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  1. How stressed are you? Your earwax could hold the answer. A new method of collecting and analyzing earwax for levels of the stress hormone cortisol may be a simple and cheap way to track the mental health of people with depression and anxiety. Cortisol is a crucial hormone that spikes when a person is stressed and declines when they're relaxed. In the short-term, the hormone is responsible for the "fight or flight" response, so it's important for survival. But cortisol is often consistently elevated in people with depression and anxiety, and persistent high levels of cortisol can have negative effects on the immune system, blood pressure and other bodily functions. There are other disorders which involve abnormal cortisol, including Cushing's disease (caused by the overproduction of cortisol) and Addison's disease (caused by the underproduction of cortisol). People with Cushing's disease have abnormal fat deposits, weakened immune systems and brittle bones. People with Addison's disease have dangerously low blood pressure. There are a lot of ways to measure cortisol: in saliva, in blood, even in hair. But saliva and blood samples capture only a moment in time, and cortisol fluctuates significantly throughout the day. Even the experience of getting a needle stick to draw blood can increase stress, and thus cortisol levels. Hair samples can provide a snapshot of cortisol over several months instead of several minutes, but hair can be expensive to analyze — and some people don't have much of it. Andrés Herane-Vives, a lecturer at University College London's Institute of Cognitive Neuroscience and Institute of Psychiatry, and his colleagues instead turned to the ear. Earwax is stable and resistant to bacterial contamination, so it can be shipped to a laboratory easily for analysis. It also can hold a record of cortisol levels stretching over weeks. But previous methods of harvesting earwax involved sticking a syringe into the ear and flushing it out with water, which can be slightly painful and stressful. So Herane-Vives and his colleagues developed a swab that, when used, would be no more stressful than a Q-tip. The swab has a shield around the handle, so that people can't stick it too far into their ear and damage their eardrum, and a sponge at the end to collect the wax. In a small pilot study, researchers collected blood, hair and earwax from 37 participants at two different time points. At each collection point, they sampled earwax using a syringe from one ear, and using the new self-swab method from the other. The researchers then compared the reliability of the cortisol measurements from the self-swab earwax with that of the other methods. They found that cortisol was more concentrated in earwax than in hair, making for easier analysis. Analyzing the self-swabbed earwax was also faster and more efficient than analyzing the earwax from the syringe, which had to be dried out before using. Finally, the earwax showed more consistency in cortisol levels compared with the other methods, which were more sensitive to fluctuations caused by things like recent alcohol consumption. Participants also said that self-swabbing was more comfortable than the syringe method. The researchers reported their findings Nov. 2 in the journal Heliyon. Herane-Vives is also starting a company called Trears to market the new method. In the future, he hopes that earwax could also be used to monitor other hormones. The researchers also need to follow up with studies of Asian individuals, who were left out of this pilot study because a significant number only produce dry, flaky earwax as opposed to wet, waxy earwax. "After this successful pilot study, if our device holds up to further scrutiny in larger trials, we hope to transform diagnostics and care for millions of people with depression or cortisol-related conditions such as Addison's disease and Cushing syndrome, and potentially numerous other conditions," he said in a statement. Originally published in Live Science.
    3 points
  2. Christina Tatsi, Maria E. Bompou, Chelsi Flippo, Meg Keil, Prashant Chittiboina, Constantine A. Stratakis First published: 25 August 2021 https://doi.org/10.1111/cen.14560 Abstract Objective Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD. Patients Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included. Measurements Clinical, imaging and biochemical data were analysed. Results One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1–6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7–5.8). Conclusions Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings. Full text at https://onlinelibrary.wiley.com/doi/full/10.1111/cen.14560
    2 points
  3. SAN DIEGO, CA, USA I August 10, 2021 I Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, today announced positive preliminary findings from the single ascending dose (SAD) portion of a first-in-human Phase 1 clinical study with CRN04894 demonstrating pharmacologic proof-of-concept for this first-in-class, investigational, oral, nonpeptide adrenocorticotropic hormone (ACTH) antagonist that is being developed for the treatment of conditions of ACTH excess, including Cushing’s disease and congenital adrenal hyperplasia. “ACTH is the central hormone of the endocrine stress response. Even though we’ve known about its clinical significance for more than 100 years, there has never been an ACTH antagonist available to intervene in diseases of excess stress hormones. This is an important milestone for the field of endocrinology and for our company,” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “I am extremely proud of our team that conceived, discovered and developed CRN04894 this far. This is the second molecule to emerge from our in-house discovery efforts and demonstrate pharmacologic proof of concept. I am very excited to see what it can do in upcoming clinical studies.” The 39 healthy volunteers who enrolled in the SAD cohorts were administered oral doses of CRN04894 (10 mg to 80 mg, or placebo) two hours prior to a challenge with synthetic ACTH. Analyses of basal cortisol levels (before ACTH challenge) showed that CRN04894 produced a rapid and dose-dependent reduction of cortisol by 25-56%. After challenge with a supra-pathophysiologic dose of ACTH (250 mcg), CRN04894 suppressed cortisol (as measured by AUC) up to 41%. After challenge with a disease-relevant dose of ACTH (1 mcg), CRN04894 showed a clinically meaningful reduction in cortisol AUC of 48%. These reductions in cortisol suggest that CRN04894 is bound with high affinity to its target receptor on the adrenal gland and blocking the activity of ACTH. CRN04894 was well tolerated in the healthy volunteers who enrolled in these SAD cohorts and all adverse events were considered mild. “We are very encouraged by these single ascending dose data which clearly demonstrate proof of ACTH antagonism with CRN04894 exposure in healthy volunteers,” stated Alan Krasner, M.D., chief medical officer of Crinetics. “We look forward to completing this study and assessing results from the multiple ascending dose cohorts. As a clinical endocrinologist, I recognize the pioneering nature of this work and eagerly look forward to further understanding the potential of CRN04894 for the treatment of diseases of ACTH excess.” Data Review Conference Call Crinetics will hold a conference call and live audio webcast today, August 10, 2021 at 4:30 p.m. Eastern Time to discuss the results of the CRN04894 SAD cohorts. To participate, please dial 800-772-3714 (domestic) or 212-271-4615 (international) and refer to conference ID 21996541. To access the webcast, please visit the Events page on the Crinetics website. The archived webcast will be available for 90 days. About the CRN04894-01 Phase 1 Study Crinetics is enrolling healthy volunteers in this double-blind, randomized, placebo-controlled Phase 1 study of CRN04894. Participants will be divided into multiple cohorts in the single ascending dose (SAD) and multiple ascending dose (MAD) phases of the study. In the SAD phase, safety and pharmacokinetics are assessed. In addition, pharmacodynamic responses are evaluated before and after challenges with injected synthetic ACTH to assess pharmacologic effects resulting from exposure to CRN04894. In the MAD phase, participants will be administered placebo or ascending doses of study drug daily for 10 days. Assessments of safety, pharmacokinetics and pharmacodynamics will also be performed after repeat dosing. About CRN04894 Adrenocorticotropic hormone (ACTH) is synthesized and secreted by the pituitary gland and binds to melanocortin type 2 receptor (MC2R), which is selectively expressed in the adrenal gland. This interaction of ACTH with MCR2 stimulates the adrenal production of cortisol, a stress hormone that is involved in the regulation of many systems. Cortisol is involved for example in the regulation of blood sugar levels, metabolism, inflammation, blood pressure, and memory formulation, and excess adrenal androgen production can result in hirsutism, menstrual dysfunction, infertility in men and women, acne, cardiometabolic comorbidities and insulin resistance. Diseases associated with excess of ACTH, therefore, can have significant impact on physical and mental health. Crinetics’ ACTH antagonist, CRN04894, has exhibited strong binding affinity for MC2R in preclinical models and demonstrated suppression of adrenally derived glucocorticoids and androgens that are under the control of ACTH, while maintaining mineralocorticoid production. About Cushing’s Disease and Congenital Adrenal Hyperplasia Cushing’s disease is a rare disease with a prevalence of approximately 10,000 patients in the United States. It is more common in women, between 30 and 50 years of age. Cushing’s disease often takes many years to diagnose and may well be under-diagnosed in the general population as many of its symptoms such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity can be incorrectly attributed to other more common disorders. Congenital adrenal hyperplasia (CAH) encompasses a set of disorders that are caused by genetic mutations that result in impaired cortisol synthesis with a prevalence of approximately 27,000 patients in the United States. This lack of cortisol leads to a loss of feedback mechanisms and results in persistently high levels of ACTH, which in turn causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects from improper gonadal development to life-threatening adrenal crisis. About Crinetics Pharmaceuticals Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors. The company’s lead product candidate, paltusotine, is an investigational, oral, selective nonpeptide somatostatin receptor type 2 agonist for the treatment of acromegaly, an orphan disease affecting more than 26,000 people in the United States. A Phase 3 program to evaluate safety and efficacy of paltusotine for the treatment of acromegaly is underway. Crinetics also plans to advance paltusotine into a Phase 2 trial for the treatment of carcinoid syndrome associated with neuroendocrine tumors. The company is also developing CRN04777, an investigational, oral, nonpeptide somatostatin receptor type 5 (SST5) agonist for congenital hyperinsulinism, as well as CRN04894, an investigational, oral, nonpeptide ACTH antagonist for the treatment of Cushing’s disease, congenital adrenal hyperplasia, and other diseases of excess ACTH. All of the company’s drug candidates are new chemical entities resulting from in-house drug discovery efforts and are wholly owned by the company. SOURCE: Crinetics Pharmaceuticals From https://pipelinereview.com/index.php/2021081178950/Small-Molecules/Crinetics-Pharmaceuticals-Oral-ACTH-Antagonist-CRN04894-Demonstrates-Pharmacologic-Proof-of-Concept-with-Dose-Dependent-Cortisol-Suppression-in-Single-Ascending-Dose-Port.html
    2 points
  4. All of our country is very encouraged by the declining rates in both COVID-19 infections and death, due mostly to President Trump’s vaccine production and trial effort called Operation Warp Speed and President Biden’s vaccine distribution efforts. As of July 2021, The United States has administered 334,600,770 doses of COVID-19 vaccines, 184,132,768 people had received at least one dose while 159,266,536 people are fully vaccinated. The pandemic is by no means over, as people are still getting infected with COVID-19 with the emergence of the Delta Variant. In fact, recently cases, hospitalizations and deaths due to COVID-19 have gone up. In Los Angeles, the increased infection rate has led to indoor mask requirements. The main reason that COVID-19 has not been eliminated is because of vaccine hesitancy, which is often due to misinformation propagated on websites and social media. One of Dr. Friedman's patients gave him a link of an alternative doctor who gave multiple episodes of misinformation subtitled “Evidence suggests people who have received the COVID “vaccine” may have a reduced lifespan” about the COVID-19 vaccine that Dr. Friedman wants to address. Almost 30% of American say they will not get the vaccine, up from 20% a few months ago. Statistics are that people who are vaccinated have a 1:1,000,000 chance of dying from COVID, while people who are unvaccinated have a 1:500 chance of dying from COVID. I think most people would take the 1:1,000,000 risk. Dr. Friedman has always been a proponent of the COVID-19 vaccine because he is a scientist and bases his decisions on peer-reviewed literature and not social media posts. As we are getting to the stage where the COVID-19 pandemic could end if vaccination rates increase, he feels that it is even more important for people to get correct information about the COVID-19 vaccine. MYTH: People are dying at high rates from the COVID-19 vaccine and the rates of complications and deaths are underreported. FACT: The rates of complications and deaths from the vaccine are overreported. It is a fact that when 200 million people get a vaccine, some of them will get blood clots, some of them will have a heart attack, some of them will have strokes, some of them will have optic neuritis and some will have Guillain-Barré syndrome. These complications may not be due to the vaccine, but people remember that they got the vaccine recently. Anti-vaccine websites seem to play up on this and give false information that COVID-19 complications are underreported and fail to note that there is no control group, so we do not know how many people would have gotten blood clots, strokes, and heart attacks if they did not get the vaccine. For example, one anti-vaccine website highlighted a Tamil (Indian) actor Vivek, who died of a massive heart attack 5 days after getting the COVID-19 vaccine and tried to make a case that the vaccine caused that. Of course, the massive heart attack was due to years of buildup of cholesterol in his coronary arteries and had nothing to do with the COVID-19 vaccine. In fact, the complications attributed to the COVID-19 vaccine occur less frequently in those vaccinated than unvaccinated. The only complication that seems to possibly be more common in people who get vaccinated is blood clots, and the rate of that is still quite low. Overwhelmingly, the COVID-19 vaccine is effective and safe. MYTH: I had COVID-19 before. I don't need a vaccine. Natural immunity is better than a vaccine immunity. FACT: Most studies have shown that the COVID-19 vaccines are more effective, with longer-lasting immunity, than only having the COVID-19 infection. The immunity after natural infection varies and may be quite minimal in patients who had mild COVID-19 and likely declines within a couple of months of infection. In contrast, those who got the vaccine seem to have high levels of immunity even months after getting the vaccine. The vaccine also protects against the COVID-19 variants. If someone had one variant, it is unlikely that their natural immunity would protect them against other variants. MYTH: The COVID-19 vaccine leads to spike proteins circulating in your body for months after the vaccine. FACT: The mRNA from the vaccine, the spike protein that it generates, and all of the products of the COVID-19 vaccine are gone within hours, if not days, and do not hang around the body. MYTH: There is likely to be long-term effects, including infertility effects, of the COVID-19 vaccine. FACT: As the viral particles and proteins are gone within a couple hours to days and the vaccine only enters the cytoplasm and does not enter the DNA, it is very unlikely that there will be long-term effects. So far, the clinical trials of the COVID-19 vaccine have not resulted in any detrimental effects, and it has been a year since the trials started. Other vaccines have been used safely and do not give long-term side effects. There is no reason to think that this vaccine would give long-term side effects, and we have not seen any evidence of long-term side effects currently. Pregnant women who received COVID-19 vaccines have similar rates adverse pregnancy and neonatal outcomes (e.g., fetal loss, preterm birth, small size for gestational age, congenital anomalies, and neonatal death) as with pregnant women who did not receive vaccines. MYTH: People with autoimmune disease should not get the vaccine. FACT: Persons with autoimmune disease are likely more susceptible to COVID-19, and they should especially get the vaccine. People with preexisting conditions, including autoimmune diseases, have been shown to be give generally excellent immune responses to the vaccine, and it should especially be given to patients with Addison’s disease or Cushing's disease who may have higher rates of getting more severe COVID-19. In fact, the CDC as well Dr. Friedman recommends EVERYONE getting the vaccine, except 1) those under 12, 2) those who had an anaphylactic reaction to their first COVID-19 vaccine. Patients with AIDS, and those on immunosuppressive therapy for cancers, organ transplants and rheumatological conditions, may not be fully protected from vaccines and should be cautious (including wearing masks and social distancing), but still should get vaccinated. MYTH: Patients with autoimmune diseases, and other conditions do not mount an adequate immune response to the vaccine and may even should get a booster shot. FACT: The only patients that have been found not to have a good immune response to the vaccine is those with AIDS or on immunosuppressive drugs that are used in people with rheumatological diseases or transplants. With these exception, patients appear to mount a good immune response to the vaccine regardless of their preexisting condition and do not need a booster shot. MYTH: Why should I bother with the vaccine if it is going to require a booster shot? FACT: It is unclear whether booster shots will be required or not. Currently, the CDC and FDA do not recommend a booster shot, but Pfizer has petitioned the FDA to consider it and is starting more studies on whether a booster shot is effective. It is currently believed that the vaccine retains effectiveness for months to years after it is given. MYTH: We are almost at herd immunity now. Why bother getting a vaccine? FACT: We are not at herd immunity as people are still getting sick and dying from COVID-19. Dr. Friedman recently lost to COVID-19 his 43-year old patient with obesity and diabetes at MLK Outpatient Center. There are pockets in the United States with low vaccine rates, especially in the South. The vaccine is spreading among unvaccinated people, while the rate of spread among vaccinated people is quite low. Approximately 98% of those hospitalized with COVID-19 are unvaccinated. It is important from a public health viewpoint for all Americans to get vaccinated. MYTH: There is nothing to be concerned with about the variants. FACT: Especially the delta variant appears to be more contagious and aggressive than the other variants currently. The vaccines do appear to be effective against the delta variant but possibly a little less so. Variants multiply and can generate new variants only if they are infected into patients who are unvaccinated. To end the emergence of new variants, it is important for all Americans to get vaccinated. MYTH: I could just be careful, and I will not get the COVID-19 vaccine. FACT: Thousands of people who were careful and got COVID-19 and either died from it or became extremely sick. The best prevention against getting COVID-19 is to get vaccinated. MYTH: I am young. I do not have to worry about getting COVID. FACT: Many young people have gotten sick and died of COVID-19 and also, they are contagious and can spread COVID-19 if they are not vaccinated. Everyone, regardless of their age, as long as they are over 12, should get vaccinated. MYTH: If children under 12 are not vaccinated, the virus will still spread. FACT: The FDA and CDC do not recommend the vaccine for those under 12. They are very unlikely to get COVID-19 and are very unlikely to transmit it to others. They are the one group that does not need to get vaccinated. MYTH: COVID-19 vaccines are an experimental vaccine. FACT: While it is true that the FDA approved COVID-19 vaccines were granted emergency use authorization in December 2020 (Pfizer and Moderna) and Johnson and Johnson in February 2021. Both Pfizer and Moderna have petitioned the FDA for full approval, but by no means are these vaccines experimental. As mentioned, over 180 million Americans and many more worldwide have received the vaccine. This is more than any other FDA approved medication. Clinical trials are still ongoing and have enrolled thousands of people and Israel has monitored the effect of COVID-19 vaccines in 7 million Israelis. MYTH: The COVID-19 vaccine is a government plot to kill or injure people or a war against G-d. FACT: Yeah right If you want the pandemic to end, please get vaccinated and encourage your friends and colleagues to get vaccinated. For more information or to schedule an appointment with Dr. Friedman, go to goodhormonehealth.com
    2 points
  5. Rachel Acree, Caitlin M Miller, Brent S Abel, Nicola M Neary, Karen Campbell, Lynnette K Nieman Journal of the Endocrine Society, Volume 5, Issue 8, August 2021, bvab109, https://doi.org/10.1210/jendso/bvab109 Abstract Context Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure. Objective To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL. Design Cross-sectional observational survey. Participants Patients (n = 341) had undergone surgery for CS and were members of the Cushing’s Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS. Results Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P < 0.0001), exercise (40.9% vs 77.6%, P = 0.0001), and activities (44.8% vs 75.5%, P = 0.0016) as useful coping mechanisms in the postsurgical period. Most patients considered family/friends (83.4%) and rest (74.7%) to be helpful. All physicians endorsed educating patients on recovery, but 32.4% (95% CI, 27.3-38.0) of patients denied receiving sufficient information. Some patients did not feel prepared for the postsurgical experience (32.9%; 95% CI, 27.6-38.6) and considered physicians not familiar enough with CS (16.1%; 95% CI, 12.2-20.8). Conclusion Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery. Read the entire article in the enclosed PDF. bvab109.pdf
    2 points
  6. Mayela, I'm so sorry you went through COVID but glad you're on the other side of it now. And a relapse doesn't sound like any fun Thanks for the update on The GRACE trial, though. Please keep us updated on your recovery from COVID and your relapse.
