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Found 22 results

  1. Increased cortisol secretion may follow a cyclic pattern in patients with adrenal incidentalomas, a phenomenon that may lead to misdiagnosis, a study reports. Since cyclic subclinical hypercortisolism may increase the risk for heart problems, researchers recommend extended follow-up with repeated tests to measure cortisol levels in these patients. The study, “Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas,” was published in the Journal of Endocrine Society. Adrenal incidentalomas (AI) are asymptomatic masses in the adrenal glands discovered on an imaging test ordered for a problem unrelated to adrenal disease. While most of these benign tumors are considered non-functioning, meaning they do not produce steroid hormones like cortisol, up to 30% do produce and secrete steroids. Subclinical Cushing’s syndrome is an asymptomatic condition characterized by mild cortisol excess without the specific signs of Cushing’s syndrome. The long-term exposure to excess cortisol may lead to cardiovascular problems in these patients. While non-functioning adenomas have been linked with metabolic problems, guidelines say that if excess cortisol is ruled out after the first evaluation, patients no longer need additional follow-up. However, cortisol secretion can be cyclic in Cushing’s syndrome, meaning that clinicians might not detect excess amounts of cortisol at first and misdiagnose patients. In an attempt to determine whether cyclic cortisol production is also seen in patients with subclinical Cushing’s syndrome and whether these patients have a higher risk for metabolic complications, researchers in Brazil reviewed the medical records of 251 patients with AI — 186 women, median 60 years old — followed from 2006 to 2017 in a single reference center. Cortisol levels were measured after a dexamethasone suppression test (DST). Dexamethasone is used to stop the adrenal glands from producing cortisol. In healthy patients, this treatment is expected to reduce cortisol levels, but in patients whose tumors also produce cortisol, the levels often remain elevated. Patients were diagnosed with cyclic subclinical Cushing’s syndrome if they had at least two normal and two abnormal DST tests. From the 251 patients, only 44 performed the test at least three times and were included in the analysis. The results showed that 20.4% of patients had a negative DST test and were considered non-functioning adenomas. An additional 20.4% had elevated cortisol levels in all DST tests and received a diagnosis of sustained subclinical Cushing’s syndrome. The remaining 59.2% had discordant results in their tests, with 18.3% having at least two positive and two negative test results, matching the criteria for cyclic cortisol production, and 40.9% having only one discordant test, being diagnosed as possibly cyclic subclinical Cushing’s syndrome. Interestingly, 20 of the 44 patients had a normal cortisol response at their first evaluation. However, 11 of these patients failed to maintain normal responses in subsequent tests, with four receiving a diagnosis of cyclic subclinical Cushing’s syndrome and seven as possibly cyclic subclinical Cushing’s. Overall, the findings suggest that patients with adrenal incidentalomas should receive extended follow-up with repeated DST tests, helping identify those with cyclic cortisol secretion. “Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk,” the study concluded. From https://cushingsdiseasenews.com/2019/04/11/cyclic-cortisol-production-may-lead-to-misdiagnosis-in-cushings-study-finds/
  2. A simple test that measures free cortisol levels in saliva at midnight — called a midnight salivary cortisol test — showed good diagnostic performance for Cushing’s syndrome among a Chinese population, according to a recent study. The test was better than the standard urine free cortisol levels and may be an alternative for people with end-stage kidney disease, in whom measuring cortisol in urine is challenging. The study, “Midnight salivary cortisol for the diagnosis of Cushing’s syndrome in a Chinese population,” was published in Singapore Medical Journal. Cushing’s syndrome, defined by excess cortisol levels, is normally diagnosed by measuring the amount of cortisol in bodily fluids. Traditionally, urine free cortisol has been the test of choice, but this method is subject to complications ranging from improper collection to metabolic differences, and its use is limited in people with poor kidney function. Midnight salivary cortisol is a test that takes into account the normal fluctuation of cortisol levels in bodily fluids. Cortisol peaks in the morning and declines throughout the day, reaching its lowest levels at midnight. In Cushing’s patients, however, this variation ceases to exist and cortisol remains elevated throughout the day. Midnight salivary cortisol was first proposed in the 1980s as a noninvasive way to measure cortisol levels, but its efficacy and cutoff value for Cushing’s disease in the Chinese population remained unclear. Researchers examined midnight salivary cortisol, urine free cortisol, and midnight serum cortisol in Chinese patients suspected of having Cushing’s syndrome and in healthy volunteers. These measurements were then combined with imaging studies to make a diagnosis. Overall, the study included 29 patients with Cushing’s disease, and 19 patients with Cushing’s syndrome — 15 caused by an adrenal mass and four caused by an ACTH-producing tumor outside the pituitary. Also, 13 patients excluded from the suspected Cushing’s group were used as controls and 21 healthy volunteers were considered the “normal” group. The team found that the mean midnight salivary cortisol was significantly higher in the Cushing’s group compared to both control and normal subjects. Urine free cortisol and midnight serum cortisol were also significantly higher than those found in the control group, but not the normal group. The optimal cutoff value of midnight salivary cortisol for diagnosing Cushing’s was 1.7 ng/mL, which had a sensitivity of 98% — only 2% are false negatives — and a specificity of 100% — no false positives. While midnight salivary cortisol levels correlated with urine free cortisol and midnight serum cortisol — suggesting that all of them can be useful diagnostic markers for Cushing’s — the accuracy of midnight salivary cortisol was better than the other two measures. Notably, in one patient with a benign adrenal mass and impaired kidney function, urine free cortisol failed to reach the necessary threshold for a Cushing’s diagnosis, but midnight salivary and serum cortisol levels both confirmed the diagnosis, highlighting how midnight salivary cortisol could be a preferable diagnostic method over urine free cortisol. “MSC is a simple and non-invasive tool that does not require hospitalization. Our results confirmed the accuracy and reliability of [midnight salivary cortisol] as a diagnostic test for [Cushing’s syndrome] for the Chinese population,” the investigators said. The team also noted that its study is limited: the sample size was quite small, and Cushing’s patients tended to be older than controls, which may have skewed the results. Larger studies will be needed to validate these results in the future. From https://cushingsdiseasenews.com/2019/01/10/midnight-salivary-cortisol-test-helps-diagnose-cushings-chinese-study-shows/
  3. If you’ve got your finger on the pulse of health trends, it’s likely you’ve been hearing the current buzzwords “cortisol creates belly fat” and “cortisol causes muscle wasting and fat storage.” These are the type of catch phrases that gain momentum every few years. And although some of the fads and trends showing up seasonally in fitness are myths, this caution about chronically elevated cortisol is true. Cortisol is also deeply connected with the dangers of chronic inflammation, which I described in another article, “Inflammation Creates Diseases.” Like many hormones, cortisol has an effect on a wide variety of functions in the body. Although it’s getting particularly demonized lately, cortisol serves some very important and positive functions in the body. It’s an essential component of the flight or flight response, so it gives us energy, focus, strength, motivation and courage. But, like with sugar or caffeine, it comes with a crash that feels like an emotional, psychological and physical drain. Cortisol is important for survival, but we didn’t evolve to have high levels of it all the time. According to hormone.org, cortisol isn’t only a stress hormone: “Because most bodily cells have cortisol receptors, it affects many different functions in the body. Cortisol can help control blood sugar levels, regulate metabolism, help reduce inflammation and assist with memory formulation. It has a controlling effect on salt and water balance and helps control blood pressure. In women, cortisol also supports the developing fetus during pregnancy. All of these functions make cortisol a crucial hormone to protect overall health and well-being.” (hormone.org/hormones-and-health/hormones/cortisol) There are many symptoms of chronically elevated cortisol levels. With that said, the way a spike of cortisol gives you a jolt of energy is by raising blood sugar. It