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MaryO

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  1. Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society's virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rates, hyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights: More Safety Data on Jatenzo In a study of 81 men with hypogonadism -- defined as a serum testosterone level below 300 ng/dL -- oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study. After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range. And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study -- including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL). Throughout the trial, only one participant had elevation of liver function tests. "Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration," said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement. In addition, for many men with hypogonadism, "an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children," he said. "Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage." Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history. COVID-19 Risk With Adrenal Insufficiency Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%). These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001). Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries. "It's really important that you take your hydrocortisone medications and start stress dosing as soon as you're sick," study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children's in Little Rock, explained during a press conference. "This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids." And with kids starting to return back to in-person schooling, "parents should also be reeducated about using the emergency injections of hydrocortisone," Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well. Cushing's Death Risk In a systematic review and meta-analysis of 87 studies -- including data on 17,276 patients with endogenous Cushing's syndrome -- researchers found that these patients face a much higher death rate than those without this condition. Overall, patients with endogenous Cushing's syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing's disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%). And those with adrenal Cushing's syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%). The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%). "The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, and good infection control, and emphasize the need to achieve disease remission, normalizing cortisol levels," said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement. From https://www.medpagetoday.com/meetingcoverage/endo/91808
  2. Zarina Brady, Aoife Garrahy, Claire Carthy, Michael W. O’Reilly, Christopher J. Thompson, Mark Sherlock, Amar Agha & Mohsen Javadpour BMC Endocrine Disorders volume 21, Article number: 36 (2021) Cite this article 160 Accesses Metricsdetails Abstract Background Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing’s disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012–February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. Results A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4–79) months. Conclusion Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus. Peer Review reports Introduction With an estimated annual incidence of 1.7 per million [1], Cushing’s disease is rare. Untreated, it poses serious complications including osteoporosis, hypertension, dyslipidaemia, insulin resistance, and hypercoagulability [2] and is associated with a 4.8 fold increase in mortality rate [3,4,5]. Patients who are in remission from CD have a mortality rate which decreases towards (although not reaching) that of the general population [6]. Endoscopic transsphenoidal surgery (ETSS) offers patients potential remission from Cushing’s disease, although long term surveillance is required as recurrence rates range from 5 to 22%% [7,8,9,10,11,12]. Since the first report in 1997 [13], the selective removal of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma by endoscopic transsphenoidal surgery has gained popularity as the first line treatment for Cushing’s disease. The primary goal of ETSS treatment in Cushing’s disease is to produce disease remission and to provide long-term control, while minimising complications. Remission rates are dependent on tumour size, preoperative MRI, cavernous sinus invasion, intraoperative visualisation of the tumour and pre- and postoperative ACTH and cortisol concentration [11]. Several studies also report pituitary neurosurgeon experience as a major factor for operative success [2, 14, 15]. Reported remission and recurrence rates after TSS for CD vary widely according to the criteria utilised to define remission [11], and in some studies due to limited patient numbers or short follow-up periods. Indeed, there is no clear consensus on how best to define post-operative remission; an early morning serum cortisol concentration < 138 nmol/L (5μg/dl) within 7 days of TSS is quoted in the 2015 Endocrine Society Clinical Practice Guideline as indicative of remission [16]. A more strict day 3 cut-off of 50 nmol/L (1.8 μg/dl) has been reported in paediatric studies [17], and also included in the Endocrine Society Guideline [16]; the literature suggests this cut-off is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. The main objective of this study was to assess the outcomes of endoscopic transsphenoidal surgery for Cushing’s disease in a tertiary pituitary centre; remission using two widely accepted criteria [16], recurrence and postoperative complications. Methods Study design This is a retrospective analysis of a prospectively-maintained database of patients operated on by a single neurosurgeon (MJ), via image-guided endoscopic transsphenoidal approach for Cushing’s disease. Patient data was gathered over 8 years (January 2012 to February 2020) and identified from the institution’s prospective database. Clinical and biochemical data during the follow-up period was reviewed. Approval was granted by the Hospital Audit Committee. Study population Patients were screened for Cushing’s syndrome by the presence of typical clinical features, together with failure to adequately suppress cortisol to < 50 nmol/L following overnight dexamethasone suppression test (ONDST) and/or elevated late night salivary cortisol (LNSF) concentration and/or elevated 24 h urinary free cortisol measurements. As per standard guidelines, Cushing’s disease was diagnosed on the basis of elevated serum ACTH measurements, along with confirmatory hormone responses to peripheral corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPSS). Patients with previous TSS prior to the study period were excluded. Surgical procedure A single neurosurgeon subspecialising in endoscopic pituitary and anterior skull base surgery, M.J, carried out all ETSS surgical procedures. The surgical technique has been described in detail in publications by Cappabianca et al. (1998, 1999) and Jho et al. (1997, 2000, 2001) [13, 18,19,20,21]. In summary, the procedure consists of a binostril endoscopic transsphenoidal approach. A selective adenomectomy was performed on patients with adenomas noted on pre-operative MRI. In cases of negative pre-operative MRI, exploration of the pituitary gland was performed. To confirm the diagnosis of ACTH-secreting adenoma or hyperplasia, all specimens removed underwent histopathological and immunohistochemical staining for pituitary hormones. Postoperative assessment Patients received empiric oral hydrocortisone on day 1 and on the morning of day 2 post-operatively, prior to assessment of 0800 h serum cortisol on day 3. A blood sample for serum cortisol was drawn at 0800 h on the morning of day 3, if clinically stable, prior to administration of hydrocortisone. The Endocrine Society Clinical Practice Guideline define post-operative biochemical remission as morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively [16], ‘standard criteria’. In our institution, we also apply a biochemical cut-off of < 50 nmol/L (1.8 μg/dl) at day 3 postoperatively to allow early indication of biochemical remission, ‘strict criteria’. If serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical sequalae of hypercortisolaemia made (such as improvement in blood pressure or glycaemic control), before repeat endoscopic transsphenoidal surgery is considered. Transient cranial diabetes insipidus (DI) was defined as the development of hypotonic polyuria postoperatively requiring at least one dose of desmopressin [22], which resolved prior to discharge. Permanent DI was confirmed by water deprivation test according to standard criteria [23]. Thyroid stimulating hormone (TSH) deficiency was defined by low fT4 with either low or inappropriately normal TSH. Growth hormone (GH) deficiency was confirmed using either Insulin Tolerance Test or Glucagon Stimulation Test [24]. Gonadotrophin deficiency was defined in premenopausal women as amenorrhoea with inappropriately low FSH and LH concentration, and in postmenopausal patients as inappropriately low FSH and LH concentration. Recovery of hypothalamic-pituitary-adrenal axis was assessed by short synacthen (250 μg) test or insulin tolerance test 3 months post-operatively, and every 3–6 months thereafter in cases of initial fail or borderline result. Patients were assessed annually for recurrence of Cushing’s disease, recurrence was defined by failure to suppress cortisol to < 50 nmol/L following an 1 mg overnight dexamethasone suppression test, an elevated late night salivary cortisol (LNSF) or urinary free cortisol (UFC) in patients no longer taking hydrocortisone. Laboratory analysis Prior to 2019, serum cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter UniCel Dxl 800. Intra-assay CV for serum cortisol was 8.3, 5 and 4.6% at concentrations of 76, 438 and 865 nmol/L, respectively. From January 2019 onwards, serum cortisol was measured using Elecsys® Cortisol II assay on the Roche Cobas e801; intra-assay precision for serum cortisol was 1.2, 1.1 and 1.6% at concentrations of 31.8, 273 and 788 nmol/L, respectively. Statistics Data are expressed as median (range) and number (%). The Fishers Exact test was used to compare categorical variables between groups. All p-values were considered statistically significant at a level < 0.05. Statistical analysis was performed using GraphPad Prism 8 statistical software (GraphPad Software, La Jolla, California, USA). Results Demographics Forty-three endoscopic transsphenoidal procedures were performed in 39 patients. Demographics are summarised in Table 1. Median (range) age was 37 years (8–75), 30 were female. Median (range) duration of symptoms was 24 months (6–144), 72% (28/39) had hypertension, and 28% (11/39) had type 2 diabetes. Table 1 Summary of demographics and post-operative outcomes Full size table Preoperative imaging and IPSS Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). No adenoma was identified in 17 patients (44%). IPSS was carried out in 33 (85%) patients. Postoperative remission Post-operative outcomes are summarised in Table 1 and Fig. 1. Using standard criteria (0800 h serum cortisol < 138 nmol/l within 7 days of operation and improvement in clinical features of hypercortisolism), postoperative remission rates for initial surgery were 87% (34/39) for the entire group and 89% (31/35) when patients with macroadenomas were excluded, Fig. 1. Three patients had an early repeat ETSS for persistent disease; day 3 serum cortisol ranged from 306 to 555 nmol/L and interval to repeat ETSS from 10 days–3 months. When the outcome of early repeat ETSS was factored in, overall remission rate was 92% (36/39) overall, and 94% (33/35) when patients with macroadenomas were excluded. Fig. 1 Schema of patients who underwent ETSS. *Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids Full size image Using strict criteria of early remission (day 3 serum cortisol concentration < 50 nmol/L), postoperative remission rates were 58% (22/38) overall, and 62% (21/34) excluding macroadenomas. Including the three patients with early repeat ETSS, remission rate was 61% (23/38) overall, and 65% excluding macroadenomas (22/34). Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids. Eleven patients (28%) had a cortisol measurement between 50 and 138 nmol/L on day 3, seven of whom had received metyrapone therapy prior to ETSS. Six patients had serial measurements of 0800 h cortisol up to a maximum follow-up of 14 days post-op, serum cortisol concentration fell after day 3 in all six patients. Ten (91%) were glucocorticoid-dependent at 3 months based on synacthen/ITT; 0800 h cortisol had fallen to < 50 nmol/L in six patients. Predictors of remission No statistical difference was found in the rates of remission in those patients with or without tumour target on preoperative MRI, using either strict criteria for remission (12/21 target vs 10/17 no target, p > 0.99) or standard criteria (19/22 target vs 15/17 no target, p > 0.99). Similar results were found when the four patients with macroadenoma were excluded. Persistent disease Five patients (13%) had persistent hypercortisolaemia after the initial endoscopic transsphenoidal surgery (Table 2). Three patients underwent a repeat early endoscopic transsphenoidal surgery, Fig. 1. Remission rate after repeat early ETSS was 67% (2/3) using standard criteria, and 33% (1/3), using the strict criteria. Of the patients with persistent disease following repeat ETSS, one received radiosurgery, while the other has been commenced on medical therapy, with a view to refer for radiotherapy. Table 2 Outcome of five patients with persistent hypercortisolaemia after initial ETSS Full size table Postoperative complications The rate of transient diabetes insipidus after first ETSS was 33% (13/39), while permanent diabetes insipidus occurred in 23% (9/39). Postoperatively, there were five cases of new thyroid stimulating hormone deficiency (13%) and four cases of gonadotrophin deficiency (10%) (in pre-menopausal females). There were no cases of postoperative CSF leak, no cases of meningitis and no visual complications. There were no other complications. Recurrence No patients were lost to follow-up. Over a median (range) duration of follow-up of 24 (4–79) months, one patient had recurrence of Cushing’s disease. Pre-operative MRI had shown a macroadenoma; serum cortisol on day 3 after the initial ETSS was 71 nmol/L, which fulfilled standard criteria for remission, but not the more strict criteria. The patient underwent a second ETSS 13 months later. No tumour was visible intra-operatively so no tissue was removed, day 3 serum cortisol concentration was 308 nmol/L and the patient was commenced on a trial of metyrapone. Recovery of the hypothalamic-pituitary-adrenal axis Recovery of the hypothalamic-pituitary-adrenal axis occurred in nine patients (27%), at median 13 (3–27) months post-operatively. There was no statistical difference in rates of recovery of HPA axis in patients with day 3 cortisol < 50 nmol/l, and those who only passed standard criteria for remission (< 138 nmol/l) [7/20 (follow-up 25 (3–59) months) versus 2/11 (follow-up 16 (3–79) months) respectively, p = 0.43]. One patient died 5 weeks post-operatively; post-mortem revealed bilateral haemorrhagic adrenal necrosis. Discussion Reported remission rates following ETSS in patients with Cushing’s disease (CD) vary widely, predominantly due to differences in criteria used to define remission [11]. There is no uniform consensus on the criteria used to define ‘remission’, with institutions using a combination of biochemical and clinical criteria; this makes comparing surgical outcome studies challenging. The normal corticotroph cells of the pituitary gland are suppressed due to sustained hypercortisolaemia, therefore following successful removal of the ACTH-secreting adenoma, serum ACTH and cortisol concentrations should fall postoperatively. A morning serum cortisol concentration < 138 nmol/L (5 μg/dl) within 7 days of ETSS is usually indicative of remission, and this biochemical cut-off is quoted in the Endocrine Society Clinical Practice Guideline [16], and many surgical outcome studies [8, 11, 25]. Other studies have applied a more strict serum cortisol cut-off of < 50 nmol/L (1.8 μg/L) at day 3 postoperatively to allow early indication of biochemical remission [10, 11, 26,27,28]; the literature suggests this cutoff is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. Our practice is to apply this latter approach; if serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical signs of hypercortisolaemia made, before repeat endoscopic transsphenoidal surgery is considered. It is important to ensure that serum cortisol has reached a nadir, before further intervention is considered. In this single-centre single-surgeon study, we report two very different remission rates using these two widely accepted criteria. Our remission rate, including those patients who had an early second ETSS, using standard guidelines, is 92%, on par with other larger studies [7, 8, 11, 25, 29]. When patients with corticotroph macroadenomas were excluded, the remission rate was even higher at 94%. In comparison, when we applied the more strict criteria of day 3 cortisol < 50 nmol/L, the remission rate was considerably lower at 61%. This criteria is in place in our institution so that we can safely identify patients who have early signs of remission to facilitate discharge on day 3 post-operatively; however reporting these rates in isolation lead to a misleadingly low remission rate compared to the more lenient criteria proposed by the Endocrine Society [16]. Evidence has suggested that higher day 3 cortisol concentration is associated with greater risk of recurrence of CD. A recent retrospective cohort analysis of 81 ETSS for CD by Mayberg et al. reported significantly higher recurrence rates in patients with post-operative cortisol nadir between 58 and 149 nmol/L (2.1–5.4 μg/dL) compared with those with cortisol < 55 nmol/L (2 μg/dL) (33% vs 6%, p = 0.01) [30]. Recurrence of CD was low in our series at 3%, and occurred in a patient with a corticotroph macroadenoma, which have been shown to be associated with higher rates of recurrence [31]. On post-operative assessment, serum cortisol fell between the two criteria for remission and if remission was strictly defined as a day 3 cortisol < 50 nmol/L, then this patient had in fact persistent hypercortisolaemia. This case highlights the difficulty when comparing studies reporting ETSS outcomes in CD – the distinction between persistent post-operative hypercortisolism and early recurrence of CD is not always clear-cut, and is dictated by the local protocol. Whilst our recurrence data are encouraging in comparison to other reports on CD recurrence, which published rates of up to 22% [11], longer term follow-up is necessary before recurrence rates can be accurately defined. The criteria used to define long term recurrence of CD also varies widely in the literature; a large systematic review (n = 6400) by Petersenn et al. (2015) reported decreased recurrence rates when studies used UFC with ONDST vs. UFC only, and UFC with morning serum cortisol vs. UFC only [11]. This highlights the requirement for standardization of remission and recurrence criteria, for consistency in clinical practice and in the literature. The post-operative surgical complication rate in our series was very low, with no cases of CSF leak, vascular injury or visual compromise. Other published case series have reported incidence rates for CSF leakage and meningitis of 0–7.2% and 0–7.9% [2, 12, 32, 33] respectively. Postoperative meningitis is strongly associated with CSF leakage [34]. Some studies suggest that the endoscopic approach results in higher rates of carotid artery injury compared with the microscopic approach, which could be attributed to the nature of the extended lateral approach [35]. However, in this series of 43 ETSS, we report no cases of surgical related carotid artery injury, similar to other studies reporting 0% serious morbidity or mortality due to carotid artery injury [33, 36]. Finally, postoperative visual disturbance is a major concern, as it can be life changing for patients. Factors linked with visual complications include tumour size, patient age and any pre-existing visual conditions [37,38,39]. Visual deterioration after TSS for Cushing’s disease has been reported to occur in some large case series at rates of 1.9% [32] and 0.86% [12]. There were no cases of postoperative visual disturbance in our series. While the surgical complication rate was low, our endocrine complication rate was higher than that reported in other studies, particularly the rate of DI. Transient DI occurred in 33% of cases, and permanent DI in 23%. These relatively high rates of transient DI may be due to the diagnostic criteria used in our protocol; we defined transient