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MaryO

~Chief Cushie~
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  1. Ahead of its New Year's Day decision deadline at the FDA, Xeris Biopharma has snagged an approval for Recorlev, a drug formerly known as levoketoconazole. Based on results from phase 3 studies called SONICS and LOGICS, the FDA approved the drug for adults with Cushing’s syndrome. Xeris picked up Recorlev earlier this year in its acquisition of rare disease biotech Strongbridge Biopharma. It's planning to launch in the first quarter of 2022. Recorlev's approval covers the treatment of endogenous hypercortisolemia in adults with Cushing’s syndrome who aren't eligible for surgery or haven't responded to surgery. Endogenous Cushing's disease is caused by a benign tumor in the pituitary gland that prompts the body to produce elevated levels of cortisol, which over time triggers a range of devastating physical and emotional symptoms for patients. In the SONICS study, the drug significantly cut and normalized mean urinary free cortisol concentrations without a dose increase, according to the company. The LOGICS trial confirmed the drug's efficacy and safety, Xeris says. Cushion's is a potentially fatal endocrine disease, and patients often experience years of symptoms before an accurate diagnosis, the company says. After a diagnosis, they're presented with limited effective treatment options. Following the approval, the company's "experienced endocrinology-focused commercial organization can begin rapidly working to help address the needs of Cushing’s syndrome patients in the U.S. who are treated with prescription therapy,” Xeris CEO Paul R. Edick said in a statement. Aside from its forthcoming Recorlev launch, Xeris markets Gvoke for severe hypoglycemia and Keveyis for primary periodic paralysis. Back in October, the company partnered up with Merck to help reformulate some of the New Jersey pharma giant's monoclonal antibody drugs. From https://www.fiercepharma.com/pharma/xeris-biopharma-scores-fda-approval-for-endogenous-cushing-s-syndrome-drug-recorlev
  2. From https://medicaldialogues.in/diabetes-endocrinology/news/new-test-may-help-in-early-diagnosis-of-cushings-syndrome-frontiers-86467
  3. The National Organization for Rare Disorders (NORD) asks Americans to plan ahead to participate in the Light Up for Rare campaign to raise awareness of rare diseases. NORD is the U.S. sponsor for Rare Disease Day on Feb. 28. The annual awareness day spotlights approximately 7,000 rare diseases that affect more than 300 million people worldwide. More than 25 million Americans and their families are believed to be affected by rare diseases. Participants are encouraged to light or decorate their homes in blue, green, pink, and purple at 7 p.m. local time on Feb. 28. (Blue should be used if only one color is possible.) NORD suggests using NovaBright to light up a building, monument, home, or neighborhood in these rare disease colors. To join the Light Up for Rare campaign, sign up here. Participants should complete the applications required by the landmarks they pledge to light up, which could include historic buildings and homes, schools and universities, businesses, stadiums, bridges, and monuments. A downloadable template request is available to ask cities and buildings to participate in the initiative. Once requests are approved, participants should inform NORD so the organization can track the buildings that will be illuminated for Rare Disease Day. Light Up for Rare is part of the Global Chain of Lights campaign, which aims to unite the rare disease community across the globe and symbolically break the isolation caused by the COVID-19 pandemic. The European Organization for Rare Diseases (EURORDIS), NORD’s counterpart in Europe, is coordinating the Feb. 28 awareness day there along with several patient advocacy groups. On leap years, Rare Disease Day falls on Feb. 29, the rarest day of the year. Download the Light Up for Rare toolkit here. Information on how to illuminate a building can be found here. The general public, as well as caregivers, healthcare professionals, researchers, clinicians, policymakers, and industry representatives are encouraged to participate in Rare Disease Day advocacy and events. Other toolkits and resources for Rare Disease Day are available here. After buildings and landmarks are lit up in Rare Disease Day colors, participants are encouraged to share photos and videos on social media. Please use the #RareDiseaseDay and #ShowYourStripes hashtags so the efforts can be spotlighted. More information at https://rarediseases.org/rare-disease-day/rare-disease-day-light-up-for-rare/
  4. The National Organization for Rare Disorders (NORD) asks Americans to plan ahead to participate in the Light Up for Rare campaign to raise awareness of rare diseases. NORD is the U.S. sponsor for Rare Disease Day on Feb. 28. The annual awareness day spotlights approximately 7,000 rare diseases that affect more than 300 million people worldwide. More than 25 million Americans and their families are believed to be affected by rare diseases. Participants are encouraged to light or decorate their homes in blue, green, pink, and purple at 7 p.m. local time on Feb. 28. (Blue should be used if only one color is possible.) NORD suggests using NovaBright to light up a building, monument, home, or neighborhood in these rare disease colors. To join the Light Up for Rare campaign, sign up here. Participants should complete the applications required by the landmarks they pledge to light up, which could include historic buildings and homes, schools and universities, businesses, stadiums, bridges, and monuments. A downloadable template request is available to ask cities and buildings to participate in the initiative. Once requests are approved, participants should inform NORD so the organization can track the buildings that will be illuminated for Rare Disease Day. Light Up for Rare is part of the Global Chain of Lights campaign, which aims to unite the rare disease community across the globe and symbolically break the isolation caused by the COVID-19 pandemic. The European Organization for Rare Diseases (EURORDIS), NORD’s counterpart in Europe, is coordinating the Feb. 28 awareness day there along with several patient advocacy groups. On leap years, Rare Disease Day falls on Feb. 29, the rarest day of the year. Download the Light Up for Rare toolkit here. Information on how to illuminate a building can be found here. The general public, as well as caregivers, healthcare professionals, researchers, clinicians, policymakers, and industry representatives are encouraged to participate in Rare Disease Day advocacy and events. Other toolkits and resources for Rare Disease Day are available here. After buildings and landmarks are lit up in Rare Disease Day colors, participants are encouraged to share photos and videos on social media. Please use the #RareDiseaseDay and #ShowYourStripes hashtags so the efforts can be spotlighted. More information at https://rarediseases.org/rare-disease-day/rare-disease-day-light-up-for-rare/
  5. This article was originally published here J Endocr Soc. 2021 Nov 24;6(1):bvab176. doi: 10.1210/jendso/bvab176. eCollection 2022 Jan 1. ABSTRACT CONTEXT: Acromegaly (ACM) and Cushing’s disease (CD) are caused by functioning pituitary adenomas secreting growth hormone and ACTH respectively. OBJECTIVE: To determine the impact of race on presentation and postoperative outcomes in adults with ACM and CD, which has not yet been evaluated. METHODS: This is a retrospective study of consecutive patients operated at a large-volume pituitary center. We evaluated (1) racial distribution of patients residing in the metropolitan area (Metro, N = 124) vs 2010 US census data, and(2) presentation and postoperative outcomes in Black vs White for patients from the entire catchment area (N = 241). RESULTS: For Metro area (32.4% Black population), Black patients represented 16.75% ACM (P = .006) and 29.2% CD (P = .56). Among the total 112 patients with ACM, presentations with headaches or incidentaloma were more common in Black patients (76.9% vs 31% White, P = .01). Black patients had a higher prevalence of diabetes (54% vs 16% White, P = .005), significantly lower interferon insulin-like growth factor (IGF)-1 deviation from normal (P = .03) and borderline lower median growth hormone levels (P = .09). Mean tumor diameter and proportion of tumors with cavernous sinus invasion were similar. Three-month biochemical remission (46% Black, 55% White, P = .76) and long-term IGF-1 control by multimodality therapy (92.3% Black, 80.5% White, P = .45) were similar. Among the total 129 patients with CD, Black patients had more hypopituitarism (69% vs 45% White, P = .04) and macroadenomas (33% vs 15% White, P = .05). At 3 months, remission rate was borderline higher in White (92% vs 78% Black, P = 0.08), which was attributed to macroadenomas by logistic regression. CONCLUSION: We identified disparities regarding racial distribution, and clinical and biochemical characteristics in ACM, suggesting late or missed diagnosis in Black patients. Large nationwide studies are necessary to confirm our findings. PMID:34934883 | PMC:PMC8677529 | DOI:10.1210/jendso/bvab176 From https://www.docwirenews.com/abstracts/journal-abstracts/racial-disparities-in-acromegaly-and-cushings-disease-a-referral-center-study-in-241-patients/
  6. 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
  7. 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
  8. This article involves discussion on the use of standard and advanced magnetic resonance imaging (MRI) sequences to diagnose and characterize pituitary adenomas (PAs), including MRI characteristics related to treatment response that could assist in presurgical assessment and planning, and red flags that could suggest an alternative diagnosis. Besides PAs, several other lesions may be found in the sellar region, such as meningiomas, craniopharyngiomas and aneurysms. For assessing lesions in the sella turcica, sellar MRI is preferred. With a systematic MRI approach to the pituitary region, generally the obtained information comprises: the size and shape of the PA, the presence of cysts or hemorrhage within the tumor, its link with the optic pathways and surrounding structures, potential cavernous sinus invasion, sphenoid sinus pneumatization type, and differential diagnosis with other sellar lesions. In the majority of cases, standard protocol serves the purpose; but additional information could be obtained by using some advanced techniques (susceptibility imaging, diffusion-weighted imaging, 3D T2-weighted high-resolution sequences, magnetic resonance elastography, perfusion-weighted imaging) and such information may be important for some cases. Journal Summary Read the full article on Journal of Clinical Endocrinology and Metabolism.
  9. Please help us spread the word to other patients and caregivers about Rare Patient Voice by submitting a short video about your experience with us. Using the Storyvine app, recording a video on your phone is quick, easy, and fun! Videos will be featured on our website, on social media, and in newsletters. Check out and join the growing group of RPV patients and caregivers who have recorded stories! https://rarepatientvoice.com#sharevoice Follow these steps to record and submit your own video! Step 1: Scan with code below with the camera app from your Apple/Android mobile device or click the link below! https://admin.storyvine.com/app_users/sign_up/Sharing_My_Voice Step 2: Download the Storyvine app from the App Store or Google Play Step 3: Film and upload your video! To thank you for recording a video, we will send you a Rarity zebra plushie AND enter you in a raffle to win a $100 Amazon gift card. Congratulations to Stacy of South Carolina, our December 1 raffle winner! Our next raffle will be held in early January.
  10. Extracted and adapted from this series: Post 1) I was officially diagnosed with Cushing's yesterday. I have a CT scan to check on my adrenal tumor and a meeting with my surgeon tomorrow. Hopefully they will schedule surgery for Monday or Tuesday. I have suffered over a year with this, been in congestive heart failure, and believe this cortisol caused my son to be stillborn in March. It's been the year from hell. Please pray that all goes well tomorrow and that I will be cured of this once and for all!! Post 2) Surgery set for the 23rd!!!!! He is planning a right adrenaltectomy. I am so darn excited... Post 3) I'm almost two weeks out of adrenal surgery. He removed the tumor & my gland. This has been the hardest and most painful two weeks of my life. I am already noticing little changes in my body. My skin is getting texture, my hair is not as brittle, my swelling goes down each day, and my nails are white instead of yellow and are stronger. I am getting hair back on my arms, legs, & feet too. I can't wait to continue to get well. I am ready to be able to get out and about. I am pretty much housebound now because of the pain of the withdrawal from the cortisol. I stay on my painkillers and rest in my recliner. Hubby bought it for me because I can't sleep in the bed comfortably. He's the best. He's been sleeping on our air mattress in the living room with me for almost 2 weeks now. He is always there to help me get out of the recliner when I need to. He is amazing. Just wanted to update you all. Getting better everyday. Post 4) I am on 40mg Hydrocortisone daily right now. I will have my first wean close to Christmas. I have an appt. on the 21st with my endo. She is fantastic and saved my life from this stuff. I am so blessed. Today is a rough day. I did have 2 good days in a row which was a huge blessing. Thanks for thinking of me! Post 5) Well, I just survived month 1 of recovery. It was HORRIBLE. I have never had so much pain in my life. I am still on 40 mg and my endo. wants me to wean 10 mg starting on the 27th. We'll see how it goes. I have so much pain, shaking, chills, no sleep NOW. I can't imagine how its going to be on a lower dose. My cortisol level was SO HIGH (2107) before surgery. I knew this withdrawal was going to be terrible. SHe had never seen a level as high as mine before. The lab actually tested my urine twice because they didn't believe it the first time. I am doing a lot of resting right now. I am very nervous about my mother leaving on New Year's Day. I don't know how I am going to handle my 3 year old on my own. I hurt so badly and my vision isn't the greatest yet. Thanks for thinking of me and writing me back. Post 6) We have another call into my endo about my suffering. I have done nothing but shake uncontrollably all day so far. I hurt so badly. I am up every hour at night writhing in pain. I refuse to suffer like this anymore. I want some relief. Thank you so much for all of the advice. It means the world to me. Great news is that I am off my BP meds as of today!! Cardiologist's office said I could quit them. I am thrilled. Now to get this pain under control. Post 7) Endo said we can do whatever I can tolerate. I am now doing 20/20/10 instead of 20/10/10. I am still in pain, but it's a little more tolerable. She said if I am just miserable and can't take the pain, then I can do a bedtime dose. I am going to try melatonin to help me sleep per her suggestion. She wants to see how I do on this new dose and start a slow wean in a few weeks. Post 8) Things have been getting better by the week. New years day was my best physical and mental day so far. I can actually feel my old self returning! !! Today I have lots of bone/muscle pain. Its better than a few weeks ago by far. Yesterday I was able to enjoy my son and play with him for the first time in a long time. I could even dance a little with him. He was so happy. I am down to 20/17.5/10& am handling it well. The pain is tolerable. My hump is almost gone, my stomach is mushy and shrinking, skin is peeling and improving, hair is growing in normally. I will be six weeks out this Wed.
