Accidental Cushing Syndrome

Posted on February 5, 2024 by MaryO

Abstract

We present a patient with Cushing syndrome secondary to accidental intake of corticosteroid tablets—a 66-year-old woman with a history of well-controlled hypertension, who over the course of a few weeks developed full-blown Cushing syndrome with uncontrolled blood pressure, typical central fat accumulation, and easy bruising. The clinical features further worsened upon increase of the dosage of her antihypertensive medication because of rising blood pressure. Biochemical analyses showed low cortisol and ACTH concentrations. Inspection of the patient’s medications revealed that she had accidentally been taking corticosteroids tablets, prescribed for her husband, instead of antihypertensives, ie, dexamethasone 4 mg and then 8 mg, instead of candesartan at the same dose.

This case highlights the necessity of a thorough review of the medications taken by patients suspected to have exogenous Cushing syndrome, including inspection of the original packaging, and not just relying on information from the patient and electronic health records. This case also highlights the need of special labeling on the packaging for the easy identification of corticosteroid-containing medications given their widespread availability.

Introduction

Cushing syndrome (CS) is a disorder caused by prolonged and excessive exposure to glucocorticoids. The most common cause of CS is exogenous or iatrogenic, ie, CS caused by administration of glucocorticoids due to inflammatory, autoimmune, or neoplastic diseases. Endogenous CS is a rare condition, caused by either hypersecretion of ACTH from the pituitary gland, ectopic ACTH production, or hypersecretion of cortisol from the adrenal glands.

It is of great importance to exclude exogenous CS in all patients who present with signs and symptoms compatible with the syndrome. The following case highlights the need to rule out exogenous CS via a face-to-face review of the medications taken by a patient with CS, rather than only relying on the patient’s history and electronic health record.

Case Presentation

A 66-year-old woman was referred to our department for investigation of suspected CS. She was diagnosed with essential hypertension a couple of years earlier and was prescribed tablet candesartan 4 mg daily. Apart from an otherwise well-controlled hypertension, the patient had a history of bilateral hip replacement, the first performed in 2020 and the second 2 years later.

During the 6 weeks prior to our evaluation, the patient had noticed an increasing fat accumulation around her abdomen, upper back, neck, and over the collar bones, despite minimal increase of her body weight. Moreover, the patient had developed a rounded face and increased growth of facial hair, especially on the chin, as well as thin and fragile skin that bruised easily. About 1.5 weeks before she was referred to our clinic, the dose of candesartan was increased by her general practitioner from 4 to 8 mg daily because of rapidly worsening hypertension, confirmed by monitoring 24-hour ambulatory blood pressure.

Diagnostic Assessment

The physical examination of the patient revealed central obesity and multiple bruises that the patient could not recall. Increased growth of fine hairs on the chin and facial plethora was present. Blood pressure was 165/88 mmHg. The patient did not have any signs of abdominal stretch marks, nor did she have any obvious muscle wasting in the arms and legs (Fig. 1). When comparing to photographs taken about 6 months prior to the examination, the differences were obvious (Fig. 2).

 

Figure 1.

The patient few weeks prior to admission for evaluation of Cushing syndrome.

 

Figure 2.

The patient many months before the onset of Cushing syndrome.

Biochemical evaluation revealed unmeasurable plasma cortisol at 12:00 PM, 4:00 PM, and 6:00 AM (<28 nmol/L, reference 102-535 nmol/L; <1.01 μg/dL, reference 3.69-19.39 μg/dL). Serum ACTH was also undetectable (<0.2 pmol/L, reference 1.6-13.9 pmol/L; <0.91 pg/mL, reference 2.27-63.18 pg/mL), which raised suspicion of exogenous CS. The patient firmly denied any intake of anything other than her candesartan tablets. She even stated that she avoided any analgesics after the hip replacement previously the same year, nor had she received any intra-articular cortisone injection. The patient gave a very trustworthy and consistent impression, which inevitably led us to proceed to further investigation of the adrenal glands and the pituitary gland to exclude rarer forms of CS, such as cyclic CS and/or pituitary apoplexy of an ACTH-producing pituitary adenoma. The magnetic resonance imaging of the pituitary and the computed tomography of the adrenal glands were normal. Except for the low cortisol and ACTH levels, endocrine workup was unremarkable (Table 1).

