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  1. Clinical trial analyses focus on the human body’s homeostatic response to potent HSD-1 inhibition by SPI-62 Results highlight that urinary free cortisol is distinct from intracellular cortisol that causes symptoms in patients with Cushing’s syndrome or autonomous cortisol secretion May 24, 2022 07:20 AM Eastern Daylight Time PORTLAND, Ore.--(BUSINESS WIRE)--Sparrow Pharmaceuticals, an emerging, clinical-stage biopharmaceutical company developing novel, targeted therapies for disorders of glucocorticoid excess, today presented new pharmacological data during a poster session and a Rapid Communications session titled, “HPA axis modulation by a potent inhibitor indicates 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) is a main source of cortisol that can bind intracellular receptors” at the 24th European Congress of Endocrinology (ECE 2022). Sparrow scientists examined the steroid hormone changes after administration of its lead therapeutic candidate, SPI-62, an HSD-1 inhibitor, to healthy adults. “Normalized urinary free cortisol, or UFC, is a standard therapeutic target for patients with Cushing’s syndrome,” said David A. Katz, Ph.D., CSO at Sparrow Pharmaceuticals, “But that biomarker doesn’t measure the cortisol that can access intracellular receptors and cause symptoms. UFC normalization has been shown not to correlate with clinical endpoints in patients with Cushing’s syndrome. Many patients with autonomous cortisol secretion have normal UFC, yet substantial cortisol morbidity. As we conduct clinical trials for patients with those diseases, we’re in search of better ways to measure the cortisol that makes patients ill.” The study analyzed historical clinical trial data to better characterize how SPI-62 impacts cortisol levels and the body’s homeostatic response to those changes. Conclusions of the study include: Half of hepatocellular cortisol with access to intracellular receptors is generated in healthy adults by HSD-1. ACTH increase compensates for the effect of HSD-1 inhibition on systemic cortisol levels. Secondary increases of androgen levels have not been associated to date with clinical consequences. Large changes of the amount of cortisol that can bind intracellular receptors, and thus cause cortisol-related morbidity, can occur independently of urinary free cortisol levels. HSD-1 converts cortisone to cortisol in tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, and brain. SPI-62 is a potent HSD-1 inhibitor in clinical development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition. To register and view the abstracts, visit ECE’s website here. From https://www.businesswire.com/news/home/20220524005465/en/Sparrow-Pharmaceuticals-Presents-New-Clinical-Trial-Data-Analyses-on-HSD-1-Inhibitor-SPI-62-at-the-24th-European-Congress-of-Endocrinology
  2. Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX) today announced positive results from the multiple-ascending dose (MAD) portion of a first-in-human Phase 1 clinical study of CRN04894, the company's first-in-class, investigational, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist that is being developed for the treatment of Cushing’s disease, congenital adrenal hyperplasia (CAH) and other conditions of excess ACTH. Following administration of CRN04894, results showed serum cortisol below normal levels and a marked reduction in 24-hour urine free cortisol excretion in the presence of sustained, disease-like ACTH concentrations. “The design of our Phase 1 healthy volunteer study allowed us to demonstrate CRN04894’s potent pharmacologic activity in the presence of ACTH levels that were in similar range to those seen in CAH and Cushing’s disease patients,” said Alan Krasner, M.D., Crinetics’ chief medical officer. “The observation of dose-dependent reductions in serum cortisol levels to below the normal range even in the presence of high ACTH indicates that CRN04894 was effective in blocking the key receptor responsible for regulating cortisol secretion. We believe this is an important finding that may be predictive of CRN04894’s efficacy in patients.” ACTH is the key regulator of the hypothalamic-pituitary adrenal (HPA) axis controlling adrenal activation. It is regulated by cortisol via a negative feedback loop that acts to inhibit ACTH secretion. This feedback loop is dysregulated in diseases of excess ACTH. In Cushing’s disease, a benign pituitary tumor drives excess ACTH secretion even in the presence of excess cortisol. While in CAH, an enzyme deficiency results in excess androgen synthesis without normal cortisol synthesis, allowing unchecked ACTH production and requiring lifelong glucocorticoid use. In both diseases, excess ACTH drives over-stimulation of the adrenal gland and leads to a host of symptoms including infertility, adrenal rest tumors, and metabolic complications in CAH and, in Cushing’s disease, symptoms include hypertension, central obesity, neuropsychiatric disorders and metabolic complications. To our knowledge, no other ACTH antagonists are currently in clinical development for diseases of ACTH excess such as Cushing’s disease or CAH. The 49 healthy adults evaluated in the multiple ascending dose portion of the Phase 1 study were administered 40, 60 or 80 mg doses of CRN04894, or placebo, daily for 10 days. After 10 days of dosing was complete, evaluable participants were administered an ACTH challenge to stimulate adrenal activation to disease relevant levels. Safety and pharmacokinetic data were consistent with expectations from the single-ascending dose cohorts in the Phase 1 study. There were no discontinuations due to treatment-related adverse events and no serious adverse events reported. Glucocorticoid deficiency was the most common treatment-related adverse event in the MAD cohorts. This was an expected extension of pharmacology given the mechanism of action of CRN04894. CRN04894 showed consistent oral bioavailability in the MAD cohorts with a half-life of approximately 24 hours, which is anticipated to support once-daily dosing. Participants in the MAD cohorts who were administered once nightly CRN04894 experienced a dose-dependent suppression of adrenal function as measured by suppression of serum cortisol production of 17%, 29% and 37% on average from baseline over 24 hours for the 40, 60 or 80 mg dosing groups respectively, (despite requirement for glucocorticoid supplementation in some of these subjects to prevent clinical adrenal insufficiency), compared to an average 2% increase in serum cortisol for individuals receiving placebo. The strong, dose-dependent suppression of serum and urine free cortisol was achieved despite ACTH levels in subjects in the 60 and 80 mg cohorts similar to those typically seen in patients with CAH and Cushing’s disease. Even when an additional exogenous ACTH challenge was administered on top of the already increased ACTH levels, cortisol levels remained below the normal range in subjects receiving CRN04894, indicating clinically significant suppression of adrenal activity. “Due to its central position in HPA axis, ACTH is the obvious target for inhibiting excessive stimulation of the adrenal in diseases of ACTH excess. Even though the field of endocrinology has known about its clinical significance for more than 100 years, we are not aware of any other ACTH antagonist that has entered clinical development. This is an important milestone for endocrinology and for our company.” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “We are very excited to initiate patient studies in Cushing’s disease and CAH with CRN04894, which will be our third home-grown NCE to demonstrate pharmacologic proof-of-concept and enter patient trials.” Crinetics plans to present additional details of safety, efficacy, and biomarker results from the CRN04894 Phase 1 study at an endocrinology-focused medical meeting in 2022. Data Review Conference Call Crinetics will hold a conference call and live audio webcast today, May 25, 2022, at 8:00 a.m. Eastern Time to discuss results from the MAD cohorts of the Phase 1 study of CRN04894. To participate, please dial 1-877-407-0789 (domestic) or 1-201-689-8562 (international) and refer to conference ID 13730000. To access the webcast, click here. Following the live event, a replay will be available on the Events page of the Company’s website. About the CRN04894 Phase 1 Study Crinetics has completed enrollment of the 88 healthy volunteers in this double-blind, randomized, placebo-controlled Phase 1 study. Participants were divided into multiple cohorts in the single ascending dose (n=39) and multiple ascending dose (n=49) portions of the study. In both the SAD and MAD portions of the study, safety and pharmacokinetics were assessed. In addition, pharmacodynamic responses were evaluated before and after challenges with injected synthetic ACTH to assess pharmacologic effects resulting from exposure to CRN04894. From https://www.streetinsider.com/Corporate+News/Crinetics+Pharmaceuticals+(CRNX)+Reports+Positive+Top-line+Results+Including+Strong+Adrenal+Suppression+from+CRN04894+Phase+1+Study/20126484.html
  3. Compared with placebo, levoketoconazole improved cortisol control and serum cholesterol levels for adults with endogenous Cushing’s syndrome, according to results from the LOGICS study presented here. Safety and efficacy of levoketoconazole (Recorlev, Xeris Biopharma) for treatment of Cushing’s syndrome were established in the pivotal phase 3, open-label SONICS study. The phase 3, double-blind LOGICS study sought to demonstrate the drug specificity of levoketoconazole in normalizing mean urinary free cortisol (mUFC) level. “Treatment with levoketoconazole benefited patients with Cushing’s syndrome of different etiologies and a wide range in UFC elevations at baseline by frequent normalization of UFC,” Ilan Shimon, MD, professor at the Sackler Faculty of Medicine at Tel Aviv University and associate dean of the Faculty of Medicine at Rabin Medical Center and director of the Institute of Endocrinology in Israel, told Healio. “This is a valuable Cushing’s study as it includes a placebo-controlled randomized withdrawal phase.” LOGICS participants were drawn from a cohort of 79 adults with Cushing’s syndrome with a baseline mUFC at least 1.5 times the upper limit of normal who participated in a single-arm, open-label titration and maintenance phase of approximately 14 to 19 weeks. Researchers randomly assigned 39 of those participants plus five from SONICS who had normalized mUFC levels on stable doses of levoketoconazole for at least 4 weeks to continue to receive the medication (n = 22) or to receive placebo with withdrawal of the medication (n = 22) for 8 weeks. At the end of the withdrawal period, all participants received levoketoconazole for 8 more weeks. Primary endpoint was proportion of participants who lost mUFC normalization during the randomized withdrawal period, and secondary endpoints included proportion with normalized mUFC and changes in total and LDL cholesterol at the end of the restoration period. During the withdrawal period, 95.5% of participants receiving placebo vs. 40.9% of those receiving levoketoconazole experienced loss of mUFC response, for a treatment difference of –54.5% (95% CI, –75.7 to –27.4; P = .0002). At the end of the withdrawal period, 4.5% of participants receiving placebo vs. 50% of those receiving levoketoconazole maintained normalized mUFC, for a treatment difference of 45.5% (95% CI, 19.2-67.9; P = .0015). Among participants who had received placebo and lost mUFC response, 60% regained normalized mUFC at the end of the restoration period. During the withdrawal period, participants in the placebo group had increases of 0.9 mmol/L in total cholesterol and 0.6 mmol/L in LDL cholesterol vs. decreases of 0.04 mmol/L (P = .0004) and 0.006 mmol/L (P = .0056), respectively, for the levoketoconazole group. The increases seen in the placebo group were reversed when participants restarted the medication. The most common adverse events with levoketoconazole were nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest were liver-related (10.7%), QT interval prolongation (10.7%) and adrenal insufficiency (9.5%). “This study has led to the FDA decision to approve levoketoconazole for the treatment of Cushing’s syndrome after surgical failure or if surgery is not possible,” Shimon said. From https://www.healio.com/news/endocrinology/20220512/logics-levoketoconazole-improves-cortisol-control-in-endogenous-cushings-syndrome
  4. She experienced extreme weight gain, thin skin and a racing heart. It took years to finally solve the medical mystery. Angela Yawn went to a dozen doctors before finally getting a diagnosis for her life-disrupting symptoms.Courtesy Angela Yawn April 27, 2022, 10:52 AM EDT / Source: TODAY By A. Pawlowski When a swarm of seemingly unrelated symptoms disrupted Angela Yawn’s life, she thought she was going crazy. She gained weight — 115 pounds over six years — even as she tried to eat less. Her skin tore easily and bruises would stay on her body for months. Her face would suddenly turn blood red and hot to the touch as if she had a severe sunburn. She suffered from joint swelling and headaches. She felt tired, anxious and depressed. Her hair was falling out. Then, there was the racing heart. “I would put my hand on my chest because it made me feel like that’s what I needed to do to hold my heart in,” Yawn, 49, who lives in Griffin, Georgia, told TODAY. “I noticed it during the day, but at night when I was trying to lie down and sleep, it was worse because I could do nothing but hear it beat, feel it thump." Yawn, seen here before the symptoms began, had no problems with weight before.Courtesy Angela Yawn Yawn was especially frustrated by the weight gain. Even when she ate just 600 calories a day — consuming mostly lettuce leaves — she was still gaining about 2 pounds a day, she recalled. A doctor told her to exercise more. Yawn gained 115 pounds over six years. "When the weight really started to pile on, I stayed away from cameras as I felt horrible about myself and looking back at this picture is still very embarrassing for me but I wanted (people) to see what this disease has the potential to do if not diagnosed," she said.Courtesy Angela Yawn In all, Yawn went to a dozen doctors and was treated for high blood pressure and congestive heart failure, but nothing helped. As a last resort, she sought out an endocrinologist in February of 2021 and broke down in her office. “That was the last hope I had of just not lying down and dying because at that point, that’s what I wanted to do,” Yawn said. “I thought the problem was me. I thought that I’m making up these issues, that maybe I’m bipolar. I was going crazy.” What is Cushing disease? When the endocrinologist suddenly started listing all of her symptoms without being prompted, Yawn stopped crying. Blood tests and an MRI finally confirmed the doctor’s suspicion: Yawn had a tumor in her pituitary gland — a pea-size organ at the base of the brain — that was causing the gland to release too much adrenocorticotropic hormone. That, in turn, flooded her body with cortisol, a steroid hormone that’s normally released in response to stress or danger. The resulting condition is called Cushing disease. Imagine the adrenaline rush you’d get while jumping out of an airplane and skydiving — that’s what Yawn felt all the time, with harmful side-effects. Yawn was making six times the cortisol she needed, said Dr. Nelson Oyesiku, chair of neurosurgery at UNC Health in Chapel Hill, North Carolina, who removed her tumor last fall. “That’s a trailer load of cortisol. Day in, day out, morning, noon and night, whether you need it or not, your body just keeps making this excess cortisol. It can wreak havoc in the body physiology and metabolism,” Oyesiku told TODAY. The steroid regulates blood pressure and heart rate, which is why Yawn's skin was flushed and her heart was racing, he noted. It can regulate how fat is burned and deposited in the body, which is why Yawn was gaining weight. Other effects of the steroid's overproduction include fatigue, thin skin with easy bruising, mental changes and high blood sugar. Cushing disease is rare, affecting about five people per million each year, so most doctors will spend their careers without ever coming across a case, Oyesiku said. That’s why patients often go years without being diagnosed: When they complain of blood sugar problems or a racing heart, they’ll be treated for much more common issues like diabetes or high blood pressure. Pituitary gland is hard to reach Removing Yawn’s tumor in September of 2021 would require careful maneuvering. If you think of the head as a ball, the pituitary gland sits right at the center, between the ears, between the eyes and about 4 inches behind the nose, Oyesiku said. It’s called the “master gland” because it regulates other glands in the body that make hormones, he noted. The location of the pituitary gland makes it heard to reach.janulla / Getty Images It’s a very difficult spot to reach. To get to it, Oyesiku made an incision deep inside Yawn’s nose in a small cavity called the sphenoid sinus. Using a long, thin tube that carried a light and a camera, he reached the tiny tumor — about the size of a rice grain — and removed it using special instruments. The surgery took four hours. The potential risk is high: The area is surrounded by vessels that carry blood to the brain, and it’s right underneath optic nerves necessary for a person to see. If things go wrong, patients can become blind, brain dead, or die. Recovery from surgery Today, Yawn is slowly returning to normal. She has lost 41 pounds and continues to lose weight. Her hair is no longer falling out. But patients sometimes require months or even a few years to adjust to normal cortisol levels. “It takes some time to unwind the effects of chronic exposure to steroids, so your body has to adapt to the new world order as the effects of the steroids recede,” Oyesiku said. "My life was on hold for five years... I'm trying not to be too impatient," Yawn said.Courtesy Angela Yawn Yawn’s body was so used to that higher cortisol level that she’s had to rely on steroid supplements to feel normal after the surgery. It’s like an addict going through withdrawal, she noted. The next step is finishing another cycle of supplements and then slowly tapering off them so that her body figures out how to function without the steroid overload. “I am definitely moving in the right direction,” she said. "I hope that I’ll get back to that woman I used to be — in mind, body and spirit." From https://www.today.com/health/health/cushing-disease-pituitary-gland-tumor
  5. Abstract Summary Here, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Learning points Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome. Ketoconazole and osilodrostat appear to act in a synergistic manner. This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Considering the current cost of newly-released drugs, such a strategy could lower the financial costs for patients and/or society. Keywords: Adult; Male; White; France; Adrenal; Adrenal; Novel treatment; December; 2021 Background Untreated or inadequately treated Cushing’s syndrome (CS) is a morbid condition leading to numerous complications. The latter ultimately results in an increased mortality that is mainly due to cardiovascular events and infections. The goal of the treatment with steroidogenesis inhibitors is normalization of cortisol production allowing the improvement of comorbidities (1). Most studies dealing with currently available steroidogenesis inhibitors used as monotherapy reported an overall antisecretory efficacy of roughly 50% in CS. Steroidogenesis inhibitors can be combined to better control hypercortisolism. To the best of our knowledge, we report here for the first time a patient treated with a ketoconazole–osilodrostat combination therapy. Case presentation Here, we report the case of Mr D.M., 53-years old, diagnosed with adrenocorticotrophic hormone (ACTH)-independent CS 6 months earlier. At diagnosis, he presented with resistant hypertension, hypokalemia, diabetes mellitus, easy bruising, purple abdominal striae and major oedema of the lower limbs. Investigations A biological assessment was performed, and the serum cortisol levels are depicted in Table 1. ACTH levels were suppressed (mean levels 1 pg/mL). Mean late-night salivary cortisol showed a four-fold increase (Table 2), and mean 24 h-urinary cortisol showed a two-fold increase. Serum cortisol was 1000 nmol/L at 08:00 h after 1 mg dexamethasone dose at 23:00 h. The rest of the adrenal hormonal workup was within normal ranges (aldosterone: 275 pmol/L and renin: 15 mIU/L). An adrenal CT was performed (Fig. 1) and exhibited a 70-mm left adrenal mass (spontaneous density: 5 HU and relative washout: 65%) and a 45-mm right adrenal mass (spontaneous density: −2 HU and relative washout: 75%). The case was discussed in a multidisciplinary team meeting, which advised to perform 18F-FDG PET-CT and 123I-Iodocholesterol scintigraphy before considering surgery. A genetic screening was performed, testing for ARMC5 and PRKAR1A pathogenic variants. View Full Size Figure 1 Adrenal CT depicting the bilateral macronodular adrenocortical hyperplasia. Citation: Endocrinology, Diabetes & Metabolism Case Reports 2021, 1; 10.1530/EDM-21-0071 Download Figure Download figure as PowerPoint slide Table 1 Serum cortisol levels at diagnosis (A), using ketoconazole monotherapy (B), using osilodrostat monotherapy (C) and using osilodrostat–ketoconazole combination therapy (D). Serum cortisol (nmol/L) 08:00 h 24:00 h 16:00 h 20:00 h 12:00 h 16:00 h A. At diagnosis 660 615 716 566 541 561 B. Ketoconazole monotherapy 741 545 502 224 242 508 C. Osilodrostat monotherapy 658 637 588 672 486 692 D. Osilodrostat–ketoconazole combination 436 172 154 103 135 274 Table 2 Salivary cortisol levels at diagnosis (A), using ketoconazole monotherapy (B), using osilodrostat monotherapy (C) and using osilodrostat-ketoconazole combination therapy (D). Salivary cortisol (nmol/L) 23:00 h 12:00 h 13:00 h Mean A. At diagnosis 47 62 38 49 B. Ketoconazole monotherapy 20 15 21 18 C. Osilodrostat monotherapy 85 90 56 77 D. Osilodrostat–ketoconazole combination 10 14 9 11 Treatment As this condition occurred during the COVID-19 pandemic, it was decided to first initiate steroidogenesis inhibitors to lower the patient’s cortisol levels. Initially, ketoconazole was initiated and uptitrated up to 1000 mg per day based on close serum cortisol monitoring, with a three-fold increase of liver enzymes and poor control of cortisol levels (Table 1). In the absence of biological efficacy, ketoconazole was replaced by osilodrostat, which was gradually increased up to 30 mg per day (10 mg at 08:00 h and 20 mg at 20:00 h) without reaching normal cortisol levels (Table 1) and with slightly increased blood pressure levels. Considering the lack of efficacy of anticortisolic drugs used as monotherapy, we combined osilodrostat (30 mg per day) to ketoconazole (600 mg per day), that is, at the last maximal tolerated dose as monotherapy of each drug. Outcome This combination of steroidogenesis inhibitors achieved a good control in cortisol levels, mimicking a physiological circadian rhythm (Table 1D). The patient did not exhibit any side effect and the control of cortisol levels resulted in a rapid improvement of hypertension, kalemia, diabetes control and disappearance of lower limbs oedema. The patient underwent a 18F-FDG PET-CT that did not exhibit any increased uptake in both adrenal masses and a 123I-Iodocholesterol scintigraphy exhibiting a highly increased uptake in both adrenal masses, predominating in the left adrenal mass (70 mm). Unilateral adrenalectomy of the larger mass was then performed, and as the immediate post-operative serum cortisol level was 50 nmol/L, hydrocortisone was administered at a dose of 30 mg per day, with a stepwise decrease to 10 mg per day over 3 months. Pathological examination exhibited macronodular adrenal hyperplasia with a 70-mm adreno cortical adenoma (WEISS score: 1 and Ki67: 1%). The genetic screening exhibited a c.1908del p.