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  1. Osilodrostat is associated with improvements in physical manifestations of hypercortisolism and reductions in mean body weight and BMI in adults with Cushing’s syndrome, according to a speaker. As Healio previously reported, in findings from the LINC 4 phase 3 trial, osilodrostat (Isturisa, Recordati) normalized mean urinary free cortisol level at 12 weeks in more than 75% of adults with Cushing’s disease. In new findings presented at the AACE Annual Scientific and Clinical Conference, most adults with Cushing’s syndrome participating in the LINC 3 phase 3 trial had improvements in physical manifestations of hypercortisolism 72 weeks after initiating osilodrostat, with more than 50% having no dorsal fat pad, supraclavicular fat pad, facial rubor, proximal muscle atrophy, striae, ecchymoses and hirsutism for women at 72 weeks. Source: Adobe Stock “Many patients with Cushing’s syndrome suffer from clinical manifestations related to hypercortisolism,” Albert M. Pedroncelli, MD, PhD, head of clinical development and medical affairs for Recordati AG in Basel, Switzerland, told Healio. “The treatment with osilodrostat induced a rapid normalization of cortisol secretion, and improvements in physical manifestations associated with hypercortisolism were observed soon after initiation of osilodrostat and were sustained throughout the study.” Albert M. Pedroncelli Pedroncelli and colleagues analyzed changes in the physical manifestations of hypercortisolism in 137 adults with Cushing’s syndrome (median age, 40 years; 77.4% women) assigned osilodrostat. Dose titration took place from baseline to 12 weeks, and therapeutic doses were administered from 12 to 48 weeks, with some participants randomly assigned to withdrawal between 26 and 34 weeks. An extension phase of the trial took place from 48 to 72 weeks. Investigators subjectively rated physical manifestations of hypercortisolism in participants as none, mild, moderate or severe. Participants were evaluated at baseline and 12, 24, 34, 48 and 72 weeks. At baseline, the majority of the study cohort had mild, moderate or severe physical manifestations of hypercortisolism in most individual categories, including dorsal fat pad, central obesity, supraclavicular fat pad, facial rubor, hirsutism in women and striae. Central obesity was the most frequent physical manifestation rated as severe. The percentage of participants with improvements in physical manifestations of hypercortisolism increased from week 12 on for all individual manifestations evaluated in the study, and improvements were maintained through week 72. At 72 weeks, the percentage of participants who had no individual physical manifestations was higher than 50% for each category except central obesity, where 30.6% of participants had no physical manifestations. In addition to improvement in physical manifestations, the study cohort had decreases in body weight, BMI and waist circumference at weeks 48 and 72 compared with baseline. “The main goal of treating patients with Cushing’s syndrome is to normalize cortisol secretion,” Pedroncelli said. “The rapid reduction and normalization of cortisol levels is accompanied by improvement in the associated clinical manifestations. This represents an important objective for patients.” From https://www.healio.com/news/endocrinology/20220512/osilodrostat-improves-physical-manifestations-of-hypercortisolism-for-most-adults
  2. https://doi.org/10.1016/j.aace.2022.04.003Get rights and content Under a Creative Commons license Open access Highlights • We describe a rare case of a patient with a sparsely granulated corticotroph pituitary macroadenoma with pituitary apoplexy who underwent transsphenoidal resection resulting in remission of hypercortisolism. • Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors. • macroadenomas account for 7-23% of patients with pituitary corticotroph adenomas • Sparsely granulated corticotroph tumors are associated with longer duration of Cushing disease prior to diagnosis, larger tumor size at diagnosis, decreased immediate remission rate, increased proliferative marker Ki-67 and increased recovery time of hypothalamic-pituitary-adrenal axis after surgery. • Granulation pattern is an important clinicopathological distinction impacting the behavior and treatment outcomes of pituitary corticotroph adenomas Abstract Background /Objective: Pituitary corticotroph macroadenomas, which account for 7% to 23% of corticotroph adenomas, rarely present with apoplexy. The objective of this report is to describe a patient with a sparsely granulated corticotroph tumor (SGCT) presenting with apoplexy and remission of hypercortisolism. Case Report A 33-year-old male presented via ambulance with sudden onset of severe headache and nausea/vomiting. Physical exam revealed bitemporal hemianopsia, diplopia from right-sided third cranial nerve palsy, abdominal striae, facial plethora, dorsal and supraclavicular fat pad. Magnetic resonance imaging (MRI) demonstrated a 3.2 cm mass arising from the sella turcica with hemorrhage compressing the optic chiasm, extension into the sphenoid sinus and cavernous sinus. Initial investigations revealed plasma cortisol of 64.08 mcg/dL (Reference Range (RR), 2.36 – 17.05). He underwent emergent transsphenoidal surgery. Pathology was diagnostic of SGCT. Post-operatively, cortisol was <1.8ug/dL (RR, 2.4 – 17), adrenocorticotropic hormone (ACTH) 36 pg/mL (RR, 0 – 81), thyroid stimulating hormone (TSH) 0.07 uIU/mL (RR, 0.36 - 3.74), free thyroxine 1 ng/dL (RR, 0.8 – 1.5), luteinizing hormone (LH) <1 mIU/mL (RR, 1 – 12), follicle stimulating hormone (FSH) 1 mIU/mL (RR, 1 – 12) and testosterone 28.8 ng/dL (RR, 219.2 – 905.6) with ongoing requirement for hydrocortisone, levothyroxine, testosterone replacement and continued follow-up. Discussion Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors. Sparsely granulated pattern is associated with larger tumor size and decreased remission rate after surgery. Conclusion This report illustrates a rare case of hypercortisolism remission due to apoplexy of a SGCT with subsequent central adrenal insufficiency, hypothyroidism and hypogonadism. Keywords pituitary apoplexy pituitary macroadenoma pituitary tumor sparsely granulated corticotroph tumor Cushing disease Introduction The incidence of Cushing Disease (CD) is estimated to be between 0.12 to 0.24 cases per 100,00 persons per year1,2. Of these, 7-23% are macroadenomas (>1 cm)3, 4, 5. Pituitary apoplexy is a potentially life-threatening endocrine and neurosurgical emergency which occurs due to infarction or hemorrhage in the pituitary gland. Apoplexy occurs most commonly in non-functioning macroadenomas with an estimated prevalence of 6.2 cases per 100,000 persons and incidence of 0.17 cases per 100,00 persons per year6. Corticotroph macroadenoma presenting with apoplexy is uncommon with only a handful of reports in the literature7. We present a case of a sparsely granulated corticotroph (SGCT) which presented with apoplexy leading to remission of hypercortisolism and subsequent central adrenal insufficiency. Case Presentation A 33-year-old male who was otherwise healthy and not on any medications presented to a community hospital with sudden and severe headache accompanied by hypotension, nausea, vomiting, bitemporal hemianopsia and diplopia. Computed Tomography (CT) scan of the brain demonstrated a hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica with extension into the right cavernous sinus and encasement of the right internal carotid arteries (Figure 1A). He was transferred to a tertiary care center for neurosurgical management with endocrinology consultation post-operatively. Download : Download high-res image (404KB) Download : Download full-size image Figure 1. hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica on unenhanced CT (A); MRI demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogeneous mass on T1 (B) and T2-weighted imaging (C) showing small hyperintense areas in solid part of the sella mass with flattening of the optic chiasm, remodeling/dehiscence of the floor of the sella and extending into the right cavernous sinus with at least partial encasement of the ICA In retrospect, he reported a 3-year history of ongoing symptoms of hypercortisolism including increased central obesity, dorsal and supraclavicular fat pad, facial plethora, abdominal purple striae, easy bruising, fatigue, decreased libido and erectile dysfunction. Notably, at the time of presentation he did not have a history of diabetes, hypertension, osteoporosis, fragility fractures or proximal muscle weakness. He fathered 2 children previously. His physical examination was significant for Cushingoid facies, facial plethora, dorsal and supraclavicular fat pads and central obesity with significant axillary and abdominal wide purple striae (Figure 2). Neurological examination revealed bitemporal hemianopsia, right third cranial nerve palsy with ptosis and impaired extraocular movement. The fourth and sixth cranial nerves were intact as was the rest of his neurological exam. These findings were corroborated by Ophthalmology. Download : Download high-res image (477KB) Download : Download full-size image Figure 2. Representative images illustrating facial plethora (A); abdominal striae (B, C); supraclavicular fat pad (D); dorsal fat pad (E) Initial laboratory data at time of presentation to the hospital included elevated plasma cortisol of 64.08ug/dL (RR, 2.36 – 17.05), ACTH was not drawn at the time of presentation, normal TSH 0.89 mIU/L (RR, 0.36 – 3.74), free thyroxine 0.91ng/dL (RR, 0.76 – 1.46), evidence of central hypogonadism with low total testosterone 28.8 ng/dL (RR, 219.2 – 905.6) and inappropriately normal luteinizing hormone (LH) 1mIU/mL (RR, 1 – 12) and follicle stimulating hormone (FSH) 3mIU/mL (RR, 1 – 12), low prolactin <1 ng/mL (RR, 3 – 20), and normal insulin growth factor – 1 (IGF–1) 179ng/mL (RR, 82 – 242). A pituitary gland dedicated MRI was performed to further characterize the mass, which re-demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogenous mass at the sella turcica extending superiorly and flattening the optic chiasm, remodeling of the floor of the sella and bulging into the sphenoid sinus and extending laterally into the cavernous sinus with encasement of the right internal carotid artery (ICA). As per the radiologist’s diagnostic impression, this appearance was most in keeping with a pituitary macroadenoma with apoplexy (Figure 1B – C). The patient underwent urgent TSS and decompression with no acute complications. Pathological examination of the pituitary adenoma showed features characteristic of sparsely granulated corticotroph pituitary neuroendocrine tumor (adenoma)8, with regional hemorrhage and tumor necrosis (apoplexy). The viable tumor exhibited a solid growth pattern (Figure 3A), t-box transcription factor (T-pit) nuclear immunolabeling (Figure 3B), diffuse cytoplasmic CAM5.2 (low molecular weight cytokeratin) immunolabeling (Figure 3C), and regional weak to moderate intense granular cytoplasmic ACTH immuno-staining (Figure 3D). The tumor was immuno-negative for: pituitary-specific positive transcription factor 1 (Pit-1) and steroidogenic factor 1 (SF-1) transcription factors, growth hormone, prolactin, TSH, FSH, LH, estrogen receptor-alpha, and alpha-subunit. Crooke hyalinization was not identified in an adjacent compressed fragment of non-adenomatous anterior pituitary tissue. Ki-67 immunolabeling showed a 1.5% proliferative index (11 of 726 nuclei). Download : Download high-res image (2MB) Download : Download full-size image Figure 3. Hematoxylin phloxine saffron staining showing adenoma with solid growth pattern (A); immunohistochemical staining showing T-pit reactivity of tumor nuclei (B); diffuse cytoplasmic staining for cytokeratin CAM5.2 (C); and regional moderately intense granular cytoplasmic staining for ACTH (D). Scale bar = 20 μm Post-operatively, he developed transient central diabetes insipidus requiring desmopressin but resolved on discharge. His postoperative cortisol was undetectable, ACTH 36 pg/mL (RR, 0 - 81), TSH 0.07 mIU/mL (RR, 0.36 - 3.74), free thyroxine 1 ng/dL (RR, 0.8 - 1.5), LH <1mIU/mL (RR, 1 - 12), FSH 1 mIU/mL (RR, 1 - 12) and testosterone 28.8 ng/dL (RR, 219.2 - 905.6) (Table 1 and Figure 4). One month later, he reported 15 pounds of weight loss and a 5-inch decrease in waist circumference. He also noted a reduction in the dorsal and supraclavicular fat pads, facial plethora, and Cushingoid facies as well as fading of the abdominal stretch marks. His visual field defects and right third cranial nerve palsy resolved on follow up with ophthalmology post-operatively. Repeat MRI six months post-operatively showed minor residual soft tissue along the floor of the sella. He is being followed by Neurosurgery, Ophthalmology, and Endocrinology for monitoring of disease recurrence, visual defects, and management of hypopituitarism. Table 1. Pre- and post-operative hormonal panel POD -1 POD 0 POD1 POD2 POD3 POD16 6 -9 months Comments Cortisol(2.4 – 17 ug/dL) 64↓ 32↓ 11↓ <1.8↓ <1.8↓ 1.8↓ HC started POD3 post bloodwork ACTH(0 – 81 pg/mL) 41↓ 36↓ 28↓ 13↓ TSH(0.36 - 3.74 uIU/mL) 0.89 0.43 0.12↓ 0.07↓ 0.05↓ 0.73 Thyroxine, free(0.8 – 1.5 ng/dL) 0.9 0.9 1.1 1 2.1↑ 1 Levothyroxine started POD4 LH(1 – 12 miU/mL) 1↓ <1↓ 1↓ 3 FSH(1 – 12 mIU/mL) 3↓ 1↓ 1↓ 3 Testosterone(219.2 – 905.6 ng/dL) 28.8↓ <20↓ 175.9↓ Testosterone replacement started as outpatient Testosterone, free(160 - 699 pmol/L) <5.8↓ 137↓ IGF-1(82 – 242 ng/mL) 179 79 GH(fasting < 6 mIU/L) 4.5 <0.3 Prolactin(3 – 20 ng/mL) <1↓ <1↓ POD, postoperative day; HC, hydrocortisone; ACTH, adrenocorticotropic hormone; TSH, thyroid stimulating hormone; LH, luteinizing Hormone; FSH, follicle stimulating hormone; IGF-1, insulin like growth factor - 1; GH, growth hormone Download : Download high-res image (259KB) Download : Download full-size image Figure 4. Trend of select pituitary hormonal panel with key clinical events denoted by black arrows. Discussion Microadenomas account for the majority of corticotroph tumors, but 7% – 23% of patients are diagnosed with a macroadenoma3, 4, 5. It is even rarer for a corticotroph macroadenoma to present with apoplexy with only a handful of case reports or series in the literature7. Due to its rarity, appropriate biochemical workup on presentation, such as including an ACTH with the blood work, may be omitted especially if the patient is going for emergent surgery. In this case, the undetectable prolactin can reflect loss of anterior pituitary function and also suggest a functioning corticotroph adenoma due to the inhibitory effect of long term serum glucocorticoids on prolactin secretion9. After undergoing TSS, the patient developed central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement. Presumably, the development of adrenal insufficiency demonstrated the remission of hypercortisolism as a result of apoplexy and/or TSS. The ACTH remains detectable likely representing residual tumor that was not obliterated by apoplexy nor excised by TSS given it location near the carotid artery and cavernous sinus. The presence of adrenal insufficiency in the setting of detectable ACTH is not contradictory as the physiological hypothalamic-pituitary-adrenal axis has been suppressed by the long-term pathological production of ACTH. IGF-1 and prolactin also failed to recover post-operatively. In CD where the production of IGF-1 and prolactin are attenuated by elevated cortisol, it would then be expected that IGF-1 and prolactin recover after hypercortisolism remission. However, the absence of