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MaryO

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  1. Abstract Cushing's syndrome is a rare cause of myocardial infarction and heart failure. Herein, we report a female patient who presented acute myocardial infarction and heart failure with reduced ejection fraction. The patient was found to have hypercortisolism secondary to adrenocortical adenoma and responded well to therapy. This case underlines the effects of hypercortisolism on the cardiovascular system. The clinical presentation of this patient is unique because non-atherosclerotic myocardial infarction is rarely reported in Cushing's syndrome patients. Introduction Cushing's syndrome is an endocrine condition associated with excessive secretion of cortisol. Hypertension, vascular atherosclerosis, and chronic cardiac remodelling and dysfunction are commonly recognized cardiovascular complications in Cushing's syndrome patients.1 Herein, we report a rare case of Cushing's syndrome patient with a primary diagnosis of non-atherosclerotic myocardial infarction and heart failure (HF). Case Report A 61-year-old female with a past medical history of chronic obstructive pulmonary disease was admitted with sudden onset chest pain on 6 February 2018. Electrocardiogram showed ST-segment elevation in leads V3–V5. Blood biochemical results of 1 h after the onset of chest pain: cardiac troponin I (cTnI) 0.06 ug/L↑, creatine kinase (CK) 63 U/L, creatine phosphokinase-MB (CK-MB) 22 U/L, aspartate transferase (AST) 19 U/L, and lactic dehydrogenase (LDH) 482 U/L. Myocardial injury markers were markedly elevated at the time point of 18 h after onset: cTnI 13.9 ug/L↑, CK 613 U/L↑, CK-MB 102 U/L↑, AST 112 U/L↑, and LDH 833 U/L↑. Due to the acute ECG changes and elevated myocardial injury markers, the patient was preliminarily diagnosed as ST-segment elevation myocardial infarction (STEMI) and underwent coronary angiography, which showed no stenosis, occlusion or dissection of coronary arteries (Figure 1). Echocardiography showed enlarged left atrial dimension (LAD, 55 mm) and left ventricular end diastolic dimension (LVDd, 57 mm), and reduced ejection fraction (EF, 33%). The patient was treated for STEMI and HF, and was started on aspirin, statin, diuretic of furosemide and spirolactone, metoprolol, and Sacubitril/valsartan (SV, initiated June, 2020). The patient was strictly adherent to the medication prescribed (Table 1). Figure 1 Open in figure viewerPowerPoint Coronary angiogram demonstrating no significant obstruction in coronary artery circulation. Table 1. Echocardiography results 2020-06-22 2020-09-02 2021-03-29 2021-06-02 2021-09-01 2021-10-22 2021-12-21 LAD (mm) 55 55 46 52 47 44 41 LVDd (mm) 57 57 53 55 54 51 55 IVS (mm) 10 10 11 10 10 10 11 LVPW (mm) 11 11 11 10 11 9 10 EF (%) 33 30 31 39 47 49 52.5 EF, ejection fraction; IVS, interventricular septum; LAD, left atrium dimension; LVDd, left ventricular end diastolic dimension; LVPW, left ventricular posterior wall. However, the patient's condition was not improved despite optimized medication. On 26 January 2021, the patient was re-admitted with recurrent chest distress and oedema, with new symptoms of facial plethora, centripetal obesity, and hyperglycaemia (Figure S1). Abdominal CT scan showed a right adrenal adenoma (Figure 2). Cardiac magnetic resonance imaging revealed enlarged LVDd (62 mm), and reduced EF, with delayed myocardial enhancement and evidence of myocardial fibrosis and fatty deposits (Figure 3). Laboratory findings showed hypokalaemia: potassium 3.0 mmol/L, elevated serum cortisol level, low plasma ACTH level, and positive 1-mg overnight dexamethasone suppression test. Based on the above findings, the patient was diagnosed with Cushing's syndrome and started treatment with the glucocorticoid receptor inhibitor mifepristone on 5 February 2021. Figure 2 Open in figure viewerPowerPoint Abdominal CT scan showed adrenal adenoma at the right. Figure 3 Open in figure viewerPowerPoint Cardiac magnetic resonance imaging revealed enlarged LVDd, reduced EF, with delayed myocardial enhancement, evidence of myocardial fibrosis and fatty deposits. With mifepristone added to the previous medical therapy (aspirin, statin, sacubitril/valsartan, metoprolol and diuretic of furosemide and spirolactone, and mifepristone), the patient's condition and cardiac function improved, and echocardiography (21 December 2021) showed increased EF (52.5%). The patient underwent partial adrenalectomy on 22 December 2021. Postoperative pathology confirmed adrenal cortical adenoma. At last follow-up on 29 May 2023, the patient showed marked improvement in face and body shape, with no complaints of chest distress or oedema (Figure S2). Discussion In this case, the patient was first evaluated for STEMI due to her symptoms of chest pain, and the elevated ST-segment on ECG, along with the moderately elevated troponin I and other cardiac enzyme levels. However, coronary atherosclerotic heart disease was ruled out by the normal cardiac catheterization. We presume that a possible reason for acute myocardial infarction (AMI) might be vasospastic angina due to abnormal hormone levels with Cushing's syndrome, leading to increased excessive myocardial metabolic demand and relative myocardial hypoxia, which eventually induced myocardial infarction. Although coronary atherosclerotic heart disease is the main cause of AMI, many non-atherosclerotic processes can lead to an imbalance between decreased coronary blood flow and increased myocardial metabolic demand. To date, non-atherosclerotic myocardial infarction has rarely been reported in Cushing's syndrome patients. Vieira JT et al. reported that a patient with Cushing's disease was considered to have spontaneous coronary artery dissection, which is a rare reason for AMI.2 Cushing's syndrome is associated with an increased risk of cardiac failure,3 with both structural alterations and functional impairment. In our case, the patient's CMR imaging showed typical features of cardiac geometry, function, and fibrosis, in accordance with previous reports.4 The underlying mechanisms may be the enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in direct response to cortisol excess.5 Our patient responded well to the therapy of conventional anti-HF medication of sacubitril/valsartan, metoprolol, and diuretic, once mifepristone was added. This favourable response to the pharmacological regimen supports the benefits of the agents for the normalization of excess cortisol. This case indicates that early diagnosis and effective treatment of Cushing's syndrome may be crucial in preventing irreversible cardiac dysfunction secondary to cardiovascular events and heart failure. Acknowledgements This work was financially supported by the National Natural Science Foundation of China (81900409 and 82172182) and the PLA Youth Training Project for Medical Science (19QNP037). Conflict of interest The authors declares that there is no conflict of interest. From https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14548
  2. Abstract Gastrointestinal perforation is a well-addressed complication of exogenous hypercortisolism; however, patients with endogenous Cushing's syndrome (CS) do not usually experience this condition in clinical practice. The literature on this subject is limited and consists solely of clinical case reports/series with only 23 instances of gastrointestinal perforation occurring in individuals with endogenous Cushing's syndrome. This is mainly attributed to the rarity of Cushing's syndrome itself and the low chance of occurrence of such complications. We report a case of a recently diagnosed adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a 30-years-old female who presented initially with a three-month history of progressive weight gain, generalized weakness, acne, menstrual irregularity, and severe hypokalemia, and then developed a gastric ulcer perforation only one month after her ACTH-dependent Cushing's syndrome diagnosis and was managed through emergent surgery. Introduction A disorder of the endocrine system characterized by excessive cortisol production, known as Cushing's syndrome, rarely occurs. The main causes are pituitary tumors, ectopic adrenocorticotropic hormone (ACTH)-secreting tumors, or adrenal tumors that secrete cortisol independently [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur, especially when the diagnosis is not established at an early stage [2]. There is a possibility of gastrointestinal complications among patients receiving exogenous glucocorticoids. However, there is limited information on gastrointestinal complications associated with endogenous hypercortisolemia [3,4]. Thus far, only 23 instances have been published addressing the co-occurrence of gastrointestinal perforation with endogenous Cushing's syndrome [5-17]. To the best of our knowledge, this is the first case reporting gastric perforation in an ACTH-dependent Cushing's syndrome, while the vast majority reported diverticular, sigmoid, or duodenal perforation with Cushing's syndrome [5-17]. Herein, we describe the medical history, physical examination, and investigatory findings of a 30-year-old female with a recent diagnosis of ACTH-dependent Cushing's syndrome that was complicated by gastric ulcer perforation, necessitating an urgent exploratory laparotomy. The primary motivator of this case report was the rarity of the described condition, the atypical location of the perforation in such patient group, and the relatively young age of the patient. Case Presentation History and examination A 30-year-old female with a history of mental retardation was admitted to our emergency department (ER) with progressive weakness and fatigue. Upon taking the history, she had been having menstrual irregularities, progressive weight gain, and generalized weakness, which was significant enough to limit her physical activity and hinder her movement for the past three months. Initial vital signs showed that the patient had a body temperature of 37°C, a pulse rate of 90 beats per minute, and a blood pressure of 130/80 mmHg. On physical examination, the patient had a moon face with supraclavicular fullness, dorsocervical fat pad, purple abdominal striae, facial signs of hirsutism, and acne all over the face, shoulders, chest, and back. Investigations In the initial laboratory examination, hypokalemia of 2.1 mEq/L, hyperglycemia of 12.1 mmol/L, and metabolic alkalosis were detected (Table 1). The cortisol level after 1 mg dexamethasone suppression test was 2204 nmol/L (normal range 140-690), ACTH 123 pg/mL (normal range 7.2-63.3), DHEA-S 27.85 umol/L (normal range 2.6-13.9), And 24-hour urine cortisol level was 1560 mg/day (normal range 30-350) (Table 1). No suppression was observed in cortisol level with 8 mg dexamethasone suppression test. Parameter Initial presentation Perforation presentation Refrence range Na+ 143 mEq/L 139 mmol/L 135-147 mEq/L Cl- 85 mEq/L 105 mmol/L 98-108 mEq/L K+ 2.1 mEq/L 2.8 mmol/L 3.5-5.0 mEq/L Mg2+ 0.79 mmol/L 0.77 mmol/L 0.85-1.110 mmol/L PO3- 0.88 mmol/L 1.23 mmol/L 0.97-1.46 mmol/L PH 7.54 7.36 7.35-7.45 PCO2 67.5 mmHg 42.7 mmHg 35-45 mmHg PO2 27.7 mmHg 62.2 mmHg 75-100 mmHg HCO3 49.8 mEq/L 23.6 mEq/L 22-26 mEq/L Random blood glucose 12.1 mmol/L 24.1 mmol/L <5.5 mmol/L Hemoglobin 13.5 g/dL 14.9 g/dL 13.7-16.8 g/dL White blood cells 9,720 /uL 11,100 /uL 3,300-8,600 /uL Lymphocyte 0.48% 0.33% - Neutrophil 8.55% 9.66% - Eosinophil 0.0% 0.0% - TSH 0.55 mIU/L Was not ordered 0.4-4.0 mIU/L Cortisol 2204 nmol/L 4842 nmol/L 140-690 nmol/L ACTH 123 pg/mL Was not ordered 7.2-63.3 pg/mL Table 1: Laboratory findings on initial presentation and on perforation day TSH - thyroid stimulating hormone; ACTH - adrenocorticotropic hormone A series of CT scans for the neck, chest, abdomen, and pelvis was performed and failed to localize any tumors acting as an ectopic source. A pituitary MRI was performed, and no adenoma was found. To complete the diagnostic workup, we decided to do an inferior petrosal sinus sampling (IPSS) and PET scan with Gallium 68; however, the patient's family refused and requested discharge and outpatient follow-ups. These results, together with the biochemical and clinical findings, supported the diagnostic hypothesis of ACTH-dependent Cushing's syndrome. Treatment/management When addressing the issue of hypokalemia that the patient presented with initially, it was found to be resistant and difficult to correct. The patient was put on spironolactone 50 mg BID, and potassium chloride 20 mEq q8h, and her potassium level barely reached 3.5 mmol/L after several days. In addition, her magnesium level was corrected with magnesium oxide 800 mg every six hours. Her blood glucose level was controlled with insulin glargine 6 units daily and Novorapid as per the sliding scale. The patient was discharged on spironolactone tablets 50 mg BID (oral), potassium chloride 20 mEq q8h, cholecalciferol, calcium carbonate, insulin glargine 6 units daily, and Novorapid 4 units TID before meals. Follow-up and outcomes Seven days after discharge, she presented to the ER complaining of a new onset of abdominal pain, constipation, and reduced urine output. Her Glasgow Coma Scale (GCS) was 15, her blood pressure measurement was 146/90 mmHg, her pulse rate was 66 beats per minute, her respiratory rate was 21 breaths per minute, and her temperature was 36.7°C. Upon physical examination, the patient had distended non-tender abdomen without any other significant findings. Blood work was done, including renal functions, and all parameters, including potassium, were within normal limits. A chest X-ray was also performed and revealed no evidence of pneumoperitoneum. The patient was clinically stable after managing her abdominal pain with acetaminophen injection and administering fleet enema for constipation. After instructions on when to come again to the ER were given, the patient was discharged home on lactulose and paracetamol, and a close outpatient follow-up appointment was scheduled. Five days after the ER visit, the patient presented again to the ER. She was still complaining of severe non-resolving abdominal pain, constipation, and reduced urine output. Upon physical examination in the ER, the patient was found to have developed a new onset of lower limb edema, abdominal rebound tenderness, and abdominal rigidity and guarding. She was hypotensive with a blood pressure of 91/46 mmHg, pulse rate of 80 beats per minute, respiratory rate of 16 breaths per minute, temperature of 38.2 °C, and SpO2 of 96%. The only significant laboratory finding was her potassium level dropping low to 2.8 mEq/L (Table 1). An X-ray of the chest was requested and showed a large pneumoperitoneum (Figure 1). Figure 1: Posteroanterior chest X-ray at the time of gastric perforation displaying severe air under the diaphragm with bilateral obstruction indicating massive pneumoperitoneum (red arrow) Abdominal CT was also urgently performed and confirmed the presence of gastric perforation likely related to an underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature (Figures 2, 3). Figure 2: Coronal-section CT image of abdomen and pelvis at the time of gastric perforation showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature Figure 3: Horizontal-section CT image showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature The patient underwent an emergent gastric wedge resection for gastric perforation, and the pathology reported evidence of gastric ulcer with no evidence of malignancy. Furthermore, Helicobacter pylori test was performed on the sample, and it came back positive. The patient tolerated the surgery very well, and postoperative recovery was without any complications. Later, the patient was prescribed metyrapone 250 mg Q4h, which was then increased to 500 mg Q4h four days after surgery, and her cortisol level significantly dropped to 634nmol/L. During that time, a gastrin level test was also performed to exclude the presence of gastrinomas, and the level was 45 pg/ml (normal range 13-115). Discussion A small percentage of the population suffers from Cushing's syndrome, which is an endocrine disorder characterized by an endogenous overproduction of glucocorticoids, resulting in hypercortisolemia [1]. It is estimated to affect 0.7 to 2.4 people per million annually [1]. Hypercortisolemia alters psychologic, metabolic, and cardiovascular functions, resulting in increased mortality and morbidity rates, particularly if the diagnosis is delayed and long-term exposure to high cortisol levels occurs [2]. Women are more likely to suffer from this condition than men, and people in their 40s to 60s are most vulnerable to it [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur [1]. Due to the rarity of this condition, there is often a significant delay in diagnosis and treatment, which could eventually lead to complications from prolonged hypercortisolism. From another standpoint, in a systematic review, the incidence of peptic ulcer perforation ranges from 3.8 to 14 per 100,000 individuals in the general population [18]. In under-developed countries, patients are typically young, tobacco-using males [19]. However, patients in industrialized countries are typically older with multiple co-morbidities and are on long-term non-steroidal anti-inflammatory drugs (NSAIDs) or steroid use [19]. Patients may present with an abrupt onset of abdominal discomfort, abdominal rigidity, and tachycardia in the early stages of a perforated peptic ulcer [19]. Later, abdominal distention, pyrexia, hypotension, fever, and vomiting can occur [19]. Furthermore, when the diagnosis is made early, a perforated ulcer often has a good prognosis. However, the risk of adverse events increases if there is a delay in the diagnosis [20]. Therefore, making an early detection through different imaging modalities is crucial [20]. A history of peptic ulcer disease, NSAIDs, physiological stress, smoking, corticosteroids, and Helicobacter pylori are some of the well-established risk factors for a perforated peptic ulcer [20]. The prevalence of Helicobacter pylori among Saudi patients is high; in one study, the overall prevalence was 46.5% in patients with dyspepsia using gastric biopsy [21]. Several studies have explored the relationship between Helicobacter pylori and gastrointestinal perforation, but the results have been mixed. Some studies have suggested a higher prevalence of Helicobacter pylori infection among individuals with gastrointestinal perforation compared to those without, indicating a potential association. However, other studies have found no significant difference in the prevalence of Helicobacter pylori infection between perforated and non-perforated gastrointestinal ulcer cases [22]. Furthermore, they suggested that the presence of other risk factors like the use of NSAIDs, smoking, and alcohol may interact with Helicobacter pylori infection and contribute to the development of complications such as gastrointestinal perforation [22]. However, in our case, the patient did not have any established risk factors for gastric perforation, such as NSAIDs, smoking, or alcohol. Therefore, considering the low incidence of gastrointestinal perforation and high prevalence of Helicobacter pylori, the conflicting data regarding the association between Helicobacter pylori and gastrointestinal perforation, and the lack of established risk factors for gastrointestinal perforation in our patient, we suggest that prolonged excess glucocorticoids from Cushing's syndrome may have contributed to the gastric perforation either independently or synergistically with Helicobacter pylori since hypercortisolism can lead to a weakened gastrointestinal wall integrity due to decreased collagen turnover and disruption of mucosal protection by prostacyclin [15]. In addition, because of hypercortisolism, perforation may not be contained or healed initially due to the immunosuppressive effects of hypercortisolism, whether endogenous or exogenous [15]. Additionally, high levels of cortisol may delay the diagnosis and treatment since it may mask the symptoms of the perforation [14]. Moreover, our patient was treated for severe hypokalemia with potassium supplementation for an extended period of time. Previous studies have linked potassium chloride supplementation to gastrointestinal ulceration and perforation, making this a possible additive cause of our patient's condition [23,24]. A limited number of studies have addressed gastrointestinal perforations associated with endogenous hypercortisolemia [5-17]. The correlation between Cushing's syndrome and gastrointestinal perforation is highlighted in our study and in the case reports that have been previously published (Table 2). Similar to our case, a female predominance was seen in gastrointestinal perforation among the reported cases of Cushing's syndrome [6,7,12,13,15,16]. Additionally, the average age at which gastrointestinal perforation occurred in patients with endogenous hypercortisolism ranged from 45 to 80, which is a noticeably higher age range than the case we are presenting here (aged 30) [6-10,12]. Furthermore, unlike our case, in which gastrointestinal perforation occurred four months after the onset of Cushing's symptoms, Intestinal perforation occurs approximately 9.8 months after Cushing's symptoms first appear [15]. Furthermore, in our patient, gastric perforation occurred while she was hypercortisolemic and not in a remission state. Hence, in association with Helicobacter pylori infection, severe hypercortisolemia could have been a secondary contributing factor to gastric perforation. The complications of gastric ulceration, specifically with endogenous Cushing's syndrome, have been addressed in two case reports [25,26]. It must be noted, however, that neither case is similar to ours. A case of gastric perforation was reported by Kubicka et al. in a patient who had a confirmed diagnosis of gastrinoma, and the patient was diagnosed with ectopic Cushing's syndrome seven months after gastric perforation [25]. Therefore, since ectopic Cushing's syndrome was diagnosed seven months after the perforation, it is more likely that the gastrinoma contributed to this complication. In contrast, our patient's serum gastrin level was within the normal range, ruling out gastrinoma. Further, Hoshino et al. reported a case of gastrointestinal bleeding in a 39-year-old man with a confirmed diagnosis of Cushing's disease secondary to pituitary adenoma [26]. He was found to have gastric ulceration and bleeding along with Helicobacter pylori infection and elevated cortisol levels [26]. In spite of the patient not developing a gastric perforation, it was suggested by the author that hypercortisolism might be a contributing factor for gastric ulcer complications by slowing down the ulcer healing process [26] Reference Year of publication Age, gender Highest cortisol level plasma cortisol (PC, nmol/L) / UFC (nmol/L) Cause of Cushing's syndrome Time from onset of Cushing's symptoms to perforation (months) Reported site of gastrointestinal perforation Current 2023 30, Female PC 4842 ACTH-dependant 4 Gastric perforation Ishinoda et al. [17] 2023 24, Male PC 1647 Cushing's disease 12 Sigmoid colon perforation Wijewickrama et al. [16] 2021 32, Female PC 1147 Pituitary microadenoma 1 Diverticular perforation Shahidi et al. [15] 2019 72, Female UFC 5296 Pancreatic neuroendocrine tumor 12 Diverticular perforation Shahidi et al. [15] 2019 61, Female PC 1925 Metastatic medullary carcinoma of thyroid 12 Sigmoid colon and diverticular perforation Shahidi et al. [15] 2019 68, Female UFC 410 Cushing's disease 12 Sigmoid colon perforation Shahidi et al. [15] 2019 71, Female UFC 1533 Cushing's disease 4 Diverticular perforation Shahidi et al. [15] 2019 54, Male UFC 374 Cushing's disease 3 Sigmoid colon perforation Shahidi et al. [15] 2019 52, Female UFC 885 Cushing's disease 16 Diverticular perforation Sater et al. [14] 2018 80, Female UFC 5601 Lung carcinoid 36 Diverticular perforation Sater et al. [14] 2018 60, Female UFC 72726 Metastatic islet cell carcinoma 36 Diverticular perforation Sater et al. [14] 2018 31, Male UFC 1297 Cushing's disease 20 Diverticular perforation Sater et al. [14] 2018 52, Female UFC 2371 Lung carcinoid 4 Diverticular perforation Sater et al. [14] 2018 67, Male UFC 3836 Ectopic ACTH 10 Diverticular perforation Sater et al. [14] 2018 51, Male UFC 13552 Metastatic thymic carcinoma 4 Diverticular perforation Kaya et al. [9] 2016 70, Male PC 1432 Small cell lung cancer 1 Diverticular perforation Dacruz et al. [12] 2016 60, Female UFC 4481 Metastatic parotid tumor 5 Sigmoid colon and diverticular perforation Matheny et al. [10] 2016 67, Male UFC 11119 Metastatic medullary carcinoma of thyroid 4 Diverticular perforation Flynn et al. [13] 2016 63, Female UFC 12465 Pheochromocytoma 1 Perforation at the splenic flexure Balestrieri et al. [11] 2016 75, Male PC 2272 Neuroendocrine tumor 1 Intestinal perforation Hara et al, [8] 2013 79, Male PC 1230 Cushing's disease 6 Diverticular perforation De Havenon et al. [7] 2011 71, Female PC 2593 Cushing's disease 9 Diverticular perforation Lutgers et al. [6] 2010 55, Female UFC 10152 Right pheochromocytoma 1 Sigmoid colon and diverticular perforation Drake et al. [5] 1998 35, Male PC 1442 Islet cell tumor 4 Duodenal perforation and rupture of pancreatic pseudocyst Table 2: Current case and previous reported 23 cases of patients with Cushing's syndrome and gastrointestinal perforation UFC - urinary free cortisol; PC - plasma cortisol; ACTH - adrenocorticotropic hormone Conclusions A high blood cortisol level can be associated with various clinical manifestations and diverse sets of complications. This case report sheds light on one of the less common complications of hypercortisolism in patients with Cushing's syndrome, which is gastrointestinal perforation. Our report further supports the published evidence that gastrointestinal perforation is a rare but potentially fatal complication among patients with Cushing's syndrome. Moreover, it highlights the possibility of developing gastric perforations in this patient group, even at younger ages than expected. This should elicit a high clinical suspicion and demand prompt investigation of Cushing's syndrome patients in a hypercortisolism state presenting with modest gastrointestinal symptoms. References Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A: Cushing's syndrome. Endocrinol Metab Clin North Am. 2008, 37:135-49. 10.1016/j.ecl.2007.10.010 Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing's syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6 Goethals L, Nieboer K, De Smet K, De Geeter E, Tabrizi NH, Van Eetvelde E, de Mey J: Cortisone associated diverticular perforation. JBR-BTR. 2011, 94:348-9. 10.5334/jbr-btr.705 Piekarek K, Israelsson LA: Perforated colonic diverticular disease: the importance of NSAIDs, opioids, corticosteroids, and calcium channel blockers. Int J Colorectal Dis. 2008, 23:1193-7. 10.1007/s00384-008-0555-4 Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM: Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis. J Clin Endocrinol Metab. 1998, 83:3542-4. 10.1210/jcem.83.10.5156 Lutgers HL, Vergragt J, Dong PV, de Vries J, Dullaart RP, van den Berg G, Ligtenberg JJ: Severe hypercortisolism: a medical emergency requiring urgent intervention. Crit Care Med. 2010, 38:1598-601. 10.1097/CCM.0b013e3181e47b7a de Havenon A, Ehrenkranz J: A perforated diverticulum in Cushing's disease. Int J Surg Case Rep. 2011, 2:215-7. 10.1016/j.ijscr.2011.06.009 Hara T, Akutsu H, Yamamoto T, Ishikawa E, Matsuda M, Matsumura A: Cushing's disease presenting with gastrointestinal perforation: a case report. Endocrinol Diabetes Metab Case Rep. 2013, 2013:130064. 10.1530/EDM-13-0064 Kaya T, Karacaer C, Açikgöz SB, Aydemir Y, Tamer A: Severe hypokalaemia, hypertension, and intestinal perforation in ectopic adrenocorticotropic hormone syndrome. J Clin Diagn Res. 2016, 10:OD09-11. 10.7860/JCDR/2016/17198.7127 Matheny LN, Wilson JR, Baum HB: Ectopic ACTH production leading to diagnosis of underlying medullary thyroid carcinoma. J Investig Med High Impact Case Rep. 2016, 4:2324709616643989. 10.1177/2324709616643989 Balestrieri A, Magnani E, Nuzzo F: Unusual Cushing's syndrome and hypercalcitoninaemia due to a small cell prostate carcinoma. Case Rep Endocrinol. 2016, 2016:6308058. 10.1155/2016/6308058 Dacruz T, Kalhan A, Rashid M, Obuobie K: An ectopic ACTH secreting metastatic parotid tumour. Case Rep Endocrinol. 2016, 2016:4852907. 10.1155/2016/4852907 Flynn E, Baqar S, Liu D, et al.: Bowel perforation complicating an ACTH-secreting phaeochromocytoma. Endocrinol Diabetes Metab Case Rep. 2016, 2016:10.1530/EDM-16-0061 Sater ZA, Jha S, McGlotten R, Hartley I, El Lakis M, Araque KA, Nieman LK: Diverticular perforation: A fatal complication to forestall in Cushing syndrome. J Clin Endocrinol Metab. 2018, 103:2811-4. 10.1210/jc.2018-00829 Shahidi M, Phillips RA, Chik CL: Intestinal perforation in ACTH-dependent Cushing's syndrome. Biomed Res Int. 2019, 2019:9721781. 10.1155/2019/9721781 Wijewickrama PS, Ratnasamy V, Somasundaram NP, Sumanatilleke M, Ambawatte SB: A challenging case of Cushing's disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report. BMC Endocr Disord. 2021, 21:29. 10.1186/s12902-021-00701-0 Ishinoda Y, Uto A, Meshino H, et al.: Bowel perforation associated with Cushing's disease: a case report with literature review. Endocr J. 2023, 70:933-9. 10.1507/endocrj.EJ23-0110 Lau JY, Sung J, Hill C, Henderson C, Howden CW, Metz DC: Systematic review of the epidemiology of complicated peptic ulcer disease: incidence, recurrence, risk factors and mortality. Digestion. 2011, 84:102-13. 10.1159/000323958 Chung KT, Shelat VG: Perforated peptic ulcer - an update. World J Gastrointest Surg. 2017, 9:1-12. 10.4240/wjgs.v9.i1.1 Weledji EP: An overview of gastroduodenal perforation. Front Surg. 2020, 7:573901. 10.3389/fsurg.2020.573901 Akeel M, Elmakki E, Shehata A, Elhafey A, Aboshouk T, Ageely H, Mahfouz MS: Prevalence and factors associated with H. pylori infection in Saudi patients with dyspepsia. Electron Physician. 2018, 10:7279-86. 10.19082/7279 Thirupathaiah K, Jayapal L, Amaranathan A, Vijayakumar C, Goneppanavar M, Nelamangala Ramakrishnaiah VP: The association between Helicobacter pylori and perforated gastroduodenal ulcer. Cureus. 2020, 12:e7406. 10.7759/cureus.7406 Farquharson-Roberts MA, Giddings AE, Nunn AJ: Perforation of small bowel due to slow release potassium chloride (slow-K). Br Med J. 1975, 3:206. 10.1136/bmj.3.5977.206 Payan H, Blaustein A: Potassium chloride and small bowel perforation. Gastroenterology. 1965, 48:877-8. 10.1016/S0016-5085(65)80073-7 Kubicka E, Zawadzka K, Syrycka J, Kałużny M, Pawluś A, Bolanowski M: A case of gastrinoma associated with ectopic Cushing syndrome. Pol Arch Intern Med. 2020, 130:328-9. 10.20452/pamw.15201 Hoshino C, Satoh N, Narita M, Kikuchi A, Inoue M: Another 'Cushing ulcer'. BMJ Case Rep. 2011, 2011:10.1136/bcr.02.2011.3888 From https://www.cureus.com/articles/196132-adrenocorticotropic-hormone-dependent-cushings-syndrome-complicated-with-gastric-ulcer-perforation-in-a-30-year-old-saudi-female-a-case-report-and-a-review-of-the-literature#!/
