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Cushing's syndrome (CS) is associated with a hypercoagulable state resulting in an increased risk on venous thromboembolism (VTE). In patients with untreated active CS VTE incidence is up to 18-fold higher compared to the general population, whereas after pituitary and adrenal surgery a postoperative VTE risk between 2.6 and 5.6% has been reported. Interestingly, after surgery the VTE risk is not only increased in the first week but also during several months postoperatively. The hypercoagulable state in CS is thought to be caused, at least in part, by an imbalance between activity of pro- and anticoagulant pathways. However, changes in activated partial thromboplastin time and plasma concentrations of pro-and anticoagulant factors are not observed in every CS patient. Only retrospective studies have shown that thromboprophylaxis lowers VTE risk in CS. Future prospective studies should asses the optimal timing, duration and type of thromboprophylaxis in CS to improve VTE-related morbidity and mortality.

Context Confirming a diagnosis of Cushing disease (CD) remains challenging, yet is critically important before recommending transsphenoidal surgery for adenoma resection. Objective To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. Design, Setting, Patients, Interventions Patients (n = 105; 86% female) who underwent surgery from 2007 through 2020 were classified into 3 groups: group A (n = 84) pathology-proven ACTH adenoma; group B (n = 6) pathology-unproven but with postoperative hypocortisolemia consistent with CD; and group C (n = 15) pathology-unproven, without postoperative hypocortisolemia. Group A + B were combined as confirmed CD and group C as unconfirmed CD. Main outcomes Group A + B was compared with group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1-mg dexamethasone suppression test (DST), plasma ACTH, and pituitary magnetic resonance imaging (MRI). Results All groups had a similar clinical phenotype. Compared with group C, group A + B had higher mean UFC (P Conclusions Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.

Background Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. Methods We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. Results Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity. Conclusion Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.

Objective We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). Methods Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. Results Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. Conclusions This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).

Background We do not fully understand how hypercortisolism causes central hypothyroidism or what factors influence recovery of the hypothalamic-pituitary-thyroid axis. We evaluated thyroid function during and after cure of Cushing syndrome (CS). Methods We performed a retrospective cohort study of adult patients with CS seen from 2005 to 2018 (cohort 1, c1, n = 68) or 1985 to 1994 (cohort 2, c2, n = 55) at a clinical research center. Urine (UFC) and diurnal serum cortisol (F: ~8 am and ~midnight [pm]), morning 3,5,3′-triiodothyronine (T3), free thyroxine (FT4), and thyrotropin (TSH) (c1) or hourly TSH from 1500 to 1900 h (day) and 2400 to 04000 h (night) (c2), were measured before and after curative surgery. Results While hypercortisolemic, 53% of c1 had central hypothyroidism (low/low normal FT4 + unelevated TSH). Of those followed long term, 31% and 44% had initially subnormal FT4 and T3, respectively, which normalized 6 to 12 months after cure. Hypogonadism was more frequent in hypothyroid (69%) compared to euthyroid (13%) patients. Duration of symptoms, morning and midnight F, adrenocorticotropin, and UFC were inversely related to TSH, FT4, and/or T3 levels (r = –0.24 to –0.52, P < .001 to 0.02). In c2, the nocturnal surge of TSH (mIU/L) was subnormal before (day 1.00 ± 0.04 vs night 1.08 ± 0.05, P = .3) and normal at a mean of 8 months after cure (day 1.30 ± 0.14 vs night 2.17 ± 0.27, P = .01). UFC greater than or equal to 1000 μg/day was an independent adverse prognostic marker of time to thyroid hormone recovery. Conclusions Abnormal thyroid function, likely mediated by subnormal nocturnal TSH, is prevalent in Cushing syndrome and is reversible after cure.

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing's syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2–3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.

Endogenous Cushing’s syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed “Cushing’s disease”) and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.

Summary Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8–10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

Context Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure. Objective To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL. Design Cross-sectional observational survey. Participants Patients (n = 341) had undergone surgery for CS and were members of the Cushing’s Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS. Results Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P Conclusion Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery.

Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.

In MRI-negative cases Cushing’s disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission. 18F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving 18F-FDG-PET detection of adenomas in CD. Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two 18F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read 18F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins. The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas. The results of the current study suggest that oCRH-stimulation may lead to increased 18F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging. 18F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541).

Summary Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome.

Steroidogenesis inhibitors can be given to control the hypercortisolism of Cushing’s syndrome in various situations: when surgery has been unsuccessful or not possible; in metastatic adrenocorticotropin hormone (ACTH) or cortisol-secreting tumors; when waiting for the maximal efficacy of radiation techniques; for rapid treatment of severe hypercortisolism in patients with occult ACTH-producing tumors; or as a presurgical treatment in patients with severe comorbidities. Whilst biochemical “control” can be achieved in more than 50% of cases, daily management of such drugs can be challenging. Indeed, with a “dose-titration” or a “block and replace” approach, defining eucortisolism is usually difficult, requiring the measurement of several biological markers. Moreover, each drug has its own side effects, which must be monitored closely. The aim of this “approach to the patient” is to shed light on the management of hypercortisolism with 4 steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, osilodrostat) to help endocrinologists dealing with patients with Cushing’s syndrome. Various points will be discussed, such as initial dose of treatment, dose schedule, monitoring of efficacy, and side effects of monotherapy. The combination of steroidogenesis inhibitors will also be discussed.

