escasos reportes bibliográficos existentes, sumando evidencia sobre el perfil de seguridad del fármaco en esta población de pacientes.

Purpose: In Cushing's disease (CD) patients, the aim of the present study is to confirm sensitivity of several ACTH and cortisol concentration values in different time points, during corticotropin-releasing hormone (CRH) stimulation test and during CRH stimulation following dexamethasone suppression (DEX-CRH) test., Methods: We retrospectively analyzed cortisol and ACTH concentration increment during CRH and DEX-CRH tests in 23 patients with confirmed CD. Cortisol and ACTH concentrations were determined immediately before, 15 min and 30 min after CRH stimulation. We evaluated the sensitivity of different cutoff values including those reported in previous studies, in the diagnosis of CD., Results: During DEX-CRH test, 15 min serum cortisol concentration of 1.4 μg/dl (38 nmol/L) had a sensitivity of 90.9%, and serum cortisol concentration ≥1.27 μg/dl (35 nmol/L) had a sensitivity of 100%. For plasma ACTH, sensitivity of 100% was obtained using ACTH ≥3.5pmol/L (16 pg/ml) at 30 min. During CRH test, 35% increase from baseline in ACTH concentration had a sensitivity of 72.7%. Twenty percent increase in cortisol 30 minutes after stimulation yielded a sensitivity of 85.7%. The best sensitivity of ACTH and cortisol increment was obtained 15 min after stimulation, using 19% and 9% increase, respectively (sensitivity of 100% and 92.8%, respectively)., Conclusion: During CRH and DEX-CRH tests, the study findings agree with the good sensitivity of ACTH and cortisol cutoff values suggested in previous studies; yet, other cutoff values may give a higher diagnostic sensitivity.

Objective: Endogenous Cushing's syndrome (CS) is a severe condition, often diagnosed at a late stage. To reduce mortality, early diagnosis plays an important role. Two screening tools for early identification of patients with CS have been developed in multicentric cohorts, but have not yet been validated in cohorts with different geographic backgrounds., Design: We validated the Spanish score published by Leon-Justel et al. in 2016 and the Italian score by Parasiliti-Caprino et al. published in 2021 in our cohort., Methods: In the multicentric German Cushing registry, patients with confirmed and expected but ruled out Cushing's syndrome are prospectively diagnosed and followed up. We validated both scores in a cohort of 458 subjects: 176 patients with confirmed CS and 282 patients with suspected, but finally excluded CS., Results: Using the Spanish score, 17.5% of our patients with proven CS biochemical screening would not have been recommended. This concerned patients with pituitary CS (22%) and with adrenal CS (10%). On the contrary, only 14% of patients without CS would have received a recommendation for biochemical screening. Using the Italian score, 29% of patients with proven CS were classified into the low-risk classes not recommended for biochemical screening. This mostly affected patients with adrenal (31%) and pituitary CS (30%). About 12% of subjects without CS would have received a biochemical screening recommendation., Conclusions: Both scores had limited sensitivity and high specificity in a German validation cohort. Further research is necessary to develop a screening score, which is effective in different healthcare systems and ethnicities., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cushing's disease (CD) is associated with an increased risk of venous thromboembolic events. The purpose of this review is to discuss preventive strategies for post-operative thrombosis in CD patients and their impact on patient outcomes. A systematic review under PRISMA guidelines was conducted within PubMed, Embase, Web of Science, and Cochrane databases through July 2022. Of the 3207 papers retrieved, seven articles were included in this systematic review. Four hundred forty-eight patients were presented in the reviewed studies and the overall reported mortality was 2.67% (12/448). Three studies utilized prophylaxis methods including graduated compression stockings (GCS) and early ambulation (EA) while the remaining four studies only used anticoagulation medicine. Only 20 patients received pre-operative prophylactic treatment, while 366 patients received post-operative prophylaxis which was delivered either immediately after surgery or at different time intervals within 2 days following the surgery. Thrombotic events mainly occurred within two to 3 months after surgery. Overall, a higher frequency of thromboembolic events and mortality was observed in the control groups in comparison to groups receiving prophylaxis. A combination of anticoagulation, EA, and GCS might reduce thrombotic events and mortality in CD patients after treatment. Although the early commencement of a prophylactic anticoagulation regimen on the same day of surgery and continuing up to 3 months seems beneficial, the application of a prophylactic regimen should be utilized with caution since the number of included studies was insufficient to draw a strong conclusion, as well as neither prospective study nor randomized controlled trials existed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol is a major response mechanism to stress and plays a critical role in many psychiatric disorders. Cushing's disease (CD) serves as a valuable in vivo "hyperexpression" model to elucidate the effect of cortisol on brain function and mental disorders. Changes in brain macroscale properties measured by magnetic resonance imaging (MRI) have been detailed demonstrated, but the biological and molecular mechanisms underlying these changes remain poorly understood., Material and Methods: Here we included 25 CD patients and matched 18 healthy controls for assessment, and performed transcriptome sequencing of peripheral blood leukocytes. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network of the relationships between genes and we identified a significant module and hub gene types associated with neuropsychological phenotype and psychiatric disorder identified in enrichment analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis preliminarily explored the biological functions of these modules., Results: The WGCNA and enrichment analysis indicated that module 3 of blood leukocytes was enriched in broadly expressed genes and was associated with neuropsychological phenotypes and mental diseases enrichment. GO and KEGG enrichment analysis of module 3 identified enrichment in many biological pathways associated with psychiatric disorders., Conclusion: Leukocyte transcriptome of Cushing's disease is enriched in broadly expressed genes and is associated with nerve impairment and psychiatric disorders, which may reflect some changes in the affected brain.