this observation in our case is likely a sequalae of the apoplexy and extensive surgery leading to pituitary hypofunction. We also want to highlight features of the pre-operative radiographical findings which can provide valuable insight into the subsequent histology. Previous literature has shown that, on T2-weight MRI, silent corticotroph adenomas are strongly correlated with characteristic a multimicrocystic appearance while nonfunctional gonadotroph macroadenomas are not correlated with this MRI finding10. The multimicrocystic appearance is described as small hyperintense areas with hyperintense striae in the solid part of the tumor (Figure 1C)10. This is an useful predictive tool for silent corticotroph adenomas with a sensitivity of 76%, specificity of 95% and a likelihood ratio of 15.310. The ability to distinguish between silent corticotroph macroadenoma and other macroadenomas is important for assessing rate of remission and recurrence risk. In 2017, the WHO published updated classification for pituitary tumors. In this new classification, corticotroph adenomas are further divided into densely granulated, sparsely granulated and Crooke’s cell tumors11. DGCT are intensely Periodic Acid Schiff (PAS) stain positive and exhibit strong diffuse pattern of ACTH immunoreactivity, whereas SGCT exhibit faintly positive PAS alongside weak focal ACTH immunoreactivity4,12. Crooke’s cell tumors are characterized by Crooke’s hyaline changes in more than 50% of the tumor cells4. In the literature, SGCT account for an estimated 19-29% of corticotroph adenomas13, 14, 15. The clinicopathological relevance of granulation pattern in corticotroph tumors was unclear until recently. In multiple studies examining granulation pattern and tumor size, SGCT were statistically larger13,15,16. Hence, we suspect that many of the previously labelled silent corticotroph macroadenomas in the literature were SGCT. The traditional teaching of CD has been “small tumor, big Cushing and big tumor, small Cushing” which reflects the inverse relationship between tumor size and symptomatology17. This observation appears to hold true as Doğanşen et al. found a trend towards longer duration of CD in SGCT of 34 months compared to 26 months in DGCT based on patient history13,17. It has been postulated that the underlying mechanism of the inverse relationship between tumor size and symptomatology is impaired processing of proopiomelanocortin resulting in less effective secretion of ACTH in corticotroph macroadenomas3. Doğanşen et al. also found that the recurrence rate was doubled for SGCT, while Witek et al. showed that SGCT were less likely to achieve remission postoperatively13,16. Similar to other cases of SGCT, the diagnosis was only arrived retrospective after pathological confirmation10. Interestingly, the characteristic Crooke’s hyaline change of surrounding non-adenomatous pituitary tissue was not observed as one would expect in a state of prolonged glucocorticoid excess in this case. Although classically described, the absence of this finding does not rule out CD. As evident in a recent retrospective study where 10 out of 144 patients with CD did not have Crooke’s hyaline change18. In patients without Crooke’s hyaline change, the authors found a lower remission rate of 44.4% compared to 73.5% in patients with Crooke’s hyaline change. Together with the detectable post-operative ACTH, sparsely granulated pattern and absence of Crooke’s hyaline change in surrounding pituitary tissue, the risk of recurrence is increased. These risk factors emphasize the importance of close monitoring to ensure early detection of recurrence. Declaration of Interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Conclusion We present a case of a sparsely granulated corticotroph macroadenoma presenting with apoplexy leading to remission of hypercortisolism and development of central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement. References 1 J. Lindholm, S. Juul, J.O. Jørgensen, et al. Incidence and late prognosis of cushing's syndrome: a population-based study J Clin Endocrinol Metab, 86 (1) (2001), pp. 117-123 View Record in ScopusGoogle Scholar 2 J. Etxabe, J.A. Vazquez Morbidity and mortality in Cushing's disease: an epidemiological approach Clin Endocrinol (Oxf), 40 (4) (1994), pp. 479-484 View PDF CrossRefView Record in ScopusGoogle Scholar 3 L. Katznelson, J.S. Bogan, J.R. Trob, et al. Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas J Clin Endocrinol Metab, 83 (5) (1998), pp. 1619-1623 View Record in ScopusGoogle Scholar 4 L.V. Syro, F. Rotondo, M.D. Cusimano, et al. Current status on histological classification in Cushing's disease Pituitary, 18 (2) (2015), pp. 217-224 View PDF CrossRefView Record in ScopusGoogle Scholar 5 Y.S. Woo, A.M. Isidori, W.Z. Wat, et al. Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas J Clin Endocrinol Metab, 90 (8) (2005), pp. 4963-4969 View PDF CrossRefView Record in ScopusGoogle Scholar 6 C. Briet, S. Salenave, J.F. Bonneville, E.R. Laws, P. Chanson Pituitary Apoplexy Endocr Rev, 36 (6) (2015), pp. 622-645 View PDF CrossRefView Record in ScopusGoogle Scholar 7 K. Siwakoti, S.B. Omay, S.E. Inzucchi SPONTANEOUS RESOLUTION OF PRIMARY HYPERCORTISOLISM OF CUSHING DISEASE AFTER PITUITARY HEMORRHAGE AACE Clin Case Rep, 6 (1) (2020), pp. e23-e29 ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar 8 S.L. Asa, O. Mete What's new in pituitary pathology? Histopathology, 72 (1) (2018), pp. 133-141 View PDF CrossRefView Record in ScopusGoogle Scholar 9 M.E. Freeman, B. Kanyicska, A. Lerant, G. Nagy Prolactin: Structure, Function, and Regulation of Secretion Physiological Reviews, 80 (4) (2000), pp. 1523-1631 View PDF CrossRefView Record in ScopusGoogle Scholar 10 L. Cazabat, M. Dupuy, A. Boulin, et al. Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas Clin Endocrinol (Oxf), 81 (4) (2014), pp. 566-572 View PDF CrossRefView Record in ScopusGoogle Scholar 11 M.B.S. Lopes The 2017 World Health Organization classification of tumors of the pituitary gland: a summary Acta Neuropathol, 134 (4) (2017), pp. 521-535 View PDF CrossRefView Record in ScopusGoogle Scholar 12 W. Saeger, J. Honegger, M. Theodoropoulou, et al. Clinical Impact of the Current WHO Classification of Pituitary Adenomas Endocr Pathol, 27 (2) (2016), pp. 104-114 View PDF CrossRefView Record in ScopusGoogle Scholar 13 S. Doğanşen, B. Bilgiç, G.Y. Yalin, S. Tanrikulu, S. Yarman Clinical Significance of Granulation Pattern in Corticotroph Pituitary Adenomas Turk Patoloji Derg, 35 (1) (2019), pp. 9-14 Google Scholar 14 O. Mete, A. Cintosun, I. Pressman, S.L. Asa Epidemiology and biomarker profile of pituitary adenohypophysial tumors Mod Pathol, 31 (6) (2018), pp. 900-909 View PDF CrossRefView Record in ScopusGoogle Scholar 15 B. Rak, M. Maksymowicz, M. Pękul, G. Zieliński Clinical, Biological, Radiological Pathological and Immediate Post-Operative Remission of Sparsely and Densely Granulated Corticotroph Pituitary Tumors: A Retrospective Study of a Cohort of 277 Patients With Cushing's Disease Front Endocrinol (Lausanne), 12 (2021) 672178 Google Scholar 16 P. Witek, G. Zieliński, K. Szamotulska, M. Maksymowicz, G. Kamiński Clinicopathological predictive factors in the early remission of corticotroph pituitary macroadenomas in a tertiary referral centre Eur J Endocrinol, 174 (4) (2016), pp. 539-549 View PDF CrossRefView Record in ScopusGoogle Scholar 17 A.M. McNicol Tumors of the pituitary gland. S. L. Asa. AFIP atlas of tumor pathology, third series The Journal of Pathology, 188 (1) (1999), pp. 115-116 View Record in ScopusGoogle Scholar 18 A. Akirov, V. Larouche, I. Shimon, et al. Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease Front Endocrinol (Lausanne), 12 (2021) 620005 Google Scholar From https://www.sciencedirect.com/science/article/pii/S2376060522000268#!