post-operative DI as one episode of hypotonic polyuria in the setting of normal or elevated plasma sodium concentration, requiring at least one dose of desmopressin. In contrast, some studies discount any polyuria which lasts less than 2 days [10], while others require the documentation of hypernatremia for the diagnosis of DI [40]. These more stringent criteria will not capture cases of mild transient DI; therefore it is not surprising that the rates of transient DI reported in a 2018 meta-analysis were lower than that in our study, 11.3% [29]. The rates of permanent DI in our study merits particular attention. TSS for CD has been shown to be associated with a higher risk of post-operative DI [41, 42]. It may be that a more aggressive surgical approach resulted in high remission rates, but at a cost of higher rates of DI. All patients are reviewed post-operatively in the National Pituitary Centre, where there is a low threshold for water deprivation testing and/or 3% saline testing. We did not routinely re-test patients for resolution of DI after their initial water deprivation test at 3 months, and it is possible that some cases subsequently resolved after 3 months [41, 43]. Regardless, the rate reported in this study is significant, and emphasises the importance of counselling the patient about the risk of DI long-term. Strengths and limitations The reporting of two remission rates based on widely accepted criteria is a strength of this study, and allows for direct comparison of our outcomes with other studies. All ETSS were performed by a single pituitary surgeon; while this removes bias from surgeon experience, the disadvantage of this is that the sample size is relatively low. Furthermore, because we included patients who were recently operated on to maximise numbers for analysis of surgical complications, the follow-up period is relatively short. A longer follow-up is required to comment accurately on recurrence of CD. We did not have full ascertainment of longitudinal post-operative data including dexamethasone suppression tests, and this has highlighted the need for protocolised follow-up to allow for consistency when reporting our results. Conclusion Endoscopic transsphenoidal surgery in patients with Cushing’s disease offers excellent remission rates and low morbidity. Remission rates are much higher when standard criteria [morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively] are used compared with day 3 cortisol < 50 nmol/l. Higher remission rates were found for patients with microadenomas. Patients should be counselled regarding risk of post-operative endocrine deficiencies, in particular permanent diabetes insipidus. Longer follow-up is required to accurately assess recurrence rates. Availability of data and materials The data that support the findings of this study are not publicly available due to restrictions by General Data Protection Regulation (GDPR), but are available from the corresponding author on reasonable request. Abbreviations TSS: Transsphenoidal surgery ACTH: Adrenocorticotropic hormone CD: Cushing’s disease ETSS: Endoscopic transsphenoidal surgery ONDST: Overnight dexamethasone suppression test LNSF: Late night salivary cortisol CRH: Corticotropin releasing hormone IPSS: Inferior petrosal sinus sampling DI: Diabetes insipidus TSH: Thyroid stimulating hormone GH: Growth hormone UFC: Urinary free cortisol References 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117–23. CAS PubMed PubMed Central Google Scholar 2. Broersen LHA, van Haalen FM, Biermasz NR, et al. 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Clin Endocrinol. 2019;90(1):23–30. Article Google Scholar 24. Glynn N, Agha A. Diagnosing growth hormone deficiency in adults. Int J Endocrinol. 2012;2012:972617. PubMed PubMed Central Article CAS Google Scholar 25. Starke RM, Reames DL, Chen CJ, et al. Pure endoscopic transsphenoidal surgery for Cushing’s disease: techniques, outcomes, and predictors of remission. Neurosurgery. 2013;72:240–7. PubMed Article PubMed Central Google Scholar 26. McCance DR, Besser M, Atkinson AB. Assessment of cure after transsphenoidal surgery for Cushing's disease. Clin Endocrinol. 1996;44:1–06. CAS Article Google Scholar 27. Trainer PJ, Lawrie HS, Verhelst J, et al. Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment. Clin Endocrinol. 1993;38:73–8. CAS Article Google Scholar 28. Yap LB, Turner HE, Adams CBT, et al. Undetectable postoperative cortisol does not always predict long-term remission in Cushing’s disease: a single Centre audit. Clin Endocrinol. 2002;56:25–31. CAS Article Google Scholar 29. Broersen LHA, Biermasz NR, van Furth WR, et al. Endoscopic vs. microscopic transsphenoidal surgery for Cushing's disease: a systematic review and meta-analysis. Pituitary. 2018;21(5):524–34. PubMed PubMed Central Article Google Scholar 30. Mayberg M, Reintjes S, Patel A, et al. Dynamics of postoperative serum cortisol after transsphenoidal surgery for Cushing's disease: implications for immediate reoperation and remission. J Neurosurg. 2018;129(5):1268–77. PubMed Article PubMed Central Google Scholar 31. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93:358–62. CAS PubMed Article PubMed Central Google Scholar 32. Fahlbusch R, Buchfelder M, Müller OA. Transsphenoidal surgery for Cushing's disease. J R Soc Med. 1986;79(5):262–9. CAS PubMed PubMed Central Article Google Scholar 33. Sarkar S, Rajaratnam S, Chacko G, et al. Pure endoscopic transsphenoidal surgery for functional pituitary adenomas: outcomes with Cushing's disease. Acta Neurochir. 2016;158(1):77–86. PubMed Article PubMed Central Google Scholar 34. Magro E, Graillon T, Lassave J, et al. Complications related to the endoscopic Endonasal Transsphenoidal approach for nonfunctioning pituitary macroadenomas in 300 consecutive patients. World Neurosurg. 2016;89:442–53. PubMed Article PubMed Central Google Scholar 35. Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84(8):843–9. PubMed Article PubMed Central Google Scholar 36. Dehdashti AR, Gentili F. Current state of the art in the diagnosis and surgical treatment of Cushing disease: early experience with a purely endoscopic endonasal technique. Neurosurg Focus. 2007;23:E9. PubMed Article PubMed Central Google Scholar 37. Barzaghi LR, Medone M, Losa M, et al. Prognostic factors of visual field improvement after trans-sphenoidal approach for pituitary macroadenomas: review of the literature and analysis by quantitative method. Neurosurg Rev. 2012;35(3):369–78. PubMed Article PubMed Central Google Scholar 38. Mortini P, Losa M, Barzaghi R, et al. Results of transsphenoidal surgery in a large series of patients with pituitary adenoma. Neurosurgery. 2005;56(6):1222–33. PubMed Article PubMed Central Google Scholar 39. Nomikos P, Buchfelder M, Fahlbusch R. Current management of prolactinomas. J Neuro-Oncol. 2001;54(2):139–50. CAS Article Google Scholar 40. Mamelak AN, Carmichael J, Bonert VH, et al. Single-surgeon fully endoscopic endonasal transsphenoidal surgery: outcomes in three-hundred consecutive cases. Pituitary. 2013;16(3):393–401. PubMed Article PubMed Central Google Scholar 41. Hensen J, Henig A, Fahlbusch R, et al. Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas. Clin Endocrinol. 1999;50:431–9. CAS Article Google Scholar 42. Nemergut EC, Zuo Z, Jane JA Jr, et al. Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. J Neurosurg. 2005;103(3):448–54. PubMed Article PubMed Central Google Scholar 43. Adams JR, Blevins LS Jr, Allen GS, et al. Disorders of water metabolism following transsphenoidal pituitary surgery: a single institution's experience. Pituitary. 2006;9(2):93–9. PubMed Article PubMed Central Google Scholar
  3. A large study of mortality in Cushing’s syndrome calculated a threefold higher mortality rate for these patients, with cerebrovascular and atherosclerotic vascular diseases and infection accounting for 50% of deaths, researchers reported. “[We have seen] improvement in outcome since 2000, but mortality is still unacceptably high,” Padiporn Limumpornpetch, MD, an endocrinologist at Prince of Songkla University in Thailand and PhD student at the University of Leeds, U.K., told Healio during the ENDO annual meeting. “The mortality outcome has shown an unacceptable standardized mortality rate of 3:1, with poorer outcomes in patients with adrenal Cushing’s [and] active and larger tumors in Cushing’s disease.” Atherosclerotic vascular disease was the top cause of death in Cushing's disease, with infection coming in as the second-highest cause of death. Data were derived from Limumpornpetch P. OR04-4. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting). For a meta-analysis and meta-regression analysis of cause of death among patients with benign endogenous Cushing’s syndrome, Limumpornpetch and colleagues reviewed data published from 1952 to January 2021 from 92 study cohorts with 19,181 patients that reported mortality rates, including 66 studies that reported causes of death. The researchers calculated the standardized mortality rate (SMR) for Cushing’s syndrome at 3 (95% CI, 2.3-3.9). For patients with adrenal Cushing’s syndrome, SMR was 3.3 (95% CI, 0.5-6.6) — higher than for those with Cushing’s disease, with an SMR of 2.8 (95% CI, 2.1-3.7). Rates were similar by sex and by type of adrenal tumor. Deaths occurring within 30 days of surgery for Cushing’s syndrome fell to 3% after 2000 from 10% before that date (P < .005). During the entire study period, atherosclerotic vascular disease accounted for 27.4% of deaths in Cushing’s syndrome, and 12.7% were attributable to infection, 11.7% to cerebrovascular diseases, 10.6% to malignancy, 4.4% to thromboembolism, 2.9% to active disease, 3% to adrenal insufficiency and 2.2% to suicide. “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population,” Limumpornpetch said. From https://www.healio.com/news/endocrinology/20210322/mortality-rate-in-cushings-syndrome-unacceptably-high
  4. Adrenal insufficiency increases the risk for severe outcomes, including death, 23-fold for children who contract COVID-19, according to a data analysis presented at the ENDO annual meeting. “Adrenal insufficiency in pediatrics does increase risk of complications with COVID-19 infections,” Manish Gope Raisingani, MD, assistant professor in the department of pediatrics in the division of pediatric endocrinology at Arkansas Children's Hospital, University of Arkansas for Medical Sciences, told Healio. “The relative risk of complications is over 20 for sepsis, intubation and mortality, which is very significant.” Source: Adobe Stock Using the TriNetX tool and information on COVID-19 from 54 health care organizations, Raisingani and colleagues analyzed data from children (aged 0-18 years) with COVID-19; 846 had adrenal insufficiency and 252,211 did not. The mortality rate among children with adrenal insufficiency was 2.25% compared with 0.097% for those without, for a relative risk for death of 23.2 (P < .0001) for children with adrenal insufficiency and COVID-19. RRs for these children were 21.68 for endotracheal intubation and 25.45 for sepsis. “Children with adrenal insufficiency should be very careful during the pandemic,” Raisingani said. “They should take their steroid medication properly. They should also be appropriately trained on stress steroids for infection, other significant events.” From https://www.healio.com/news/endocrinology/20210321/severe-covid19-risks-greatly-increased-for-children-with-adrenal-insufficiency
  5. Here's your chance to make your voice heard on Growth Hormone Issues. Anyone interested would sign up with Rare Patient Voice using the CushingsHelp referral Link. You would then get an email invite to the actual study. Study Opportunity for Idiopathic Short Stature (ISS) Caregivers This is a 30 min online survey and Compensation is $50 Please sign up at the link below for more information or to see if you qualify https://rarepatientvoice.com/CushingsHelp/
  6. WASHINGTON--Endogenous Cushing's syndrome, a rare hormonal disorder, is associated with a threefold increase in death, primarily due to cardiovascular disease and infection, according to a study whose results will be presented at ENDO 2021, the Endocrine Society's annual meeting. The research, according to the study authors, is the largest systematic review and meta-analysis to date of studies of endogenous (meaning "inside your body") Cushing's syndrome. Whereas Cushing's syndrome most often results from external factors--taking cortisol-like medications such as prednisone--the endogenous type occurs when the body overproduces the hormone cortisol, affecting multiple bodily systems. Accurate data on the mortality and specific causes of death in people with endogenous Cushing's syndrome are lacking, said the study's lead author, Padiporn Limumpornpetch, M.D., an endocrinologist from Prince of Songkla University, Thailand and Ph.D. student at the University of Leeds in Leeds, U.K. The study analyzed death data from more than 19,000 patients in 92 studies published through January 2021. "Our results found that death rates have fallen since 2000 but are still unacceptably high," Limumpornpetch said. Cushing's syndrome affects many parts of the body because cortisol responds to stress, maintains blood pressure and cardiovascular function, regulates blood sugar and keeps the immune system in check. The most common cause of endogenous Cushing's syndrome is a tumor of the pituitary gland called Cushing's disease, but another cause is a usually benign tumor of the adrenal glands called adrenal Cushing's syndrome. All patients in this study had noncancerous tumors, according to Limumpornpetch. Overall, the proportion of death from all study cohorts was 5 percent, the researchers reported. The standardized mortality ratio--the ratio of observed deaths in the study group to expected deaths in the general population matched by age and sex--was 3:1, indicating a threefold increase in deaths, she stated. This mortality ratio was reportedly higher in patients with adrenal Cushing's syndrome versus Cushing's disease and in patients who had active disease versus those in remission. The standardized mortality ratio also was worse in patients with Cushing's disease with larger tumors versus very small tumors (macroadenomas versus microadenomas). On the positive side, mortality rates were lower after 2000 versus before then, which Limumpornpetch attributed to advances in diagnosis, operative techniques and medico-surgical care. More than half of observed deaths were due to heart disease (24.7 percent), infections (14.4 percent), cerebrovascular diseases such as stroke or aneurysm (9.4 percent) or blood clots in a vein, known as thromboembolism (4.2 percent). "The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism and good infection control and emphasize the need to achieve disease remission, normalizing cortisol levels," she said. Surgery is the mainstay of initial treatment of Cushing's syndrome. If an operation to remove the tumor fails to put the disease in remission, other treatments are available, such as medications. Study co-author Victoria Nyaga, Ph.D., of the Belgian Cancer Centre in Brussels, Belgium, developed the Metapreg statistical analysis program used in this study. ### Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world's oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions. The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system. From https://www.eurekalert.org/pub_releases/2021-03/tes-lao031621.php
  7. John P H Wilding 1 Affiliations expand PMID: 32061161 DOI: 10.1530/EJE-20-0099 Abstract Endocrine disorders such as Cushing's syndrome and hypothyroidism may cause weight gain and exacerbate metabolic dysfunction in obesity. Other forms of endocrine dysfunction, particularly gonadal dysfunction (predominantly testosterone deficiency in men and polycystic ovarian syndrome in women), and abnormalities of the hypothalamic-pituitary-adrenal axis, the growth hormone-IGF-1 system and vitamin D deficiency are common in obesity. As a result, endocrinologists may be referred people with obesity for endocrine testing and asked to consider treatment with various hormones. A recent systematic review and associated guidance from the European Society of Endocrinology provide a useful evidence summary and clear guidelines on endocrine testing and treatment in people with obesity. With the exception of screening for hypothyroidism, most endocrine testing is not recommended in the absence of clinical features of endocrine syndromes in obesity, and likewise hormone treatment is rarely needed. These guidelines should help reduce unnecessary endocrine testing in those referred for assessment of obesity and encourage clinicians to support patients with their attempts at weight loss, which if successful has a good chance of correcting any endocrine dysfunction. Similar articles Classical endocrine diseases causing obesity. Weaver JU.Front Horm Res. 2008;36:212-228. doi: 10.1159/000115367.PMID: 18230905 Review. Is obesity an endocrine condition? Stocks AE.Aust Fam Physician. 1977 Feb;6(2):109-16.PMID: 558747 FPIN’s clinical inquiries. Secondary causes of obesity. Allen G, Safranek S.Am Fam Physician. 2011 Apr 15;83(8):972-3.PMID: 21524038 No abstract available. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease]. Hagymási K, Reismann P, Rácz K, Tulassay Z.Orv Hetil. 2009 Nov 29;150(48):2173-81. doi: 10.1556/OH.2009.28749.PMID: 19923096 Review. Hungarian. Obesity and endocrine disease. Kokkoris P, Pi-Sunyer FX.Endocrinol Metab Clin North Am. 2003 Dec;32(4):895-914. doi: 10.1016/s0889-8529(03)00078-1.PMID: 14711067 Review. From https://pubmed.ncbi.nlm.nih.gov/32061161/
  8. There is an absence of online information regarding the risks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nasopharyngeal swab (NPS) testing for patients with a history of sinus and/or pituitary surgery, according to a research letter published online March 4 in JAMA Otolaryngology-Head & Neck Surgery. Noting that blind NPS testing poses a risk to patients with sinus pathology, Taylor Fish, from the University of Texas Health San Antonio, and colleagues examined online preoperative and postoperative patient information regarding the potential risks of SARS-CoV-2 NPS testing for individuals with a history of sinus or skull-base surgery. The top 100 sites for searches on “sinus surgery instructions” and “pituitary surgery instructions” were identified. The authors also noted the presence of any of the following terms on the webpages: COVID-19, SARS-CoV-2, coronavirus, or nasopharyngeal swab. Searches for sinus surgery instructions and pituitary surgery instructions returned 6,600,000 and 1,200,000 results, respectively. The researchers identified 79 websites that displayed the date of the last update, and nine of these had been updated since the declaration of COVID-19 as an international health emergency on Jan. 30, 2020. None of the top 200 websites (53 academic, 93 private practice, and 54 other sites) contained warnings for high-risk patients or information pertaining to SARS-CoV-2 NPS testing. “Otolaryngologists should inform at-risk patients about blind NPS testing and alternative diagnostic methods,” the authors write. “Health care professionals ordering or administering testing must prescreen patients with a history of sinus and skull-base surgery prior to NPS testing and use alternative testing.” One author disclosed financial ties to the medical device industry. Abstract/Full Text From https://www.physiciansweekly.com/nasal-swab-test-for-covid-19-risky-for-sinus-surgery-patients/
  9. This sounds a lot like what we have been doing for the last 20 years... HRA Pharma Rare Diseases, an affiliate of global consumer healthcare company HRA Pharma, has announced it is funding an online platform containing information and news on Cushing’s Syndrome. The ‘Cushing’s Hub’, developed by Springer Healthcare Education, is set to make all information on the rare condition available in one place for medical professionals to access. Cushing’s Syndrome affects less than one in 10,000 people in the EU, and is categorised as a rare and severe condition caused by prolonged high levels of cortisol in the blood. The new hub is managed by an independent editorial board consisting of three international Cushing’s Syndrome experts - Professor Frédéric Castinetti from France, Dr Niki Karavitaki from the UK and Associate Professor Dr Greisa Vila from Austria. According to HRA Pharma Rare Diseases, the ‘Cushing’s Hub’ is the first online platform dedicated to all aspects of the rare condition. “As a company which is dedicated to improving the lives of those with rare diseases, we felt it was crucial to support the development of a platform that can help healthcare professionals in the diagnosis, management and follow up of Cushing’s Syndrome. We are confident the platform will help improve the lives of many,” said Evelina Paberžė, COO of HRA Pharma Rare Diseases.