Background: Cushing's syndrome consists of signs and symptoms related to prolonged exposure to high levels of glucocorticoid, and should be considered in individuals with the discriminatory signs and symptoms. Proximal myopathy is an important discriminatory sign., Case Presentation: We report the case of a 36-year-old Iranian man who presented with proximal muscle weakness. He visited a rheumatologist in an outpatient clinic, and according to proximal muscle weakness and heliotrope rash (based on the rheumatologist's notes) with the impression of dermatomyositis, prednisolone and azathioprine were prescribed for him that did not improve his clinical status and he was gradually wheelchair dependent. He was admitted to the hospital for evaluation of paraneoplastic syndromes. Standard laboratory tests and imaging were unremarkable, other than a brain magnetic resonance imaging that demonstrated a 30 × 12 mm homogeneously enhancing mass in the sellar region with extension to the suprasellar area. He had serum cortisol of 295 ng/mL, and adrenocorticotropic hormone of 222 pg/mL (on 5 mg prednisolone twice daily), with a diagnosis of Cushing's disease. He underwent two sessions of trans-sphenoidal surgery 4 months apart. After the first surgery, the proximal muscle weakness improved dramatically and he was walking with the aid of a walker, and after the second surgery he is walking without any aids., Conclusion: This case report emphasizes the high diagnostic importance of proximal muscle weakness as the sole presenting manifestation of Cushing's syndrome/disease., (© 2022. The Author(s).)

Corticotroph tumor progression after bilateral adrenalectomy/Nelson's syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing's disease (CD) included in the European Registry on Cushing's Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2-9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5-6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1-5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