  3. Abstract Objective Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. Design National, multicenter and retrospective study. Patients All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. Measurements Diagnostic tests of CD and tumour size. Results Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enrolled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. Conclusions Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery. From https://onlinelibrary.wiley.com/doi/10.1111/cen.14980
  4. Abstract Cushing’s syndrome is a condition leading to overproducing of cortisol by the adrenal glands. If the pituitary gland overproduces cortisol, it is called Cushing’s disease. Cushing’s syndrome and even Cushing’s disease during and after pregnancy are rare events. There is not enough literature and guidance for managing and treating these patients. The diagnosis of Cushing’s syndrome in pregnancy is often delayed because the symptoms overlap. We presented a thin 31-year-old woman, admitted 2 months after a normal-term delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course. She had no clinical discriminatory features of Cushing’s syndrome. Given that the patient only presented with psychosis and proximal myopathy and had an uncomplicated pregnancy, our case was considered unusual. The patients also had hyperpigmentation and severe muscle weakness which are among the less common presentations of Cushing’s syndrome. Our findings suggest that an early diagnosis of Cushing’s disease is important in pregnancy period for its prevalent fetal and maternal complications, and it should be treated early to optimize fetal and maternal outcomes as there is an increasing trend toward live births in treated participants. Introduction Cushing’s syndrome is a condition that originates from excessive production of glucocorticoids. The condition is most common in women of childbearing age and is characterized by altered distribution of the adipose tissue to the central and upper regions of the trunk (central obesity and buffalo hump), face (moon face), capillary wall integrity (easy bruising), hyperglycemia, hypertension, mental status changes and psychiatric symptoms, muscle weakness, signs associated with hyperandrogenism (acne and hirsutism), and violaceous striae among other signs. Hypercortisolism and hyperandrogenism suppress the production of the pituitary gonadotropins, which in turn leads to menstrual irregularities and infertility.1-3 Moreover, the main common cause of developing Cushing’s syndrome is the use of exogenic steroid.3 Cushing’s disease is a form of Cushing’s syndrome with overproduction of adrenocorticotropic hormone (ACTH) due to pituitary adenoma. The diagnosis is made using clinical features and paraclinical tests including urinary free cortisol (UFC), serum ACTH, dexamethasone suppression tests (DSTs), pituitary magnetic resonance imaging (MRI), and sometimes by inferior petrosal sinus sampling (IPSS).4 Although women with Cushing’s disease are less likely to become pregnant, timely diagnosis and appropriate management are especially important during possible pregnancy, preventing neonatal and maternal complications and death. The diagnosis is challenging due to the overlap of the disease symptoms with the changes associated with a normal pregnancy. Moreover, the hormonal milieu during pregnancy has recently been proposed as a potential trigger for Cushing’s disease in some cases; hence, the term “pregnancy-associated Cushing’s disease” has been used for the disease in the recent literature. In this study, we presented a thin 31-year-old woman who was referred to our clinic 2 months after a normal delivery, with an atypical presentation of Cushing’s disease, unusual clinical features, and a challenging clinical course. Case Presentation Our patient was a 31-year-old woman who presented 2 months after the delivery of her second child. She had a history of type 2 diabetes mellitus and hypertension in the past 2 years prior to her presentation. She had been admitted to another center following an episode of falling and muscle weakness. Two weeks later, she was admitted to our center with an impression of pulmonary thromboembolism due to tachypnea, tachycardia, and dyspnea. During follow-up, she was found to have leukocytosis, hyperglycemia (random blood sugar: 415 mg/d; normal level: up to 180 mg/dL) and hypokalemic metabolic alkalosis (PH: 7.5, HCO3 [bicarbonate]: 44.7 mEq/L, paO2 [partial pressure of oxygen]: 73 mm Hg, pCO2: 51.7 mm Hg, potassium: 2.7 mEq/L [normal range: 3.5-5.1 mEq/L]), which was refractory to the treatment; therefore, an endocrinology consultation was first requested. On physical examination, the patient was agitated, confused, and psychotic. Her vital signs were: blood pressure 155/100 mm Hg, heart rate: 130 bpm, and respiratory rate: 22 bpm, temperature: 39°C. As it has shown in Figure 1A, her face is not typical for moon face of Cushing’s syndrome, but facial hirsutism (Figure 1A) and generalized hyperpigmentation is obvious (Figure 1A-C). She was a thin lady and had a normal weight and distribution of adiposity (Body Mass Index [BMI] = 16.4 kg/m2; weight: 40 kg, and height: 156 cm). Aside from thinness of skin, she did not have the cutaneous features of Cushing’s syndrome (e.g. purpura, acne, and violaceous striae) and did not have supraclavicular and dorsocervical fat pad (buffalo hump), or plethora. In other words, she had no clinical discriminatory features of Cushing’s syndrome despite the high levels of cortisol, as confirmed by severely elevated UFC (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). In addition, as will be mentioned later, the patient had axonal neuropathy which is a very rare finding in Cushing’s syndrome. Figure 1. Clinical finding of our case with Cushing’s disease. (A) Hirsutism, (B) muscle atrophy seen in proximal portion of lower limbs, and (C) hyperpigmentation specially on the skin of the abdominal region. OPEN IN VIEWER She had a markedly diminished proximal muscle force of 1 out of 5 across all extremities; the rest of the physical examinations revealed no significant abnormalities (Figure 1B). On the contrary, based on her muscle weakness, hirsutism, psychosis and hyperpigmentation and refractory hypokalemic alkalosis, hyperglycemia, and hypertension, Cushing’s syndrome was suspected; therefore, 24-hour UFC level was checked that the results showed a severely elevated urinary cortisol (5000 μg/24 h and 8000 μg/24 h; normal level: 4-40 μg/24 h). Serum ACTH level was also inappropriately elevated (45 pg/mL; normal range: 10-60 pg/mL). High-dose dexamethasone failed to suppress plasma cortisol level and 24-hour urine cortisol level. A subsequent pituitary MRI showed an 8-mm pituitary mass, making a diagnosis of Cushing’s disease more probable. Meanwhile, the patient was suffering from severe muscle weakness that did not improve after the correction of hypokalemia. Then, a neurology consultation was requested. The neurology team evaluated laboratory data as well as EMG (Electromyography) and NCV (Nerve Conduction Velocity) of the patient, and based on their findings, “axonal neuropathy” was diagnosed for her weakness; so they ruled out the other neuromuscular diseases. A 5-day course of intravenous immunoglobulin (IVIG) was started for her neuropathy; however, the treatment did not improve her symptoms and the patient developed fungal sepsis and septic shock. Therefore, she was processed with broad-spectrum antibiotics and antifungal agents and recovered from the infection. Mitotane was started for the patient before definitive surgical treatment to suppress hormonal production due to her poor general condition. Despite the 8-mm size of the pituitary mass which is likely to be a source of ACTH, our patient was underweight and showed the atypical clinical presentation of Cushing’s disease, making us suspect an ectopic source for the ACTH. Therefore, a Gallium dotatate scan was performed to find any probable ectopic sources; however, the results were unremarkable. The patient underwent Trans-Sphenoidal Surgery (TSS) to resect the pituitary adenoma because it was not possible to perform IPSS in our center. Finally, the patient’s condition including electrolyte imbalance, muscle weakness, blood pressure, and hyperglycemia started to improve significantly. The pathologist confirmed the diagnosis of a corticotropic adenoma. Nevertheless, the patient suddenly died while having her meal a week after her surgery; most likely due to a thromboembolic event causing a cardiac accident. Discussion Our patient was significantly different from other patients with Cushing’s disease because of her atypical phenotype. She was unexpectedly thin and had psychosis, hyperpigmentation, proximal myopathy, axonal neuropathy and no clinical discriminatory features of Cushing’s syndrome such as central adiposity, dorsocervical or supraclavicular fat pad, plethora or striae. She had also a history of type 2 diabetes and hypertension 2 years before her admission. The patient was diagnosed with Cushing’s later. From what was presented, the patient did not know she had Cushing’s until after her delivery and despite the highly elevated UFC, and she completed a normal-term delivery. Given that she only presented with psychosis and proximal myopathy, her pregnancy was considered unusual. Her clinical features such as hyperpigmentation and severe muscle weakness are among less common presentations.5 11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) is an enzyme responsible for converting cortisone (inactive glucocorticoid) into cortisol (active). It is speculated that this enzyme has a role in obesity (Figure 2).6,7 Figure 2. The enzymatic actions of 11β-hydroxysteroid dehydrogenase on its substrate interconverting inactive and active glucocorticoid. OPEN IN VIEWER In a case reported by Tomlinson, a 20-year-old female was diagnosed with Cushing’s disease despite not having the classical features of the disease. It has been suggested that the mechanism is a partial defect in 11β-HSD1 activity and concomitant increase in cortisol clearance rate. Thus, the patient did not have a classic phenotype; the defect in the conversion of cortisone to cortisol rises cortisol clearance and protects the patient from the effects of cortisol excess. This observation may help explain individual susceptibility to the side effects of glucocorticoids.6 Further studies of Tomlinson et al showed that a deficit in the function of (and not a mutation related to) 11β-HSD2 might have been responsible for the absence of typical Cushing’s symptoms. 11-HSD2 keeps safe the mineralocorticoid receptor from excess cortisol. Mutation in the HSD11B2 gene explains an inherited form of hypertension, apparent mineralocorticoid excess syndrome, in which Cushing’s disease results in cortisol-mediated mineralocorticoid excess affecting the kidney and leads to both hypokalemia and hypertension.8 It is frequent in Cushing’s syndrome that the patients usually have no mineralocorticoid hypertension; however, it is still proposed that a defect in 11β-HSD1 can be responsible for the presence of mineralocorticoid hypertension in a subgroup of patients. In fact, 11β-HSD1 is expressed in several tissues like the liver, kidneys, placenta, fatty tissues and gonads,9 meaning that this enzyme may potentially affect the results of cortisol excess in Cushing’s syndrome/disease. Abnormality in the function of this enzyme could explain the absence of the symptoms like central obesity, easy bruising, and typical striae during Cushing’s disease. Several factors affect the action of glucocorticoids. In this regard, the impact of the different types and levels of impairment in glucocorticoid receptors have been highlighted in some studies, as it can lead to different levels of response to glucocorticoids10 as well as a variety in the symptoms observed in Cushing’s disease. The predominant reaction of the NADP(H)-dependent enzyme 11-Tukey’s honestly significant difference (HSD)1 happens through the catalysis of the conversion of inactive cortisol into receptor-active cortisol. The reverse reaction is mediated through the unidirectional NAD-dependent 11-HSD type 2 (Figure 2).11 In another case reported by Ved V. Gossein, a 41-year-old female was evaluated for hirsutism and irregular menstrual cycles. Her BMI was 22.6 kg/m2. The patient had no signs or symptoms of overnight recurrent Cushing’s syndrome, the 48-hour DST failed to suppress cortisol levels, and 24-hour urinary cortisol levels were persistently elevated on multiple occasions. Adrenocorticotropic hormone levels were unreasonably normal, suggesting ACTH-dependent hypercortisolism. Despite these disorders, she had 2 children. Magnetic resonance imaging (MRI) of the pituitary did not show any abnormalities. Moreover, abdominal MRI did not show adrenal mass or enlargement. Genetic testing to determine glucocorticoid resistance syndrome showed no mutation.12 Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized or partial insensitivity of target tissues to glucocorticoids.13-17 There is a compensatory increase in hypothalamic-pituitary activity due to decreased sensitivity of peripheral tissues to glucocorticoids systems.13-17 Excessive ACTH secretion leads to high secretion of cortisol and mineralocorticoids and/or androgens. However, the clinical features of Cushing’s syndrome do not develop after resistance to the effects of cortisol. Generalized glucocorticoid resistance is a rare condition characterized by high cortisol levels but no scarring of Cushing’s syndrome.18 An important aspect of our case was her pregnancy. Our patient had a history of hypertension and diabetes type 2, 2 years before her presentation to our center that could be because of an undiagnosed Cushing’s disease. The patient’s pregnancy terminated 2 months prior the admission and she had a normal vaginal delivery. So, we suspect that she become pregnant while involved with the disease. Aside from focusing on how this can happen in a patient with such high levels of glucocorticoids, more attention should be paid to occurring pregnancy in the background of Cushing’s disease. In fact, up to 250 patients were reported, of which less than 100 were actively treated.19-22 Cushing’s disease is associated with serious complications in up to 70% of the cases coinciding with pregnancy.21 The most frequent maternal complications reported in the literature are hypertension and impaired glucose tolerance, followed by preeclampsia, osteoporosis, severe psychiatric complications, and maternal death (in about 2% of the cases). Prematurity and intrauterine growth retardation account for the most prevalent fetal complications. Stillbirth, intrauterine deaths, intrauterine hemorrhage, and hypoadrenalism have also been reported.23 Early diagnosis is especially challenging during pregnancy because of many clinical and biochemical shared features of the 2 conditions.23,24 These features include an increase in ACTH production, corticosteroid-binding globulin (CBG) 1 level, level of cortisol (urinary, plasma and free), hyperglycemia, weight gain, and an increased chance for occurrence of bruising, hypertension (mistaken with preeclampsia), gestational diabetes mellitus, weight gain, and mood swings.3 There are some suggestions proposed in the studies that help in screening and differentiation of Cushing’s from the normal and abnormal effects of pregnancy and Cushing’s disease from Cushing’s syndrome in suspected pregnant patients. Contrary to Cushing’s syndrome, the nocturnal minimum level of cortisol is preserved in pregnancy.23,25 There is not yet a diagnostic cut-off determined on mentioned level; however, a few studies elucidate the evaluation of hypercortisolemia in a pregnant patient.26-28 Urinary free cortisol, a measure that reflects the amount of free cortisol in circulation, normally increases during pregnancy, and it can increase up to 8 times the normal level with Cushing’s disease during the second and the third trimesters,23,29 which is a useful tool to evaluate cortisol levels in a suspected pregnant woman. Because the suppression of both UFC and plasma cortisol is decreased in pregnancy,23,30 a low-dose DST is not very helpful for screening Cushing’s disease in pregnant patients. However, a high-dose DST with a <80% cortisol suppression might only indicate Cushing’s disease.3,31 Thus, it helps differentiating between ectopic ACTH syndrome and Cushing’s disease.32 The use of high-dose DST can distinguish between adrenal and pituitary sources of CS in pregnancy. Owing to the limited evidence available and the lack of data on normal pregnancies, the use of corticotropin-releasing hormone (CRH), desmopressin, and high-dose DST in pregnancy is not recommended yet.33 More timely diagnosis as well as timely intervention may have saved the life of our patient. To differentiate between ectopic ACTH syndrome and Cushing’s disease, adrenal imaging should be considered. For higher plasma levels, combined employment of CRH stimulation test and an 8-mg DST can be helpful.3 Bilateral inferior petrosal sinus sampling (B-IPSS) might be needed when the findings are not in accordance with other results, but it is recommended to perform B-IPSS only if the noninvasive studies are inconclusive and only if there is enough expertise, experience, and technique for its performance.3 Although axonal neuropathy has been reported as a rare syndrome associated with paraneoplastic ectopic Cushing’s syndrome and exogenous Cushing’s syndrome, its association with Cushing’s disease has not been reported.5,32 Our patient had severe muscle weakness that we initially attributed it to myopathy and hypokalemia associated with Cushing’s syndrome. In our study, the diagnosis of axonal neuropathy was made based on electrophysiological studies by a neurology consultant and then IVIG was administered; however, the patient’s weakness did not improve after this treatment. The co-occurrence of Guillain-Barré syndrome which may also be classified as axonal neuropathy has also been reported in a pregnant woman with ectopic Cushing’s syndrome.34,35 Whether this finding is coincidental or the result of complex immune reactions driven by Cushing’s disease, or the direct effect of steroids, these results cannot be deduced from current data.36 Some data suggest that the fluctuations and inferior petrosal sinus sampling may trigger the flare of autoimmune processes, specifically when the cortisol levels start to decline during the course of Cushing’s syndrome.35,8 Also, due to COVID-19 pandemic affecting vital organs like kidney, paying attention to COVID-19 is suggested.37-40 Conclusions We presented a thin young female with psychosis, proximal myopathy, and axonal neuropathy with Cushing’s disease who had a recent pregnancy that was terminated without any fetal or maternal complications despite the repeated elevated serum cortisol and 24-hour UFC; therefore, we suggest that she might have glucocorticoid resistance. Glucocorticoid resistance is a rare disease in which the majority, but not all, of patients have a genetic mutation in the hGR-NR3C1 gene. As we did not perform genetic testing for our patient, the data are lacking. Another clue to the absence of the classic Cushing’s disease phenotype in our case is the role of isoenzymes of 11-HSD1 and 11-HSD2. Other mechanisms, such as the defect somewhere in the glucocorticoid pathway of action such as a decreased number of receptors, a reduction in ligand affinity, or a postreceptor defect, play an important role in nonclassical clinical manifestations of Cushing’s syndrome. Acknowledgments The authors thank the patient for allowing us to publish this case report. The authors show their gratitude to the of the staff of the Rasool Akram Medical Complex Clinical Research Development Center (RCRDC) specially Mrs. Farahnaz Nikkhah for its technical and editorial assists. Ethics Approval Our institution does not require ethical approval for reporting individual cases or case series. Informed Consent Written informed consent was obtained from the patient and for her anonymized information to be published in this article. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1. Guilhaume B, Sanson ML, Billaud L, Bertagna X, Laudat MH, Luton JP. Cushing’s syndrome and pregnancy: aetiologies and prognosis in twenty-two patients. Eur J Med. 1992; 1(2):83-89. GO TO REFERENCE PubMed Google Scholar 2. Lin W, Huang HB, Wen JP, et al. Approach to Cushing’s syndrome in pregnancy: two cases of Cushing’s syndrome in pregnancy and a review of the literature. Ann Transl Med. 2019; 7(18):490. 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GO TO REFERENCE Crossref PubMed Google Scholar Related content Similar articles: Open Access Ectopic ACTH Production Leading to Diagnosis of Underlying Medullary Thyroid Carcinoma Show details Open Access Muscle Weakness: A Misleading Presentation in Children With Distinctive Syndromic Entities (Clinical Case Reports) Show details Open Access A Pitfall of Falsely Elevated ACTH: A Case Report and Literature Review Show details View more Sage recommends: SAGE Knowledge Entry Hypothalamic-Pituitary-Adrenal Axis Show details SAGE Knowledge Entry Congenital Adrenal Hyperplasia Show details SAGE Knowledge Entry Guillain-Barré Syndrome Show details View more From https://journals.sagepub.com/doi/full/10.1177/23247096231204732
  5. Abstract Cushing’s disease is a rare neuroendocrine disorder with excessive endogenous cortisol, impaired cognition, and psychiatric symptoms. Evidence from resting-state fMRI revealed the abnormalities of static brain connectivity in patients with Cushing’s disease (CD patients). However, it is unknown whether the CD patients’ dynamic functional connectivity would be abnormal and whether the dynamic features are associated with deficits in cognition and psychopathological symptoms. Here, we evaluated 50 patients with Cushing’s disease and 57 healthy participants by using resting-state fMRI and dynamic functional connectivity (dFNC) approach. We focused on the dynamic features of default mode network (DMN), salience network (SN), and central executive network (CEN) because these are binding sites for the cognitive-affective process, as well as vital in understanding the pathophysiology of psychiatric disorders. The dFNC was further clustered into four states by k-mean clustering. CD patients showed more dwell time in State 1 but less time in State 4. Intriguingly, group differences in dwell time in these two states can explain the cognitive deficits of CD patients. Moreover, the inter-network connections between DMN and SN and the engagement time in State 4 negatively correlated with anxiety and depression but positively correlated with cognitive performance. Finally, the classifier trained by the dynamic features of these networks successfully classified CD patients from healthy participants. Together, our study revealed the dynamic features of CD patients’ brains and found their associations with impaired cognition and emotional symptoms, which may open new avenues for understanding the cognitive and affective deficits induced by Cushing’s disease. Introduction Cushing’s disease is characterized by excess endogenous cortisol secretion [1] and served as a unique and natural model for investigating the effects of elevated endogenous cortisol levels on brain functions and structure [2]. It is also a good model for unraveling the linkage between stress-related brain dysfunctions and psychiatric symptoms [3]. Long-term exposure to hypercortisolism negatively affects patients’ physical and mental health, such as depression, anxiety, and psychosis [1, 4], as well as shows deleterious effects on cognitive function including impaired executive function, working memory, and attention [5,6,7]. Research progress on Cushing’s disease, which depends on static resting-state fMRI, revealed that patients with Cushing’s disease showed increased functional connectivity between the default mode network (DMN) and left lateral occipital cortex [2], and hippocampus [8]. Cortisol increase would induce connectivity changes within the DMN and salience network (SN) [9], and the DMN’s activity correlated with the morning cortisol level of patients with Cushing’s disease [10]. Despite these advances leading to an improved understanding of Cushing’s disease, it remains enigmatic how the abnormal brain connectivity within large-scale networks and how the different brain networks interact would contribute to the deficits in impaired cognitive function, as well as psychopathological symptoms. Furthermore, recent years have witnessed an increasing number of studies providing solid evidence that the brain is a dynamic system rather than a static one on a micro-time scale [11, 12]. Dynamic functional connectivity (dFNC), which is implemented by the sliding window method [13], is an ideal approach to characterize the dynamic nature of brain [11], as well as detect and predict diseases [14, 15]. However, to our knowledge, no studies have ever investigated dynamic brain functional connectivity for patients with CD. We focus here on dynamic functional connectivity and emphasize the role of default mode network (DMN), salience network (SN), and central executive network (CEN). These large-scale neurocognitive networks are critical for cognitive and affective processing [16] and are highly related to stress and cortisol level. Deficits or abnormal connectivity within these three networks are associated with a wide range of stress-related psychiatric disorders [17], as well as the high level of cortisol production [18, 19]. For example, the network-connectivity changes between SN and DMN [20, 21], SN and CEN [22] corresponded to increased cortisol levels. Furthermore, our previous studies also identified that CD patients would show dysregulations of resting-state functional connectivity patterns with DMN [10, 23]. Since CD patients also suffer from cognitive impairment and neuropsychological symptoms, including depression and anxiety, which DMN, SN, and CEN mainly modulate, we hypothesized that these three networks are critical to understanding Cushing’s disease and its comorbidity. Here we aimed to investigate two research questions. First, whether there are group differences (CD patients vs. healthy controls) in the dynamic functional connectivity within DMN, SN, and CEN; second, whether the differences can explain the psychiatric symptoms and cognitive impairments in CD patients. We configure our design with a sliding-window approach [11, 13] to portray the features of dynamic functional connectivity (dFNC) within DMN, SN, and CEN among patients with Cushing’s disease (N = 50) and healthy controls (N = 57). We first compared the temporal properties between healthy and CD patients. Then we conducted correlation and mediation analysis to see whether and how the differences in dFNC would contribute to patients’ psychiatric and physiological symptoms and cognitive deficits. We finally implemented a classification machine learning algorithm based on dynamic FNC features within these three networks to see whether these dynamic features would identity CD patients successfully. Materials and methods Ethic approval The experimental protocol was in accordance with principles of the Declaration of Helsinki and approved by a local research ethics Committee of The First Medical Center of Chinese PLA General Hospital (Beijing, China). All participants provided written informed consent after the experimental procedure had been fully explained and were reminded of their right to withdraw at any time during the study. Participants The current study recruited 50 patients with