  10. A CORONER has recorded a verdict of accidental death at the inquest held into the death of a 40-year-old Wrexham mother. Marie Richardson, of Bryn Hafod, died in March at the Maelor Hospital. A post mortem examination found that she had died as a result of a haemorrhage involving the pituitary gland, which plays a key role in the body's hormonal system. The inquest was told a post mortem examination had been conducted by Dr Anthony Burdge. Giving evidence, Dr Burdge said that it was probable the bleeding had been caused as a result of thinning of the blood and not a trauma such as a fall. Contributory factors in Mrs Richardson's death had been Cushing's disease, a very rare condition involving a hormone disorder, and bronchial pneumonia. The court was told by Mrs Richardson's husband, Andrew, that his wife had started to experience ill health, including swollen legs and constant backache. Her mobility was badly affected. Mrs Richardson was admitted to the Maelor Hospital. Consultant physician Dr Stephen Stanaway said that as part of the treatment, Mrs Richardson received a small dose of a blood-thinning drug to help ensure she did not fall victim to clots. She had been given a scan involving the pituitary and there was no evidence of a tumor. It transpired the post-mortem had found Mrs Richardson did have a tumor, which had experienced bleeding. Dr Stanaway said that Mrs Richardson had not liked the scanning process and moved at one point – it was important for patients to remain still. Acting coroner John Gittins asked if Mrs Richardson would have been administered with blood thinner if the tumour had been known about at the time of treatment. Dr Stanaway said it would have to be a balanced decision but he felt that she would have been. Legal representatives for Mrs Richardson's family and the NHS Trust were present at the inquest. Dr Stanaway was asked a series of questions about whether anything further could have been done about Mrs Richardson's treatment while at the Maelor. He said that with hindsight the only potential other avenue may have been if she had been given steroids. But Dr Stanaway stressed he doubted this would have been successful, emphasizing Mrs Richardson was a very poorly woman and it would be impossible to say that administering steroids would have saved her. Recording his verdict of accidental death Mr Gittins emphasized: "This is not an indication of responsibility, blame or judgment. "That is not my jurisdiction. My very sincere condolences go to the family." HOME | Sitemap | Adrenal Crisis! | Abbreviations | Glossary | Forums | Donate | Bios | Add Your Bio | Add Your Doctor | MemberMap | CushieWiki
  11. From board member @sharm Please Join Us to Celebrate 20 Years-Pituitary Patient Support Group. Saturday April 10, 2021: 9:00am-11:00am (PST) (Scroll below for Zoom meeting links) We invite you to join the conversation with our experts: Pejman Cohan, neuro-endocrinologist & Daniel Kelly, neurosurgery. Email me or leave your questions in the chat below. We will answer as many questions as time allows. We can't wait to see you on Zoom! Thank you, Sharmyn McGraw, patient advocate, community outreach. pituitarybuddy@hotmail.com Meeting ID: 849 6356 9824 Passcode: 596170 Zoom: https:/zoom.us/join One tap mobile +16699006833,,84963569824#,,,,*596170# US (San Jose) +12532158782,,84963569824#,,,,*596170# US (Tacoma) Dial by your location +1 669 900 6833 US (San Jose) +1 253 215 8782 US (Tacoma) +1 346 248 7799 US (Houston) +1 929 205 6099 US (New York) +1 301 715 8592 US (Washington DC) +1 312 626 6799 US (Chicago) Meeting ID: 849 6356 9824 Passcode: 596170 Find your local number: https://us02web.zoom.us/u/kdgrvRLBP7
  12. From board member @sharm - Please Join Us to Celebrate 20 Years-Pituitary Patient Support Group. Saturday April 10, 2021: 9:00am-11:00am (PST) (Scroll below for Zoom meeting links) We invite you to join the conversation with our experts: Pejman Cohan, neuro-endocrinologist & Daniel Kelly, neurosurgery. Email me or leave your questions in the chat below. We will answer as many questions as time allows. We can't wait to see you on Zoom! Thank you, Sharmyn McGraw, patient advocate, community outreach. pituitarybuddy@hotmail.com Meeting ID: 849 6356 9824 Passcode: 596170 Zoom: https:/zoom.us/join One tap mobile +16699006833,,84963569824#,,,,*596170# US (San Jose) +12532158782,,84963569824#,,,,*596170# US (Tacoma) Dial by your location +1 669 900 6833 US (San Jose) +1 253 215 8782 US (Tacoma) +1 346 248 7799 US (Houston) +1 929 205 6099 US (New York) +1 301 715 8592 US (Washington DC) +1 312 626 6799 US (Chicago) Meeting ID: 849 6356 9824 Passcode: 596170 Find your local number: https://us02web.zoom.us/u/kdgrvRLBP7
  13. Patients with adrenal insufficiency may have higher rates of cardiovascular events due to the presence of cardiovascular comorbidities, shows a study published in The Journal of Clinical Endocrinology and Metabolism. Led by Kanchana Ngaosuwan, MD, PhD, of Imperial College London, UK, the authors of this population-based matched cohort study also found that cerebrovascular events were independently increased in patients with secondary adrenal insufficiency, particularly in those treated with irradiation therapy. Cardiovascular mortality, specifically from ischemic heart disease, was higher regardless of having secondary adrenal insufficiency or primary adrenal insufficiency (Addison’s disease). Adrenal insufficiency occurs when the adrenal glands fail to produce adequate glucocorticoids. In Addison’s disease, it arises from the adrenal glands, but in secondary adrenal insufficiency, it occurs as a result of a pituitary or hypothalamic condition. Glucocorticoid replacement therapy is usually the first line of defense, but the treatment is associated with a number of adverse events, such as cardiovascular disease. Ischemic heart disease is the leading cause of death for patients with Addison’s disease. Data from this study was sourced from the Clinical Practice Research Datalink which collected information from 15,354,125 individuals living in the United Kingdom between 1987 and 2017. Data from patients prescribed glucocorticoid prescriptions for adrenal insufficiency (primary: n=2,052; secondary: n=3,948) and random age and gender matched controls (primary: n=20,366; secondary: n=39,134) were assessed for comorbidities and clinical outcomes. Patients and controls had previous cardiovascular disease (17.5% vs 11.2%), diabetes (10.4% vs 4.8%), hypertension (22.1% vs 13.6%), dyslipidemia (20.5% vs 5.0%), and 19.6% and 4.9% of patients and controls were taking statins, respectively. Composite cardiovascular events occurred at a rate of 31.4 (95% CI, 29.6-33.3) per 1,000 person-years among the patients and 24.4 (95% CI, 23.9-24.9; P <.0001) per 1,000 person years among the controls. Stratified by adrenal insufficiency subtype, after correcting for cofounders, patients with primary (adjusted hazard ratio [aHR], 1.08; 95% CI, 0.96-1.22) and secondary (aHR, 1.10; 95% CI, 1.01-1.19) adrenal insufficiency were at marginally increased risk for composite cardiovascular events. Cerebrovascular disease occurred at a rate of 10.4 (95% CI, 9.5-11.5) per 1.000 person years among the patients and 7.2 (95% CI, 7.0-7.5; P <.0001) per 1,000 person years among the controls. Only patients with secondary adrenal insufficiency were at increased risk for cerebrovascular disease (aHR, 1.53; 95% CI, 1.34-1.74). All patients had increased risk for hospitalization due to cardiovascular diseases (aHR, 1.41; 95% CI, 1.28-1.55) and only the patients with secondary adrenal insufficiency were more likely to be hospitalized with cerebrovascular disease (aHR, 1.63; 95% CI, 1.28-2.08). Patients had increased rates of cardiovascular mortality compared with controls (9.9 vs 6.4 per 1,000 person years; P <.0001). Both patients with primary (aHR, 1.58; 95% CI, 1.19-2.10) and secondary (aHR, 1.23; 95% CI, 0.99-1.52) insufficiency were at increased risk for cardiovascular mortality. Risk for cerebrovascular mortality was elevated for patients with secondary insufficiency (aHR, 1.14; 95% CI, 0.78-1.67). Stratified by secondary insufficiency, age, and sex, women (aHR, 1.18; 95% CI, 1.04-1.31; P =.016) and patients who were less than 50 years old (aHR, 1.58; 95% CI, 1.22-2.03; P <.0001) were at increased risk for composite cardiovascular events. Similarly, patients 50 years old or younger were at increased risk for cerebrovascular disease (aHR, 3.67; 95% CI, 2.60-5.17; P <.0001). These data may be limited by the cohort imbalance of disease risk factors, although the investigators corrected for these features, some residual biases may remain. While further study is needed to assess changes in treatment approaches, the authors suggested that “these findings support further optimization of glucocorticoid replacement in conjunction with cardio protective interventions in patients with adrenal insufficiency.” Reference Ngaosuwan K, Johnston D G, Godsland I F, et al. Cardiovascular disease in patients with primary and secondary adrenal insufficiency and the role of comorbidities. J Clin Endocrinol Metab. 2021;dgab063. doi:10.1210/clinem/dgab063. From https://www.endocrinologyadvisor.com/home/topics/cardiovascular-and-metabolic-disorders/adrenal-insufficiency-associated-with-increased-cvd-and-cerebrovascular-disease/
  14. Yu Wang, Zhixiang Sun, Zhiquan Jiang Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, People’s Republic of China Correspondence: Zhiquan Jiang Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui 233004, People’s Republic of China Tel +86-13966075971 Email bbjiangzhq@163.com Abstract: Cushing’s disease (CD), also known as adrenocorticotropic hormone (ACTH)-dependent pituitary Cushing’s syndrome, is a rare and serious chronic endocrine disease that is usually caused by a pituitary adenoma (especially a pituitary microadenoma). Meningioma is the most common type of primary intracranial tumor and is usually benign. The patient in this case report presented with CD coexisting with pituitary microadenoma and meningioma, which is an extremely rare comorbidity. The pathogenesis of CD associated with meningioma remains unclear. Here, we describe the case of bilateral lower extremity edema, lower limb pain, abdominal purplish striae, and abdominal distension for 9 months in a 47-year-old woman. Two years ago, the patient underwent a hysterectomy at a local hospital for hysteromyoma. She had no previous radiotherapeutic treatment or other medical history. Magnetic resonance imaging of her head revealed a sellar lesion (7.8 mm × 6.4 mm) and a spherical mass (3.0 cm × 3.0 cm) in the right frontal convexity. Her level of serum adrenocorticotropic hormone (ACTH) was 169 pg/mL, and her cortisol levels were 933 nmol/mL and 778 nmol/mL at 8 am and 4 pm, respectively. Preoperatively, she was diagnosed with ACTH-secreting pituitary microadenoma and meningioma. Excision of the meningioma was performed through a craniotomy, while an endoscopic endonasal transsphenoidal approach was used to remove the pituitary adenoma. Meningioma and pituitary adenoma were confirmed by postoperative pathology. On the basis of this unusual case, the relevant literature was reviewed to illustrate the diagnosis and treatment of Cushing’s disease and to explore the pathogenesis of pituitary adenoma associated with meningioma. Keywords: Cushing’s disease, pituitary adenoma, meningioma Introduction Cushing’s disease (CD) is a severe condition caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor that accounts for approximately 70% of all cases of endogenous Cushing’s syndrome. It has a total incidence of 1–2 cases per million per year and a prevalence rate of approximately 30 patients per million per year, making it an uncommon disease.1 Meningiomas account for 15–25% of all intracranial tumors, with an annual incidence of 6 cases per 100,000 persons.2 CD combined with meningioma is a rare condition, and even rarer in patients who have no previously known risk factors for either tumor. To the best of our knowledge, its pathogenesis have not been clearly described to date. Case Presentation Clinical History and Laboratory Findings A 47-year-old woman was admitted to the endocrinology department of our hospital with chief complaints of bilateral lower extremity edema, left lower limb pain, abdominal purplish striae, and abdominal distension for 9 months. Two years ago, the patient had a hysterectomy at a local hospital for hysteromyoma. She had no previous radiotherapeutic treatment or other medical history. She weighed 90 kg and was 165 cm tall with a body mass index (BMI) of 33. Physical examination showed typical features of Cushing’s syndrome, including centripetal obesity, moon face, pedal edema, and buffalo hump. Her skin was thin and dry, with acne and hirsutism. On admission, her blood pressure was 146/115 mmHg and routine biochemical blood tests confirmed comorbidity with diabetes mellitus, hyperlipidemia, and hypokalemia. Endocrine measurements showed that her serum ACTH was 169 pg/mL (reference value: 5–50 pg/mL), cortisol (8 am) was 933 nmol/L (reference value: 138–690 nmol/L), and cortisol (4 pm) was 778 nmol/L (reference value: 69–345 nmol/L), indicating that her ACTH and cortisol levels were dramatically increased. Cortisol secretion was increased and had lost its circadian rhythm. The low-dose dexamethasone suppression test showed that cortisol suppression was < 50%, while a >50% suppression of cortisol was found in the high-dose dexamethasone suppression test. Serum prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone, free thyroid hormone (FT3 and FT4), and thyrotropin values were normal. Endocrinological evaluation suspected that pituitary lesions caused Cushing syndrome. Imaging Analysis The patient underwent a magnetic resonance imaging (MRI) scan to image her head. T1-weighted MRI with contrast enhancement showed a spherical enhancing mass (3.0 cm × 3.0 cm) in the right frontal convexity and a dural tail sign (Figure 1A). In the sellar area, the enhancement degree of the lesion (7.8 mm × 6.4 mm) was significantly lower than that of the surrounding pituitary tissue, and the pituitary stalk was displaced to the right (Figure 1A and B). No abnormalities were found on plain or enhanced adrenal computed tomography scans. Figure 1 Enhanced magnetic resonance imaging (MRI) of the patient’s head: (A) Coronal view of the gadolinium-enhanced T1-weighted image showing a spherical enhancing mass in the right frontal convexity and a dural tail sign. A round low-intensity lesion can be seen on the right side of the pituitary gland, and the pituitary stalk is displaced to the right. (B) Sagittal T1-weighted sequence with contrast showing the degree of enhancement is lower than that of the pituitary in the sellar region. Treatment and Pathological Examination Physical examination, endocrine examination, and head MRI successfully proved that pituitary microadenoma caused Cushing’s syndrome (specifically CD) comorbid with asymptomatic meningioma. In order to receive surgical treatment, the patient was referred from the endocrinology department to neurosurgery. She underwent neuroendoscopic transsphenoidal surgery and the pituitary microadenoma was removed. The sellar floor was reconstructed with artificial dura mater, and after this reconstruction, no cerebrospinal fluid leakage was observed. The pathological specimen was examined and was determined to be consistent with a pituitary microadenoma (Figure 2A). One month later, excision of the meningioma was performed through a right frontal trephine craniotomy. Histological examination revealed a WHO grade I meningioma (Figure 2B). Figure 2 (A) Histopathologic examination revealed a pituitary adenoma (Hematoxylin and eosin staining, 100×). (B) Histopathologic examination revealed a meningioma (Hematoxylin and eosin staining, 100×). Outcome and Follow Up On the second day after the operation, her cortisol level dropped below the normal range in the morning. Hydrocortisone replacement therapy was started on the same day. In addition, she had developed transient diabetes insipidus, which was treated with desmopressin. Three months postoperatively, after hydrocortisone replacement therapy, the symptoms of Cushing’s disease were alleviated, and the cortisol level returned to normal, which was 249nmol/L (reference value: 138~690nmol/L). At the 1-year follow-up, no lesions were observed on the MRI scan and the symptoms of Cushing’s syndrome were in remission. The use of hydrocortisone supplements were discontinued and hormone levels remained normal, indicating recovery of the hypothalamic–pituitary–adrenal (HPA) axis. The