does this by way of gluconeogenesis. This literally means “creating new sugar,” and it happens by way of breaking protein down into amino acids that are then turned into sugar by the liver. What is a large source of protein in the body? Yep, muscles. This is what is meant by “cortisol causes muscle loss.” This in turn contributes to muscle weakness. Whereas normal levels of cortisol help to regulate blood sugar levels by breaking down only a little muscle (which can be replaced with exercise), excessive levels cause muscle wasting. Why does cortisol cause fat gain? Remember those cortisol receptors most cells have? Fat cells have four times as many, so they are particularly responsive to cortisol. Okay, remember all that glucose the cortisol surge dumped into your blood for energy? Well, that also came with an insulin response to get your blood sugar levels back down, and insulin causes energy storage. And where do you store the energy? Yep, in those hypersensitive fat cells that cortisol just turned on. And what happens when you have too much insulin over time? Yep, diabetes. Also, another reason stress can cause emotional and/or binge eating is because cortisol also fires up your sense of purpose, as well as your appetite. So now stress has made you feel motivated…to eat. Emotionally and psychologically, chronically high cortisol can exacerbate depression, anxiety, irritability and lack of emotional control. Cortisol triggers a release of tryptophan oxygenase. This enzyme breaks down tryptophan. Tryptophan is required for creating serotonin. Serotonin gives us the ability to feel happiness, and it also affects appetite, sleep and sexual desire. Since extended exposure to high levels of cortisol inhibits the production of serotonin, all the symptoms of low serotonin become problematic (decreased appetite, insomnia, impotence, etc.). In short, prolonged stress causes depression. Cortisol also plays a role in the circulatory system. It manipulates blood pressure by acting as a diuretic. Excess cortisol causes an electrolyte imbalance, whereby sodium is retained, but potassium is excreted. Let me take you back to your high school biology days: Muscles fire because of the sodium potassium pump. The sodium potassium pump also effects the firing of nerves, including those impulses that cause your heart to beat and your kidneys to take in water for filtration. That sodium potassium pump is important throughout the entire body, across many of its biological functions. Because cortisol increases the concentration of sodium in your body, it has a direct impact on your blood pressure. Remember why excess salt can cause high blood pressure? Because it contains sodium. For all these reasons and more, chronically elevated cortisol also causes muscle weakness (ironic, since short bursts of it temporarily increase strength). Cortisol has other effects on minerals. According to the Hindawi Journal of Sports Medicine, “Cortisol triggers bone mineral resorption (removal) in order to free amino acids for use as an energy source through gluconeogenesis. Cortisol indirectly acts on bone by blocking calcium absorption, which decreases bone cell growth.” As you can see, excess cortisol causes osteoporosis. It also exacerbates other bone mineral density diseases, which means cortisol can leave you literally brittle with stress. Practically anything can become a stressor in the right conditions, and fight or flight is our only biological response to stress. Some triggers of stress include conflict, worry, alcohol and drug consumption, processed foods, excess exercise (especially prolonged and repeated sessions of low-level steady-state cardio training), sleep deprivation, thirst and hunger. As much as possible, protect yourself from stress with rest, relaxation, meditation, play time and healthy foods full of antioxidants, which reduce inflammation and thus the risks for practically all diseases. Jack Kirven completed the MFA in Dance at UCLA, and earned certification as a personal trainer through NASM. His wellness philosophy is founded upon integrated lifestyles as opposed to isolated workouts. Visit him at jackkirven.com and INTEGRE8Twellness.com. Adapted from https://goqnotes.com/61597/stress-cortisol-and-weight-gain/
  4. Strongbridge Biopharma released additional positive results from a Phase 3 trial evaluating whether the company’s investigational therapy Recorlev (levoketoconazole) is safe and effective for people with endogenous Cushing’s syndrome. The latest results were presented in the scientific poster “Safety and Efficacy of Levoketoconazole in Cushing Syndrome: Initial Results From the Phase 3 SONICS Study,\” at the 18th Annual Congress of the European NeuroEndocrine Association (ENEA), which took place in Wrocław, Poland, last month. The SONICS study (NCT01838551) was a multi-center, open-label Phase 3 trial evaluating Recorlev’s safety and effectiveness in 94 patients with endogenous Cushing’s syndrome. The trial consisted of three parts: a dose-escalation phase to determine the appropriate Recorlev dose that achieved normalization of cortisol levels; a maintenance phase in which patients received the established dose for six months; and a final extended phase, in which patients were treated with Recorlev for an additional six months, with the possibility of dose adjustments. Its primary goal was a reduction in the levels of cortisol in the patients’ urine after six months of maintenance treatment, without any dose increase during that period. Among secondary goals was a reduction in the characteristically high risk of cardiovascular disease in these people, through the assessment of multiple cardiovascular risk markers. Strongbridge announced top-line results of the SONICS study in August, which showed that the trial had reached its primary and secondary goals. It concluded last month. After six months of maintenance therapy, Recorlev successfully lowered to normal the levels of cortisol in 30% of patients without a dose increase. It also led to statistically and clinically significant reductions in cardiovascular risk biomarkers, including blood sugar, cholesterol levels, body weight, and body mass index. Maria Fleseriu, MD, director of the Oregon Health Sciences University Northwest Pituitary Center, presented additional and detailed results of SONICS at the congress. Additional analyses showed that among the 77 patients who completed the dose-escalation phase and entered the study’s maintenance phase, 81% had their cortisol levels normalized. At the end of the six months of maintenance treatment, 29 (53%) of the 55 patients who had their cortisol levels assessed at the beginning of the study and at the end of the maintenance phase had achieved normalization of cortisol levels, regardless of dose increase. Among all patients who completed maintenance treatment (including patients with some missing data) and regardless of dose increase, 38% had achieved normalization of cortisol levels and 48% recorded a 50% or more decrease or normalization. The results also highlighted that Recorlev substantially reduced patients’ cortisol levels regardless of their levels at the study’s beginning (which were on average about five-fold higher than the upper limit of normal). In those patients with the highest levels of cortisol in their urine, Recorlev led to a median reduction of more than 80%. As previously reported, Recorlev was found to be generally well-tolerated, with no new safety concerns, and only 12 participants (12.8%) stopped treatment due to adverse events. Ten patients had three- or five-fold increased levels of alanine aminotransferase — a liver enzyme used to assess liver damage — which were fully resolved without further complications. These liver-related adverse events “were all noted in the first 60 days, thus suggesting a timeline interval for monitoring,” Fleseriu said in a press release. “We continue to be encouraged by the positive efficacy results of SONICS and the overall benefit-to-risk profile of Recorlev and look forward to sharing additional planned analyses from the study in the near future,” said Fredric Cohen, Strongbridge’s chief medical officer. From https://cushingsdiseasenews.com/2018/11/01/new-data-from-phase-3-trial-supports-recorlev-ability-to-safely-treat-cushings-syndrome/