The treatment of choice for Cushing's disease (CD) is trans-sphenoidal surgery (TSS). However, TSS is not always curative and, even when curative it is associated with a substantial rate of recurrence. Published recurrence rates vary between 5 and 20%; half of these recurrences appear within 5-years and the remaining half within or even after 10 years post-surgery. A low or undetectable cortisol in the immediate post-op period is regarded as the best criterion of remission. However, low post-op cortisol levels do not accurately predict long-term remission. Moreover, there are no other robust predictors providing certainty about the long-term outcomes. Interestingly, several studies have shown that the desmopressin test performed in the early post-op period may have some promise in predicting more precisely the risk of recurrence. In view of the lack of robust ways to predict long-term outcomes, current guidelines suggest that every patient in remission should be monitored for the possibility of recurrence. The methods used to detect recurrence are similar to those used to assess the cortisol secretory status and include assessment of: (i) abnormal circadian rhythm by late night salivary cortisol (LNSC) or midnight serum cortisol; (ii) impaired cortisol feedback by the dexamethasone suppression test and; (iii) increased 24-h bioavailable cortisol by urinary free cortisol. The timing of evaluation begins when HPA axis recovers, and then annually or sooner in case of clinical suspicion. Currently LNSC is regarded as the earliest and most sensitive biochemical alteration in detecting recurrence; a major caveat for LNSC, however, is its great variability. In practice, the diagnosis of recurrence is a challenge due to the fact that recurrence is usually a slow process with apparent clinical manifestations that may be delayed and alterations of classical biomarkers that may be delayed as well., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Late night salivary cortisol (LNSC) is a mainstay in the diagnosis of neoplastic hypercortisolism (Cushing's syndrome) with a sensitivity and specificity of > 90% in patients with syndromic signs and symptoms. Intermittent hormonogenesis (day to day variation) is common in milder Cushing's disease whereas true cyclic Cushing's syndrome (weeks to months of tumor quiescence) is unusual. In both cases, LNSC is useful as a sensitive evaluative diagnostic tool, although its lower specificity may lead to false positive results in patients without Cushing's disease. Furthermore, intermittent hormonogenesis may lead to false negative LNSC results in patients with mild Cushing's disease. Finally, LNSC is useful as an approach to follow patients after pituitary surgery to detect a recurrence even many years after a full remission., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of this study was to evaluate the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin for pediatric Cushing’s disease (CD)., Methods: We reviewed studies performed in children that evaluated the accuracy of BIPSS with desmopressin., Results: All included studies were case series of children with adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. The overall accuracy of BIPSS before stimulation was 84.1% (37/44), and after stimulation it was 92.3% (36/39). The overall lateralizing accuracy of BIPSS was 50.0%., Conclusion: Considering that available evidence is limited, it appears that BIPSS with desmopressin stimulation is accurate for the diagnosis of pediatric CD, but its lateralizing accuracy is probably not suitable for pediatric clinical practice.

This review presents the data on clinical presentation at diagnosis in 1564 patients included in the European Registry on Cushing's syndrome (ERCUSYN), of whom 1045 (67%) had pituitary-dependent Cushing's syndrome (CS) (PIT-CS), 385 (25%) had adrenal dependent CS (ADR-CS) and 89 (5%) had ectopic adrenocorticotropic hormone syndrome (ECT-CS). The most frequent symptoms in the overall series were weight gain (83%), hypertension (79%), skin alterations (76%) and myopathy (70%). Diabetes mellitus was present in 32% and depression in 35% of patients. Skin alterations, menstrual irregularities and reduced libido were more prevalent in PIT-CS patients compared to ADR-CS patients, whereas patients with ECT-CS more frequently had diabetes mellitus, myopathy, hirsutism and vertebral fractures compared to the other etiologies, consistent with a more severe clinical scenario. Reduced libido and bone fractures were more prevalent in men compared to women. Quality of life was poor at diagnosis, irrespective of the etiology of CS, and also associated with the presence of depression at baseline. A delay of 2 years between the onset of symptoms and diagnosis was also observed, with a high number of specialists consulted, who often missed the correct diagnosis. To develop strategies aimed at shortening the time elapsed to diagnosis, it is important to rapidly start treatment and reduce the burden of the disease on patient psychophysical health and longevity., (© 2022 British Society for Neuroendocrinology.)

