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So, these are only seven of the many, many symptoms of Cushing’s. I had those above – and I often felt like I looked like one of those little bearded dwarves. Cushing’s affects every part of the body. It’s not like when I had kidney cancer and only the kidney was affected. Here are some of the many areas affected. Progressive obesity and skin changes Weight gain and fatty tissue deposits, particularly around the midsection and upper back, in the face (moon face) and between the shoulders (buffalo hump). Some symptoms such as sudden weight gain, are caused by excess cortisol. The excess cortisol in the body does not increase protein and carbohydrate metabolism. It slows or nearly disables metabolism function, which can cause weight gain (fat accumulation) in the buttocks, abdomen, cheeks, neck, or upper back. Loss of muscle mass. Some areas of the body, such as the arms and legs, will remain thin. Pink or purple stretch marks (striae) on the skin of the abdomen, thighs, breasts and arms Thinning, fragile skin that bruises easily Slow healing of cuts, insect bites and infections Acne Women with Cushing’s syndrome may experience: Thicker or more visible body and facial hair (hirsutism) Irregular or absent menstrual periods Men with Cushing’s syndrome may experience: Decreased libido Decreased fertility Erectile dysfunction Other signs and symptoms include: Fatigue Muscle weakness Depression, anxiety and irritability Loss of emotional control Cognitive difficulties New or worsened high blood pressure Glucose intolerance that may lead to diabetes Headache Bone loss, leading to fractures over time Hyperlipidemia (elevated lipids – cholesterol – in the blood stream) Recurrent opportunistic or bacterial infections Think you have Cushing’s? Get to a doctor and don’t give up!

Abstract Purpose This study was undertaken to assess the unmet needs within the endogenous Cushing’s syndrome (CS) care paradigm from the endocrinologist’s perspective, including data abstracted from patient charts. The study evaluated endocrinologists’ perceptions on burden of illness and treatment rationale along with the long-term clinical burden of CS, tolerability of CS treatments, and healthcare resource utilization for CS. Methods Retrospective medical chart data from treated patients with a confirmed diagnosis of CS was abstracted using a cross-sectional survey to collect data from qualified endocrinologists. The survey included a case report form to capture patient medical chart data and a web-enabled questionnaire to capture practitioner-level data pertaining to endocrinologists’ perceptions of disease burden, CS treatments, and treatment attributes. Results Sixty-nine endocrinologists abstracted data from 273 unique medical charts of patients with CS. Mean patient age was 46.5 ± 13.4 years, with a 60:40 (female:male) gender split. The mean duration of endogenous CS amongst patients was 4.1 years. Chart data indicated that patients experienced a high burden of comorbidities and symptoms, including fatigue, weight gain, and muscle weakness despite multi-modal treatment. When evaluating treatments for CS, endocrinologists rated improvement in health-related quality of life (HRQoL) as the most important treatment attribute (mean score = 7.8; on a scale of 1 = Not at all important to 9 = Extremely important). Surgical intervention was the modality endocrinologists were most satisfied with, but they agreed that there was a significant unmet treatment need for patients with CS. Conclusion Endocrinologists recognized that patients with CS suffered from a debilitating condition with a high symptomatic and HRQoL burden and reported that improvement in HRQoL was the key treatment attribute influencing their treatment choices. This study highlights unmet needs for patients with CS. Patients with CS have a high rate of morbidity and comorbidity, even after treatment. Introduction Endogenous Cushing’s syndrome (CS) is a rare, debilitating disorder caused by chronic overproduction of cortisol [1,2,3]. CS has an estimated incidence of 0.7 to 2.4 cases per million per year, with a majority of cases (~ 70%) occurring in women [1, 4, 5]. Active CS is characterized by a variety of signs and symptoms, including muscle weakness, obesity, depression, menstrual changes, facial redness, decreased libido, hirsutism, acne, ecchymoses, hypertension, diabetes, and neurocognitive deficits [6]. Because of the diverse constellation of associated symptoms, many of which are common in the general population, CS can be challenging to diagnose and patients often seek input from multiple specialists (i.e., orthopedists, rheumatologists, gynecologists, and endocrinologists) prior to receiving a correct diagnosis [6]. Current treatment options for CS include surgery as the first line of treatment, followed by pharmacotherapies as the second line option and radiation therapy, among other treatments, as a potential third line option. Pharmacotherapies include steroidogenesis inhibitors (e.g., ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane), glucocorticoid receptor antagonists (e.g., mifepristone), and medications that inhibit tumoral ACTH secretion (e.g., pasireotide, cabergoline) [6,7,8,9,10]. These pharmacotherapies can be administered as monotherapy or in combination. The impact of CS on overall health-related quality of life (HRQoL) has been previously described [11]. However, studies reporting both the patient burden (via medical charts) and physician perceptions of burden are lacking, and studies examining healthcare resource utilization (HCRU) and the economic burden of CS are limited. The current study reviewed medical charts of patients with CS to characterize the overall burden of CS (including symptoms, treatments, and HCRU) as well as physician perceptions of available treatments for CS and the rationale behind associated treatment decisions. Methods Study design and recruitment This quantitative, cross-sectional study was conducted to collect disease burden data pertaining to patients with CS from qualified physician respondents. All study materials were reviewed and granted exemption by a central Institutional Review Board (IRB) prior to study execution (Advarra; Columbia, MD; https://www.advarra.com/). HCPs were recruited via a physician panel through an independent recruitment partner (Toluna) and received an appropriate honorarium for their time participating in the study. This study was fielded between May 26 and July 27, 2021, and involved the abstraction of retrospective medical chart data from patients with a confirmed diagnosis of CS by endocrinologists. The survey included a 45–60-min web-enabled questionnaire, including a case report form (CRF) component, to capture patient medical chart data and health care practitioner (HCP)-level data in order to assess perceptions of CS disease burden, treatments, and attributes associated with treatments. Considering the rarity of CS, each HCP was required to abstract information from a minimum of 2 patient charts, and a maximum of 8 patient charts. Selection of study population HCPs were able to participate in the study if they: 1. Were board-certified or board-eligible in endocrinology in the United States. 2. Had been in practice for more than 3 years and less than 35 years post residency. 3. Spent at least 25% of their professional time providing direct patient care. 4. Had treated or managed at least 40 unique patients (of any condition) in an average month. 5. Had managed (i.e., had an appointment with) at least 3 patients with CS in the past year. 6. Had access to confirmed CS patient chart(s) at the time of the study. Each HCP who qualified to participate provided information via chart abstraction from the medical records of 2–8 patients with CS. The selected medical charts were from patients ≥ 21 years of age who had received a physician confirmed diagnosis of CS at least 3 months before the time of the study, and had received at least one therapy (surgical, radiological, or pharmacological) to treat their CS within the past 12 months. Patients who were diagnosed with adrenal or pituitary carcinomas were excluded. Data analysis The data analysis was conducted in SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and Q Research Software 5.6. (Q Research Software, New York, NY). After pilot interviews and throughout the fielding, quality control checks of all the case report forms were conducted to ensure that charts with logical inconsistencies were removed from the sample. Descriptive statistics (such as means, medians, and frequencies) were used to describe the study population across various patient and physician level metrics. Results Endocrinologists’ demographics and practice characteristics Endocrinologists’ demographic information and practice characteristics are presented in Table 1. A total of 69 endocrinologists were surveyed and they provided information on 273 unique patient charts. The majority of the 69 endocrinologists surveyed (53/69, 73%) were male. The mean (± SD) time in practice was 17.3 (± 7.6) years. The majority of endocrinologists (35/69, 51%) worked in urban practices and were in private practice settings (47/69, 68%) (Table 1). The sample was almost equally distributed between physicians from the northern (26%), southern (29%), eastern (25%) and western (22%) regions of the United States. The mean (± SD) estimated number of patients with endogenous CS seen in the last 6 months was 30 (± 34.4) patients. Table 1 Endocrinologist demographics and practice characteristics Full size table aEndocrinologist were allowed to select multiple practice settings, if applicable Patient demographics Patient demographics and clinical characteristics at the time of the survey are shown in Table 2. The majority of patients (165/273, 60%) were female with a mean (± SD) age at diagnosis of 40.2 (± 12.3) years and a mean (± SD) age at the most recent visit of 46.5 (± 13.4) years. Mean (± SD) BMI was 33.3 (± 8.3) kg/m2, with 50.5% of patients categorized as obese, 33.0% of patients categorized as overweight, 14.7% of patients categorized as normal or healthy weight, and 1.8% of patients categorized as underweight (Table 2). Most patients (167/273, 61%) had private or commercial health insurance. Patient demographics and clinical characteristics at disease diagnosis are shown in Table 2. A majority of patients (194/273, 79%) originally saw their primary care physician (PCP) prior to diagnosis and were diagnosed in a private practice setting (182/273, 67%). At the time of diagnosis, 46/273 patients (17%) had poor health, 107/273 patients (39%) had fair health, 68/273 patients (25%) had neutral health, 45/273 patients (16%) had good health, and 7/273 patients (3%) had excellent health, according to the responding physician. Table 2 Patient demographics, clinical characteristics and therapy experience at diagnosis and time of the study Full size table Treatment of endogenous Cushing’s syndrome The patient treatment experience at the time of the study is presented in Table 2. Of the 273 patients, 79 (28.9%) underwent surgery only, 11 patients (4.0%) underwent surgery and radiation therapy, 4 patients (1.4%) underwent radiation therapy and pharmacotherapy, 5 patients (1.8%) underwent surgery, radiation therapy, and pharmacotherapy, 85 patients (31.1%) underwent surgery and pharmacotherapy, 2 patients (< 1%) underwent radiation alone and 87 patients (31.9%) underwent pharmacotherapy alone. Symptomatic burden of endogenous Cushing’s syndrome At diagnosis, 34% of patients presented with 1–3 symptoms, 33% of patients presented with 4–6 symptoms, 20% of patients presented with 7–9 symptoms, 8% of patients presented with 10–12 symptoms, and 5% of patients presented with > 13 symptoms (Fig. 1). Symptoms of CS at the time of diagnosis are shown in Fig. 2. The top 10 most common symptoms of CS at the time of diagnosis (Fig. 3) included fatigue, weight gain (in the midsection and upper back), acne, muscle weakness, facial weight gain (i.e., facial roundness), decreased libido, headache, edema, emotional lability, and hirsutism. Although symptoms decreased post-treatment, a large proportion of subjects still exhibited these symptoms post-treatment (Fig. 3). The most commonly reported comorbidities observed in patients with CS at the time of CS diagnosis (i.e., those affecting ≥ 20% of patients) included obesity, hypertension, depression, diabetes, dyslipidemia, anxiety, and impaired glucose tolerance (Table 2). Fig. 1 Number of CS symptoms reported at diagnosis Full size image Fig. 2 Symptoms of CS at diagnosis (N = 273) Full size image Fig. 3 Top 10 symptoms of CS over time. Responses were restricted for Erectile Dysfunction and Irregular Menstrual Periods. Hirsutism was not restricted to females only. All denominators in the table reflect the entire patient cohort, while the metrics below are based on only the affected genders: Female Only Hirsutism: 19% of the cohort (= 52/273), 32% of the females (= 52/165), Erectile Dysfunction: 6% of the cohort (= 17/273), 16% of the males (= 17/108) and, Irregular Menstrual Period: 11% of the cohort (= 30/273), 18% of the females (= 30/165) Full size image Economic burden of Cushing’s syndrome Healthcare resource utilization was assessed (Table 3). Patients required a mean (± SD) of 1 (± 1.4) hospitalization annually with a mean (± SD) length of impatient stay of 4.3 (± 3.1) days. Patients required a mean (± SD) of 0.6 (± 1.3) annual emergency room (ER) visits, and 4.3 (± 6.3) outpatient visits. Table 3 Healthcare resource utilization Full size table Endocrinologists’ perceptions of disease burden Endocrinologists were asked if they agreed with a series of statements regarding their perception of CS burden and impact on a scale of 1–9, where 1 = Not at all agree and 9 = Completely agree (Fig. 4). The highest proportion of endocrinologists responded “Completely agree” with the statements “CS patients can have reduced ability to function at work or school due to their condition” (percent of endocrinologists who responded “Completely agree” = 35%), “patients with CS feel the impact of their condition every day” (30%), that “CS is a debilitating condition” (28%), “patients with CS often have impaired health-related quality of life” (28%), and “CS results in sleep disturbances that adversely impact patient’s HRQoL” (26%). Fig. 4 Physicians’ perceptions of CS burden and impact. On a scale of 1–9, where 1 = Not at all agree and 9 = Completely agree Full size image Endocrinologists’ treatment perceptions Endocrinologists were asked for their perceptions of the most important treatment attributes on a scale of 1 to 5, where 1 = the least important and 5 = the most important (Table 4). The two most important treatment attributes included treatments that were efficacious post-surgery (mean score = 4.0) and efficacious as a combination therapy (3.7). Endocrinologists were asked to rank satisfaction with currently available treatments for CS including surgical intervention, pharmacotherapy, and radiological or other interventions on a scale of 1–9, where 1 = Not at all satisfied and 9 = Extremely satisfied (Table 5). Overall, endocrinologists reported highest satisfaction with surgical intervention with regards to initial efficacy (mean score = 7.2), durability (6.9), safety (6.3), side effects (6.2), tolerability (6.4), and patient’s overall experience (6.9). Endocrinologists also ranked pharmacotherapy higher than radiation therapy for the treatment of CS for initial efficacy (5.9 versus 5.2), safety (5.9 versus 5.4), side effects (5.3 versus 5.2), tolerability (5.7 versus 5.5), and patient’s overall experience (5.9 versus 5.4). Table 4 Top 5 highest rated treatment attributes Full size table Table 5 Physicians’ satisfaction across therapeutic categories Full size table Endocrinologists’ attitudes toward treatments and interventions Key factors for evaluating and selecting a CS treatment were rated on a scale of 1–9, with 1 = Not at all important and 9 = Extremely important (Fig. 5). Improving HRQoL (mean score = 7.8) was rated as the most important attribute. Similarly, improving cardiovascular complications/events (e.g., myocardial infarction, stroke, embolism) (7.6), psychiatric symptoms (e.g., depression, anxiety, mood changes) (7.6), skeletal/muscular symptoms (e.g., muscular weakness, decrease in bone mineral density, bone fractures) (7.5), and neurologic symptoms (e.g., headaches, memory, and cognitive difficulties including brain fog) (7.5) were ranked as key factors when choosing CS treatment. While factors in the survey such as “causes high rate of adrenal insufficiency” and “label contains a warning against use in CS” were ranked as less important, none of the factors listed were considered unimportant by physician respondents for choosing CS treatment. Fig. 5 Key factors for evaluating CS treatments that influence medication selection. On a scale of 1–9, where 1 = Not at all important and 9 = Extremely important Full size image Endocrinologists were asked if they agreed with a series of statements regarding CS treatment and intervention attitudes on a scale of 1–9, where 1 = strongly disagree and 9 = strongly agree (Table 6). The three highest scoring statements were “there is a significant clinical unmet need for patients with endogenous CS” (mean score = 6.6), “better patient support services for CS medications often leads to better patient adherence” (6.5), and “patient out of pocket cost is a significant burden for CS patients on a pharmacological therapy” (6.5). The lowest scoring statement was “patient out of pocket cost is not a significant factor when prescribing pharmacological therapy for my CS patients” (4.6). Table 6 Physicians’ attitudes toward CS treatment and intervention Full size table Discussion This study provides valuable information on the physician’s perspective of unmet needs and treatment goals for patients with CS. Endocrinologists in our sample strongly agreed that patients with CS suffered from a debilitating daily condition with a high HRQoL burden. Endocrinologists also strongly agreed with the view that “there is a significant clinical unmet need for patients with endogenous CS” and ranked prescribing treatments to improve HRQoL, cardiovascular events, depression, and anxiety as key factors influencing treatment decisions. The importance providers place on the availability of post-surgery treatment options reflects the inability of many patients with CS to achieve complete post-surgical symptom resolution and suggests all symptoms in patients with CS are not currently addressed with available treatments. Multiple treatment modalities were utilized by endocrinologists in the care of patients with CS, including surgery, pharmacotherapy, and/or radiation therapy. Improvement in HRQoL was the key treatment attribute influencing CS treatment choices, followed by the goal of reducing cardiovascular complications, and decreasing psychiatric symptoms. However, the prevalence of comorbidities after CS treatment as well as endocrinologists’ perceptions and attitudes regarding an unmet need for CS treatments and ongoing disease burden showed that few therapies are able to improve patients’ ongoing disease burden. New CS treatments are needed that have long-term efficacy, fewer side effects, and effective reimbursement. Patients with CS have a high symptomatic disease burden at diagnosis. This study and others have demonstrated that many of these signs and symptoms (e.g., hypertension, obesity, and depression) persist even after receiving treatment aimed at normalizing cortisol levels [12,13,14,15]. Results from the present study show that many patients continue to experience fatigue, weight gain, muscle weakness, and emotional lability even after treatment, indicating an unmet need for CS treatments that can effectively manage these persistent symptoms. The persistence of symptoms after treatment for CS is likely multifactorial, and may, at least in part, be due to complications of prolonged hypercortisolism, given diagnostic and