Introduction: Sporadic pituitary adenomas are common (>10%) in the general population. Microadenomas (< 1 cm across) can become symptomatic with adrenocorticotropin oversecretion causing Cushing’s disease (CD), leading to high morbidity and mortility. Pathogenic mechanisms in a majority of adenomas including wildtype CD adenomas remain unknown. Mechanistic studies are hindered by a lack of in-vitro models and normal human pituitary gland controls. We hypothesized that comparative analysis of human adenomas with syngeneic normal pituitary glands could reveal pathogenic mechanisms driving CD. Methods: We surgically annotated adenomas and en-route adjacent normal glands in 34 patients. We performed single cell RNAseq and captured 28,724 cells in 6 patients (3 CD and 3 non-CD; 5 pairwise), bulk RNAseq in 7 patients (5 CD and 2 non-CD; 5 pairwise) and DNA methylation analysis in 6 patients (3 CD and 3 non-CD). We confirmed the mechanisms of sporadic CD adenoma pathogenesis in 2 additional syngeneic pairs of human cell lines and using a novel murine normal corticotroph-enriched cell line. Results: Using marker-based classification, we confirmed canonical resident cell classes including corticotrophs in the human pituitary gland. We found SOX2+/S100B+ folliculostellate cells which play a role in pituitary cell replenishment and homeostasis in the normal gland but not in the adenoma compartment. Within the terminally differentiated corticotrophs in the adenoma compartment, we discovered a subset of proliferating cells with upregulation of canonical oncogenes, histone modifiers and DNA repair genes. We also found that consensus dominant genes including PMAIP1 (encoding the pro-apoptotic BH3 only Bcl-2 protein noxa) sharply demarcated adenoma cells from normal gland. The PMAIP1 locus was hypomethylated in CD adenomas compared to non-CD samples. However, despite epigenetic and transcriptional upregulation, we found proteasomal degradation of noxa protein in CD adenomas. Using the selective proteasomal inhibitor bortezomib, we were able to rescue noxa ex-vivo and in-vitro, induce apoptosis, and reduce cell survival of adenoma cell lines. Conclusions: We defined the transcriptionl and DNA methylation landscape of human pituitary adenomas compared to adjacent normal gland tissue. We identified proteasomal-mediated noxa degradation despite PMAIP1 overexpression as an escape mechanism from apoptosis in adenomatous corticotrophs. The proteasomal inhibitor bortezomib rescued noxa and induced apoptosis in adenoma cells, highlighting its potential as a novel therapeutic strategy in CD.

Background: Hypothalamic-pituitary-gonadal (HPG) dysfunction is known to occur in male patients with Cushing Syndrome (CS) but the underlying mechanisms of HPG dysfunction remain unclear. We performed frequent blood sampling and GnRH stimulation tests to assess gonadotropin secretion in males before and after surgical cure of CS. Methods: We evaluated eight males age 32.5±12 years (mean ± SD) enrolled for surgical cure of ACTH-dependent CS at a tertiary care research center. Urinary free cortisol (UFC) was measured before and after surgery. Blood was sampled every 20 minutes for 24-hours with measurement of LH and FSH, before and 2 weeks to 160 weeks (median 80 weeks) after surgery. Patients received 100 μg of gonadotropin releasing hormone (GnRH) iv with measurement of LH and FSH at 0, 10 and 20 min before and 15, 30, 45, 60, 120 and 180 min after administration. Non-normative data was log-transformed before analysis using paired two-tail t-tests. A p-value of

Background: Previous studies of the oCRH test for the differential diagnosis of ACTH-dependent Cushing’s syndrome gave imprecise point estimates of specificity because of small numbers (n

BACKGROUND: Remission of Cushing’s syndrome (CS) is generally defined as morning serum cortisol values Methods: We reviewed 235 ACTH stimulation (stim) tests conducted on 76 patients with secondary adrenal insufficiency following remission of CS. Patients had resection of a single adrenal gland (n=7), pituitary adenoma [with (n=3) or without (n = 47) subsequent radiation], 70% of pituitary tissue (n=5), or ACTH secreting intrathoracic tumor (n=13). One had an ectopic ACTH secreting tumor in spontaneous remission (n=1). ACTH stim tests were conducted between 0800h and 0900h, 24 hours after the last dose of glucocorticoid, using 250 mcg of cosyntropin intravenously. Cortisol levels were measured just before administration of cosyntropin, and 30 and 60 minutes afterwards. Patients were considered to have passed the test if baseline or peak cortisol values reached > 18mcg/dL. Baseline cortisol values were compared to the ‘pass’ rate. Results: Baseline F values (ug/dL) and passing rates (# pass/total) were: 4-4.9: 2/27; 5-5.9: 8/31; 6-6.9: 2/21; 7-7.9: 7/25; 8-8.9: 4/12; 9-9.9: 8/12; >10 - < 15: 6/11 15 – 19.5: 5/5 Thus, Am cortisol values >9 ug/dl were significantly more likely to predict a normal response to ACTH stim than lower values (p Conclusion: Baseline cortisol can be a guide as to whether the more costly stimulation test is needed. In the small cohort with baseline 0800h – 0900h cortisol >15 ug/dL, all passed the test, suggesting that it is not needed in such patients. We recommend use of an ACTH stimulation test to assess recovery of the HPA axis when a morning cortisol reaches 9 mcg/dL, with an expected pass rate of about 66%. Reference: 1. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 100:2807, 2015.