  11. A retrospective analysis of data from more than 170 patients with Cushing syndrome and hyperglycemia provides insight into the effects of curative treatment on hyperglycemia among these patients. Irina Bancos, MD An analysis of retrospective data from a 20-year period details the impact of curative treatment on hyperglycemia among patients with Cushing syndrome. Led by a team of investigators from the Mayo Clinic in Rochester, MN, the study examined a cohort of 174 adult patients with Cushing Syndrome and determined 2-in-3 patients with hyperglycemia experienced resolution or improvement of hyperglycemia after a curative procedure. “This is the first study to analyze the quantitative changes based on the time from the curative surgery, to assess the changes in the intensity of hyperglycemia therapy and identify predictors for hyperglycemia improvement,” wrote investigators. A team led by Irina Bancos, MD, endocrinologist at the Mayo Clinic Rochester, designed the current study with an interest in examining the impact of curative procedures on hyperglycemia and its management in patients with Cushing syndrome from electronic medical record data of patients treated at a referral center from 2000-2019. The primary purpose of the study was to assess the impact of curative procedures on extent of hyperglycemia and the secondary aim was to investigators how baseline factors might influence improvement of hyperglycemia at follow-up. For inclusion in the analysis, patients needed to be at least 18 years of age, diagnosed with Cushing syndrome, and have hyperglycemia treated with a curative procedure from January 1, 2000-November 1, 2019. For the purpose of analysis, Cushing syndrome was diagnosed based on clinical evaluation by an endocrinologist and diagnosed according to the most recent guidelines. Hyperglycemia was defined according to American Diabetes Association guidelines. The primary outcome of interest for the study was the resolution of hyperglycemia following resolution of Cushing syndrome. For the purpose of analysis, resolution was defined as absence of hyperglycemia without the need for antihyperglycemic therapy. Secondary outcomes of interest included changes in HbA1c, and the intensity of hyperglycemia management. Overall, 174 patients were identified for inclusion in the study. This cohort had a median age of diagnosis of 51 (range, 16-82) years and 73% (n=127) were women. When assessing subtype of Cushing syndrome, the most common form was pituitary Cushing syndrome (60.9%), followed by ectopic (14.4%), and adrenal (24.7%). The median baseline HbA1c was 6.9% (range, 4.9-13.1), 24% of patients were not on any therapy for hyperglycemia, 52% were on oral medications, and 37% were on insulin (mean daily units, 58; range, 10-360). When assessing differences between subtypes, results indicated those with pituitary Cushing syndrome were younger at the time of surgery (P=.0009), and included more women (P=.0023), and reported a longer duration of symptoms prior to diagnosis. Investigators noted patients with pituitary Cushing syndrome also had the highest clinical severity score (P <.0001), but patients with ectopic Cushing syndrome had the highest biochemical severity score (P <.0001). Following Cushing syndrome remission and at the end of follow-up, which occurred at a median of 10.5 months, 21% of patients demonstrated resolution of hyperglycemia, 47% demonstrated improvement, and 32% had no change or worsening hyperglycemia. When assessing secondary end points, results indicate HbA1c decreased by 0.84% (P <.0001) and daily insulin dose decreased by a mean of 30 units (P <.0001). Further analysis indicated hypercortisolism severity score (severe vs moderate/mild: OR, 2.4; 95% CI, 1.1-4.9) and Cushing syndrome subtype (nonadrenal vs adrenal: OR, 2.9; 95% CI, 1.3-6.4) were associated with hyperglycemia improvement, but not type of hyperglycemia (diabetes vs prediabetes: OR, 2,1; 95% CI, 0.9-4.9) at the end of follow-up. “We demonstrated that almost 70% of patients with CS demonstrate either resolution or improvement in hyperglycemia following CS remission. As a group, patients demonstrate a decrease in HbA1c, and can be treated with less insulin and fewer non-insulin agents. Patients with more severe hyperglycemia, ACTH-dependent CS, and more severe CS are more likely to improve after surgery,” added investigators. This study, “The impact of curative treatment on hyperglycemia in patients with Cushing syndrome,” was published in The Journal of the Endocrine Society. From https://www.endocrinologynetwork.com/view/obesity-overweight-responsible-for-1-in-5-future-thyroid-cancers-in-australia
  12. https://doi.org/10.1016/j.amsu.2021.102978Get rights and content Under a Creative Commons license open access Highlights • Cushing syndrome is an abnormality resulting from high level of blood glucocorticoids. • Iatrogenic Cushing syndrome due to the overuse of topical corticosteroids is rarely reported. • This report presents a case of topical corticosteroid induced iatrogenic Cushing syndrome in an infant. Abstract Introduction Cushing syndrome (CS) is an endocrinological abnormality that results from a high level of glucocorticoids in the blood. Iatrogenic CS due to the overuse of topical corticosteroids is rarely reported. The current study aims to present a rare case of topical corticosteroid induced iatrogenic CS in an infant. Case presentation A 4-month-old female infant presented with an insidious onset of face puffiness that progressed over a 2-month period. The mother reported to have used a cream containing Betamethasone corticosteroid 5–8 times a day for a duration of 3 months to treat diaper dermatitis. Laboratory findings revealed low levels of adrenocorticotrophic hormone (ACTH) and serum. Abdominal ultrasound showed normal adrenal glands. The topical corticosteroid was halted and physiologic topical hydrocortisone doses were administered. Clinical discussion Infants are more likely to acquire topical corticosteroid induced iatrogenic CS due to their thin and absorptive skin, higher body surface area, and the high prevalence of conditions that necessitates the use of these medications. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis that are most commonly treated with Clobetasol and Bethamethasone. Conclusion Infants are susceptible to develop CS due to topical corticosteroid overuse. Hence, physicians need to consider this in infantile CS cases, and take appropriate measures to avoid their occurrence. Previous article in issue Next article in issue Keywords Cushing syndrome Infant Iatrogenic Topical corticosteroid 1. Introduction Cushing syndrome (CS) is a reversible endocrinological abnormality that results from high level of cortisol or other glucocorticoids in the blood [1]. It can be caused by either endogenous factors such as excess steroid production and secretion due to adrenal or pituitary tumors, or exogenously through prolonged use of corticosteroid medications resulting in iatrogenic CS [2]. Iatrogenic CS due to the overuse of oral or parenteral corticosteroids is common, however, while topical corticosteroids are one of the most widely prescribed medications by dermatologists, they are less frequently reported to cause iatrogenic CS [3,4]. Even though CS is very rare in the pediatric population with an annual incidence of only 5 cases per million, children of the pediatric age have a higher risk of developing iatrogenic CS, which is likely due to the high prevalence of conditions that necessitates the use of topical corticosteroids and the thinness of their skin that can more easily absorb the steroid [5,6]. The aim of the current study is to present a rare case of topical corticosteroid induced iatrogenic CS in an infant. SCARE guidelines are considered in writing this report [7]. 2. Case presentation 2.1. Patient information A 4-month-old female infant presented with an insidious onset of puffiness of the face; the swelling progressed over a period of 2 months without any other associated symptoms. The infant's prenatal, developmental, and family history were insignificant, and she was born full term to consanguineous parents via caesarian delivery. After delivery she did not require neonatal intense care unit (NICU) and was discharged in good health. She has been given both bottle and breastfeeding every one to two hrs, and she has received all the required vaccinations at their proper times. The mother reported to have used a topical corticosteroid cream (Optizol-B cream; a combination of Clotrimazole and Betamethasone) for a period of 3 months with a dose of 5–8 times a day to treat diaper dermatitis of the infant. 2.2. Clinical findings The infant's physical examination revealed facial puffiness (Moon face) with no body edema, and cutaneous examination showed the diaper rash without any other cutaneous manifestations. The infant was vitally stable with no dysmorphic features and no skeletal deformities. Her growth parameters were within normal limits, and her systemic examination was unremarkable. 2.3. Diagnostic approach Laboratory findings revealed low adrenocorticotropic hormone (ACTH) level in the blood measuring 5.9 p.m./l, a serum cortisol level of 24 nmol/l, and normal serum sodium and potassium levels of 144 mEq/l and 4.8 mmol/l, respectively. Abdominal ultrasonography (US) showed normal adrenal glands. 2.4. Therapeutic intervention The topical corticosteroid cream that contained Bethamethasone was halted and oral hydrocortisone was given (10 mg/m2) tapered over one month. The patient was given a card addressing Cushing syndrome to inform the health care providers in case of emergency situation or unexpected surgical intervention. 2.5. Follow-up and outcome The infant's facial puffiness was significantly improved after 7-month follow-up of the patient. 3. Discussion CS is an endocrinological disorder resulting from high glucocorticoid level in the blood, it is categorized into ACTH dependent (due to pituitary tumors or excess ACTH administration) or ACTH independent CS (due to adrenal neoplasms or excessive glucocorticoid intake) [8,9]. Under normal circumstances, ACTH is secreted by the pituitary gland which in turn stimulates the secretion of cortisol by the adrenal glands [10]. Prolonged exogenous corticosteroid administration can lead to a number of adverse effects based on potency and duration of the treatment, including the suppression of hypothalamic-pituitary-adrenal (HPA) axis and iatrogenic CS, severe infections, and failure to thrive [11]. While iatrogenic CS is frequent with prolonged administration of oral or parenteral corticosteroids, it is occurrence due to topical corticosteroids have rarely been reported [12]. Multiple factors can increase the probability of acquiring the condition, such as corticosteroid potency, amount and frequency of application, age, skin quality, presence of occlusion, and duration of application [4]. In general, infants are more likely to develop topical corticosteroid induced iatrogenic CS, this is due to their thin and absorptive skin, higher body surface area, underdeveloped skin barrier, and the high prevalence of conditions that necessitates the use of these medications [5,6]. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis [8]. This was also the case in this study. This is likely because the diaper area provides occlusion, the perineal skin has intrinsically absorptive properties, the steroid causes local skin atrophy, and percutaneous absorption is even more increased as the result of skin inflammation [13]. The most frequently used corticosteroid for the treatment of diaper dermatitis is reported to be Clobetasol followed by Bethamethasone, with a mean application duration of 2.75 (1–17) months to induce cortisol and ACTH levels suppression [4]. Typical clinical manifestations of CS include facial puffiness (Moon face), generalized body edema and obesity, hirsutism, buffalo hump, hypertension, skin fragility, and purple striae [3,5]. The causative corticosteroid in the current case was Bethamethasone that only resulted in facial puffiness (Moon face) without generalized body edema. A specific and definitive diagnostic approach for iatrogenic CS is currently lacking [5]. However, prolonged exogenously administered glucocorticoids can suppress ACTH secretion which results in dismissing the need for proper endogenous production of cortisol [14]. Hence, almost all iatrogenic CS cases are associated with low ACTH and cortisol levels which can aid in the diagnosis of the condition [8]. Same findings were observed in this case. According to multiple studies, exogenous corticosteroid administration can often lead to HPA axis suppression alongside CS [15,16]. However, topical corticosteroid induced iatrogenic CS has been reported without HPA axis suppression [8]. The management of these cases start with the cessation of the causative corticosteroid medication and administration of physiologic topical hydrocortisone [5]. The same approach was followed in this study. In order to prevent the development of this condition in the first-place; clinicians should avoid prescribing high potency corticosteroids in the treatment of infantile dermatological disorders and instead choose low potency topical steroids, and also parents should be advised not to overuse these medications and only apply a thin layer to the affected area [6]. In conclusion, even though iatrogenic CS in infants is rare, overuse of topical corticosteroids can lead to their occurrence. Hence, physicians need to consider extensive steroid use as a causative agent of infantile CS. Appropriate measures need to be taken to avoid their occurrence by prescribing less potent steroids, limiting the use of high potent steroids, and informing parents about adverse effects of steroid overuse in infants. Source of funding None is found. Author statement Soran Mohammed Ahmed: physician managing the case, follow up the patient, and final approval of the manuscript. Shaho F. Ahmed, Snur Othman, Berwn A. Abdulla, Shvan M.Hussein, Abdulwahid M.Salih, and Fahmi H. Kakamad: literature review, writing the manuscript, final approval of the manuscript. Patient consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Provenance and peer review Not commissioned, externally peer-reviewed. Guarantor Fahmi Hussein Kakamad. Declaration of competing interest None to be declared. References [1] A. Tiwari, M. Goel, P. Pal, P. Gohiya Syndrome in the pediatric age group: a rare case report Indian journal of endocrinology and metabolism, 17 (1) (2013), pp. S257-S258 View Record in ScopusGoogle Scholar [2] R.R. Lonser, L. Nieman, E.H. Oldfield Cushing's disease: pathobiology, diagnosis, and management J. Neurosurg., 126 (2) (2017), pp. 404-417 View PDF View Record in ScopusGoogle Scholar [3] A. Ozdemir, V.N. Bas Iatrogenic Cushing's syndrome due to overuse of topical steroid in the diaper area J. Trop. Pediatr., 60 (5) (2014), pp. 404-406 View PDF CrossRefView Record in ScopusGoogle Scholar [4] T. Tempark, V. Phatarakijnirund, S. Chatproedprai, S. Watcharasindhu, V. Supornsilchai, S. Wananukul Exogenous Cushing's syndrome due to topical corticosteroid application: case report and review literature Endocrine, 38 (3) (2010), pp. 328-334 View PDF CrossRefView Record in ScopusGoogle Scholar [5] L. Alkhuder, H. Mawlawi Infantile iatrogenic cushing syndrome due to topical steroids Case reports in pediatrics, 9 (1) (2019), pp. 1-4 View PDF CrossRefView Record in ScopusGoogle Scholar [6] C.W. Ho, K.Y. Loke, Y.Y. Lim, Y.S. Lee Exogenous Cushing syndrome: a lesson of diaper rash cream Hormone research in paediatrics, 82 (6) (2014), pp. 415-418 View PDF CrossRefView Record in ScopusGoogle Scholar [7] R.A. Agha, T. Franchi, C. Sohrabi, G. Mathew, A. Kerwan, A. Thoma, et al. The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg., 84 (2020), pp. 226-230 ArticleDownload PDFView Record in ScopusGoogle Scholar [8] F. Özgüç Çömlek, S. Örüm, S. Aydın, F. Tütüncüler Exogenous Cushing syndrome due to misuse of potent topical steroid Pediatr. Dermatol., 35 (2) (2018), pp. e121-e123 View PDF CrossRefView Record in ScopusGoogle Scholar [9] A. Rustowska, A. Wilkowska, R. Nowicki Iatrogenic Cushing syndrome due to topical glicocorticosteroid therapy Dermatol. Online J., 4 (4) (2013), pp. 503-505 View PDF CrossRefView Record in ScopusGoogle Scholar [10] C.A. Stratakis Diagnosis and clinical genetics of Cushing syndrome in pediatrics Endocrinol. Metabol. Clin, 45 (2) (2016), pp. 311-328 ArticleDownload PDFView Record in ScopusGoogle Scholar [11] M.K. George, A. James, S. Reddy, B. Yasaswini, T.R. Ak, T. Sivakumar Topical steroid induced iatrogenic cushing syndrome in young adult age group: a case report Indian Journal of Pharmacy Practice, 8 (2) (2015), pp. 87-88 View PDF CrossRefView Record in ScopusGoogle Scholar [12] Z. Şiklar, İ. Bostanci, Ö. Atli, Y. Dallar An infantile Cushing syndrome due to misuse of topical steroid Pediatr. Dermatol., 21 (5) (2004), pp. 561-563 View PDF CrossRefView Record in ScopusGoogle Scholar [13] O. Taylor, J.D. Mejia‐Otero, G.M. Tannin, K. Gordon Topical triamcinolone induced Cushing syndrome: a case report Pediatr. Dermatol., 37 (3) (2020), pp. 582-584 View PDF CrossRefView Record in ScopusGoogle Scholar [14] A.W. Root, D.I. Shulman Clinical adrenal disorders Pediatric Endocrinology, Mechanisms, Manifestations, and Management, Lippincott Williams & Wilkins, Philadelphia (2004), pp. 568-600 Google Scholar [15] A. Güven, Ö. Gülümser, T. Özgen Cushing's syndrome and adrenocortical insufficiency caused by topical steroids: misuse or abuse? J. Pediatr. Endocrinol. Metab., 20 (11) (2007), pp. 1173-1182 View Record in ScopusGoogle Scholar [16] F. Tütüncüler, M. Tekin, D. Balci, Ö. Şahaloğlu Iatrogenic Cushing syndrome due to topical steroid administration in an infant Balkan Med. J., 27 (1) (2010), pp. 95-97 View PDF View Record in ScopusGoogle Scholar © 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. From https://www.sciencedirect.com/science/article/pii/S2049080121009286?via%3Dihub