(Phe637Leufs*6) variant of ARMC5 (pathogenic), located in exon 5. The patient has no offspring and is no longer in contact with the rest of his family. Discussion The goal of the treatment with steroidogenesis inhibitors is normalization of cortisol production allowing the improvement of comorbidities (1). Most studies dealing with currently available steroidogenesis inhibitors used as monotherapy reported an overall antisecretory efficacy of roughly 50% in CS. This rate of efficacy was probably underestimated in retrospective studies due to the lack of adequate uptitration of the dose; For example, the median dose reported in the French retrospective study on ketoconazole was only 800 mg/day, while 50% of the patients were uncontrolled at the last follow-up (2). Steroidogenesis inhibitors can be combined to better control hypercortisolism. Up to now, such combinations, mainly ketoconazole and metyrapone, were mainly reported in patients with severe CS (median urinary-free Cortisol (UFC) 30- to 40-fold upper-limit norm (ULN)) and life-threatening comorbidities (3, 4). Normal UFC was reported in up to 86% of these patients treated with high doses of ketoconazole and metyrapone. Expected side effects (such as increased liver enzymes for ketoconazole or worsened hypertension and hypokalemia for metyrapone) were reported in the majority of the patients. The fear of these side effects probably explains the lack of uptitration in previous reports. Combination of steroidogenesis inhibitors has previously been described by Daniel et al. in the largest study reported on the use of metyrapone in CS; 29 patients were treated with metyrapone and ketoconazole or mitotane, including 22 in whom the second drug was added to metyrapone monotherapy because of partial efficacy or adverse effects. The final median metyrapone dose in patients controlled with combination therapy was 1500 mg per day (5). Combination of adrenal steroidogenesis inhibitors should not be reserved to patients with severe hypercortisolism. In the case shown here, the association was highly effective in terms of secretion, using lower doses than those applied as a single treatment, but without the side effects previously observed with higher doses of each treatment used as a monotherapy. To our knowledge, the association of ketoconazole and osilodrostat had never been reported. Ketoconazole blocks several enzymes of the adrenal steroidogenesis such as CYP11A1, CYP17, CYP11B2 (aldosterone synthase) and CYP11B1 (11-hydroxylase), leading to decreased cortisol and occasionally testosterone concentrations. Though liver enzymes increase is not dose-dependent, it usually happens at doses exceeding 400–600 mg per day (2). Osilodrostat blocks CYP11B1 and CYP11B2; a combination should thus allow for a complete blockade of these enzymes that are necessary for cortisol secretion. Short-term side effects such as hypokalemia and hypertension are similar to those observed with metyrapone, due to increased levels of the precursor deoxycorticosterone, correlated with the dose of osilodrostat (6). As for our patient, the occurrence of side effects should not lead to immediately switch to another drug, but rather to decrease the dose and add another cortisol-lowering drug. Moreover, considering the current cost of newly-released drugs such a strategy could lower financial costs for patients and/or society. Another point to take into account is the current COVID-19 pandemic, for which, as recently detailed in experts’ opinion (7), the main aim is to reach eucortisolism, whatever the way. Indeed patients presenting with CS usually also present with comorbidities such as obesity, hypertension, diabetes mellitus and immunodeficiency (8). Surgery, which represents the gold standard strategy in the management of CS (1, 9), might be delayed to reduce the hospital-associated risk of COVID-19, with post-surgical immunodepression and thromboembolic risks (7). Because immunosuppression and thromboembolic diathesis are common CS features (9, 10), during the COVID-19 pandemic, the use of steroidogenesis inhibitors appears of great interest. In these patients, combing steroidogenesis inhibitors at intermediate doses might allow for a rapid control of hypercortisolism without risks of major side effects if a single uptitrated treatment is not sufficient. Obviously, the management of associated comorbidities would also be crucial in this situation (11). To conclude, we report for the first time a case of CS, in the context of primary bilateral macronodular adrenocortical hyperplasia successfully treated with a well-tolerated combination of ketoconazole and osilodrostat. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Declaration of interest F C and T B received research grants from Recordati Rare Disease and HRA Pharma Rare Diseases. Frederic Castinetti is on the editorial board of Endocrinology, Diabetes and Metabolism case reports. Frederic Castinetti was not involved in the review or editorial process for this paper, on which he is listed as an author. Funding This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Patient consent Informed written consent has been obtained from the patient for publication of the case report. Author contribution statement V A was the patient’s physician involved in the clinical care and collected the data. T B and F C supervised the management of the patient. F C proposed the original idea of this case report. V A drafted the manuscript. F C critically reviewed the manuscript. T B revised the manuscript into its final version. References 1↑ Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A & Endocrine Society. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2015 100 2807–2831. (https://doi.org/10.1210/jc.2015-1818) Search Google Scholar Export Citation 2↑ Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, Caron P, Luca F, Donadille B & Vantyghem MC et al.Ketoconazole in Cushing’s disease: is it worth a try? Journal of Clinical Endocrinology and Metabolism 2014 99 1623–1630. (https://doi.org/10.1210/jc.2013-3628) Search Google Scholar Export Citation 3↑ Corcuff JB, Young J, Masquefa-Giraud P, Chanson P, Baudin E, Tabarin A. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. European Journal of Endocrinology 2015 172 473–481. (https://doi.org/10.1530/EJE-14-0913) Search Google Scholar Export Citation 4↑ Kamenický P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier JF, Brailly-Tabard S, Leboulleux S, Schlumberger M & Baudin E et al.Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism 2011 96 2796–2804. (https://doi.org/10.1210/jc.2011-0536) Search Google Scholar Export Citation 5↑ Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert K, Chortis V, Cuthbertson DJ, Daousi C & Rajeev SP et al.Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients. Journal of Clinical Endocrinology and Metabolism 2015 100 4146–4154. (https://doi.org/10.1210/jc.2015-2616) Search Google Scholar Export Citation 6↑ Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, Gu F, Auchus R, Leelawattana R & Lee EJ et al.Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet: Diabetes and Endocrinology 2020 8 748–761. (https://doi.org/10.1016/S2213-8587(2030240-0) Search Google Scholar Export Citation 7↑ Newell-Price J, Nieman LK, Reincke M, Tabarin A. ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of Cushing’s syndrome. European Journal of Endocrinology 2020 183 G1–G7. (https://doi.org/10.1530/EJE-20-0352) Search Google Scholar Export Citation 8↑ Kakodkar P, Kaka N, Baig MN. A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19). Cureus 2020 12 e7560. (https://doi.org/10.7759/cureus.7560) Search Google Scholar Export Citation 9↑ Pivonello R, De M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocrine Reviews 2015 36 385–486. (https://doi.org/10.1210/er.2013-1048) Search Google Scholar Export Citation 10↑ Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The immune system in Cushing’s syndrome. Trends in Endocrinology and Metabolism 2020 31 655–669. (https://doi.org/10.1016/j.tem.2020.04.004) Search Google Scholar Export Citation 11↑ Pivonello R, Ferrigno R, Isidori AM, Biller BMK, Grossman AB, Colao A. COVID-19 and Cushing’s syndrome: recommendations for a special population with endogenous glucocorticoid excess. Lancet: Diabetes and Endocrinology 2020 8 654–656. (https://doi.org/10.1016/S2213-8587(2030215-1) Search Google Scholar Export Citation From https://edm.bioscientifica.com/view/journals/edm/2021/1/EDM21-0071.xml?body=fullHtml-9967
  6. Cushing’s disease is a progressive pituitary disorder in which there is an excess of cortisol in the body. While the disease can be treated surgically, this option is not possible for all patients. This is one of the approved medications that assist in controlling cortisol levels in people with Cushing’s disease. Recorlev Recorlev was approved by the FDA in December 2021 to treat those Cushing’s patients for whom surgery is not a choice or has failed to lower cortisol levels. The medication is an oral cortisol synthesis inhibitor that prevents the adrenal glands — sitting atop the kidneys — from producing too much cortisol, thereby easing Cushing’s symptoms. Recorlev (levoketoconazole) is a treatment that Strongbridge Biopharma — now acquired by Xeris Pharmaceuticals — developed for endogenous Cushing’s syndrome. Endogenous Cushing’s is a form of the disease in which symptoms occur because the body produces too much cortisol. Abnormally high cortisol levels in Cushing’s syndrome may be primarily due to a tumor in the brain’s pituitary gland — a type of the condition called Cushing’s disease. The first treatment option is surgery to remove those tumors. However, in some patients, this procedure is not an option or is ineffective at lowering cortisol levels. Recorlev was approved by the U.S. Food and Drug Administration (FDA) in December 2021 to treat those Cushing’s patients for whom surgery is not a choice or has failed to lower cortisol levels. How does Recorlev works? Cortisol plays several important roles in the body, including regulating salt and sugar levels, blood pressure, inflammation, breathing, and metabolism. Too much cortisol, however, throws the body off balance, causing a wide range of symptoms, such as obesity, high blood sugar levels, bone problems, and fatigue. Recorlev is an oral cortisol synthesis inhibitor that prevents the adrenal glands — sitting atop the kidneys — from producing too much cortisol, thereby easing Cushing’s symptoms. Recorlev in clinical trials Recorlev’s approval was mainly supported by data from two Phase 3 clinical trials: one called SONICS (NCT01838551) and the other LOGICS (NCT03277690). SONICS was a multicenter, open-label, three-part trial that evaluated the safety and effectiveness of Recorlev in 94 patients with endogenous Cushing’s syndrome who were not candidates for radiation therapy or surgery, and whose cortisol levels in the urine were at least 1.5 times higher than normal. Top-line data from SONICS revealed that nearly a third of patients saw their urinary cortisol levels drop to a normal range after six months of maintenance treatment with Recorlev, without requiring any dose increments in that period of time. A subgroup analysis of the study also showed Recorlev helped control cortisol and blood sugar levels in patients with both Cushing’s and diabetes. The study also showed that Recorlev was able to lessen symptoms, ease depression, and improve patients’ quality of life. LOGICS was a double-blind, randomized, withdrawal and rescue study that assessed the safety, efficacy, and pharmacological properties of Recorlev in patients with endogenous Cushing’s syndrome who had previously participated in SONICS, or who had never been treated with Recorlev. After a period of taking Recorlev, some participants were switched to a placebo while others remained on the medication. This design allowed researchers to assess the effects of treatment withdrawal. According to patients who stopped using Recorlev and moved to a placebo saw their urine cortisol levels rise in response to the lack of treatment, compared with those who remained on Recorlev. Additional data from the study also showed that patients who switched to a placebo lost Recorlev’s cholesterol-lowering benefits. Safety data from an ongoing open-label Phase 3 extension study called OPTICS (NCT03621280) also supported Recorlev’s approval. This trial, which is expected to conclude in June 2023, is designed to assess the long-term effects of Recorlev in patients who completed one or both previous studies, for up to three years. Other details Recorlev’s starting dose is 150 mg twice daily and should be taken orally with or without food. The maximum recommended dose is 1,200 mg per day, given as 600 mg twice daily. The most common side effects associated with Recorlev include nausea, vomiting, increased blood pressure, abnormally low blood potassium levels, fatigue, headache, abdominal pain, and unusual bleeding. Liver enzymes should be monitored before and during the treatment since this therapy can cause hepatotoxicity, or liver damage, in some individuals. For this reason, it is contraindicated in people with liver diseases such as cirrhosis. Recorlev should be immediately stopped if signs of hepatotoxicity are observed. Recorlev also can influence heartbeat. As such, patients with certain heart conditions should be closely monitored before and during treatment. Hypocortisolism, or lower-than-normal levels of cortisol, also may occur during treatment with Recorlev. For this reason, patients should have their cortisol levels closely monitored, and lessen or interrupt treatment if necessary. Recorlev interacts with medicines on which certain liver enzymes act, such as CYP3A4. Treatment also is an inhibitor of P-gp, OCT2, and MATE1, which are transporters of certain medicines. The use of Recorlev with these medicines may increase the risk of adverse reactions.
  7. Authors Nisticò D , Bossini B, Benvenuto S, Pellegrin MC, Tornese G Received 29 October 2021 Accepted for publication 28 December 2021 Published 11 January 2022 Volume 2022:18 Pages 47—60 DOI https://doi.org/10.2147/TCRM.S294065 Checked for plagiarism Yes Review by Single anonymous peer review Peer reviewer comments 2 Editor who approved publication: Professor Garry Walsh Download Article [PDF] Daniela Nisticò,1 Benedetta Bossini,1 Simone Benvenuto,1 Maria Chiara Pellegrin,1 Gianluca Tornese2 1University of Trieste, Trieste, Italy; 2Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy Correspondence: Gianluca Tornese Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste, 34137, Italy Tel +39 040 3785470 Email gianluca.tornese@burlo.trieste.it Abstract: Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason. Keywords: adrenal gland, primary adrenal insufficiency, central adrenal insufficiency, Addison disease, children, adrenal crisis, hydrocortisone Introduction Primary adrenal insufficiency (PAI) is a condition resulting from impaired steroid synthesis, adrenal destruction, or abnormal gland development affecting the adrenal cortex.1 Acquired primary adrenal insufficiency is termed Addison disease. Central adrenal insufficiency (CAI) is caused by an impaired production or release of adrenocorticotropic hormone (ACTH). It can originate either from a pituitary disease (secondary adrenal insufficiency) or arise from an impaired release of corticotropin-releasing hormone (CRH) from the hypothalamus (tertiary adrenal insufficiency). An underlying genetic cause should be investigated in every case of adrenal insufficiency (AI) presenting in the neonatal period or first few months of life, although AI is relatively rare at this age (1:5.000–10.000).2 Physiology of the Adrenal Gland The adrenal cortex consists of three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis, responsible for aldosterone, cortisol, and androgens synthesis, respectively.3 Aldosterone production is under the control of the renin-angiotensin system, while cortisol is regulated by the hypothalamic-pituitary-adrenal axis (HPA).4 This explains why patients affected by CAI only manifest glucocorticoid deficiency while mineralocorticoid function is spared. CRH is secreted from the hypothalamic paraventricular nucleus into the hypophyseal-portal venous system in response to light, stress, and other inputs. It binds to a specific cell-surface receptor, the melanocortin 2 receptor, stimulating the release of preformed ACTH and the de novo transcription of the precursor molecule pro-opiomelanocortin (POMC). ACTH is derived from the cleavage of POMC by proprotein convertase-1.5–9 ACTH binds to steroidogenic cells of both the zona fasciculata and reticularis, activating adrenal steroidogenesis. It also has a trophic effect on adrenal tissue; therefore, ACTH deficiency determines adrenocortical atrophy and decreases the capacity to secrete glucocorticoids. Circulating cortisol is 75% bound to corticosteroid-binding protein, 15% to albumin, and 10% free. The endogenous production rate is estimated between 6 and 10 mg/m2/day, even though it depends on age, gender, and pubertal development. Glucocorticoids have multiple effects: they regulate immune, circulatory, and renal function, influence growth, development, energy and bone metabolism, and central nervous system activity. Several studies reported higher cortisol plasma concentrations in girls than in boys and younger children.3,4,8 Cortisol secretion follows a circadian and ultradian rhythm according to varying amplitudes of ACTH pulses. Pulses of ACTH and cortisol occur every 30–120 minutes, are highest at about the time of waking, and decline throughout the day, reaching a nadir overnight.3,8,9 This pattern can change in the presence of serious illness, major surgery, and sleep deprivation. During stressful situations, glucocorticoid secretion can increase up to 10-fold to enhance survival through increased cardiac contractility and cardiac output, sensitivity to catecholamines, work capacity of the skeletal muscles, and availability of energy stores.3 The interaction between the hypothalamus and the two endocrine glands is essential to maintain plasma cortisol homeostasis (Figure 1). Cortisol exerts double-negative feedback on the HPA axis. It acts on the hypothalamus and the corticotrophin cells of the anterior pituitary, reducing CRH and ACTH synthesis and release.6 ACTH inhibits its secretion through a feedback effect mediated at the level of the hypothalamus.3 Increased androgen production occurs in the case of cortisol biosynthesis enzymatic deficits. Figure 1 The hypothalamic–pituitary–adrenal axis. Primary Adrenal Insufficiency PAI affects 10–15 per 100,000 individuals and recognizes different classes of genetic causes (Table 1). Congenital adrenal hyperplasia (CAH) is the main cause of PAI in the neonatal period, being included among the disorders of steroidogenesis secondary to deficits in enzymes. It has an autosomal recessive transmission.1,10,11 The estimated incidence ranges between 1:10,000 and 1:20,000 births. CAH phenotype depends on disease-causing mutations and residual enzyme activity. 