patient had lost 30 kg and her BMI had dropped to 22, while her blood glucose, triglyceride level, and blood pressure had all returned to normal. Physical changes in the patient pre- and post-treatment are shown in Figure 3A and B. Figure 3 Abdominal appearance with striae (A) preoperation and (B) 4 months postoperation. Discussion Cushing’s Disease CD is a serious clinical condition caused by a pituitary adenoma secreting a high level of ACTH, leading to hypercortisolism. The proportion of ACTH-secreting pituitary adenomas (corresponding to CD) among hormone-secreting pituitary adenomas is 4.8%–10%, which affects women three times more frequently than men, mainly occurs in those 40–60 years old.3,4 Exposure to excessive cortisol can lead to various manifestations of Cushing’s syndrome and increases in morbidity and mortality.5 Therefore, early diagnosis and treatment of CD are very important. The diagnosis and differential diagnosis of CD is very complicated, and these have always been challenging problems in clinical endocrinology. Once Cushing’s syndrome is diagnosed, its etiology should be determined. A diagnosis of Cushing’s disease is made based on a biochemical examination confirming the pituitary origin of the condition and exclude other sources (namely, ectopic ACTH secretion and adrenocortical tumors).3 High-dose dexamethasone suppression and corticotropin-releasing-hormone stimulation tests may be used to distinguish high-secretion sources of pituitary and ectopic ACTH. More than 90% of the pituitary adenomas that cause CD are microadenomas (≤10 mm in diameter), and 40% of the cases cannot be located by radiological examination.5 Examination with bilateral inferior petrosal sinus sampling (BIPSS) is necessary for CD patients in whom noninvasive biochemical and imaging examinations do not lead to a definitive diagnosis.6 The first-line treatment for CD is transsphenoidal selective tumor resection (TSS) with approximately 78% of the patients in remission after the operation, and 13% of patients relapse within 10 years after surgery. Therefore, there are a considerable number of patients who have experienced long-term surgical failure and require additional second-line treatment, such as radiotherapy, bilateral adrenalectomy, or medication.4 The pathogenesis of CD is unclear, but recent studies have confirmed that there are somatic activation mutations of multiple genes in adrenocorticotropin adenomas, while ubiquitin specific peptidase 8 (USP8) is the most common, accounting for about 50% of the mutations in these adenomas.7 Pituitary Adenoma Associated with Meningioma Radiotherapy used to treat pituitary tumors is a well-known reason for the development of meningiomas. Gene mutations are a common molecular characteristic of meningiomas, with inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene found in 55% of meningiomas, and a further 25% of meningiomas accounted for by recently described mutations in other genes.8 Simultaneous occurrence of pituitary adenoma and meningioma without a history of radiotherapy is a rare condition clinically, having only been described in 49 cases before 2019,9 while ACTH-secreting pituitary adenomas (CD) comorbid with meningioma have been reported even less frequently. In the reported cases, the most common site of meningioma is parasellar, accounting for 44.9%, while meningioma located in the distant part of the adenoma is rare.9,10 A number of clinicians have suggested that the coexistence of meningiomas and pituitary adenomas is incidental, with no relationship between the two diseases.2,11 Genetic imbalances have been found in pituitary adenomas, including in particular the chromosomal deletions of 1p, 2q, 4, 5, 6, 11q, 12q, 13q, and 18q, and the overexpression of 9q, 16p, 17p, 19, and 20q. Functional adenomas have more such imbalances than nonfunctional adenomas, corresponding in particular to deletions of chromosomes 4 and 18q, and the overexpression of chromosomes 17 and 19.12 Meanwhile, estrogen receptor positive de novo meningiomas significantly involve chromosomes 14 and 22.13 The study by Hwang et al14 reported that the expression levels of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins were significantly higher in pituitary adenomas and meningiomas than that in normal brain tissues. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) and its downstream signaling pathways play an pivotal role in pituitary tumor, meningioma, and other brain tumors. Zhu et al15 reported that multiple endocrine neoplasia type 1 (MEN1) plays an important role in pituitary adenoma associated with meningioma by upregulating the mammalian target of rapamycin signaling pathway. They found that rapamycin treatment promotes apoptosis in primary cells of the pituitary adenoma and meningioma in cases of pituitary adenoma associated with meningioma. Recurrence of pituitary adenoma, younger age, and larger size of meningioma have been shown to be significantly associated with MEN1 mutation.16 Mathuriya et al17 suggested that hormones may contribute to the occurrence of meningiomas. de Vries et al9 reported that compared with other types of adenomas, the proportion of growth hormone adenomas is higher, accounting for about one third of cases. Meanwhile, Friend et al18 demonstrated that activation of GH/insulin-like growth factor-1 (IGF-1) axis clearly increased the growth rate of meningiomas. However, in the present case, we observed the coexistence of ACTH-secreting adenoma and meningioma. Further studies are required to understand whether ACTH or cortisol are related to the occurrence and development of meningioma. In our case, pituitary microadenoma was the cause of Cushing’s syndrome, while the meningioma was an incidental imaging observation. With the popularity and technological progress of high-resolution imaging technology, the reported prevalence of intracranial lesions related to dominant pathology has increased.2 However, when imaging examinations are limited to specific regions, the diagnosis of lesions in other locations is likely to be omitted. For example, in our case, performing MRI of the sellar region alone may have meant that the meningioma was missed. Conclusion Cushing’s disease is the most common cause of endogenous Cushing’s syndrome and is caused by ACTH-secreting pituitary adenoma.It is associated with severe complications and reduced quality of life, so early diagnosis and treatment are critical. The coexistence of CD, pituitary adenoma, and meningioma is very rare, and the exact mechanisms underlying such comorbidity are currently unclear and need further study. Data Sharing Statement The data that support the findings of this study are available on request from the corresponding author, Zhiquan Jiang. Ethics and Consent Statement Based on the regulations of the department of research of the Bengbu Medical College, institutional review board approval is not required for case reports. Consent for Publication Written informed consent has been provided by the patient to have the case details and any accompanying images published. Author Contributions All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. Funding The authors declared that this case has received no financial support. Disclosure The authors report no conflicts of interest in this work. References 1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913–927. doi:10.1016/S0140-6736(14)61375-1 2. Curto L, Squadrito S, Almoto B, et al. MRI finding of simultaneous coexistence of growth hormone-secreting pituitary adenoma with intracranial meningioma and carotid artery aneurysms: report of a case. Pituitary. 2007;10(3):299–305. doi:10.1007/s11102-007-0011-4 3. Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neuro Oncol. 2017;19(6):762–773. doi:10.1093/neuonc/now130 4. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385–486. doi:10.1210/er.2013-1048 5. Tritos NA, Biller BMK. Current management of Cushing’s disease. J Intern Med. 2019;286(5):526–541. doi:10.1111/joim.12975 6. Fan C, Zhang C, Shi X, et al. Assessing the value of bilateral inferior petrosal sinus sampling in the diagnosis and treatment of a complex case of Cushing’s disease. Intractable Rare Dis Res. 2013;2(1):24–29. doi:10.5582/irdr.2013.v2.1.24 7. Sbiera S, Kunz M, Weigand I, Deutschbein T, Dandekar T, Fassnacht M. The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight. Cancers. 2019;11(11):1761. doi:10.3390/cancers11111761 8. Apra C, Peyre M, Kalamarides M. Current treatment options for meningioma. Expert Rev Neurother. 2018;18(3):241–249. doi:10.1080/14737175.2018.1429920 9. de Vries F, Lobatto DJ, Zamanipoor Najafabadi AH, et al. Unexpected concomitant pituitary adenoma and suprasellar meningioma: a case report and review of the literature. Br J Neurosurg. 2019:1–5. doi:10.1080/02688697.2018.1556782. 10. Gosal JS, Shukla K, Praneeth K, et al. Coexistent pituitary adenoma and frontal convexity meningioma with frontal sinus invasion: a rare association. Surg Neurol Int. 2020;11:270. doi:10.25259/SNI_164_2020 11. Cannavo S, Curto L, Fazio R, et al. Coexistence of growth hormone-secreting pituitary adenoma and intracranial meningioma: a case report and review of the literature. J Endocrinol Invest. 1993;16(9):703–708. doi:10.1007/BF03348915 12. Szymas J, Schluens K, Liebert W, Petersen I. Genomic instability in pituitary adenomas. Pituitary. 2002;5(4):211–219. doi:10.1023/a:1025313214951 13. Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. J Neurosurg. 2006;105(2):163–173. doi:10.3171/jns.2006.105.2.163 14. Hwang M, Han MH, Park HH, et al. LGR5 and downstream intracellular signaling proteins play critical roles in the cell proliferation of neuroblastoma, meningioma and pituitary adenoma. Exp Neurobiol. 2019;28(5):628–641. doi:10.5607/en.2019.28.5.628 15. Zhu H, Miao Y, Shen Y, et al. The clinical characteristics and molecular mechanism of pituitary adenoma associated with meningioma. J Transl Med. 2019;17(1):354. doi:10.1186/s12967-019-2103-0 16. Zhu H, Miao Y, Shen Y, et al. Germline mutations in MEN1 are associated with the tumorigenesis of pituitary adenoma associated with meningioma. Oncol Lett. 2020;20(1):561–568. doi:10.3892/ol.2020.11601 17. Mathuriya SN, Vasishta RK, Dash RJ, Kak VK. Pituitary adenoma and parasagittal meningioma: an unusual association. Neurol India. 2000;48(1):72. 18. Friend KE, Radinsky R, McCutcheon IE. Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist. J Neurosurg. 1999;91(1):93–99. doi:10.3171/jns.1999.91.1.0093 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. From https://www.dovepress.com/cushingrsquos-disease-caused-by-a-pituitary-microadenoma-coexistent-wi-peer-reviewed-fulltext-article-IJGM
  15. For years before and after their diagnosis, people with Cushing’s disease use more psychotropic medications — those that affect mood, thoughts, or perception — for mental health problems than their healthy peers, a study in Sweden found. Notably, patients experiencing long-term disease remission still showed higher use of antidepressants and sleeping pills than healthy individuals. These findings highlight Cushing’s persistent negative effects on mental health, according to researchers. Additionally, the results of this study, based on prescribed medication dispenses in Sweden, support the importance of earlier diagnoses of Cushing’s disease — and the need for close and long-term monitoring of neuropsychiatric symptoms in this patient population, the researchers said. The study, “Psychotropic drugs in patients with Cushing’s disease before diagnosis and at long-term follow-up — a nationwide study,” was published in the Journal of Clinical Endocrinology & Metabolism. Mental health issues such as anxiety, depression, sleep disturbances, and cognitive impairments are part of the wide range of symptoms caused by the abnormally high levels of the cortisol hormone that characterize Cushing’s syndrome. Of note, Cushing’s disease is a form of Cushing’s syndrome caused by a tumor in the pituitary gland. A “few” studies have reported the elimination or partial lessening of neuropsychiatric symptoms after successful Cushing’s treatment, according to the researchers. But others noted that “impaired cognitive function and quality of life seemed to persist for a long time after biochemical [cortisol level-based] remission had been achieved,” the team wrote. Now, these researchers, from several universities in Sweden, have assessed the use of psychotropic medications — reflecting mental health burden — in 372 people with Cushing’s disease. The use of such medications was assessed five years before diagnosis, at the time of diagnosis, and at five and 10 years post-diagnosis. The patients, diagnosed between 1990 and 2018, were identified through the Swedish Pituitary Register, which covers 95% of all people with Cushing’s disease in the country. Most of the patients (76%) were women. Altogether, the patients’ mean age at diagnosis was 44 years. For each individual with Cushing’s, four sex-, age-, and residential area-matched healthy individuals were used as controls for comparative analyses. Data on each individual’s dispenses of medications commonly used for neuropsychiatric issues were obtained from the Swedish Prescribed Drug Register. This register, which fully covers all prescribed medications given throughout the country, also was used to determine each patient’s dispenses of other medications for Cushing’s disease symptoms, such as high blood pressure, also called hypertension, and diabetes. The results showed that the use of antidepressants, anxiolytics — medications to lessen anxiety — and sleeping pills was at least twofold higher in Cushing’s patients than in healthy individuals during the five-year period before diagnosis, and at the time of diagnosis. Five years after diagnosis, the proportion of patients using antidepressants (26%) and sleeping pills (22%) remained unchanged, and even individuals in remission showed significantly higher use of such medications than did controls (20–26% vs. 8.6–12%). According to the results, one-third of the patients on antidepressants since their diagnosis were able to discontinue treatment before the five-year assessment — most having achieved disease remission. However, 47% of those receiving antidepressants at five years had initiated such treatment at a median of 2.4 years after diagnosis. During the five-year follow-up, older age and being a woman appeared to increase the risk of antidepressant use among Cushing’s disease patients. At 10 years of follow-up, the use of antidepressants and sleeping pills was not significantly different between groups, despite the fact that antidepressants use remained about the same among patients. Notably, researchers conducted an analysis of 76 patients with sustained remission for a median of 9.3 years, and 292 matching controls. That analysis showed that the use of antidepressants and sleeping pills was significantly higher among patients. The use of other medications, such as those for hypertension and diabetes, also was significantly more common among Cushing’s disease patients before, at diagnosis, and at five years post-diagnosis — although the post-diagnosis numbers dropped by half during that period. After 10 years, only the use of anti-diabetic medications remained significantly higher in patients as compared with controls. These findings suggest that other conditions associated with Cushing’s disease, such as hypertension and diabetes, are effectively lessened with treatment. However, they also highlight that “many patients with CD [Cushing’s disease] will have persistent mental health problems,” the researchers wrote. In addition, visits to a psychiatrist and hospital admissions for treatment of psychiatric disorders tended to be more common among Cushing’s disease patients, even before diagnosis, the team noted. “This nationwide register-based study shows that use of psychotropic drugs in CD patients is increased from several years before diagnosis,” the researchers wrote, adding that this use “remained elevated regardless of remission status, suggesting persisting negative effects on mental health,” the researchers wrote. These findings highlight the importance of early diagnosis of Cushing’s disease and of considering neuropsychiatric symptoms “as an important part of the disease,” they concluded. There is a “need for long-term monitoring of mental health” in Cushing’s, they wrote. From https://cushingsdiseasenews.com/2021/02/24/cushings-found-to-cause-persistent-negative-mental-health-effects-swedish-study/
