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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

Seems that this isn't just for pediatric patients!

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

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.

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