    2 points
  7. Osilodrostat therapy was found to be effective in improving blood pressure parameters, health-related quality of life, depression, and other signs and symptoms in patients with Cushing disease, regardless of the degree of cortisol control, according to study results presented at the 30th Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists (ENVISION 2021). Investigators of the LINC 3 study (ClinicalTrials.gov Identifier: NCT02180217), a phase 3, multicenter study with a double-blind, randomized withdrawal period, sought to assess the effects of twice-daily osilodrostat (2-30 mg) on signs, symptoms, and health-related quality of life in 137 patients with Cushing disease. Study endpoints included change in various parameters from baseline to week 48, including mean urinary free cortisol (mUFC) status, cardiovascular-related measures, physical features, Cushing Quality-of-Life score, and Beck Depression Inventory score. Participants were assessed every 2, 4, or 12 weeks depending on the study period, and eligible participants were randomly assigned 1:1 to withdrawal at week 24. The median age of participants was 40.0 years, and women made up 77.4% of the cohort. Of 137 participants, 132 (96%) achieved controlled mUFC at least once during the core study period. At week 24, patients with controlled or partially controlled mUFC showed improvements in blood pressure that were not seen in patients with uncontrolled mUFC; at week 48, improvement in blood pressure occurred regardless of mUFC status. Cushing Quality-of-Life and Beck Depression Inventory scores, along with other metabolic and cardiovascular risk factors, improved from baseline to week 24 and week 48 regardless of degree of mUFC control. Additionally, most participants reported improvements in physical features of hypercortisolism, including hirsutism, at week 24 and week 48. The researchers indicated that the high response rate with osilodrostat treatment was sustained during the 48 weeks of treatment, with 96% of patients achieving controlled mUFC levels; improvements in clinical signs, physical features, quality of life, and depression were reported even among patients without complete mUFC normalization. Disclosure: This study was sponsored by Novartis Pharma AG; however, as of July 12, 2019, osilodrostat is an asset of Recordati AG. Please see the original reference for a full list of authors’ disclosures. Visit Endocrinology Advisor‘s conference section for complete coverage from the AACE Annual Meeting 2021: ENVISION. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Effect of osilodrostat on clinical signs, physical features and health-related quality of life (HRQoL) by degree of mUFC control in patients with Cushing’s disease (CD): results from the LINC 3 study. Presented at: 2021 AACE Virtual Annual Meeting, May 26-29, 2021. From https://www.endocrinologyadvisor.com/home/conference-highlights/aace-2021/osilodrostat-improves-blood-pressure-hrqol-and-depression-in-patients-with-cushing-disease/
    2 points
  8. HRA Pharma Rare Diseases, an affiliate of privately-held French healthcare company HRA Pharma, has revealed data from the six-month extension of PROMPT, the first ever prospective study designed to evaluate metyrapone long-term efficacy and tolerability in endogenous Cushing’s syndrome. After confirming good efficacy and safety of metyrapone in the first phase of the study that ran for 12 weeks, the results of the six-month extension showed that metyrapone successfully maintains low urinary free cortisol (UFC) levels with good tolerability. The data will be presented at the European Congress of Endocrinology 2021 next week. Metyrapone is approved in Europe for the treatment of endogenous Cushing’s syndrome. It works by inhibiting the 11-beta-hydroxylase enzyme, the final step in cortisol synthesis. From https://www.thepharmaletter.com/in-brief/brief-metyrapone-effective-and-safe-in-endogenous-cushing-s-syndrome-in-long-term-says-hra-pharma-rare-diseases
    2 points
  9. WASHINGTON--Endogenous Cushing's syndrome, a rare hormonal disorder, is associated with a threefold increase in death, primarily due to cardiovascular disease and infection, according to a study whose results will be presented at ENDO 2021, the Endocrine Society's annual meeting. The research, according to the study authors, is the largest systematic review and meta-analysis to date of studies of endogenous (meaning "inside your body") Cushing's syndrome. Whereas Cushing's syndrome most often results from external factors--taking cortisol-like medications such as prednisone--the endogenous type occurs when the body overproduces the hormone cortisol, affecting multiple bodily systems. Accurate data on the mortality and specific causes of death in people with endogenous Cushing's syndrome are lacking, said the study's lead author, Padiporn Limumpornpetch, M.D., an endocrinologist from Prince of Songkla University, Thailand and Ph.D. student at the University of Leeds in Leeds, U.K. The study analyzed death data from more than 19,000 patients in 92 studies published through January 2021. "Our results found that death rates have fallen since 2000 but are still unacceptably high," Limumpornpetch said. Cushing's syndrome affects many parts of the body because cortisol responds to stress, maintains blood pressure and cardiovascular function, regulates blood sugar and keeps the immune system in check. The most common cause of endogenous Cushing's syndrome is a tumor of the pituitary gland called Cushing's disease, but another cause is a usually benign tumor of the adrenal glands called adrenal Cushing's syndrome. All patients in this study had noncancerous tumors, according to Limumpornpetch. Overall, the proportion of death from all study cohorts was 5 percent, the researchers reported. The standardized mortality ratio--the ratio of observed deaths in the study group to expected deaths in the general population matched by age and sex--was 3:1, indicating a threefold increase in deaths, she stated. This mortality ratio was reportedly higher in patients with adrenal Cushing's syndrome versus Cushing's disease and in patients who had active disease versus those in remission. The standardized mortality ratio also was worse in patients with Cushing's disease with larger tumors versus very small tumors (macroadenomas versus microadenomas). On the positive side, mortality rates were lower after 2000 versus before then, which Limumpornpetch attributed to advances in diagnosis, operative techniques and medico-surgical care. More than half of observed deaths were due to heart disease (24.7 percent), infections (14.4 percent), cerebrovascular diseases such as stroke or aneurysm (9.4 percent) or blood clots in a vein, known as thromboembolism (4.2 percent). "The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism and good infection control and emphasize the need to achieve disease remission, normalizing cortisol levels," she said. Surgery is the mainstay of initial treatment of Cushing's syndrome. If an operation to remove the tumor fails to put the disease in remission, other treatments are available, such as medications. Study co-author Victoria Nyaga, Ph.D., of the Belgian Cancer Centre in Brussels, Belgium, developed the Metapreg statistical analysis program used in this study. ### Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world's oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions. The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system. From https://www.eurekalert.org/pub_releases/2021-03/tes-lao031621.php
    2 points
  10. Context Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing’s syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically. Objective, Setting, and Main Outcome Measures Prospectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS. Design Patients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis. Results We identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for ACTH-independent CS (5 patients with at least one and 11 without any elevated salivary result). In patients with Cushing’s disease (CD), most non-elevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD. Conclusions Since the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing’s syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS. Cushing’s disease, ectopic ACTH, adrenal Cushing’s syndrome, diagnosis, assay performance Issue Section: Clinical Research Article From https://academic.oup.com/jes/advance-article/doi/10.1210/jendso/bvaa107/5876040
    2 points
  11. Ieva Lase, Malin Grönberg, Olov Norlén, Peter Stålberg, Staffan Welin, Eva Tiensuu Janson First published: 13 August 2021 https://doi.org/10.1111/jne.13030 Abstract Neuroendocrine neoplasms (NENs) causing ectopic Cushing's syndrome (ECS) are rare and challenging to treat. In this retrospective cohort study, we aimed to evaluate different approaches for bilateral adrenalectomy (BA) as a treatment option in ECS. Fifty-three patients with ECS caused by a NEN (35 females/18 men; mean ± SD age: 53 ± 15 years) were identified from medical records. Epidemiological and clinical parameters, survival, indications for surgery and timing, as well as duration of surgery, complications and surgical techniques, were collected and further analysed. The primary tumour location was thorax (n = 30), pancreas (n = 14) or unknown (n = 9). BA was performed in 37 patients. Median time from diagnosis of ECS to BA was 2 months (range 1–10 months). Thirty-two patients received different steroidogenesis inhibitors before BA to control hypercortisolaemia. ECS resolved completely after surgery in 33 patients and severe peri- or postoperative complications were detected in 12 patients. There were fewer severe complications in the endoscopic group compared to open surgery (p = .030). Posterior retroperitoneoscopic BA performed simultaneously by a two surgeon approach had the shortest operating time (p = .001). Despite the frequent use of adrenolytic treatment, BA was necessary in a majority of patients to gain control over ECS. Complication rate was high, probably as a result of the combination of metastatic disease and metabolic disorders caused by high cortisol levels. The two surgeon approach BA may be considered as the method of choice in ECS compared to other BA approaches as a result of fewer complications and a shorter operating time. 1 INTRODUCTION Endogenous Cushing's syndrome (CS) has an estimated incidence of 0.2–5.0 per million people per year.1 In 5–10% of these, it is caused by ectopic secretion of adrenocorticotrophic hormone (ACTH) or, in extremely rare cases, corticotrophin-releasing hormone, from a non-pituitary tumour.1, 2 The treatment of neuroendocrine neoplasms (NENs) with ectopic secretion of ACTH is challenging. Because of the rarity and heterogeneity of this condition, there is no established evidence-based recommendation.3 Most patients with ectopic Cushing's syndrome (ECS) have severe hypercortisolaemia leading to disrupted electrolyte and glucose levels, metabolic alkalosis, thrombosis and life-threatening infections, amongst many other manifestations. Initiation of oncological treatment is often delayed as a result of the consequences of high cortisol levels. A reduction of the cortisol level is crucial for survival and hypercortisolaemia and hypokalaemia are negative prognostic factors.4, 5 If radical surgery of the tumour is not possible because of metastatic disease, normo-cortisolaemia can be achieved either by medical treatment with steroidogenesis inhibitors (SI) or bilateral adrenalectomy (BA),6 and BA has also been considered a treatment option for patients with occult or cyclic ECS. In patients with metastatic neuroendocrine carcinomas, platinum-based chemotherapy may be applied as first-line action, combined by SI and/or followed by BA. Computed tomography-guided percutaneous adrenal ablation has been reported in several case reports as a possible therapeutic alternative for patients in whom medical treatment has failed and BA is not feasible,7-10 althhough more data is needed to recommend this method in daily practice. In the 1930s, transabdominal open access BA was introduced as a treatment option for uncontrolled cortisol secretion.11 Sixty years later, in the 1990s, laparoscopic methods were established12, 13 and are now considered as the gold standard for BA (except for adrenal carcinomas) because they result in less postoperative pain, a shorter hospitalisation time and faster recovery.14 Laparoscopic transperitoneal adrenalectomy (LTA) is the most frequently applied surgical method. However, posterior retroperitoneoscopic adrenalectomy (PRA), introduced in 1995 by Walz et al,15 is gaining popularity.16 Using PRA compared to LTA offers a more direct approach to the adrenal glands, a shorter operating time (no need for reposition of the patient), less blood loss and faster recovery, and it aso has advantages for patients with obesity or a history of previous abdominal surgery.16 There are centres where PRA is performed by a two surgeon approach; thus, a simultaneous bilateral approach offers the possibility of decreasing the surgical time by up to 50% and reducing operative stress.17-19 The present study aimed to evaluate BA as a treatment option for ECS, as well as the effects of different approaches on morbidity and mortality. We hypothesised that endoscopic surgery methods could be superior regarding complication rate, operating and hospitalisation time compared to open access surgery and also influence overall survival. 2 MATERIALS AND METHODS 2.1 Patients and data A cohort of 59 patients with ECS was identified retrospectively from medical records of 894 patients with NENs, referred to the Department of Endocrine Oncology, Uppsala University Hospital between 1984 and 2019. None of the patients had a small-cell lung cancer (SCLC) because these tumours are not treated at our centre and possibly have a different mechanism behind ACTH production compared to that of NENs. Furthermore, SCLCs have a much more severe course of disease compared to well differentiated NENs and including them in the present study could mask any results important for NEN clinical management. Six patients were from outside Sweden and were excluded from further analysis because of a lack of follow-up data; thus, in total, 53 patients were available for analysis. Diagnosis of ECS was confirmed by histopathological examination of tumour specimen (n = 48) together with the clinical and biochemical picture of ACTH-dependent Cushing’s syndrome (elevated serum and urinary cortisol, high ACTH and pathological functional tests). In five patients where neither primary tumor, nor metastatic disease was found despite several PET examinations, including 68 Ga- DOTATOC-PET, 11C-5HTP-PET and 18FDG-PET in four of the five patients, ECS was confirmed on the basis of the clinical/biochemical picture and exclusion of pituitary origin by magnetic resonance imaging, as well as inferior sinus petrosus sampling. Epidemiological data, data on clinical parameters, survival, indication and duration of surgery, complications and surgical technique were extracted and further analysed. 2.2 Surgery BA was performed either by an open access approach, LTA or PRA. PRA was performed either by one surgeon (PRA-1S) or by two surgeons operating on both sides simultaneously (PRA-2S). Some patients were operated twice (one adrenal at the time) and, for those patients, operating time was pooled from both surgeries, if both sessions were performed within 1 week. Cases where conversion from an endoscopic to an open access approach was made peroperatively were grouped as open access surgery in further analysis. Patients who died during the postoperative stage (within 30 days) were excluded from calculation of hospitalisation time. Postoperative complications were graded using the Clavien–Dindo classification where complications of Grade 1 are defined as “any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions. Allowed therapeutic regimens are drugs as antiemetics, antipyretics, analgesics, diuretics and electrolytes and physiotherapy”.20 Because almost all patients had mild, Grade 1 postoperative complications (metabolic disturbances caused by hypercortisolaemia), this variable is not described. We defined complications up to Grade 2 as mild and Grade 3–5 as severe. 2.3 Statistical analysis All parameters were analysed by descriptive statistics: normally distributed data as the mean ± SD, and data with skewed distribution and/or outliers were described as medians, accompanied by the 25th to 75th percentile ranges (Q1-Q3) or minimum-maximum (min-max). The defined event was death from any cause. Overall survival (OS) was defined as time from diagnosis of ECS or time of BA until date of death or, if the event was not found, censored at date of last observation, 31 December 2019. Kaplan-Meier plots were used for survival analysis and the log-rank test was used for comparison. Chi-squared was used for testing relationships between categorical variables. p < .05 was considered statistically significant. All statistical analyses were performed using IBM, version 27 (IBM Corp., Armonk, USA). 3 RESULTS 3.1 Studied patients ECS represented six% (n = 59) of NENs in our cohort. Six patients were excluded from further analysis, resulting in 53 ECS patients who were analysed; there were 35 females and 18 males with a mean ± SD age of 53 ± 15 years. The localisation of the primary NEN was thorax (n = 30), pancreas (n = 14) or unknown (n = 9). Histopathological staining for Ki-67 was available in 38 patients and Ki-67 was < 2% in five patients, 3–20% in 22 patients and > 20% in 11 patients. Patient characteristics are shown in Tables 1 and 2. Twenty-two patients (41.5%) in this cohort had concomitant hypersecretion of hormones other than ACTH from their tumour (5-HIAA, n = 10; calcitonin, n = 3; 5-HIAA + calcitonin, n = 2; glucagon, n = 3, gastrin, n = 2; growth hormone, n = 1; insulin + gastrin + vasointestinal peptide, n = 1). 3.2 Surgery Adrenalectomy was performed in 37 patients (70%); 24 patients were operated at Uppsala University Hospital, nine at Karolinska University Hospital in Stockholm and four at Umeå University Hospital. Median time from diagnosis of ECS to BA was 2 months (range 1–10 months). Median Ki-67 in patients who were operated within 2 months after ECS diagnosis was higher (Ki-67 18.5%) compared to those with BA performed later in the course of disease (Ki-67 9.5%), although the difference was not statistically significant (p = .085). Thirty-two (86%) patients received different SI prior to BA to control hypercortisolaemia. Eight of those were treated with chemotherapy as well in an attempt to reduce cortisol levels. The majority of patients was treated with ketoconazole, often in combination with other drugs (Table 3). Indications for BA in our cohort included (1) persistent hypercortisolaemia despite use of SI (n = 30); (2) BA as first choice of treatment to reduce cortisol levels (n = 5); and (3) no effect combined with severe side effects from SI including liver toxicity and severe leukopenia (n = 2). In 16 patients, BA was not performed as a result of (1) good control of ECS with SI (n = 4); (2) radical surgery of the primary tumour (n = 3); (3) good control of ECS with SI followed by radical surgery of the primary tumour (n = 5) and (4) the bad condition of the patient (n = 4). 3.3 Survival analysis There was no operative mortality in this cohort. Four patients died within 1 month after adrenalectomy (on day 5, 16, 22 and 30, respectively) as a result of multiple organ dysfunction syndrome and progression of NEN. At the end of the follow-up period, 14 patients were still alive and 39 had died. Median survival after BA was 24 months (95% confidence interval [CI] = 7–41, min-max: 0–428) with a 5-year survival of 22%. Median follow-up time for all patients from time of ECS diagnosis was 26 (range 6–62) months and after BA was 19 (range 3–50) months. OS was longer in patients where ECS was treated by radical surgery of the primary tumour or where good biochemical control was achieved by SI compared to patients who underwent BA, 96 months (95% CI 0–206) vs 29 months (95% CI 7–51), respectively. However, this difference was not statistically significant (p = .086), most likely as a result of the small sample size. Multiple hormone secretion correlated with shorter OS after BA (p = .009; hazard ratio = 2.9; 95% CI= 1.3–6.7). There was no significant difference in OS after BA depending on localisation of primary tumour (thoracic NENs 24 months [95% CI = 8–40, min-max: 0–428], pancreatic NENs 19 months [95% CI = 0–43, min-max: 0–60], p = .319) or surgical approach (open access approach 24 months [95% CI = 1–47], endoscopic approach 19 months [95% CI = 1–37], p = .720). Median time from ECS diagnosis to BA was 2 months (range 1–10). Patients who underwent BA within 2 months after ECS diagnosis had shorter OS compared to those who were operated at a later stage: 6 months (95% CI = 0–18) and 45 months (95% CI = 3–86) respectively (p = .007). The former group had a slightly higher median Ki-67 level (18% vs 9%), lower potassium (2.7 mmol L-1 vs 3.0 mmol L-1) and higher hormone levels (ACTH 217 vs 120 ng mL-1, morning cortisol 1448 vs 1181 nmol L-1 and UFC 5716 vs 4234 nmol per 24 h) at diagnosis compared to those who were operated later in the course of disease. 