Cushing’s disease (CD patients) and 57 healthy controls (HC) who were matched in age, gender, and education (Table 1). The CD patients were recruited from the Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, between May 2017 and November 2019. The following criteria confirmed Cushing’s disease and its etiology: clinical features (e.g., moon face, supraclavicular fat pad, truncal obesity), elevated 24-h urinary free cortisol (24-h UFC, reference range 98.0–500.1 nmol/24 h), absence of normal cortisol circadian rhythm, elevated ACTH levels (reference range at 0800 h: <10.12 pmol/L), elevated cortisol secretion rates (reference range of cortisol level at 0800 h, 198.7–797.5 nmol/L), absence of normal suppression in midnight (1 mg) dexamethasone suppression test and low dose (2 mg) dexamethasone suppression test (but >50% suppression with a high dose (8 mg) of dexamethasone), and a central to peripheral ACTH ratio >2 for petrosal sinus sampling and pathology after surgery. Healthy controls (HC) were recruited from the local community through poster advertisements and were interviewed by experienced psychiatrists to ensure the absence of current or history of any mental disorder. Demographic information and clinical characteristics of all CD patients and healthy controls were shown in Table 1. Table 1 Demographic and clinical data from healthy controls and CD patients. Full size table Clinical data acquisition, neuropsychological and neuropsychiatric assessment Biometric measurements of the CD patients, including 24-h urinary free cortisol (UFC) levels, plasma Cortisol level (at 0000 h, 0800 h, 1600 h) and adrenocorticotropin (ACTH) level (at 0000 h, 0800 h, 1600 h) from a peripheral vein. Clinical severity of CD patients was obtained using the Cushing Quality of Life Scale (Cushing QOL) [24]. We also included the neuropsychological and neuropsychiatric assessments such as Self-Rating Depression Scale (SDS) [25], Self-Rating Anxiety Scale (SAS) [26], Montreal Cognitive Assessment-Beijing Version (MoCA-BJ) [27], and Chinese version of neuropsychiatric inventory (CNPI) [28]. Image acquisition Functional brain images were acquired using a 3-Tesla GE750 scanner at the First Medical Center of Chinese PLA General Hospital (Beijing, China). Blood oxygen level-dependent (BOLD) gradient echo planar images (EPIs) were obtained using an 8-channel head coil [64 × 64 × 36 matrix with 3.5 × 3.5 × 3.5 mm spatial resolution, repetition time (TR) = 2000 ms, echo time (TE) = 30 ms, flip angle = 90°, field of view (FOV) = 256 × 256 mm2]. A high-resolution T1-weighted structural image (256 × 256 × 144 matrix with a spatial resolution of 1 × 1 × 1 mm, repetition time (TR) = 6700 ms, echo time (TE) = 29 ms, flip angle = 7°) was subsequently acquired. During scanning, all participants were fitted with soft earplugs, and were requested to keep their eyes closed, to stay awake and not to think of anything. Data preprocessing The fMRI data was preprocessed using SPM12 (Wellcome Trust Centre for Neuroimaging, London). The first 10 volume of the functional images were discarded to avoid initial steady-state problems. Then functional images were spatially realigned to the first image for motion correction and corrected for slice acquisition temporal delay. Subsequently, functional images were co-registered to each participant’s segmented gray matter T1 image, then spatially normalized to the Montreal Neurological Institute (MNI) coordinate system, resampled to 3 × 3 × 3 mm voxels. Finally, all functional images were spatially smoothed with an isotropic 4 mm FWHM Gaussian kernel. Group ICA and post-processing Preprocessed data were decomposed into functional components that exhibited a unique time course profile using the group-level spatial independent component analysis, which was implemented in the GIFT toolbox (http://mialab.mrn.org/software/gift/) [29]. First, a subject-specific data reduction principal component analysis (PCA) was performed in which 120 principal components remained. Then at group level, we adopted a high model order ICA to reduce the resting state data into 100 group independent components [30] using the expectation-maximization (EM) algorithm [31] in GIFT. Further, the Infomax ICA algorithm in ICASSO [32] was repeated 20 times [33] to ensure the reliability and stability. Subject-specific spatial maps and time-courses were estimated using the back-reconstruction approach (GICA) [34]. We characterized 50 components as intrinsic connectivity networks (ICNs) by applying the following criteria:[13, 35] whether the peak activation coordinates of the functional components were primarily located in gray matter, and with minimal spatial overlap with white matter structures, vascular, ventricular, edge regions corresponding to artefacts, and susceptibility artifacts. We sorted these 50 meaningful independent components into the interested functional networks including: default mode network (DMN), central executive network (CEN) and salience network (SN) (Fig. 1) according to the spatial correlation values between independent components and the given template [36]. Additional post-processing was conducted to remove remaining noise. Time-courses of the seven components were detrended, despiked and low-pass filtered with a high-frequency cutoff of 0.15 Hz [13]. Moreover, we regressed out the six parameters of head movement. Fig. 1: Composite map of the three networks. And the pipeline of dynamic functional connectivity and clustering analyses. A The three brain networks, default mode network (DMN, including 7 components), central executive network (CEN, including 9 components) and salience network (SN, including 7 components) are derived from group spatial independent components analyses among all participants. B First, for each participant, the dynamic functional connectivity (FNC) matrices are estimated on each sliding window (200 windows) of a set of components within the three networks. Then we applied k-means clustering algorithm on the dynamic FNC matrices across all subjects to assess the reoccurring FNC’s states. Optimal number of states was determined by elbow method. We showed the averaged FNC pattern and the corresponding total number of windows in each state, percentage of each occurrence was presented in parentheses. The color bar represents the z value of FNC. Full size image Dynamic functional connectivity Sliding window approach is the most common way to investigate the nonstationary nature of functional connectivity (FC) of fMRI data. We conducted dynamic FC analysis using the DFC network toolbox in GIFT. In line with previous studies [13, 36], a window of 60 s width (30 TR), sliding in steps of one repetition time was applied to divide the time-courses of each independent components into 200 windows. As covariance estimation using time series of shorter length can be noisy, the regularized inverse covariance matrix (ICOV) was adopted [37]. Following graphic LASSO framework [38], we imposed an additional L1 norm of the precision matrix to enforce sparsity. Clustering analysis Based on previous studies, we applied a k-means clustering algorithm on windowed functional connectivity matrices [39] to assess the frequency and structure of reoccurring functional connectivity patterns (states) across all subjects. We used Manhattan distance function to estimate the similarity between different time windows of FC matrices, which had been demonstrated as an effective measure for high-dimensional data [40]. To obtain the optimal number of states, a cluster validity analysis (silhouette) was conducted on the exemplars of all the subjects. To avoid cost function convergence to the local optimal solution, all clustering analyses were iterated 5 times in GIFT, and the best result was used. Finally, we determined the optimal number of clusters as equal to four (k = 4). According to the clustering results, three temporal properties of dynamic FC states derived from each subject’s state vector were calculated: (i) mean dwell time, measured as the average number of consecutive windows belonging to one state; (ii) fraction of time, measured as the proportions of total windows in one state; (iii) number of transitions, defined as the number of state transitions during the entire scan. Mediation analyses Bootstrapping method was used to estimate the mediation effect. Bootstrapping is a nonparametric approach to effect-size estimation and hypothesis testing that is increasingly recommended for many types of analyses, including mediation [41, 42]. Bootstrapping generates an empirical approximation of the sampling distribution of a statistic by repeated random resampling from the available data and uses this distribution to calculate p-values and construct confidence intervals (5000 resamples were taken for these analyses). Moreover, this procedure supplies superior confidence intervals (CIs) that are bias-corrected and accelerated [43, 44]. Classification analyses using dynamic functional connectivity We conducted classification analyses based on dynamic FNC features [35] to classify each kind of patients. Specifically, we firstly formed a regression matrix, Rgroups × cluster centroids, then regressed out the windowed FNC matrices at each time window using the regression matrix for each participant. These analyses end up with eight β coefficients for each time window for each participant. Next, we computed the mean β coefficients for all time windows. Thus, we got eight mean β coefficients for each participant. These mean β coefficients served as the dynamic FNC features for the classification analysis. The classification analysis using supervised machine learning method, linear support vector machine algorithm (http://www.csie.ntu.edu.tw/~cjlin/libsvm/) with a standard 10-fold cross-validation. We randomly divided the data into 10 subgroups, used the trained classifier from the nine subgroups to predict the performance on the left one subgroup, and repeated the procedure for 100 times. We reported the averaged classification accuracy for each group across these 100 times. Results Neuropsychological and neuropsychiatric difference between healthy controls and CD patients Patients with Cushing’s disease reported higher depression, anxiety, and higher frequency and severity mental illness than healthy controls. Additionally, CD patients also behaved impaired cognitive ability than healthy controls (see Table 1) Functional connectivity within DMN, CEN and SN networks in the four states Spatial map of default mode network, central executive network and salience network identified using the group independent component analysis was shown in Fig. 1A. Independent components were grouped based on their anatomical and presumed functional properties: default mode network (ICs, 9, 12, 27, 28, 32, 44, 74), central executive network (ICs, 15, 21, 26, 48, 50, 63, 85, 89, 97), and salience network (ICs, 20, 43, 57, 59, 76, 82, 92). We adopted a k-means clustering algorithm on the dynamic functional connectivity (dFNC) from all subjects into four connectivity states. Figure 1B shows the cluster centroid and the percentage of occurrences of each state (arranged in the order of emergence). Different temporal properties between HC and CD patients We firstly compared the mean dwell time between healthy controls and CD patients in each state (Fig. 2A–D). Using independent T test, we found that the CD patients had higher mean dwell time than HC in State 1 (CD patients: 89.040 ± 59.216 vs. HC: 57.491 ± 40.671; t(105) = 3.244, p = 0.002), but less mean dwell time than HC in State 4 (CD patients: 31.300 ± 39.413 vs. HC: 66.438 ± 45.734; t(105) = −4.227, p < 0.001). We did not observe significant difference in State 2 (CD patients vs. HC: t(105) = 1.700, p = 0.092), nor in State3 (CD patients vs. HC: t(105) = −1.517, p = 0.132). For the switch time (i.e., the number of transitions), CD patients revealed less transition number than healthy controls did (CD patients: 6.600 ± 3.187 vs. HC: 7.824 ± 3.059; t(105) = −2.205, p = 0.045; Fig. 2E). Multiple comparisons were corrected by false-discovery rate (FDR), p < 0.05. All contrasts remained the same after FDR correction excepted the results of switch time became marginally significant, FDR corrected p = 0.075. Group difference on fraction of time in each state was similar with the mean dwell time (see Supplementary Table S1). Levene’s test is used to check that variances are equal for all samples. Fig. 2: Mean dwell time of dynamic FNC states and number of transitions between CD patients and healthy controls. A In State 1, CD patients engaged higher mean dwell time than healthy control did. B, C In State 2 and State 3, no difference was found between CD patients and healthy controls. D In State 4, CD patients showed significant less mean dwell time than healthy controls. E There was marginally significant difference (after FDR correction) on number of transitions between CD patients and healthy controls. Multiple comparisons were corrected by FDR, p < 0.05 (Error bars represent standard error. p < 0.01**, p < 0.001***, p < 0.08+, N.S not significant). HC Healthy controls, CD patients with Cushing’s disease. Full size image Correlation between dynamic FNC properties and clinical characteristics To examined whether the dynamic FNC properties were associated with clinical characteristics, we did Pearson correlation analyses. Since the group differences were found in State 1 and State 4, we only restricted our analyses on these two states. Notably, we found that the dwell time in State 1 positively correlated with the self-reported anxiety (SAS), and cortisol level at 8:00, 16:00, 00:00, ACTH at 8:00, 16:00, as well as elevated 24-h urinary free cortisol. That is, the longer time spent on State 1 which with more sparsely connected pattern, the worse the mental health and higher cortisol level. We also detected a robust negative correlation between dwell time of State 1 and global cognitive scales (MoCA), which indicated that more time spent in State 1, the worse cognitive ability would be. In the contrary, dwell time in State 4 showed significant negative correlation with the self-reported depression, anxiety, and cortisol level at 8:00, 16:00, 00:00. More dwell time in State 4 predicted better cognitive performance measured by MoCA (all results see Table 2). Multiple comparisons were conducted by FDR, p < 0.05. Table 2 Correlations between dynamic functional connectivity temporal properties in cognitive control network and clinical data. Full size table Dwell time in State 1 and State 4 within cognitive control network mediate group difference in cognitive performance Interestingly, we found the dwell time in State 1 and State 4 significantly mediated the difference between individuals with excessive high cortisol level (CD patients) and healthy controls on cognitive performance. That is, lower cognitive performance in CD patients was linked with more dwell time in State 1 (Fig. 3A), and less dwell time in State 4 (Fig. 3B) within the three networks. Fig. 3: Mediation effect of dwell time in State 1 and State 4 on group difference on cognitive performance. A Dwell time in State 1 and B dwell time in State 4 significant partially mediated the difference between CD patients and healthy controls on cognitive performance measured by MoCA. HC Healthy controls, CD patients with Cushing’s disease. Full size image Distinct network-based functional connectivity between CD patients and healthy controls and its associations with psychiatric symptoms and cognitive performance We have already known that the difference on dwell time in State 1 and State 4 can explain the group difference (i.e., CD patients vs. healthy controls) on cognitive performance. We further characterized the State 1 and State 4 by analyzing functional connectivity between the three networks, as well as the functional connectivity within each network. Results showed that in State 1, the CD patients had weaker connectivity within DMN (t(104)1 = −2.584, p = 0.011), and the connections between CEN and DMN (t(104) = −5.141, p < 0.001), CEN and SN (t(104) = −4.732, p < 0.001) were also weaker than healthy controls. And in State 4, CD patients showed weaker functional connections between DMN and SN (t (84)2 = −4.203, p < 0.001), as well as DMN and CEN (t(84) = −3.547, p = 0.001). Moreover, in State 4, functional connection between DMN and SN was negatively correlated with anxiety level measured by SAS (r(68) = −0.336, p = 0.005), and depression level measured by SDS (r(68) = −0.320, p = 0.008), but positively correlated with cognitive performance measured by MoCA (r(65) = 0.421, p < 0.001). Since CD patients showed decreased connection between DMN and SN, these results may suggest that the connection between DMN and SN was critical for understanding the psychiatric symptoms and cognitive deficits in CD patients. All significant results reported here were survived after FDR (p < 0.05) correction. We did not find significant associations between functional connectivity of neither inter-network and intra-network and psychiatric symptoms and cognitive deficits in State 1. No significant correlation results were found between the inter-network and intra-network connectivity and physiological indices (i.e., cortisol, ACTH, and UFC) in these two states, which may suggest that the dwell time in specific state would be more sensitive to physiological change. Classification results based on dynamic FNC features The support vector machine (SVM) based on dynamic FNC approach (Fig. 4A, details see Method) showed classification accuracy of 84.76% for CD patients, 88.98% for healthy controls (Fig. 4B). The classification scores were evaluated using a receiver operating characteristic (ROC) curve aiming to visualize the performance of the classifier. The classification results may further indicate that the dynamic functional connectivity pattern within these three networks would be the potential biomarker of individuals with excessive higher cortisol level. Fig. 4: The results of classification. A An overview of classification approach. We first extracted the averaged FNC pattern for each state for each group. Then we performed Pearson correlation between the FNC in each window and the FNC pattern in all states among all groups. These procedures ended up with 8 averaged features for each participant. B Receiver Operating Characteristic (ROC) curves for classification. SVM support vector machine, AUC area under the curve. Full size image Discussion In the current study, we adopted independent component analysis (ICA) and dynamic functional connectivity (FNC) approaches to reveal the difference in dynamic FNC within DMN, SN, and CEN networks between CD patients and healthy controls. Using clustering algorithm, we defined four reoccurring FNC states during resting-state scanning. Wherein State 1 and State 4 exhibited significant differences between healthy control and CD patients. Patients generally showed more dwell time in State 1 but less in State 4 than healthy controls. Specifically, in State 1, the CD patients showed weaker connections within DMN, as well as weaker intra-network connectivity between DMN and CEN, SN and CEN than healthy controls. In State 4, connections between DMN and SN, DMN and CEN showed weaker connection in CD patients than in healthy participants. Further correlation and mediation analyses showed that the dwell time in State 1 significantly negatively correlated with cognitive performance. While dwell time in State 4, as well as the connections between DMN and SN in State 4, were found to positively correlate with cognitive performance, and negatively associated with depression and anxiety symptoms. Both states were associated with physiological indices including cortisol, ACTH and 24-hour UFC. Importantly, results from mediation analysis indicated the difference between CD patients and healthy controls on dwell time in State 1 and State 4 can be used to explain their cognitive performance difference. Intriguingly, adopting support vector machine algorithm based on dynamic FNC within DMN, SN and CEN network generally showed ideal classification accuracy for CD patients and healthy controls. These findings begin to delineate the dynamic properties of the three brain networks, which are critical for cognitive and neuropsychiatric, and open new avenues for understanding and explaining the impaired cognitive performance and psychiatric symptoms induced by Cushing’s disease. We found two distinct functional connectivity states across two groups. State 1 can be characterized as having weak connections among the three networks, while State 4 showed relatively strong inter-network and intra-network connections. We observed that in patients with Cushing’s disease, State 1 occurred more often, while State 4 occurred less than in healthy controls. These results help to confirm CD patients’ weaker connections within DMN, SN, and CEN. Previous studies identified that white matter integrity was generally decreased throughout the whole brain rather than just on individual fasciculus [45,46,47]. One possible explanation is that the extensive decline in white matter structural integrity leads to the decreased connectivity of the three networks, which are critical for the cognitive-affective process. We found that in State 1, CD patients showed decreased local synchronization (i.e., within network connectivity) of DMN, and weak inter-network connections between CEN and DMN, CEN and SN. The DMN’s integrity appears crucial for cognitive performance. For example, patients with Alzheimer’s disease showed decreased connectivity within DMN [48]. Since dwell time of State 1 was negatively correlated with MoCA and mediated the group differences on MoCA. We may infer that cognitive deficit may be due to that CD patients engaged more time in State 1 with weak connections of DMN. Interestingly, the more dwell time in State 4, the less anxiety and depression symptoms individuals would have. Moreover, our further analyses found that connections between DMN and SN during State 4 would also negatively affect anxiety and depression. And the CD patients had weaker DMN-SN connections than healthy controls in this state. In line with previous studies, effective connectivity from DMN to SN was lower in major depression disorders compared to healthy controls when processing negative information [49]. And the inter-network connections between the SN and DMN were inversely associated with trait anxiety levels [50]. Therefore, the time engaged in State 4 and the weak inter-network connectivity between SN and DMN may contribute to psychopathological symptoms in CD patients. Dynamic functional connectivity provides time-varying rather than static features over time [11], and it is more effective to capture various aspects of brain connectivity. The dFNC approach has obvious advantages for classification purposes [35]. For example, previous research showed high classification accuracy for psychiatric diseases such as schizophrenia [51], and bipolar [35]. In our study, the SVM based on dynamic functional connectivity features within DMN, SN and CEN showed high classification accuracy for CD patients and healthy controls, which may indicate that the dynamic properties in these three networks would be potential biomarkers for individuals with excessive higher cortisol level. The long-term remitted CD (LTRCD)-patients still suffered from cognitive impairments and emotional symptoms such as anxiety and depression, even though their cortisol levels back to normal after the removal of the adenoma [2, 52, 53]. We revealed that the dynamic features in DMN, SN, and CEN correlate with depression and anxiety symptoms in CD patients and are strongly associated with cognitive performance. Our findings may contribute to developing further neuro-modulation targets to help CD patients improve cognitive ability and mental health. Several limitations of the present study should be mentioned. First, Cushing’s disease is rare, and it is more common in women [1, 3]. We only showed results based on a female sample (healthy controls were all female). Therefore, our conclusion may not be adaptive for the male population. Second, some research suggested that the dynamic functional connectivity analyses should be performed in resting state acquisitions of at least ten minutes [54]. The length of current resting-state scan was eight minutes, although many previous studies studied dynamic FNC based on resting-state data in eight minutes or even less [13, 20, 51], further studies should consider longer scanning to capture more dynamic spontaneous features. Thirdly, our results revealed that cortisol concentrations were significantly associated with dwell time in State 1 and 4 but were not correlated with inter-network or intra-network connections. Human cortisol secretion has apparent circadian rhythmicity [55], but our resting state acquisitions were not collected multiple times. Our conclusions may not be informative to understand the relationships between dynamic functional connections and dynamic cortisol levels. In conclusion, our study delineates the differences in dynamic properties between CD patients and healthy participants. It unravels its associations with cognitive deficits, impaired affective processes, and physiological indices in CD patients. We believe the temporal dynamics of functional connectivity within the three crucial cognitive and affective brain networks could be a promising imaging biomarker to monitor cognitive changes and psychiatric symptoms in Cushing’s disease. Data availability All datasets are available on figshare. https://figshare.com/projects/Dynamic_functional_connectivity_changes_associated_with_psychiatric_traits_and_cognitive_deficits_in_Cushing_s_disease/170343. Code availability All code used for all analyses and plots are publicly available on GitHub at https://github.com/psywalkeryanxy/paper_CD_ICA. References Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386:913–27. Article CAS PubMed Google Scholar van der Werff SJA, Pannekoek JN, Andela CD, Meijer OC, van Buchem MA, Rombouts SARB, et al. Resting-state functional connectivity in patients with long-term remission of Cushing’s disease. Neuropsychopharmacology. 2015;40:1888–98. Article PubMed PubMed Central Google Scholar Swearingen B, Biller BMK, editors. Cushing’s disease. vol. 31, US: Springer; 2011. Piasecka M, Papakokkinou E, Valassi E, Santos A, Webb SM, Vries F, et al. 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Article CAS PubMed Google Scholar Download references Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 82001798 and No. 81871087) and China Brain Project (2021ZD0200407). Author information Authors and Affiliations Department of Neurosurgery, Chinese PLA General Hospital, Haidian District, Beijing, PR China Zhebin Feng, Tao Zhou, Xinguang Yu & Yanyang Zhang Department of Respiratory Medicine, Anhui Provincial Children’s Hospital, Hefei, Anhui, PR China Haitao Zhang Neurosurgery Institute, Chinese PLA General Hospital, Beijing, PR China Xinguang Yu & Yanyang Zhang Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA Xinyuan Yan Contributions YZ and XGY, TZ conceived the project and designed research, HZ performed research, XY and ZF, YZ analyzed data and interpreted results, ZF and XY wrote the paper. All authors approved the final version of the manuscript for submission. Corresponding authors Correspondence to Yanyang Zhang or Xinyuan Yan. Ethics declarations Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information Supporting information From https://www.nature.com/articles/s41398-023-02615-y
  6. Current Study Opportunities We have hundreds of studies open for patients and caregivers! Some of the studies we are working to fill immediately are listed below. 1. If you are already a member of Rare Patient Voice and want to be considered for a study listed below, please contact study.inquiries@rarepatientvoice.com 2. If you are NOT a member, please click here to complete the sign-up process and include all medical conditions to be considered for one or more of the studies below and any other relevant studies. Please feel free to share this page with friends or family who might be interested! United States Growth Hormone Deficiency, Noonan Syndrome, Small for Gestational Age (SGA) patients and caregivers United States 90-150-minute in-person interview, compensation is $180-$300 Growth Hormone Deficiency patients and caregivers (3-12 years) United States 45-minute web-assisted phone interview (WATI) + COD (confirmation of diagnosis), compensation is $125 Frequently Asked Questions Why sign up with Rare Patient Voice? Who knows better than you about your journey and experiences? We connect you with researchers who are developing products and services which can help you and others with your condition. These researchers need patient input so that they develop products and services that have a meaningful impact on patients’ lives. How will I be paid? As of January 1, 2023, you will earn $120 per hour for participating in new studies. We pay by check to ensure patients can use their compensation in any way they wish. About Rare Patient Voice Rare Patient Voice connects patients and caregivers with researchers who are developing products and services to help you and others with your condition. RPV has paid patients and family caregivers over $10 million dollars since 2013 for participating in research studies.