treatment delays; however, the ability to predict which patients will continue to experience persistent symptoms after treatment is challenging [14, 16, 17]. Additionally, the effects of inadequate cortisol control, symptoms due to glucocorticoid withdrawal, and side effects from medications taken to address comorbidities may contribute to persistent symptoms after treatment for CS. Although there are currently established reference values and treatment guidelines used to stratify patients, there are no current clear guidelines on management of ongoing symptoms after cortisol levels have been addressed [18]. Additionally, the present study indicated that only 32% of patients were diagnosed at the first presentation of their CS symptoms, underscoring the importance of increasing awareness of CS and its presentation among PCPs to expedite diagnosis and treatment. The economic burden of illness from CS includes both the direct impact on HCRU, and the indirect impact on the patient due to loss of work productivity. The present study determined that the mean (± SD) annual number of hospitalization among patients with CS was 1 (± 1.4) day with an average length of inpatient stay of 4.3 days, similar in duration to the mean length of stay for all hospitalizations in the US [19]. However, the average number of outpatient visits among patients with CS was 4.3 visits per year, slightly lower than described in a recent study of patients with CS [11], but almost twice the rate of the average American, indicating a substantial direct cost burden [20]. Patients’ reduced ability to function at work or at school could limit their full economic potential, not only for themselves, but for family members and caregivers, indicating an indirect economic cost. The degree of concordance between patients’ chart data and the perceptions of providers regarding disease symptoms is an important issue raised, but not directly addressed, by this study. Although endocrinologists agreed that there was a high HRQoL burden attributable to CS, this study did not analyze patients’ perceptions of HRQoL burden of CS. Discordance between patients’ perceptions and the perceptions of their healthcare providers, as well as the tendency of providers to perceive disease burden as less impactful or severe than is perceived by patients, has been reported in other medical conditions such as acromegaly, rheumatoid arthritis and chronic pain. The result of this is often worse medical outcomes for patients with rheumatoid arthritis or worse pain and functioning in patients with chronic pain [21,22,23,24]. Further study is necessary to analyze the concordance between the perceptions of physicians and patients with CS. A recent cross-sectional web-enabled survey burden of illness study and a recent systemic literature review [11, 25, 26], conducted by the authors of this study, elucidated both the burden of CS as well as unmet needs in the healthcare system for patients with CS. The results of the current study corroborate the findings of both of these studies, confirming that patients experience a substantial and complex burden of cumulative CS symptoms that impacts their HRQoL. Similar to prior studies, the current results also demonstrate that although symptoms improve with treatment, some symptoms such as weight gain, pain, and anxiety persist even after treatment interventions, including surgery, pharmacotherapy, and radiation therapy. Patients with CS have previously been shown to have worse HRQoL scores compared to healthy counterparts [26], underscoring the long-term effects of CS despite treatment. This study and others have demonstrated that current therapies do not completely mitigate this HRQoL burden and indicate an unmet need among many patients with CS for additional treatments to control symptoms after cortisol level normalization. Study limitations During the time in which this study was conducted, additional CS treatments could have been approved, potentially changing the treatment landscape, and thereby altering the proportion of patients that continued to have symptoms after treatment (Fig. 3) or the proportion of patients with a particular comorbidity after treatment. Physician response may have been subject to recall bias; although this may have been mitigated by the use of patient chart data the possibility that details were omitted at the time of patient visits exists. Additionally, when physicians were asked about working in a Center of Excellence, the term was not explicitly defined which may have led to varying interpretations by respondents. Due to the nature of the method used (i.e., a survey given to endocrinologists treating patients at the present time), we have limited historical chart data on the entire medical journey of each patient and all important medical events may not have been captured. For example, treatments administered to patients prior to this study (i.e., those administered by previous doctors or from a different hospital) may not be present in the patients’ charts and were not captured by our survey. Additionally, we did not capture biochemical data to make definitive statements on disease status based on patient cortisol levels. Updated guidelines on cortisol levels indicative of disease severity have recently been issued by the Pituitary Society [18], and a shift toward standardized clinical guidelines may help physicians provide timely and appropriate treatment for patients with CS. Future patient-centered research in CS should focus on identifying biomarkers associated with persistent symptoms after initial treatment, which could influence the development of guidelines for managing ongoing symptoms as current treatments are focused on cortisol management. The cohort of patients with CS included in our study is also not representative of the full spectrum of patients with CS as they were required to have received at least one pharmacological therapy to be eligible for the study. This requirement was added to our eligibility criteria as the aim of our study was to evaluate the burden of illness faced by patients with Cushing’s Syndrome, post-treatment, in the real world. Future studies evaluating concordance between patient chart data and physician perceptions of CS symptoms are also likely to be of interest. Finally, patient symptoms in this study could potentially have been masked due to the use of over-the-counter medications or other prescription treatments not fully captured in charts. Conclusion Patients with CS continue to experience symptoms such as fatigue, weight gain, muscle weakness, and emotional instability even after seeking and receiving treatment, indicating an unmet need for treatments that control symptoms. Future research is needed to develop a treatment paradigm that alleviates disease burden in patients with CS and that results in long-term disease control with a favorable side effect profile. Data availability The authors confirm that all pertinent data generated or analyzed during this study are included in this manuscript or Supplementary Materials. Consent to publish Study participants consented to the publication of their data anonymously on an aggregate basis. References Lacroix A et al (2015) Cushing’s syndrome. 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Pituitary 23(2):140–148 Article PubMed Google Scholar Panda M et al (2006) The influence of discordance in pain assessment on the functional status of patients with chronic nonmalignant pain. Am J Med Sci 332(1):18–23 Article PubMed Google Scholar Page-Wilson GO, Maguire A, O'Hara M, Moloney S, Eliza G (2022) Patient-reported burden of illness in endogenous Cushing’s syndrome Page-Wilson GO, Bhagyashree O, Silber A, Meyer J, O'Hara M, Geer E (2022) Physician perceptions on the treatment and health-related quality of life burden of endogenous Cushing’s syndrome Download references Acknowledgements Medical editorial assistance was provided by Amal Gulaid, MPH from Trinity Life Sciences. Medical writing assistance was provided by Iona Bartek, PhD. Funding for this study was provided by Strongbridge Biopharma plc, a wholly owned subsidiary of Xeris BioPharma Holdings, Inc. Target Journal Pituitary. Funding Funding for this study was provided by Strongbridge Biopharma plc, a wholly-owned subsidiary of Xeris Biopharma Holdings, Inc. Gabrielle Page-Wilson, MD and Eliza B. Geer, MD were contracted by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to provide expert guidance for this study. Bhagyashree Oak, PhD, Abigail Silber, MPH, and Mathew O’Hara, MBA are employees of Trinity Life Sciences, which was commissioned by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to conduct the current study. James Meyer, MBA, PharmD is an employee and shareholder of Xeris Pharmaceuticals, Inc. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Author information Authors and Affiliations Division of Endocrinology, Columbia University Irving Medical Center, New York, NY, USA Gabrielle Page-Wilson Trinity Life Sciences, Waltham, MA, USA Bhagyashree Oak, Abigail Silber & Matthew O’Hara Xeris Pharmaceuticals, Inc, Chicago, IL, USA James Meyer Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA Eliza B. Geer Contributions All authors contributed to the study conception and design. Study material preparation, data collection, analyses, and manuscript development were conducted by BO, AS, and MO. JM provided overall strategic guidance. GP-W and EBG provided expert reviews of the work. All authors read and approved the final published version. Corresponding author Correspondence to Eliza B. Geer. Ethics declarations Conflict of interest Funding for this study was provided by Strongbridge Biopharma plc, a wholly-owned subsidiary of Xeris Biopharma Holdings, Inc. Gabrielle Page-Wilson, MD and Eliza B. Geer, MD were contracted by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to provide expert guidance for this study. Bhagyashree Oak, PhD, Abigail Silber, MPH, and Mathew O’Hara, MBA are employees of Trinity Life Sciences, which was commissioned by Strongbridge Biopharma, a wholly owned subsidiary of Xeris Biopharma Holdings, Inc. to conduct the current study. James Meyer, MBA, PharmD is an employee and shareholder of Xeris Pharmaceuticals, Inc. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Ethical approval This was an observational study conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. As this was not a randomized clinical trial, the study was not registered as such. The ADVARRA Institutional Review Board (Columbia, MD; https://www.advarra.com/) has granted the study exemption from IRB oversight using the Department of Health and Human Services regulations found at 45 CFR 46.104(d)(2). The IRB also completed the necessary additional limited review considerations as set forth under the Revised Common Rule, 45 CFR 46.104(d). Informed consent Informed consent was obtained from all participants included in the study during the screening process and this was required to successfully enroll into the study. Participants were able to exit the study at any time or refuse to answer any questions. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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Lydia, a 28-year-old Florida resident, wife, and mother of two, first noticed a drastic increase in her weight around Easter of 2022 in a family photo. She was shocked by how different she looked despite not making any drastic changes to her diet. “While those I loved would say ‘you look beautiful’, to me I looked like a completely different person,” recalled Lydia. When Lydia asked her mother, Jeanne, if she had noticed her weight gain, her mother observed that some days Lydia’s face looked swollen. They both recognized that this was not normal, and decided, like many pituitary patients, to make an appointment with a primary care provider. “I remember her saying to me ‘something is wrong with me’ and ‘something is not right’”, recalled Jeanne. Lydia’s weight gain was most noticeable in her face and around her abdomen. “She was exercising all the time and trying to watch what she ate and cut down on sugars,” said Jeanne. “But she kept putting on more weight. We knew something was not right.” Lydia scheduled the first of what would be many doctor appointments hoping for answers. Her primary care provider recognized that her rapid weight gain was abnormal and ordered standard blood work. When that blood work came back normal, her doctor referred her to an endocrinologist and to her OBGYN. In addition to her weight gain, Lydia had begun developing other symptoms including excessive sweating day and night, severe acne, hair loss, hair gain on her face, insomnia, thin skin, and brittle nails. “The worst symptom was the constant feeling of fight or flight,” recalled Lydia. “I always felt on edge and was letting things bother me.” Lydia would later learn that this feeling was caused by the drastic increase of cortisol in her body. When Lydia first met with her OBGYN to address her weight gain and the overall feeling that something was wrong with her body, her concerns were quickly dismissed. “He told me ‘You’re almost 30 and you’ve had two kids, no wonder you feel the way that you do,’” said Lydia. “He blew me off and told me that I needed more diet and exercise. He didn’t order other tests.” Figure illustrates the drastic physical changes and symptoms caused by a pituitary tumor and Cushing’s disease. (Medical illustration by Mark Schornak, MS, CMI) A couple of months later, Lydia went to see an endocrinologist. Despite watching her calories and exercising almost every day of the week, she had gained more weight and felt more miserable. When her labs came back, Lydia’s cortisol levels were so high that the endocrinologist thought there had been a lab error. A 24-hour urine test confirmed that Lydia’s cortisol levels were off the charts. “I was in full panic mode at this point,” said Lydia. Lydia could not get back in to see her endocrinologist in a timely manner, so she ended up back at her primary care provider’s office. Her primary care provider suggested that it could be a tumor on her adrenal glands and that it was probably not in her brain since she was not experiencing headaches. A CT scan of the adrenal glands came back clean. “I remember telling my primary care doctor ‘I just don’t feel normal’”, recalls Lydia. “His response was ‘everyone’s normal is different’ and I told him ‘I’m not normal for me.’” At this point, Lydia was desperate for answers. “All these doctors were telling me it could be in my head or because I was almost 30,” said Lydia. “I kept getting shut down. I told friends and family that there was something seriously wrong with me and no one was believing me.” Finally, a friend sent Lydia information on another endocrinologist in Florida. “He was the first doctor to care about me,” said Lydia. “He said, ‘I’m so sorry you’ve been treated like this. Everyone you have seen before me is an idiot.’” More specific bloodwork and an MRI confirmed that Lydia had a macroadenoma, a benign tumor in the pituitary gland, and Cushing’s disease. After the diagnosis, Lydia was told that she would need to have the tumor removed. “He told me, ‘Find where you want to go and I’ll refer you,’” said Lydia. Lydia and her mother Jeanne began searching online for the right pituitary tumor surgeon. “Once I realized how serious it was, we started researching different doctors,” recalled Jeanne. Both Lydia and Jeanne spent time researching different doctors, but could not find a doctor that had experience treating Cushing’s disease. “We researched all kinds of surgeons to find the best one,” said Jeanne. “Then we found Dr. Oyesiku. He understood Cushing’s disease. That was important to me.” Jeanne is the one who found world-renowned pituitary tumor surgeon, Dr. Nelson Oyesiku. “I called him and said, ‘I have a 28-year-old daughter with a pituitary tumor and Cushing’s disease and I need you to operate on her,’” said Jeanne. Dr. Oyesiku has performed over 4,000 pituitary tumor operations and is currently the Chair of the Department of Neurosurgery at UNC Health. “Cushing’s is a rare disease so not many surgeons have a lot of experience with the various technical nuances required to achieve a high likelihood of cure and reduce the incidence of re-operations and complications,” said Dr. Oyesiku. Since Lydia lives in Florida, her initial consultation with Dr. Oyesiku was over Zoom. “I Zoomed with another local neurosurgeon and I was going back and forth,” said Lydia. “Dr. Oyesiku told me that he looks at the whole picture and what the tumor is doing to you. He said that he wanted to get the tumor out and then cure the Cushing’s disease.” Jeanne was also with her daughter during the initial Zoom appointment with Dr. Oyesiku. “I couldn’t find anyone else that had that background knowledge for Cushing’s disease,” said Jeanne. Dr. Oyesiku ordered more labs. “He told me ‘I want to measure twice and cut once,’” recalled Lydia. “That phrase is something my dad always said growing up and that felt like fate. So that made my decision for me and made me want to see him.” After her initial consultation with Dr. Oyesiku, both Lydia and her mother felt confident that they had found the right surgeon. Lydia met with Dr.Oyesiku in December of 2022, then had her surgery on January 23, 2023. “I called UNC and made sure that I could go in with her and stay while she was recovering,” said Jeanne. “We had contacted a different hospital early on, and I would have had to drop her off and not see her until after her surgery and only during visiting hours.” Patient coordinator David Baker, who also played an important role in Lydia’s care, helped Lydia and Jeanne find a local hotel for them to stay in before surgery at a discounted rate. After surgery, UNC Health endocrinologist Dr. Atil Kargi spoke with Lydia and her mom to help them understand the severity of Cushing’s disease and the importance of monitoring Lydia closely. “Dr. Kargi and David Baker really helped us to truly understand Cushing’s disease,” said Jeanne. Jeanne was impressed with the level of patient care that Lydia experienced during her surgery at UNC Health. “Lydia had her own nurse that would text me or call me to let me know how things were progressing.” Jeanne said. Jeanne explained that the same nurse was with her daughter going into the surgery and when she woke up after the surgery. She was also able to stay with Lydia in the hospital while she recovered from the surgery. “UNC was such an uplifting place. All these residents, they all love what they’re doing,” said Jeanne. Lydia stayed in the hospital for six days so Dr. Oyesiku and the endocrine team could monitor her levels. “I was in the normal range, and then I started to tank,” said Lydia. “I had read that a lot of patients are sent home right after surgery. If they would have sent me, I would have been adrenally insufficient.” Lydia also expressed gratitude for ENT surgeon, Dr. Brian Thorp. “During my surgery, Dr. Thorp also repaired my deviated septum,” said Lydia. “Even after surgery when I was home miles away in Florida, he was always available to me. I appreciate Dr. Oyesiku and everyone at UNC,” said Lydia. “I can’t imagine going anywhere else for this. Dr. Oyesiku truly saved my life.” After her discharge, Jeanne drove Lydia back to Florida. “Dr. Oyesiku followed-up after surgery with the Cushing’s disease treatment,” said Jeanne. “Our local endocrinologist could not believe how fast she recovered.” Jeanne also noted that she was always able to get ahold of Dr. Oyesiku, Dr. Thorp, or David Baker to answer her questions. “You feel like you’re their only patient,” said Jeanne. “We are 8-9 hours away, and it didn’t feel like it.” After Lydia weaned off of her medication, she started to lose weight, her face changed, and her body started to feel “normal” again. “My biggest symptom that I am thankful went away was my literally going crazy feeling,” said Lydia. “I am very thankful that I was able to catch it early enough so that this awful disease didn’t leave me with any lifelong complications.” Lydia, like many pituitary tumor patients, still has lingering feelings of anxiety and frustration with the long road from initial symptoms to diagnosis. It takes the average pituitary tumor patient 5-8 years to be properly diagnosed. Lydia and her mother were extremely proactive and still spent 18 months looking for answers. Lydia went to her primary care provider, her OB, a second OB, and two endocrinologists before she had a proper diagnosis. “Cushing’s disease can mimic many other vastly common medical disorders and is often misdiagnosed or mistaken for something else such as diabetes, hypertension, obesity, infertility, depression, or autoimmune disorders,” said Dr. Oyesiku. “Making the diagnosis requires expert clinical acumen supported by sophisticated medical tests, and many of these tests have to be repeated to confirm the diagnosis.” Because Cushing’s disease is so rare, many of the providers that initially saw Lydia dismissed it. After her surgery, Lydia returned to her OB office in Florida for her annual exam and was seen by the OB that told her that her symptoms were “all in her head”. “I told him, ‘Remember that you blew me off? I had a brain tumor that caused Cushing’s disease,’” said Lydia. “He told me that in all his years practicing, he had never had a patient with an endocrine disorder caused by a pituitary tumor.” Lydia’s story and other pituitary tumor patient stories serve as a reminder that while Cushing’s disease is rare, it is worth ruling out when a patient complains of these symptoms. “Part of the problem is that people just do not have access to good doctors,” said Jeanne. “If we had not had that endocrinologist, I don’t know how much longer it would have taken. It makes me sad that other women and even men can have it for so long because they cannot figure out what is going on.” Both Jeanne and Lydia are thankful that the surgery was a success, but the symptoms and long road to a diagnosis left Lydia with a few emotional scars. “I’m fine and healthy on paper, but still battling the mental aspects and the toll it took on me,” said Lydia. “Sometimes I feel resentful because it took away a year and a half of my life. I feel very blessed to be on the other side of this disease, but I’m ready to not be a patient anymore.” From https://www.med.unc.edu/neurosurgery/i-dont-feel-normal-the-diagnosis-of-a-pituitary-tumor-cushings-disease/?fbclid=IwAR1I12ND084Ato5lloDalTEcIFycV5HpLiR7S1brNxr7Lux1BZ6g_vySHOA