21-hydroxylase deficiency (21OHD) accounts for more than 90% of cases, 21-hydroxylase converts cortisol and aldosterone precursors, respectively 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and progesterone to deoxycortisone. Less frequent forms of CAH include 11 β -hydroxylase deficiency (11BOHD, 8% of cases), 17α-hydroxylase/17–20 lyase deficiency (17OHD), 3β-hydroxysteroid dehydrogenase deficiency (3BHDS), P450 oxidoreductase deficiency (PORD).12 Steroidogenesis may also be impaired by steroidogenic acute regulatory (StAR) protein deficiency, which is involved in cholesterol transport into mitochondria, or P450 cytochrome side-chain cleavage (P450scc) deficiency, that converts cholesterol into pregnenolone.12,13 Of these conditions, 21OHD and 11BOHD only affect adrenal steroidogenesis, whereas the other deficits also impact gonadal steroid production. In classic CAH, enzyme activity can be absent (salt-wasting form) or low (1–2% enzyme activity, simple virilizing form). The salt-wasting form is the most severe and affects 75% of patients with classic 21OHD.1,10,12,14 Non-classic CAH (NCCAH) is more prevalent than the classic form, in which there is 20–50% of residual enzymatic activity. Two-thirds of NCCAH individuals are compound heterozygotes with different CYP21A2 mutations in two different alleles (classic severe mutation plus mild mutation in two different alleles or homozygous with two mild mutations). Notably, 70% of NCCAH patients carry the point mutation Val281Leu. Table 1 Causes of Primary Adrenal Insufficiency (PAI) Central Adrenal Insufficiency CAI incidence is estimated between 150 and 280 per million, and it should be suspected when mineralocorticoid function is preserved. When, rarely, isolated is due to iatrogenic HPA suppression secondary to prolonged glucocorticoid therapy or the removal of an ACTH- or cortisol-producing tumor (Cushing syndrome).15 Defects in POMC,16 characterized by red or auburn-haired children, pale skin (due to melanocyte stimulating hormone [MSH] - deficiency) and hyperphagia later in life, and in transcription factor TPIT,17 which regulates POMC synthesis in corticotrope cells, are the two leading genetic causes of isolated ACTH deficiency (Table 2). Mainly, it occurs as part of complex syndromes in which a combined multiple pituitary hormone deficiency (CMPD) is associated with craniofacial and midline defects, such as Prader-Willi syndrome, CHARGE syndrome, Pallister-Hall syndrome (anatomical pituitary abnormalities), white vanishing matter disease (progressive leukoencephalopathy).5 Individuals with an isolated pituitary deficiency, usually a growth hormone deficiency (GHD), may develop multiple pituitary hormone deficiencies over the years. Therefore, excluding a latent CAI at GHD onset and periodically monitoring of HPA axis is of utmost importance. Notably, cortisol reduction secondary to an increased basal metabolism when starting GHD or thyroxin substitutive therapy may unleash a misdiagnosed CAI. CMPD can be caused by several defective genes, such as GLI1, LHX3, LHX4, SOX2, SOX3, HESX1: in such cases, hypoglycemia or small penis with undescended testes may respectively suggest concomitant GH and gonadotropins deficits.18 Table 2 Causes of Central Adrenal Insufficiency (CAI) Clinical Manifestations of Adrenal Insufficiency AI is an insidious diagnosis presenting non-specific symptoms and may be mistaken with other life-threatening endocrine conditions (septic shock unresponsive to inotropes or recurrent sepsis, acute surgical abdomen).1,19 Children can be initially misdiagnosed as having sepsis, metabolic disorders, or cardiovascular disease, highlighting the need to consider adrenal dysfunction as a differential diagnosis for an unwell or deteriorating infant. With age-related items, clinical features depend on the type of AI (primary or central) and could manifest in an acute or chronic setting (Table 3). Table 3 Features of Isolated Adrenal Insufficiency in Pediatric Age Clinical signs of PAI are based on the deficiency of both gluco- and mineralocorticoids. Signs due to glucocorticoid deficiency are weakness, anorexia, and weight loss. Hypoglycemia with normal or low insulin levels is frequent and often severe in the pediatric population. Mineralocorticoid deficiency contributes to hyponatremia, hyperkalemia, acidosis, tachycardia, hypotension, and salt craving. The lack of glucocorticoid-negative feedback is responsible for the elevated ACTH levels. The high levels of ACTH and other POMC peptides, including the various forms of MSH, cause melanin hypersecretion, stimulating mucosal and cutaneous hyperpigmentation. Searching for an increased pigmentation may represent an essential diagnostic tool since all the other symptoms of PAI are non-specific. However, hyperpigmentation is variable, dependent on ethnic origin, and more prominent in skin exposed to sun and in extension surface of knees, elbows, and knuckles.15 In autoimmune PAI, vitiligo may be associated with hyperpigmentation. In the classic CAH simple virilizing form, salt wasting is absent due to the presence of aldosterone production. In males, diagnosis typically occurs between 3 and 4 years of age with pubarche, accelerated growth velocity, and advanced bone age at presentation.1,10,12,14 NCCAH may occur in late childhood with signs of hyperandrogenism (premature pubarche, acne, adult apocrine odor, advanced bone age) or be asymptomatic. In adolescents and adult women, conditions of androgen excess (acne, oligomenorrhea, hirsutism) may underlie an NCCAH.20,21 The clinical presentation of CAI may be more complex when caused by an underlying central nervous system disease or by CMPD. In the case of a pituitary or hypothalamic tumor, patients may present headache, vomiting, visual disturbances, short stature, delayed or precocious puberty. In the case of CMPD, manifestations vary considerably and depend on the number and severity of the associated hormonal deficiencies. In CAI, aldosterone production is spared, which means that serum electrolytes are usually normal. However, cortisol contributes to regulating free water excretion, so patients with CAI are at risk for dilutional hyponatremia, with normal serum potassium levels. Since adrenal androgen secretion is under the control of ACTH, girls with ACTH deficiency may present light pubic hair. Patients with partial and isolated ACTH defects can be “asymptomatic”, and adrenal crisis appears during stress or in case of major illness (high fever, surgery). The acute adrenal crisis is a life-threatening condition in all ages. Patients present with profound malaise, fatigue, nausea, vomiting, abdominal or flank pain, muscle pain or cramps, and dehydration, which lead to hypotension, shock, and metabolic acidosis. Hyponatremia and hyperkalemia are less common in CAI than in PAI, but possible in acute AI. Severe hypoglycemia causes weakness, pallor, sweatiness, and impaired cognitive function, including confusion, loss of consciousness, and coma. Immediate treatment is required (see below). Children and adolescents affected by autoimmune primary adrenal insufficiency develop a chronic AI, with an insidious onset and slow progress to an acute adrenal crisis over months or even years. Initial symptoms are decreased appetite, anorexia, nausea, abdominal pain, unintentional weight loss, lethargy, headache, weakness, and fatigue, with prominent pain in the joints and muscles. Due to salt loss through the urine and the subsequent reduction in blood volume, blood pressure decreases, and orthostatic hypotension develops together with salt craving. An increased risk of infection in AI patients is reported only in those exposed to glucocorticoids. However, in APECED (Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal-Dystrophy) patients, there is an increased risk of candidiasis and splenic atrophy increases the likelihood for severe infections. In neonates, AI classically presents with failure to thrive and hypoglycemia, commonly severe and associated with seizures. The condition can be life-threatening and, if misdiagnosed, may result in coma and unexplained neonatal death. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice with persistently raised serum liver enzymes. The cholestasis can be resolved within ten weeks of correct treatment. StAR deficiency and P450scc cause salt-losing AI with female external genitalia in genetically male neonates.22 In the classic CAH salt-wasting form, the mineralocorticoid deficiency presents with the adrenal crisis at 10–20 days of life. Females show atypical genitalia with signs of virilization (clitoral enlargement, labial fusion, urogenital sinus), whereas males have normal-appearing genitalia, except for subtle signs as scrotal hyperpigmentation and enlarged phallus.1,10,12,14 Neonates with CMPD may display non-specific symptoms including hypoglycemia, lethargy, apnea, poor feeding, jaundice, seizures, hyponatremia without hyperkalemia, temperature and hemodynamic instability, recurrent sepsis, and poor weight gain. A male with hypogonadism may have undescended testes and micropenis. Infants with optic nerve hypoplasia or agenesis of the corpus callosum may present with nystagmus. Furthermore, infants with midline defects may have various neuro-psychological problems or sensorineural deafness. Genetic Disorders and Other Conditions at Increased Risk for Adrenal Insufficiency Among the cholesterol biosynthesis disorder, there is the Smith-Lemli-Opitz syndrome,23 where microcephaly, micrognathia, low-set posteriorly rotated ears, syndactyly of the second and third toes, and atypical genital may, although rarely, combine with AI; this autosomal recessive disorder is due to defective 7-dehydrocholesterol reductase so that elevated 7-dehydrocholesterol is diagnostic. In lysosomal acid lipase A deficiency,24 AI is due to calcification of the adrenal gland as a result of the accumulation of esterified lipids; in infantile form, that is Wolman disease, hepatosplenomegaly with hepatic fibrosis and malabsorption lead to death in the first year of life, if not treated with enzyme replacement therapy such as sebelipase alfa.25 Adrenal development may be impaired in X-linked congenital adrenal hypoplasia (AHC),13,26 a disorder caused by defective nuclear receptor DAX-1, presenting with salt-losing AI in infancy in approximately half of the cases, but also later in childhood or adolescence with two other key features such as hypogonadotropic hypogonadism and impaired spermatogenesis. Two syndromes combine adrenal hypoplasia with intrauterine growth restriction (IUGR): in IMAGe syndrome,27 caused by CDKN1C gain-of-function mutations, IUGR and AI present with metaphyseal dysplasia and genitourinary anomalies; MIRAGE syndrome28 is instead characterized by myelodysplasia, infections, genital abnormalities, and enteropathy, as a result of gain-of-function mutations in SAMD9, with elevated mortality rates. In some other conditions, AI is due to ACTH resistance. Familial Glucocorticoid Deficiency type 1 (FGD1)13,29 and type 2 (FGD2)30 derive from defective ACTH receptor (MC2R) or its accessory protein MRAP, and both present with early glucocorticoid insufficiency (hypoglycemia, prolonged jaundice) and pronounced hyperpigmentation; there is usually an excellent response to cortisol replacement therapy, even though ACTH levels remain elevated. In Allgrove or Triple-A Syndrome,13,31 defective Aladin protein (an acronym for alacrimia-achalasia-adrenal insufficiency) leads to primary ACTH-resistant adrenal insufficiency with achalasia and absent lacrimation, often combined with neurological dysfunction, either peripheral, central, or autonomic. It is an autosome recessive condition, phenotypically characterized by microcephaly, short stature, and skin hyperpigmentation.32,33 Among metabolic disorders associated with AI, Sphingosine-1-Phosphate Lyase (SGPL1) Deficiency34 is a sphingolipidosis with various features such as steroid-resistant nephrotic syndrome, primary hypothyroidism, undescended testes, neurological impairment, lymphopenia, ichthyosis; interestingly, in cases where nephrotic syndrome develops before AI, the latter may be masked by glucocorticoid treatment. Adrenoleukodystrophy (ALD)35–37 is an X-linked recessive proximal disorder of beta-oxidation due to defective ABCD1, where the accumulation of very-long-chain fatty acids (VLCFA) affects in almost all cases adrenal gland among other tissues. Most patients present with progressive neurological impairment, but in some, AI is the only (approximately 10%) or first manifestation, so that every unexplained AI in boys should receive plasma VLCFA evaluation to diagnose ALD and reduce cerebral involvement through a low VLCFAs diet (Lorenzo’s oil) and allogeneic bone marrow transplantation. Early disease-modifying therapies have been developed. Gene therapy adds new functional copies of the ABCD1 gene in hematopoietic stem cells through a lentiviral vector reinfusing the modified cells in the patient’s bloodstream. Recent trials show encouraging results.38 In Zellweger syndrome, caused by mutations in peroxin genes (PEX), peroxisomes are absent, and disease presentation occurs in the neonatal period, with low survival rates after the first year of life. Finally, mitochondrial disorders have been described to occasionally develop AI: Pearson syndrome (sideroblastic anemia, pancreatic dysfunction), MELAS syndrome (encephalopathy with stroke-like episodes), and Kearns-Sayre syndrome (external ophthalmoplegia, heart block, retinal pigmentary changes) belong to this class.39 Autoimmune pathogenesis (Addison disease) accounts for approximately 15% of cases of primary AI in children, in contrast with adolescents and adults where it is the most common mechanism; half of these children present other glands involvement as well. Two syndromes recognize specific combinations: in Autoimmune Polyglandular Syndrome Type 1 (APS1, or APECED)40 defective autoimmune regulator AIRE causes AI, hypoparathyroidism, hypogonadism, malabsorption, chronic mucocutaneous candidiasis; APS2 usually present later in life (third-fourth decades) with AI, thyroiditis, and type 1 diabetes mellitus (T1DM). Antibodies against 21-hydroxylase enzyme are the hallmark of APS. Apart from a genetic disorder, a strong link between autoimmune conditions and autoimmune primary AI has been established, with more than 50% of patients with the latter also having one or more other autoimmune endocrine disorders; on the other hand, only a few patients with T1DM or autoimmune thyroiditis or Graves’ disease develop AI. As an example, in a study of 629 patients with T1DM, only 11 (1.7%) presented 21-hydroxylase autoantibodies, with three of them having AI.41 Nevertheless, these patients are to be considered at increased risk for a condition that is potentially fatal yet easy to diagnose and treat; that is why it is reasonable to screen for autoimmune AI at least patients with T1DM, significantly if associated with DQ8 HLA combined with DRB*0404 HLA alleles, who have been observed to develop AI in 80% of cases if also 21-hydroxylase autoantibodies positive.42 Regarding immunological disruption, the link with celiac disease is instead well established: celiac patients have an 11-fold increased risk for AI, while in a study, 6 of 76 patients with AI had celiac disease, so that mutual evaluation should be granted in these patients.43,44 Subclinical Adrenal Insufficiency Subclinical AI is a particularly insidious challenge for a pediatric endocrinologist. It represents the preclinical stage of Addison disease when 21-hydroxylase autoantibodies are already detectable but still absent from evident symptoms. 21-hydroxylase autoantibodies positivity carries a greater risk to develop overt AI in children than in adults: in a study, estimated risk was 100% in children versus 32% in adults on a medium six-year period of follow-up.45 As the adrenal crisis is a potentially lethal condition, it is essential to recognize and adequately manage subclinical AI. Although asymptomatic by definition, subclinical AI may present with non-specific symptoms such as fatigue, lethargy, gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation), hypotension; physical or psychosocial stresses may sometimes exacerbate these symptoms. When symptoms lack, subclinical AI may be identified thanks to the co-occurrence with other autoimmune endocrinopathies.46 21-hydroxylase autoantibodies titer is considered a marker of autoimmune activity and correlates with disease progression.47 Other reported risk factors for the disease evolution include young age, male sex, hypoparathyroidism or candidiasis coexistence, increased renin activity, or an altered synacthen test with normal baseline cortisol and ACTH.45 ACTH elevation has been reported as the best predictor of progression to the clinical stage in 2 years (94% sensitivity and 78% specificity).48 Management of patients with subclinical AI should include serum cortisol, ACTH, renin measurement, and a synacthen test. If normal, cortisol and ACTH should be repeated in 12–18 months, while synacthen test every two years. After synacthen test results are subnormal, cortisol and ACTH should be assessed every 6–9 months if ACTH remains in range or every six months if ACTH becomes elevated.49 In the latter case, therapy with hydrocortisone should be started.19 This strategy will prevent acute crises and possibly improve the quality of life in patients reporting non-specific symptoms. Diagnosis Laboratory evaluation of a stable patient with suspected AI should start with combined early morning (between 6 and 8 AM) serum cortisol and ACTH measurements (Figure 2). Figure 2 Diagnostic algorithm for adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually challenging to interpret: circadian cortisol rhythm is highly variable and morning peak is unpredictable; morning cortisol levels in children with diagnosed AI may range up to 706 nmol/L (97th percentile); several factors, such as exogenous estrogens, may alter total serum cortisol values by influencing the free cortisol to cortisol binding globulin or albumin-bound cortisol ratio.7 Significant variability is also observed depending on the specific type of cortisol assay; therefore, it is recommended to check the reference ranges with the laboratory. Mass spectrometry analysis and the new platform methods (Roche Diagnostics Elecsys Cortisol II)50 have more specificity because it detects lower cortisol concentrations than standard immunoassays.15 Low serum cortisol with normal or low ACTH levels is compatible with CAI. In such cases, morning serum cortisol levels below 3 µg/dL (83 nmol/L) best predict AI, while greater than 13 µg/dL (365 nmol/L) values tend to exclude it.51 This is why in most cases, a dynamic test is required for diagnosis and has been introduced to assess the hypothalamic-pituitary-adrenal (HPA) axis in case of intermediate values.5 The insulin tolerance test (ITT) is considered the gold standard for CAI diagnosis as hypoglycemia results in an excellent HPA axis activation; moreover, it allows simultaneous growth hormone evaluation in patients with suspected CPHD. Serum cortisol is measured at baseline and 15, 30, 45, 60, 90, and 120 minutes after intravenous administration of 0.1 UI/Kg regular insulin; the test is valid if serum glucose is reduced by 50% or below 2.2 mmol/L (40 mg/dL).52 CAI is diagnosed for a <20 µg/dL (550 nmol/L) cortisol value at its peak.15 Hypoglycemic seizures and hypokalemia (due to glucose infusion) are the main risks of this test so that it is contraindicated in case of a history of seizures or cardiovascular disease. Glucagon stimulation test (GST, 30 µg/Kg up to 1 mg i.m. glucagon with cortisol measurements every 30 min for 180 min) allows both CAI and growth hormone deficiency evaluation as well but is characterized by frequent gastrointestinal side effects and poor specificity.8 Metyrapone is an 11-hydroxylase inhibitor, thereby decreasing cortisol synthesis and removing its negative feedback on ACTH release. Overnight metyrapone test is based on oral administration of 30 mg/Kg metyrapone at midnight, and 11-deoxycortisol measurement on the following morning: in case of CAI, its level will not reach 7 µg/dL (200 nmol/L). This test may, however, induce an adrenal crisis so that it is rarely performed. Given their safety profile and accuracy, corticotropin analogs such as tetracosactrin (Synacthen®) or cosyntropin (Cortrosyn®) are recommended as first-line stimulation tests. Nevertheless, false-negative results are probable in the case of recent or moderate ACTH deficiency, which would not have induced adrenal atrophy. The standard dose short synacthen test (SDSST) is based on a 250 µg Synacthen vial administration with serum cortisol measurement at baseline and 30 and 60 minutes after. CAI is diagnosed if peak cortisol level is <16 µg/dL (440 nmol/L), or excluded if >39 µg/dL (1076 nmol/L). However, the cut-offs for both the new platform immunoassay and mass spectrometry serum cortisol assays are 13.5 to 14.9 mcg/dL (373 to 412 nmol/L).53 The 250 µg Synacthen dose is considered a supraphysiological stimulus since it is 500 times greater than the minimum ACTH dose reported to induce a maximal cortisol response (500 ng/1.73 m2). The low dose short synacthen test (LDSST) has been introduced as a more sensitive first-line test in children greater than two years.54 The recommended dose is 1 µg55, which is contained in 1 mL of the solution obtained by diluting a 250 µg vial into 250 mL saline. Serum cortisol level is then measured at baseline and after 30 minutes, resulting in diagnose of CAI if <16 µg/dL (440 nmol/L), otherwise ruling it out if >22 µg/dL (660 nmol/L). Using these thresholds, LDSST is more precise than SDSST in children, with an area under the ROC curve of 0.99 (95% CI 0.98–1.00).56 LDSST has not been validated in acutely ill patients, pituitary acute disorders or surgery or radiation therapy, and impaired sleep-wake cycle. Patients with an indeterminate LDSST result should be furtherly studied with ITT or metyrapone test. Finally, the CRH test is based on 1 µg/Kg human CRH (Ferring®) administration and may differentiate secondary from tertiary AI, but its thresholds are still not precisely defined.57 Once CAI is diagnosed, other pituitary hormones should be assessed (prolactin, IGF1, LH, FSH, fT4, TSH), and an MRI of the pituitary region should be performed to exclude neoplastic or infiltrative processes. Primary adrenal insufficiency (PAI) should be suspected in case of low serum cortisol with elevated ACTH levels. When hypocortisolemia has been confirmed, ACTH levels >66 pmol/L or greater than twice the upper limit best predict PAI. Nevertheless, a confirmatory dynamic test is always recommended for diagnosis.19 Given the comparable accuracy between standard and low dose SST reported in these patients, SDSST is recommended as the most feasible test.58 Moreover, suspected PAI cases should receive plasma renin activity or direct renin and aldosterone assessment to evaluate mineralocorticoid deficiency. Etiologic work-up of confirmed PAI should start from 21-hydroxylase antibodies assessment: if positive, differential diagnosis will include Addison disease and APS1 or APS2. Adrenal autoantibody negative patients should instead be screened for CAH by measuring 17-hydroxyprogesterone, ALD (if young male) by assessing VLCFA, and tuberculosis if endemic; adrenal glands imaging will complete the work-up in order to exclude infection, hemorrhage, or tumor.6 While universal newborn screening is already implemented for CAH in many countries, allowing a timely replacement therapy, basal salivary cortisol, and