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  14. Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. Keywords: insulin-like growth factor I, growth hormones, Laron syndrome, growth In recent years, new technologies have enabled many advances in the so called growth hormone (GH) axis (fig 1▶). Thus, it has been found that GH secretion from the anterior pituitary is regulated not only by GH releasing hormone (GHRH) and somatostatin (GH secretion inhibiting hormone),1 but also by other hypothalamic peptides called GH secretagogues,2 which seem to act in synergism with GHRH3 by inhibiting somatostatin.4 One of these has been cloned and named Ghrelin.5 The interplay between GHRH and somatostatin induces a pulsatile GH secretion,6 which is highest during puberty. GH induces the generation of insulin-like growth factor 1 (IGF-1, also called somatomedin 1) in the liver and regulates the paracrine production of IGF-1 in many other tissues.7 Figure 1 The cascade of the growth hormone axis. CNS, central nervous system; GH, growth hormone; GHBP, GH binding protein; GH-S, GH secretagogues; IGF-1, insulin-like growth factor 1; IGFBPs, IGF binding proteins; +, stimulation; –, inhibition. Go to: IGF-1 IGF-1 and IGF-2 were identified in 1957 by Salmon and Daughaday8 and designated “sulphation factor” by their ability to stimulate 35-sulphate incorporation into rat cartilage. Froesch et al described the non-suppressible insulin-like activity (NSILA) of two soluble serum components (NSILA I and II).9 In 1972, the labels sulphation factor and NSILA were replaced by the term “somatomedin”, denoting a substance under control and mediating the effects of GH.10 In 1976, Rinderknecht and Humbel11 isolated two active substances from human serum, which owing to their structural resemblance to proinsulin were renamed “insulin-like growth factor 1 and 2” (IGF-1 and 2). IGF-1 is the mediator of the anabolic and mitogenic activity of GH.12 CHEMICAL STRUCTURE The IGFs are members of a family of insulin related peptides that include relaxin and several peptides isolated from lower invertebrates.13 IGF-1 is a small peptide consisting of 70 amino acids with a molecular weight of 7649 Da.14 Similar to insulin, IGF-1 has an A and B chain connected by disulphide bonds. The C peptide region has 12 amino acids. The structural similarity to insulin explains the ability of IGF-1 to bind (with low affinity) to the insulin receptor. THE IGF-1 GENE The IGF-1 gene is on the long arm of chromosome 12q23–23.15,16 The human IGF-1 gene consists of six exons, including two leader exons, and has two promoters.17 Go to: IGF binding proteins (IGFBPs) In the plasma, 99% of IGFs are complexed to a family of binding proteins, which modulate the availability of free IGF-1 to the tissues. There are six binding proteins.18 In humans, almost 80% of circulating IGF-1 is carried by IGFBP-3, a ternary complex consisting of one molecule of IGF-1, one molecule of IGFBP-3, and one molecule of an 88 kDa protein named acid labile subunit.19 IGFBP-1 is regulated by insulin and IGF-120; IGFBP-3 is regulated mainly by GH but also to some degree by IGF-1.21 Go to: The IGF-1 receptor The human IGF-1 receptor (type 1 receptor) is the product of a single copy gene spanning over 100 kb of genomic DNA at the end of the long arm of chromosome 15q25–26.22 The gene contains 21 exons (fig 2▶) and its organisation resembles that of the structurally related insulin receptor (fig 3▶).23 The type 1 IGF receptor gene is expressed by almost all tissues and cell types during embryogenesis.24 In the liver, the organ with the highest IGF-1 ligand expression, IGF-1 receptor mRNA is almost undetectable, possibly because of the “downregulation” of the receptor by the local production of IGF-1. The type 1 IGF receptor is a heterotetramer composed of two extracellular spanning α subunits and transmembrane β subunits. The α subunits have binding sites for IGF-1 and are linked by disulphide bonds (fig 3▶). The β subunit has a short extracellular domain, a transmembrane domain, and an intracellular domain. The intracellular part contains a tyrosine kinase domain, which constitutes the signal transduction mechanism. Similar to the insulin receptor, the IGF-1 receptor undergoes ligand induced autophosphorylation.25 The activated IGF-1 receptor is capable of phosphorylating other tyrosine containing substrates, such as insulin receptor substrate 1 (IRS-1), and continues a cascade of enzyme activations via phosphatidylinositol-3 kinase (PI3-kinase), Grb2 (growth factor receptor bound protein 2), Syp (a phophotyrosine phosphatase), Nck (an oncogenic protein), and Shc (src homology domain protein), which associated to Grb2, activates Raf, leading to a cascade of protein kinases including Raf, mitogen activated protein (MAP) kinase, 5 G kinase, and others.26 Figure 2 Type 1 insulin-like growth factor receptor gene and mRNA. Reproduced with permission from Werner.22 Figure 3 Resemblance between the insulin and insulin-like growth factor 1 (IGF-1) receptors. Go to: Physiology IGF-1 is secreted by many tissues and the secretory site seems to determine its actions. Most IGF-1 is secreted by the liver and is transported to other tissues, acting as an endocrine hormone.27 IGF-1 is also secreted by other tissues,28 including cartilagenous cells, and acts locally as a paracrine hormone (fig 4▶).29 It is also assumed that IGF-1 can act in an autocrine manner as an oncogene.30 The role of IGF-1 in the metabolism of many tissues including growth has been reviewed recently.31,32 Figure 4 Paracrine insulin-like growth factor 1 (IGF-1) secretion and endocrine IGF-1 targets in the various zones of the epiphyseal cartilage growth zone. The following is an analysis of whether IGF-1, the anabolic effector hormone of pituitary GH, is the “real growth hormone”. Go to: Is IGF-1 “a” or “the” growth hormone? The discussion on the role of IGF-1 in body growth will be based on growth in states of IGF-1 deficiency and the effects of exogenous IGF-1 administration. Experiments in nature (gene deletion or gene mutations) or experimental models in animals, such as gene knockouts, help us in this endeavour. In 1966 and 1968,33,34 we described a new type of dwarfism indistinguishable from genetic isolated GH deficiency (IGHD), but characterised by high serum GH values. Subsequent studies revealed that these patients cannot generate IGF-1.35 This syndrome of GH resistance (insensitivity) was named by Elders et al as Laron dwarfism,36 a name subsequently changed to Laron syndrome (LS).37 Molecular studies revealed that the causes of GH resistance are deletions38 or mutations39 in the GH receptor gene, resulting in the failure to generate IGF-1 and a reduction in the synthesis of several other substances, including IGFBP-3. This unique model in humans has enabled the study of the differential effects of GH and IGF-1. Go to: Growth and development in congenital (primary) IGF-1 deficiency (LS) Our group has studied and followed 52 patients (many since birth) throughout childhood, puberty, and into adulthood. We found that newborns with LS are slightly shorter at birth (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine linear growth.40 This fact is enforced by the findings that already at birth, and throughout childhood, skeletal maturation is retarded, as is organ growth.41 These growth abnormalities include a small brain (as expressed by head circumference),41 a small heart (cardiomicria),42 and acromicria (small chin, resulting from underdevelopment of the facial bones, small hands, and small feet).33,34 IGF-1 deficiency also causes underdevelopment and weakness of the muscular system,43 and impairs and weakens hair44 and nail growth. These findings are identical to those described in IGHD.45 IGF-1 deficiency throughout childhood causes dwarfism (final height if untreated, 100–135 cm in female and 110–142 cm in male patients),40,41 with an abnormally high upper to lower body ratio.41 One patient reported from the UK was found to have a deletion of exons 4 and 5 of the IGF-1 gene and he too was found to have severe growth retardation.46 Impaired growth and skeletal development in the absence of IGF-1 were confirmed in mice using knockout (KO) of the IGF-1 gene or GH receptor gene.47–49 Knockout of the IGF-1 gene or the IGF-1 receptor gene reduces the size of mice by 40–45%.49 Lack of the IGF-1 receptor is lethal at birth in mice owing to respiratory failure caused by impaired development of the diaphragm and intercostal muscles.49 In another model, the mice remained alive and their postnatal growth was reduced.50 In conclusion, findings in humans and in animals show that IGF-1 deficiencies causes pronounced growth retardation in the presence of increased GH values. The following is a summary of the results of the growth stimulating effects of the administration of exogenous IGF-1 to children and experimental data. Go to: Growth promoting effects of IGF-1 The first demonstration that exogenous IGF-1 stimulates growth was the administration of purified hormone to hypophysectomised rats.51,52 After the biosynthesis of IGF-1 identical to the native hormone,53 trials of its use in humans were begun; first in adults54 and then in children.55,56 Our group was the first to introduce long term administration of biosynthetic IGF-1 to children with primary IGF-1 deficiency—primary GH insensitivity or LS.57 The finding that daily IGF-1 administration raises serum alkaline phosphatose, which is an indicator of osteoblastic activity, and serum procollagen,57,58 in addition to IGFBP-3,21 led to long term treatment. Treatment of patients with LS was also initiated in other parts of the world.59–62 The difference between us and the other groups was that we used a once daily dose, whereas the others administered IGF-1 twice daily.60 Table 1▶ compares the linear growth response of children with LS treated by four different groups. It can be seen that before treatment the mean growth velocity was 3–4.7 cm/year and that this increased after IGF-1 treatment to 8.2–9.1 cm/year, followed by a lower velocity of 5.5–6.4 cm/year in the next two years. (In GH treatment the highest growth velocity registered is also in the first year of treatment.) Figure 5▶ illustrates the growth response to IGF-1 in eight children during the first years of treatment.65 Ranke and colleagues60 reported that two of their patients had reached the third centile (Tanner), as did the patient of Krzisnik and Battelino66; however, most patients did not reach a normal final height. The reasons may be late initiation of treatment, irregular IGF-1 administration, underdosage, etc. Ranke et al conclude that long term treatment of patients with LS promoted growth and, if treatment is started at an early age, there is a considerable potential for achieving height normalisation.60 Because no patient in our group was treated since early infancy to final height we cannot confirm this opinion. Figure 5 Growth velocity before and during insulin-like growth factor 1 (IGF-1) treatment. Note that in infancy, when the non-growth hormone/IGF-1 dependent growth velocity is relatively high (but low for age), the change induced by IGF-1 administration is less than in older children. Table 1 Linear growth response of children with Laron syndrome treated by means of insulin-like growth factor 1 (IGF-1) At start Growth velocity (cm/year) Year of treatment Authors Year Ref. N Age range (years) BA (years) Ht SDS (m) IGF-1 dose (μg/kg/day) 0 1st 2nd 3rd (n = 26) (n = 18) Ranke et al 1995 61 31 3.7–19 1.8–13.3 −6.5 40–120 b.i.d. 3.9 (1.8) 8.5 (2.1) 6.4 (2.2) (n = 5) (n = 5) (n = 1) Backeljauw et al 1996 62 5 2–11 0.3–6.8 −5.6 80–120 b.i.d. 4.0 9.3 6.2 6.2 (n = 9) (n = 6) (n = 5) Klinger and Laron 1995 63 9 0.5–14 0.2–11 −5.6 150–200 i.d 4.7 (1.3) 8.2 (0.8) 6 (1.3) 4.8 (1.3)* (n = 15) (n = 15) (n = 6) Guevarra-Aguirre et al 1997 64 15 3.1–17 4.5–9.3 120 b.i.d. 3.4 (1.4) 8.8 (11) 6.4 (1.1) 5.7 (1.4) (n = 😎 (n = 😎 Guevarra-Aguire et al 64 8 80 b.i.d. 3.0 (1.8) 9.1 (2.2) 5.6 (2.1) Open in a separate window Growth velocity values are mean (SD). *The younger children had a growth velocity of 5.5 and 6.5 cm/year. BA, bone age; b.i.d., twice daily; CA, chronological age; i.d., once daily; Ht SDS, height standard deviation score. When the growth response to GH treatment in infants with IGHD was compared with that of IGF-1 in infants with LS we found that the infants with IGHD responded faster and better than those with LS.67 However, the small number of patients and the differences in growth retardation between the two groups makes it difficult to reach a conclusion. Both hormones stimulated linear growth, but GH seemed more effective than IGF-1. One cause may be the greater growth deficit of the infants with LS than those with IGHD, an insufficient dose of IGF-1, or that there is a need for some GH to provide an adequate stem cell population of prechondrocytes to enable full expression of the growth promoting action of IGF-1, as postulated by Green and colleagues68 and Ohlson et al.69 All the above findings based on a few clinical studies with small groups of patients and a few experimental studies remain at present controversial. The crucial question is whether there are any, and if so, whether there are sufficient IGF-1 receptors in the “progenitor cartilage zone” of the epiphyseal cartilage (fig 4▶) to respond to endocrine and exogenous IGF-1. Using the mandibular condyle of 2 day old ICR mice, Maor et al showed that these condyles, which resemble the epiphyseal plates of the long bones, contain IGF-1 and high affinity IGF-1 receptors also in the chondroprogenitor cell layers, which enables them to respond to IGF-1 in vitro.70 Sims et al,71 using mice with GH receptor KO showed that IGF-1 administration stimulates the growth (width) of the tibial growth plate and that IGF-1 has a GH independent effect on the growth plate. These findings are similar to those found when treating hypophysectomised rats with IGF-1.51,52 In conclusion, IGF-1 is an important growth hormone, mediating the anabolic and linear growth promoting effect of pituitary GH protein. 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  15. Endocrinology Research Centre, 117292 Moscow, Russia Author to whom correspondence should be addressed. Academic Editor: Spyridon N. Karras Nutrients 2021, 13(12), 4329; https://doi.org/10.3390/nu13124329 Received: 12 November 2021 / Revised: 26 November 2021 / Accepted: 27 November 2021 / Published: 30 November 2021 (This article belongs to the Special Issue Vitamin D in the New Decade: Facts, Controversies, and Future Perspectives for Daily Clinical Practice) Download PDF Browse Figures Citation Export Abstract In this study we aimed to assess vitamin D metabolism in patients with Cushing’s disease (CD) compared to healthy individuals in the setting of bolus cholecalciferol treatment. The study group included 30 adults with active CD and the control group included 30 apparently healthy adults with similar age, sex and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. All data were analyzed with non-parametric statistics. Patients with CD had similar to healthy controls 25(OH)D3 levels (p > 0.05) and higher 25(OH)D3/24,25(OH)2D3 ratios (p < 0.05) throughout the study. They also had lower baseline free 25(OH)D levels (p < 0.05) despite similar DBP levels (p > 0.05) and lower albumin levels (p < 0.05); 24-h urinary free cortisol showed significant correlation with baseline 25(OH)D3/24,25(OH)2D3 ratio (r = 0.36, p < 0.05). The increase in 25(OH)D3 after cholecalciferol intake was similar in obese and non-obese states and lacked correlation with BMI (p > 0.05) among patients with CD, as opposed to the control group. Overall, patients with CD have a consistently higher 25(OH)D3/24,25(OH)2D3 ratio, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. The observed difference in baseline free 25(OH)D levels is not entirely clear and requires further study. Keywords: vitamin D; pituitary ACTH hypersecretion; cholecalciferol; vitamin D-binding protein 1. Introduction Cushing’s disease (CD) is one of the disorders associated with endogenous hypercortisolism and is caused by adrenocorticotropic hormone (ACTH) hyperproduction originating from pituitary adenoma [1]. Skeletal fragility is a frequent complication of endogenous hypercortisolism, and fragility fractures may be the presenting clinical feature of disease. The prevalence of osteoporosis in endogenous hypercortisolism as assessed by dual-energy X-ray absorptiometry (DXA) or incidence of fragility fractures has been reported to be up to 50%. Osteoporosis in CD patients has a complex multifactorial pathogenesis, characterized by a low bone turnover and severe suppression of bone formation [2]. Exogenous glucocorticoids are used in the treatment of a wide range of diseases and it is estimated that 1–2% of the population is receiving long-term glucocorticoid therapy. As a consequence, glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis [3]. Native vitamin D (in particular D3, or cholecalciferol) and its active metabolites (such as alfacalcidol) are universally considered as the essential components of the osteoporosis management [4,5]. The search for the optimal treatment of bone complications during chronic exposure to glucocorticoid excess provoked the investigation of vitamin D metabolism in this state. Early studies on this topic were focused predominantly on the general vitamin D status (assessed as 25(OH)D level) and on the levels of the active vitamin D metabolite (1,25(OH)2D). These studies showed inconsistent results, reporting that the chronic excess of glucocorticoids decreased [6,7,8,9], increased [10,11,12] or did not change [13,14,15] the levels of 25(OH)D or 1,25(OH)2D. A likely reason for such inconsistency might have been the high heterogeneity of the studied groups. Some of these studies were performed in humans [6,7,9,10,11,12,13,15] and some in animal models [8,14], and only several of them included subjects with specifically endogenous hypercortisolism [10,12,14,15]. Only two studies assessed both the levels of the active (1,25(OH)2D) and the inactive (24,25(OH)2D) vitamin D metabolites in endogenous hypercortisolism. One of them lacked control group and reported low-normal 24,25(OH)2D levels in patients with Cushing’s syndrome [10]. The second study by Corbee et al. reported similar circulating concentrations of 25(OH)D, 1,25(OH)2D and 24,25(OH)2D in studied groups of dogs regardless of either the presence of CD or hypophysectomy status [14]. Several experimental studies were performed to evaluate the impact of glucocorticoid excess on the enzymes involved in vitamin D metabolism. In mouse kidney glucocorticoid treatment increased 24-hydroxylase expression [16] and 