  3. The LINC 4 study demonstrated superiority of Isturisa® (osilodrostat) over placebo in achieving cortisol normalisation during the 12-week, double-blind, randomised phase (77% vs 8%, P<0.0001). Isturisa provided rapid and sustained control of cortisol secretion in the majority of patients throughout the 48-week core phase of the study. PUTEAUX, France, March 29, 2022--(BUSINESS WIRE)--Recordati Rare Diseases announce today the publication of positive results from the Phase III LINC 4 study of Isturisa in The Journal of Clinical Endocrinology & Metabolism.1 These data reinforce Isturisa as an effective and well-tolerated oral therapy for patients with Cushing’s disease. Isturisa is indicated in the EU for the treatment of adult patients with endogenous Cushing’s syndrome,2 a rare and debilitating condition of hypercortisolism that is most commonly caused by a pituitary adenoma (Cushing’s disease).3 The LINC 4 study augments the efficacy and safety data for Isturisa in patients with Cushing’s disease, confirming the results from the Phase III LINC 3 study. This study in 73 adults is the first Phase III study of a medical treatment in patients with Cushing’s disease to include an upfront, randomised, double-blind, placebo-controlled period during which 48 patients received Isturisa and 25 received placebo for the first 12 weeks, followed by an open-label period during which all patients received Isturisa until week 48; thereafter, patients could enter an optional extension phase. Key findings published in the manuscript entitled ‘Randomised trial of osilodrostat for the treatment of Cushing’s disease’ include:1 LINC 4 met the primary endpoint: Isturisa was significantly superior to placebo at normalising mUFC at the end of a 12-week randomised, double-blind period (77% vs 8%; P<0.0001). Effects of Isturisa were rapid. Over one-quarter of patients randomised to Isturisa achieved normal mUFC as early week 2 and 58% achieved control by week 5. The key secondary endpoint was also met, with 81% of all patients in the study having normal mUFC at week 36. Improvements in cardiovascular and metabolic parameters of Cushing’s disease, including blood pressure and blood glucose metabolism, were seen by week 12 and were maintained throughout the study. Physical features of hypercortisolism improved during Isturisa treatment, including fat pads, facial rubor, striae, and muscle wasting. Improvements were observed by week 12, with continued improvement throughout the study to week 48. Patient-reported QoL scores (CushingQoL and Beck Depression Inventory) also improved during Isturisa treatment. Isturisa was well tolerated in the majority of patients, with no unexpected adverse events (AEs). The most common AEs overall were decreased appetite, arthralgia, fatigue and nausea. "These results show convincingly that osilodrostat is an effective treatment for Cushing’s disease," said Peter J. Snyder MD, Professor of Medicine at the University of Pennsylvania. "Osilodrostat rapidly lowered cortisol excretion to normal in most patients with Cushing’s disease and maintained normal levels throughout the core phase of the study. Importantly, this normalisation was accompanied by improvements in cardiovascular and metabolic parameters, which increase morbidity and mortality in Cushing’s disease." "These compelling data build on the positive Phase III LINC 3 study, published in The Lancet Diabetes & Endocrinology in 2020,4 demonstrating that Isturisa enables most patients with Cushing’s disease to gain rapid control of their cortisol levels, which in turn provides relief from a host of undesirable symptoms," said Alberto Pedroncelli, Clinical Development & Medical Affairs Lead, Global Endocrinology, Recordati AG. "Recordati Rare Diseases is committed to improving the lives of patients with this rare, debilitating and life-threatening condition. I would like to thank everyone who has contributed to LINC 4 and the LINC clinical programme." "I had Cushing's disease for 8 years without being diagnosed," said Thérèse Fournier from L'association "Surrénales". "I was trapped in a vicious circle of missed diagnoses and worsening physical and psychological symptoms that became life-threatening. I lost everything – my job, my house, my partner, my friends – I was isolated. When I finally received my diagnosis, I was relieved because I knew the truth. Since my surgery, I have been learning to live again, enjoying the moments that make a life. I am still on the path to remission, but I feel deeply happy, even if I carry this journey that nobody can understand." About Cushing’s syndrome Cushing’s syndrome is a rare disorder caused by chronic exposure to excess levels of cortisol from either an exogenous (eg medication) or an endogenous source.5 Cushing’s disease is the most common cause of endogenous Cushing’s syndrome and arises as a result of excess secretion of adrenocorticotropic hormone from a pituitary adenoma, a tumour of the pituitary gland.5,6 There is often a delay in diagnosing Cushing’s syndrome, which consequently leads to a delay in treating patients.7 Patients who are exposed to excess levels of cortisol for a prolonged period have increased comorbidities associated with the cardiovascular and metabolic systems, which consequently reduce QoL and increase the risk of mortality.3,6 To alleviate the clinical signs associated with excess cortisol exposure, the primary treatment goal in Cushing’s syndrome is to reduce cortisol levels to normal.8 About LINC 4 LINC 4 is a multicentre, randomised, double-blind, 48-week study with an initial 12-week placebo-controlled period to evaluate the safety and efficacy of Isturisa® in patients with Cushing’s disease. The LINC 4 study enrolled patients with persistent or recurrent Cushing’s disease or those with de novo disease who were ineligible for surgery; 73 randomised patients were treated with Isturisa® (n=48) or placebo (n=25).1 The primary endpoint of the study is the proportion of randomised patients with a complete response (mUFC ≤ULN) at the end of the placebo-controlled period (week 12). The key secondary endpoint is the proportion of patients with an mUFC ≤ULN at week 36.1,9 About Isturisa® Isturisa® is an oral inhibitor of 11β-hydroxylase (CYP11B1), which catalyses the final step of cortisol synthesis in the adrenal glands.2 Isturisa® is available as 1 mg, 5 mg and 10 mg film-coated tablets.2 Isturisa® is approved for the treatment of adult patients with endogenous Cushing’s syndrome in the EU and is now available in France, Germany, Greece and Austria.2 Isturisa® was granted marketing authorisation by the European Commission on 9 January 2020. For detailed recommendations on the appropriate use of this product, please consult the summary of product characteristics.2 References 1. Gadelha M, Bex M, Feelders RA et al. Randomised trial of osilodrostat for the treatment of Cushing's disease. J Clin Endocrinol Metab 2022; dgac178, https://doi.org/10.1210/clinem/dgac178. 2. Isturisa® summary of product characteristics. May 2020. 3. Ferriere A, Tabarin A. Cushing's syndrome: Treatment and new therapeutic approaches. Best Pract Res Clin Endocrinol Metab 2020;34:101381. 4. Pivonello R, Fleseriu M, Newell-Price J et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020;8:748-61. 5. Lacroix A, Feelders RA, Stratakis CA et al. Cushing's syndrome. Lancet 2015;386:913-27. 6. Pivonello R, Isidori AM, De Martino MC et al. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol 2016;4:611-29. 7. Rubinstein G, Osswald A, Hoster E et al. Time to diagnosis in Cushing's syndrome: A meta-analysis based on 5367 patients. J Clin Endocrinol Metab 2020;105:dgz136. 8. Nieman LK, Biller BM, Findling JW et al. Treatment of Cushing's syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015;100:2807-31. 9. ClinicalTrials.gov. NCT02697734; available at https://clinicaltrials.gov/ct2/show/NCT02697734 (accessed March 2021). Recordati Rare Diseases, the company’s EMEA headquarters are located in Puteaux, France, with global headquarter offices in Milan, Italy. For a full list of products, please click here: www.recordatirarediseases.com/products. Recordati, established in 1926, is an international pharmaceutical group, listed on the Italian Stock Exchange (Reuters RECI.MI, Bloomberg REC IM, ISIN IT 0003828271), with a total staff of more than 4,300, dedicated to the research, development, manufacturing and marketing of pharmaceuticals. Headquartered in Milan, Italy, Recordati has operations in Europe, Russia and the other C.I.S. countries, Ukraine, Turkey, North Africa, the United States of America, Canada, Mexico, some South American countries, Japan and Australia. An efficient field force of medical representatives promotes a wide range of innovative pharmaceuticals, both proprietary and under license, in several therapeutic areas including a specialized business dedicated to treatments for rare diseases. Recordati is a partner of choice for new product licenses for its territories. Recordati is committed to the research and development of new specialties with a focus on treatments for rare diseases. Consolidated revenue for 2021 was € 1,580.1 million, operating income was € 490.2 million and net income was € 386.0 million. For further information: Recordati website: www.recordatirarediseases.com This document contains forward-looking statements relating to future events and future operating, economic and financial results of the Recordati group. By their nature, forward-looking statements involve risk and uncertainty because they depend on the occurrence of future events and circumstances. Actual results may therefore differ materially from those forecast as a result of a variety of reasons, most of which are beyond the Recordati group’s control. The information on the pharmaceutical specialties and other products of the Recordati group contained in this document is intended solely as information on the Recordati group’s activities and therefore, as such, it is not intended as medical scientific indication or recommendation, nor as advertising. View source version on businesswire.com: https://www.businesswire.com/news/home/20220325005169/en/ Contacts Celine Plisson, MD Medical Affairs Director Telephone: +33(0)147739463 Email: PLISSON.C@recordati.com Related Quotes Symbol Last Price Change % Change REC Emles Real Estate Credit ETF 22.89 +0.13 +0.57% TRENDING 1. Oil Climbs After Two-Day Drop as Investors Assess Ukraine Talks 2. Stocks Fall, Oil Rises as Russia Concerns Return: Markets Wrap 3. Truckmaker MAN to shorten hours of up to 11,000 workers on Ukraine crisis 4. UPDATE 1-Sri Lanka suffers long power cuts as currency shortage makes fuel scarce 5. German inflation rises more than expected in March From https://finance.yahoo.com/news/recordati-rare-diseases-announce-publication-070000542.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAABds3nKexRHBGxK9BEM1W93vciZ-QM8hw9-QOcCELZxkbW8U7OfcYw-GBd_tvRaS9mnjvRvdhI1sQaBD2jkR6yvqhUZsHw6f7CfO78LaGvdTRWhjaIy7b5IcPvPpOCGzR0Ex1_8t1TFNqxMkSr7OmIxfDflflXrh4cHI8Ze3okeU