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    Register Now! 2nd annual WAPO eSummit March 19 & 20, 2021 World Alliance of Pituitary Organizations represents the voice of 37 patient advocacies around the globe. This event is also translated into Español, there’s something for everyone! The World Alliance of Pituitary Organizations (‘WAPO’) represents the voice of 37 patient advocacies around the globe. We seek to empower and improve the Quality of Life of Pituitary Patients, by sharing knowledge and inform you about treatment choices. By registering to the WAPO eSummit 2021, you will have a unique opportunity to learn about the latest medical research, raise questions and dialogue with international experts on the pituitary gland! Get involved and register in one of the provided languages. We are looking forward to meeting you! For more information visit the link below. https://web.cvent.com/event/aaf5e35f-793d-49ff-9f4b-138f155dbbc2/summary?fbclid=IwAR0-ah0tkUnx7HmBkQlEoIMOEBvQOGxnvz_XP7fC7BDKhEKkuBhgXfVQL04
  17. Register Now! 2nd annual WAPO eSummit March 19 & 20, 2021 World Alliance of Pituitary Organizations represents the voice of 37 patient advocacies around the globe. This event is also translated into Español, there’s something for everyone! The World Alliance of Pituitary Organizations (‘WAPO’) represents the voice of 37 patient advocacies around the globe. We seek to empower and improve the Quality of Life of Pituitary Patients, by sharing knowledge and inform you about treatment choices. By registering to the WAPO eSummit 2021, you will have a unique opportunity to learn about the latest medical research, raise questions and dialogue with international experts on the pituitary gland! Get involved and register in one of the provided languages. We are looking forward to meeting you! For more information visit the link below. https://web.cvent.com/event/aaf5e35f-793d-49ff-9f4b-138f155dbbc2/summary?fbclid=IwAR0-ah0tkUnx7HmBkQlEoIMOEBvQOGxnvz_XP7fC7BDKhEKkuBhgXfVQL04
  18. ~ RECORLEV® (levoketoconazole) New Drug Application is Supported by Previously-Reported Positive and Statistically Significant Results from the Phase 3 SONICS and LOGICS Studies ~ ~ Nearly 40 Percent of Prescription-Treated Endogenous Cushing’s Syndrome Patients in the U.S. Are Not Well-Controlled, Underscoring Need for New, Safe and Effective Pharmaceutical Options to Help Regulate Cortisol Levels ~ ~ If Approved Following a Projected 10-Month Review Cycle, RECORLEV is Anticipated to Launch in First Quarter of 2022 ~ DUBLIN, Ireland and TREVOSE, Pa., March 02, 2021 (GLOBE NEWSWIRE) -- Strongbridge Biopharma plc, (Nasdaq: SBBP), a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs, today announced that it submitted a New Drug Application (NDA) for RECORLEV® (levoketoconazole) for the treatment of endogenous Cushing’s syndrome to the U.S. Food and Drug Administration (FDA). The submission is supported by previously reported positive and statistically significant results of the SONICS and LOGICS trials: two Phase 3 multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat adults with endogenous Cushing’s syndrome. “The submission of the New Drug Application for RECORLEV® (levoketoconazole) represents not only a significant milestone for Strongbridge but also for the Cushing’s syndrome community as a whole. As an organization focused on developing treatments for underserved rare disease patient populations, we are one step closer to helping address the needs of the estimated 8,000 Cushing’s syndrome patients in the U.S. who are treated with prescription therapy, many of whom, as we learned in our market research, are not well-controlled with current therapies,” said John H. Johnson, chief executive officer of Strongbridge Biopharma. “We look forward to working with the FDA through their review of our application, and we are actively preparing for the potential launch of RECORLEV in the first quarter of 2022, if approved.” RECORLEV, the pure 2S,4R enantiomer of the enantiomeric pair comprising ketoconazole, is a next-generation steroidogenesis inhibitor being investigated as a chronic therapy for adults with endogenous Cushing’s syndrome. Two Phase 3 studies have demonstrated substantial evidence of efficacy and safety in a combined study population of 166 patients that was representative of the adult drug-treated U.S. population with Cushing’s syndrome. The SONICS study met its primary and key secondary endpoints, demonstrating a statistically significant rate of mean urinary free cortisol normalization after six months of maintenance therapy without a dose increase (detailed results here). LOGICS, a double-blind, placebo-controlled randomized-withdrawal study, which also had statistically significant primary and key secondary endpoints, confirmed that the long-term cortisol-normalizing efficacy demonstrated in SONICS was due to use of levoketoconazole specifically (detailed results here). The long-term open-label extension study, OPTICS, is contributing safety information to the NDA. “We want to thank the patients, their families, investigators, collaborators, and employees who have contributed to the RECORLEV clinical program leading to this important regulatory milestone,” said Fredric Cohen, M.D., chief medical officer of Strongbridge Biopharma. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. Strongbridge will host a conference call tomorrow, Wednesday, March 3, 2021 at 8:30 a.m. ET to discuss the Company’s fourth quarter and full-year 2020 financial results and recent corporate highlights, including the RECORLEV NDA submission. About Cushing’s Syndrome Endogenous Cushing’s syndrome is a rare, serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure - often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, and this often results in undesirable physical changes. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Women with Cushing's syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne. Additionally, the internal manifestations of the disease are potentially life threatening. These include metabolic changes such as high blood sugar, or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle and bone, and psychologic disturbances such as depression, anxiety and insomnia. Untreated, the five-year survival rate is only approximately 50 percent. About the SONICS Study SONICS is an open-label, Phase 3 study of RECORLEV as a treatment for endogenous Cushing’s syndrome that enrolled 94 patients at centers in North America, Europe and the Middle East. Following a screening phase, SONICS has three treatment phases: (1) Dose Titration Phase: Patients started RECORLEV at 150 mg twice daily (300 mg total daily dose) and titrated in 150 mg increments with the goal of achieving a therapeutic dose – a dose resulting in mUFC normalization – at which point titration was stopped; (2) Maintenance Phase: The dose was fixed and should not have been changed other than for safety reasons or loss of efficacy. At the end of the six-month maintenance phase, the mUFC response rate was measured; and (3) Extended Evaluation Phase: Patients continued on RECORLEV for another six months to evaluate long-term safety and tolerability and explore efficacy durability. About the LOGICS Study The Phase 3, multinational, double-blind, placebo-controlled, randomized-withdrawal study, LOGICS, randomized Cushing’s syndrome patients with baseline mean urinary free cortisol (mUFC) at least 1.5 times the upper limit of normal (ULN) following completion of a single-arm, open-label treatment phase of approximately 14 to 19 weeks, with RECORLEV individually titrated according to mUFC response. A total of 79 patients were dosed during the open-label titration-maintenance phase, 7 of whom had previously received RECORLEV during the SONICS study, and 72 who had not previously received RECORLEV. At study baseline, the median mUFC was 3.5 times the ULN, indicative of significant hypercortisolemia. A total of 44 patients (39 who had completed the titration-maintenance phase and five who directly enrolled from the SONICS study), were randomized to either continue RECORLEV (n=22) or to have treatment withdrawn by receiving a matching placebo regimen (n=22) for up to 8 weeks, followed by restoration to the prior regimen using blinded drug. Of the 44 patients randomized, 11 patients (25 percent) had previously received RECORLEV during the SONICS study. Patients who required rescue treatment with open-label RECORLEV during the randomized-withdrawal phase were considered to have lost mUFC response at the visit corresponding to their first dose of rescue medication. Patients who did not qualify for randomization were removed from open-label treatment prior to randomization and excused from the study. About RECORLEV RECORLEV® (levoketoconazole) is an investigational cortisol synthesis inhibitor in development for the treatment of patients with endogenous Cushing’s syndrome, a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure. RECORLEV is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor. RECORLEV has demonstrated in two successful Phase 3 studies to significantly suppress serum cortisol and has the potential to be a next-generation cortisol inhibitor. The Phase 3 program for RECORLEV includes SONICS and LOGICS: two multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, demonstrating a statistically significant normalization rate of urinary free cortisol at six months. The LOGICS study, which met its primary endpoint, is a double-blind, placebo-controlled randomized-withdrawal study of RECORLEV that is designed to supplement the long-term efficacy and safety information supplied by SONICS. The ongoing long-term open label OPTICS study will gather further useful information related to the long-term use of RECORLEV. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. About Strongbridge Biopharma Strongbridge Biopharma is a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs. Strongbridge’s rare endocrine franchise includes RECORLEV® (levoketoconazole), a cortisol synthesis inhibitor currently being studied in Phase 3 clinical studies for the treatment of endogenous Cushing’s syndrome, and veldoreotide extended release, a pre-clinical next-generation somatostatin analog being investigated for the treatment of acromegaly and potential additional applications in other conditions amenable to somatostatin receptor activation. Both RECORLEV and veldoreotide have received orphan drug designation from the FDA and the European Medicines Agency. The Company’s rare neuromuscular franchise includes KEVEYIS® (dichlorphenamide), the first and only FDA-approved treatment for hyperkalemic, hypokalemic, and related variants of primary periodic paralysis. KEVEYIS has orphan drug exclusivity in the United States. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the federal securities laws. The words “anticipate,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “project,” “target,” “will,” “would,” or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements of historical facts, contained in this press release, are forward-looking statements, including statements related to data from the LOGICS and SONICS studies, the potential advantages of RECORLEV, the anticipated timing for potential approval of a marketing authorization for RECORLEV and for the potential launch of RECORLEV, Strongbridge’s strategy, plans, outcomes of product development efforts and objectives of management for future operations. Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed in such statement, including risks and uncertainties associated with clinical development and the regulatory approval process, the reproducibility of any reported results showing the benefits of RECORLEV, the adoption of RECORLEV by physicians, if approved, as treatment for any disease and the emergence of unexpected adverse events following regulatory approval and use of the product by patients. Additional risks and uncertainties relating to Strongbridge and its business can be found under the heading “Risk Factors” in Strongbridge’s Annual Report on Form 10-K for the year ended December 31, 2019 and its subsequent Quarterly Reports on Form 10-Q, as well as its other filings with the SEC. These forward-looking statements are based on current expectations, estimates, forecasts and projections and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors. The forward-looking statements contained in this press release are made as of the date of this press release, and Strongbridge Biopharma does not assume any obligation to update any forward-looking statements except as required by applicable law. Contacts: Corporate and Media Relations Elixir Health Public Relations Lindsay Rocco +1 862-596-1304 lrocco@elixirhealthpr.com Investor Relations Solebury Trout Mike Biega +1 617-221-9660 mbiega@soleburytrout.com From https://www.biospace.com/article/releases/strongbridge-biopharma-plc-announces-submission-of-new-drug-application-for-recorlev-levoketoconazole-for-the-treatment-of-endogenous-cushing-s-syndrome-to-the-u-s-food-and-drug-administration/
  19. A Golden Oldie We sadly learned that Liz died in March 2012 at the age of 45. She was an active member of the Cushing’s Help Message Boards. She had a photo gallery there. The photo below is from that gallery. The image at left is from 2002. Liz wrote in her bio: Hello, I’m from Hampton, just outside London. Same old story – at least 6 years of various illnesses, including four operations for various crap (kidney stones, gallbladder removal, and 2 cysts on my coccyx) I then went from being very skinny (even after childbirth) to very fat in about a year (from 7.5 stones to 13 stones). You could roll me down our local hill! I wear maternity clothes as my tum is so disproportionate to my legs & arms (size 26 vs size 12!). My face, chest, neck and back look like someone’s put padding in, and my nice red glow brings all sort of compliments about how healthy i look, grr! I’ll post some photos later. So far, a left adrenal tumor has turned up, but I have abnormally high ACTH (60) with a highish cortisol of about 600. This apparently implies a pituitary source – but the pituitary MRI was clear. I’m waiting on a second one with gadolinium this time, but here in London MRIs take AGES. The wait at our local hospital is currently 10 months. In the meantime, I’m frustrated and feeling lousy and v tired. I have to work full time (luckily I’m an accountant, not something overly physical) as I’m a single mum to a lovely 8 year old girl who does not deserve all this. The guilt eats me up, but she is thankfully not the outward bound type! Walking is a struggle as my legs seem to suddenly buckle on me, and sitting up without support at say the hairdressers or a restaurant is really difficult. So my (thinning) hair’s a mess and I don’t eat out much! I veer about – someone at work told my boss I couldn’t walk in a straight line! Highly amusing as I haven’t touched a drop in ages! Other symptoms that have developed more recently include interimittently high blood sugar, intermittently high blood pressure, have to shave every day, horrid night and day sweats, red marks up my arms, but none on my body, intermittently rotten swollen ankles and feet, recurrently horrid kidney stones, and of course, an attractive buffalo hump (moo). And the final insult – can’t get into any of my shoes any more so shuffle about at work in my oversize carpet slippers. Very popular amongst my grey accountant colleagues. As so many of the symptoms are intermittent, the endo says he is convinced it is cushing’s, but cylical, due to (again) interimittent high blood cortisol and ACTH, and non suppression on three low dose dex tests. Then the first 24 hr ufc came back normal which was very frustrating. I’m not particularly religious but i pray he won’t give up on me as it is a long journey compared to the diagnosis of other equally horrid diseases. Feel quite isolated from my mates and lovely mum, although they are trying hard to be supportive – I’m surprised my mood swings haven’t frightened them all off lately. It’s so difficult to explain how rough it feels to take part in normal activities, especially when every symptom is something most people consider they have in everyday life to some degree. As well as the physical exhaustion/pain/weakness, my body image distresses me enormously. Recurrent kidney stones are pretty painful too (but not as bad as childbirth as a lot of men claim!). Hope to be there soon. Great to read all your stories and know that so many of you know how it all feels – and have felt it for umpteen years too. All the best. Liz Update April 21, 2005. Following dex/CRH test, which even included a dexamethasone assay to make sure the levels were adequate (took forever to come back from the lab), my endo confirmed cushings. The bad news is I need the IPSS which will be in May. My ACTHs are between 80-100 so it is most likely a pituitary cause despite my adrenals showing a small adenoma – a red herring! It’s a very odd feeling after waiting so long, knowing something was very wrong, but not knowing what, and thinking i would go on for ever in misery. So to all you guys out there feeling like this, and i know you’re out there(!), don’t give up!! Wish me luck … Posts in Liz’s memory: Terry: Oh no, that is terribly sad. Jenny: Oh no, what happened, did he say? 