Abstract Background There is an increasing number of cases of aldosterone- and cortisol-producing adenomas (A/CPAs) reported in the context of primary aldosteronism (PA). Most of these patients have PA complicated with subclinical Cushing's syndrome; cases of apparent Cushing's syndrome (CS) complicated with aldosteronism are less reported. However, Co-secretory tumors were present in the right adrenal gland, a cortisol-secreting adenoma and an aldosterone-producing nodule (APN) were present in the left adrenal gland, and aldosterone-producing micronodules (APMs) were present in both adrenal glands, which has not been reported. Here, we report such a case, offering profound insight into the diversity of clinical and pathological features of this disease. Case presentation The case was a 45-year-old female from the adrenal disease diagnosis and treatment centre in West China Hospital of Sichuan University. The patient presented with hypertension, moon-shaped face, central obesity, fat accumulation on the back of the neck, disappearance of cortisol circadian rhythm, ACTH < 5 ng/L, failed elevated cortisol inhibition by dexamethasone, orthostatic aldosterone/renin activity > 30 (ng/dL)/(ng/mL/h), and plasma aldosterone concentration > 10 ng/dL after saline infusion testing. Based on the above, she was diagnosed with non-ACTH-dependent CS complicated with PA. Adrenal vein sampling showed no lateralization for cortisol and aldosterone secretion in the bilateral adrenal glands. The left adrenocortical adenoma was removed by robot-assisted laparoscopic resection. However, hypertension, fatigue and weight gain were not alleviated after surgery; additionally, purple striae appeared in the lower abdomen, groin area and inner thigh, accompanied by systemic joint pain. One month later, the right adrenocortical adenoma was also removed. CYP11B1 were expressed in the bilateral adrenocortical adenomas, and CYP11B2 was also expressed in the right adrenocortical adenomas. APN existed in the left adrenal gland and APMs in the adrenal cortex adjacent to bilateral adrenocortical adenomas. After another surgery, her serum cortisol and plasma aldosterone returned to normal ranges, except for slightly higher ACTH. Conclusions This case suggests that it is necessary to assess the presence of PA, even in CS with apparent symptoms. As patients with CS and PA may have more complicated adrenal lesions, more data are required for diagnosis. Peer Review reports Background Because both adrenal Cushing's syndrome and primary aldosteronism (PA) can manifest as adrenocortical adenomas, it is difficult to distinguish between them on the sole basis of adrenal computed tomography (CT). There may also be multiple adenomas with different functions in the same adrenal gland [1], which also leads to the difficulty in the interpretation of adrenal vein blood collection results. With the increased reports on cases of PA complicated with subclinical Cushing's syndrome in clinical practice, increasing attention is being given to the screening of PA complicated with subclinical Cushing's syndrome. However, PA screening may be ignored in the diagnosis and treatment of adrenal Cushing's syndrome. Although it has been reported that PA with a diameter > 2 cm may be complicated with aldosterone- and cortisol-producing adenomas (A/CPAs) [2], cases of apparent Cushing's syndrome complicated with PA are less well known. Recently, Y. Fushimi et al. [3] reported a case of apparent Cushing's syndrome complicated with PA. The cortisol-producing enzyme cytochrome P450 (CYP) 11B1 was diffusely expressed in the adenoma, but based on staining, the aldosterone synthase CYP11B2 was significantly expressed in the adjacent adrenal cortex. This finding indicated that aldosterone-producing micronodules (APMs) in the adjacent adrenal cortex may be the pathological basis of PA. Here, a case of bilateral co-secretory lesions presenting with coexisting Cushing syndrome and primary aldosteronism detected by AVS and confirmed by immunohistochemical analysis after surgical resection is reported. Moreover, APMs were found in the adrenal cortex adjacent to bilateral adrenocortical adenomas; an aldosterone-producing nodule was detected adjacent to the unilateral adenoma. Case presentation A 45-year-old female patient was admitted to the adrenal disease diagnosis and treatment centre in West China Hospital of Sichuan University due to "increased blood pressure, weight gain for one year and facial oedema for half a year". After nifedipine controlled-release tablets 30 mg daily and terazosin 2 mg daily were applied, the blood pressure of this patient was still as high as 179/113 mmHg. She had no family history of endocrine disease or malignant tumour. Her body mass index (BMI) was 25.6 kg/m2 at admission, with a moon-shaped face, fat accumulation on the back of the neck and thin skin. Hormonal, glucose, renal function, lipid, and blood electrolyte tests were completed, and the physiological rhythm of cortisol had disappeared. Aldosterone-renin-angiotensin system (RAAS) results showed a significant decrease in renin activity and a significantly higher aldosterone/renin ratio (ARR) (as provided in Table 1). Dynamic testing for hormones was conducted, and the results were as follows: (i) in terms of the saline infusion test (SIT) in supine position, the before and after aldosterone level was 17.03 ng/dL and 15.45 ng/dL, respectively; (ii) in terms of the captopril challenge test (CCT), the before and after aldosterone level was 18.49 ng/dl and 15.25 ng/mL, respectively, with an inhibition rate of 17.52%; (iii) in terms of the standard low-dose dexamethasone suppression test, the before and after serum cortisol level was 467.9 nmol/L and 786.3 nmol/L, respectively; the before and after 24-h urine free cortisol (24-h UFC) level was 332.3 µg/24 and 480.4 µg/24, respectively. An enhanced CT scan revealed adenoma lesions in both adrenal glands (Fig. 1a and b). Bone mineral density measurement with dual-energy X-ray absorptiometry indicated osteoporosis. Chest CT showed old fractures of the 9th rib on the left side and the 2nd rib on the right side. Table 1 Peripheral blood laboratory data for this case Full size table Fig. 1 Adrenal CT of the patient: A nodule with a size of approximately 1.6 × 1.5 cm was found in the left adrenal gland, and a nodule with a size of approximately 2.2 × 1.8 cm was found in the right adrenal gland. Irregular mild to moderate enhancement was on enhanced CT, and the surrounding fat gap was clear Full size image Based on the above clinical features, the patient was diagnosed with "non-ACTH-dependent Cushing's syndrome complicated with PA". To assess lateralization, adrenal vein sampling (AVS) stimulated by ACTH was performed after obtaining informed consent. The results showed no lateralization of cortisol and aldosterone secretion (Table 2). Table 2 Results of AVS Full size table After communicating with the patient, the left adrenocortical adenoma was first removed by robot-assisted laparoscopic resection; the thickened adrenal cortex near the left adrenocortical adenoma was also resected during the surgery. The pathological report revealed adrenocortical adenoma, the Weiss score was 1, and immunohistochemistry showed weak CYP11B1 expression in the adenoma and positive CYP11B2 expression in an adjacent nodule. Hypertension was not alleviated after surgery. One month later, purple lines appeared on both sides of the lower abdomen, groin area and inner thigh, accompanied by weight gain, apparent systemic joint pain and fatigue in both lower limbs. The patient was readmitted to the hospital, and examination revealed orthostatic ALD at 11.99 ng/dL, PRA at 0.08 ng/mL/h, angiotensin II at 39.38 ng/L (reference range: 55.3–115.3 ng/L) and ARR at 149.88 (ng/dL)/(ng/mL/h). In addition, ACTH was 2.37 ng/L, serum cortisol was 352.30–353.50–283.90 nmol/L at 8 h-16 h-24 h, 24-h UFC was 112.8 µg, and serum cortisol was 342.10 nmol/L in the morning after the 1 mg dexamethasone suppression test. Enhanced CT of the kidneys and adrenal glands showed no solid nodules or masses in the left adrenal gland, though a nodule with a size of approximately 2.2*1.8 cm was detected in the right adrenal gland. Enhanced CT showed irregular mild to moderate enhancement. Therefore, the diagnosis was still "non-ACTH-dependent Cushing's syndrome complicated with PA". Subsequently, the right adrenocortical adenoma and the thickened adrenal cortex near the right adrenocortical adenoma were removed by robot-assisted laparoscopic resection. The pathological report indicated adrenocortical adenoma, and immunohistochemistry showed diffuse homogeneous expression of CYP11B1 and CYP11B2. Antibodies against CYP11B1 (MABS502) and CYP11B1 (MABS1251) were purchased from the Millipore Corporation. There were APMs in the adrenal cortex adjacent to the bilateral cortical adenomas. The fluorescence staining image of the left cortical adenoma is shown in Fig. 2. The immunohistochemistry image of the left adrenal gland is given in Fig. 3 and that of the right adrenal gland in Fig. 4. The immunofluorescence method used in this study was indirect immunofluorescence double staining procedure. Paraffin-embedded human adrenal tissues were prepared using heat-induced epitope retrieval after deparaffinization. Tissue sections were blocked with 5% goat serum in PBS, pH 7.4, containing 0.5% SDS, for 1 h. The slides were incubated with individual primary antibodies at 4℃ overnight, followed by incubation with Alexa Fluor 488-, and Alexa Fluor 647-conjugated secondary antibodies specific to the species of the primary antibodies with DAPI for immunofluorescence staining. Antibodies used included anti-CYP11B1 (Millipore, Cat. No. MABS502, 1:100), anti-CYP11B2(Millipore, Cat. No. MABS1251, 1:100), Alexa Fluor 488-conjugated anti-rat IgG secondary antibody (CYP11B1; Green) and Alexa Fluor 647-conjugated anti-mouse IgG secondary antibody (CYP11B2; Red). Nuclei were stained with DAPI. Fig. 2 Routine hematoxylin and eosin (H&E) staining and immunofluorescence of the left adrenocortical adenoma (green represents expression of CYP11B1 and red that of CYP11B2). This adrenocortical adenoma and the surrounding cortex was cut into three parts. A and C show the overall appearance of the resected portion, with a nodule adjacent to the adenoma. B shows a neoplastic lesion formed by clear cells (aldosterone-producing cell) within nodules, lacking a fibrous envelope. C clearly shows the weak and diffuse expression of CYP11B1 in adrenocortical adenoma and CYP11B2 expression in a nodule in the cortex adjacent to the adenoma. D shows local enlargement of the aldosterone-producing nodule and three aldosterone-producing micronodules adjacent to it Full size image Fig. 3 Resected adrenocortical adenoma and part of the adrenal cortex on the left side. A shows expression of Aldosterone-producing micronodule CYP11B2 in the cortex adjacent to the adenoma. B shows an aldosterone-producing nodule with a diameter of approximately 2 mm. C shows weak positive expression of CYP11B1 in the adenoma and D negative expression of CYP11B1 in the aldosterone-producing nodule Full size image Fig. 4 Resected adrenocortical adenoma and part of the adrenal cortex on the right side. A and B show several Aldosterone-producing micronodules (positive expression of CYP11B2) in the cortex adjacent to the adenoma. C shows diffuse expression of CYP11B1 in the adenoma. D shows diffuse expression of CYP11B2 in the adenoma Full size image The Cushing's syndrome in this patient disappeared after surgery, and glucocorticoids were discontinued after 15 months according to medical advice. Follow-up was conducted for half a year after drug discontinuance, and the patient had no fatigue or dizziness; she was satisfied with the outcomes. Her systolic and diastolic blood pressure remained at 100–120 mmHg and 70–80 mmHg, respectively. During the most recent re-examination, the following results were obtained: (1) orthostatic ALD of 19.1 ng/dL and orthostatic renin concentration of 12.59 µIU/mL, with an aldosterone/renin ratio (ARR) of 1.52; (2) PTC at 8 AM of 247 nmol/L, ACTH of 93.55 ng/L and 24-h UFC of 26.8 µg; (3) parathyroid hormone of 3.86 pmol/L; (4) 25-OH-VitD of 119.5 nmol/L; (5) serum creatinine of 60 µmol/L; (6) serum sodium of 140.4 nmol/L, serum potassium of 3.87 mmol/L and serum calcium of 2.27 mmol/L. Discussion and conclusions Adrenal Cushing's syndrome is caused by excessive autonomic secretion of cortisol induced by adrenal cortical tumours or adrenal cortical hyperplasia; primary aldosteronism (PA) is caused by excessive autonomic secretion of aldosterone induced by adrenal cortical tumours or adrenal cortical hyperplasia. More adverse symptoms occur if aldosterone and cortisol-producing adenomas are present. Specifically, (1) it is more difficult to control hypertension; (2) the incidence of major adverse cardiovascular and cerebrovascular events would increase [4]; (3) glucose intolerance and other metabolic complications would be aggravated [5, 6]; (4) patients would be prone towards osteoporosis [7, 8]; (5) adrenal vein sampling results may be misinterpreted [9]; and (6) adrenal insufficiency may occur after surgery. Therefore, it is of great clinical significance to avoid missed diagnosis of A/CPAs. Despite many reports on A/CPAs, the majority of these patients may have subclinical Cushing's syndrome (SCS), and cases of apparent Cushing's syndrome complicated with PA are rarely reported. In the present case, the clinical manifestation of Cushing's syndrome were more apparent, and it would be appropriate to call it cortisol-aldosterone cosecretoma. Naoyoshi Onoda et al. [10] reported a case of Cushing's syndrome caused by a left adrenocortical adenoma (30 mm in diameter) and PA caused by a right adrenocortical adenoma (20 mm in diameter), and Fushimi et al. [3] reported a case of right A/CPA (25 mm*22 mm in size). Interestingly, in the present report, the patient had bilateral A/CPAs, and the clinical manifestations of Cushing's syndrome became more apparent after unilateral resection was performed. Similar to the above two cases, APMs were found in the adrenal cortex adjacent to the A/CPAs, but aldosterone-producing nodules were found near the cortisol-producing adenoma on the left side. The biochemical phenotype of APM-inducing autonomic aldosterone secretion has not been clarified. APMs can also be found in the adrenal tissue of 30% of individuals with normal blood pressure [11] and surrounding areas of APA [12, 13]. APMs do not express CYP11B1 or CYP17A1, which are necessary for the generation of cortisol [12, 14]. In our patient, the aldosterone-producing nodule in the left adrenal gland may have developed from APM. More than one-third of APMs carry known mutations in CACNA1D and ATP1A1, promoting the generation of aldosterone [14, 15]. Unfortunately, we did not perform whole-exome sequencing on the DNA of the peripheral blood and adenoma tissues of this patient. Due to the existence of APMs adjacent to the adenoma, it remains unclear whether there is a risk of the relapse of PA in these cases after resection of adrenal the adenoma. Therefore, it was necessary to conduct medical follow-up for this patient. Remi Goupil et al. performed AVS on 8 patients with cortisol-producing adenoma (CPA), and the results showed that cortisol on the CPA side was higher than that on the contralateral side (median, 6.7 times [range: 2.4–27.2]); P = 0.012]) [16]. There was no significant difference in bilateral cortisol and aldosterone concentrations after AVS in this patient, which is consistent with bilateral A/CPA. Although immunohistochemical results revealed weak expression of CYP11B1 for the first time, expression of cortisol in bilateral adrenal venous blood samples increased significantly after ACTH stimulation. Hence, cortisol was over-synthesized on both sides, and bilateral A/CPAs was definitively diagnosed. In summary, this case highlights the need for A/CPA screening. The complicated pathological features of these cases impose challenges to our understanding of this disease. Due to the presence of APMs in the adrenal cortex near bilateral adrenocortical adenomas, more clinical data are required to identify whether the disease might relapse after simple resection of the adenoma in these patients. Therefore, further medical follow-up of these patient is needed. Availability of data and materials Not applicable. Abbreviations CS: Cushing's syndrome PA: Primary aldosteronism ACTH: Adrenocorticotropic hormone UFC: Urinary free cortisol AVS: Adrenal vein sampling A/CPA: Aldosterone-and cortisol producing adenoma APN: Aldosterone-producing nodules APM: Aldosterone-producing micronodule CYP: Cytochrome P450 CT: Computed tomography PAC: Plasma aldosterone concentration PRA: Plasma renin activity ARR: Aldosterone /renin ratio References Stenman A, Shabo I, Ramström A, Zedenius J, Juhlin CC: Synchronous aldosterone- and cortisol-producing adrenocortical adenomas diagnosed using CYP11B immunohistochemistry. SAGE open medical case reports. 2019, 7:2050313x19883770. Hiraishi K, Yoshimoto T, Tsuchiya K, Minami I, Doi M, Izumiyama H, Sasano H, Hirata YJ. Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome. Endocr J. 2011;58(7):543–51. Article CAS PubMed Google Scholar Fushimi Y, Tatsumi F, Sanada J, Shimoda M, Kamei S, Nakanishi S, Kaku K, Mune T, Kaneto H. 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Article CAS PubMed Google Scholar Download references Acknowledgements Not applicable Funding This study was supported by the Discipline Excellence Development 1.3.5 Project of West China Hospital, Sichuan University (No. ZYGD18022). Author information Authors and Affiliations Department of Endocrinology and Metabolism, Adrenal Center, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China Hongjiao Gao, Yan Ren, Tao Chen & Haoming Tian Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi), Zunyi, Guizhou, China Hongjiao Gao Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China Li Li & Fei Chen Contributions HG, TC researched data and/or wrote the manuscript. LL, FC contributed to immumohistochemical staining. HT, TC, YR contributed to discussion. All authors have read and approved the manuscript. Corresponding authors Correspondence to Tao Chen or Haoming Tian. Ethics declarations Ethics approval and consent to participate Not applicable. Consent for publication 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 of this journal. Competing interests We do not have any potential conflicts of interest relevant to this article. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Reprints and Permissions Cite this article Gao, H., Li, L., Chen, F. et al. Bilateral co-secretory lesions presenting with coexisting Cushing syndrome and primary aldosteronism: a case report. BMC Endocr Disord 23, 263 (2023). https://doi.org/10.1186/s12902-023-01454-8 Download citation Received08 April 2022 Accepted24 August 2023 Published29 November 2023 DOIhttps://doi.org/10.1186/s12902-023-01454-8 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Cushing’s syndrome Primary aldosteronism Adrenal vein sampling Immunohistochemistry Aldosterone-producing cell cluster Download PDF Sections Figures References Abstract Background Case presentation Discussion and conclusions Availability of data and materials Abbreviations References Acknowledgements Funding Author information Ethics declarations Additional information Rights and permissions About this article From https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-023-01454-8

