MaryO

Personal Stories: From my bio: (At the NIH in October 1987) The MRI still showed nothing, so they did a Petrosal Sinus Sampling Test. That scared me more than the prospect of surgery. (This test carries the risk of stroke and uncontrollable bleeding from the incision points.) Catheters were fed from my groin area to my pituitary gland and dye was injected. I could watch the whole procedure on monitors. I could not move during this test or for several hours afterwards to prevent uncontrollable bleeding from a major artery. The test did show where the tumor probably was located. Also done were more sophisticated dexamethasone suppression tests where drugs were administered by IV and blood was drawn every hour (they put a heplock in my arm so they don't have to keep sticking me). I got to go home for a weekend and then went back for the surgery... _____ From Karen's Story: https://cushingsbios.com/2016/11/18/doc-karen-pituitary-and-bla-bio/ At that time, there was evidence of a pit tumor but it wasn’t showing up on an MRI. So, I had my IPSS scheduled. An IPSS stands for Inferior Petrosal Sinus Sampling. It is done because 60 % of Cushing’s based pituitary tumors are so small that they do not show up on an MRI. Non Cushing’s experts do not know this so they often blow patients off, even after the labs show a high level of ACTH in the brain through blood work. An overproduction of the hormone ACTH from the pituitary communicates to the adrenal glands to overproduce cortisol. Well, the IPSS procedure is where they put catheters up through your groin through your body up into your head to draw samples to basically see which side of your pituitary the extra hormone is coming from, thus indicating where the tumor is. U of C is the only place in IL that does it. ... I was scheduled to get an IPSS at U of C on June 28th, 2011 to locate the tumor. Two days after the IPSS, I began having spontaneous blackouts and ended up in the hospital for 6 days. The docs out here had no clue what was happening and I was having between 4-7 blackouts a day! My life was in danger and they were not helping me! We don’t know why, but the IPSS triggered something! But, no one wanted to be accountable so they told me the passing out, which I was not doing before, was all in my head being triggered by psychological issues. They did run many tests. But, they were all the wrong tests. I say all the time; it’s like going into Subway and ordering a turkey sandwich and giving them money and getting a tuna sandwich. You would be mad! What if they told you, “We gave you a sandwich!” Even if they were to give you a dozen sandwiches; if it wasn’t turkey, it wouldn’t be the right one. This is how I feel about these tests that they ran and said were all “normal”. The doctors kept telling us that they ran all of these tests so they could cover themselves. Yet, they were not looking at the right things, even though, I (the patient) kept telling them that this was an endocrine issue and had something to do with my tumor! Well, guess how good God is?!!!! ... Fast forward, I ended up in the hospital with these blackouts after my IPSS. The doctors, including MY local endocrinologist told me there was no medical evidence for my blackouts. In fact, he told the entire treatment team that he even doubted if I even had a tumor! However, this is the same man who referred me for the IPSS in the first place! I was literally dying and no one was helping me! We reached out to Dr. Ludlam in Seattle and told him of the situation. He told me he knew exactly what was going on. For some reason, there was a change in my brain tumor activity that happened after my IPSS. No one, to this day, has been able to answer the question as to whether the IPSS caused the change in tumor activity. The tumor, for some reason, began shutting itself on and off. When it would shut off, my cortisol would drop and would put me in a state of adrenal insufficiency, causing these blackouts! Dr. Ludlam said as soon as we were discharged, we needed to fly out to Seattle so that he could help me! The hospital discharged me in worse condition then when I came in. I had a blackout an hour after discharge! But get this…The DAY the hospital sent me home saying that I did not have a pit tumor, my IPSS results were waiting for me! EVIDENCE OF TUMOR ON THE LEFT SIDE OF MY PITUITARY GLAND!!! _____ From Kirsty: https://cushingsbios.com/2013/06/25/kirsty-kirstymnz-ectopic-adrenal-bio/ The hardest of all these was what they call a petrusal vein sampling (this is where they insert a catheter into the groin through the femoral vein which goes up to the base of the brain to look at the pituitary, they do this while awake – I could actually feel them moving around in my head.) This test concluded that my Cushing’s was being caused by a tumor somewhere other than the pituitary (this only happens in 1% of cases, and there is about a 1 in 10 million chance of getting it). The question now was “where is the tumor?” _____ Find other bios with which mention this test at https://cushingsbios.com/tag/ipss/ __________ This topic on these message boards: https://cushings.invisionzone.com/forum/54-css-ct-ipss-ivp-mri-np-59-scan-octreoscan-pss-sonogram-ultrasound/ __________ Thoughts from Dr. James Findling: https://cushieblogger.com/2019/03/24/cushings-syndrome-expert-a-standout-in-clinical-practice/ Another defining moment in my career from a research perspective was when I was a fellow, I had to do a project. We were seeing a lot of patients with Cushing’s — of course, that’s why I went there — and in those days we had no good imaging. There were no CT scans, no MRI, there was no way to image the pituitary gland to find out whether there was a tumor. By the late ’70s it became obvious that some patients with Cushing’s syndrome didn’t have pituitary tumors. They had tumors in their lungs and other places, and there was no good way of sorting these patients from the pituitary patients. My mentor at UCSF, Blake Tyrrell, MD, had the idea of sampling from the jugular vein to see if there was a gradient across the pituitary. I took the project up because I didn’t think this is going to be helpful due to there being too much venous admixture in the jugular vein from other sources of cerebral venous drainage. We went into the radiology suite to do the first patient. As I was sampling blood from the peripheral veins, the interventional radiologist, David Norman, MD, says, “Would you like to sample the inferior petrosal sinus?” I said, “Why not? It sounds like a good idea to me.” That turned out to be helpful. We then studied several patients, and it eventually went to publication. Now everybody acknowledges it is necessary, maybe not in all patients with Cushing’s, but in many patients with Cushing’s to separate pituitary from nonpituitary Cushing’s syndrome. __________ Official information Patient information from Canterbury Health Limited Endocrine Services INFERIOR PETROSAL SINUS SAMPLING WITH CRH STIMULATION Introduction You have been diagnosed with Cushing's syndrome which results from excessive production of the hormone cortisol, made by the adrenal glands. In your case, the adrenal glands are being driven by excessive amounts of another hormone called ACTH. This test is to determine where that ACTH is coming from. Constant high levels of ACTH are usually caused by a tumor. Approximately 80% of cases are tumors of the pituitary gland while the remainder may occur in the lung, pancreas and other sites (known as "ectopic" sites). This test relies on the fact that if the source of your high ACTH is the pituitary gland blood levels taken from very near the gland will be higher than the blood level in an arm vein. Pituitary gland tumors are often tiny and can't be seen even with the most modern scanners. This test will help your endocrinologist to know with almost 100% certainty whether the pituitary gland is the source or if a search is needed elsewhere (for example in the lungs or abdomen). This guides treatment, for example the recommendation for Pituitary surgery. Procedure You are allowed water only from midnight the night before (nothing else to eat or drink). You will be given a light sedative, but will be awake during the procedure. You will be taken to the Radiology Department where the procedure will take place. The radiologist will place some local anesthetic into the groin on each side over the main vein that drains blood from each leg. Then a fine bore catheter will be passed up the vein, past the heart and into the major vein in the neck (the jugular vein). From there it is passed into a smaller vein that drains blood directly from the pituitary gland, known as the inferior petrosal sinus. The procedure is repeated for the other side. X-ray screening guides the radiologist