😦 Beth: omg, I felt sick reading this. I knew of her, but never got to know her. I’m so sorry. 😦 Regina: How tragic! Liz: This is just so sad !! And yet he reaches out to us in his time of sadness, please forward to him my deepest sympathies Nancy: Oh no!!” This makes my physically ill! I’m fighting tears.PLEASE get details so we can try to learn about what happened and prevent any other Cushie from loosing their life.. Hugs and prayers to Liz’s family! MaryO: He didn’t say – I just responded to his email and we’ll see if he has any more to say. I hate when Cushies die 😦 Sandra: Omg liz was my friend! We used to chat on the phone when I was seriously ill too! Omg I cannot belkieve it! Mary cud u pm his email add pls xxx Liz: Me too Mary me too, just brings everything to a scary place for all of us !! Trisha: I am so sorry to hear this. I remember Liz from the boards. Sandra: Have just spoken to ciara lizs daughter who said it was a massive heart attack in the end! Her funeral is on thursday! God bless u my friend xxxxx Lisa: God bless her family..so sad 😦 Kim: So sad Jennyfer: Oh no no more cushies down please send my love Judy: So sad. Does anyone know how old she was, I had never figured that out. Mary: Oh no! I loved our Lizzy girl and have been thinking of her recently. I hadn’t heard from her in awhile. So very sad. Please pass along my deepest condolences. Linda: No! Not Liz! No no no MaryO: She was 45. On the C-H boards, her name was Lizr007 Shauna: News like this breaks my heart over and over again. Mary, please let him know that her Cushie family mourns her loss deeply. Linda: Please do tell Liz’s brother how much she was loved. I can’t believe she is gone…. Judy: Thanks, Mary. I sometimes haven’t converted who they were on the boards to their real life name. I know who she was. That is so young. Adrienne: so sorry, so sad!!! Linda: Please let Liz’s brother know that I adored her. She was one of the first people I met on the Cushings boards many years ago, and she was one of my “rocks”. She was such a supportive, loving person with a great sense of humor. I am heartbroken that she is gone. Stephanie: How tragic!! Thoughts and Prayers for her family and friends. Lisa: Poor Liz. My heart breaks for her family. I remember her struggles Mary: You have my permission to send my condolences. Grace: This is such sad news! Prayers and hugs for Liz’s family. How sad that we lose even one of us to the complications of this disease. Sandra: RIP liz u were such a wonderful person and a dear friend! I’m sure suziQ was waiting for u along with all our other cushies that have past over! God bless u huni I will miss u! Xx Joanne: Im so sorry to hear another precious life taken by this illness, prayers for her and her family.. Anne : Oh not Liz!! She was an awesome person! She had such a great spirit. How horribly awful. Janelle: So sad.. Please let us know what the complications were.. 😦 Alicia: So sad. We are losing way too many people to this disease. Praying for her family. Robin: Oh, this breaks my heart. Please tell Liz’s brother we will miss her terribly. Heather: I’m so sorry. I loved Liz. Her spirit and sense of humor were amazing. I was actually thinking about her the other day as well. Please feel free to convey my condolences to her family. Melissa: As soon as I saw her name — Liz Rafferty — I started to cry. Liz was part of our group there on the Cushing’s- Help message boards. She posted over 2000 times. When you posted her screen name, I could see her avatar in my mind. I am so sad to hear that she is not with us, her family or friends. I am so upset as I wonder why this has to happened to her, to us, to our community. Please send my condolences along to Liz’ brother, and make sure they know that she was caring and supportive of many as well as loved by many. I will miss her. And Mary, please be sure to tell him she was part of our group, too. I bet he would want to make a donation to you and Cushing’s-Help if he knew how extensively she participated in our group. Hugging all of you a little tighter today. — Melissa, TX Beth: Another person with my disease has passed. I didn’t know her personally, but the hurt is still there.. As is the fear. RIP Liz R. Chanelle: Omg!! Ugh my head hurts :(( Sandra: Beth she was a dear friend and such a sweet sweet girl! Even at her worst she was cheerful and lovely ! She has left behind her daughter and her mum god bless em x Christina: 😦 so sad to hear this, RIP to her. Mary: I loved Liz. She was so funny and upbeat and helpful. RIP old friend. Linda: Rest in peace, Liz. You were very loved and and I’m thankful to have met you on my Cushings journey. Susan: Thanks for posting this, MaryO. My sympathies to Liz’s family for their loss. As a member of this community, we will miss you. missaf: My heart goes out to her family. I’m glad she started to feel better for a little while and got to smile more in life. Damn Cushing’s. Sherry: Not another Cushie:( I am so sad to hear this news, Liz was well known on the boards and she will be greatly missed. I just hate this. My deepest sympathies go out to her family. Elizabeth: Deepest sympathy & many prayers. This is so heartbreaking. Dawn: I did not know her, but her passing has affected me. I am sorry that the world has lost her and I’m sad that it was a result of this horrible disease. It always hits close to the heart. My condolences to her family and friends. Ami: I am completely heartbroken. She was a dear. Please include my condolences to her brother. I too would very much like to hear what the cause of death was. Kristin: I’m so upset about this, all I can say is I’m sorry for her family. Leaving a 16 yo without her mommy is so terrible. Somehow the medical community needs to realize how many of our group are not making it needlessly… Prayers for her family. Very nice of her brother to let us know. Melanie: OMG! I feel ill. I loved Liz dearly, she helped me keep my sanity when I first arrived on the biards and gave me such great support – we had some great laughs together and spoke on the phone for hours at a time. I cannot believe another one of us has gone. This damn disease is so bloody unfair. Just read it was a heart attack (Thanks Sandra). – heartbreaking. Gumdrop: So sad to hear this. I pray her family is comforted. Sandra: If I find any more info out I will post Mary: She and I had SIADH in common and the continuing electrolyte issues afterwards, too. I think when I was hospitalized with it, she was the only other person on the boards who’d experienced it at that time. Bernadette: I didn’t know her, but am so saddened by her much-too-early death. My thoughts and prayers are with her family, and with all the rest of you who knew her. Ami: I know she and I exchanged posts on the boards. I wish I remembered more about her… Shelley: I’m sorry to hear about her passing. She and her family and loved ones are in my thoughts and prayers. Mary: oh no! devastating news. so sorry and saddened to hear. 😦 Amy: I am so broken hearted. 😦 Liz was one of the very first people to make friends with me on the cushings website. So sweet and funny, what a wonderful person she was. I have just cried and cried ever since learning of her passing. She really struggled to get her BLA for a long time. May God rest her soul. She truly was “one of a kind” Dacia: Please send my love, my thoughts and prayers to all… AuntSha: Condolences to her family…. My prayers and thoughts are with them. She certainly has been taken too young and much too soon :-(!!! Diane: My beautiful, funny, smart dear friend Liz. You carried me through my journey and held my hand through some of the worst times I can remember. You were my rock, you were my shoulder. Words cannot express how I feel right now. I am heartbroken. I am so sad. The heavens are blessed with another beautiful soul. Love to you my dear friend xx The last time we saw each other was when you had your adrenal operation. I was so thrilled to finally see you in the flesh after spending months posting to each other here and emailing and chatting on the phone. I met Liz at Cromwell Hospital in London where she was recovering from her adrenal operation. I bought her a massive bunch of stocks that filled her hospital room with a glorious heady scent and I bought along a few things to pamper her with. We spent the afternoon chatting non-stop and I remember giving her Mum a big hug. Those memories will stay with me and that is how I remember Liz. A happy smile and a big heart. Rest in peace lovely lady…. Your Cushy friend, always, Diane x Ellen: My deepest condolences to her family. This is such a stark reminder of how cruel this disease is. Monica: Oh Liz. I’ll miss her, she was such a good person and gave support to us all even while fighting her own battle. Melly: So tragic! May God welcome Liz and bless her family with peace and strength during this horrible time. Such a reminder that each day I breathe is a gift. love, melly 3v3: I am new here so I am not familiar with Liz, but I am so sorry to read this. Condolences to her friends and family. I was trying to find her bio info/old posts and it seemed like she was cured or at least recovering? 😦 Judy: Mine too. It’s just so sad. I pray for the family. Beth: Such a tragic loss.. I wish her family and friends strength and peace. 😦 Sandra: Have spoken to aLex woore who was also a cushie friend wiv liz and apparantly she had a bla smtime ago but they cudnt get her sodium n potassium levels right so whether that had anything to do with it I dnt knw but have left my no wiv ciara and her nan so if they call I will let u all knw! X Karen: Please send my condolences also, such sad news . This disease is awful, we are losing so many amazing people to it. Many prayers, Monica: Thinking of Liz tonight. I pray for comfort for her family, especially her 16 year old daughter. Far too many friends lost to this disease over the years. Stanley : I’m sorry to hear that. Melissa: This makes me cry all over again. Mary, could you offer our services in helping to decipher what could have led to Liz’s death? For example, we could guide the family on getting copies of her hospital, doctor, surgical, and lab records. Susan: I am just devastated by this news. Liz was so kind and caring. So tragic to lose someone so young. Rissa: This is so sad. Praying for Liz and her family tonight. Ikho: This news makes me so sad. My condolences to her family. Lorrie: I am so sorry. My prayers go out to her family. 45 years old….such a young woman. God Bless them. Amy: I’m still just in shock. Thinking back I can remember that sweet pic she had of her cat playing with something. I never could figure out what that cat was doing though. LOL This is just surreal to me . . . 😦 Jenny: Please pass on my condolences, her family will be in my prayers. Just so unbelievably sad. 😥 Jo: cant believe it. very sad, god bless our dear friend Liz.taken far too soon. Jenny: The Cushings community has lost yet another dear member. Liz was only 45, please pray for her family and friends. 😦 Lisa: One of our fellow “cushies” (Cushings patient) sadly passed away. Liz was a wonderful 45 yr old mother of a 16 yr old and a friend to us that got so many through this. She was an inspiration and someone that kept her chin up and a smile on her face and ours on our message board. She will be missed. Mary R: We’ve lost another Cushing’s Warrior from complications of this rotten disease. Her name is Liz and leaves behind a 16 yr old daughter. This is the 3rd Cushie in 8 months!!! It doesn’t have to be this way! Just because it’s rare, doesn’t mean that the Dr.s should doubt us and our biochemical/imaging evidence. Please say a prayer for Liz’s daughter and family. PLEASE promise me that if this disease takes me from my family at a young age, that you will bring Cushing’s awareness & education to others on my behalf. Jen: I remember Liz well and I am so sorry to hear that she has passed. My condolences to her family. Diane: It’s been a day since I found out and I am still numb with shock. There are moments in your life when things happen that change your whole outlook on things. Cushings was that something for me. However with all the difficulties of coping with such a terrible disease I managed to find many special friendships and was given support by such a special group of ladies that I will treasure in my heart forever. Liz was one of those special people. We had a giggle, we had a moan about the whole NHS process and testing, we shared some of our most painful moments going through this disease. I will miss you so much Liz. Shine a bright light in heaven lovely lady xxx Mary – you certainly have my permission xx Thank you for creating a place where I had an opportunity to meet someone like Liz xx Amy: I was so very fond of Liz and my heart is still broken in two. 😦 Diane: I’ve just been reading some of Liz’s old posts on the site…more tears are flowing but with a big smile on my face. I forgot just how much of a laugh we had despite the fact we were going through hell…I particularly like the fact that alot of people didn’t understand Liz and my British sense of humour. It just reminded that some great bonds were forged during hours of such need and loneliness, stress and depression, and a fight to get heard and a struggle to get diagnosed. Jo: do you remember when her endo put her in the priory, & she met Ronnie Wood ? Liz Thought she looked better than he did.I cant count how many times K didn’t get his dinner because we were too busy on the phone.Still cant believe it. Sally: I am so sad to read this. Liz, myself and a few others had said we needed to get together in Bermuda (half way) when we were all finally healthy to celebrate our 40th birthdays. I don’t know if any of us managed to hit that milestone healthy, I know I didn’t and I know Liz didn’t. I’m heartbroken, it’s so very sad. betseebee: Such devastating news! Liz’s bio was one of the first I read when I joined the boards. I also distinctly remember her kitty avatar and that I could relate to things in her bio, like being grateful that my daughter was also not an outward bound type, which made it a little easier to be at home so much. My most heartfelt condolences to her beautiful daughter, Ciara, as well as the rest of her family. Liz, may you rest in peace, and dance among the angels. Sherry: My deepest sympaties go out to her family. This disease is awful, Liz was a wonderful person, she and I joined around the same time, I am very sad to hear of this disease taking another precoius life. RIP Liz. Diane: That is so funny Jo, I did not know that. I think Liz would have had no problem looking better than Ronnie!! Have you seen his program on SkyArts right now?!! Sally – I am 40 in June and this has just brought home to me how precious life is and. Not sure I’ll get to Bermuda, maybe Bognor…!! xx Sandra: Sally I remember that convo ! I was one of them then, and yes I made my 40 th prob the healthiest I’m ever going to b now despite battling fibro still! And diane I knw what u mean about the british sense of humour! So not only did we laugh about the joke we cracked up with the fall out of being misunderstood (in a goodway) of course! Lol …..I thought about her sooo much yesterday and poor ciara bless her! Just stil can’t beleve it x Jean: Im soo sorry to hear abt this ;( Really shows how this disease is serious n deadly, if not treated properly or from complications from surgery…my condolences to her family n all who knew her. Dave: Liz, we never got to share that coffee. You were so helpful to me in researching my various problems and I know that there are many many friends who don’t come here any more but we will all miss you. Sincere sympathies to all your loved ones. Sheila: A tragic loss at such a young age. Sad to know that death happens with Cushing’s when we are in the year of 2012. Hopefully more doctors will take an interest in this little known disease of Cushing’s Syndrome. Tanya: 😦 OMG rest in peace Liz. I’ve heard “I wish cancer would get cancer and die.” Well ‘I wish cushing’s would get cushing’s and die.’