  7. Abstract Summary This case report describes a rare presentation of ectopic Cushing’s syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous. Learning points Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases. Keywords: Adult; Male; White; Denmark; Pituitary; Pituitary; Thyroid; Error in diagnosis/pitfalls and caveats; September; 2023 Background The common denominator of Cushing’s syndrome (CS) is autonomous hypersecretion of cortisol (1) and it is subdivided into ACTH-dependent and ACTH-independent causes. The majority of CS cases are ACTH-dependent (80–85%) with a pituitary corticotroph tumor as the most prevalent cause (Cushing’s disease), and less frequently an ectopic ACTH-producing tumor (2). The gold standard method to ascertain the source of ACTH secretion in CS patients is inferior petrosal sinus sampling (IPSS) with measurement of plasma ACTH levels in response to systemic corticotropin-releasing hormone (CRH) stimulation (3). The IPSS has a very high sensitivity and specificity of 88–100% and 67–100%, respectively (4), but pitfalls do exist, including the rare ectopic CRH-producing tumor, which may yield a false positive test result (3). Here, we describe a very rare case masquerading as CS including a positive IPSS test. Case presentation A 69-year-old man presented at a local hospital with a 6-month history of progressive fatigue, muscle weakness and wasting, easy bruising, facial plethora, and fluid retention. His serum potassium level was 2.6 mmol/L (reference range: 3.5–4.2 mmol/L) without a history of diuretics use. His previous medical history included spinal stenosis, benign prostatic hyperplasia, and hypertension. An electromyography showed no sign of polyneuropathy and an echocardiography showed no signs of heart failure with an ejection fraction of 55%. MRI of the spine revealed multiple compression fractures, and the patient underwent spinal fusion and decompression surgery; during this admission he was diagnosed with type 2 diabetes (HbA1c: 55 mmol/mol). After spine surgery, the patient developed a pulmonary embolism and initiated treatment with rivaroxaban. Establishing the diagnosis of ACTH-dependent CS Six months after his spine surgery, the patient was referred to the regional department of endocrinology for osteoporosis management. Blood tests revealed a low serum testosterone level with non-elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels (Table 1). An overnight 1 mg dexamethasone suppression test was positive with a morning cortisol level of 254 nmol/L and three consecutive 24-h urinary cortisol levels were markedly elevated with mean level of ≈600 nmol/24 h (reference range: 12–150 nmol/24 h). A single plasma ACTH was 37 ng/L (Table 1). Table 1 Baseline endocrine assessment. Parameters Patient’s values Reference range ACTH, ng/L 37 7–64 UFC, nmol/day 588 12–150 Urinary cortisol, nmol/L 600 171–536 OD, nmol/L 254 <50 Free testosterone, nmol/L 0.061 0.17–0.59 HbA1c, mmol/mol 55 <48 FSH, IU/L 7.4 1.2–15.8 LH, IU/L 2.2 1.7–8.6 ACTH, adrenocorticotropin; FSH, follicle-stimulating hormone; IU, international units; LH, luteinizing hormone; OD, plasma cortisol levels after a 1 mg overnight dexamethasone suppression test; UFC, urine free cortisol hormone. Differential diagnostic tests The patient was referred to a tertiary center for further examinations. Ketoconazole treatment was started to alleviate the consequences of hypercortisolism. A pituitary MRI revealed an intrasellar microtumor with a maximal diameter of 6 mm and an IPSS was ordered. A whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) was also performed to evaluate the presence of a potential neuroendocrine tumor. This revealed multiple areas of enhanced uptake including the right thyroid lobe and cervical lymph nodes in the neck (with CT correlates), as well as in the duodenum (with no CT correlate). Concomitantly, a grossly elevated serum calcitonin level of 528 pmol/L (reference range <2.79 pmol/L) was measured. Subsequently, the IPSS revealed pituitary ACTH secretion with a central-to-peripheral ACTH ratio >3 (Table 2). The right petrosal sinus was not successfully catheterized; thus, lateralization could not be determined. To corroborate the diagnosis MTC, a 18F-DOPA PET/CT scan (FDOPA) was performed (5), which showed pathologically enhanced uptake in the right thyroid lobe and regional lymph nodes (Fig. 1). An ultrasound-guided core needle biopsy from the thyroid nodule was inconclusive; however, the patient underwent total thyroidectomy and regional lymph node resection, from which histology confirmed the diagnosis of disseminated MTC. Standard replacement with levothyroxine, calcium, and vitamin D was initiated. A blood sample was collected, and genomic DNA was extracted. The DNA analysis for RET germline mutation was negative. View Full Size Figure 1 18F-DOPA PET/CT scan with pathologically enhanced uptake in the right thyroid lobe (large blue arrow on the left side) and regional lymph nodes (small blue arrows). Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 3; 10.1530/EDM-23-0057 Download Figure Download figure as PowerPoint slide Table 2 Results from the inferior petrosal sinus sampling.* Time (min) Left IPSS Peripheral L/P -5 42 36 1.2 -1 116 33 3.5 2 120 32 3.8 5 209 28 7.5 7 180 43 4.2 10 529 34 15.6 15 431 37 11.6 *Data represents ACTH levels in ng/L. IPSS Inferior petrosal sampling ACTH Adrenocorticotropin hormone CRH Corticotropin-releasing hormone, L/P Ratio of left (L) inferior petrosal sinus to peripheral venous ACTH concentrations. Pathology Total thyroidectomy and bilateral cervical lymph node dissection (level six and seven) were performed. Macroscopic evaluation of the right thyroid lobe revealed a 24 mm, irregular solid yellow tumor. Microscopically the tumor showed an infiltrating architecture with pseudofollicles and confluent solid areas. Calcification was prominent, but no amyloid deposition was seen. The tumor cells were pleomorphic with irregular nuclei and heterogenic chromatin structure. No mitotic activity or necrosis was observed. On immunohistochemical analysis, the tumor cells expressed thyroid transcription factor 1 and stained strongly for carcinoembryonic antigen and calcitonin; tumor cells were focally positive for cytokeratin 19. The tumor was completely negative for ACTH, thyroid peroxidase, and the Hector Battifora mesothelial-1 antigen. Further analysis revealed positive immunostaining for CRH (Fig. 2). The Ki-67 index was very low (0–1%), indicating a low cellular proliferation. Molecular testing for somatic RET mutation was not performed. View Full Size Figure 2 Histopathological findings and immunohistochemical studies of MTC. (A) Microscopic features of medullary thyroid carcinoma. (B) Polygonal tumor cells (hematoxylin and eosin, ×40). (C) Tumor cells stain for calcitonin (×20). (D) Immunohistochemical stain (×400) for CRH showing cells being positive (brown). (E) Pituitary tissue from healthy control staining positive for ACTH in comparison to (F) ACTH-negative cells MTC tissue from the patient (×20). Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 3; 10.1530/EDM-23-0057 Download Figure Download figure as PowerPoint slide No malignancy was found in the left thyroid lobe and there was no evidence of C-cell hyperplasia. Regional lymph node metastasis was found in 13 out of 15 nodes with extranodal extension. Outcome and follow-up Follow-up Serum calcitonin levels declined after neck surgery but remained grossly elevated (118 pmol/L 3 weeks post surgery) and cortisol levels remained high. Ketoconazole treatment was poorly tolerated and not sufficiently effective. Plasma levels of CRH were measured by a competitive-ELISA kit (EKX-KIZI6R-96 Nordic BioSite), according to the instructions provided by the manufacturer. The intra- and interassay %CV (coefficient of variability) were below 8% and 10%, respectively, and the assay sensitivity was 1.4 pg/mL. The plasma CRH was distinctly elevated compared to in-house healthy controls both before and after thyroid surgery (Fig. 3). View Full Size Figure 3 Plasma CRH levels before and after total thyroidectomy compared to three healthy controls. Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 3; 10.1530/EDM-23-0057 Download Figure Download figure as PowerPoint slide The patient subsequently underwent uneventful bilateral laparoscopic adrenalectomy followed by standard replacement therapy with hydrocortisone and fludrocortisone. The symptoms and signs of his CS gradually subsided. Pathology revealed bilateral cortical hyperplasia as expected. The patient continues follow-up at the Department of Oncology and the Department of Endocrinology and Internal Medicine. At 13-month follow-up, 68Ga-DOTATOC shows residual disease with pathologically enhanced uptake in two lymph nodes, whereas the previously described focal DOTATOC uptake in the duodenum was less pronounced (still no CT correlate). Serum calcitonin was 93 pmol/L at the 13-month follow-up. Discussion Diagnostic challenges remain in the distinction between pituitary and ectopic ACTH-dependent CS, and several diagnostic tools are used in combination, none of which is infallible, including IPSS (6). Our case and others illustrate that ectopic CRH secretion may yield a false positive IPSS test result (3). Measurement of circulating CRH levels is relevant if an ectopic CRH producing tumor is suspected, but the assay is not routinely available in clinical practice (Lynnette K Nieman M. Measurement of ACTH, CRH, and other hypothalamic and pituitary peptides https://www.uptodate.com/contents/measurement-of-acth-crh-and-other-hypothalamic-and-pituitary-peptides: UpToDate; 2019). In our case, the presence of elevated plasma CRH levels after thyroidectomy strengthened the indication for bilateral adrenalectomy. The most common neoplasm causing ectopic CS is small-cell lung cancer, whereas MTC accounts for 2–8% of ectopic cases (7). The development of CS in relation to MTC is generally associated with advanced disease and poor prognosis of an otherwise relatively indolent cancer (8), and the clinical progression of CS is usually rapid, why an early recognition and rapid control of hypercortisolemia and MTC is necessary to decrease morbidity and mortality (7, 9). Our case does have residual disease; however, he remains progression-free with stable and relatively low calcitonin levels within 1-year follow-up. Only a very limited number of cases of ectopic tumors with either combined ACTH and CRH secretion or isolated CRH secretion have been reported, with ectopic CRH secretion accounting for less than 1% of CS (9). An ACTH- or CRH-producing tumor can be difficult to localize and may include gastric ACTH/CRH-secreting neuroendocrine tumors (9). In our case, the 68Ga-DOTATOC identified a possible duodenal site, in addition to the MTC, but an upper gastrointestinal endoscopy revealed no pathological findings and there was no CT correlate. Thus, we concluded that the most likely and sole source of ectopic CRH was the MTC and its metastases. To our knowledge, no official guidelines for managing ectopic ACTH-dependent CS have been established. In a recent publication by Alba et al. (10), the authors demonstrated a clinical algorithm (The Mount Sinai Clinical Pathway, MSCP) and recommendation for the management of CS due to ectopic ACTH secretion. Essentially, our approach in this particular case followed these recommendations, including source location by CT and 68Ga-DOTATATE PET/CT imaging, acute management with ketoconazole, and finally, bilateral adrenalectomy as curative MTC surgery was not possible. In retrospect, performance of the IPSS could be questioned in view of the MTC diagnosis. In real time, however, a pituitary MRI performed early in the diagnostic process revealed a microadenoma, which prompted the IPSS. In parallel, a somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) was also done, which raised the suspicion of an MTC. Conclusion We report a very rare case of an ectopic CS caused by a CRH-secreting MTC. Although IPSS has stood the test of time in the differential diagnosis of ACTH-dependent CS, this case illustrates a rare pitfall. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Funding This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector. Patient consent Written informed consent for publication of their clinical details was obtained from the patient. Author contribution statement JOJ and MJO are the physicians responsible for the patient. LR performed the thyroidectomy and bilateral adrenalectomy. SHM and SLA assessed and reassessed the histopathology and the immunohistochemical analysis. MB measured plasma CRH. VM, JOJ, and MJO drafted the manuscript. All authors contributed to critical revision of the manuscript. References 1↑ Raff H, & Carroll T. Cushing's syndrome: from physiological principles to diagnosis and clinical care. Journal of Physiology 2015 593 493–506. (https://doi.org/10.1113/jphysiol.2014.282871) PubMed Search Google Scholar Export Citation 2↑ Hatipoglu BA. Cushing's syndrome. Journal of Surgical Oncology 2012 106 565–571. (https://doi.org/10.1002/jso.23197) PubMed Search Google Scholar Export Citation 3↑ Vassiliadi DA, Mourelatos P, Kratimenos T, & Tsagarakis S. Inferior petrosal sinus sampling in Cushing’s syndrome: usefulness and pitfalls. Endocrine 2021 73 530–539. (https://doi.org/10.1007/s12020-021-02764-4) PubMed Search Google Scholar Export Citation 4↑ Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, & Loli P. Bilateral inferior petrosal sinus sampling. Endocrine Connections 2016 5 R12–R25. (https://doi.org/10.1530/EC-16-0029) PubMed Search Google Scholar Export Citation 5↑ Treglia G, Rufini V, Salvatori M, Giordano A, & Giovanella L. PET imaging in recurrent medullary thyroid carcinoma. International Journal of Molecular Imaging 2012 2012 324686. (https://doi.org/10.1155/2012/324686) PubMed Search Google Scholar Export Citation 6↑ Fasshauer M, Lincke T, Witzigmann H, Kluge R, Tannapfel A, Moche M, Buchfelder M, Petersenn S, Kratzsch J, Paschke R, et al.Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery. BMC Cancer 2006 6 108. (https://doi.org/10.1186/1471-2407-6-108) PubMed Search Google Scholar Export Citation 7↑ Chrisoulidou A, Pazaitou-Panayiotou K, Georgiou E, Boudina M, Kontogeorgos G, Iakovou I, Efstratiou I, Patakiouta F, & Vainas I. Ectopic Cushing's syndrome due to CRH secreting liver metastasis in a patient with medullary thyroid carcinoma. Hormones 2008 7 259–262. (https://doi.org/10.1007/BF03401514) PubMed Search Google Scholar Export Citation 8↑ Corsello A, Ramunno V, Locantore P, Pacini G, Rossi ED, Torino F, Pontecorvi A, De Crea C, Paragliola RM, Raffaelli M, et al.Medullary thyroid cancer with ectopic Cushing's syndrome: a case report and systematic review of detailed cases from the literature. Thyroid 2022 32 1281–1298. (https://doi.org/10.1089/thy.2021.0696) PubMed Search Google Scholar Export Citation 9↑ Sharma ST, Nieman LK, & Feelders RA. Cushing's syndrome: epidemiology and developments in disease management. Clinical Epidemiology 2015 7 281–293. (https://doi.org/10.2147/CLEP.S44336) PubMed Search Google Scholar Export Citation 10↑ Alba EL, Japp EA, Fernandez-Ranvier G, Badani K, Wilck E, Ghesani M, Wolf A, Wolin EM, Corbett V, Steinmetz D, et al.The Mount Sinai clinical pathway for the diagnosis and management of hypercortisolism due to ectopic ACTH syndrome. Journal of the Endocrine Society 2022 6 bvac073. (https://doi.org/10.1210/jendso/bvac073) PubMed Search Google Scholar Export Citation From https://edm.bioscientifica.com/view/journals/edm/2023/3/EDM23-0057.xml
  8. Ball-and-stick model of the cortisol (hydrocortisone) molecule. Credit: Public Domain A first-of-its kind hormone replacement therapy that more closely replicates the natural circadian and ultradian rhythms of our hormones has shown to improve symptoms in patients with adrenal conditions. Results from the University of Bristol-led clinical trial are published today in the Journal of Internal Medicine. Low levels of a key hormone called cortisol is typically a result of conditions such as Addison's and congenital adrenal hyperplasia. The hormone regulates a range of vital processes, from cognitive processes such as memory formation, metabolism and immune responses, through to blood pressure and blood sugar levels. When low, it can trigger symptoms of debilitating fatigue, nausea, muscle weakness, dangerously low blood pressure and depression. Although rare, these adrenal conditions require lifelong daily hydrocortisone replacement therapy. Although existing oral hormone replacement treatment can restore cortisol levels, it is still associated with an impaired quality of life for patients. Scientists believe this is because the current treatment does not mimic the body's normal physiological timing, missing cortisol's anticipatory rise and lacking its underlying ultradian and circadian rhythms. The new "pulsatility" therapy, the culmination of ten years' research by the Bristol team, is designed to deliver standard hydrocortisone replacement to patients via a pump which replicates more closely cortisol's natural rhythmic secretion pattern. The pulsatile subcutaneous pump has now revealed promising results in its first clinical trial. Twenty participants aged 18 to 64 years with adrenal insufficiency conditions were assessed during the double-blinded PULSES six-week trial and treated with usual dose hydrocortisone replacement therapy administered either via the pump or the standard three times daily oral treatment. While only psychological and metabolic symptoms were assessed during the trial, results revealed the pump therapy decreased fatigue by approximately 10%, improved mood and increased patient energy levels by 30% first thing in the morning—a key time frame when many patients struggle. Patient MRI scans also revealed alteration in the way that the brain processes emotional information. Dr. Georgina Russell, Honorary Lecturer at the University's Bristol Medical School, and the lead author, explained, "Patients on cortisol replacement therapy often have side effects which makes it difficult for them to lead normal lives. We hope this new therapy will offer greater hope for the thousands of people living with hormone insufficiency conditions." Stafford Lightman, a neuroendocrinology expert and Professor of Medicine at Bristol Medical School: Translational Health Sciences (THS), and the study's joint lead author, added, "Besides reduction in dosage, cortisol replacement has remained unchanged for many decades. It is widely recognized that current replacement therapy is unphysiological due to its lack of pre-awakening surge, ultradian rhythmicity, and post dose supraphysiological peaks. The new therapy clearly shows that the timing of cortisol delivery- in line with the body's own rhythmic pattern of cortisol secretion—is important for normal cognition and behavior. "Our findings support the administration of hormone therapy that mimics natural physiology, and is one of the first major advances in adrenal insufficiency treatment to date." Joe Miles, a participant on the PULSES trial, explained, "The Crono P pump has been life-changing. I noticed a very quick improvement compared to tablets when I was on the PULSES study. I went from feeling tired all the time to having sudden energy. "When the PULSES study ended and I had to return the pump, I simply couldn't cope with going back to how I used to be, so I made it my mission to write to as many doctors to have it prescribed privately. "I've now been on it for six years and have introduced a number of other people with Addison's disease to the pump, and all of them have said it's life changing. Some have gone from being seriously ill to feeling better than they have done for years." Dr. Russell said, "Approximately 1% of the UK population is taking steroids at any moment in time; these individuals can experience debilitating psychological side effects. This trial has shown that even at physiological levels, brain functioning is disrupted and that we need to explore not only the dose but the pattern of steroids delivery when considering any type of steroid treatment." More information: Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial, Journal of Internal Medicine (2023). DOI: 10.1111/joim.13721 Journal information: Journal of Internal Medicine Provided by University of Bristol From https://medicalxpress.com/news/2023-10-first-of-its-kind-hormone-treatment-patient.html
  9. This is an older post but I think it deserves another look because people are still having trouble getting diagnosed.
  10. I'm not sure I like this! STORY: Could artificial intelligence be used to make brain surgery safer? At this university in London, trainee surgeon Danyal Khan is taking part in a mock operation during which he's assisted by a real-time video feed, as is typical in brain surgery. But what's new here is that the footage is being analyzed by AI to help Khan better understand what he's seeing. The AI system, which is under development at University College London (UCL), highlights sensitive or critical structures in the brain. Neurosurgeon Hani Marcus believes it has the potential to make brain surgery safer and more effective: "So I'm very bullish that in the medium to long term, the A.I. will be helping lots of surgeons do lots of operations better than they otherwise can." Marcus says the AI system analyzed video of more than 200 pituitary gland tumor operations, and gained around 10 years-worth of experience in a fraction of the time. That knowledge means the AI can now not only help navigate to the correct area of the brain, but also know what should be happening at any stage of the procedure, making it a valuable training aid. "So, what we're really trying to do is apply AI or artificial intelligence to support surgeons doing brain tumor surgery at the base of the brain. And what this practically entails is us training the AI with hundreds of videos, telling it, if you like, what structures are what and then at some point over that period, the AI becomes really good itself at recognising things, and able to support other surgeons who're perhaps less experienced in advising them what to do next." Assistant Professor of Robotics and A.I. Sophia Bano explains how that might look in a real operation: "There can be scenarios where clinicians, unintentionally, are very close to a very critical structure such as the optic nerve. This can have, any damage or a slight more pressure on the optic nerve, can have long term complications on the patient side. So, this whole tool will alert the surgeon during the procedure if there is any risk of potential complication so they can recalibrate themselves during the procedure." Khan, who was also involved in developing the software that is now helping him learn, says the A.I. system has been a valuable tool in his training. It could also provide him with step-by-step guidance during a procedure, similar to having a senior surgeon standing over your shoulder. "I think as I progress as a surgeon, there might be stages where I wonder, you know, have I done enough of a particular part of the procedure and should I move on? And actually having that sort of assistant in the background as a reassurance to look at and say, 'well, yeah, actually, at this stage, out of the hundreds of videos of experts that this algorithm has watched, the experts would probably start moving on to the next phase'. It's a useful double check." According to UCL, the system could be ready to be used in operating theaters within two years. From https://news.yahoo.com/ai-could-help-brain-surgery-080156167.html
  11. In a recent study published in Hypertension Research, scientists examine the endocrine causes of hypertension (HTN) and investigate the efficacy of treatments to alleviate HTN. What is HTN? About 30% of the global population is affected by HTN. HTN is a modifiable cardiovascular (CV) risk factor that is associated with a significant number of deaths worldwide. There are two types of HTN known as primary and secondary HTN. As compared to primary HTN, secondary HTN causes greater morbidity and mortality. The most common endocrine causes of HTN include primary aldosteronism (PA), paragangliomas and pheochromocytomas (PGL), Cushing’s syndrome (CS), and acromegaly. Other causes include congenital adrenal hyperplasia, mineralocorticoid excess, cortisol resistance, Liddle syndrome, Gordon syndrome, and thyroid and parathyroid dysfunction. What is PA? PA is the most common endocrine cause of hypertension, which is associated with excessive aldosterone secretion by the adrenal gland and low renin secretion. It is difficult to estimate the true prevalence of PA due to the complexity of its diagnosis. Typically, the plasma aldosterone-to-renin ratio (ARR) is measured to diagnose PA. The diagnosis of PA can also be confirmed using other diagnostic tools like chemiluminescent enzyme immunoassays (CLEIAs) and radio immune assay (RIA). Continuous aldosterone secretion is associated with organ damage due to chronic activation of the mineralocorticoid (MR) receptor in many organs, including fibroblasts and cardiomyocytes. An elevated level of aldosterone causes diastolic dysfunction, endothelial dysfunction, left ventricular hypertrophy, and arterial stiffness. Increased aldosterone secretion also leads to obstructive sleep apnea and increases the risk of osteoporosis. This is why individuals with PA are at a higher risk of cardiovascular events (CVDs), including heart failure, myocardial infarction, coronary artery disease, and atrial fibrillation. PA is treated by focusing on normalizing potassium and optimizing HTN and aldosterone secretion. Unilateral adrenalectomy is a surgical procedure proposed to treat PA. Young patients who are willing to stop medication are recommended surgical treatment. The most common pharmaceutical treatment for PA includes mineralocorticoid receptor antagonists such as spironolactone and eplerenone. Pheochromocytomas and paragangliomas PGL are tumors that develop at the thoracic-abdominal-pelvic sympathetic ganglia, which are present along the spine, as well as in the parasympathetic ganglia located at the base of the skull. The incidence rate of PGL is about 0.6 for every 100,000 individuals each year. PGL tumors synthesize excessive catecholamines (CTN), which induce HTN. Some of the common symptoms linked to HTN associated with PGL are palpitations, sweating, and headache. PGL can be diagnosed by determining metanephrines (MN) levels, which are degraded products of CTN. Bio-imaging tools also play an important role in confirming the diagnosis of PGL. Excessive secretion of CTN increases the risk of CVDs, including Takotsubo adrenergic heart disease, ventricular or supraventricular rhythm disorders, hypertrophic obstructive or ischaemic cardiomyopathy, myocarditis, and hemorrhagic stroke. Excessive CTN secretion also causes left ventricular systolic and diastolic dysfunction. Typically, PGL treatment is associated with surgical procedures. Two weeks before the surgery, patients are treated with alpha-blockers. For these patients, beta-blockers are not used as the first line of treatment without prior use of alpha-adrenergic receptors. Patients with high CTN secretion are treated with metyrosine, as this can inhibit tyrosine hydroxylase. Hydroxylase converts tyrosine into dihydroxyphenylalanine, which is related to CTN synthesis. What is CS? CS, which arises due to persistent exposure to glucocorticoids, is a rare disease with an incidence rate of one in five million individuals each year. The most common symptoms of CS include weight gain, purple stretch marks, muscle weakness, acne, and hirsutism. A high cortisol level causes cardiovascular complications such as HTN, hypercholesterolemia, and diabetes. CS is diagnosed based on the presence of two or more biomarkers that can be identified through pathological tests, such as salivary nocturnal cortisol, 24-hour urinary-free cortisol, and dexamethasone suppression tests. CS is treated through surgical procedures based on the detected lesions. Patients with severe CS are treated with steroidogenic inhibitors, such as metyrapone, ketoconazole, osilodrostat, and mitotane. Pituitary radiotherapy and bilateral adrenalectomy are performed when other treatments are not effective. Acromegaly Acromegaly arises due to chronic exposure to growth hormone (GH), leading to excessive insulin-like growth factor 1 (IGF1) synthesis. This condition has a relatively higher incidence rate of 3.8 million person-years. Clinical symptoms of acromegaly include thickened lips, widened nose, a rectangular face, prominent cheekbones, soft tissue overgrowth, or skeletal deformities. Prolonged exposure to GH leads to increased water and sodium retention, insulin resistance, reduced glucose uptake, and increased systemic vascular resistance. These conditions increase the risk of HTN and diabetes in patients with acromegaly. Acromegalic patients are also at a higher risk of cancer, particularly those affecting the thyroid and colon. Acromegaly is diagnosed using the IGF1 assay, which determines IGF1 levels in serum. After confirming the presence of high IGF1 levels, a GH suppression test must be performed to confirm the diagnosis. Bioimaging is also conducted to locate adenoma. Acromegaly is commonly treated through surgical procedures. Patients who refuse this line of treatment are treated with somatostatin receptor ligands, growth hormone receptor antagonists, dopaminergic agonists, or radiotherapy. Journal reference: De Freminville, J., Amar, L., & Azizi, M. (2023) Endocrine causes of hypertension: Literature review and practical approach. Hypertension Research; 1-14. doi:10.1038/s41440-023-01461-1 From https://www.news-medical.net/news/20231015/Hormones-and-high-blood-pressure-Study-reveals-endocrine-culprits-and-targeted-treatments.aspx
  12. Niall Cavanagh, now aged 48, bravely fought and beat a brain tumour diagnosis when he was a teenager. He shared his experience with The Kerryman in an interview conducted ahead of the seventeenth annual International Brain Tumour Awareness Week. This week-long event, running from October 28th to November 4th, aims to raise awareness about brain tumours and support those affected by them. Niall’s journey was not an easy one. Leading up to his diagnosis in 1992, he experienced symptoms such as excessive thirst, urination, severe headaches, vomiting, and stunted growth. It was when he went for an eye examination for double vision that the examiner noticed something seriously wrong with his retinas. Further tests revealed a germinoma brain tumour pressing on the pituitary gland. To relieve the pressure caused by the tumour, Niall underwent an emergency ventriculoperitoneal shunt procedure. This involved inserting a tube from his brain to his abdomen to drain the excess cerebrospinal fluid. He also underwent extensive radiotherapy to shrink the tumour and prevent its spread. The tumour affected Niall’s pituitary gland, resulting in a condition known as hypopituitarism. This condition causes a deficiency in various hormones, including growth hormone and anti-diuretic hormone. Niall experienced adverse effects on his physical and mental health due to the tumour and subsequent treatments. Despite the challenges, Niall gained a clearer perspective on life. He learned to appreciate what is truly important and developed compassion through his own struggles with depression and anxiety. He emphasized that each person’s experience with a brain tumour is unique, and it’s essential to show support and understanding to others facing similar battles. Niall’s health has gradually improved over the years, although he still faces challenges due to a weakened immune system. However, he remains resilient and has pursued higher education, obtaining two degrees in IT and a Masters in information systems. He currently works part-time in an administrative role with the Renewable Energy Centre in Killarney. Throughout his journey, Niall received invaluable support from his family and various organizations, including the Cork Brain Tumour Support Group (now Brain Tumour Ireland), the Pituitary Foundation, and Headway in Tralee. Niall’s story serves as an inspiration and a reminder of the importance of raising awareness and providing support to those affected by brain tumours. International Brain Tumour Awareness Week aims to continue spreading awareness and fostering understanding of this life-changing condition. Sources: – The Kerryman From https://www.expresshealthcaremgmt.com/news2/kerry-man-reflects-on-beating-brain-tumour-diagnosis-as-a-teenager-you-have-to-sink-or-swim/156637/