to know where the catheters are positioned. A small butterfly needle is inserted into an arm vein. Once the catheters are in place, blood samples will be taken from the right and left petrosal sinus, and an arm vein at exactly the same time. After two baseline samples, a hormone called CRH is injected into the arm vein. This increases ACTH when a pituitary gland tumor is present, but has no effect on ectopic ACTH production. Further blood samples are taken for another 10 to 15 minutes, then the catheters are withdrawn. Pressure is applied to the groins to minimize bruising. Often sampling is continued from the arm vein only, for a total of 90 minutes. You will have to remain lying on your back for at least 2 hours afterwards. Risks This procedure is very safe when performed by an experienced radiologist. Rarely, there have been reports of people having a stroke at the time of this procedure but this was related to a catheter of faulty design which is now no longer used. Bruising, which is common in Cushing's syndrome, may occur after the catheters are pulled out. Some people notice flushing of the face after the CRH and rarely it can result in a fall in blood pressure. From: http://www.pituitarycenter.com/html/article1.html INFERIOR PETROSAL SINUS SAMPLING Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive. The inferior petrosal sinus sampling procedure is performed in the radiology department. With the patient on the angiography table both groin regions are partially shaved, sterilized, and a local anesthetic is injected into the skin to provide pain relief. A tiny incision is made within the skin and a needle is inserted to puncture the femoral vein which drains blood from the leg. A small catheter is then inserted into the vein and flushed with an intravenous solution. Longer catheters are passed into the shorter catheters and advanced through the large veins traversing the torso into the neck and then into the base of the skull. Thereafter, a microcatheter is advanced through each of these larger guiding catheters and threaded into the inferior petrosal sinuses which lie along the internal aspect of the skull base and drain blood from the pituitary gland. Once these microcatheters have been positioned, contrast dye is injected and X-rays are taken to verify their position in the inferior petrosal sinuses. Next, blood samples are collected from both catheters in the inferior petrosal sinuses and from a peripheral (usually arm) vein. Thereafter, corticotropin-releasing hormone is administered through the peripheral vein. Repeat blood samples are drawn 2, 5, and 10 minutes after the injection. Additional X-rays are taken to confirm that the catheters were not dislodged from their site during the sampling procedure. Thereafter, the catheters are removed and direct pressure is applied to the groin region to decrease the likelihood of bruising. Patients are observed for 4 hours following the procedure to ensure that no bleeding from the femoral vein puncture sites will occur. Normal non-strenuous activity may be resumed 48 hours after the procedure. Sedatives and pain relievers may be administered during the procedure as necessary. A blood thinner might be used depending on the patient's anatomy and the clinical suspicion of developing a blood clot. If a blood thinner is used, this may be counteracted with medication at the conclusion of the procedure to ensure that normal blood clotting resumes while removing the catheters. Overall, the inferior petrosal sinus sampling procedure involves minimal discomfort. The risks of the procedure are small. X-rays are used but the radiation doses are minimized. Infection is controlled by using sterile technique. Some patients might have an unexpected allergic reaction to the dye used during the study. A bruise may develop within the groin. Although rare, blood clots have developed in the groin veins following this procedure. Again, steps are taken to minimize the likelihood of each and every one of these complications. ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source. ___ From: http://www.mc.vanderbilt.edu/pituitarycenter/html/article1.html Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive. The inferior petrosal sinus sampling procedure is performed in the radiology department. With the patient on the angiography table both groin regions are partially shaved, sterilized, and a local anesthetic is injected into the skin to provide pain relief. A tiny incision is made within the skin and a needle is inserted to puncture the femoral vein which drains blood from the leg. A small catheter is then inserted into the vein and flushed with an intravenous solution. Longer catheters are passed into the shorter catheters and advanced through the large veins traversing the torso into the neck and then into the base of the skull. Thereafter, a microcatheter is advanced through each of these larger guiding catheters and threaded into the inferior petrosal sinuses which lie along the internal aspect of the skull base and drain blood from the pituitary gland. Once these microcatheters have been positioned, contrast dye is injected and X-rays are taken to verify their position in the inferior petrosal sinuses. Next, blood samples are collected from both catheters in the inferior petrosal sinuses and from a peripheral (usually arm) vein. Thereafter, corticotropin-releasing hormone is administered through the peripheral vein. Repeat blood samples are drawn 2, 5, and 10 minutes after the injection. Additional X-rays are taken to confirm that the catheters were not dislodged from their site during the sampling procedure. Thereafter, the catheters are removed and direct pressure is applied to the groin region to decrease the likelihood of bruising. Patients are observed for 4 hours following the procedure to ensure that no bleeding from the femoral vein puncture sites will occur. Normal non-strenuous activity may be resumed 48 hours after the procedure. Sedatives and pain relievers may be administered during the procedure as necessary. A blood thinner might be used depending on the patient's anatomy and the clinical suspicion of developing a blood clot. If a blood thinner is used, this may be counteracted with medication at the conclusion of the procedure to ensure that normal blood clotting resumes while removing the catheters. Overall, the inferior petrosal sinus sampling procedure involves minimal discomfort. The risks of the procedure are small. X-rays are used but the radiation doses are minimized. Infection is controlled by using sterile technique. Some patients might have an unexpected allergic reaction to the dye used during the study. A bruise may develop within the groin. Although rare, blood clots have developed in the groin veins following this procedure. Again, steps are taken to minimize the likelihood of each and every one of these complications. ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source. ___ From https://www.uclahealth.org/radiology/interventional-neuroradiology/inferior-petrosal-sinus-sampling The IPSS test is done in some patients to identify if there is too much ACTH is causing the excess production of cortisol, and where it is coming from. How do we do an IPSS procedure? Typically under general anesthesia, we place small tubes (catheters) into the femoral veins (the main vein draining the legs) at the level of the groin. From there, under X-ray guidance, we navigate those catheters to the main veins which drain the Pituitary gland. These are the inferior petrosal sinuses (right and left). We then draw samples from those veins and the main vein of the abdomen and test those samples for ACTH. We also take timed samples after giving a dose of medication which would normally stimulate the production of ACTH to improve the sensitivity of the test. When we get the results, the different levels of ACTH may help the endocrinologist determine where the tumor is located that is causing the adrenal gland to produce the excess cortisol. If it is from the Pituitary gland, any difference between the right and left samples may help the surgeon determine the surgical plan to remove the tumor yet preserve the normal Pituitary gland. Example of testing results: Time Right IPS Left IPS Inf Vena Cava Cortisol Baseline 1 09:32 40 pg/ml 17 18 25 mcg/dl Baseline 2 09:34 45 18 15 24 DDAVP inj 09:38 Post 2min 09:40 72 21 18 Post 5min 09:43 157 20 19 Post 10min 09:48 161 30 25 Post 15min 09:53 162 33 26 Post 30min 10:08 124 32 29 30 This example shows elevation of ACTH in the right inferior petrosal sinus, likely indicating a tumor in the right side of the pituitary gland causing Cushing’s Disease. Picture of contrast injection of the inferior petrosal sinuses: Tips of the catheters in the inferior petrosal sinuses.

