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– AI false positives pose serious danger to patients; cutoff changes recommended by Scott Harris , Contributing Writer, MedPage Today November 15, 2021 share to facebook share to twitter share to linkedin email article This Reading Room is a collaboration between MedPage Today® and: For adrenal insufficiency (AI), reducing false positives means more than reducing resource utilization. Treatments like glucocorticoid replacement therapy can cause serious harm in people who do not actually have AI. Research published in the Journal of the Endocrine Society makes multiple findings that report authors say could help bring down false positive rates for AI. This retrospective study ultimately analyzed 6,531 medical records from the Imperial College Healthcare NHS Trust in the United Kingdom. Sirazum Choudhury, MBBS, an endocrinologist-researcher with the trust, served as a co-author of the report. He discussed the study with MedPage Today. The exchange has been edited for length and clarity. This study ultimately addressed two related but distinct questions. What was the first? Choudhury: Initially the path we were following had to do with when cortisol levels are tested. Cortisol levels follow a diurnal pattern; levels are highest in the morning and then decline to almost nothing overnight. This means we ought to be measuring the level in the morning. But there are logistical issues to doing so. In many hospitals, we end up taking measurements of cortisol in the afternoon. That creates a dilemma, because if it comes back low, there's an issue as to what we ought to do with the result. Here at Imperial, we call out results of <100 nmol/L among those taken in the afternoon. Patients and doctors then have to deal with these abnormal results, when in fact they may not actually be abnormal. We may be investigating individuals who should really not be investigated. So the first aim of our study was to try and ascertain whether we could bring that down to a lower level and in doing so stop erroneously capturing people who are actually fine. What was the second aim of the study? Choudhury: As we went through tens of thousands of data sets, we realized we could answer more than that one simple question. So the next part of the study became: if an individual is identified as suspicious for AI, what's the best way to prove this diagnosis? We do this with different tests like short Synacthen Tests (SST), all with different cutoff points. Obviously, we want to get the testing right, because if you falsely label a person as having AI, the upshot is that treatments will interfere with their cortisol access and they will not do well. Simply put, we would be shortening their life. So, our second goal was to look at all the SSTs we've done at the center and track them to see whether we could do better with the benchmarks. What did you find? Choudhury: When you look at the data, you see that you can bring those benchmarks down and potentially create a more accurate test. First, we can be quite sure that a patient who is tested in the afternoon and whose cortisol level is >234 does not have AI. If their level is <53.5 then further investigation is needed There were similar findings for SSTs, which in our case were processed using a platform made by Abbott. For this platform, we concluded that the existing cut-offs should be dropped down to 367 at 30 minutes or 419 at about 60 minutes. Did anything surprise you about the study or its findings? Choudhury: If you look at the literature, the number of individuals who fail at 30 minutes but pass at 60 minutes is around 5%. But I was very surprised to see that our number at Imperial was about 20%. This is a key issue because, as I mentioned, if individuals are wrongly labelled adrenally insufficient, you're shortening their life. It's scary to think about the number of people who might have been given steroids and treated for AI when they didn't have the condition. What do you see as the next steps? Choudhury: I see centers unifying their cutoffs for SST results and making sure we're all consistent in the way we treat these results. From a research perspective, on the testing we're obviously talking about one specific platform with Abbott, so research needs to be done on SST analyzers from other manufacturers to work out what their specific cutoffs should be. Read the study here and expert commentary on the clinical implications here. The study authors did not disclose any relevant relationship with industry. Primary Source Journal of the Endocrine Society Source Reference: Ramadoss V, et al "Improving the interpretation of afternoon cortisol levels and SSTs to prevent misdiagnosis of adrenal insufficiency" J Endocrine Soc 2021; 5(11): bvab147. From https://www.medpagetoday.com/reading-room/endocrine-society/adrenal-disorders/95661

From https://rarediseases.org/for-patients-and-families/help-access-medications/patient-assistance-programs-2/ Cushing’s Syndrome | Accepting Applications Medical Assistance Co-Pay Assistance Premium Assistance Contact: 1-855-864-4018 Email: cushings@rarediseases.org Fax: 1-203-517-0978

The endocrine system is a complex network of glands and organs. It uses hormones to control and coordinate your body's metabolism, energy level, reproduction, growth and development, and response to injury, stress, and mood. The following are integral parts of the endocrine system: Hypothalamus. The hypothalamus is located at the base of the brain, near the optic chiasm where the optic nerves behind each eye cross and meet. The hypothalamus secretes hormones that stimulate or suppress the release of hormones in the pituitary gland, in addition to controlling water balance, sleep, temperature, appetite, and blood pressure. Pineal body. The pineal body is located below the corpus callosum, in the middle of the brain. It produces the hormone melatonin, which helps the body know when it's time to sleep. Pituitary. The pituitary gland is located below the brain. Usually no larger than a pea, the gland controls many functions of the other endocrine glands. Thyroid and parathyroid. The thyroid gland and parathyroid glands are located in front of the neck, below the larynx (voice box). The thyroid plays an important role in the body's metabolism. The parathyroid glands play an important role in the regulation of the body's calcium balance. Thymus. The thymus is located in the upper part of the chest and produces white blood cells that fight infections and destroy abnormal cells. Adrenal gland. An adrenal gland is located on top of each kidney. Like many glands, the adrenal glands work hand-in-hand with the hypothalamus and pituitary gland. The adrenal glands make and release corticosteroid hormones and epinephrine that maintain blood pressure and regulate metabolism. Pancreas. The pancreas is located across the back of the abdomen, behind the stomach. The pancreas plays a role in digestion, as well as hormone production. Hormones produced by the pancreas include insulin and glucagon, which regulate levels of blood sugar. Ovary. A woman's ovaries are located on both sides of the uterus, below the opening of the fallopian tubes (tubes that extend from the uterus to the ovaries). In addition to containing the egg cells necessary for reproduction, the ovaries also produce estrogen and progesterone. Testis. A man's testes are located in a pouch that hangs suspended outside the male body. The testes produce testosterone and sperm.

Mineur L. · Boustany R. · Vazquez L. Author affiliations Corresponding Author Keywords: Ectopic Cushing syndromeNeuroendocrine tumoursWHO grade 1Paraneoplastic syndromesChromogranin A Case Rep Oncol 2021;14:1407–1413 https://doi.org/10.1159/000518316 Abstract Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient’s prognosis and quality of life. © 2021 The Author(s). Published by S. Karger AG, Basel Introduction Neuroendocrine tumours (NETs) are a relatively rare and heterogeneous tumour type, comprising about 2% of all malignancies [1]. The gastrointestinal (GI) and pancreatic tract and lungs are the most common primary tumour sites, with 62%–67% and 22%–27%, respectively, and within the GI tract, most of them occurs in the small bowel or the appendix [2, 3]. Since 2010 and the latest version of the WHO classification, GI and pancreatic NETs are subdivided according to their mitotic count or Ki67 index, associated with cellular proliferation. Well-differentiated NETs are relatively low-aggressive tumours, with a rather indolent disease course and a good prognosis in most patients. Nevertheless, some NETs with a low-grade histologic appearance may behave aggressively with rapid growth and metastasis proliferation [4, 5]. Because of this low incidence, tumour heterogeneity, lack of awareness, and non-uniform classifications, GI and pancreatic NETs remain a poorly understood disease, and delayed diagnosis is common among these [6, 7]. Paraneoplastic Cushing syndrome (PCS) represents approximately 10% of all Cushing syndrome and is frequently caused by NETs [8, 9]. While PCS is common with lung NETs (>50% of PCS), this paraneoplastic syndrome is relatively uncommon associated with GI NETs and only described in isolated case reports. Nevertheless, knowing the indolent course of low-grade NETs and the clinical symptoms of cushingoid appearance resulting from prolonged exposure to excessive glucocorticoids, PCS is typically present before cancer detection [8], and surgery is curative in >80% of patients [10, 11]. For the remaining 20%, effective management is necessary, given the risk of infections and thromboembolic events due to the immunosuppressive effect and the hypercoagulable state [11]. For patients with medically unmanageable hypercortisolism, synchronous bilateral adrenalectomy is an effective and safe treatment [12]. We describe a case of typical metastatic intestinal NETs associated with a late ectopic Cushing syndrome, which was managed with synchronous bilateral adrenalectomy. Case Presentation We describe the case of a 50-year-old man admitted to the emergency department for an intestinal obstruction caused by an intestinal tumour. Anatomopathological analysis of the resected specimen and lymph nodes revealed an NET. Three nodes out of 12 removed were positive for cancer localization. The tumour presented serosa infiltration and perineural, vascular and lymphatics vessel invasion. The primary location could not be confirmed histologically between the ileum and appendix. Our diagnosis was pT3N1 according to the American Joint Committee on Cancer (AJCC) classification. An immunohistochemistry analysis revealed a Ki-67 expression <2%. Mitotic count/10 was 2 × 10 high-power fields, and cells showed well differentiation. So, according to the WHO classification, this tumour was classified as G1 NET. 111In-Octreoscan (Octreoscan) revealed lymph node and multifocal liver metastases. After discussion with a multidisciplinary team, the patient was started treatment with somatostatin analogue. Twelve months later, although computerized tomography (CT) scan showed stable disease, patient physical examination revealed facial puffiness with fatty tissue deposits in the face, generalized oedema, muscle weakness, and wasting. He also reports polydipsia, insomnia, and balance disorders. We noted however a discreet increase in the chromogranin A (CgA) value, from 55 ng/mL to 199 ng/mL (with a diagnostic value of 1,700 ng/mL) without an increase in the urinary 5-HIAA level. Laboratory tests revealed an 8.00 a.m. cortisol level of 888 nmol/L, an adrenocorticotropic hormone (ACTH) level of 96.5 pg/mL, and 24-h urine free cortisol of 1,494 μg. A high-dose dexamethasone suppression test showed no cortisol suppression. The patient was diagnosed with ACTH-dependent Cushing syndrome. Magnetic resonance imaging (MRI) of the brain showed a normal pituitary gland, confirming the PCS diagnosis. Ketoconazole treatment associated with sandostatin alleviated hypercortisolism within a month, with a cortisol level within normal laboratory ranges. Two months later, secondary diabetes mellitus was discovered and managed effectively with insulin glargine. Four months later and despite stable disease according to RECIST criteria, cortisol levels increased considerably, with cortisol values similar to diagnosis without ketoconazole increased response. Moreover, diabetes became complicated to manage. Also we noted an increase in CgA value, from 165 ng/mL to 393 ng/mL. Chemoembolization was performed on liver metastases without any effectiveness on hypercortisolism. Adding targeted therapy with mTOR inhibitor (everolimus) was considered. Nevertheless, given the magnitude of drug interaction, the use of everolimus should be avoided in ketoconazole-treated patients, or vice versa. Considering the risks for the patient and expected benefits, synchronous bilateral adrenalectomy was performed. It resolved hypercortisolism and permitted to stabilize diabetes (shown in Fig. 1). Everolimus treatment has been started 1 month after the surgery. Twelve months after everolimus initiation, the patient CT scan still showed stable disease, according to RECIST criteria and a stable CgA value. Fig. 1. Histogram of 8:00 a.m. plasmatic cortisol, ACTH, 24-h urinary cortisol, and CgA levels from Cushing syndrome diagnosis to bilateral adrenalectomy. ACTH, adrenocorticotropic-hormone; ULN, upper limit of normal; 8:00 a.m. cortisol normal ranges (172–497) nmol/L; ACTH normal ranges (7–63) ng/L; 24-h urinary cortisol normal ranges (20–50) µg/24 h; CgA normal ranges (27–94) ng/mL. ACTH, adrenocorticotropic hormone; CgA, chromogranin A. Discussion Approximately 10% of Cushing syndrome is paraneoplastic and may result in many tumours, preferentially lung cancer (50–60% of time), with 1–2% of lung NET and about 5% of small-cell lung cancer associated with Cushing syndrome [8, 11, 13]. Others reported sites of malignancy include the thymus, thyroid, pancreas, and adrenals. Except for the pancreas, PCS secondary to GI NET (appendix, duodenum, ileum, colon, and anal canal) is extremely rare, and only isolated case reports have described this syndrome. In paraneoplastic endocrine syndrome cases, symptoms are due to secretion of hormones by malignant cells or secondary to the impact of neoplastic cell antibodies on normal cells. PCS arises from tumour secretion of ACTH or CRH, resulting in production and release of cortisol from the adrenal glands. Unlike paraneoplastic endocrine syndromes that present most of the time after cancer diagnosis, PCS typically appears before cancer detection and similarly relapse may herald tumour recurrence [11, 14]. In our case, no symptoms related to hypercortisolaemia led the patient to consult before obstructive syndrome. The occurrence of hypercortisolaemia 12 months after diagnosis was not linked to imaging progression according to RECIST criteria. However, concurrent CgA increase should be noted. Commonly measured tumour markers in NETs include serum CgA and 5-HIAA, the final secreted product of serotonin, levels in a 24-h urine sample. Elevated levels of circulating of CgA have been associated with almost all types of NETs, including those arising from GI tract but also pheochromocytomas [15]. The clinical sensitivity of CgA has been demonstrated to depend on the threshold cut-off, on NET primary location, and on the spread of the disease, especially the existence of liver metastases [16]. Indeed, a higher sensitivity was found in patients with midgut NETs and liver metastases, as in our patient. Moreover, with our cut-off level (94 ng/mL) approximately the same as used in 2 studies [16, 17], sensitivity was 62%–67% and specificity was 96%. Furthermore, Korse et al. [18]. postulated that serum CgA was superior to urinary 5-HIAA concerning the prognostic relevance in the follow-up of metastatic midgut NETs. These data are consistent with our patient outcomes for which 5-HIAA was not increased unlike CgA. However, although CgA is currently the best available tumour marker indicating tumour recurrence [19], there are many comorbidities and drugs that may increase CgA levels and lead to false-positive results. As a result, it is questionable whether the CgA increase in our patient was not rather secondary to cardiovascular or GI disorders, inflammatory diseases, diabetes, or even food intake before CgA measurement [16, 20, 21]. Similarly, many drugs, foods, natural stimulants, and comorbidities may alter the level of 24-h urinary 5-HIAA, positively or negatively. Cushing syndrome is due to hypercortisolism. Two-thirds of endogenous elevated cortisol is caused by ACTH-secreting pituitary tumours, 15% by primary adrenal glands and 15% by ectopic PCS [22]. The first step is laboratory tests with cortisol and ACTH levels to differentiate ACTH-dependent or ACTH-independent Cushing syndrome. When ACTH-dependent Cushing syndrome is confirmed, differentiation between PCS and Cushing disease can be difficult. The high-dose dexamethasone suppression tests help distinguish Cushing disease from PCS, as in our presented case. Indeed, no decrease in blood cortisol during the high-dose test and high ACTH levels are consistent with PCS. Nevertheless, 21–26% of ectopic ACTH secretions have a positive suppression, about one-third of MRI scans for pituitary adenoma exclusion are false-negative, and occult ectopic ACTH-secreting tumours have been described in about 15% of adult patients [23-26]. In our patient, both MRI and high-dose dexamethasone suppression test are consistent with PCS. The gold standard diagnosis – inferior petrosal sinus sampling – that demonstrates gradient in ACTH concentration between the affected side sinus and the periphery in pituitary lesions, whereas the absence of this gradient in PCS was not performed because of its invasiveness and its neurological accident risks [27]. Note however although the ACTH level at diagnosis suggests ACTH-dependent Cushing syndrome, the occurrence of adrenal metastasis few months after the diagnosis and explaining the sudden deregulation could be possible and consistent with the CgA increase but refuted by adrenal gland histology. Clinical features of PCS depend on the source of production and rate of ACTH synthesis. Characteristically, these patients have severe hypercortisolaemia, leading to low serum potassium levels, diabetes, generalized infections, hypertension, and psychosis. To confirm whether rapidly growing tumours produce sudden onset of symptoms, gradual physical signs are noticed in slower growing tumours [28], as for our patient for whom we suppose that liver metastases started to produce ACTH ectopically. An option for non-resectable neuroendocrine liver lesions, given that the majority of them are hypervascular, is hepatic directed procedures, which include ablative therapy, transarterial embolization, transarterial chemoembolization, and selective internal radiation therapy with yttrium-90 microspheres [29]. Hepatic artery chemoembolization for the treatment of liver metastases from NETs is useful for tumour size reduction and symptom palliation and can be associated with prolonged survival [30]. Nevertheless, chemoembolization on NET liver metastasis-producing ACTH is not well documented. Given the fact that hepatic metastasis chemoembolization was ineffective on hypercortisolism and despite Octreoscan results, there is still a small chance that he harbours somewhere else metastasis-producing ACTH. Indeed, PET-CT imaging with 68Gallium-DOTATATE has recently replaced Octreoscan as the new gold standard with a higher detection rate in GI NETs [31]. Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potentially fatal emergency. Synchronous bilateral adrenalectomy is an effective and safe treatment for patient with unmanageable ACTH-dependent hypercortisolism [12]. Taking account of the risks to the patient and the lack of effective medical therapeutic possibilities, we have chosen to perform this surgery. According to the recent consensus guidelines for digestive NETs of the jejunum and ileum, the 5-year survival rate is 36% in patients with distant metastases [32]. Several analyses suggest a significant survival benefit in patients who received surgery for the primary tumour even in the presence of metastasis [33]. Moreover, the impact of liver resection or liver-directed therapies on the survival of patients with liver metastasis is unclear with conflicting results [33]. PCS can cause a poor clinical outcome due to various complications with an increase in susceptibility to infection and GI ulceration. Indeed, for small-cell lung cancer and gynaecological malignancies, PCS is associated with accelerated decompensation and poorer response to chemotherapy (Mitchell et al. [14]). Whether these findings can be extrapolated to other malignancies is unknown. However, an early diagnosis and a prompt management can improve patient outcomes through earlier cancer diagnosis or relapse and thus earlier administration of treatment, as was the case with our patient. Conclusion We report an uncommon case with PCS due to a GI NET. The identification of this rare cause of ectopic ACTH secretion can be challenging, but aggressive management is critical to prevent or decelerate the acute decompensation of cancer patients and prolong overall survival. In this context, synchronous bilateral adrenalectomy may be the unique answer. Statement of Ethics Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal. Conflict of interest Statement The authors have no conflict of interest to declare. Funding Sources No funding was received for this study. Author Contributions L.M. conceived the study and participated in data collection. L.V. performed the literature search and wrote the manuscript. L.M. and R.B. critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript version. Data Availability Statement The datasets used and analysed during the current study are available from the corresponding author on reasonable request. From https://www.karger.com/Article/FullText/518316

Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use. Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score. Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 μg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 μg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≥ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve. Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted. Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases Introduction Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.1 In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.1 Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.2 These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.3 One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.9 Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.10 Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.10 However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.2 Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients. Materials and Methods This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≥18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki. Adrenal Function Evaluation Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 µg/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 µg ACTH was administered intravenously. Data Collection Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (Elecsys® Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany). Definitions An 8AM cortisol level of ❤️ µg/dL or a peak serum cortisol level of <18 µg/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.14 Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).15 Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)16 multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.17 Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities. Statistical Analysis All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant. Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.4 There was no missing data in this study. Results Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m2 and 10.7 ±11.7 m2, p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 µg/dL) than in the non-AI group (10.48 ± 3.45 µg/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 µg/dL vs 13.39 ± 15.68 µg/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI. Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42) Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 µg/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements. Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38) Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3). Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38) The cut-off point of ≥50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well. Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42). Discussion The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities. Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants. In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).19 The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement. In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.20 Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.21 Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol22 which supports our finding that serum basal cortisol <7 µg/dL is one of the significant factors related to AI. The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.6 Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression. To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance. There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 µg/dL) than the previous one (18 µg/dL).23 However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI. Conclusions The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted. Acknowledgments The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript. Disclosure The authors report no conflict of interest in this work. References 1. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–140. 2. Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1–15;quiz 16–8. doi:10.1016/j.jaad.2005.01.010 3. Rathi SK, D’Souza P. Rational and ethical use of topical corticosteroids based on safety and efficacy. Indian J Dermatol. 2012;57(4):251–259. doi:10.4103/0019-5154.97655 4. Carruthers JA, August PJ, Staughton RC. Observations on the systemic effect of topical clobetasol propionate (Dermovate). Br Med J. 1975;4(5990):203–204. doi:10.1136/bmj.4.5990.203 5. Staughton RC, August PJ. Cushing’s syndrome and pituitary-adrenal suppression due to clobetasol propionate. Br Med J. 1975;2(5968):419–421. doi:10.1136/bmj.2.5968.419 6. Young CA, Williams IR, MacFarlane IA. Unrecognised Cushing’s syndrome and adrenal suppression due to topical clobetasol propionate. Br J Clin Pract. 1991;45(1):61–62. 7. Abma EM, Blanken R, De Heide LJ. Cushing’s syndrome caused by topical steroid therapy for psoriasis. Neth J Med. 2002;60(3):148–150. 8. Böckle BC, Jara D, Nindl W, Aberer W, Sepp NT. Adrenal insufficiency as a result of long-term misuse of topical corticosteroids. Dermatology. 2014;228(4):289–293. doi:10.1159/000358427 9. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700 10. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55(3):420–426. doi:10.1002/art.21984 11. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47–58. doi:10.2165/00128071-200203010-00005 12. Dhar S, Seth J, Parikh D. Systemic side-effects of topical corticosteroids. Indian J Dermatol. 2014;59(5):460–464. doi:10.4103/0019-5154.139874 13. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am J Clin Dermatol. 2002;3(3):141–147. doi:10.2165/00128071-200203030-00001 14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710 15. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs. 1988;36(Suppl 5):51–61. doi:10.2165/00003495-198800365-00011 16. Davallow Ghajar L, Wood Heickman LK, Conaway M, Rogol AD. Low risk of adrenal insufficiency after use of low- to moderate-potency topical corticosteroids for children with atopic dermatitis. Clin Pediatr. 2019;58(4):406–412. doi:10.1177/0009922818825154 17. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician. 2014;89(9):718–722. 18. Melian EB, Spencer CM, Jarvis B. Clobetasol propionate foam, 0.05%. Am J Clin Dermatol. 2001;2(2):89–92;discussion 93. doi:10.2165/00128071-200102020-00005 19. Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6):2171–2180. doi:10.1210/jc.2015-1218 20. Kerner M, Ishay A, Ziv M, Rozenman D, Luboshitzky R. Evaluation of the pituitary-adrenal axis function in patients on topical steroid therapy. J Am Acad Dermatol. 2011;65(1):215–216. doi:10.1016/j.jaad.2010.12.033 21. Malzfeldt E, Lehmann P, Goerz G, Lippold BC. Influence of drug solubility in the vehicle on clinical efficacy of ointments. Arch Dermatol Res. 1989;281(3):193–197. doi:10.1007/bf00456392 22. Manosroi W, Phimphilai M, Khorana J, Atthakomol P. Diagnostic performance of basal cortisol level at 0900-1300h in adrenal insufficiency. PLoS One. 2019;14(11):e0225255. doi:10.1371/journal.pone.0225255 23. Vogeser M, Kratzsch J, Ju Bae Y, et al. Multicenter performance evaluation of a second generation cortisol assay. Clin Chem Lab Med. 2017;55(6):826–835. doi:10.1515/cclm-2016-0400 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF] From https://www.dovepress.com/novel-predictive-model-for-adrenal-insufficiency-in-dermatological-pat-peer-reviewed-fulltext-article-IJGM

An updated guideline for the treatment of Cushing’s disease focuses on new therapeutic options and an algorithm for screening and diagnosis, along with best practices for managing disease recurrence. Despite the recent approval of novel therapies, management of Cushing’s disease remains challenging. The disorder is associated with significant comorbidities and has high mortality if left uncontrolled. Source: Adobe Stock “As the disease is inexorable and chronic, patients often experience recurrence after surgery or are not responsive to medications,” Shlomo Melmed, MB, ChB, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, and an Endocrine Today Editorial Board Member, told Healio. “These guidelines enable navigation of optimal therapeutic options now available for physicians and patients. Especially helpful are the evidence-based patient flow charts [that] guide the physician along a complex management path, which usually entails years or decades of follow-up.” Shlomo Melmed The Pituitary Society convened a consensus workshop with more than 50 academic researchers and clinical experts across five continents to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, participants reviewed data from January 2015 to April 2021 on screening and diagnosis; surgery, medical and radiation therapy; and disease-related and treatment-related complications of Cushing’s disease, all summarized in recorded lectures. The guideline includes recommendations regarding use of laboratory tests, imaging and treatment options, along with algorithms for diagnosis of Cushing’s syndrome and management of Cushing’s disease. Updates in laboratory, testing guidance If Cushing’s syndrome is suspected, any of the available diagnostic tests could be useful, according to the guideline. The authors recommend starting with urinary free cortisol, late-night salivary cortisol, overnight 1 mg dexamethasone suppression, or a combination, depending on local availability. If an adrenal tumor is suspected, the guideline recommends overnight dexamethasone suppression and using late-night salivary cortisol only if cortisone concentrations can also be reported. The guideline includes several new recommendations in the diagnosis arena, particularly on the role of salivary cortisol assays, according to Maria Fleseriu, MD, FACE, a Healio | Endocrine Today Co-editor, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland. Maria Fleseriu “Salivary cortisol assays are not available in all countries, thus other screening tests can also be used,” Fleseriu told Healio. “We also highlighted the sequence of testing for recurrence, as many patients’ urinary free cortisol becomes abnormal later in the course, sometimes up to 1 year later.” The guideline states combined biochemical and imaging for select patients could potentially replace petrosal sinus sampling, a very specialized procedure that cannot be performed in all hospitals, but more data are needed. “With the corticotropin-releasing hormone stimulation test becoming unavailable in the U.S. and other countries, the focus is now on desmopressin to replace corticotropin-releasing hormone in some of the dynamic testing, both for diagnosis of pseudo-Cushing’s as well as localization of adrenocorticotropic hormone excess,” Fleseriu said. The guideline also has a new recommendation for anticoagulation for high-risk patients; however, the exact duration and which patients are at higher risk remains unknown. “We always have to balance risk for clotting with risk for bleeding postop,” Fleseriu said. “Similarly, recommended workups for bone disease and growth hormone deficiency have been further structured based on pitfalls specifically related to hypercortisolemia influencing these complications, as well as improvement after Cushing’s remission in some patients, but not all.” New treatment options The guideline authors recommended individualizing medical therapy for all patients with Cushing’s disease based on the clinical scenario, including severity of hypercortisolism. “Regulatory approvals, treatment availability and drug costs vary between countries and often influence treatment selection,” the authors wrote. “However, where possible, it is important to consider balancing cost of treatment with the cost and the adverse consequences of ineffective or insufficient treatment. In patients with severe disease, the primary goal is to treat aggressively to normalize cortisol concentrations.” Fleseriu said the authors reviewed outcomes data as well as pros and cons of surgery, repeat surgery, medical treatments, radiation and bilateral adrenalectomy, highlighting the importance of individualized treatment in Cushing’s disease. “As shown over the last few years, recurrence rates are much higher than previously thought and patients need to be followed lifelong,” Fleseriu said. “The role of adjuvant therapy after either failed pituitary surgery or recurrence is becoming more important, but preoperative or even primary medical treatment has been also used more, too, especially in the COVID-19 era.” The guideline summarized data on all medical treatments available, either approved by regulatory agencies or used off-label, as well as drugs studied in phase 3 clinical trials. “Based on great discussions at the meeting and subsequent emails to reach consensus, we highlighted and graded recommendations on several practical points,” Fleseriu said. “These include which factors are helpful in selection of a medical therapy, which factors are used in selecting an adrenal steroidogenesis inhibitor, how is tumor growth monitored when using an adrenal steroidogenesis inhibitor or glucocorticoid receptor blocker, and how treatment response is monitored for each therapy. We also outline which factors are considered in deciding whether to use combination therapy or to switch to another therapy and which agents are used for optimal combination therapy.” Future research needed The guideline authors noted more research is needed regarding screening and diagnosis of Cushing’s syndrome; researchers must optimize pituitary MRI and PET imaging using improved data acquisition and processing to improve microadenoma detection. New diagnostic algorithms are also needed for the differential diagnosis using invasive vs. noninvasive strategies. Additionally, the researchers said the use of anticoagulant prophylaxis and therapy in different populations and settings must be further studied, as well as determining the clinical benefit of restoring the circadian rhythm, potentially with a higher nighttime medication dose, as well as identifying better markers of disease activity and control. “Hopefully, our patients will now experience a higher quality of life and fewer comorbidities if their endocrinologist and care teams are equipped with this informative roadmap for integrated management, employing a consolidation of surgery, radiation and medical treatments,” Melmed told Healio. From https://www.healio.com/news/endocrinology/20211029/updated-cushings-disease-guideline-highlights-new-diagnosis-treatment-roadmap