  13. Abstract Cushing’s disease (CD) is an extremely rare diagnosis in children. In this report, we present the case of an almost 16-year-old, short and thin boy with CD, the first symptoms of which were spinal pain and vertebral fractures as a result of osteoporosis. In light of his growth retardation and short stature, the boy underwent diagnostics, which excluded growth hormone (GH) deficiency, hypothyroidism and celiac disease. Finally, based on cortisol profile results, dexamethasone suppression tests and bilateral sampling during catheterization of the inferior petrosal sinuses, CD was diagnosed. Keywords: Cushing’s disease; obesity; growth retardation; osteoporosis 1. Introduction Cushing’s disease (CD) is an extremely rare diagnosis in children; however, if it occurs, it is more likely to present in older children [1,2]. It is a type of ACTH-dependent Cushing’s syndrome (CS), in which the pituitary gland is the source of ACTH secretion. The highest incidence of CD occurs in children aged 12.3–14.1 years [3]. The incidence of CD during this developmental age is approximately 5% of that seen in adults (with an annual incidence of 0.89–1 per million pediatric patients) [1,2,4]. The rarest form of ACTH-dependent CS in children is ectopic Cushing’s syndrome (ECS), associated with ectopic production of ACTH or CRH, most commonly by neuroendocrine tumors such as bronchial carcinoids, gastrointestinal tumors, medullary thyroid carcinoma, or pheochromocytomas [2,4,5]. Children with ECS constitute 1% of patients with CS in the developmental age [2]. An even rarer disease is ACTH-independent Cushing’s syndrome—associated with adrenal lesions (adenoma, carcinoma, bilateral macronodular adrenal hyperplasia (BMAH), or primary pigmented nodular adrenocortical disease (PPNAD)) [2]. Regarding CD, ACTH is secreted in an overwhelming majority of cases by pituitary corticotropic microadenomas and—less commonly—by macroadenomas, the latter occurring in only 10% of adult CD cases and even more rarely in children (2%) [1,3]. Long-term hypercortisolemia can also lead to bone-mineralization disorders, including osteoporosis, especially in the bones of the central skeleton [4,6,7]. In children, the most common features of CD are rapid weight gain (93–98%), growth retardation (63–100%) and/or facial changes (63–100%) [4]. Mood disturbances, muscle weakness, osteopenia, and headaches are less frequent symptoms. Limited data are available about bone mineral density (BMD) in children with CD. Lonser et al. [8] observed fractures in 7% of patients with CD that were studied. Chronic glucocorticoid excess associated with CD has negative effects on bone turnover, leading to bone-mineralization disorders in both adults and children. Multiple factors contribute to decreased bone mineral density in CD, including the direct effect of glucocorticoids on osteoclasts and osteoblasts, both impairing bone formation and enhancing bone resorption. Glucocorticoids also act to decrease gastrointestinal calcium absorption and renal calcium reabsorption. Bone loss occurs more frequently in Cushing’s syndrome caused by adrenal tumors in CD [6,7]. An additional factor involved in bone-mineralization disorders, particularly in adult patients with CD, may be hypogonadotropic hypogonadism. Reproductive and sexual dysfunctions are highly prevalent in CS, with higher frequency observed in patients with pituitary-related CS, compared to those with adrenal-related CS. Hypogonadism is identified in as much as 50–75% of men with CS and menstrual irregularities are present in 43–80% of women diagnosed with this condition. During active disease, there is a significant reduction in plasma testosterone and gonadotropin levels in men [7,9]. These testosterone levels typically normalize during remission of the disease. Pivonello et al. [7] suggest that the lack of testosterone normalization three months after CS treatment indicates the need for administration of testosterone to protect the patient’s bone mass. In children, cortisol excess can also suppress gonadotropin, TSH and growth hormone secretion, contributing to the absence of pubertal characteristics or inhibiting its progression in patients who have already entered puberty [1]. So far, to our knowledge, there have been no reports on children where bone-mineralization disorders (without weight gain and hirsutism) are the first sign of CD. 2. Case Presentation We present the case of an almost 16-year-old boy with short stature who, in May 2021, was referred to the Osteoporosis Outpatient Clinic of the Polish Mother’s Memorial Hospital—Research Institute (PMMH-RI) in Lodz, Poland, due to severe back pain. Low bone mass was diagnosed via dual-energy X-ray absorptiometry (DXA). Initially, it seemed that the occurrence of those symptoms might be related to steroid therapy, because in November 2020 (just after SARS-CoV-2 infection) the child had developed severe abdominal pain, accompanied by an increase in the activity of liver enzymes, and after excluding an infectious cause, autoimmune hepatitis was diagnosed. Deflazacort (Calcort) therapy was prescribed in gradually reduced doses, with the initial dose being 24 mg in the morning and 18 mg in the afternoon. This therapy was discontinued on 1 October 2021. As early as on the fifth day of glucocorticosteroid treatment, pain presented in the lumbar spine region, increasing with movement. Initially, the pain was intermittent, then it became constant. No painkillers were needed. On 7 May 2021, on the basis of DXA, low bone mass was diagnosed (Z-score Spine: −4.2, Z-score TBLH: −1.9). In June 2021 (while still undergoing treatment with steroids) the boy was admitted to the Department of Endocrinology and Metabolic Diseases PMMH-RI for further diagnostics (Table 1). Table 1. The medical history and the course of diagnostics and treatment. The patient was a second child, born at 40 weeks of gestational age, weighing 4150 g, measuring 56 cm, and achieving a 10-point Apgar score. During infancy, he received vitamin D supplementation in accordance with Polish recommendations at that time. However, after his first year of life, the supplementation was not taken regularly. The boy received vaccinations according to the standard immunization schedule. There was no significant family medical history. During the physical examination, apart from the presence of short stature, no other notable abnormalities were detected. The skin was clear, without pathological lesions; no features of hyperandrogenism were observed. The boy’s body weight was 47.4 kg (3rd–10th centile); his height, 162 cm (<3rd centile); and height SDS, −2.36; while his BMI was 18.06 kg/m2 (10th–25th centile). Pubarche was assessed as stage 4 according to the Tanner scale; the volume of the testes was 10–12 mL each. After available anthropometric measurements from the patient’s medical history were plotted on the growth chart for sex and chronological age, it became evident that the boy experienced growth retardation from the age of 11 (Figure 1). Figure 1. Growth chart for boys. The red line represents growth retardation from the age of 11. Apart from slightly increased calcium excretion in the 24 h urine collection (Calcium: 9.52 mmol/24 h), there were no significant abnormalities in the laboratory tests assessing calcium–phosphate metabolism (Calcium: 2.41 mmol/L, Phosphorus: 1.3 mmol/L). Serum parathormone (PTH) and vitamin D concentrations remained normal (PTH: 22.9 pg/mL, 25(OH)D: 46.7 ng/mL). Due to the described pain complaints, a thoracolumbar spine X-ray was performed. A decrease in the height of the Th5-Th9 vertebrae and central lowering of the upper border plate of the L4 and L5 were observed (Figure 2). Figure 2. A thoracolumbar spine X-ray with multilevel vertebral fractures. Decrease in the height of the Th5–Th9 vertebrae and central lowering of the upper border plate of the L4 and L5 were found. Magnetic resonance imaging (MRI) of the spine confirmed multilevel vertebral fractures, which, together with the presence of low bone mass on DXA examination, allowed a diagnosis (according to ISCD guidelines) of osteoporosis to be made. Treatment included calcium supplements and cholecalciferol. The parents did not consent to treatment with bisphosphonates (sodium pamidronate), which is an off-label treatment. In light of the patient’s short stature and growth retardation, an endocrinological assessment was conducted. The possibility of growth hormone (GH) deficiency and hypothyroidism as underlying causes for the growth retardation was ruled out. Gonadotropin and androgen levels were adequate for the pubertal stage (FSH—8.3 IU/L, LH—4.7 IU/L, testosterone—4.750 ng/mL, DHEA-S—230.30 µg/dL (normal range: 70.2–492), 17-OH-progesterone—0.78 ng/mL). The bone age was assessed to be 15 years. Alongside continued steroid therapy for autoimmune hepatitis, profiles of cortisol and ACTH secretion were performed. Due to the patient’s elevated cortisol levels during night hours (cortisol 24:00—10.7 µg/dL), an overnight dexamethasone suppression test (DST) and low-dose dexamethasone suppression test (LDDST) were performed. After administering 1 mg dexamethasone (23:00), his morning cortisol level (8:00) still remained elevated (cortisol—3.4 µg/dL). However, after administering 0.5 mg dexamethasone every 6 h for the next 2 days, cortisol levels (8:00) normalized (cortisol—1.0 µg/dL). An MRI of the pituitary gland showed only a poorly demarcated area in the anterior part of the glandular lobe, measuring approximately 2.0 × 3.5 × 5.0 mm on T2W images (Figure 3). A follow-up MRI examination was recommended, which was performed during the child’s next hospitalization in January 2022. The previously described area was still very faint. Figure 3. MRI examination image depicting the poorly demarcated area in the anterior part of the glandular lobe. The arrows point to a structure suspected of being an adenoma. In October 2021, the administration of deflazocort as a treatment was discontinued. During hospitalization in January 2022, the diurnal pattern of ACTH and cortisol secretion was re-evaluated, yet no consistent diurnal rhythm was observed; cortisol levels remained elevated at night. For this reason, overnight DST and then LDDST were carried out again (Figure 4), in which no suppression of cortisol concentrations was obtained. Only after a high-dose DST (HDDST), in which a high 1.5 mg of dexamethasone was administered every 6 h (125 µg/kg/24 h), was cortisol secretion suppressed. Figure 4. Laboratory findings indicating the diagnosis of ACTH-dependent Cushing’s syndrome. Based on the above results, CD was suspected as the cause of osteoporosis and growth retardation. In February 2022, a CRH test was performed upon the patient, which revealed a four-fold increase in ACTH levels and a two-fold increase in serum cortisol levels (Table 2). Table 2. The results of human CRH (hCRH) stimulation test and bilateral inferior petrosal sinus sampling (BIPSS). The CRH stimulation test was administered in the morning using human synthetic CRH (Ferring) at a dose of 1 μg/kg of body weight. During the test, cortisol and ACTH levels were measured in serum at the following time points: −15, 0, 15, 30, 60, and 90 min (see Table 2). As part of the diagnostic process, urinary free cortisol excretion was also measured over two consecutive days. Only on the first day was there a slight elevation in urinary free cortisol concentration, measuring 183.60 μg/24 h (normal range: 4.3–176). The measurement performed on the second day showed a normal urinary free cortisol concentration of 145.60 μg/24 h (normal range: 4.3–176). On 2 March 2022, the patient underwent a bilateral inferior petrosal sinus sampling (BIPSS). Human CRH stimulation was also used during the procedure. The presence of ACTH-dependent hypercortisolemia of pituitary origin was confirmed. The outcome of the CRH stimulation during the BIPSS is presented in Table 2. The boy qualified for transsphenoidal surgery (TSS) of the pituitary adenoma and was successfully operated on (8 March 2022). Postoperative histopathological examination revealed features of a corticotroph-rich pituitary adenoma. 3. Discussion Osteoporosis, like CD, is extremely rare in the developmental age population. Bone-mineralization disorders among children may be primary (e.g., osteogenesis imperfecta), or secondary to other diseases or their treatment (e.g., with glucocorticosteroids). This case report presents a boy with osteoporosis, the cause of which was originally attributed to the treatment of autoimmune hepatitis with glucocorticosteroids. Steroid therapy is the most common cause of bone-mineralization disorders in children. However, osteoporosis is a late complication of steroid treatment. Briot et al. [10] demonstrated that the risk of fractures increases as early as 3 months after initiating steroid therapy. An additional factor increasing the risk of fractures is the dose of glucocorticosteroids used, corresponding to 2.5–5 mg of prednisolone per day [10]. In the case of the present patient, the appearance of spinal pain and thus vertebral fractures could not have been related to the deflazacort treatment started 5 days earlier. The bone-mineralization disorder must therefore have occurred much earlier. For this reason, the authors considered it necessary to search for other endocrine causes of osteoporosis development, including hypogonadism, growth hormone deficiency or Cushing’s syndrome/disease. The serum vitamin D concentration can also influence bone mineral density. Every patient with mineralization disorders, especially with osteoporosis, requires a thorough assessment of calcium–phosphate metabolism [11]. Until the initiation of steroid therapy in March 2021, the patient did not undergo regular vitamin D supplementation. At the start of deflazacort treatment, his serum 25(OH)D concentration was 12.4 ng/mL. Consequently, additional cholecalciferol supplementation at a dose of 3000 IU/day was introduced. In a subsequent measurement conducted in June 2021, the concentration was within the reference range [25(OH)D: 46.7 ng/mL]. Considering the lack of regular supplementation before March 2021, it can be assumed that in October 2020, when the boy experienced SARS-CoV-2 infection, his serum vitamin D concentration was likely decreased as well, which could have had a further negative impact on the patient’s bone mineralization. Scientific reports indicate that adequate vitamin D levels reduce the risk of viral infections, including SARS-CoV-2 [12]. Di Filippo et al. [13] demonstrated that vitamin D deficiency observed in 68.2% of SARS-CoV-2-infected individuals correlated with a more severe course of the infection. In our patient, the course of COVID-19 was asymptomatic, and the diagnosis was established based on positive IgM antibody titers against SARS-CoV-2. The vitamin deficiency was most likely associated with irregular supplementation and lack of exposure to UV radiation (due to lockdown measures in Poland at that time). A reduced serum 25(OH)D concentration could have contributed to worsened bone mineral density and increased susceptibility to SARS-CoV-2 infection; however, it is the chronic hypercortisolism characteristic of CD that most likely led to the development of osteoporosis with accompanying fractures. Another factor necessitating further diagnostic investigation into CD was the patient’s growth retardation observed since the age of 11. Both the pubertal state of the boy, and his gonadotropin and testosterone serum levels, allowed us to exclude hypogonadism. Maximum spontaneous nocturnal secretion of the growth hormone was 31.84 ng/mL. The diagnosis of CD was established on the basis of elevated cortisol levels at night and the lack of cortisol suppression in the test after administering dexamethasone. Final confirmation of the diagnosis was obtained in a post-CRH stimulation test. In pediatric cases, the absence of typical diurnal variation in serum corticosolemia, especially the nocturnal decline, and the inability to suppress cortisol secretion at midnight, are highly sensitive indicators of hypercortisolemia [6,8]. Consequently, in our patient, osteoporosis was a complication of diagnosed CD. The patient in question was not obese, which is the predominant symptom of CD. This symptom, according to Ferrigno et al. [1], is present in 92–98% of examined children diagnosed with CD. Storr et al. [14] showed that facial changes and facial swelling were observed in 100% of subjects with CD, whereas Lonser et al. [8] observed this in only 63% of children with CD. In our patient, no changes in facial appearance were observed. Other symptoms typical of CS, such as hirsutism, acne, or bruises, were not noticed either. These symptoms were observed in all children with CD studied by Wędrychowicz et al. [3]. Non-specific symptoms of this condition may include mood changes, depression and emotional vacillation [1,8]. However, our patient’s parents did not observe any changes in the boy’s behavior. The indication for initiating the whole diagnostic process was (in addition to osteoporosis) growth retardation. Ferrigno et al. [1] point out that chronic hypercortisolemia most often leads to growth disorders accompanied by excessive weight gain. This is an early, highly sensitive and characteristic sign of CD. Short stature is not always observed and occurs in one in two children diagnosed with CD. The patient we present was short (height—162 cm (<3rd centile hSDS: −2.36)); growth retardation was observed from the age of 11 years. The occurrence of vertebral fractures and the accompanying pain as the initial symptoms of hypercortisolism, the absence of obesity, and the confirmation of CD, an exceedingly rare condition in the pediatric population, collectively underscore the uniqueness of our patient’s disease presentation. A case involving a child with such an atypical course of ACTH-dependent CS has not been described before. Han et al. [15] reported a case of a 28-year-old lean woman (BMI: 19 kg/m²) with ACTH-independent CS due to a left adrenal adenoma, where, similarly to our patient, the initial manifestation of hypercortisolism was compression fractures of the thoracic vertebrae. The authors emphasize that vertebral fractures may affect 30–50% of patients with Cushing’s syndrome, with a higher frequency observed in patients with ACTH-independent CS compared to those in whom hypercortisolism results from the presence of pituitary adenoma [15]. The lack of obesity in a patient with hypercortisolism could be attributed to malnutrition, which accompanies the growth process in ECS. Hence, a crucial aspect was the differential diagnosis between CD and ECS. To this end, we performed a stimulation test using hCRH. We considered cut-off points for diagnosing CD to be a 35% increase in ACTH concentration at 15 and/or 30 min, and at least a 20% increase in cortisol concentration at 30 and 45 min [16,17]. In the case of ECS, a significant rise in CRH and cortisol concentrations is not observed. Recently published reports emphasize the need to explore new cut-off points to enhance the sensitivity and specificity of this test. Detomas et al. [5] indicate that an increase in ACTH ≥ 31% and cortisol ≥ 12% in the 30th minute of CRH tests allows for a highly sensitive and specific differentiation between CD and ECS. The authors highlight that measuring these hormones at the 60 min stage of the test does not provide diagnostic benefits. Notably, the study employed ovine CRH, which exhibits stronger and more prolonged stimulatory effects compared to the hCRH available in Europe that was used to diagnose our patient [5]. Conversely, Elenius et al. [16] suggest that optimal values for distinguishing between CD and ECS in the CRH stimulation test involve an increase in ACTH and/or cortisol levels of more than 40% during the test. In our patient, an over four-fold increase in ACTH levels and a more than two-fold increase in cortisol levels were observed at the 30 min mark of the test, thus independently and definitively excluding ECS regardless of the adopted cut-off points. Our patient’s case also demonstrates that MRI is not a perfect method of visualizing an ACTH-secreting pituitary adenoma. In the first MRI examination performed upon our patient, a poorly demarcated area (2.0 × 3.5 × 5.0 mm) was described in the anterior part of the glandular lobe; in the examination performed 6 months later, this area maintained poor visibility, while laboratory results at the time clearly indicated an ACTH-dependent form of CS. It was only the bilateral inferior petrosal sinus sampling (BIPSS) that allowed a clear diagnosis. Data from the literature indicate that microadenomas smaller than 3–4 mm are visible on MRI in only half of cases. In two large studies including children, pituitary adenomas were found on MRI in 63% and 55% of cases [18]. Among the patients with CD studied by Wędrychowicz et al. [3], pituitary adenomas were described on MRI in all of them, but in two patients (50%) this was only achieved upon follow-up. In the standard procedure, in the absence of a pituitary lesion in the MRI examination, it is recommended that a BIPSS be performed. In the case of our patient, this examination was necessary to make a definitive diagnosis. When analyzing the results of the BIPSS with hCRH stimulation, we employed the classical cut-offs for the ACTH IPS:P (Inferior Petrosal Sinus: Peripheral) ratio (i.e., ≥2 at baseline and ≥3 after hCRH stimulation) [1]. This allowed the confirmation of CD and determination of the pituitary adenoma’s localization, followed by the procedure for its surgical removal. The optimal cut-off values for the IPS:P ratio remain controversial. There are ongoing efforts to establish new, more precise cut-off points. Detomas et al. [19] demonstrated that an IPS:P ratio ≥ 2.1 during desmopressin stimulation in the BIPSS most accurately differentiates CD from ECS. Conversely, Chen et al. [20] showed that the optimal pre-desmopressin stimulation IPS:P ratio cut-off is 1.4, and post-stimulation it is 2.8. Both studies suggest the utilization of lower cut-off values for the IPS:P ratio than those traditionally adopted. Chen et al. [20] also advocate for avoiding stimulation during BIPSS. In most cases, the IPS:P ratio before stimulation is sufficient for diagnosing CD. According to the authors, desmopressin stimulation should be reserved for patients with ambiguous MRI findings or with a pituitary adenoma with diameter less than 6 mm. However, considering that the concentration of ACTH in the right inferior petrosal sinus in our patient was over 4 times higher than in the peripheral vessel and nearly 14 times higher after hCRH stimulation, regardless of the applied criteria, CD could be unequivocally diagnosed in our patient, and the lateralization of the microadenoma could be determined with certainty. The rarity of CD, and the diagnostic difficulties stemming from its oligosymptomatic or atypical course, encourage description in the form of case reports. Eviz et al. [21] delineate the occurrence of cerebral cortical atrophy in two children with ECS. Additionally, other researchers have underscored the potential for thyroid disorders to manifest alongside hypercorticosolemia [22]. Although obesity typically stands out as a primary symptom of CD, Pomahacova et al. [23] reported a case involving two children with CD who maintained normal body weight, mirroring our patient’s situation. The symptoms that prompted diagnostic investigation in these instances included weakness, sleep disturbances and growth retardation. Interestingly, growth retardation, along with facial changes, was observed in all examined children with CD [23]. Nonetheless, to the best of our knowledge, we have yet to encounter a case report resembling ours. Therefore, it remains crucial to share our experiences. 4. Conclusions Cushing’s disease is an extremely rare diagnosis in children. In Poland, there is no statistical record of occurrences of this disease among children. Wędrychowicz et al. reported that in their single Polish center, between 2012 and 2018, they identified four cases of children aged 7–15 who were diagnosed with CD [3]. The case we present shows that obesity, commonly considered as a predominant symptom of CD, is not necessarily observed in patients with this diagnosis in the developmental age population. Among children, it is growth disturbance that may be the first manifestation. On the other hand, a late complication of CD may be osteoporosis, so whenever a child is diagnosed with a bone-mineralization disorder, the cause of its development should be sought. Diagnosis should be pursued until all potential causes of the described symptoms, including the rarest ones, are definitively ruled out—even if the clinical presentation, as in the case of our patient, initially does not point towards the final diagnosis. Thus far, no case of a child with CD exhibiting such subtle symptomatology has been described in the literature. The challenges in diagnosis we encountered primarily resulted from the atypical clinical outcome of CD in our patient—normal body weight, absence of hyperandrogenism, mood disturbances not apparent to caregivers and the patient’s immediate environment, as well as normal progression of puberty, did not immediately lead to the consideration of endocrinological causes of osteoporosis. The steroid therapy employed due to autoimmune hepatitis also complicated the diagnostic process. Only after discontinuing deflazacort treatment was it possible to definitively diagnose CD. Our patient required hydrocortisone replacement in gradually decreasing doses for a year following TSS. Considering that pituitary adenomas in children can be genetically predisposed (e.g., MEN 1 mutation, AIP mutation, USP8 mutation, and other rarer ones), genetic consultation was sought [1]. However, the conducted tests have thus far excluded the most common mutations in our patient. Due to the diagnosed osteoporosis, chronic supplementation with calcium and cholecalciferol was recommended, along with annual follow-up DXA scans. Studies indicate that patients in remission from CD experience a gradual improvement in bone mineral density [3]. While we can currently observe remission in our patient’s case, the advanced bone age of the child (indicating the completion of the growth process) left limited potential for significant improvement in final growth. The patient still requires regular endocrinological and neurosurgical follow-ups, hormonal assessments, and pituitary MRI examinations. Author Contributions Conceptualization—R.S. and A.Ł.; software—S.A.; formal analysis—R.S.; investigation—A.Ł. and G.Z.; data curation—A.Ł.; writing—original draft preparation—A.Ł., R.S. and S.A.; writing—review and editing—A.L.; visualization—S.A.; supervision—A.L. All authors have read and agreed to the published version of the manuscript. Funding This study was funded by statutory funds from the Medical University of Lodz, Lodz, Poland (503/1-107-03/503-11-001). Institutional Review Board Statement Not applicable. Informed Consent Statement Written informed consent has been obtained from the patient to publish this paper. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. References Ferrigno, R.; Hasenmajer, V.; Caiulo, S.; Minnetti, M.; Mazzotta, P.; Storr, H.L.; Isidori, A.M.; Grossman, A.B.; De Martino, M.C.; Savage, M.O. Paediatric Cushing’s disease: Epidemiology, pathogenesis, clinical management and outcome. Rev. Endocr. Metab. Disord. 2021, 22, 817–835. [Google Scholar] [CrossRef] Stratakis, A. Cushing syndrome in pediatrics. Endocrinol. Metab. Clin. N. Am. 2012, 41, 793–803. [Google Scholar] [CrossRef] Wędrychowicz, A.; Hull, B.; Tyrawa, K.; Kalicka-Kasperczyk, A.; Zieliński, G.; Starzyk, J. 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MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Share and Cite MDPI and ACS Style Łupińska, A.; Aszkiełowicz, S.; Zieliński, G.; Stawerska, R.; Lewiński, A. Osteoporosis as the First Sign of Cushing’s Disease in a Thin 16-Year-Old Boy—A Case Report. J. Clin. Med. 2023, 12, 5967. https://doi.org/10.3390/jcm12185967 AMA Style Łupińska A, Aszkiełowicz S, Zieliński G, Stawerska R, Lewiński A. Osteoporosis as the First Sign of Cushing’s Disease in a Thin 16-Year-Old Boy—A Case Report. 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  14. Abstract Background and Objectives Crooke cell adenomas (CCA) are a rare, aggressive subset of adrenocorticotrophin secreting pituitary corticotroph adenomas (sCTA) found in 5–10% of patients with Cushing’s disease. Multiple studies support worse outcomes in CCA but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers. Methods Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included. Results 2826 patients from 12 international centers were compared (n=20 CCA and n=480 sCTA). No difference in baseline demographics, tumor characteristics or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection (GTR) was higher in CCA patients (100% vs. 83%, p=0.05). Among patients that had GTR according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, p<0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, p<0.01). This was present despite CCA having better local control rates (100% vs. 96%, p<0.01) and fewer patients with remnant on MRI (0% vs. 7.2%, p<0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients. Conclusion This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced post-surgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches. References (0) Cited by (0) Previous presentations: none Previous publications: none Disclosures No relevant disclosures to report CREDIT statement Matthew Finlay: conceptualization, writing – review and editing Richard Drexler: conceptualization, writing – review and editing All: data curation, writing – review and editing Michael Karsy: conceptualization, data curation, methodology, writing – original draft, writing – review and editing, supervision Funding and Disclosures: none View full text From https://www.sciencedirect.com/science/article/abs/pii/S187887502301344X