Kate** on the Cushing’s support board (Cushing’s Help and Support) wrote this letter after having pituitary surgery… Dear friends and family: I am writing this letter to share with you some basic facts about Cushing’s Disease/Syndrome and the recovery process so that you will have sufficient information to form realistic expectations about me and my ability to engage in certain activities in light of this disease and its aftermath. As you know, Cushing’s is a rarely diagnosed endocrine disorder characterized by hypercortisolism. Cortisol is a hormone produced by the adrenal glands and is vital to regulate the body’s cardivoascular functions and metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to stress. The adrenal glands release cortisol in response to stress, so atheletes, women experiencing pregnancy, and those suffering from alcoholism, panic disorders and malnutrition naturally have higher-than-normal levels of cortisol. People with Cushing’s Syndrome live life with too much cortisol for their bodies as a result of a hormone-secreting tumor. Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the body in a constant state of “fight or flight,” which ravages the body and tears down the body’s major systems including cardivascular, musculo-skeletal, endocrine, etc. Symptoms vary, but the most common symptoms include rapid, unexplained weight gain in the upper body with increased fat around the neck and face (“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the arms and legs; purplish striae (stretch marks) on the abdomen, thighs, buttocks, arms and breasts; poor wound healing and bruising; severe fatigue; depression, anxiety disorders and emotional lability; cognitive difficulties; sleep disorders due to abnormally high nighttime cortisol production; high blood pressure and high blood sugar/diabetes; edema; vision problems; premature osteoperosis; and, in women, signs of hyperandrogenism such as menstrual irregularities, infertility, hirsutism, male-patterned balding and steroid-induced acne. Cushing's Symptoms http://www.cushings-info.com/images/1/12/Lady.gif A sketch of a typical Cushing’s patient. As you can see, the effects of the disease on the body are dramatic. Worse, the psychological and emotional effects of having a chronic, debilitating and disfiguring disease range from distressing to demoralizing. Imagine that, in the space of a year, you became unrecognizable to those around you and to yourself. You look in the mirror, but the person staring back a tyou is a stranger. You endure the stares and looks of pity from those who knew you before Cushing’s, fully aware that they believe you have “let yourself go” or otherwise allowed this to happen to your body. Nothing you can say or do will persuade them otherwise, so at some point, you stop trying and resolve to live your life in a stranger’s body. You feel increasingly sick, but when you explain your array of symptoms to your doctor, you are dismissed as a depressed hypochondriac who needs to diet and exercise more. Worse, your family members think the same thing — and are often quick to tell you how you need to “change your lifestyle” to overcome the effects of what you eventually will discover, once properly diagnosed, is a serious and rare disease. If only it were so simple! No one would choose to have Cushing’s. Those of us who have it would not wish it even on our worst enemy. Most people with Cushing’s long for the ability to do simple things, like walk a flight of stairs without having to sit for half an hour afterwards, or vacuum the house or even unload a dishwasher. One of the worst parts about this disease is the crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism. Not only do we become socially isolated because of the virilzing effects of an endocrine tumor, which drastically alters our appearance, but we no longer feel like ourselves with regard to energy. We would love to take a long bike ride, run three miles or go shopping like we used to — activities, which we took for granted before the disease struck. Those activities are sadly impossible at times for those with advanced stages of the disease. Sometimes, as with any serious illness, performing even basic tasks of daily care such as showering and dressing can exhaust the limited reserves of energy available to a Cushing’s patient. How do we explain to you what it’s like to watch our lives slip away? What response is sufficient to express the grief and frustration over losing so much of ourselves? It is often difficult to find the strength to explain how your well-meaning words of prompting and encouragement (to diet or exercise) only serve to leave us more isolated and feeling alone. Though we wouldn’t want it, we wish our disease were as well-understood as cancer so that those who love us would have a frame of reference for what we go through. With Cushing’s, there is such limited public awareness that we are left to describe the effects of the disease from a void, often with limited understanding from those who love us most, which is disheartening. The most frustrating misconception about this disease is that we somehow are “doing this to ourselves,” or delaying recovery because we need to continue steroid replacement or lack the energy to excercise often, which is sadly false. Trust me that we would love to have that much control over such a terrible disease. Fortunately, there is a good likelihood of remission from Cushing’s in the hands of a skilled pituitary surgeon. Unfortunately, the long-term remission rate is only 56%, meaning that 44% of people with Cushing’s will require a second (sometimes third) pituitary surgery, radiation or bilateraly adrenalectomy to resolve the hypercortisolism. Without successful treatment, Cushing’s leads to death. Even with successful treatment, I will have to be monitored for possible recurrence for the rest of my life. After surgery or other treatment, the recovery period can last months or even years. Because the tumor takes over control of the body’s production of cortisol, the adrenal glands, which had lain dormant prior to surgery, require time to start functioning properly again. Until this happens, we must take synthetic steroids or else risk adrenal insufficiency or adrenal crisis, which can be quickly life-threatening. Careful monitoring of our cortisol levels is critical during the weaning period. It is a rare but sad fact that some people’s adrenal glands never return to normal, and those people must continue to take hydrocortisone or prednisone — sometimes for life — simply in order for the body to perform correctly its basic systemic functions. The physical recovery from surgery can be quick, but the withdrawal from hydrocortisone can be a lengthy and extremely painful process. As I described above, Cushing’s causes a tearing-down of muscles and bone. While there is an over-abundance of cortisol in our bodies (as a result of the tumor), we often can’t feel the effects of the muscle-wasting and bone deterioration because of the anti-inflammatory action of cortisol. Upon weaning, however, these become painfully (literally!) evident. The physical pain experienced while weaning from cortisol has been described as worse than weaning from heroin. When cortisol levels are low, one experiences the symptoms akin to a really bad flu, including severe fatigue (”like a wet cement blanket laid on top of me”); weakness and exhaustion; nausea; headache; vomiting; mental confusion. It is imperative for people who are on replacement steroids after Cushing’s surgery to carry extra Cortef (or injectable Solu-Cortef) with them at all times in addition to wearing a medic alert bracelet so that medical professionals will be alerted to the possiblity of adrenal insufficiency in the event of an adrenal crisis. People who have struggled with Cushing’s Syndrome all hope to return to “normal” at