Jessica Rotham, National Center for Health Research What is it? Cushing’s syndrome is a condition you probably have never heard of, but for those who have it, the symptoms can be quite scary. Worse still, getting it diagnosed can take a while. Cushing’s syndrome occurs when the tissues of the body are exposed to high levels of cortisol for an extended amount of time. Cortisol is the hormone the body produces to help you in times of stress. It is good to have cortisol at normal levels, but when those levels get too high it causes health problems. Although cortisol is related to stress, there is no evidence that Cushing’s syndrome is directly or indirectly caused by stress. Cushing’s syndrome is considered rare, but that may be because it is under-reported. As a result, we don’t have good estimates for how many people have it, which is why the estimates for the actual number of cases vary so much–from 5 to 28 million people.[1] The most common age group that Cushing’s affects are those 20 to 50 years old. It is thought that obesity, type 2 diabetes, and high blood pressure may increase your risk of developing this syndrome.[2] What causes Cushing’s Syndrome? Cushing’s syndrome is caused by high cortisol levels. Cushing’s disease is a specific form of Cushing’s syndrome. People with Cushing’s disease have high levels of cortisol because they have a non-cancerous (benign) tumor in the pituitary gland. The tumor releases adrenocorticotropin hormone (ACTH), which causes the adrenal glands to produce excessive cortisol. Cushing’s syndrome that is not Cushing’s disease can be also caused by high cortisol levels that result from tumors in other parts of the body. One of the causes is “ectopic ACTH syndrome.” This means that the hormone-releasing tumor is growing in an abnormal place, such as the lungs or elsewhere. The tumors can be benign, but most frequently they are cancerous. Other causes of Cushing’s syndrome are benign tumors on the adrenal gland (adrenal adenomas) and less commonly, cancerous adrenal tumors (adrenocortical carcinomas). Both secrete cortisol, causing cortisol levels to get too high. In some cases, a person can develop Cushing’s syndrome from taking steroid medications, such as prednisone. These drugs, known as corticosteroids, mimic the cortisol produced by the body. People who have Cushing’s syndrome from steroid medications do not develop a tumor.[3] What are the signs and symptoms of Cushing’s Syndrome? The appearance of people with Cushing’s syndrome starts to change as cortisol levels build up. Regardless of what kind of tumor they have or where the tumor is located, people tend to put on weight in the upper body and abdomen, with their arms and legs remaining thin; their face grows rounder (“moon face”); they develop fat around the neck; and purple or pink stretch marks appear on the abdomen, thighs, buttocks or arms. Individuals with the syndrome usually experience one or more of the following symptoms: fatigue, muscle weakness, high glucose levels, anxiety, depression, and high blood pressure. Women are more likely than men to develop Cushing’s syndrome, and when they do they may have excess hair growth, irregular or absent periods, and decreased fertility.[4] Why is Cushing’s Syndrome so frequently misdiagnosed? These symptoms seem distinctive, yet it is often difficult for those with Cushing’s syndrome to get an accurate diagnosis. Why? While Cushing’s is relatively rare, the signs and symptoms are common to many other diseases. For instance, females with excess hair growth, irregular or absent periods, decreased fertility, and high glucose levels could have polycystic ovarian syndrome, a disease that affects many more women than Cushing’s. Also, people with metabolism problems (metabolic syndrome), who are at higher than average risk for diabetes and heart disease, also tend to have abdominal fat, high glucose levels and high blood pressure.[5] Problems in testing for Cushing’s When Cushing’s syndrome is suspected, a test is given to measure cortisol in the urine. This test measures the amount of free or unbound cortisol filtered by the kidneys and then released over a 24 hour period through the urine. Since the amount of urinary free cortisol (UFC) can vary a lot from one test to another—even in people who don’t have Cushing’s—experts recommend that the test be repeated 3 times. A diagnosis of Cushing’s is given when a person’s UFC level is 4 times the upper limit of normal. One study found this test to be highly accurate, with a sensitivity of 95% (meaning that 95% of people who have the disease will be correctly diagnosed by this test) and a specificity of 98% (meaning that 98% of people who do not have the disease will have a test score confirming that).[6] However, a more 2010 study estimated the sensitivity as only between 45%-71%, but with 100% specificity.[7] This means that the test is very accurate at telling people who don’t have Cushing’s that they don’t have it, but not so good at identifying the people who really do have Cushing’s. The authors that have analyzed these studies advise that patients use the UFC test together with other tests to confirm the diagnosis, but not as the initial screening test.[8] Other common tests that may be used to diagnose Cushing’s syndrome are: 1) the midnight plasma cortisol and late-night salivary cortisol measurements, and 2) the low-dose dexamethasone suppression test (LDDST). The first test measures the amount of cortisol levels in the blood and saliva at night. For most people, their cortisol levels drop at night, but people with Cushing’s syndrome have cortisol levels that remain high all night. In the LDDST, dexamethasone is given to stop the production of ACTH. Since ACTH produces cortisol, people who don’t have Cushing’s syndrome will get lower cortisol levels in the blood and urine. If after giving dexamethasone, the person’s cortisol levels remain high, then they are diagnosed with Cushing’s.[9] Even when these tests, alone or in combination, are used to diagnose Cushing’s, they don’t explain the cause. They also don’t distinguish between Cushing’s syndrome, and something called pseudo-Cushing state. Pseudo-Cushing state Some people have an abnormal amount of cortisol that is caused by something unrelated to Cushing’s syndrome such as polycystic ovarian syndrome, depression, pregnancy, and obesity. This is called pseudo-Cushing state. Their high levels of cortisol and resulting Cushing-like symptoms can be reversed by treating whatever disease is causing the abnormal cortisol levels. In their study, Dr. Giacomo Tirabassi and colleagues recommend using the desmopressin (DDAVP) test to differentiate between pseudo-Cushing state and Cushing’s. The DDAVP test is especially helpful in people who, after being given dexamethasone to stop cortisol production, continue to have moderate levels of urinary free cortisol (UFC) and midnight serum cortisol.[10] An additional test that is often used to determine if one has pseudo-Cushing state or Cushing’s syndrome is the dexamethasone-corticotropin-releasing hormone (CRH) test. Patients are injected with a hormone that causes cortisol to be produced while also being given another hormone to stop cortisol from being produced. This combination of hormones should make the patient have low cortisol levels, and this is what happens in people with pseudo-Cushing state. People with Cushing’s syndrome, however, will still have high levels of cortisol after being given this combination of hormones.[11] How can Cushing’s be treated? Perhaps because Cushing’s is rare or under-diagnosed, few treatments are available. There are several medications that are typically the first line of treatment. None of the medications can cure Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails. The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and remove the tumor. Radiation may also be used instead of surgery to shrink the tumor. In patients whose Cushing’s is caused by ectopic ACTH syndrome, all cancerous cells need to be wiped out through surgery, chemotherapy, radiation or a variety of other methods, depending on the location of the tumor. Surgery is also recommended for adrenal tumors. If Cushing’s syndrome is being caused by corticosteroid (steroid medications) usage, the treatment is to stop or lower your dosage.[12] Medications to control Cushing’s (before treatment or if treatment fails) According to a 2014 study in the Journal of Clinical Endocrinology and Metabolism, almost no new treatment options have been introduced in the last decade. Researchers and doctors have focused most of their efforts on improving existing treatments aimed at curing Cushing’s. Unfortunately, medications used to control Cushing’s prior to treatment and when treatment fails are not very effective. Many of the medications approved by the FDA for Cushing’s syndrome and Cushing’s disease, such as pasireotide, metyrapone, and mitotane, have not been extensively studied. The research presented to the FDA by the makers of these three drugs did not even make clear what an optimal dose was.[13] In another 2014 study, published in Clinical Epidemiology, researchers examined these three same drugs, along with ten others, and found that only pasireotide had moderate evidence to support its approval. The other drugs, many of which are not FDA approved for Cushing’s patients, had little or no available evidence to show that they work.[14] They can be sold, however, because the FDA has approved them for other diseases. Unfortunately, that means that neither the FDA nor anyone else has proven the drugs are safe or effective for Cushing patients. Pasireotide, the one medication with moderate evidence supporting its approval, caused hyperglycemia (high blood sugar) in 75% of patients who participated in the main study for the medication’s approval for Cushing’s. As a result of developing hyperglycemia, almost half (46%) of the participants had to go on blood-sugar lowering medications. The drug was approved by the FDA for Cushing’s anyway because of the lack of other effective treatments. Other treatments used for Cushing’s have other risks. Ketoconazole, believed to be the most commonly prescribed medications for Cushing’s syndrome, has a black box warning due to its effect on the liver that can lead to a liver transplant or death. Other side effects include: headache, nausea, irregular periods, impotence, and decreased libido. Metyrapone can cause acne, hirsutism, and hypertension. Mitotane can cause neurological and gastrointestinal symptoms such as dizziness, nausea, and diarrhea and can cause an abortion in pregnant women.[15] So, what should you do if you suspect you have Cushing’s Syndrome? Cushing’s syndrome is a serious disease that needs to be treated, but there are treatment options available for you if you are diagnosed with the disease. If the symptoms in this article sound familiar, it’s time for you to go see your doctor. Make an appointment with your general practitioner, and explain your symptoms to him or her. You will most likely be referred to an endocrinologist, who will be able to better understand your symptoms and recommend an appropriate course of action. All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff. Nieman, Lynette K. Epidemiology and clinical manifestations of Cushing’s syndrome, 2014. UpToDate: Wolters Kluwer Health Cushing’s syndrome/ disease, 2013. American Association of Neurological Surgeons. http://www.aans.org/Patient Information/Conditions and Treatments/Cushings Disease.aspx Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Newell-Price, John, Peter Trainer, Michael Besser and Ashley Grossman. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states, 1998. Endocrine Reviews: Endocrine Society Carroll, TB and JW Findling. The diagnosis of Cushing’s syndrome, 2010. Reviews in Endocrinology and Metabolic Disorders: Springer Ifedayo, AO and AF Olufemi. Urinary free cortisol in the diagnosis of Cushing’s syndrome: How useful?, 2013. Nigerian Journal of Clinical Practice: Medknow. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society. Galdelha, Monica R. and Leonardo Vieira Neto. Efficacy of medical treatment in Cushing’s disease: a systematic review, 2014. Clinical Endocrinology: John Wiley & Sons. Adler, Gail. Cushing syndrome treatment & management, 2014. MedScape: WebMD. Adapted from https://www.center4research.org/cushings-syndrome-frequent-misdiagnosis/?fbclid=IwAR1lfJPilmaTl1BhR-Esi69eU7Xjm3RlO4f8lmFBIviCtHHXmVoyRxOlJqE

TAMPA, Fla., Nov. 3, 2021 /PRNewswire/ -- The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer adrenal vein sampling and curative surgery in one visit. The novel protocol and diagnostic method for adrenal tumors will condense a 2–4-week process of localization of hyper-secreting adrenal tumors and subsequent curative surgery down to just one day. The innovative approach combines highly specialized adrenal vein sampling with rapid adrenal hormone lab testing and then consultation with the world's highest volume adrenal surgeon. If appropriate, a patient may even complete their mini-surgery during that same visit. Established by Dr. Tobias Carling in 2020, the Carling Adrenal Center located at the Hospital for Endocrine Surgery in Tampa FL, is the highest volume adrenal surgical center in the world. The Center now averages nearly 20 adrenal tumor patients every week that could benefit from this novel diagnostic and treatment approach to address a decades-long problem for patients with adrenal tumors. The Endocrine Society Clinical Practice Guideline recommends adrenal vein sampling (AVS) as the preferred method to select patients with primary hyperaldosteronism for an adrenalectomy. "The difficulty and complexity of testing and diagnosing adrenal tumors secreting excess aldosterone is the primary reason why less than 5% of these adrenal tumors are diagnosed and treated," says Dr. Carling. "By combining expertise in interventional radiology for adrenal vein sampling and rapid laboratory measurements of adrenal hormones with our unique international consulting capability, we can determine which adrenal gland is bad and whether or not the patient needs that adrenal gland removed." Adrenal vein sampling is performed through small catheters placed in very specific veins where blood samples are obtained from both adrenal veins and the inferior vena cava. In experienced centers, the bilateral adrenal veins are catheterized and sampled with a success rate exceeding 90%. Technical success is directly associated with operator experience, leading to the recommendation that the procedure only be performed by true experts or the test will very likely be of no help. Dr. Carling's very high volume of adrenal surgery for many years has allowed him to publish scientific studies demonstrating that in aldosterone-producing adenomas, there is a strong correlation between the imaging phenotype (i.e., what the tumor looks like on a CT scan), histology (what the tumor looks like under the microscope) and genotype (what gene is mutated in the tumor). This knowledge allows Dr. Carling and his team at the Hospital for Endocrine Surgery to predict who can go straight to surgery with an excellent outcome, and who may first need adrenal vein sampling to determine which adrenal gland is over-producing the hormone causing significant morbidity and mortality. With adrenal vein sampling proving lateralization, the next step is surgical removal of the adrenal tumor. Dr. Carling has more experience with all types of adrenal surgery than any surgeon in the United States, but especially with advanced, minimally invasive adrenal operations which are the best options for aldosterone-secreting adrenal tumors. A fellow of the American College of Surgeons, Dr. Carling is a member of both the American Association of Endocrine Surgeons (AAES) and the International Association of Endocrine Surgeons (IAES). Dr. Carling moved his world-renowned adrenal surgery program from Yale University to Tampa, Florida in early 2020 to start the Carling Adrenal Center. Here, patients needing adrenal surgery have access to the best practices and best techniques the world has to offer. In January 2022, the Carling Adrenal Center will unite with the Norman Parathyroid Center, the Clayman Thyroid Center and the Scarless Thyroid Surgery Center at the brand-new Hospital for Endocrine Surgery located in Tampa, Florida. About the Carling Adrenal Center: Founded by Dr. Tobias Carling, one of the world's leading experts in adrenal gland surgery, the Carling Adrenal Center is a worldwide destination for the surgical treatment of adrenal tumors. Dr. Carling spent nearly 20 years at Yale University, including 7 as the Chief of Endocrine Surgery before leaving in 2020 to open to Carling Adrenal Center, which performs more adrenal operations than any other hospital in the world. More about adrenal vein sampling for adrenal tumors can be found at the Center's website www.adrenal.com and here. (813) 972-0000. Contact: Julie Canan, Director of Marketing Carling Adrenal Center juliec@parathyroid.com SOURCE Carling Adrenal Center From https://www.prnewswire.com/news-releases/innovative-one-visit-adrenal-tumor-diagnosis-and-treatment-program-begins-in-tampa-301414465.html