BACKGROUND Double pituitary adenomas are rare presentations of two distinct adenohypophyseal lesions seen in <1% of surgical cases. Increased rates of recurrence or persistence are reported in the resection of Cushing microadenomas and are attributed to the small tumor size and localization difficulties. The authors report a case of surgical treatment failure of Cushing disease because of the presence of a secondary pituitary adenoma. OBSERVATIONS A 32-year-old woman with a history of prolactin excess and pituitary lesion presented with oligomenorrhea, weight gain, facial fullness, and hirsutism. Urinary and nighttime salivary cortisol elevation were elevated. Magnetic resonance imaging confirmed a 4-mm3 pituitary lesion. Inferior petrosal sinus sampling was diagnostic for Cushing disease. Primary endoscopic endonasal transsphenoidal resection was performed to remove what was determined to be a lactotroph-secreting tumor on immunohistochemistry with persistent hypercortisolism. Repeat resection yielded a corticotroph-secreting tumor and postoperative hypoadrenalism followed by long-term normalization of the hypothalamic-pituitary-adrenal axis. LESSONS This case demonstrates the importance of multidisciplinary management and postoperative hormonal follow-up in patients with Cushing disease. Improved strategies for localization of the active tumor in double pituitary adenomas are essential for primary surgical success and resolution of endocrinopathies. Keywords: pituitary neuroendocrine tumor; PitNET; pituitary adenoma; Cushing disease; prolactinoma; transsphenoidal ABBREVIATIONS ACTH = adrenocorticotrophic hormone; BMI = body mass index; DHEA-S = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; GH = growth hormone; IHC = immunohistochemical; IPSS = inferior petrosal sinus sampling; LH = luteinizing hormone; MRI = magnetic resonance imaging; POD = postoperative day; T4 = thyroxine; TF = transcription factor; TSH = thyroid-stimulating hormone; UFC = urinary free cortisol Pituitary adenomas are adenohypophyseal tumors that can cause endocrinopathies, such as pituitary hormone hypersecretion or anterior hypopituitarism. Cell lineages are used to classify these tumors on the basis of immunohistochemical (IHC) staining of transcription factors, hormones, and other biomarkers.1 Pituitary adenomas differentiate from pluripotent stem cells along one of three lineage pathways, depending on the following active transcription factors (TFs): pituitary transcription factor 1 (PIT-1), T-box transcription factor (TPIT), or steroidogenic factor-1 (SF-1). Rarely, two or more discrete pituitary adenomas from different lineages are identified in patients; however, the etiology remains unclear.2 The incidence of multiple pituitary adenomas has been reported to be 1%–2% of all resected pituitary adenomas but is likely underestimated based on data from large autopsy series.1–4 Pluri-hormonal adenomas are also rare entities in which a single tumor contains multiple TF lineages with one or more hormonal excesses.1–3 Preoperative recognition of multiple or pluri-hormonal pituitary adenomas is rare, and most tumors are discovered incidentally upon autopsy, intraoperatively, or on histological analysis.2,3,5 In cases of multiple synchronous pituitary adenomas, only one hormone excess syndrome is most frequently evident on clinical presentation and endocrine workup. Silent pituitary tumors positive for prolactin on immunohistochemistry are the most prevalent additional, incidentally found tumor in cases of multiple pituitary adenomas.5 This is particularly true in Cushing disease.6,7 It is important to recognize the presence of multiple pituitary adenomas especially in the setting of hormonally active pituitary adenomas to provide optimal management for this subset of patients. Complete resection is curative for Cushing disease with the standard of care achieved through a transsphenoidal approach. Localization of the tumor presents a challenge because of suboptimal sensitivity of magnetic resonance imaging (MRI) in demonstrating microadenomas, the inconsistency of lateralization with inferior petrosal sinus sampling (IPSS), and delays in pathological analysis.1,8,9 Additionally, the presence of an additional pituitary adenoma can obscure the microtumor through its large size and mass effect and can act as a “decoy lesion” during MRI, IPSS, and resection.6 Consideration of multiple pituitary tumors is necessary for successful resection. In a patient with a biochemical picture of Cushing disease, the demonstration of an adenoma with negative adrenocorticotrophic hormone (ACTH) immunostaining and the absence of postoperative hypoadrenalism may indicate the existence of a double adenoma. Few cases have described a lack of remission of an endocrinopathy after transsphenoidal resection due to the presence of an additional adenoma,2,6,10 and even less so in the instance of the persistence of Cushing disease.6 We present a rare case of double pituitary adenomas in a patient presenting with Cushing disease who underwent two endoscopic endonasal transsphenoidal resections and immunostaining for prolactin and ACTH, respectively, with long-term normalization of her hypothalamic-pituitary-adrenal (HPA) axis. Illustrative Case History and Presentation A 32-year-old female, gravida 0 para 0, with a history of a pituitary lesion and hyperprolactinemia presented to our institution for the evaluation for Cushing disease. Ten years earlier, the patient had presented to a gynecologist with hirsutism, galactorrhea, and oligomenorrhea. Her endocrine workup was remarkable for an elevated prolactin at 33.8 ng/mL (2.3–23.3 ng/mL), while follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) levels were normal. No ACTH or cortisol levels were available. MRI demonstrated a 5 × 6 × 5–mm T1-weighted isointense pituitary lesion protruding into the suprasellar cistern due to a small sella size. She was treated with bromocriptine 2.5 mg daily for 5 years, with normalization of her prolactin level. Subsequent MRI demonstrated a stable lesion size and T1 and T2 hyperintensity in the region of the known pituitary lesion, considered to be posttreatment cystic change with proteinaceous contents and blood. After the normalization of her prolactin levels, she continued to have oligomenorrhea and abnormal hair growth. Polycystic ovaries were not visualized on ultrasound. She was started on oral contraceptives and then switched to the etonorgestrel implant. A decade after initial presentation, she presented to endocrinology at our institution with 3 years of weight gain, hirsutism, and potential oligomenorrhea. Vital signs were stable (blood pressure: 122/86; heart rate: 72 beats/min), and facial fullness and striae on her bilateral breasts were appreciated on physical examination. She was taking isoniazid and pyridoxine for a recent diagnosis of latent tuberculosis and had discontinued bromocriptine 5 years earlier. Her weight was 66.3 kg and body mass index (BMI) was 23.9 kg/m2. She reported that her maternal uncle had a pituitary tumor. Laboratory analysis was positive for elevated urinary free cortisol (UFC) of 109 µg per 24 hours (2.5–45 µg/24 h; Table 1) and nighttime salivary cortisol of 142 ng/mL (<100 ng/dL) with high-normal prolactin of 22.8 ng/mL (2.3–23.3 ng/dL) and normal FSH, LH, TSH, and thyroxine (T4). Dehydroepiandrosterone sulfate (DHEA-S) was 128 µg/dL (98.8–340.0 µg/dL). Imaging demonstrated a 4 × 4 × 4–mm pituitary lesion with decreased T1-weighted and increased central T2-weighted signal intensity in the left lateral pituitary (Fig. 1A–C). Desmopressin (Ferring Pharmaceuticals DDAVP) stimulation increased a basal ACTH of 49.9 pg/mL to ACTH of 91.2 pg/mL, and cortisol increased from 13.7 µg/dL to 21.2 µg/dL, consistent with neoplastic hypercortisolism. IPSS was performed, which showed a right-sided, central-to-peripheral ACTH gradient (Table 2). The patient elected to undergo endoscopic endonasal resection with the initial target as the left-lateral pituitary mass to achieve a cure for Cushing disease. TABLE 1 Urinary free cortisol at baseline and 3, 5, and 7 months after the primary resection Variable Baseline 3 Mos 5 Mos 7 Mos on Osilodrostat Urinary free cortisol (4–50 µg/24 hrs) 109 134.2 125.4 40.3 Urinary creatinine (0.5–2.5 g/24 hrs) 0.995 1.17 1.42 1.11 Urinary vol (mL) 1950 2300 2100 2125 FIG. 1 Preoperative coronal precontrast (A) and postcontrast (B) T1-weighted magnetic resonance imaging (MRI) and T2-weighted MRI (C) demonstrated a 4-mm3 lesion (arrows) with decreased T1 and increased central T2 signal intensity in the left lateral pituitary. Two days after surgery, coronal precontrast (D) and postcontrast T1-weighted (E) and T2-weighted (F) MRI demonstrated the unchanged adenoma. TABLE 2 Preoperative inferior petrosal sinus sampling with corticorelin ovine triflutate 68 µg Time (mins) ACTH (pg/mL) Prolactin (ng/mL) Peripheral Petrosal Sinus ACTH Ratio Peripheral Petrosal Sinus Prolactin Ratio Rt Lt Rt Lt Rt Lt Rt Lt −5 50.6 225 1586 4.45 31.34 21 124 295 5.90 14.05 0 48.8 389 1376 7.97 28.20 22.2 185 198 8.33 8.92 3 69.8 4680 1333 67.05 19.1 22.1 396 32.5 17.92 1.47 5 80.9 4590 1623 56.74 20.06 22.1 436 32.2 19.73 1.46 10 112 4160 1660 37.14 14.82 20.2 367 42 17.90 2.05 ACTH or prolactin ratio = inferior petrosal sinus ACTH or prolactin/peripheral blood ACTH or prolactin. Primary Resection and Outcomes During the primary resection, abnormal tissue was immediately visible after a linear incision along the bottom of the dura, with an excellent plane of dissection. The inferomedial adenoma was distinct from the known left lateral lesion, and the resection was considered complete by the primary neurosurgeon. Subsequently, the left-sided adenoma was not pursued because of the historical prolactinoma diagnosis and an assumption that the newly discovered adenoma was the cause of ACTH hypersecretion. However, pathology of the inferomedial tumor was strongly and diffusely positive for prolactin (Fig. 2B), synaptophysin, and cytokeratin, with an Mindbomb Homolog-1 (MIB-1) proliferative index of 2.4%. ACTH, growth hormone (GH), FSH, LH, and TSH immunostaining were negative. TF immunohistochemistry was not available. On postoperative day (POD) 1, pituitary MRI was performed and demonstrated the unchanged 4-mm3 T1-weighted hypointense lesion with small central T2-weighted hyperintensity in the left lateral gland (Fig. 1D–F). Cortisol levels ranged from 9.7 to 76.2 µg/dL (4.8–19.5 µg/dL), and ACTH was 19.5 pg/mL (7.2–63.3 pg/mL) on POD 1. FIG. 2 Histological examination of surgical specimens from the inferomedial (A–C) and left lateral (D–F) lesions. The initial resection (hematoxylin and eosin [H&E], A) was strongly and diffusely positive for prolactin (B) with normal reticulin levels (C) indicating a lactotrophic pituitary adenoma. The second operation (H&E, D) was diagnostic for a corticotropic pituitary adenoma with diffusely positive adrenocorticotrophic hormone (ACTH) (E) and decreased reticulin (F). Original magnification ×100. Early reoperation was discussed with the patient based on the pathology and persistent hypercortisolism; however, she elected to pursue conservative management with close follow-up. Postoperative cortisol nadir was 4.8 µg/dL (4.8–19.5 µg/dL) on POD 2 during her 4-day hospital stay. DHEA-S was significantly decreased from baseline at 22.3 µg/dL (98.8–340.0 µg/dL) and a prolactin level of 3.4 ng/mL (2.3–23.3 ng/dL) was low-normal. No glucocorticoids were administered during her hospital course. There was no clinical evidence of vasopressin deficiency while she was an inpatient. Three months postoperatively, the patient reported insomnia, poor hair quality, fatigue, nocturnal sweating, and continued increasing weight gain with fat accumulation in the supraclavicular and dorsal cervical area. She had one spontaneous menstrual period despite the use of etonogestrel implant. UFC was increased at 134.2 µg/24 hours (4–50 µg/24 h; Table 1). The 8:00 am serum cortisol was 10.2 µg/dL (5.0–25.0 µg/dL). She was started on osilodrostat 2 mg twice daily for her persistent hypercortisolism, and she reported some clinical improvement; however, she had continued elevation in her late-night salivary cortisol levels up to 7.0 nmol/L. Other endocrine lab work was normal, with a prolactin of 13.5 ng/mL (2.8–23.3 ng/mL) and TSH of 3.67 µIU/mL (0.4–4.0 µIU/mL). Her weight had increased by 4.9 kg to 71.2 kg with a BMI of 25.3 kg/m2. Approximately 6 months postoperatively, she was amenable to a secondary resection targeting the remaining left lateral pituitary adenoma. Secondary Resection and Outcomes After obtaining adequate exposure for the secondary resection, the lesion in the left lateral aspect of the pituitary was targeted. The tumor was clearly identified and completely resected without intraoperative complication. IHC staining was diffusely positive for ACTH (Fig. 2E), synaptophysin, and cytokeratin with decreased reticulin and an MIB-1 index of 3.3%. Prolactin, GH, TSH, LH, and FSH immunostaining were negative. Postoperative cortisol monitoring demonstrated decreased levels, with a nadir of 2.0 µg/dL on POD 0. Levels of ACTH and DHEA-S were decreased at 4.4 pg/mL (7.2–63.3 pg/mL) and 13.3 µg/dL (98.8–340 µg/dL), respectively, on POD 1. Prolactin remained within the normal range at 8.2 ng/mL (2.8–23.3 ng/mL). The patient was started on intravenous hydrocortisone 50 mg every 8 hours for adrenal insufficiency. Postoperative symptoms of nausea, headache, and muscle weakness resolved with hydrocortisone administration. She was discharged on hydrocortisone 60 mg daily in divided doses for adrenal insufficiency and had no signs of vasopressin deficiency during her 2-day hospital course. By 3 months, the patient reported decreased fatigue, myalgia, and insomnia and improved overall well-being and physical appearance. She was weaned down to a total daily dose of 20 mg of hydrocortisone and had lost 5.2 kg. Her menstruation returned while having an etonogestrel implant. Rapid ACTH stimulation was abnormal, with decreased cortisol at 30 minutes of 4.1 µg/dL (7.2–63.3 pg/mL) demonstrating continued adrenal insufficiency. Follow-up MRI demonstrated miniscule remaining left pituitary adenoma (Fig. 3). Seven months after her second surgery, she was started on 50 µg levothyroxine for primary hypothyroidism in the setting of slightly elevated TSH of 4.1 µIU/mL (0.4–4.0 µIU/mL) and a low-normal T4 of 0.8 ng/dL (0.7–1.5 ng/dL). FIG. 3 Postoperative imaging 3 months after the second operation demonstrates near gross-total resection (yellow arrows: surgical cavity) of the left lateral pituitary adenoma on coronal precontrast (A) and postcontrast T1-weighted (B) and T2-weighted (C) MRI. Two years after the second resection, the patient lost 10.1 kg (weight, 61.1 kg; BMI, 21.76 kg/m2). Her ACTH stimulation test became normal, and hydrocortisone therapy was discontinued. At the 2-year time point, the patient and her husband successfully conceived a child. Patient Informed Consent The necessary patient informed consent was obtained in this study. Discussion Double or multiple pituitary adenomas are discovered in 0.37%–2.6% of resected pituitary lesions.3,4,6,11,12 A majority of multiple pituitary adenomas are not suspected before surgery with an inconclusive clinical presentation or endocrine laboratory workup.6 The presentation of multiple synchronous neoplasms is thought to be more common than having a single neoplasm with multiple lineages.1 Studies have shown that additional pituitary adenomas are seen at a rate of 1.6%–3.3% in Cushing disease in studies including both contiguous and noncontiguous double pituitary adenomas.6 Additional pituitary adenomas that are hormonally active make up 40% of resected double pituitary adenomas, with most staining for gonadotroph adenoma.13 Overall, the most common incidental pituitary adenoma is prolactinoma,6 which occurs most frequently with GH or ACTH adenomas.5 In very rare instances, Cushing cases can present with hyperprolactinemia and Cushing synchronously.6 Hormonal secretion and clinical presentation are variable, with the pathology most often attributed to only one component of double pituitary adenoma.3,14 The multiple-hit theory is the most common hypothesis for double pituitary adenoma etiology with coincidental monoclonal expansion of two or more lineages, which present with separate pseudo-capsules for each lesion.15 Observations On presenting with Cushing disease, the differential diagnosis before the initial operation considered that the known left lateral pituitary adenoma could be a mixed tumor with both prolactin and ACTH lineages. Therefore, it was the initial target of the resection until discovering the second adenoma intraoperatively. With two distinct adenomas, the inferomedial adenoma was presumed to be the source of the ACTH hypersecretion and was subsequently resected. The left lesion was thought to be a prolactinoma and hormonally inactive after historical dopaminergic therapy and thus was not pursued during the initial surgery. However, pathology confirmed that the opposite was true. Few cases have also involved incidental pituitary tumors that look like the hormonally active adenoma and encourage resection of it, leaving the primary pituitary adenoma behind.6,7 It has been reported that these “decoy lesions” can cause surgical failure and require secondary operations.6,7,10,16 Intraoperative localization and confirmation of the adenoma classification may have also been helpful during the case, including tissue-based ACTH antibody assay,9 plasma ACTH measurements with a immunochemiluminometric method,17 or intraoperative ultrasound.5,6 The inferomedial second tumor was not appreciated or reported throughout her serial MRI studies from 2010 to 2020. Interestingly, imaging did demonstrate the left pituitary adenoma that was medically treated as a prolactinoma, although it was later diagnosed as an ACTH-secreting lesion on IHC staining. Preoperative visualization of a pituitary adenoma in Cushing disease is reported to be limited, with a reported 50% incidence with negative MRI with standard 1.5 T.1,18,19 MRI