 
Table 1.

Biochemical evaluation of the patient with Cushing syndrome at baseline, ie, at admission

Hormone tested Value Normal Range
Plasma cortisol at 08:00 AM <1.01 mcg/dL (<28 nmol/L) 3.70-19.39 mcg/dL (102-535 nmol/L)
ACTH <0.91 pg/mL (<0.2 pmol/L) 7.27-63.18 pg/mL (1.6-13.9 pmol/L)
TSH 1.0 mIU/L (1.0 mIU/L) 0.4-3.7 mIU/L (0.4-3.7 mIU/L)
Free T4 1.01 ng/dL (13 pmol/L) 0.76-1.32 ng/dL (9.8-17 pmol/L)
IGF-1 142 ng/mL (18.60 nmol/L) 38-162 ng/mL (4.98-21.22 nmol/L)
Prolactin 374 mIU/L (17.58 mcg/L) 63-561 mIU/L (2.96-26.37 mcg/L)
FSH 90 mIU/mL (90 IU/L) 27-133 mIU/mL (post-menopausal) (27-133 IU/L)
LH 16 mIU/mL (16 IU/L) 5.2-62 mIU/mL (post-menopausal) (5.2-62 IU/L)
SHBG 6.07 mcg/mL (54 nmol/L) 2.25-17.42 mcg/mL (20-155 nmol/L)
Testosterone 8.65 ng/dL (0.30 nmol/L) 11.53-34.58 ng/dL (0.4-1.2 nmol/L)
Estradiol <19.07 pg/mL (<70 pmol/L) <28.06 pg/mL (<103 pmol/L) (post-menopausal with no hormone substitute)
Aldosterone 9.05 ng/dL 0.251 pmol/L <23.61 ng/dL (recumbent position) <655 nmol/L
Renin 8.25 mIU/L 2.8-40 mIU/L (recumbent position)
DHEAS 14.81 mcg/dL (0.4 µmol/L) 29.63-181.48 mcg/dL (0.8-4.9 µmol/L)
HbA1c 45 mmol/mol (6.3 %) 31-46 mmol/mol (5-6.4 %)

Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI).

Abbreviations: ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; T4, thyroxine; IGF-1, insulin-like growth factor 1; FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin; DHEAS, dehydroepiandrosterone sulfate; HbA1c, glycated hemoglobin.

On day 3 after admission, we noted that plasma cortisol at 8:00 AM was measurable, though still low, at 134 nmol/L (4.86 μg/dL), which reinforced our first suspicion of exogenous CS and prompted a more thorough review of the patient’s medication. At this time, we asked the patient to show us the tablets that she had been taking at home and that she still carried in her purse. To the patient’s frank surprise, it turned out that she was indeed carrying tablets containing 4 mg dexamethasone in the belief that they were candesartan 4 mg tablets. The dexamethasone 4 mg tablet the patient had (generic) was white, scored with a diameter of 6 mm (Fig. 3A). The candesartan 4 mg tablet the patient had been dispensed (generic) was also white, scored and with a diameter of 7 mm (Fig. 3B).

 

Figure 3.

A. Tablet Dexamethasone 4 mg. White, scored, diameter 6 × 6 mm. B. Tablet Candesartan 4 mg. White, scored, diameter 7 × 7 mm.

Treatment

The patient was discharged with the same antihypertensive medications as prior to the deterioration and referred to her general practitioner for follow-up of blood pressure. Upon clinical evaluation 5 months after discharge, she showed no signs or symptoms of CS (Fig. 4).

 

Figure 4.

The patient 5 months after the resolution of Cushing syndrome.

Outcome and Follow-up

Thus, the patient had accidentally been taking her husband’s medication, with which the patient had been aiding her husband, and developed a surreptitious iatrogenic CS. In hindsight, the severity of the clinical features had been worsening and resulted in rapid deterioration alongside the increase of the dosage of the antihypertensives from 4 to 8 mg because of the rising blood pressure.