4 DISCUSSION The present study highlights new aspects of the advantages of an endoscopic approach of BA compared to open access surgery, regarding the incidence of severe complications graded using the Clavien-Dindo classification, as well as operation- and hospitalisation time. Our results indicate that PRA performed by two surgeons simultaneously is the method of choice for patients with ECS. However, despite these advantages, the endoscopic approach did not appear to improve overall survival. Recent Endocrine Society guidelines recommend SI as primary treatment for ECS in patients with occult or metastatic ECS followed by BA.6 Although the toxicity of SI in our cohort was low (n = 2; 6%), 32 patients (73%) had persistent hypercortisolaemia despite medical treatment and proceeded to BA. BA, especially with an endoscopic approach, with a short operating time and low complication risk, appears to play a major role in the appropriate management of hypercortisolaemia in ECS, where rapid reduction of cortisol levels is very important. Prolonged exposure to high cortisol levels, in combination with high risk for hepatotoxic and nephrotoxic SI side effects, increases morbidity and risk for severe complications, and often delays the start of oncological treatment. However, the trauma caused by surgery can also postpone initiation of chemotherapy.21 Therefore, a fast and minimally invasive surgical procedure appears to be a crucial factor for the better survival in ECS. The endoscopic approach is now considered as the gold standard for BA. Our study presents fewer severe complications, as well as shorter operating and hospitalisation times, when the endoscopic approach is compared with open surgery. In line with previous studies,19, 22 we observed a significantly shorter operating time when applying PRA compared to LTA because there is no need for repositioning of the patient during PRA. PRA-2S had the shortest operating time and should be considered as the best choice of surgical approach in ECS. This result ties well with previous studies reporting the median operating time to be between 43 and 157 min in PRA-2S, which is significantly shorter compared to LTA and PRA-1S.17-19 The median time from diagnosis to BA was 2 months, which is consistent with a previous study.23 However, OS was significantly shorter in patients who were operated within 2 months after diagnosis of ECS in our cohort compared to those operated at a later stage. These early operated patients probably had a more aggressive clinical course of disease, as indicated by slightly higher median Ki-67, lower potassium and higher hormone levels at diagnosis, and they were operated as a result of more acute indications (without time to proper pre-treatment with SI) than the other group. In our previous report on patients with ACTH-producing NENs, multiple hormone secretion was identified as the strongest indicator of a worse prognosis.4 A similar pattern of results was observed in this cohort, showing that patients with NENs, with concomitant hypersecretion of other hormones than ACTH from their tumour, had a shorter OS after BA compared to those with ACTH hypersecretion only. As a result of the extremely high preoperative cortisol levels in ECS, the substitution therapy needed after successful BA may be challenging.21 Over-replacement of glucocorticoids may lead to higher morbidity24 and mortality, especially in patients with metastatic NENs, who often have impaired immune function because of oncological treatment. Many patients suffer from glucocorticoid withdrawal syndrome, despite adequate replacement therapy, and it can take ≥ 1 year to gain control over these symptoms.6 This frequently leads to high dosage of glucocorticoids. The Endocrine Society guidelines recommend glucocorticoid replacement with hydrocortisone, 10–12 mg m-2 day-1 in divided doses.6 If we assume that most of our patients have body surface area around 2 m2 or less, the daily hydrocortisone dose should not exceed 25 mg. However, 1 year after BA, only one patient received 25 mg of hydrocortisone daily, with the majority receiving 30 mg or more. One-third of the patients had residual arterial hypertension and diabetes 3 months after BA, probably partially depending on too high a dose of glucocorticoids. There was a higher complication rate in our cohort compared to other studies19, 25, 26 and five patients needed conversion from an endoscopic approach to open surgery. In particular, the outcome of BA in ECS has not previously been systematically evaluated27 because most of the reports include patients with various aetiologies of CS.19, 22, 23, 28, 29 In a systematic review of the literature published between 1980 and 2012 on BA in CS, Reincke et al23 identified 37 studies and ECS was present in 13% of the patients. There are only few papers focused on BA in ECS solely21, 25, 26, 30, 31 and only one has a cohort with > 50 patients (n = 54).26 Patients with ECS have almost always a more aggressive course and more severe metabolic disturbance than patients with other types of Cushing’s syndrome, which probably leads to higher risk for postoperative complications. Furthermore, multiple liver metastases, fibrotic processes in the abdomen as a result of previous surgery or large primary tumour in pancreas could be some of the factors influencing surgical outcome in ECS. The present study has several limitations. First, all data were collected retrospectively from patient records and not all the preferred parameters were available for all patients. Second, even if our cohort is one of the largest regarding studies on BA in ECS, the number of patients is too low for reliable statistical analysis. Finally, our study covered more than three decades, BAs were performed at different clinics and by different surgeons. Therefore, the data should be interpreted carefully. In conclusion, the present study is one of few reports focusing on BA in specifically NEN patients with ECS and includes one of the largest patient cohorts analysed in the field. PRA-2S can be considered as method of choice in ECS compared to other BA approaches. The aim is to avoid administrating too high a hydrocortisone replacement dosage postoperatively because this can worsen the metabolic disturbance. As a result of the rarity of the condition, multicentre studies are needed with large, prospective cohorts and standardised inclusion criteria, aiming to further improve our knowledge about the management of ECS. ACKNOWLEDGEMENTS This study was funded by the Swedish Cancer Society (grant number CAN 18 0576), the Lions Foundation for Cancer Research at Uppsala University Hospital, Selanders Foundation and Söderbergs foundation at Uppsala University. CONFLICT OF INTERESTS The authors declare that they have no conflicts of interest. AUTHOR CONTRIBUTIONS Ieva Lase: Conceptualisation; Data curation; Formal analysis; Investigation; Methodology; Visualisation; Writing – original draft; Writing – review & editing. Malin Grönberg: Formal analysis; Supervision; Visualisation; Writing – review & editing. Olov Norlén: Conceptualisation; Writing – review & editing. Peter Stålberg: Conceptualisation; Writing – review & editing. Staffan Welin: Conceptualisation; Supervision; Writing – review & editing. Eva Tiensuu Janson: Conceptualisation; Funding acquisition; Methodology; Supervision; Writing – review & editing. ETHICAL APPROVAL The need for informed consent was waived by the local ethics committee. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethics committee, Regionala etikprövningsnämnden (EPN), in Uppsala, Sweden. PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/jne.13030. The entire article, PDF, supporting tables and more can be found at https://onlinelibrary.wiley.com/doi/full/10.1111/jne.13030
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  12. This article was originally published here J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print. ABSTRACT CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection. OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD. MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI. RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion. CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing. PMID:34478542 | DOI:10.1210/clinem/dgab659
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  13. Cushing disease is caused by tumour in the pituitary gland which leads to excessive secretion of a hormone called adrenocorticotrophic (ACTH), which in turn leads to increasing levels of cortisol in the body. Cortisol is a steroid hormone released by the adrenal glands and helps the body to deal with injury or infection. Increasing levels of cortisol increases the blood sugar and can even cause diabetes mellitus. However the disease is also caused due to excess production of hypothalamus corticotropin releasing hormone (CRH) which stimulates the synthesis of cortisol by the adrenal glands. The condition is named after Harvey Cushing, the doctor who first identified the disease in 1912. Cushing disease results in Cushing syndrome. Cushing syndrome is a group of signs and symptoms developed due to prolonged exposure to cortisol. Signs and symptoms of Cushing syndrome includes hypertension, abdominal obesity, muscle weakness, headache, fragile skin, acne, thin arms and legs, red stretch marks on stomach, fluid retention or swelling, excess body and facial hair, weight gain, acne, buffalo hump, tiredness, fatigue, brittle bones, low back pain, moon shaped face etc. Symptoms vary from individual to individual depending upon the disease duration, age and gender of the patient. Get Sample Copy of this Report @ https://www.persistencemarketresearch.com/samples/14155 Disease diagnosis is done by measuring levels of cortisol in patient’s urine, saliva or blood. For confirming the diagnosis, a blood test for ACTH is performed. The first-line treatment of the disease is through surgical resection of ACTH-secreting pituitary adenoma, however disease management is also done through medications, Cushing disease treatment market comprises of the drugs designed for lowering the level of cortisol in the body. Thus patients suffering from Cushing disease are prescribed medications such as ketoconazole, mitotane, aminoglutethimide metyrapone, mifepristone, etomidate and pasireotide. Cushing’s disease treatment market revenue is growing with a stable growth rate, this is attributed to increasing number of pipeline drugs. Also increasing interest of pharmaceutical companies to develop Cushing disease drugs is a major factor contributing to the revenue growth of Cushing disease treatment market over the forecast period. Current and emerging players’ focuses on physician education and awareness regarding availability of different drugs for curing Cushing disease, thus increasing the referral speeds, time to diagnosis and volume of diagnosed Cushing disease individuals. Growing healthcare expenditure and increasing awareness regarding Cushing syndrome aids in the revenue growth of Cushing’s disease treatment market. Increasing number of new product launches also drives the market for Cushing’s disease Treatment devices. However availability of alternative therapies for curing Cushing syndrome is expected to hamper the growth of the Cushing’s disease treatment market over the forecast period. For entire list of market players, request for Table of content here @ https://www.persistencemarketresearch.com/toc/14155 The Cushing’s disease Treatment market is segment based on the product type, technology type and end user Cushing’s disease Treatment market is segmented into following types: By Drug Type Ketoconazole Mitotane Aminoglutethimide Metyrapone Mifepristone Etomidate Pasireotide By End User Hospital Pharmacies Retail Pharmacies Drug Stores Clinics e-Commerce/Online Pharmacies Cushing’s disease treatment market revenue is expected to grow at a good growth rate, over the forecast period. The market is anticipated to perform well in the near future due to increasing awareness regarding the condition. Also the market is anticipated to grow with a fastest CAGR over the forecast period, attributed to increasing investment in R&D and increasing number of new product launches which is estimated to drive the revenue growth of Cushing’s disease treatment market over the forecast period. Depending on geographic region, the Cushing’s disease treatment market is segmented into five key regions: North America, Latin America, Europe, Asia Pacific (APAC) and Middle East & Africa (MEA). North America is occupying the largest regional market share in the global Cushing’s disease treatment market owing to the presence of more number of market players, high awareness levels regarding Cushing syndrome. Healthcare expenditure and relatively larger number of R&D exercises pertaining to drug manufacturing and marketing activities in the region. Also Europe is expected to perform well in the near future due to increasing prevalence of the condition in the region. Asia Pacific is expected to grow at the fastest CAGR because of increase in the number of people showing the symptoms of Cushing syndrome, thus boosting the market growth of Cushing’s disease treatment market throughout the forecast period. Some players of Cushing’s disease Treatment market includes CORCEPT THERAPEUTICS, HRA Pharma, Strongbridge Biopharma plc, Novartis AG, etc. However there are numerous companies producing branded generics for Cushing disease. The companies in Cushing’s disease treatment market are increasingly engaged in strategic partnerships, collaborations and promotional activities to capture a greater pie of market share. The research report presents a comprehensive assessment of the market and contains thoughtful insights, facts, historical data, and statistically supported and industry-validated market data. It also contains projections using a suitable set of assumptions and methodologies. The research report provides analysis and information according to categories such as market segments, geographies, types, technology and applications.
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  14. With the goal of reducing false positives for adrenal insufficiency (AI), scientists are recommending a new, more precise diagnostic cutoff of 14-15 μg/dL of serum cortisol, rather than the current 18 μg/dL. The new data were published in the Journal of the Endocrine Society. Among the 110 patients evaluated in the retrospective analysis, new cortisol cutoffs after adrenocorticotropic hormone (ACTH) stimulation were identified when using several of the newer, more widely used diagnostic assays currently available, including Elecsys II (14.6 μg/dL), Access (14.8 μg/dL), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (14.5 μg/dL). Bradley Javorsky, MD, an endocrinologist and researcher at the Medical College of Wisconsin, served as the study's first author. He recently discussed the findings with MedPage Today. The exchange has been edited for length and clarity. What was the key knowledge gap your study was designed to address? Javorsky: It is safe to say that most clinicians, including many endocrinologists -- not to mention practice guidelines and clinical information resources -- still regard 18 μg/dL as the cutoff for making the biochemical diagnosis of AI after ACTH stimulation testing. However, this cutoff was derived from older polyclonal immunoassays that are no longer being used in many institutions. Newer, more specific monoclonal immunoassays and LC-MS/MS are being used instead. With these more specific assays, one might expect the cutoffs to be lower. What was your finding? Javorsky: After ACTH stimulation, the cutoff values for the newer, more specific cortisol assays were indeed lower at 14-15 μg/dL. Although there was excellent correlation between the new and older assays, the results from the new assays were 22-39% lower than those found by the older and less-specific Elecsys I assay, hence the lowered threshold. Did anything surprise you about the study results? Javorsky: Baseline cortisol had to be very low (approximately <2 μg/dL) in order to be predictive of subnormal cortisol values. This underscores the observation that ACTH stimulation testing is not perfectly sensitive. What are the clinical takeaways from these results? Javorsky: To avoid false-positive ACTH stimulation testing results -- and by extension avoid over-treating patients with glucocorticoids -- clinicians should be aware of the cortisol assay used in their institution and the new cortisol cutoff when evaluating patients for adrenal insufficiency. It should also be reinforced that careful interpretation in the context of clinical history is still essential to making the correct diagnosis. Discordant results among different assays underscore the importance of clinical judgment from an experienced physician when diagnosing AI. What are the takeaways? Javorsky: I think it is important that laboratories make the type of cortisol assay used in their institution easily accessible to clinicians and strongly consider posting the new cortisol cutoff after ACTH stimulation testing when reporting results. Read the study here and expert commentary on the clinical implications here. Disclosures Javorsky reported being a consultant for Clarus Therapeutics and a research investigator for Novartis Pharmaceuticals. Primary Source Journal of the Endocrine Society Source Reference: Javorsky BR, et al "New cutoffs for the biochemical diagnosis of adrenal insufficiency after ACTH stimulation using specific cortisol assays" J Endocrine Soc 2021; 5(4): bvab022. From https://www.medpagetoday.com/endocrine-society/adrenal-disorders/93188
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  15. DEER PARK, Ill., June 15, 2021 (GLOBE NEWSWIRE) -- Eton Pharmaceuticals, Inc (Nasdaq: ETON), the U.S. marketer of ALKINDI SPRINKLE®, a treatment for adrenocortical insufficiency in pediatric patients, today announced that it has acquired U.S. and Canadian rights to Crossject’s ZENEO® hydrocortisone needleless autoinjector, which is under development as a rescue treatment for adrenal crisis. “The ZENEO autoinjector is a revolutionary delivery system, and this product is a terrific strategic fit with our current adrenal insufficiency business. Patients, advocacy groups, and physicians in the adrenal insufficiency community have repeatedly expressed to us the need for a hydrocortisone autoinjector, so we are excited to be partnering with Crossject to bring this product to patients in need,” said Sean Brynjelsen, CEO of Eton Pharmaceuticals. Patrick Alexandre, CEO of Crossject, added: ‘‘We are proud to announce a sound commercial agreement for ZENEO® Hydrocortisone in the US and Canada with an American leader in adrenal insufficiency. ETON has successfully established strong relations with the patient communities and medical specialists that are its core focus. ZENEO® Hydrocortisone answers a medical need. This strong partnership will contribute to saving lives by bringing to patients and their families a modern autoinjection possibility.’’ “We are delighted about Eton Pharmaceuticals' plans to partner with Crossject to bring this incredibly needed product to patients in the U.S.”, said Dina Matos, Executive Director of CARES Foundation, a leading North American advocacy foundation for patients with congenital adrenal hyperplasia, the most common presentation of adrenal insufficiencies in children. “The challenge for patients and caregivers facing an adrenal crisis is serious; an easy-to-use needleless autoinjector of hydrocortisone will be a game changer for our patients. We welcome this advancement.” ZENEO® is a proprietary needleless device developed and manufactured by Crossject. The pre-filled, single-use device propels medication through the skin in less than a tenth of a second. The device’s compact form factor, simple two-step administration, and needle-free technology make it an ideal delivery system for emergency medications that need to be administered in stressful situations by non-healthcare professionals. Crossject holds more than 400 global patents on the device, including 24 issued in the United States that extend as far as 2037, and has successfully completed bioequivalence and human factor studies with the ZENEO device using various medications. Crossject has developed a proprietary, room-temperature stable liquid formulation of hydrocortisone to be delivered via the ZENEO device. ZENEO hydrocortisone is expected to be the first and only hydrocortisone autoinjector available for patients that require a rescue dose of hydrocortisone. Currently, injectable hydrocortisone is only available in the United States in a lyophilized powder formulation that must be reconstituted and manually delivered via a traditional syringe. Eton expects to submit a New Drug Application for the product to the U.S. Food and Drug Administration in 2023 and plans to request Orphan Drug Designation. In the United States, it is estimated that approximately 100,000 patients currently suffer from adrenocortical insufficiency and are at risk for adrenal crisis. Under the terms of the agreement, Crossject will receive development and regulatory milestone payments from Eton of up to $5.0 million, commercial milestones of up to $6.0 million, and a 10% royalty on net sales of the product. Crossject will be responsible for the management and expense of development, clinical, and manufacturing activities. Eton will be responsible for all regulatory and commercial activities. About Adrenal Crisis Patients with adrenal insufficiency can go into adrenal crisis if their cortisol levels are too low. Adrenal crisis is typically caused by missed doses of maintenance hydrocortisone, trauma, surgery, illness, fever, or major psychological distress. Signs of adrenal crisis include hyperpigmentation, severe weakness, nausea, abdominal pain, and confusion. It is estimated that approximately 8% of adrenal insufficiency patients will report an adrenal crisis in any given year and more than 6% of cases result in death. About Crossject Crossject (ISIN: FR0011716265; Ticker: ALCJ; LEI: 969500W1VTFNL2D85A65) is developing and is soon to market a portfolio of drugs dedicated to emergency situations: epilepsy, overdose, allergic shock, severe migraine and asthma attack. The company’s portfolio currently contains eight products in advanced stages of development, including 7 emergency treatments, 5 of which are intended for life-threatening situations. Thanks to its patented needle-free self-injection system, Crossject aims to become the world leader in self-administered emergency drugs. The company has been listed on the Euronext Growth market in Paris since 2014, and benefits from Bpifrance funding. About Eton Pharmaceuticals Eton Pharmaceuticals, Inc. is an innovative pharmaceutical company focused on developing and commercializing treatments for rare diseases. The company currently owns or receives royalties from three FDA-approved products, including ALKINDI® SPRINKLE, Biorphen®, and Alaway Preservative Free®, and has six additional products that have been submitted to the FDA. Company Contact: David Krempa dkrempa@etonpharma.com 612-387-3740 From https://www.globenewswire.com/news-release/2021/06/15/2247745/0/en/Eton-Pharmaceuticals-Acquires-U-S-and-Canadian-Rights-to-ZENEO-Hydrocortisone-Autoinjector.html
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  17. Those who wish to gain practical tools for living optimally with rare diseases are encouraged to attend the annual Living Rare Living Stronger Patient and Family Forum, hosted by the National Organization for Rare Disorders (NORD) and set this year for June 26-27. The conference brings together patients, families, healthcare professionals, and other supporters for learning, sharing, and connecting. Due to the ongoing COVID-19 pandemic, the general sessions, breakout workshops, and networking will again be virtual. The sessions, which will offer perspectives from patients, caregivers, and the medical community, will air live and be recorded for later viewing. Throughout the forum, participants will be able to visit the exhibit hall and have peer meetings with other attendees. Also this year, the Rare Impact Awards will return as part of the program. That presentation, on June 28, honors individuals, organizations, and industry innovators for exceptional work benefitting the rare disease community. “The health and well-being of people living with rare diseases, their loved ones and those working to improve their lives continues to remain a top priority for all of us here at NORD,” the organization stated in its forum announcement. “The COVID-19 pandemic brought us new ways to engage with our community and our 2020 virtual program was the most successful forum to date! In 2021 we will continue to work hard to keep our community healthy and safe while engaging in this impactful program,” NORD said. Registration for the “patient-centric” event is $39 for patients, caregivers, students, and NORD patient organization representatives. The cost is $75 for professional advocates, people from academia, physicians, and government representatives, and $500 for NORD corporate council members. For pharmaceutical, insurance, or other representatives, registration is $650. As for the agenda, the opening discussion will be on “The Patient-Professional Partnership” and will include three stories on the close bond between patients and their care professionals. Breakout sessions for Saturday, June 26 will include “Coping with Grief and Anticipatory Grief,” “Shared Decision-Making with Your Care Team,” and “Working While Rare” as first offerings, followed by “Getting Involved in Clinical Research: Finding and Preparing for Clinical Trials,” “Navigating Insurance, Social Security Disability and Patient Assistance Programs,” and “The ABCs of Advocating for Your Child’s Education” in the second group of workshops. Those will be followed by a plenary discussion on the topic “Building Resilience in a Time of Unknowns.” The speakers will explore how patients coped while waiting for a diagnosis, how they are faring while waiting for new treatments, and how they have kept it together during the pandemic. June 27 will start with an opening plenary discussion titled “The Rare Sibling Experience.” Here, three siblings of rare disease patients will share their experiences, including how they became advocates. Breakout sessions on this day will include “Fighting Back and Fighting Forward Through Advocacy,” “Palliative Care: Debunking the Myths,” “Rare in the Family: Navigating the Roles of Patient, Parent, and Caregiver” in the first set of discussion groups. Later offerings that Sunday will include “Aging with a Rare Condition,” “Finding Your Community and Building Your Support Network,” and “The Intersection of Race, Ethnicity, and Equity with Diagnosis and Treatment Access.” The closing plenary discussion, titled “Rare Breakthroughs Now and on the Horizon,” will cover the latest advances in the diagnosis, treatment, and care of rare diseases. Early this year, NORD put out a call out for individuals who were willing to share their real-life experiences with rare diseases at the conference. In all, including physicians, nurses, and other healthcare professionals, the conference will feature some 55 speakers. Access to the virtual program will be provided via email the week of the event.