  5. Minimally invasive diagnostic methods and transnasal surgery may lead to remission in nearly all children with Cushing’s disease, while avoiding more aggressive approaches such as radiation or removal of the adrenal glands, a study shows. The study, “A personal series of 100 children operated for Cushing’s disease (CD): optimizing minimally invasive diagnosis and transnasal surgery to achieve nearly 100% remission including reoperations,” was published in the Journal of Pediatric Endocrinology and Metabolism. Normally, the pituitary produces adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol. When a patient has a pituitary tumor, that indirectly leads to high levels of cortisol, leading to development of Cushing’s disease (CD). In transnasal surgery (TNS), a surgeon goes through the nose using an endoscope to remove a pituitary tumor. The approach is the first-choice treatment for children with Cushing’s disease due to ACTH-secreting adenomas — or tumors — in the pituitary gland. Micro-adenomas, defined as less than 4 mm, are more common in children and need surgical expertise for removal. It is necessary to determine the exact location of the tumor before conducting the surgery. Additionally, many surgeons perform radiotherapy or bilateral adrenalectomy (removal of both adrenal glands) after the surgery. However, these options are not ideal as they can be detrimental to children who need to re-establish normal growth and development patterns. Dieter K. Lüdecke, a surgeon from Germany’s University of Hamburg, has been able to achieve nearly 100% remission while minimizing the need for pituitary radiation or bilateral adrenalectomy. In this study, researchers looked at how these high remission rates can be achieved while minimizing radiotherapy or bilateral adrenalectomy. Researchers analyzed 100 patients with pediatric CD who had been referred to Lüdecke for surgery from 1980-2009. Data was published in two separate series — series 1, which covers patients from 1980-1995, and series 2, which covers 1996-2009. All the surgeries employed direct TNS. Diagnostic methods for CD have improved significantly over the past 30 years. Advanced endocrine diagnostic investigations, such as testing for levels of salivary cortisol in the late evening and cortisol-releasing hormone tests, have made a diagnosis of CD less invasive. This is particularly important for excluding children with obesity alone from children with obesity and CD. Methods to determine the precise location of micro-adenomas have also improved. The initial methodology to localize tumors was known as inferior petrosal sinus sampling (IPSS), an invasive procedure in which ACTH levels are sampled from the veins that drain the pituitary gland. In series 1, IPSS was performed in 24% of patients, among which 46% were found to have the wrong tumor location. Therefore, IPSS was deemed invasive, risky, and unreliable for this purpose. All adenomas were removed with extensive pituitary exploration. Two patients in series 1 underwent early repeat surgery; all were successful. Lüdecke introduced intraoperative cavernous sinus sampling (CSS), an improved way to predict location of adenomas. This was found to be very helpful in highly select cases and could also be done preoperatively for very small adenomas. In series 2, CSS was used in only 15% of patients thanks to improved MRI and endocrinology tests. All patients who underwent CSS had correct localization of their tumors, indicating its superiority over IPSS. In series 2, three patients underwent repeat TNS, which was successful. In these recurrences, TNS minimized the need for irradiation. The side effects of TNS were minimal. Recurrence rate in series 1 was 16% and 11% in series 2. While Lüdecke’s patients achieved a remission rate of 98%, other studies show cure rates of 45-69%. Only 4% of patients in these two series received radiation therapy. “Minimally invasive unilateral, microsurgical TNS is important functionally for both the nose and pituitary,” the researchers concluded. “Including early re-operations, a 98% remission rate could be achieved and the high risk of pituitary function loss with radiotherapy could be avoided.” From https://cushingsdiseasenews.com/2018/09/04/minimally-invasive-methods-yield-high-remission-in-cushings-disease-children/
  6. A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary. “Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.” In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies. On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3. At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests. The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve. The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas. Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers. The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers. “A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission
  7. The ratio between adrenocorticotropic hormone levels and cortisol levels in the blood is higher among Cushing’s disease patients than in healthy people, a new study has found, suggesting that measurement could be used to help diagnose the disease. Also, higher values at diagnosis could predict if the disease will recur and indicate larger and more invasive tumors. The research, “The Utility of Preoperative ACTH/Cortisol Ratio for the Diagnosis and Prognosis of Cushing’s Disease,” was published in the Journal of Neurosciences in Rural Practice. Cushing’s syndrome (CS) is characterized by excess levels of cortisol. In patients with suspected CS, clinicians recommend testing late-night salivary or plasma (blood) cortisol, 24-hour urine-free cortisol (UC), as well as morning cortisol levels after low-dose suppression with dexamethasone, a corticosteroid. CS may be ACTH-dependent or ACTH-independent, meaning that the high cortisol levels are caused by excess ACTH production. Patients with CD have elevated levels of ACTH. A tumor, usually an adenoma, causes the pituitary gland to produce excess levels of ACTH, which stimulate the release of cortisol from the adrenal glands. Cortisol usually inhibits ACTH production. However, in CD patients, this feedback mechanism is absent. Despite extensive research and clinical data, the variable and usually nonspecific signs and symptoms of CD still represent relevant challenges for diagnosis. Clinical manifestations must be associated with biochemical tests, which often have led to conflicting results. Studies showed that although ACTH levels correlate with the size of the pituitary adenoma, the levels of cortisol do not increase as much. In fact, lower cortisol/ACTH ratios have been reported in patients with macroadenoma – which is greater than 10 millimeters in size – than in those with microadenoma, which is smaller than 10 millimeters. Conversely, the research team hypothesized that besides their utility for determining the cause of CS, the inverse ratio – ACTH/cortisol – also may be useful for diagnosis. The team evaluated the pretreatment plasma ACTH/cortisol levels in CS patients with excess cortisol production due to abnormal pituitary or adrenal function. Data from patients were compared with that of individuals without CS. The study included 145 CS patients diagnosed from 2007 to 2016, 119 patients with CD, 26 with ACTH-independent CS (AICS), and 114 controls with no CS. Patients’ clinical, laboratory, imaging, postsurgical and follow-up data were analyzed. Results showed that patients with CD had a significantly higher basal ACTH/cortisol ratio than controls or those with AICS. “These results showed ACTH/cortisol ratio might be a simple and useful test for the diagnosis of ACTH-dependent CS,” the researchers wrote. Importantly, the scientists observed that a ACTH/cortisol ratio above 2.5 indicated identified 82 percent of positive CS cases and 63 percent of controls. Overall, “an ACTH/cortisol ratio [greater than] 2.5 would be beneficial to diagnose CD together with other diagnostic tests,” they concluded. Patients with recurrent CD showed higher pretreatment ACTH levels and ACTH/cortisol ratio than those who achieved sustained remission. CD patients also exhibited more invasive, atypical and larger tumors, as well as lower postoperative remission and higher recurrence rates. “Higher ACTH/cortisol ratio might predict poorer prognosis,” the investigators said. From https://cushingsdiseasenews.com/2018/03/16/acth-cortisol-ratio-reliable-test-diagnose-cushings-disease/
  8. Children with Cushing’s syndrome are at risk of developing new autoimmune and related disorders after being cured of the disease, a new study shows. The study, “Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children,” was published in Hormone and Metabolic Research. Patients with Cushing’s syndrome have excess levels of the hormone cortisol, a corticosteroid that inhibits the effects of the immune system. As a result, these patients are protected from autoimmune and related diseases. But it is not known if the risk rises after their disease is resolved. To address this, researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) examined 127 children with Cushing’s syndrome at the National Institutes of Health from 1997 until 2017. Among the participants, 77.5 percent had a pituitary tumor causing the disease, 21.7 percent had ACTH-independent disease, and one patient had ectopic Cushing’s syndrome. All patients underwent surgery to treat their symptoms. After a mean follow-up of 31.2 months, 7.8 percent of patients developed a new autoimmune or related disorder. Researchers found no significant differences in age at diagnosis, gender, cortisol levels, and urinary-free cortisol at diagnosis, when comparing those who developed autoimmune disorders with those who didn’t. However, those who developed an immune disorder had a significantly shorter symptom duration of Cushing’s syndrome. This suggests that increased cortisol levels, even for a short period of time, may contribute to more reactivity of the immune system after treatment. The new disorder was diagnosed, on average, 9.8 months after Cushing’s treatment. The disorders reported were celiac disease, psoriasis, Hashimoto thyroiditis, Graves disease, optic nerve inflammation, skin hypopigmentation/vitiligo, allergic rhinitis/asthma, and nerve cell damage of unknown origin responsive to glucocorticoids. “Although the size of our cohort did not allow for comparison of the frequency with the general population, it seems that there was a higher frequency of optic neuritis than expected,” the researchers stated. It is still unclear why autoimmune disorders tend to develop after Cushing’s resolution, but the researchers hypothesized it could be a consequence of the impact of glucocorticoids on the immune system. Overall, the study shows that children with Cushing’s syndrome are at risk for autoimmune and related disorders after their condition is managed. “The presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise,” the researchers stated. Additional studies are warranted to further explore this link and improve care of this specific population. From https://cushingsdiseasenews.com/2018/03/06/after-cushings-cured-autoimmune-disease-risk-looms-study/
