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She experienced extreme weight gain, thin skin and a racing heart. It took years to finally solve the medical mystery. Angela Yawn went to a dozen doctors before finally getting a diagnosis for her life-disrupting symptoms.Courtesy Angela Yawn April 27, 2022, 10:52 AM EDT / Source: TODAY By A. Pawlowski When a swarm of seemingly unrelated symptoms disrupted Angela Yawn’s life, she thought she was going crazy. She gained weight — 115 pounds over six years — even as she tried to eat less. Her skin tore easily and bruises would stay on her body for months. Her face would suddenly turn blood red and hot to the touch as if she had a severe sunburn. She suffered from joint swelling and headaches. She felt tired, anxious and depressed. Her hair was falling out. Then, there was the racing heart. “I would put my hand on my chest because it made me feel like that’s what I needed to do to hold my heart in,” Yawn, 49, who lives in Griffin, Georgia, told TODAY. “I noticed it during the day, but at night when I was trying to lie down and sleep, it was worse because I could do nothing but hear it beat, feel it thump." Yawn, seen here before the symptoms began, had no problems with weight before.Courtesy Angela Yawn Yawn was especially frustrated by the weight gain. Even when she ate just 600 calories a day — consuming mostly lettuce leaves — she was still gaining about 2 pounds a day, she recalled. A doctor told her to exercise more. Yawn gained 115 pounds over six years. "When the weight really started to pile on, I stayed away from cameras as I felt horrible about myself and looking back at this picture is still very embarrassing for me but I wanted (people) to see what this disease has the potential to do if not diagnosed," she said.Courtesy Angela Yawn In all, Yawn went to a dozen doctors and was treated for high blood pressure and congestive heart failure, but nothing helped. As a last resort, she sought out an endocrinologist in February of 2021 and broke down in her office. “That was the last hope I had of just not lying down and dying because at that point, that’s what I wanted to do,” Yawn said. “I thought the problem was me. I thought that I’m making up these issues, that maybe I’m bipolar. I was going crazy.” What is Cushing disease? When the endocrinologist suddenly started listing all of her symptoms without being prompted, Yawn stopped crying. Blood tests and an MRI finally confirmed the doctor’s suspicion: Yawn had a tumor in her pituitary gland — a pea-size organ at the base of the brain — that was causing the gland to release too much adrenocorticotropic hormone. That, in turn, flooded her body with cortisol, a steroid hormone that’s normally released in response to stress or danger. The resulting condition is called Cushing disease. Imagine the adrenaline rush you’d get while jumping out of an airplane and skydiving — that’s what Yawn felt all the time, with harmful side-effects. Yawn was making six times the cortisol she needed, said Dr. Nelson Oyesiku, chair of neurosurgery at UNC Health in Chapel Hill, North Carolina, who removed her tumor last fall. “That’s a trailer load of cortisol. Day in, day out, morning, noon and night, whether you need it or not, your body just keeps making this excess cortisol. It can wreak havoc in the body physiology and metabolism,” Oyesiku told TODAY. The steroid regulates blood pressure and heart rate, which is why Yawn's skin was flushed and her heart was racing, he noted. It can regulate how fat is burned and deposited in the body, which is why Yawn was gaining weight. Other effects of the steroid's overproduction include fatigue, thin skin with easy bruising, mental changes and high blood sugar. Cushing disease is rare, affecting about five people per million each year, so most doctors will spend their careers without ever coming across a case, Oyesiku said. That’s why patients often go years without being diagnosed: When they complain of blood sugar problems or a racing heart, they’ll be treated for much more common issues like diabetes or high blood pressure. Pituitary gland is hard to reach Removing Yawn’s tumor in September of 2021 would require careful maneuvering. If you think of the head as a ball, the pituitary gland sits right at the center, between the ears, between the eyes and about 4 inches behind the nose, Oyesiku said. It’s called the “master gland” because it regulates other glands in the body that make hormones, he noted. The location of the pituitary gland makes it heard to reach.janulla / Getty Images It’s a very difficult spot to reach. To get to it, Oyesiku made an incision deep inside Yawn’s nose in a small cavity called the sphenoid sinus. Using a long, thin tube that carried a light and a camera, he reached the tiny tumor — about the size of a rice grain — and removed it using special instruments. The surgery took four hours. The potential risk is high: The area is surrounded by vessels that carry blood to the brain, and it’s right underneath optic nerves necessary for a person to see. If things go wrong, patients can become blind, brain dead, or die. Recovery from surgery Today, Yawn is slowly returning to normal. She has lost 41 pounds and continues to lose weight. Her hair is no longer falling out. But patients sometimes require months or even a few years to adjust to normal cortisol levels. “It takes some time to unwind the effects of chronic exposure to steroids, so your body has to adapt to the new world order as the effects of the steroids recede,” Oyesiku said. "My life was on hold for five years... I'm trying not to be too impatient," Yawn said.Courtesy Angela Yawn Yawn’s body was so used to that higher cortisol level that she’s had to rely on steroid supplements to feel normal after the surgery. It’s like an addict going through withdrawal, she noted. The next step is finishing another cycle of supplements and then slowly tapering off them so that her body figures out how to function without the steroid overload. “I am definitely moving in the right direction,” she said. "I hope that I’ll get back to that woman I used to be — in mind, body and spirit." From https://www.today.com/health/health/cushing-disease-pituitary-gland-tumor

I don't know if there's anything of interest here - or the cost - but possibly useful to someone. Cushing’s Syndrome Diagnostic and Treatment Market research report is the new statistical data source added by Research Cognizance. “Cushing’s Syndrome Diagnostic and Treatment Market is growing at a High CAGR during the forecast period 2022-2029. The increasing interest of the individuals in this industry is that the major reason for the expansion of this market”. Cushing’s Syndrome Diagnostic and Treatment Market research is an intelligence report with meticulous efforts undertaken to study the right and valuable information. The data which has been looked upon is done considering both, the existing top players and the upcoming competitors. Business strategies of the key players and the new entering market industries are studied in detail. Well explained SWOT analysis, revenue share, and contact information are shared in this report analysis. 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We have an opportunity for you to take part in a Acromegaly and Human Growth Hormone Deficiency (GHD) Study for patients and caregivers. Our project number for this study is IQV_6382. Project Details: Survey is 20-minutes long $35 Reward Things to Note: We recommend using the web browsers Google Chrome or FireFox Study is open to patients and caregivers Please do not share study links One participant per household only Want to share this opportunity? Let us know and we can provide a new link Please use a laptop/computer ONLY. No smartphones or tablets - Preliminary questions are mobile friendly! Save this email to reference if you have any questions about the study! If you have any problems, email lejla.zonic@rarepatientvoice.com and reference the project number. If you are interested in this study, please sign up for Rare Patient Voice here: https://rarepatientvoice.com/CushingsHelp/ Thanks as always for your participation! Please be aware that by entering this information you are not guaranteed that you will be selected to participate. As always, we do not share any of your contact information without your permission.

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#!

This is another semi-religious post so feel free to skip it 🙂 I’m sure that many would think that Abide With Me is a pretty strange choice for my all-time favorite hymn. My dad was a Congregational (now United Church of Christ) minister so I was pretty regular in church attendance in my younger years. Some Sunday evenings, he would preach on a circuit and I’d go with him to some of these tiny churches. The people there, mostly older folks, liked the old hymns best – Fanny Crosby and so on. So, some of my “favorite hymns” are those that I sang when I was out with my Dad. Fond memories from long ago. In 1986 I was finally diagnosed with Cushing’s after struggling with doctors and trying to get them to test for about 5 years. I was going to go into the NIH (National Institutes of Health) in Bethesda, MD for final testing and then-experimental pituitary surgery. I was terrified and sure that I wouldn’t survive the surgery. Somehow, I found a 3-cassette tape set of Readers Digest Hymns and Songs of Inspiration and ordered that. The set came just before I went to NIH and I had it with me. At NIH I set up a daily “routine” of sorts and listening to these tapes was a very important part of my day and helped me get through the ordeal of more testing, surgery, post-op and more. When I had my kidney cancer surgery, those tapes were long broken and irreplaceable, but I had replaced all the songs – this time on my iPod. Abide With Me was on this original tape set and it remains a favorite to this day. Whenever we have an opportunity in church to pick a favorite, my hand always shoots up and I request page 700. When someone in one of my handbell groups moves away, we always sign a hymnbook and give it to them. I sign page 700. I think that many people would probably think that this hymn is depressing. Maybe it is but to me it signifies times in my life when I thought I might die and I was so comforted by the sentiments here. This hymn is often associated with funeral services and has given hope and comfort to so many over the years – me included. If you abide in Me, and My words abide in you, you will ask what you desire, and it shall be done for you. ~John 15:7 Abide With Me Words: Henry F. Lyte, 1847. Music: Eventide, William H. Monk, 1861. Mrs. Monk described the setting: This tune was written at a time of great sorrow—when together we watched, as we did daily, the glories of the setting sun. As the last golden ray faded, he took some paper and penciled that tune which has gone all over the earth. Lyte was inspired to write this hymn as he was dying of tuberculosis; he finished it the Sunday he gave his farewell sermon in the parish he served so many years. The next day, he left for Italy to regain his health. He didn’t make it, though—he died in Nice, France, three weeks after writing these words. Here is an excerpt from his farewell sermon: O brethren, I stand here among you today, as alive from the dead, if I may hope to impress it upon you, and induce you to prepare for that solemn hour which must come to all, by a timely acquaintance with the death of Christ. For over a century, the bells of his church at All Saints in Lower Brixham, Devonshire, have rung out “Abide with Me” daily. The hymn was sung at the wedding of King George VI, at the wedding of his daughter, the future Queen Elizabeth II, and at the funeral of Nobel peace prize winner Mother Teresa of Calcutta in1997. Abide with me; fast falls the eventide; The darkness deepens; Lord with me abide. When other helpers fail and comforts flee, Help of the helpless, O abide with me. Swift to its close ebbs out life’s little day; Earth’s joys grow dim; its glories pass away; Change and decay in all around I see; O Thou who changest not, abide with me. Not a brief glance I beg, a passing word; But as Thou dwell’st with Thy disciples, Lord, Familiar, condescending, patient, free. Come not to sojourn, but abide with me. Come not in terrors, as the King of kings, But kind and good, with healing in Thy wings, Tears for all woes, a heart for every plea— Come, Friend of sinners, and thus bide with me. Thou on my head in early youth didst smile; And, though rebellious and perverse meanwhile, Thou hast not left me, oft as I left Thee, On to the close, O Lord, abide with me. I need Thy presence every passing hour. What but Thy grace can foil the tempter’s power? Who, like Thyself, my guide and stay can be? Through cloud and sunshine, Lord, abide with me. I fear no foe, with Thee at hand to bless; Ills have no weight, and tears no bitterness. Where is death’s sting? Where, grave, thy victory? I triumph still, if Thou abide with me. Hold Thou Thy cross before my closing eyes; Shine through the gloom and point me to the skies. Heaven’s morning breaks, and earth’s vain shadows flee; In life, in death, O Lord, abide with me. http://cushieblog.files.wordpress.com/2012/04/maryo-butterfly-script1.gif?resize=251%2C121