Cortisol is a hormone which produced by the adrenal gland (cortex) to control blood sugar. The production of cortisol is triggered by the pituitary hormone ACTH. Cortisol is a glucocorticoid which stimulates an increase in blood glucose. Cortisol will also stimulate the release of amino acids from muscle tissue and fatty acids from adipose tissue. The amino acids are then converted in the liver to glucose (for use by the brain). The fatty acids can be used by skeletal muscles for energy (rather than glucose) thereby freeing up glucose for selective utilization by the brain. Cortisol levels are often measured to evaluate the function of the pituitary or adrenal glands. Some of the cortisol is metabolized by the liver to produce 17 hydroxycorticosteroids, which is then excreted in the urine. The primary stress hormone. Cortisol is the major natural GLUCOCORTICOID (GC) in humans. Synthetic cortisol, also known as hydrocortisone, is used as a drug mainly to fight allergies and inflammation. A certain amount of cortisol is necessary for life. Without cortisol even a small amount of stress will kill you. Addison's disease is a disease which causes low cortisol levels, and which is treated by cortisol replacement therapy. Cortisol...

https://doi.org/10.1016/j.aace.2021.10.004Get rights and content Under a Creative Commons license open access Highlights • Cushing’s Disease (CD) in pregnancy is rare, but poses many risks to the mother and fetus • Although surgery is still considered first line, this CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure • The dose of metyrapone can be titrated to a goal urinary free cortisol of < 150 ug/24 hours given the known rise in cortisol during gestation • Though no fetal adverse events have been reported, metyrapone does cross the placenta and long-term effects are unknown. ABSTRACT Background Cushing Disease (CD) in pregnancy is a rare, but serious, disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience using it to treat a pregnant patient with CD. Case Report 34-year-old woman with hypertension who was diagnosed with adrenocorticotropic hormone-dependent CD based on a urinary free cortisol (UFC) of 290 μg/24hr (reference 6-42μg/dL) and abnormal dexamethasone suppression test (cortisol 12.4 μg/dL) before becoming pregnant. She conceived naturally 12 weeks post-transsphenoidal surgery, and was subsequently found to have persistent disease with UFC 768μg/dL. Surgery was deemed high risk given the proximity of the tumor to the right carotid artery and high likelihood of residual disease. Instead, she was managed with metyrapone throughout her pregnancy and titrated to goal UFC of <150μg/24hr due to the known physiologic rise in cortisol during gestation. The patient had diet-controlled gestational diabetes, and well-controlled hypertension. She gave birth at 37 weeks gestation to a healthy baby boy, without adrenal insufficiency in the baby or mother. Discussion This CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure. While metyrapone is effective, close surveillance is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency. Though no fetal adverse events have been reported, this medication crosses the placenta and long-term effects are unknown. Conclusion We describe a CASE of CD during pregnancy that was successfully treated with metyrapone. Key words Cushing disease metyrapone pregnancy cortisol INTRODUCTION Cushing disease (CD) is caused by endogenous overproduction of glucocorticoids due to hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. CD in pregnancy is very rare, and when it occurs, it is considered a high-risk pregnancy with many potential adverse outcomes for both the mother and fetus.1 Infertility is common in CD due to cortisol and androgen excess leading to hypogonadotropic hypogonadism.1 Due to the rarity of CD in pregnancy, there is little guidance in terms of treatment for this patient population. Similar to non-pregnant patients, the first-line treatment is transsphenoidal pituitary adenoma resection, with medical therapy as a second-line treatment option. This report presents a CASE that highlights the use of metyrapone, a steroidogenesis inhibitor, as a sole therapy in cases where surgery is deemed to be high risk and unlikely curative due to location of the tumor. CASE REPORT A 34-year-old woman with a past medical history of hypertension and infertility for six years presented to endocrinology for evaluation. Aside from difficulty conceiving, her only complaints were nausea and easy bruising. On exam she did not have clinical features of CD –abdominal violaceous striae, moon facies or a dorsocervical fat pad were absent. Her laboratory results revealed an elevated prolactin level (50-60ng/mL, reference range 1.4-24), an elevated ACTH level (61 pg/mL, reference range 0-46), and low FSH and LH levels (1.7mIU/mL and 1.76mIU/mL, respectively). Further testing demonstrated an elevated urinary free cortisol level (UFC) (290μg/24 hour, reference range 6-42) and her cortisol failed to suppress on a 1mg dexamethasone suppression test (cortisol 12.4μg/dL). Magnetic resonance imaging (MRI) of the pituitary with and without contrast showed a T2 hyperintense, hypoenhancing lesion within the right side of the sella touching the right cavernous internal carotid artery measuring 8x8x9 mm consistent with a pituitary adenoma (Figure 1). Download : Download high-res image (247KB) Download : Download full-size image Figure 1. Caption: T1 weighted post gadolinium coronal image of the pituitary gland with a small hypoenhancing lesion within the right side of the sella. After the presumed diagnosis of CD was made, she was referred to neurosurgery for transsphenoidal resection of the adenoma, which she underwent a few months later. Intra-operatively, a white friable tumor was found, and otherwise the surgery was uneventful. Three months later, however, she was found to have a persistent 8x8x9mm hypoenhancing lesion extending laterally over the right cavernous carotid artery on MRI. The mass approximated but did not contact the right intracranial optic nerve. The pathology from resected tissue was consistent with normal pituitary tissue with staining for growth hormone (80%), ACTH (30%), prolactin (40%), follicle stimulating hormone (5%), luteinizing hormone (40%) and thyroid stimulating hormone (15%), proving the surgery to have been unsuccessful. Twelve weeks post-operatively, the patient discovered she was pregnant. At 12 weeks gestation, her UFC was 768μg/24h and two midnight salivary cortisol levels were elevated at 0.175 and 0.625μg/dL (reference <0.010-0.090). She was experiencing easy bruising and taking labetalol 400 mg twice daily for hypertension. She had gained 10 pounds by 12 weeks gestation. A second transsphenoidal surgery during pregnancy was deemed high risk, with a high likelihood of residual disease due to the proximity of the tumor to the right carotid artery. The decision was made to treat the patient medically with metyrapone which was started at 250 mg twice per day at 12 weeks gestation and was eventually uptitrated based on UFC levels every 3-4 weeks (goal of <150μg /24h) to 1000 mg three times per day by the time of delivery with an eventual UFC level of 120μg/24h (Figure 2) . Morning ACTH and serum cortisol levels were monitored for potential adrenal insufficiency. Download : Download high-res image (375KB) Download : Download full-size image Figure 2. Caption: This figure depicts the patient’s 24 hour urinary cortisol levels over time as well as the titration of metyrapone dosage in mg/day. Her hypertension was well controlled throughout pregnancy on labetalol with the addition of nifedipine XL 30mg daily in the second trimester. She remained normokalemic with potassium ranging from 3.8-4.1mEq/L. She was diagnosed with gestational diabetes at 24 weeks by an abnormal two-step oral glucose tolerance test, which was diet-controlled. The patient was induced at 37 weeks gestation due to cervical insufficiency with cerclage in place, and was given stress dose steroids along with metyrapone. She delivered a healthy baby boy vaginally without complications. His Apgar scores were 9 and 9 and he weighed 6 pounds and 5 ounces. At the time of delivery and one week later, the baby’s cortisol levels were normal (6 μg/dL, normal 4-20), without evidence of adrenal insufficiency. The patient’s metyrapone dose was reduced to 500mg three times a day after pregnancy and her 2 month postpartum 24 hour UFC was 42μg/24hr. The patient stopped the metyrapone on her own four months later and her UFC was found to be elevated at 272ug/24hr (normal 6-42μg/24hr). An MRI one year postpartum revealed a 10x10x9 mm adenoma in the right sella with some suprasellar extension without compression of the optic chiasm, but with abutment of the right carotid artery. Due to the persistently elevated cortisol, large size of the tumor, and potential for cure, especially if followed by radiation therapy, a second transsphenoidal surgery was recommended. However, due to the COVID-19 pandemic the patient underwent a delayed surgery 1.5 years postpartum. The pathology was consistent with a pituitary adenoma that stained strongly and diffusely for ACTH and synaptophysin, only. Her postoperative day 2 cortisol was 1.1μg/dL (reference range 6.7-22.6) and hydrocortisone 20mg in the morning and 10mg in the afternoon was started. She remains on hydrocortisone replacement and went on to conceive again, one month after her second surgery. DISCUSSION We describe a patient with pre-existing CD who became pregnant and was managed successfully with metyrapone throughout her pregnancy. Although CD is rare in pregnancy, it can occur, and poses risks to both the mother and fetus.1,2 Potential maternal complications include hypertension, preeclampsia, diabetes, fractures and more uncommonly, cardiac failure, psychiatric disorders, infection and maternal death.1,2 There is also increased fetal morbidity including prematurity, intrauterine growth retardation and less commonly CD can lead to stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism.1,2 It is, therefore, imperative that these patients receive prompt care to control cortisol levels. The treatment of CD in pregnancy is challenging as there are no large research trials studying the efficacy and safety of medications in CD during pregnancy. Pituitary surgery is first-line recommendation and should be done late in the first trimester or in the second trimester to prevent spontaneous pregnancy loss.3 In this CASE, however, it was felt that a second surgery would be high-risk given the proximity of the tumor to the right carotid artery and possibly not curative, and thus surgery was not a feasible option. She was therefore successfully managed with medical therapy with metyrapone alone throughout her pregnancy. Metyrapone use in pregnancy has been previously reported in the literature and has been shown to be effective in reducing cortisol levels.4,5,6 Although not approved for use in pregnancy, this steroidogenesis inhibitor is the most commonly used medication to treat Cushing’s syndrome in pregnant women.3,5 Due to metyrapone’s inhibition of 11-beta-hydroxylase, there is a buildup of steroidogenesis precursors such as 11-deoxycorticosterone, which can worsen hypertension, increase frequency of preeclampsia, and cause hypokalemia.3 Metyrapone also leads to elevation of adrenal androgens, which in conjunction with accumulation of 11-deoxycorticosterone, can cause hirsutism and virilization. 8 Though the use of Cabergoline has been reported in cases with Cushing disease during pregnancy, no long term safety data is available regarding it effects on pregnancy as well as the fetus. Moreover, studies assessing the effect of cabergoline in persistent or recurrent CD show a response rate of 20-30% only in cases with mild hypercortisolism. 9 There is no consensus on how to medically treat patients with CD during pregnancy. We chose a goal UFC of <150μg/24 hours because of the physiological rise of cortisol to two to three times the upper limit of normal during pregnancy.3,7 During pregnancy, there is an increase in corticotropin-releasing hormone from the placenta, which is identical in structure to the hypothalamic form.7 This leads to increased levels of ACTH which stimulates the maternal adrenal glands to become slightly hypertrophic and accounts for the rise in serum cortisol levels in pregnancy.7 Corticosteroid-binding globulin also increases in pregnancy, along with serum free cortisol, leading to urinary free cortisol increasing to 3-fold the normal range.7 We therefore aimed to keep our patient’s urinary free cortisol approximately 3 times the upper limit of normal on our assay, to maintain normal cortisol levels for pregnancy. Close surveillance of patients is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency.3 Although no fetal adverse events from metyrapone have been reported, the medication does cross the placenta, leading to the potential for fetal adrenal insufficiency, and long-term effects are unknown.3 CONCLUSION This CASE demonstrates the successful use of metyrapone alone to treat CD throughout pregnancy resulting in the birth of a healthy baby without adrenal insufficiency. These cases are particularly challenging given the lack of FDA-approved therapies and the lack of consensus on directing titration of medications and the duration of therapy. Uncited reference 4., 6.. REFERENCES: 1 T. Brue, V. Amodru, F. Castinetti MANAGEMENT OF ENDOCRINE DISEASE: Management of Cushing's syndrome during pregnancy: solved and unsolved questions Eur J Endocrinol, 178 (6) (2018 Jun), pp. R259-R266, 10.1530/EJE-17-1058 Epub 2018 Mar 9. PMID: 29523633 View PDF CrossRefView Record in ScopusGoogle Scholar 2 F. Caimari, E. Valassi, P. Garbayo, C. Steffensen, A. Santos, R. Corcoy, S.M. Webb Cushing's syndrome and pregnancy outcomes: a systematic review of published cases Endocrine, 55 (2) (2017 Feb), pp. 555-563, 10.1007/s12020-016-1117-0 Epub 2016 Oct 4. PMID: 27704478 View PDF CrossRefView Record in ScopusGoogle Scholar 3 M.D. Bronstein, M.C. Machado, M.C. Fragoso MANAGEMENT OF ENDOCRINE DISEASE: Management of pregnant patients with Cushing's syndrome Eur J Endocrinol, 173 (2) (2015 Aug), pp. R85-91, 10.1530/EJE-14-1130 Epub 2015 Apr 14. PMID: 25872515 View PDF View Record in ScopusGoogle Scholar 4 Azzola A, Eastabrook G, Matsui D, Berberich A, Tirona RG, Gray D, Gallego P, Van Uum S. Adrenal Cushing Syndrome Diagnosed During Pregnancy: Successful Medical Management With Metyrapone. J Endocr Soc. 2020 Nov 5;5(1):bvaa167. doi: 10.1210/jendso/bvaa167. PMID: 33305159; PMCID: PMC7712789. Google Scholar 5 W.H. Lim, D.J. Torpy, W.S. Jeffries The medical management of Cushing's syndrome during pregnancy Eur J Obstet Gynecol Reprod Biol, 168 (1) (2013 May), pp. 1-6, 10.1016/j.ejogrb.2012.12.015 Epub 2013 Jan 8. PMID: 23305861 ArticleDownload PDFView Record in ScopusGoogle Scholar 6 Gormley MJ, Hadden DR, Kennedy TL, Montgomery DA, Murnaghan GA, Sheridan B. Cushing's syndrome in pregnancy--treatment with metyrapone. Clin Endocrinol (Oxf). 1982 Mar;16(3):283-293. doi: 10.1111/j.1365-2265.1982.tb00718.x. PMID: 7074978. Google Scholar 7 M.C. Machado, M.C.B.V. Fragoso, M.D. Bronstein Pregnancy in Patients with Cushing's Syndrome Endocrinol Metab Clin North Am, 47 (2) (2018 Jun), pp. 441-449, 10.1016/j.ecl.2018.02.004 PMID: 29754643 ArticleDownload PDFView Record in ScopusGoogle Scholar 8 Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CR, Besser GM. Metyrapone in long-term management of Cushing's disease. Br Med J. 1977 Jul 23;2(6081):215-217. doi: 10.1136/bmj.2.6081.215. PMID: 195666; PMCID: PMC1631369. Google Scholar 9 Stalldecker G, Mallea-Gil MS, Guitelman M, Alfieri A, Ballarino MC, Boero L, Chervin A, Danilowicz K, Diez S, Fainstein-Day P, García-Basavilbaso N, Glerean M, Gollan V, Katz D, Loto MG, Manavela M, Rogozinski AS, Servidio M, Vitale NM. Effects of cabergoline on pregnancy and embryo-fetal development: retrospective study on 103 pregnancies and a review of the literature. Pituitary. 2010 Dec;13(4):345-350. doi: 10.1007/s11102-010-0243-6. PMID: 20676778. Google Scholar Clinical Relevance: Cushing’s Disease (CD) in pregnancy is a rare, but serious, disease that has potential adverse effects on maternal and fetal health. Surgery is considered first line therapy, and there is little consensus on medical treatment of CD in pregnancy. This CASE demonstrates the successful use and titration of metyrapone throughout pregnancy. From https://www.sciencedirect.com/science/article/pii/S2376060521001164