some point. Though none of us want to have Cushing’s, it is often a relief finally to have a correct diagnosis and treatment plan. For many, there is a gradual resolution of many Cushing’s symptoms within a few years of surgery or other successful treatment, and a good quality of life can be achieved. But regrettably, this is not possible in every case. Depending on the severity of the disease and the length of time before diagnosis and treatment, the prognosis can be poor and lead to shortened life expectancy and diminished quality of life. This is not a choice or something we can control, but it is the reality for some people who have suffered the consequences of long-term hypercortisolism. The best support you can give someone who is suffering from Cushing’s or its aftermath is to BELIEVE them and to understand that they are not manufacturing their illness or prolonging recovery. Ask them what they are able (and not able) to do, and then be prepared to help them in ways that matter — whether that be to bring them a meal or help them to run errands, pick up prescriptions from the pharmacy or clean their house. Because it’s these little everyday tasks, which can fall by the wayside when someone has (or has had) Cushing’s, and these are the things we miss the most: doing for ourselves. Ask us questions about the disease, and then actively listen to what we say. We know you don’t know much about Cushing’s — even our doctors sometimes lack information about this rare disease. But know we appreciate the interest and will tell you everything you want to know, because those of us who have it necessarily become experts in it just in order to survive. Thank you for caring about me and for hearing what I am saying in this letter. I know you love me and are concerned about me, and I appreciate that so much. Thank you also for taking the time to read this letter. I look forward to discussing further any questions you might have. In the meantime, I am attaching a brief article written by a woman who recently was diagnosed with Cushing’s. I hope hearing another person’s experiences will help you to understand what I’m going through so that when we talk, we will be coming from a similar starting place. Endocrinologists (doctors who specialize in Cushing's Syndrome and its related issues) realize the medical aspect and know the damaging effects that Cushing's has on the body. Family and friends see their Cushie suffering and know they are hurting physically and often times mentally and emotionally. However, understanding the debilitation of Cushing's and how it can affect every aspect of a person's life can only be truly realized by those who have experienced the syndrome. Cushings Help Organization, Inc., a non-profit family of websites maintained by MaryO, a pituitary Cushing's survivor, provides this letter for patients to provide to their family and friends in hopes of providing a better understanding Cushing's and it's many aspects. We're sorry to hear that your family member or friend has Cushing's Syndrome or suspected Cushing's. A person may feel better at times then at other times. It's common for a Cushing's patient to have burst of energy and then all of a sudden they become lethargic and don't feel like moving a muscle. There are many symptoms that are associated with Cushing's. They include weight gain, fatigue, muscle weakness, shortness of breath, feeling achy all over, headaches, blurred vision, mood swings, high blood pressure, stretch marks (straie), buffalo hump, diabetes, edema and the list goes on. Hormones affect every area of the body. It is important to note that not all patients have every symptom. Even some hallmark symptoms, such as straie or the "buffalo hump", may not be noticable on every patient. Not everyone who has Cushing's will experience the same symptoms, treatment, or recovery. Because not all "Cushies" have these symptoms, it makes diagnosis even more difficult. Cushing's can cause the physical appearance change due to weight gain, hair loss, rosacea, acne, etc. This can be very disturbing when looking in the mirror. Changes in appearance can often cause the Cushing's patient to withdraw from family and friends making it a very lonely illness. Patients often feel alone or withdrawn because few others understand. Cushing's can affect affect anyone of any age although it is more commen in women. Cushing's patients need to be able to take one day at time and learn to listen to their bodies. There will most likely be times when naps are needed during the day and often times may not be able to sleep at night due to surges of cortisol. Your Cushie doesn't expect you to understand Cushing's Syndrome completely. They do need you to be there for them and try to understand to the best of your ability what they feel and not give up on them. Often a Cushing's patient may be moody and say things that they don't mean. If this should happen with your Cushie try not to take it personally and know that it's most likely caused by the elevated cortisol and disturbances in other hormone levels caused by the Cushing's and not from the heart or true feelings of your Cushie. It can be very depressing and frustrating having so many limitations and experience things in life being taken from you. Cushing's patients are sick, not lazy, not hypochondriacs or even the newer term "Cyberchondriacs". If a Cushing's patient says they don't feel like doing something or they express how bad they feel let them know that you believe them. One of the most frustrating things to someone who is sick is to have those you love not believe you or support you. Telling a Cushie to think positive thoughts will not make him/her well and will just be aggrivating. Testing procedures can be lengthy and this can become frustrating for the patient and family. Often, it takes a while for results to come back and this can be stressful. Don't look to far ahead just take one day at a time and deal with the situation that is at hand at the present time. After a diagnosis is made then it's time for treatment. Surgery is usually the best treatment option for Cushing's that is caused by tumors. Don't be surprised if the surgeon's facility wants to run even more tests or redo some of those that have already been done. Your Cushie may have to travel a ways to find a surgeon who is trained in these delicate surgeries and who has performed many of them. Once the diagnosis has been made and treatment has finished then it's time for the recovery process. Not all patients who have surgery are cured and they have to make a choice along with the advice of their doctor as to what their next treatment option will be. The recovery from the surgery itself is similar to any other surgery and will take a while to recover. The recovery process obtained from getting a cure from Cushing's is quiet different from other surgeries. A Cushing's patients body has been exposed to excess cortisol, usually for quite a long time, and has become accustomed it. When the tumor is removed that has been responsible for the excessive cortisol and the body is no longer getting it this causes the body to have withdrawal symptoms. Withdrawal can be very hard causing an array of symptoms muscle aches, weakness, bone and joint pain, emotional disturbances etc. Thank you for reading this and we hope it will help you to understand a little more about Cushing's and the dibilating affect it can have on a person. Thank you for being there and supporting your Cushie during this time in their life. We realize that when a family member has Cushing's it not only affects the individual but other family members and those around them as well. Showing your love and support will encourage a speedy recovery for your Cushie. **Note: Kate died on on June 23, 2014. Read her In Memory page here: http://cushingsbios.com/2014/06/25/in-memory-kate-meyers/