I wrote parts of this in 2008, so all the “yesterdays” and “last weeks” are a little off. Wow. That’s about all I can say. Yesterday was possibly the best day of my life since I started getting Cushing’s symptoms, and that was over 30 years ago. More than a quarter of a century of feeling exhausted, fatigued. A quarter of my life spent taking naps and sleeping. Last week in this post I wrote in part: So, yesterday I was supposed to go to a conference on web design for churches. My church sent me because they want me to spiff up their site and make them a new one for Christmas. I wanted to go because, well, I like learning new stuff about the web. I figured that I would learn stuff that would also be useful to me in others of my sites. And I did! But the amazing thing is this. My son had told me about a medication that was very similar to Provigil, that he had tried it while he was writing his doctoral thesis and it had helped him. So, having tried the official doctor route and being rebuffed – again – I had decided to try this stuff on my own. Just the night before I had written a response on Robin’s wonderful blog that reads in part: As I said earlier, I have a history of daily naps of at least 3 hours a day. It cuts into everything and prevents me from doing many things. I have to schedule my life around these naps and it’s awful. A few years ago I went on a Cushie trip to Rockford. I’ve been there a few times and it’s always so much fun. But this first year, we were going to another Cushie’s home for barbecue. I didn’t drive, I rested in the back of the car during the drive. We got there and I managed to stay awake for a little while. Them I put my head down on the dining room table and fell asleep. Our hostess kindly suggested that I move over to the sofa. So, I have a long history of daily naps, not getting through the day, yadda, yadda. So, I was a little nervous about yesterday. I really wanted to go to this conference, and was afraid I’d have to go nap in my car. I got up at 5:30 am yesterday. Before I left at 7:15, I took my Cortef and then I took my non-FDA approved simulated Provigil. (Although it’s not FDA approved, it is not illegal to possess without a prescription and can be imported privately by citizens) I stayed awake for the whole conference, went to a bell rehearsal, did Stacey’s interview, had dinner and went to bed about 10:30PM. NO NAP! I did close my eyes a little during the 4:00PM session but it was also b-o-r-i-n-g. I stayed awake, I enjoyed myself, I learned stuff, I participated in conversations (completely unlike shy me!). I felt like I think normal people feel. I was amazed. Half my life wasted and I finally (thank you Michael!) had a good day. My kidney doctor and my endo would probably be appalled but it’s about time that I had some life again! Maybe in another 25 years, I’ll take another pill. LOL Well, the energy from the Adrafinil was a one day thing. I felt great on Thursday. Friday and Saturday I slept more than usual. Saturday, today, was one of those days where I sleep nearly all day. Maybe if I took the drug more it would build up in my system, maybe not. But it was still worth having that one day where I felt what I imagine normal to be. While I was being a slug today, my husband painted the entire house. I’m not sure if I would have been this tired today or if I was somehow making up for the nap I didn’t get on Thursday. Whatever the case, I’m glad that I had the opportunity to try this and to experience the wonderful effects, if only for one day. Information from a site that sells this: There’s more info about Adrafinil on Wikipedia It’s interesting that that snipped report that people become more talkative. I reported that in the original post, too, even though I didn’t realize that this was a possibility. A good quote that I wish I could relate to better: 2011 stuff starts here: Awhile ago I went to a handbell festival. I took a bit of adrafinil on the main day to try to stay awake for the whole day. It didn’t seem to keep me as on as it did before. I can’t be used to it already. Maybe I’m just that much more tired than I was before. Our son lives in New York and every few years he gives us tickets to see a Broadway show. A couple years ago we took the train to NY to see Wicked. Usually my DH wants to go out and see sights while we’re there. I usually want to nap. This time we got up on Saturday morning, went out for breakfast. I wanted to take in the whole day and enjoy Wicked so I took some Adrafinil. We got back to the hotel and got ready to go to a museum or other point of interest. But, DH wanted to rest a bit first. Then our son closed his eyes for a bit… So, I found myself the only one awake for the afternoon. They both work up in time for the show… Sigh It was a great show, though. A recent Christmas I was going to get my son some Adrafinil as a gift. The original place we bought it didn’t have any more stock so I tracked it down as a surprise. He was going to give me some, as well, but couldn’t get it from the original source, either. So he found something very similar called Modafinil. GMTA! And 2016.. Saturday, 4/23/16 really was one of the best days I’ve had in a long time. I’ll be writing a longer post about that later on my travel blog but here’s the original plan: https://maryoblog.com/2016/04/23/busy-saturday/ Suffice it to say, we arrived at the Tattoo and I got no nap at all, all day!

This is a tough one. Sometimes I’m in “why me” mode. Why Cushing’s? Why cancer? Unfortunately, there’s not a thing I can do about either. Cushing’s, who knows the risk factors? For kidney cancer, I found out the risk factors and nearly none apply to me. So why? But why not? No particular reason why I should be exempt from anything. Since there’s nothing to be done with the exception of trying to do things that could harm my remaining kidney, I have to try to make the best of things. This is my life. It could be better but it could be way worse. One of the Challenge topics was to write about “My Dream Day” so here’s mine… I’d wake up on my own – no snooze alarms – at about 8 am, sun streaming through the window. I’d we well rested and not have had any nightmares the night before. I remember my son is home for a visit but I let him sleep in for a while. I’d get out for a bike ride or a brisk walk, come home, head for the hot tub then shower. I’d practice the piano (or recorder or Aerophone) for a bit, then go out to lunch with friends, taking Michael with me. While we’re out, the maid will come in and clean the house. After lunch, maybe a little technology shopping/buying. Then the group of us go to one of our homes for piano duets, trios, 2-piano music. When we get home, it’s immaculately clean and I find that the Prize Patrol has visited and left a substantial check. I had wisely left something for dinner in the Ninja so dinner is ready. After dinner, I check online and find no urgent email, no work that needs to be done, no bills that need to be paid, no blog challenge posts to write… I wake up from My Dream Day and realize that this is so far from real life, so I re-read The Best Day of My Life and am happy that I’m not dealing with anything worse.

Since I’m posting this on April 21, I had a built-in topic. http://cushieblog.files.wordpress.com/2012/04/nataile-blog.jpg?w=500 The image above is from our first local meeting, here in Northern VA – note the 6 Cushing St. sign behind us. Natalie was the Cushie in the middle. Today is the anniversary of Natalie’s death. Last month was the anniversary of Sue’s death. I wrote about Janice earlier. It’s just not right that this disease has been known for so many years, yet doctors still drag their feet diagnosing it and getting people into remission. Why is it that we have to suffer so much, so long, and still there are so many deaths from Cushing’s or related to Cushing’s symptoms? I know far too many people, good people, who suffered for many years from this disease that doctors said they didn’t have. Then they died. It’s time this stopped! Speaking of death – what a cheery blog post this is turning out to be. NOT! Unfortunately, this seems to be one of the realities of Cushing’s. Tomorrow will be cheerier – watch for it!