This article was originally published here Proc (Bayl Univ Med Cent). 2021 Jul 29;34(6):715-717. doi: 10.1080/08998280.2021.1953950. eCollection 2021. ABSTRACT Cushing’s disease (CD) is the most common cause of endogenous cortisol excess. We discuss the case of a 60-year-old woman with recurrent venous thromboembolism, refractory hypokalemia, and lumbar vertebrae compression fractures with a rapidly progressive disease course. Ectopic hypercortisolism was suspected given the patient’s age and rapid onset of disease. Investigations revealed cortisol excess from a pituitary microadenoma. This case demonstrates that CD can present with severe findings and highlights the increased risk of venous thromboembolism in hypercortisolism, especially in CD. PMID:34732999 | PMC:PMC8545141 | DOI:10.1080/08998280.2021.1953950

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This article was originally published here J Med Case Rep. 2021 Nov 1;15(1):544. doi: 10.1186/s13256-021-03127-3. ABSTRACT BACKGROUND: This report describes the case of a patient whose pituitary microadenoma resolved after he contracted coronavirus disease 2019. To our knowledge, this is one of the first reported cases of pituitary tumor resolution due to viral illness. We present this case to further investigate the relationship between inflammatory response and tumor remission. CASE PRESENTATION: A 32-year-old man in Yemen presented to the hospital with fever, low blood oxygen saturation, and shortness of breath. The patient was diagnosed with coronavirus disease 2019. Past medical history included pituitary microadenoma that was diagnosed using magnetic resonance imaging and secondary adrenal insufficiency, which was treated with steroids. Due to the severity of coronavirus disease 2019, he was treated with steroids and supportive care. Three months after his initial presentation to the hospital, brain magnetic resonance imaging was performed and compared with past scans. Magnetic resonance imaging revealed changes in the microadenoma, including the disappearance of the hypointense lesion and hyperintense enhancement observed on the previous scan. CONCLUSIONS: Pituitary adenomas rarely undergo spontaneous resolution. Therefore, we hypothesized that tumor resolution was secondary to an immune response to coronavirus disease 2019. PMID:34724974 | DOI:10.1186/s13256-021-03127-3

By Ed Miseta, Chief Editor, Clinical Leader Follow Me On Twitter @EdClinical Sparrow Pharmaceuticals is an emerging biopharma company on a mission to help patients suffering from an excess of corticosteroids, with a focus on Cushing’s syndrome, autonomous cortisol secretion (ACS), and polymyalgia rheumatica (PMR). Cushing’s and ACS are both caused by an excess of cortisol produced by tumors. Patients with Cushing’s can present physically with a fatty hump between their shoulders, a rounded face, and pink or purple stretch marks on their skin. Cushing’s syndrome and ACS can both result in high blood pressure, bone loss, type 2 diabetes, weight gain, and mood, cognition, and sleep disorders. Any of those symptoms may be side effects for patients with conditions such as PMR who rely on long-term treatment with corticosteroid medications such as prednisone. “Cushing’s syndrome impacts around 20,000 patients in the U.S. alone,” says David Katz, Chief Scientific Officer for Sparrow. “Approximately 50% of those patients can be cured by surgery, but some will develop another tumor years later. ACS is an under-recognized condition, but it may affect up to 3 million patients in the U.S. There are also around 2 million people in the U.S. who rely on long-term use of corticosteroid medications to control autoimmune diseases and other conditions.” The treatments being developed by Sparrow are based on recognition that cortisol and corticosteroid medications are activated in certain tissues such as the liver, bone, fat, and brain, where in excess they act to cause toxicity. The company’s investigational drugs inhibit HSD-1, the enzyme responsible for that activation. Sparrow is about to launch a Phase 2 trial for Cushing’s syndrome. In early 2022 the company will also begin two additional Phase 2 trials for ACS and PMR, a common autoimmune disease in elderly patients. PMR is an arthritic syndrome characterized by a phenomenon known as claudication, which means the more you use a limb, the more it hurts and the harder it is to use. “For example, the more a PMR patient walks, the more painful and stiff their legs will become,” says Katz. “If they're trying to do anything with their arms, the arms will get stiffer and more painful. The disease is pretty debilitating in terms of physical function. The only approved treatment for PMR is steroids, which have side effects such as diabetes, hypertension, osteoporosis, and fractures.” Unknown Clinical Challenges Katz is excited about the clinical trials for ACS and PMR because no sizable interventional trials have been reported in either of those conditions. “We're going into a completely new area, and we don't know what we're going to encounter in terms of patient recruitment and retention,” says Katz. “There is also no strong precedent for how to get approval for a drug in these conditions. The only treatment indicated for PMR is steroids, and that came without any efficacy clinical trials. There are no drugs approved for ACS. It’s hard to anticipate the challenges we will face when we are in an area that is very new.” Patient centricity is a topic that is very important to Katz, and he spends a lot of time thinking about how to make trials a more pleasant experience for patients by limiting the burden placed on them. He notes that can sometimes be a difficult trade-off because of the procedures that must be performed to meet regulatory standards. “In Cushing’s syndrome clinical care and clinical trials, the standard way for someone's cortisol level to be measured is a 24-hour urine collection,” states Katz. “That involves looking at the amount of cortisol in the urine over a 24-hour period. That collection is inconvenient and burdensome, and the patient must then carry it somewhere to be analyzed.” Sparrow hopes to shift that collection to a spot urine sample, like what patients would experience during a physical. The patient would urinate into a cup and hand it off to a clinic employee for analysis. The process would be much simpler and less burdensome for the patient. Sparrow will first need to prove that in a clinical trial the spot sample will work as well or better than the 24-hour collection. Subjects in the initial clinical trials will have to contribute the 24-hour collections so that Sparrow can demonstrate that future patients will not need to do so. The Future of Endocrinology Katz has a positive outlook on the future of endocrinology. Sparrow’s leading drug candidate, SPI-62, is an oral, small-molecule HSD-1 inhibitor. In four clinical trials, it demonstrated potent targeting of HSD-1 in both the brain and liver, and significantly lowered cortisol levels in the liver. The studies also showed a favorable safety and tolerability profile. “If we are successful at developing SPI-62, I believe it will change the field of endocrinology,” says Katz. “We aim to shift the focus in Cushing’s syndrome to intracellular cortisol as the main driver of symptoms. What I mean by that is if we find that SPI-62 substantially reduces symptoms and that the degree of inhibition of our target HSD-1 correlates well with clinical improvement, then we can get to a new standard of care. We can potentially get rid of the 24-hour urine collections, which will be a big relief to patients. Additionally, many of today's drugs have a side effect called adrenal insufficiency, which results when the drugs either reduce cortisol too much or completely block activity. Many of today's drugs also require frequent monitoring and dose titration to prevent adrenal insufficiency. We believe that with HSD-1 inhibition we might avoid adrenal insufficiency as well.” Katz is hopeful patients treated with SPI-62 will not require monitoring and dose titration. That proof will take years and lots of clinical trials. Sparrow may also produce the first targeted therapy for ACS. That could improve the recognition of ACS as a prevalent form of hypercortisolism and a substantial cause of morbidity and mortality. “ACS is probably the most under-recognized condition in endocrinology based on recent epidemiological studies,” adds Katz. “It's possible that as few as 3% of patients who have ACS actually have a diagnosis. That is shocking for a condition that is associated with a lot of cardiometabolic and bone morbidity, negative effects on mood and cognition, sleep, and muscle strength, and is associated with excess mortality. We want to bring attention to this condition by bringing out a targeted therapy to treat a spectrum of symptoms by getting to the root cause of them.” From https://www.clinicalleader.com/doc/sparrow-pharmaceuticals-hopes-to-change-the-future-of-endocrinology-0001

Abstract Cushing’s disease is an abnormal secretion of ACTH from the pituitary that causes an increase in cortisol production from the adrenal glands. Resultant manifestations from this excess in cortisol include multiple metabolic as well as psychiatric disturbances which can lead to significant morbidity and mortality. In this report, 23-year-old woman presented to mental health facility with history of severe depression and suicidal ideations. During evaluation, she found to have Cushing’s disease, which is unusual presentation. She had significant improvement in her symptoms with reduction of antidepressant medications after achieving eucortisolism. Cushing syndrome can present with wide range of neuropsychiatric manifestations including major depression. Although presentation with suicidal depression is unusual. Early diagnosis and prompt management of hypercortisolsim may aid in preventing or lessening of psychiatric symptoms The psychiatric and neurocognitive disorders improve after disease remission (the normalization of cortisol secretion), but some studies showed that these disorders can partially improve, persist, or exacerbate, even long-term after the resolution of hypercortisolism. The variable response of neuropsychiatric disorders after Cushing syndrome remission necessitate long term follow up. Keywords cushing syndrome, cushing disease, hypercortisolism Introduction Endogenous Cushing syndrome is a complex disorder caused by chronic exposure to excess circulating glucocorticoids. It has a wide range of clinical signs and symptoms as a result of the multisystem effects caused by excess cortisol.1 The hypercortisolism results in several complications that include glucose intolerance, diabetes, hypertension, dyslipidemia, thromboembolism, osteoporosis, impaired immunity with increased susceptibility to infection as well as neuropsychiatric disorders.2,3 Cushing syndrome presents with a wide variety of neuro-psychiatric manifestations like anxiety, major depression, mania, impairments of memory, sleep disturbance, and rarely, suicide attempt as seen in this case.2,4 The mechanism of neuropsychiatric symptoms in Cushing’s syndrome is not fully understood, but multiple proposed theories have been reported, one of which is the direct brain damage secondary to excess of glucocorticoids.5 Case Report A 23-year-old female presented to Al-Amal complex of mental health in Riyadh, Saudi Arabia with history of suicidal tendencies and 1 episode of suicidal attempt which was aborted because of religious reasons. She reported history of low mood, having disturbed sleep, loss of interest, and persistent feeling of sadness for 4 months. She also reported history of weight gain, facial swelling, hirsutism, and irregular menstrual cycle with amenorrhea for 3 months. She was prescribed fluoxetine 40 mg and quetiapine 100 mg. She was referred to endocrinology clinic at King Fahad Medical City, Riyadh for evaluation and management of possible Cushing syndrome as the cause of her abnormal mental health. She was seen in the endocrinology clinic where she reported symptoms as mentioned above in addition to headache, acne, and proximal muscle weakness. On examination her vital signs were normal. She had depressed affect, rounded face with acne and hirsutism, striae in the upper limb, and abdomen with proximal muscle weakness (4/5). Initial investigations showed that 24 hour urinary free cortisol was more than 633 µg which is more than 3 times upper limit of normal (this result was confirmed on second sample with level more than 633 µg/24 hour), cortisol level of 469 nmol/L after low dose 1 mg-dexamethasone suppression test and ACTH level of 9.8 pmol/L. Levels of other anterior pituitary hormones tested were within normal range. She also had prediabetes with HbA1c of 6.1 and dyslipidemia. Serum electrolytes, renal function and thyroid function tests were normal. MRI pituitary showed left anterior microadenoma with a size of 6 mm × 5 mm. MRI pituitary (Figure 1). Figure 1. (A-1) Coronal T2, (B-1) post contrast coronal T1 demonstrate small iso intense T1, heterogeneous mixed high, and low T2 signal intensity lesion in the left side of anterior pituitary gland which showed micro adenoma with a size of 6 mm × 5 mm. (A-2) Post-operative coronal T2 and (B-2) post-operative coronal T1. Demonstrates interval resection of the pituitary micro adenoma with no recurrence or residual lesion and minimal post-operative changes. There is no abnormal signal intensity or abnormal enhancing lesion seen. No further hormonal work up or inferior petrosal sinus sampling were done as the tumor size is 6 mm and ACTH level consistent with Cushing’s disease (pituitary source). She was referred to neurosurgery and underwent trans-sphenoidal resection of the tumor. Histopathology was consistent with pituitary adenoma and positive for ACTH. Her repeated cortisol level after tumor resection was less than 27 and ACTH 2.2 with indicated excellent response to surgery. She was started on hydrocortisone until recovery of her hypothalamic pituitary adrenal axis documented by normal morning cortisol 3 months after surgery (Table 1). Table 1. Labs. Table 1. Labs. View larger version During follow up with psychiatry her depressive symptoms improved but not resolved and she was able to stop fluoxetine 5 months post-surgery. Currently she is maintained on quetiapine 100 mg with significant improvement in her psychiatric symptoms. Currently she is in remission from Cushing’s disease based on the normal level of repeated 24 hour urinary free cortisol and with an over-all improvement in her metabolic profile. Discussion Cushing syndrome is a state of chronic hypercortisolism due to either endogenous or exogenous sources. Glucocorticoid overproduction by adrenal gland can be adrenocorticotropic (ACTH) hormone dependent which represent most of the cases and ACTH independent.6 To the best of our knowledge this is the first case documented in Saudi Arabia. There are multiple theories behind the neuropsychiatric manifestations in Cushing syndrome. These include increased stress response leading to behavioral changes, prolonged cortisol exposure leading to decreased brain volume especially in the hippocampus, reduced dendritic mass, decreased glial development, trans-cellular shift of water and synaptic loss, and excess glucocorticoid levels inhibiting neurogenesis and promoting neuronal tendency to toxic insult.3,7 In this report, the patient presented with severe depression with suicidal attempt. She had significant improvement in her symptoms with reduction of antidepressant medications but her depression persisted despite remission of Cushing disease. A similar case has been reported by Mokta et al,1 about a young male who presented with suicidal depression as initial manifestation of Cushing disease. As opposed to the present case he had complete remission of depression within 1 month of resolution of hypercortisolism. In general, psychiatric and neurocognitive disorders secondary to Cushing syndrome improves after normalization of cortisol secretion, but some studies showed that these disorders can partially improve, persist, or exacerbate, even long-term after the resolution of hypercortisolism. This may be due to persistence hypercortisolism creating toxic brain effects that occur during active disease.2,8 Similar patients need to be followed up for mental health long after Cushing syndrome has been resolved. Conclusion Depression is a primary psychiatric illness, that is, usually not examined for secondary causes. Symptoms of depression and Cushing syndrome overlap, so diagnosis and treatment of Cushing disease can be delayed. Early diagnosis and prompt management of hypercortisolsim may aid in preventing or lessening psychiatric symptoms. The variable neuropsychiatric disorders associated with Cushing syndrome post-remission necessitates long term follow up. Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. Informed Consent Written informed consent was obtained from the patient for the publication of this case and accompanying images. ORCID iD Sultan Dheafallah Al-Harbi https://orcid.org/0000-0001-9877-9371 References 1. Mokta, J, Sharma, R, Mokta, K, Ranjan, A, Panda, P, Joshi, I. Cushing’s disease presenting as suicidal depression. J Assoc Physicians India. 2016;64:82-83. Google Scholar | Medline 2. Pivonello, R, Simeoli, C, De Martino, MC, et al. Neuropsychiatric disorders in cushing’s syndrome. Front Neurosci. 2015;9:1-6. Google Scholar | Crossref | Medline 3. Pereira, AM, Tiemensma, J, Romijn, JA. Neuropsychiatric disorders in Cushing’s syndrome. Neuroendocrinology. 2010;92:65-70. Google Scholar | Crossref | Medline | ISI 4. Tang, A, O’Sullivan, AJ, Diamond, T, Gerard, A, Campbell, P. Psychiatric symptoms as a clinical presentation of Cushing’s syndrome. Ann Gen Psychiatry. 2013;12:1. Google Scholar | Crossref | Medline 5. Sonino, N, Fava, GA, Raffi, AR, Boscaro, M, Fallo, F. Clinical correlates of major depression in Cushing’s disease. Psychopathology. 1998;31:302-306. Google Scholar | Crossref | Medline 6. Wu, Y, Chen, J, Ma, Y, Chen, Z. Case report of Cushing’s syndrome with an acute psychotic presentation. Shanghai Arch Psychiatry. 2016;28:169-172. Google Scholar | Medline 7. Rasmussen, SA, Rosebush, PI, Smyth, HS, Mazurek, MF. Cushing disease presenting as primary psychiatric illness: a case report and literature review. J Psychiatr Pract. 2015;21:449-457. Google Scholar | Crossref | Medline 8. Sonino, N, Fava, GA. Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs. 2001;15:361-373. Google Scholar | Crossref | Medline From https://journals.sagepub.com/doi/10.1177/11795476211027668