  15. Context: Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma. Objective: Aim to investigate the efficacy and toxicity of IMRT in treating Cushing’s Disease (CD). Methods: 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record. Results: At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. Conclusion: IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS. Introduction Cushing’s disease (CD) is characterized by hypersecretion of adrenocorticotropic hormone (ACTH) from pituitary adenoma. As the state of hypercortisolemia considerably increases morbidity and mortality, normalizing cortisol levels is regarded as the major treatment goal in patients with CD (1). Transsphenoidal selective adenomectomy (TSS) is now established as the first-line treatment of CD. Despite the satisfactory remission rate that can be achieved with TSS (ranging from 59-97%), delayed recurrences have also been reported in up to 50% of patients (2). The Endocrine Society guidelines suggest a shared decision-making approach in patients who underwent a noncurative surgery or for whom surgery was not possible (3). Second-line therapeutic options include repeat transsphenoidal surgery, medical therapy, radiotherapy and bilateral adrenalectomy. Radiotherapy (RT) is generally used in patients who have failed TSS or have recurrent CD, as well as in progressively growing or invasive corticotroph tumors (3, 4). Both stereotactic radiosurgery(SRS)and fractionated radiotherapy (FRT) have been used in the treatment of CD. Conventional radiotherapy as one of the technique for FRT has been used with a long experience, but its benefits were hindered by high risk of toxicity, mainly attributed to the harm to healthy surrounding structures (4). Previous studies on conventional RT in treating CD showed high efficacy (tumor control rate of 92-100% and hormonal control rate of 46-89%), but RT-induced hypopituitarism (30-58%) and recurrence (16-21%) were also commonly reported (1, 4–7). Modern precise radiotherapy, especially intensity-modulated radiotherapy (IMRT), can spare the surrounding normal structure better by a more conformal and precise dose distribution (8). However, a large cohort study on long-term efficacy and toxicity of IMRT for CD is still lacking. Therefore, in the current study, we aim to analyze the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in treating CD. We also investigated the predictors of endocrine remission in aid of further management. Methods Patient We collected 115 cases of Cushing’s disease treated at our center from April 2012 to August 2021. Patients were excluded under the following conditions: (1) follow-up time less than 3 months, (2) lacking evaluation of serum cortisol (F), adrenocorticotropic hormone (ACTH) or 24-hour urinary free cortisol (24hUFC) before or after RT, (3) underwent uni or bilateral adrenalectomy, (4) having received RT at other institutes before admitted to our center. At last, a total of 70 cases were included in this study. Radiotherapy parameters RT was administrated by a linear accelerator (6 MV X-ray). Intensity-modulated radiation therapy was applied for all patients. Including fix-filde IMRT (FF-IMRT), volumetric modulated arc therapy (VMAT) or Tomotherapy. We immobilized the patient with an individualized thermoplastic head mask and then conducted a computed tomography (CT) simulation scan at 2- to 3-mm intervals. The target volume and organs at risks (OARs) were delined with a contrast enhanced T1-weighted image (T1WI) magnetic resonance imaging (MRI) fusing with planning CT. The gross tumor volume (GTV) was defined with the lesion visible on MRI or CT. The clinical target volume (CTV) included microscopic disease, especially when the tumor invaded cavernous sinus and surrounding bones. The planning target volume (PTV) was defined as CTV plus a margin of 2- to 3-mm in three dimensions. The prescription dose was defined at 100% isodoseline to cover at least 95% PTV. The maximum dose was limited to less than 54 Gy for the brain stem and optic pathway structures. Radiotherapy was performed once a day and five fractions a week during five to six weeks. The total dose was 45-60 Gy, delivered in 25-30 fractions, with most patients (78.6%) receiving 45-50 Gy in 25 fractions. The fractionated dose was 1.8-2.0 Gy. Data collection and clinical evaluation Baseline characteristics were collected at the last outpatient visit before RT, including demographic characteristics, biochemical data, tumor characteristics and details of previous treatments. After RT, endocrine evaluations were performed every 6 months. Endocrine remission was considered when 1 mg dexamethasone suppression test (DST)<1.8 mg/dl. If 1mg DST results were lacking, then 24hUFC within the normal range was used as a remission criterion. Patients who regained elevated hormone levels after achieving remission were considered to have endocrine recurrence. For patients receiving medications that could interfere with the metabolism of cortisol, hormonal evaluation was performed at least 3 months after the cessation of the therapy. Tumor size was measured on magnetic resonance imaging (MRI) before RT and annually after the completion of RT. Any reduction in or stabilization of tumor size was considered as tumor control. Tumor recurrence was defined as an increase of 2 millimeters in 2 dimensions comparing to MRI before RT, or from invisible tumor to a visible tumor on MRI (9). Anterior pituitary function was assessed before RT and every 6 months during the follow-up after RT. RT-induced hypopituitarism was defined as the development of new onset hormone deficiency after RT. The diagnostic criteria for growth hormone deficiency (GHD), central hypothyroidism and hypogonadotropic hypogonadism (HH) refer to previous literature (10–12). Panhypopituitarism referred to three or more anterior pituitary hormone deficiencies (13). Statistical analysis Statistical analysis was performed with SPSS version 25.0. Longitudinal analysis was performed with Kaplan-Meier method. For time-dependent variable, Log rank test was used for univariate analysis and Cox regression for multivariate analysis. The cut-off of F, ACTH and 24hUFC were defined as their median value. All variants in the univariate analysis were included in the model of multivariate analysis. P value < 0.05 was considered statistically significant. Plot was created with GraphPad Prism version 9.4. Results Patient characteristics Of 70 cases included in the study, the median age was 32 years (range, 11-66 years). 60 (85.7%) were female and 10 (14.3%) were male (F:M= 6:1). The median follow-up time was 36.8 months (range, 3.0-111.0 months). 68 patients received RT as a second-line treatment because of incomplete tumor resection, failure to achieve complete endocrine remission or recurrence postoperative, and 2 were treated with RT alone because of contraindication of surgery. The frequency of surgical treatment was 1 for 42 patients, 2 for 21 and more than 3 for 5. A total of 8 patients received medical treatment before RT. 5 of them used pasireotide, 2 used ketoconazole and 1 used mifepristone. The median ACTH level was 58.7 pg/ml (range 14.9-265 pg/ml), F, 26.2μg/dl (range 11.8-72.6 μg/dl) and 24hUFC, 355.7 μg/24hr (range 53.5-3065 μg/24hr) before RT. Tumor size evaluation was performed in all 70 patients before RT. Among them, 36 patients showed no visible residual tumor identified on MRI and only 5 patients showed tumor size more than 1 cm. Hypopituitarism was found in 31 patients (38.8%) before RT. HH was the most common (21 patients, 26.3%), followed by central hypothyroidism (13 patients, 16.3%) and GHD (9 patients, 11.3%). Panhypopituitarism was found in 4 patients (5.0%). (Table 1). Table 1 Table 1 Patient characteristics. Endocrine remission Endocrine remission was achieved in 37 of 70 patients during the follow-up. Six of them were evaluated by 1mg DST. The hormonal remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively, gradually increasing with follow-up time (Figure 1). The median time to remission was 24.0 months (95%CI: 14.0-34.0 months). Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. There was no significant correlation between remission and age, sex, tumor size, the frequency of surgery, medication prior RT. The hormone levels (F, ACTH and 24hUFC prior RT) were divided into high and low groups by the median value, and were also not found to be associated with endocrine remission (Table 2). Since only Ki-67 was significant in the univariate analysis and all other parameters were far from significant, a multivariate analysis was no longer performed. Figure 1 Figure 1 Endocrine remission rate during the follow-up after RT. Table 2 Table 2 Univariate predictors of endocrine remission. Endocrine recurrence was found in 5 patients till the last follow-up, with an overall recurrence rate of 13.5% (5/37). The median time to recurrence after reaching endocrine remission was 22.5 months. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively (Figure 2). Figure 2 Figure 2 Recurrence free rate after endocrine emission. Tumor control A total of 51 patients had repeated MRI examinations before and after treatment. During the follow-up, 20 patients showed reduction and 30 patoents remained stable in tumor size, with a tumor control rate of 98%. Only 1 patient showed enlargement tumor 1 year after RT, with F, ACTH and 24hUFC increase continuously. Complications At the last follow-up, 16 patients developed new onset hypopituitarism after RT. The overall incidence of RT-induced hypopituitarism was 22.9%. Hypothyroidism was the most common of hypopituitarism (8 patients), followed by HH (7 patients), adrenal insufficiency (4 patients) and GHD (3 patients). Only 1 patient (1.3%) with systemic lupus erythematosus (SLE) comorbidity complained of progressively worsening visual impairment during the follow up. No cerebrovascular event or radiation associated intracranial malignancy was found in our cohort. Discussion Efficacy and radiotherapy techniques RT has been emerged as an effective second-line treatment for CD for many years. Although conventional fractionated RT has been used for a long experience in patients with CD, study on the modern precise radiotherapy, particularly IMRT, is rare and reports limited evidence on its long-term treatment outcome. IMRT can be implemented in many different techniques, such as fixed-field intensity-modulated radiotherapy (FF-IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy. Compared with conventional RT, IMRT allows a better target volume conformity while preserves adequate coverage to the target (14, 15). Our study reported that IMRT for CD has an endocrine remission rate of 74.0% at 5 years, with a median time to remission of 24.0 months (95%CI: 14.0-34.0 months). The endocrine remission rate at 5 years was comparable to those reported in previous series of FRT, with a median time to remission within the reported range (4.5-44 months) (9, 16–18) (Table 3). Compared with SRS in treating CD, the endocrine remission rate and median time to remission were also similar. Pivonello et al (19) summarized 36 studies of SRS for CD between 1986 to 2014, the mean endocrine remission rate was 60.8% and the median time to remission was 24.5 months. Tumor control rate was 98% in our cohort, only one patient showed enlargement tumor with elevating hormones. This local control rate was also comparable to that reported in a series of pituitary adenoma treated with FRT (93-100%) and SRS(92-96%) (9, 16–18, 20, 21). Indeed, despite the lack of controlled studies about SRS and FRT in treating CD, many reviews that summarize the biochemical control and tumor contral of both are similar (2, 6, 19). Table 3 Table 3 Literature review of FRT and SRS in patients with CD published in recent years. The overall endocrine recurrence rate in our study was 13.5%, with a median time to recurrence of 22.5 months. We, for the first time, reported the actuarial recurrence free rate at 1, 2, 3 and 5 years in CD patients treated with IMRT. The recurrence free rate at 3 and 5 years was 88.7% in our study. Outcomes were comparable to those reported in patients treated with conventional RT or SRS, with a mean recurrence rate and a median recurrence time of 15.9% (range, 0-62.5%) and 28.1 months, or 12.3% (range, 0-100%) and 33.5 months, according to a review conducted by Pivonello et al (19). At 2020, we reported the outcomes of pituitary somatotroph adenomas treated with IMRT at our institution (20). Compared with pituitary somatotroph adenomas, CD has a similar 5-year remission rate (74.0% vs 74.3%) but a shorter median time to remission (24.0m vs 36.2m) (Figure 3). The tumor contral rates were similar, at 98% and 99%, respectively. The endocrine recurrence rate was significantly different, with CD being about one-fold higher than the pituitary somatotroph adenoma (13.8% vs 6.1%). This may be due to the majority of microadenomas in CD and that of macroadenomas in pituitary somatotroph adenomas. Figure 3 Figure 3 Endocrine remission rate of CD and pituitary somatotroph adenoma. Predictors of endocrine remission In the univariate analysis, we found that only Ki-67 index ≥ 3% was correlated with better endocrine remission (p=0.044). Cortisol levels before RT and tumor size were not predictors of endocrine remission. For surgery in treating CD, higher preoperative ACTH level was considered as unfavorable prognostic factor for endocrine remission in a few studies (22, 23). For radiotherapy, some previous studies also have reported a faster endocrine remission in patients with lower serum cortisol level. Minniti et al. reported that hormone level was normalized faster in patients with lower urinary and plasma cortisol level at the time of RT (16). Apaydin also reported that low postoperative cortisol and 1mg DST was a favorable factors for faster remission in patients treated with gamma knife surgery (GKS) and hypofractionated radiotherapy (HFRT), although no significant relationship was found between remission rate and plasma cortisol level prior RT in both studies (9, 16). Castinetti et al. found that initial 24hUFC was a predicative factor of endocrine remission in patients treated with GKS, which was not reported in our cohort treated with IMRT (24). However, the discrepancy between the results can be attributed to various factors, including selection bias of retrospective study, duration of follow-up, endocrine remission criteria and cut-off value. Tumor size before RT was considered as a significant predictor for endocrine remission in some published series of patients treated with SRS. Jagannathan et al. reported a significant relationship between preoperative tumor volume and endocrine remission in patients with CD treated with GKS (25). However no significant correlation between tumor size and endocrine remission was found in series of patients treated with FRT (5, 9, 16, 17). But our study found no significant correlation between tumor size (visible or no-visible residual tumor on MRI) before RT and endocrine remission. The frequency of surgery before RT was also not found to be associated with endocrine remission in our study, which reached a similar conclusion with some previous studies (9, 17, 18, 26). Abu Dabrh et al. reported a higher remission rate in patients receiving TSS prior RT in their meta-analysis (5). Similar result was also reported in a review on the treatment outcome of GKS in patients with CD, that postoperative GKS was more effective than primary GK (19). However, analysis on this parameter was difficult in our cohort considering the low number of patients who received IMRT as the first-line treatment. Reports on the effect of medical treatment on endocrine remission have been controversial. Some studies reported a negative effect of medical treatment at the time of SRS on endocrine remission in patients with CD. Castinetti et al. showed a significant higher rate of endocrine remission in patients who were not receiving ketoconazole at the time of GKS, compared to those who were (27). Sheehan et al. also found a significantly shorter time to remission in patients who discontinued ketoconazole at the time of GKS (28). However, no such correlation was found in patients treated with FRT (9, 17). Like previous studies on FRT, we also noted no significant relationship between preradiation use of medication and endocrine remission, but our statistical analysis may be hindered by the low proportion of patients undergoing medical treatment before RT. Moreover, the anticortisolic drugs used in previous studies were mainly ketoconazole or cabergoline, while most of our patient have received pasireotide, whose effect have not been well-studied yet. Further studies are necessary to understand the effect of somatostatin receptor ligands on the outcome of radiotherapy in patients with CD. Complications Hypopituitarism is the most common complication secondary to radiotherapy, with the rate of new-onset hypopituitarism ranging widely in previous report. Pivonello et al. reviewed series of CD patients who were treated with conventional RT with a follow-up of at least 5 years (19). The reported mean and median rates of hypopituitarism were 50% and 48.3%, respectively (range, 0-100%). As regards FRT, the overall rate of new-onset hypopituitarism was 22.2-40% at a median follow-up ranging from 29-108 months, with both incidence and severity increasing with longer follow-up (9, 16–19). The incidence of hypopituitarism in our series was 22.9%, which was within the reported range of new onset hypopituitarism after FRT. Lower rate of hypopituitarism after SRS compared to conventional RT has been recognized in previous reviews (2, 6). Our study showed that new onset hypopituitarism was less prevalent after IMRT than after conventional RT. This can be attributed to a higher precision in contouring the target volume and OARs, allowing these modern radiotherapy techniques to provide a better protection to hypothalamus-pituitary axes. In previous studies, potential risk factors for new onset hypopituitarism included suprasellar extension, higher radiation dose to the tumor margin and lower isodose line prescribed (29, 30). Sensitivity of individual hormonal axes to RT varies in different series. In our study, central hypothyroidism was the most common individual axis deficiency, followed by HH, adrenal insufficiency and GHD. This sequence was similar to that reported by Sheehan et al., whose series included 64 CD patients treated with SRS, as well as some other series (29, 31). It is noted in some studies that GHD is the most vulnerable axes (19, 32, 33). Limited number of patients undergoing stimulation test may underestimate the prevalence of GHD in our study and some previous series, and longer follow-up is needed to generate a more accurate, time-dependent rate of new onset hypopituitarism. In our study, only one patient complained of mild visual impairment, which was comparable to the rate ranging from 0-4.5% in previous series of FRT treating pituitary adenoma (9, 16–18, 26, 32, 34, 35). This patient had concomitant SLE and the associated microangiopathy may render the optic nerve intolerant to radiotherapy. Cranial nerve damage was acknowledged as an uncommon complication, with an estimated risk of vision deterioration below 1% if single radiation dose was no more than 2.0 Gy and total dose no more than 45-50 Gy (2, 36). The actuarial rate of optic neuropathy at 10 years was 0.8% in a series containing 385 patients with pituitary adenoma (37). No patient in our cohort developed cerebrovascular accident or secondary brain tumor. This finding was consistent with the low actuarial prevalence of these complications reported in other published series of FRT. Secondary brain tumor was extremely rare after SRS, with an overall incidence of 6.80 per patients-year, or a cumulative incidence of 0.00045% over 10 years in a multicenter cohort study containing 4905 patients treated with GKS (38). Ecemis et al. reviewed cohort studies of conventional RT in treating pituitary adenoma from 1990 to 2013 and found that 1.42% of patients developed secondary brain tumor, with a latency period of 19.6 years for meningioma, 11 years for glioma and 9 years for astrocytoma (39). As for cerebrovascular accident, Minniti et al. reported two patients (in a total of 40 patients) who had stroke 6 and 8 years after FRT (16). Data was still limited for FRT. Considering the low incidence and long latency period, large, controlled cohort study with long follow-up of FRT is still needed to accurately evaluate these complications. Limitations Our study has several limitations. First, not all patients rigorously followed regular follow-up time points, making time-dependent statistical analysis less accurate. In addition, the excessively low number of cases with 1mg DST as the endocrine remission criterion may affect the accuracy of the remission rate.Moreover, a median follow-up time of about 3 years hampered evaluation on some late complications, including cerebrovascular events and secondary brain tumor. In conclusion, our study revealed that IMRT was a highly effective second-line therapy with low side effect profile for CD patients, and it’s endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS. Data availability statement The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author. Author contributions 1. Conceptualization: FZ and HZ 2. Data curation: XL and ZX. 3. Funding acquisition: FZ. 4. Investigation: XL and ZX 5. Methodology: WW 6. Resources: XL, SS and XH 7. Validation: LL and HZ. 8. Writing – original draft: ZX 9. Writing – review and editing: XL. All authors contributed to the article and approved the submitted version. Funding Supported by grants National High Level Hospital Clinical Research Funding (No.2022-PUMCH-B-052) and National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China.(Grant No. 2022YFC2407100, 2022YFC2407101). Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Katznelson L. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Fuquan Zhang, zhangfq@pumch.cn †These authors have contributed equally to this work Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. From https://www.frontiersin.org/articles/10.3389/fendo.2023.1241669/full
  16. Bridget Houser felt despairing. In the months before her 2018 wedding, Houser, who had never struggled with her weight, noticed that it inexplicably began to creep up. In response she doubled the length of her runs to eight miles, took back-to-back high intensity workout classes and often consumed only water, coffee and fruit during the day before a spartan, mostly vegetable, dinner. Yet no matter what Houser did, her weight stubbornly increased and her oval face grew round, a transformation that was glaringly obvious in comparison with her identical twin sister. Houser wondered whether the five pounds she gained despite her herculean effort was a corollary of other problems. For the previous two years she had battled a string of maladies: first daily headaches, then crippling anxiety, followed by insomnia, hair loss and acne, something she’d never endured as a teenager. “Stress was the universal explanation,” recalled Houser, a controller for a small business in Chicago. When doctors suggested that her upcoming marriage might be a cause of her problems, Houser considered, then rejected, the theory. It just didn’t jibe with her feelings. In early 2019, about six months after her wedding, Houser insisted that her doctors perform several tests. They ultimately revealed that her symptoms weren’t the result of stress or marital misgivings but of a serious illness that had been smoldering for years. After successful treatment followed by a long recovery Houser, now 34, feels far better than she did during those miserable years in her late 20s. “I wish I’d been nicer to myself and not blamed myself for what was going on,” she said. Getting through the wedding In 2016 Houser began experiencing daily pain in the back of her head, a common spot for tension headaches. When the headaches failed to improve with dietary changes or nonprescription pain relievers, she consulted her primary care doctor, followed by a neurologist who told her she had migraines. Houser, then 27, noticed that the headaches were worse when she wore contact lenses. “It was affecting my daily life and I talked myself into thinking the problem was my contacts,” she said. She decided Lasik surgery might help and in October 2017 underwent the procedure, which uses a laser to reshape the cornea, reducing or eliminating dependence on contacts or glasses. Her vision improved and the pain disappeared — briefly. A week after eye surgery, her headaches returned. “I wasn’t overly concerned,” Houser said. “I know a lot of people have headaches.” A few months later for no apparent reason Houser developed “really bad anxiety. It wasn’t just like I was anxious,” she recalled. “I couldn’t function. I’m Type A so I knew what anxiety is, but not to this degree.” One weekday morning in early 2018 she felt so overwhelmed that she took a sick day, then called her twin, Molly, and their mother and told them she needed help immediately. They managed to schedule a same-day appointment with a psychiatrist whom Houser began seeing regularly, along with a therapist. The psychiatrist zeroed in on her impending wedding and told Houser that the event can cause “huge anxiety.” She began taking an antidepressant along with Ativan, an anti-anxiety drug she used when things got really bad. She also ramped up her yoga practice, hoping it might calm her. Houser vividly remembers riding the escalator to her office one morning “and in my head I kept saying, ‘I’m in trouble, I’m in trouble,’” although she didn’t know what was wrong. Her changing appearance had become a source of great unhappiness. Although her weight remained in the normal range, Houser couldn’t figure out why she was gaining weight after drastically slashing her food intake and dramatically ramping up exercise. Her normally thick hair had thinned so noticeably that her hairdresser gently advised her to consult a doctor. Houser’s psychiatrist thought her hair loss might be caused by her antidepressant and switched medications. That didn’t seem to help. Houser was particularly bothered by her newly chubby face. “It was like a joke in my family,” she said, adding that she was teased about being overly sensitive. Even her wedding day was colored by unhappiness about her appearance and the intense amorphous anxiety that seemed omnipresent. “Rather than think about how excited I was,” Houser recalled, “it was ‘How can I get through this day?’” Normal thyroid After her wedding Houser felt worse. She developed severe insomnia, night sweats and acne. In February 2019 a nurse practitioner in her primary care practice ordered tests of her thyroid, which were normal. When Houser pressed for additional testing, she was referred to an endocrinologist. He told her she was stressed. Dissatisfied, she saw a second endocrinologist who agreed with the first. “She said ‘I don’t think there’s anything wrong with you’” metabolically, Houser recalled. The second endocrinologist’s nurse even revisited the marriage question in the presence of Houser’s husband, Doug, who had accompanied her to the appointment. “She said ‘I knew on my honeymoon I shouldn’t have gotten married,’” Houser remembered her saying. “‘Are you in a happy marriage?’ I couldn’t believe it.” Months earlier, the nurse practitioner who ordered the thyroid tests briefly mentioned measuring levels of cortisol, a hormone involved in the body’s response to stress and other functions. Elevated levels of cortisol can indicate Cushing’s syndrome, an uncommon hormonal disorder that occurs when the body produces too much of the hormone over a prolonged period. “She had thrown cortisol testing out there and I think it was always in the back of my mind,” Houser said. She asked the second endocrinologist to order cortisol tests. The doctor agreed, but not before telling Houser that she didn’t think she had Cushing’s because she lacked the classic symptoms: major weight gain, purple stretch marks and a fatty hump between the shoulders. Houser did have the “moon face” characteristic of Cushing’s that is also seen in people who take high doses of steroids for long periods to treat various illnesses — but Houser wasn’t taking steroids. Insomnia, headaches, acne and anxiety can be symptoms of Cushing’s. There are several forms of Cushing’s syndrome, which typically results from a tumor — usually benign but sometimes cancerous — in the pituitary or adrenal gland that pumps out excess cortisol. Sometimes tumors develop elsewhere in the body such as the lungs or pancreas. Cushing’s affects roughly five times as many women as men and typically occurs between the ages of 30 and 50. If left untreated, it can be fatal. A trio of tests measuring cortisol levels in Houser’s blood, urine and saliva were significantly elevated; the amount in her urine was eight times higher than normal. The formerly skeptical Chicago endocrinologist told Houser she had Cushing’s and referred her to James Findling, a Milwaukee endocrinologist who is internationally recognized for his treatment of the disease. “I was just so happy to have a diagnosis,” Houser recalled. Revealing photos Findling asked Houser to bring photographs taken several years earlier to her October 2018 appointment. It is a request he makes of patients as a way of spotting telltale physical manifestations. In Houser’s case, the facial change was particularly striking because she is an identical twin. Findling noted that delayed diagnosis is typical, because physical changes and other symptoms tend to occur gradually and insidiously. Houser, he added, “didn’t look like the typical Cushing’s patient. She wasn’t obese and she didn’t have diabetes or hypertension. It was more subtle than many cases.” The next step was determining the location of the tiny tumor. Tests found nothing in Houser’s pituitary or adrenal glands, and CT scans of her pelvis, chest and abdomen were clean. Findling ordered a dotatate PET scan, a highly sensitive CT scan that can find tumors that elude conventional imaging. The scan revealed a nodule in Houser’s left lung. Houser sought a second opinion from a thoracic surgeon in Chicago. While Findling and a thoracic surgeon at Milwaukee’s Froedtert Hospital strongly recommended that she undergo surgery to remove the tumor, the Chicago doctor disagreed. He said he didn’t think the lung nodule was causing Cushing’s and recommended that Houser continue therapy and anti-anxiety medication. “Do you know what it’s like to wake up from surgery and to not be better?” she remembers him asking her. After deliberating with her husband and conferring with her Milwaukee doctors, Houser opted for surgery performed Oct. 30, which removed part of her left lung. A pathologist determined that the nodule was a rare, slow-growing neuroendocrine lung cancer known as a bronchial carcinoid, which can cause Cushing’s. The Stage 2 cancer had spread to a nearby lymph node. “Fortunately I think we got it early,” Findling said. “She’s had a sustained remission and a cure of her Cushing’s.” “The cancer didn’t rock my world,” said Houser, who had previously had a melanoma skin cancer removed. (Doctors have told her they don’t think the cancers are related.) “It was about not having Cushing’s anymore, which was more important.” So why didn’t Houser’s doctors, among them endocrinologists, suspect Cushing’s? Findling, who estimates he has treated as many as 2,000 people with the disease in his 40-year career, said that while doctors are taught that Cushing’s is rare, it’s not. He cites a 2016 study, which that found that 26 of 353 endocrinology patients were found to have the disease. Textbook descriptions, which include the presence of purple stretch marks and a hump, are “almost a caricature,” Findling observed. “It’s pretty well recognized that Cushing’s is more subtle than that … and can cause neuropsychiatric and neurocognitive problems.” Houser’s normal weight and the fact that she didn’t have high blood pressure or diabetes may have misled doctors. “I think we’ve moved the needle a little bit, especially among endocrinologists,” he continued, adding that “the threshold for screening has got to change. Once you tell a primary care doctor that it’s a rare disorder, it goes in one ear and out the other. They think they’ll never see it.” “When you make this diagnosis it can have fabulous outcomes,” he added, citing Houser’s case. “That’s why I’m still doing this at my age.” Houser considers Findling to be her “literal lifesaver.” She spent the next year seeing him as she was slowly weaned off medications to normalize her hormone levels and recover her strength. She is monitored for Cushing’s annually, remains cancer-free and, other than residual fatigue, feels well. In October 2021 she gave birth to a daughter. Her son was born eight weeks ago. Houser regards the help provided by her family, particularly her husband whom she called “my biggest supporter,” as essential. That seems especially ironic because stress about their marriage had been blamed for symptoms that were actually caused by a cancer. “He was a huge help in calling doctors and making the necessary appointments when I didn’t have the energy to fight anymore.” His unwavering love, she said, was “a testament to our strong marriage.” From https://www.washingtonpost.com/wellness/2023/10/07/weight-anxiety-wedding-medical-mysteries/