24-hydroxylase activity [17]. An increased expression of 24-hydroxylase was also shown in rat osteoblastic and pig renal cell cultures treated with 1,25(OH)2D [18]. Dhawan and Christakos showed that 1,25(OH)2D-induced transcription of 24-hydroxylase was glucocorticoid receptor-dependent [19]. However, some works showed conflicting results. In particular, the steroid and xenobiotic receptor (SXR) which is activated by glucocorticoids [20], repressed 24-hydroxylase expression in human liver and intestine in work by Zhou et al. [21]. Lower 24-hydroxylase expression was observed in the brain and myocardium of glucocorticoid-treated rats [22] as well as in human osteosarcoma cells and human osteoblasts [23]. Nevertheless, based on experimental data, it has been suggested that the acceleration of 25(OH)D catabolism in the presence of glucocorticoid excess may predispose to vitamin D deficiency. Yet, relatively recent meta-analysis of the studies assessing 25(OH)D levels in chronic glucocorticoid users showed that serum 25(OH)D levels in these patients were suboptimal and lower than in healthy controls, but similar to steroid-naive disease controls [24]. Glucocorticoids also affect calcium and phosphorus homeostasis. In particular, they were shown to reduce gastrointestinal absorption by antagonizing vitamin D action (reducing the expression of genes for proteins involved in calcium transport—epithelial Ca channel TRPV6 and calcium-binding protein calbindin-D9K) [25]. Glucocorticoids increased fractional calcium excretion due to mineralocorticoid receptor-mediated action on epithelial sodium channels [26]. Hypercalciuria is highly prevalent in people with CD [27]. These effects might result in a negative calcium balance, although plasma ionized calcium was normal in people and dogs with hypercortisolism compared to control subjects [12,28]. Glucocorticoids also reduced tubular phosphate reabsorption by inhibiting tubular expression of the sodium gradient-dependent phosphate transporter, and induced phosphaturia [29], which was accompanied by phosphate lowering in humans [12]. Overall, current data on vitamin D status in hypercortisolism are conflicting and need clarification. In particular, clinical data on the state of vitamin D metabolism in the state of glucocorticoids excess are quite scarce. Studies were very heterogeneous in design, some lacked a control group, and the absolute majority of the studies were performed before the introduction of vitamin D measurement standardization [30]. Nevertheless, determining the optimal vitamin D treatment regimen in these high-risk patients is fairly relevant. The aim of this study was to assess vitamin D metabolism in patients with CD compared to healthy individuals particularly in the setting of cholecalciferol treatment. 2. Materials and Methods 2.1. Study Population and Design The study group included 30 adult patients with CD admitted for inpatient treatment at a tertiary pituitary center. Diagnosis of CD was established in accordance with the federal guidelines [31]. All patients were confirmed to be positive for endogenous hypercortisolism in at least two of the following tests: 24-h urine free cortisol (UFC) greater than the normal range for the assay and/or serum cortisol > 50 nmol/L after the 1-mg overnight dexamethasone suppression test and/or late-night salivary cortisol greater than 9.4 nmol/L). All patients also had morning ACTH ≥ 10 pg/mL and pituitary adenoma ≥ 6 mm identified by magnetic resonance imaging (MRI) or a positive for CD bilateral inferior petrosal sinus sampling (BIPSS). MRI was performed using a GE Optima MR450w 1.5T with Gadolinium (Boston, MA, USA). BIPSS was performed according to the standard procedure described elsewhere [32,33]. The control group included 30 apparently healthy adult individuals recruited from the staff and the faculty of the facility. Inclusion criteria were age from 18 to 60 for both groups and the presence of the disease activity for the study group (defined as the presence of endogenous hypercortisolism at the time of participation in the study). Exclusion criteria for both groups were: vitamin D supplementation for 3 months prior to the study; severe obesity (body mass index (BMI) ≥ 35 kg/m2); pregnancy; the presence of granulomatous disease, malabsorption syndrome, liver failure; decreased GFR (less than 60 mL/min per 1.73 m2); severe hypercalcemia (total serum calcium > 3.0 mmol/L); allergic reactions to vitamin D medications; 25(OH)D level more than 60 ng/mL (determined by immunochemiluminescence analysis). All patients were recruited in the period from October 2019 to April 2021. The study protocol (ClinicalTrials.gov Identifier: NCT04844164) was approved by the Ethics Committee of Endocrinology Research Centre, Moscow, Russia on 10 April 2019 (abstract of record No. 6), all patients signed informed consent to participate in the study. All participants received standard therapeutic dose (150,000 IU) of an aqueous solution of cholecalciferol (Aquadetrim®, Medana Pharma S.A., Sieradz, Poland) orally as a single dose [34]. Blood and urine samples were obtained before the intake as well as on days 1, 3 and 7 after administration; time points of sample collection were determined based on the authors’ previous work evaluating changes in 25(OH)D levels after a therapeutic dose of cholecalciferol [35]. The assessment included serum biochemical parameters (total calcium, albumin, phosphorus, creatinine, magnesium), parathyroid hormone (PTH), vitamin D-binding protein (DBP), vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D and urine biochemical parameters (calcium- and phosphorus-creatinine ratios in spot urine). 2.2. Socio–Demographic and Anthropometric Data Collection At the baseline visit, patients underwent a questionnaire aimed to assess their lifestyle: the presence of unhealthy habits, physical activity level, balanced diet (consumption of dairy products, meat, coffee, soft drinks), exposure to ultraviolet (UV) radiation (solarium and sunscreen usage, traveling south and the number of daytime walks in the sunny weather in the 3 months preceding study participation). Smoking status was classified as current smoker, former smoker and non-smoker; current and former smokers were collectively referred to as total smokers. A unit of alcohol was defined as a glass of wine, a bottle of beer or a shot of spirits, approximating 10–12 g ethanol. Serving of dairy products was defined as 100 g of cottage cheese, 200 mL of milk, 125 g of yogurt or 30 g of cheese. Patients’ weight was measured in light indoor clothing with a medical scale to the nearest 100 g, and their height with a wall-mounted stadiometer to the nearest centimeter. BMI was calculated as weight in kilograms divided by height in meters squared. 2.3. Laboratory Measurements Morning ACTH (reference range 7–66 pg/mL), serum cortisol after a low-dose dexamethasone suppression test (cutoff value for suppression, 50 nmol/L [36]), late-night salivary cortisol (reference range 0.5–9.4 nmol/L [37]) were assayed by electrochemiluminescence assay using a Cobas 6000 Module e601 (Roche, Rotkreuz, Switzerland). The 24-h UFC (reference range 60–413 nmol/24 h) was measured by an immunochemiluminescence assay (extraction with diethyl ether) on a Vitros ECiQ (Ortho Clinical Diagnostics, Raritan, NJ, USA). Total 25(OH)D levels (25(OH)D2 + 25(OH)D3; reference range 30–100 ng/mL) at the baseline visit were determined by the immunochemiluminescence analysis (Liaison, DiaSorin, Saluggia, Italy). PTH levels were evaluated by the electrochemiluminescence immunoassay (ELECSYS, Roche, Basel, Switzerland; reference range for this and subsequent laboratory parameters are given in the Results section for easier reading). Biochemical parameters of blood serum and urine were assessed by the ARCHITECT c8000 analyzer (Abbott, Chicago, IL, USA) using reagents from the same manufacturer according to the standard methods. Serum DBP and free 25(OH)D levels were measured by enzyme-linked immunosorbent assay (ELISA) using commercial kits. The assay used for free 25(OH)D levels assessment (DIAsource, ImmunoAssays S.A., Ottignies-Louvain-la-Neuve, Belgium) has <6.2% intra- and inter-assay coefficient of variation (CV) at levels 5.8–9.6 pg/mL. The assay used for DBP levels assessment (Assaypro, St Charles, MO, USA) has 6.2% average intra-assay CV and 9.9% average inter-assay CV. The levels of vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3) in serum were determined by ultra-high performance liquid chromatography in combination with tandem mass spectrometry (UPLC-MS/MS) using an in-house developed method, described earlier [38]. With this technique, the laboratory participates in DEQAS quality assurance program (lab code 2388) and the results fall within the target range for the analysis of 25(OH)D and 1,25(OH)2D metabolites in human serum (Supporting Information, Figures S1 and S2). All UPLC-MS/MS measurements were made after the first successful completion (5/5 samples within the target range) of the DEQAS distributions for both analytes simultaneously. Each batch contained control samples (analytes in blank serum) with both high and low analyte concentrations. The samples were barcoded and randomized prior to the measurements to eliminate analyst-related errors. Serum samples (3 aliquots) collected at each visit were either transferred directly to the laboratory for biochemical analyzes, total 25(OH)D and PTH measurement (1 aliquot) or were stored at −80 °C avoiding repeated freeze-thaw cycles for measurement of DBP, free 25(OH)D and vitamin D metabolites at a later date (2 aliquots). Albumin-adjusted serum calcium levels were calculated using the formula [39]: total plasma calcium (mmol/L) = measured total plasma calcium (mmol/L) + 0.02 × (40 − measured plasma albumin (g/L)). Baseline free 25(OH)D levels were also calculated using the formula introduced by Bikle et al. [40,41]. The affinity constant for 25(OH)D and albumin binding (Kalb) used for the calculation was equal 6 × 105 M−1, and affinity constant for 25(OH)D and DBP binding (KDBP) was equal 7 × 108 M−1. Free 25(OH)D=total 25(OH)D1+Kalb∗albumin+KDBP∗DBP 2.4. Statistical Analysis Statistical analysis was performed using Statistica version 13.0 (StatSoft, Tulsa, OK, USA). All data were analyzed with non-parametric statistics and expressed as median [interquartile range] unless otherwise specified. Mann-Whitney U-test and Fisher’s exact two-tailed test were used for comparisons between two groups. Friedman ANOVA was performed to evaluate changes in indices throughout the study and pairwise comparisons using Wilcoxon test with adjustment for multiple comparisons (Bonferroni) were also made if the Friedman ANOVA was significant. Spearman rank correlation method was used to obtain correlation coefficients among indices. A p-value of less than 0.05 was considered statistically significant. When adjusting for multiple comparisons, a p-value greater than the significance threshold, but less than 0.05 was considered as a trend towards statistical significance. 3. Results The groups were similar in terms of age, sex and BMI (p > 0.05). Both groups consisted predominantly of young and middle-aged women and the majority of patients were overweight or moderately obese (Table 1). Patients from the study group presented with lower screening levels of total 25(OH)D (p < 0.05). Table 1. General characteristics of the patients at the baseline visits. For detailed description of the data format please refer to the Section 2. The features of the underlying disease course in the study group are listed in Table 2. 15 patients (50%) had diabetes mellitus with an almost compensated state at the time of participation in the study, and 7 patients (23%) reported a history of low-energy fractures. Table 2. Characteristics of the patients with Cushing’s disease (CD) in terms of the underlying disease. The groups did not differ significantly in the reported smoking status, the level of daily physical activity, dietary habits and UV exposure (p > 0.05) and although there was a slight difference in alcohol consumption (p < 0.05), the absolute values were minor in both groups (Table 3). Table 3. Questionnaire results. 3.1. Baseline Laboratory Evaluation Detailed results of laboratory studies are presented in Table 4 and Table 5. Table 4. Changes in the levels of the biochemical parameters and parathyroid hormone (PTH) during the study. Table 5. Changes in the levels of free 25(OH)D, vitamin D-binding protein (DBP) and vitamin D metabolites during the study. Patients with CD had several alterations in biochemical parameters, in particular, lower baseline serum creatinine and albumin levels, while magnesium levels were higher than in the control group (p < 0.05). They also had higher levels of urine phosphorus-creatinine ratio (p < 0.05). The rest of the studied biochemical parameters did not show significant difference between the groups (p > 0.05). 3 patients (10%) from the study group and 5 patients (17%) from the control group had secondary hyperparathyroidism, one patient with CD (3%) was diagnosed with mild primary hyperparathyroidism. As for the assessment of vitamin D metabolism, unexpectedly the levels of 25(OH)D3 occurred to be equal in the groups (p > 0.05), with only two patients (7%) from the study group and one patient (3%) from the control group having sufficient vitamin D levels, according to the Endocrine Society and the Russian Association of Endocrinologists guidelines (≥30 ng/mL [34,42]). The levels of the active vitamin D metabolite—1,25(OH)2D3—were equal between the groups as well (p > 0.05), whereas the levels of 3-epi-25(OH)D3 and 24,25(OH)2D3 were lower in CD patients. Further calculation of 25(OH)D3/24,25(OH)2D3 and 25(OH)D3/1,25(OH)2D3 ratios corresponded to the observed levels of metabolites: 25(OH)D3/24,25(OH)2D3 ratio was higher in the study group (p < 0.05) assuming lower 24-hydroxylase activity and 25(OH)D3/1,25(OH)2D3 ratio was equal between the groups (p > 0.05). Levels of free 25(OH)D were lower in CD patients (p < 0.05) and the levels of DBP did not differ between the groups (p > 0.05). Although calculated free 25(OH)D showed prominent positive correlation with the measured free 25(OH)D in both groups (r = 0.63 in the study group, r = 0.87 in the control group, p < 0.05), the association appeared to be weaker in the study group. In the control group, DBP levels correlated with both measured and calculated 25(OH)D levels (r = −0.48, p < 0.05 and r = −0.69, p < 0.05 respectively), while in patients with CD there was no association with measured free 25(OH)D levels (r = 0.04, p > 0.05 and r = −0.50, p < 0.05 respectively). Correlation with 24-h UFC in CD patients was observed for serum albumin level (r = −0.37, p < 0.05) and urine calcium-creatinine ratio (r = 0.51, p < 0.05) among assessed biochemical parameters, and only with 25(OH)D3/24,25(OH)2D3 ratio among the parameters of vitamin D metabolism (r = 0.36, p < 0.05). 3.2. Laboratory Evaluation after the Intake of Cholecalciferol All patients from the study group and 28 patients (93%) from the control group completed the study. The observed baseline differences in biochemical parameters mostly preserved during the follow-up. In the study group there was an increase in serum phosphorus levels by Day 1 (p = 0.006) and a tendency to an increase in the urine phosphorus-creatinine ratio by Day 7 (p = 0.02). Patients from the control group showed a clinically insignificant increase in serum creatinine levels by Day 1 (p = 0.002) and a non-significant trend towards an increase in serum total and albumin-adjusted calcium (p = 0.01 for both measurements). No change in PTH levels was observed in patients with CD during the follow-up (p > 0.05), while in the control group there was a tendency for PTH to decrease by Day 3 (p = 0.02). There were no new cases of hypercalcemia in both groups during the follow-up. One patient from the study group and one patient from the control group had persistently increased urine calcium-creatinine ratio throughout the study. Four patients from the study group (13%) and none from the control group developed hypercalciuria during the follow-up, however these patients had no clinical manifestations during the observation period. By Day 7, 25 patients (83%) from the study group and 22 patients (79%) reached sufficient 25(OH)D3 levels (≥30 ng/mL). Levels of 25(OH)D3 continued to increase by Day 3 in both groups (p < 0.001), after which tended to decrease in the study group (p = 0.01) and remained stable in the control group (p = 0.65). The increase in 25(OH)D3 after cholecalciferol intake was equal between the groups (18.5 [15.9; 22.5] ng/mL in the study group vs. 16.6 [13.1; 19.8] ng/mL in the control group, p > 0.05). In the presence of obesity, Δ25(OH)D3 was higher in the CD patients than in the control group (18.3 [14.2; 23.0] vs. 12.1 [10.0; 13.1] ng/mL, p < 0.05), while in non-obese patients no difference was observed (p > 0.05). Obese and non-obese patients with CD had equal Δ25(OH)D3 (18.3 [14.2; 23.0] vs. 19.6 [16.0; 21.5] ng/mL, p > 0.05), while in the control group it was significantly lower in obese patients (12.1 [10.0; 13.1] vs. 18.3 [15.3; 21.4] ng/mL, p < 0.05). BMI showed significant correlation with Δ25(OH)D3 only in the control group (r = −0.47, p < 0.05), while in CD patients there was no such association (r = −0.06, p > 0.05) (Figure 1). Figure 1. Relationship between Δ25(OH)D3 and BMI in groups. 1,25(OH)2D3 levels increased in CD patients by Day 1 and were stable during the follow-up in the control group. The rest of the studied parameters of vitamin D metabolism changed in a similar way between groups: 3-epi-25(OH)D3 levels increased until the Day 3, after which they decreased by the Day 7; 24,25(OH)2D3 levels showed more graduate elevation throughout the follow-up. In both groups 25(OH)D3/24,25(OH)2D3 ratios increased by Day 1, after which they decreased by Day 7, and 25(OH)D3/1,25(OH)2D3 ratios increased by Day 1, after which they remained stable. DBP levels didn’t change and free 25(OH)D levels showed an increase in both groups during the follow-up. The levels of 25(OH)D2 did not exceed 0.5 ng/mL in all examined individuals throughout the study. Among assessed parameters of vitamin D metabolism, higher 25(OH)D3/24,25(OH)2D3 ratios in the study group was the only difference between the groups which remained significant throughout the observation period (p < 0.05) (Figure 2). Figure 2. Dynamic evaluation of 25(OH)D3/24,25(OH)2D3 ratios in groups. 