technical refinements in magnet strength, slice thickness, or enhanced spin sequences have increased sensitivity, but one-third of patients with Cushing disease still have negative scans.20 Small prolactinomas, especially those near the cavernous sinus, are also notoriously difficult to visualize on MRI, although recent advances using co-registration of 11C-methionine positron emission tomography–computed tomography with MRI (Met-PET/MRICR) may prove useful.21 Difficulty with preoperative visualization complicates a diagnosis of multiple adenomas, with or without multiple endocrinopathies, and negatively affects surgical planning. In a single-institution retrospective review of MRI in all cases of double pituitary tumors, only one of eight patients (12.5%) over 16 years of age had a positive MRI for double pituitary tumors and was diagnosed preoperatively.2 The patient’s preoperative IPSS demonstrated a right central-to-peripheral gradient. This was incongruent with the MRI demonstrating the single left-sided tumor. While IPSS is useful in confirming Cushing disease, its sensitivity for lateralization has been reported at only 59%–71%.9 With this in mind and a known left-sided adenoma on MRI, exploration of the right side of the pituitary was not originally planned. Ultimately, the left-sided adenoma was the source of ACTH hypersecretion, which remains incongruent with preoperative IPSS. It has been suggested that multiple pituitary adenomas in Cushing disease could further decrease its accuracy.1,6 The patient’s initial historical prolactin levels (33.8 ng/dL) were lower than reported levels of 100–250 ng/dL for microadenoma and >250 ng/dL in cases of macroadenoma. Normally, in active single prolactinoma, prolactin secretion is correlated to size. We do not suspect that the presence of more than one pituitary adenoma would affect the level of prolactin hypersecretion.6 Slight elevations in prolactin can be attributed to causes such as pituitary stalk effect, medications, and physiological stimulation. During the 5 years of bromocriptine therapy, the effect on the inferomedial prolactinoma was unknown, as it was not appreciated on MRI. There are reports of prolactinomas being less responsive to dopaminergic agonist therapy in cases of double adenomas.14,22 Upon resection of the inferomedial prolactinoma during the initial operation, there was no further change in the patient’s prolactin levels, which could most likely be attributed to prior dopaminergic therapy. Unfortunately, the initial endocrine laboratory workup did not include levels of ACTH or cortisol. In addition to hyperprolactinemia, Cushing disease can also present with changes in menstruation. After the secondary resection and removal of the ACTH-secreting pituitary adenoma, the patient’s oligomenorrhea resolved and she achieved pregnancy. Retrospectively, it remains unclear if the prolactinoma was once truly active hormonally. Lessons The rare presence of two pituitary adenomas can complicate the diagnosis, medical and surgical management, and long-term outcomes for patients. A complete endocrine workup is essential when a pituitary adenoma is suspected and can help screen for pluri-hormonal and multiple pituitary adenomas. In our patient, it is unknown when the onset of hypercortisolism was with the limited initial hormonal workup. Currently, localizing and resecting the hormonally active adenoma in double or multiple pituitary adenomas remain a challenge, with limitations in preoperative imaging and intraoperative measures. After encountering the additional inferomedial lesion during surgery, resection of both adenomas during the initial surgery may have been prudent to ensure the resolution of Cushing disease. Although exploration for additional pituitary adenomas is not usually recommended, it could be considered in cases of multiple pituitary adenomas and uncertainty of the culprit of Cushing disease. The current characterization of pituitary tumors by the World Health Organization includes immunohistochemistry for both transcription factors and pituitary hormones, with clinical usefulness to be determined by future studies. Multiple lineages can occur mixed in a single pituitary adenoma or across different noncontiguous adenomas and can only be determined by TF immunostaining. The left ACTH-staining lesion in our patient had some shrinkage and MRI changes, which may have been a response to dopaminergic therapy. Full characterization of the tumor cell lineages in this case remains undetermined without staining for TFs. In conclusion, we report a rare case of Cushing disease concurrent with a prolactinoma leading to the need for repeat resection. This is one of the few reported cases of a double pituitary adenoma leading to a lack of biochemical remission of hypercortisolism after the initial surgery. 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Abstract Gastrointestinal perforation is a well-addressed complication of exogenous hypercortisolism; however, patients with endogenous Cushing's syndrome (CS) do not usually experience this condition in clinical practice. The literature on this subject is limited and consists solely of clinical case reports/series with only 23 instances of gastrointestinal perforation occurring in individuals with endogenous Cushing's syndrome. This is mainly attributed to the rarity of Cushing's syndrome itself and the low chance of occurrence of such complications. We report a case of a recently diagnosed adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a 30-years-old female who presented initially with a three-month history of progressive weight gain, generalized weakness, acne, menstrual irregularity, and severe hypokalemia, and then developed a gastric ulcer perforation only one month after her ACTH-dependent Cushing's syndrome diagnosis and was managed through emergent surgery. Introduction A disorder of the endocrine system characterized by excessive cortisol production, known as Cushing's syndrome, rarely occurs. The main causes are pituitary tumors, ectopic adrenocorticotropic hormone (ACTH)-secreting tumors, or adrenal tumors that secrete cortisol independently [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur, especially when the diagnosis is not established at an early stage [2]. There is a possibility of gastrointestinal complications among patients receiving exogenous glucocorticoids. However, there is limited information on gastrointestinal complications associated with endogenous hypercortisolemia [3,4]. Thus far, only 23 instances have been published addressing the co-occurrence of gastrointestinal perforation with endogenous Cushing's syndrome [5-17]. To the best of our knowledge, this is the first case reporting gastric perforation in an ACTH-dependent Cushing's syndrome, while the vast majority reported diverticular, sigmoid, or duodenal perforation with Cushing's syndrome [5-17]. Herein, we describe the medical history, physical examination, and investigatory findings of a 30-year-old female with a recent diagnosis of ACTH-dependent Cushing's syndrome that was complicated by gastric ulcer perforation, necessitating an urgent exploratory laparotomy. The primary motivator of this case report was the rarity of the described condition, the atypical location of the perforation in such patient group, and the relatively young age of the patient. Case Presentation History and examination A 30-year-old female with a history of mental retardation was admitted to our emergency department (ER) with progressive weakness and fatigue. Upon taking the history, she had been having menstrual irregularities, progressive weight gain, and generalized weakness, which was significant enough to limit her physical activity and hinder her movement for the past three months. Initial vital signs showed that the patient had a body temperature of 37°C, a pulse rate of 90 beats per minute, and a blood pressure of 130/80 mmHg. On physical examination, the patient had a moon face with supraclavicular fullness, dorsocervical fat pad, purple abdominal striae, facial signs of hirsutism, and acne all over the face, shoulders, chest, and back. Investigations In the initial laboratory examination, hypokalemia of 2.1 mEq/L, hyperglycemia of 12.1 mmol/L, and metabolic alkalosis were detected (Table 1). The cortisol level after 1 mg dexamethasone suppression test was 2204 nmol/L (normal range 140-690), ACTH 123 pg/mL (normal range 7.2-63.3), DHEA-S 27.85 umol/L (normal range 2.6-13.9), And 24-hour urine cortisol level was 1560 mg/day (normal range 30-350) (Table 1). No suppression was observed in cortisol level with 8 mg dexamethasone suppression test. Parameter Initial presentation Perforation presentation Refrence range Na+ 143 mEq/L 139 mmol/L 135-147 mEq/L Cl- 85 mEq/L 105 mmol/L 98-108 mEq/L K+ 2.1 mEq/L 2.8 mmol/L 3.5-5.0 mEq/L Mg2+ 0.79 mmol/L 0.77 mmol/L 0.85-1.110 mmol/L PO3- 0.88 mmol/L 1.23 mmol/L 0.97-1.46 mmol/L PH 7.54 7.36 7.35-7.45 PCO2 67.5 mmHg 42.7 mmHg 35-45 mmHg PO2 27.7 mmHg 62.2 mmHg 75-100 mmHg HCO3 49.8 mEq/L 23.6 mEq/L 22-26 mEq/L Random blood glucose 12.1 mmol/L 24.1 mmol/L <5.5 mmol/L Hemoglobin 13.5 g/dL 14.9 g/dL 13.7-16.8 g/dL White blood cells 9,720 /uL 11,100 /uL 3,300-8,600 /uL Lymphocyte 0.48% 0.33% - Neutrophil 8.55% 9.66% - Eosinophil 0.0% 0.0% - TSH 0.55 mIU/L Was not ordered 0.4-4.0 mIU/L Cortisol 2204 nmol/L 4842 nmol/L 140-690 nmol/L ACTH 123 pg/mL Was not ordered 7.2-63.3 pg/mL Table 1: Laboratory findings on initial presentation and on perforation day TSH - thyroid stimulating hormone; ACTH - adrenocorticotropic hormone A series of CT scans for the neck, chest, abdomen, and pelvis was performed and failed to localize any tumors acting as an ectopic source. A pituitary MRI was performed, and no adenoma was found. To complete the diagnostic workup, we decided to do an inferior petrosal sinus sampling (IPSS) and PET scan with Gallium 68; however, the patient's family refused and requested discharge and outpatient follow-ups. These results, together with the biochemical and clinical findings, supported the diagnostic hypothesis of ACTH-dependent Cushing's syndrome. Treatment/management When addressing the issue of hypokalemia that the patient presented with initially, it was found to be resistant and difficult to correct. The patient was put on spironolactone 50 mg BID, and potassium chloride 20 mEq q8h, and her potassium level barely reached 3.5 mmol/L after several days. In addition, her magnesium level was corrected with magnesium oxide 800 mg every six hours. Her blood glucose level was controlled with insulin glargine 6 units daily and Novorapid as per the sliding scale. The patient was discharged on spironolactone tablets 50 mg BID (oral), potassium chloride 20 mEq q8h, cholecalciferol, calcium carbonate, insulin glargine 6 units daily, and Novorapid 4 units TID before meals. Follow-up and outcomes Seven days after discharge, she presented to the ER complaining of a new onset of abdominal pain, constipation, and reduced urine output. Her Glasgow Coma Scale (GCS) was 15, her blood pressure measurement was 146/90 mmHg, her pulse rate was 66 beats per minute, her respiratory rate was 21 breaths per minute, and her temperature was 36.7°C. Upon physical examination, the patient had distended non-tender abdomen without any other significant findings. Blood work was done, including renal functions, and all parameters, including potassium, were within normal limits. A chest X-ray was also performed and revealed no evidence of pneumoperitoneum. The patient was clinically stable after managing her abdominal pain with acetaminophen injection and administering fleet enema for constipation. After instructions on when to come again to the ER were given, the patient was discharged home on lactulose and paracetamol, and a close outpatient follow-up appointment was scheduled. Five days after the ER visit, the patient presented again to the ER. She was still complaining of severe non-resolving abdominal pain, constipation, and reduced urine output. Upon physical examination in the ER, the patient was found to have developed a new onset of lower limb edema, abdominal rebound tenderness, and abdominal rigidity and guarding. She was hypotensive with a blood pressure of 91/46 mmHg, pulse rate of 80 beats per minute, respiratory rate of 16 breaths per minute, temperature of 38.2 °C, and SpO2 of 96%. The only significant laboratory finding was her potassium level dropping low to 2.8 mEq/L (Table 1). An X-ray of the chest was requested and showed a large pneumoperitoneum (Figure 1). Figure 1: Posteroanterior chest X-ray at the time of gastric perforation displaying severe air under the diaphragm with bilateral obstruction indicating massive pneumoperitoneum (red arrow) Abdominal CT was also urgently performed and confirmed the presence of gastric perforation likely related to an underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature (Figures 2, 3). Figure 2: Coronal-section CT image of abdomen and pelvis at the time of gastric perforation showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature Figure 3: Horizontal-section CT image showing features of gastric perforation likely related to the underlying perforated peptic ulcer with 0.8 cm defect at the distal greater curvature The patient underwent an emergent gastric wedge resection for gastric perforation, and the pathology reported evidence of gastric ulcer with no evidence of malignancy. Furthermore, Helicobacter pylori test was performed on the sample, and it came back positive. The patient tolerated the surgery very well, and postoperative recovery was without any complications. Later, the patient was prescribed metyrapone 250 mg Q4h, which was then increased to 500 mg Q4h four days after surgery, and her cortisol level significantly dropped to 634nmol/L. During that time, a gastrin level test was also performed to exclude the presence of gastrinomas, and the level was 45 pg/ml (normal range 13-115). Discussion A small percentage of the population suffers from Cushing's syndrome, which is an endocrine disorder characterized by an endogenous overproduction of glucocorticoids, resulting in hypercortisolemia [1]. It is estimated to affect 0.7 to 2.4 people per million annually [1]. Hypercortisolemia alters psychologic, metabolic, and cardiovascular functions, resulting in increased mortality and morbidity rates, particularly if the diagnosis is delayed and long-term exposure to high cortisol levels occurs [2]. Women are more likely to suffer from this condition than men, and people in their 40s to 60s are most vulnerable to it [1]. Patients initially present with a wide range of symptoms, including weight gain, proximal myopathy, skin thinning, and abdominal striae [1]. Additionally, several metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia, can occur [1]. Due to the rarity of this condition, there is often a significant delay in diagnosis and treatment, which could eventually lead to complications from prolonged hypercortisolism. From another standpoint, in a systematic review, the incidence of peptic ulcer perforation ranges from 3.8 to 14 per 100,000 individuals in the general population [18]. In under-developed countries, patients are typically young, tobacco-using males [19]. However, patients in industrialized countries are typically older with multiple co-morbidities and are on long-term non-steroidal anti-inflammatory drugs (NSAIDs) or steroid use [19]. Patients may present with an abrupt onset of abdominal discomfort, abdominal rigidity, and tachycardia in the early stages of a perforated peptic ulcer [19]. Later, abdominal distention, pyrexia, hypotension, fever, and vomiting can occur [19]. Furthermore, when the diagnosis is made early, a perforated ulcer often has a good prognosis. However, the risk of adverse events increases if there is a delay in the diagnosis [20]. Therefore, making an early detection through different imaging modalities is crucial [20]. A history of peptic ulcer disease, NSAIDs, physiological stress, smoking, corticosteroids, and Helicobacter pylori are some of the well-established risk factors for a perforated peptic ulcer [20]. The prevalence of Helicobacter pylori among Saudi patients is high; in one study, the overall prevalence was 46.5% in patients with dyspepsia using gastric biopsy [21]. Several studies have explored the relationship between Helicobacter pylori and gastrointestinal perforation, but the results have been mixed. Some studies have suggested a higher prevalence of Helicobacter pylori infection among individuals with gastrointestinal perforation compared to those without, indicating a potential association. However, other studies have found no significant difference in the prevalence of Helicobacter pylori infection between perforated and non-perforated gastrointestinal ulcer cases [22]. Furthermore, they suggested that the presence of other risk factors like the use of NSAIDs, smoking, and alcohol may interact with Helicobacter pylori infection and contribute to the development of complications such as gastrointestinal perforation [22]. However, in our case, the patient did not have any established risk factors for gastric perforation, such as NSAIDs, smoking, or alcohol. Therefore, considering the low incidence of gastrointestinal perforation and high prevalence of Helicobacter pylori, the conflicting data regarding the association between Helicobacter pylori and gastrointestinal perforation, and the lack of established risk factors for gastrointestinal perforation in our patient, we suggest that prolonged excess glucocorticoids from Cushing's syndrome may have contributed to the gastric perforation either independently or synergistically with Helicobacter pylori since hypercortisolism can lead to a weakened gastrointestinal wall integrity due to decreased collagen turnover and disruption of mucosal protection by prostacyclin [15]. In addition, because of hypercortisolism, perforation may not be contained or healed initially due to the immunosuppressive effects of hypercortisolism, whether endogenous or exogenous [15]. Additionally, high levels of cortisol may delay the diagnosis and treatment since it may mask the symptoms of the perforation [14]. Moreover, our patient was treated for severe hypokalemia with potassium supplementation for an extended period of time. Previous studies have linked potassium chloride supplementation to gastrointestinal ulceration and perforation, making this a possible additive cause of our patient's condition [23,24]. A limited number of studies have addressed gastrointestinal perforations associated with endogenous hypercortisolemia [5-17]. The correlation between Cushing's syndrome and gastrointestinal perforation is highlighted in our study and in the case reports that have been previously published (Table 2). Similar to our case, a female predominance was seen in gastrointestinal perforation among the reported cases of Cushing's syndrome [6,7,12,13,15,16]. Additionally, the average age at which gastrointestinal perforation occurred in patients with endogenous hypercortisolism ranged from 45 to 80, which is a noticeably higher age range than the case we are presenting here (aged 30) [6-10,12]. Furthermore, unlike our case, in which gastrointestinal perforation occurred four months after the onset of Cushing's symptoms, Intestinal perforation occurs approximately 9.8 months after Cushing's symptoms first appear [15]. Furthermore, in our patient, gastric perforation occurred while she was hypercortisolemic and not in a remission state. Hence, in association with Helicobacter pylori infection, severe hypercortisolemia could have been a secondary contributing factor to gastric perforation. The complications of gastric ulceration, specifically with endogenous Cushing's syndrome, have been addressed in two case reports [25,26]. It must be noted, however, that neither case is similar to ours. A case of gastric perforation was reported by Kubicka et al. in a patient who had a confirmed diagnosis of gastrinoma, and the patient was diagnosed with ectopic Cushing's syndrome seven months