And today, we talk about pink jeeps and ziplines… How in the world did we get here in a Cushing’s Challenge? I’m sliding these in because earlier I linked (possibly!) my growth hormone use as a cause of my cancer – and I took the GH due to Cushing’s issues. Clear? LOL http://cushieblog.files.wordpress.com/2012/04/pink-jeep.jpg?w=300&h=225&resize=300%2C225 I had found out that I had my kidney cancer on Friday, April 28, 2006 and my surgery on May 9, 2006. I was supposed to go on a Cushie Cruise to Bermuda on May 14, 2006. My surgeon said that there was no way I could go on that cruise and I could not postpone my surgery until after that cruise. I got out of the hospital on the day that the other Cushies left for the cruise and realized that I wouldn’t have been much (ANY!) fun and I wouldn’t have had any. An especially amusing thread from that cruise is The Adventures of Penelopee Cruise (on the Cushing’s Help message boards). Someone had brought a UFC jug and decorated her and had her pose around the ship. The beginning text reads: Although I missed this trip, I was feeling well enough to go to Sedona, Arizona in August, 2006. I convinced everyone that I was well enough to go off-road in a pink jeep, DH wanted to report me to my surgeon but I survived without to much pain and posed for the header image. In 2009, I figured I have “extra years” since I survived the cancer and I wanted to do something kinda scary, yet fun. So, somehow, I decided on ziplining. Tom wouldn’t go with me but Michael would so I set this up almost as soon as we booked a Caribbean cruise to replace the Cushie Cruise to Bermuda. Enough of adventures – fun ones like these, and scary ones like transsphenoidal surgery and radical nephrectomy!

In case you haven’t guessed it, my cause seems to be Cushing’s Awareness. I never really decided to devote a good portion of my life to Cushing’s, it just fell into my lap, so to speak – or my laptop. I had been going along, raising my son, keeping the home fires burning, trying to forget all about Cushing’s. My surgery had been a success, I was in remission, some of the symptoms were still with me but they were more of an annoyance than anything. I started being a little active online, especially on AOL. At this time, I started going through real-menopause, not the fake one I had gone through with Cushing’s. Surprisingly, AOL had a group for Cushing’s people but it wasn’t very active. What was active, though, was a group called Power Surge (as in I’m not having a hot flash, I’m having a Power Surge). I became more and more active in that group, helping out where I could, posting a few links here and there. Around this time I decided to go back to college to get a degree in computer programming but I also wanted a basic website for my piano studio. I filled out a form on Power Surge to request a quote for building one. I was very surprised when Power Surge founder/webmaster Alice (AKA Dearest) called me. I was so nervous. I’m not a good phone person under the best of circumstances and here she was, calling me! I had to go to my computer class but I said I’d call when I got back. Alice showed me how to do some basic web stuff and I was off. As these things go, the O’Connor Music Studio page grew and grew… And so did the friendship between Alice and me. Alice turned out to be the sister I never had, most likely better than any sister I could have had. In July of 2000, Alice and I were wondering why there weren’t many support groups online (OR off!) for Cushing’s. This thought percolated through my mind for a few hours and I realized that maybe this was my calling. Maybe I should be the one to start a network of support for other “Cushies” to help them empower themselves. I wanted to educate others about the awful disease that took doctors years of my life to diagnose and treat – even after I gave them the information to diagnose me. I didn’t want anyone else to suffer for years like I did. I wanted doctors to pay more attention to Cushing’s disease. The first website (http://www.cushings-help.com) went “live” July 21, 2000. It was just a single page of information. The message boards began September 30, 2000 with a simple message board which then led to a larger one, and a larger. Today, in 2022, we have over 73 thousand members. Some “rare disease”! This was on the intro page of Cushing’s Help until 2013… In August 2013 my friend died. In typical fashion, I started another website… I look around the house and see things that remind me of Alice. Gifts, print outs, silly stuff, memories, the entire AOL message boards on floppy disks… Alice, I love you and will miss you always… http://powersurgedotco.files.wordpress.com/2013/10/maryoonerose.gif?w=1000&resize=191%2C256

Cushie Crusader, that’s me…and many others. I think we all have an opportunity to be Cushie Crusaders every time we tell others about our illness, share our story on or offline, post about our struggles – and triumphs – on the message boards, write blog posts in this Cushing’s Awareness Challenge… When we have prayer time in my handbell practice or choir rehearsals I try to mention issues that are going on in the Cushing’s community. People are slowly but steadily learning about Cushing’s week by week. A piano student mentioned that a person in a group she is in has Cushing’s, a non-Cushie friend mentioned last week that she had gone with a friend of hers to an endo appointment to discuss Cushing’s. Get out there and talk about Cushing’s. Let people know that it’s not just for dogs and horses (and sometimes ferrets)! Here’s something I had made for Sue with SuperSue embroidered on the back. Picture your name instead: http://cushieblog.files.wordpress.com/2012/04/supersue.jpg?resize=425%2C600

I used to carry a print out of this everywhere I go because I find it very soothing. This print out was in a plastic page saver. On the other side there is a Psalm 116, part of the post from Day Nineteen of the 2015 Cushing’s Challenge. These days, both these readings are available on my phone. I first read this in Chicken Soup for the Surviving Soul and is posted several places online. The Best Day Of My Life by Gregory M Lousignont Today, when I awoke, I suddenly realized that this is the best day of my life, ever! There were times when I wondered if I would make it to today; but I did! And because I did I’m going to celebrate! Today, I’m going to celebrate what an unbelievable life I have had so far: the accomplishments, the many blessings, and, yes, even the hardships because they have served to make me stronger. I will go through this day with my head held high, and a happy heart. I will marvel at God’s seemingly simple gifts: the morning dew, the sun, the clouds, the trees, the flowers, the birds. Today, none of these miraculous creations will escape my notice. Today, I will share my excitement for life with other people. I’ll make someone smile. I’ll go out of my way to perform an unexpected act of kindness for someone I don’t even know. Today, I’ll give a sincere compliment to someone who seems down. I’ll tell a child how special he is, and I’ll tell someone I love just how deeply I care for her and how much she means to me. Today is the day I quit worrying about what I don’t have and start being grateful for all the wonderful things God has already given me. I’ll remember that to worry is just a waste of time because my faith in God and his Divine Plan ensures everything will be just fine. And tonight, before I go to bed, I’ll go outside and raise my eyes to the heavens. I will stand in awe at the beauty of the stars and the moon, and I will praise God for these magnificent treasures. As the day ends and I lay my head down on my pillow, I will thank the Almighty for the best day of my life. And I will sleep the sleep of a contented child, excited with expectation because know tomorrow is going to be the best day of my life, ever! When I’m feeling down, depressed or low, reading my 2 special pages can help me more than anything else.

The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer the use of amniotic membrane during adrenal surgery which saves functional adrenal tissue in patients undergoing adrenal surgery. This novel technique enables more patients to have a partial adrenalectomy thereby preserving some normal adrenal physiology, potentially eliminating life-long adrenal hormone replacement. Preliminary clinical data from the Carling Adrenal Center suggest that the use of a human amniotic membrane allograph on the adrenal gland remnant following partial adrenal surgery leads to faster recovery of normal adrenal gland function. Rather than removing the entire adrenal gland—which has been standard of care for decades—a portion of the adrenal gland is able to be salvaged with amniotic membrane placed upon the remnant as a biologic covering. The preliminary data from an ongoing clinical trial shows this technique translates into fewer patients needing steroid hormone replacement following adrenal surgery, and if they do, it is for a significantly shorter period of time. "Sometimes it is possible, and preferable, to remove the adrenal tumor without removing the entire adrenal gland. This is called partial adrenal surgery and our study shows this technique is more successful when amniotic membrane is used," said Dr. Carling. He further stresses that "removing only part of the adrenal gland is a more advanced operation and is typically only performed by expert adrenal surgeons. The goal is to leave some normal adrenal tissue so that the patient can avoid adrenal insufficiency which requires a daily dose of several adrenal hormones and steroids. Partial adrenal surgery is especially beneficial for patients with pheochromocytoma, as well as Conn's and Cushing's syndrome. Avoiding daily steroids is life-changing for these patients so this is a major breakthrough." So how does it work? The increased viability of the adrenal gland remnant is presumed to be related to the release of growth factors known to be present in amniotic tissue which is in direct contact with the adrenal gland remnant as a covering. The results are improved rates of viable adrenal cortical tissues with faster regeneration and recovery to normal endocrine physiology by the adrenal cortical cells. These findings come during Adrenal Disease Awareness Month. Adrenal gland diseases cause many debilitating symptoms like chronic headaches, anxiety, depression, fatigue, brain fog, memory loss, dangerously high blood pressure, heart arrythmia, weight gain, tremors, and more, yet they are often misdiagnosed or improperly treated. Since many doctors are inexperienced in the workup of adrenal hormone problems and only see a handful of adrenal tumors during their careers, it is important for patients to know about the symptoms of adrenal tumor disease and request their doctor measure adrenal hormones. Adrenal.com is the leading resource for adrenal gland function, tumors and cancers, and an award-winning resource for adrenal gland surgery. The diagnosis and surgical treatment of all types of adrenal tumor types are discussed. Adrenal.com is edited by Dr. Tobias Carling who has performed more adrenal surgery than any other surgeon and has published some of the most important scientific studies of adrenal disease and adrenal surgery including the understanding of the pathogenesis of pheochromocytoma and adrenal tumors causing Conn's and Cushing's syndrome. Established by Dr. Tobias Carling in 2020, the Carling Adrenal Center located at the Hospital for Endocrine Surgery in Tampa FL, is the highest volume adrenal surgical center in the world. The Center now averages nearly 20 adrenal tumor patients every week. Dr Carling was the Director of Endocrine Surgery at Yale University prior to opening the Center in Tampa. At the new Hospital for Endocrine Surgery, Dr Carling joins the Norman Parathyroid Center, the Clayman Thyroid Center and the Scarless Thyroid Surgery Center as the highest volume endocrine surgery center in the world. About the Carling Adrenal Center: Founded by Dr. Tobias Carling, one of the world's leading experts in adrenal gland surgery, the Carling Adrenal Center is a worldwide destination for the surgical treatment of adrenal tumors. Dr. Carling spent nearly 20 years at Yale University, including 7 as the Chief of Endocrine Surgery before leaving in 2020 to open to Carling Adrenal Center, which performs more adrenal operations than any other hospital in the world. (813) 972-0000. More about partial adrenalectomy for adrenal tumors can be found at the Center's website www.adrenal.com. From https://www.streetinsider.com/PRNewswire/Novel+application+of+amniotic+membrane+saves+adrenal+tissue+in+patients+undergoing+adrenal+surgery/19915274.html