Abstract Background The most common etiologies of Cushing's syndrome (CS) are adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients. Methods A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009–2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups. Results Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, P = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, LDL-C, HDL-C, triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two. Conclusions Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics. Keywords Cushing's syndrome Pituitary Cushing's Adrenal Cushing's Metabolic disturbance From https://www.sciencedirect.com/science/article/pii/S2095882X21000669

I really don't understand why they aren't removing the adrenal gland, then - is she doing testing with an endocrinologist, Bizzyusual? She would need to be diagnosed with Cushing's before they do anything with the adrenal tumor and that means testing, sometimes lots of it. I hope she sees that and gets started with endo appointments. Thanks for being good parents-in-law!

https://doi.org/10.1016/j.radcr.2021.07.093 Abstract The chronic excess of glucocorticoids results in Cushing's syndrome. Cushing's syndrome presents with a variety of signs and symptoms including: central obesity, proximal muscle weakness, fatigue striae, poor wound healing, amenorrhea, and others. ACTH independent Cushing's syndrome is usually due to unilateral adenoma. A rare cause of it is bilateral adrenal adenomas. In this paper we report a case of a 43-year-old woman with Cushing's syndrome due to bilateral adrenal adenoma. Read the case report at https://www.sciencedirect.com/science/article/pii/S1930043321005690

The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background. Introduction Endogenous Cushing´s syndrome (CS) is a rare disorder with an incidence of 0.2–5.0 per million people per year (1, 2). The predominant subtype (accounting for about 80%) is adrenocorticotropic hormone (ACTH)-dependent CS. The vast majority of this subtype is due to an ACTH-secreting pituitary adenoma [so called Cushing´s disease (CD)], whereas ectopic ACTH-secretion (e.g. through pulmonary carcinoids) is much less common. In contrast, ACTH-independent CS can mainly be attributed to cortisol-producing adrenal adenomas. Adrenocortical carcinomas, uni-/bilateral adrenal hyperplasia, and primary pigmented nodular adrenocortical disease (PPNAD) may account for some of these cases as well (3, 4). Coexistence of different subtypes of endogenous CS in single individuals is even rarer but has been described in few reports. These cases were usually observed in the context of prolonged ACTH stimulation on the adrenal glands, resulting in micronodular or macronodular hyperplasia (5–9). A sequence of CD and PPNAD was also described in presence of Carney complex, a genetic syndrome characterized by the loss of function of the gene encoding for the regulatory subunit type 1α of protein kinase A (PRKAR1A) (10). Moreover, another group reported the case of a patient with Cushing's disease followed by ectopic Cushing's syndrome more than 30 years later (8). To our knowledge, however, we here describe the first case report on a single patient with a cortisol-producing adrenocortical adenoma and subsequent CD. Read the rest of the article at https://www.frontiersin.org/articles/10.3389/fendo.2021.731579/full

Urine Tests: These involve collecting urine, usually for periods of twenty-four hours at a time. Twenty-four Hour Urine: The doctor will give you a gallon collection jug, usually with boric acid in it. The instructions are usually printed on the side. Generally, you urinate first thing in the morning, as usual. after that, you collect the rest of the urine for the next 24 hours in the jug. The directions usually tell you to refrigerate the jug. Directions for the Twenty-four Hour Urine Test Physicians have always relied upon analysis of urine specimens in order to diagnosis and treat many disease processes. Twenty-four hour urine collections are often employed to estimate the production rates of various hormones. The accuracy of test results depends entirely on the accuracy of the urine collection technique. These instructions are provided as a guide to ensure that your 24-hour urine collection is obtained in a manner that will permit reliance upon the test results. Urine samples should be collected in a large cup, urine collection hat or other container and then poured into the large bottle. Do not try to urinate directly into the bottle. Void urine prior to bowel movements in order to avoid losing urine that might normally be passed during a bowel movement. Urine collection hats can usually be purchased at medical supply stores if not provided by your physician or lab. If you should have a bowel movement while urinating the urine collection hat should keep the urine clean if used correctly. Urine samples should be collected in a large cup or other container and then poured into the large bottle. Do not try to urinate directly into the bottle. Void urine prior to bowel movements in order to avoid losing urine that might normally be passed during a bowel movement. Some patients are asked to collect more than one consecutive 24-hour urine sample. If that is the case, you should complete the first collection as instructed. Then, begin the second collection by adding any urine made in the next 24-hours to the second bottle. You should not discard any urine when starting the second or any subsequent collections. Simply change bottles at the stop and start times after adding that last sample required to complete the previous collection. The bottles for some tests contain a weak acid as a preservative. Do not discard the acid. If you accidentally get acid or urine from the bottle on your skin or clothing, rinse the effected area immediately with plenty of cold water. Collection bottles must be refrigerated. This is best accomplished by using an ice chest, cooler, or if so inclined, your refrigerator. If you forget to collect all of the urine or perform the test improperly, discard the specimen and start again on another day. If the bottle contained an acid preservative, you will need to obtain a new bottle from the laboratory or your physician's office. Otherwise, you may reuse the bottle after rinsing it with distilled water. Finally, please remember to call your physician, medical provider or nurse if you have any questions about the proper collection of a 24-hour urine sample. This Topic on the Message Boards.