Background: Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear., Methods: A total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays., Results: A novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETs in vitro and in vivo., Conclusion: Our studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This pilot study investigated the performance of C-X-C motif chemokine receptor 4 (CXCR4) molecular imaging ( 68 Ga-pentixafor PET/CT) in Cushing syndrome (CS) and the correlation between CXCR4 signaling interactions and glucose metabolism in adrenocorticotropin-cortisol pathway., Methods: We retrospectively evaluated 31 patients (16 patients with CS and 15 patients with nonfunctioning pituitary or adrenal adenomas). All patients underwent 68 Ga-pentixafor PET/CT, and 11 with pituitary adenoma also underwent 18 F-FDG PET/CT. The diagnosis accuracy of 68 Ga-pentixafor PET/CT was calculated. The correlation between radiouptake along the pituitary-adrenal axis and hormone levels was calculated., Results: Patients with Cushing disease characterized a focal uptake in adrenocorticotropic hormone-producing pituitary adenoma (ACTH-PA). In ACTH-independent CS, there was increased uptake of 68 Ga-pentixafor in adrenal lesions but not in the pituitary fossa. The nonfunctioning pituitary or adrenal adenomas showed negative 68 Ga-pentixafor signal. The one patient with metastatic ectopic ACTH syndrome had multiple 68 Ga-pentixafor-avid lesions. Using the threshold of SUV max >8.5 in the adrenal lesions, the sensitivity and specificity of 68 Ga-pentixafor PET/CT to diagnose cortisol-producing adenoma were 100% and 84.9%. A cutoff SUV max value of 3.0 on 68 Ga-pentixafor PET/CT had 100% sensitivity and specificity for differentiating ACTH-PA. The corresponding hormone level was significantly correlated with uptake of 68 Ga-pentixafor in pituitary adenoma and adrenal tissue but not with glucose metabolism., Conclusion: We have characterized the performance of 68 Ga-pentixafor in different subtypes of CS. 68 Ga-pentixafor PET/CT is promising in the differential diagnosis of both ACTH-independent and ACTH-dependent CS. Activated CXCR4 molecular signaling along the pituitary-adrenal axis was found in patients with Cushing disease., Competing Interests: Conflicts of interest and sources of funding: SCINTOMICS owns the IP on pentixafor. This work was sponsored in part by the National Natural Science Foundation of China (no. 82071967); CAMS Innovation Fund for Medical Science (no. CIFMS-2021-I2M-1-025, CIFMS-2021-I2M-1-002, CIFMS-2021-I2M-1-003); National Key Research and Development Program of China (no. 2016YFC0901500); CAMS Fund for Rare Diseases Research (no. 2016ZX310174-4); and Tsinghua University and Peking Union Medical College Hospital joint fund (no. PTQH201906006)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Quantification of salivary cortisol is one of the highly sensitive and specific screening parameters for Cushing's syndrome (CS). However, only late-night salivary cortisol is part of the standard screening procedure. In this study, we aimed to analyze salivary cortisol day profiles in patients with different types of CS to test whether specific patterns might be relevant for diagnosis and subtyping., Material and Methods: Among 428 patients including those with confirmed Cushing's syndrome (N=111, of those 75 with Cushing's disease, 27 patients with adrenal CS and nine patients with ectopic CS), autonomous cortisol secretion (N=39) or exclusion of CS (control group, N=278) salivary cortisol was measured five times a day., Results: At each of the five time points, salivary cortisol was significantly higher in patients with CS compared to the control group (p≤0.001). Using the entire profile instead of one single salivary cortisol at 11 p.m. improved diagnostic accuracy (85 vs. 91%) slightly. Patients with ACTH-dependent CS had higher salivary cortisol levels than patients with adrenal CS. Also, morning cortisol was significantly higher in patients with ectopic CS than in patients with Cushing's disease (p=0.04). Nevertheless, there was a strong overlap between diurnal profiles, and the diagnostic yield for subtyping was low., Discussion: The study results show that using diurnal salivary cortisol profiles for CS diagnosis results in a limited increase in diagnostic accuracy. With significant differences between Cushing subtypes, cortisol profiles are not useful in everyday clinical practice for subtyping of CS., Competing Interests: The authors state that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: In this systematic review and meta-analysis, we review the literature regarding patients with Cushing's disease (CD) with negative or inconclusive magnetic resonance imaging (MRI)., Methods: A quantitative systematic review was performed. Article selection was performed by searching MEDLINE (using PubMed), EMBASE, and Cochrane electronic bibliographic databases., Results: 28 articles described surgical management of inconclusive MRI or MRI-negative CD. A total of 858 patients underwent surgery for their Cushing adenoma. Different types of surgery, including endoscopic endonasal transsphenoidal surgery (EETS) (190 cases) and microscopic endonasal transsphenoidal surgery (METS) (488 cases), were performed on patients with MRI-negative CD. 7 studies, which included 164 patients, did not describe any surgery. EETS and METS are conducted to achieve selective adenomectomy (231 cases), partial adenomectomy (80 cases), total adenomectomy (13 cases), hemihypophysectomy (15 cases), or enlarged adenomectomy (48 cases). Based on available data on these studies, the remission rate, persistence rate, and recurrence rate after different types of surgeries on patients with MRI-negative CD were 72.97%, 27.03%, and 12.05%, respectively. There was no statistically significant difference between EETS and METS in the subanalysis regarding recurrence rate, remission rate, and persistence rate. However, the recurrence rate in the METS group is almost 3 times higher than in the EETS group., Conclusions: Surgery has a good prognosis in patients with MRI-negative CD in terms of remission, and EETS has a lower rate of disease recurrence than METS; therefore, EETS seems to be the potential recommended treatment technique, while to confirm the therapeutic method of choice, further investigations should be done., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Cushing disease is a potentially fatal endocrine disorder caused by adrenocorticotropin (ACTH)-secreting microadenomas in the pituitary gland. Accurate detection and localization of the adenomas is the key to clinical treatment. This study analysed the value of contrast-enhanced Sampling Perfection with Application-optimized Contrasts using different flip angle Evolutions (SPACE) sequence in magnetic resonance imaging (MRI) assessment of ACTH-secreting pituitary microadenomas., Design and Patients: We carried out a retrospective study in which 45 patients with ACTH-secreting pituitary microadenomas were enrolled. Dynamic contrast-enhanced (DCE) coronal T1-SE sequence was performed. A contrast-enhanced coronal SPACE sequence was added immediately after DCE MRI finished. Two independent observers assessed the tumour existence and location, then the results were compared with surgical findings., Results: Twenty-four lesions (53.3%) were detected by the DCE T1-SE sequence alone, while 35 lesions (80.0%) were detected with the addition of contrast-enhanced SPACE sequence. The sensitivity (58.5% vs. 85.3%; p < .05) and best diagnostic accuracy (62.0% vs. 84.4%; p < .05) were significantly better for addition with SPACE sequence than DCE-SE images alone in detection of ACTH-secreting pituitary microadenomas. For lesions <5 mm, the detected numbers were 4 (16.6%) versus 10 (27.8%) by DCE T1-SE sequence and combined DCE T1-SE with SPACE sequence., Conclusions: A combination of contrast-enhanced SPACE with DCE T1-SE sequence could improve the detection of ACTH-secreting pituitary microadenomas. Contrast-enhanced SPACE sequence could be a supplementary sequence for imaging of ACTH-secreting pituitary adenomas when T1-SE sequence provides negative or equivocal findings., (© 2021 John Wiley & Sons Ltd.)