Today’s Cushing’s Awareness Challenge post is about kidney cancer (renal cell carcinoma). You might wonder how in the world this is related to Cushing’s. I think it is, either directly or indirectly. I alluded to this a couple days ago when I said: So, as I said, I started Growth Hormone for my panhypopituitarism on December 7, 2004. I took it for a while but never really felt any better, no more energy, no weight loss. Sigh. April 14 2006 I went back to the endo and found out that the arginine test that was done in 2004 was done incorrectly. The directions were written unclearly and the test run incorrectly, not just for me but for everyone who had this test done there for a couple years. My endo discovered this when he was writing up a research paper and went to the lab to check on something. So, I went off GH again for 2 weeks, then was retested. The “good news” was that the arginine test is only 90 minutes now instead of 3 hours. Wow, what a nightmare my arginine retest started! I went back for that Thursday, April 27, 2006. Although the test was shorter, I got back to my hotel and just slept and slept. I was so glad that I hadn’t decided to go right home after the test. Friday I felt fine and drove back home, no problem. I picked up my husband for a biopsy he was having and took him to an outpatient surgical center. While I was there waiting for the biopsy to be completed, I started noticing blood in my urine and major abdominal cramps. There were signs all over that no cellphones were allowed so I sat in the restroom (I had to be in there a lot, anyway!) and I left messages for several of my doctors on what I should do. It was Friday afternoon and most of them were gone 🙁 I finally decided to see my PCP after I got my husband home. When Tom was done with his testing, his doctor took one look at me and asked if I wanted an ambulance. I said no, that I thought I could make it to the emergency room ok – Tom couldn’t drive because of the anaesthetic they had given him. I barely made it to the ER and left the car with Tom to park. Tom’s doctor followed us to the ER and instantly became my new doctor. They took me in pretty fast since I was in so much pain, and had the blood in my urine. At first, they thought it was a kidney stone. After a CT scan, my new doctor said that, yes, I had a kidney stone but it wasn’t the worst of my problems, that I had kidney cancer. Wow, what a surprise that was! I was admitted to that hospital, had more CT scans, MRIs, bone scans, they looked everywhere. My new “instant doctor” felt that he wasn’t up to the challenge of my surgery, so he called in someone else. My next new “instant doctor” came to see me in the ER in the middle of the night. He patted my hand, like a loving grandfather might and said “At least you won’t have to do chemotherapy”. And I felt so reassured. It wasn’t until later, much after my surgery, that I found out that there was no chemo yet that worked for my cancer. I was so thankful for the way he told me. I would have really freaked out if he’d said that nothing they had was strong enough! My open radical nephrectomy was May 9, 2006 in another hospital from the one where the initial diagnosis was made. My surgeon felt that he needed a specialist from that hospital because he believed preop that my tumor had invaded into the vena cava because of its appearance on the various scans. Luckily, that was not the case. My entire left kidney and the encapsulated cancer (10 pounds worth!) were removed, along with my left adrenal gland and some lymph nodes. Although the cancer (renal cell carcinoma AKA RCC) was very close to hemorrhaging, the surgeon believed he got it all. He said I was so lucky. If the surgery had been delayed any longer, the outcome would have been much different. I will be repeating the CT scans every 3 months, just to be sure that there is no cancer hiding anywhere. As it turns out, I can never say I’m cured, just NED (no evidence of disease). This thing can recur at any time, anywhere in my body. I credit the arginine re-test with somehow aggravating my kidneys and revealing this cancer. Before the test, I had no clue that there was any problem. The arginine test showed that my IGF is still low but due to the kidney cancer I couldn’t take my growth hormone for another 5 years – so the test was useless anyway, except to hasten this newest diagnosis. So… either Growth Hormone helped my cancer grow or testing for it revealed a cancer I might not have learned about until later. My five years are up now. When I was 10 years free of this cancer my kidney surgeon *thought* it would be ok to try the growth hormone again. I was a little leery about this, especially where I didn’t notice that much improvement. What to do? BTW, I decided to…

Way back when we first got married, my husband thought we might have a big family with a lot of kids. He was from a family of 6 siblings, so that’s what he was accustomed to. I am an only child so I wasn’t sure about having so many. I needn’t have worried. In January 1974 I had a miscarriage. I was devastated. My father revealed that my mother had also had a miscarriage. I had no idea. At some point later I tried fertility drugs. Clomid and another drug. One or both drugs made me very angry/depressed/bitchy (one dwarf I left off the image) Little did I know that these meds were a waste of time. Eventually, I did get pregnant and our wonderful son, Michael was born. It wasn’t until he was seven that I was finally, actually diagnosed with Cushing’s. When I had my early Cushing’s symptoms, I thought I was pregnant again but it was not to be. I’ll never forget the fall when he was in second grade. He was leaving for school and I said goodbye to him. I knew I was going into NIH that day for at least 6 weeks and my future was very iffy. The night before, I had signed my will – just in case. He just turned and headed off with his friends…and I felt a little betrayed. Michael wrote this paper on Cushing’s when he was in the 7th grade. From the quality of the pages, he typed this on typing paper – no computers yet! Click on each page to enlarge. http://cushieblog.files.wordpress.com/2012/04/michael-1.jpg?w=150&h=150&resize=150%2C150 http://cushieblog.files.wordpress.com/2012/04/michael2.jpg?w=150&h=150&resize=150%2C150 When Michael started having headache issues in middle school, I had him tested for Cushing’s. I had no idea yet if it could be familial but I wasn’t taking any chances. It turned out that my father had also had some unnamed endocrine issues. Hmmm… I survived my time and surgery at NIH and Michael grew up to be a wonderful young man, if an only child. 🙂 http://cushieblog.files.wordpress.com/2012/04/michael-belize.jpg?w=300&h=225&resize=300%2C225After I survived kidney cancer (Day Twelve, Cushing’s Awareness Challenge 2015) Michael and I went zip-lining – a goal of mine after surviving that surgery. This photo was taken in a treetop restaurant in Belize. For the mathematically inclined, this is his blog. Xor’s Hammer. I understand none of it. He also has a page of Math and Music, which I also don’t understand. I know it doesn’t fit into a Cushing’s awareness post but just because I’m a very proud mama – Michael got a PhD in math from Cornell and his thesis was Using Tree Automata to Investigate Intuitionistic Propositional Logic Michael explains How do we know the quintic is unsolvable? And, from his wedding: And, as of March 7, 2021:

http://cushieblog.files.wordpress.com/2012/04/uva20041.jpg?w=1428&resize=468%2C351 Cushing’s Conventions have always been special times for me – we learn a lot, get to meet other Cushies, even get referrals to endos! As early as 2001 (or before) my pituitary function was dropping. My former endo tested annually but did nothing to help me with the symptoms. In the fall of 2002 my endo refused to discuss my fatigue or anything at all with me until I lost 10 pounds. He said I wasn’t worth treating in my overweight condition and that I was setting myself up for a heart attack. He gave me 3 months to lose this weight. Those 3 months included Thanksgiving, Christmas and New Years. Needless to say, I left his office in tears, again. Fast forward 2 years to 2004. I had tried for a while to get my records from this endo. He wouldn’t send them, even at doctors’ or my requests. I wanted to go see Dr. Vance at UVa but I had no records so she wouldn’t see me until I could get them. Finally, my husband went to the former endo’s office and threatened him with a court order. The office manager managed to come up with about 13 pages of records. For going to him from 1986 to 2001 including weeks and weeks at NIH and pituitary surgery, that didn’t seem like enough records to me. In April of 2004, many of us from the message boards went to the UVa Pituitary Days Convention. That’s where the picture above comes in. Other pictures from that convention are here. By chance, we met a wonderful woman named Barbara Craven. She sat at our table for lunch on the last day and, after we learned that she was a dietitian who had had Cushing’s, one of us jokingly asked her if she’d do a guest chat for us. I didn’t follow through on this until she emailed me later. In the email, she asked how I was doing. Usually I say “fine” or “ok” but for some reason, I told her exactly how awful I was feeling. Barbara emailed me back and said I should see a doctor at Johns Hopkins. I said I didn’t think I could get a recommendation to there, so SHE referred me. The doctor got right back to me, set up an appointment. Between his vacation and mine, that first appointment turned out to be Tuesday, Sept 14, 2004. Just getting through the maze at Johns Hopkins was amazing. They have the whole system down to a science, moving from one place to another to sign in, then go here, then window 6, then… But it was very efficient. My new doctor was wonderful. Understanding, knowledgeable. He never once said that I was “too fat” or “depressed” or that all this was my own fault. I feel so validated, finally. He looked through my records, especially at my 2 previous Insulin Tolerance Tests (ITT). From those, he determined that my growth hormone has been low since at least August 2001 and I’ve been adrenal insufficient since at least Fall, 1999 – possibly as much as 17 years! I was amazed to hear all this, and astounded that my former endo not only didn’t tell me any of this, he did nothing. He had known both of these things – they were in the past records that I took with me. Perhaps that was why he had been so reluctant to share copies of those records. He had given me Cortef in the fall of 1999 to take just in case I had “stress” and that was it. The new endo took a lot of blood (no urine!) for cortisol and thyroid stuff. I went back on Sept. 28, 2004 for arginine, cortrosyn and IGF testing. He said that I would end up on daily cortisone – a “sprinkling” – and some form of GH, based on the testing the 28th. For those who are interested, my new endo is Roberto Salvatori, M.D. Assistant Professor of Medicine at Johns Hopkins Medical School: Catholic University School of Medicine, Rome, Italy Residency: Montefiore Medical Center Fellowship: Cornell University, Johns Hopkins University Board Certification: Endocrinology and Metabolism, Internal Medicine Clinical Interests: Neuroendocrinology, pituitary disorders, adrenal disorders Research Interests: Control of growth hormone secretion, genetic causes of growth hormone deficiency, consequences of growth hormone deficiency. Although I have this wonderful doctor, a specialist in growth hormone deficiency at Johns Hopkins, in November, 2004, my insurance company saw fit to over-ride his opinions and his test results based on my past pharmaceutical history! Hello??? How could I have a history of taking GH when I’ve never taken it before? Of course, I found out late on a Friday afternoon. By then it was too late to call my case worker at the drug company, so we had to appeal on Monday. My local insurance person also worked on an appeal, but the whole thing was just another long ordeal of finding paperwork, calling people, FedExing stuff, too much work when I just wanted to start feeling better by Thanksgiving. As it turned out the insurance company rejected the brand of hGH that was prescribed for me. They gave me the ok for a growth hormone was just FDA-approved for adults on 11/4/04. The day this medication was approved for adults was the day after my insurance said that’s what is preferred for me. In the past, this form of hGH was only approved for children with height issues. Was I going to be a guinea pig again? The new GH company assigned a rep for me, submitted info to pharmacy, and waited for insurance approval, again. I finally started the Growth Hormone December 7, 2004. Was the hassle and 3 year wait worth it? Stay tuned when all will be revealed. Read Dr. Barbara Craven’s Guest Chat, October 27, 2004 Thanks for reading 🙂 http://cushieblog.files.wordpress.com/2012/04/maryo-butterfly-script.gif?w=468&resize=251%2C121

In March of 1987, after the endo finally confirmed that I had Cushing’s, I was sent to a local hospital where they repeated all those same tests for another week and decided that it was not my adrenal gland (Cushing’s Syndrome) creating the problem. The doctors and nurses had no idea what to do with me, so they put me on the brain cancer ward. When I left this hospital after a week, we didn’t know any more than we had before. As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection. My husband asked my endo if it were his wife, if he would recommend this surgery. The endo responded that he was divorcing his wife – he didn’t care what happened to her. Oh, my! I chose NIH – closest and free. After I was interviewed by the doctors there, I got a letter that I had been accepted into the clinical trial. The night before I was admitted, I signed my will. I was sure I was going to die there. If not during testing, as a result of surgery. The first time I was there was for 6 weeks as an inpatient. More of the same tests. There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Several were from Greece. My first roommate was a nurse. She spent the entire first night screaming in pain. I was very glad when they moved me to a new room! Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with – either a cure or dying. While I was at NIH, I was gaining about a pound a day! During the time I was home the weekend before surgery, a college classmate of mine (I didn’t know her) DID die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until reading the alumnae magazine a couple months later! She was the same class, same major, same home-town, same disease… We have a Scottish doctor named James Lind to thank for the clinical trial. He conducted the first ever clinical trial in 1747 and developed the theory that citrus fruits cured scurvy. Lind compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days. I’d like to think that I advanced the knowledge of Cushing’s at least a little bit by being a guinea pig in 1987-1989. From the NIH: http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx Hope through Research Several components of the National Institutes of Health (NIH) conduct and support research on Cushing’s syndrome and other disorders of the endocrine system, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Center for Research Resources. NIH-supported scientists are conducting intensive research into the normal and abnormal function of the major endocrine glands and the many hormones of the endocrine system. Researchers continue to study the effects of excess cortisol, including its effect on brain structure and function. To refine the diagnostic process, studies are under way to assess the accuracy of existing screening tests and the effectiveness of new imaging techniques to evaluate patients with ectopic ACTH syndrome. Researchers are also investigating jugular vein sampling as a less invasive alternative to petrosal sinus sampling. Research into treatment options includes study of a new drug to treat the symptoms of Cushing’s syndrome caused by ectopic ACTH secretion. Studies are under way to understand the causes of benign endocrine tumor formation, such as those that cause most cases of Cushing’s syndrome. In a few pituitary adenomas, specific gene defects have been identified and may provide important clues to understanding tumor formation. Endocrine factors may also play a role. Increasing evidence suggests that tumor formation is a multistep process. Understanding the basis of Cushing’s syndrome will yield new approaches to therapy. The NIH supports research related to Cushing’s syndrome at medical centers throughout the United States. Scientists are also treating patients with Cushing’s syndrome at the NIH Clinical Center in Bethesda, MD. Physicians who are interested in referring an adult patient may contact Lynnette Nieman, M.D., at NICHD, 10 Center Drive, Room 1-3140, Bethesda, MD 20892-1109, or by phone at 301-496-8935. Physicians interested in referring a child or adolescent may contact Constantine Stratakis, M.D., D.Sc., at NICHD, 10 Center Drive, Room 1-3330, Bethesda, MD 20892-1103, or by phone at 301-402-1998.

Blue and Yellow – we have those colors on ribbons, websites, T-shirts, Cushing’s Awareness Challenge logos and even cars. This is the yellow PT cruiser I had rented for the Columbus, OH meeting in 2007. I didn’t ask for yellow. That’s just what the rental company gave me. Somehow, they knew. This meeting is the one when we all met at Hoggy’s for dinner although some of us travelers stayed at this hotel. I’m the one in yellow and blue. Later in 2007, I bought my own truly Cushie Car. I even managed to get a butterfly on the tags. http://cushieblog.files.wordpress.com/2012/04/cushie-car1.jpg?w=1428&resize=468%2C351 So, where did all this blue and yellow come from, anyway? The answer is so easy and without any thought that it will amaze you! In July of 2000, I was talking with my dear friend Alice, who ran a wonderful menopause site, Power Surge. We wondering why there weren’t many support groups online (OR off!) for Cushing’s and I wondered if I could start one myself and we decided that maybe I could. This website (http://www.cushings-help.com) first went “live” July 21, 2000. It was a one-page bit of information about Cushing’s. Nothing fancy. No message boards, no blogs, no wiki, no image galleries… Certainly no Cushing’s Awareness Challenges. I didn’t know much about HTML (yet!) but I knew a little from what Alice had taught me and I used on my music studio site. I didn’t want to put as much work <COUGH!> into the Cushing’s site as I had on the music studio site so I used a now defunct WYSIWYG (What You See Is What You Get) web editor called Microsoft FrontPage. One of their standard templates was – you guessed it! – blue and yellow. TaDa! Instant Cushie color scheme forever. Turns out that the HTML that this software churned out was really awful and had to be entirely redone as the site grew. But the colors stuck. Now, in this day of mobile web browsers and people going online on their cellphones, the website is being redone yet again. But the colors are still, and always, blue and yellow.