salivary cortisone measurements could improve CAI screening in the future: this technique is simple, cost-effective, and independent of binding proteins.15 Treatment All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy. Individuals with PAI also require mineralocorticoids replacement, together with salt intake as required (Table 4). Otherwise, guidelines do not recommend androgen replacement.5,9,19 Table 4 Management of Adrenal Insufficiency (AI) Oral hydrocortisone is the first-choice replacement treatment in children due to its short half-life, rapid peak in plasma concentration, lower potency, and fewer adverse effects than prednisolone and dexamethasone.5,8 Based on endogenous production, dosing replacement regimens vary from 7.5 to 15 mg/m2/day, divided into two, three, or four doses.19 The first and largest dose should be taken at awakening, the next in the early afternoon to avoid sleep disturbances. Small and frequent dosing mimic the physiological rhythm of cortisol secretion, but high peak cortisol levels after drug assumption and prolonged periods of hypocortisolemia between doses are described.8,9 Some children experience low cortisol concentrations and symptoms of cortisol insufficiency (eg, fatigue, nausea, headache) despite modifications in dosing. This cohort of patients can take advantage of using a modified-release hydrocortisone formulation, such as Chronocort® and Plenadren®. Plenadren®, approved for adults, consists of a coating of hydrocortisone released rapidly, followed by a slow release of hydrocortisone from the tablet center. It is available as 5 and 20 mg tablets. Park et al demonstrate smoother cortisol profiles and normal growth and weight gain patterns using Plenadren® in children.59 In a few cases, the continuous subcutaneous infusion of hydrocortisone using insulin pump technology proved to be a feasible, well-tolerated and safe option for selected patients with poor response to conventional therapy.19 Monitoring glucocorticoid therapy is based on growth, weight gain, and well-being. Cortisol measurements are usually not useful, apart from cases when a discrepancy between daily doses and patient symptoms exists.15 The concomitant use of hydrocortisone and CYP3A4 inducers, such as Rifampicin, Phenytoin, Carbamazepine, requires an increased dose of glucocorticoids. Conversely, the inhibition of CYP3A4 impairs hydrocortisone metabolism.5 Mineralocorticoid replacement is unnecessary if the patient has a normal renin-angiotensin-aldosterone axis and, hence, normal aldosterone secretion, as well as in CAI. By contrast, patients with PAI and confirmed aldosterone deficiency need fludrocortisone at the dosage of 0.1–0.2 mg/day when given together with hydrocortisone, which has some mineralocorticoid activity. When using other synthetic glucocorticoids for replacement, higher fludrocortisone doses may be needed. Infants younger than one year should also be supplemented with sodium chloride due to their relatively low dietary sodium intake and relative renal resistance to mineralocorticoids. The dose is approximately 1 gram (17 mEq) daily.19 Surgery and anesthesia increase the glucocorticoid requirement during the pre-, intra-, and post-operative periods (Table 4). All children with AI should receive an intravenous dose of hydrocortisone at induction (2 mg/kg for minor or major surgery under general anesthesia). For minor procedures or sedation, the child should receive a double morning dose of hydrocortisone orally.60 Adrenal crisis is a life-threatening condition, treatment is effective if administered promptly, and it must not be delayed for any reason. Hydrocortisone should be administered as soon as possible with an intravenous bolus of 4 mg/kg followed by a continuous infusion of 2 mg/kg/day until stabilization. In the alternative, it can be administered as a bolus every four hours intravenous or intramuscular. In difficult peripheral venous access, the intramuscular route must be used as the first choice. In order to counteract hypotension, a bolus of normal saline 0.9% should be given at a dose of 20 mL/kg; it can repeat up to a total of 60 mL/kg within one hour for shock. If there is hypoglycemia, 10% dextrose at a 5 mL/kg dose should be administered.5,19,61,62 Patients with AI require additional doses of glucocorticoids in case of physiologic stress such as illness or surgical procedures to avoid an adrenal crisis. Home management of illness with a fever (> 38°C), vomiting or diarrhea, is based on the increase from two to three times the usual dose orally. If the child is unable to tolerate oral therapy, intramuscular injection of hydrocortisone should be administered (Table 4). Education for caregivers and patients (if adolescent) is crucial to prevent adrenal crisis. They should recognize signs and symptoms of adrenal crisis and should receive a steroid emergency card with the sick day rules. Prescribing doctors should provide for additional oral glucocorticoids and adequate training in hydrocortisone emergency self-injection. Abbreviations AI, adrenal insufficiency; PAI, primary adrenal insufficiency; CAI, central adrenal insufficiency; HPA, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; CAH, congenital adrenal hyperplasia; STAR, steroidogenic acute regulatory; 21OHD, 21-hydroxylase deficiency; 11BOHD, 11-B-hydroxylase deficiency; P450scc, P450 cytochrome side-chain cleavage deficiency; 17-OHP, 17-hydroxyprogesterone; NCCAH, non-classic congenital adrenal hyperplasia; ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acids; CMPD, combined multiple pituitary hormone deficiency; GHD, growth hormone deficiency; MSH, melanocyte stimulating hormone; IUGR, intrauterine growth restriction; APS1, autoimmune polyglandular syndrome type 1; SDSST, standard dose short synacthen test; LDSST, low dose short synacthen test. Take Home Messages In neonates and infants CAH is the commonest cause of PAI, causing almost 71.8% of cases. Adrenoleukodystrophy should be considered in any male with hypoadrenalism. Unexplained hyponatremia, hyperpigmentation and the loss of pubic and axillary hair should raise the suspicion of AI. Adrenal insufficiency can present with non-specific clinical features; therefore a single cortisol measurement should be included in the biochemical work-up of an unwell child. Patients and parents should be well-trained in adrenal crisis recognition and management. Disclosure The authors report no conflicts of interest in this work. References 1. Charmandari E, Nicolaides N, Chrousos G. Adrenal insufficiency. Lancet. 2021;383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0 2. White PC. Adrenocortical insufficiency. In: Nelson Textbook of Pediatrics. Elsevier. 2019:11575–11617. 3. White PC. Physiology of the adrenal gland. Nelson Textbook of Pediatrics. Elsevier. 2019. 4. 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Clinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassay. Clin Biochem. 2017;50(9):475–480. doi:10.1016/j.clinbiochem.2017.02.008 54. Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CGD. Tests of adrenal insufficiency. Arch Dis Child. 1999;80(4):330–333. doi:10.1136/adc.80.4.330 55. Maghnie M, Uga E, Temporini F, et al. Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur J Endocrinol. 2005;152:735–741. doi:10.1530/eje.1.01911 56. Kazlauskaite R, Maghnie M. Pitfalls in the diagnosis of central adrenal insufficiency in children. Endocr Dev. 2010;17:96e107. 57. Chanson P, Guignat L, Goichot B, et al. Group 2: adrenal insufficiency: screening methods and confirmation of diagnosis. Ann Endocrinol. 2017;78:495e511. doi:10.1016/j.ando.2017.10.005 58. Ospina N, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700 59. Park J, Das U, Didi M, et al. The challenges of cortisol replacement therapy in childhood: observations from a case series of children treated with modified-release hydrocortisone. Pediatr Drugs. 2018;20(6):567–573. doi:10.1007/s40272-018-0306-0 60. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insuf fi ciency Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia. 2020;75:654–663. doi:10.1111/anae.14963 61. Rushworth R, Torpy DJ, Falhammar H. Adrenal crisis. N Engl J Med. 2019;381(9):852–861. doi:10.1056/NEJMra1807486 62. Miller BS, Spencer SP, Geffner ME, et al. Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings. J Investig Med. 2020;68:16–25. doi:10.1136/jim-2019-000999 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF] From https://www.dovepress.com/pediatric-adrenal-insufficiency-challenges-and-solutions-peer-reviewed-fulltext-article-TCRM
  8. Millions of people are at increased risk of type 2 diabetes and high blood pressure and don't even know it, due to a hidden hormone problem in their bodies. As many as 1 in 10 people have a non-cancerous tumor on one or both of their adrenal glands that could cause the gland to produce excess amounts of the stress hormone cortisol. Up to now, doctors have thought that these tumors had little impact on your health. But a new study out of Britain has found that up to half of people with these adrenal tumors are secreting enough excess cortisol to raise their risk of diabetes and high blood pressure. Nearly 1.3 million adults in the United Kingdom alone could suffer from this disorder, which is called Mild Autonomous Cortisol Secretion (MACS), the researchers said. Anyone found with one of these adrenal tumors should be screened to see if their health is at risk, said senior researcher Dr. Wiebke Arlt, director of the University of Birmingham Institute of Metabolism and Systems Research in England. "People who are found to have an adrenal tumor should undergo assessment for cortisol excess and if they are found to suffer from cortisol overproduction they should be regularly screened for type 2 diabetes and hypertension and receive treatment if appropriate," Arlt said. These tumors are usually discovered during imaging scans of the abdomen to treat other illnesses, said Dr. André Lacroix, an endocrinologist at the University of Montreal Hospital Center, who wrote an editorial accompanying the study. Both were published Jan. 4 in the Annals of Internal Medicine. Adrenal glands primarily produce the hormone adrenaline, but they are also responsible for the production of a number of other hormones, including cortisol, Lacroix said. Cortisol is called the "fight-or-flight" hormone, and can cause blood sugar levels to rise and blood pressure to surge -- usually in response to some perceived bodily threat. Previous studies had indicated that about 1 in 3 adrenal tumors secrete excess cortisol, and an even lower number caused cortisol levels to rise so high that they affected health, researchers said in background notes. But this new study of more than 1,300 people with adrenal tumors found that previous estimates were wrong. About half of these patients had excess cortisol due to their adrenal tumors. Further, more than 15% had levels high enough to impact their health, compared to those with truly benign tumors. MACS patients were more likely to be diagnosed with high blood pressure, and were as much as twice as likely to be on three or more blood pressure medications. They also were more likely to have type 2 diabetes, and were twice as likely to require insulin to manage their blood sugar, the study found. "This study clearly shows that mild cortisol production is more frequent than we thought before, and that the more cortisol you produce, the more likely to you are to have consequences such as diabetes and hypertension," Lacroix said. About 70% of people with MACS were women, and most were of postmenopausal age, the researchers said. "Adrenal tumor-related cortisol excess is an important previously overlooked health issue that particularly affects women after the menopause," Arlt said. Lacroix agreed that guidelines should be changed so that people with adrenal tumors are regularly screened. "Everybody who is found to have an adrenal nodule larger than 1 centimeter needs to be screened to see if they're producing excess hormone or not," he said. "That's very clear." A number of medications can reduce cortisol overproduction or block cortisol action, if an adrenal tumor is found to be causing an excess of hormone. People with severe cortisol excess can even have one of their two adrenal glands removed if necessary, Lacroix said. "It is quite possible to live completely normally with one adrenal gland," he said. More information The Cleveland Clinic has more about adrenal tumors. SOURCES: Wiebke Arlt, MD, DSc, director, Institute of Metabolism and Systems Research, University of Birmingham, U.K.; André Lacroix, MD, endocrinologist, University of Montreal Hospital Center; Annals of Internal Medicine, Jan. 4, 2022 From https://consumer.healthday.com/1-4-benign-adrenal-gland-tumors-might-cause-harm-to-millions-2656172346.html
  9. Researchers in Europe say they have shown for the first time that the SARS-CoV-2 virus attacks the human stress system by limiting how our adrenal glands can respond to the threat of Covid-19. According to a study, the coronavirus targets the adrenal glands, thereby weakening the body’s ability to produce the stress hormones cortisol and adrenaline needed to help battle a serious infection. Part of the body’s defence mechanism, these glands are indispensable for our survival of stressful situations, particularly with a coronavirus infection. The research was published by a group of scientists in London, United Kingdom; Zurich, Switzerland; and Dresden and Regensburg in Germany, in the journal The Lancet Diabetes and Endocrinology last month (November 2021). “The results of our latest work now show for the first time that the virus directly affects the human stress system to a relevant extent,” says Dr Stefan Bornstein, director of the Medical Clinic and Polyclinic III and the Centre for Internal Medicine at the University Hospital in Dresden. Whether these changes directly contribute to adrenal insufficiency, or even lead to long Covid is still unclear, he says. This question must be investigated in further clinical studies. Pointing to recent research showing the effect of inhaling steroids to prevent clinical deterioration in patients with Covid-19, the researchers say certain drugs may be able to help limit this effect of the SARS-CoV-2 virus. “This evidence underlines the potentially important role for adrenal steroids in coping with Covid-19,” scientists at the University of Zurich say. The researchers analysed the data of 40 deceased Covid-19 patients in Dresden and found that their tissue samples showed clear signs of adrenal gland inflammation. From https://www.thestar.com.my/lifestyle/health/2021/12/22/how-the-sars-cov-2-virus-undermines-our-bodys-039fight039-response
  10. 6. Cushing syndrome This disorder occurs when your body makes too much of the hormone cortisol over a long period of time, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Although cortisol is notorious for driving up your stress, this hormone has other tasks on its docket, including regulating the way you metabolize food, the Mayo Clinic says. So, when you produce too much of it, it can interfere with your metabolism and cause you to gain weight, Peter LePort, M.D., a bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California, tells SELF. Beyond weight gain, symptoms of Cushing syndrome include deposits of fat-based tissue at the midsection, upper back, face, and between the shoulders, stretch marks due to rapid weight gain, thinning skin prone to bruising, increased body hair, irregular or missing periods, and more, according to the Mayo Clinic. Check out the other 12 at https://www.self.com/story/conditions-weight-gain-loss
  11. This article is based on reporting that features expert sources. Adrenal Fatigue: Is It Real? More You may have heard of so-called 'adrenal fatigue,' supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money. (GETTY IMAGES) Physicians tend to talk about 'reaching' or 'making' a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as 'perpetrating a diagnosis,' 'misdiagnosis,' 'made-up diagnosis,' 'a fallacy' and 'nonsense.' About 20 years ago, the term "adrenal fatigue" was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue. "The phenomenon emerged from the world of integrative medicine and naturopathic medicine," says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. "It has no scientific basis, and there's no merit to it as a clinical diagnosis." An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for 'adrenal fatigue' among the 331 diagnoses related either to fatigue or adrenal conditions or procedures. In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements "to treat common nonspecific symptoms due to 'adrenal fatigue,' an entity that has not been recognized as a legitimate diagnosis." The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system. Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: "Adrenal fatigue does not exist," according to review authors in the journal BMC Endocrine Disorders. Adrenal Action You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone. Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle. As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis. While some health conditions really do affect the body's cortisol-making ability, adrenal fatigue isn't among them. "There's no evidence to support that adrenal fatigue is an actual medical condition," says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. "There's no stress connection in the sense that someone's adrenal glands will all of a sudden just stop producing cortisol because they're so inundated with emotional stress." If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. "The last thing in the body that's going to fatigue are your adrenal glands," says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. "Adrenal glands are built for stress – that's what they do. Adrenal glands don't fatigue. This is made up – it's a fallacy." The idea of adrenal glands crumbling under stress is "ridiculous," Findling agrees. "In reality, if you take a person and subject them to chronic stress, the adrenal glands don't shut down at all," Findling says. "They keep making cortisol – it's a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don't stop." Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. "Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day," he says. "And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue." Saliva cortisol is a legitimate test that's frequently used in diagnosing Cushing's syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. "What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day," he says. "Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support." Loaded Supplements How do you know what you're actually getting if you buy a dietary supplement marketed for adrenal fatigue or 'adrenal support' use? To find out, researchers purchased 12 such supplements over the counter in the U.S. Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. "These results may highlight potential risks for hidden ingredients in unregulated supplements," the authors concluded. Supplements containing thyroid hormones or steroids can interact with a patient's prescribed medications or have other side effects. "Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times," Vouyiouklis Kellis says. "Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better." Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows' adrenal glands, "can shut off the pituitary," Vouyiouklis Kellis explains. "Because it's signaling to the pituitary like: Hey, you don't need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn't produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol." Some adrenal support products, such as herbal-only supplements, may be harmless. However, they're unlikely to relieve chronic fatigue. Fatigue: No Easy Answers If you're suffering from ongoing fatigue, it's frustrating. And you're not alone. "I have fatigue," Young Jr. says. "Go to the lobby any given day and say, 'Raise your hand if you have fatigue.' Most of the people are going to raise their hands. It's a common human symptom and people would like an easy answer for it. Usually there's not an easy answer. I think 'adrenal fatigue' is attractive because it's like: Aha, here's the answer." There aren't that many causes of endocrine-related fatigue, Young Jr. notes. "Hypothyroidism – when the thyroid gland is not working – is one." Addison's disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated. "In adrenal insufficiency, there is an intrinsic problem in the adrenal gland's inability to produce cortisol," Vouyiouklis Kellis explains. "That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol." Issues can arise even with necessary medications. "For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems," Vouyiouklis Kellis says. "And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol." Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency. Common symptoms of adrenal insufficiency include: Fatigue. Weight loss. Decreased appetite. Salt cravings. Low blood pressure. Abdominal pain. Nausea, vomiting or diarrhea. Muscle weakness. Hyperpigmentation (darkening of the skin). Irritability. Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland. "If the person does not have adrenal insufficiency and they're still fatigued, it's important to get to the bottom of it," Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes. "It's very important to tease out what's going on," Vouyiouklis Kellis emphasizes. "It can be multifactorial – multiple things contributing to the patient's feeling of fatigue." The blood condition anemia – a lack of healthy red blood cells – is another potential cause. "If you are fatigued, do not treat yourself," Vouyiouklis Kellis says. "Please seek a physician or a primary care provider for evaluation, because you don't want to go misdiagnosed or undiagnosed. It's very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first." SOURCES The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines. James Findling, MD Findling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. Mary Vouyiouklis Kellis, MD Vouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic. William F. Young Jr., MD Young Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?