4. Discussion The main goal of our study was to evaluate the 25(OH)D3 levels and its response to the therapeutic dose of cholecalciferol in patients with CD as compared to healthy individuals. We observed no difference in baseline 25(OH)D3 assessed by UPLC-MS/MS between groups. Similar to our data were obtained in most studies conducted specifically in the state of endogenous hypercortisolism in humans [12,15] and dogs [14]. The study by Kugai et al. lacked control group and reported plasma levels of 25(OH)D corresponding to the vitamin D deficiency in most of the examined patients [10], while in our study only 2/3 of the patients with CD had 25(OH)D levels below 20 ng/mL. As for exogenous hypercortisolism, the meta-analysis aimed to explore serum 25(OH)D levels in glucocorticoid users showed lower levels than in healthy controls, but similar to steroid-naive disease controls, thus causing concern regarding the influence of the disease status on 25(OH)D levels [24]. Somewhat surprisingly, we obtained significantly discordant results in the study group when screening total 25(OH)D by ELISA and when measuring baseline 25(OH)D3 by UPLC-MS/MS, since the initial difference between the groups revealed by ELISA data with lower total 25(OH)D levels in the study group was not replicated by UPLC-MS/MS. It should be noted that our ELISA method did not participate in an external quality control program at the time of the study unlike UPLC-MS/MS; furthermore, a lower analytical performance was previously described for this technique with tendency for low specificity and lower measurement results [45]. When assessing other parameters of vitamin D metabolism, the most significant finding was the higher 25(OH)D3/24,25(OH)2D3 ratio in CD patients, both initially and during the observation after the intake of the cholecalciferol loading dose, indicating consistently reduced activity of 24-hydroxylase, the main enzyme of vitamin D catabolism. Earlier clinical and experimental studies also suggested altered activity of enzymes of vitamin D metabolism in hypercortisolism. However, these studies were heterogeneous and aimed predominantly at studying the activity of 1α-hydroxylase [7,8,10,11,12,14], which was not altered in patients with CD as compared to healthy individuals in our study. In the setting of the short-term glucocorticoid administration, Lindgren et al. showed transient increase in 24,25(OH)2D3 levels in rats [8], while in the study of Hahn et al. there was no change in 24,25(OH)2D3 levels [11]. Dogs with CD had similar 24,25(OH)2D3 levels before and after hypophysectomy as well as compared to control dogs [14]. The only study of considerably similar design by Kugai et al. reported low-normal 24,25(OH)2D3 in patients with Cushing’s syndrome [10], which is consistent with our result, as well as some experimental works indicative of suppression on CYP24A1 expression by glucocorticoids in human osteoblasts [23], liver and intestine [21] and in rat brain and myocardium [22]. However, in the present work, the activity of 24-hydroxylase in patients with hypercortisolism was for the first time evaluated by calculating the 25(OH)D3/24,25(OH)2D3 ratio, which has recently emerged as a new tool for vitamin D status assessment [46,47]. Given the correlation of this parameter with laboratory marker of the underlying disease activity (24-h UFC), a direct effect of cortisol overproduction on 24-hydroxylase activity might be assumed. Interestingly, it seems that the decreased activity of 24-hydroxylase observed in CD influenced the effectiveness of cholecalciferol treatment, decreasing the negative effect of obesity, as patients with CD had similar increase in 25(OH)D3 in obese and non-obese state and lacked correlation between Δ25(OH)D3 and BMI, as opposed to the control group. Moreover, the increase in 25(OH)D3 in obese patients from the control group was lower not only than in non-obese controls, but also than in obese patients with CD. Another intriguing finding was lower levels of free 25(OH)D observed in patients with CD despite similar DBP levels and lower albumin levels, which, on the contrary, allows one to expect higher values of free 25(OH)D. Considering the weaker correlation between the measured and calculated free 25(OH)D in patients with CD, as well as the lack of correlation of the measured 25(OH)D with the main transport protein, an altered affinity of DBP might be suspected. One possible explanation is protein glycosylation as a consequence of diabetes mellitus, which was present in half of the patients [38,48,49]. After cholecalciferol intake, which was accompanied by an increase in free 25(OH)D, the differences between the groups were leveled; therefore, another suggested explanation might be competitive binding to the ligand. Since actin binds DBP with high affinity [50] and considering catabolic action of glucocorticoids on muscle tissue [51], actin is a presumable competing ligand candidate. Although this is mostly speculative, as far as the authors are aware, the present work was the first to assess free vitamin D in the glucocorticoid excess, so the described findings require verification of reproducibility and further evaluation. The obtained discrepancies in the biochemical parameters characterizing calcium and phosphorus metabolism were generally consistent with the data of early studies discussed in the introduction [12,25,26,27,28,29], except for similar to controls serum phosphorus levels and lower prevalence of hypercalciuria. An interesting observation was the complete absence of the PTH decrease in patients with CD after receiving a loading dose of cholecalciferol. The mechanism of this phenomenon is not entirely clear, we tend to agree with the earlier hypothesis that this may be an adaptation to chronic urinary calcium loss [52]. Our research is distinguished by a number of important strengths: a prospective design, substantial sample of patients with CD, accounting for social and behavioral factors affecting vitamin levels D, comprehensive spectrum of vitamin D metabolism parameters investigated and participation in an external quality control program for vitamin D metabolites measurement. Nevertheless, the study also had several limitations: the amount of dietary vitamin D and phosphorus, as well as possible differences in DBP affinity to vitamin D metabolites due to genetic isoforms of DBP [53] or other possible involved parameters (e.g., fibroblast growth factor-23) were not taken into account. A few patients from both groups received therapy with possible impact on vitamin D and calcium metabolism within 3 months preceding the participation in the study (spironolactone, diuretics, proton pump inhibitors, oral contraceptives, antifungal treatment, antidepressants, barbiturates, antiepileptic drugs). The groups had a trend for differences in sex and BMI (p = 0.07 for both parameters). Also, the study lacked a study group of patients with remission of CD to test the hypotheses put forward, however, this is a promising direction for further research. 5. Conclusions We report that patients with endogenous ACTH-dependent hypercortisolism of pituitary origin have a consistently higher 25(OH)D3/24,25(OH)2D3 ratio than healthy controls, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. There is also a lack of clarity regarding the lower levels of free 25(OH)D observed in patients with CD, which require further study. To test the proposed hypotheses and to develop specialized clinical guidelines for these patients, longer-term randomized clinical trials are needed. Supplementary Materials The following are available online at https://www.mdpi.com/article/10.3390/nu13124329/s1, Method validation against DEQAS, Figure S1: Comparison between DEQAS data for 25(OH)D scheme and our lab results, Figure S2: Comparison between DEQAS data for 1,25(OH)2D scheme and our lab results. Author Contributions Conceptualization, L.R., E.P., A.P. and A.Z.; methodology, V.B., Z.B., L.R. and G.M.; formal analysis, A.P.; investigation, A.P., V.B., E.P., L.D. and A.Z.; data curation, A.P. and V.B.; writing—original draft preparation, A.P.; writing—review and editing, V.B., E.P., A.Z., Z.B., L.R.; visualization, V.B.; supervision, L.D., L.R., G.M. and N.M.; project administration, L.R. and N.M.; funding acquisition, L.R. and N.M. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by the Russian Science Foundation, grant number 19-15-00243. Institutional Review Board Statement This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Endocrinology Research Centre, Moscow, Russia on 10 April 2019 (abstract of record No. 6). Informed Consent Statement Written informed consent was obtained from all individual participants included in the study. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgments We express our deep gratitude to our colleagues: Natalya M. Malysheva, Vitaliy A. Ioutsi, Larisa V. Nikankina for the help with the laboratory research. Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. References Nishioka, H.; Yamada, S. Cushing’s disease. J. Clin. Med. 2019, 8, 1951. [Google Scholar] [CrossRef] Mazziotti, G.; Frara, S.; Giustina, A. Pituitary Diseases and Bone. Endocr. Rev. 2018, 39, 440–488. [Google Scholar] [CrossRef] [PubMed] Compston, J. Glucocorticoid-induced osteoporosis: An update. Endocrine 2018, 61, 7–16. 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  16. We are thrilled to invite you to join us and hundreds of others virtually for Rare Disease Week on Capitol Hill from February 22nd to March 2nd, for a week that can change your life. In 2022 advocates will once again have the opportunity to participate in the Points for Advocacy Scavenger Hunt and the EveryLife Foundation will award a total of $100,000 to the top-50 point earners' rare disease non-profit organization of choice! Over the last 11 years, thousands of rare disease patients, family members, friends, and health care providers have joined together to give rare disease patients a voice on Capitol Hill. Meeting virtually during the pandemic has not slowed us down but has reenergized many of us on the importance of our advocacy work. Both of our first times attending Rare Disease Week, Sarah in 2017 and Sarita in 2021, sparked our passion for advocacy! We hope that you will join us for Rare Disease Week which brings the community together to learn, network and advocate. Please reach out to RDLA staff Katelyn Laws at klaws@everylifefoundation.org if you have any questions or need more information.
  17. We are thrilled to invite you to join us and hundreds of others virtually for Rare Disease Week on Capitol Hill from February 22nd to March 2nd, for a week that can change your life. In 2022 advocates will once again have the opportunity to participate in the Points for Advocacy Scavenger Hunt and the EveryLife Foundation will award a total of $100,000 to the top-50 point earners' rare disease non-profit organization of choice! Over the last 11 years, thousands of rare disease patients, family members, friends, and health care providers have joined together to give rare disease patients a voice on Capitol Hill. Meeting virtually during the pandemic has not slowed us down but has reenergized many of us on the importance of our advocacy work. Both of our first times attending Rare Disease Week, Sarah in 2017 and Sarita in 2021, sparked our passion for advocacy! We hope that you will join us for Rare Disease Week which brings the community together to learn, network and advocate. Please reach out to RDLA staff Katelyn Laws at klaws@everylifefoundation.org if you have any questions or need more information.
  18. A TSH test is done to find out if your thyroid gland is working the way it should. It can tell you if it’s overactive (hyperthyroidism) or underactive (hypothyroidism). The test can also detect a thyroid disorder before you have any symptoms. If untreated, a thyroid disorder can cause health problems. TSH stands for “thyroid stimulating hormone” and the test measures how much of this hormone is in your blood. TSH is produced by the pituitary gland in your brain. This gland tells your thyroid to make and release the thyroid hormones into your blood. The Test The TSH test involves simply drawing some blood from your body. The blood will then be analyzed in a lab. This test can be performed at any time during the day. No preparation is needed (such as overnight fasting). You shouldn’t feel any pain beyond a small prick from the needle in your arm. You may have some slight bruising. In general, there is no need to stop taking your medicine(s) before having your TSH level checked. However, it is important to let the doctor know what medications you are taking as some drugs can affect thyroid function. For example, thyroid function must be monitored if you are taking lithium. While taking lithium, there is a high chance that your thyroid might stop functioning correctly. It's recommended that you have a TSH level test before starting this medicine. If your levels are normal, then you can have your levels checked every 6 to 12 months, as recommended by your doctor. If your thyroid function becomes abnormal, you should be treated. High Levels of TSH TSH levels typically fall between 0.4 and 4.0 milliunits per liter (mU/L), according to the American Thyroid Association. Ranges between laboratories will vary with the upper limit generally being between 4 to 5. If your level is higher than this, chances are you have an underactive thyroid. In general, T3 and T4 levels increase in pregnancy and TSH levels decrease. Low Levels of TSH It's also possible that the test reading comes back showing lower than normal levels of TSH and an overactive thyroid. This could be caused by: Graves’ disease (your body’s immune system attacks the thyroid) Too much iodine in your body Too much thyroid hormone medication Too much of a natural supplement that contains the thyroid hormone If you're on medications like steroids, dopamine, or opioid painkillers (like morphine), you could get a lower-than-normal reading. Taking biotin (B vitamin supplements) also can falsely give lower TSH levels. The TSH test usually isn’t the only one used to diagnose thyroid disorders. Other tests, like the free T3, the free T4, the reverse T3, and the anti-TPO antibody, are often used too when determining whether you need thyroid treatment or not. Treatment Treatment for an underactive thyroid usually involves taking a synthetic thyroid hormone by pill daily. This medication will get your hormone levels back to normal, and you may begin to feel less tired and lose weight. To make sure you're getting the right dosage of medication, your doctor will check your TSH levels after 2 or 3 months. Once they are sure you are on the correct dosage, they will continue to check your TSH level each year to see whether it is normal. If your thyroid is overactive, there are several options: Radioactive iodine to slow down your thyroid Anti-thyroid medications to prevent it from overproducing hormones Beta blockers to reduce a rapid heart rate caused by high thyroid levels Surgery to remove the thyroid (this is less common) Your doctor may also regularly check your TSH levels if you have an overactive thyroid. From https://www.webmd.com/women/what-is-tsh-test
  19. Patient: Female, 74-year-old Final Diagnosis: ACTH-dependent Cushing’s syndrome • ectopic ACTH syndrome Symptoms: Edema • general fatigue • recurrent mechanical fall Medication: — Clinical Procedure: — Specialty: Critical Care Medicine • Endocrinology and Metabolic • Family Medicine • General and Internal Medicine • Nephrology • Oncology Objective: Unusual clinical course Background: Adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) secondary to an ectopic source is an uncommon condition, accounting for 4–5% of all cases of CS. Refractory hypokalemia can be the presenting feature in patients with ectopic ACTH syndrome (EAS), and is seen in up to 80% of cases. EAS can be rapidly progressive and life-threatening without timely diagnosis and intervention. Case Report: We present a case of a 74-year-old White woman who first presented with hypokalemia, refractory to treatment with potassium supplementation and spironolactone. She progressively developed generalized weakness, recurrent falls, bleeding peptic ulcer disease, worsening congestive heart failure, and osteoporotic fracture. A laboratory workup showed hypokalemia, hypernatremia, and primary metabolic alkalosis with respiratory acidosis. Hormonal evaluation showed elevated ACTH, DHEA-S, 24-h urinary free cortisol, and unsuppressed cortisol following an 8 mg dexamethasone suppression test, suggestive of ACTH-dependent CS. CT chest, abdomen, and pelvis, and FDG/PET CT scan showed a 1.4 cm right lung nodule and bilateral adrenal enlargement, confirming the diagnosis of EAS, with a 1.4-cm lung nodule being the likely source of ectopic ACTH secretion. Due to the patient’s advanced age, comorbid conditions, and inability to attend to further evaluation and treatment, her family decided to pursue palliative and hospice care. Conclusions: This case illustrates that EAS is a challenging condition and requires a multidisciplinary approach in diagnosis and management, which can be very difficult in resource-limited areas. In addition, a delay in diagnosis and management often results in rapid deterioration of clinical status. Keywords: Cushing Syndrome, Endocrine System, Hypokalemia Go to: Background Cushing’s syndrome (CS) has a variety of clinical manifestations resulting from excess steroid hormone production from adrenal glands (endogenous) or administration of glucocorticoids (exogenous) [1,2]. Endogenous CS is classified into 2 main categories: ACTH-dependent and ACTH-independent disease. In ACTH-dependent disease, the source of ACTH can further be subdivided into either the pituitary gland or an ectopic source [2]. Ectopic ACTH syndrome (EAS) results from excess production of ACTH from extra-pituitary sources [2] and accounts for approximately 4–5% of cases of CS [3,4]. Common clinical manifestations of CS include weight gain, central obesity, fatigue, plethoric facies, purple striae, hirsutism, irregular menses, hypertension, diabetes/glucose intolerance, anxiety, muscle weakness, bruising, and osteoporosis [2]. Hypokalemia