Introduction: In patients with Cushing’s Disease (CD), intrapatient variability of hormone measurements creates significant clinical challenges, therefore multiple measurements are recommended.1 Urinary and salivary cortisol variation has been well described. However, intrapatient variation of adrenocorticotropic hormone (ACTH) in CD remains unknown. In CD patients, ACTH levels are inherently elevated from baseline but the coefficient of diurnal variation is reduced.2Additionally, at each diurnal time point, these exists a significant variation around the mean for the ACTH levels. In this study, we first analyzed the intrapatient variablility of ACTH at each diurnal timepoint in patients with CD. CD is primarily a disorder of ACTH excess, and treatment directed at pituitary adenomas would presumably perturb ACTH levels prior to affecting serum or urine cortisol. We hypothesized that the coefficient of variation at each diurnal time-point can help predict remission from CD following surgery. Methods: We conducted a retrospective review of patients (n = 645) who had histopathologically confirmed diagnosis of CD from 2005-2019 (NCT NCT00060541). We selected patients that had ≥ 3 plasma ACTH values over a 7 day span prior to surgical or medical intervention. We grouped the ACTH measurements into morning (AM) and midnight (PM) values to account for diurnal variation in ACTH secretion. We then analyzed post-operative hormone measurements performed every 6 hours prior to administration of replacement corticosteroids. Remission was assigned to patients with nadir serum cortisol level ≤5 mcg/dL within ten days post-operatively3,4. Results: We found 54 patients with multiple PM (n = 27) and AM (n = 41) ACTH measurements within a 7 day span. We found that the median coefficient of variation (CV) of intra-patient variability was 19.7% (N=41) (95% CI:12.5-27.5) for the AM and was 24% (N=27) (95% CI: 9.6-31.8) for the PM. Age, the number of tests, or the length of test period were not correlated with CV or absolute levels of ACTH. The intraclass correlation coefficient (ICC) of the AM data set was 0.59 and the PM data set was 0.79 which demonstrates a good and excellent reliability respectively. We found that that, in general, 30-60% decrease from pre-operative ACTH levels predicted remission from CD. ACTH decrease >50% on POD2 and 3 had 100% specificity and sensitivity in predicting remission. The decrease in ACTH preceded cortisol nadir in 3/10 patients by 24 hours. Conclusion: We found significant intra-patient variability in plasma levels of ACTH at individual diurnal timepoints in CD patients. We also found that the change in ACTH >50% on POD2 or 3 is an excellent predictor of remission from CD.

Introduction:Cell rests of self-renewing Sox2+ progenitor cells have been identified in the normal pituitary glands1, however their role in human pituitary tumorigenesis is not understood. Adrenocorticotropic hormone (ACTH) producing microadenomas that cause Cushing’s disease frequently (~70%) lack pathogenic genetic mutations.2 In mice, targeted expression of oncogenic β-catenin in Sox2+ cells generate microadenomas. Interestingly, the Sox2+ cells reside within the adjacent normal gland and drive adenomas in a paracrine fashion.3 We hypothesized that Sox2+ progenitors in human pituitary gland may drive the formation of microadenomas that cause Cushing’s disease (CD). Methods:Four ACTH producing adenomas and two non-functional adenomas (NFPA) with separately annotated adjacent normal tissue (henceforward called ‘microenvironment’) were procured for this study (NCT00060541). We performed RNA deep sequencing (RNAseq) and compared expression of lineage-specific markers and progenitor markers using two-sample T-tests after testing for variance equality and using Welch’s approximation for degrees of freedom. Results:We found expected overexpression of ACTH preprohormone POMC in CD adenomas compared to adjacent microenvironment (?-fold) and NFPA (?-fold). The microenvironment in Cushing’s disease showed increased expression of progenitor markers including SOX2, SOX9, CDH1, GRFA2, and KLF4 compared with microenviroment in NFPA. Likewise, the Cushing’s disease microenvironment showed increased expression ofPOMC (26.98 - fold, P = 0.004) as well as PRLR (FC 17.39, P = 0.006) and GH1 (FC 29.91, P = 0.003) implying that increased Sox2+ progenitors contribute to terminally differentiated corticotrope, lactotroph and somatotroph lineages in-vivo. Conclusions:We report increased expression of several progenitor markers and concomitant elevation in tissues-specific markers in the microenvironment of Cushing’s disease patients. Our results indicate that increased pituitary progenitors in the microenvironment of human corticotropinomas may signal in paracrine fashion and may contribute to the pathogenesis of Cushing’s disease. References:1. Cox, B. et al. J. Endocrinol.234, R135-R158 (2017).2. Bi, W. L. et al. Clin. Cancer Res.23, 1841-1851 (2017).3. Andoniadou, C. L. et al. Cell Stem Cell13, 433-445 (2013).