  9. Measuring cortisol levels in saliva multiple times a day is a convenient and useful way to determine the best course of treatment for patients with Cushing’s syndrome, a preliminary study shows. The research, “Multiple Salivary Cortisol Measurements Are a Useful Tool to Optimize Metyrapone Treatment in Patients with Cushing’s Syndromes Treatment: Case Presentations,” appeared in the journal Frontiers of Endocrinology. Prompt and effective treatment for hypercortisolism — the excessive amount of cortisol in the blood — is essential to lowering the risk of Cushing’s-associated conditions, including infections, cardiovascular disease, and stroke. Steroid hormone inhibitors, such as HRA Pharma’s Metopirone (metyrapone), have been used significantly in Cushing’s syndrome patients. These therapies not only suppress cortisol levels, but also avoid adrenal insufficiency (where not enough cortisol is produced) and restore the circadian rhythm, which is disrupted in Cushing’s patients. However, effective medical treatment requires monitoring cortisol activity throughout the day. Salivary measurements of cortisol are a well-known method for diagnosing and predicting the risk of recurrence of Cushing’s syndrome. The method is convenient for patients and can be done in outpatient clinics. However, the medical field lacks data on whether measuring cortisol in saliva works for regulating treatment. Researchers analyzed the effectiveness of salivary cortisol measurements for determining the best dosage and treatment timing of Cushing’s patients with Metopirone. The study included six patients, three with cortisol-secreting masses in the adrenal glands and and three with ACTH (or adrenocorticotropin)-secreting adenomas in the pituitary glands, taking Metopirone. Investigators collected samples before and during treatment to assess morning serum cortisol and urinary free cortisol (UFC). Patients also had salivary cortisol assessments five times throughout the day. Saliva samples were collected at 6 a.m. (wake-up time), 8 a.m. (before breakfast), noon (before lunch), 6 p.m. (before dinner), and 10 p.m. (before sleep). Other studies have used UFC assessments to monitor treatment. However, the inability of this parameter to reflect changes in diurnal cortisol requires alternative approaches. Results showed that although UFC was normalized in five out of six patients, multiple salivary cortisol measurements showed an impaired diurnal cortisol rhythm in these patients. Whereas patients with cortisol-secreting adrenocortical adenoma showed elevated cortisol levels throughout the day, those with ACTH-secreting pituitary adenoma revealed increased levels mainly in the morning. This finding indicates that “the significance of elevated morning cortisol levels is different depending on the disease etiology,” the researchers wrote. In a prospective case study to better assess the effectiveness of performing multiple salivary cortisol assessments, the research team analyzed one of the participants who had excessive cortisol production that was not controlled with four daily doses of Metoripone (a daily total of 2,250 mg). Results revealed that cortisol levels increased before each dosage. After the patient’s treatment regimen was changed to a 2,500 mg dose divided into five daily administrations, researchers observed a significant improvement in the diurnal cortisol pattern, as well as in UFC levels. Subsequent analysis revealed that performing multiple salivary cortisol measurements helps with a more precise assessment of excess cortisol than analyzing UFC levels, or performing a unique midnight salivary cortisol collection, the researchers said. Although more studies are required, the results “suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone [Metopirone] during the treatment in patients with [Cushing’s syndrome],” the researchers wrote. Future studies should include a larger sample size, evaluate changes over a longer term, use a standardized protocol for treatment dosing and timing, and evaluate changes in a patient’s quality of life, the investigators said. From https://cushingsdiseasenews.com/2018/02/15/multiple-saliva-cortisol-checks-cushings-metyrapone-study/
  10. Patients with different subtypes of Cushing’s syndrome (CS) have distinct plasma steroid profiles. This could be used as a test for diagnosis and classification, a German study says. The study, “Plasma Steroid Metabolome for Diagnosis and Subtyping Patients with Cushing Syndrome,” appeared in the journal Clinical Chemistry. A quick diagnosis of CS is crucial so that doctors can promptly give therapy. However, diagnosing CS is often complicated by the multiple tests necessary not just to diagnose the disease but also to determine its particular subtype. Cortisol, which leads to CS when produced at high levels, is a steroid hormone. But while earlier studies were conducted to determine whether patients with different subtypes of CS had distinct steroid profiles, the methods researchers used were cumbersome and have been discontinued for routine use. Recently, a technique called LC-MS/MS has emerged for multi-steroid profiling in patients with adrenocortical dysfunction such as congenital adrenal hyperplasia, adrenal insufficiency and primary aldosteronism. Researchers at Germany’s Technische Universität in Dresden used that method to determine whether patients with the three main subtypes of CS (pituitary, ectopic and adrenal) showed differences in plasma steroid profiles. They measured levels of 15 steroids produced by the adrenal glands in single plasma samples collected from 84 patients with confirmed CS and 227 age-matched controls. They found that CS patients saw huge increases in the plasma steroid levels of 11-deoxycortisol (289%), 21-deoxycortisol (150%), 11-deoxycorticosterone (133%), corticosterone (124%) and cortisol (122%), compared to patients without the disease. Patients with the ectopic subtype had the biggest jumps in levels of these steroids. However, plasma 18-oxocortisol levels were particularly low in ectopic disease. Other steroids demonstrated considerable variation. Patients with the adrenal subtype had the lowest concentration of dehydroepiandrosterone (DHEA) and DHEA-SO4, which are androgens. Patients with the ectopic and pituitary subtype had the lowest concentration of aldosterone. Through the use of 10 selected steroids, patients with different subtypes of CS could be identified almost as closely as with other tests, including the salivary and urinary free cortisol test, the dexamethasone-suppressed cortisol test, and plasma adrenocorticotropin levels. The misclassification rate using steroid levels was 9.5 percent, compared to 5.8 percent in other tests. “This study using simultaneous LC-MS/MS measurements of 15 adrenal steroids in plasma establishes distinct steroid metabolome profiles that might be useful as a test for CS,” the team concluded, adding that using LC-MS/MS is advantageous, as specimen preparation is simple and the entire panel takes 12 minutes to run. This means it could be offered as a single test for both identification and subtype classification. From https://cushingsdiseasenews.com/2018/01/02/plasma-steroid-levels-used-screen-diagnosis-subtyping-patients-cushing-syndrome/
  11. Addison’s disease: Hyperpigmentation is a classic symptom of Addison’s disease, an endocrine disorder in which the adrenal glands fails to produce steroid hormone. The disease causes darkening of the skin in certain areas. Cushing’s syndrome: The abnormal amount of cortisol in the human body causes a condition known as the Cushing’s syndrome. And one of the symptoms of the disorder is hyperpigmentation of the skin. Adapted from http://www.thehealthsite.com/diseases-conditions/health-conditions-that-can-cause-hyperpigmentation/