  4. From https://medicaldialogues.in/diabetes-endocrinology/news/new-test-may-help-in-early-diagnosis-of-cushings-syndrome-frontiers-86467
  5. An assessment of free cortisol after a dexamethasone suppression test could add value to the diagnostic workup of hypercortisolism, which can be plagued by false-positive results, according to data from a cross-sectional study. A 1 mg dexamethasone suppression test (DST) is a standard of care endocrine test for evaluation of adrenal masses and for patients suspected to have endogenous Cushing’s syndrome. Interpretation of a DST is affected by dexamethasone absorption and metabolism; several studies suggest a rate of 6% to 20% of false-positive results because of inadequate dexamethasone concentrations or differences in the proportion of cortisol bound to corticosteroid-binding globulin affecting total cortisol concentrations. Source: Adobe Stock “As the prevalence of adrenal adenomas is around 5% to 7% in adults undergoing an abdominal CT scan, it is important to accurately interpret the DST,” Irina Bancos, MD, associate professor in the division of endocrinology at Mayo Clinic in Rochester, Minnesota, told Healio. “False-positive DST results are common, around 15% of cases, and as such, additional or second-line testing is often considered by physicians, including measuring dexamethasone concentrations at the time of the DST, repeating DST or performing DST with a higher dose of dexamethasone. We hypothesized that free cortisol measurements during the DST will be more accurate than total cortisol measurements, especially among those treated with oral contraceptive therapy.” Diverse cohort analyzed Bancos and colleagues analyzed data from adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy) and participants undergoing evaluation for hypercortisolism (n = 196; 16 women on oral contraceptives). The researchers assessed levels of post-DST dexamethasone and free cortisol, using mass spectrometry, and total cortisol, via immunoassay. The primary outcome was a reference range for post-DST free cortisol levels and the diagnostic accuracy of post-DST total cortisol level. Irina Bancos “A group that presents a particular challenge are women treated with oral estrogen,” Bancos told Healio. “In these cases, total cortisol increases due to estrogen-stimulated cortisol-binding globulin production, potentially leading to false-positive DST results. We intentionally designed our study to include a large reference group of women treated with oral contraceptive therapy allowing us to develop normal ranges of post-DST total and free cortisol, and then apply these cutoffs to the clinical practice.” Researchers observed adequate dexamethasone concentrations ( 0.1 µg/dL) in 97.6% of healthy volunteers and in 96.3% of patients. Among women volunteers taking oral contraceptives, 25.5% had an abnormal post-DST total cortisol measurement, defined as a cortisol level of at least 1.8 µg/dL. Among healthy volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not taking oral contraceptives, and 79 ng/dL for women taking oral contraceptives. Compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol level was 87.3% (95% CI, 81.7-91.7). All false-positive results occurred among patients with a post-DST cortisol level between 1.8 µg/dL and 5 µg/dL, according to researchers. Oral contraceptive use was the only factor associated with false-positive results (21.1% vs. 4.9%; P = .02). Findings challenge guidelines Natalia Genere “We were surprised by several findings of our study,” Natalia Genere, MD, instructor in medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine in St. Louis, told Healio. “First, we saw that with a standardized patient instruction on DST, we found that optimal dexamethasone concentrations were reached in a higher proportion of patients than previously reported (97%), suggesting that rapid metabolism or poor absorption of dexamethasone may play a lower role in the rate of false positives. Second, we found that measurements of post-DST total cortisol in women taking oral contraceptive therapy accurately excluded [mild autonomous cortisol secretion] in three-quarters of patients, suggesting discontinuation of oral contraceptives, as suggested in prior guidelines, may not be routinely necessary.” Genere said post-DST free cortisol performed “much better” than total cortisol among women treated with oral estrogen. Stepwise approach recommended Based on the findings, the authors suggested a sequential approach to dexamethasone suppression in clinical practice. “We recommend a stepwise approach to enhance DST interpretation, with the addition of dexamethasone concentration and/or free cortisol in cases of abnormal post-DST total cortisol,” Bancos said. “We found dexamethasone concentrations are particularly helpful when post-DST total cortisol is at least 5 µg/dL and free cortisol is helpful in a patient with optimal dexamethasone concentrations and a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL. We believe that DST with free cortisol is a useful addition to the repertoire of available testing for [mild autonomous cortisol secretion], and that its use reduces need for repetitive assessments and patient burden of care, especially in women treated with oral contraceptive therapy.” PERSPECTIVE BACK TO TOP Ricardo Correa, MD, EsD, FACE, FACP, CMQ In the evaluation of endogenous Cushing’s disease, the guideline algorithm recommends two of three positive tests — 24-hour free urine cortisol, late midnight salivary cortisol level and 1 mg dexamethasone suppression test, or DST — for diagnosing hypercortisolism. Of those tests, the most accurate to detect adrenal secretion of cortisol when a patient may have an adrenal incidentaloma is the 1 mg DST. The caveat with this specific test is that it is affected by dexamethasone absorption and metabolism and the proportion of cortisol bound to corticosteroid-binding globulin. Up to 20% of these tests report false-positive findings. This study by Genere and colleagues aimed to determine the normal range of free cortisol during the 1 mg DST. The researchers conducted a prospective, cross-sectional study that included volunteers without adrenal disorders and patients assessed for cortisol excess for clinical reasons. In the volunteer group, 168 volunteers were enrolled, including 47 women that were taking oral contraceptives. After excluding patients with inadequate dexamethasone levels and other outliers, the post-DST free cortisol maximum level was less than 48 ng/dL for men and women who were not taking oral contraceptive pills and less than 79 ng/dL for women taking oral contraceptive pills. In the patient group, 100% of post-DST free cortisol levels were above the upper limit of normal among those with a post-DST cortisol of at least 5 µg/dL; however, this was true for only 70.7% of those with post-DST cortisol between 1.8 µg/dL and 5 µg/dL. This study found that a post-DST free cortisol assessment is helpful in patients with a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL, but was not beneficial for patients with a post-DST total cortisol of less than 1.8 µg/dL or more than 5 µg/dL. Performing free cortisol assessments in this subgroup will reduce the number of false positives. The authors recommend performing a 1 mg post-DST free cortisol analysis for this subgroup; the levels to confirm cortisol excess are at least 48 ng/dL in men and women not taking oral contraceptive pills and at least 79 ng/dL for women taking oral contraceptive pills. Furthermore, the study presents a stepwise approach algorithm that will be very useful for clinical practice. Ricardo Correa, MD, EsD, FACE, FACP, CMQ Endocrine Today Editorial Board Member Program Director of Endocrinology Fellowship and Director for Diversity University of Arizona College of Medicine-Phoenix Phoenix Veterans Affairs Medical Center Disclosures: Correa reports no relevant financial disclosures. From https://www.healio.com/news/endocrinology/20211117/free-cortisol-evaluation-useful-after-abnormal-dexamethasone-test
  6. Kate** on the Cushing’s support board (Cushing’s Help and Support) wrote this letter after having pituitary surgery… Dear friends and family: I am writing this letter to share with you some basic facts about Cushing’s Disease/Syndrome and the recovery process so that you will have sufficient information to form realistic expectations about me and my ability to engage in certain activities in light of this disease and its aftermath. As you know, Cushing’s is a rarely diagnosed endocrine disorder characterized by hypercortisolism. Cortisol is a hormone produced by the adrenal glands and is vital to regulate the body’s cardivoascular functions and metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to stress. The adrenal glands release cortisol in response to stress, so atheletes, women experiencing pregnancy, and those suffering from alcoholism, panic disorders and malnutrition naturally have higher-than-normal levels of cortisol. People with Cushing’s Syndrome live life with too much cortisol for their bodies as a result of a hormone-secreting tumor. Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the body in a constant state of “fight or flight,” which ravages the body and tears down the body’s major systems including cardivascular, musculo-skeletal, endocrine, etc. Symptoms vary, but the most common symptoms include rapid, unexplained weight gain in the upper body with increased fat around the neck and face (“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the arms and legs; purplish striae (stretch marks) on the abdomen, thighs, buttocks, arms and breasts; poor wound healing and bruising; severe fatigue; depression, anxiety disorders and emotional lability; cognitive difficulties; sleep disorders due to abnormally high nighttime cortisol production; high blood pressure and high blood sugar/diabetes; edema; vision problems; premature osteoperosis; and, in women, signs of hyperandrogenism such as menstrual irregularities, infertility, hirsutism, male-patterned balding and steroid-induced acne. Cushing's Symptoms http://www.cushings-info.com/images/1/12/Lady.gif A sketch of a typical Cushing’s patient. As you can see, the effects of the disease on the body are dramatic. Worse, the psychological and emotional effects of having a chronic, debilitating and disfiguring disease range from distressing to demoralizing. Imagine that, in the space of a year, you became unrecognizable to those around you and to yourself. You look in the mirror, but the person staring back a tyou is a stranger. You endure the stares and looks of pity from those who knew you before Cushing’s, fully aware that they believe you have “let yourself go” or otherwise allowed this to happen to your body. Nothing you can say or do will persuade them otherwise, so at some point, you stop trying and resolve to live your life in a stranger’s body. You feel increasingly sick, but when you explain your array of symptoms to your doctor, you are dismissed as a depressed hypochondriac who needs to diet and exercise more. Worse, your family members think the same thing — and are often quick to tell you how you need to “change your lifestyle” to overcome the effects of what you eventually will discover, once properly diagnosed, is a serious and rare disease. If only it were so simple! No one would choose to have Cushing’s. Those of us who have it would not wish it even on our worst enemy. Most people with Cushing’s long for the ability to do simple things, like walk a flight of stairs without having to sit for half an hour afterwards, or vacuum the house or even unload a dishwasher. One of the worst parts about this disease is the crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism. Not only do we become socially isolated because of the virilzing effects of an endocrine tumor, which drastically alters our appearance, but we no longer feel like ourselves with regard to energy. We would love to take a long bike ride, run three miles or go shopping like we used to — activities, which we took for granted before the disease struck. Those activities are sadly impossible at times for those with advanced stages of the disease. Sometimes, as with any serious illness, performing even basic tasks of daily care such as showering and dressing can exhaust the limited reserves of energy available to a Cushing’s patient. How do we explain to you what it’s like to watch our lives slip away? What response is sufficient to express the grief and frustration over losing so much of ourselves? It is often difficult to find the strength to explain how your well-meaning words of prompting and encouragement (to diet or exercise) only serve to leave us more isolated and feeling alone. Though we wouldn’t want it, we wish our disease were as well-understood as cancer so that those who love us would have a frame of reference for what we go through. With Cushing’s, there is such limited public awareness that we are left to describe the effects of the disease from a void, often with limited understanding from those who love us most, which is disheartening. The most frustrating misconception about this disease is that we somehow are “doing this to ourselves,” or delaying recovery because we need to continue steroid replacement or lack the energy to excercise often, which is sadly false. Trust me that we would love to have that much control over such a terrible disease. Fortunately, there is a good likelihood of remission from Cushing’s in the hands of a skilled pituitary surgeon. Unfortunately, the long-term remission rate is only 56%, meaning that 44% of people with Cushing’s will require a second (sometimes third) pituitary surgery, radiation or bilateraly adrenalectomy to resolve the hypercortisolism. Without successful treatment, Cushing’s leads to death. Even with successful treatment, I will have to be monitored for possible recurrence for the rest of my life. After surgery or other treatment, the recovery period can last months or even years. Because the tumor takes over control of the body’s production of cortisol, the adrenal glands, which had lain dormant prior to surgery, require time to start functioning properly again. Until this happens, we must take synthetic steroids or else risk adrenal insufficiency or adrenal crisis, which can be quickly life-threatening. Careful monitoring of our cortisol levels is critical during the weaning period. It is a rare but sad fact that some people’s adrenal glands never return to normal, and those people must continue to take hydrocortisone or prednisone — sometimes for life — simply in order for the body to perform correctly its basic systemic functions. The physical recovery from surgery can be quick, but the withdrawal from hydrocortisone can be a lengthy and extremely painful process. As I described above, Cushing’s causes a tearing-down of muscles and bone. While there is an over-abundance of cortisol in our bodies (as a result of the tumor), we often can’t feel the effects of the muscle-wasting and bone deterioration because of the anti-inflammatory action of cortisol. Upon weaning, however, these become painfully (literally!) evident. The physical pain experienced while weaning from cortisol has been described as worse than weaning from heroin. When cortisol levels are low, one experiences the symptoms akin to a really bad flu, including severe fatigue (”like a wet cement blanket laid on top of me”); weakness and exhaustion; nausea; headache; vomiting; mental confusion. It is imperative for people who are on replacement steroids after Cushing’s surgery to carry extra Cortef (or injectable Solu-Cortef) with them at all times in addition to wearing a medic alert bracelet so that medical professionals will be alerted to the possiblity of adrenal insufficiency in the event of an adrenal crisis. People who have struggled with Cushing’s Syndrome all hope to return to “normal” at some point. Though none of us want to have Cushing’s, it is often a relief finally to have a correct diagnosis and treatment plan. For many, there is a gradual resolution of many Cushing’s symptoms within a few years of surgery or other successful treatment, and a good quality of life can be achieved. But regrettably, this is not possible in every case. Depending on the severity of the disease and the length of time before diagnosis and treatment, the prognosis can be poor and lead to shortened life expectancy and diminished quality of life. This is not a choice or something we can control, but it is the reality for some people who have suffered the consequences of long-term hypercortisolism. The best support you can give someone who is suffering from Cushing’s or its aftermath is to BELIEVE them and to understand that they are not manufacturing their illness or prolonging recovery. Ask them what they are able (and not able) to do, and then be prepared to help them in ways that matter — whether that be to bring them a meal or help them to run errands, pick up prescriptions from the pharmacy or clean their house. Because it’s these little everyday tasks, which can fall by the wayside when someone has (or has had) Cushing’s, and these are the things we miss the most: doing for ourselves. Ask us questions about the disease, and then actively listen to what we say. We know you don’t know much about Cushing’s — even our doctors sometimes lack information about this rare disease. But know we appreciate the interest and will tell you everything you want to know, because those of us who have it necessarily become experts in it just in order to survive. Thank you for caring about me and for hearing what I am saying in this letter. I know you love me and are concerned about me, and I appreciate that so much. Thank you also for taking the time to read this letter. I look forward to discussing further any questions you might have. In the meantime, I am attaching a brief article written by a woman who recently was diagnosed with Cushing’s. I hope hearing another person’s experiences will help you to understand what I’m going through so that when we talk, we will be coming from a similar starting place. Endocrinologists (doctors who specialize in Cushing's Syndrome and its related issues) realize the medical aspect and know the damaging effects that Cushing's has on the body. Family and friends see their Cushie suffering and know they are hurting physically and often times mentally and emotionally. However, understanding the debilitation of Cushing's and how it can affect every aspect of a person's life can only be truly realized by those who have experienced the syndrome. Cushings Help Organization, Inc., a non-profit family of websites maintained by MaryO, a pituitary Cushing's survivor, provides this letter for patients to provide to their family and friends in hopes of providing a better understanding Cushing's and it's many aspects. We're sorry to hear that your family member or friend has Cushing's Syndrome or suspected Cushing's. A person may feel better at times then at other times. It's common for a Cushing's patient to have burst of energy and then all of a sudden they become lethargic and don't feel like moving a muscle. There are many symptoms that are associated with Cushing's. They include weight gain, fatigue, muscle weakness, shortness of breath, feeling achy all over, headaches, blurred vision, mood swings, high blood pressure, stretch marks (straie), buffalo hump, diabetes, edema and the list goes on. Hormones affect every area of the body. It is important to note that not all patients have every symptom. Even some hallmark symptoms, such as straie or the "buffalo hump", may not be noticable on every patient. Not everyone who has Cushing's will experience the same symptoms, treatment, or recovery. Because not all "Cushies" have these symptoms, it makes diagnosis even more difficult. Cushing's can cause the physical appearance change due to weight gain, hair loss, rosacea, acne, etc. This can be very disturbing when looking in the mirror. Changes in appearance can often cause the Cushing's patient to withdraw from family and friends making it a very lonely illness. Patients often feel alone or withdrawn because few others understand. Cushing's can affect affect anyone of any age although it is more commen in women. Cushing's patients need