Background: Obesity, diabetes and hypertension are common in the general population, and do not discriminate between patients (pts) with or without Cushing’s syndrome (CS). Thus, Endocrine Society guidelines recommend biochemical testing in pts with multiple features compatible with the diagnosis (1). A 24-hour (d) urine cortisol (UF) is one of the recommended screening tests. However, tandem mass spectrometry (MS/MS) measurement of UF may be less sensitive than immunoassay because of antibody cross-reactivity with cortisol-like compounds. Cortisone (E), the product of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) inactivation of cortisol, can be measured in the urine (UE) by MS/MS and might improve the sensitivity of UF alone. The goal of this study was to compare the diagnostic utility of UE, UF, their sum (UF+UE) and their ratio (rUF/UE) for the detection of CS. Methods: We retrospectively reviewed 35 pts evaluated for CS from 1/2017 to 9/2019. UF (reference range (RR), 3.5-45 ug/d) and UE (RR 17-129 ug/d) were measured by MS/MS. CS etiology was later confirmed in 24 pts by pathology and/or tumor localization [14 female; 14 Cushing’s disease, 7 ectopic ACTH secretion (EAS), 3 presumed EAS awaiting surgery; 46 UF and UEs], and was excluded (noCS) in 11 pts followed over time [8 female; 65 UF and UEs with salivary cortisol and/or dexamethasone suppression]. For CS patients with multiple results, the sample with the lowest UF was compared with all available samples from the NoCS group. Results: Using a single result for each CS pt, the median (range) for UF, UE, UF+UE and rUF/UE were 281 ug/d (34 - 32,444), 358 ug/d (171 - 802), 642 ug/d (232 - 33246) and 0.78 (0.13 - 40.5). By contrast, using all observations in noCS pts, median (range) for UF, UE, UF+UE and rUF/UE were 13.6 ug/d (2.2 - 88.8), 79.5 ug/d (4.9 - 253), 98.2 ug/d (7.1 - 342) and 0.2 (0.05-0.67). Using the upper RR (or their sum) as a criterion for abnormality, all CS pts had abnormal UE and UF+UE; 45/46 had abnormal UF. In noCS samples, abnormal values were seen in 12/65 UF (3 pts), 14/65 UE (4 pts), and 13/65 UF+UE (3 pts). The rUF/UE was < 0.70 in all noCS pts and in 9/24 CS patients. Within this group, the UF+UE was > 230 ug/d in two noCS patients (2/3 and 2/7 samples/pt), and in all 9 CS patients, including two with normal UF and two with UF 170 ug/d identified the same noCS and CS patients. Conclusion: UF remains an important tool for screening of CS. The addition of UE and UF+UE may provide additional information to discriminate CS from noCS in patients with rUF/UE < 0.70. In contrast to CS pts, noCS pt consistently had UF+UE > 230 ug/d or UE > 170/d, underscoring the importance of multiple samples. Additional study, especially of pts with mild hypercortisolism, is needed to determine optimal diagnostic criteria. 1.Nieman L et al. J Clin Endocrinol Metab 93:1526, 2008

Background: Hypercortisolemia adversely affects thyroid hormone secretion. We previously described the temporal pattern of thyroid function recovery in 23 patients (1). However, the factors leading to suppression and recovery of the hypothalamic-pituitary-thyroid (HPT) axis in Cushing’s syndrome (CS) are not fully understood. We performed two separate studies to investigate these factors. Methods: In study 1, we examined patients (pts, n=62) with CS who underwent curative surgery and recorded their serum morning and evening cortisol, ACTH, tumor volume and duration of symptoms and 24-hour urine free cortisol (UFC) at baseline and the morning serum free T4, TSH and T3 at six-month intervals after cure. Data were log-transformed and Pearson correlations were performed. Linear mixed models were used to study factors that predict recovery of thyroid function. In study 2, we examined the diurnal variation of TSH by performing hourly TSH measurement between 3—7 PM and 12—4 AM on a cohort of pts (n=45) before surgery. Wilcoxon Signed-Rank method was used for comparisons of mean TSH across time and Pearson correlations were performed on log-transformed data. P values

Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogenous hypercortisolism and eucortisolism. A literature survey of 60 adult patients with CCS found 15 to have ectopic ACTH secretion (EAS) (1). The duration and frequency of hypercortisolemia are unpredictable, creating a diagnostic challenge. Objective: Describe biochemical and clinical characteristics of patients with CCS due to occult or histologically proven ectopic ACTH-secreting neuroendocrine tumor (NET). Methods: We conducted a retrospective medical record review of 12 adults with EAS admitted to our institution. Inclusion required 1) evidence of ectopic ACTH tumor from biochemical testing (CRH stimulation, 8 mg dexamethasone suppression [DST], and/or inferior petrosal sinus sampling [IPSS]) or pathology results and 2) cycles of hypercortisolism (Hi-F) to eucortisolism (Eu-F) off medical treatment. Results: Average age on admission was 61 (46-79) years; 58% were women. All 12 had biochemical evidence of ACTH-dependent Hi-F. IPSS results suggested EAS in 9 patients, 8 of whom had Hi-F for more than two months, and 1 whose cycles occurred every 5 - 7 days. IPSS was consistent with Cushing’s disease (CD) in 2 patients after Hi-F of only 6 -7 weeks and one with Eu-F on admission, estimated duration < 4 weeks. DST suggested EAS in 9 patients, and CD in the one with recent Eu-F. CRH was consistent with EAS in 10 patients, but suggested CD in 2 with marginal increases in ACTH (34.5%, 38%) but not cortisol. 7 patients had ACTH-secreting tumor on pathology (5 pulmonary, 1 pancreas, 1 appendix NET), and 5 had occult presumed EAS. Time from one Hi-F episode to the next ranged from 1 week to 6 years with Hi-F duration of 3 days to 5 years. 24-hour urine free cortisol (UFC) levels were 17 - 301 times the upper reference range (RR) during Hi-F periods. During Eu-F, lowest UFCs were within RR in 9 patients and subnormal in 3. Hypokalemia occurred in 11 patients with Hi-F; increasing values paralleled movement to Eu-F. Conclusion: Patients with possible ectopic ACTH-secretion and CCS may pose a diagnostic challenge: clinical and biochemical evidence of hypercortisolemia may not be present, depending on the timing and/or duration of hypercortisolism. Furthermore, test results may inappropriately suggest Cushing’s disease if performed after less than 8 weeks of hypercortisolism, or with recent eucortisolism. Thus, weekly UFC measurement may facilitate diagnosis of cyclical Cushing’s syndrome and determine appropriate timing of dynamic testing such as inferior petrosal sinus sampling. Potassium may be a useful marker to determine when medical treatment can be tapered or stopped. 1. Meinardi JR, et al. Eur J Endocrinol. 157:245, 2007.