Dr. Friedman will host Tobias Carling, MD, PhD, FACS Surgeon-in-Chief & Founder Carling Adrenal Center Hospital for Endocrine Surgery www.adrenal.com Who will talk on: The 20-minute Mini Back Scope Adrenalectomy (MBSA) The Carling Adrenal Center is the world's busiest adrenal surgery center, operating on patients from all 50 states and all over the world. Dr. Carling is the most experienced adrenal surgeon in the United States, and by far the world's most knowledgeable surgeon-scientist when it comes to adrenal gland function and disease, adrenal tumors and cancer, and all forms of adrenal gland surgery. Dr. Carling has more experience with advanced minimally invasive adrenal and endocrine operations than any surgeon in the United States. A fellow of the American College of Surgeons, Dr. Carling is a significant member of both the American Association of Endocrine Surgeons (AAES) and the International Association of Endocrine Surgeons (IAES). Dr. Carling spent 17.5 years at Yale University and the Yale University School of Medicine where he served as the Chief of Endocrine Surgery, Associate Professor of Surgery, Program Director of the Yale Endocrine Surgery Fellowship and the Founder & Director of the Yale Endocrine Neoplasia Laboratory, a supreme scientific program focused on the molecular pathogenesis of tumors arising in the adrenal, thyroid and parathyroid glands. Dr. Carling moved his world-renowned adrenal surgery program to Tampa, Florida in early 2020 to start the Carling Adrenal Center. Here, patients needing adrenal surgery have access to the best practices and best techniques the world has to offer. Dr. Carling works closely with Dr. Friedman and will be able to perform a Mini Back Scope Adrenalectomy with a referral from Dr. Friedman. Sunday • November 7• 6 PM PST Via Zoom Click here to join the meeting or https://us02web.zoom.us/j/4209687343?pwd=amw4UzJLRDhBRXk1cS9ITU02V1pEQT09 OR +16699006833,,4209687343#,,,,*111116# Slides will be available before the webinar and recording after the meeting at slides Your phone/computer will be muted on entry. There will be plenty of time for questions using the chat button. For more information, email us at mail@goodhormonehealth.com

I'm getting mine (Moderna) on Wednesday. Quick takeaway: I have adrenal insufficiency (one adrenal was removed with my kidney due to cancer, steroid-dependent (post-Cushing’s Disease), growth hormone insufficiency, panhypopituitary. I had some issues after my first COVID-19 injection (Moderna) but not too bad. My second injection was March 15, 2021. This time I was smart and updosed on my Cortef (hydrocortisone) right after the shot. My main side effects this time were chills, extreme thirst, fatigue…and a craving for salad(!) For Immediate Release: Thursday, October 21, 2021 Contact: Media Relations (404) 639-3286 Today, CDC Director Rochelle P. Walensky, M.D., M.P.H., endorsed the CDC Advisory Committee on Immunization Practices’ (ACIP) recommendation for a booster shot of COVID-19 vaccines in certain populations. The Food and Drug Administration’s (FDA) authorization and CDC’s recommendation for use are important steps forward as we work to stay ahead of the virus and keep Americans safe. For individuals who received a Pfizer-BioNTech or Moderna COVID-19 vaccine, the following groups are eligible for a booster shot at 6 months or more after their initial series: 65 years and older Age 18+ who live in long-term care settings Age 18+ who have underlying medical conditions Age 18+ who work or live in high-risk settings For the nearly 15 million people who got the Johnson & Johnson COVID-19 vaccine, booster shots are also recommended for those who are 18 and older and who were vaccinated two or more months ago. There are now booster recommendations for all three available COVID-19 vaccines in the United States. Eligible individuals may choose which vaccine they receive as a booster dose. Some people may have a preference for the vaccine type that they originally received, and others may prefer to get a different booster. CDC’s recommendations now allow for this type of mix and match dosing for booster shots. Millions of people are newly eligible to receive a booster shot and will benefit from additional protection. However, today’s action should not distract from the critical work of ensuring that unvaccinated people take the first step and get an initial COVID-19 vaccine. More than 65 million Americans remain unvaccinated, leaving themselves – and their children, families, loved ones, and communities– vulnerable. Available data right now show that all three of the COVID-19 vaccines approved or authorized in the United States continue to be highly effective in reducing risk of severe disease, hospitalization, and death, even against the widely circulating Delta variant. Vaccination remains the best way to protect yourself and reduce the spread of the virus and help prevent new variants from emerging. The following is attributable to Dr. Walensky: “These recommendations are another example of our fundamental commitment to protect as many people as possible from COVID-19. The evidence shows that all three COVID-19 vaccines authorized in the United States are safe – as demonstrated by the over 400 million vaccine doses already given. And, they are all highly effective in reducing the risk of severe disease, hospitalization, and death, even in the midst of the widely circulating Delta variant.” ### U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESexternal icon CDC works 24/7 protecting America’s health, safety and security. Whether disease start at home or abroad, are curable or preventable, chronic or acute, or from human activity or deliberate attack, CDC responds to America’s most pressing health threats. CDC is headquartered in Atlanta and has experts located throughout the United States and the world.