is a less defining feature, seen in roughly 20% of cases with CS. However, it is present in up to 90% of cases with EAS [2,5], which is attributed to the mineralocorticoid action of steroid [6]. Hypercortisolism due to EAS is usually severe and rapid in onset, and excess cortisol levels can lead to severe clinical manifestations, including life-threatening infections [7]. Moreover, in most patients with EAS, the source of excess ACTH is an underlying malignancy that can further result in rapid deterioration of the overall clinical condition. Although numerous malignancies have been associated with EAS, lung neuroendocrine tumors (NETs) are the most common [2,8]. Since the treatment of choice for EAS is complete resection of the tumor, the correct localization of the source of ectopic ACTH is crucial in managing these patients. Traditional radiological investigations can localize these tumors in up to 50% of cases [9]; however, recent studies utilizing somatostatin receptor (SSTR) analogs have increased the sensitivity and specificity of tumor localization [9–11]. This case report describes a challenging case of an elderly patient with EAS who presented with refractory hypokalemia. Her clinical condition deteriorated rapidly in the absence of surgical intervention. Go to: Case Report A 74-year-old White woman was brought to the Emergency Department from her nephrologist’s office with a chief concern of persistent anasarca and recurrent hypokalemia of 1-month duration. In addition, she reported generalized weakness and recurrent mechanical falls in the preceding 3 months. Before presentation in March 2021, she had a medical history of type 2 diabetes, chronic kidney disease stage 3b, atrial fibrillation on chronic anticoagulation, heart failure with reduced ejection fraction (EF 35–40%), hypothyroidism, hypertension, and hyperlipidemia. Home medications included diltiazem, apixaban, insulin glargine, levothyroxine, simvastatin, carvedilol, glimepiride, sacubitril, valsartan, and furosemide. On presentation, she was hemodynamically stable with temperature 36.5°C, heart rate 67 beats per min, blood pressure 139/57 mmHg, respiratory rate 20 per min, and saturation 98% on 2 L oxygen supplementation. Her height was 162.6 cm, and weight was 80.88 kg, with a body mass index (BMI) of 30.6 kg/m2. A physical exam showed central obesity, bruising in extremities, generalized facial swelling mainly in the periorbital region, severe pitting edema in bilateral lower extremities, and moderate pitting edema in bilateral upper extremities. A laboratory workup revealed serum potassium 2.4 mmol/L (3.6–5.2 mmol/L), serum sodium 148 mmol/L (133–144 mmol/L), and eGFR 31.5 mL/min/1.73 m2. Arterial blood gas analysis showed pH 7.6, PaCO2 48.9 mmHg (35.0–45.0 mmHg), and serum bicarbonate 32 mmol/L (22–29 mmol/L), which was consistent with primary metabolic alkalosis, appropriately compensated by respiratory acidosis. Due to concerns of loop diuretic-induced hypokalemia, she was started on spironolactone and potassium replacement. However, potassium levels persistently remained in the low range of 2–3.5 mmol/L (3.6–5.2 mmol/L) despite confirming compliance to medications and adequate up-titration in the dose of spironolactone and potassium chloride. Hence, the workup for the secondary cause of persistent hypokalemia was pursued. Hormonal evaluation revealed plasma aldosterone concentration (PAC) <1.0 ng/dL, plasma renin activity (PRA) 0.568 ng/mL/h (0.167–5.380 ng/mL/h), 24-h urine free cortisol (UFC) 357 mg/24h (6–42 mg/24h), ACTH 174 pg/mL, and DHEA-S 353 ug/dL (20.4–186.6 ug/dL). ACTH levels on 2 repeat testings were 229 pg/mL and 342 pg/mL. The rest of the laboratory workup is summarized in Table 1. Considering elevated ACTH and 24-h UFC, a preliminary diagnosis of ACTH-dependent Cushing syndrome was made. An 8-mg dexamethasone suppression test revealed non-suppressed cortisol of 62.99 ug/dL along with dexamethasone 4050 ng/dL (1600–2850 ng/dL). A pituitary MRI was unremarkable for any focal lesion suggesting a diagnosis of ACTH-dependent Cushing’s syndrome secondary to an ectopic source. Imaging studies were then performed to determine the source. A CT scan of the chest and abdomen revealed adenomatous thickening with nodularity of bilateral adrenal glands, and a 1.4-cm nodule in the right middle lobe (Figure 1A, 1B). FDG-PET/CT showed severe bilateral enlargement of the adrenal glands with severe hyper-metabolic uptake (mSUV 9.2 and 9.1 for left and right adrenal glands, respectively) (Figure 2A). The uptake of the right lung nodule on PET/CT was 1.4 mSUV (Figure 2B). Figure 1. CT chest, abdomen, and pelvis w/o contrast showed bilateral enlargement of adrenal glands (A, red arrows) and a 1.4-cm nodule in the right middle lobe of the lung (B, blue arrow). Figure 2. Whole-body PET/CT following intravenous injection of 40 mCi FDG showed diffuse enlargement of the bilateral adrenal glands with mSUV of 9.2 on the left and 9.1 on the right adrenal gland, respectively (A, red arrows) and low-grade activity with an MSUV of 1.4 in right lung nodule (B, blue arrow). Table 1. Laboratory on initial presentation. Laboratory test Level Reference range WBCs 7.8 k/uL 3.7–10.3 k/uL RBCs 3.05 M/mL 3.–5.2 M/mL Hemoglobin 9.6 g/dL 11.2–15.7 g/dL Hematocrit 27.3% 34–45% Platelets 98 k/mL 155–369 k/mL MCV 89.7 fl 78.2–101.8 fl MCH 31.5 pg 26.4–33.3 pg MCHC 35.2 g/dL 32.5–35.3 g/dL RDW 15.8% 10.1–16.2% Glucose 73 mg/dL 74–90 mg/dL Sodium 148 mmol/L 136–145 mmol/L Potassium 2.4 mmol/L 3.7–4.8 mmol/L Bicarbonate 32 mmol/L 22–29 mmol/L Chloride 108 mmol/L 97–107 mmol/L Calcium 7.0 mg/dL 8.9–10.2 mg/dL Magnesium 1.7 mg/dL 1.7–2.4 mg/dL Phosphorus 2.3 mg/dL 2.5–4.9 mg/dL Albumin 2.4 g/dL 3.3–4.6 g/dL Blood urea nitrogen 41 mg/dL 0–30 ng/dL Creatinine 1.60 mg/dL 0.60–1.10 mg/dL Estimated GFR 31.5 mL/min/1.73m2 >60 mL/min/1.73 m2 Aspartate transaminase 42 U/L 9–36 U/L Alanine transaminase 67 U/L 8–33 U/L Alkaline phosphatase 90 U/L 46–142 U/L Total protein 4.8 g/dL 6.3–7.9 g/dL Arterial blood gas analysis PaCO2 48.9 mmHg 35.0–45.0 mmHg PaO2 63.1 mmHg 85.0–100.0 mmHg %SAT 92.8% 93.0–97.0 HCO3 47.8 mm/L 20.0–26.0 mm/L Base excess 26.3 mm/L <2.0 mm/L pH 7.599 7.350–7.450 Adrenocorticotropic hormone (ACTH) 174, 229 and 342 pg/mL 15–65 pg/mL Urine free cortisol, 24 h 357 ug/24 hr 6–42 mg/24 hr 8: 00 AM cortisol following 8 mg dexamethasone (4×2 mg doses) previous day 62.99 mg/dL 8: 00 AM dexamethasone following 8 mg dexamethasone (4×2 mg doses) previous day 4050 ng/dL 1600–2850 ng/dL Based on unsuppressed cortisol following an 8-mg dexamethasone suppression test, negative pituitary MRI, and 1.4-cm lung nodule, we diagnosed ACTH-dependent CS secondary to an ectopic source, most likely from the 1.4-cm lung nodule. While awaiting localization studies, within 3 months of initial presentation, she had 2 hospitalizations, one in May 2021 for acute anemia secondary to bleeding peptic ulcer disease (PUD) requiring endoscopic clipping of the bleeding ulcer, and another in June 2021 for acute on chronic congestive heart failure. The patient’s overall condition continued to deteriorate, and she became progressively weak and wheelchair-bound. A 68-Ga-DOTATATE was planned to establish the source of ectopic ACTH definitively; however, she developed a left hip fracture in July 2021 and could not present for follow-up care. Therefore, she was started on Mifepristone until curative surgery. However, considering the patient’s advanced comorbid conditions, the increased burden of the patient’s health care needs on her elderly husband, and the inability of other family members to provide necessary healthcare-related support, palliative care was pursued. In August 2021, she developed a sacral decubitus ulcer and community-acquired pneumonia. However, she was still alive while receiving palliative care in a nursing home until September 2021. Go to: Discussion Ectopic ACTH syndrome (EAS) is defined as secretion of ACTH from an extra-pituitary source and is the cause of Cushing’s syndrome (CS) in approximately 4–5% of cases [3,4]. Clinical features of EAS depend on the rate and amount of ACTH production [12]. Among all forms of Cushing’s (excluding adrenal cortical carcinoma), EAS has the worst outcome, with one of the most extensive combined UK & Athens study demonstrating a 5-year survival rate of 77.6%. Compared to Cushing’s disease (CD), patients with EAS have severe and excessive production of ACTH, resulting in highly elevated cortisol levels. This leads to hypokalemia, metabolic alkalosis, worsening glycemia, hypertension, psychosis, and infections. Metabolic alkalosis and hypokalemia are the 2 most common acid-base and electrolyte abnormalities associated with glucocorticoid excess among these patients. Studies have shown that hypokalemia is seen in up to 90% of patients with EAS. Although hypertension and hypokalemia are often attributed to primary hyperaldosteronism, other causes should be sought. Under normal circumstances, the mineralocorticoid effect of cortisol is insignificant due to local conversion to cortisone by the action of 11 beta-hydroxysteroid dehydrogenase. Excessive cortisol in patients with EAS saturates the action of 11 beta-hydroxysteroid dehydrogenase and leads to the appearance of mineralocorticoid action of cortisol [6]. In our patient, the initial treatment of hypokalemia was unsatisfactory, so additional endocrine workup was pursued. Elevated urinary cortisol excretion, plasma ACTH levels, unsuppressed cortisol following 8 mg dexamethasone, and lung mass on CT scan strongly suggested that the clinical symptoms were due to EAS. Unfortunately, despite diagnosing the underlying condition contributing to the patient’s symptoms, her clinical condition rapidly deteriorated without surgical treatment. Various factors resulted in delayed diagnosis in our patient. First, the patient sought medical care only 3 months after symptom onset. Second, furosemide, a medication commonly used to treat patients with HFrEF, is a frequent culprit of hypokalemia and often is treated with adequate potassium supplementation. Third, multiple hospitalizations resulted in delays in the proper endocrine workup necessary for establishing hypercortisolism. Fourth, localization of the ectopic source requires advanced imaging studies, which are only available in a few tertiary care centers. Fifth, even after tumor localization with PET/CT scan, there is still a need for a more definitive localization study using Ga-DOTATATE scan, which has a higher specificity. However, it was unavailable in our institution and was only available in a few tertiary care centers, with the nearest center being 2.5 h away. Sixth, the impact of the COVID-19 pandemic also played a critical role in promptly providing critical care necessary to the patient. In addition to those, the social situation of our patient also played an essential role in contributing to delays in diagnosis. It is well recognized that EAS is associated with various malignancies, mostly of neuroendocrine origin. The most common location of these tumors was found to be the lung (55.3%), followed by the pancreas (8.5%), mediastinum-thymus (7.9%), adrenal glands (6.4%), and gastrointestinal tract (5.4%) [9]. Prompt surgical removal of ectopic ACTH-secreting tumors is the mainstay of therapy in patients with EAS [13]. However, localization of such tumors with conventional therapy is often challenging as the sensitivity to localize the tumor is 50–60% for conventional imaging such as CT, MRI, and FDG-PET [9]. In a study by Isidori et al, nuclear imaging improved the sensitivity of conventional radiological imaging [9]. Moreover, newer imaging technologies using somatostatin receptor (SSTR) analogs such as 68Ga-DOTATATE PET/CT further improve the ability to localize the tumor. 68Ga-DOTATATE PET/CT, approved in 2016 by the Federal Drug Administration (FDA) for imaging well-differentiated NETs, has a high sensitivity (88–93%) and specificity (88–95%) to diagnose carcinoid tumor [14]; however, a systematic review reported a significantly lower sensitivity (76.1%) of 68Ga-DOTATATE PET/CT to diagnose EAS [15]. Once localized, the optimal management of EAS is surgical re-section of the causative tumor, which is often curative. However, until curative surgery is done, patients should be medically managed. Drugs used to reduce cortisol levels include ketoconazole, mitotane, and metyrapone [16, 17]. These are oral medications and decrease cortisol synthesis by inhibiting adrenal enzymes [17]. Etomidate is the only intravenous drug that immediately reduces adrenal steroid production and can be used when acute reduction in cortisol production is desired [16]. Medical management requires frequent monitoring of cortisol levels and titration of dose to achieve low serum and urine cortisol levels. Mifepristone, an anti-progesterone at a higher dose, works as a glucocorticoid receptor antagonist and can be used to block the action of cortisol. Its use results in variable levels of ACTH and cortisol levels in patients with EAS. Hence, hormonal measurement cannot be used to judge therapeutic response, and clinical improvement is the goal of treatment [18]. Drugs inhibiting ACTH secretion by NETs such as kinase inhibitors (vandetanib, sorafenib, or sunitinib) are effective in treating EAS secondary to medullary thyroid cancer [19]. Somatostatin analogs such as octreotide and lanreotide have demonstrated short- and medium-term efficacy in a few EAS patients; however, a few patients failed to improve, necessitating the use of more effective treatment options [19,20]. Hence, they are not considered a first-line drug as monotherapy and should be used in combination with other agents, or as anti-tumoral therapy in non-excisable metastatic well-differentiated NETs [19,20]. Cabergoline, a dopamine agonist, has been used with variable therapeutic effects in a few patients [19]. In 1 patient, the use of combination therapy using Mifepristone and a long-acting octreotide significantly improved EAS [21]. In our patient, we initiated Mifepristone to reduce the burden associated with frequent biochemical monitoring and planned 68Ga-DOTATATE PET/CT to localize the tumor; however, further diagnostic and therapeutic approaches could not be further undertaken per family wishes. Go to: Conclusions EAS can present with refractory hypokalemia, especially in patients who are already at risk of developing hypokalemia. Diagnosis of EAS is often challenging and requires a multidisciplinary approach. Localization of source of EAS should be done using nuclear imaging, preferably using SSTR analogs, when available. Urgent surgical evaluation remains the mainstay of treatment following tumor localization and can result in a cure. EAS is a rapidly progressive and life-threatening situation that can be fatal if diagnosis or timely intervention is delayed. Go to: Abbreviations ACTH adrenocorticotropic hormone; CS Cushing’s syndrome; CT computed tomography; EAS ec-topic ACTH syndrome; MRI magnetic resonance imaging; FDG/PET 18-F-fluorodeoxyglucose positron emission tomography; NET neuroendocrine tumors; SSTR somatostatin receptor; EF ejection fraction; PAC plasma aldosterone concentration; PRA plasma renin activity; UFC urine free cortisol; DHEA-S dehydroepiandrosterone sulfate; 68-Ga-DOTATATE Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tet-raacetic acid (DOTA)-octreotate; PUD peptic ulcer disease Go to: Footnotes Financial support: None declared Go to: References: 1. Pluta RM, Burke AE, Golub RM. JAMA patient page. Cushing syndrome and Cushing disease. JAMA. 2011;306:2742. [PubMed] [Google Scholar] 2. Melmed SKR, Rosen C, Auchus R, Goldfine A. Williams textbook of endocrinology. Elsevier; 2020. [Google Scholar] 3. Rubinstein G, Osswald A, Hoster E, et al. 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  20. The pituitary gland works hard to keep you healthy, doing everything from ensuring proper bone and muscle growth to helping nursing mothers produce milk for their babies. Its functionality is even more remarkable when you consider the gland is the size of a pea. “The pituitary is commonly referred to as the ‘master’ gland because it does so many important jobs in the body,” says Karen Frankwich, MD, a board-certified endocrinologist at Mission Hospital. “Not only does the pituitary make its own hormones, but it also triggers hormone production in other glands. The pituitary is aided in its job by the hypothalamus. This part of the brain is situated above the pituitary, and sends messages to the gland on when to release or stimulate production of necessary hormones.” These hormones include: Growth hormone, for healthy bone and muscle mass Thyroid-stimulating hormone, which signals the thyroid to produce its hormones that govern metabolism and the body’s nervous system, among others Follicle-stimulating and luteinizing hormones for healthy reproductive systems (including ovarian egg development in women and sperm formation in men, as well as estrogen and testosterone production) Prolactin, for breast milk production in nursing mothers Adrenocorticotropin (ACTH), which prompts the adrenal glands to produce the stress hormone cortisol. The proper amount of cortisol helps the body adapt to stressful situations by affecting the immune and nervous systems, blood sugar levels, blood pressure and metabolism. Antidiuretic (ADH), which helps the kidneys control urine levels Oxytocin, which can stimulate labor in pregnant women The work of the pituitary gland can be affected by non-cancerous tumors called adenomas. “These tumors can affect hormone production, so you have too little or too much of a certain hormone,” Dr. Frankwich says. “Larger tumors that are more than 1 centimeter, called macroadenomas, can also put pressure on the area surrounding the gland, which can lead to vision problems and headaches. Because symptoms can vary depending on the hormone that is affected by a tumor, or sometimes there are no symptoms, adenomas can be difficult to pinpoint. General symptoms can include nausea, weight loss or gain, sluggishness or weakness, and changes in menstruation for women and sex drive for men.” If there’s a suspected tumor, a doctor will usually run tests on a patient’s blood and urine, and possibly order a brain-imaging scan. An endocrinologist can help guide a patient on the best course of treatment, which could consist of surgery, medication, radiation therapy or careful monitoring of the tumor if it hasn’t caused major disruption. “The pituitary gland is integral to a healthy, well-functioning body in so many ways,” Dr. Frankwich says. “It may not be a major organ you think about much, but it’s important to know how it works, and how it touches on so many aspects of your health.” Adapted from http://www.stjhs.org/HealthCalling/2016/December/The-Pituitary-Gland-Small-but-Mighty.aspx