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  18. Wow, that's tough but thank you for being a concerned mom. Does she know your family history? Maybe talking about that would be a way in to discus symptoms and so on. Is she aware/concerned about any of the symptoms she's dealing with? If she doesn't live at home, perhaps she's already seeking medical attention but hasn't shared that with you to keep you from worrying. Please keep us posted on how this goes. Best of luck!
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  19. Thank you very much Mary Hugs, MAYELA
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  20. Eleni Papakokkinou, Marta Piasecka, Hanne Krage Carlsen, Dimitrios Chantzichristos, Daniel S. Olsson, Per Dahlqvist, Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye, Britt Edén Engström, Pia Burman, Cecilia Follin, David Petranek, Eva Marie Erfurth, Jeanette Wahlberg, Bertil Ekman, Anna-Karin Åkerman, Erik Schwarcz, Gudmundur Johannsson, Henrik Falhammar & Oskar Ragnarsson Abstract Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)]. Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS. Introduction Cushing´s disease (CD) is a rare disorder associated with excess morbidity and increased mortality [1, 2]. Previously, bilateral adrenalectomy (BA) was the mainstay treatment for CD. During the last decades, however, other treatment modalities have emerged, including pituitary surgery, radiotherapy and medical treatments. Despite this, BA is still considered when other treatment options have failed to achieve remission, or when a rapid relief of hypercortisolism is necessary [3]. BA is considered to be a safe and effective treatment for CD [4], especially after the laparoscopic approach was introduced during the 1990s [5]. There are, however, significant drawbacks with BA, mainly the unavoidable chronic adrenal insufficiency, as well as the risk for Nelson’s syndrome (NS), i.e., growth of the remaining pituitary tumor and excessive production of ACTH, that may cause optic nerve or chiasmal compression and mucocutaneous hyperpigmentation [6]. The prevalence of NS varies between studies, mainly due to a lack of consensus on the definition and diagnostic criteria for the syndrome [7, 8]. Previously published studies are also inconsistent as to whether factors such as previous radiotherapy, age at BA, gender and duration of CD, may affect the risk of developing NS. Furthermore, high ACTH concentrations after BA have been suggested as a risk factor for developing NS [9,10,11,12]. Thus, the primary aim of this systematic review and meta-analysis was to estimate the prevalence of NS after BA for CD, both the total prevalence of NS as well the prevalence of NS requiring treatment with pituitary surgery and/or radiotherapy. The secondary aim was to investigate risk factors associated with development of NS. Methods A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13]. The PICO process was applied for the definition of the research question and eligibility criteria for the literature search. The protocol of this review was registered in the PROSPERO database (CRD42020163918). Search strategy We searched PubMed, Embase, Cochrane Library and Web of Science on February 25th 2020, with no start date restriction, for relevant articles by using the following terms: “Cushing´s syndrome” or “Cushing´s disease” or “Hypercortisolism” or “Pituitary ACTH hypersecretion” or “corticotroph tumor” or “corticotroph tumors” or “corticotroph adenoma” or “corticotroph adenomas” or “corticotropinoma” or “corticotropinomas” or “corticotrophinoma” or “corticotrophinomas” or “ACTH pituitary adenoma” or “ACTH pituitary adenomas” or “adrenocorticotropin pituitary adenoma” or “adrenocorticotropin pituitary adenomas” AND “bilateral adrenalectomy” or “bilateral adrenalectomies” or “total adrenalectomy” or “total adrenalectomies”. A detailed description of the search strategy is given in the Supplementary. Also, references of the included studies and relevant review articles were checked manually for additional articles. A new search was performed on January 12th 2021, prior submission, to identify any new publications. Study selection and eligibility criteria Eligible studies were observational studies (cohort or cross-sectional studies) reporting the prevalence of NS in adult patients with CD treated with BA. Studies including only children (age < 18 years), review articles, letters, commentaries and meeting abstracts were excluded. Moreover, case reports, case-series and studies with a population of fewer than 10 cases were excluded. Also, studies written in languages other than English were not considered for inclusion. Data collection process and data extraction Titles and abstracts from all identified articles were screened for eligibility and further full-text assessment by three independent investigators (EP, MP, OR). Discrepancies were resolved through discussion and consensus. Duplicate articles and studies with overlapping populations were excluded. In the latter case, the publication with the largest population, more comprehensive information on relevant clinical variables and/or lowest risk of bias was included. Full-text assessment and data extraction were conducted independently by the same investigators as above. Data on the following predefined variables were extracted: first author, year of publication, region/hospital, study period, characteristics of the study population (number of patients, gender, follow-up, age at CD, age at BA, previous treatment with radiotherapy and/or pituitary surgery, ACTH concentrations at BA, MRI findings at CD and at BA), intervention (BA as primary or secondary treatment, remission status) and outcome (criteria for NS, number of patients with NS, age at NS, time from BA to NS, ACTH concentrations one year after BA, number of patients treated for NS, type of treatment; pituitary radiotherapy and/or pituitary surgery). One of the studies included in the meta-analysis is our nationwide Swedish study on CD [2]. Additional clinical data, not provided in the original publication, was retrieved and used in the current analysis (Table 1). Table 1 Characteristics of the included studies Full size table Risk of bias assessment The Newcastle–Ottawa Scale [14], modified to suit the current study, was used for assessment of risk of bias of all included studies. Three investigators (EP, MP, OR) assessed the studies independently, and any disagreements were resolved by discussion. Selection, comparability and outcome were assessed through predefined criteria. All studies that provided information on NS as outcome, and/or corticotroph tumor progression, were included, and the definition as well as the treatment of NS were recorded (Table 1 and Table S1). A clear definition of NS and information on treatment were considered to be two of the most important components of the quality assessment. We considered the definition of NS to be clear when it included either a new visible pituitary tumor or progression of a pituitary tumor remnant following BA, alone, or in combination with high ACTH concentrations and/or hyperpigmentation. Detailed description of the criteria for the risk of bias assessment is provided in the Supplementary file. Studies with an overall score ≥ 5 (max overall grade 😎 and a clear definition of NS, were considered to have a low risk of bias. Data synthesis and statistical analysis Primary endpoints were the prevalence of NS, as well as the prevalence of pituitary-specific treatment for NS. Descriptive data are presented as median (range or interquartile range; IQR). Meta-analysis was performed by using the meta package in R (version 4.0.3) [15]. Statistical pooling was performed according to random-effects model due to the clinical heterogeneity among the included studies [16]. For all analyses, indices of heterogeneity, I2 statistics and Cochrane’s Q test, are reported. For the primary outcomes we estimated pooled prevalence with 95% confidence intervals (95% CI). Statistical significance was defined as P < 0.05. The possibility of publication bias was assessed by visual inspection of funnel plots as well as with the Egger’s test [17]. Sensitivity analyses were performed by excluding studies with an overall risk of bias < 5, and studies where information on diagnostic criteria for NS was lacking. By choosing the overall risk of bias < 5, all studies without adequate follow-up were also excluded (Table S2). Also, another sensitivity analysis was performed by including all studies reporting the number of patients with NS who received treatment for NS (Table 1). Subgroup analyses were performed to investigate factors that may affect the prevalence of NS, namely pituitary radiotherapy prior to BA, prophylactic pituitary radiotherapy, overall radiotherapy (prior to BA or prophylactic), pituitary surgery (transcranial or transsphenoidal surgery) prior to BA, and BA as primary or secondary treatment. For these outcomes, we estimated relative risks (RRs), or pooled prevalence, with 95% CIs. Also, in a subgroup analysis, the prevalence (with 95% CI) of NS and treatment for NS were estimated in studies where MRI was used at diagnosis and during follow-up. Uni- and bivariate meta-regression was used to investigate whether the prevalence of NS was influenced by median follow-up time or age at BA. The meta-analysis was performed by using the Metareg command in R. The estimated association is reported as β coefficient. Role of funding source The funding source had no role in the design and conduction of the study; i.e., collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Results Identification and description of included studies After removal of duplicates, 1702 articles were identified (Fig. 1). Three additional articles were found after checking the reference lists of identified articles and review papers. After reviewing titles, abstracts and full-text articles, 48 articles were considered eligible for further analysis. Of these, however, 11 articles were excluded due to overlapping or identical patient cohorts. Thus, 37 studies published between 1976 and 2020, were included in the current meta-analysis (Fig. 1). All studies had a retrospective observational design. Characteristics of the included studies are presented in Table 1. Two of the included studies had an overlapping cohort where one was used for the main outcome [18] and one [19] for the subgroup analyses on the influence of radiotherapy on the development of NS. An overview of risk of bias assessment of the eligible studies is provided in Table S2. Fig. 1 Flowchart of study selection Full size image In total, 1316 patients with CD treated with BA were included. The median follow-up after BA was 7 years (23 studies, range 3.3–22). Median age at BA in patients with NS was 31 years (13 studies, IQR 26–34). Median time from BA to the diagnosis of NS was 4 years (19 studies) with the shortest reported time being 2 months [20] and the longest 39 years [2]. At diagnosis of NS, hyperpigmentation was reported in 155 of 188 (82%) patients (19 studies) and chiasmal compression in 24 of 129 (19%) patients [11 studies]. Prevalence of NS Thirty-six of 37 studies, with total 1316 patients with CD treated with BA, were included [2, 18, 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Reported prevalence of NS ranged from 4 to 60%. The mean pooled prevalence was 26% (95% CI 22–31%) with a moderate to high heterogeneity (I2 67%, P < 0.01) (Fig. 2). The Egger’s test was statistically significant (P = 0.01), but visual inspection showed no obvious asymmetry. The significant Egger’s test indicates publication bias, probably explained by the fact that case reports and cohorts with fewer than 10 participants were excluded (Fig. S1). Fig. 2 Forest plot showing individual studies and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease. *Additional data Full size image In a sensitivity analysis, excluding all studies with high risk of bias (overall score < 5) and no clear definition of NS, the pooled prevalence was 31% (95% CI 24–38%; I2 76%, 17 studies, 822 patients; P < 0.01) (Fig. S2). In a subgroup analysis, the prevalence of NS in studies where MRI was used at diagnosis and during follow-up was 38% (Fig. 3; 95% CI 27–50%; I2 71%, 7 studies, 280 patients; P < 0.01). Fig. 3 Forest plot showing individual studies using magnetic resonance imaging and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease Full size image Prevalence of treated NS The pooled prevalence of treatment for NS was 21% (95% CI 18–26%; I2 52%, P < 0.01) (Table 1; 29 studies with 1074 patients). Thus, the pooled prevalence was slightly lower, compared to the pooled prevalence of NS in total, as well as the heterogeneity (Fig. S3). The funnel plot showed no asymmetry and Egger’s test was not statistically significant, indicating low possibility of publication bias (Fig. S4). In a subgroup analysis, the prevalence of treated NS in studies where MRI was used at diagnosis and during follow-up was 25% (95% CI 17–35%; I2 61%, 7 studies; P = 0.02). The indication for treatment was progression of the pituitary tumor in 23 out of 28 patients (82%, five studies), optic chiasmal compression in 11 out of 91 patients (12%, 11 studies), while four patients out of 14 (one study) had both these indications for treatment. Twenty-six studies provided information on treatment modalities (pituitary surgery and/or radiotherapy). Seventy-three out of 201 patients with NS (36%) were treated with pituitary surgery, 86 (43%) with radiotherapy and 41 (20%) received both treatments. Radiotherapy Nineteen studies provided information on radiotherapy prior to BA. However, nine studies had no events and no patients in one of the arms (radiotherapy or no radiotherapy) (Table S3). Thus, ten studies were eligible for further estimation, showing that the risk for NS in patients treated with radiotherapy prior to BA was comparable to the risk in patients not treated with radiotherapy (RR 0.9, 95% CI 0.5–1.6; 10 studies with 564 patients) (Fig. 4). Fig. 4 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with radiotherapy prior to bilateral adrenalectomy versus no radiotherapy. RR could not be calculated when there were no cases in the RTX or no RTX arms, and when no events in either arm. *Additional data. RTX, radiotherapy prior to bilateral adrenalectomy or prophylactic radiotherapy Full size image Thirteen studies provided information on prophylactic radiotherapy. However, only one study provided applicable data for calculating RR, thus subgroup analysis was not performed (Table S4). In that study [20], none of the seventeen patients who received prophylactic radiotherapy developed NS, while 11 of 22 patients without radiotherapy developed NS after a mean follow-up of 4.4 years (range 10–16 years). By using studies with information on either previous or prophylactic radiotherapy (11 studies with 603 patients; Table S5), the pooled RR was 0.8 (95% CI 0.5–1.5). Pituitary surgery prior to BA Of 21 studies with information on pituitary surgery prior to BA (Table S6), only ten provided information for estimation of RR. A pooled RR of 0.6 (10 studies with 430 patients; 95% CI 0.4–1.0) was found (Fig. 5), indicating that the risk for developing NS was not influenced by previous pituitary surgery. Fig. 5 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with pituitary surgery prior to bilateral adrenalectomy versus no pituitary surgery. RR could not be calculated when there were no cases in the surgery or no surgery arms, and when no events in either arm. *additional data. Abbreviations: Surgery, pituitary surgery prior to bilateral adrenalectomy Full size image BA as primary or secondary treatment for CD Information on whether patients with NS were treated primarily with BA or not, was provided in ten and nine studies, respectively (Fig. S5 and S6). The pooled prevalence of NS was 26% (95% CI 20–33%) for patients treated primarily with BA and 22% (95% CI 15–31%) for patients who had been treated with pituitary surgery and/or radiotherapy prior to BA. ACTH concentrations one year after BA Four studies provided information on ACTH concentrations during the first year after BA [45, 49, 52, 53]. In a study by Assié et al. the median ACTH concentration in patients who developed NS was 301 pmol/L, compared to 79 pmol/L in patients without NS (upper range of limit; URL 13 pmol/L) [52]. The median ACTH concentration in a study by Cohen et al. was 105 pmol/L in the NS group compared to 18 pmol/L in patients without NS (P = 0.007) (URL 10 pmol/L) [49]. Also, in a study by Das et al., there was a statistically significant difference in ACTH concentrations one year after BA between patients with and without NS (110 vs 21 pmol/L respectively; P = 0.002) [53]. On the contrary, Espinosa-de-Los-Monteros et al.found no difference in ACTH concentrations between the patients with NS and those without NS [45]. Thus, three of four studies found that high ACTH concentrations one year after BA were associated with the development of NS. However, since the ACTH assays and the conditions when ACTH was collected were different in these studies (Table S7), further comparison or a meta-analysis on ACTH levels after BA was not considered feasible. Influence of age at BA and duration of follow-up on prevalence of NS In a meta-regression analysis, age at BA (β-coefficient = – 0.03, P = 0.4; Fig. 6) and median duration of follow-up (β-coefficient = 0.01, P = 0.7; Fig. S7) were not associated with prevalence of NS. After adjustment for follow-up, age at BA was still not associated with prevalence of NS (β-coefficient = -0.03, P = 0.4). Fig. 6 Bubble plot showing the influence of age at BA on the prevalence of Nelson’s syndrome. The bubble sizes are proportional to the weight of the studies in the meta-analysis. Coefficient estimate (β) and p value for the effect of age at BA are indicated by the regression line Full size image Discussion In this study we have for the first time evaluated the pooled prevalence of NS by using a meta-analysis on data from 36 studies, including more than 1300 patients with CD treated with BA. The overall prevalence of NS was 26% and the median time from BA to diagnosis of NS was 4 years, ranging from 0.2 to 39 years. The prevalence of patients requiring pituitary-specific treatment for NS was 21%. Furthermore, radiotherapy and pituitary surgery prior to BA, as well as age at BA, did not seem to affect the risk of developing NS. Various definitions have been used for NS over the past decades [12]. Historically, the diagnosis was based on clinical findings related to mucocutaneous hyperpigmentation and chiasmal compression, together with signs of an enlarged sella turcica on skull radiography [6]. Since then, the diagnosis of NS in most studies has been based on (i) radiological evidence of a pituitary tumor that becomes visible, or a progression of a preexisting tumor, (ii) “high” ACTH concentrations, and (iii) hyperpigmentation [54]. In the studies with the highest prevalence of NS [45, 46], the diagnosis was based on rising ACTH concentrations and an expanding pituitary mass, where 2 mm increment in tumor size on MRI was considered to be a significant growth. On the contrary, the criteria for NS in studies with the lowest prevalence were based on hyperpigmentation, often but not always combined with a pituitary tumor responding to radiotherapy and/or a radiographic evidence of pituitary tumor on skull radiography [21, 23]. Thus, the great variance in the prevalence of NS between studies can, at least partly, be explained by the different definitions of NS. Consequently, in an expert opinion published in 2010, it was suggested that the diagnosis of NS should be based on an elevated level of ACTH >500 ng/L (110 pmol/L) in addition to rising levels of ACTH on at least three consecutive occasions and/or an expanding pituitary mass on MRI or CT following BA [54]. Similarly, in a recently published expert consensus recommendation, based on a systematic review, it was suggested that NS should be defined as radiological progression or new detection of a pituitary tumor on a thin-section MRI [55]. Furthermore, the authors recommend active surveillance with MRI three months after BA, and every 12 months for the first 3 years, and every 2–4 years thereafter, based on clinical findings. The meta-regression of the current analysis did not show an association between median follow-up time and prevalence of NS. Nevertheless, NS occurred as early as 2 months [20], and up to 39 years after BA [2], supporting that life-long surveillance after BA is necessary for patients with CD. Active surveillance with MRI was more common in studies published during the last two decades. In fact, the use of MRI in recent studies resulted in earlier detection of a growing pituitary adenoma and, subsequently, contributed to a higher prevalence of NS. Namely, the seven studies including patients treated with BA after 1990 and using MRI reported higher prevalence of NS, both overall NS and treated NS. Whether factors such as pituitary radiotherapy affects the risk for development of NS has been evaluated in several studies. Some studies have shown that radiotherapy prior to BA, or administrated prophylactically, can prevent or delay the development of NS [20, 39]. On the contrary, other studies have not demonstrated a protective effect of radiotherapy prior to BA [18, 37] and, moreover, one study found an association with tumor progression [46]. Nevertheless, the current meta-analysis indicates that radiotherapy prior to BA does not decrease the risk of developing NS. Neither did previous pituitary surgery affect the risk for NS. Elevated ACTH concentrations during the first year after BA have been considered to be a strong predictor of NS [49, 52]. In fact, seven studies in the current analysis included cut-off levels for ACTH concentration, arbitrarily defined, for the diagnosis of NS [18, 25, 34, 36, 41, 45, 49]. Due to the different ACTH assays, and different conditions when ACTH was collected, no further analysis on ACTH levels was performed. Nevertheless, four studies [45, 49, 52, 53] reported ACTH concentrations one year after BA in both patients with and without NS. Three of these studies found that high ACTH concentrations one year after BA [49, 52, 53] were associated with pituitary tumor progression. Thus, these findings support the suggestion that ACTH should be monitored following BA in patients with CD [54, 55]. The prevalence of treatment for NS (21%), and the heterogeneity index (52%), were slightly lower than in the analysis of total prevalence of NS (26%, I2 67%). The majority of the patients was treated with radiotherapy, followed by pituitary surgery and combination of pituitary surgery and radiotherapy. Today, surgical removal of the pituitary tumor is considered to be the first-line therapy of NS whereas radiotherapy is considered if surgery has failed or is not possible [12, 54, 56]. In a large multi-center study by Fountas et al., the 10-year progression-free survival rates after surgery alone, or with radiotherapy, for patients with NS was 80% and 81%, respectively [57]. In comparison, progression-free survival rate in patients who did not receive treatment was 51%. Reports on the efficacy of medical therapy for NS have shown inconsistent results [56]. Strengths and limitations This is the largest systematic review, and the first meta-analysis, on NS published to date. However, some limitations have to be acknowledged. Most important are the different diagnostic methods used to detect NS, and the different definitions of the syndrome between the studies. The majority of the studies have used the combination of hyperpigmentation, high ACTH concentrations and radiological findings for the diagnosis of NS. Notwithstanding these common criteria, there were still differences in the cut-offs of ACTH levels, the use of different radiological modalities over time as well as the radiological definition of progress of pituitary tumors. Moreover, in some studies radiological findings were used solely or in combination with either hyperpigmentation and/or bitemporal hemianopsia, ACTH concentrations or response to treatment of NS. Furthermore, in several studies a clear definition of NS was not provided. Nevertheless, we consider our attempt to address the heterogeneity of the included studies, through systematic review, quality assessment, and sensitivity and subgroup analyses to be a strength. Conclusions The risk of NS after BA in patients with CD is considerable and may first become clinically evident many decades later. Thus, life-long close follow-up is necessary for an early detection of a growing pituitary tumor, and adequate treatment when needed. Although this meta-analysis did not find prior surgery or radiotherapy to be associated with risk of NS, the findings are based on a limited number of studies. Thus, in order to individualize the treatment for patients with CD, further studies are needed where these and other factors possibly associated with risk of NS are evaluated. Data availability The data generated or analyzed during this study are included in this published article or in the Supplementary file. Abbreviations CD: Cushing's disease BA: Bilateral adrenalectomy NS: Nelson’s syndrome ACTH: Adrenocorticotropic hormone RR: Relative risk MRI: Magnet resonance imaging CT: Computer tomography References 1. Papakokkinou E, Olsson DS, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G, Ragnarsson O (2020) Excess morbidity persists in patients with cushing's disease during long-term remission: a swedish nationwide study. J Clin Endocrinol Metab 105(8):2616–2624 2. Ragnarsson O, Olsson DS, Papakokkinou E, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G (2019) Overall and disease-specific mortality in patients with cushing disease: a swedish nationwide study. J Clin Endocrinol Metab 104(6):2375–2384 PubMed Article Google Scholar 3. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A, Endocrine S (2015) Treatment of cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100(8):2807–2831 CAS PubMed PubMed Central Article Google Scholar 4. Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, Reincke M (2013) Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. 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Fountas A, Lim ES, Drake WM, Powlson AS, Gurnell M, Martin NM, Seejore K, Murray RD, MacFarlane J, Ahluwalia R, Swords F, Ashraf M, Pal A, Chong Z, Freel M, Balafshan T, Purewal TS, Speak RG, Newell-Price J, Higham CE, Hussein Z, Baldeweg SE, Dales J, Reddy N, Levy MJ, Karavitaki N (2020) Outcomes of patients with Nelson's syndrome after primary treatment: a multicenter study from 13 UK pituitary centers. J Clin Endocrinol Metab 105(5):1527–1537 Download references Acknowledgements We would like to thank Therese Svanberg, librarian at the Medical Library at Sahlgrenska University Hospital for her expert assistance with the literature search. Funding Open access funding provided by University of Gothenburg. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-593301) and a grant from the Gothenburg Society of Medicine. Author information Affiliations Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson The Department of Endocrinology, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson Department of Environmental and Occupational Health School of Public Health and Community Medicine, University of Gothenburg, 4053, Gothenburg, Sweden Hanne Krage Carlsen Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, Sweden Per Dahlqvist Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology, Karolinska University Hospital, 171 76, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology and Diabetes, Uppsala University Hospital, and Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, 751 85, Uppsala, Sweden Britt Edén Engström Department of Endocrinology, Skåne University Hospital, University of Lund, 205 02, Malmö, Sweden Pia Burman Department of Endocrinology, Skåne University Hospital, 222 42, Lund, Sweden Cecilia Follin, David Petranek & Eva Marie Erfurth Department of Endocrinology and Department of Medical and Health Sciences, Linköping University, 581 83, Linköping, Sweden Jeanette Wahlberg & Bertil Ekman Department of Internal Medicine, School of Health and Medical Sciences, Örebro University, 702 81, Örebro, SE, Sweden Jeanette Wahlberg, Anna-Karin Åkerman & Erik Schwarcz Corresponding author Correspondence to Oskar Ragnarsson. Ethics declarations Conflict of interest The authors have nothing to disclose. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 1208 kb) Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions About this article Cite this article Papakokkinou, E., Piasecka, M., Carlsen, H.K. et al. Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis. Pituitary (2021). https://doi.org/10.1007/s11102-021-01158-z Download citation Accepted18 May 2021 Published25 May 2021 DOIhttps://doi.org/10.1007/s11102-021-01158-z Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Bilateral adrenalectomy Cushing’s disease Corticotroph adenoma Nelson’s syndrome From https://link.springer.com/article/10.1007/s11102-021-01158-z
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  21. Wow, Letisia - your numbers are very high. I'd definitely ask the endo about your numbers and the possibility of Cushing's. If s/he blows you off please try to find another one. You said you were taking progesterone. That can cause your cortisol numbers to go up but you need to talk to your doctor so s/he is aware of your concerns. What are your symptoms? Your doctor needs to hear about those, too. If you have "before" pictures, those can be really useful, especially if you've gained a lot of weight, gotten a buffalo hump, grown facial hair, etc. Best of luck to you and please keep up posted! If you join these boards, you'll find lots of potentially helpful info already available to you.
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  22. — Gradual dose escalation had fewer adverse events, same therapeutic benefit, as quicker increases by Kristen Monaco, Staff Writer, MedPage Today May 27, 2021 A more gradual increase in oral osilodrostat (Isturisa) dosing was better tolerated among patients with Cushing's disease, compared with those who had more accelerated increases, a researcher reported. Looking at outcomes from two phase III trials assessing osilodrostat, only 27% of patients had hypocortisolism-related adverse events if dosing was gradually increased every 3 weeks, said Maria Fleseriu, MD, of Oregon Health & Science University in Portland, in a presentation at the virtual meeting of the American Association of Clinical Endocrinology (AACE). On the other hand, 51% of patients experienced a hypocortisolism-related adverse event if osilodrostat dose was increased to once every 2 weeks. Acting as a potent oral 11-beta-hydroxylase inhibitor, osilodrostat was first approved by the FDA in March 2020 for adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. The drug is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets. The approval came based off of the positive findings from the complementary LINC3 and LINC4 trials. The LINC3 trial included 137 adults with Cushing's disease with a mean 24-hour urinary free cortisol concentration (mUFC) over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). During the open-label, dose-escalation period, all the participants were given 2 mg of osilodrostat twice per day, 12 hours apart. Over this 12-week titration phase, dose escalations were allowed once every 2 weeks if there were no tolerability issues to achieve a maximum dose of 30 mg twice a day. After this 12-week dose-escalation schedule, additional bumps up in dose were permitted every 4 weeks. The median daily osilodrostat dose was 7.1 mg. The LINC4 trial included 73 patients with Cushing's disease with an mUFC over 1.3 times the upper limit of normal. The 48 patients randomized to receive treatment were likewise started on 2 mg bid of osilodrostat. However, this trial had a more gradual dose-escalation schedule, as doses were increased only every 3 weeks to achieve a 20 mg bid dose. After the 12-week dose-escalation phase, patients on a dose over 2 mg bid were restarted on 2 mg bid at week 12, where dose escalations were permitted once every 3 weeks thereafter to achieve a maximum 30 mg bid dose during this additional 36-week extension phase. Patients in this trial achieved a median daily osilodrostat dose of 5.0 mg. In both studies, patients' median age was about 40 years, the majority of patients were female, and about 88% had undergone a previous pituitary surgery. When comparing the adverse event profiles of both trials, Fleseriu and colleagues found that more than half of patients on the 2-week dose-escalation schedule experienced any grade of hypercortisolism-related adverse events. About 10.2% of these events were considered grade 3. About 28% of these patients had adrenal insufficiency -- the most common hypercortisolism-related adverse event reported. This was a catch-all term that include events like glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased cortisol, Fleseriu explained. Conversely, only 27.4% of patients on a 3-week dose escalation schedule experienced a hypercortisolism-related adverse event, and only 2.7% of these were grade 3. No grade 4 events occurred in either trial, and most events were considered mild or moderate in severity. "These adverse events were not associated with any specific osilodrostat dose of mean UFC level," Fleseriu said, adding that most of these events occurred during the initial dose-escalation periods. About 60% and 58% of all hypocortisolism-related adverse events occurred during the dose titration period in the 2-week and 3-week dose-escalation schedules, respectively. These events were managed via dose reduction, a temporary interruption in medication, and/or a concomitant medication. Very few patients in either trial permanently discontinued treatment due to these adverse events, Fleseriu noted. "Despite differences in the frequency of dose escalation, the time to first mUFC normalization was similar in the LINC3 and LINC4 studies," she said, adding that "gradual increases in osilodrostat dose from a starting dose of 2 mg bid can mitigate hypocortisolism-related adverse events without affecting mUFC control." "For patients with Cushing's disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response and tolerability aimed at normalizing cortisol levels," Fleseriu concluded. Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years. Disclosures The LINC3 and LINC4 trials were funded by Novartis. Fleseriu reported relationships with Novartis, Recordati, and Strongbridge Biopharma. Primary Source American Association of Clinical Endocrinology Source Reference: Fleseriu M, et al "Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing's disease (CD): Results from two phase III trials (LINC3 and LINC4)" AACE 2021. From https://www.medpagetoday.com/meetingcoverage/aace/92824?xid=nl_mpt_DHE_2021-05-28&eun=g1406328d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily Headlines Top Cat HeC 2021-05-28&utm_term=NL_Daily_DHE_dual-gmail-definition
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  23. High blood sugar or glucose, also called hyperglycemia, occurs when there is too much sugar in the blood. High blood sugar is the primary symptom that underlies diabetes, but it can also occur in people who don’t have type 1 or type 2 diabetes, either because of stress or trauma, or gradually as a result of certain chronic conditions. It is important to manage high blood sugar, even if you don’t have diabetes, because elevated blood glucose can delay your ability to heal, increase your risk of infections, and cause irreversible damage to your nerves, blood vessels, and organs, such as your eyes and kidneys. Blood vessel damage from high blood sugar also increases your risk of heart attack and stroke. Non-Diabetic Hyperglycemia and Prediabetes You are considered to have impaired glucose tolerance or prediabetes if you have a fasting glucose level between 100–125 mg/dL, and hyperglycemia if your fasting blood glucose level is greater than 125 mg/dL, or greater than 180 mg/dL one to two hours after eating. The body obtains glucose mainly through carbohydrate consumption, but also through the breakdown of glycogen to glucose—a process called glycogenolysis—or conversion of non-carbohydrate sources to glucose—called gluconeogenesis—that primarily occurs in the liver. While 50% to 80% of glucose is used by the brain, kidneys, and red blood cells for energy, the remaining supply of glucose is used to produce energy. It is stored as glycogen in the liver and muscles, and can be tapped into at a later time for energy or converted into fat tissue. In healthy people, blood glucose levels are regulated by the hormone insulin to stay at a steady level of 80–100 mg/dL. Insulin maintains steady blood sugar by increasing the uptake and storage of glucose and decreasing inflammatory proteins that raise blood sugar when there is an excess of glucose in the blood. Certain conditions can increase your blood glucose levels by impairing the ability of insulin to transport glucose out of the bloodstream. When this occurs, you develop hyperglycemia, which puts you at an increased risk of prediabetes, diabetes, and related complications. Common Causes Cushing’s Syndrome Cushing’s syndrome results from excess secretion of the adrenocorticotropic hormone, a hormone produced in the anterior portion of the pituitary gland that causes excess cortisol to be produced and released from the adrenal glands. Pituitary adenomas, or tumors of the pituitary gland, are the cause of Cushing’s syndrome in more than 70% of cases, while prolonged use of corticosteroid medication can also significantly increase the risk. People with Cushing’s syndrome are at an increased risk of developing impaired glucose tolerance and hyperglycemia as a result of increased levels of cortisol throughout the body. Cortisol is a hormone that counteracts the effects of insulin by blocking the uptake of glucose from the bloodstream, thereby increasing insulin resistance and maintaining high blood sugar levels. Elevated cortisol levels also partially decrease the release of insulin from where it is produced in the pancreas. Approximately 10% to 30% of people with Cushing’s syndrome will develop impaired glucose tolerance, while 40% to 45% will develop diabetes. Corticosteroid medication is often prescribed to decrease inflammation throughout the body, but can lead to the development of Cushing’s syndrome and hyperglycemia because it activates specific enzymes that increase the conversion of non-carbohydrate molecules into glucose (gluconeogenesis). Corticosteroids also disrupt pancreatic cell function by inhibiting cell signaling pathways involved in the release of insulin from the pancreas. Read other causes at https://www.verywellhealth.com/causes-blood-sugar-rise-in-non-diabetics-5120349
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  24. Please note that if you buy through links in this article, Medical News Today may earn a small commission. Here’s their process. Cortisol is a hormone with various functions throughout the body. However, if a person’s body cannot regulate their cortisol levels, it could lead to a serious health condition. In these cases, home cortisol tests may be useful to indicate when someone might need medical attention. This article discusses: what cortisol is what a home cortisol test is why a person might buy a home cortisol test some home cortisol tests to purchase online when to see a doctor What is cortisol? Cortisol is the stress hormone that affects several systems in the body, including the: nervous system immune system cardiovascular system respiratory system reproductive system musculoskeletal system integumentary system The adrenal glands produce cortisol. Most human body cells have cortisol receptors, and the hormone can help in several ways, including: reducing inflammation regulating metabolism assisting with memory formation controlling blood pressure developing the fetus during pregnancy maintaining salt and water balance in the body controlling blood sugar levels All these functions make cortisol a vital part of maintaining overall health. If the body can no longer regulate cortisol levels, it can lead to several health disorders, such as Cushing’s syndrome and Addison’s disease. Without treatment, these conditions could cause life threatening complications. The body requires certain cortisol levels during times of stress, such as: in the event of an injury during illness during a surgical procedure What are home cortisol tests? A cortisol test usually involves a blood test. However, some may require saliva and urine samples instead. There are several home cortisol tests available to purchase over the counter or online. These allow a person to take a sample of blood, urine, or saliva before sending it off for analysis. After taking a home cortisol test, people can usually receive their results within 2–5 days online or via a telephone call with a healthcare professional. However, there are currently no studies investigating the reliability of these home cortisol tests. Therefore, people should follow up on their test results with a healthcare professional. Why and when do people need them? A person should take a home cortisol test if they feel they may have a cortisol imbalance. If cortisol levels are too high, a person may notice the following: rapid weight gain in the face, chest, and abdomen high blood pressure osteoporosis bruises and purple stretch marks mood swings muscle weakness an increase in thirst and need to urinate If cortisol levels are too low, a person may experience the following symptoms: fatigue loss of appetite unintentional weight loss muscle weakness abdominal pain Additionally, low cortisol levels may lead to: low blood pressure low blood sugar low blood sodium high blood potassium A test can help individuals check their cortisol levels. If the test results show these levels are too high or too low, people should seek medical advice. A cortisol imbalance may be a sign of an underlying condition, which can lead to serious complications without treatment. If a person cannot carry out a home cortisol test, they should speak to a medical professional who can arrange a cortisol test at a healthcare facility. What to look for in a home cortisol test At a clinic or hospital setting, a medical professional will usually take a blood sample and analyze it for an individual’s cortisol levels. Home cortisol tests involve a person taking a sample of blood, urine, or saliva. There are currently no studies investigating the accuracy of these results. However, home cortisol tests may be faster and more convenient than making an appointment with a doctor to take a sample. People may consider several factors when deciding to purchase a home cortisol test, including: Sample type: Some tests require a blood sample, while others need a sample of urine or saliva. With this in mind, a person may wish to buy a product that uses a testing method they are comfortable providing. Test analysis: A person may wish to purchase a product from a company that sends tests to Clinical Laboratory Improvement Amendments (CLIA)-certified labs for analysis. The Food and Drug Administration (FDA), Center for Medicaid Services, and the Centers for Disease Control and Prevention (CDC) regulate these labs to help ensure safety and accuracy. Accuracy: Individuals may wish to speak to a pharmacist or other healthcare professional before purchasing to ensure the test is reliable and accurate. Products Several online retailers offer home cortisol tests. It is important to follow all test instructions to ensure a valid result. Please note, the writer has not tested these products. All information is research-based. LetsGetChecked – Cortisol Test This cortisol test uses the finger prick method to draw blood for the sample. Here are the steps to take and send off a blood sample: Individuals fill in their details on the collection box and activate their testing kit online at the LetsGetChecked website. People need to wash their hands with warm soapy water before using an alcohol swab to clean the finger that they will prick. Once the finger is completely dry, individuals pierce the skin using the lancet in the test kit. A person must wipe away the first drop of blood before squeezing some into the blood collection tube. After closing the tube, individuals must invert it 5–10 times before placing it in the included biohazard bag, which they then place in the box. After following these steps, people can send the sample back to LetsGetChecked using the kit’s prepaid envelope. Test results usually come back within 2–5 days. LetsGetChecked tests samples in the same labs that primary care providers, hospitals, and government schemes use. These labs are CLIA-certified and CAP-accredited. The company also has a team of nurses and doctors available 24 hours a day, 7 days a week, to offer ongoing support. These healthcare professionals are on hand to discuss a person’s results with them over the phone. Everlywell At-Home Cortisol Levels Test Kit – Sleep & Stress Test This Everlywell product uses a urine sample to test a person’s cortisol levels. The test measures the levels of three hormones in a person’s body: cortisol, cortisone, and melatonin. It also measures a person’s creatinine levels. There are three steps with this test: Individuals register their testing kit on Everlywell’s website. A person follows the instructions carefully to take their urine sample. Once they have their urine sample, they place it in the prepaid package and send it off to Everlywell’s labs. Within a few days, individuals will receive their results digitally via the Everlywell website. Medical professionals can also offer helpful insights via their secure platform. As well as sending a personalized report of each marker, Everlywell also sends detailed information about what the results mean. The labs where Everlywell tests samples all carry certification with CLIA. The company also ensures that all results are reviewed and certified by independent board-certified physicians within the person’s specific state.SHOP NOW Healthlabs Cortisol, AM & PM Test Healthlabs offers a cortisol test that tests a person’s cortisol levels twice — once in the morning and once in the evening. The company says they do this because a person’s cortisol levels fluctuate throughout the day. Therefore, by testing twice, they can gather information on this fluctuation. This test uses a blood sample, which a person takes once in the morning and once in the afternoon. They must follow the instructions clearly to ensure they take suitable samples. The manufacturer says that people should collect a morning sample between 7–9 a.m. and an evening sample between 3–5 p.m. They then need to send off their sample for analysis. After testing is complete at a CLIA-certified lab, a person will receive their results, which usually takes between 1–2 days. SHOP NOW When to speak with a doctor A person should undergo a cortisol test if they believe they may have high or low cortisol levels. They can do this at home or speak with a medical professional who can carry out the test for them. People may also wish to seek medical help if they show signs of too much or too little cortisol. This could indicate a potentially serious underlying health issue. Summary Cortisol is an important hormone that affects almost all parts of the body. It has many functions, including reducing inflammation, regulating metabolism, and controlling blood pressure. If a person believes they have high or low cortisol levels, they may wish to take a cortisol test. Usually, these tests take place at a medical practice. However, several home cortisol tests are available to purchase. A person can take these tests at home by providing a urine, blood, or saliva sample. Once a lab analyzes the test, people usually receive their results within a few days. Individuals should follow up any test results with a healthcare professional. No clinics, no stress. Test your cortisol levels from home Test your cortisol level from home with LetsGetChecked. Get free shipping, medical support, and results from accredited labs within 2–5 days. Order today for 30% off. LEARN MORE Last medically reviewed on April 29, 2021 at https://www.medicalnewstoday.com/articles/3-of-the-best-home-cortisol-tests
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  25. Donkey, I am so sorry to read all that you've been through. Getting a Cushing's diagnosis is the worst, especially when doctors don't believe us. You didn't know what kind of doctor you have that doubts you have Cushing's but it sounds like you need another. Your best choice would be an endocrinologist who has had other Cushing's patients. Even though you aren't obese with striae...not every person has every symptom. The only way to diagnose Cushing's is with testing, not by a list of symptoms. Best of luck to you. I hope you keep us posted on your progress!