  12. All patients who undergo removal of one adrenal gland due to Cushing’s syndrome (CS) or adrenal incidentaloma (AI, adrenal tumors discovered incidentally) should receive a steroid substitutive therapy, a new study shows. The study, “Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH‐independent hypercortisolism,” was published in the Journal of Endocrinological Investigation. CS is a rare disease, but subclinical hypercortisolism, an asymptomatic condition characterized by mild cortisol excess, has a much higher prevalence. In fact, subclinical hypercortisolism, is present in up to 20 percent of patients with AI. The hypothalamic-pituitary-adrenal axis (HPA axis) is composed of the hypothalamus, which releases corticotropin-releasing hormone (CRH) that acts on the pituitary to release adrenocorticotropic hormone (ACTH), that in turn acts on the adrenal gland to release cortisol. To avoid excess cortisol production, high cortisol levels tell the hypothalamus and the pituitary to stop producing CRH and ACTH, respectively. Therefore, as CS and AI are characterized by high levels of cortisol, there is suppression of the HPA axis. As the adrenal gland is responsible for the production of cortisol, patients might need steroid substitutive therapy after surgical removal of AI. Indeed, because of HPA axis suppression, some patients have low cortisol levels after such surgeries – clinically known as post-surgical hypocortisolism (PSH), which can be damaging to the patient. While some researchers suggest that steroid replacement therapy should be given only to some patients, others recommend it should be given to all who undergo adrenalectomy (surgical removal of the adrenal gland). Some studies have shown that the severity of hypercortisolism, as well as the degree of HPA axis suppression and treatment with ketoconazole pre-surgery in CS patients, are associated with a longer duration of PSH. Until now, however, there have been only a few studies to guide in predicting the occurrence and duration of PSH. Therefore, researchers conducted a study to determine whether HPA axis activity, determined by levels of ACTH and cortisol, could predict the occurrence and duration of PSH in patients who undergo an adrenalectomy. Researchers studied 80 patients who underwent adrenalectomy for either CS or AI. Prior to the surgery, researchers measured levels of ACTH, urinary free cortisol (UFC), and serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST). After the surgery, all patients were placed on steroid replacement therapy and PSH was determined after two months. For those with PSH, levels of cortisol were determined every six months for at least four years. Results showed that PSH occurred in 82.4 percent of CS patients and 46 percent of AI patients. PSH lasted for longer than 18 months in 50 percent of CS and 30 percent of AI patients. Furthermore, it lasted longer than 36 months for 35.7 percent of CS patients. In all patients, PSH was predicted by pre-surgery cortisol levels after the 1 mg-DST, but with less than 70 percent accuracy. In AI patients, a shorter-than-12-month duration of PSH was not predicted by any HPA parameter, but was significantly predicted by an absence of pre-surgery diagnosis of subclinical hypercortisolism. So, this study did not find any parameters that could significantly predict with high sensitivity and specificity the development or duration of PSH in all patients undergoing adrenalectomy. Consequently, the authors concluded that “the PSH occurrence and its duration are hardly predictable before surgery. All patients undergoing unilateral adrenalectomy should receive a steroid substitutive therapy.” From https://cushieblog.com/2017/12/14/patients-undergoing-adrenalectomy-should-receive-steroid-substitutive-therapy/
  13. People with high cortisol levels have lower muscle mass and higher visceral fat deposits, putting them at a greater risk for cardiovascular disease, new research shows. High levels of cortisol can result from a variety of reasons, including Cushing’s disease and adrenal tumors. Most adrenal tumors are found to be non-functioning, meaning they do not produce excess hormones. However, up to 47 percent of patients have mild autonomous cortisol excess (MACE). The study, “Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas,” was published in the journal Clinical Endocrinology. Long-term studies have shown that as a group, patients with MACE tend to have increased cardiovascular risk factors, such as hypertension, type 2 diabetes mellitus (DM2), obesity, and high lipid levels, which are associated with higher cardiovascular death rates. Abdominal adiposity, which refers to fat deposits around the abdomen and stomach, and central sarcopenia, referring to loss of skeletal muscle mass, are both known to be linked to higher cardiovascular risk and increased mortality. Overt hypercortisolism is known to lead to increased visceral adiposity (body fat stored within the abdominal cavity) and muscle loss. However, little is known about the body composition of patients with adrenal adenomas and MACE. Therefore, researchers set out to determine whether central sarcopenia and adiposity are present in patients with MACE, and whether they can be markers of disease severity in patients with adrenal adenomas. To determine this, researchers used body composition measurements of 25 patients with Cushing’s disease, 48 patients with MACE, and 32 patients with non-functioning adrenal tumors (NFAT) using abdominal CTs. Specifically, researchers looked at visceral fat, subcutaneous fat, and total abdominal muscle mass. Visceral fat refers to fat around organs, and it is “deeper” than subcutaneous fat, which is closer to the skin. Results showed that, compared to patients with non-functional tumors, those with Cushing’s disease had a higher visceral to total (V/T) fat ratio but a lower visceral to subcutaneous (V/S) fat ratio. In MACE patients, however, both ratios were decreased compared to patients with non-functional tumors. Cushing’s disease patients also had 10 cm2 less total muscle mass, compared to patients with non-functional tumors. An overnight dexamethasone suppression test was conducted in these patients to determine levels of cortisol in the blood. The next morning, cortisol levels were checked. High levels of cortisol indicate the presence of a disease, such as MACE or Cushing’s disease. After administering the test, researchers determined that for an increase in cortisol in the morning, there was a correlating increase in the V/T ratio and the V/S fat ratio, and a decrease in the mean total muscle mass. Therefore, the higher the degree of hypercortisolism, the lower the muscle mass and the higher the visceral adiposity. These results could prove to be clinically useful as both visceral adiposity and low muscle mass are risk factors of a number of diseases, including cardiovascular disease. “Body composition measurement may provide an additive value in making a diagnosis of clinically important MACE and aid in individualizing management of patients with ACAs and MACE,” the researchers concluded. From https://cushieblog.com/2017/12/01/high-cortisol-levels-as-seen-in-cushings-can-lead-to-greater-risk-of-heart-disease-study-finds/
  14. The effects of obesity on the diagnosis of Cushing’s syndrome and strategies to alter the traditional approaches have been addressed in a new review study. The study, “Diagnosis and Differential Diagnosis of Cushing’s Syndrome,” appeared in The New England Journal of Medicine. The author was Dr. Lynn D. Loriaux, MD and PhD, and a professor of medicine at the Division of Endocrinology, Diabetes and Clinical Nutrition at the School of Medicine, Oregon Health & Science University (OHSU), in Portland, Oregon. Traditionally, exams of patients with glucocorticoid excess focused on the presence of changes in anabolism (the chemical synthesis of molecules). Given the increase in obesity in the general population, changes in anabolism can no longer distinguish Cushing’s syndrome from metabolic syndrome. However, analyses of anti-anabolic changes of cortisol – including osteopenia (lower bone density), thin skin, and ecchymoses (injury that causes subcutaneous bleeding) – are an effective way to make this distinction. The worldwide prevalence of metabolic syndrome in obese people is estimated at about 10%. Conversely, the incidence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million people. Cushing’s and metabolic syndrome share significant clinical similarities, including obesity, hypertension, and type 2 diabetes. Therefore, “making the diagnosis is the least certain aspect in the care of patients with [Cushing’s],” Loriaux wrote. Regarding a physical examination, patients with osteoporosis, reduced skin thickness in the middle finger, and three or more ecchymoses larger than 1 cm in diameter and not associated with trauma are more likely to have Cushing’s. Researchers estimate the probability of people with all three of these symptoms having Cushing’s syndrome is 95%. Measuring 24-hour urinary-free cortisol levels allows the assessment of excess glucocorticoid effects, typical of Cushing’s syndrome. The test, which should be done with the most stringent techniques available, averages the augmented secretion of cortisol in the morning and the diminished secretion in the afternoon and at night. Dexamethasone suppression is one of the currently used screening tests for Cushing’s syndrome. Patients with obesity and depression should not show decreased plasma cortisol levels when dexamethasone is suppressed. However, given its low estimated predictive value (the proportion of positive results that are “true positives”), “this test should not influence what the physician does next and should no longer be used” to screen for Cushing’s, the author