  12. An assessment of free cortisol after a dexamethasone suppression test could add value to the diagnostic workup of hypercortisolism, which can be plagued by false-positive results, according to data from a cross-sectional study. A 1 mg dexamethasone suppression test (DST) is a standard of care endocrine test for evaluation of adrenal masses and for patients suspected to have endogenous Cushing’s syndrome. Interpretation of a DST is affected by dexamethasone absorption and metabolism; several studies suggest a rate of 6% to 20% of false-positive results because of inadequate dexamethasone concentrations or differences in the proportion of cortisol bound to corticosteroid-binding globulin affecting total cortisol concentrations. Source: Adobe Stock “As the prevalence of adrenal adenomas is around 5% to 7% in adults undergoing an abdominal CT scan, it is important to accurately interpret the DST,” Irina Bancos, MD, associate professor in the division of endocrinology at Mayo Clinic in Rochester, Minnesota, told Healio. “False-positive DST results are common, around 15% of cases, and as such, additional or second-line testing is often considered by physicians, including measuring dexamethasone concentrations at the time of the DST, repeating DST or performing DST with a higher dose of dexamethasone. We hypothesized that free cortisol measurements during the DST will be more accurate than total cortisol measurements, especially among those treated with oral contraceptive therapy.” Diverse cohort analyzed Bancos and colleagues analyzed data from adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy) and participants undergoing evaluation for hypercortisolism (n = 196; 16 women on oral contraceptives). The researchers assessed levels of post-DST dexamethasone and free cortisol, using mass spectrometry, and total cortisol, via immunoassay. The primary outcome was a reference range for post-DST free cortisol levels and the diagnostic accuracy of post-DST total cortisol level. Irina Bancos “A group that presents a particular challenge are women treated with oral estrogen,” Bancos told Healio. “In these cases, total cortisol increases due to estrogen-stimulated cortisol-binding globulin production, potentially leading to false-positive DST results. We intentionally designed our study to include a large reference group of women treated with oral contraceptive therapy allowing us to develop normal ranges of post-DST total and free cortisol, and then apply these cutoffs to the clinical practice.” Researchers observed adequate dexamethasone concentrations ( 0.1 µg/dL) in 97.6% of healthy volunteers and in 96.3% of patients. Among women volunteers taking oral contraceptives, 25.5% had an abnormal post-DST total cortisol measurement, defined as a cortisol level of at least 1.8 µg/dL. Among healthy volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not taking oral contraceptives, and 79 ng/dL for women taking oral contraceptives. Compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol level was 87.3% (95% CI, 81.7-91.7). All false-positive results occurred among patients with a post-DST cortisol level between 1.8 µg/dL and 5 µg/dL, according to researchers. Oral contraceptive use was the only factor associated with false-positive results (21.1% vs. 4.9%; P = .02). Findings challenge guidelines Natalia Genere “We were surprised by several findings of our study,” Natalia Genere, MD, instructor in medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine in St. Louis, told Healio. “First, we saw that with a standardized patient instruction on DST, we found that optimal dexamethasone concentrations were reached in a higher proportion of patients than previously reported (97%), suggesting that rapid metabolism or poor absorption of dexamethasone may play a lower role in the rate of false positives. Second, we found that measurements of post-DST total cortisol in women taking oral contraceptive therapy accurately excluded [mild autonomous cortisol secretion] in three-quarters of patients, suggesting discontinuation of oral contraceptives, as suggested in prior guidelines, may not be routinely necessary.” Genere said post-DST free cortisol performed “much better” than total cortisol among women treated with oral estrogen. Stepwise approach recommended Based on the findings, the authors suggested a sequential approach to dexamethasone suppression in clinical practice. “We recommend a stepwise approach to enhance DST interpretation, with the addition of dexamethasone concentration and/or free cortisol in cases of abnormal post-DST total cortisol,” Bancos said. “We found dexamethasone concentrations are particularly helpful when post-DST total cortisol is at least 5 µg/dL and free cortisol is helpful in a patient with optimal dexamethasone concentrations and a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL. We believe that DST with free cortisol is a useful addition to the repertoire of available testing for [mild autonomous cortisol secretion], and that its use reduces need for repetitive assessments and patient burden of care, especially in women treated with oral contraceptive therapy.” PERSPECTIVE BACK TO TOP Ricardo Correa, MD, EsD, FACE, FACP, CMQ In the evaluation of endogenous Cushing’s disease, the guideline algorithm recommends two of three positive tests — 24-hour free urine cortisol, late midnight salivary cortisol level and 1 mg dexamethasone suppression test, or DST — for diagnosing hypercortisolism. Of those tests, the most accurate to detect adrenal secretion of cortisol when a patient may have an adrenal incidentaloma is the 1 mg DST. The caveat with this specific test is that it is affected by dexamethasone absorption and metabolism and the proportion of cortisol bound to corticosteroid-binding globulin. Up to 20% of these tests report false-positive findings. This study by Genere and colleagues aimed to determine the normal range of free cortisol during the 1 mg DST. The researchers conducted a prospective, cross-sectional study that included volunteers without adrenal disorders and patients assessed for cortisol excess for clinical reasons. In the volunteer group, 168 volunteers were enrolled, including 47 women that were taking oral contraceptives. After excluding patients with inadequate dexamethasone levels and other outliers, the post-DST free cortisol maximum level was less than 48 ng/dL for men and women who were not taking oral contraceptive pills and less than 79 ng/dL for women taking oral contraceptive pills. In the patient group, 100% of post-DST free cortisol levels were above the upper limit of normal among those with a post-DST cortisol of at least 5 µg/dL; however, this was true for only 70.7% of those with post-DST cortisol between 1.8 µg/dL and 5 µg/dL. This study found that a post-DST free cortisol assessment is helpful in patients with a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL, but was not beneficial for patients with a post-DST total cortisol of less than 1.8 µg/dL or more than 5 µg/dL. Performing free cortisol assessments in this subgroup will reduce the number of false positives. The authors recommend performing a 1 mg post-DST free cortisol analysis for this subgroup; the levels to confirm cortisol excess are at least 48 ng/dL in men and women not taking oral contraceptive pills and at least 79 ng/dL for women taking oral contraceptive pills. Furthermore, the study presents a stepwise approach algorithm that will be very useful for clinical practice. Ricardo Correa, MD, EsD, FACE, FACP, CMQ Endocrine Today Editorial Board Member Program Director of Endocrinology Fellowship and Director for Diversity University of Arizona College of Medicine-Phoenix Phoenix Veterans Affairs Medical Center Disclosures: Correa reports no relevant financial disclosures. From https://www.healio.com/news/endocrinology/20211117/free-cortisol-evaluation-useful-after-abnormal-dexamethasone-test
  13. Any condition that causes the adrenal gland to produce excessive cortisol results in the disorder Cushing's syndrome. Cushing syndrome is characterized by facial and torso obesity, high blood pressure, stretch marks on the belly, weakness, osteoporosis, and facial hair growth in females. Cushing's syndrome has many possible causes including tumors within the adrenal gland, adrenal gland stimulating hormone (ACTH) produced from cancer such as lung cancer, and ACTH excessively produced from a pituitary tumors within the brain. ACTH is normally produced by the pituitary gland (located in the center of the brain) to stimulate the adrenal glands' natural production of cortisol, especially in times of stress. When a pituitary tumor secretes excessive ACTH, the disorder resulting from this specific form of Cushing's syndrome is referred to as Cushing's disease. As an aside, it should be noted that doctors will sometimes describe certain patients with features identical to Cushing's syndrome as having 'Cushingoid' features. Typically, these features are occurring as side effects of cortisone-related medications, such as prednisone and prednisolone.
  14. – AI false positives pose serious danger to patients; cutoff changes recommended by Scott Harris , Contributing Writer, MedPage Today November 15, 2021 share to facebook share to twitter share to linkedin email article This Reading Room is a collaboration between MedPage Today® and: For adrenal insufficiency (AI), reducing false positives means more than reducing resource utilization. Treatments like glucocorticoid replacement therapy can cause serious harm in people who do not actually have AI. Research published in the Journal of the Endocrine Society makes multiple findings that report authors say could help bring down false positive rates for AI. This retrospective study ultimately analyzed 6,531 medical records from the Imperial College Healthcare NHS Trust in the United Kingdom. Sirazum Choudhury, MBBS, an endocrinologist-researcher with the trust, served as a co-author of the report. He discussed the study with MedPage Today. The exchange has been edited for length and clarity. This study ultimately addressed two related but distinct questions. What was the first? Choudhury: Initially the path we were following had to do with when cortisol levels are tested. Cortisol levels follow a diurnal pattern; levels are highest in the morning and then decline to almost nothing overnight. This means we ought to be measuring the level in the morning. But there are logistical issues to doing so. In many hospitals, we end up taking measurements of cortisol in the afternoon. That creates a dilemma, because if it comes back low, there's an issue as to what we ought to do with the result. Here at Imperial, we call out results of <100 nmol/L among those taken in the afternoon. Patients and doctors then have to deal with these abnormal results, when in fact they may not actually be abnormal. We may be investigating individuals who should really not be investigated. So the first aim of our study was to try and ascertain whether we could bring that down to a lower level and in doing so stop erroneously capturing people who are actually fine. What was the second aim of the study? Choudhury: As we went through tens of thousands of data sets, we realized we could answer more than that one simple question. So the next part of the study became: if an individual is identified as suspicious for AI, what's the best way to prove this diagnosis? We do this with different tests like short Synacthen Tests (SST), all with different cutoff points. Obviously, we want to get the testing right, because if you falsely label a person as having AI, the upshot is that treatments will interfere with their cortisol access and they will not do well. Simply put, we would be shortening their life. So, our second goal was to look at all the SSTs we've done at the center and track them to see whether we could do better with the benchmarks. What did you find? Choudhury: When you look at the data, you see that you can bring those benchmarks down and potentially create a more accurate test. First, we can be quite sure that a patient who is tested in the afternoon and whose cortisol level is >234 does not have AI. If their level is <53.5 then further investigation is needed There were similar findings for SSTs, which in our case were processed using a platform made by Abbott. For this platform, we concluded that the existing cut-offs should be dropped down to 367 at 30 minutes or 419 at about 60 minutes. Did anything surprise you about the study or its findings? Choudhury: If you look at the literature, the number of individuals who fail at 30 minutes but pass at 60 minutes is around 5%. But I was very surprised to see that our number at Imperial was about 20%. This is a key issue because, as I mentioned, if individuals are wrongly labelled adrenally insufficient, you're shortening their life. It's scary to think about the number of people who might have been given steroids and treated for AI when they didn't have the condition. What do you see as the next steps? Choudhury: I see centers unifying their cutoffs for SST results and making sure we're all consistent in the way we treat these results. From a research perspective, on the testing we're obviously talking about one specific platform with Abbott, so research needs to be done on SST analyzers from other manufacturers to work out what their specific cutoffs should be. Read the study here and expert commentary on the clinical implications here. The study authors did not disclose any relevant relationship with industry. Primary Source Journal of the Endocrine Society Source Reference: Ramadoss V, et al "Improving the interpretation of afternoon cortisol levels and SSTs to prevent misdiagnosis of adrenal insufficiency" J Endocrine Soc 2021; 5(11): bvab147. From https://www.medpagetoday.com/reading-room/endocrine-society/adrenal-disorders/95661
  15. An updated guideline for the treatment of Cushing’s disease focuses on new therapeutic options and an algorithm for screening and diagnosis, along with best practices for managing disease recurrence. Despite the recent approval of novel therapies, management of Cushing’s disease remains challenging. The disorder is associated with significant comorbidities and has high mortality if left uncontrolled. Source: Adobe Stock “As the disease is inexorable and chronic, patients often experience recurrence after surgery or are not responsive to medications,” Shlomo Melmed, MB, ChB, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, and an Endocrine Today Editorial Board Member, told Healio. “These guidelines enable navigation of optimal therapeutic options now available for physicians and patients. Especially helpful are the evidence-based patient flow charts [that] guide the physician along a complex management path, which usually entails years or decades of follow-up.” Shlomo Melmed The Pituitary Society convened a consensus workshop with more than 50 academic researchers and clinical experts across five continents to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, participants reviewed data from January 2015 to April 2021 on screening and diagnosis; surgery, medical and radiation therapy; and disease-related and treatment-related complications of Cushing’s disease, all summarized in recorded lectures. The guideline includes recommendations regarding use of laboratory tests, imaging and treatment options, along with algorithms for diagnosis of Cushing’s syndrome and management of Cushing’s disease. Updates in laboratory, testing guidance If Cushing’s syndrome is suspected, any of the available diagnostic tests could be useful, according to the guideline. The authors recommend starting with urinary free cortisol, late-night salivary cortisol, overnight 1 mg dexamethasone suppression, or a combination, depending on local availability. If an adrenal tumor is suspected, the guideline recommends overnight dexamethasone suppression and using late-night salivary cortisol only if cortisone concentrations can also be reported. The guideline includes several new recommendations in the diagnosis arena, particularly on the role of salivary cortisol assays, according to Maria Fleseriu, MD, FACE, a Healio | Endocrine Today Co-editor, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland. Maria Fleseriu “Salivary cortisol assays are not available in all countries, thus other screening tests can also be used,” Fleseriu told Healio. “We also highlighted the sequence of testing for recurrence, as many patients’ urinary free cortisol becomes abnormal later in the course, sometimes up to 1 year later.” The guideline states combined biochemical and imaging for select patients could potentially replace petrosal sinus sampling, a very specialized procedure that cannot be performed in all hospitals, but more data are needed. “With the corticotropin-releasing hormone stimulation test becoming unavailable in the U.S. and other countries, the focus is now on desmopressin to replace corticotropin-releasing hormone in some of the dynamic testing, both for diagnosis of pseudo-Cushing’s as well as localization of adrenocorticotropic hormone excess,” Fleseriu said. The guideline also has a new recommendation for anticoagulation for high-risk patients; however, the exact duration and which patients are at higher risk remains unknown. “We always have to balance risk for clotting with risk for bleeding postop,” Fleseriu said. “Similarly, recommended workups for bone disease and growth hormone deficiency have been further structured based on pitfalls specifically related to hypercortisolemia influencing these complications, as well as improvement after Cushing’s remission in some patients, but not all.” New treatment options The guideline authors recommended individualizing medical therapy for all patients with Cushing’s disease based on the clinical scenario, including severity of hypercortisolism. “Regulatory approvals, treatment availability and drug costs vary between countries and often influence treatment selection,” the authors wrote. “However, where possible, it is important to consider balancing cost of treatment with the cost and the adverse consequences of ineffective or insufficient treatment. In patients with severe disease, the primary goal is to treat aggressively to normalize cortisol concentrations.” Fleseriu said the authors reviewed outcomes data as well as pros and cons of surgery, repeat surgery, medical treatments, radiation and bilateral adrenalectomy, highlighting the importance of individualized treatment in Cushing’s disease. “As shown over the last few years, recurrence rates are much higher than previously thought and patients need to be followed lifelong,” Fleseriu said. “The role of adjuvant therapy after either failed pituitary surgery or recurrence is becoming more important, but preoperative or even primary medical treatment has been also used more, too, especially in the COVID-19 era.” The guideline summarized data on all medical treatments available, either approved by regulatory agencies or used off-label, as well as drugs studied in phase 3 clinical trials. “Based on great discussions at the meeting and subsequent emails to reach consensus, we highlighted and graded recommendations on several practical points,” Fleseriu said. “These include which factors are helpful in selection of a medical therapy, which factors are used in selecting an adrenal steroidogenesis inhibitor, how is tumor growth monitored when using an adrenal steroidogenesis inhibitor or glucocorticoid receptor blocker, and how treatment response is monitored for each therapy. We also outline which factors are considered in deciding whether to use combination therapy or to switch to another therapy and which agents are used for optimal combination therapy.” Future research needed The guideline authors noted more research is needed regarding screening and diagnosis of Cushing’s syndrome; researchers must optimize pituitary MRI and PET imaging using improved data acquisition and processing to improve microadenoma detection. New diagnostic algorithms are also needed for the differential diagnosis using invasive vs. noninvasive strategies. Additionally, the researchers said the use of anticoagulant prophylaxis and therapy in different populations and settings must be further studied, as well as determining the clinical benefit of restoring the circadian rhythm, potentially with a higher nighttime medication dose, as well as identifying better markers of disease activity and control. “Hopefully, our patients will now experience a higher quality of life and fewer comorbidities if their endocrinologist and care teams are equipped with this informative roadmap for integrated management, employing a consolidation of surgery, radiation and medical treatments,” Melmed told Healio. From https://www.healio.com/news/endocrinology/20211029/updated-cushings-disease-guideline-highlights-new-diagnosis-treatment-roadmap