By day 5 after admission, the patient’s plasma cortisol and ACTH concentrations had normalized, as had her blood pressure.

Discussion

Exogenous hypercortisolism is the most common cause of CS, though seldomly published in the literature, and is mainly iatrogenic because of prolonged use of high doses of synthetic glucocorticoids prescribed for the treatment of nonendocrine diseases (1). A recent study has shown that as many as every seventh resident in western Sweden received a glucocorticoid prescription between 2007 and 2014 (2).

The rising use of generic medications during the past decade has resulted in corticosteroids being available in different forms, shapes, and packages that make them less easily recognizable. In many countries, corticosteroids are available over-the-counter in almost any form, whereas a variety of agents such as herbal preparations, tonics, and skin-bleaching creams may also contain corticosteroids to the unawareness of the people using them (3, 4).

There are no large studies regarding how common the unintentional use of medicines or products that contain corticosteroids. However, studies on traditional Chinese medicine have shown that illegally impure herbs and medicines containing corticosteroids are widely used, suggesting that the accidental intake of corticosteroids is more frequent than we may think (3, 5). Many cases of factitious CS have been reported as a cause of exogenous CS, which makes the diagnosis even more challenging (6-8).

The Endocrine Society Clinical Practice Guidelines for the diagnosis of CS recommend that exogenous CS be always excluded before starting the investigation of endogenous CS (9). However, a specific and definitive approach for diagnosing, respectively excluding, exogenous CS is currently lacking. In a recent review, the authors recommend that in addition to asking the patient which medicines they take, the physician should review the electronic health record and ask particularly for medications that are administered via nonoral routes, as well as over-the-counter agents as mentioned earlier (10).

If not confirmed by history, the physician is advised to proceed to the measurement of ACTH and/or dehydroepiandrosterone sulfate as well as screening for synthetic glucocorticoids (10). The results usually show low ACTH, dehydroepiandrosterone sulfate, and cortisol levels even though the clinical picture suggests CS. The cross-reactivity of hydrocortisone or cortisone, which is similar to endogenous steroids, in immunoassay-based measurements of plasma and urinary cortisol may show variable levels of cortisol. These measurements combined with low ACTH can make the diagnostic workup much more complex (7). Screening for exogenous substances with the help of high-performance liquid chromatography is usually positive and constructive (7).

It is increasingly clear that the risk of accidental ingestion of potent medicines can have deleterious effects on health. This leads us to conclude that thorough face-to-face review of the packaging of medications taken by the patient is mandatory and can spare both physicians and patients from a series of unnecessary investigations. Given the high availability, easy access, and catastrophic adverse effects of the unintentional use of corticosteroids, we therefore propose that all corticosteroid-including medications and agents be marked with a recognizable label.

Learning Points

  • Exogenous CS should be always excluded before starting investigation of endogenous CS.
  • Concerning exogenous CS, practitioners should always think broadly and ask for use of herbal preparations, skin-bleaching creams, and any over-the-counter products.
  • Unintentional use of corticosteroids can still be the case even after a thorough review of the electronic records; practitioners should always inspect the medicines the patient has taken.

Contributors

All authors (K.K., O.R., P.T.) made equal contributions to authorship. K.K., O.R., and P.T. were involved in the diagnosis and management of this patient, as well as in manuscript submission. K.K. and P.T. authored the manuscript draft. All authors (K.K., O.R., P.T.) reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent was obtained directly from the patient.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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A Medical Chart Audit to Assess Endocrinologist Perceptions of the Burden of Endogenous Cushing’s Syndrome

Posted on January 27, 2024 by MaryO

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. 1.Were board-certified or board-eligible in endocrinology in the United States.
  2. 2.Had been in practice for more than 3 years and less than 35 years post residency.
  3. 3.Spent at least 25% of their professional time providing direct patient care.
  4. 4.Had treated or managed at least 40 unique patients (of any condition) in an average month.
  5. 5.Had managed (i.e., had an appointment with) at least 3 patients with CS in the past year.
  6. 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

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

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

figure 1

Number of CS symptoms reported at diagnosis

Fig. 2

figure 2

Symptoms of CS at diagnosis (N = 273)

Fig. 3
figure 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)

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

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

figure 4

Physicians’ perceptions of CS burden and impact. On a scale of 1–9, where 1 = Not at all agree and 9 = Completely agree

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
Table 5 Physicians’ satisfaction across therapeutic categories

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

figure 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

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

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.