Richard M. Plotzker, MD Although adrenal insufficiency is uncommon, it is not so infrequent that we never encounter patients who have it. The sometimes-tricky presentations, along with the glorious responses to therapy, provide many endocrinologists with a blend of fascination and professional gratification. We think of the condition as a possibility more often than we find the real thing, doing cosyntropin tests that yield normal results for a variety of presentations, from critical illness to hyponatremia. We inherit people with panhypopituitarism and figure it out ourselves when an adult survivor of cancer who received central nervous system radiation years ago begins to gradually underperform. Despite our fascination with the condition and the frequent challenge of figuring out a clinical puzzle, few of us see more than a few dozen of these individuals, each unique in glucocorticoid and mineralocorticoid replacement requirements, and often without reliable laboratory tracking of our therapeutic judgments. These people have a way of generating calls to our offices, either from their own setbacks or emergency department (ED) doctors and surgeons who are skittish about elective outpatient surgery. But despite the central role of the endocrinologist in ongoing care, we have surprisingly little data on how these patients fare over time as they navigate the increasingly baffling maze of medical care of chronic diseases. Until now. A group in Alberta, Canada, performed a review of medical encounters among patients with primary or secondary adrenal insufficiency over a 5-year interval. An accumulation of data from a few central locations combined with computerized sorting capabilities has enabled better exploration of relatively rare conditions like adrenal insufficiency, which, when pooled, exposes common paths this condition takes. We sense from our phone calls that these people need emergency care, but the frequency of setbacks varies from never to a lot. Thus, large clinical databases have made health planning less laborious and more reliable but, as this study reveals, not exactly glitch-free. In Alberta, each person is assigned a personal identification number (PIN) that remains constant for all physician and pharmacy encounters. This allowed the research group to match diagnostic codes for primary and secondary adrenal insufficiency, and to capture individuals receiving multiple refills of glucocorticoids and mineralocorticoids. Because there were three active databases, however, some encounters appeared in multiple places, which the authors corrected to avoid overcounting. They found 2637 unique individuals seeking outpatient or ED care who had a coding diagnosis of primary or secondary adrenal insufficiency. An estimated prevalence of 839 per million Alberta residents exceeded the frequency of other national or regional estimates. The limitations of teasing out the realities of medical care from administrative codes may be best illustrated by the researchers' attempts to sort out how much medical care these people received and for what purpose. On average, the claims and encounter data show 2.2 ED visits and 17.8 outpatient visits per person with adrenal insufficiency. However, the diagnostic codes show that only a small fraction of these have an adrenal or pituitary diagnostic code for most episodes of medical care. The inclusion of physical therapy and radiologic procedures as outpatient visits makes it difficult to assess how the adrenal insufficiency affected other elements of health. The ED visits may be more revealing. Adrenal or pituitary codes rarely appeared as the primary diagnosis; however, among the top 10 were abdominal pain, volume depletion, electrolyte disorders, chest pain, and abscesses, often the sequelae of either adrenal insufficiency or its treatment. The authors determined who the patients were by their PINs and got some sense of what happened to them by tabulating the complications that resulted in emergency care. Unfortunately, the top 10 primary ED codes comprised only a small fraction of the 2699 different diagnostic codes submitted, so it remains unclear how much ED attention was directly or indirectly a consequence of hypoadrenalism, only that these patients seek emergency care considerably more frequently than others in Alberta. This analysis of administrative data confirms what most clinicians providing longitudinal care to these patients already suspected: they need more than average amounts of physician attention and they sometimes need rescue from crises unique to adrenal impairment. However, as we depend more and more on large amounts of aggregated data to isolate specific conditions and assess the treatment history, this study also exposes some of the limitations of how we code, classify, sort, and retrieve these patient encounters. Even data that should be binary, such as you went to the doctor or you didn't, have a way of slipping through the cracks, as not all medical visits in Alberta needed to be centrally reported. As much as physicians, myself among them, dislike our secondary roles as coding clerks, the defaults permitted, including "follow-up visit," often give no medical information yet are sufficient for payment. Having 2699 unique ED visit diagnoses impedes sorting them into the manageable categories we depend on as clinicians to understand diseases and as planners to assess public needs. Even things as basic as why the adrenals or pituitary failed, whether by immune, surgical, trauma, or medication (including opiate use) causes, are not adequately captured for later assessment. Big Data and the ability to access it has expanded our capabilities but, as this study demonstrates, more can be done to make it reveal to clinicians and planners what we most need to know. How many people with other uncommon but threatening diseases still drift in and out of our exam rooms and EDs, controlled by the appropriate specialist but shared with many others? It looks like we can figure out from administrative data more than we knew before but less than we would seek to find out. From https://www.medscape.com/viewarticle/971618

This is one of the suggestions from the Cushing’s Awareness Challenge post: This one is so easy. I’ve said it a thousand times – you know your own body better than any doctor will. Most doctors have never seen a Cushing’s patient, few ever will in the future. If you believe you have Cushing’s (or any other rare disease), learn what you can about it, connect with other patients, make a timeline of symptoms and photographs. Read, take notes, save all your doctors’ notes, keep your lab findings, get second/third/ten or more opinions. Make a calendar showing which days you had what symptoms. Google calendars are great for this. This is your life, your one and only shot (no pun intended!) at it. Make it the best and healthiest that you can. When my friend and fellow e-patient Dave deBronkart learned he had a rare and terminal kidney cancer, he turned to a group of fellow patients online and found a medical treatment that even his own doctors didn’t know. It saved his life. In this video, he calls on all patients to talk with one another, know their own health data, and make health care better one e-Patient at a time.

More than three-quarters of adults with Cushing’s disease assigned osilodrostat had a normalized mean urinary free cortisol level at 12 weeks and maintained a normal level at 36 weeks, according to data from the LINC 4 phase 3 trial. In findings published in The Journal of Clinical Endocrinology & Metabolism, 77% of adults with Cushing’s disease randomly assigned to osilodrostat (Isturisa, Recordati) had mean urinary free cortisol (UFC) levels reduced to below the upper limit of normal at 12 weeks compared with 8% of adults assigned to placebo. Most adults with Cushing's disease taking 2 mg twice daily osilodrostat had normalized mean UFC levels at 12 weeks compared with placebo. Data were derived from Gadelha M, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac178. “Osilodrostat is a highly effective treatment for Cushing’s disease, normalizing urinary free cortisol excretion in 77% of patients after 12 weeks’ treatment,” Mônica Gadelha, MD, professor of endocrinology at The Federal University of Rio de Janeiro, and colleagues wrote. “Cortisol reductions were maintained throughout 48 weeks of treatment and were accompanied by improvements in clinical signs of hypercortisolism and quality of life.” Gadelha and colleagues enrolled 73 adults aged 18 to 75 years with Cushing’s disease from 40 centers in 14 countries into the LINC 4 phase 3 trial. Participants were randomly assigned to 2 mg osilodrostat twice daily (n = 48) or placebo (n = 25) for 12 weeks. Urinary samples were collected at weeks 2, 5 and 8 to measure mean UFC, and dosage was adjusted based on efficacy and tolerability. After 12 weeks, participants from both groups received osilodrostat in a 36-week open-label treatment period. All participants restarted the open-label portion of the trial at 2 mg osilodrostat unless they were on a lower dose at week 12. Dose adjustments in the open-label phase were made using the same guidelines in the randomized, double-blind, placebo-controlled trial. The primary endpoint was the efficacy of osilodrostat at achieving a mean UFC below the upper limit of normal of 138 nmol per 24 hours at 12 weeks vs. placebo; the key secondary endpoint was the percentage of participants achieving a normal mean UFC at 36 weeks. At 12 weeks, the percentage of adults with a normalized mean UFC level was higher in the osilodrostat group compared with placebo (77.1% vs. 8%; P < .0001). At 36 weeks, 80.8% of all participants had a normal mean UFC level. The overall response rate was 79.5% at 48 weeks. Median time to first controlled mean UFC response was 35 days for those randomly assigned to osilodrostat as well as those randomly assigned to placebo who crossed over to osilodrostat for the open-label phase. At 48 weeks, 84% of participants were receiving 10 mg or less of osilodrostat per day, including 56% receiving 4 mg or less daily. At 12 weeks, the osilodrostat group had several cardiovascular and metabolic-related improvements, including systolic and diastolic blood pressure, HbA1c, HDL cholesterol, body weight and waist circumference. No changes were observed in the placebo group. “The improvements in cardiovascular and metabolic parameters were sustained throughout osilodrostat treatment and have the potential to alleviate the burden of comorbidities in many patients with Cushing’s disease,” the researchers wrote. At 12 weeks, 52.5% of those receiving osilodrostat had a reduction in supraclavicular fat pad and 50% had a reduction in dorsal fat pad. At least 25% of participants also had improvements in facial redness, striae, proximal muscle atrophy and central obesity. Improvements were sustained through week 48. During the placebo-controlled trial, grade 3 and 4 adverse events occurred for about 20% of participants in both groups. For the entire study, 38.4% of adults reported grade 3 and 4 adverse events, with the most common being hypertension. Eight participants discontinued the study due to adverse events. From https://www.healio.com/news/endocrinology/20220408/osilodrostat-normalizes-urinary-free-cortisol-in-most-adults-with-cushings-disease