Cushing’s syndrome is a rare disorder that occurs when the body is exposed to too much cortisol. Cortisol is produced by the body and is also used in corticosteroid drugs. Cushing's syndrome can occur either because cortisol is being overproduced by the body or from the use of drugs that contain cortisol (like prednisone). Cortisol is the body’s main stress hormone. Cortisol is secreted by the adrenal glands in response to the secretion of adrenocorticotropic hormone (ACTH) by the pituitary. One form of Cushing’s syndrome may be caused by an oversecretion of ACTH by the pituitary leading to an excess of cortisol. Cortisol has several functions, including the regulation of inflammation and controlling how the body uses carbohydrates, fats, and proteins. Corticosteroids such as prednisone, which are often used to treat inflammatory conditions, mimic the effects of cortisol. Stay tuned for more basic info...

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

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

As of September 1, 2021, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for the coronavirus disease 2019 (COVID-19), has infected over 219 million and caused the deaths of over 4.5 million worldwide. Although COVID-19 has been traditionally associated with its ability to cause varied symptoms resembling acute respiratory distress syndrome (ARDS), emerging scientific evidence has demonstrated that SARS-CoV-2 causes much more damage beyond its effects on the upper respiratory tract. To this end, in a recent study published in Reviews in Endocrine and Metabolic Disorders, the researchers discuss the extra-pulmonary manifestations of COVID-19. Risk factors for severe COVID-19 It is now a well-known fact that the likelihood of people falling severely ill or dying from COVID-19 is increases if these individuals are obese, or have certain comorbidities like diabetes mellitus (DM), vitamin D deficiency, and vertebral fractures (VFs). Any abnormality in the pituitary gland may lead to metabolic disorders, impaired immunity, and a host of other conditions that also make the body susceptible to infections. Since such conditions are common in patients with COVID-19 as well, it has been hypothesized that there might be a relationship between COVID-19 and pituitary gland disorders. On the other hand, researchers have also observed that COVID-19 causes increased severity of pituitary-related disorders, and even pituitary apoplexy, which is a condition defined as internal bleeding or impaired blood supply in the pituitary gland. A group of Italian researchers has reviewed this bidirectional relationship between the pituitary gland abnormalities and COVID-19 in their study recently published in Reviews in Endocrine and Metabolic Disorders. The link between pituitary gland abnormalities and COVID19 The pituitary gland releases hormones that regulate and control some of the most important functions of the body like growth, metabolism, energy levels, bone health, mood swings, vision, reproduction, and immunity, to name a few. The inability of the pituitary gland to release one or more of these hormones is known as ‘hypopituitarism.’ Factors responsible for hypopituitarism include traumatic brain injury, pituitary adenomas (tumors), genetic mutations, as well as infiltrative and infectious diseases. Hypopituitarism can lead to severe cases of DM, growth hormone deficiency (GHD), abnormal lipid profile, obesity, arterial hypertension, and immune dysfunctions. Interestingly, similar consequences of COVID-19 have also been reported. SARS-CoV-2 infects the human body by binding to a special class of receptors known as the angiotensin-converting enzyme 2 (ACE2) receptors. These receptors are located in the endothelial linings of most organs like the brain, heart, lungs, kidneys, intestine, liver, and pancreas, among others. The main function of the ACE2 receptors is binding to specific target molecules to maintain the renin-angiotensin system that is crucial for regulating dilation of blood vessels, as well as maintain blood glucose levels, the immune system, and homeostasis. Therefore, SARS-CoV-2 binding to these ACE2 receptors facilitates the entry of this virus into all the organs that have these receptors, thus leading to the ability of SARS-CoV-2 to cause widespread damage in the body. Upon entry into the pancreas, for example, SARS-CoV-2 can inhibit ß-cells function, which worsens hyperglycemia and increases the risk for acute diabetic complications. Similarly, the presence of ACE2 receptors in brain tissues may cause invasion into the pituitary gland and lead to pituitary apoplexy. The entry of SARS-CoV-2 into the brain can also cause neurological damage in infected patients, which may account for some of the common neurological complaints of COVID-19 including headaches, confusion, dysgeusia, anosmia, nausea, and vomiting. Study findings Hypopituitarism leading to metabolic syndrome has been scientifically linked to higher mortality in COVID-19 patients. In fact, the presence of a single metabolic syndrome component has been observed to double the risk of death by COVID-19. This risk was even higher among patients with DM and hypertension. There was also an increased incidence of VFs in COVID-19 patients with hypopituitarism. Hence, patients with DM, obesity, hypertension, and chronic inflammatory disease, are all at an increased risk of poor outcomes and death in COVID-19. Arterial hypertension is a common finding in adults with GHD, which is another consequence of hypopituitarism. Hypopituitarism also causes adrenal insufficiency, a condition that is primarily managed with glucocorticoids and hormonal replacement therapies. Notably, patients with COVID-19 are often treated for prolonged periods with high-dose exogenous glucocorticoids, which is a class of steroids that suppress some activities of the immune system. This treatment approach may result in suppression of the hypothalamic-pituitary–adrenal axis that can lead to adrenal insufficiency. Hypogonadism is another aspect of pituitary insufficiency that predisposes patients, especially males, to COVID-19. Evidence shows that males with hypogonadism were more frequently affected by metabolic syndrome. Pituitary apoplexy, albeit rare, has also been linked to COVID-19, especially in patients with pituitary adenomas and those who are being treated with anticoagulant therapy. This may be because the pituitary gland becomes overstimulated during an infectious disease, which may increase pituitary blood demand and lead to sudden infarction precipitating acute apoplexy. This phenomenon has also been shown in patients suffering from infectious diseases that cause hemorrhagic fevers. Taken together, pituitary apoplexy complicates treatment and management procedures in COVID-19 patients. Despite the use of steroids in COVID-19 patients, there have been no contraindications for vaccination in such patients. However, those on extensive hormonal therapies need constant monitoring for best results. Implications The pituitary gland acts like a double-edged sword for COVID-19. On one end, hypopituitarism predisposes patients to metabolic disorders like DM, obesity, and VFs, all of which are known risk factors for COVID-19. On the other hand, COVID-19 may cause direct or indirect damage to the pituitary glands by entering the brain and inducing unfavorable vascular events – though evidence on this remains lesser in comparison to that of hypopituitarism. Ultimately, the researchers of the current study conclude that managing patients with hormonal insufficiencies optimally with steroids is likely to improve outcomes in severe COVID-19. Journal reference: Frara, S., Loli, P., Allora, A., et al. (2021). COVID-19 and hypopituitarism. Reviews in Endocrine and Metabolic Disorders. doi:10.1007/s11154-021-09672-y. https://rd.springer.com/article/10.1007/s11154-021-09672-y#citeas. From https://www.news-medical.net/news/20210905/Hypopituitarism-and-COVID-19-e28093-exploring-a-possible-bidirectional-relationship.aspx