to be able to take one day at time and learn to listen to their bodies. There will most likely be times when naps are needed during the day and often times may not be able to sleep at night due to surges of cortisol. Your Cushie doesn't expect you to understand Cushing's Syndrome completely. They do need you to be there for them and try to understand to the best of your ability what they feel and not give up on them. Often a Cushing's patient may be moody and say things that they don't mean. If this should happen with your Cushie try not to take it personally and know that it's most likely caused by the elevated cortisol and disturbances in other hormone levels caused by the Cushing's and not from the heart or true feelings of your Cushie. It can be very depressing and frustrating having so many limitations and experience things in life being taken from you. Cushing's patients are sick, not lazy, not hypochondriacs or even the newer term "Cyberchondriacs". If a Cushing's patient says they don't feel like doing something or they express how bad they feel let them know that you believe them. One of the most frustrating things to someone who is sick is to have those you love not believe you or support you. Telling a Cushie to think positive thoughts will not make him/her well and will just be aggrivating. Testing procedures can be lengthy and this can become frustrating for the patient and family. Often, it takes a while for results to come back and this can be stressful. Don't look to far ahead just take one day at a time and deal with the situation that is at hand at the present time. After a diagnosis is made then it's time for treatment. Surgery is usually the best treatment option for Cushing's that is caused by tumors. Don't be surprised if the surgeon's facility wants to run even more tests or redo some of those that have already been done. Your Cushie may have to travel a ways to find a surgeon who is trained in these delicate surgeries and who has performed many of them. Once the diagnosis has been made and treatment has finished then it's time for the recovery process. Not all patients who have surgery are cured and they have to make a choice along with the advice of their doctor as to what their next treatment option will be. The recovery from the surgery itself is similar to any other surgery and will take a while to recover. The recovery process obtained from getting a cure from Cushing's is quiet different from other surgeries. A Cushing's patients body has been exposed to excess cortisol, usually for quite a long time, and has become accustomed it. When the tumor is removed that has been responsible for the excessive cortisol and the body is no longer getting it this causes the body to have withdrawal symptoms. Withdrawal can be very hard causing an array of symptoms muscle aches, weakness, bone and joint pain, emotional disturbances etc. Thank you for reading this and we hope it will help you to understand a little more about Cushing's and the dibilating affect it can have on a person. Thank you for being there and supporting your Cushie during this time in their life. We realize that when a family member has Cushing's it not only affects the individual but other family members and those around them as well. Showing your love and support will encourage a speedy recovery for your Cushie. **Note: Kate died on on June 23, 2014. Read her In Memory page here: http://cushingsbios.com/2014/06/25/in-memory-kate-meyers/
  7. Ahmed Saeed Mubarak Mohamed1, Ahmed Iqbal2, Suveera Prasad3, Nigel Hoggard4, Daniel Blackburn1 Correspondence to Dr Daniel Blackburn, Sheffield Teaching Hospitals NHS Foundation Trust Department of Clinical Neurology, Sheffield S10 2JF, UK; d.blackburn@sheffield.ac.uk Abstract Cushing’s disease is a rare endocrine condition in which a pituitary corticotroph adenoma drives excess adrenal cortisol production, and is one cause of endogenous Cushing’s syndrome. We present a young woman with 3 weeks of headaches and cognitive disturbance who subsequently developed florid psychosis requiring multiple admissions under neurology and psychiatry. Her clinical stigmata of hypercortisolism and biochemical abnormalities prompted an MR scan of the pituitary, which confirmed a pituitary microadenoma. Treatment with metyrapone and subsequent surgery led to complete recovery within 2 months. Cushing’s disease commonly causes neuropsychiatric symptoms and can present with psychosis. Diagnosing Cushing’s disease can be challenging, but with early diagnosis and treatment it has an excellent prognosis. http://dx.doi.org/10.1136/practneurol-2021-002974 Get the full text
  8. 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
  9. Osilodrostat treatment was found to be associated with a rapid and sustained reduction in mean concentration of urinary free cortisol (UFC) and improved clinical symptoms in patients with Cushing’s disease, according to the results of a prospective, multicenter, open-label, phase 3 study published in the Lancet Diabetes Endocrinology. Osilodrostat is an oral inhibitor of 11-β hydroxylase cytochrome P450. Adults aged 18 to 75 years of age with diagnosed persistent or recurrent Cushing’s disease were recruited between 2014 and 2017 at 66 hospitals in 19 countries. Cushing’s disease was defined by a mean UFC concentration over a 24-hour period >1.5 times greater than the upper limit of normal (ULN) and morning plasma adrenocorticotropic hormone level above normal limits. Participants (n=137) received 30 mg osilodrostat twice daily, dose which was adjusted every 2 weeks until week 12 on the basis of mean 24-hour UFC concentration. The determined maintenance dose was continued until week 24. At week 26, participants who had achieved 24-hour UFC concentration ≤ ULN and did not need titration after week 12 were randomly assigned in an equal ratio to maintain osilodrostat treatment or were switched to a placebo for 8 weeks. This 8-week period of the study was double-blinded. During weeks 35 to 48, all patients were returned to osilodrostat treatment. In this cohort, mean age was 40.0 years (range, 19.0-70.0 years), 77% of participants were women, the average time since diagnosis was 47.2 months (interquartile range [IQR], 19.0-88.3), 88% had previous pituitary surgery, 16% had pituitary radiation therapy, and 74% had medicinal therapy. At baseline, the mean 24-hour UFC concentration was 1006±1590 nmol/24 h. At week 24, 53% of participants achieved a mean 24-hour UFC concentration ≤ULN without increases in dose after week 12 and were eligible for randomization (osilodrostat, n=36; placebo, n=35). At week 34, more patients receiving osilodrostat vs placebo maintained a complete response (86% vs 29%, respectively; odds ratio [OR], 13.7; 95% CI, 3.7-53.4; P <.0001). Improvements in cardiovascular-related metabolic parameters associated with hypercortisolism and overall measures of well-being were observed. Levels of high-density lipoprotein decreased by week 48 (-0.3 mmol/L; 95% CI, .0.3 to -0.2), mean Cushing’s quality of life score increased by 52.4% (95% CI, 32.3-72.7), and Beck Depression Inventory score decreased by 31.8% (95% CI, -44.3 to -19.3). Adverse events were hypocortisolism (51%), adverse events related with adrenal hormone precursors (42%), nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%). A total of 18% of participants dropped out of the study due to adverse events. The major limitation of this study was the short withdrawal period (8 weeks) which may not have permitted to observe symptoms of hypercortisolism. “Alongside careful dose adjustments and monitoring of known risks associated with osilodrostat, our findings indicate a positive benefit– risk consideration of treatment for most patients with Cushing’s disease,” concluded the study authors. Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a doubleblind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;S2213-8587(20)30240-0. doi:10.1016/S2213-8587(29)30240-0 From https://www.endocrinologyadvisor.com/home/topics/general-endocrinology/osilodrostat-sustained-reduction-mean-ufc-concentration-cushings-disease/
  10. Hypercortisolism Quickly Reversed With Oral Tx Oral osilodrostat (Isturisa) normalized cortisol levels in Cushing's disease patients who were ineligible for or not cured with pituitary surgery, according to the phase III LINC 3 trial. After 24 weeks of open-label treatment with twice-daily osilodrostat, 53% of patients (72 of 137; 95% CI 43.9-61.1) were able to maintain a complete response -- marked by mean 24-hour urinary free cortisol concentration of the upper limit of normal or below -- without any uptitration in dosage after the initial 12-week buildup phase, reported Rosario Pivonello, MD, of the Università Federico II di Napoli in Italy, and colleagues. As they explained in their study online in The Lancet Diabetes & Endocrinology, following the 24-week open-label period these complete responders to treatment were then randomized 1:1 to either remain on osilodrostat or be switched to placebo. During this 10-week randomization phase, 86% of patients maintained their complete cortisol response if they remained on osilodrostat versus only 29% of those who were switched to placebo (odds ratio 13.7, 95% CI 3.7-53.4, P<0.0001) -- meeting the trial's primary endpoint. As for adverse events, more than half of patients experienced hypocortisolism, and the most common adverse events included nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%). "Alongside careful dose adjustments and monitoring of known risks associated with osilodrostat, our findings indicate a positive benefit-risk consideration of treatment for most patients with Cushing's disease," the researchers concluded. This oral inhibitor of 11β-­hydroxylase -- the enzyme involved in the last step of cortisol synthesis -- was FDA approved in March 2020 based on these findings, and is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets. The prospective trial, consisting of four periods, included individuals between the ages of 18 and 75 with confirmed persistent or recurrent Cushing's disease -- marked by a mean 24-h urinary free cortisol concentration over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). All individuals had either undergone prior pituitary surgery or irradiation, were not deemed to be candidates for surgery, or had refused to have surgery. During the first open-label study period, all participants took 2 mg of oral osilodrostat