wrote. Some patients may show evidence of Cushing’s syndrome at a physical examination, but low urinary free cortisol excretion. This may be due to glucocorticoids being administered to the patient. In this case, the glucocorticoid must be identified and discontinued. Periodic Cushing’s assessments that measure urinary free cortisol should be performed. The opposite can also occur: no clinical symptoms of Cushing’s, but elevated urinary free cortisol excretion and detectable plasma levels of the hormone corticotropin. In these patients, the source of corticotropin secretion, which can be a tumor or the syndrome of generalized glucocorticoid resistance, must be determined. The disease process can be corticotropin-dependent or independent, depending on whether the hormone is detectable. Corticotropin in Cushing’s syndrome can come from the pituitary gland (eutopic) or elsewhere in the body (ectopic). Loriaux recommends that the source of corticotropin secretion be determined before considering surgery. Up to 40% of patients with pituitary adenomas have nonfunctioning tumors (the tumor does not produce any hormones) and the corticotropin source is elsewhere. If misdiagnosed, patients will likely undergo an unnecessary surgery, with a mortality rate of 1%. Patients with an ectopic source of corticotropin should undergo imaging studies in the chest, followed by abdominal and pelvic organs. If these tests fail to detect the source, patients should undergo either the blockade of cortisol synthesis or an adrenalectomy (removal of adrenal glands). However, corticotropin-independent Cushing’s is usually caused by a benign adrenal tumor that uniquely secretes cortisol. “Such tumors can be treated successfully with laparoscopic adrenalectomy,” Loriaux wrote. If the tumor secretes more than one hormone, it is likely malignant. Surgical to remove the tumor and any detectable metastases should be conducted. Overall, “the treatment for all causes of [Cushing’s syndrome], other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed,” Loriaux wrote in the study. “This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with [Cushing’s syndrome] should be referred to such a center for treatment.” From https://cushingsdiseasenews.com/2017/10/24/diagnosing-cushings-syndrome-amid-challenge-of-obesity-and-strategies-to-improve-methods/
  15. The glucocorticoid receptor antagonist CORT125134 is safe and has shown preliminary signs of efficacy in healthy volunteers participating in a Phase 1 trial, say researchers in England. Their study, “Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study,” appeared in the journal Clinical Pharmacology in Drug Development.” Cortisol signaling is indirectly controlled by the glucocorticoid receptor (GR). When cortisol binds the GR, the receptor becomes activated and migrates to the nucleus, where it regulates the expression of many genes. This influences a myriad of processes, including inflammation, immune response and brain function. CORT125134, also known as relacorilant, is being developed by Corcept Therapeutics of Menlo Park, California, for Cushing’s disease patients and others who may benefit from it. The drug is a GR antagonist, blocking the receptor’s activity. In order to evaluate the safety and tolerability of CORT125134, and learn how it behaves in the body, Corcept researchers conduced a Phase 1 trial in healthy subjects. The British study, conducted at the Quotient Clinical in Nottingham, included 81 adults who received a single ascending-dose of CORT125134 or placebo, and 48 subjects who received multiple-ascending doses of the drug versus placebo. Single doses were tested in nine distinct groups. Six tested six different doses of CORT125134, one tested a 150 mg dose in subjects receiving a high-fat meal, and two groups included patients receiving prednisone (a well-known GR activator), prednisone plus Korlym (mifepristone), or prednisone plus CORT125134. Korlym is a medicine approved for Cushing’s patients with high blood sugar levels due to high cortisol in circulation. But the drug targets the progesterone receptor and is associated with side effects like pregnancy termination and irregular vaginal bleeding. Multiple doses, given for up to 14 days, were tested in four additional cohorts. Researchers observed that CORT125134 was rapidly absorbed and eliminated, presenting a suitable profile for once-daily dosing. Efficacy was determined by CORT125134’s ability to counteract the effects of prednisone. In addition, a single dose of 500 mg or multiple dosing with 250 mg had similar effects as those seen with 600 mg of Korlym — the therapeutic dose used for Cushing’s treatments. Most common treatment-related adverse events reported in the single-ascending dose part of the study were nausea, vomiting and thirst; most were mild. In those given multiple-ascending doses, adverse events included mild musculoskeletal and connective tissue disorders, as well as gastrointestinal system disorders. Multiple 500 mg doses exceeded the maximum tolerated dose, as it led to musculoskeletal symptoms that forced researchers to stop treatment. “This first-in-human study has demonstrated that CORT125134 is well tolerated following single doses up to 500 mg and repeated doses up to 250 mg once daily for 14 days,” researchers wrote. “Pharmacological activity was confirmed following the administration of a single 500-mg dose and daily administration of 250 mg.” Corcept is now enrolling participants into a Phase 2 open-label trial (NCT02804750) to evaluate CORT125134 in patients with Cushing’s syndrome. This trial is being conducted in the United States and Europe and will include 80 participants. Top-line results are expected in the first quarter of 2018. From https://cushingsdiseasenews.com/2017/10/10/phase-1-data-demonstrates-efficacy-safety-of-cort125134-in-healthy-volunteers/
  16. Early and midterm nonremission after transsphenoidal surgery in people with Cushing’s disease may be predicted by normalized early postoperative values for adrenocorticotropic hormone and cortisol, study data show. Prashant Chittiboina, MD, MPH, assistant clinical investigator in the neurosurgery unit for pituitary and inheritable diseases at the National Institute of Neurological Diseases and Stroke at the NIH, and colleagues evaluated 250 patients with Cushing’s disease who received 291 transsphenoidal surgery procedures during the study period to determine remission after the procedure. Patients were treated between December 2003 and July 2016. Early remission was assessed at 10 days and medium-term remission was assessed at 11 months. Early nonremission was predicted by normalized early postoperative values for cortisol (P = .016) and by normalized early postoperative values for adrenocorticotropic hormone (ACTH; P = .048). Early nonremission was further predicted with 100% sensitivity, 39% specificity, 100% negative predictive value and 18% positive predictive value for a cutoff of –12 µg/mL in normalized early postoperative values for cortisol and with 88% sensitivity, 41% specificity, 96% negative predictive value and 16% positive predictive value for a cutoff of –40 pg/mL in normalized early postoperative values for ACTH. Medium-term nonremission was also predicted by normalized early postoperative values for cortisol (P = .023) and ACTH (P = .025). “We evaluated the utility of early postoperative cortisol and ACTH levels for predicting nonremission after transsphenoidal adenomectomy for Cushing’s disease,” the researchers wrote. “Postoperative operative day 1 values at 6 a.m. performed best at predicting early nonremission, albeit with a lower [area under the receiver operating characteristic curve]. Normalizing early cortisol and ACTH values to post-[corticotropin-releasing hormone] values improved their prognostic value. Further prospective studies will explore the utility of normalized very early postoperative day 0 cortisol and ACTH levels in identifying patients at risk for nonremission following [transsphenoidal surgery] in patients with [Cushing’s disease].” – by Amber Cox Disclosure: The researchers report no relevant financial disclosures. From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B7de200ed-c667-4b48-ab19-256d90a7bbc5%7D/postoperative-acth-cortisol-levels-may-predict-cushings-disease-remission-rate