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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

  1. Division of Endocrinology, Columbia University Irving Medical Center, New York, NY, USA

    Gabrielle Page-Wilson

    1. Trinity Life Sciences, Waltham, MA, USA

      Bhagyashree Oak, Abigail Silber & Matthew O’Hara

    2. Xeris Pharmaceuticals, Inc, Chicago, IL, USA

      James Meyer

    3. 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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Paediatric Cushing Syndrome: Prospective, Multisite, Observational Cohort Study

Posted on January 19, 2024 by MaryO

Summary

Background

Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management.

Methods

In this prospective, multisite cohort study, we studied children and adolescents (≤18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants’ clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment.

Findings

Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1·0–3·0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10·4 years [IQR 7·4–13·6] vs 13·0 years [10·5–15·3] for Cushing disease vs 13·4 years [11·0–13·7] for ectopic Cushing syndrome; p<0·0001). Body-mass index z-scores did not differ between the diagnostic groups (1·90 [1·19–2·34] for adrenal-associated Cushing syndrome vs 2·18 [1·60–2·56] for Cushing disease vs 2·22 [1·42–2·35] for ectopic Cushing syndrome; p=0·26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15·5 [IQR 12·7–18·0]) than patients with adrenal-associated Cushing syndrome (1·5 [0·6–5·7]) or Cushing disease (3·9 [2·3–6·9]; p<0·0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease.

Interpretation

This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition.

Funding

Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health.

Introduction

Paediatric endogenous Cushing syndrome is a rare disorder accounting for 5–7% of all reported cases of endogenous Cushing syndrome.1, 2, 3 In children older than 5–7 years and adolescents, endogenous Cushing syndrome is most commonly caused by corticotroph pituitary neuroendocrine tumours (PitNETs) and is termed Cushing disease. By contrast, Cushing syndrome in children younger than 5 years is often associated with adrenal disorders and is termed adrenal-associated Cushing syndrome.4 Albeit rare, a third type termed ectopic Cushing syndrome is caused by neuroendocrine tumours outside the hypothalamic–pituitary axis that secrete adrenocorticotropin or corticotropin-releasing hormone.5, 6 Thus endogenous Cushing syndrome is caused by either adrenocorticotropin-dependent sources (pituitary or ectopic) or adrenocorticotropin-independent (adrenal) hypercortisolemia.

Patients with adults-onset Cushing syndrome typically present with weight gain, skin manifestations (striae, hirsutism, acne, and easy bruising), and abnormal fat deposition.7, 8, 9 Paediatric Cushing syndrome differs from adult-onset Cushing syndrome in aspects including effects on growth (weight gain with concomitant height deceleration), atypical physical presentation (such as lack of centripetal obesity or typical striae), delayed or suppressed puberty, and variable mental health problems and neurocognitive function deficits.10 Diagnosis of paediatric Cushing syndrome is therefore challenging, and delayed evaluation is common.

Research in context

Evidence before this study

Endogenous Cushing syndrome is a rare endocrine condition. Diagnosis can be challenging and delay treatment. We searched PubMed for articles published in English on paediatric Cushing syndrome using terms “Cushing” AND “children” from database inception to May 5, 2023. Although several case series of paediatric Cushing disease were identified, only a few studies of the various causes of paediatric endogenous Cushing syndrome were available.

Added value of this study

To our knowledge, this cohort of paediatric endogenous Cushing syndrome of various causes is one of the largest sources of cumulative clinical, anthropometric, and biochemical data on the presentation, diagnosis, and management. We confirm that baseline biochemical data cannot aid differential diagnosis of Cushing syndrome subtypes. However, evidence suggests that minimally invasive stimulation tests could be a safe alternative to interventional sampling procedures such as inferior petrosal sinus sampling. We provide the prevalence of complications related to Cushing syndrome. Long-term outcomes of paediatric patients with pituitary corticotroph tumours recurrence is possible up to 8 years after initial remission.