Cushing's Help Podcast: Adrenal Crisis Be sure to print this page to carry with you. Definition: Acute adrenal crisis is a life-threatening state caused by insufficient levels of cortisol, which is a hormone produced and released by the adrenal gland. Alternative Names: Adrenal crisis; Addisonian crisis; Acute adrenal insufficiency Causes, incidence, and risk factors: The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, all of which are called corticosteroids. Cortisol is a glucocortoid, a corticosteroid that maintains glucose (blood sugar) regulation, suppresses the immune response, and is released as part of the body's response to stress. Cortisol production is regulated by a small gland just below the brain called the pituitary gland. Cortisol is essential for life. Acute adrenal crisis is a medical emergency caused by a lack of cortisol. Patients may experience lightheadedness or dizziness, weakness, sweating, abdominal pain, nausea and vomiting, or even loss of consciousness. Adrenal crisis occurs if the adrenal gland is deteriorating (Addison's disease, primary adrenal insufficiency), if there is pituitary gland injury (secondary adrenal insufficiency), or if adrenal insufficiency is not adequately treated. Risk factors for adrenal crisis include physical stress such as infection, dehydration, trauma, or surgery, adrenal gland or pituitary gland injury, and ending treatment with steroids such as prednisone or hydrocortisone too early. Symptoms: Headache Profound weakness Fatigue Slow, sluggish movement Nausea Vomiting Low blood pressure Dehydration High fever Shaking chills Confusion or coma Darkening of the skin Rapid heart rate Joint pain Abdominal pain Unintentional weight loss Rapid respiratory rate (see tachypnea) Unusual and excessive sweating on face and/or palms Skin rash or lesions may be present Flank pain Loss of appetite Signs and tests: An ACTH (cortrosyn) stimulation test shows low cortisol. The baseline cortisol level is low. Fasting blood sugar may be low. Serum potassium is elevated ( usually primary adrenal insufficiency). Serum sodium is decreased (usually primary adrenal insufficiency). Treatment: In adrenal crisis, an intravenous or intramuscular injection of hydrocortisone (an injectable corticosteroid) must be given immediately. Supportive treatment of low blood pressure with intravenous fluids is usually necessary. Hospitalization is required for adequate treatment and monitoring. If infection is the cause of the crisis, antibiotic therapy may be needed. Expectations (prognosis): Death may occur due to overwhelming shock if early treatment is not provided. Complications: shock coma seizures Calling your health care provider: Call your health care provider if you have Addison's disease and are unable to retain usual medications because of vomiting.Go to the emergency room or call the local emergency number (such as 911) if symptoms of acute adrenal crisis develop. Prevention: People who have Addison's disease should be taught to recognize signs of potential stress that may cause an acute adrenal crisis. Most people with Addison's disease are taught to give themselves an emergency injection of hydrocortisone or increase their dose of oral prednisone in times of stress. It is important for the individual with Addison's disease to always carry a medical identification card that states the type of medication and the proper dose needed in case of an emergency. Never omit medication. If unable to retain medication due to vomiting, notify the health care provider. Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated With hGH Recently, doctors conducting the follow-up study of individuals treated with hGH looked at causes of death among recipients and found some disturbing news. Many more people have died from a treatable condition called adrenal crisis than from CJD. THIS RISK DOES NOT AFFECT EVERY RECIPIENT. IT CAN AFFECT THOSE WHO LACK OTHER HORMONES IN ADDITION TO GROWTH HORMONE. Please read on to find out if this risk applies to you. Death from adrenal crisis can be prevented. Adrenal crisis is a serious condition that can cause death in people who lack the pituitary hormone ACTH. ACTH is responsible for regulating the adrenal gland. Often, people are unaware that they lack this hormone and therefore do not know about their risk of adrenal crisis. Most people who were treated with hGH did not make enough of their own growth hormone. Some of them lacked growth hormone because they had birth defects, tumors or other diseases that cause the pituitary gland to malfunction or shut down. People with those problems frequently lack other key hormones made by the pituitary gland, such as ACTH, which directs the adrenal gland to make cortisol, a hormone necessary for life. Having too little cortisol can be fatal if not properly treated. TREATMENT WITH HGH DOES NOT CAUSE ADRENAL CRISIS, but because a number of people lacking growth hormone also lack ACTH, adrenal crisis has occurred in some people who were treated with hGH. In earlier updates we have talked about how adrenal crisis can be prevented, but people continue to die from adrenal crisis, which is brought on by lack of cortisol. These deaths can be prevented. Please talk to your doctor about whether you are at risk for adrenal crisis. Why should people treated with hGH know about adrenal crisis? Among the people who received hGH, those who had birth defects, tumors, and other diseases affecting the brain lacked hGH and often, other hormones made by the pituitary gland. A shortage of the hormones that regulate the adrenal glands can cause many health problems. It can also lead to death from adrenal crisis. This tragedy can be prevented. What are adrenal hormones? The pituitary gland makes many hormones, including growth hormone and ACTH, a hormone which signals the adrenal glands to make cortisol, a hormone needed for life. If the adrenal gland doesn't make enough cortisol, replacement medications must be taken. The most common medicines used for cortisol replacement are: Hydrocortisone Prednisone Dexamethasone What is adrenal crisis? Adrenal hormones are needed for life. The system that pumps blood through the body cannot work during times of physical stress, such as illness or injury, if there is a severe lack of cortisol (or its replacement). People who lack cortisol must take their cortisol replacement medication on a regular basis, and when they are sick or injured, they must take extra cortisol replacement to prevent adrenal crisis. When there is not enough cortisol, adrenal crisis can occur and may rapidly lead to death. What are the symptoms of lack of adrenal hormones? If you don't have enough cortisol or its replacement, you may have some of these problems: feeling weak feeling tired all the time feeling sick to your stomach vomiting no appetite weight loss When someone with adrenal gland problems has weakness, nausea, or vomiting, that person needs immediate emergency treatment to prevent adrenal crisis and possible death. • Why are adrenal hormones so important? Cortisol (or its replacement) helps the body respond to stress from infection, injury, or surgery. The normal adrenal gland responds to serious illness by making up to 10 times more cortisol than it usually makes. It automatically makes as much as the body needs. If you are taking a cortisol replacement drug because your body cannot make these hormones, you must increase the cortisol replacement drugs during times of illness, injury, or surgery. Some people make enough cortisol for times when they feel well, but not enough to meet greater needs when they are ill or injured. Those people might not need cortisol replacement every day but may need to take cortisol replacement medication when their body is under stress. Adrenal crisis is extremely serious and can cause death if not treated promptly. Discuss this problem with your doctor to help decide whether you need more medication or other treatment to protect your health. • How is adrenal crisis treated? People with adrenal crisis need immediate treatment. ANY DELAY CAN CAUSE DEATH. When people with adrenal crisis are vomiting or unconscious and cannot take medicine, the hormones can be given as an injection. Getting an injection of adrenal hormones can save your life if you are in adrenal crisis. If you lack the ability to make cortisol naturally, you should carry a medical ID card and wear a Medic-Alert bracelet to tell emergency workers that you lack adrenal hormones and need treatment. This precaution can save your life if you are sick or injured. • How can I prevent adrenal crisis? • If you are always tired, feel weak, and have lost weight, ask your doctor if you might have a shortage of adrenal hormones. • If you take hydrocortisone, prednisone, or dexamethasone, learn how to increase the dose when you become ill. • If you are very ill, especially if you are vomiting and cannot take pills, seek emergency medical care immediately. Make sure you have a hydrocortisone injection with you at all times, and make sure that you and those around you (in case you're not conscious) know how and when to administer the injection. • Carry a medical ID card and wear a bracelet telling emergency workers that you have adrenal insufficiency and need cortisol. This way, they can treat you right away if you are injured. Remember: SOME PEOPLE WHO LACKED GROWTH HORMONE MAY ALSO LACK CORTISOL, A HORMONE NECESSARY FOR LIFE. LACK OF CORTISOL CAN CAUSE ADRENAL CRISIS, A PREVENTABLE CONDITION THAT CAN CAUSE DEATH IF TREATED IMPROPERLY . Deaths from adrenal crisis can be prevented if patients and their families recognize the condition and are careful to treat it right away. Adrenal crisis is a medical emergency. Know the symptoms and how to adjust your medication when you are ill. TAKING THESE PRECAUTIONS CAN SAVE YOUR LIFE. DebMV suggested that you should have a Medic Alert bracelet from medicalert.org Toll free number in the USA is: by phone 7 days a week, 24 hours a day: 888-633-4298 209-668-3333 from outside the U.S. Lorrie got this important info for us. Alternative names: adrenal crisis; Addisonian crisis; acute adrenal insufficiency Definition: An abrupt, life-threatening state caused by insufficient cortisol, a hormone produced and released by the adrenal gland. Causes, incidence, and risk factors: The two adrenal glands are located on top of the kidneys. They consist of the outer portion, called the cortex, and the inner portion, called the medulla. The cortex produces three types of hormones, which are called corticosteroids. The androgens and estrogens affect sexual development and reproduction. The glucocorticoids maintain glucose regulation, suppress the immune response, and provide for the response to stress (cortisol). The mineralocorticoids regulate sodium and potassium balance. These hormones are essential for life. Acute adrenal crisis is an emergency caused by decreased cortisol. The crisis may occur in a person with Addison's disease, or as the first sign of adrenal insufficiency. More uncommonly, it may be caused by a pituitary gland disorder. It may also be caused by sudden withdrawal of corticosteroids, removal or injury of the adrenal glands, or destruction of the pituitary gland. Risk factors are stress, trauma, surgery, or infection in a person with Addison's disease, or injury or trauma to the adrenal glands or the pituitary gland. The incidence is 4 out of 100,000 people. Prevention: People who have Addison's disease should be taught to recognize signs of potential stress that may precipitate an acute adrenal crisis (cause it to occur suddenly and unexpectedly). Most people with Addison's disease are taught to give themselves an emergency injection of hydrocortisone in times of stress. It is important for the individual with Addison's disease to always carry a medical identification card that states the type of medication and the proper dose needed in case of an emergency. Never omit medication. If unable to retain medication due to vomiting, notify the health care provider. Symptoms: headache profound weakness fatigue slow, sluggish, lethargic movement nausea vomiting low blood pressure dehydration high fever chills shaking confusion or coma darkening of the skin rapid heart rate joint pain abdominal pain unintentional weight loss rapid respiratory rate unusual and excessive sweating on face and/or palms skin rash or lesion may be present flank pain appetite, loss Signs and tests: An ACTH (cortrosyn) stimulation test shows low cortisol. The cortisol level is low. The fasting blood sugar may be low. The serum potassium is elevated. The serum sodium is decreased. This disease may also alter the results of the following tests: sodium, urine 17-hydroxycorticosteroids Treatment: In adrenal crisis, an intravenous or intramuscular injection of hydrocortisone (an injectable corticosteroid) must be given immediately. Supportive treatment of low blood pressure is usually necessary. Hospitalization is required for adequate treatment and monitoring. Low blood pressure may be treated with intravenous fluids. If infection is the cause of the crisis, antibiotic therapy is indicated. Expectations (prognosis): Death may occur due to overwhelming shock if early treatment is not provided. Complications: shock coma seizures For more personal experiences, see the message boards A Personal Experience Shauna Wrote...What adrenal crisis feels like As with most mornings, this one began with nausea. I'm used to it, so didn't think much about it. I made it to the bathroom and was feeling really awful. Decided to just go to the toilet because I had that impending feeling. Next thing I knew I was waking up, but it wasn't like a normal awakening. I remember being in a tunnel and then thinking, "Well, this isn't where I normally sleep." Then I realized of course it wasn't where I normally slept! Normally I sleep in a bed, not wedged between a wall and the toilet. (Not that I was that coherent). I was completely disoriented as to time, place, etc. I had one big yell in me and yelled "HELP". My four year old brought me the phone and my son got me a towel. I called 911 (thank God I had a 911 sticker on the phone because I really couldn't remember the number). I kept telling the dispatcher I was in adrenal crisis. Of course, that meant nothing to him. I had my son get my shot but somewhere I knew that I wasn't together enough to give myself the shot. So I puked a few more times and told my son to take my daughter upstairs so she wasn't scared when the ambulance came. I decided to rest on the floor of the bathroom. I had, at first, tried to go to the couch but I was much, much too weak. So my son directed the medics into the bathroom. They eventually carried me to the couch. I kept telling them about my shot, but couldn't remember where I had my letter from Dr. Cook. They thought I was an overdose or a psych case (they told me later). They had all my pills lined up and were asking when I took this or that one last. I finally told them to look at the friggin date on the bottle and see that they were all 3/4 full. (I was agitated, too) They put the heart monitor on me and inserted an IV and took me to the hospital. I puked one more time in the ambulance and when we arrived (though my tummy was empty). My brother and sister-in-law where there (hospital) when I arrived and my mom had arrived at my house to take care of the kids as we were leaving. Then she met us up there. Before we arrived at the hospital, my husband had faxed a copy of Dr. Cook's letter on how to treat me over (Brian was at work when this happened). So they came in and inserted another fluid bag. Then about ten minutes later (after my brother told the doctor, "I fully expect that my sister will have her shot withing the next ten minutes" - patient advocates are a good thing because I could've cared less at that point) I had my 100 mg shot of solu-medrol. I was lucky because my doctor in the ER knew about adrenal crisis. Then I had another bag and repeated tests of my bp and heartrate. It wasn't pretty - every time my bp was low, generally around 80/50, sometimes lower and my heart rate was 120+. They decided to admit me, but I fought and fought. Once I got a shot of Zofran (anti-nausea, best in the world) and my cortisone and some fluid, I was feeling decent. I look and feel like I've been through a war, but I'm alive. As to why this happened, we're not entirely sure at this point. I have one urine test that they're culturing or something. I might also have shingles, but again - that'll show up in due time (a day or two, if I have it). Or, as Dr. Cook said when I talked to him, sometimes we just don't know. I was doing so well on my meds, back up to 27.5 and feeling good. Now I'm on 40 for the next day, and 30 for a week. Frustrating. Adrenal crisis is awful. It's terrifying. And what makes me want to cry as I write this (who am I kidding, I am crying) is that I couldn't have cared less if I lived or died. I was not in my right mind, I felt so horrid. All the surgeries combined, today was the worst day I've ever had. And it was a huge wake-up call. I need to have a better medic-alert bracelet because they had no idea what "Stress dose steroids" were. I need to have a list of what to do in crisis on my fridge, in my purse and with every family member. Same with the letter from my endo on how to treat me. Because when I'm in crisis, I don't know any better. I need to have things that speak for me. Thank God for family that knows, and for good doctors. Anyway, I didn't post this to scare anyone but Adrenal Crisis is not something to take lightly. When I felt myself hurting the night before (back pain, possibly shingles though I doubt it) I should've just taken an extra 5 mgs. Would've been a heck of a lot easier than what happened today. A few funny parts of the day: My daughter had to dress herself and my mom was in a hurry to get her to daycare and come see me. So my daughter spent the day at daycare in tights, too small shorts and a turtleneck (none of which came close to matching). Oh, and black patent leather shoes. Also, the medics asked what I weighed. Out of habit, I said 222 (my highest Cushing's weight). They ALL did a double take and said no way. One guessed 140 - bless his heart. I never did get myself weighed so I don't even know. Oh, and if any of you called at about 8 am and spoke with a medic, call me back. lol I had a blocked call at 8am, and I vaguely remember the medic talking to someone but I wasn't with it enough to ask who called. lol Something I don't say enough: I love and value you all. More personal experiences. Sue sent this along: Early Crisis Intervention The following is from the June 2002 issue of Addison News. Joan Hoffman, editor/publisher, kindly sent this issue to me and I wanted to share this with you. This is a flow chart to show the pathway of events in a crisis. It is very important to intervene as early as possible. Use your injectable and head for the hospital! The rate at which these events take varies with individuals and circumstances. The chart is a variation of one found in a nursing encyclopedia.