  17. Scalp hair cortisol measurement is an accurate first-line diagnostic test for Cushing’s syndrome in adults and offers several advantages over other first-line diagnostic procedures, according to findings published in the European Journal of Endocrinology. “[Hair cortisol content] has practical advantages over currently used diagnostic tests, since sample collection can easily be performed in an outpatient setting and is not dependent on patient adherence to sampling instructions,” Elisabeth F. C. van Rossum, MD, PhD, professor at Erasmus MC, University Medical Center Rotterdam in the Netherlands, and colleagues wrote. “Furthermore, [hair cortisol content] measurement offers retrospective information about cortisol levels over months of time in a single measurement, thereby potentially circumventing the limitations posed by the variability in cortisol secretion in endogenous [Cushing’s syndrome].” Van Rossum and colleagues analyzed data from 43 patients with confirmed endogenous Cushing’s syndrome and 35 patients with suspected Cushing’s syndrome in whom diagnosis was excluded after testing (patient controls), all evaluated between 2009 and 2016 at an endocrinology outpatient clinic at Erasmus MC. Adults from a previously published validation study served as healthy controls (n = 174). Researchers measured scalp hair samples, 24-hour urinary free cortisol, serum cortisol and salivary cortisol, and used Pearson’s correlation to determine associations between hair cortisol content and first-line screening tests for Cushing’s syndrome. Hair cortisol content was highest in patients with Cushing’s syndrome (geometric mean, 106.9 pg/mg; 95% CI, 77.1-147.9) and higher compared with both healthy controls (mean, 8.4 pg/mg; 95% CI, 7-10) and patient controls (mean, 12.7 pg/mg; 95% CI, 8.6-18.6). Using healthy controls as the reference population, researchers found that the optimal cutoff for diagnosis of Cushing’s syndrome via hair cortisol content was 31.1 pg/mg; sensitivity and specificity were 93% and 90%, respectively (area under the curve = 0.958). Results were similar when using patient controls as the reference population, according to the researchers. Hair cortisol content was correlated with urinary free cortisol (P < .001), serum cortisol (P < .001) and late-night salivary cortisol (P < .001). In addition, in two patients with ectopic Cushing’s syndrome, researchers observed a gradual rise in hair cortisol content in the 3 to 6 months before disease diagnosis. “Together with a straightforward sample collection procedure, this method may prove to be a convenient noninvasive screening test for [Cushing’s syndrome],” the researchers wrote. “Additionally, our results indicate that hair cortisol measurements provide clinicians a tool to retrospectively assess cortisol secretion in patients with [Cushing’s syndrome], months to years back in time. This also offers the opportunity to estimate the onset of hypercortisolism and thus the duration of the disease before diagnosis.” – by Regina Schaffer Disclosure: The researchers report no relevant financial disclosures. From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B72da0183-e1a8-48cb-a1fd-332c7999beb5%7D/scalp-hair-cortisol-accurate-in-cushings-syndrome-diagnosis
  18. When we become stressed out bodies release cortisol – the stress hormone – which helps us cope with challenges. Cortisol’s role is to convert protein into energy by releasing glycogen and counteract inflammation. When cortisol is released in the body temporarily, this is okay and won’t have long-lasting detrimental effects to health as it is a natural response to a stressor. But when cortisol levels remain high chronically it can eventually begin to tear your body down thus causing health complications. This is why numerous health experts recommend the reduction of stress as much as possible because in the long run it can harm our health. High cortisol levels over the long term can destroy healthy muscle and bone, slow down healing, impair digestion, metabolism and mental function, and weaken the immune system. Additionally, adrenal fatigue has been linked to numerous other health conditions including fibromyalgia, hypothyroidism, chronic fatigue syndrome, arthritis, premature menopause, and many others. High cortisol levels are also associated with many unwanted symptoms which we will outline below. High cortisol symptoms If you’re concerned about your cortisol levels, the following signs and symptoms associated with high cortisol levels can alert you and prompt you to make the necessary changes in order to reduce cortisol levels. Unexplained weight gain Skin symptoms including acne, skin infections, lesions, thin-appearing skin, bruising, growing facial hair, and reddish purple streaks on skin Muscle and bone symptoms like a deep pain in the bones, weak muscles, chronic backaches, increased risk of bone fractures Gender specific changes such as women developing male-pattern hair growth, irregular menstrual cycles, low libido, infertility Neurological symptoms such as depression, irritability, headaches, chronic fatigue, and anxiety High blood pressure (hypertension) Poor sleep or lack of sleep Swelling of hands and feet If you notice any of the above symptoms, you may want to have your cortisol levels checked to confirm diagnosis. Living with high cortisol levels over the long term can have detrimental effects on a person’s health. Treating high cortisol as soon as possible can lower the risk of long-term health problems. Causes of high cortisol There are two main causes of high cortisol: Chronic stress and more rarely, Cushing’s disease. Cushing’s disease is caused by a hormone-secreting tumor on the adrenal gland which results in the release more cortisol than required. Living with chronic stress also leads to high cortisol because the release of cortisol is a natural response from the body when it is stressed. The hypothalamic–pituitary-adrenal [HPA] axis is what regulates the timely release of cortisol during acute stress, but when stress becomes chronic the feedback from the HPA becomes damaged and so cortisol continues to be released. Conditions that can contribute to chronic stress and high cortisol include: Depression Panic disorder Generalized anxiety disorder Post traumatic stress disorder (PTSD) Anorexia nervosa Bulimia nervosa Alcoholism Diabetes Severe obesity Metabolic syndrome Polycystic ovary syndrome (PCOS) Obstructive sleep apnea Working in shifts End-stage kidney disease Chronic pain Tips to lower high cortisol Here are some tips that can help you lower your high cortisol levels and thus prevent long-term health problems associated with high cortisol. [MaryO'Note: These will not work if you have active Cushing's! You must remove the source of your Cushing's first.] Eat a well balanced meal with plenty of fruits and vegetables, avoid sugars, consume low glycemic index foods, avoid processed foods, eat a wide variety of health foods to ensure you receive all essential vitamins and nutrients Exercise on a regular basis Take time out of each day to relax – listen to music, meditate, pray, perform your favorite hobby, anything that promotes relaxation Take up yoga or tai chi Ensure you are getting adequate sleep Drink tea Watch funny videos or hang out with a funny friend Go for a massage Do something spiritual – attend a service Chew gum Limit caffeine intake Stretch By incorporating these helpful tips into your life you will find that your high cortisol symptoms begin to diminish and your overall health begins to improve. From http://www.belmarrahealth.com/high-cortisol-symptoms-signs-look/
  19. Even after successful treatment, patients with Cushing’s disease who were older when diagnosed or had prolonged exposure to excess cortisol face a greater risk of dying or developing cardiovascular disease, according to a recent study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM). Cushing’s disease is a rare condition where the body is exposed to excess cortisol – a stress hormone produced in the adrenal gland – for long periods of time. Researchers have long known that patients who have Cushing’s disease are at greater risk of developing and dying from cardiovascular disease than the average person. This study examined whether the risk could be eliminated or reduced when the disease is controlled. Researchers found that these risk factors remained long after patients were exposed to excess cortisol. “The longer patients with Cushing’s disease are exposed to excess cortisol and the older they are when diagnosed, the more likely they are to experience these challenges,” said Eliza B. Geer, MD, of Mount Sinai Medical Center and lead author of the study. “The findings demonstrate just how critical it is for Cushing’s disease to be diagnosed and treated quickly. Patients also need long-term follow-up care to help them achieve good outcomes.” The study found cured Cushing’s disease patients who had depression when they started to experience symptoms of the disease had an elevated risk of mortality and cardiovascular disease. Men were more at risk than women, a trend that may be explained by a lack of follow-up care, according to the study. In addition, patients who had both Cushing’s syndrome and diabetes were more likely to develop cardiovascular disease. The study examined one of the largest cohorts of Cushing’s disease patients operated on by a single surgeon. The researchers retrospectively reviewed charts for 346 Cushing’s disease patients who were treated between 1980 and 2011. Researchers estimated the duration of exposure to excess cortisol by calculating how long symptoms lasted before the patient went into remission. The patients who were studied had an average exposure period of 40 months. The findings may have implications for people who take steroid medications, Geer said. People treated with high doses of steroid medications such as prednisone, hydrocortisone or dexamethasone are exposed to high levels of cortisol and may experience similar conditions as Cushing’s disease patients. “While steroid medications are useful for treating patients with a variety of conditions, the data suggests health care providers need to be aware that older patients or those who take steroid medications for long periods could be facing higher risk,” Geer said. “These patients should be monitored carefully while more study is done in this area.” From http://www.medicalnewstoday.com/releases/256284.php