Background: The primary objective of the study was to assess serum 25-hydroxyvitamin D [25(OH)D] values in patients with Cushing’s disease (CD), compared to controls. The secondary objective was to assess the response to a load of 150,000 U of cholecalciferol. Methods: In 50 patients with active CD and 48 controls, we evaluated the anthropometric and biochemical parameters, including insulin sensitivity estimation by the homeostatic model of insulin resistance, Matsuda Index and oral disposition index at baseline and in patients with CD also after 6 weeks of cholecalciferol supplementation. Results: At baseline, patients with CD showed a higher frequency of hypovitaminosis deficiency (p = 0.001) and lower serum 25(OH)D (p < 0.001) than the controls. Six weeks after cholecalciferol treatment, patients with CD had increased serum calcium (p = 0.017), 25(OH)D (p < 0.001), ISI-Matsuda (p = 0.035), oral disposition index (p = 0.045) and decreased serum PTH (p = 0.004) and total cholesterol (p = 0.017) values than at baseline. Multivariate analysis showed that mean urinary free cortisol (mUFC) was independently negatively correlated with serum 25(OH)D in CD. Conclusions: Serum 25(OH)D levels are lower in patients with CD compared to the controls. Vitamin D deficiency is correlated with mUFC and values of mUFC > 240 nmol/24 h are associated with hypovitaminosis D. Cholecalciferol supplementation had a positive impact on insulin sensitivity and lipids.