  21. Best friends Charly Clive and Ellen Robertson thought carefully about what to call the tumour that was growing in Charly’s brain. The doctors had their own name for the golf-ball-sized growth sitting right behind Charly’s left eye — a pituitary adenoma — but the friends decided they needed something less scary. They flirted with calling it Terry Wogan (‘as in Pitui-Terry Wogan,’ says Ellen), but that didn’t seem quite right. So Britney Spears fan Charly, then 23, suggested Britney. Bingo! Not only was she ‘iconic and fabulous’, but Britney was also one of life’s survivors. From then on, they were a threesome — Charly, Ellen and Britney the brain tumour — although Ellen is at pains to point out that this Britney was never a friend. What a thing to have to deal with, so young. The pair, who met at school in rural Oxfordshire, are now actresses. Charly’s biggest role to date has been in the critically acclaimed 2019 Channel 4 series Pure, while Ellen starred in the Agatha Christie mini-series The Pale Horse. But this week they appeared together in Britney, a BBC comedy based on the story of Charly’s brain tumour. The TV pilot (and yes, they are hoping for a full series) is an expansion of a sell-out stage show they performed at the Edinburgh Fringe in 2016. The production is admittedly surreal. Viewers are led inside Charly’s brain and the show includes a scene where Charly dons an inflatable sumo-wrestler suit on the day of her diagnosis. Poetic licence? No, it really happened. ‘My dad’s mate had given him a sumo suit as a silly Christmas present and so, on Doomsday, we took photos of me in it.’ The tone was set for how these friends would deal with the biggest challenge of their lives: they would laugh through it, somehow. As the women, now 28, point out, what was the alternative? Charly says: ‘It was that thing of laughing at the monster so you are not scared of it. If you cry when do you stop? It was easier to make light of it.’ Their show is not really about a brain tumour. It’s a celebration of friendship. Ellen pretty much moved in with Charly’s family during this time (‘To be in place when I exploded, so she could pick up the debris,’ says Charly). The pair live together today, finishing each other’s sentences as we speak on Zoom — and at one point both miming Charly’s brain surgery (with gruesome sound effects). This sort of silliness rooted their friendship, which started at the age of 14 when they wrote their own plays (Finding Emo, anyone?) while at school together in Abingdon. Charly later moved to New York to study dramatic arts, and Ellen studied at Cambridge. In 2015, Charly came home for a visit, and went to see her GP (played in the drama by Omid Djalili) about her lack of periods and a blind spot in her peripheral vision. An MRI scan showed a mass on her brain. ‘They said it had eroded the bone in my nose and was pressing on the optic nerve, and it was lucky we had caught it,’ she says. ‘The next step would have been discovering it because I’d gone blind.’ Even worse, the tumour was so close to her carotid artery that removal might kill her — and they still had no idea if it was cancerous. Into the breach stepped Ellen. ‘I saw it as my job to make her laugh, which is what I’d always done anyway,’ she says. They both talk of toppling into limbo, ‘almost like a fantasy world’, says Charly. ‘As I was going through the tests, we’d do impressions of the doctors and create our own scenarios.’ The friends talk about sitting up into the night, watching TV. There is a touching moment when Charly admits she was afraid to sleep, and Ellen knew it. ‘It’s hard when you are thinking “What if the tumour grows another inch in the night and I don’t wake up?” ’ Charly was operated on in March 2016, and Ellen remembers the anaesthetist confiding that Charly’s heart had stopped on the operating table. ‘He wasn’t the most tactful person we’ve ever met. He said “Oh my God, guys, she died”.’ Charly makes a jazz hands gesture. ‘And guess who is alive again?’ Even at that darkest moment, there were flashes of humour. Ellen laughs at the memory of the surgeon in his scrubs, with wellies on. ‘They had blood on them. I was transfixed. I wanted to ask “Is that Charly’s . . . brain blood?” ’ In the stage version of the show, the anaesthetist gets two full scenes. ‘He’s the heartthrob of the piece,’ says Charly. ‘A sexy rugger bloke who is crap at talking to people.’ The days that followed the surgery were hideous — and yet they, too, have been mined for comedy. Charly’s face was bandaged, ‘as if I’d had a Beverly Hills facelift’, and she was warned that she could not sneeze. ‘If I did, bits of my brain would come out my nose,’ she says. Ellen read her extracts from Harry Potter but ‘made them smutty’, which confused the already confused Charly further. ‘I was drug-addled and not myself, and in the most bizarre pain, concentrated in my face’. ‘That week after the surgery was the worst part of all,’ says Ellen, suddenly serious. ‘She was behaving oddly and there was this unacknowledged fear: was this Charly for ever?’ Oh, the relief when the old Charly eventually re-emerged — albeit a more fragile, often tearful version. It was Ellen who persuaded Charly to take their stage show about her illness public — and it went on to win much critical acclaim. ‘I wanted Charly to see it as something other than just this rubbish chapter that needed to be forgotten about,’ says Ellen. For her part, Charly credits her best friend as her saviour: ‘I don’t know how I would have got through it all without Ellen.’ The good news is that Britney was not cancerous, although surgery did not obliterate her entirely. ‘She’s still there, but tiny — just a sludge. I’ve been told that she won’t grow though. If I ever do get another brain tumour, it won’t be Britney.’ Off they go again, imagining what is happening now inside Charly’s brain. ‘Britney is still in there, trying on outfits for a comeback tour, but it won’t happen,’ says Charly. Ellen nods. ‘It’s over,’ she says. ‘But she’s just left a pair of shoes behind.’ Britney is available to watch on BBC Three and BBC iPlayer Adapted from https://www.dailymail.co.uk/femail/article-10264203/I-laughed-brain-tumour-Id-never-stop-crying-Actress-Charly-Clive.html
  22. https://doi.org/10.1016/j.aace.2021.11.005Get rights and content Under a Creative Commons license open access Highlights • Due to the physiologic rise of ACTH during pregnancy, unstimulated ACTH levels may not be an accurate marker to differentiate between adrenal and ACTH-independent Cushing's syndrome. • The desmopressin stimulation test can be done during pregnancy to investigate the etiology of Cushing's syndrome. • Non-gadolinium enhanced pituitary imaging may not detect pituitary adenoma, which is the most common cause of Cushing's disease. Contrast-enhanced pituitary magnetic resonance imaging should be considered in pregnant women with ACTH-dependent Cushing's syndrome. • Due to increase maternal and fetal morbidities in active Cushing's syndrome, prompt diagnosis and appropriate treatment are essential. The treatment of choice is transsphenoidal surgery during the second trimester, preferably at a high-volume pituitary center. • There were significantly lower rates of fetal complications in women with active Cushing's syndrome than a cured disease, including low birth weight. Abstract Objective The hypothalamic-pituitary-adrenal axis stimulation during pregnancy complicates the investigation of Cushing's syndrome. Our objective is to present a pregnant patient with Cushing syndrome caused by pituitary tumor in which the desmopressin stimulation test helped in the diagnosis and led to appropriate management. Case report A 27-year-old woman with 9-week gestation presented with proximal myopathy for 2 months. She had high blood pressure, wide abdominal purplish striae, and proximal myopathy. Her past medical history revealed hypertension and dysglycemia for 1 year. The 8 AM cortisol was 32.4 μg/dL (5-18), late-night salivary cortisol at 11 PM was 0.7 μg/dL (<0.4), and the mean 24-hour urinary free cortisol was 237.6 μg/day (21.0-143.0). The mean ACTH concentrations at 8 AM were 44.0 pg/mL (0-46.0). Non-gadolinium enhanced pituitary magnetic resonance imaging (MRI) reported no obvious lesion. The desmopressin stimulation test showed a 70% increase in ACTH levels from baseline after desmopressin administration. The pituitary MRI with gadolinium showed an 8x8x7-mm pituitary adenoma. Transsphenoidal surgery with tumor removal was done, which showed ACTH-positive tumor cells. After the surgery, the patient carried on the pregnancy uneventfully. Discussion During pregnancy, the ACTH level may not be an accurate marker to help in the differential diagnosis of Cushing's syndrome. Moreover, non-gadolinium pituitary imaging may not detect small pituitary lesions. Conclusion In the present Case, the desmopressin stimulation test suggested the diagnosis of Cushing's disease, which subsequently led to successful treatment. This suggested that the desmopressin test may serve as a useful test to diagnose Cushing's disease in pregnant individuals. Keywords Cushing's disease Cushing's syndrome desmopressin stimulation test pregnancy Introduction Pregnancy rarely occurs during the course of Cushing's syndrome (CS).1,2 Given the increase in maternal and fetal morbidities in women with active CS, early diagnosis and treatment of CS are essential.2 The diagnosis of CS using the usual diagnostic tests is challenging due to stimulation of the hypothalamic-pituitary-adrenal axis during pregnancy. The physiologic rise of ACTH from the 7th week of pregnancy also complicates the investigation for the etiology of CS.1 The concern of gadolinium use during pregnancy can affect the sensitivity in detecting small pituitary lesions in ACTH-dependent CS if using non-gadolinium pituitary imaging. Desmopressin is a vasopressin analog selective for V2 receptors. The desmopressin stimulation test has been proposed as a useful procedure for the differential diagnosis of CS.3 Desmopressin stimulates the increase in ACTH and cortisol in patients with CS caused by pituitary tumor or Cushing's disease (CD) but not in the majority of normal, obese subjects and patients with adrenal CS or ectopic ACTH syndrome.3,4 However, there were limited data on the desmopressin stimulation test during pregnancy. Here we present the 27-year-old woman with CS in which the desmopressin stimulation test helped in the diagnosis of CD and led to successful treatment. Case presentation A 27-year-old woman with 9-week gestation was referred from the orthopedic department to evaluate CS. She presented with proximal myopathy for 2 months. On physical examination, she had Cushingoid appearance, wide purplish striae, bruising, and proximal muscle weakness. Her blood pressure was 160/100 mmHg, and her body mass index was 32.2 kg/m2. Her past medical history revealed that she had hypertension, dyslipidemia, and impaired fasting glucose for 1 year without taking any medication. She also gained 20 kg in the past 2 years. The 8 AM cortisol (chemiluminescent immunometric assay, Immulite/Siemens) was 32.4 μg/dL (normal , 5.0-18.0), late-night salivary cortisol at 11 PM (electrochemiluminescence immunoassay, Roche Cobas) was 0.7 μg/dL (normal, <0.4), and the mean 24-hour urinary free cortisol (UFC) (radioimmunoassay, Immulite/Siemens) was 237.6 μg/day (normal, 21.0-143.0). ACTH concentrations at 8 AM (chemiluminescent immunometric assay, Immulite/Siemens) were 48.4 and 39.6 pg/mL (normal, 0-46.0) (Table 1). At 12 weeks of gestation, non-gadolinium enhanced pituitary magnetic resonance imaging (MRI) reported a mild bulging contour of the right lateral aspect of the pituitary gland without an obvious abnormal lesion (Figure 2A). The desmopressin stimulation test was then carried out at 14 weeks of gestation. Serial blood samples for ACTH and cortisol were obtained basally (at 8 AM) and at 15, 30, 45, and 60 minutes after the intravenous administration of 10 μg of desmopressin. The results were shown in Table 2. Compared with baseline, ACTH levels increased from 34.7 to 58.9 pg/mL (70%) at 15 minutes after desmopressin administration (a ≥35% increase in ACTH levels was considered an indication of CD in non-pregnant individuals)3 (Figure 1). The pituitary MRI with gadolinium revealed an 8x8x7-mm circumscribed lesion with heterogeneous iso- to hyperintensity on T2W in the right inferolateral aspect of the anterior pituitary lobe. The lesion had a delayed enhancement compared to normal pituitary tissue (Figure 2B). Non-contrast MRI adrenal glands showed bilateral normal adrenal glands without mass or nodule. Other abdominal organs were unremarkable. Regarding comorbidities, she had hypertension and gestational diabetes mellitus (GDM). The HbA1c level was 5.7% (39 mmol/mol). Using a two-step strategy, GDM was diagnosed at 12 weeks of gestation. Hypertension and GDM were controlled with 750 mg of methyldopa and 50 units of insulin per day, respectively. Table 1. Laboratory investigations of the present Case Variable At 9 weeks of gestation 8 AM cortisol, μg/dL (5.0-18.0) 32.4 Salivary cortisol (11 PM , <0.4 μg/dL) 0.7 UFC (21.0-143.0 μg/day) 183.5 and 291.6 ACTH, pg/mL (8 AM, 0-46.0) 48.4 and 39.6 DHEAS (8 AM, 35.0-430.0 μg/dL) 378.0 PAC (upright position, 8 AM), ng/dL 5.2 PRA (upright position, 8 AM), ng/mL/hr 2.1 Potassium, mmol/L 3.6 UFC, urinary free cortisol; ACTH, adrenocorticotrophic hormone; DHEAS, dehydroepiandrosterone sulphate; PAC, plasma aldosterone concentration; PRA, plasma renin activity. Download : Download high-res image (130KB) Download : Download full-size image Figure 2. Pituitary imaging of the present Case. (A) A non-gadolinium MRI of the pituitary gland at 12 weeks of gestation showing a mild bulging contour of the right lateral aspect of the pituitary gland without an obvious abnormal lesion (B) An MRI of the pituitary gland with gadolinium at 14 weeks of gestation showing an 8x8x7-mm circumscribed lesion with heterogeneous iso- to hyperintensity on T2W in the right inferolateral aspect of the anterior pituitary lobe. The lesion had a delayed enhancement compared to normal pituitary tissue. Table 2. Desmopressin stimulation test results performing at 14 weeks of gestation Time 0 min 15 min 30 min 45 min 60 min ACTH (pg/mL) 34.7 58.9 57.4 49.9 38.2 Cortisol (μg/dL) 30.6 30.2 29.7 29.6 31.0 ACTH, adrenocorticotrophic hormone Download : Download high-res image (76KB) Download : Download full-size image Figure 1. Percentage of ACTH increase after desmopressin administration (time 0 min). Transsphenoidal surgery with tumor removal was performed at 18 weeks of gestation. Pathological findings showed a 1.3x1.0x0.3 cm of tissue with segments of the pituitary gland and tumor. There were monomorphous round nuclei, stippled chromatin, indistinct nucleoli, and pale eosinophilic cytoplasm cells. These cells were reactive with ACTH and showed loss of reticulin framework, unlike the normal pituitary gland. The next day after the surgery, her 8 AM cortisol was 6.0 μg/dL. Hydrocortisone supplement was started and continued throughout pregnancy. Antihypertensives were discontinued, and the insulin dosages decreased to less than 20 units per day. At 38 weeks of gestation, she gave birth to a 2300-gm male newborn (small for gestational age). Dysglycemia and hypertension resolved after the delivery. One year after the first child's delivery, the patient had a spontaneous pregnancy without GDM or hypertension. The 8 AM cortisol was 3.9 μg/dL, and hydrocortisone replacement was continued. The patient successfully delivered a term 3300-gm male infant without fetal or maternal complications. Two years after the first transsphenoidal surgery, a 1-μg cosyntropin stimulation test was performed, the basal cortisol was 11.7 μg/dL, and the peak serum cortisol was 23.8 μg/dL. Steroid replacement was withdrawn. Discussion Herein we present a 27-year-old woman who was evaluated during her first pregnancy for clinical and laboratory features suggestive of CD. Her morning serum and late-night salivary cortisol concentrations were elevated in addition to non-suppressed ACTH, but a definitive diagnosis was not obtained by a non-gadolinium pituitary MRI. The diagnosis of CD was suggested, however, by the results of a desmopressin stimulation test. The pituitary MRI with gadolinium was proceeded and revealed a pituitary lesion greater than 6 mm. The prevalence of pregnancy is low due to reduced fertility in CS. To date, there have been less than 300 pregnant patients with CS reported in the literature.2 In pregnancy, the most frequent etiology of CS is adrenal CS (60%), followed by ACTH-producing pituitary adenomas or CD (35%), and very rarely ectopic ACTH (<5%).1 In contrast, CD is the most common cause of CS in non-pregnant people (approximately 70 percent). The clinical diagnosis of CS during pregnancy may be missed due to overlapping features between pregnancy and CS. However, wide purplish cutaneous striae and proximal myopathy are signs with high discrimination index when CS is suspected.5 These signs are not present in normal pregnancy. In this present Case, CS was diagnosed with apparent clinical features of CS in addition to an elevated UFC and late-night salivary cortisol. The patient denied taking any supplements and her 8 AM cortisol was not suppressed and therefore did not suggest an etiology of exogenous steroid use. Pregnant women without CS may have elevated UFC and late-night salivary cortisol due to increased total and free plasma cortisol from the first trimester until the end of pregnancy.6 This results from an elevated concentration of cortisol transport protein and the increase in placental ACTH and CRH. According to the current guideline, UFC is the recommended test when CS is suspected during pregnancy.5 Since UFC increases during the second trimester, it may not be a reliable marker after the first trimester of pregnancy unless the