  20. Rosario Pivonello,a,b Rosario Ferrigno,a Andrea M Isidori,c Beverly M K Biller,d Ashley B Grossman,e,f and Annamaria Colaoa,b Over the past few months, COVID-19, the pandemic disease caused by severe acute respiratory syndrome coronavirus 2, has been associated with a high rate of infection and lethality, especially in patients with comorbidities such as obesity, hypertension, diabetes, and immunodeficiency syndromes.1 These cardiometabolic and immune impairments are common comorbidities of Cushing's syndrome, a condition characterised by excessive exposure to endogenous glucocorticoids. In patients with Cushing's syndrome, the increased cardiovascular risk factors, amplified by the increased thromboembolic risk, and the increased susceptibility to severe infections, are the two leading causes of death.2 In healthy individuals in the early phase of infection, at the physiological level, glucocorticoids exert immunoenhancing effects, priming danger sensor and cytokine receptor expression, thereby sensitising the immune system to external agents.3 However, over time and with sustained high concentrations, the principal effects of glucocorticoids are to produce profound immunosuppression, with depression of innate and adaptive immune responses. Therefore, chronic excessive glucocorticoids might hamper the initial response to external agents and the consequent activation of adaptive responses. Subsequently, a decrease in the number of B-lymphocytes and T-lymphocytes, as well as a reduction in T-helper cell activation might favour opportunistic and intracellular infection. As a result, an increased risk of infection is seen, with an estimated prevalence of 21–51% in patients with Cushing's syndrome.4 Therefore, despite the absence of data on the effects of COVID-19 in patients with Cushing's syndrome, one can make observations related to the compromised immune state in patients with Cushing's syndrome and provide expert advice for patients with a current or past history of Cushing's syndrome. Fever is one of the hallmarks of severe infections and is present in up to around 90% of patients with COVID-19, in addition to cough and dyspnoea.1 However, in active Cushing's syndrome, the low-grade chronic inflammation and the poor immune response might limit febrile response in the early phase of infection.2 Conversely, different symptoms might be enhanced in patients with Cushing's syndrome; for instance, dyspnoea might occur because of a combination of cardiac insufficiency or weakness of respiratory muscles.2 Therefore, during active Cushing's syndrome, physicians should seek different signs and symptoms when suspecting COVID-19, such as cough, together with dysgeusia, anosmia, and diarrhoea, and should be suspicious of any change in health status of their patients with Cushing's syndrome, rather than relying on fever and dyspnoea as typical features. The clinical course of COVID-19 might also be difficult to predict in patients with active Cushing's syndrome. Generally, patients with COVID-19 and a history of obesity, hypertension, or diabetes have a more severe course, leading to increased morbidity and mortality.1 Because these conditions are observed in most patients with active Cushing's syndrome,2 these patients might be at an increased risk of severe course, with progression to acute respiratory distress syndrome (ARDS), when developing COVID-19. However, a key element in the development of ARDS during COVID-19 is the exaggerated cellular response induced by the cytokine increase, leading to massive alveolar–capillary wall damage and a decline in gas exchange.5 Because patients with Cushing's syndrome might not mount a normal cytokine response,4 these patients might parodoxically be less prone to develop severe ARDS with COVID-19. Moreover, Cushing's syndrome and severe COVID-19 are associated with hypercoagulability, such that patients with active Cushing's syndrome might present an increased risk of thromboembolism with COVID-19. Consequently, because low molecular weight heparin seems to be associated with lower mortality and disease severity in patients with COVID-19,6 and because anticoagulation is also recommended in specific conditions in patients with active Cushing's syndrome,7 this treatment is strongly advised in hospitalised patients with Cushing's syndrome who have COVID-19. Furthermore, patients with active Cushing's syndrome are at increased risk of prolonged duration of viral infections, as well as opportunistic infections, particularly atypical bacterial and invasive fungal infections, leading to sepsis and an increased mortality risk,2 and COVID-19 patients are also at increased risk of secondary bacterial or fungal infections during hospitalisation.1 Therefore, in cases of COVID-19 during active Cushing's syndrome, prolonged antiviral treatment and empirical prophylaxis with broad-spectrum antibiotics1, 4 should be considered, especially for hospitalised patients (panel ). Panel Risk factors and clinical suggestions for patients with Cushing's syndrome who have COVID-19 Reduction of febrile response and enhancement of dyspnoea Rely on different symptoms and signs suggestive of COVID-19, such as cough, dysgeusia, anosmia, and diarrhoea. Prolonged duration of viral infections and susceptibility to superimposed bacterial and fungal infections Consider prolonged antiviral and broad-spectrum antibiotic treatment. Impairment of glucose metabolism (negative prognostic factor) Optimise glycaemic control and select cortisol-lowering drugs that improve glucose metabolism. Hypertension (negative prognostic factor) Optimise blood pressure control and select cortisol-lowering drugs that improve blood pressure. Thrombosis diathesis (negative prognostic factor) Start antithrombotic prophylaxis, preferably with low-molecular-weight heparin treatment. Surgery represents the first-line treatment for all causes of Cushing's syndrome,8, 9 but during the pandemic a delay might be appropriate to reduce the hospital-associated risk of COVID-19, any post-surgical immunodepression, and thromboembolic risks.10 Because immunosuppression and thromboembolic diathesis are common Cushing's syndrome features,2, 4 during the COVID-19 pandemic, cortisol-lowering medical therapy, including the oral drugs ketoconazole, metyrapone, and the novel osilodrostat, which are usually effective within hours or days, or the parenteral drug etomidate when immediate cortisol control is required, should be temporarily used.9 Nevertheless, an expeditious definitive diagnosis and proper surgical resolution of hypercortisolism should be ensured in patients with malignant forms of Cushing's syndrome, not only to avoid disease progression risk but also for rapidly ameliorating hypercoagulability and immunospuppression;9 however, if diagnostic procedures cannot be easily secured or surgery cannot be done for limitations of hospital resources due to the pandemic, medical therapy should be preferred. Concomitantly, the optimisation of medical treatment for pre-existing comorbidities as well as the choice of cortisol-lowering drugs with potentially positive effects on obesity, hypertension, or diabates are crucial to improve the eventual clinical course of COVID-19. Once patients with Cushing's syndrome are in remission, the risk of infection is substantially decreased, but the comorbidities related to excess glucocorticoids might persist, including obesity, hypertension, and diabetes, together with thromboembolic diathesis.2 Because these are features associated with an increased death risk in patients with COVID-19,1 patients with Cushing's syndrome in remission should be considered a high-risk population and consequently adopt adequate self-protection strategies to minimise contagion risk. In conclusion, COVID-19 might have specific clinical presentation, clinical course, and clinical complications in patients who also have Cushing's syndrome during the active hypercortisolaemic phase, and therefore careful monitoring and specific consideration should be given to this special, susceptible population. Moreover, the use of medical therapy as a bridge treatment while waiting for the pandemic to abate should be considered. Go to: Acknowledgments RP reports grants and personal fees from Novartis, Strongbridge, HRA Pharma, Ipsen, Shire, and Pfizer; grants from Corcept Therapeutics and IBSA Farmaceutici; and personal fees from Ferring and Italfarmaco. AMI reports non-financial support from Takeda and Ipsen; grants and non-financial support from Shire, Pfizer, and Corcept Therapeutics. BMKB reports grants from Novartis, Strongbridge, and Millendo; and personal fees from Novartis and Strongbridge. AC reports grants and personal fees from Novartis, Ipsen, Shire, and Pfizer; personal fees from Italfarmaco; and grants from Lilly, Merck, and Novo Nordisk. All other authors declare no competing interests. Go to: References 1. Kakodkar P, Kaka N, Baig MN. A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19) Cureus. 2020;12 [PMC free article] [PubMed] [Google Scholar] 2. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4:611–629. [PubMed] [Google Scholar] 3. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17:233–247. [PubMed] [Google Scholar] 4. Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The immune system in Cushing's syndrome. Trends Endocrinol Metab. 2020 doi: 10.1016/j.tem.2020.04.004. published online May 6, 2020. 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  21. About Who Should Attend: Individuals with Cushing’s disease and their caregivers. When: Thursday, March 4, 2021, 6 PM, Eastern Where: Virtual presentation via Zoom. Click the Zoom link for the online event or call one of the phone numbers below: 833-548-0276 (US Toll-free) 833-548-0282 (US Toll-free) 877-853-5257 (US Toll-free) 888-475-4499 (US Toll-free) Whether you log on via computer or telephone, you will be asked for the meeting ID and password. Meeting ID: 969 3392 7432 Passcode: 945590 Attendees will be muted until the end of the presentation, at which time we will take questions. There is no fee for this event. Contact Maggie Bobrowitz with any questions: Margaret.Bobrowitz@DignityHealth.org or (888) 726-9370.
  22. About Who Should Attend: Individuals with Cushing’s disease and their caregivers. When: Thursday, March 4, 2021, 6 PM, Eastern Where: Virtual presentation via Zoom. Click the Zoom link for the online event or call one of the phone numbers below: 833-548-0276 (US Toll-free) 833-548-0282 (US Toll-free) 877-853-5257 (US Toll-free) 888-475-4499 (US Toll-free) Whether you log on via computer or telephone, you will be asked for the meeting ID and password. Meeting ID: 969 3392 7432 Passcode: 945590 Attendees will be muted until the end of the presentation, at which time we will take questions. There is no fee for this event. Contact Maggie Bobrowitz with any questions: Margaret.Bobrowitz@DignityHealth.org or (888) 726-9370.
  23. The Journal of Clinical Endocrinology & Metabolism, dgab079, https://doi.org/10.1210/clinem/dgab079 Abstract Context Psychiatric symptoms are common in Cushing’s disease (CD) and seem only partly reversible following treatment. Objective To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. Design Nationwide longitudinal register-based study. Setting University Hospitals in Sweden. Subjects CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. Main outcome measures Data from the Swedish Prescribed Drug Register and the Patient Register. Results In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension. Conclusions Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health. Cushing’s syndrome, hypercortisolism, neuropsychiatry, depression, sleeping disorder Issue Section: Clinical Research Article Read more at https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab079/6132459?rss=1
  24. https://doi.org/10.1002/jbmr.4033 ABSTRACT Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long‐term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide (PINP), alkaline bone phosphatase, CTX‐I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex‐, age‐, and body mass index (BMI)‐matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T‐score = −1.4 ± 1.1). Two years after successful surgery, the T‐score had improved in 78% of patients (mean T‐score 2 years postoperatively −1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX‐I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three‐ to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. Introduction Cushing's syndrome (CS) is a rare disease with approximately 0.7 to 2.4 new cases per 1 million per year.1 Osteoporosis and osteopenia are typical comorbidities of patients with endogenous and exogenous CS. Depending on the study, 60% to 80% of patients have evidence for a reduced bone mineral density2 characteristically affecting the entire skeleton.3 About 5% of all cases of secondary osteoporosis are caused by hypercortisolism.4 However, data from prospective, well‐powered studies are rare, and few risk factors that would predict bone health have been identified so far. Guidelines for the management of osteoporosis due to endogenous CS are still missing.5 In terms of risk assessment, the subtype of CS does not seem to influence osteoporosis risk,6 whereas the morning cortisol levels are negatively correlated with lumbar bone mineral density.6 The duration of endogenous Cushing's syndrome (or the duration of exogenous replacement therapy after successful surgery) obviously affects bone mineral density.7 Whether the T‐score is the best predictor for fracture risk is not quite clear.2 Another area of uncertainty is the natural course of osteoporosis and bone turnover markers once the diagnosis of Cushing's syndrome has been established. A number of studies have addressed this topic, but the interpretation of the results is hampered because of limited patient numbers, concomitant osteoanabolic treatment, or both.8-10 In‐depth insight on bone remodeling in CS might come from bone turnover marker studies. For example, the bone formation marker osteocalcin is suppressed in untreated CS,3 a consistent observation making it useful as a diagnostic marker for CS.2 Based on the paucity of data, the lack of evidence for treatment guidelines, and the pressing open questions regarding risk assessment and management of osteoporosis, we performed a sufficiently powered study to analyze the natural course of bone turnover and bone mineral density in a monocentric cohort of patients with endogenous Cushing's syndrome. To the best of our knowledge, this is the first such study, and the data obtained will be instrumental for clinicians who care for patients with Cushing's syndrome. Materials and Methods Patients This study was performed as part of the prospective German Cushing registry, which has included 450 consecutive patients referred to our department for suspected CS since 2012. Structure and general characteristics of the registry have been described in detail previously.11-14 All patients included in the registry underwent a standardized biochemical screening and clinical examination at time of diagnosis and a yearly follow‐up after treatment to treat comorbidities and diagnose recurrence of the disease early. In all patients, standard screening for CS with a 1 mg low‐dose overnight dexamethasone suppression test (LDDST), collection of 24‐hour urine (UFC), and sampling of midnight salivary cortisol were performed. When the diagnosis of CS was confirmed, further subtyping was based on plasma adrenocorticotropic hormone (ACTH), corticotropin‐releasing hormone (CRH) test, high‐dose dexamethasone suppression test, imaging, and inferior petrosal sinus sampling (in case of ACTH dependence). Final diagnosis was CS in 156 patients and exclusion of CS in the remaining 294 patients. Patients with excluded CS were a quite heterogenic group with lead symptoms such as obesity (73%), arterial hypertension (50%), or hirsutism (33%). Final diagnoses in these subjects were metabolic syndrome, polycystic ovary syndrome (PCOS), obesity, depression, or primary hyperaldosteronism. Patient selection is shown in Fig. 1. Figure 1 Open in figure viewerPowerPoint Patient selection. *Very young age; patient conducted densitometry in a different clinic/outpatient clinic; patient refused densitometry. CS = Cushing's syndrome; BMD = bone mineral density; BMI = body mass index. Bold text indicates actual cohort of the study. In our analysis, we excluded patients for whom no densitometry data were available (n = 63) and patients receiving pharmacologic treatment for osteoporosis following diagnosis (n = 4). Densitometry data were not available for multiple reasons (very young age, external densitometry in a different clinic, missing consent to perform densitometry). We matched the remaining 89 patients with 71 controls subjects selected from those subjects in whom CS was excluded. Matching was done according to sex, age, and body mass index (BMI). None of the patients and controls received specific osteoanabolic or antiresorptive treatment, but 47% of patients with CS received vitamin D supplementation after remission. At time of diagnosis, 11% of controls and 17% of patients with CS received vitamin D supplementation. Methods In patients with confirmed CS, a bone mineral densitometry was conducted. Bone mineral density (BMD) was determined at the lumbar spine and the femur (neck and total femur). If a reduced bone mineral density was diagnosed, a follow‐up densitometry was performed 2 years after surgery. If bone mineral density was normal initially or during follow‐up, only one further densitometry was performed 2 or 3 years after initial diagnosis. An improvement or decrease of bone mineral density was defined according to the least significant change (LSC = 2.8 × 1.8%).15 Accordingly, an alteration of more than 5.04% of BMD was rated as significant. A detailed fracture history was taken and X‐ray of the spine was performed when clinical suspicion for fractures was high. In all patients, blood samples (serum and plasma) were taken at time of diagnosis and also 1 and 2 years after successful transsphenoidal surgery or adrenalectomy. Blood was taken in the fasting state between 8:00 and 10:00 a.m. Samples were centrifuged within 20 minutes at 4°C