  16. Jessica Rotham, National Center for Health Research What is it? Cushing’s syndrome is a condition you probably have never heard of, but for those who have it, the symptoms can be quite scary. Worse still, getting it diagnosed can take a while. Cushing’s syndrome occurs when the tissues of the body are exposed to high levels of cortisol for an extended amount of time. Cortisol is the hormone the body produces to help you in times of stress. It is good to have cortisol at normal levels, but when those levels get too high it causes health problems. Although cortisol is related to stress, there is no evidence that Cushing’s syndrome is directly or indirectly caused by stress. Cushing’s syndrome is considered rare, but that may be because it is under-reported. As a result, we don’t have good estimates for how many people have it, which is why the estimates for the actual number of cases vary so much–from 5 to 28 million people.[1] The most common age group that Cushing’s affects are those 20 to 50 years old. It is thought that obesity, type 2 diabetes, and high blood pressure may increase your risk of developing this syndrome.[2] What causes Cushing’s Syndrome? Cushing’s syndrome is caused by high cortisol levels. Cushing’s disease is a specific form of Cushing’s syndrome. People with Cushing’s disease have high levels of cortisol because they have a non-cancerous (benign) tumor in the pituitary gland. The tumor releases adrenocorticotropin hormone (ACTH), which causes the adrenal glands to produce excessive cortisol. Cushing’s syndrome that is not Cushing’s disease can be also caused by high cortisol levels that result from tumors in other parts of the body. One of the causes is “ectopic ACTH syndrome.” This means that the hormone-releasing tumor is growing in an abnormal place, such as the lungs or elsewhere. The tumors can be benign, but most frequently they are cancerous. Other causes of Cushing’s syndrome are benign tumors on the adrenal gland (adrenal adenomas) and less commonly, cancerous adrenal tumors (adrenocortical carcinomas). Both secrete cortisol, causing cortisol levels to get too high. In some cases, a person can develop Cushing’s syndrome from taking steroid medications, such as prednisone. These drugs, known as corticosteroids, mimic the cortisol produced by the body. People who have Cushing’s syndrome from steroid medications do not develop a tumor.[3] What are the signs and symptoms of Cushing’s Syndrome? The appearance of people with Cushing’s syndrome starts to change as cortisol levels build up. Regardless of what kind of tumor they have or where the tumor is located, people tend to put on weight in the upper body and abdomen, with their arms and legs remaining thin; their face grows rounder (“moon face”); they develop fat around the neck; and purple or pink stretch marks appear on the abdomen, thighs, buttocks or arms. Individuals with the syndrome usually experience one or more of the following symptoms: fatigue, muscle weakness, high glucose levels, anxiety, depression, and high blood pressure. Women are more likely than men to develop Cushing’s syndrome, and when they do they may have excess hair growth, irregular or absent periods, and decreased fertility.[4] Why is Cushing’s Syndrome so frequently misdiagnosed? These symptoms seem distinctive, yet it is often difficult for those with Cushing’s syndrome to get an accurate diagnosis. Why? While Cushing’s is relatively rare, the signs and symptoms are common to many other diseases. For instance, females with excess hair growth, irregular or absent periods, decreased fertility, and high glucose levels could have polycystic ovarian syndrome, a disease that affects many more women than Cushing’s. Also, people with metabolism problems (metabolic syndrome), who are at higher than average risk for diabetes and heart disease, also tend to have abdominal fat, high glucose levels and high blood pressure.[5] Problems in testing for Cushing’s When Cushing’s syndrome is suspected, a test is given to measure cortisol in the urine. This test measures the amount of free or unbound cortisol filtered by the kidneys and then released over a 24 hour period through the urine. Since the amount of urinary free cortisol (UFC) can vary a lot from one test to another—even in people who don’t have Cushing’s—experts recommend that the test be repeated 3 times. A diagnosis of Cushing’s is given when a person’s UFC level is 4 times the upper limit of normal. One study found this test to be highly accurate, with a sensitivity of 95% (meaning that 95% of people who have the disease will be correctly diagnosed by this test) and a specificity of 98% (meaning that 98% of people who do not have the disease will have a test score confirming that).[6] However, a more 2010 study estimated the sensitivity as only between 45%-71%, but with 100% specificity.[7] This means that the test is very accurate at telling people who don’t have Cushing’s that they don’t have it, but not so good at identifying the people who really do have Cushing’s. The authors that have analyzed these studies advise that patients use the UFC test together with other tests to confirm the diagnosis, but not as the initial screening test.[8] Other common tests that may be used to diagnose Cushing’s syndrome are: 1) the midnight plasma cortisol and late-night salivary cortisol measurements, and 2) the low-dose dexamethasone suppression test (LDDST). The first test measures the amount of cortisol levels in the blood and saliva at night. For most people, their cortisol levels drop at night, but people with Cushing’s syndrome have cortisol levels that remain high all night. In the LDDST, dexamethasone is given to stop the production of ACTH. Since ACTH produces cortisol, people who don’t have Cushing’s syndrome will get lower cortisol levels in the blood and urine. If after giving dexamethasone, the person’s cortisol levels remain high, then they are diagnosed with Cushing’s.[9] Even when these tests, alone or in combination, are used to diagnose Cushing’s, they don’t explain the cause. They also don’t distinguish between Cushing’s syndrome, and something called pseudo-Cushing state. Pseudo-Cushing state Some people have an abnormal amount of cortisol that is caused by something unrelated to Cushing’s syndrome such as polycystic ovarian syndrome, depression, pregnancy, and obesity. This is called pseudo-Cushing state. Their high levels of cortisol and resulting Cushing-like symptoms can be reversed by treating whatever disease is causing the abnormal cortisol levels. In their study, Dr. Giacomo Tirabassi and colleagues recommend using the desmopressin (DDAVP) test to differentiate between pseudo-Cushing state and Cushing’s. The DDAVP test is especially helpful in people who, after being given dexamethasone to stop cortisol production, continue to have moderate levels of urinary free cortisol (UFC) and midnight serum cortisol.[10] An additional test that is often used to determine if one has pseudo-Cushing state or Cushing’s syndrome is the dexamethasone-corticotropin-releasing hormone (CRH) test. Patients are injected with a hormone that causes cortisol to be produced while also being given another hormone to stop cortisol from being produced. This combination of hormones should make the patient have low cortisol levels, and this is what happens in people with pseudo-Cushing state. People with Cushing’s syndrome, however, will still have high levels of cortisol after being given this combination of hormones.[11] How can Cushing’s be treated? Perhaps because Cushing’s is rare or under-diagnosed, few treatments are available. There are several medications that are typically the first line of treatment. None of the medications can cure Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails. The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and remove the tumor. Radiation may also be used instead of surgery to shrink the tumor. In patients whose Cushing’s is caused by ectopic ACTH syndrome, all cancerous cells need to be wiped out through surgery, chemotherapy, radiation or a variety of other methods, depending on the location of the tumor. Surgery is also recommended for adrenal tumors. If Cushing’s syndrome is being caused by corticosteroid (steroid medications) usage, the treatment is to stop or lower your dosage.[12] Medications to control Cushing’s (before treatment or if treatment fails) According to a 2014 study in the Journal of Clinical Endocrinology and Metabolism, almost no new treatment options have been introduced in the last decade. Researchers and doctors have focused most of their efforts on improving existing treatments aimed at curing Cushing’s. Unfortunately, medications used to control Cushing’s prior to treatment and when treatment fails are not very effective. Many of the medications approved by the FDA for Cushing’s syndrome and Cushing’s disease, such as pasireotide, metyrapone, and mitotane, have not been extensively studied. The research presented to the FDA by the makers of these three drugs did not even make clear what an optimal dose was.[13] In another 2014 study, published in Clinical Epidemiology, researchers examined these three same drugs, along with ten others, and found that only pasireotide had moderate evidence to support its approval. The other drugs, many of which are not FDA approved for Cushing’s patients, had little or no available evidence to show that they work.[14] They can be sold, however, because the FDA has approved them for other diseases. Unfortunately, that means that neither the FDA nor anyone else has proven the drugs are safe or effective for Cushing patients. Pasireotide, the one medication with moderate evidence supporting its approval, caused hyperglycemia (high blood sugar) in 75% of patients who participated in the main study for the medication’s approval for Cushing’s. As a result of developing hyperglycemia, almost half (46%) of the participants had to go on blood-sugar lowering medications. The drug was approved by the FDA for Cushing’s anyway because of the lack of other effective treatments. Other treatments used for Cushing’s have other risks. Ketoconazole, believed to be the most commonly prescribed medications for Cushing’s syndrome, has a black box warning due to its effect on the liver that can lead to a liver transplant or death. Other side effects include: headache, nausea, irregular periods, impotence, and decreased libido. Metyrapone can cause acne, hirsutism, and hypertension. Mitotane can cause neurological and gastrointestinal symptoms such as dizziness, nausea, and diarrhea and can cause an abortion in pregnant women.[15] So, what should you do if you suspect you have Cushing’s Syndrome? Cushing’s syndrome is a serious disease that needs to be treated, but there are treatment options available for you if you are diagnosed with the disease. If the symptoms in this article sound familiar, it’s time for you to go see your doctor. Make an appointment with your general practitioner, and explain your symptoms to him or her. You will most likely be referred to an endocrinologist, who will be able to better understand your symptoms and recommend an appropriate course of action. All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff. Nieman, Lynette K. Epidemiology and clinical manifestations of Cushing’s syndrome, 2014. UpToDate: Wolters Kluwer Health Cushing’s syndrome/ disease, 2013. American Association of Neurological Surgeons. http://www.aans.org/Patient Information/Conditions and Treatments/Cushings Disease.aspx Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Newell-Price, John, Peter Trainer, Michael Besser and Ashley Grossman. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states, 1998. Endocrine Reviews: Endocrine Society Carroll, TB and JW Findling. The diagnosis of Cushing’s syndrome, 2010. Reviews in Endocrinology and Metabolic Disorders: Springer Ifedayo, AO and AF Olufemi. Urinary free cortisol in the diagnosis of Cushing’s syndrome: How useful?, 2013. Nigerian Journal of Clinical Practice: Medknow. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society. Galdelha, Monica R. and Leonardo Vieira Neto. Efficacy of medical treatment in Cushing’s disease: a systematic review, 2014. Clinical Endocrinology: John Wiley & Sons. Adler, Gail. Cushing syndrome treatment & management, 2014. MedScape: WebMD. Adapted from https://www.center4research.org/cushings-syndrome-frequent-misdiagnosis/?fbclid=IwAR1lfJPilmaTl1BhR-Esi69eU7Xjm3RlO4f8lmFBIviCtHHXmVoyRxOlJqE
  17. Cortisol is a hormone which produced by the adrenal gland (cortex) to control blood sugar. The production of cortisol is triggered by the pituitary hormone ACTH. Cortisol is a glucocorticoid which stimulates an increase in blood glucose. Cortisol will also stimulate the release of amino acids from muscle tissue and fatty acids from adipose tissue. The amino acids are then converted in the liver to glucose (for use by the brain). The fatty acids can be used by skeletal muscles for energy (rather than glucose) thereby freeing up glucose for selective utilization by the brain. Cortisol levels are often measured to evaluate the function of the pituitary or adrenal glands. Some of the cortisol is metabolized by the liver to produce 17 hydroxycorticosteroids, which is then excreted in the urine. The primary stress hormone. Cortisol is the major natural GLUCOCORTICOID (GC) in humans. Synthetic cortisol, also known as hydrocortisone, is used as a drug mainly to fight allergies and inflammation. A certain amount of cortisol is necessary for life. Without cortisol even a small amount of stress will kill you. Addison's disease is a disease which causes low cortisol levels, and which is treated by cortisol replacement therapy. Cortisol...
  18. This article was originally published here Proc (Bayl Univ Med Cent). 2021 Jul 29;34(6):715-717. doi: 10.1080/08998280.2021.1953950. eCollection 2021. ABSTRACT Cushing’s disease (CD) is the most common cause of endogenous cortisol excess. We discuss the case of a 60-year-old woman with recurrent venous thromboembolism, refractory hypokalemia, and lumbar vertebrae compression fractures with a rapidly progressive disease course. Ectopic hypercortisolism was suspected given the patient’s age and rapid onset of disease. Investigations revealed cortisol excess from a pituitary microadenoma. This case demonstrates that CD can present with severe findings and highlights the increased risk of venous thromboembolism in hypercortisolism, especially in CD. PMID:34732999 | PMC:PMC8545141 | DOI:10.1080/08998280.2021.1953950
  19. By Ed Miseta, Chief Editor, Clinical Leader Follow Me On Twitter @EdClinical Sparrow Pharmaceuticals is an emerging biopharma company on a mission to help patients suffering from an excess of corticosteroids, with a focus on Cushing’s syndrome, autonomous cortisol secretion (ACS), and polymyalgia rheumatica (PMR). Cushing’s and ACS are both caused by an excess of cortisol produced by tumors. Patients with Cushing’s can present physically with a fatty hump between their shoulders, a rounded face, and pink or purple stretch marks on their skin. Cushing’s syndrome and ACS can both result in high blood pressure, bone loss, type 2 diabetes, weight gain, and mood, cognition, and sleep disorders. Any of those symptoms may be side effects for patients with conditions such as PMR who rely on long-term treatment with corticosteroid medications such as prednisone. “Cushing’s syndrome impacts around 20,000 patients in the U.S. alone,” says David Katz, Chief Scientific Officer for Sparrow. “Approximately 50% of those patients can be cured by surgery, but some will develop another tumor years later. ACS is an under-recognized condition, but it may affect up to 3 million patients in the U.S. There are also around 2 million people in the U.S. who rely on long-term use of corticosteroid medications to control autoimmune diseases and other conditions.” The treatments being developed by Sparrow are based on recognition that cortisol and corticosteroid medications are activated in certain tissues such as the liver, bone, fat, and brain, where in excess they act to cause toxicity. The company’s investigational drugs inhibit HSD-1, the enzyme responsible for that activation. Sparrow is about to launch a Phase 2 trial for Cushing’s syndrome. In early 2022 the company will also begin two additional Phase 2 trials for ACS and PMR, a common autoimmune disease in elderly patients. PMR is an arthritic syndrome characterized by a phenomenon known as claudication, which means the more you use a limb, the more it hurts and the harder it is to use. “For example, the more a PMR patient walks, the more painful and stiff their legs will become,” says Katz. “If they're trying to do anything with their arms, the arms will get stiffer and more painful. The disease is pretty debilitating in terms of physical function. The only approved treatment for PMR is steroids, which have side effects such as diabetes, hypertension, osteoporosis, and fractures.” Unknown Clinical Challenges Katz is excited about the clinical trials for ACS and PMR because no sizable interventional trials have been reported in either of those conditions. “We're going into a completely new area, and we don't know what we're going to encounter in terms of patient recruitment and retention,” says Katz. “There is also no strong precedent for how to get approval for a drug in these conditions. The only treatment indicated for PMR is steroids, and that came without any efficacy clinical trials. There are no drugs approved for ACS. It’s hard to anticipate the challenges we will face when we are in an area that is very new.” Patient centricity is a topic that is very important to Katz, and he spends a lot of time thinking about how to make trials a more pleasant experience for patients by limiting the burden placed on them. He notes that can sometimes be a difficult trade-off because of the procedures that must be performed to meet regulatory standards. “In Cushing’s syndrome clinical care and clinical trials, the standard way for someone's cortisol level to be measured is a 24-hour urine collection,” states Katz. “That involves looking at the amount of cortisol in the urine over a 24-hour period. That collection is inconvenient and burdensome, and the patient must then carry it somewhere to be analyzed.” Sparrow hopes to shift that collection to a spot urine sample, like what patients would experience during a physical. The patient would urinate into a cup and hand it off to a clinic employee for analysis. The process would be much simpler and less burdensome for the patient. Sparrow will first need to prove that in a clinical trial the spot sample will work as well or better than the 24-hour collection. Subjects in the initial clinical trials will have to contribute the 24-hour collections so that Sparrow can demonstrate that future patients will not need to do so. The Future of Endocrinology Katz has a positive outlook on the future of endocrinology. Sparrow’s leading drug candidate, SPI-62, is an oral, small-molecule HSD-1 inhibitor. In four clinical trials, it demonstrated potent targeting of HSD-1 in both the brain and liver, and significantly lowered cortisol levels in the liver. The studies also showed a favorable safety and tolerability profile. “If we are successful at developing SPI-62, I believe it will change the field of endocrinology,” says Katz. “We aim to shift the focus in Cushing’s syndrome to intracellular cortisol as the main driver of symptoms. What I mean by that is if we find that SPI-62 substantially reduces symptoms and that the degree of inhibition of our target HSD-1 correlates well with clinical improvement, then we can get to a new standard of care. We can potentially get rid of the 24-hour urine collections, which will be a big relief to patients. Additionally, many of today's drugs have a side effect called adrenal insufficiency, which results when the drugs either reduce cortisol too much or completely block activity. Many of today's drugs also require frequent monitoring and dose titration to prevent adrenal insufficiency. We believe that with HSD-1 inhibition we might avoid adrenal insufficiency as well.” Katz is hopeful patients treated with SPI-62 will not require monitoring and dose titration. That proof will take years and lots of clinical trials. Sparrow may also produce the first targeted therapy for ACS. That could improve the recognition of ACS as a prevalent form of hypercortisolism and a substantial cause of morbidity and mortality. “ACS is probably the most under-recognized condition in endocrinology based on recent epidemiological studies,” adds Katz. “It's possible that as few as 3% of patients who have ACS actually have a diagnosis. That is shocking for a condition that is associated with a lot of cardiometabolic and bone morbidity, negative effects on mood and cognition, sleep, and muscle strength, and is associated with excess mortality. We want to bring attention to this condition by bringing out a targeted therapy to treat a spectrum of symptoms by getting to the root cause of them.” From https://www.clinicalleader.com/doc/sparrow-pharmaceuticals-hopes-to-change-the-future-of-endocrinology-0001
  20. Abstract Cushing’s disease is an abnormal secretion of ACTH from the pituitary that causes an increase in cortisol production from the adrenal glands. Resultant manifestations from this excess in cortisol include multiple metabolic as well as psychiatric disturbances which can lead to significant morbidity and mortality. In this report, 23-year-old woman presented to mental health facility with history of severe depression and suicidal ideations. During evaluation, she found to have Cushing’s disease, which is unusual presentation. She had significant improvement in her symptoms with reduction of antidepressant medications after achieving eucortisolism. Cushing syndrome can present with wide range of neuropsychiatric manifestations including major depression. Although presentation with suicidal depression is unusual. Early diagnosis and prompt management of hypercortisolsim may aid in preventing or lessening of psychiatric symptoms The psychiatric and neurocognitive disorders improve after disease remission (the normalization of cortisol secretion), but some studies showed that these disorders can partially improve, persist, or exacerbate, even long-term after the resolution of hypercortisolism. The variable response of neuropsychiatric disorders after Cushing syndrome remission necessitate long term follow up. Keywords cushing syndrome, cushing disease, hypercortisolism Introduction Endogenous Cushing syndrome is a complex disorder caused by chronic exposure to excess circulating glucocorticoids. It has a wide range of clinical signs and symptoms as a result of the multisystem effects caused by excess cortisol.1 The hypercortisolism results in several complications that include glucose intolerance, diabetes, hypertension, dyslipidemia, thromboembolism, osteoporosis, impaired immunity with increased susceptibility to infection as well as neuropsychiatric disorders.2,3 Cushing syndrome presents with a wide variety of neuro-psychiatric manifestations like anxiety, major depression, mania, impairments of memory, sleep disturbance, and rarely, suicide attempt as seen in this case.2,4 The mechanism of neuropsychiatric symptoms in Cushing’s syndrome is not fully understood, but multiple proposed theories have been reported, one of which is the direct brain damage secondary to excess of glucocorticoids.5 Case Report A 23-year-old female presented to Al-Amal complex of mental health in Riyadh, Saudi Arabia with history of suicidal tendencies and 1 episode of suicidal attempt which was aborted because of religious reasons. She reported history of low mood, having disturbed sleep, loss of interest, and persistent feeling of sadness for 4 months. She also reported history of weight gain, facial swelling, hirsutism, and irregular menstrual cycle with amenorrhea for 3 months. She was prescribed fluoxetine 40 mg and quetiapine 100 mg. She was referred to endocrinology clinic at King Fahad Medical City, Riyadh for evaluation and management of possible Cushing syndrome as the cause of her abnormal mental health. She was seen in the endocrinology clinic where she reported symptoms as mentioned above in addition to headache, acne, and proximal muscle weakness. On examination her vital signs were normal. She had depressed affect, rounded face with acne and hirsutism, striae in the upper limb, and abdomen with proximal muscle weakness (4/5). Initial investigations showed that 24 hour urinary free cortisol was more than 633 µg which is more than 3 times upper limit of normal (this result was confirmed on second sample with level more than 633 µg/24 hour), cortisol level of 469 nmol/L after low dose 1 mg-dexamethasone suppression test and ACTH level of 9.8 pmol/L. Levels of other anterior pituitary hormones tested were within normal range. She also had prediabetes with HbA1c of 6.1 and dyslipidemia. Serum electrolytes, renal function and thyroid function tests were normal. MRI pituitary showed left anterior microadenoma with a size of 6 mm × 5 mm. MRI pituitary (Figure 1). Figure 1. (A-1) Coronal T2, (B-1) post contrast coronal T1 demonstrate small iso intense T1, heterogeneous mixed high, and low T2 signal intensity lesion in the left side of anterior pituitary gland which showed micro adenoma with a size of 6 mm × 5 mm. (A-2) Post-operative coronal T2 and (B-2) post-operative coronal T1. Demonstrates interval resection of the pituitary micro adenoma with no recurrence or residual lesion and minimal post-operative changes. There is no abnormal signal intensity or abnormal enhancing lesion seen. No further hormonal work up or inferior petrosal sinus sampling were done as the tumor size is 6 mm and ACTH level consistent with Cushing’s disease (pituitary source). She was referred to neurosurgery and underwent trans-sphenoidal resection of the tumor. Histopathology was consistent with pituitary adenoma and positive for ACTH. Her repeated cortisol level after tumor resection was less than 27 and ACTH 2.2 with indicated excellent response to surgery. She was started on hydrocortisone until recovery of her hypothalamic pituitary adrenal axis documented by normal morning cortisol 3 months after surgery (Table 1). Table 1. Labs. Table 1. Labs. View larger version During follow up with psychiatry her depressive symptoms improved but not resolved and she was able to stop fluoxetine 5 months post-surgery. Currently she is maintained on quetiapine 100 mg with significant improvement in her psychiatric symptoms. Currently she is in remission from Cushing’s disease based on the normal level of repeated 24 hour urinary free cortisol and with an over-all improvement in her metabolic profile. Discussion Cushing syndrome is a state of chronic hypercortisolism due to either endogenous or exogenous sources. Glucocorticoid overproduction by adrenal gland can be adrenocorticotropic (ACTH) hormone dependent which represent most of the cases and ACTH independent.6 To the best of our knowledge this is the first case documented in Saudi Arabia. There are multiple theories behind the neuropsychiatric manifestations in Cushing syndrome. These include increased stress response leading to behavioral changes, prolonged cortisol exposure leading to decreased brain volume especially in the hippocampus, reduced dendritic mass, decreased glial development, trans-cellular shift of water and synaptic loss, and excess glucocorticoid levels inhibiting neurogenesis and promoting neuronal tendency to toxic insult.3,7 In this report, the patient presented with severe depression with suicidal attempt. She had significant improvement in her symptoms with reduction of antidepressant medications but her depression persisted despite remission of Cushing disease. A similar case has been reported by Mokta et al,1 about a young male who presented with suicidal depression as initial manifestation of Cushing disease. As opposed to the present case he had complete remission of depression within 1 month of resolution of hypercortisolism. In general, psychiatric and neurocognitive disorders secondary to Cushing syndrome improves after normalization of cortisol secretion, but some studies showed that these disorders can partially improve, persist, or exacerbate, even long-term after the resolution of hypercortisolism. This may be due to persistence hypercortisolism creating toxic brain effects that occur during active disease.2,8 Similar patients need to be followed up for mental health long after Cushing syndrome has been resolved. Conclusion Depression is a primary psychiatric illness, that is, usually not examined for secondary causes. Symptoms of depression and Cushing syndrome overlap, so diagnosis and treatment of Cushing disease can be delayed. Early diagnosis and prompt management of hypercortisolsim may aid in preventing or lessening psychiatric symptoms. The variable neuropsychiatric disorders associated with Cushing syndrome post-remission necessitates long term follow up. 