level is clearly increased (up to 2- to 3-fold the upper limit of normal values).1 Late-night salivary cortisol is also one of the useful tests to diagnose CS during pregnancy because the circadian rhythm of cortisol is preserved in normal pregnancy. Furthermore, it is not influenced by the changes in the binding proteins.7 However, the previous study has shown that late-night salivary cortisol increased progressively throughout pregnancy. When compared with non-pregnant women, median values of late-night salivary cortisol in pregnant women were 1.1, 1.4, and 2.1 times higher in the first, second, and third trimesters respectively. The cutoff values for late-night salivary cortisol on each gestational trimester were: first trimester 0.255 μg/dL, second trimester 0.260 μg/dL, and third trimester 0.285 μg/dL. The respective sensitivities and specificities in each trimester were: first trimester 92 and 100%, second trimester 84 and 98%, and third trimester 80 and 93%.8 Given the non-suppressed ACTH levels after the 7th week of gestation, we were not able to summarize whether the etiology was adrenal CS or ACTH-dependent CS which could be either CD or ectopic ACTH syndrome. In non-pregnant individuals, ACTH suppression usually identifies adrenal CS. However, in pregnancy, ACTH levels were non-suppressed in half of those with adrenal CS due to continued stimulation of maternal hypothalamic-pituitary-adrenal axis by placental CRH.1 Therefore, using the ACTH thresholds in general populations can lead to misdiagnosis when investigating the etiology of CS in pregnant individuals. The hypothalamic-pituitary-adrenal axis response to exogenous glucocorticoids is blunted in pregnant women. Following an overnight dexamethasone administration, pregnant women without CS may have non-suppressed plasma cortisol and UFC.6 In non-pregnant individuals with CS, the high-dose dexamethasone suppression test identify CD with a sensitivity of 82% and a specificity of 50%.4 During pregnancy, the high-dose dexamethasone suppression test failed to identify almost half of the patients with CD.1 Inferior petrosal sinus sampling is usually avoided due to the risk of excessive radiation exposure. Since the non-gadolinium MRI also showed no obvious pituitary lesion in the present Case, in addition to the limitation of the high-dose dexamethasone suppression test and inferior petrosal sinus sampling in pregnancy, we used desmopressin stimulation to help in the investigation of CD since desmopressin can stimulate an ACTH response in a considerable proportion of patients with CD but not in most patients with adrenal CS or ectopic ACTH syndrome.3,4 Desmopressin has been assigned to pregnancy category B by the US Food and Drug Administration (FDA). In the most recent guideline update on the diagnosis and management of CD, the desmopressin stimulation test can be used to differentiate ectopic CS and CD in patients with normal or high ACTH and have no adenoma or equivocal results of pituitary MRI. However, the guideline did not mention the use of this test in pregnant individuals.9 The literature regarding the use of desmopressin stimulation tests in pregnancy is limited. We were able to identify one study in a pregnant patient with active CS, who was surgically confirmed as CD, in which the desmopressin stimulation test was performed at 10 weeks of gestation and after the delivery. Compared with age-matched healthy non-pregnant women, there were different responses of cortisol and ACTH after desmopressin administration in a pregnant patient with active CS.10 The ACTH peaks after the administration of desmopressin were higher in the pregnant patient. CRH stimulation test was also performed in the pregnant patient with CD. Desmopressin stimulated ACTH values during pregnancy and after the delivery were not significantly different, while the CRH stimulated ACTH values were significantly higher when the test was performed after the delivery. The authors did not mention optimal cutoff values for these diagnostic tests.10 In non-pregnant individuals, the ACTH increase of more than 35% at 15 minutes after the desmopressin administration gave the sensitivity of 84% and the specificity of 43% in the diagnosis of CD.3 Another recent study in ACTH-dependent CS showed that the threshold increase in the ACTH level after desmopressin stimulation of 45% identified CD with a sensitivity of 91% and a specificity of 75%.4 Using the non-pregnant cutoff values for the desmopressin stimulation test, the diagnosis of CD was made in our patient who was later surgically confirmed as CD. Pituitary microadenomas were the cause of CD in almost 90% of non-pregnant individuals.11 In pregnant women with CD, pituitary microadenomas were also reported to be more common than macroadenomas.1,12 Almost 40% of pituitary microadenomas in CD were invisible or poorly visible in non-contrast MRI, in which contrast-enhanced MRI detected them.13 In the Case series from Lindsay et al., the non-contrast MRI could not correctly identify pituitary adenomas in 38% of pregnant patients with available data.1 The same case series reported a pregnant patient having normal pituitary MRI and was later surgically confirmed as having CD from a 3x3 adenoma with positive staining for ACTH. In the present case, a mild bulging contour of the pituitary gland, although without an obvious abnormal lesion, in addition to desmopressin test results, suggested the need for contrast-enhanced pituitary MRI. Gadolinium contrast is FDA pregnancy category C since it is water-soluble and can cross the placenta into the fetus and amniotic fluid.14 However, since a non-gadolinium MRI may not detect pituitary microadenoma even in patients with normal imaging results,1,15 we suggested physicians consider pituitary MRI with gadolinium as initial imaging in pregnant patients with clinical suspicion of CD. Prompt diagnosis and treatment of CS are essential due to a higher rate of fetal loss in active CS patients without treatment than those who received either medical or surgical treatment. There are significantly lower rates of various fetal complications, including low birth weight, in women with active CS than in cured CS.2 Although medical and surgical treatment were not compared as prognostic factors for complications, experts recommend transsphenoidal surgery in the second trimester as the treatment of choice for CD in pregnancy.1,15 Medical treatment should be the second choice when surgery cannot be carried out or late diagnosis is made. Conclusion In the present Case, the results from the desmopressin stimulation test and the pituitary MRI with gadolinium suggested the diagnosis of CD, which subsequently led to successful treatment. This suggested that the desmopressin test may serve as a useful test to diagnose CD even in the context of pregnancy. Conflicts of Interest None of the authors have any potential conflicts of interest associated with this research. References 1 J.R. Lindsay, J. Jonklaas, E.H. Oldfield, L.K. Nieman Cushing's syndrome during pregnancy: personal experience and review of the literature J Clin Endocrinol Metab, 90 (5) (2005), pp. 3077-3083 CrossRefView Record in ScopusGoogle Scholar 2 F. Caimari, E. Valassi, P. Garbayo, C. Steffensen, A. Santos, R. Corcoy, et al. Cushing's syndrome and pregnancy outcomes: a systematic review of published cases Endocrine, 55 (2) (2017), pp. 555-563 CrossRefView Record in ScopusGoogle Scholar 3 M. Moro, P. Putignano, M. Losa, C. Invitti, C. Maraschini, F. Cavagnini The desmopressin test in the differential diagnosis between Cushing's disease and pseudo-Cushing states J Clin Endocrinol Metab, 85 (10) (2000), pp. 3569-3574 View Record in ScopusGoogle Scholar 4 J. Qiao, J. Li, W. Zhang, C. Wang, J. Li, S. Jiang, et al. The usefulness of the combined high-dose dexamethasone suppression test and desmopressin stimulation test in establishing the source of ACTH secretion in ACTH-dependent Cushing's syndrome Endocr J, 68 (7) (2021), pp. 839-848 CrossRefView Record in ScopusGoogle Scholar 5 L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab, 93 (5) (2008), pp. 1526-1540 CrossRefView Record in ScopusGoogle Scholar 6 J.R. Lindsay, L.K. Nieman The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment Endocr Rev, 26 (6) (2005), pp. 775-799 CrossRefView Record in ScopusGoogle Scholar 7 E.M. Scott, H.H. McGarrigle, G.C. Lachelin The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels J Clin Endocrinol Metab, 71 (3) (1990), pp. 639-644 CrossRefView Record in ScopusGoogle Scholar 8 L.M. Lopes, R.P. Francisco, M.A. Galletta, M.D. Bronstein Determination of nighttime salivary cortisol during pregnancy: comparison with values in non-pregnancy and Cushing's disease Pituitary, 19 (1) (2016), pp. 30-38 CrossRefView Record in ScopusGoogle Scholar 9 M. Fleseriu, R. Auchus, I. Bancos, A. Ben-Shlomo, J. Bertherat, N.R. Biermasz, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update Lancet Diabetes Endocrinol (2021) Google Scholar 10 M. Ragonese, O.R. Cotta, F. Ferraù, F. Trimarchi, S. Cannavò How to diagnose and manage Cushing's disease during pregnancy, when hypercortisolism is mild? Gynecol Endocrinol, 28 (8) (2012), pp. 637-639 CrossRefView Record in ScopusGoogle Scholar 11 R. Pivonello, M. De Leo, A. Cozzolino, A. Colao The Treatment of Cushing's Disease Endocr Rev, 36 (4) (2015), pp. 385-486 CrossRefView Record in ScopusGoogle Scholar 12 A. Tabarin, F. Laurent, B. Catargi, F. Olivier-Puel, R. Lescene, J. Berge, et al. Comparative evaluation of conventional and dynamic magnetic resonance imaging of the pituitary gland for the diagnosis of Cushing's disease Clin Endocrinol (Oxf), 49 (3) (1998), pp. 293-300 View Record in ScopusGoogle Scholar 13 S.K. Palejwala, A.R. Conger, A.A. Eisenberg, P. Cohan, C.F. Griffiths, G. Barkhoudarian, et al. Pregnancy-associated Cushing's disease? An exploratory retrospective study Pituitary, 21 (6) (2018), pp. 584-592 CrossRefView Record in ScopusGoogle Scholar 14 Committee Opinion No. 723: Guidelines for Diagnostic Imaging During Pregnancy and Lactation Obstet Gynecol, 130 (4) (2017), pp. e210-e216 Google Scholar 15 A.H. Affinati, R.J. Auchus Endocrine causes of hypertension in pregnancy Gland Surg, 9 (1) (2020), pp. 69-79 CrossRefView Record in ScopusGoogle Scholar Funding Statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements The authors would like to thank you all the colleagues in the Division of Endocrinology and Metabolism, Department of Medicine, Faculty of medicine, Chulalongkorn University for all the support. © 2021 Published by Elsevier Inc. on behalf of the AACE. From https://www.sciencedirect.com/science/article/pii/S2376060521001231
  23. 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?
  24. The CAHmelia clinical trials are exploring a new investigational treatment for classic CAH. CAHmelia 203 and CAHmelia 204 are clinical trials to test tildacerfont in adults with classic CAH, which may offer you and your loved ones hope of a brighter future – one where you may not have to choose between symptom management and long-term health. Tildacerfont is a new type of oral, once-daily investigational treatment – one that is not a steroid – that is currently being tested in adults with classic CAH. By reducing the amount of androgens your body makes, tildacerfont may improve your classic CAH symptoms. This investigational treatment will not replace your steroid treatment but may allow you to manage your disease with lower amounts of steroids at normal or near-normal doses. Who can take part in this trial? You may be able to take part if you: Are at least 18 years of age Have a confirmed diagnosis of classic CAH due to 21-OH deficiency Have been on the same daily dose of steroids (GCs and/or mineralocorticoids) for at least 1 month before starting the trial Both trials are now open for enrollment. Tildacerfont is an investigational treatment not authorized for use in people outside the clinical trial. For more information, go to: clarahealth.com/studies/cahmelia
  25. Dexamethasone suppression test measures whether adrenocorticotrophic hormone (ACTH) secretion by the pituitary can be suppressed. How the Test is Performed During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medicine. Afterward, your blood is drawn so that the cortisol level in your blood can be measured. There are two different types of dexamethasone suppression tests: low dose and high dose. Each type can either be done in an overnight (common) or standard (3-day) method (rare). There are different processes that may be used for either test. Examples of these are described below. Common: Low-dose overnight -- You will get 1 milligram (mg) of dexamethasone at 11 p.m., and a health care provider will draw your blood the next morning at 8 a.m. for a cortisol measurement. High-dose overnight -- The provider will measure your cortisol on the morning of the test. Then you will receive 8 mg of dexamethasone at 11 p.m. Your blood is drawn the next morning at 8 a.m. for a cortisol measurement. Rare: Standard low-dose -- Urine is collected over 3 days (stored in 24-hour collection containers) to measure cortisol. On day 2, you will get a low dose (0.5 mg) of dexamethasone by mouth every 6 hours for 48 hours. Standard high-dose -- Urine is collected over 3 days (stored in 24-hour collection containers) for measurement of cortisol. On day 2, you will receive a high dose (2 mg) of dexamethasone by mouth every 6 hours for 48 hours. Read and follow the instructions carefully. The most common cause of an abnormal test result is when instructions are not followed. How to Prepare for the Test The provider may tell you to stop taking certain medicines that can affect the test, including: Antibiotics Anti-seizure drugs Medicines that contain corticosteroids, such as hydrocortisone, prednisone Estrogen Oral birth control (contraceptives) Water pills (diuretics) How the Test will Feel When the needle is inserted to draw blood, some people feel moderate pain. Others feel only a prick or stinging. Afterward, there may be some throbbing or slight bruising. This soon goes away. Why the Test is Performed This test is done when the provider suspects that your body is producing too much cortisol. It is done to help diagnose Cushing syndrome and identify the cause. The low-dose test can help tell whether your body is producing too much ACTH. The high-dose test can help determine whether the problem is in the pituitary gland (Cushing disease) or from a different site in the body (ectopic). Dexamethasone is a man-made (synthetic) steroid that binds to the same receptor as cortisol. Dexamethasone reduces ACTH release in normal people. Therefore, taking dexamethasone should reduce ACTH level and lead to a decreased cortisol level. If your pituitary gland produces too much ACTH, you will have an abnormal response to the low-dose test. But you can have a normal response to the high-dose test. Normal Results Cortisol level should decrease after you receive dexamethasone. Low dose: Overnight -- 8 a.m. plasma cortisol lower than 1.8 micrograms per deciliter (mcg/dL) or 50 nanomoles per liter (nmol/L) Standard -- Urinary free cortisol on day 3 lower than 10 micrograms per day (mcg/day) or 280 nmol/L High dose: Overnight -- greater than 50% reduction in plasma cortisol Standard -- greater than 90% reduction in urinary free cortisol Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or may test different specimens. Talk to your doctor about the meaning of your specific test results. What Abnormal Results Mean An abnormal response to the low-dose test may mean that you have abnormal release of cortisol (Cushing syndrome). This could be due to: Adrenal tumor that produces cortisol Pituitary tumor that produces ACTH Tumor in the body that produces ACTH (ectopic Cushing syndrome) The high-dose test can help tell a pituitary cause (Cushing disease) from other causes. An ACTH blood test may also help identify the cause of high cortisol. Abnormal results vary based on the condition causing the problem. Cushing syndrome caused by an adrenal tumor: Low-dose test -- no decrease in blood cortisol ACTH level -- low In most cases, the high-dose test is not needed Ectopic Cushing syndrome: Low-dose test -- no decrease in blood cortisol ACTH level -- high High-dose test -- no decrease in blood cortisol Cushing syndrome caused by a pituitary tumor (Cushing disease) Low-dose test -- no decrease in blood cortisol High-dose test -- expected decrease in blood cortisol False test results can occur due to many reasons, including different medicines, obesity, depression, and stress. False results are more common in women than men. Most often, the dexamethasone level in the blood is measured in the morning along with the cortisol level. For the test result to be considered accurate, the dexamethasone level should be higher than 200 nanograms per deciliter (ng/dL) or 4.5 nanomoles per liter (nmol/L). Dexamethasone levels that are lower can cause a false-positive test result. Risks There is little risk involved with having your blood taken. Veins and arteries vary in size from one patient to another, and from one side of the body to the other. Taking blood from some people may be more difficult than from others. Other risks associated with having blood drawn are slight, but may include: Excessive bleeding Fainting or feeling lightheaded Multiple punctures to locate veins Hematoma (blood accumulating under the skin) Infection (a slight risk any time the skin is broken) Alternative Names DST; ACTH suppression test; Cortisol suppression test References Chernecky CC, Berger BJ. Dexamethasone suppression test - diagnostic. In: Chernecky CC, Berger BJ, eds. Laboratory Tests and Diagnostic Procedures. 6th ed. St Louis, MO: Elsevier Saunders; 2013:437-438. Guber HA, Oprea M, Russell YX. Evaluation of endocrine function. In: McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 24th ed. St Louis, MO: Elsevier; 2022:chap 25. Newell-Price JDC, Auchus RJ. The adrenal cortex. In: Melmed S, Auchus RJ, Goldfine AB, Koenig RJ, Rosen CJ, eds. Williams Textbook of Endocrinology. 14th ed. Philadelphia, PA: Elsevier; 2020:chap 15. Review Date 5/13/2021 Updated by: Brent Wisse, MD, Board Certified in Metabolism/Endocrinology, Seattle, WA. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team. From https://medlineplus.gov/ency/article/003694.htm
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