  20. LA JOLLA, CA—Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing’s disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder. The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body’s 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing’s disease (CD). The findings were published in the May 6 early online edition of Proceedings of the National Academy of Sciences. “We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked,” says senior author Ronald M. Evans, a professor in Salk’s Gene Expression Laboratory and a lead researcher in the Institute’s Helmsley Center for Genomic Medicine. “TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD.” In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced. First described more than 80 years ago, Cushing’s disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations. While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases. Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing’s disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD. “Pituitary tumors are extremely difficult to control,” says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. “To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone.” Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. “Our discovery,” says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, “might lead clinicians to an existing drug that could be used to treat Cushing’s disease.” Source: Salk Institute
  21. Corcept Therapeutics (NASDAQ:CORT) announced that it would be ready to ship Korlym to patients by April 11th, three weeks ahead of the company’s previously announced launch date. “Cushing’s syndrome is a life altering and life threatening disease,” said Joseph K. Belanoff, M.D., the company’s Chief Executive Officer. “We have worked hard to bring this first-in-class treatment to patients as quickly as possible.” On February 17, 2012, the U.S. Food and Drug Administration (FDA) approved KorlymTM (mifepristone) 300 mg Tablets as a once-daily oral medicine to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. Physicians and patients seeking more information can visit http://www.korlym.com. Korlym is distributed in 300 milligram tablets to be taken once each day. The wholesale acquisition price of Korlym is $0.62 per milligram. The FDA-approved labeling instructs physicians to titrate each patient’s Korlym dose to clinical efficacy by assessing tolerability and degree of improvement in Cushing’s syndrome manifestations. In the first six weeks, these manifestations may include changes in glucose control, anti-diabetic medication requirements, insulin levels and psychiatric symptoms. After two months, assessment may also be based on improvements in cushingoid appearance, acne, hirsutism, striae or decreased body weight, along with further changes in glucose control. Patient Assistance Programs “Our highest priority is that every patient who is prescribed Korlym will receive it,” said Dr. Belanoff. To that end, the company has launched a comprehensive financial assistance and patient support program. A dedicated team of Corcept case managers will help patients understand their insurance benefits and the financial and medical support programs available to them. “Patients face tremendous challenges managing their illness – from finding physicians familiar with the disease to navigating the complexities of insurance reimbursement to paying for the cost of care,” said Dr. Belanoff. “We are determined that none of these barriers will keep patients from receiving the benefits of Korlym.” About Cushing’s Syndrome Endogenous Cushing’s syndrome is a rare and life-threatening endocrine disorder that results from long-term exposure to excess levels of the hormone cortisol. This excess is caused by tumors that usually occur in the pituitary or adrenal glands that over-produce, or prompt the over-production of, cortisol. Although cortisol at normal levels is essential to health, in excess it causes a variety of problems, including hyperglycemia, upper body obesity, a rounded face, stretch marks on the skin, an accumulation of fat on the back, thin and easily bruised skin, muscle weakness, bone weakness, persistent infections, high blood pressure, fatigue, irritability, anxiety, psychosis and depression. Women may have menstrual irregularities and facial hair growth, while men may have decreased fertility or erectile dysfunction. More than 70 percent of Cushing’s syndrome patients suffer from glucose intolerance or diabetes. The treatment of an endogenous Cushing’s syndrome patient depends on the cause. The first-line approach is surgery to remove the tumor. If surgery is not successful or is not an option, radiation may be used, but that therapy can take up to ten years to achieve full effect. Surgery and radiation are successful in only approximately one-half of all cases. If left untreated, Cushing’s syndrome has a five-year mortality rate of 50 percent. An orphan disease, Cushing’s syndrome occurs in about 20,000 people in the United States, mostly women between the ages of 20 and 50. About Korlym™ (mifepristone) 300 mg Tablets Korlym is a once-daily oral medication that blocks the glucocorticoid receptor type II (GR-II) to which cortisol normally binds. By blocking this receptor, Korlym inhibits the effects of excess cortisol in Cushing’s syndrome patients. The FDA has designated Korlym as an Orphan Drug, a special status designed to encourage the development of medicines for rare diseases and conditions. Because Korlym is an Orphan Drug, Corcept will have marketing exclusivity for the FDA-approved indication until February 2019. IMPORTANT SAFETY INFORMATION WARNING: TERMINATION OF PREGNANCY See full prescribing information for complete boxed warning. Mifepristone has potent antiprogestational effects and will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym, or if treatment is interrupted for more than 14 days in females of reproductive potential. Contraindications Pregnancy Use of simvastatin or lovastatin and CYP 3A substrates with narrow therapeutic range Concurrent long-term corticosteroid use Women with history of unexplained vaginal bleeding Women with endometrial hyperplasia with atypia or endometrial carcinoma Warnings and Precautions Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency. Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment. Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy. QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval. Use of Strong CYP3A Inhibitors: Concomitant use can increase plasma levels significantly. Use only when necessary and limit dose to 300 mg. Adverse Reactions Most common adverse reactions in Cushing’s syndrome (≥ 20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy. To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Drug Interactions Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Limit mifepristone dose to 300 mg per day when used with strong CYP3A inhibitors. CYP3A inducers: Do not use Korlym with CYP3A inducers. Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym. Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz. Hormonal contraceptives: Do not use with Korlym. Use in Specific Populations Nursing mothers: Discontinue drug or discontinue nursing. Please see the accompanying full Prescribing Information including boxed warning atwww.corcept.com/prescribinginfo.pdf Please see the accompanying Medication Guide at www.corcept.com/medicationguide.pdf About Corcept Therapeutics Incorporated Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. Korlym, a first generation GR-II antagonist, is the company’s first FDA-approved medication. The company has a portfolio of new selective GR-II antagonists that block the effects of cortisol but not progesterone. Corcept also owns an extensive intellectual property portfolio covering the use of GR-II antagonists, including mifepristone, in the treatment of a wide variety of psychiatric and metabolic disorders. The company also holds composition of matter patents for its selective GR-II antagonists. Statements made in this news release, other than statements of historical fact, are forward-looking statements. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances that clinical results will be predictive of real-world use, or regarding the pace of Korlym’s acceptance by physicians and patients, the reimbursement decisions of government or private insurance payers, the effects of rapid technological change and competition, the protections afforded by Korlym’s Orphan Drug Designation or by Corcept’s other intellectual property rights, and the cost, pace and success of Corcept’s other product development efforts. These and other risks are set forth in the Company's SEC filings, all of which are available from our website (www.corcept.com) or from the SEC's website (www.sec.gov). We disclaim any intention or duty to update any forward-looking statement made in this news release. CONTACT: Investor Contact Charles Robb Chief Financial Officer Corcept Therapeutics 650-688-8783
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