MeganOrrMD, JamesFindlingMD, NathanZwagermanMD, JenniferConnellyMD, KatherineAlbanoMS, JosephBoviMD Show more https://doi.org/10.1016/j.adro.2021.100813Get rights and content Under a Creative Commons license open access Abstract Pituitary carcinoma (PC) is an uncommon intracranial malignancy with a high rate of metastasis, mortality, and inconsistent response to therapy. Because PC is a rare condition (0.1%-0.2% of pituitary tumors), prospective studies and observable data are scarce. Some PC may have an endocrine secretory function and can arise from existing pituitary adenomas. Treatment often includes a combination of surgical resection, radiotherapy, and systemic therapies. Because of the poor treatment response rate and rapid progression, treatment is often palliative. Here we describe a unique, complete amelioration of severe Cushing's disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation with concurrent temozolomide. Summary Pituitary carcinoma is a rare malignancy with high rates of metastases at diagnosis, inconsistent therapeutic response, and high mortality. Treatment includes a combination of surgical resections, radiotherapy, and medications. Because of the poor treatment response rate and rapid progression, treatment is often palliative. This report describes the complete resolution of severe Cushing's disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation and concurrent temozolomide radio-sensitization. Introduction Pituitary adenomas (PA) are a common, benign tumor managed with combinations of surgery, radiotherapy, and medication. While uncommon, there are atypical PA with aggressive behaviors that are refractory to treatment. In rare instances, pituitary tumors can metastasize or spread. These malignant behaving tumors are called pituitary carcinomas (PC). PC is challenging to manage as they metastasize early and have a poor response to treatment. In reported PC cases, malignant transformation of atypical adrenocorticotrophic hormone (ACTH) secreting PA is a common pathogenesis.1 Features of PC include functional ACTH production and resistance to radiation. Because of the aggressive nature and systemic spread, the prognosis is poor with a high mortality rate of 66% at one year.2 Prospective studies and observable data are scarce. Prior reports of treatment include a combination of surgical resection, radiotherapy, and medication with inconsistent responses. Because of the poor treatment response rate and rapid progression, treatment is often palliative. This report describes a complete resolution of severe Cushing disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation with concurrent temozolomide. Case Description A 53-year female presented with complaints of blurry vision, right-sided cranial nerve (CN) III palsy, diffuse edema of her face and extremities, and a 15 lb. weight gain over 2 weeks. Visual field testing revealed bitemporal hemianopsia which prompted imaging. MRI demonstrated a large intracranial sellar mass (4.0 × 4.3 cm) invading the suprasellar cistern and compressing the optic chiasm. ACTH and cortisol were elevated, which combined with radiographic evidence, established a diagnosis of an ACTH-secreting pituitary macroadenoma and Cushing's disease (CD). The patient underwent a transsphenoidal tumor debulking, followed by CyberKnife stereotactic radiosurgery two months after surgery (treated to 24 Gy, seeTable 2). Pathology revealed an atypical PA, positive for p53 and with a low Ki-67 index. Table 1. Clinical Course Date Condition 24 h urinary cortisol* Late salivary cortisol* Serum morning cortisol* ACTH* Nov 2009 Before 1st debulking surgery 3,192 N/A N/A 635 Feb 2010 Cyberknife 6.9 1.5 9.6 134 May 2014 Redo-Debulking 40.2 5.5 11.8 190.0 August 2017 3 months post RT 20.1 5.5 39.4 240.8 May 2018 1 year post RT 16.0 5.9 12.6 199.8 Feb 2019 1 year and 6 months post RT 2.1 3.6 6.8 111.8 Jan 2020 Post 3rd Debulking N/A N/A 8.4 88.5 ⁎ 24h urinary cortisol (NR:30-310 ug/24h). Late salivary cortisol(NR < 0.13 ug/dL). Serum morning cortisol (NR: 5-25 ug/dL). ACTH (NR <46 pg/dL) GC: glucocorticoids, CS: Cushing syndrome Table 2. CyberKnife Radiation Treatment Plan Cyber Knife Feb 2010 Target/OAR Volume(cm3) Max Dose(cGy) Min Dose(cGy) Mean Dose(cGy) Standard deviation (SD)(cGy) CTV 7 2817 1214 2403 240 PTV 6 2817 1323 2457 204 Brain Stem 34 1023 28 250 160 Left Eye 7 65 16 29 7 LON 2 1069 39 233 223 Optic Chiasm 1 845 194 448 164 Right Eye 7 164 16 31 12 RON 2 1267 48 298 216 After three years in remission, she experienced worsening symptoms associated with cortisol excess. Medical management of cabergoline (D2 receptor agonist) followed by pasireotide (somatostatin analog) was tried without clinical improvement. Imaging demonstrated the mass had recurred with non-congruent intracranial spread. This noncontiguous intracranial growth met the criteria for PC. A second transsphenoidal subtotal resection was performed. Pathology revealed atypical ACTH secreting adenoma with a similarly low Ki-67, but with a new loss of p53 signaling. Despite debulking, she had biochemical persistence of hypercortisolism. Over the next two months, the patient declined rapidly with weakness, and worsening Cushing's symptoms. She was enrolled in a Phase III clinical trial with osilodrostat (11-Beta hydroxylase inhibitor) however, could not tolerate the investigational drug and was taken off. Subsequent MRI showed evidence of progression with gross residual disease and interval growth. She was referred to radiation oncology. She completed a course of image-guided, intensity modulated, radiotherapy (IG-IMRT) with concurrent temodar (TMZ) radiosensitization. TMZ was dosed at 75 mg/m2 per day for 42 days during radiation. Her IG-IMRT plan consisted of a gross tumor volume (GTV); drawn for MR defined gross disease and a clinical target volume (CTV) encompassing gross disease at risk areas of microscopic disease extension (Figure 1). These volumes were then expanded to 2 planning target volumes (PTV). The first, and larger, PTV was created by expanding the CTV to PTV1 and treated to 50.4 Gy in 28 fractions (180 cGy/fraction). The GTV alone was expanded to PTV2 (integrated boost) and was treated to a total dose of 56 Gy in 28 fractions (200 cGy/fraction) (See Table 3). Over the next two years, the patient had a steady decline in ACTH and cortisol levels and experienced a significant improvement in CD symptoms. Amazingly, she developed hypocortisolemia. Following concurrent chemo-RT, her leg strength and ambulation improved, and she endorsed improvements in vision. Surveillance images taken a year and a half after chemo-RT showed stable size and configuration of the residual sella and parasellar lesion with obvious shrinkage of the residual PC compared to prior scans. Download : Download high-res image (798KB) Download : Download full-size image Figure 1. IG-IMRT Planning Images Radiotherapy Planning session MRI T1 weighted images with contrast (March 2017) showing PTV's and prescribed isodose lines. Red lines: 5600 cGy, dose1. Yellow lines: 5040 cGy, dose 2. Orange lines: PTV1. Purple lines: PTV2. Table 3. IG-IMRT Radiation Treatment Plan IG-IMRT May 2017 Target/OAR Volume(cm3) Max Dose(cGy) Min Dose(cGy) Mean Dose(cGy) SD(cGy) EqD2 (cGy) GTV 83 6091 4922 5621 233 CTV 24 6083 5292 5793 102 PTV 1 241 6118 4753 5423 270 PTV 2 51 6118 5074 5779 106 Brain Stem 32 5784 2374 4701 586 4324 CHIASM PRV 5 5640 4881 5266 171 5109 Eye_L 8 3173 537 1355 574 841 Eye_R 7 3680 542 1551 644 990 EyeLens_L 0.1 997 614 765 81 435 EyeLens_R 0.1 830 626 719 41 406 InnerEar_L 0.5 5088 4235 4687 164 4305 InnerEar_R 0.4 5673 4853 5165 112 5175 LacrimalGland_L 0.7 2207 734 1313 382 810 LacrimalGland_R 0.8 2518 1064 1736 340 1137 OpticChiasm 0.8 5367 4881 5177 89 4981 OpticNerve_L 0.5 5325 2742 4723 592 4353 OpticNerve_R 0.6 5327 3149 4799 493 4456 EqD2: Equivalent dose in 2 Gy fractions Two years following concurrent chemo-RT, a new clival nodule was noted on imaging. Biopsy confirmed pituitary carcinoma. This was managed with single fraction Gamma Knife delivering a margin dose of 16 Gy (Figure 2) to the biopsied area of recurrence. She remains in clinical remission with stable tumor appearance on recent imaging (Figure 3). Download : Download high-res image (686KB) Download : Download full-size image Figure 2. Gamma Knife Radiation Therapy Planning Images Gamma Knife Planning session MRI T1 weighted images with contrast (May 2020) showing GTV and prescribed isodose line. Red lines: 1600 cGy prescribed dose. Blue lines: GTV. Download : Download high-res image (469KB) Download : Download full-size image Figure 3. Follow-up Imaging Follow up MRI imaging (Jan 2021) showing stable tumor appearance at 8 months post-GK, and 46 months post-IGMRT with TMZ. Discussion Over a ten-year history of persistent symptoms and aggressive tumor behavior, this patient's diagnosis evolved from an atypical ACTH secreting pituitary macroadenoma to an invasive ACTH secreting pituitary carcinoma (PC) that was managed by fractionated imaged-guided intensity modulated radiotherapy (IG-IMRT) with concurrent temozolomide (TMZ). Approximately two years post-IG-IMRT, ACTH/cortisol labs had declined, and the lesion was reduced radiographically. Remarkably, she developed hypocortisolemia mandating hydrocortisone replacement therapy despite an elevated plasma ACTH. It is postulated that the remission of Cushing's disease was likely related to chemo-radiotherapy-induced alterations in the post-translation processing of proopiomelanocortin (POMC) with the production of biologically inactive ACTH and significant decreases in cortisol biosynthesis.4 To date, the patient endorses substantial strength, visual, and cognitive improvement. The mainstay of PC treatment begins with surgical transsphenoidal resection, followed by radiotherapy for residual tumor growth, and adjuvant medical treatment. Studies show in the case of atypical PA that progress to PC, early and aggressive treatment provides the longest survival.3 Surgical resection is the initial intervention to avoid morbidity and mortality related to mass effect of these large aggressive tumors, however, it is rarely complete.3 As a result, the residual disease progresses, and multiple surgeries may be performed after a recurrence of disease. Primary pituitary tumors that present with metastases at diagnosis are termed PC. If no metastases are present, histological evaluation can aid in the management of the tumor.3 Tumors with a high mitotic index, high Ki-67 index >3%, and/or p53 immunoreactivity are termed atypical PA for their aggressive growth and tendency to recur after resection.3 In both PC and atypical PA guidelines, evidence of post-surgical growth is treated with radiation therapy. In general, radiotherapy provides a modest benefit of local tumor control, especially when administered before distant metastases arise in atypical PA with malignant potential.3 Focal stereotactic treatment has shown mostly palliative benefit with little prognostic improvement.3 Finally, medical therapy is used to combat tumor growth and hypersecretory function. Non-chemotherapy biotherapy includes somatostatin analogs, particularly in the case of GH and TSH-producing tumors, with variable tumor reduction and a limited period of control. Chemotherapy agents such as doxorubicin, cisplatin, and etoposide-based chemotherapy have been implicated in the treatment of PC.3 Responses are variable and not widely replicated, but observational studies indicated prolonged survival in cases of distant metastases, and in aggressive atypical PA before malignant transformation.1-3 One report demonstrated significant regression of an ACTH-secreting PC and distant metastases induced with cisplatin and etoposide, two cytotoxic platinum-based chemotherapy drugs.4 These agents have variable CNS penetrance, unlike TMZ, but have potential benefit in cases of PC with high mitotic indices. Without prospective, randomized studies, significant conclusions on the benefits of chemotherapeutic agents have yet to be made. Current guidelines for PC that demonstrate progression after primary tumor debulking and radiotherapy include further surgery (alpha), focused radiotherapy (beta), chemotherapy (gamma), and treatment with radionuclides (delta).3 In this case, a complex PC/recurrent atypical PA had a stable positive response to combined fractionated IG-IMRT and TMZ, demonstrating radiological decrease in tumor volume, clinical improvement, and endocrine remission status post 1 year and 8 months. The lasting results of a combined therapy approach in treating PC have been illustrated in other literature examples. In a similar case, an ACTH secreting PC was treated with a course of concurrent radiotherapy, TMZ, and bevacizumab, an anti-VEGF monoclonal antibody.5 The multimodality course was implemented six weeks post-resection. At eight weeks, the resolution of a distant metastasis helped established a positive outcome. The patient followed up this course with a year of adjuvant TMZ. Five years post treatment, there has been no evidence of recurrent disease on imaging or with ACTH monitoring.5 Another report found that an aggressive, functional ACTH-producing pituitary adenoma was managed with concurrent TMZ and radiotherapy after failing maximal conventional therapy. As in the presented PC case, this PA was recurrent after surgical, medical, and radiotherapy interventions. It rapidly progressed biochemically, radiologically, and clinically. After initiating the combined concurrent TMZ and radiation, a rapid biochemical response was observed with cortisol normalization and regression of intracranial tumor volume on MRI at 3 and 6 months. The TMZ therapy was stopped after the sixth cycle, and at twenty-two months out from treatment, the patient continues to have stable tumor volume and biochemical remission. Although the patient did not have metastasis necessary for classification of PC, the recurrent clinical course and aggressive functional nature of the tumor demonstrate the lasting positive outcome of a combined modality approach on tumor growth and endocrine remission.6 In presenting this case, fractionated IG-IMRT with TMZ was effective in achieving stable endocrine remission and partial tumor regression for several years’ duration. The recurrent clival PA is ACTH non-secreting after IG-IMRT and concurrent TMZ which has improved the patient's clinical condition. Although this mass recurred after treatment, it is quite remarkable that her tumor has remained hormonally nonfunctional, and the patient continues to have a resolution of CD symptoms. Limited clinical information exists on successful treatment options for PC. Recurrence, metastasis, and mortality are high after exhausting conventional treatment. The alternative combined therapeutic approach of current TMZ and radiation has shown rare, and lasting effects in this patient. These findings may further support the use of combined fractionated radiotherapy with concurrent TMZ treating in patients with ACTH-secreting PC who fail standard surgical and medical interventions. References 1 Joehlin-Price, A. S., Hardesty, D. A., Arnold, C. A., Kirschner, L. S., Prevedello, D. M., & Lehman, N. L. (2017). Case report: ACTH-secreting pituitary carcinoma metastatic to the liver in a patient with a history of atypical pituitary adenoma and Cushing's disease. Diagnostic Pathology, 12(1), 1–8. https://doi.org/10.1186/s13000-017-0624-5 2 Borba, C. G., Batista, R. L., Musolino, N. R. de C., Machado, V. C., Alcantara, A. E. E., Silva, G. O. da, … Cunha Neto, M. B. C. da. (2015). Progression of an Invasive ACTH Pituitary Macroadenoma with Cushing's Disease to Pituitary Carcinoma. Case Reports in Oncological Medicine, 2015(Cd), 1–4. https://doi.org/10.1155/2015/810367 3 Kaltsas, G. A., Nomikos, P., Kontogeorgos, G., Buchfelder, M., & Grossman, A. B. (2005). Clinical review: Diagnosis and management of pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism, 90(5), 3089–3099. https://doi.org/10.1210/jc.2004-2231 4 Cornell, R.F., Kelly, D. F., Bordo, G., Corroll, T. B., Duong, H. T., Kim, J., Takasumi, Y., Thomas, J. P., Wong, Y. L., & Findling, J. W. (2013). Chemotherapy-Induced Regression of an Adrenocorticotropin-Secreting Pituitary Carcinoma Accompanied by Secondary Adrenal Insufficiency. Case Reports in Endocrinology, 2013;2013:675298 https://doi.org/10.1155/2013/675298 5 Touma, W., Hoostal, S., Peterson, R. A., Wiernik, A., SantaCruz, K. S., & Lou, E. (2017). Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. Journal of Clinical Neuroscience, 41, 75–77. https://doi.org/10.1016/j.jocn.2017.02.052 6 Misir Krpan, A., Dusek, T., Rakusic, Z., Solak, M., Kraljevic, I., Bisof, V., … Kastelan, D. (2017). A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma. Case Reports in Endocrinology, 2017, 1–5. https://doi.org/10.1155/2017/2419590 Funding: None Disclosures: Dr. Findling reports grants, personal fees and other from Novartis, personal fees and other from Corcept Therapeutics, personal fees from Recordati, outside the submitted work. Research data are stored in an institutional repository and will be shared upon request to the corresponding author. © 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. From https://www.sciencedirect.com/science/article/pii/S2452109421001718

A team of scientists in Montreal and Paris has succeeded in identifying the gene responsible for the development of a food-dependent form of Cushing’s Syndrome, a rare disease affecting both adrenal glands. In their study published in The Lancet Diabetes & Endocrinology, Dr. Isabelle Bourdeau and Dr. Peter Kamenicky identify in the gene KDM1A the mutations responsible for the development of this unusual form of the disease. The scientists also show, for the first time, that the disease is genetically transmitted. Bourdeau is a researcher and a Université de Montréal medical professor practising at the CHUM Research Centre (CRCHUM), while Kamenicky works at the Hôpital de Bicêtre, part of the Assistance publique-hôpitaux de Paris network in France. Cushing’s Syndrome is caused by the overproduction of cortisol, a steroid hormone, by the two adrenal glands located above the kidneys. “When the tissues of the human body are exposed to this excess of cortisol, the effects for those with the disease are serious: weight gain, high blood pressure, depression, osteoporosis, and heart complications, for example,” said Bourdeau, co-lead author of the study with Dr. Fanny Chasseloup, a colleague from the French team. This discovery comes nearly 30 years after food-induced Cushing’s Syndrome was first described in 1992 by a research group led by Dr. André Lacroix at the CRCHUM and his colleagues Drs. Johanne Tremblay and Pavel Hamet. The form of the disease being studied by Bourdeau and her colleagues is caused specifically by the abnormal expression of the receptors of a hormone named GIP (glucose-dependent insulinotropic peptide), in both adrenal glands of patients. This hormone is produced by the small intestine in response to food intake. For people with the disease, cortisol concentrations increase abnormally every time they ingest food. The discovery of the genetic mechanism by the French and Quebec teams was made possible through the use of recent cutting-edge genetic techniques on tissues of patients including those investigated by Dr Lacroix at CHUM. Bourdeau was aided by CRCHUM researcher Martine Tétreault during the computer analyses related to the research project. Earlier diagnosis thanks to genetic analysis “In general, rare diseases are generally underdiagnosed in clinics,” said Bourdeau, the medical director of the adrenal tumors multidisciplinary team at the CHUM. “By identifying this new gene, we now have a way of diagnosing our patients and their families earlier and thus offer more personalized medicine. At the CHUM, genetic analysis is already offered in our Genetic Medicine Division.” In a remarkable demonstration of scientific cooperation, the Quebec and French teams were able to collect and study tissue specimens available in local and international biobanks in Canada, France, Italy, Greece, Belgium and the Netherlands. Blood and adrenal gland tissue samples of 17 patients—mostly women—diagnosed with GIP-dependent Cushing’s Syndrome were compared genetically with those of 29 others with non-GIP-dependent bilateral adrenal Cushing’s Syndrome. This was quite an accomplishment, given the rarity of the disease in the general population. It allowed the researchers to identify the genetic mutations of the KDM1A gene and to determine that the disease is genetically transmitted. Since 2009, the CHUM has been designated as the adrenal tumors quaternary care centre of the Quebec Cancer Program. About this study  “Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: a multicenter retrospective cohort study,” by Drs. Fanny Chasseloup, Isabelle Bourdeau and their colleagues, was published Oct. 13, 2021, in The Lancet Diabetes & Endocrinology. Funding was provided by the Agence nationale de la recherche, the Fondation du Grand défi Pierre Lavoie, the Institut national du cancer, the Fonds de recherche du Québec-Santé, INSERM and Assistance publique-hôpitaux de Paris. About the CRCHUM The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students Media contact Jeff HeinrichUniversité de MontréalTel: 514 343-7593 Lucie DufresneCentre hospitalier de l’Université de MontréalTel: 514 890-8000 p. 15380

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What You Need to Know COVID-19 Vaccine booster shots are available for the following Pfizer-BioNTech vaccine recipients who completed their initial series at least 6 months ago and are: 65 years and older Age 18+ who live in long-term care settings Age 18+ who have underlying medical conditions Age 18+ who work in high-risk settings Age 18+ who live in high-risk settings Those "underlying medical conditions" include diabetes and obesity.

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/