Immunotherapy has changed the treatment landscape for cancer patients; however, immune‐related adverse events, such as primary and secondary adrenal insufficiency, can be life threatening, with potential differences in population incidence. This letter to the editor reports a real‐world experience of Hispanic/Latino patients treated with immunotherapy and the incidence of adrenal insufficiency.

Introduction: Recurrence of Cushing’s disease (CD) caused by benign pituitary microadenomas are challenging clinical problems. Mechanisms underlying adenoma formation and recurrence remain unknown. PMAIP1 gene codes for Noxa, a Bcl-2 homology 3 (BH3) pro-apoptotic protein frequently downregulated in malignant human tumors.1-6 The role of dysregulated apoptosis remains largely unknown in benign tumors and in CD. We hypothesized that altered expression of Noxa protein is a pro-survival adaptation employed by CD adenomas. Methods: Syngeneic human pituitary adenoma and adjacent normal gland pairs (n=2), and an additional CD adenoma were analyzed with RNAseq. 10 CD, 1 growth hormone (GH) and 1 non-functioning adenoma (NFPA) underwent immunohistochemical (IHC) analysis for Noxa expression, which was graded by a neuropathologist as 0=none, 1=light, 2=medium, 3=strong. Staining grade represents relative protein expression. Results: Compared to adjacent normal pituitary tissue, we found that adenomas (n = 3) had a 3.76 fold increase in PMAIP1 mRNA. However, there was attenuated Noxa IHC staining in adenomas compared to normal pituitary in 8 of 10 CD patients (2:3, respectively), but similar staining in 2 of 10 CD patients (2:2 and 2-3:2-3). In GH and NFPA, we found similar patterns of Noxa suppression in the adenomas compared to the normal gland. Conclusion: Despite elevated PMAIP1 (Noxa) gene expression in adenomas compared to adjacent normal gland in CD, protein expression was reduced in adenomas. This downregulation of Noxa protein expression may contribute to reduced apoptosis of tumor cells. These findings suggest that CD adenomas gain pro-survival advantage by downregulating Noxa protein at post-transcriptional or post-translational level. References 1. Escobar, D. et al. Cell Death Dis.6, 1-14 (2015).2. Brinkmann, K. et al. Cell Rep.3, 881-891 (2013).3. Liu, Y. L. et al. Oncotarget5, 11237-11251 (2014).4. Dengler, M. A. et al. Cell Death Dis.5, 1-10 (2014).5. Liang, L. et al. J. Oral Pathol. Med.48, 52-59 (2019).6. Tahir, S. K. et al. Cancer Res.67, 1176-1183 (2007).

OBJECTIVEAccurate presurgical localization of microadenomas in Cushing’s disease (CD) leads to improved remission rates and decreased adverse events. Volumetric gradient recalled echo (3D-GRE) MRI detects pituitary microadenomas in CD in up to 50%–80% cases as a focus of hypointensity due to delayed contrast wash-in. The authors have previously reported that postcontrast FLAIR imaging may be useful in detecting otherwise MRI-negative pituitary microadenomas as foci of hyperintensity. This reflects theoretically complementary imaging of microadenomas due to delayed contrast washout. The authors report on the diagnostic accuracy and clinical utility of FLAIR imaging in the detection of microadenomas in patients with CD.METHODSThe authors prospectively analyzed imaging findings in 23 patients (24 tumors) with biochemically proven CD who underwent transsphenoidal surgery for CD. Preoperatively, the patients underwent pituitary MRI with postcontrast FLAIR and postcontrast 3D-GRE sequences.RESULTSPostcontrast FLAIR hyperintensity was detected in macroadenomas, and in 3D-GRE–positive or –negative microadenomas. Overall, 3D-GRE was superior in detecting surgically and histopathologically confirmed, location-concordant microadenomas. Of 24 pituitary adenomas, 18 (75%; sensitivity 82%, positive predictive value 95%) were found on 3D-GRE, and 13 (50% [1 was false positive]; sensitivity 55%, positive predictive value 92%) were correctly identified on FLAIR. The stand-alone specificity of 3D-GRE and FLAIR was similar (50%). These results confirm the superiority of 3D-GRE as a stand-alone imaging modality. The authors then tested the utility of FLAIR as a complementary tool to 3D-GRE imaging. All 5 patients with negative 3D-GRE MRI displayed a distinct focus of FLAIR enhancement. Four of those 5 cases (80%) had location-concordant positive histopathological results and achieved postsurgical biochemical remission. The remaining patient was not cured, because resection did not include the region of FLAIR hyperintensity.CONCLUSIONSThis study suggests that delayed microadenoma contrast washout may be detected as FLAIR hyperintensity in otherwise MRI-negative CD cases. The authors propose adding postcontrast FLAIR sequences to complement 3D-GRE for surgical planning in patients with CD.Clinical trial registration no.: NIH protocol 03-N-0164, NCT00060541 (clinicaltrials.gov)