Implications of all the available evidence

Data from this large paediatric cohort inform the evaluation, diagnosis, and long-term care of patients with paediatric Cushing syndrome. We recommend an algorithm for the diagnosis of patients and screening of complications. Screening for recurrence in patients with Cushing disease is indicated for this age group, at least for the first decade after surgery.

We have evaluated a large cohort of children and adolescents with endogenous Cushing syndrome of various causes. The aim of the study was to document anthropometric, clinical, and biochemical characteristics, complications, and outcomes of paediatric endogenous Cushing syndrome to aid clinicians in the diagnosis and management of these patients.

Section snippets

Study design and participants

In this prospective, multisite cohort study, we screened participants who, from 1995 to 2023, had enrolled in studies under protocols 97-CH-0076 (clinicaltrials.gov, NCT00001595), 95-CH-0059 (NCT00001452), and 00-CH-0160 (NCT00005927) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, Bethesda, MD, USA). Paediatric patients (18 years or younger at time of presentation) with a diagnosis of Cushing syndrome were eligible for inclusion in the study. We

Results

342 patients with paediatric Cushing syndrome were included in the study (table 1). 278 patients were referred from centres in the USA, and 64 patients were referred from centres outside of the USA. 261 (76%) patients were diagnosed with Cushing disease, 74 (22%) patients were diagnosed with adrenal-associated Cushing syndrome, and seven (2%) patients were diagnosed with ectopic Cushing syndrome. Patients with adrenal-associated Cushing syndrome were diagnosed at a younger age than patients

Discussion

We present extensive and unique data on presentation, diagnosis, and follow-up of paediatric patients with three diagnostic types of endogenous Cushing syndrome. Clinical and anthropometric characteristics were similar across subtypes of Cushing syndrome, but biochemical tests differed. We also present extensive information on complications; hypertension, insulin resistance, dyslipidaemia, and elevated ALT were common. Long-term follow-up of patients revealed excellent postoperative prognosis,

Data sharing

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declaration of interests

CAS holds patents on the function of the PRKAR1A, PDE11A, and GPR101 genes and related issues; his laboratory had received research funding on GPR101, and on abnormal growth hormone secretion and its treatment by Pfizer. CAS receives support from ELPEN and has been consulting for Lundbeck Pharmaceuticals and Sync. CT reports receiving research funding on treatment of abnormal growth hormone secretion by Pfizer.

References (38)

Filed under: Cushing's, Rare Diseases, symptoms, Treatments | Tagged: , , , , | Leave a comment »

Metformin Inhibits Cell Proliferation and ACTH Secretion In AtT20 Cells Via Regulating the Mapk Pathway

Posted on January 16, 2024 by MaryO

Abstract

We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing’s disease.

Introduction

Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors with an incidence of 1/1000, and pituitary corticotroph tumors (corticotroph PitNETs) account for approximately 15% of all PitNETs. Most corticotroph PitNETs are functional tumors with clinical manifestations of Cushing’s disease characterized by central obesity, hypertension, diabetes mellitus, and psychosis (Cui et al., 2021). The increased cortisol due to the overproduction of adrenocorticotropic hormone (ACTH) significantly reduces the overall quality of survival and life expectancy of patients (Sharma et al., 2015; Barbot et al., 2018). Currently, treatment of corticotroph PitNETs mainly relies on surgery resection, pharmacologic therapy or radiotherapy may be considered for patients with residual tumors or those who are unable to undergo surgery. While several agents, such as cabergoline and pasireotide, are clinically approved, the effect is unsatisfactory, and potentially serious side effects exist. Therefore, there is an urgent need to develop novel therapeutic drugs for corticotroph PitNETs.