and stored at −80° until assayed. Three bone formation markers and two bone resorption markers were measured: osteocalcin, intact procollagen I‐N‐propeptide (PINP), and bone alkaline phosphatase (BAP) as bone formation markers, and CrossLaps (CTX‐I) and tartrate‐resistant acid phosphatase (5b TrAcP5b) as bone resorption marker, on basis of published data demonstrating their usefulness in CS and primary osteoporosis.2, 16 Samples were measured at the Endocrine Laboratory of the Department of Internal Medicine IV on the iSYS automated analyzer (IDS‐iSYS, Boldon, UK) by well‐validated assays.17, 18 Published, method‐specific reference intervals are available from a large healthy population.19, 20 For the determination of osteocalcin, an N‐MID assay was used, as pre‐analytics are less critical in this assay.21 TrAcp 5b is a new marker, which, in contrast to CTX‐1, can also reliably be measured in the non‐fasting state.22 Statistical analysis In a priori power analysis, we calculated that a total sample size of 102 would be sufficient to identify significant differences between groups, assuming a medium effect size (0.5), a power of 1 – β = 0.80 and a type I error of α = 0.05, with 51 subjects having Cushing's syndrome and 51 subjects being control subjects after excluding Cushing's syndrome. For statistical analysis, SPSS 25 (IBM Corp., Armonk, NY, USA) was used. Clinical characteristics are shown as mean and standard deviation when data is normal distributed; otherwise as median and ranges. Because of the lack of normal distribution of bone turnover markers, nonparametric tests were used to test differences between groups. Differences between bone turnover markers at different times were tested by Friedman test. Multiple regression analysis was used to investigate differences between CS and the control group regarding bone turnover markers adjusted for sex, age, and BMI. Any p values < 0.05 were considered to indicate statistical significance. Results Patient characteristics The clinical and biochemical characteristics of the patient sample are summarized in Table 1. Sixty‐five percent of patients had pituitary CS, 28% adrenal, and 7% suffered from ectopic CS. Patients and controls were well‐matched regarding sex, age, and vitamin D levels and supplementation, but differed in terms of diabetes prevalence. Table 1. Clinical and Biochemical Baseline Characteristics of Patients with Cushing's Syndrome (CS) and Control Subjects in Whom CS Has Been Excluded CS at time of diagnosis (n = 89) CS excluded (n = 71) p Value Sex 66 women (74%), 23 men (26%) 53 women (75%), 18 men (25%) 0.94 Age (years) 44 ± 13 43 ± 14 0.56 BMI 30 ± 7 31 ± 6 0.11 Vitamin D (ng/mL) 24 ± 10 24 ± 12 0.59 Vitamin D supplementation 17% 11% 0.37 Diabetes mellitus 30% (26) 11% (7) 0.007 Morning serum cortisol (μg/dL) 18 (11.7–24.9) 8.4 (5.9–11.6) ≤0.001 LDDST (μg/dL) 14.7 (7.7–23.7) 1.0 (0.8–1.2) ≤0.001 UFC (μg/24 h) 587 (331–843) 140 (78–216) ≤0.001 ACTH (pg/mL) 47 (9–76) 13 (9–18) ≤0.001 Late‐night salivary cortisol (ng/mL) 7.9 (3.3–11.8) 1.2 (0.6–1.8) ≤0.001 Bone turnover markers Osteocalcin (ng/mL) 8 (5–13) 13 (10–17) <0.001 PINP (ng/mL) 35 (29–62) 52 (35–73) 0.025 BAP (μg/L) 23 (16–31) 17 (14–24) 0.006 CTX‐I (ng/mL) 0.28 (0.17–0.42) 0.23 (0.12–0.32) 0.033 TrAcP (U/L) 2.3 (1.7–3.4) 1.9 (1.3–2.4) 0.009 Date are shown as mean ± standard deviation or median and ranges. BMI = body mass index; LDDST = low‐dose dexamethasone suppression test; UFC = urinary free cortisol; ACTH = adrenocorticotropic hormone; PINP = intact procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance. Baseline evaluation At time of diagnosis, the mean levels of bone formation markers osteocalcin and intact PINP were significantly decreased compared with the controls, and the bone formation marker bone alkaline phosphatase was increased (Table 1; Fig. 2). Both bone degradation markers CTX and TrAcP were increased (Table 1). Taken together, this demonstrates increased bone resorption and decreased bone formation in florid CS. Results of multiple linear regression analysis comparing Cushing's syndrome patients and controls are shown in Table 2. Bone markers were similar in patients with a reduced bone mass versus those with a normal bone mass (data not shown). Figure 2 Open in figure viewerPowerPoint Bone turnover markers and bone mineral density at baseline and 1 and 2 years after remission. Boxplot = median and ranges of bone turnover marker in patients with Cushing's syndrome.Gray box = median and ranges of bone turnover markers in the control group.PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; TrAcP = tartrate‐resistant acid phosphatase; CTX‐I = CrossLaps. Table 2. Results of Multiple Linear Regression Analysis Comparing Cushing's Syndrome Patients Versus Controls Dependent variable Standardized regression coefficient and p value for group variable Unadjusted Adjusted for age, sex, and BMI Osteocalcin (ng/mL) −0.392, 0.006 −0.375, 0.010 PINP (ng/mL) −0.215, 0.204 −0.256, 0.145 BAP (μg/L) 0.404, 0.001 0.470, <0.001 CTX‐I (ng/mL) 0.111, 0.366 0.065, 0.616 TrAcP (U/L) 0.227, 0.014 0.186, 0.069 PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance. Overall, bone mineral density was decreased with an average lowest T‐score of −1.4 (±1.1). BMD was significantly lower (p = 0.001) at the femoral neck (T‐score = −0.9 ± 1.0) and the spine (T‐score = −1.0 ± 1.5) compared with the total femur (T‐score = −0.5 ± 1.2). Twenty‐eight patients (32%) had a normal bone mineral density, 46 (52%) osteopenia, and the other 15 patients (17%) osteoporosis with a T‐score lower than −2.5. Seventeen of the patients (19%) had a history of low‐trauma osteoporotic fractures (9 vertebral fractures, 8 nonvertebral fractures). The fractures took place shortly before diagnosis (58%) or more than 2 years before diagnosis of the CS (42%). Patients with osteoporotic fractures had a significantly lower T‐score than patients without fractures (T‐score = −1.9 ± 0.8 versus −1.3 ± 1.1, p = 0.03) but did not differ in the values of the bone turnover markers or standard biochemical screening. Subtype, age, or BMI also did not differ between groups. However, men were significantly at higher risk of having fractures than women (35% of men had fractures versus 14% of women, p = 0.03). Both severity of hypercortisolism and duration of CS did not contribute to fractures rates (data not shown), but UFC was significantly higher in patients with a T‐score lower than −1.5 (Table 3). Table 3. Biochemical Markers in Patients With Cushing's Syndrome With a T‐Score Lower Than −1.5 and Above −1.5 Shown in Median and Ranges Variable T‐score < −1.5 (n = 39) T‐score ≥ −1.5 (n = 42) p Values LDDST (μg/dL) 16.6. (10.3–28.3) 11.9 (6.1–21.9) 0.12 UFC (μg/24 h) 706 (410–906) 398 (285–787) 0.03 Late‐night salivary cortisol (ng/mL) 8.3 (3.5–13.6) 5.7 (2.9–11.7) 0.39 ACTH (pg/mL) 53 (16–73) 42 (6–82) 0.88 LDDST = low‐dose dexamethasone suppression test; UFC = urinary free cortisol; ACTH = adrenocorticotropic hormone. Bold numbers indicate statistical significance. One‐ and 2‐year follow‐up Surgical tumor resection leading to biochemical remission of CS resulted in a strong increase of bone formation markers tested at 1‐year follow‐up (Table 4; Fig. 2A, B). After 2 years, the markers had decreased slightly but remained elevated. Bone resorption markers were mildly increased at time of diagnosis, increased further at 1 year post‐surgery, and returned almost to normal levels at 2 years (Table 4; Fig. 2D, E). A follow‐up bone densitometry conducted in 40 patients showed a parallel increase of the T‐score of 0.6 ± 0.8 (Fig. 2F). In particular, BMD of the spine improved (Table 5). Table 4. Bone Turnover Markers and Bone Mass in Patients With Cushing's Syndrome at Time of Diagnosis and During 2 Years of Follow‐Up Time of diagnosis (n = 50) 1 year in remission (n = 45) 2 years in remission (n = 38) p (0 versus 1) p (0 versus 2) p (1 versus 2) T‐score −1.5 (−2.0 to −0.8) – −1.1 (−1.5 to −0.4) – <0.001 – Osteocalcin (ng/mL) 8 (5–13) 30 (14–60) 21 (13–31) <0.001 0.008 0.3 PINP (ng/mL) 35 (29–62) 117 (52–221) 69 (46–113) <0.001 0.1 0.1 BAP (μg/L) 23 (16–31) 26 (19–38) 22 (15–31) 0.2 0.4 0.1 CTX‐I (ng/mL) 0.28 (0.17–0.42) 0.51 (0.22–0.91) 0.25 (0.18–0.73) 0.01 0.1 0.04 TrAcP (U/L) 2.3 (1.7–3.4) 2.8 (1.8–4.0) 2.3 (2–3.2) 0.1 0.6 0.002 PINP = procollagen I‐N‐propeptide; BAP = bone alkaline phosphatase; CTX‐I = CrossLaps; TrAcP = tartrate‐resistant acid phosphatase. Bold numbers indicate statistical significance. Table 5. Overview: T‐Scores, Z‐Scores, and BMD Values With Percent Changes (Mean and Standard Deviation) Variable CS at time of diagnosis CS 2 years in remission p Values, percent changes (↑) Femoral neck T‐score femoral neck −0.81 ± 0.97 −0.59 ± 0.86 0.06 Z‐score femoral neck −0.59 ± 0.98 −0.28 ± 0.79 0.02 BMD (g/cm2) femoral neck 0.91 ± 0.12 0.95 ± 0.12 0.16; 4% ↑ Femur T‐score femur −0.49 ± 1.11 −0.42 ± 1.04 0.67 Z‐score femur −0.40 ± 1.04 −0.37 ± 0.85 0.31 BMD (g/cm2) femur 0.95 ± 0.15 0.97 ± 0.14 0.77, 2% ↑ Spine T‐score spine −0.96 ± 1.56 −0.55 ± 1.25 <0.001 Z‐score spine −0.85 ± 1.53 −0.58 ± 1.14 <0.001 BMD (g/cm2) spine 1.08 ± 0.22 1.13 ± 0.15 0.001, 0.6% ↑ BMD = bone mineral density; CS = Cushing's syndrome. Bold numbers indicate statistical significance. In 78% of patients, bone mineral density improved after 2 years; in 45% of patients, T‐score improved more than 0.5. No clinical fractures occurred after successful treatment of the CS. There was no significant correlation between improvement of bone mineral density and any of the bone turnover markers. Discussion This study investigated for the first time to our knowledge a panel of bone formation and resorption markers in a large cohort of patients with CS over the long term. The unique and comprehensive data show that initially bone metabolism is characterized by decreased bone formation and increased bone resorption, in line with the classical action of glucocorticoids. Successful treatment of endogenous Cushing's syndrome leads to a strong activation of bone turnover, characterized by increased bone formation and bone resorption, a process that is continuous beyond year 2 after remission of CS, although at a reduced activity level. In parallel, bone mineral density increases in the majority of patients. Although 19% had low‐trauma fractures at baseline, none of the subjects experienced clinical fractures during follow‐up. In summary, these data give new insight into bone healing after remission of CS. They strongly suggest that an observational approach to the bone phenotype is justified as long as remission from CS is secured. Reversibility of osteoporosis and bone turnover markers Although established in osteoporosis research, bone turnover markers are not measured on a routine basis in patients with CS. However, it is a consistent result from different studies that osteocalcin is depressed in patients with CS. In fact, this finding is so reliable that it was even suggested to use osteocalcin in the diagnosis of CS.2 P1NP and procollagen carboxy‐terminal propeptide (P1CP) have also been studied in several studies, with contradictory results.23 In a retrospective study with 21 patients with CS, it was shown that osteocalcin is depressed; this applies also for PINP, whereas CTX is increased.24 Some studies already have focused on the reversibility of osteoporosis after treatment of CS. In the majority of patients, bone mineral density increased within 2 years after successful treatment8-10, 25 Hermus and colleagues showed in a study with 20 patients that bone mineral density did not change 3 or 6 months after surgery but increased thereafter in almost all patients.8 In a study with 68 patients, the patients were followed up for 4 years. Bone mineral density increased over lumbar spine and femur but decreased at the forearm.25 The authors concluded that bone minerals were redistributed from the peripheral to the axial skeleton. In our study, bone mineral density also improved in the majority of patients but remained reduced in some. We did not find any difference in bone turnover markers between patients with improvement and without improvement. Current treatment guidelines and treatment suggestions As observed in our study, bone formation markers increase significantly after surgical cure, whereas bone degradation markers are mildly elevated at baseline and increase slightly at 1 year, returning within the normal range at 2 years. So far, there is no international guideline on the treatment of osteoporosis induced by endogenous CS and very few controlled interventional studies. In an opinion paper, Scillitani and colleagues recommended to treat all patients with vitamin D and calcium but not with bisphosphonates.5 In a randomized open‐label study by Di Somma and colleagues,26 39 patients (18 patients with active CS and 21 patients with CS in remission) received alendronate or no medication. Patients with active CS also received ketoconazole to control hypercortisolism. Bone mineral density improved and serum levels of osteocalcin increased in patients who received alendronate to a greater extent than those receiving no alendronate. In a small study by the same research group,27 15 patients with CS (9 adolescent patients and 6 adults) were observed for 2 years after successful treatment, showing that osteocalcin levels and bone mineral density increased significantly. Strengths and limitations Although this study has several strengths, including the large prospective design and measuring a panel of bone formation and resorption markers, there are a few limitations. Some asymptomatic fractures may have been overlooked because an X‐ray was not taken systematically in each patient. Furthermore, a follow‐up bone densitometry was not available for all patients. Additionally, patients in the control group suffered from diabetes, overweight, arterial hypertension, or other diseases. Novel aspects and outlook This study analyzes for the first time in a comprehensive way bone turnover markers during the course of CS. The data show that cure from CS leads to increases in bone remodeling and bone mineral density, in line with spontaneous “bone healing.” Our data support a wait‐and‐watch strategy despite a high endogenous risk for additional fractures, based on the baseline assessment. This observation will influence future therapeutic strategies in patients with CS. Our data suggest that the phase immediately after remission from CS is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients. Both bone attachment and bone degradation markers increase significantly, leading to an increase in bone mass and to a reduced risk of osteoporotic fractures. This unconstrained increase in bone formation markers after remission should be considered before specific therapy is initiated. Our data do not favor specific pharmacologic interventions with bisphosphonates or denosumab during this phase of remodeling because they may disrupt the osteoblast‐mediated bone mass increase. Disclosures All authors state that they have no conflicts of interest. Acknowledgments This work is part of the German Cushing's Registry CUSTODES and has been supported by a grant from the Else Kröner‐Fresenius Stiftung to MR (2012_A103 and 2015_A228). Additionally, AR, FB, and MR received funding by the Deutsche Forschungsgemeinschaft (CRC/TRR 205/1 “The Adrenal Gland”). Furthermore, funds for this project were provided by the Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der Ludwig‐Maximilians‐Universität München eV to LB. The data are stored on the following repository: https://figshare.com/ and will be made accessible after publication of the article. Authors’ roles: LB served as the principal investigator in this work and was responsible for the study conception and design, the analysis and interpretation of the data, and the drafting of the manuscript. JF, SZ, AO, AR, GR and SB contributed to the collection and analysis of the data. MS, FB, MD, MB substantially contributed to the interpretation of the data and the drafting of the manuscript. RS contributed to the conceptual design of the study, the interpretation of data and the revision of the paper. MR contributed to the conceptual design of the study, the collection, analysis and interpretation of data, and the drafting and revision of the paper. All authors contributed to the critical revision of the manuscript and approved the final version for publication. From https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.4033
  25. A retrospective cohort study was performed to compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Researchers examined 6,821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 6,7564 individually-matched controls (primary, 20366; secondary, 39134). It was shown that in adrenal insufficiency, mortality was elevated, particularly primary, even with individual matching, and was found early in the disease course. The data demonstrated that cardiovascular disease was the major cause but mortality from infection was also high. The adrenal crisis was a common contributor. The outcomes suggested that early education for prompt treatment of infections and avoidance of adrenal crisis hold the potential to decrease mortality. The Journal of Clinical Endocrinology & Metabolism, dgab096, https://doi.org/10.1210/clinem/dgab096 Abstract Context Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations. Objective To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Design Retrospective cohort study. Setting UK general practitioner database (CPRD). Participants 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134). Main outcome measures All-cause and cause-specific mortality; hospital admission from adrenal crisis. Results With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 - 1.77]. HRs were greater in primary (1.83 [1.66 - 2.02]) than in secondary (1.52 [1.40 - 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 - 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 - 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years. Conclusion Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality. PDF available at https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab096/6141434?redirectedFrom=fulltext
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