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. Informed Consent Written informed consent was obtained from the patient for the publication of this case and accompanying images. ORCID iD Sultan Dheafallah Al-Harbi https://orcid.org/0000-0001-9877-9371 References 1. Mokta, J, Sharma, R, Mokta, K, Ranjan, A, Panda, P, Joshi, I. Cushing’s disease presenting as suicidal depression. J Assoc Physicians India. 2016;64:82-83. Google Scholar | Medline 2. Pivonello, R, Simeoli, C, De Martino, MC, et al. Neuropsychiatric disorders in cushing’s syndrome. Front Neurosci. 2015;9:1-6. Google Scholar | Crossref | Medline 3. Pereira, AM, Tiemensma, J, Romijn, JA. Neuropsychiatric disorders in Cushing’s syndrome. Neuroendocrinology. 2010;92:65-70. Google Scholar | Crossref | Medline | ISI 4. Tang, A, O’Sullivan, AJ, Diamond, T, Gerard, A, Campbell, P. Psychiatric symptoms as a clinical presentation of Cushing’s syndrome. Ann Gen Psychiatry. 2013;12:1. Google Scholar | Crossref | Medline 5. Sonino, N, Fava, GA, Raffi, AR, Boscaro, M, Fallo, F. Clinical correlates of major depression in Cushing’s disease. Psychopathology. 1998;31:302-306. Google Scholar | Crossref | Medline 6. Wu, Y, Chen, J, Ma, Y, Chen, Z. Case report of Cushing’s syndrome with an acute psychotic presentation. Shanghai Arch Psychiatry. 2016;28:169-172. Google Scholar | Medline 7. Rasmussen, SA, Rosebush, PI, Smyth, HS, Mazurek, MF. Cushing disease presenting as primary psychiatric illness: a case report and literature review. J Psychiatr Pract. 2015;21:449-457. Google Scholar | Crossref | Medline 8. Sonino, N, Fava, GA. Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs. 2001;15:361-373. Google Scholar | Crossref | Medline From https://journals.sagepub.com/doi/10.1177/11795476211027668
  21. Cushing's Help Podcast: Adrenal Crisis Be sure to print this page to carry with you. Definition: Acute adrenal crisis is a life-threatening state caused by insufficient levels of cortisol, which is a hormone produced and released by the adrenal gland. Alternative Names: Adrenal crisis; Addisonian crisis; Acute adrenal insufficiency Causes, incidence, and risk factors: The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, all of which are called corticosteroids. Cortisol is a glucocortoid, a corticosteroid that maintains glucose (blood sugar) regulation, suppresses the immune response, and is released as part of the body's response to stress. Cortisol production is regulated by a small gland just below the brain called the pituitary gland. Cortisol is essential for life. Acute adrenal crisis is a medical emergency caused by a lack of cortisol. Patients may experience lightheadedness or dizziness, weakness, sweating, abdominal pain, nausea and vomiting, or even loss of consciousness. Adrenal crisis occurs if the adrenal gland is deteriorating (Addison's disease, primary adrenal insufficiency), if there is pituitary gland injury (secondary adrenal insufficiency), or if adrenal insufficiency is not adequately treated. Risk factors for adrenal crisis include physical stress such as infection, dehydration, trauma, or surgery, adrenal gland or pituitary gland injury, and ending treatment with steroids such as prednisone or hydrocortisone too early. Symptoms: Headache Profound weakness Fatigue Slow, sluggish movement Nausea Vomiting Low blood pressure Dehydration High fever Shaking chills Confusion or coma Darkening of the skin Rapid heart rate Joint pain Abdominal pain Unintentional weight loss Rapid respiratory rate (see tachypnea) Unusual and excessive sweating on face and/or palms Skin rash or lesions may be present Flank pain Loss of appetite Signs and tests: An ACTH (cortrosyn) stimulation test shows low cortisol. The baseline cortisol level is low. Fasting blood sugar may be low. Serum potassium is elevated ( usually primary adrenal insufficiency). Serum sodium is decreased (usually primary adrenal insufficiency). Treatment: In adrenal crisis, an intravenous or intramuscular injection of hydrocortisone (an injectable corticosteroid) must be given immediately. Supportive treatment of low blood pressure with intravenous fluids is usually necessary. Hospitalization is required for adequate treatment and monitoring. If infection is the cause of the crisis, antibiotic therapy may be needed. Expectations (prognosis): Death may occur due to overwhelming shock if early treatment is not provided. Complications: shock coma seizures Calling your health care provider: Call your health care provider if you have Addison's disease and are unable to retain usual medications because of vomiting.Go to the emergency room or call the local emergency number (such as 911) if symptoms of acute adrenal crisis develop. Prevention: People who have Addison's disease should be taught to recognize signs of potential stress that may cause an acute adrenal crisis. Most people with Addison's disease are taught to give themselves an emergency injection of hydrocortisone or increase their dose of oral prednisone in times of stress. It is important for the individual with Addison's disease to always carry a medical identification card that states the type of medication and the proper dose needed in case of an emergency. Never omit medication. If unable to retain medication due to vomiting, notify the health care provider. Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated With hGH Recently, doctors conducting the follow-up study of individuals treated with hGH looked at causes of death among recipients and found some disturbing news. Many more people have died from a treatable condition called adrenal crisis than from CJD. THIS RISK DOES NOT AFFECT EVERY RECIPIENT. IT CAN AFFECT THOSE WHO LACK OTHER HORMONES IN ADDITION TO GROWTH HORMONE. Please read on to find out if this risk applies to you. Death from adrenal crisis can be prevented. Adrenal crisis is a serious condition that can cause death in people who lack the pituitary hormone ACTH. ACTH is responsible for regulating the adrenal gland. Often, people are unaware that they lack this hormone and therefore do not know about their risk of adrenal crisis. Most people who were treated with hGH did not make enough of their own growth hormone. Some of them lacked growth hormone because they had birth defects, tumors or other diseases that cause the pituitary gland to malfunction or shut down. People with those problems frequently lack other key hormones made by the pituitary gland, such as ACTH, which directs the adrenal gland to make cortisol, a hormone necessary for life. Having too little cortisol can be fatal if not properly treated. TREATMENT WITH HGH DOES NOT CAUSE ADRENAL CRISIS, but because a number of people lacking growth hormone also lack ACTH, adrenal crisis has occurred in some people who were treated with hGH. In earlier updates we have talked about how adrenal crisis can be prevented, but people continue to die from adrenal crisis, which is brought on by lack of cortisol. These deaths can be prevented. Please talk to your doctor about whether you are at risk for adrenal crisis. Why should people treated with hGH know about adrenal crisis? Among the people who received hGH, those who had birth defects, tumors, and other diseases affecting the brain lacked hGH and often, other hormones made by the pituitary gland. A shortage of the hormones that regulate the adrenal glands can cause many health problems. It can also lead to death from adrenal crisis. This tragedy can be prevented. What are adrenal hormones? The pituitary gland makes many hormones, including growth hormone and ACTH, a hormone which signals the adrenal glands to make cortisol, a hormone needed for life. If the adrenal gland doesn't make enough cortisol, replacement medications must be taken. The most common medicines used for cortisol replacement are: Hydrocortisone Prednisone Dexamethasone What is adrenal crisis? Adrenal hormones are needed for life. The system that pumps blood through the body cannot work during times of physical stress, such as illness or injury, if there is a severe lack of cortisol (or its replacement). People who lack cortisol must take their cortisol replacement medication on a regular basis, and when they are sick or injured, they must take extra cortisol replacement to prevent adrenal crisis. When there is not enough cortisol, adrenal crisis can occur and may rapidly lead to death. What are the symptoms of lack of adrenal hormones? If you don't have enough cortisol or its replacement, you may have some of these problems: feeling weak feeling tired all the time feeling sick to your stomach vomiting no appetite weight loss When someone with adrenal gland problems has weakness, nausea, or vomiting, that person needs immediate emergency treatment to prevent adrenal crisis and possible death. • Why are adrenal hormones so important? Cortisol (or its replacement) helps the body respond to stress from infection, injury, or surgery. The normal adrenal gland responds to serious illness by making up to 10 times more cortisol than it usually makes. It automatically makes as much as the body needs. If you are taking a cortisol replacement drug because your body cannot make these hormones, you must increase the cortisol replacement drugs during times of illness, injury, or surgery. Some people make enough cortisol for times when they feel well, but not enough to meet greater needs when they are ill or injured. Those people might not need cortisol replacement every day but may need to take cortisol replacement medication when their body is under stress. Adrenal crisis is extremely serious and can cause death if not treated promptly. Discuss this problem with your doctor to help decide whether you need more medication or other treatment to protect your health. • How is adrenal crisis treated? People with adrenal crisis need immediate treatment. ANY DELAY CAN CAUSE DEATH. When people with adrenal crisis are vomiting or unconscious and cannot take medicine, the hormones can be given as an injection. Getting an injection of adrenal hormones can save your life if you are in adrenal crisis. If you lack the ability to make cortisol naturally, you should carry a medical ID card and wear a Medic-Alert bracelet to tell emergency workers that you lack adrenal hormones and need treatment. This precaution can save your life if you are sick or injured. • How can I prevent adrenal crisis? • If you are always tired, feel weak, and have lost weight, ask your doctor if you might have a shortage of adrenal hormones. • If you take hydrocortisone, prednisone, or dexamethasone, learn how to increase the dose when you become ill. • If you are very ill, especially if you are vomiting and cannot take pills, seek emergency medical care immediately. Make sure you have a hydrocortisone injection with you at all times, and make sure that you and those around you (in case you're not conscious) know how and when to administer the injection. • Carry a medical ID card and wear a bracelet telling emergency workers that you have adrenal insufficiency and need cortisol. This way, they can treat you right away if you are injured. Remember: SOME PEOPLE WHO LACKED GROWTH HORMONE MAY ALSO LACK CORTISOL, A HORMONE NECESSARY FOR LIFE. LACK OF CORTISOL CAN CAUSE ADRENAL CRISIS, A PREVENTABLE CONDITION THAT CAN CAUSE DEATH IF TREATED IMPROPERLY . Deaths from adrenal crisis can be prevented if patients and their families recognize the condition and are careful to treat it right away. Adrenal crisis is a medical emergency. Know the symptoms and how to adjust your medication when you are ill. TAKING THESE PRECAUTIONS CAN SAVE YOUR LIFE. DebMV suggested that you should have a Medic Alert bracelet from medicalert.org Toll free number in the USA is: by phone 7 days a week, 24 hours a day: 888-633-4298 209-668-3333 from outside the U.S. Lorrie got this important info for us. Alternative names: adrenal crisis; Addisonian crisis; acute adrenal insufficiency Definition: An abrupt, life-threatening state caused by insufficient cortisol, a hormone produced and released by the adrenal gland. Causes, incidence, and risk factors: The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, which are called corticosteroids. The androgens and estrogens affect sexual development and reproduction. The glucocorticoids maintain glucose regulation, suppress the immune response, and provide for the response to stress (cortisol). The mineralocorticoids regulate sodium and potassium balance. These hormones are essential for life. Acute adrenal crisis is an emergency caused by decreased cortisol. The crisis may occur in a person with Addison's disease, or as the first sign of adrenal insufficiency. More uncommonly, it may be caused by a pituitary gland disorder. It may also be caused by sudden withdrawal of corticosteroids, removal or injury of the adrenal glands, or destruction of the pituitary gland. Risk factors are stress, trauma, surgery, or infection in a person with Addison's disease, or injury or trauma to the adrenal glands or the pituitary gland. The incidence is 4 out of 100,000 people. Prevention: People who have Addison's disease should be taught to recognize signs of potential stress that may precipitate an acute adrenal crisis (cause it to occur suddenly and unexpectedly). Most people with Addison's disease are taught to give themselves an emergency injection of hydrocortisone in times of stress. It is important for the individual with Addison's disease to always carry a medical identification card that states the type of medication and the proper dose needed in case of an emergency. Never omit medication. If unable to retain medication due to vomiting, notify the health care provider. Symptoms: headache profound weakness fatigue slow, sluggish, lethargic movement nausea vomiting low blood pressure dehydration high fever chills shaking confusion or coma darkening of the skin rapid heart rate joint pain abdominal pain unintentional weight loss rapid respiratory rate unusual and excessive sweating on face and/or palms skin rash or lesion may be present flank pain appetite, loss Signs and tests: An ACTH (cortrosyn) stimulation test shows low cortisol. The cortisol level is low. The fasting blood sugar may be low. The serum potassium is elevated. The serum sodium is decreased. This disease may also alter the results of the following tests: sodium, urine 17-hydroxycorticosteroids Treatment: In adrenal crisis, an intravenous or intramuscular injection of hydrocortisone (an injectable corticosteroid) must be given immediately. Supportive treatment of low blood pressure is usually necessary. Hospitalization is required for adequate treatment and monitoring. Low blood pressure may be treated with intravenous fluids. If infection is the cause of the crisis, antibiotic therapy is indicated. Expectations (prognosis): Death may occur due to overwhelming shock if early treatment is not provided. Complications: shock coma seizures For more personal experiences, see the message boards A Personal Experience Shauna Wrote...What adrenal crisis feels like As with most mornings, this one began with nausea. I'm used to it, so didn't think much about it. I made it to the bathroom and was feeling really awful. Decided to just go to the toilet because I had that impending feeling. Next thing I knew I was waking up, but it wasn't like a normal awakening. I remember being in a tunnel and then thinking, "Well, this isn't where I normally sleep." Then I realized of course it wasn't where I normally slept! Normally I sleep in a bed, not wedged between a wall and the toilet. (Not that I was that coherent). I was completely disoriented as to time, place, etc. I had one big yell in me and yelled "HELP". My four year old brought me the phone and my son got me a towel. I called 911 (thank God I had a 911 sticker on the phone because I really couldn't remember the number). I kept telling the dispatcher I was in adrenal crisis. Of course, that meant nothing to him. I had my son get my shot but somewhere I knew that I wasn't together enough to give myself the shot. So I puked a few more times and told my son to take my daughter upstairs so she wasn't scared when the ambulance came. I decided to rest on the floor of the bathroom. I had, at first, tried to go to the couch but I was much, much too weak. So my son directed the medics into the bathroom. They eventually carried me to the couch. I kept telling them about my shot, but couldn't remember where I had my letter from Dr. Cook. They thought I was an overdose or a psych case (they told me later). They had all my pills lined up and were asking when I took this or that one last. I finally told them to look at the friggin date on the bottle and see that they were all 3/4 full. (I was agitated, too) They put the heart monitor on me and inserted an IV and took me to the hospital. I puked one more time in the ambulance and when we arrived (though my tummy was empty). My brother and sister-in-law where there (hospital) when I arrived and my mom had arrived at my house to take care of the kids as we were leaving. Then she met us up there. Before we arrived at the hospital, my husband had faxed a copy of Dr. Cook's letter on how to treat me over (Brian was at work when this happened). So they came in and inserted another fluid bag. Then about ten minutes later (after my brother told the doctor, "I fully expect that my sister will have her shot withing the next ten minutes" - patient advocates are a good thing because I could've cared less at that point) I had my 100 mg shot of solu-medrol. I was lucky because my doctor in the ER knew about adrenal crisis. Then I had another bag and repeated tests of my bp and heartrate. It wasn't pretty - every time my bp was low, generally around 80/50, sometimes lower and my heart rate was 120+. They decided to admit me, but I fought and fought. Once I got a shot of Zofran (anti-nausea, best in the world) and my cortisone and some fluid, I was feeling decent. I look and feel like I've been through a war, but I'm alive. As to why this happened, we're not entirely sure at this point. I have one urine test that they're culturing or something. I might also have shingles, but again - that'll show up in due time (a day or two, if I have it). Or, as Dr. Cook said when I talked to him, sometimes we just don't know. I was doing so well on my meds, back up to 27.5 and feeling good. Now I'm on 40 for the next day, and 30 for a week. Frustrating. Adrenal crisis is awful. It's terrifying. And what makes me want to cry as I write this (who am I kidding, I am crying) is that I couldn't have cared less if I lived or died. I was not in my right mind, I felt so horrid. All the surgeries combined, today was the worst day I've ever had. And it was a huge wake-up call. I need to have a better medic-alert bracelet because they had no idea what "Stress dose steroids" were. I need to have a list of what to do in crisis on my fridge, in my purse and with every family member. Same with the letter from my endo on how to treat me. Because when I'm in crisis, I don't know any better. I need to have things that speak for me. Thank God for family that knows, and for good doctors. Anyway, I didn't post this to scare anyone but Adrenal Crisis is not something to take lightly. When I felt myself hurting the night before (back pain, possibly shingles though I doubt it) I should've just taken an extra 5 mgs. Would've been a heck of a lot easier than what happened today. A few funny parts of the day: My daughter had to dress herself and my mom was in a hurry to get her to daycare and come see me. So my daughter spent the day at daycare in tights, too small shorts and a turtleneck (none of which came close to matching). Oh, and black patent leather shoes. Also, the medics asked what I weighed. Out of habit, I said 222 (my highest Cushing's weight). They ALL did a double take and said no way. One guessed 140 - bless his heart. I never did get myself weighed so I don't even know. Oh, and if any of you called at about 8 am and spoke with a medic, call me back. lol I had a blocked call at 8am, and I vaguely remember the medic talking to someone but I wasn't with it enough to ask who called. lol Something I don't say enough: I love and value you all. More personal experiences. Sue sent this along: Early Crisis Intervention The following is from the June 2002 issue of Addison News. Joan Hoffman, editor/publisher, kindly sent this issue to me and I wanted to share this with you. This is a flow chart to show the pathway of events in a crisis. It is very important to intervene as early as possible. Use your injectable and head for the hospital! The rate at which these events take varies with individuals and circumstances. The chart is a variation of one found in a nursing encyclopedia.