Seems that this isn't just for pediatric patients!

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

This article was originally published here J Clin Endocrinol Metab. 2021 Jul 29:dgab557. doi: 10.1210/clinem/dgab557. Online ahead of print. ABSTRACT CONTEXT: Coronavirus disease 2019 (COVID-19) is a proinflammatory and prothrombotic condition, but its impact on adrenal function has not been adequately evaluated. CASE REPORT: A 46-year-old woman presented with abdominal pain, hypotension, and skin hyperpigmentation after COVID-19 infection. The patient had hyponatremia, serum cortisol <1.0 µg/dL, adrenocorticotropin (ACTH) of 807 pg/mL, and aldosterone ❤️ ng/dL. Computed tomography (CT) findings of adrenal enlargement with no parenchymal and minimal peripheral capsular enhancement after contrast were consistent with bilateral adrenal infarction. The patient had autoimmune hepatitis and positive antiphospholipid antibodies, but no previous thrombotic events. The patient was treated with intravenous hydrocortisone, followed by oral hydrocortisone and fludrocortisone. DISCUSSION: We identified 9 articles, including case reports, of new-onset adrenal insufficiency and/or adrenal hemorrhage/infarction on CT in COVID-19. Adrenal insufficiency was hormonally diagnosed in 5 cases, but ACTH levels were measured in only 3 cases (high in 1 case and normal/low in other 2 cases). Bilateral adrenal nonhemorrhagic or hemorrhagic infarction was identified in 5 reports (2 had adrenal insufficiency, 2 had normal cortisol levels, and 1 case had no data). Interestingly, the only case with well-characterized new-onset acute primary adrenal insufficiency after COVID-19 had a previous diagnosis of antiphospholipid syndrome. In our case, antiphospholipid syndrome diagnosis was established only after the adrenal infarction triggered by COVID-19. CONCLUSION: Our findings support the association between bilateral adrenal infarction and antiphospholipid syndrome triggered by COVID-19. Therefore, patients with positive antiphospholipid antibodies should be closely monitored for symptoms or signs of acute adrenal insufficiency during COVID-19. PMID:34463766 | DOI:10.1210/clinem/dgab557

Dr. Friedman is getting a lot of emails on booster shots versus third shots. Third shots are for immuno-compromised patients that the FDA is recommending for a small group of patients The FDA also has the intention to soon make booster doses widely available to all healthy individuals. I am writing to clarify the difference between booster shots and third doses. Third Doses for Immuno-Compromised Patients The purpose of a third dose of mRNA vaccine is to give immuno-compromised patients the same level of protection that two doses provide someone who has a normal immune system. It is recommended that the following people get a third dose Been receiving cancer treatment for tumors or cancers of the blood Received an organ transplant and are taking medicine to suppress the immune system Received a stem cell transplant within the last two years or are taking medicine to suppress the immune system Been diagnosed with moderate or severe immunodeficiency conditions (such as DiGeorge syndrome, Wiskott-Aldrich syndrome) An advanced or untreated HIV infection Been under active treatment with high-dose corticosteroids (> 20 mg of prednisone or 100 mg of hydrocortisone) or other drugs that may suppress immune response Dr. Friedman thinks it is unlikely that any of his patients have these conditions. Patients with Cushing’s syndrome, Addison’s, diabetes or thyroid disorders do not qualify. In contrast, a Booster Dose is for Patients With Healthy Immune Systems A booster dose—which is different from a third dose for immuno-compromised patients—is for healthy patients and is meant to enhance immunity and may protect against new variants of the virus. The Biden administration has announced that it intends to make booster doses available for people with healthy immune systems in September 2021, after they are authorized or approved by the FDA. This has not happened yet, but when it happens, Dr. Friedman would encourage his patients to get it. Dr. Friedman is expecting a booster shot against the Delta variant to be released in the fall of 2021 and would recommend that for his patients. Dr. Friedman wishes everyone to stay healthy.

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.

1) Visit RareVoiceAwards.org 2) Review the 2021 RareVoice categories 3) Nominate an advocate who gave rare disease patients a voice on Capitol Hill and in state government in 2020 and 2021. 4) Submit! The RareVoice Awards recipients are chosen by a committee from nominations received from the rare disease community. Nominations close August 27th, 2021 Federal Advocacy – Congressional Staff Honors congressional staffers who have worked to create and enact policies for the rare disease community Federal Advocacy – Patient/Organization Honors advocates or organizations that have worked to create and pass federal legislation State Advocacy – State Legislator Honors state legislators who have worked to create and enact policies for the rare disease community State Advocacy – Patient/Organization Honors advocates or organizations that have worked to create and pass state legislation Federal or State Advocacy by a Teenager Honors teen advocates that have advocated for state or federal legislation Diversity Empowerment - Patient/Organization Honors advocates or organizations that empowered diverse voices in advocacy Artist-to-Advocate Honors individuals who have utilized their artwork to advocate for federal or state legislation For information about sponsorship, please contact Elissa Taylor, etaylor@everylifefoundation.org EveryLife Foundation For Rare Diseases 1012 14th Street, NW, Suite 500 | Washington, District of Columbia 20005 202-697-7273 | info@everylifefoundation.org