after gastric perforation [25]. Therefore, since ectopic Cushing's syndrome was diagnosed seven months after the perforation, it is more likely that the gastrinoma contributed to this complication. In contrast, our patient's serum gastrin level was within the normal range, ruling out gastrinoma. Further, Hoshino et al. reported a case of gastrointestinal bleeding in a 39-year-old man with a confirmed diagnosis of Cushing's disease secondary to pituitary adenoma [26]. He was found to have gastric ulceration and bleeding along with Helicobacter pylori infection and elevated cortisol levels [26]. In spite of the patient not developing a gastric perforation, it was suggested by the author that hypercortisolism might be a contributing factor for gastric ulcer complications by slowing down the ulcer healing process [26] Reference Year of publication Age, gender Highest cortisol level plasma cortisol (PC, nmol/L) / UFC (nmol/L) Cause of Cushing's syndrome Time from onset of Cushing's symptoms to perforation (months) Reported site of gastrointestinal perforation Current 2023 30, Female PC 4842 ACTH-dependant 4 Gastric perforation Ishinoda et al. [17] 2023 24, Male PC 1647 Cushing's disease 12 Sigmoid colon perforation Wijewickrama et al. [16] 2021 32, Female PC 1147 Pituitary microadenoma 1 Diverticular perforation Shahidi et al. [15] 2019 72, Female UFC 5296 Pancreatic neuroendocrine tumor 12 Diverticular perforation Shahidi et al. [15] 2019 61, Female PC 1925 Metastatic medullary carcinoma of thyroid 12 Sigmoid colon and diverticular perforation Shahidi et al. [15] 2019 68, Female UFC 410 Cushing's disease 12 Sigmoid colon perforation Shahidi et al. [15] 2019 71, Female UFC 1533 Cushing's disease 4 Diverticular perforation Shahidi et al. [15] 2019 54, Male UFC 374 Cushing's disease 3 Sigmoid colon perforation Shahidi et al. [15] 2019 52, Female UFC 885 Cushing's disease 16 Diverticular perforation Sater et al. [14] 2018 80, Female UFC 5601 Lung carcinoid 36 Diverticular perforation Sater et al. [14] 2018 60, Female UFC 72726 Metastatic islet cell carcinoma 36 Diverticular perforation Sater et al. [14] 2018 31, Male UFC 1297 Cushing's disease 20 Diverticular perforation Sater et al. [14] 2018 52, Female UFC 2371 Lung carcinoid 4 Diverticular perforation Sater et al. [14] 2018 67, Male UFC 3836 Ectopic ACTH 10 Diverticular perforation Sater et al. [14] 2018 51, Male UFC 13552 Metastatic thymic carcinoma 4 Diverticular perforation Kaya et al. [9] 2016 70, Male PC 1432 Small cell lung cancer 1 Diverticular perforation Dacruz et al. [12] 2016 60, Female UFC 4481 Metastatic parotid tumor 5 Sigmoid colon and diverticular perforation Matheny et al. [10] 2016 67, Male UFC 11119 Metastatic medullary carcinoma of thyroid 4 Diverticular perforation Flynn et al. [13] 2016 63, Female UFC 12465 Pheochromocytoma 1 Perforation at the splenic flexure Balestrieri et al. [11] 2016 75, Male PC 2272 Neuroendocrine tumor 1 Intestinal perforation Hara et al, [8] 2013 79, Male PC 1230 Cushing's disease 6 Diverticular perforation De Havenon et al. [7] 2011 71, Female PC 2593 Cushing's disease 9 Diverticular perforation Lutgers et al. [6] 2010 55, Female UFC 10152 Right pheochromocytoma 1 Sigmoid colon and diverticular perforation Drake et al. [5] 1998 35, Male PC 1442 Islet cell tumor 4 Duodenal perforation and rupture of pancreatic pseudocyst Table 2: Current case and previous reported 23 cases of patients with Cushing's syndrome and gastrointestinal perforation UFC - urinary free cortisol; PC - plasma cortisol; ACTH - adrenocorticotropic hormone Conclusions A high blood cortisol level can be associated with various clinical manifestations and diverse sets of complications. This case report sheds light on one of the less common complications of hypercortisolism in patients with Cushing's syndrome, which is gastrointestinal perforation. Our report further supports the published evidence that gastrointestinal perforation is a rare but potentially fatal complication among patients with Cushing's syndrome. Moreover, it highlights the possibility of developing gastric perforations in this patient group, even at younger ages than expected. This should elicit a high clinical suspicion and demand prompt investigation of Cushing's syndrome patients in a hypercortisolism state presenting with modest gastrointestinal symptoms. References Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A: Cushing's syndrome. Endocrinol Metab Clin North Am. 2008, 37:135-49. 10.1016/j.ecl.2007.10.010 Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing's syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6 Goethals L, Nieboer K, De Smet K, De Geeter E, Tabrizi NH, Van Eetvelde E, de Mey J: Cortisone associated diverticular perforation. JBR-BTR. 2011, 94:348-9. 10.5334/jbr-btr.705 Piekarek K, Israelsson LA: Perforated colonic diverticular disease: the importance of NSAIDs, opioids, corticosteroids, and calcium channel blockers. 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In a recent study published in Hypertension Research, scientists examine the endocrine causes of hypertension (HTN) and investigate the efficacy of treatments to alleviate HTN. What is HTN? About 30% of the global population is affected by HTN. HTN is a modifiable cardiovascular (CV) risk factor that is associated with a significant number of deaths worldwide. There are two types of HTN known as primary and secondary HTN. As compared to primary HTN, secondary HTN causes greater morbidity and mortality. The most common endocrine causes of HTN include primary aldosteronism (PA), paragangliomas and pheochromocytomas (PGL), Cushing’s syndrome (CS), and acromegaly. Other causes include congenital adrenal hyperplasia, mineralocorticoid excess, cortisol resistance, Liddle syndrome, Gordon syndrome, and thyroid and parathyroid dysfunction. What is PA? PA is the most common endocrine cause of hypertension, which is associated with excessive aldosterone secretion by the adrenal gland and low renin secretion. It is difficult to estimate the true prevalence of PA due to the complexity of its diagnosis. Typically, the plasma aldosterone-to-renin ratio (ARR) is measured to diagnose PA. The diagnosis of PA can also be confirmed using other diagnostic tools like chemiluminescent enzyme immunoassays (CLEIAs) and radio immune assay (RIA). Continuous aldosterone secretion is associated with organ damage due to chronic activation of the mineralocorticoid (MR) receptor in many organs, including fibroblasts and cardiomyocytes. An elevated level of aldosterone causes diastolic dysfunction, endothelial dysfunction, left ventricular hypertrophy, and arterial stiffness. Increased aldosterone secretion also leads to obstructive sleep apnea and increases the risk of osteoporosis. This is why individuals with PA are at a higher risk of cardiovascular events (CVDs), including heart failure, myocardial infarction, coronary artery disease, and atrial fibrillation. PA is treated by focusing on normalizing potassium and optimizing HTN and aldosterone secretion. Unilateral adrenalectomy is a surgical procedure proposed to treat PA. Young patients who are willing to stop medication are recommended surgical treatment. The most common pharmaceutical treatment for PA includes mineralocorticoid receptor antagonists such as spironolactone and eplerenone. Pheochromocytomas and paragangliomas PGL are tumors that develop at the thoracic-abdominal-pelvic sympathetic ganglia, which are present along the spine, as well as in the parasympathetic ganglia located at the base of the skull. The incidence rate of PGL is about 0.6 for every 100,000 individuals each year. PGL tumors synthesize excessive catecholamines (CTN), which induce HTN. Some of the common symptoms linked to HTN associated with PGL are palpitations, sweating, and headache. PGL can be diagnosed by determining metanephrines (MN) levels, which are degraded products of CTN. Bio-imaging tools also play an important role in confirming the diagnosis of PGL. Excessive secretion of CTN increases the risk of CVDs, including Takotsubo adrenergic heart disease, ventricular or supraventricular rhythm disorders, hypertrophic obstructive or ischaemic cardiomyopathy, myocarditis, and hemorrhagic stroke. Excessive CTN secretion also causes left ventricular systolic and diastolic dysfunction. Typically, PGL treatment is associated with surgical procedures. Two weeks before the surgery, patients are treated with alpha-blockers. For these patients, beta-blockers are not used as the first line of treatment without prior use of alpha-adrenergic receptors. Patients with high CTN secretion are treated with metyrosine, as this can inhibit tyrosine hydroxylase. Hydroxylase converts tyrosine into dihydroxyphenylalanine, which is related to CTN synthesis. What is CS? CS, which arises due to persistent exposure to glucocorticoids, is a rare disease with an incidence rate of one in five million individuals each year. The most common symptoms of CS include weight gain, purple stretch marks, muscle weakness, acne, and hirsutism. A high cortisol level causes cardiovascular complications such as HTN, hypercholesterolemia, and diabetes. CS is diagnosed based on the presence of two or more biomarkers that can be identified through pathological tests, such as salivary nocturnal cortisol, 24-hour urinary-free cortisol, and dexamethasone suppression tests. CS is treated through surgical procedures based on the detected lesions. Patients with severe CS are treated with steroidogenic inhibitors, such as metyrapone, ketoconazole, osilodrostat, and mitotane. Pituitary radiotherapy and bilateral adrenalectomy are performed when other treatments are not effective. Acromegaly Acromegaly arises due to chronic exposure to growth hormone (GH), leading to excessive insulin-like growth factor 1 (IGF1) synthesis. This condition has a relatively higher incidence rate of 3.8 million person-years. Clinical symptoms of acromegaly include thickened lips, widened nose, a rectangular face, prominent cheekbones, soft tissue overgrowth, or skeletal deformities. Prolonged exposure to GH leads to increased water and sodium retention, insulin resistance, reduced glucose uptake, and increased systemic vascular resistance. These conditions increase the risk of HTN and diabetes in patients with acromegaly. Acromegalic patients are also at a higher risk of cancer, particularly those affecting the thyroid and colon. Acromegaly is diagnosed using the IGF1 assay, which determines IGF1 levels in serum. After confirming the presence of high IGF1 levels, a GH suppression test must be performed to confirm the diagnosis. Bioimaging is also conducted to locate adenoma. Acromegaly is commonly treated through surgical procedures. Patients who refuse this line of treatment are treated with somatostatin receptor ligands, growth hormone receptor antagonists, dopaminergic agonists, or radiotherapy. Journal reference: De Freminville, J., Amar, L., & Azizi, M. (2023) Endocrine causes of hypertension: Literature review and practical approach. Hypertension Research; 1-14. doi:10.1038/s41440-023-01461-1 From https://www.news-medical.net/news/20231015/Hormones-and-high-blood-pressure-Study-reveals-endocrine-culprits-and-targeted-treatments.aspx

Bridget Houser felt despairing. In the months before her 2018 wedding, Houser, who had never struggled with her weight, noticed that it inexplicably began to creep up. In response she doubled the length of her runs to eight miles, took back-to-back high intensity workout classes and often consumed only water, coffee and fruit during the day before a spartan, mostly vegetable, dinner. Yet no matter what Houser did, her weight stubbornly increased and her oval face grew round, a transformation that was glaringly obvious in comparison with her identical twin sister. Houser wondered whether the five pounds she gained despite her herculean effort was a corollary of other problems. For the previous two years she had battled a string of maladies: first daily headaches, then crippling anxiety, followed by insomnia, hair loss and acne, something she’d never endured as a teenager. “Stress was the universal explanation,” recalled Houser, a controller for a small business in Chicago. When doctors suggested that her upcoming marriage might be a cause of her problems, Houser considered, then rejected, the theory. It just didn’t jibe with her feelings. In early 2019, about six months after her wedding, Houser insisted that her doctors perform several tests. They ultimately revealed that her symptoms weren’t the result of stress or marital misgivings but of a serious illness that had been smoldering for years. After successful treatment followed by a long recovery Houser, now 34, feels far better than she did during those miserable years in her late 20s. “I wish I’d been nicer to myself and not blamed myself for what was going on,” she said. Getting through the wedding In 2016 Houser began experiencing daily pain in the back of her head, a common spot for tension headaches. When the headaches failed to improve with dietary changes or nonprescription pain relievers, she consulted her primary care doctor, followed by a neurologist who told her she had migraines. Houser, then 27, noticed that the headaches were worse when she wore contact lenses. “It was affecting my daily life and I talked myself into thinking the problem was my contacts,” she said. She decided Lasik surgery might help and in October 2017 underwent the procedure, which uses a laser to reshape the cornea, reducing or eliminating dependence on contacts or glasses. Her vision improved and the pain disappeared — briefly. A week after eye surgery, her headaches returned. “I wasn’t overly concerned,” Houser said. “I know a lot of people have headaches.” A few months later for no apparent reason Houser developed “really bad anxiety. It wasn’t just like I was anxious,” she recalled. “I couldn’t function. I’m Type A so I knew what anxiety is, but not to this degree.” One weekday morning in early 2018 she felt so overwhelmed that she took a sick day, then called her twin, Molly, and their mother and told them she needed help immediately. They managed to schedule a same-day appointment with a psychiatrist whom Houser began seeing regularly, along with a therapist. The psychiatrist zeroed in on her impending wedding and told Houser that the event can cause “huge anxiety.” She began taking an antidepressant along with Ativan, an anti-anxiety drug she used when things got really bad. She also ramped up her yoga practice, hoping it might calm her. Houser vividly remembers riding the escalator to her office one morning “and in my head I kept saying, ‘I’m in trouble, I’m in trouble,’” although she didn’t know what was wrong. Her changing appearance had become a source of great unhappiness. Although her weight remained in the normal range, Houser couldn’t figure out why she was gaining weight after drastically slashing her food intake and dramatically ramping up exercise. Her normally thick hair had thinned so noticeably that her hairdresser gently advised her to consult a doctor. Houser’s psychiatrist thought her hair loss might be caused by her antidepressant and switched medications. That didn’t seem to help. Houser was particularly bothered by her newly chubby face. “It was like a joke in my family,” she said, adding that she was teased about being overly sensitive. Even her wedding day was colored by unhappiness about her appearance and the intense amorphous anxiety that seemed omnipresent. “Rather than think about how excited I was,” Houser recalled, “it was ‘How can I get through this day?’” Normal thyroid After her wedding Houser felt worse. She developed severe insomnia, night sweats and acne. In February 2019 a nurse practitioner in her primary care practice ordered tests of her thyroid, which were normal. When Houser pressed for additional testing, she was referred to an endocrinologist. He told her she was stressed. Dissatisfied, she saw a second endocrinologist who agreed with the first. “She said ‘I don’t think there’s anything wrong with you’” metabolically, Houser recalled. The second endocrinologist’s nurse even revisited the marriage question in the presence of Houser’s husband, Doug, who had accompanied her to the appointment. “She said ‘I knew on my honeymoon I shouldn’t have gotten married,’” Houser remembered her saying. “‘Are you in a happy marriage?’ I couldn’t believe it.” Months earlier, the nurse practitioner who ordered the thyroid tests briefly mentioned measuring levels of cortisol, a hormone involved in the body’s response to stress and other functions. Elevated levels of cortisol can indicate Cushing’s syndrome, an uncommon hormonal disorder that occurs when the body produces too much of the hormone over a prolonged period. “She had thrown cortisol testing out there and I think it was always in the back of my mind,” Houser said. She asked the second endocrinologist to order cortisol tests. The doctor agreed, but not before telling Houser that she didn’t think she had Cushing’s because she lacked the classic symptoms: major weight gain, purple stretch marks and a fatty hump between the shoulders. Houser did have the “moon face” characteristic of Cushing’s that is also seen in people who take high doses of steroids for long periods to treat various illnesses — but Houser wasn’t taking steroids. Insomnia, headaches, acne and anxiety can be symptoms of Cushing’s. There are several forms of Cushing’s syndrome, which typically results from a tumor — usually benign but sometimes cancerous — in the pituitary or adrenal gland that pumps out excess cortisol. Sometimes tumors develop elsewhere in the body such as the lungs or pancreas. Cushing’s affects roughly five times as many women as men and typically occurs between the ages of 30 and 50. If left untreated, it can be fatal. A trio of tests measuring cortisol levels in Houser’s blood, urine and saliva were significantly elevated; the amount in her urine was eight times higher than normal. The formerly skeptical Chicago endocrinologist told Houser she had Cushing’s and referred her to James Findling, a Milwaukee endocrinologist who is internationally recognized for his treatment of the disease. “I was just so happy to have a diagnosis,” Houser recalled. Revealing photos Findling asked Houser to bring photographs taken several years earlier to her October 2018 appointment. It is a request he makes of patients as a way of spotting telltale physical manifestations. In Houser’s case, the facial change was particularly striking because she is an identical twin. Findling noted that delayed diagnosis is typical, because physical changes and other symptoms tend to occur gradually and insidiously. Houser, he added, “didn’t look like the typical Cushing’s patient. She wasn’t obese and she didn’t have diabetes or hypertension. It was more subtle than many cases.” The next step was determining the location of the tiny tumor. Tests found nothing in Houser’s pituitary or adrenal glands, and CT scans of her pelvis, chest and abdomen were clean. Findling ordered a dotatate PET scan, a highly sensitive CT scan that can find tumors that elude conventional imaging. The scan revealed a nodule in Houser’s left lung. Houser sought a second opinion from a thoracic surgeon in Chicago. While Findling and a thoracic surgeon at Milwaukee’s Froedtert Hospital strongly recommended that she undergo surgery to remove the tumor, the Chicago doctor disagreed. He said he didn’t think the lung nodule was causing Cushing’s and recommended that Houser continue therapy and anti-anxiety medication. “Do you know what it’s like to wake up from surgery and to not be better?” she remembers him asking her. After deliberating with her husband and conferring with her Milwaukee doctors, Houser opted for surgery performed Oct. 30, which removed part of her left lung. A pathologist determined that the nodule was a rare, slow-growing neuroendocrine lung cancer known as a bronchial carcinoid, which can cause Cushing’s. The Stage 2 cancer had spread to a nearby lymph node. “Fortunately I think we got it early,” Findling said. “She’s had a sustained remission and a cure of her Cushing’s.” “The cancer didn’t rock my world,” said Houser, who had previously had a melanoma skin cancer removed. (Doctors have told her they don’t think the cancers are related.) “It was about not having Cushing’s anymore, which was more important.” So why didn’t Houser’s doctors, among them endocrinologists, suspect Cushing’s? Findling, who estimates he has treated as many as 2,000 people with the disease in his 40-year career, said that while doctors are taught that Cushing’s is rare, it’s not. He cites a 2016 study, which that found that 26 of 353 endocrinology patients were found to have the disease. Textbook descriptions, which include the presence of purple stretch marks and a hump, are “almost a caricature,” Findling observed. “It’s pretty well recognized that Cushing’s is more subtle than that … and can cause neuropsychiatric and neurocognitive problems.” Houser’s normal weight and the fact that she didn’t have high blood pressure or diabetes may have misled doctors. “I think we’ve moved the needle a little bit, especially among endocrinologists,” he continued, adding that “the threshold for screening has got to change. Once you tell a primary care doctor that it’s a rare disorder, it goes in one ear and out the other. They think they’ll never see it.” “When you make this diagnosis it can have fabulous outcomes,” he added, citing Houser’s case. “That’s why I’m still doing this at my age.” Houser considers Findling to be her “literal lifesaver.” She spent the next year seeing him as she was slowly weaned off medications to normalize her hormone levels and recover her strength. She is monitored for Cushing’s annually, remains cancer-free and, other than residual fatigue, feels well. In October 2021 she gave birth to a daughter. Her son was born eight weeks ago. Houser regards the help provided by her family, particularly her husband whom she called “my biggest supporter,” as essential. That seems especially ironic because stress about their marriage had been blamed for symptoms that were actually caused by a cancer. “He was a huge help in calling doctors and making the necessary appointments when I didn’t have the energy to fight anymore.” His unwavering love, she said, was “a testament to our strong marriage.” From https://www.washingtonpost.com/wellness/2023/10/07/weight-anxiety-wedding-medical-mysteries/