  22. Kate** on the Cushing’s support board (Cushing’s Help and Support) wrote this letter after having pituitary surgery… Dear friends and family: I am writing this letter to share with you some basic facts about Cushing’s Disease/Syndrome and the recovery process so that you will have sufficient information to form realistic expectations about me and my ability to engage in certain activities in light of this disease and its aftermath. As you know, Cushing’s is a rarely diagnosed endocrine disorder characterized by hypercortisolism. Cortisol is a hormone produced by the adrenal glands and is vital to regulate the body’s cardivoascular functions and metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to stress. The adrenal glands release cortisol in response to stress, so atheletes, women experiencing pregnancy, and those suffering from alcoholism, panic disorders and malnutrition naturally have higher-than-normal levels of cortisol. People with Cushing’s Syndrome live life with too much cortisol for their bodies as a result of a hormone-secreting tumor. Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the body in a constant state of “fight or flight,” which ravages the body and tears down the body’s major systems including cardivascular, musculo-skeletal, endocrine, etc. Symptoms vary, but the most common symptoms include rapid, unexplained weight gain in the upper body with increased fat around the neck and face (“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the arms and legs; purplish striae (stretch marks) on the abdomen, thighs, buttocks, arms and breasts; poor wound healing and bruising; severe fatigue; depression, anxiety disorders and emotional lability; cognitive difficulties; sleep disorders due to abnormally high nighttime cortisol production; high blood pressure and high blood sugar/diabetes; edema; vision problems; premature osteoperosis; and, in women, signs of hyperandrogenism such as menstrual irregularities, infertility, hirsutism, male-patterned balding and steroid-induced acne. Cushing's Symptoms http://www.cushings-info.com/images/1/12/Lady.gif A sketch of a typical Cushing’s patient. As you can see, the effects of the disease on the body are dramatic. Worse, the psychological and emotional effects of having a chronic, debilitating and disfiguring disease range from distressing to demoralizing. Imagine that, in the space of a year, you became unrecognizable to those around you and to yourself. You look in the mirror, but the person staring back a tyou is a stranger. You endure the stares and looks of pity from those who knew you before Cushing’s, fully aware that they believe you have “let yourself go” or otherwise allowed this to happen to your body. Nothing you can say or do will persuade them otherwise, so at some point, you stop trying and resolve to live your life in a stranger’s body. You feel increasingly sick, but when you explain your array of symptoms to your doctor, you are dismissed as a depressed hypochondriac who needs to diet and exercise more. Worse, your family members think the same thing — and are often quick to tell you how you need to “change your lifestyle” to overcome the effects of what you eventually will discover, once properly diagnosed, is a serious and rare disease. If only it were so simple! No one would choose to have Cushing’s. Those of us who have it would not wish it even on our worst enemy. Most people with Cushing’s long for the ability to do simple things, like walk a flight of stairs without having to sit for half an hour afterwards, or vacuum the house or even unload a dishwasher. One of the worst parts about this disease is the crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism. Not only do we become socially isolated because of the virilzing effects of an endocrine tumor, which drastically alters our appearance, but we no longer feel like ourselves with regard to energy. We would love to take a long bike ride, run three miles or go shopping like we used to — activities, which we took for granted before the disease struck. Those activities are sadly impossible at times for those with advanced stages of the disease. Sometimes, as with any serious illness, performing even basic tasks of daily care such as showering and dressing can exhaust the limited reserves of energy available to a Cushing’s patient. How do we explain to you what it’s like to watch our lives slip away? What response is sufficient to express the grief and frustration over losing so much of ourselves? It is often difficult to find the strength to explain how your well-meaning words of prompting and encouragement (to diet or exercise) only serve to leave us more isolated and feeling alone. Though we wouldn’t want it, we wish our disease were as well-understood as cancer so that those who love us would have a frame of reference for what we go through. With Cushing’s, there is such limited public awareness that we are left to describe the effects of the disease from a void, often with limited understanding from those who love us most, which is disheartening. The most frustrating misconception about this disease is that we somehow are “doing this to ourselves,” or delaying recovery because we need to continue steroid replacement or lack the energy to excercise often, which is sadly false. Trust me that we would love to have that much control over such a terrible disease. Fortunately, there is a good likelihood of remission from Cushing’s in the hands of a skilled pituitary surgeon. Unfortunately, the long-term remission rate is only 56%, meaning that 44% of people with Cushing’s will require a second (sometimes third) pituitary surgery, radiation or bilateraly adrenalectomy to resolve the hypercortisolism. Without successful treatment, Cushing’s leads to death. Even with successful treatment, I will have to be monitored for possible recurrence for the rest of my life. After surgery or other treatment, the recovery period can last months or even years. Because the tumor takes over control of the body’s production of cortisol, the adrenal glands, which had lain dormant prior to surgery, require time to start functioning properly again. Until this happens, we must take synthetic steroids or else risk adrenal insufficiency or adrenal crisis, which can be quickly life-threatening. Careful monitoring of our cortisol levels is critical during the weaning period. It is a rare but sad fact that some people’s adrenal glands never return to normal, and those people must continue to take hydrocortisone or prednisone — sometimes for life — simply in order for the body to perform correctly its basic systemic functions. The physical recovery from surgery can be quick, but the withdrawal from hydrocortisone can be a lengthy and extremely painful process. As I described above, Cushing’s causes a tearing-down of muscles and bone. While there is an over-abundance of cortisol in our bodies (as a result of the tumor), we often can’t feel the effects of the muscle-wasting and bone deterioration because of the anti-inflammatory action of cortisol. Upon weaning, however, these become painfully (literally!) evident. The physical pain experienced while weaning from cortisol has been described as worse than weaning from heroin. When cortisol levels are low, one experiences the symptoms akin to a really bad flu, including severe fatigue (”like a wet cement blanket laid on top of me”); weakness and exhaustion; nausea; headache; vomiting; mental confusion. It is imperative for people who are on replacement steroids after Cushing’s surgery to carry extra Cortef (or injectable Solu-Cortef) with them at all times in addition to wearing a medic alert bracelet so that medical professionals will be alerted to the possiblity of adrenal insufficiency in the event of an adrenal crisis. People who have struggled with Cushing’s Syndrome all hope to return to “normal” at some point. Though none of us want to have Cushing’s, it is often a relief finally to have a correct diagnosis and treatment plan. For many, there is a gradual resolution of many Cushing’s symptoms within a few years of surgery or other successful treatment, and a good quality of life can be achieved. But regrettably, this is not possible in every case. Depending on the severity of the disease and the length of time before diagnosis and treatment, the prognosis can be poor and lead to shortened life expectancy and diminished quality of life. This is not a choice or something we can control, but it is the reality for some people who have suffered the consequences of long-term hypercortisolism. The best support you can give someone who is suffering from Cushing’s or its aftermath is to BELIEVE them and to understand that they are not manufacturing their illness or prolonging recovery. Ask them what they are able (and not able) to do, and then be prepared to help them in ways that matter — whether that be to bring them a meal or help them to run errands, pick up prescriptions from the pharmacy or clean their house. Because it’s these little everyday tasks, which can fall by the wayside when someone has (or has had) Cushing’s, and these are the things we miss the most: doing for ourselves. Ask us questions about the disease, and then actively listen to what we say. We know you don’t know much about Cushing’s — even our doctors sometimes lack information about this rare disease. But know we appreciate the interest and will tell you everything you want to know, because those of us who have it necessarily become experts in it just in order to survive. Thank you for caring about me and for hearing what I am saying in this letter. I know you love me and are concerned about me, and I appreciate that so much. Thank you also for taking the time to read this letter. I look forward to discussing further any questions you might have. In the meantime, I am attaching a brief article written by a woman who recently was diagnosed with Cushing’s. I hope hearing another person’s experiences will help you to understand what I’m going through so that when we talk, we will be coming from a similar starting place. Endocrinologists (doctors who specialize in Cushing's Syndrome and its related issues) realize the medical aspect and know the damaging effects that Cushing's has on the body. Family and friends see their Cushie suffering and know they are hurting physically and often times mentally and emotionally. However, understanding the debilitation of Cushing's and how it can affect every aspect of a person's life can only be truly realized by those who have experienced the syndrome. Cushings Help Organization, Inc., a non-profit family of websites maintained by MaryO, a pituitary Cushing's survivor, provides this letter for patients to provide to their family and friends in hopes of providing a better understanding Cushing's and it's many aspects. We're sorry to hear that your family member or friend has Cushing's Syndrome or suspected Cushing's. A person may feel better at times then at other times. It's common for a Cushing's patient to have burst of energy and then all of a sudden they become lethargic and don't feel like moving a muscle. There are many symptoms that are associated with Cushing's. They include weight gain, fatigue, muscle weakness, shortness of breath, feeling achy all over, headaches, blurred vision, mood swings, high blood pressure, stretch marks (straie), buffalo hump, diabetes, edema and the list goes on. Hormones affect every area of the body. It is important to note that not all patients have every symptom. Even some hallmark symptoms, such as straie or the "buffalo hump", may not be noticable on every patient. Not everyone who has Cushing's will experience the same symptoms, treatment, or recovery. Because not all "Cushies" have these symptoms, it makes diagnosis even more difficult. Cushing's can cause the physical appearance change due to weight gain, hair loss, rosacea, acne, etc. This can be very disturbing when looking in the mirror. Changes in appearance can often cause the Cushing's patient to withdraw from family and friends making it a very lonely illness. Patients often feel alone or withdrawn because few others understand. Cushing's can affect affect anyone of any age although it is more commen in women. Cushing's patients need to be able to take one day at time and learn to listen to their bodies. There will most likely be times when naps are needed during the day and often times may not be able to sleep at night due to surges of cortisol. Your Cushie doesn't expect you to understand Cushing's Syndrome completely. They do need you to be there for them and try to understand to the best of your ability what they feel and not give up on them. Often a Cushing's patient may be moody and say things that they don't mean. If this should happen with your Cushie try not to take it personally and know that it's most likely caused by the elevated cortisol and disturbances in other hormone levels caused by the Cushing's and not from the heart or true feelings of your Cushie. It can be very depressing and frustrating having so many limitations and experience things in life being taken from you. Cushing's patients are sick, not lazy, not hypochondriacs or even the newer term "Cyberchondriacs". If a Cushing's patient says they don't feel like doing something or they express how bad they feel let them know that you believe them. One of the most frustrating things to someone who is sick is to have those you love not believe you or support you. Telling a Cushie to think positive thoughts will not make him/her well and will just be aggrivating. Testing procedures can be lengthy and this can become frustrating for the patient and family. Often, it takes a while for results to come back and this can be stressful. Don't look to far ahead just take one day at a time and deal with the situation that is at hand at the present time. After a diagnosis is made then it's time for treatment. Surgery is usually the best treatment option for Cushing's that is caused by tumors. Don't be surprised if the surgeon's facility wants to run even more tests or redo some of those that have already been done. Your Cushie may have to travel a ways to find a surgeon who is trained in these delicate surgeries and who has performed many of them. Once the diagnosis has been made and treatment has finished then it's time for the recovery process. Not all patients who have surgery are cured and they have to make a choice along with the advice of their doctor as to what their next treatment option will be. The recovery from the surgery itself is similar to any other surgery and will take a while to recover. The recovery process obtained from getting a cure from Cushing's is quiet different from other surgeries. A Cushing's patients body has been exposed to excess cortisol, usually for quite a long time, and has become accustomed it. When the tumor is removed that has been responsible for the excessive cortisol and the body is no longer getting it this causes the body to have withdrawal symptoms. Withdrawal can be very hard causing an array of symptoms muscle aches, weakness, bone and joint pain, emotional disturbances etc. Thank you for reading this and we hope it will help you to understand a little more about Cushing's and the dibilating affect it can have on a person. Thank you for being there and supporting your Cushie during this time in their life. We realize that when a family member has Cushing's it not only affects the individual but other family members and those around them as well. Showing your love and support will encourage a speedy recovery for your Cushie. **Note: Kate died on on June 23, 2014. Read her In Memory page here: http://cushingsbios.com/2014/06/25/in-memory-kate-meyers/
  23. Cushing’s syndrome is a rare disorder that occurs when the body is exposed to too much cortisol. Cortisol is produced by the body and is also used in corticosteroid drugs. Cushing's syndrome can occur either because cortisol is being overproduced by the body or from the use of drugs that contain cortisol (like prednisone). Cortisol is the body’s main stress hormone. Cortisol is secreted by the adrenal glands in response to the secretion of adrenocorticotropic hormone (ACTH) by the pituitary. One form of Cushing’s syndrome may be caused by an oversecretion of ACTH by the pituitary leading to an excess of cortisol. Cortisol has several functions, including the regulation of inflammation and controlling how the body uses carbohydrates, fats, and proteins. Corticosteroids such as prednisone, which are often used to treat inflammatory conditions, mimic the effects of cortisol. Stay tuned for more basic info...
  24. SAN DIEGO, CA, USA I August 10, 2021 I Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, today announced positive preliminary findings from the single ascending dose (SAD) portion of a first-in-human Phase 1 clinical study with CRN04894 demonstrating pharmacologic proof-of-concept for this first-in-class, investigational, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist that is being developed for the treatment of conditions of ACTH excess, including Cushing’s disease and congenital adrenal hyperplasia. “ACTH is the central hormone of the endocrine stress response. Even though we’ve known about its clinical significance for more than 100 years, there has never been an ACTH antagonist available to intervene in diseases of excess stress hormones. This is an important milestone for the field of endocrinology and for our company,” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “I am extremely proud of our team that conceived, discovered and developed CRN04894 this far. This is the second molecule to emerge from our in-house discovery efforts and demonstrate pharmacologic proof of concept. I am very excited to see what it can do in upcoming clinical studies.” The 39 healthy volunteers who enrolled in the SAD cohorts were administered oral doses of CRN04894 (10 mg to 80 mg, or placebo) two hours prior to a challenge with synthetic ACTH. Analyses of basal cortisol levels (before ACTH challenge) showed that CRN04894 produced a rapid and dose-dependent reduction of cortisol by 25-56%. After challenge with a supra-pathophysiologic dose of ACTH (250 mcg), CRN04894 suppressed cortisol (as measured by AUC) up to 41%. After challenge with a disease-relevant dose of ACTH (1 mcg), CRN04894 showed a clinically meaningful reduction in cortisol AUC of 48%. These reductions in cortisol suggest that CRN04894 is bound with high affinity to its target receptor on the adrenal gland and blocking the activity of ACTH. CRN04894 was well tolerated in the healthy volunteers who enrolled in these SAD cohorts and all adverse events were considered mild. “We are very encouraged by these single ascending dose data which clearly demonstrate proof of ACTH antagonism with CRN04894 exposure in healthy volunteers,” stated Alan Krasner, M.D., chief medical officer of Crinetics. “We look forward to completing this study and assessing results from the multiple ascending dose cohorts. As a clinical endocrinologist, I recognize the pioneering nature of this work and eagerly look forward to further understanding the potential of CRN04894 for the treatment of diseases of ACTH excess.” Data Review Conference Call Crinetics will hold a conference call and live audio webcast today, August 10, 2021 at 4:30 p.m. Eastern Time to discuss the results of the CRN04894 SAD cohorts. To participate, please dial 800-772-3714 (domestic) or 212-271-4615 (international) and refer to conference ID 21996541. To access the webcast, please visit the Events page on the Crinetics website. The archived webcast will be available for 90 days. About the CRN04894-01 Phase 1 Study Crinetics is enrolling healthy volunteers in this double-blind, randomized, placebo-controlled Phase 1 study of CRN04894. Participants will be divided into multiple cohorts in the single ascending dose (SAD) and multiple ascending dose (MAD) phases of the study. In the SAD phase, safety and pharmacokinetics are assessed. In addition, pharmacodynamic responses are evaluated before and after challenges with injected synthetic ACTH to assess pharmacologic effects resulting from exposure to CRN04894. In the MAD phase, participants will be administered placebo or ascending doses of study drug daily for 10 days. Assessments of safety, pharmacokinetics and pharmacodynamics will also be performed after repeat dosing. About CRN04894 Adrenocorticotropic hormone (ACTH) is synthesized and secreted by the pituitary gland and binds to melanocortin type 2 receptor (MC2R), which is selectively expressed in the adrenal gland. This interaction of ACTH with MCR2 stimulates the adrenal production of cortisol, a stress hormone that is involved in the regulation of many systems. Cortisol is involved for example in the regulation of blood sugar levels, metabolism, inflammation, blood pressure, and memory formulation, and excess adrenal androgen production can result in hirsutism, menstrual dysfunction, infertility in men and women, acne, cardiometabolic comorbidities and insulin resistance. Diseases associated with excess of ACTH, therefore, can have significant impact on physical and mental health. Crinetics’ ACTH antagonist, CRN04894, has exhibited strong binding affinity for MC2R in preclinical models and demonstrated suppression of adrenally derived glucocorticoids and androgens that are under the control of ACTH, while maintaining mineralocorticoid production. About Cushing’s Disease and Congenital Adrenal Hyperplasia Cushing’s disease is a rare disease with a prevalence of approximately 10,000 patients in the United States. It is more common in women, between 30 and 50 years of age. Cushing’s disease often takes many years to diagnose and may well be under-diagnosed in the general population as many of its symptoms such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity can be incorrectly attributed to other more common disorders. Congenital adrenal hyperplasia (CAH) encompasses a set of disorders that are caused by genetic mutations that result in impaired cortisol synthesis with a prevalence of approximately 27,000 patients in the United States. This lack of cortisol leads to a loss of feedback mechanisms and results in persistently high levels of ACTH, which in turn causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects from improper gonadal development to life-threatening adrenal crisis. About Crinetics Pharmaceuticals Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors. The company’s lead product candidate, paltusotine, is an investigational, oral, selective nonpeptide somatostatin receptor type 2 agonist for the treatment of acromegaly, an orphan disease affecting more than 26,000 people in the United States. A Phase 3 program to evaluate safety and efficacy of paltusotine for the treatment of acromegaly is underway. Crinetics also plans to advance paltusotine into a Phase 2 trial for the treatment of carcinoid syndrome associated with neuroendocrine tumors. The company is also developing CRN04777, an investigational, oral, nonpeptide somatostatin receptor type 5 (SST5) agonist for congenital hyperinsulinism, as well as CRN04894, an investigational, oral, nonpeptide ACTH antagonist for the treatment of Cushing’s disease, congenital adrenal hyperplasia, and other diseases of excess ACTH. All of the company’s drug candidates are new chemical entities resulting from in-house drug discovery efforts and are wholly owned by the company. SOURCE: Crinetics Pharmaceuticals From https://pipelinereview.com/index.php/2021081178950/Small-Molecules/Crinetics-Pharmaceuticals-Oral-ACTH-Antagonist-CRN04894-Demonstrates-Pharmacologic-Proof-of-Concept-with-Dose-Dependent-Cortisol-Suppression-in-Single-Ascending-Dose-Port.html
  25. Rachel Acree, Caitlin M Miller, Brent S Abel, Nicola M Neary, Karen Campbell, Lynnette K Nieman Journal of the Endocrine Society, Volume 5, Issue 8, August 2021, bvab109, https://doi.org/10.1210/jendso/bvab109 Abstract Context Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure. Objective To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL. Design Cross-sectional observational survey. Participants Patients (n = 341) had undergone surgery for CS and were members of the Cushing’s Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS. Results Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P < 0.0001), exercise (40.9% vs 77.6%, P = 0.0001), and activities (44.8% vs 75.5%, P = 0.0016) as useful coping mechanisms in the postsurgical period. Most patients considered family/friends (83.4%) and rest (74.7%) to be helpful. All physicians endorsed educating patients on recovery, but 32.4% (95% CI, 27.3-38.0) of patients denied receiving sufficient information. Some patients did not feel prepared for the postsurgical experience (32.9%; 95% CI, 27.6-38.6) and considered physicians not familiar enough with CS (16.1%; 95% CI, 12.2-20.8). Conclusion Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery. Read the entire article in the enclosed PDF. bvab109.pdf
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