Patients with Cushing syndrome have an increased mortality rate, primarily due to increased cardiovascular death, which is driven by hypertension, diabetes, obesity, and dyslipidemia. These should be evaluated before and after active hypercortisolism, and each should be treated specifically. Antihypertensives may be chosen based on probable pathophysiology. Thus, inhibitors of the renin-angiotensinogen system are recommended. Mineralocorticoid antagonists are helpful in hypokalemic patients. Other agents are often needed to normalize blood pressure. If medical treatment of Cushing syndrome is chosen, the goal should be to normalize cortisol (or its clinical action); if this is not achieved, it is more difficult to treat comorbidities.

Context Patients taking exogenous glucocorticoids are at risk for gastrointestinal (GI) complications, including peptic ulcer disease with perforation and gastric bleeding. However, little is known about the GI comorbidity in patients with endogenous hypercortisolemia. Case descriptions We describe six patients with endogenous Cushing syndrome (CS) who developed sudden perforation of colonic diverticula necessitating urgent exploratory laparotomy. Most of these patients shared the following features of CS: skin thinning, severe hypercortisolemia (24-hour urinary free cortisol ≥10 times the upper limit of normal), ectopic secretion of ACTH, and severe hypokalemia. At the time of diagnosis of diverticular perforation (DP), these patients had minimal signs of peritonitis and lacked fever or marked leukocytosis. The diagnosis of DP was established by having a low threshold for obtaining an imaging study for evaluation of nonspecific abdominal pain. Conclusions Patients with CS can develop spontaneous surgical abdomen with rapid decompensation within hours. Prompt recognition is critical in the successful treatment of these patients.

Background: Current guidelines for the primary prevention of atherosclerotic cardiovascular disease are based on the estimation of a predicted 10-year cardiovascular disease risk and the average relative risk reduction estimates from statin trials. In the clinical setting, however, decision-making is better informed by the expected benefit for the individual patient, which is typically lacking. Consequently, a personalized statin benefit approach based on absolute risk reduction over 10 years (ARR10 benefit threshold ≥2.3%) has been proposed as a novel approach. However, how this benefit threshold relates with coronary plaque burden in asymptomatic individuals with low/intermediate cardiovascular disease risk is unknown. Aims: In this study, we compared the predicted ARR10 obtained in each individual with plaque burden detected by coronary computed tomography angiography. Methods and Results: Plaque burden (segment volume score, segment stenosis score, and segment involvement score) was assessed in prospectively recruited asymptomatic subjects (n = 70; 52% male; median age 56 years [interquartile range 51–64 years]) with low/intermediate Framingham risk score (< 20%). The expected ARR10 with statin in the entire cohort was 2.7% (1.5–4.6%) with a corresponding number needed to treat over 10 years of 36 (22–63). In subjects with an ARR10 benefit threshold ≥2.3% (vs. < 2.3%), plaque burden was significantly higher (p = 0.02). Conclusion: These findings suggest that individuals with higher coronary plaque burden are more likely to get greater benefit from statin therapy even among asymptomatic individuals with low cardiovascular risk.

Key Points Question What is the optimal surgical management of ectopic adrenocorticotropic hormone secreting pulmonary carcinoid tumors associated with Cushing syndrome (CS)? Findings In this case series study of 68 patients with Cushing syndrome, ectopic adrenocorticotropic hormone–secreting carcinoid tumors with CS were associated with increased metastasis to lymph nodes, higher recurrence, and lower overall disease-free survival at 5 and 10years compared with quiescent bronchial carcinoid tumors, irrespective of histologic subtype, with no difference in outcome based on surgical approach. Meaning Results of this study suggest that underlying carcinoid biologic factors may not be as important as the symptomatic hormonal physiology, and a lung-sparing surgical approach coupled with routine lymphadenectomy may be an optimal intervention when CS resolves., Importance Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrome are associated with high rates of morbidity. Optimal management remains obscure because knowledge is based on rare reports with few patients. Objective To characterize the outcomes of lung neuroendocrine tumors associated with Cushing syndrome. Design, Setting, and Participants An observational case series review from 1982 to 2020 was conducted in a single institution referral center. Kaplan-Meier analysis estimated disease-free survival (DFS). Participants underwent curative-intent surgery for a lung neuroendocrine tumor causing Cushing syndrome. Exposures Lobectomy or pneumonectomy vs sublobar resection. Main Outcomes and Measures Disease-free survival, disease persistence/recurrence. Results Of the 68 patients, the median age was 41 years (range, 17-80 years), 42.6% (29 of 68) were male, 81.8% (54 of 66) were White, with a mean follow-up after surgery was 16 months (range, 0.1-341 months). Lobectomy was the most common procedure (48 of 68 [70.6%]), followed by wedge resection (16 of 68 [23.5%]) and segmentectomy (3 of 68 [4.4%]). Video-assisted thoracoscopic surgery was performed in 19 of 68 (27.9%) of patients. Surgical morbidity was 19.1% (13 of 68), and perioperative mortality was 1.5% (1 of 68). Lymph node positivity was 37% (22 of 59) when evaluable. The overall incidence of persistence/recurrence was 16.2% (11 of 68) with a median time to recurrence of 55 months (range, 18-152 months). The median DFS was reached in 12.7 years (0.1-334 months). There were no statistical differences in DFS based on tumor size, stage (8th edition TNM), whether full systematic lymphadenectomy was performed or not, nodal status, or surgical approach. Conclusions and Relevance In this case series study, neuroendocrine pulmonary tumors associated with Cushing syndrome had increased nodal metastasis, higher recurrence, and lower DFS than quiescent bronchopulmonary carcinoid tumors, but many patients experienced favorable outcomes. This observation is underscored by the discordance of TNM-stage classifications vs prognosis. Observing no difference in surgical techniques, the implication may be that a lung-sparing approach could suffice. These results may reflect the intrinsic importance of the hormone physiology instead of the carcinoid biologic factors., This case series study compares survival and disease recurrence of patients with lung neuroendocrine tumors associated with Cushing syndrome treated using lobectomy or pneumonectomy vs sublobar resection.