  17. Highlights The most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer; however it is a relatively uncommon complication of pulmonary neoplasms. The most common cause of Cushing syndrome is iatrogenic corticosteroid use and it should be considered in all patients regardless of clinical background. Low urine cortisol levels may be associated with exogenous glucocorticoid exposure. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products. Abstract Background Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background. Case report A 59 year old woman with an 11 year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Laboratory results were not consistent with an ACTH dependent Cushing Syndrome and exogenous steroids were suspected. The patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. Discussion Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing. Conclusion Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. 1. Introduction Well differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and can rarely exhibit Cushing syndrome due to ectopic production of adrenocorticotropic hormone (ACTH). However the most common cause of Cushing syndrome is iatrogenic corticosteroid use and should be considered in all patients regardless of clinical background (see Fig. 1, Fig. 2, Fig. 3, Fig. 4). Download : Download high-res image (243KB) Download : Download full-size image Fig. 1. DOTATATE PET/CT demonstrates a right upper lobe pulmonary nodule with intense uptake. Download : Download high-res image (201KB) Download : Download full-size image Fig. 2. DOTATATE PET/CT demonstrates intense uptake within a right upper lobe pulmonary nodule, consistent with biopsy-proven carcinoid tumor. There are no distant sites of abnormal uptake to suggest metastatic disease. Download : Download high-res image (399KB) Download : Download full-size image Fig. 3. Artri Ajo King Supplement (Source: FDA). The label claims that the product contains glucosamine, chondroitin, collagen, vitamin C, curcumin, nettle, omega 3, and methylsulfonylmethane. Download : Download high-res image (288KB) Download : Download full-size image Fig. 4. Artri King Supplement (Source: FDA). 2. Case report A 59–year old woman with an 11 year history of a 1.5 cm well-differentiated bronchial carcinoid, presented with 20 lb. weight gain, facial swelling, flushing, lower extremity edema and shortness of breath over 3 months. On exam, the patient was normotensive, centrally obese with mild hirsutism, facial fullness and ruddiness with evidence of a dorsocervical fat pad. Initially there was concern for hormonal activation of her known bronchial carcinoid. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n < 15 mg/dL), elevated chromogranin A (201 ng/mL, n < 103 ng/mL), normal histamine (<1.5 ng/mL, n < 1.7 ng mL), low-normal 7 AM serum cortisol (5.1 μg/dL, n 3.6–19.3 μg/dL), normal 7 AM ACTH (17 pg/mL, n < 46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0–50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4–16.8 mcg/dL). Testosterone, IGF-1, glucose and electrolytes were appropriate. An echocardiogram showed an ejection fraction of 60% with no evidence of carcinoid heart disease. A Dotatate PET-CT was obtained to evaluate for progression of the neuro-endocrine tumor and revealed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Given low cortisol levels, ectopic Cushing syndrome was excluded and exogenous steroids were suspected, however the patient denied use of oral,inhaled, or injected steroids. A cosyntropin stimulation study yielded a pre-stimulation cortisol 6.2 μg/dL with an adequate post-stimulation cortisol 23.5 μg/dL. At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King Glucosamine supplements not listed on the product label but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and even death associated with such products. The patient's symptoms gradually improved after discontinuation of the supplement. 3. Discussion 3.1. Ectopic ACTH syndrome This patient's Cushingoid features were initially suspected to be secondary to the known bronchial neuroendocrine tumor. Ectopic ACTH production accounts for about 5–10% of all Cushing Syndrome cases [1]. The most common location of ectopic ACTH is the lungs with pulmonary carcinoid tumors being the most common cause, followed by squamous cell lung cancer [2]. Despite this patient's history of bronchial carcinoid tumor and positive chromogranin histopathological marker, her laboratory results were not consistent with an ACTH dependent Cushing Syndrome. In fact, Cushing syndrome is a relatively uncommon neuroendocrine neoplasm complication. The prevalence of ectopic ACTH production in patients with lung tumors is rare, at less than 5% in squamous cell lung cancer and about 3% in patients with lung or pancreatic (non-MEN1) neuroendocrine tumors1. Patients with ACTH dependent Cushing syndrome not suspected to originate from the pituitary, undergo further testing to evaluate for an ectopic ACTH secreting tumor. These tests include conventional imaging of the chest, abdomen and pelvis, as well as functional imaging such as octreotide scans, fluoride 18-fluorodeoxyglucose-positron emission tomography [18F-FDG PET], and gallium-68 DOTATATE positron emission tomography-computed tomography [Dotatate PET-CT] scan [3]. In our literature review, we found that there was insufficient evidence to determine the sensitivity and specificity of nuclear medicine imaging techniques [4,5]. In this case, the patient had no laboratory evidence for ACTH dependent Cushing Syndrome, but given the known bronchial carcinoid tumor, a repeat Dotatate PET-CT scan was obtained which demonstrated no indication of growth or spread of the known bronchial tumor. 3.2. Supplement induced Cushing Syndrome One of the most remarkable findings in this case was the patient's low urine cortisol level in the setting of her overt Cushingoid features. In our survey of the literature, we found that low urine cortisol levels were associated with exogenous glucocorticoid use [6,7]. The low urine cortisol levels may be reflective of intermittent glucocorticoid exposure. Indeed, this patient's Cushingoid features were determined to be secondary to prolonged use of Artri King supplement. Occult glucocorticoid use is difficult to diagnose even after performing a thorough medication reconciliation as patients may unknowingly consume unregulated doses of glucocorticoids in seemingly harmless supplements and medications. The incidence of supplement induced Cushing Syndrome is currently unknown as supplements are not regularly tested to detect hidden glucocorticoid doses. Additionally, the likelihood of developing supplement induced Cushing syndrome is dependent on dosage and duration of use. In our literature review we found nine published articles describing supplement induced Cushing Syndrome [[7], [8], [9], [10], [11], [12], [13], [14], [15]], one case report of tainted counterfeit medication causing Cushing Syndrome [16], and two cases of substances with probable glucocorticoid-like activity [17,18]. Of the nine published articles of supplement induced Cushing Syndrome, six were associated with supplements marketed as arthritic joint pain relief products including ArtriKing, Maajun, and AtriVid [[7], [8], [9], [10], [11], [12]]. These products later received government issued warnings in Mexico, Malaysia, and Colombia respectively [[19], [20], [21]]. To our knowledge there have been four published reports of ArtiKing supplement induced Cushing Syndrome [[7], [8], [9], [10]]. The first documented cases were reported in 2021 in Vera Cruz, Mexico; since then the Mexican medical community reported seeing a disproportionate increase in cases of iatrogenic Cushing Syndrome due to these supplements [7]. There have also been three American published articles describing a total of 4 cases of ArtriKing supplement induced Cushing syndrome [[8], [9], [10]]. In January 2022 the FDA issued a warning about Atri Ajo King containing diclofenac, which was not listed in the product label [22]. In April 2022 the FDA expanded its warning, advising consumers to avoid all Artri and Ortiga products after the FDA found these products contained dexamethasone and diclofenac [23]. In October 2022 the FDA issued warning letters to Amazon, Walmart, and Latin Foods market for distributing Artri and Ortiga products [24]. Many supplements are not regulated by the government and may contain hidden ingredients such as glucocorticoids. In these cases further evaluation of suspected products [25], medications [16], and patient serum [26] and urine [6] utilizing techniques such as liquid chromatography may be used to confirm occult glucocorticoid exposure. This case highlights the importance of educating patients to exercise caution when purchasing health products both online and abroad. Consumers should be aware of the potential risks of taking supplements, especially those advertised as joint pain relief products. 4. Conclusion Although the most common cause of ectopic ACTH syndrome is pulmonary carcinoid tumors and squamous cell lung cancer, it is a relatively uncommon complication of pulmonary neoplasms. Exogenous Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing. Occult glucocorticoid exposure is rare but can be evaluated with liquid chromatography. This case report emphasizes the importance of teaching patients to be vigilant and appropriately research their health supplements. Patient consent Formal informed consent was obtained from the patient for publication of this case report. Declaration of competing interest The authors (Tomas Morales and Shanika Samarasinghe) of this case report declare that they have no financial conflicts of interest. Shanika Samrasinghe is an editorial member of the Journal of Clinical and Translational Endocrinology: Case Reports, and declares that she was not involved in the peer review and editorial decision making process for the publishing of this article. References [1] A.R. Hayes, A.B. Grossman The ectopic adrenocorticotropic hormone syndrome: rarely easy, always challenging Endocrinol Metab Clin N Am, 47 (2) (2018 Jun), pp. 409-425, 10.1016/j.ecl.2018.01.005 PMID: 29754641 View PDFView articleView in ScopusGoogle Scholar [2] A.M. Isidori, A. Lenzi Ectopic ACTH syndrome Arq Bras Endocrinol Metabol, 51 (8) (2007 Nov), pp. 1217-1225, 10.1590/s0004-27302007000800007 PMID: 18209859 View article View in ScopusGoogle Scholar [3] J. Young, M. Haissaguerre, O. Viera-Pinto, O. Chabre, E. Baudin, A. Tabarin Management of endocrine disease: cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion Eur J Endocrinol, 182 (4) (2020 Apr), pp. R29-R58, 10.1530/EJE-19-0877 PMID: 31999619 View article View in ScopusGoogle Scholar [4] E. Varlamov, J.M. Hinojosa-Amaya, M. Stack, M. Fleseriu Diagnostic utility of Gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience Pituitary, 22 (5) (2019 Oct), pp. 445-455, 10.1007/s11102-019-00972-w PMID: 31236798 View article View in ScopusGoogle Scholar [5] A.M. Isidori, E. Sbardella, M.C. Zatelli, M. Boschetti, G. Vitale, A. Colao, R. Pivonello, ABC Study Group Conventional and nuclear medicine imaging in ectopic cushing's syndrome: a systematic review J Clin Endocrinol Metab, 100 (9) (2015 Sep), pp. 3231-3244, 10.1210/JC.2015-1589 PMID: 26158607; PMCID: PMC4570166 View article View in ScopusGoogle Scholar [6] G. Cizza, L.K. Nieman, J.L. Doppman, M.D. Passaro, F.S. Czerwiec, G.P. Chrousos, G.B. Cutler Jr. Factitious cushing syndrome J Clin Endocrinol Metab, 81 (10) (1996 Oct), pp. 3573-3577, 10.1210/jcem.81.10.8855803 PMID: 8855803 View article View in ScopusGoogle Scholar [7] R. Patel, S. Sherf, N.B. Lai, R. Yu Exogenous cushing syndrome caused by a "herbal" supplement AACE Clin Case Rep, 8 (6) (2022 Aug 5), pp. 239-242, 10.1016/j.aace.2022.08.001 PMID: 36447831; PMCID: PMC9701910 View PDFView articleView in ScopusGoogle Scholar [8] C. Dunn, J. Amaya, P. 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  18. Adrenal incidentalomas (AI) are associated with an increased risk of cardiometabolic complications due to adrenal hyperfunction. Obtaining accurate prevalence estimates of distinct types of functioning AIs is crucial for efficient resource allocation and effective management strategies. For a study, researchers sought to ascertain the prevalence of various forms of autonomous hormone secretion in individuals diagnosed with adrenal incidentaloma, including autonomous/possible autonomous cortisol secretion (ACS), primary aldosteronism (PA), pheochromocytoma (PHEO), and Cushing syndrome (CS). A comprehensive and systematic search was conducted across multiple databases (PubMed, Ovid MEDLINE, Web of Science) up to February 2022. Among the 1,661 publications initially screened at the title and abstract levels, 161 articles underwent full-text examination, and ultimately, 36 studies were included for analysis. Three independent reviewers meticulously extracted clinical data from these selected studies. The overarching prevalence of functioning adrenal incidentalomas was 27.5% (95% CI 23.0, 32.5). The highest prevalence was observed for ACS/possible ACS, with a rate of 11.7% (95% CI 8.6, 15.7), followed by PA at 4.4% (95% CI 3.1, 6.2). Subgroup analysis unveiled a greater prevalence of PA in patients from Asian regions than those from Europe/America. Conversely, the prevalence of ACS/possible ACS was comparatively lower in Asian countries. Meta-regression analysis elucidated that the proportion of female patients influenced the prevalence of ACS/possible ACS, while PA prevalence positively correlated with the proportion of patients with hypertension and the publication year. PHEO and CS demonstrated prevalences of 3.8% (95% CI 2.8, 5.0) and 3.1% (95% CI 2.3, 4.3), respectively. The comprehensive meta-analysis offered valuable insights into the prevalence rates of diverse types of functioning adrenal incidentalomas and identified influential factors contributing to heterogeneity in these estimates. The findings contributed significantly to understanding clinical implications and aided in devising effective management strategies for individuals diagnosed with these adrenal disorders. Source: academic.oup.com/jcem/article-abstract/108/7/1813/7015785?redirectedFrom=fulltext
  19. Abstract Background As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. Methods A retrospective cohort study of patients with pituitary adenomas and Rathke’s cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. Results Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3–96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing’s disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. 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Am J Med 135(1):39–48 Article PubMed Google Scholar Download references Author information Authors and Affiliations Department of Neurosurgery, La Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, 47-83 Boulevard de L’Hôpital, 75013, Paris, France Marta Garvayo, Vincent Reina, Stephan Gaillard & Bertrand Baussart Department of Neurosurgery, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland Marta Garvayo & Mahmoud Messerer Université Paris Cité, CNRS, INSERM, Institut Cochin, 75014, Paris, France Chiara Villa, Anne Jouinot, Jérôme Bertherat, Guillaume Assié & Bertrand Baussart Department of Neuropathology, La Pitié-Salpêtière University Hospital, AP-HP, Sorbonne University, Paris, France Chiara Villa Department of Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Boulogne Billancourt, France Mirella Hage & Marie-Laure Raffin-Sanson Université de Versailles Saint-Quentin-en-Yvelines UFR Des Sciences de La Santé Simone Veil, Montigny-Le-Bretonneux, France Mirella Hage & Marie-Laure Raffin-Sanson Department of Endocrinology and Reproductive Medicine, Centre de Référence Des Maladies Endocriniennes Rares de La Croissance Et du Développement, CRMERC, Endo-ERN, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France Carine Courtillot & Anne Bachelot Université Paris-Saclay, Inserm, Physiologie Et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie Et Des Maladies de La Reproduction, Centre de Référence des Maladies Rares de L’Hypophyse, Le Kremlin-Bicêtre, France Peter Kamenicky & Philippe Chanson Sorbonne University, Endocrine Unit, Reproductive Medicine, Centre de Référence Des Maladies Endocriniennes Rares de La Croissance Et du Développement (CRMERC), Endo-ERN (Id 739527), Saint-Antoine Hospital, AP-HP, Paris, France Camille Vatier & Sophie Christin-Maitre Inserm UMRS938, Saint-Antoine Research Center, Sorbonne University, 75012, Paris, France Camille Vatier INSERM UMR-833, Trousseau Hospital, Paris, France Sophie Christin-Maitre Department of Endocrinology, Center of Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France Jérôme Bertherat & Guillaume Assié Corresponding author Correspondence to Bertrand Baussart. Ethics declarations Conflict of interest The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and Permissions From https://link.springer.com/article/10.1007/s00701-023-05809-x
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  20. Abstract Introduction Laparoscopic adrenalectomy is the standard treatment for adrenal tumors caused by Cushing's syndrome. However, few pregnant women have undergone adrenalectomy because of the risk of general anesthesia and surgery. Case presentation A 28-year-old woman presented with gradually worsening Cushing's signs at around 12 weeks of pregnancy. Magnetic resonance imaging displayed a 38-mm left adrenal tumor, which was the cause of the adrenal Cushing's syndrome. Metyrapone was started, which increased androgen levels. Since the management of Cushing's syndrome by medication alone is challenging, unilateral laparoscopic adrenalectomy by a retroperitoneal approach was performed at 23 weeks of the pregnancy. No perioperative complications were noted. Conclusion Adrenalectomy is considered safe in pregnant women with Cushing's syndrome. Laparoscopic adrenalectomy by retroperitoneal approach should be chosen and performed between 14 and 30 weeks of pregnancy to prevent mother and fetal complications. Abbreviations & Acronyms CS Cushing's syndrome MRI magnetic resonance imaging Keynote message We report a rare case of adrenalectomy performed via a retroperitoneal approach for Cushing's syndrome in a pregnant woman. Cushing's syndrome may affect the fetus, and surgery can be considered in addition to medical management. Adrenalectomy should be performed in the second trimester of pregnancy. Pneumoperitoneal pressure, position, and surgical approaches must receive careful attention. Introduction CS is characterized by excessive cortisol secretion and characteristic symptoms such as full moon-like facial features and central obesity. Premenopausal women with CS rarely become pregnant because excessive glucocorticoid secretion inhibits the synthesis of gonadotropins, leading to impaired ovarian and endometrial function, and causing amenorrhea or oligomenorrhea.1 Furthermore, even when women with CS become pregnant, the incidence of severe complications is high. CS can cause maternal hypertension, diabetes/glucose intolerance, osteopenia/osteoporosis, preeclampsia, pulmonary edema, heart failure, opportunistic infections, and even death. Additionally, CS can potentially cause stillbirth, prematurity, and intrauterine fetal growth restriction.1-6 Therefore, CS must be detected at an early stage in pregnancy; however, CS may go undetected because of the overlapping signs of preeclampsia and/or gestational diabetes. A cortisol-secreting adrenal tumor is the underlying cause of CS, and laparoscopic adrenalectomy is the standard treatment to it. Medical treatment of CS can include medications that inhibit 11β-hydroxylase, such as metyrapone and osilodrostat, but surgical treatment is considered if the disease is difficult to control with medical treatment. Nonobstetric surgery during pregnancy is performed in 1%–2% of pregnant women.7 Although general anesthesia is relatively safe during pregnancy, the indication for the surgery must be carefully considered because of potential risks such as neurodevelopmental delay, sudden death, etc. Herein, we present a case of a pregnant woman diagnosed with CS who underwent unilateral laparoscopic adrenalectomy by a retroperitoneal approach without any problems. Case presentation The patient was a 28-year-old primiparous woman. Since around 12 weeks of pregnancy, she has experienced facial and lower limb edema; gained 6-kg weight in 1 month; increased facial acne; and experienced subcutaneous bleeding on the forearms, red abdominal dermatitis, proximal muscle weakness, palpitations, insomnia, and decreased vision in eyes. Her symptoms gradually worsened from 14 weeks, and she was referred to our hospital to clarify the cause at 18 weeks of pregnancy. Adrenal CS was suspected on the basis of her Cushing's signs, cortisol 25 μg/dL, and adrenocorticotropic hormone <1.5 pg/mL. She had hypokalemia, hypogammaglobulinemia, and liver dysfunction, and her condition was rapidly worsening. Given her pregnant state, she was admitted for intensive testing for the case of CS from 19 weeks of pregnancy. MRI revealed a well-defined 38-mm left adrenal tumor, which was the cause of the adrenal CS (Fig. 1). She was started on metyrapone with 250 mg per day, which increased androgens (0.53–0.69 ng/mL in 1 week). We considered that the management of CS by medication alone would be challenging and performed adrenalectomy during her pregnancy. The dose of metyrapone was increased to 1000 mg per day eventually. Fig. 1 Open in figure viewerPowerPoint Magnetic resonance imaging on admission shows a left adrenal tumor with a long axis of 38 mm (arrowhead). Signal reduction was partially observed on opposed-phase images, leading to diagnosis of cortical adenoma. She was admitted to the hospital at 23 weeks and 2 days of gestation, and laparoscopic left adrenalectomy was performed via a retroperitoneal approach in the right lateral and jackknife position on the following day (Fig. S1). During the surgery, blood pressure was carefully controlled by an anesthesiologist and the patient's position and fetal heart rate were monitored by an obstetrician. The operation time, insufflation time, and general anesthesia time were 68, 59, and 123 min, respectively, and the blood loss volume was 75 mL, without any complications. Pathological findings revealed an adrenocortical adenoma. The specimen was positive for one of the nine Weiss criteria (Fig. 2). Fig. 2 Open in figure viewerPowerPoint (a) Intraoperative findings of the retroperitoneal approach. Arrowheads indicate the tumor. (b) Gross appearance of the resected adrenal tumor; a brownish-toned, substantial mass, 60 × 34 × 15 mm in size. (c, d) Hematoxylin–eosin staining showed that nodular lesion with a fibrous capsule, with foci of homogeneous cells with eosinophilic or pale, foamy sporangia and small round nuclei. Postoperatively, metyrapone was discontinued and both lower leg edema, facial acne, fatigue, and muscle weakness improved. Metyrapone was discontinued after surgery. Hydrocortisone, which had been administered at 150 mg/day during the perioperative period, was reduced every few weeks and was taken at 30 mg/day at delivery. She delivered by cesarean section at 38 weeks and 2 days of gestation, with good outcomes for the mother and her infant. Hydrocortisone was discontinued 15 weeks after delivery. We showed the changes in cortisol and ACTH from the first visit to postpartum (Fig. 3). Fig. 3 Open in figure viewerPowerPoint The transition of Cortisol and ACTH. Cortisol decreases rapidly after surgery and rises again before delivery. As cortisol improved, ACTH also increased. Discussion CS seldom occurs during pregnancy. Symptoms such as weight gain, skin striae, fatigue, and a round face can also occur in normal pregnancies. The dexamethasone suppression test can result in false positives because of ACTH produced by placenta in normal pregnancy. During pregnancy, there is a physiological state of high cortisol levels. The disappearance of diurnal rhythm is a useful indicator for diagnosis of CS in pregnancy because circadian rhythm is maintained in normal pregnancy. Useful diagnostic criteria include urine cortisol levels greater than three times the upper limit of normal, loss of diurnal cortisol rhythm, and presence of adrenal tumors on MRI. The pharmacologic treatment of endogenous cortisol is complex, and hormonal management is challenging. While the management of the cortisol levels is important, metyrapone is a risk factor for gestational hypertension and may inhibit fetal cortisol production by crossing the placenta.1-6, 8-12 In this case, because androgens were also elevated and drug management was expected to be challenging, the surgery was aggressively considered. Despite the reports of successful adrenalectomy is after 28 weeks of gestation,6, 13, 14 The surgery should be performed by an experienced team between 14 and 30 weeks of pregnancy, that is, after organogenesis phase and before the fetus grows too large.1, 13, 15 A few pregnant women with adrenal CS undergo adrenalectomy. However, the laparoscopic approach is safe, and maternal and fetal complications were higher in women who did not undergo surgery.16 Less postoperative pain, faster wound healing, and faster postoperative recovery are the main advantages of laparoscopic surgery.17 In pregnant women, pneumoperitoneal pressure should be kept <12 mmHg because increased intraabdominal pressure decreases placental blood flow and can cause fetal acidosis due to the absorption of carbon dioxide used for insufflation. Laparoscopic adrenalectomy can be safely performed through both transperitoneal and retroperitoneal approaches.18 However, in pregnant women, performing the surgery by the retroperitoneal approach in the lateral position is preferable to prevent putting pressure on the fetus during the surgery. The retroperitoneal approach is advantageous, as less pressure is placed on the uterus and adhesions are prevented. After taking the lateral position, the obstetrician is advised to check the position and confirm that the abdomen is not compressed and that the fetal heart rate is normal. Conclusions We present a case of a pregnant woman diagnosed with adrenal CS who underwent a unilateral laparoscopic adrenalectomy by a retroperitoneal approach without any problems. Adrenalectomy is a useful treatment when CS is difficult to control despite metyrapone and other medical support. Author contributions Nobuyoshi Takeuchi: Conceptualization; methodology; project administration; writing – original draft. Yusuke Imamura: Conceptualization; methodology; supervision; writing – review and editing. Kazuki Ishiwata: Data curation; supervision. Manato Kanesaka: Data curation; supervision. Yusuke Goto: Data curation; supervision. Tomokazu Sazuka: Data curation; supervision. Sawako Suzuki: Data curation; supervision. Hisashi Koide: Data curation; supervision. Shinichi Sakamoto: Data curation; supervision. Tomohiko Ichikawa: Data curation; supervision. Conflict of interest The authors declare no conflicts of interest. Approval of the research protocol by an Institutional Reviewer Board Not applicable. Informed consent Informed consent for the release of the case report and accompanying images has been obtained from the patient. Registry and the Registration No. of the study/trial Not applicable. From https://onlinelibrary.wiley.com/doi/10.1002/iju5.12637
  21. Introduction to Endocrinology Endocrinology is a medical specialty that focuses on the diagnosis and treatment of diseases related to hormones. Endocrinologists are experts in managing and treating diseases related to the endocrine system, which includes the thyroid, pituitary, adrenal glands, and pancreas. Endocrinologists are trained to diagnose and treat conditions such as diabetes, thyroid disorders, pituitary disorders, and other conditions related to hormones. Endocrinologists also specialize in reproductive health and fertility issues, including PCOS. Endocrinology is a complex field that requires a deep understanding of the endocrine system and its role in regulating the body’s hormones. Endocrinologists must be able to interpret laboratory tests and understand the underlying causes of endocrine disorders. They must also be able to develop individualized treatment plans to address the specific needs of each patient. Diagnosing PCOS and Diabetes Endocrinologists are experts in diagnosing and managing PCOS and diabetes. PCOS is a hormonal disorder that affects the ovaries, and it is characterized by irregular menstrual cycles, excess facial and body hair, and infertility. To diagnose PCOS, an endocrinologist will perform a physical exam and order laboratory tests to measure hormone levels. The endocrinologist will also ask the patient about her symptoms and family history to determine if PCOS is the cause. Diabetes is a chronic condition that affects the body’s ability to process sugar. To diagnose diabetes, an endocrinologist will perform a physical exam and order laboratory tests to measure blood sugar levels. The endocrinologist may also order imaging tests to check for signs of diabetes-related complications. Treating PCOS and Diabetes Once the endocrinologist has diagnosed PCOS or diabetes, they will develop an individualized treatment plan to address the patient’s specific needs. For PCOS, the endocrinologist may recommend lifestyle changes such as weight loss, exercise, and dietary changes to help manage symptoms. The endocrinologist may also prescribe medications to regulate hormone levels and improve fertility. For diabetes, the endocrinologist may recommend lifestyle changes such as weight loss, exercise, and dietary changes to help manage blood sugar levels. The endocrinologist may also prescribe medications to help regulate blood sugar levels. In addition, the endocrinologist may recommend regular check-ups to monitor the patient’s progress and to adjust the treatment plan if needed. Conclusion Endocrinology plays an important role in managing PCOS and diabetes. Endocrinologists are experts in diagnosing and treating these conditions, and they are trained to develop individualized treatment plans that address the specific needs of each patient. By working with an endocrinologist, patients can get the help they need to manage their PCOS or diabetes and achieve their health goals. Endocrinology is a complex field that requires a deep understanding of the endocrine system and its role in regulating the body’s hormones. An endocrinologist can help patients with PCOS and diabetes manage their conditions and achieve their health goals. By working with an endocrinologist, patients can get the help they need to manage their PCOS or diabetes and achieve their health goals. From https://www.diabetesincontrol.com/the-role-of-endocrinology-in-managing-polycystic-ovary-syndrome-and-diabetes/