Key takeaways: Cushing’s syndrome symptoms moderately impact quality of life for adults with the condition. Weight gain, muscle fatigue and menstrual changes decline in severity from diagnosis to follow-up. Adults with endogenous Cushing’s syndrome reported that the condition moderately affects their quality of life and causes them to have symptoms about 16 days in a given month, according to findings published in Pituitary. “Our study aimed to evaluate the ongoing burden of Cushing’s syndrome in order to identify areas of unmet need,” Eliza B. Geer, MD, medical director of the Multidisciplinary Pituitary and Skull Base Tumor Center and associate attending of endocrinology and neurosurgery at Memorial Sloan Kettering Cancer Center, told Healio. “We found that patients with treated Cushing’s continue to experience ongoing symptoms more than half of the days in a given month, miss about 25 workdays per year and need twice the average number of outpatient visits per year, indicating a significant impact on daily function and work productivity. Some of these symptoms, like fatigue and pain, have not been well studied in Cushing’s patients, and need more attention.” Geer and colleagues administered a cross-sectional survey to 55 adults aged 21 years and older who had been diagnosed with Cushing’s syndrome at least 6 months before the survey and were receiving at least one pharmacologic therapy for their disease (85% women; mean age, 43.4 years). The survey was conducted online from June to August 2021. Five patient-reported outcome scales were included. The CushingQoL was used to analyze quality of life, a visual analog scale was included to assess pain, the Brief Fatigue Inventory was used to measure fatigue, the Sleep Disturbance v1.0 scale assessed perceptions of sleep and the PROMIS Short Form Anxiety v1.0-8a scale was used to measure fear, anxious misery, hyperarousal and somatic symptoms related to arousal. Participants self-reported the impact of Cushing’s syndrome on daily life and their physician’s level of awareness of Cushing’s syndrome. Some symptoms decline in severity over time Of the study group, 81% had pituitary or adrenal tumors, and 20% had ectopic adrenocorticotropic hormone-producing tumors; 80% of participants underwent surgery to treat their Cushing’s syndrome. The frequency of reported symptoms did not change from Cushing’s syndrome diagnosis to the time of the survey. The most frequently reported symptoms were weight gain, muscle fatigue and weakness and anxiety. Participants reported a decline in symptom severity for weight gain, muscle fatigue and weakness and menstrual changes from diagnosis to the survey. Though symptom severity declined, none of the three symptoms were entirely eliminated. Adults did not report declines in severity for other symptoms. Hirsutism and anxiety were reported by few participants, but were consistently scored high in severity among those who reported it. There were no changes in patient satisfaction with medications from their first appointment to the time of the survey. “It was surprising that anxiety and pain did not improve with treatment,” Geer said. “A quarter of patients at baseline reported anxiety and this percentage was exactly the same after treatment. Same for pain — nearly a quarter of patients reported pain despite treatment. While the presence of anxiety has been well-documented in Cushing’s patients, pain has not, and needs further study.” Nearly half of primary care providers unable to diagnose Cushing’s syndrome All participants reported having at least one challenge with being diagnosed with Cushing’s syndrome. Of the respondents, 49% said their primary care provider was unable to diagnose their Cushing’s syndrome and 33% initially received the wrong diagnosis. Physicians referred 49% of participants to a specialist, and 39% of adults said their doctor lacked knowledge or understanding of their condition. The study group had a moderate level of quality of life impairment as assessed through the CushingQoL scale. The mean pain score was 3.6 of a possible 10, indicating low levels of pain. Moderate to severe levels of fatigue were reported by 69% of participants. Self-reported sleep and anxiety scores were similar to what is observed in the general population. Participants said sexual activity, self-confidence and life satisfaction were most impacted by a Cushing’s syndrome diagnosis. Adults experienced symptoms a mean 16 days in a typical month and saw their outpatient physician an average of six times per year. Those who were employed said they miss 2 days of work per month, or about 25 days per year, due to Cushing’s syndrome. “Longitudinal assessment of clinically relevant patient-reported outcomes based on validated measures and coupled with biochemical and treatment data is needed in a large cohort of Cushing’s patients,” Geer said. “This will allow us to identify clinically meaningful changes in symptom burden within each patient, as well as predictors of outcomes — which patients improve on which symptoms, and which patients do not feel better despite biochemical normalization. We need to improve our ability to help our patients feel better, not just achieve normal cortisol levels.” For more information: Eliza B. Geer, MD, can be reached at geere@mskcc.org. From https://www.healio.com/news/endocrinology/20230830/adults-with-cushings-syndrome-report-high-burden-of-illness-despite-ongoing-treatment

Abstract Importance Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders. Observations Cushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate. Conclusions and Relevance The incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy. From https://jamanetwork.com/journals/jama/article-abstract/2807073

In Italy it is estimated that there are about 3,000 patients suffering from Cushing’s syndrome, while in Europe the number rises to over 50,000. The Cushing’s syndrome, a disease caused by the excessive production of cortisol by the pituitary gland due to a benign tumor of the gland, has seen a breakthrough in its treatment. Thanks to a new drug called osilodrostat, approved in 2020 by the Food and Drug Administration and subsequently by Aifa in Italy, patients unfit for surgery can benefit from a treatment that offers the same effects as a scalpel. Furthermore, this drug reduced symptoms in 80% of cases. Cushing’s syndrome has been dubbed “full moon face disease” due to its most obvious visible effects, such as a rounding of the face caused by fat accumulation and visible weight gain also on the waist and back. Despite its symptomatic relevance, the disease has long been poorly understood by both healthcare professionals and the general public. To raise awareness of this syndrome, the #Thiscushing campaign has been launched, which aims to spread knowledge about the disease. The campaign recently stopped in Rome, during the Congress of the Italian Society of Endocrinology (SIE), where a photographic exhibition was organized which represents moments of daily life of people affected by Cushing’s syndrome and their difficulties. Despite the debilitating symptoms, Cushing’s syndrome is often underdiagnosed, resulting in delays in diagnosis of up to 5-7 years. The disease presents a wide range of symptoms, ranging from difficulty performing even simple daily activities such as tying your shoes or getting out of bed, to common manifestations such as high cholesterol, hypertension and hyperglycemia, which can be confused with symptoms of other less common pathologies. serious. It is for this reason that the EIS experts are appealing for the inclusion of Cushing’s syndrome in the list of rare pathologies recognized by the Ministry of Health, in order to facilitate timely diagnosis and faster access to the necessary treatments. From https://www.breakinglatest.news/health/cushings-syndrome-a-new-drug-allows-you-to-avoid-surgery/

YOU’RE INVITED! GoodHormoneHealth Webinar on Oh-Oh-Oh-Ozempic Dr. Theodore Friedman (The Wiz) will giving a webinar on Ozempic and other new weight loss medicines. Topics to be discussed include: Who should go on weight-loss medications? Which weight-loss medications are the best? What are the side effects? How do they work with diet and exercise? How do you get insurance coverage? There will be an opportunity for patients to share their experience on Facebook Sunday • Jul 9, 2023 • 6 PM PDT Via Zoom Click here to join the meeting orhttps://us02web.zoom.us/j/4209687343?pwd=amw4UzJLRDhBRXk1cS9ITU02V1pEQT09OR+16699006833,,4209687343#,,,,*111116#ORJoin on Facebook Live - https://www.facebook.com/goodhormonehealth Slides will be available on the day of the talk here. There will be plenty of time for questions using the chat button. For more information, email us at mail@goodhormonehealth.com

Abstract The association between empty sella turcica (EST) syndrome and Cushing's disease has been rarely reported. It is plausible to hypothesize that EST syndrome in association with Cushing's disease can be attributed to intracranial hypertension. In this case report, we present a 47-year-old male patient who presented with weight loss, fatigue, easy bruising, acanthosis nigricans, and skin creases hyperpigmentation. Investigations revealed hypokalemia and confirmed the diagnosis of Cushing's disease. Magnetic resonance imaging (MRI) brain showed a partial EST syndrome and a new pituitary nodule as compared with previous brain imaging. Transsphenoidal surgery was pursued and was complicated by cerebrospinal fluid leakage. This case reflects the rare association of EST syndrome and Cushing's disease, suggesting the increased risk of postoperative complications in this setting and the diagnostic challenge that EST syndrome imposes. We review the literature for a possible mechanism of this association. Introduction Cushing's disease is commonly caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma, which can be very challenging to be seen on brain magnetic resonance imaging (MRI) [1]. Empty sella turcica (EST) syndrome is a radiological diagnosis of apparently empty turcica secondary to outpouching of the arachnoid mater into the turcica, which can be attributed to intracranial hypertension (ICHTN). This can make the visual diagnosis of pituitary adenoma even more challenging in clinical practice. ICHTN has been also associated with Cushing's disease and might explain this infrequent association between EST and Cushing's disease [1]. EST syndrome can be either partial or complete, primary or secondary and has been seen infrequently with Cushing's disease. In this setting, not only that it is likely to obscure an underlying pituitary lesion, but also it does contribute to the risk of postoperative complications [2]. Case Presentation A 47-year-old male presented to the emergency department (ED) with slowly progressive generalized limb muscle weakness affecting both distal and proximal muscles over a few weeks and gait instability for three days prior to presentation. He also reported unintentional 40 pounds weight loss over the previous four months. Past medical history was significant for type II diabetes mellitus, hypothyroidism, hypertension, and dyslipidemia. In the ED, vital signs included a blood pressure of 140/90 mmHg, a heart rate of 66 beats per minute, a respiratory rate of 16 cycles per minute, and SpO2 of 97% on room air. Body mass index has decreased to 22 kg/m2 from a baseline of 26 kg/m2 one month prior. On the physical exam, he exhibited cachexia, easy bruising, acanthosis nigricans, and hyperpigmentation of skin creases. All other systems were negative. Complete metabolic panel and complete blood count were obtained showing hyperglycemia of 311 mg/dl, see Table 1. Further lab evaluation showed elevated salivary cortisol at 2.96 microgram/dl (reference range 0.094-1.551 mcg/dl), elevated 24-hour urinary free cortisol at 156 mcg/24 hour (reference 10-100 mcg/24h), positive overnight dexamethasone suppression test with serum cortisol at 2.8 mcg/dl (reference more than 2 mcg/dl), negative anti-adrenal antibodies, normal aldosterone, and elevated dehydroepiandrostenedione at 401 mcg/dl (reference 32-240 mcg/dl), with lack of suppression of the ACTH level at 35.1 pg/ml (reference 10-60 pg/ml). This confirmed the diagnosis of Cushing's disease. Variable Finding Reference Random glucose 311 Less than 200 mg/dl Sodium 141 137-145 mmol/L Potassium 2.5 3.5-5.1 mmol/L Chloride 96 98-107 mmol/L Bicarbonate 32 22-30 mmol/L Blood urea nitrogen 32 9-20 mg/dl Creatinine 0.52 0.66-1.25 mg/dl Calcium 8.7 8.6-10.3 mg/dl Total protein 5.5 6.5-8.5 g/dl Albumin 3.3 3.5-5 g/dl Total bilirubin 0.6 0.2-1.3 mg/dl Alkaline phosphatase 115 38-126 U/L Aspartate transaminase 17 17-59 U/L Alanine transaminase 39 Less than 49 U/L White blood cell count 10x10^3 cells/mcl 4-10x1063 cells/mcl Hemoglobin 15.3 13.7-17.5 g/dl Platelet 281 150-400x10^3 cells/mcl Table 1: Lab Findings Computed tomography (CT) scan of the head was unremarkable. CT scan of the chest was also unremarkable. CT scan of abdomen and pelvis showed no adrenal mass. Ultrasound of the kidneys was unremarkable. Pituitary MRI brain protocol for adenoma showed a partial EST, shortening within neurohypophysis and a new 10 x 8 x 4 mm nodule along the floor of pituitary sella as compared to MRI four years ago (Figure 1). Figure 1: Magnetic Resonance Imaging (MRI) Brain MRI brain showing partially empty sella turcica syndrome ( black arrow) with a small nodule at the floor of the turcica (white arrow). The diagnosis of Cushing’s disease was confirmed, and the patient underwent trans-sphenoidal resection of pituitary adenoma. Histological examination showed positive CAM 5.2, positive chromogranin, and ACTH immunostains. The patient presented to the ED five days after discharge home. He stated that he noticed drainage from the nose that transitioned from bloody to clear fluid and has been increasing in quantity for two days with associated intermittent headaches since the surgery. He was afebrile with stable vital signs. No signs of infection were noted on basic labs. These were significant only for mild asymptomatic hyponatremia of 131 mmol/L and hypokalemia of 3.3 mmol/L. The patient was diagnosed with cerebrospinal fluid (CSF) leakage and had a lumbar drain trial. The trial was unsuccessful after several days, and the patient underwent a transnasal endoscopic repair of CSF rhinorrhea using nasoseptal flaps. At an outpatient follow-up one month and three months after the surgery, prior lab abnormalities including hypokalemia, hyponatremia, and hyperglycemia resolved. No further evidence of CSF leakage was appreciated, and he remained asymptomatic. Discussion EST syndrome is characterized by herniation of the subarachnoid space into the intrasellar space with compression of the pituitary gland into the posteroinferior wall [3]. This is likely to obscure the presence of underlying pituitary mass. The incidence of EST syndrome in the general population is estimated at 20%. The association between EST syndrome and Cushing's disease has been reported infrequently. A retrospective study of 68 patients with Cushing's disease found that 16% of these have EST syndrome [3]. Cushing's disease usually results from pituitary adenomas secreting ACTH, and even the smallest microadenomas can produce a systemic disease. These microadenomas can be very difficult to recognize on brain MRI [4]. This is complicated in EST syndrome and even further with the possibility of ectopic ACTH production. A retrospective study of 197 patients diagnosed with Cushing's disease concluded that EST syndrome is associated with higher prevalence of MRI-negative Cushing's disease. This was attributed to ICHTN and pituitary gland compression [1]. Although surgery is curative in 70-90% of cases, EST syndrome was found to have higher risk of postoperative complications among those with Cushing's disease including diabetes insipidus, hypopituitarism, and CSF leakage [3]. This is usually because in the case of MRI-negative Cushing's disease with total EST syndrome, empiric surgical exploration is sought after inferior petrosal sampling confirms the pituitary origin of excess ACTH, and postoperative remission indicates adequate tumor resection [2]. This entails a higher chance of uncertainty and injury to healthy pituitary tissue. EST syndrome can be either primarily due to defects in the sellar diaphragm or anatomical variant or secondary to ICHTN. EST syndrome has been reported in association with many conditions associated with elevated intracranial pressure including tumors, thrombosis, meningitis, hydrocephalus, and Arnold-Chiari malformation [5]. Reversal of EST syndrome has been reported in those with idiopathic ICHTN with therapy by acetazolamide, ventriculoperitoneal shunt, and lumbar puncture [6,7]. A study has shown correlation between CSF circulation impairment or blockage and EST syndrome [8]. The incidence of EST syndrome in association with symptomatic intracranial hypertension is variable and ranges from 2.5% for total EST syndrome to 94% for partial EST syndrome [9]. Impaired CSF circulation and dynamics have been reported in 77% of patients with EST syndrome [10]. In addition to intracranial hypertension, EST syndrome has also been described in association with obesity, meningioma, pediatric nevoid basal cell carcinoma, therapy for growth hormone deficiency and even in healthy individuals [9]. Lack of symptoms of intracranial hypertension in this patient does not rule it out as intracranial hypertension in EST syndrome represents a spectrum that ranges from asymptomatic, milder intracranial hypertension to symptomatic intracranial hypertension with headache, visual disturbance, and papilledema [10]. This explains the fact that only 8-14% of EST syndrome progress to symptomatic ICHTN, while symptomatic ICHTN has been associated with EST syndrome in 94% of cases. ICHTN has been seen in association with disturbance of the hypothalamic-pituitary-adrenal axis. This has been reported after surgical and medical treatment of Cushing's disease, withdrawal of long-term steroid therapy, initial presentation of Addison’s disease, or relative glucocorticoids deficiency [11]. Cortisol excess increases CSF production and reduces its absorption, hence increasing intracranial pressure [12]. Another possible mechanism is the expression of both mineralocorticoid responsive epithelial sodium channel receptors on the basolateral membrane of the CSF producing epithelial cells of the choroid plexus as well as the expression of 11-beta hydroxysteroid dehydrogenase type 1 enzyme, which is a bidirectional enzyme that mainly functions to convert the inactive cortisone to active cortisol. These mechanisms play a role in maintaining the balance between CSF production and absorption [13,14]. In this case, the patient presented some clinical findings that are rarely associated with Cushing's disease, combined with a radiological feature that masked the true diagnosis. Our patient presented with significant weight loss, rather than central obesity, which is normally associated with Cushing’s disease. Although possible, the increase in ACTH due to Cushing's disease is not sufficient to cause hyperpigmentation, which is a classical finding of Addison's disease, where the entire adrenal cortex is usually affected due to an autoimmune destruction; however, the zona glomerulosa of the adrenal cortex produces aldosterone and its deficiency would lead to hyperkalemia [15]. Our patient presented with both hyperpigmentation and hypokalemia. Conclusions EST syndrome is an uncommon radiological finding of apparently EST that has been reported in association with ICHTN. The latter has also been seen in association with Cushing's disease/syndrome. This is likely to result from glucocorticoid excess-induced change in CSF flow dynamics. EST has been infrequently described in association with Cushing's disease. This association has a clinical implication as it is likely to obscure the visualization of pituitary lesions responsible for Cushing's disease, contribute to diagnostic uncertainty, and increase the risk of healthy pituitary tissue injury and the risk of postoperative complications including CSF leakage. References Himes BT, Bhargav AG, Brown DA, Kaufmann TJ, Bancos I, Van Gompel JJ: Does pituitary compression/empty sella syndrome contribute to MRI-negative Cushing's disease? A single-institution experience. Neurosurg Focus. 