Background: Metyrapone is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on observational retrospective studies published over more than 50 years. We present data from the first prospective study designed to confirm metyrapone efficacy and good tolerance in patients with CS. Methods: This single arm, open-label, multicenter, international trial enrolled 50 patients with CS who had three baseline 24 hours urine free cortisol (UFC) values at least 50% above the upper limit of normal (ULN=165 nmol/24h). Metyrapone was titrated over 12 weeks (W12) to achieve normal urine (mean of 3 values, mUFC) and serum cortisol levels. Patients whose mUFC did not exceed 2-fold the ULN could enter a 6-month extension period. The primary efficacy endpoint was the proportion of patients with mUFC ≤ ULN at W12 assessed in a central laboratory using LC-MS/MS. The most important secondary endpoint was mUFC decrease of ≥ 50% at W12. Results: At baseline: mean age was 47 years, median mUFC (range) was 570 (291 - 8476) nmol/24h (3.5 x ULN). Hypercortisolism was in 96% of patients either moderate (mUFC ≥ 2xULN; < 5x ULN) in 63% or severe (≥5 x ULN) in 33%. Hypertension (69%) and diabetes mellitus (47%) were the most common comorbidities. At W12: 47% (23/ 49) met primary endpoint. Another 40% (19 / 49) had mUFC ≤ 2xULN. Median percentage decrease in mUFC from baseline to W12 was -74%. Secondary endpoint was met by 80% of patients who had a mUFC decrease of 50%. Final median metyrapone dose was 1500 (250; 5500) mg/day. Physical signs and symptoms were normalized or improved in 66% of patients. Circulating cholesterol, HbA1C and fasting glucose and insulin improved with median decrease of 12%, 3%, 5% and 9% respectively and median systolic and diastolic blood pressure also decreased by 4 and 5mmHg respectively. Among patients with antihypertensive treatments, 10 (31%) had a decrease in number of drugs and 5 (16%) had an increase in number of drugs during the study. Median ACTH increased by 11 % from baseline. Twenty six (52%) patients experienced mild to moderate study drug related adverse events (AEs). One patient discontinued before W12 because of an unrelated SAE on day 2 (pneumonia with septic shock). The most common AEs were nausea (24%), decreased appetite (18%), fatigue (14%), headache (10%), peripheral edema (6.0%), hypokalemia (6.0%) and hypertension (6.0%). Reversible adrenal insufficiency occurred in 6 (12%) patients. Few patients 14% (7/50) experienced at least one AE that led to a dose interruption or dose adjustment. Cushing Quality of Life Questionnaire increased of 10 points from baseline which is close to minimal clinically important difference = 10.1. Conclusions: This prospective study in patients with CS confirms that metyrapone effectively lowers UFC levels with a tolerability profile similar to the previously reported safety profile and improves QoL, at Week 12.

Context: Cushing Syndrome (CS) is characterized by cortisol excess, impaired glucose tolerance, and obesity. As assessed by CT imaging, 20% of CS patients develop steatohepatitis (NASH). The gold standard test, liver biopsy, is associated with CS complications and cannot be used to confirm the diagnosis. This study evaluated the ability of magnetic resonance spectroscopy (MRS). Objective: To identify the prevalence of NASH and its temporal changes in relation to other metabolic parameters in CS before and after successful treatment. Primary Outcome Measure: PDFF measured by MRS at 3T before, 6 and 12 months after Cushing’s syndrome treatment DESIGN: In this prospective IRB-approved study, 41 consecutive CS patients (44±1.8 y; 34(85%) females, 32.6±1.5 kg/m²; urine cortisol excretion 2242.7±1806.3 [3.5–45.0 mcg/24h]) underwent MRS before, 6 and 12months after successful treatment. PDFF was measured by MRS at 3T; NASH was defined as >5% PDFF. Metabolic markers – glycohemoglobin (A1C) and body mass index (BMI) – were measured; Wilcoxon matched-pairs signed-rank test evaluated changes over time, and spearman rank test evaluated the correlation between variables. Results: At baseline, mean PDFF was 10.4±1.7 and correlated positively with BMI (r=0.5710, p Conclusions: MRS-PDFF is valuable for diagnosing NASH in Cushing Syndrome, which can affect a third of this patient population. Liver fat decreases by 6 months after normalization of cortisol and precedes the improvement of A1C. Indicating that liver insulin resistance due to fat accumulation has an essential role in diabetes pathophysiology in CS.