  22. Abstract Background 18Fluorine-Fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities. Although the usefulness of 18F-FDG PET has been reported in several endocrine diseases, studies on pituitary disease are extremely limited. To evaluate whether dexamethasone (DEX) suppression can improve 18F-FDG PET for the localization of adrenocorticotropic hormone-secreting adenomas in the pituitary gland in Cushing’s disease (CD). Methods We included 22 patients with CD who underwent PET imaging before and after DEX administration. We compared the success rates of PET before and after DEX suppression, magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus sampling (BIPSS). We determined the final locations of adenomas based on intraoperative multiple-staged resection and tumor tissue identification using frozen sections. Standardized uptake value (SUV) were analyzed to confirm the change of intensity of adenomas on PET. Results Twenty-two patients were included (age at diagnosis: 37 [13–56] years), and most were women (90.91%). Pituitary adenomas compared to normal pituitaries showed increased maximum SUV after DEX suppression but without statistical significance (1.13 versus. 1.21, z=-0.765, P = 0.444). After DEX suppression, the mean and maximum SUV of adenomas showed a positive correlation with nadir cortisol levels in high-dose DEX suppression test (Rho = 0.554, P = 0.007 and Rho = 0.503, P = 0.017, respectively). In reference sites, mean SUV of cerebellum was significantly decreased (7.65 vs. 6.40, P = 0.006*), but those of the thalamus and gray matter was increased after DEX suppression (thalamus, 8.70 vs. 11.20, P = 0.010*; gray matter, 6.25 vs. 7.95, P = 0.010*). Conclusion DEX suppression did not improve 18F-FDG PET/CT localization in patients with CD. Introduction Cushing’s disease (CD) is a rare endocrine disease that results from chronic exposure to high cortisol levels because of adrenocorticotropic hormone (ACTH)-secreting pituitary tumors and is associated with increased morbidity and mortality. It represents approximately 80% of all cases of endogenous hypercortisolism [1,2,3]. Accurate localization of primary lesions in CD leads to improved remission rates and reduced adverse events following surgery [4, 5]. A biochemical remission rate of 90–100% has been reported when tumors are localized before surgery, but it can decrease to 50–60% when surgery is performed when the location of the tumor is unknown in patients with CD [6,7,8]. Currently, magnetic resonance imaging (MRI) is the gold standard for detecting pituitary adenomas. Nevertheless, modern MRI modalities, including dynamic or volumetric sequences, can reliably detect corticotrophic adenomas in 50–90% cases of CD [9,10,11,12]. This indicates that complementary imaging strategies are required to improve the localization of primary lesions in CD. One of the most characteristic features of corticotrophic adenomas is a compromised response to negative glucocorticoid feedback, which defines glucocorticoid resistance [13]. ACTH activates the adrenal glands to synthesize and secrete cortisol, which in turn negatively modulates the release of ACTH from the pituitary gland and corticotrophin-releasing hormone (CRH) and vasopressin from the hypothalamus [1]. In CD, a corticotrophic tumor is only partially sensitive to the inhibitory feedback exerted by cortisol, which in turn is not regulating its own production and secretion of ACTH, resulting in both excessive ACTH and cortisol levels. Glucocorticoid resistance is caused by multiple factors including glucocorticoid receptor availability, splice variant expression and affinity, and imbalanced glucocorticoid receptor signaling [14, 15]. Radioactive 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) often demonstrates increased fluorodeoxyglucose (FDG) uptake in nonfunctioning and hormone-secreting pituitary adenomas [16,17,18]. In large observational studies of whole-body 18F-FDG positron emission tomography (PET) scans, incidental sellar 18F-FDG uptake was found in < 1% of cases, and this sign is highly specific for pituitary adenomas [19,20,21]. 18F-FDG PET imaging can detect up to 40% of corticotropinomas, some as small as 3 mm, and the rate of PET detection of corticotropinomas can be increased by CRH stimulation [9, 22]. Here, we evaluated whether DEX suppression could improve the localization of ACTH-secreting adenomas using 18F-FDG PET/CT in patients with CD. The rationale for this is as follows. FDG uptake of corticotrophic adenomas is less suppressed than that of normal pituitary glands after DEX suppression due to glucocorticosteroid resistance. Materials and methods Study design and population In this retrospective cohort study, we enrolled all patients with CD who underwent two rounds of 18F-FDG-PET/CT before and after 8-mg DEX suppression and pituitary MRI before surgery. Total 22 patients were included in this study, of which thirteen had bilateral inferior petrosal sinus sampling (BIPSS) results. All patients were diagnosed with CD by staff of the Department of Endocrinology and/or Neurosurgery at Severance Hospital between 2014 and 2015. The diagnosis of CD was confirmed based on biochemical test results, including the cortisol, 24-hour urine free cortisol (24 h UFC), and serum ACTH levels, overnight dexamethasone suppression test (ON DST) results, and high-dose dexamethasone suppression test (HD DST) results. Immediate remission was defined as hypocortisolism (serum cortisol level < 1.8 µg/dL) within the first 7 days after surgery. Delayed remission was defined as the achievement of hypocortisolism within 6 months, although immediate remission was not confirmed. If patients showed elevated postoperative cortisol levels and needed additional treatment within 6 months after surgery, we defined them as having persistent disease [23,24,25]. A serum cortisol concentration > 1.8 µg/dL for 8 h in the morning after 1 mg of DEX was given at midnight was considered to be a positive result in the ON DST [26]. Suppression of the serum cortisol level by > 50% for 6 h after 2 mg of DEX was administered for 2 days was defined as the suppression on the HD DST [26]. The final diagnosis was confirmed using surgical pathology and clinical follow-up. Endocrinological evaluation All laboratory analyses were performed at the Department of Laboratory Medicine, Severance Hospital. Preoperative cortisol and 24 h UFC were measured by chemiluminescence immunoassay using an automated UniCel DXC880i Synchron analyzer (Beckman Coulter, Pasadena, CA, USA; coefficient of variation [CV] ± 15 nmol/L at < 100 nmol/L and ± 15% at > 100 nmol/L). Preoperative ACTH levels were analyzed by electrochemiluminescence immunoassay using the Roche Cobas 6000 analyzer (Roche Diagnostics GmbH, Mannheim, Germany; CV ± 2.0 pmol/L at < 20 pmol/L and ± 10% at > 20 pmol/L). The serum cortisol concentration at 8:00 am the following day after 1 mg of DEX was administered at midnight was considered positive on the ON DST. We determined the result as “suppression” by the cortisol level of < 1.8 µg/dL. A serum cortisol level suppressed by > 50% of the original level after 6 hourly administrations of 2 mg of DEX for 48 h was defined as suppression on the HD DST [27]. 18F-FDG PET/CT evaluation PET/CT was performed using a GEADVANCE PET scanner (GE, Milwaukee, WI, USA) after the intravenous injection of 7–9 mCi of 18F-FDG. All patients fasted for at least 6 h before the test. Emission scanning was continued for 15 min (4.25-mm axial spatial resolution, 4.8-mm transaxial spatial resolution). Transmission scans were performed for 8 min using triple Ge-68 rod sources to correct attenuation. Gathered data were reconstructed in a 128 × 128 × 35 matrix with a pixel size of 1.95 × 1.95 × 4.25 mm by means of a filtered back-projection algorithm employing a transaxial 8.5-mm Hanning filter and 8.5-mm axial ramp filter. Two specialists independently interpreted the encoded baseline PET images, and after a two-week period, they interpreted the encoded post DEX suppression PET images. Each specialist was blinded to MRI imaging, clinical characteristics, and surgical outcomes of these subjects. Each was tasked with determining whether the PET image indicated a “negative” or “positive” result for pituitary adenoma and its location on a high-resolution computer screen. The scan after DEX suppression was performed 24 h after the oral administration of 8 mg of DEX using the same procedures as for the baseline PET/CT scan. 18F-FDG uptake analysis The Region of interest (ROI) was drawn using MIM software (version 6.5, Software INc., Cleveland, OH, USA) (Fig. 1). PET images were reviewed by experienced by an experienced specialist. The pituitary gland was identified and a circular ROI was drawn. A fixed ROI with a 3-mm diameter was used for all patients. The ROI was placed on the lesion with the highest FDG uptake. If there was no significantly increased FDG uptake, the same sized circular ROI was drawn on the suspected adenoma location. For the normal pituitary gland, the same sized 3 mm ROI was used. Fig. 1 Images of ROI for pituitary adenoma on18F-FDG PET scan Example of ROI definition in pituitary adenomas of 18F-FDG PET scan of the patients with CD. We draw the fixed circular ROI with a 3-mm diameter for pituitary adenomas (red circle) and normal pituitary gland (green circle) ROI, Reason of interest; 18F-FDG PET, 18 F-fluorodeoxyglucose positron emission tomography; CD, Cushing disease Full size image The mean standardized uptake value (SUVmean) and maximum SUV (SUVmax) for pituitary adenomas and normal pituitary glands were automatically measured using MIM, version 6.5 (Software Inc., Cleveland, OH, USA). The standardized uptake value (SUV) of the volume of interest was calculated as follows: (decoy-corrected activity (kBq) / volume (mL)) / (injected dose (kBq) / body weight (g)). SUVmean and SUVmax of pituitary adenomas were divided into the SUVmean of normal pituitary glands for adjustment. We used the ratio of SUVmax to SUVmean to analyze the homogeneity of the pituitary adenomas. MRI evaluation All patients underwent pituitary MRI with a 3.0-Tesla scanner (Achieva, Philips Medical Systems, Best, the Netherlands). Imaging protocols included T1-weighted imaging, T2-weighted imaging, and delayed gadolinium-enhanced T1-weighted imaging. The extent, location, and sizes of the pituitary tumors were reviewed based on official records determined by radiologists. Pituitary tumors were classified based on radiological findings using MRI of the sellar and parasellar regions. Type I refers to tumors < 1 cm in diameter limited to the sella. Type II tumors extend into the suprasellar space, < 1 cm from the diaphragm. Type III includes tumors extending into the suprasellar space > 1 cm from the diaphragm or sphenoid sinus and encroaching on the internal carotid arteries. Lastly, type IV refers to adenomas with obvious invasion into the cavernous sinus, as shown on MRI, and into the medial dural wall of the cavernous sinus, as confirmed during surgery. BIPSS Before surgery, BIPSS was performed to confirm the cause of CD and lateralize the tumors. A catheter was placed in patients using a unilateral femoral venous approach and 3 cc of blood was collected from the peripheral (P) and both inferior petrosal sinuses (IPS) [28]. CRH at a dose of 1 µg/kg was administered, and peripheral and petrosal samples were drawn after 5 and 10 min, respectively. The catheters and sheath were removed, and the groin was compressed under pressure until venous hemostasis was achieved. The IPS:P prolactin ratio was calculated at each time point to confirm the accuracy of the inferior petrosal venous sampling. A value of ≥1.8 was considered successful IPS catheterization. The prolactin-normalized ACTH ratio was calculated by dividing the dominant ACTH IPS:P ratio by the concurrent and ipsilateral IPS:P prolactin ratio. A value of ≥1.3 was considered diagnostic of CD. An intersinus ACTH ratio of ≥1.4 either at baseline or after stimulation was used for lateralization of the pituitary adenoma [29]. Location of the adenoma The final assignment of the true location of the pituitary adenoma was based on intraoperative multiple stage resection and tumor tissue identification using frozen sections. Surgically identified adenomas were histologically evaluated and stained for ACTH immunoreactivity. In cases of multiple specimens obtained during the procedure, the true location of the adenoma was assigned based on the original site of the specimen containing the adenoma [30]. Statistical analysis Data are presented as medians (ranges) or numbers (percentages). The baseline characteristics of the patients were compared using Kruskal–Wallis’ test with Dunn’s procedure for nonparametric continuous variables. Categorical variables were compared using Fisher’s exact test. Spearman’s correlation coefficients were used to determine the correlation between FDG uptake and hormone levels. Wilcoxon’s signed-rank test was used to identify changes in the SUV after DEX administration. The interobserver agreement for image analysis was assessed using κ statistics. κ values were categorized as follows: κ < 0.20 indicated poor agreement, κ of 0.21–0.40 indicated fair agreement, κ of 0.41–0.60 indicated moderate agreement, κ of 0.61–0.80 indicated good agreement, and κ > 0.81 indicated excellent agreement [31]. Statistical significance was set at a two-sided P < 0.05. All statistical analyses were performed using SPSS software (IBM Corp., Armonk, NY, USA). Results Patient characteristics We enrolled all patients with CD who underwent two rounds of the 18F-FDG PET/CT with or without DEX suppression and sellar MRI before transsphenoidal adenectomy (TSA). Twenty-two patients were included (age at diagnosis: 37 [13–56] years), and most were women (90.91%). Patients’ baseline characteristics are shown in Table 1. There were 16 microadenomas and 6 macroadenomas. Immediate remission was achieved in 81.82% of the patients and delayed remission in 13.64%; one patient showed persistent disease after TSA. The median preoperative 24 h UFC, serum ACTH, and cortisol levels were 443.35 (93.00–4452.00) µg/day, 36.16 (6.00–92.00) pg/mL, and 18.55 (6.00–40.00) µg/dL. The size of pituitary adenomas on MRI was 7.85 (2.00–28.00) mm. The Ki-67 index of 47.06% of adenomas ranged from 1 to 2, that of 35.29% was below 1, and that of 17.65% was 2 or higher. Overall, 75.00% of the adenomas were classified as Knosp grade 0, 5.00% as grade 1, 5.00% as grade 3b, and 15.00% as grade 4. In total, 77.27% (17/22) of patients had an ACTH-staining adenoma. Only one patient showed unsuppressed cortisol levels on the HD DST. Table 1 Patients’ imaging and clinical characteristics Full size table MRI negative but PET positive case Two patients showed negative MRI results, and one of them showed FDG uptakes on both 18F-FDG PET scans at baseline and after DEX suppression. A 26-year-old man visited our hospital complaining of weight gain and was diagnosed with ACTH-dependent CD. Cortisol secretion was suppressed on the HD DST; however, sellar MRI did not reveal any suspicious lesions. BIPSS revealed a central tumor (central/peripheral ACTH level of 36.25 after CRH stimulation) lateralized to the right side of the pituitary gland. The patient underwent 18F-FDG-PET/CT before and after DEX suppression to identify the primary lesions. Baseline PET/CT showed diffused FDG uptake with an SUVmax of 1.03 at the pituitary fossa but failed to localize the tumor. After DEX treatment, focal FDG uptake with an SUVmax of 1.06 remained at the right side of the pituitary fossa, which resulted in the successful localization of the corticotrophic adenoma. The MRI and PET/CT images of this case are presented in Fig. 2A–C. During TSA, the surgeon identified solid tumor-like tissues on the right side of the pituitary gland and successfully removed them. Results of pathology and ACTH immunohistochemistry were negative, but the patient achieved immediate biochemical remission and CD-related symptoms were relieved after surgery. We followed the patient for 98 months after the surgery and confirmed that he had lived without recurrence. Fig. 2 Images of a corticotroph with negative MRI but positive18 F-FDG PET/CT after DEX suppression An MRI-negative adenoma was detected on 18F-FDG PET/CT at baseline and after DEX suppression. In this patient, the pituitary adenoma was visible on PET scans at baseline (B) and after DEX suppression (C) at the same location, as confirmed by the surgeon A. Co-registered baseline 18F-FDG PET/CT and MRI images. Diffuse 18F-FDG uptake is detected in the pituitary fossa with an SUVmean of 0.86 and SUVmax of 1.03, but there was failure to localize the adenoma on baseline 18F-FDG PET/CT. B. Co-registered 18F-FDG PET/CT and MRI images after DEX suppression. 18F-FDG uptake is not suppressed in the right side of the pituitary gland with an SUVmean of 1.03 and SUVmax of 1.06. 18F-FDG PET/CT after DEX suppression was successful in localizing the right-sided corticotrophic adenoma C. MRI image. There is no suspicious lesion in the pituitary gland ACTH, adrenocorticotropic hormone; MRI, magnetic resonance imaging; 18F-FDG, 18 F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; DEX, dexamethasone; SUVmean, mean standardized uptake value; SUVmax, maximum standardized uptake value Full size image Change of 18F-FDG uptake after DEX suppression We included 18 pituitary adenomas that were successfully localized using PET/CT after DEX suppression, and analyzed the change of SUV for 15 adenomas, excluding outliers with SUV over 2.00. The results are presented in Fig. 3A and B. The SUVmean of adenomas did not changed after DEX suppression compared to normal pituitary glands (SUVmean of adenoma/SUVmean of normal pituitary glands: 1.13 [0.85–1.35] vs. 1.14 [0.87–1.39], z=-1.288, P = 0.198). DEX suppression increased SUVmax of adenomas compared to normal pituitary glands but without statistical significance (SUVmax of adenoma/SUVmean of normal pituitary glands: 1.13 [0.96–1.52] vs. 1.21 [0.97–1.56], z=-0.765, P = 0.444). Fig. 3 Changes in the SUVs of corticotrophs between18F-FDG PET/CT before and after DEX suppression The SUVmean (A) and SUVmax (B) of corticotrophic adenomas are shown in this pairwise analysis. The SUVmean did not changed after DEX suppression from (z=-1.288, P = 0.198). The SUVmax of the corticotrophic adenoma increased from 1.13 to 1.21 (z=-0.765, P = 0.444). In this analysis, the SUVmean and SUVmax of pituitary adenomas were adjusted using the SUVmean of the normal pituitary gland. Colored plots and bars presented median and interquartile range in this figure. We presented the tumors with size larger than 5 mm and SUV adjusted by normal pituitary>1 for blue line SUVmean, mean standardized uptake value; SUVmax, maximum standardized uptake value; DEX, dexamethasone; 18F-FDG, 18 F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography Full size image In Fig. 3, the blue line indicates change in SUV of adenomas larger than 5 mm with higher FDG uptake than the surrounding pituitary parenchyma. For these adenomas, DEX suppression did not change the SUV (SUVmean of adenoma/SUVmean of normal pituitary glands: 1.31 [1.04–2.52] vs. 1.33 [1.05–2.38], z=-0.784, P = 0.433; SUVmax of adenoma/SUVmean of normal pituitary glands: 1.36 [1.02–2.61] vs. 1.40 [1.03–2.65], z=-1.022, P = 0.307). The value of SUV increased in 73.33% adenomas, while the SUVmax increased in 66.67% compared with normal pituitary glands after DEX treatment. Correlation between the hormone level and 18F-FDG uptake Table 2 shows the results of the Spearman correlation analysis of the SUV with preoperative cortisol, ACTH, and nadir cortisol levels on the HD DST. On the baseline 18F-FDG PET scan, the SUVmax of the adenomas did not show any correlation with the levels of three hormones. The SUVmean of adenomas showed a positive correlation with nadir cortisol levels on the HD DST (P = 0.014) and preoperative ACTH levels, with marginal significance (P = 0.062). After DEX suppression, the SUVmax and SUVmean of adenomas had a positive correlation with moderate degrees of nadir cortisol on the HD DST (SUVmax: Spearman Rho = 503, P = 0.017; SUVmean: Spearman Rho = 0.554, P = 0.007). Table 2 Correlation between FDG uptakes and hormone levels Full size table FDG uptake of reference sites after DEX suppression We evaluated the FDG uptake for five types of reference areas (normal pituitary gland, cerebellum, thalamus, white matter, and gray matter) (Table 3). Normal pituitary gland and white matter did not affect the unadjusted SUVmean by DEX suppression (all P >0.05). DEX significantly increased SUVmean of the thalamus and gray matter (thalamus, 8.70 [4.40–22.70] vs. 11.20 [6.40–17.5], P = 0.010*; gray matter, 6.25 [2.50–15.00] vs. 7.95 [5.00–11.90], P = 0.010*). However, SUVmean of the cerebellum significantly decreased after DEX administration (7.65 [4.50–10.80] vs. 6.40 [2.60–12.00], P = 0.006*). Table 3 The change of FDG uptake for reference sites after DEX suppression in the patients with CD Full size table Qualitative analysis by diagnostic modalities for CD The qualitative results of localizing pituitary adenomas in CD patients are shown in Table 4 and Fig. 4. Only 13 patients had BIPSS results. The success rates were 90.91% for MRI and 84.62% for BIPSS. Table 4 Qualitative analysis by diagnostic modalities for CD Full size table Fig. 4 Images for corticotroph adenomas that appear different for localization in18F-FDG PET/CT. 9 mm sized adenoma in the left lateral wing of pituitary gland. It was found in the left lateral wing of the pituitary gland, showing an 18F-FDG uptake in the pituitary fossa with an SUVmean of 1.04 and SUVmax of 1.07. However, after DEX suppression, the left side of the pituitary gland did not exhibit suppressed 18F-FDG uptake, with SUVmean 1.05 SUVmax 1.14 (A). Co-registered baseline 18F-FDG PET/CT and MRI images. (B). Co-registered 18F-FDG PET/CT and MRI images after DEX suppression. (C). MRI image 2 mm pituitary adenoma was detected at the left lateral wing, showing diffuse FDG uptake in the pituitary fossa with an SUVmean of 0.86 and SUVmax of 1.04. After DEX suppression, focal FDG uptake was observed, with SUVmean 0.87 and SUVmax 0.98. (D). Co-registered baseline 18F-FDG PET/CT and MRI images. (E). Co-registered 18F-FDG PET/CT and MRI images after DEX suppression. (F). MRI image Full size image In baseline PET scans, the specialists agreed that pituitary adenomas were visible in 17 scans and not visible in 5 scans. They reached a consensus that the tumor was evident in two scans, but there was a discrepancy in their assessments of its location. After DEX suppression, pituitary adenomas showed positive results in 16 scans and negative results in 5 scans. Specialists disagreed on the presence of pituitary adenomas in one case only. Interobserver agreement for localizing adenomas was 0.872 (95%CI: 0.711, 1.033) for baseline PET/CT and 0.938 (95%CI: 0.762, 1.056) for post dexamethasone suppression PET/CT, confirming excellent interobserver agreements, and the result was judged reliable. Among the instances where both opinions agreed, there were no lesions that showed differences in visibility between scans before and after DEX administration. This meant that lesions were either consistently visible or invisible in both scenarios. Discussion We found that DEX suppression did not improve localization of ACTH-secreting pituitary adenomas using 18F-FDG PET/CT. Further, it did not significantly affect FDG uptakes in adrenocorticotrophic adenomas or normal pituitaries in patients with CD. The decision to administer 8 mg dexamethasone was based on the standard high-dose DST, which is internationally recommended for differentiating between ectopic ACTH secretion and CD [26]. This test involved comparing serum cortisol levels at 8 am before and after a single dose of 8 mg dexamethasone administered at 11 pm. Suppression of the serum cortisol level to less than 50% of the baseline value indicated a diagnosis of CD [32, 33]. Previous studies have reported that the 8-mg DST has a sensitivity of 90%, specificity of 100%, accuracy of 96.8%, positive predictive value of 100%, and negative predictive value of 95.5% [34, 35]. Our use of 8 mg dexamethasone was based on the theory that orally administering dexamethasone at this dose can effectively suppress cortisol levels in ACTH-secreting pituitary tumors. We expected that FDG uptake by corticotrophic adenomas would not decrease after DEX administration in patients with CD, and this change may improve the ability to discriminate the tumor location from surrounding tissues on 18F-FDG PET. The SUVmax of pituitary adenomas adjusted for the normal pituitary gland increased from 1.13 to 1.21. However, this change was not statistically significant, and the success rate of localizing corticotrophic adenomas using 18F-FDG PET was not significantly improved after DEX suppression. If the FDG uptake of adenomas changed lesser compared to that of surrounding normal tissues after DEX suppression, the tumor could be more easily visualized because of the difference. In addition, we attempted to evaluate FDG uptakes in other brain areas (cerebellum, thalamus, white matter, and gray matter) according to DEX administration in CD patients. SUVmean of the cerebellum decreased significantly, but that of the thalamus and gray matter increased after DEX suppression. DEX did not change FDG uptake in pituitary adenoma, normal pituitary, or white matter. In a previous study analyzing FDG PET in CD patients, researchers observed varying correlations between FDG uptake and blood cortisol concentration across different brain regions [35, 36]. Nevertheless, the examination did not include an analysis of FDG uptake in the pituitary gland. Additionally, no previous studies have explored the effects of high-dose dexamethasone suppression on brain glucose metabolism in individuals with CD. Further studies are needed to explain the change in FDG uptake after DEX administration in patients with CD. 18F-FDG PET/CT provides information regarding glucose metabolism in the brain in vivo and has been widely used to evaluate brain metabolism in clinical and research settings [37]. Here, the nadir cortisol level on the HD DST correlated with the SUVmean and SUVmax of pituitary adenomas on PET scans after DEX suppression. Cortisol secretion activity is thought to be associated with metabolic activity, and DEX administration altered this. Cortisol levels and FDG uptake in other regions of the brain are correlated in patients with CD, but the correlation between cortisol and FDG uptake in the pituitary glands and/or corticotrophic adenomas themselves has not been discussed [35, 36]. In our study, cortisol levels did not show a correlation with FDG uptake of corticotrophic adenomas, but after DEX suppression FDG uptake showed a correlation with the nadir cortisol level on the HD DST. This indicated that tumors in which cortisol secretion was less suppressed by on the HD DST showed higher FDG uptake than tumors with lower cortisol levels on the HD DST. Although many studies have analyzed FDG uptake of brain tumors, reference sites defined in each study varied without a uniform standard. Gray matter, white matter, or adjacent tumor tissue was defined as a reference site [38,39,40]. We measured SUVmean of normal pituitary tissues, gray matter, white matter, thalamus, and cerebellum as possible references. We defined the SUVmean of normal pituitary tissues as a reference because the localization of adenomas requires an apparent difference between the adenoma and surrounding tissues. Use of fixed ROI to measure FDG uptake caused partial volume effect in this study. However, lesions smaller than 5 mm with intense FDG uptake may still show increased FDG uptake, especially in tumors, albeit with lower SUV values compared with the actual values [41]. This study was performed because pituitary adenomas smaller than 5 mm with higher FDG uptake than the surrounding pituitary parenchyma have been observed in routine clinical practice. To control for the partial volume effect, the analysis was performed again for tumors which were larger than 5 mm and had higher FDG uptake than the surrounding pituitary parenchyma, and the results remained unchanged. PET/CT has been explored as an alternative to or combined with MRI for the localization of corticotrophic adenomas. 18F-FDG PET/CT has a limited role in CD diagnosis, but CRH stimulation can increase its success rate [22, 42]. This study is important for increasing the effectiveness of PET using DEX. In addition, data on DEX effect on brain metabolism in patients with CD will be important for future studies. Conclusions DEX suppression did not improve the localization of 18F-FDG PET/CT in patients with CD. This is considered to have sufficient significance in an effort to increase the diagnostic value of 18F-FDG PET/CT. Data Availability All datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request. Abbreviations 18F-FDG: 18F-fluorodeoxyglucose PET/CT: Positron emission tomography/computed tomography DEX: Dexamethasone MRI: Magnetic resonance imaging BIPSS: Bilateral inferior petrosal sinus sampling CD: Cushing’s disease SUV: Standardized uptake value ACTH: Adrenocorticotropic hormone CRH: Corticotrophin-releasing hormone FDG: Fluorodeoxyglucose 24hr UFC: 24-hour urine free cortisol ON DST: Overnight dexamethasone suppression test HD DST: High-dose dexamethasone suppression test SUVmean : Mean standardized uptake value SUVmax : Maximum standardized uptake value P: Peripheral IPS: Inferior petrosal sinuses TSA: Transsphenoidal adenectomy References Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. The Lancet. 2006;367:1605–17. Article CAS Google Scholar Steffensen C, Bak AM, Rubeck KZ, Jørgensen JOL. Epidemiology of Cushing’s syndrome. Neuroendocrinology. 2010;92:1–5. Article CAS PubMed Google Scholar Lacroix A, Feelders RA, Stratakis CA, Nieman LK. 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Article PubMed Google Scholar Soret M, Bacharach SL, Buvat I. Partial-volume effect in PET tumor imaging. J Nucl Med. 2007;48:932–45. Article PubMed Google Scholar Xin C, Rui-xue C, Hui P, Tao Y, Hui-Juan Z, Fang L. Value of [18F] fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in diagnosis and localization of Cushing’s disease. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2011;33:107–10. PubMed Google Scholar Download references Acknowledgements We would like to thank Editage (www.editage.co.kr) for English language editing. Funding The study was supported by the “Team Science Award” of Yonsei University College of Medicine (6-2022-0150). Author information Authors and Affiliations Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Kyungwon Kim, Cheol Ryong Ku & Eun Jig Lee Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Dong Kyu Kim Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Ju Hyung Moon, Eui Hyun Kim & Sun Ho Kim Contributions Conception and design: EJL, CRK, KK. Acquisition of data: KK, DKK. Analysis and interpretation of data: KK. Drafting the article: KK. Administrative/technical/material support: JHM, EHK, SHK. Study supervision: EJL, CRK. Writing, review, and revision of the manuscript: KK, DKK, SHK, CRK. Final approval of the manuscript: CRK, EJL. Corresponding authors Correspondence to Cheol Ryong Ku or Eun Jig Lee. Ethics declarations Ethics approval and consent to participate The data were collected under the conditions of regular clinical care with approval from the ethics committee of our hospital, and the requirement for written informed consent was waived owing to its retrospective design (institutional review board number: 2023-0110-001). Consent for publication Not applicable. Competing interests The authors declare no conflicts of interest that could be perceived as prejudicing the impartiality of this study. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic supplementary material Additional file 1 of Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors Additional file 1 Supplementary Material 1 Below is the link to the electronic supplementary material. Supplementary Material 1 Supplementary Material 2 Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Reprints and Permissions Cite this article Kim, K., Kim, D.K., Moon, J.H. et al. Dexamethasone suppression for 18F-FDG PET/CT to localize ACTH-secreting pituitary tumors. Cancer Imaging 23, 85 (2023). https://doi.org/10.1186/s40644-023-00600-8 Download citation Received09 May 2023 Accepted08 August 2023 Published12 September 2023 DOIhttps://doi.org/10.1186/s40644-023-00600-8 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords 18F-FDG PET/CT ACTH-secreting pituitary tumor Cushing’s disease Dexamethasone suppression High-dose dexamethasone suppression test From https://cancerimagingjournal.biomedcentral.com/articles/10.1186/s40644-023-00600-8
  23. Cushing syndrome is a metabolic disease caused by chronic exposure to high levels of glucocorticoids. It can present as an endocrine emergency due to a rapid increase in circulating cortisol leading to increased risk of cardiovascular disease and infection. Etomidate rapidly reduces plasma cortisol levels by inhibiting the action of 11β-hidroxilase. We report the case of a patient with severe hypercortisolaemia accompanied by metabolic and psychiatric disorders in whom administration of etomidate reduced preoperative levels of cortisol. Introduction Cushing’s syndrome is a metabolic disease caused by chronic exposure to high levels of glucocorticoids. The main causes are ectopic ACTH secretion, adrenal tumours (adenomas or carcinomas), adrenal hyperplasia, and administration of exognous glucocorticoids—the latter being the most common aetiology.1 In most cases, Cushing’s syndrome presents an indolent course for years before diagnosis is made, although it can sometime present as an endocrine emergency due to a rapid increase in circulating cortisol levels.2 In these cases, treatment to control hypercortisolaemia must be started quickly due to the high morbidity and mortality associated with the potentially life-threatening metabolic, infectious, and neuropsychiatric alterations that occur in this syndrome.1, 2, 3, 4 The options for treating Cushing’s syndrome include surgery, radiotherapy, and pharmacological treatment. The most commonly used drugs are adrenal steroidogenesis inhibitors (ketoconazole, metyrapone),3 but this treatment is not always well tolerated and its efficacy is limited.2 Etomidate is a drug from the imidazole family that inhibits the enzyme 11β-hydroxylase, and can reduce cortisol secretion within 48−72 h.2 Section snippets Case report Our patient was a 27-year-old woman with no known drug allergies or personal history of interest. She was studied in April 2021 for anxious-depressive symptoms with rapidly evolving paranoid ideation and hirsutism. A Nugent test was performed, which was positive (46.1 mcg/dl), and cortisol in urine was measured (2715 mcg/24 h), leading to a diagnosis of Cushing's syndrome. A CT scan showed a large mass on the right adrenal gland, compatible with a primary adrenal gland tumour (Fig. 1). Discussion Endogenous Cushing's syndrome is characterized by over-production of cortisol. In patients such as ours, the syndrome presents in its most serious form, with very high hypercortisolaemia and metabolic, cardiovascular, and neuropsychiatric disorders. Cushing's syndrome is a medical emergency due to its association with several comorbidities and its high rate of mortality.5 The first therapeutic option is surgical resection of the underlying tumour; however, the accompanying hypercortisolaemia Conclusion In its severe form, Cushing's syndrome is a medical emergency that must be rapidly controlled. Etomidate is both safe and effective, and has shown promising results in the treatment of severe hypercortisolaemia. We believe that these patients should be admitted to the Anaesthesia Intensive Care Unit during etomidate therapy in order to monitor their level of consciousness, lung function, and haemodynamics, and to closely monitor cortisol and electrolyte levels. Ethical considerations Informed consent was obtained for the use of patient information for teaching and research purposes in accordance with our hospital protocol. Conflict of interests None. Funding The authors have not received any funding for this manuscript. References (8) A. Ferriere et al. Cushing’s syndrome: Treatment and new therapeutic approaches Best Pract Res Clin Endocrinol Metab (2020) Juszczak A, Morris D, Grossman A. Cushing's Syndrome [Internet]. South Dartmouth (MA): MDText.com, Inc; 2000 [revised... T.B. Carroll et al. Continuous Etomidate Infusion for the Management of Severe Cushing Syndrome: Validation of a Standard Protocol J Endocr Soc (2018) V.A. Preda et al. Etomidate in the management of hypercortisolaemia in Cushing’s syndrome: a review Eur J Endocrinol (2012) There are more references available in the full text version of this article. 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  24. Please consider joining us for #Pituitary Tumor Support Group on Saturday October 7th, 2023 at 9am to discuss Current and Emerging Medical Therapies in Pituitary Tumor Treatment by Dr. Mahalakshi Honasage, #Endocrinologist, and Dr. Jack Rock, #Neurosurgery. Virtual and In-Person participation is available. RSVP to 313-916-1094
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