2020, 48:E3. 10.3171/2020.3.FOCUS2084 Sun Y, Sun Q, Fan C, et al.: Diagnosis and therapy for Cushing's disease with negative dynamic MRI finding: a single-centre experience. Clin Endocrinol (Oxf). 2012, 76:868-76. 10.1111/j.1365-2265.2011.04279.x Manavela MP, Goodall CM, Katz SB, Moncet D, Bruno OD: The association of Cushing's disease and primary empty sella turcica. Pituitary. 2001, 4:145-51. 10.1023/a:1015310806063 Chatain GP, Patronas N, Smirniotopoulos JG, et al.: Potential utility of FLAIR in MRI-negative Cushing's disease. J Neurosurg. 2018, 129:620-8. 10.3171/2017.4.JNS17234 Friedman DI, Jacobson DM: Diagnostic criteria for idiopathic intracranial hypertension. Neurology. 2002, 59:1492-5. 10.1212/01.wnl.0000029570.69134.1b Triggiani V, Giagulli VA, Moschetta M, Guastamacchia E: An unusual case of reversible empty sella. Endocr Metab Immune Disord Drug Targets. 2016, 16:154-6. 10.2174/1871530315666151001141507 Wind JJ, Lonser RR, Nieman LK, DeVroom HL, Chang R, Oldfield EH: The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing's disease. J Clin Endocrinol Metab. 2013, 98:2285-93. 10.1210/jc.2012-3943 Brismar K, Bergstrand G: CSF circulation in subjects with the empty sella syndrome. Neuroradiology. 1981, 21:167-75. 10.1007/BF00367338 Ranganathan S, Lee SH, Checkver A, Sklar E, Lam BL, Danton GH, Alperin N: Magnetic resonance imaging finding of empty sella in obesity related idiopathic intracranial hypertension is associated with enlarged sella turcica. Neuroradiology. 2013, 55:955-61. 10.1007/s00234-013-1207-0 Maira G, Anile C, Mangiola A: Primary empty sella syndrome in a series of 142 patients. J Neurosurg. 2005, 103:831-6. 10.3171/jns.2005.103.5.0831 Zada G, Tirosh A, Kaiser UB, Laws ER, Woodmansee WW: Cushing's disease and idiopathic intracranial hypertension: case report and review of underlying pathophysiological mechanisms. J Clin Endocrinol Metab. 2010, 95:4850-4. 10.1210/jc.2010-0896 Sinclair AJ, Ball AK, Burdon MA, Clarke CE, Stewart PM, Curnow SJ, Rauz S: Exploring the pathogenesis of IIH: an inflammatory perspective. J Neuroimmunol. 2008, 201:212-20. 10.1016/j.jneuroim.2008.06.029 Sinclair AJ, Onyimba CU, Khosla P, et al.: Corticosteroids, 11beta-hydroxysteroid dehydrogenase isozymes and the rabbit choroid plexus. J Neuroendocrinol. 2007, 19:614-20. 10.1111/j.1365-2826.2007.01569.x Amin MS, Wang HW, Reza E, Whitman SC, Tuana BS, Leenen FH: Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain. Am J Physiol Regul Integr Comp Physiol. 2005, 289:R1787-97. 10.1152/ajpregu.00063.2005 Stratakis CA: Skin manifestations of Cushing's syndrome. 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6. Cushing syndrome This disorder occurs when your body makes too much of the hormone cortisol over a long period of time, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Although cortisol is notorious for driving up your stress, this hormone has other tasks on its docket, including regulating the way you metabolize food, the Mayo Clinic says. So, when you produce too much of it, it can interfere with your metabolism and cause you to gain weight, Peter LePort, M.D., a bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California, tells SELF. Beyond weight gain, symptoms of Cushing syndrome include deposits of fat-based tissue at the midsection, upper back, face, and between the shoulders, stretch marks due to rapid weight gain, thinning skin prone to bruising, increased body hair, irregular or missing periods, and more, according to the Mayo Clinic. Check out the other 12 at https://www.self.com/story/conditions-weight-gain-loss

John P H Wilding 1 Affiliations expand PMID: 32061161 DOI: 10.1530/EJE-20-0099 Abstract Endocrine disorders such as Cushing's syndrome and hypothyroidism may cause weight gain and exacerbate metabolic dysfunction in obesity. Other forms of endocrine dysfunction, particularly gonadal dysfunction (predominantly testosterone deficiency in men and polycystic ovarian syndrome in women), and abnormalities of the hypothalamic-pituitary-adrenal axis, the growth hormone-IGF-1 system and vitamin D deficiency are common in obesity. As a result, endocrinologists may be referred people with obesity for endocrine testing and asked to consider treatment with various hormones. A recent systematic review and associated guidance from the European Society of Endocrinology provide a useful evidence summary and clear guidelines on endocrine testing and treatment in people with obesity. With the exception of screening for hypothyroidism, most endocrine testing is not recommended in the absence of clinical features of endocrine syndromes in obesity, and likewise hormone treatment is rarely needed. These guidelines should help reduce unnecessary endocrine testing in those referred for assessment of obesity and encourage clinicians to support patients with their attempts at weight loss, which if successful has a good chance of correcting any endocrine dysfunction. Similar articles Classical endocrine diseases causing obesity. Weaver JU.Front Horm Res. 2008;36:212-228. doi: 10.1159/000115367.PMID: 18230905 Review. Is obesity an endocrine condition? Stocks AE.Aust Fam Physician. 1977 Feb;6(2):109-16.PMID: 558747 FPIN’s clinical inquiries. Secondary causes of obesity. Allen G, Safranek S.Am Fam Physician. 2011 Apr 15;83(8):972-3.PMID: 21524038 No abstract available. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease]. Hagymási K, Reismann P, Rácz K, Tulassay Z.Orv Hetil. 2009 Nov 29;150(48):2173-81. doi: 10.1556/OH.2009.28749.PMID: 19923096 Review. Hungarian. Obesity and endocrine disease. Kokkoris P, Pi-Sunyer FX.Endocrinol Metab Clin North Am. 2003 Dec;32(4):895-914. doi: 10.1016/s0889-8529(03)00078-1.PMID: 14711067 Review. From https://pubmed.ncbi.nlm.nih.gov/32061161/

Cases of adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome are often caused by unilateral tumors in the adrenal glands, but Indian researchers have now reported a rare case where the condition was caused by tumors in both adrenal glands. Fewer than 40 cases of bilateral tumors have been reported so far, but an accurate diagnosis is critical for adequate and prompt treatment. Sampling the veins draining the adrenal glands may be a good way to diagnose the condition, researchers said. The study, “Bilateral adrenocortical adenomas causing adrenocorticotropic hormone-independent Cushing’s syndrome: A case report and review of the literature,” was published in the World Journal of Clinical Cases. Cushing’s syndrome, a condition characterized by excess cortisol in circulation, can be divided into two main forms, depending on ACTH status. Some patients have tumors that increase the amount of ACTH in the body, and this hormone will act on the adrenal glands to produce cortisol in excess. Others have tumors in the adrenal glands, which produce excess cortisol by themselves, without requiring ACTH activation. This is known as ACTH-independent Cushing’s syndrome. Among the latter, the disease is mostly caused by unilateral tumors — in one adrenal gland only — with cases of bilateral tumors being extremely rare in this population. Now, researchers reported the case of a 31-year-old Indian woman who developed ACTH-independent Cushing’s syndrome because of tumors in both adrenal glands. The patient complained of weight gain, red face, moon face, bruising, and menstrual irregularity for the past two years. She recently had been diagnosed with high blood pressure and had started treatment the month prior to the presentation. A physical examination confirmed obesity in her torso, moon face, buffalo hump, thin skin, excessive hair growth, acne, swollen legs and feet, and skin striae on her abdomen, arms, and legs. Laboratory examinations showed that the woman had an impaired tolerance to glucose, excess insulin, and elevated cortisol in both the blood and urine. Consistent with features of Cushing’s syndrome, cortisol levels had no circadian rhythm and were non-responsive to a dexamethasone test, which in normal circumstances lowers cortisol production. Because ACTH levels were within normal levels, researchers suspected an adrenal tumor, which led them to conduct imaging scans. An abdominal computed tomography (CT) scan showed adrenal adenomas in both adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). A magnetic resonance imaging (MRI) scan showed that the pituitary gland (which normally produces ACTH) was normal. To determine whether both adrenal tumors were producing cortisol, researchers sampled the adrenal veins and compared their cortisol levels to those of peripheral veins. They found that the left adrenal gland was producing higher amounts of cortisol, thought the right adrenal gland was also producing cortisol in excess. “Our case indicates that adrenal vein [blood] sampling might be useful for obtaining differential diagnoses” in cases of Cushing’s syndrome, researchers stated. Also, they may help design a surgical plan that makes much more sense.” The tumors were surgically removed — first the left, and three months later the right — which alleviated many of her symptoms. She also started prednisolone treatment, which helped resolve many disease symptoms. “Bilateral cortisol-secreting tumors are a rare cause of Cushing’s syndrome,” researchers said. So when patients present bilateral adrenal lesions, “it is crucial to make a definitive diagnosis before operation since various treatments are prescribed for different causes,” they said. The team recommends that in such cases the two tumors should not be removed at the same time, as this approach may cause adrenal insufficiency and the need for glucocorticoid replacement therapy. From https://cushingsdiseasenews.com/2019/06/27/rare-case-of-cs-due-to-bilateral-tumors-in-the-adrenal-glands/

The oral chemotherapy temozolomide might be an effective treatment for Cushing’s disease caused by aggressive tumors in the pituitary gland that continue to grow after surgery and taking other medications, a case report suggests. The study, “Successful reduction of ACTH secretion in a case of intractable Cushing’s disease with pituitary Crooke’s cell adenoma by combined modality therapy including temozolomide,” was published in the journal J-Stage. Cushing’s disease is often caused by a tumor in the pituitary gland that secretes high levels of adrenocorticotropic hormone (ACTH), leading to high levels of cortisol and other symptoms. Macroadenomas are aggressive, fast-growing tumors that reach sizes larger than 10 millimeters. Crooke’s cell adenoma is a type of macroadenoma that does not respond to conventional therapies, but has deficient mechanisms of DNA repair. That is why chemotherapeutic agents that damage the DNA, such as temozolomide, might be potential treatments. Researchers in Japan reported the case of a 56-year-old woman with Cushing’s disease caused by a Crooke’s cell adenoma in the pituitary gland who responded positively to temozolomide. The patient was diagnosed with Cushing’s disease at age 39 when she went to the hospital complaining of continuous weight gain. She also had excessive production of urine and a loss of vision in the right eye. The lab tests showed high levels of cortisol and ACTH, and the MRI detected a tumor of 4.5 centimeters in the pituitary gland. The doctors removed a part of the tumor surgically, which initially reduced the levels of ACTH and cortisol. However, the hormone levels and the size of the residual tumor started to increase gradually after the surgery, despite treatment with several medications. By the time the patient was 56 years old, she went to the hospital complaining of general fatigue, leg edema (swelling from fluid), high blood pressure, and central obesity (belly fat). Further examination showed a 5.7 cm tumor, identified as a Crooke’s cell macroadenoma. The patient underwent a second surgery to remove as much tumor as possible, but the levels of ACTH remained high. She took temozolomide for nine months, which normalized the levels of ACTH and cortisol. After the treatment, the patient no longer had high blood pressure or leg edema. The tumor shrunk considerably in the year following temozolomide treatment. The patient started radiation therapy to control tumor growth. The levels of cortisol and ACHT remained normal, and the tumor did not grow in the seven years following temozolomide treatment. “These clinical findings suggest that [temozolomide] treatment to patients with Crooke’s cell adenoma accompanied with elevated ACTH may be a good indication to induce lowering ACTH levels and tumor shrinkage,” researchers wrote. Other cases of Cushing’s disease caused by aggressive macroadenomas showed positive results, such as reduction of tumor size and decrease in plasma ACTH, after temozolomide treatment. However, more studies are needed to establish the ideal course of chemotherapy to treat these tumors, the researchers noted. From https://cushingsdiseasenews.com/2019/06/18/temozolomide-effective-cushings-disease-aggressive-tumors-case-report/

When we become stressed out bodies release cortisol – the stress hormone – which helps us cope with challenges. Cortisol’s role is to convert protein into energy by releasing glycogen and counteract inflammation. When cortisol is released in the body temporarily, this is okay and won’t have long-lasting detrimental effects to health as it is a natural response to a stressor. But when cortisol levels remain high chronically it can eventually begin to tear your body down thus causing health complications. This is why numerous health experts recommend the reduction of stress as much as possible because in the long run it can harm our health. High cortisol levels over the long term can destroy healthy muscle and bone, slow down healing, impair digestion, metabolism and mental function, and weaken the immune system. Additionally, adrenal fatigue has been linked to numerous other health conditions including fibromyalgia, hypothyroidism, chronic fatigue syndrome, arthritis, premature menopause, and many others. High cortisol levels are also associated with many unwanted symptoms which we will outline below. High cortisol symptoms If you’re concerned about your cortisol levels, the following signs and symptoms associated with high cortisol levels can alert you and prompt you to make the necessary changes in order to reduce cortisol levels. Unexplained weight gain Skin symptoms including acne, skin infections, lesions, thin-appearing skin, bruising, growing facial hair, and reddish purple streaks on skin Muscle and bone symptoms like a deep pain in the bones, weak muscles, chronic backaches, increased risk of bone fractures Gender specific changes such as women developing male-pattern hair growth, irregular menstrual cycles, low libido, infertility Neurological symptoms such as depression, irritability, headaches, chronic fatigue, and anxiety High blood pressure (hypertension) Poor sleep or lack of sleep Swelling of hands and feet If you notice any of the above symptoms, you may want to have your cortisol levels checked to confirm diagnosis. Living with high cortisol levels over the long term can have detrimental effects on a person’s health. Treating high cortisol as soon as possible can lower the risk of long-term health problems. Causes of high cortisol There are two main causes of high cortisol: Chronic stress and more rarely, Cushing’s disease. Cushing’s disease is caused by a hormone-secreting tumor on the adrenal gland which results in the release more cortisol than required. Living with chronic stress also leads to high cortisol because the release of cortisol is a natural response from the body when it is stressed. The hypothalamic–pituitary-adrenal [HPA] axis is what regulates the timely release of cortisol during acute stress, but when stress becomes chronic the feedback from the HPA becomes damaged and so cortisol continues to be released. Conditions that can contribute to chronic stress and high cortisol include: Depression Panic disorder Generalized anxiety disorder Post traumatic stress disorder (PTSD) Anorexia nervosa Bulimia nervosa Alcoholism Diabetes Severe obesity Metabolic syndrome Polycystic ovary syndrome (PCOS) Obstructive sleep apnea Working in shifts End-stage kidney disease Chronic pain Tips to lower high cortisol Here are some tips that can help you lower your high cortisol levels and thus prevent long-term health problems associated with high cortisol. [MaryO'Note: These will not work if you have active Cushing's! You must remove the source of your Cushing's first.] Eat a well balanced meal with plenty of fruits and vegetables, avoid sugars, consume low glycemic index foods, avoid processed foods, eat a wide variety of health foods to ensure you receive all essential vitamins and nutrients Exercise on a regular basis Take time out of each day to relax – listen to music, meditate, pray, perform your favorite hobby, anything that promotes relaxation Take up yoga or tai chi Ensure you are getting adequate sleep Drink tea Watch funny videos or hang out with a funny friend Go for a massage Do something spiritual – attend a service Chew gum Limit caffeine intake Stretch By incorporating these helpful tips into your life you will find that your high cortisol symptoms begin to diminish and your overall health begins to improve. From http://www.belmarrahealth.com/high-cortisol-symptoms-signs-look/