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  26. until
    I plan to do the Cushing's Awareness Challenge again. A past year info is here: https://cushieblogger.com/2018/03/11/time-to-sign-up-for-the-cushings-awareness-challenge-2018/ The original page is getting very slow loading, so I've moved my own posts to this newer blog. As always, anyone who wants to join me can share their blog URL with me and I'll add it to the links on the right side, so whenever a new post comes up, it will show up automatically. If the blogs are on WordPress, I try to reblog them all to get even more exposure on the blog, on Twitter and on Facebook at Cushings Help Organization, Inc. If you have photos, and you give me permission, I'll add them to the Pinterest page for Cushing's Help. The Cushing’s Awareness Challenge is almost upon us again! Do you blog? Want to get started? Since April 8 is Cushing’s Awareness Day, several people got their heads together to create the Tenth Annual Cushing’s Awareness Blogging Challenge. All you have to do is blog about something Cushing’s related for the 30 days of April. There will also be a logo for your blog to show you’ve participated. Please let me know the URL to your blog in the comments area of this post, on the Facebook page, in one of the Cushing's Help Facebook Groups, on the message boards or an email and I will list it on CushieBloggers ( http://cushie-blogger.blogspot.com/ ) The more people who participate, the more the word will get out about Cushing’s. Suggested topics – or add your own! In what ways have Cushing’s made you a better person? What have you learned about the medical community since you have become sick? If you had one chance to speak to an endocrinologist association meeting, what would you tell them about Cushing’s patients? What would you tell the friends and family of another Cushing’s patient in order to garner more emotional support for your friend? challenge with Cushing’s? How have you overcome challenges? Stuff like that. I have Cushing’s Disease….(personal synopsis) How I found out I have Cushing’s What is Cushing’s Disease/Syndrome? (Personal variation, i.e. adrenal or pituitary or ectopic, etc.) My challenges with Cushing’s Overcoming challenges with Cushing’s (could include any challenges) If I could speak to an endocrinologist organization, I would tell them…. What would I tell others trying to be diagnosed? What would I tell families of those who are sick with Cushing’s? Treatments I’ve gone through to try to be cured/treatments I may have to go through to be cured. What will happen if I’m not cured? I write about my health because… 10 Things I Couldn’t Live Without. My Dream Day. What I learned the hard way Miracle Cure. (Write a news-style article on a miracle cure. What’s the cure? How do you get the cure? Be sure to include a disclaimer) Give yourself, your condition, or your health focus a mascot. Is it a real person? Fictional? Mythical being? Describe them. Bonus points if you provide a visual! 5 Challenges & 5 Small Victories. The First Time I… Make a word cloud or tree with a list of words that come to mind when you think about your blog, health, or interests. Use a thesaurus to make it branch more. How much money have you spent on Cushing’s, or, How did Cushing’s impact your life financially? Why do you think Cushing’s may not be as rare as doctors believe? What is your theory about what causes Cushing’s? How has Cushing’s altered the trajectory of your life? What would you have done? Who would you have been What three things has Cushing’s stolen from you? What do you miss the most? What can you do in your Cushing’s life to still achieve any of those goals? What new goals did Cushing’s bring to you? How do you cope? What do you do to improve your quality of life as you fight Cushing’s? How Cushing’s affects children and their families Your thoughts…?
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  27. Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society's virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rates, hyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights: More Safety Data on Jatenzo In a study of 81 men with hypogonadism -- defined as a serum testosterone level below 300 ng/dL -- oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study. After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range. And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study -- including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL). Throughout the trial, only one participant had elevation of liver function tests. "Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration," said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement. In addition, for many men with hypogonadism, "an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children," he said. "Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage." Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history. COVID-19 Risk With Adrenal Insufficiency Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%). These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001). Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries. "It's really important that you take your hydrocortisone medications and start stress dosing as soon as you're sick," study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children's in Little Rock, explained during a press conference. "This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids." And with kids starting to return back to in-person schooling, "parents should also be reeducated about using the emergency injections of hydrocortisone," Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well. Cushing's Death Risk In a systematic review and meta-analysis of 87 studies -- including data on 17,276 patients with endogenous Cushing's syndrome -- researchers found that these patients face a much higher death rate than those without this condition. Overall, patients with endogenous Cushing's syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing's disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%). And those with adrenal Cushing's syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%). The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%). "The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, and good infection control, and emphasize the need to achieve disease remission, normalizing cortisol levels," said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement. From https://www.medpagetoday.com/meetingcoverage/endo/91808
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  28. Adrenal insufficiency increases the risk for severe outcomes, including death, 23-fold for children who contract COVID-19, according to a data analysis presented at the ENDO annual meeting. “Adrenal insufficiency in pediatrics does increase risk of complications with COVID-19 infections,” Manish Gope Raisingani, MD, assistant professor in the department of pediatrics in the division of pediatric endocrinology at Arkansas Children's Hospital, University of Arkansas for Medical Sciences, told Healio. “The relative risk of complications is over 20 for sepsis, intubation and mortality, which is very significant.” Source: Adobe Stock Using the TriNetX tool and information on COVID-19 from 54 health care organizations, Raisingani and colleagues analyzed data from children (aged 0-18 years) with COVID-19; 846 had adrenal insufficiency and 252,211 did not. The mortality rate among children with adrenal insufficiency was 2.25% compared with 0.097% for those without, for a relative risk for death of 23.2 (P < .0001) for children with adrenal insufficiency and COVID-19. RRs for these children were 21.68 for endotracheal intubation and 25.45 for sepsis. “Children with adrenal insufficiency should be very careful during the pandemic,” Raisingani said. “They should take their steroid medication properly. They should also be appropriately trained on stress steroids for infection, other significant events.” From https://www.healio.com/news/endocrinology/20210321/severe-covid19-risks-greatly-increased-for-children-with-adrenal-insufficiency
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  29. Here's your chance to make your voice heard on Growth Hormone Issues. Anyone interested would sign up with Rare Patient Voice using the CushingsHelp referral Link. You would then get an email invite to the actual study. Study Opportunity for Idiopathic Short Stature (ISS) Caregivers This is a 30 min online survey and Compensation is $50 Please sign up at the link below for more information or to see if you qualify https://rarepatientvoice.com/CushingsHelp/
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  30. Yu Wang, Zhixiang Sun, Zhiquan Jiang Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, People’s Republic of China Correspondence: Zhiquan Jiang Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui 233004, People’s Republic of China Tel +86-13966075971 Email bbjiangzhq@163.com Abstract: Cushing’s disease (CD), also known as adrenocorticotropic hormone (ACTH)-dependent pituitary Cushing’s syndrome, is a rare and serious chronic endocrine disease that is usually caused by a pituitary adenoma (especially a pituitary microadenoma). Meningioma is the most common type of primary intracranial tumor and is usually benign. The patient in this case report presented with CD coexisting with pituitary microadenoma and meningioma, which is an extremely rare comorbidity. The pathogenesis of CD associated with meningioma remains unclear. Here, we describe the case of bilateral lower extremity edema, lower limb pain, abdominal purplish striae, and abdominal distension for 9 months in a 47-year-old woman. Two years ago, the patient underwent a hysterectomy at a local hospital for hysteromyoma. She had no previous radiotherapeutic treatment or other medical history. Magnetic resonance imaging of her head revealed a sellar lesion (7.8 mm × 6.4 mm) and a spherical mass (3.0 cm × 3.0 cm) in the right frontal convexity. Her level of serum adrenocorticotropic hormone (ACTH) was 169 pg/mL, and her cortisol levels were 933 nmol/mL and 778 nmol/mL at 8 am and 4 pm, respectively. Preoperatively, she was diagnosed with ACTH-secreting pituitary microadenoma and meningioma. Excision of the meningioma was performed through a craniotomy, while an endoscopic endonasal transsphenoidal approach was used to remove the pituitary adenoma. Meningioma and pituitary adenoma were confirmed by postoperative pathology. On the basis of this unusual case, the relevant literature was reviewed to illustrate the diagnosis and treatment of Cushing’s disease and to explore the pathogenesis of pituitary adenoma associated with meningioma. Keywords: Cushing’s disease, pituitary adenoma, meningioma Introduction Cushing’s disease (CD) is a severe condition caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor that accounts for approximately 70% of all cases of endogenous Cushing’s syndrome. It has a total incidence of 1–2 cases per million per year and a prevalence rate of approximately 30 patients per million per year, making it an uncommon disease.1 Meningiomas account for 15–25% of all intracranial tumors, with an annual incidence of 6 cases per 100,000 persons.2 CD combined with meningioma is a rare condition, and even rarer in patients who have no previously known risk factors for either tumor. To the best of our knowledge, its pathogenesis have not been clearly described to date. Case Presentation Clinical History and Laboratory Findings A 47-year-old woman was admitted to the endocrinology department of our hospital with chief complaints of bilateral lower extremity edema, left lower limb pain, abdominal purplish striae, and abdominal distension for 9 months. Two years ago, the patient had a hysterectomy at a local hospital for hysteromyoma. She had no previous radiotherapeutic treatment or other medical history. She weighed 90 kg and was 165 cm tall with a body mass index (BMI) of 33. Physical examination showed typical features of Cushing’s syndrome, including centripetal obesity, moon face, pedal edema, and buffalo hump. Her skin was thin and dry, with acne and hirsutism. On admission, her blood pressure was 146/115 mmHg and routine biochemical blood tests confirmed comorbidity with diabetes mellitus, hyperlipidemia, and hypokalemia. Endocrine measurements showed that her serum ACTH was 169 pg/mL (reference value: 5–50 pg/mL), cortisol (8 am) was 933 nmol/L (reference value: 138–690 nmol/L), and cortisol (4 pm) was 778 nmol/L (reference value: 69–345 nmol/L), indicating that her ACTH and cortisol levels were dramatically increased. Cortisol secretion was increased and had lost its circadian rhythm. The low-dose dexamethasone suppression test showed that cortisol suppression was < 50%, while a >50% suppression of cortisol was found in the high-dose dexamethasone suppression test. Serum prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone, free thyroid hormone (FT3 and FT4), and thyrotropin values were normal. Endocrinological evaluation suspected that pituitary lesions caused Cushing syndrome. Imaging Analysis The patient underwent a magnetic resonance imaging (MRI) scan to image her head. T1-weighted MRI with contrast enhancement showed a spherical enhancing mass (3.0 cm × 3.0 cm) in the right frontal convexity and a dural tail sign (Figure 1A). In the sellar area, the enhancement degree of the lesion (7.8 mm × 6.4 mm) was significantly lower than that of the surrounding pituitary tissue, and the pituitary stalk was displaced to the right (Figure 1A and B). No abnormalities were found on plain or enhanced adrenal computed tomography scans. Figure 1 Enhanced magnetic resonance imaging (MRI) of the patient’s head: (A) Coronal view of the gadolinium-enhanced T1-weighted image showing a spherical enhancing mass in the right frontal convexity and a dural tail sign. A round low-intensity lesion can be seen on the right side of the pituitary gland, and the pituitary stalk is displaced to the right. (B) Sagittal T1-weighted sequence with contrast showing the degree of enhancement is lower than that of the pituitary in the sellar region. Treatment and Pathological Examination Physical examination, endocrine examination, and head MRI successfully proved that pituitary microadenoma caused Cushing’s syndrome (specifically CD) comorbid with asymptomatic meningioma. In order to receive surgical treatment, the patient was referred from the endocrinology department to neurosurgery. She underwent neuroendoscopic transsphenoidal surgery and the pituitary microadenoma was removed. The sellar floor was reconstructed with artificial dura mater, and after this reconstruction, no cerebrospinal fluid leakage was observed. The pathological specimen was examined and was determined to be consistent with a pituitary microadenoma (Figure 2A). One month later, excision of the meningioma was performed through a right frontal trephine craniotomy. Histological examination revealed a WHO grade I meningioma (Figure 2B). Figure 2 (A) Histopathologic examination revealed a pituitary adenoma (Hematoxylin and eosin staining, 100×). (B) Histopathologic examination revealed a meningioma (Hematoxylin and eosin staining, 100×). Outcome and Follow Up On the second day after the operation, her cortisol level dropped below the normal range in the morning. Hydrocortisone replacement therapy was started on the same day. In addition, she had developed transient diabetes insipidus, which was treated with desmopressin. Three months postoperatively, after hydrocortisone replacement therapy, the symptoms of Cushing’s disease were alleviated, and the cortisol level returned to normal, which was 249nmol/L (reference value: 138~690nmol/L). At the 1-year follow-up, no lesions were observed on the MRI scan and the symptoms of Cushing’s syndrome were in remission. The use of hydrocortisone supplements were discontinued and hormone levels remained normal, indicating recovery of the hypothalamic–pituitary–adrenal (HPA) axis. The patient had lost 30 kg and her BMI had dropped to 22, while her blood glucose, triglyceride level, and blood pressure had all returned to normal. Physical changes in the patient pre- and post-treatment are shown in Figure 3A and B. Figure 3 Abdominal appearance with striae (A) preoperation and (B) 4 months postoperation. Discussion Cushing’s Disease CD is a serious clinical condition caused by a pituitary adenoma secreting a high level of ACTH, leading to hypercortisolism. The proportion of ACTH-secreting pituitary adenomas (corresponding to CD) among hormone-secreting pituitary adenomas is 4.8%–10%, which affects women three times more frequently than men, mainly occurs in those 40–60 years old.3,4 Exposure to excessive cortisol can lead to various manifestations