Purpose: Pituitary apoplexy is a rare endocrine emergency. The purpose of this study is to characterize physiological changes involved in pituitary apoplexy, especially during the acute phase., Methods: A Cushing's disease patient experienced corticotroph releasing hormone (CRH)-induced pituitary apoplexy during inferior petrosal sinus sampling (IPSS). The IPSS blood samples from the Cushing's disease patient were retrospectively analyzed for cytokine markers. For comparison, we also analyzed cytokine markers in blood samples from two pituitary ACTH-secreting microadenoma patients and one patient with an ectopic ACTH-secreting tumor., Results: Acute elevation of interleukin 6 (IL-6) and matrix metalloproteinase 9 (MMP9) was observed in the IPSS blood sample on the apoplectic hemorrhagic site of the tumor. In contrast, such a change was not observed in the blood samples from the contralateral side of the apoplexy patient and in other IPSS samples from two non-apoplexy Cushing's disease patient and a patient with ectopic Cushing's syndrome., Conclusion: IL-6 and MMP9 may be involved in the acute process of pituitary apoplexy in Cushing's disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Pasireotide is an effective treatment for acromegaly and Cushing's disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs., Methods: Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing's disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA 1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms., Results: Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA 1c between treatment arms was - 0.28% (95% CI - 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized., Conclusion: Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383., (© 2021. The Author(s).)

In this study we aimed to assess vitamin D metabolism in patients with Cushing's disease (CD) compared to healthy individuals in the setting of bolus cholecalciferol treatment. The study group included 30 adults with active CD and the control group included 30 apparently healthy adults with similar age, sex and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D 3 , 25(OH)D 2 , 1,25(OH) 2 D 3 , 3-epi-25(OH)D 3 and 24,25(OH) 2 D 3 ), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. All data were analyzed with non-parametric statistics. Patients with CD had similar to healthy controls 25(OH)D 3 levels ( p > 0.05) and higher 25(OH)D 3 /24,25(OH) 2 D 3 ratios ( p < 0.05) throughout the study. They also had lower baseline free 25(OH)D levels ( p < 0.05) despite similar DBP levels ( p > 0.05) and lower albumin levels ( p < 0.05); 24-h urinary free cortisol showed significant correlation with baseline 25(OH)D 3 /24,25(OH) 2 D 3 ratio (r = 0.36, p < 0.05). The increase in 25(OH)D 3 after cholecalciferol intake was similar in obese and non-obese states and lacked correlation with BMI ( p > 0.05) among patients with CD, as opposed to the control group. Overall, patients with CD have a consistently higher 25(OH)D 3 /24,25(OH) 2 D 3 ratio, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. The observed difference in baseline free 25(OH)D levels is not entirely clear and requires further study.

Objective: Guidelines recommend initiating testing for Cushing syndrome (CS) based on strong clinical suspicion. Our recent experience suggests the absence of classical stigmata in the majority of patients with CS. We aimed to confirm this premise by revisiting the clinical features of this syndrome in a modern series of patients from a single center., Methods: Computerized records of subjects with CS diagnosed at Tel Aviv Sourasky Medical Center between 2000 and 2018 were reviewed. A Cushing inventory score, including all clinical components of the syndrome, was computed for each subject. Data were compared between the subtypes and evaluated in light of those in the literature., Results: Of the 76 subjects with CS (60 women/16 men), 49 (64.5%) had Cushing disease; 16 (21.1%), adrenal adenoma; 7 (9.2%), adrenocortical carcinoma; and 4 (5.3%), ectopic adrenocorticotropic hormone secretion. In only 15 of 74 cases (20.3%), clinical suspicion of CS led to testing. Catabolic signs of CS were present in less than 30% of cases. The most common symptom was weight gain (52/67, 77.6%), and the most common comorbidity was hypertension (47/76, 61.8%). There were no differences in the Cushing inventory score between the subtypes. Signs, symptoms, and comorbidities were all significantly less common than in the classical syndrome., Conclusions: Modern-day CS presents with subtler features than in the past. Initiating a testing cascade solely based on a strong clinical suspicion may lead to underdiagnosis of milder cases. A concerted effort to devise cost-efficient testing for CS in the current era is needed., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