Metformin is a biguanide hypoglycemic agent for the treatment of type 2 diabetes. In addition to its hypoglycemic effect, numerous studies identified the therapeutic role of metformin in the prevention and treatment of various tumors including small cell lung cancer, colorectal cancer, breast cancer, ovarian cancer, and neuroendocrine tumors (Lu et al., 2022; Kamarudin et al., 2019; Wang et al., 2019; Thakur et al., 2019), making metformin a promising adjuvant drug in the therapy of cancers. Besides, it has been reported that metformin improves metabolic and clinical outcomes in patients treated with glucocorticoids. However, to date, limited studies explore the potential anti-cancer effect of metformin in corticotroph PitNETs. Recent studies report the use of metformin for blood glucose and body weight control in patients with Cushing’s disease (Ceccato et al., 2015), while the role of metformin on ACTH secretion and tumor growth in corticotroph PitNETs remains to be elucidated.

In the current study, we investigated the effect of metformin in corticotroph PitNETs and performed RNA-sequencing to identify the potential mechanisms of metformin. We found that metformin inhibited cell proliferation and ACTH secretion of AtT20 cells in a dose-dependent manner. Besides, metformin induced cell cycle arrest via decreased ERK1/2 phosphorylation and increased P38 phosphorylation. Our results revealed that metformin is a potential drug for corticotroph PitNET therapy.

Section snippets

Cell culture

The ACTH-secreting mouse pituitary tumor cell line AtT-20 was purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA). Cells were cultured in F-12K medium (ATCC; Catalog No. 30-2004), supplemented with 15% fetal bovine serum (FBS; Gibco), and 2.5% horse serum (Gibco) as suggested. AtT20 cells were cultured in a humidified incubator at 37 °C in 5% CO2.

Reagents and drugs

Metformin and Ulixertinib were purchased from MedChemExpress (MCE), Metformin was dissolved in sterile H2O and prepared as a

Results

Metformin inhibits cell proliferation and ACTH secretion, and leads to cell cycle arrest in AtT20 cells.

We used CCK-8 assay to detect the cell viability of AtT20 cells after treatment with different concentrations of metformin at 24 h, 48 h, and 72 h. The results showed that metformin significantly inhibited the proliferation of AtT20 cells in a dose-dependent manner (Fig. 1A). Similarly, prolonged (6 days) treatment of AtT20 cells with a lower concentration (400 μM) of metformin also inhibited

Discussion

Metformin, acting by binding to PEN2 and initiating the subsequent AMPK signaling pathway in lysosomes, is the most commonly used oral hypoglycemic agent (Hundal et al., 2000; Ma et al., 2022). Previous reports demonstrated metformin as a potential anti-tumor agent in cancer therapy (Evans et al., 2005). Metformin, either alone or in combination with other drugs, has been shown to reduce cancer risk in a variety of tumors including pituitary neuroendocrine tumors (PitNETs) (Thakur et al., 2019;

Conclusion

Our study demonstrated that metformin suppressed cell proliferation and decreased ACTH secretion in AtT20 cells via the MAPK pathway. Our results revealed that metformin is a potential anti-tumor drug for the therapy of corticotroph PitNETs, which deserves further study.

Funding

This study was supported by the National Natural Science Foundation of China (82072804, 82071559).

CRediT authorship contribution statement

Yingxuan Sun: Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Jianhua Cheng: Data curation, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. Ding Nie: Formal analysis, Writing – review & editing. Qiuyue Fang: Data curation, Formal analysis, Writing – review & editing. Chuzhong Li: Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Funding acquisition. Yazhuo Zhang:

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

We thank Mr. Hua Gao (Cell Biology Laboratory, Beijing Neurosurgical Institute, China) for support with the techniques.

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From https://www.sciencedirect.com/science/article/abs/pii/S0303720723002915

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An Ectopic Cushing’s Syndrome with Severe Psychiatric Presentation

Posted on January 12, 2024 by MaryO

an-ectopic-cushingrsquos-syndrome-with-severe-psychiatric-presentation-9744

We report a case of severe EAS in a young Tunisian man resulting from a well differentiated Neuroendocrine Tumor (NET) of the lung. Besides catabolic signs and profound hypokalemia orienting towards Cushing’s Syndrome (CS), psychiatric symptoms were particularly severe, dominant and atypical including persecutory delusions, depression and anxiety.

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