of Cushing’s syndrome and increases in morbidity and mortality.5 Therefore, early diagnosis and treatment of CD are very important. The diagnosis and differential diagnosis of CD is very complicated, and these have always been challenging problems in clinical endocrinology. Once Cushing’s syndrome is diagnosed, its etiology should be determined. A diagnosis of Cushing’s disease is made based on a biochemical examination confirming the pituitary origin of the condition and exclude other sources (namely, ectopic ACTH secretion and adrenocortical tumors).3 High-dose dexamethasone suppression and corticotropin-releasing-hormone stimulation tests may be used to distinguish high-secretion sources of pituitary and ectopic ACTH. More than 90% of the pituitary adenomas that cause CD are microadenomas (≤10 mm in diameter), and 40% of the cases cannot be located by radiological examination.5 Examination with bilateral inferior petrosal sinus sampling (BIPSS) is necessary for CD patients in whom noninvasive biochemical and imaging examinations do not lead to a definitive diagnosis.6 The first-line treatment for CD is transsphenoidal selective tumor resection (TSS) with approximately 78% of the patients in remission after the operation, and 13% of patients relapse within 10 years after surgery. Therefore, there are a considerable number of patients who have experienced long-term surgical failure and require additional second-line treatment, such as radiotherapy, bilateral adrenalectomy, or medication.4 The pathogenesis of CD is unclear, but recent studies have confirmed that there are somatic activation mutations of multiple genes in adrenocorticotropin adenomas, while ubiquitin specific peptidase 8 (USP8) is the most common, accounting for about 50% of the mutations in these adenomas.7 Pituitary Adenoma Associated with Meningioma Radiotherapy used to treat pituitary tumors is a well-known reason for the development of meningiomas. Gene mutations are a common molecular characteristic of meningiomas, with inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene found in 55% of meningiomas, and a further 25% of meningiomas accounted for by recently described mutations in other genes.8 Simultaneous occurrence of pituitary adenoma and meningioma without a history of radiotherapy is a rare condition clinically, having only been described in 49 cases before 2019,9 while ACTH-secreting pituitary adenomas (CD) comorbid with meningioma have been reported even less frequently. In the reported cases, the most common site of meningioma is parasellar, accounting for 44.9%, while meningioma located in the distant part of the adenoma is rare.9,10 A number of clinicians have suggested that the coexistence of meningiomas and pituitary adenomas is incidental, with no relationship between the two diseases.2,11 Genetic imbalances have been found in pituitary adenomas, including in particular the chromosomal deletions of 1p, 2q, 4, 5, 6, 11q, 12q, 13q, and 18q, and the overexpression of 9q, 16p, 17p, 19, and 20q. Functional adenomas have more such imbalances than nonfunctional adenomas, corresponding in particular to deletions of chromosomes 4 and 18q, and the overexpression of chromosomes 17 and 19.12 Meanwhile, estrogen receptor positive de novo meningiomas significantly involve chromosomes 14 and 22.13 The study by Hwang et al14 reported that the expression levels of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins were significantly higher in pituitary adenomas and meningiomas than that in normal brain tissues. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) and its downstream signaling pathways play an pivotal role in pituitary tumor, meningioma, and other brain tumors. Zhu et al15 reported that multiple endocrine neoplasia type 1 (MEN1) plays an important role in pituitary adenoma associated with meningioma by upregulating the mammalian target of rapamycin signaling pathway. They found that rapamycin treatment promotes apoptosis in primary cells of the pituitary adenoma and meningioma in cases of pituitary adenoma associated with meningioma. Recurrence of pituitary adenoma, younger age, and larger size of meningioma have been shown to be significantly associated with MEN1 mutation.16 Mathuriya et al17 suggested that hormones may contribute to the occurrence of meningiomas. de Vries et al9 reported that compared with other types of adenomas, the proportion of growth hormone adenomas is higher, accounting for about one third of cases. Meanwhile, Friend et al18 demonstrated that activation of GH/insulin-like growth factor-1 (IGF-1) axis clearly increased the growth rate of meningiomas. However, in the present case, we observed the coexistence of ACTH-secreting adenoma and meningioma. Further studies are required to understand whether ACTH or cortisol are related to the occurrence and development of meningioma. In our case, pituitary microadenoma was the cause of Cushing’s syndrome, while the meningioma was an incidental imaging observation. With the popularity and technological progress of high-resolution imaging technology, the reported prevalence of intracranial lesions related to dominant pathology has increased.2 However, when imaging examinations are limited to specific regions, the diagnosis of lesions in other locations is likely to be omitted. For example, in our case, performing MRI of the sellar region alone may have meant that the meningioma was missed. Conclusion Cushing’s disease is the most common cause of endogenous Cushing’s syndrome and is caused by ACTH-secreting pituitary adenoma.It is associated with severe complications and reduced quality of life, so early diagnosis and treatment are critical. The coexistence of CD, pituitary adenoma, and meningioma is very rare, and the exact mechanisms underlying such comorbidity are currently unclear and need further study. Data Sharing Statement The data that support the findings of this study are available on request from the corresponding author, Zhiquan Jiang. Ethics and Consent Statement Based on the regulations of the department of research of the Bengbu Medical College, institutional review board approval is not required for case reports. Consent for Publication Written informed consent has been provided by the patient to have the case details and any accompanying images published. Author Contributions All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. Funding The authors declared that this case has received no financial support. Disclosure The authors report no conflicts of interest in this work. References 1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913–927. doi:10.1016/S0140-6736(14)61375-1 2. Curto L, Squadrito S, Almoto B, et al. MRI finding of simultaneous coexistence of growth hormone-secreting pituitary adenoma with intracranial meningioma and carotid artery aneurysms: report of a case. Pituitary. 2007;10(3):299–305. doi:10.1007/s11102-007-0011-4 3. Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neuro Oncol. 2017;19(6):762–773. doi:10.1093/neuonc/now130 4. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385–486. doi:10.1210/er.2013-1048 5. Tritos NA, Biller BMK. Current management of Cushing’s disease. J Intern Med. 2019;286(5):526–541. doi:10.1111/joim.12975 6. Fan C, Zhang C, Shi X, et al. Assessing the value of bilateral inferior petrosal sinus sampling in the diagnosis and treatment of a complex case of Cushing’s disease. Intractable Rare Dis Res. 2013;2(1):24–29. doi:10.5582/irdr.2013.v2.1.24 7. Sbiera S, Kunz M, Weigand I, Deutschbein T, Dandekar T, Fassnacht M. The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight. Cancers. 2019;11(11):1761. doi:10.3390/cancers11111761 8. Apra C, Peyre M, Kalamarides M. Current treatment options for meningioma. Expert Rev Neurother. 2018;18(3):241–249. doi:10.1080/14737175.2018.1429920 9. de Vries F, Lobatto DJ, Zamanipoor Najafabadi AH, et al. Unexpected concomitant pituitary adenoma and suprasellar meningioma: a case report and review of the literature. Br J Neurosurg. 2019:1–5. doi:10.1080/02688697.2018.1556782. 10. Gosal JS, Shukla K, Praneeth K, et al. Coexistent pituitary adenoma and frontal convexity meningioma with frontal sinus invasion: a rare association. Surg Neurol Int. 2020;11:270. doi:10.25259/SNI_164_2020 11. Cannavo S, Curto L, Fazio R, et al. Coexistence of growth hormone-secreting pituitary adenoma and intracranial meningioma: a case report and review of the literature. J Endocrinol Invest. 1993;16(9):703–708. doi:10.1007/BF03348915 12. Szymas J, Schluens K, Liebert W, Petersen I. Genomic instability in pituitary adenomas. Pituitary. 2002;5(4):211–219. doi:10.1023/a:1025313214951 13. Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. J Neurosurg. 2006;105(2):163–173. doi:10.3171/jns.2006.105.2.163 14. Hwang M, Han MH, Park HH, et al. LGR5 and downstream intracellular signaling proteins play critical roles in the cell proliferation of neuroblastoma, meningioma and pituitary adenoma. Exp Neurobiol. 2019;28(5):628–641. doi:10.5607/en.2019.28.5.628 15. Zhu H, Miao Y, Shen Y, et al. The clinical characteristics and molecular mechanism of pituitary adenoma associated with meningioma. J Transl Med. 2019;17(1):354. doi:10.1186/s12967-019-2103-0 16. Zhu H, Miao Y, Shen Y, et al. Germline mutations in MEN1 are associated with the tumorigenesis of pituitary adenoma associated with meningioma. Oncol Lett. 2020;20(1):561–568. doi:10.3892/ol.2020.11601 17. Mathuriya SN, Vasishta RK, Dash RJ, Kak VK. Pituitary adenoma and parasagittal meningioma: an unusual association. Neurol India. 2000;48(1):72. 18. Friend KE, Radinsky R, McCutcheon IE. Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist. J Neurosurg. 1999;91(1):93–99. doi:10.3171/jns.1999.91.1.0093 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. From https://www.dovepress.com/cushingrsquos-disease-caused-by-a-pituitary-microadenoma-coexistent-wi-peer-reviewed-fulltext-article-IJGM
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  31. The Journal of Clinical Endocrinology & Metabolism, dgab079, https://doi.org/10.1210/clinem/dgab079 Abstract Context Psychiatric symptoms are common in Cushing’s disease (CD) and seem only partly reversible following treatment. Objective To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. Design Nationwide longitudinal register-based study. Setting University Hospitals in Sweden. Subjects CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. Main outcome measures Data from the Swedish Prescribed Drug Register and the Patient Register. Results In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension. Conclusions Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health. Cushing’s syndrome, hypercortisolism, neuropsychiatry, depression, sleeping disorder Issue Section: Clinical Research Article Read more at https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab079/6132459?rss=1
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  32. Biomarkers in a majority of Cushing’s syndrome patients with surgically induced disease remission showed a high rate of bone turnover and greater bone mineral density one and two years later, a study reports. Before treatment, these patients were found to have greater bone degradation and poorer bone formation, as can be common to disease-related bone disorders. Researchers believe their work is the first study of its kind, “and the data obtained will be instrumental for clinicians who care for patients with Cushing’s syndrome.” The study, “The Effect of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome: A 2‐Year Follow‐Up Study,” was published in the Journal of Bone and Mineral Research. Two common co-conditions of Cushing’s syndrome are osteopenia, a loss of bone mass, and osteoporosis, in which the body makes too little bone, loses too much bone, or both. Studies suggest up to 80% of people with Cushing’s have evidence of reduced bone mineral density affecting the entire skeleton. However, few risk factors to predict bone health have been identified so far, and guidelines for osteoporosis management due to Cushing’s are lacking. Uncertainty as to the natural course of osteoporosis once a diagnosis of Cushing’s syndrome has been made is also still evident. Investigators at the University of Munich, reportedly for a first time, analyzed the natural course of bone mineral density and bone turnover (recycling) in a group of people with endogenous Cushing’s syndrome — which refers to the disease caused by excess cortisol in the bloodstream, often due to a tumor in the adrenal or pituitary glands. They examined medical records of 89 Cushing syndrome patients with a mean age of 44, of which 74% were women. Of these, 65% had pituitary Cushing’s (Cushing’s disease), 28% had adrenal, and 7% had ectopic Cushing’s, which is caused by tumors outside the adrenal or pituitary glands. A group of 71 age- and sex-matched healthy participants were included as controls. In all patients, blood samples were collected at the time of diagnosis (baseline) and one and two years after removing one or both adrenal glands or moving tumors affecting the pituitary gland. Blood samples were analyzed for biomarkers related to bone formation and degradation (resorption). At the study’s beginning, the mean levels of two bone formation markers, osteocalcin and intact PINP, were significantly decreased in patients compared with controls, whereas the bone formation marker alkaline phosphatase was increased. Both markers for bone degradation — called CTX and TrAcP — were also high, which demonstrated “increased bone resorption and decreased bone formation in [Cushing’s syndrome],” the team wrote. While bone markers were similar in participants with a reduced bone mass relative to those with a normal bone mass, bone mineral density was lower overall. Bone mineral density was significantly lower in the neck and spine compared with the femur (thigh bone). Normal bone mineral density was reported in 28 (32%) patients, while 46 (52%) had osteopenia, and the remaining 15 (17%) lived with osteoporosis. A history of low-trauma bone fractures due to osteoporosis occurred in 17 (19%) patients, taking place shortly before diagnosis in more than half of these (58%) people, and more than two years before a Cushing’s diagnosis in the remaining group (42%). Compared to patients without fractures, those with fractures had a significantly lower T‐score, a bone density measure that represents how close a person is to average peak bone density. While Cushing’s subtype, age, or body mass index (BMI, body fat based on height) did not differ between groups, men had a significantly higher risk of fractures than women (35% of men vs. 14% of women). Both disease severity and duration did not contribute to fractures rates, but urinary free cortisol (a circulating cortisol measure) was significantly higher in patients with a low T‐score. At the one year after tumor removal, which led to Cushing’s remission based on blood tests, a significant increase in bone formation markers was reported. These biomarkers decreased slightly at two years post-surgery, but remained elevated. At the beginning of the study, bone resorption markers were mildly increased, which rose further one year after surgery before returning almost to normal levels by two years. In parallel, bone density measures conducted in 40 patients showed a matching increase in T-score, particularly in the spine. After two years, bone mineral density improved in 78% of patients, and T-scores improved in 45% of them. No fractures occurred after Cushing’s treatment, and there was no significant correlation between bone turnover markers and better bone mineral density. “This study analyzes for the first time in a comprehensive way bone turnover markers during the course of [Cushing’s syndrome],” the researchers wrote. “Our data suggest that the phase immediately after remission from [Cushing’s syndrome] is characterized by a high rate of bone turnover, resulting in a spontaneous net increase in bone mineral density in the majority of patients.” These results “will influence future therapeutic strategies in patients” with Cushing’s syndrome, they added. Steve Bryson PhD Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone. From https://cushingsdiseasenews.com/2021/02/19/successful-cushings-surgery-leads-to-better-bone-density-study-finds/
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  33. It's because desmopressin stimulates ACTH release in corticotrophs (normal cells) and in corticotrophinomas, i.e., tumor cells in the case of Cushing's disease. This effect has been shown to be higher in CD than in non-CD patients. However, I think the ability of the DDAVP test to discriminate between CD and non-CD is questionable, although I'm not too familiar with that area of the literature. What does your MRI say?