Background: Patients who require higher than replacement glucocorticoid doses to avoid symptoms of adrenal insufficiency (AI) may have inadequate adherence or abnormal drug absorption or metabolism. The goal of this study was to identify why excessive glucocorticoid doses were needed in patients with ongoing AI symptoms. Methods: We performed pharmacokinetic (PK) analysis of glucocorticoid plasma concentrations (prednisone, prednisolone and dexamethasone measured by tandem mass spectrometry, Mayo Laboratories, and cortisol by immunoassay, Clinical Center) in 8 AI patients after weight-based oral hydrocortisone (HC) dose (1), IV HC 20 mg and /or prednisone 5 mg PO. The time (Tmax) to maximal plasma concentrations (Cmax), time to a 50% decrease in concentration (T1/2), elimination rate (ER) and area under the concentration curve (AUC) were determined using MATLAB and SimBiology, and compared to literature reference ranges (RR) (1,2). Results: Patients included one man; six had secondary AI due to previous supraphysiologic hydrocortisone or prednisone treatment and two had primary autoimmune AI. One of the latter was appropriately replaced with thyroid hormone. No patient was taking any medication known to be a strong inhibitor or inducer of CYP3A4 and none were taking oral estrogens. To study the potential contribution of intestinal absorption to abnormal pharmacokinetics, serum cortisol values were compared to expected values at 3.5 or 4 hours after a weight-based oral dose of HC in eight patients (1); 7 patients had values at the 50 - 80th centile of expected values. The eighth patient’s cortisol level at 4 hours after 5 mg HC was 30.3 nmol/L, below the 10th centile. She then underwent the same sampling with a 15 mg dose, with values also at the 10th centile. To uncover any discrepancy between PK oral and IV HC administration, four patients, including the patient with a low 4 hour value (LowHC4h) underwent sampling after 20 mg hydrocortisone, IV (2). Tmax and Cmax were within the RR in all four patients, while one patient had a faster T1/2 but an AUC similar to others. The LowHC4h patient had a dexamethasone level 8 hours after a 1 mg dose that was also within the RR and was maintained on dexamethasone. All others were eventually able to be weaned to a conventional glucocorticoid replacement dose. Conclusions: Evaluation of oral and IV HC PK may be useful in patients suspected of having abnormal absorption of oral glucocorticoids. Ref: 1. Mah PM et al. Clin Endo 61:367,20042. Thomson AH et al. Clin Endo 66:789,2007

Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the current pathophysiological principles, diagnostic methods, and management of CD.

Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P

Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17β-estradiol (100 mcg/day) or placebo patch. Over 6 weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI

CONTEXT Hypertension associated with Cushing's syndrome (CS) increases cardiovascular risk. The time-course of improvement after cure is unclear. OBJECTIVE To describe the time-course and predictors of blood pressure (BP) normalization during one year after surgical cure of CS. DESIGN Retrospective chart review of 75 hypertensive adults cured of CS (72 with ACTH-dependent CS; 3 with adrenal adenoma). Hypertension was defined as current use of antihypertensives, a systolic BP >130 mm Hg, or diastolic BP >80 mm Hg. MAIN OUTCOME MEASURE(S) Remission of hypertension: BP ≤130/80 mm Hg and no antihypertensive medications. Improvement in hypertension: BP >130/80 mm Hg and decreased number or dose of medications, or blood pressure ≤130/80 with continued use of medications at constant dose. RESULTS At postoperative discharge, 17 (23%, P

Background: Remission of Cushings syndrome (CS) is generally defined as morning serum cortisol (F) values 1.8mcg/dl, late night serum F levels were collected at 2330 and 2359. Definition of remission was established as late night F level < 7.5mcg/dl.Results: Of 19 pts, 11 had Ectopic ACTH Syndrome (EAS) and 8 had Cushing’s disease (CD). The median age was 54, 12/19 were female. 15 were deemed to be in surgical remission, 10 having passed the DST with F value 2mcg/dl; one had a 2cm adrenal nodule secondary to CD, one had bilateral adrenal hyperplasia, and in the 3rd case a dexamethasone level was not measured. These 3 cases underwent 24 hour urine cortisol measurements, all found within the lower end of the reference range; 5mcg/24hr, 8mcg/24h and 5.2ug/24hr respectively. 12/15 had documented or reported history of cyclic CS and/or were treated with steroidogenesis inhibitors prior to surgery. 21% (4/19) pts were concluded to have persistent hypercortisolemia based on abnormal DST results (F range 4.7-10.8mcg/dl) with 2 also having abnormal night serum F (>20mcg/d). All had CD, and of these 2 had no tumor identified on pathology, one had persistent disease requiring a repeat pituitary surgery with subsequent cure and positive adenoma on pathology, and the 4th had residual disease. Conclusion: In cases of cyclic CS, or where medical management was used prior to surgical resection, normal corticotrophs may not be suppressed, resulting in measurable or normal serum cortisol values post operatively. We suggest the use of the 1 mg DST and/or night time serum cortisol samples to differentiate between persistent hypercortisolism and remission after successful tumor resection.