Highlights • Cushing syndrome (CS) is a rare disorder with a variety of underlying etiologies. • CS is expected to affect 0.2 to 5 people per million per year. • Adrenal-dependent CS is an uncommon variant of CS. • This study reports a rare occurrence of pituitary and adrenal adenoma with CS. Abstract Introduction Cushing syndrome is a rare disorder with a variety of underlying etiologies, that can be exogenous or endogenous (adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent). The current study aims to report a case of ACTH-independent Cushing syndrome with adrenal adenoma and nonfunctioning pituitary adenoma. Case report A 37–year–old female presented with amenorrhea for the last year, associated with weight gain. She had a moon face, buffalo hump, and central obesity. A 24-hour urine collection for cortisol was performed, revealing elevated cortisol. Cortisol level was non-suppressed after administering dexamethasone. MRI of the pituitary revealed a pituitary microadenoma, and the CT scan of the abdomen with adrenal protocol revealed a left adrenal adenoma. Discussion Early diagnosis may be postponed due to the variety of clinical presentations and the referral of patients to different subspecialists based on their dominant symptoms (gynecological, dermatological, cardiovascular, psychiatric); it is, therefore, critical to consider the entire clinical presentation for correct diagnosis. Conclusion Due to the diversity in the presentation of CS, an accurate clinical, physical and endocrine examination is always recommended. Keywords Cushing syndrome Cushing's disease Adrenal adenoma Pituitary adenoma Urine free cortisol 1. Introduction Cushing syndrome (CS) is a collection of clinical manifestations caused by an excess of glucocorticoids [1]. CS is a rare disorder with a variety of underlying etiologies that can be exogenous due to continuous corticosteroid therapy for any underlying inflammatory illness or endogenous due to either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent [2], [3]. Cushing syndrome is expected to affect 0.2 to 5 people per million per year. Around 10% of such cases involve children [4], [5]. ACTH-dependent glucocorticoid excess owing to pituitary adenoma accounts for the majority (60–70%) of endogenous CS, with primary adrenal causes accounting for only 20–30% and ectopic ACTH-secreting tumors accounting for the remaining 5–10% [6]. Adrenal-dependent CS is an uncommon variant of CS caused mostly by benign (90%) or malignant (8%) adrenal tumors or, less frequently, bilateral micronodular (1%) or macronodular (1%) adrenal hyperplasia [7]. The current study aims to report a case of ACTH-independent Cushing syndrome with adrenal adenoma and nonfunctioning pituitary adenoma. The report has been arranged in line with SCARE guidelines and includes a brief literature review [8]. 2. Case report 2.1. Patient's information A 37–year–old female presented with amenorrhea for the last year, associated with weight gain. She denied having polyuria, polydipsia, headaches, visual changes, dizziness, dryness of the skin, cold intolerance, or constipation. She had no history of chronic disease and denied using steroids. She visited an internist, a general surgeon, and a gynecologist and was treated for hypothyroidism. She was put on Thyroxin 100 μg daily, and oral contraceptive pills were given for her menstrual problems. Last time, the patient was referred to an endocrinology clinic, and they reviewed the clinical and physical examinations. 2.2. Clinical examination She had a moon face, buffalo hump, central obesity, pink striae over her abdomen, and proximal weakness of the upper limbs. After reviewing the history and clinical examination, CS was suspected. 2.3. Diagnostic assessment Because the thyroid function test revealed low thyroid-stimulating hormone (TSH), free T3, and freeT4, the patient was sent for a magnetic resonance imaging (MRI) of the pituitary, which revealed a pituitary microadenoma (7 ∗ 6 ∗ 5) mm (Fig. 1). Since the patient was taking thyroxin and oral contraceptive pills, the investigations were postponed for another six weeks due to the contraceptive pills' influence on the results of the hormonal assessment for CS. After six weeks of no medication, a 24-hour urinary free cortisol (UFC) was performed three times, revealing elevated cortisol levels (1238, 1100, and 1248) nmol (normal range, 100–400) nmol. A dexamethasone suppression test was done (after administering dexamethasone tab 1 mg at 11 p.m., serum cortisol was measured at 9 a.m.). The morning serum cortisol level was 620 nmol (non-suppressed), which normally should be less than 50 nmol. The ACTH level was below 1 pg/mL. Download : Download high-res image (103KB) Download : Download full-size image Fig. 1. Contrast enhanced T1W weighted MRI (coronal section) showing small 7 mm hypo-enhanced microadenoma (yellow arrow) in right side of pituitary gland with mild superior bulge. Based on these findings, ACTH independent CS was suspected. The computerized tomography (CT) scan of the abdomen with adrenal protocol revealed a left adrenal adenoma (33 mm × 25 mm) without features of malignancy (Fig. 2). Download : Download high-res image (168KB) Download : Download full-size image Fig. 2. Computed tomography scan of the abdomen with IV contrast, coronal section, showing 33 mm × 25 mm lobulated enhanced left adrenal tumor (yellow arrow), showing absolute washout on dynamic adrenal CT protocol, consistent with adrenal adenoma. 2.4. Therapeutic intervention The patient was referred to the urologist clinic for left adrenalectomy after preparation for surgery and perioperative hormonal management. She underwent laparoscopic adrenalectomy and remained in the hospital for two days. The histopathology results supported the diagnosis of adrenal adenoma. 2.5. Follow-up She was released home after two days on oral hydrocortisone 20 mg in the morning and 10 mg in the afternoon. After one month of follow-up, serum cortisol was 36 nmol, with the resolution of some features such as weight reduction (3 kg) and skin color (pink striae became white). 3. Discussion Cushing's syndrome is a serious and well-known medical condition that results from persistent exposure of the body to excessive glucocorticoids, either from endogenous or, most frequently, exogenous sources [9]. The average age of diagnosis is 41.4 years, with a female-to-male ratio of 3:1 [10]. ACTH-dependent CS accounts for almost 80% of endogenous CS, while ACTH-independent CS accounts for nearly 20% [10]. This potentially fatal condition is accompanied by several comorbidities, including hypertension, diabetes, coagulopathy, cardiovascular disease, infections, and fractures [11]. Exogenous CS, also known as iatrogenic CS, is more prevalent than endogenous CS and is caused by the injection of supraphysiologic glucocorticoid dosages [12]. ACTH-independent CS is induced by uncontrolled cortisol release from an adrenal gland lesion, most often an adenoma, adrenocortical cancer, or, in rare cases, ACTH-independent macronodular adrenal hyperplasia or primary pigmented nodular adrenal disease [13]. The majority of data suggests that early diagnosis is critical for reducing morbidity and mortality. Detection is based on clinical suspicion initially, followed by biochemical confirmation [14]. The clinical manifestation of CS varies depending on the severity and duration of glucocorticoid excess [14]. Some individuals may manifest varying symptoms and signs because of a rhythmic change in cortisol secretion, resulting in cyclical CS [15]. The classical symptoms of CS include weight gain, hirsutism, striae, plethora, hypertension, ecchymosis, lethargy, monthly irregularities, diminished libido, and proximal myopathy [16]. Neurobehavioral presentations include anxiety, sadness, mood swings, and memory loss [17]. Less commonly presented features include headaches, acne, edema, abdominal pain, backache, recurrent infection, female baldness, dorsal fat pad, frank diabetes, electrocardiographic abnormalities suggestive of cardiac hypertrophy, osteoporotic fractures, and cardiovascular disease from accelerated atherosclerosis [10]. The current case presented with amenorrhea, weight gain, moon face, buffalo hump, and skin discoloration of the abdomen. Similar to the current case, early diagnosis may be postponed due to the variety of clinical presentations and the referral of patients to different subspecialists based on their dominant symptoms (gynecological, dermatological, cardiovascular, psychiatric); it is, therefore, critical to consider the entire clinical presentation for correct diagnosis [18]. Weight gain may be less apparent in children, but there is frequently an arrest in growth with a fall in height percentile and a delay in puberty [19]. The diagnosis and confirmation of the etiology can be difficult and time-consuming, requiring a variety of laboratory testing and imaging studies [20]. According to endocrine society guidelines, the initial assessment of CS must include one or more of the three following tests: 24-hour UFC measurement; evaluation of the diurnal variation of cortisol secretion by assessing the midnight serum or salivary cortisol level; and a low-dose dexamethasone suppression test, typically the 1 mg overnight test [21]. Although UFC has sufficient sensitivity and specificity, it does not function well in milder cases of Cushing's syndrome [22]. In CS patients, the typical circadian rhythm of cortisol secretion is disrupted, and a high late-night cortisol serum level is the earliest and most sensitive diagnostic indicator of the condition [23]. In the current case, the UFC was elevated, and cortisol was unsuppressed after administration of dexamethasone. All patients with CS should have a high-resolution pituitary MRI with a gadolinium-based contrast agent to prove the existence or absence of a pituitary lesion and to identify the source of ACTH between pituitary adenomas and ectopic lesions [24]. Adrenal CT scan is the imaging modality of choice for preoperatively localizing and subtyping adrenocortical lesions in ACTH-independent Cushing's syndrome [9]. MRI of the pituitary gland of the current case showed a microadenoma and a CT scan of the adrenals showed left adrenal adenoma. Surgical resection of the origin of the ACTH or glucocorticoid excess (pituitary adenoma, nonpituitary tumor-secreting ACTH, or adrenal tumor) is still the first-line treatment of all forms of CS because it leaves normal adjacent structures and results in prompt remission and inevitable recovery of regular adrenal function [12], [25]. Laparoscopic (retroperitoneal or transperitoneal) adrenalectomy has become the gold standard technique for adrenal adenomas since it is associated with fewer postoperative morbidity, hospitalization, and expense when compared to open adrenalectomy [17]. In refractory cases, or when a patient is not a good candidate for surgery, cortisol-lowering medication may be employed [26]. The current case underwent left adrenalectomy. Symptoms of CS, such as central obesity, muscular wasting or weakness, acne, hirsutism, and purple striae generally improve first and may subside gradually over a few months or even a year; nevertheless, these symptoms may remain in 10–30% of patients [27]. Glucocorticoid replacement is essential after adrenal-sparing curative surgery until the pituitary-adrenal function returns, which might take up to two years, especially if adrenal adenomas have been resected [25]. Chronic glucocorticoid excess causes lots of new co-morbidities, lowering the quality of life and increasing mortality. The most common causes of mortality in CS are cardiovascular disease and infections [28]. After one month of follow-up, serum cortisol was 36 nmol, and several features, such as weight loss (3 kg) and skin color, were resolved (pink striae became white). In conclusion, the coexistence of adrenal adenoma and pituitary adenoma with CS is a rare possibility. Due to the diversity in the presentation of CS, an accurate clinical, physical and endocrine examination is always recommended. Laparoscopic adrenalectomy is the gold standard for treating adrenal adenoma. Consent Written informed consent was obtained from the patient's family for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Provenance and peer review Not commissioned, externally peer-reviewed. Ethical approval Approval is not necessary for case report (till 3 cases in single report) in our locality. The family gave consent for the publication of the report. Funding None. Guarantor Fahmi Hussein Kakamad, Fahmi.hussein@univsul.edu.iq. Research registration number Not applicable. CRediT authorship contribution statement Abdulwahid M. Salh: major contribution of the idea, literature review, final approval of the manuscript. Rawa Bapir: Surgeon performing the operation, final approval of the manuscript. Fahmi H. Kakamad: Writing the manuscript, literature review, final approval of the manuscript. Soran H. Tahir, Fattah H. Fattah, Aras Gh. Mahmood, Rawezh Q. Salih, Shaho F. Ahmed: literature review, final approval of the manuscript. Declaration of competing interest None to be declared. References [1] S.M. Ahmed, S.F. Ahmed, S. Othman, B.A. Abdulla, S.H. Mohammed, A.M. Salih, et al. 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Uh, Oh – I’m nearly a day late (and a dollar short?)…and I’m not yet sure what today’s topic will be. I seem swamped by everything lately, waking up tired, napping, going to bed tired, waking up in the middle of the night, starting all over again…and the coronavirus which makes everything more hectic, stressful and tiring. It’s been like this since I was being diagnosed with Cushing’s in the mid-1980’s. You’d think things would be improved in the last 33 years. But, no. My mind wants things to have improved, so I’ve taken on more challenges, and my DH has provided some for me (see one of my other blogs, MaryOMedical). Thank goodness, I have only part-time jobs (4 0f them!), that I can mostly do from home. I don’t know how anyone post-Cushing’s could manage a full-time job! I can see this post morphing into the topic “My Dream Day“… I’d wake up refreshed and really awake at about 7:00AM and take the dog out for a brisk run. Get home about 8:00AM and start on my website work. Later in the morning, I’d get some bills paid – and there would be enough money to do so! After lunch, out with the dog again, then practice the piano some, read a bit, finish up the website work, teach a few piano students, work on my church job, then dinner. After dinner, check email, out with the dog, maybe handbell or choir practice, a bit of TV, then bed about 10PM Nothing fancy but NO NAPS. Work would be getting done, time for hobbies, the dog, 3 healthy meals. Just a normal life that so many take for granted. Or, do they?