A 68-year-old woman presented with right arm cellulitis, not responsive to oral antibiotics. Intravenous antibiotics were commenced, and an ultrasound scan confirmed a collection that was surgically drained. She developed refractory hypokalaemia with normal magnesium, no gastrointestinal losses and no iatrogenic cause. She was hypertensive, hyperglycaemic, alkalotic, clinically obese with proximal myopathy and skin bruising. These clinical findings and refractory hypokalaemic hypertension with metabolic alkalosis raised a suspicion of Cushing's syndrome (CS). 24-hour urinary free cortisol (24 hours) was grossly raised on two occasions. The adrenocorticotropic hormone (ACTH) was significantly raised at 154 ng/L, confirming ACTH-dependant CS. A CT scan of the thorax, abdomen and pelvis excluded an ectopic source of hypercortisolaemia. MRI pituitary revealed an invasive macroadenoma. Treatment with endoscopic debulking resulted in the resolution of hypokalaemia and metabolic alkalosis with significant improvement in hyperglycaemia and hypertension., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Functional pituitary adenomas (FPAs) cause severe neuro-endocrinopathies including Cushing's disease (CD) and acromegaly. While many are effectively cured following FPA resection, some encounter disease recurrence/progression or hormonal non-remission requiring adjuvant treatment. Identification of risk factors for suboptimal postoperative outcomes may guide initiation of adjuvant multimodal therapies., Methods: Patients undergoing endonasal transsphenoidal resection for CD, acromegaly, and mammosomatotroph adenomas between 1992 and 2019 were identified. Good outcomes were defined as hormonal remission without imaging/biochemical evidence of disease recurrence/progression, while suboptimal outcomes were defined as hormonal non-remission or MRI evidence of recurrence/progression despite adjuvant treatment. Multivariate regression modeling and multilayered neural networks (NN) were implemented. The training sets randomly sampled 60% of all FPA patients, and validation/testing sets were 20% samples each., Results: 348 patients with mean age of 41.7 years were identified. Eighty-one patients (23.3%) reported suboptimal outcomes. Variables predictive of suboptimal outcomes included: Requirement for additional surgery in patients who previously had surgery and continue to have functionally active tumor (p = 0.0069; OR = 1.51, 95%CI 1.12-2.04), Preoperative visual deficit not improved after surgery (p = 0.0033; OR = 1.12, 95%CI 1.04-1.20), Transient diabetes insipidus (p = 0.013; OR = 1.27, 95%CI 1.05-1.52), Higher MIB-1/Ki-67 labeling index (p = 0.038; OR = 1.08, 95%CI 1.01-1.15), and preoperative low cortisol axis (p = 0.040; OR = 2.72, 95%CI 1.06-7.01). The NN had overall accuracy of 87.1%, sensitivity of 89.5%, specificity of 76.9%, positive predictive value of 94.4%, and negative predictive value of 62.5%. NNs for all FPAs were more robust than for CD or acromegaly/mammosomatotroph alone., Conclusion: We demonstrate capability of predicting suboptimal postoperative outcomes with high accuracy. NNs may aid in stratifying patients for risk of suboptimal outcomes, thereby guiding implementation of adjuvant treatment in high-risk patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Competing Interests: Competing interests: None declared.

Purpose: It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition., Methods: Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC)., Results: At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND., Conclusions: These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.

Background: Only a few studies have established the epidemiology of prolactinoma and Cushing's disease in Korea. Furthermore, the incidence of these disease are increasing than before associated with the development of technologies. This study was designed to evaluate the epidemiology of prolactinoma and Cushing's disease and their survival analysis according to treatment., Methods: The nationwide, population-based study evaluated incidence and prevalence of prolactinoma and Cushing's disease using de-identified claims data in The Korean Health Insurance Review and Assessment Service database between 2013 and 2017. The survival analysis investigated regarding treatment over a period of 6 years. A log-rank test and Cox proportional hazard regression analysis were used., Results: The 6,056 patients with newly diagnosed prolactinoma and 584 patients with Cushing's disease were recorded between 2013 and 2017. The annual incidence of prolactinoma was 23.5 cases per million, and its prevalence was 82.5 cases per million, and 2.3 cases per million/year and 9.8 cases per million for Cushing's disease. The survival benefit was insignificant in prolactinoma according to treatment, but treatment of Cushing's disease ameliorated the survival rate significantly., Conclusion: Overall, the incidence of prolactinoma and Cushing's disease was similar with those found previously, but the prevalence of two diseases were inconsistent when compared with the early studies. The present study also proposed necessity of treatment in Cushing's disease for improving the survival rate.