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  34. Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition. Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison's disease, a condition where the body's immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone. Groundbreaking study The rarity of Addison's disease has until now made scanning of the whole genome for clues to the disease's genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world's two largest Addison's disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator). AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life. Knowing what predisposes people to develop Addison's disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye's lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future. ### Contact information: Professor at the University of Bergen, Eystein Husebye - Eystein.Husebye@uib.no - cell phone +47 99 40 47 88 Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system. From https://www.eurekalert.org/pub_releases/2021-02/tuob-nsi021221.php
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  35. The cancer medicine bexarotene may hold promise for treating Cushing’s disease, a study suggests. The study, “Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT‐20 cells,” was published in the Journal of Cellular and Molecular Medicine. Cushing’s disease is caused by a tumor on the pituitary gland, leading this gland to produce too much adrenocorticotropic hormone (ACTH). Excess ACTH causes the adrenal glands to release too much of the stress hormone cortisol; abnormally high cortisol levels are primarily responsible for the symptoms of Cushing’s. Typically, first-line treatment is surgical removal of the pituitary tumor. But surgery, while effective in the majority of cases, does not help all. Additional treatment with medications or radiation therapy (radiotherapy) works for some, but not others, and these treatments often have substantial side effects. “Thus, the development of new drugs for CD [Cushing’s disease] treatment is extremely urgent especially for patients who have low tolerance for surgery and radiotherapy,” the researchers wrote. Recent research has shown that a protein called testicular receptor 4 (TR4) helps to drive ACTH production in pituitary cancers. Thus, blocking the activity of TR4 could be therapeutic in Cushing’s disease. Researchers conducted computer simulations to screen for compounds that could block TR4. This revealed bexarotene as a potential inhibitor. Further biochemical tests confirmed that bexarotene could bind to, and block the activity of, TR4. Bexarotene is a type of medication called a retinoid. It is approved to treat cutaneous T-cell lymphoma, a rare cancer that affects the skin, and available under the brand name Targretin. When pituitary cancer cells in dishes were treated with bexarotene, the cells’ growth was impaired, and apoptosis (a type of programmed cell death) was triggered. Bexarotene treatment also reduced the secretion of ACTH from these cells. In mice with ACTH-secreting pituitary tumors, bexarotene’s use significantly reduced tumor size, and lowered levels of ACTH and cortisol. Cushing’s-like symptoms also eased; for example, bexarotene treatment reduced the accumulation of fat around the abdomen in these mice. Additional cellular experiments suggested that bexarotene specifically works on TR4 by changing the location of the protein. Normally, TR4 is present in the nucleus — the cellular compartment that houses DNA — where it helps to control the production of ACTH. But with bexarotene treatment, TR4 tended to go outside of the nucleus, leading to lower ACTH production. The researchers noted that other mechanisms may also be involved in the observed effects of bexarotene. “In summary, our work demonstrates that bexarotene is a potential inhibitor for TR4. Importantly, bexarotene may represent a new drug candidate to treat CD,” the researchers concluded. From https://cushingsdiseasenews.com/2021/02/05/bexarotene-cancer-drug-t-cell-lymphoma-acth-production/?preview_id=39289
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  36. Abstract Cushing's syndrome is a rare entity in children. Adrenal tumour is the common cause of this syndrome in young children, whereas, iatrogenic causes are more common among older children. We report a 4 year old male child diagnosed with Cushing syndrome due to a right adrenal adenoma; the child presented with obesity and increase distribution of body hair. After thorough investigation and control of hypertension and dyselectrolytemia, right adrenalectomy was performed. The patient had good clinical recovery with weight loss and biochemical resolution of Cushing's syndrome. 1. Introduction Cushing's syndrome (CS) is rarely encountered in children. The overall incidence of Cushing syndrome is approximately 2–5 new cases per million people per year. Only approximately 10% of the new cases each year occur in children [1]. Unlike in adults, a male-to-female predominance have been observed in infants and young toddlers [[1], [2], [3]]. Although iatrogenic causes are common in children above seven years of age, adrenal causes (adenoma, carcinoma or hyperplasia) are common in children of younger age [4]. We report a 4 year old boy diagnosed with Cushing syndrome caused by a right adrenal adenoma, who had presented with obesity and increase distribution of body hair. Right adrenalectomy was performed and clinical stabilization resulted in weight loss and biochemical resolution of Cushing's syndrome. (see Fig. 5) 2. Case report A 4 years old boy presented with complaints of excessive weight gain of 5 months duration and increase frequency of micturition and appearance of body hair for 4 months. There was no history of any other illness, medication or steroid intake. The child was first born at term by normal vaginal delivery and birth weight of 3 kg. Physical examination revealed a chubby boy with moon face, buffalo hump, protruding abdomen, increase body hair and appearance of coarse pubic hair (Fig. 1). His intelligent quotient (IQ) was appropriate for his age and sex. His younger sibling was in good health and other family members did not have any metabolic or similar problems. Download : Download high-res image (710KB) Download : Download full-size image Fig. 1. The child with moon face, protruded abdomen and coarse body hair. The patient's body length was 92cm (between -2SD to -3SD), weight 20kg (between 1 SD and 2 SD), weight for height >3SD, and BMI was 23.6 (BMI for age >3 SD). His blood pressure on right arm in lying position was 138/76 mm Hg (above 99th percentile for height and age). Investigations: Morning 8am serum cortisol level - 27.3 μg/dl (normal: 6–23 μg/dl). with a concurrent plasma ACTH level of < 5 pg/ml (n value < 46 pg/ml). His serum cortisol following low dose dexamethasone suppression test (1mg dexamethasone at 11pm) at 8 am next morning was 22.1 μug/dl and his 24 hours urine catecholamine fraction was within normal limit. HB % -- 10.3 gm/dl; LDDST -- 25 μg/dl; FBS -- 106 mg/dl. Serum Na+ - 140.6mmol/l; K+ - 2.83mmol/l; Ca+ - 8.7 mg/dl. S. Creatinine −0.3 mg/dl. Ultrasonography of abdomen revealed a heterogenous predominantly hypoechoic right supra renal mass. Contrast enhanced CT abdomen revealed well defined soft tissue density lesion (size −5.2 cm × 5.2 cm x 5.7cm) in right adrenal gland with calcifications and fat attenuations showing mild attenuation on post contrast study (Fig. 2). Download : Download high-res image (703KB) Download : Download full-size image Fig. 2. CECT shows right adrenal mass with calcification and mild attenuation on post-contrast study. The child was started on oral amlodipine 2.5mg 12hourly; after 5days blood pressure became normal. For hypokalemia oral potassium was given @20 meq 8 hourly and serum potassium value became normal after 4 days. Right laparoscopic adrenalectomy was planned. but due to intra operative technical problems it was converted to an open adrenalectomy with right subcostal incision. A lobulated mass of size 9 cm × 5 cm x 4 cm with intact capsule was excised. The tumour weighed 230 gm. There was no adhesion with adjacent organs, three regional nodes were enlarged but without any tumour tissue. Inferior vena cava was spared. Histopathology report was consistent with adrenal adenoma (Fig. 3) (see Fig. 4). Download : Download high-res image (427KB) Download : Download full-size image Fig. 3. Cut section of tumour shows fleshy mass with fatty tissue. Download : Download high-res image (618KB) Download : Download full-size image Fig. 4. Microphotograph (100 × 10) showing intact capsule and adrenal tumour cells, which are larger in size with nuclear pleomorphism, inconspicuous nucleoli, cytoplasm of the tumour cells are abundant, eosinophilic and vacuolated. Download : Download high-res image (593KB) Download : Download full-size image Fig. 5. Physical appearance 4 months after adrenalectomy. Post operative management: during post operative period hypokalemia and flaxuating blood sugar level was managed with oral potassium and oral glucose supplement. patient developed mild cough and respiratory distress on post op day 2, it was managed with salbutamol nebulization and respiratory physio therapy. Patient developed minor ssi and discharged on 10 th post operative day with oral prednisolone supplementation. Follow up: the patient was followed up 2week after discharge and then every monthly, the oral prednisolone was gradually tapered and completely withdrawn on 2nd month after surgery.The patient experienced no post-surgical complications. After 4 months of surgery he reduces 6 kgs of his body weight with BMI of 16.5 (between median and 1SD) & BP 100/74 mm hg (within normal range), the moon face, buffalo hump, central obesity disappeared, morning 8am serum cortisol level was found within normal range 14 μg/dl (n value 6–23 μg/dl). 3. Discussion Cushing's syndrome is caused by prolonged exposure to supraphysiological levels of circulating glucocorticoids, which may be endogenously or exogenously derived. During infancy, CS is usually associated with McCune-Albright syndrome; adrenocortical tumours most commonly occur in children under four years of age and Cushing's disease (ACTH dependent) is the commonest cause of CS after five years of age [5]. Primary adrenocortical tumours (ACTs) account for only 0.3–0.4% of all childhood neoplasms. Almost a third of these tumours manifests as Cushing syndrome and over 70% of the unilateral tumours in young children are often malignant [2,3,6,7]. There seems to be a bimodal incidence of these tumours, with one peak at under 5 years of age and the second one in the fourth or fifth decades of life. ACTs may be associated with other syndromes, such as, Li-Fraumeni syndrome, Beckwith-wiedemann syndrome, isolated hemihypertrophy, or even a germline point mutation of P53 tumour suppressor gene as reported in a series from Brazil [8]. In comparison to adult CS, growth failure with associated weight gain is one of the most reliable indicators of hypercortisolaemia in pediatric CS. The parents often fail to notice facial changes and growth failure and hence the diagnosis is often delayed. In one study, the mean time from appearing symptoms to diagnosis in 33 children with Cushing's disease was 2.5 years [5]. More recently the comparison of height and BMI SDS measurements provided a sensitive diagnostic discriminator in pediatric patients with CD and those with simple obesity [9]. In the present case, the parents observed noticeable changes in his face and presence of body hair, which made them to bring the child to medical attention. A review of 254 children on the International Pediatric Adrenocortical Tumour Registry identified virilization as the most common manifestation [10]. About 10% of the tumours can be non-functional at presentation, and approximately one third of pediatric patients present with hypertension. Majority of patients (192/254) in the Registry had localized disease and metastatic disease was found in less than 5% of cases. Older children with CS or mixed androgen and cortisol secreting adrenocortical tumours had a worse prognosis compared to younger children [10]. The present case had mild hypertension as well as dyselectrolytemia at presentation, which could be controlled with medication. He had a single adenoma confined to the adrenal gland and there was no evidence of malignancy. After surgical excision of the tumour and the right adrenal gland, the patient made rapid improvement in clinical condition and has been on follow up for last 7 months. 4. Conclusion Pediatric adrenocortical tumours (ACTs) are most commonly encountered in females and in children less than four years. But our case being an 4-year-old boy forms a rare presentation of endogenous Cushing's syndrome due to adrenal adenoma. Cushing's syndrome in this child was controlled after right adrenalectomy. Patient consent Informed written consent was taken. Funding No funding or grant support. Authorship All authors attest that they meet the current ICMJE criteria for authorship. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] M.A. Magiakou, G. Mastorakos, E.H. Oldfield, et al. Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy N Engl J Med, 331 (10) (1994), pp. 629-636 [PubMed: 8052272] [2] C. Tsigos, G.P. Chrousos Differential diagnosis and management of Cushing's syndrome Annu Rev Med, 47 (1996), pp. 443-461 [PubMed: 8712794] [3] D.N. Orth Cushing's syndrome N Engl J Med, 332 (12) (1995), pp. 791-803 [PubMed: 7862184] [4] C.J. Migeon, R. Lanes (fifth ed.)F. Lifshitz (Ed.), “Adrenal cortex: hypo and hyper_x0002_function,” in Pediatric Endocrinology, vol. 8, Informa Healthcare, London, UK (2007), p. 214 [5] L.F. Chan, H.L. Storr, A.B. Grossman, M.O. Savage Pediatric Cushing's syndrome: clinical features, diagnosis, and treatment Arq Bras Endocrinol Metabol, 51 (8) (2007), pp. 1261-1271, 10.1590/S0004-273 [6] C.A. Stratakis, L.S. Kirschner Clinical and genetic analysis of primary bilateral adrenal diseases(micro- and macronodular disease) leading to Cushing syndrome Horm Metab Res, 30 (6–7) (1998), pp. 456-463 [PubMed: 9694579] [7] W.L. Miller, J.J. Townsend, M.M. Grumbach, S.L. Kaplan An infant with Cushing's disease due to anadrenocorticotropin-producing pituitary adenoma J Clin Endocrinol Metabol, 48 (6) (1979), pp. 1017-1025 [8] R.C. Ribeiro, F. Sandrini, B. Figueiredo, G.P. Zambetti, E. Michalkiewicz, A.R. Lafferty, et al. An inherited P53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma Proc Natl Acad Sci U S A, 98 (16) (2001), pp. 9330-9335 [9] J.E. Greening, H.L. Storr, S.A. McKenzie, K.M. Davies, L. Martin, A.B. Grossman, et al. Linear growth and body mass index in pediatric patients with Cushing's disease or simple obesity J Endocrinol Invest, 29 (10) (2006), pp. 885-887 [10] E. Michalkiewicz, R. Sandrini, B. Figueiredo, E.C. Miranda, E. Caran, A.G. Oliveira-Filho, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the international pediatric adrenocortical tumor Registry J Clin Oncol, 22 (5) (2004), pp. 838-845 From https://www.sciencedirect.com/science/article/pii/S2213576620303833
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  37. Researchers conducted this retrospective cohort study to investigate acute and life-threatening complications in patients with active Cushing syndrome (CS). Participants in the study were 242 patients with CS, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. In patients with benign pituitary CS, the prevalence of acute complications was 62%, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Infections, thromboembolic events, hypokalemia, hypertensive crises, cardiac arrhythmias and acute coronary events were complications reported in patients with benign CS. The whole spectrum of acute and life-threatening complications in CS and their high prevalence was illustrated in this study both before disease diagnosis and after successful surgery. Read the full article on Journal of Clinical Endocrinology and Metabolism.
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  38. Hello Mary & Dear Cushies! Hoping you are all doing ok during this pandemic I ‘m sending blessings to all of you for this 2021 ... expecting this will be a better year for all of us!! As I’ve had so many delay with the procedures to get Isturisa, because as you know all Mexican public hospitals are closed only receiving COVID-19 patients... now I’ve spoken to an endo who told me about Relacorilant.... which is finishing this year the Phase 3 trials and expecting its approval by the end of the year... and guess what ? It’s a specific antagonist cortisol receptor !!! So it’s so much better than mifepristone and will work as Argentinian Dr. Burton’s 22OH-6OP. So I think these are great news for all of us !! We can have another choice to improve our life quality and restore many hormone levels.... Hoping this could help any of us... here’s the link. Greetings from Querétaro, México Stay safe Mayela https://cushingsdiseasenews.com/2019/12/10/phase-3-trial-of-relacorilant-in-endogenous-cushings-patients-starts-dosing-in-europe/
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  39. Dr. Theodore Friedman will host a webinar on COVID-19 Vaccines for Endocrine Patients Dr. Friedman will discuss topics including: How do the vaccines work? What did the New England Journal of Medicine article say about the Pfizer vaccine? What are the different vaccine options? What are the side effects? Who should and shouldn’t get a vaccine? What about Dr. Friedman’s vaccine studies? Sunday • December 27 • 6 PM PST Click here on start your meeting or https://axisconciergemeetings.webex.com/axisconciergemeetings/j.php?MTID=m5085619c25d8a2417d9316b56fe7830b OR Join by phone: (855) 797-9485 Meeting Number (Access Code): 177 542 2496 Your phone/computer will be muted on entry. Slides will be available on the day of the talk here There will be plenty of time for questions using the chat button. Meeting Password: pcos For more information, email us at mail@goodhormonehealth.com
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  40. We have an opportunity for you to take part in a Cushing's Disease study(IPS_4636) for Patients. Our project number for this study is IPS_4636. Project Details: Web- Camera Interview There is a homework component Interview is 75-minutes long 125 Reward + 100 homework Things to Note: Patient study only, Caregivers please pass the link along Unique links, please do not pass along for 2nd use One Participant per household Want to share this opportunity? Let us know and we can provide a new link Preliminary questions are Mobile Friendly! Save this email to reference if you have any questions about the study! If you have any problems, email pm3@rarepatientvoice.com and reference the project number. If you hit reply, you will get an auto do-not-reply email. If you are interested in this study, please click the link below to answer a few questions to see if you qualify. Study Link: Link OR if the Study Hyperlink is not clickable above, please copy/paste this URL below. https://panel.rarepatientvoice.com/newdesign/site/rarepatientvoice/surveystart.php?surveyID=hld5jbejublj&panelMemberID=trfnbc7mvduh1gseff1h&invite=email Thanks as always for your participation! Please be aware that by entering this information you are not guaranteed that you will be selected to participate. As always, we do not share any of your contact information without your permission.
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  41. Presented by Dr. Magge, Assistant Professor of Neurology at Weill Cornell Medical College and an Assistant Attending Neurologist at New York-Presbyterian Hospital. Dr. Ranakrishna, Chief of Neurological Surgery at NewYork-Presbyterian Brooklyn Methodist Hospital, Associate Professor of Neurological Surgery at Avina and Willis Murphy at Weill Cornell Medicine Click here to attend. Date: Tuesday, October 13, 2020 Time: 10:00 AM Eastern Daylight Time Learning objectives: - the basic characteristics of the different types of pituitary adenomas - the potential predictors of recurrence and aggressiveness in pituitary adenomas - the surgical and radiotherapy options for recurrent pituitary adenomas - the potential medical interventions, including chemotherapy, for recurrent pituitary adenomas
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  42. Health Condition: All Conditions Demographics: Ages 18+, United States Resident Special Request(s): Everyone who has taken part in a clinical trial is asked to share. We are interested in learning why you decided to take part in a clinical trial and how your experience went. Honoraria: Some respondents may be asked to participate in a clinical trial awareness network where there are paid opportunities to tell their stories. Apply to learn more.
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  43. Presented by Ahmad Sedaghat, MD, PhD - Associate Professor and Director of the Division of Rhinology, Allergy and Anterior Skull Base Surgery in the Department of Otolaryngology - Head and Neck Surgery at the University of Cincinnati College of Medicine and UC Health. Norberto Andaluz, MD, MBA, FACS - Professor of Neurosurgery and Otolaryngology/Head and Neck Surgery - Director, Division of Skull Base Surgery University of Cincinnati College of Medicine and University of Cincinnati Gardner Neuroscience Institute - UC Health Click here to attend Date: Wednesday, Sept 23, 2020 Time: 3:00 PM Eastern Daylight Time Learning objectives: 1. To understand the surgical steps of endoscopic pituitary surgery 2. To understand how the surgical steps of endoscopic pituitary surgery translate to post-operative outcomes 3. To understand surgical factors that can modify post-operative outcomes after endoscopic pituitary surgery 4. To understand post-operative care that can modify post-operative outcomes after endoscopic pituitary surgery
    1 point
  44. Presented by Ahmad Sedaghat, MD, PhD - Associate Professor and Director of the Division of Rhinology, Allergy and Anterior Skull Base Surgery in the Department of Otolaryngology - Head and Neck Surgery at the University of Cincinnati College of Medicine and UC Health. Norberto Andaluz, MD, MBA, FACS - Professor of Neurosurgery and Otolaryngology/Head and Neck Surgery - Director, Division of Skull Base Surgery University of Cincinnati College of Medicine and University of Cincinnati Gardner Neuroscience Institute - UC Health Click here to attend Date: Wednesday, Sept 23, 2020 Time: 3:00 PM Eastern Daylight Time Learning objectives: 1. To understand the surgical steps of endoscopic pituitary surgery 2. To understand how the surgical steps of endoscopic pituitary surgery translate to post-operative outcomes 3. To understand surgical factors that can modify post-operative outcomes after endoscopic pituitary surgery 4. To understand post-operative care that can modify post-operative outcomes after endoscopic pituitary surgery
    1 point
  45. Osilodrostat treatment was found to be associated with a rapid and sustained reduction in mean concentration of urinary free cortisol (UFC) and improved clinical symptoms in patients with Cushing’s disease, according to the results of a prospective, multicenter, open-label, phase 3 study published in the Lancet Diabetes Endocrinology. Osilodrostat is an oral inhibitor of 11-β hydroxylase cytochrome P450. Adults aged 18 to 75 years of age with diagnosed persistent or recurrent Cushing’s disease were recruited between 2014 and 2017 at 66 hospitals in 19 countries. Cushing’s disease was defined by a mean UFC concentration over a 24-hour period >1.5 times greater than the upper limit of normal (ULN) and morning plasma adrenocorticotropic hormone level above normal limits. Participants (n=137) received 30 mg osilodrostat twice daily, dose which was adjusted every 2 weeks until week 12 on the basis of mean 24-hour UFC concentration. The determined maintenance dose was continued until week 24. At week 26, participants who had achieved 24-hour UFC concentration ≤ ULN and did not need titration after week 12 were randomly assigned in an equal ratio to maintain osilodrostat treatment or were switched to a placebo for 8 weeks. This 8-week period of the study was double-blinded. During weeks 35 to 48, all patients were returned to osilodrostat treatment. In this cohort, mean age was 40.0 years (range, 19.0-70.0 years), 77% of participants were women, the average time since diagnosis was 47.2 months (interquartile range [IQR], 19.0-88.3), 88% had previous pituitary surgery, 16% had pituitary radiation therapy, and 74% had medicinal therapy. At baseline, the mean 24-hour UFC concentration was 1006±1590 nmol/24 h. At week 24, 53% of participants achieved a mean 24-hour UFC concentration ≤ULN without increases in dose after week 12 and were eligible for randomization (osilodrostat, n=36; placebo, n=35). At week 34, more patients receiving osilodrostat vs placebo maintained a complete response (86% vs 29%, respectively; odds ratio [OR], 13.7; 95% CI, 3.7-53.4; P <.0001). Improvements in cardiovascular-related metabolic parameters associated with hypercortisolism and overall measures of well-being were observed. Levels of high-density lipoprotein decreased by week 48 (-0.3 mmol/L; 95% CI, .0.3 to -0.2), mean Cushing’s quality of life score increased by 52.4% (95% CI, 32.3-72.7), and Beck Depression Inventory score decreased by 31.8% (95% CI, -44.3 to -19.3). Adverse events were hypocortisolism (51%), adverse events related with adrenal hormone precursors (42%), nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%). A total of 18% of participants dropped out of the study due to adverse events. The major limitation of this study was the short withdrawal period (8 weeks) which may not have permitted to observe symptoms of hypercortisolism. “Alongside careful dose adjustments and monitoring of known risks associated with osilodrostat, our findings indicate a positive benefit– risk consideration of treatment for most patients with Cushing’s disease,” concluded the study authors. Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a doubleblind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;S2213-8587(20)30240-0. doi:10.1016/S2213-8587(29)30240-0 From https://www.endocrinologyadvisor.com/home/topics/general-endocrinology/osilodrostat-sustained-reduction-mean-ufc-concentration-cushings-disease/
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  46. Susanne, this is not a blog. It is a message board about Cushing's Syndrome and Disease. I would suggest you do a google search for how to write blog posts.
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  47. Wow 8.4 on the first try. These are textbook adrenal numbers. I hope your doctors come to their senses.
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  48. Hi Kathy and welcome! You are in a good place for support, information and understanding. Please don't let your son stop looking for help just because his current doctors don't understand this disease. His feeling is right---cushing's kills. I've been on this board for 6 years now and have seen many wonderful people succomb to this disease, some because they didn't see the right doctors. There is a helpful doctors tab at the top of the page...maybe there is a good one on the island. Otherwise, we will be happy to suggest a doctor who understands cushings. His insurance may or may not cover the doctors who can help him. Please stick around and read all you can and ask any questions you might have. 3 high ufc's plus his symptoms should not be ignored. love, melly
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