It’s Here! Dr. Cushing was born in Cleveland Ohio. The fourth generation in his family to become a physician, he showed great promise at Harvard Medical School and in his residency at Johns Hopkins Hospital (1896 to 1900), where he learned cerebral surgery under William S. Halsted After studying a year in Europe, he introduced the blood pressure sphygmomanometer to the U.S.A. He began a surgical practice in Baltimore while teaching at Johns Hopkins Hospital (1901 to 1911), and gained a national reputation for operations such as the removal of brain tumors. From 1912 until 1932 he was a professor of surgery at Harvard Medical School and surgeon in chief at Peter Bent Brigham Hospital in Boston, with time off during World War I to perform surgery for the U.S. forces in France; out of this experience came his major paper on wartime brain injuries (1918). In addition to his pioneering work in performing and teaching brain surgery, he was the reigning expert on the pituitary gland since his 1912 publication on the subject; later he discovered the condition of the pituitary now known as “Cushing’s disease“. Read more about Dr. Cushing Today, April 8th, is Cushing’s Awareness Day. Please wear your Cushing’s ribbons, t-shirts, awareness bracelets or Cushing’s colors (blue and yellow) and hand out Robin’s wonderful Awareness Cards to get a discussion going with anyone who will listen. And don’t just raise awareness on April 8. Any day is a good day to raise awareness. I found this biography fascinating! I found Dr. Cushing’s life to be most interesting. I had previously known of him mainly because his name is associated with a disease I had – Cushing’s. This book doesn’t talk nearly enough about how he came to discover the causes of Cushing’s disease, but I found it to be a valuable resource, anyway. I was so surprised to learn of all the “firsts” Dr. Cushing brought to medicine and the improvements that came about because of him. Dr. Cushing introduced the blood pressure sphygmomanometer to America, and was a pioneer in the use of X-rays. He even won a Pulitzer Prize. Not for medicine, but for writing the biography of another Doctor (Sir William Osler). Before his day, nearly all brain tumor patients died. He was able to get the number down to only 5%, unheard of in the early 1900s. This is a very good book to read if you want to learn more about this most interesting, influential and innovative brain surgeon. What Would Harvey Say? http://cushieblog.files.wordpress.com/2013/08/harvey-book.jpeg?resize=183%2C276 (BPT) – More than 80 years ago renowned neurosurgeon, Dr. Harvey Cushing, discovered a tumor on the pituitary gland as the cause of a serious, hormone disorder that leads to dramatic physical changes in the body in addition to life-threatening health concerns. The discovery was so profound it came to be known as Cushing’s disease. While much has been learned about Cushing’s disease since the 1930s, awareness of this rare pituitary condition is still low and people often struggle for years before finding the right diagnosis. Read on to meet the man behind the discovery and get his perspective on the present state of Cushing’s disease. * What would Harvey Cushing say about the time it takes for people with Cushing’s disease to receive an accurate diagnosis? Cushing’s disease still takes too long to diagnose! Despite advances in modern technology, the time to diagnosis for a person with Cushing’s disease is on average six years. This is partly due to the fact that symptoms, which may include facial rounding, thin skin and easy bruising, excess body and facial hair and central obesity, can be easily mistaken for other conditions. Further awareness of the disease is needed as early diagnosis has the potential to lead to a more favorable outcome for people with the condition. * What would Harvey Cushing say about the advances made in how the disease is diagnosed? Significant progress has been made as several options are now available for physicians to use in diagnosing Cushing’s disease. In addition to routine blood work and urine testing, health care professionals are now also able to test for biochemical markers – molecules that are found in certain parts of the body including blood and urine and can help to identify the presence of a disease or condition. * What would Harvey Cushing say about disease management for those with Cushing’s disease today? Patients now have choices but more research is still needed. There are a variety of disease management options for those living with Cushing’s disease today. The first line and most common management approach for Cushing’s disease is the surgical removal of the tumor. However, there are other management options, such as medication and radiation that may be considered for patients when surgery is not appropriate or effective. * What would Harvey Cushing say about the importance of ongoing monitoring in patients with Cushing’s disease? Routine check-ups and ongoing monitoring are key to successfully managing Cushing’s disease. The same tests used in diagnosing Cushing’s disease, along with imaging tests and clinical suspicion, are used to assess patients’ hormone levels and monitor for signs and symptoms of a relapse. Unfortunately, more than a third of patients experience a relapse in the condition so even patients who have been surgically treated require careful long-term follow up. * What would Harvey Cushing say about Cushing’s disease patient care? Cushing’s disease is complex and the best approach for patients is a multidisciplinary team of health care professionals working together guiding patient care. Whereas years ago patients may have only worked with a neurosurgeon, today patients are typically treated by a variety of health care professionals including endocrinologists, neurologists, radiologists, mental health professionals and nurses. We are much more aware of the psychosocial impact of Cushing’s disease and patients now have access to mental health professionals, literature, patient advocacy groups and support groups to help them manage the emotional aspects of the disease. Learn More Novartis is committed to helping transform the care of rare pituitary conditions and bringing meaningful solutions to people living with Cushing’s disease. Recognizing the need for increased awareness, Novartis developed the “What Would Harvey Cushing Say?” educational initiative that provides hypothetical responses from Dr. Cushing about various aspects of Cushing’s disease management based on the Endocrine Society’s Clinical Guidelines. For more information about Cushing’s disease, visit www.CushingsDisease.com or watch educational Cushing’s disease videos on the Novartis YouTube channel at www.youtube.com/Novartis. From http://www.jsonline.com/sponsoredarticles/health-wellness/what-would-harvey-cushing-say-about-cushings-disease-today8087390508-253383751.html

The above is the official Cushing’s path to a diagnosis but here’s how it seems to be in real life: http://cushieblog.files.wordpress.com/2012/03/cushie-diagnosis.gif?resize=500%2C500 Egads! I remember the naive, simple days when I thought I’d give them a tube or two of blood and they’d tell me I had Cushing’s for sure. Who knew that diagnosing Cushing’s would be years of testing, weeks of collecting every drop of urine, countless blood tests, many CT and MRI scans… Then going to NIH, repeating all the above over 6 weeks inpatient plus an IPSS test, apheresis (this was experimental at NIH) and specialty blood tests… The path to a Cushing’s diagnosis is a long and arduous one but you have to stick with it if you believe you have this Syndrome.