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

An international panel reached consensus for pre- and postoperative endocrine testing to manage adults undergoing transsphenoidal surgery, including measurement of prolactin and insulin-like growth factor I levels for all pituitary tumors. In adults and children, transsphenoidal surgery represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas, Maria Fleseriu, MD, FACE, an Endocrine Today Editorial Board Member, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland, and colleagues wrote in Pituitary. Endocrine evaluation and management are an essential part of perioperative care; however, the details of endocrine assessment and care are not universally agreed on. “Perioperative management of patients undergoing pituitary surgery is fascinating, as it involves many specialties — endocrinology, neurosurgery and ENT — and patients also get discharged very quickly in some countries, such as the United States,” Fleseriu told Healio. “At the start of the COVID-19 pandemic, the Physician Education Committee of the Pituitary Society, comprised of members from four continents, met to discuss a more streamlined process for workup before and after surgery for patients undergoing pituitary surgery. We have noticed big differences in management, but also some common themes, and decided to have a formal evaluation using a Delphi consensus and a much larger representation, with members from five continents.” Building consensus The task force behind the project, co-led by Nicholas A. Tritos, MD, DSc, associate professor of medicine at Harvard Medical School, and Pouneh K. Fazeli, MD, MPH, director of the neuroendocrinology unit and associate professor of medicine at University of Pittsburgh School of Medicine, created 35 questions and invited 55 pituitary endocrinologists to answer the questions in two Delphi rounds. Participants rated their extent of agreement with statements pertaining to perioperative endocrine evaluation and management, using a Likert-type scale. Strong consensus, defined as at least 80% of panelists rating their agreement as 6 to 7 on a scale from 1 to 7, was achieved for 24 of 35 items. Less strict agreement, defined as ratings of 5 to 7, was reached for 31 of 35 items. There were several significant findings, Fleseriu said. Despite uncertainty in previous guidelines, panelists reached consensus to measure serum IGF-I for all patients with pituitary tumors preoperatively to ensure proper diagnosis of growth hormone excess, Fleseriu said. “This is important because patients with GH-secreting adenomas do not always present with classic manifestations of acromegaly, require additional evaluation for comorbidities and postoperatively may benefit from further medical therapy or other adjuvant treatment,” Fleseriu said. Panelists also expressed agreement on preoperative administration of glucocorticoid and thyroid hormone replacement for patients with diagnosed deficiencies, as well as perioperative use of stress-dose glucocorticoid coverage for patients with known or suspected hypoadrenalism, but not for all patients undergoing transsphenoidal surgery. Panelists also agreed on postoperative monitoring of serum sodium and cortisol and the use of desmopressin on-demand, required to control hypernatremia and/or polyuria, for patients with central diabetes insipidus. “Agreement was achieved on postoperative monitoring of endocrine function, including morning serum cortisol in patients with Cushing’s disease, as well as serum IGF-I in patients with acromegaly,” Fleseriu said. More research needed Panelists did not reach consensus for a minority of items, representing areas where further research is needed, including measuring serum prolactin in dilution for all patients with large macroadenomas, Fleseriu said. “Prolactin immunoassays can be susceptible to the ‘hook effect’ artifact, which may lead to substantial underreporting of prolactin values in sera containing very high prolactin concentrations, thus having important implications for patient management,” Fleseriu said. “Newer automated immunoassay platforms are likely to detect the hook effect; however, this may not be the case in older assays, which are still in use in many countries or laboratories. Therefore, especially when surgery is performed at an institution where automated assays are available to detect hook effect, yet patient workup has been carried out at an outside laboratory, additional lab workup might be needed. We envision this scenario can occur more often with the widespread use of telemedicine and endocrine testing being carried out at a distant laboratory.” Additionally, there was a lack of consensus regarding preoperative testing for hypercortisolism in all patients with an apparently nonfunctioning pituitary adenoma. “This might reflect concern about false-positive results of endocrine testing in some individuals,” Fleseriu said. “On the other hand, published data suggest that some patients with Cushing’s disease may lack typical symptoms and signs and can present with an incidentally found sellar mass.” Panelists did not reach consensus on items concerning preoperative medical therapy for patients with acromegaly or Cushing’s disease, potentially reflecting differences in practice among international centers, the clinical heterogeneity of patient populations, and ongoing uncertainties regarding the benefits of preoperative medical therapy. “Single-center clinical experience suggests that preoperative medical therapy may be helpful in patients with Cushing’s disease and severe acute psychiatric illness or sepsis,” Fleseriu said. “Studies on acromegaly have very discordant results. “With this study — the largest international Delphi consensus on perioperative management of patients undergoing pituitary surgery — we identified key steps in protocols which are ready to be implemented in most centers, especially for preoperative evaluation, sodium abnormalities and glucocorticoids administration postop,” Fleseriu said. “We have also highlighted several areas where need for more research is needed to optimize patients’ outcomes.” For more information: Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu; Twitter: @MariaFleseriu. From https://www.healio.com/news/endocrinology/20210810/experts-offer-recommendations-for-management-of-pituitary-tumors

Ahmed Saeed Mubarak Mohamed1, Ahmed Iqbal2, Suveera Prasad3, Nigel Hoggard4, Daniel Blackburn1 Correspondence to Dr Daniel Blackburn, Sheffield Teaching Hospitals NHS Foundation Trust Department of Clinical Neurology, Sheffield S10 2JF, UK; d.blackburn@sheffield.ac.uk Abstract Cushing’s disease is a rare endocrine condition in which a pituitary corticotroph adenoma drives excess adrenal cortisol production, and is one cause of endogenous Cushing’s syndrome. We present a young woman with 3 weeks of headaches and cognitive disturbance who subsequently developed florid psychosis requiring multiple admissions under neurology and psychiatry. Her clinical stigmata of hypercortisolism and biochemical abnormalities prompted an MR scan of the pituitary, which confirmed a pituitary microadenoma. Treatment with metyrapone and subsequent surgery led to complete recovery within 2 months. Cushing’s disease commonly causes neuropsychiatric symptoms and can present with psychosis. Diagnosing Cushing’s disease can be challenging, but with early diagnosis and treatment it has an excellent prognosis. http://dx.doi.org/10.1136/practneurol-2021-002974 Get the full text

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

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

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