twice daily, spaced 12 hours apart. This dose was then titrated up if the average of three 24-h urinary free cortisol concentration samples exceeded the upper limit of normal. During the second study period, which spanned weeks 12 through 24, all participants remained on their osilodrostat therapeutic dose. By week 24, about 62% of the participants were taking a therapeutic dose of 5 mg or less twice daily; only about 6% of patients needed a dose higher than 10 mg twice daily. In the third study period, which spanned weeks 26 through 34, "complete responders" who achieved normal cortisol levels were then randomized to continue treatment or be switched to placebo, while those who did not fully respond to treatment continued on osilodrostat. For the fourth study period, from weeks 24 through 48, all participants were switched back to active treatment with osilodrostat. Overall, 96% of participants were able to achieve a complete response at some point while on osilodrostat treatment, with two-thirds of these responders maintaining this normalized cortisol level for at least 6 months. The median time to first complete response was 41 days. Metabolic profiles also improved along with this reduction in cortisol levels. These included improvements in body weight, body mass index, fasting plasma glucose, both systolic and diastolic blood pressures, and total cholesterol levels. "Given the known clinical burden of cardiovascular risk associated with Cushing's disease, the improvement in clinical features shown here indicates important benefits of osilodrostat," the researchers said. "By improving multiple cardiovascular risk factors, our findings are likely to be clinically relevant." Along with metabolic improvements, patients also had "clinically meaningful improvements" in quality of life, as well as reductions in depressive symptoms measured by the Beck Depression Inventory score, the investigators reported. One limitation to the trial, they noted, was an inability to control for concomitant medications, since nearly all participants were taking other medications, particularly antihypertensive and antidiabetic therapies. "Further examination of the effects of osilodrostat on the clinical signs of Cushing's disease, and the reasons for changes in concomitant medications and the association between such medications and clinical outcomes would be valuable," Pivonello's group said. From https://www.medpagetoday.com/endocrinology/generalendocrinology/87827
  11. MENLO PARK, Calif., Aug. 28, 2019 (GLOBE NEWSWIRE) -- Corcept Therapeutics Incorporated (NASDAQ: CORT) announced today that the United States Patent and Trademark Office has issued a Notice of Allowance for a patent covering the administration of Korlym® with food. The patent will expire in November 2032. “This patent covers an important finding of our research – that for optimal effect, Korlym must be taken with food,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “Korlym’s label instructs doctors that ‘Korlym must always be taken with a meal.’” Upon issuance, Corcept plans to list the patent, entitled “Optimizing Mifepristone Absorption” (U.S. Pat. App. 13/677,465), in the U.S. Food and Drug Administration’s Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”). Korlym is currently protected by ten patents listed in the Orange Book. Hypercortisolism Hypercortisolism, often referred to as Cushing’s syndrome, is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. In the United States, an estimated 20,000 patients have Cushing’s syndrome, with about 3,000 new patients diagnosed each year. Symptoms vary, but most people with Cushing’s syndrome experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Hypercortisolism can affect every organ system in the body and can be lethal if not treated effectively. About Corcept Therapeutics Incorporated Corcept is a commercial-stage company engaged in the discovery and development of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of the stress hormone cortisol. Korlym® (mifepristone) was the first treatment approved by the U.S. Food and Drug Administration for patients with Cushing’s syndrome. Corcept has discovered a large portfolio of proprietary compounds, including relacorilant, exicorilant and miricorilant, that selectively modulate the effects of cortisol but not progesterone. Corcept owns extensive United States and foreign intellectual property covering the composition of its selective cortisol modulators and the use of cortisol modulators, including mifepristone, to treat a variety of serious disorders. Forward-Looking Statements Statements in this press release, other than statements of historical fact, are forward-looking statements, which are based on Corcept’s current plans and expectations and are subject to risks and uncertainties that might cause actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, Corcept’s ability to generate sufficient revenue to fund its commercial operations and development programs; the availability of competing treatments, including generic versions of Korlym; Corcept’s ability to obtain acceptable prices or adequate insurance coverage and reimbursement for Korlym; and risks related to the development of Corcept’s product candidates, including regulatory approvals, mandates, oversight and other requirements. These and other risks are set forth in Corcept’s SEC filings, which are available at Corcept’s website and the SEC’s website. In this press release, forward-looking statements include those concerning Corcept’s plans to list the patent “Optimizing Mifepristone Absorption” in the Orange Book; Korlym’s current protection by ten patents listed in the Orange Book; and the scope and protective power of Corcept’s intellectual property. Corcept disclaims any intention or duty to update forward-looking statements made in this press release. CONTACT: Christopher S. James, MD Director, Investor Relations Corcept Therapeutics 650-684-8725 cjames@corcept.com www.corcept.com
  12. I think I knew this already but it's still hard to read in print Functional remission did not occur in most patients with Cushing syndrome who were considered to be in biochemical and clinical remission, according to a study published in Endocrine. This was evidenced by their quality of life, which remained impaired in all domains. The term “functional remission” is a psychiatric concept that is defined as an “association of clinical remission and a recovery of social, professional, and personal levels of functioning.” In this observational study, investigators sought to determine the specific weight of psychological (anxiety and mood, coping, self-esteem) determinants of quality of life in patients with Cushing syndrome who were considered to be in clinical remission. The cohort included 63 patients with hypercortisolism currently in remission who completed self-administered questionnaires that included quality of life (WHOQoL-BREF and Cushing QoL), depression, anxiety, self-esteem, body image, and coping scales. At a median of 3 years since remission, participants had a significantly lower quality of life and body satisfaction score compared with the general population and patients with chronic diseases. Of the cohort, 39 patients (61.9%) reported having low or very low self-esteem, while 16 (25.4%) had high or very high self-esteem. Depression and anxiety were seen in nearly half of the patients and they were more depressed than the general population. In addition, 42.9% of patients still needed working arrangements, while 19% had a disability or cessation of work. Investigators wrote, “This impaired quality of life is strongly correlated to neurocognitive damage, and especially depression, a condition that is frequently confounded with the poor general condition owing to the decreased levels of cortisol. A psychiatric consultation should thus be systematically advised, and [selective serotonin reuptake inhibitor] therapy should be discussed.” Reference Vermalle M, Alessandrini M, Graillon T, et al. Lack of functional remission in Cushing's Syndrome [published online July 17, 2018]. Endocrine. doi:10.1007/s12020-018-1664-7 From https://www.endocrinologyadvisor.com/general-endocrinology/functional-remission-quality-of-life-cushings-syndrome/article/788501/
  13. Metyrapone treatments helped patients with Cushing syndrome reach normal, urinary-free cortisol levels in the short-term and also had long-term benefits, according to a study published in Endocrine. This observational, longitudinal study evaluated the effects of the 11β -hydroxylase inhibitor metyrapone on adult patients with Cushing syndrome. Urinary-free cortisol and late-night salivary cortisol levels were evaluated in 31 patients who were already treated with metyrapone to monitor cortisol normalization and rhythm. The average length of metyrapone treatment was 9 months, and 6 patients had 24 months of treatment. After 1 month of treatment, the mean urinary-free cortisol was reduced from baseline by 67% and mean late-night salivary cortisol level decreased by 57%. Analyzing only patients with severe hypercortisolism, after 1 month of treatment, the mean urinary-free cortisol decreased by 86% and the mean late-night salivary cortisol level decreased 80%. After 3 months, normalization of the mean urinary-free cortisol was established in 68% of patients. Mean late-night salivary cortisol levels took longer to decrease, especially in severe and very severe hypercortisolism, which could take 6 months to drop. Treatment was more successful at normalizing cortisol excretion (70%) than cortisol rhythm (37%). Nausea, abdominal pain, and dizziness were the most common adverse events, but no severe adverse event was reported. Future research is needed to evaluate a larger cohort with randomized dosages and stricter inclusion criteria to evaluate metyrapone's effects on cortisol further. Study researchers conclude that metyrapone was successful and safe in lowering urinary-free cortisol after just 1 month of treatment and controlling long-term levels in patients with Cushing syndrome. This study was supported by Novartis. Reference Ceccato F, Zilio M, Barbot M, et al. Metyrapone treatment in Cushing's syndrome: a real-life study [published online July 16, 2018]. Endocrine. doi: 10.1007/s12020-018-1675-4 From https://www.endocrinologyadvisor.com/general-endocrinology/metyrapone-cushing-syndrome/article/786716/
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