Co-Occurrence of Endogenous and Exogenous Cushing’s Syndromes: Does “Double Cushing Syndrome” Really Exist? A Case Report

Posted on December 1, 2025 by MaryO

ABSTRACT

Double Cushing syndrome exists: exogenous steroid use can mask concurrent adrenal hypercortisolism. When symptoms persist and cortisol remains high after tapering or stopping prescribed glucocorticoids, an endogenous source is likely. Early recognition with ACTH testing, dexamethasone suppression, and adrenal imaging reduces misdiagnosis, favors timely surgery, and supports safe tapering.

1 Introduction

Cushing syndrome (CS) is a non-physiological increase in plasma glucocorticoids [1]. In most cases, the source of increased plasma glucocorticoids is caused by exogenous steroid administration, which is quite common, and about 1% of the world population is on long-term (more than 3 months) oral glucocorticoids [1, 2]. On the contrary, endogenous overproduction of glucocorticoids is rare, and annually, only two to eight per million people are diagnosed with endogenous CS [3]. The simultaneous occurrence of endogenous and exogenous CS is an exceptionally uncommon phenomenon. This dual manifestation has been reported in a few case reports, highlighting its rarity and the complex diagnostic and therapeutic challenges it poses [4, 5]. Therefore, in this study, we discuss a patient who presented with cushingoid features and was simultaneously diagnosed with both endogenous and exogenous CS or, as it is called, double CS.

2 Case Presentation

The patient was a 46-year-old male with a history of new-onset hypertension and recurrent deep vein thrombosis (DVT) who was referred to our endocrinology clinic with a chief complaint of hip pain and weakness of the lower limbs. In the past 3 years, the patient had been receiving 50 mg/day of oral prednisolone and inhalation powder of Umeclidinium and Vilanterol (62.5/25 μg/dose) because of respiratory complications that started after Coronavirus Disease 2019 (COVID-19) vaccination. After 3 months of corticosteroid treatment, he experienced DVT for the first time when he was started on rivaroxaban. However, while he was on treatment, the second DVT occurred 1 month before his referral, and therefore, rivaroxaban was changed to warfarin 5 mg/day.

The patient also mentioned weight gain with his body mass index (BMI) rising from 26 to 31 kg/m2, progressive weakness of proximal muscles, easy bruising, decreased libido, mood changes with mostly euphoric mood, and irritability during the last 2 years. Moreover, multiple osteoporotic fractures of ribs, clavicle, sternum, and lumbar vertebrae were added to his symptoms in the past 5 months. At that time, he underwent bone densitometry, which revealed osteopenia of the left hip with a Z-score of −1.3 and severe osteoporosis of total lumbar spine with a T-score of −3.9. He started taking calcium and vitamin D3 supplements and received a single injection of 750 μg/3 mL teriparatide 30 days before his referral to our center.

Two months ago, the patient gradually reduced the dosage of prednisolone by tapering the dose to 12.5 mg/day. However, a month later, the hip pain and muscle weakness worsened to such an extent that the patient was unable to walk. Due to his signs and symptoms, the patient was referred to our center for further evaluation of CS. The patient also mentioned a history of nephrolithiasis, new-onset hypertension, and lower limb edema, for which he was started on eplerenone 25 mg and furosemide 20 mg tablets once daily. In his family history, the patient’s mother had type 2 diabetes mellitus, and his two sisters had a history of nephrolithiasis. The patient did not mention any history of allergies to medications or foods. He was addicted to opium and had 15 pack-years of smoking, but he did not mention alcohol consumption.

Upon admission, the patient presented with a blood pressure of 150/83 mmHg, heart rate of 74 bpm, respiratory rate of 20/min, temperature of 36.5°C, oxygen saturation of 93%, and BMI of 31 kg/m2. He was sitting in a wheelchair due to weakness and severe pain in the hip. On physical examination, the patient showed the features of CS, including moon face, buffalo hump, central obesity, facial plethora, thin and brittle skin, acne, and purple stretch marks (striae) on the flanks (Figure 1). Proximal muscle weakness in the lower limbs with a muscle force grade of 4/5 and 3+ edema was also observed. Laboratory investigations are shown in Table 1.

Details are in the caption following the image

De-identified clinical photographs illustrating the Cushingoid phenotype. (A) Overall habitus with marked central (truncal) adiposity. (B) Rounded plethoric face (“moon facies”). (C) Relatively slender distal extremities compared with truncal obesity. (D) Dorsocervical fat pad (“buffalo hump”). (E) Upper thoracic/supraclavicular fat accumulation. (F) Protuberant abdomen with wide violaceous striae.
TABLE 1. Laboratory findings of case report.
Laboratory test Patient value (in-hospital) Patient value (follow-up) Reference range
On admission
Hemoglobin (g/dL) 16.6 13.6 13.5–17.5
Hematocrit (%) 49.5 42.1 42–52
WBC (white blood cells; 103/μL) 11.8 7.1 4.0–11.0
PLT (platelet count; 103/μL) 286 294 150–450
BUN (blood urea nitrogen; mg/dL) 10 11 7–18
Cr (creatinine; mg/dL) 0.9 0.9 0.7–1.3
ALP (alkaline phosphatase; IU/L) 1016 129 44–147
AST (aspartate aminotransferase; IU/L) 48 30 < 31
ALT (alanine transaminase; IU/L) 88 21 < 31
CRP (C-reactive protein; mg/dL) 31 3 < 5
ESR (erythrocyte sedimentation rate; mm/h) 63 24 < 15
Sodium (mEq/L) 148 141 136–145
Potassium (mEq/L) 4.8 4.3 3.5–5
FBS (fasting blood glucose; mg/dL) 97 89 80–100
TC (total cholesterol; mg/dL) 267 182 < 200
TG (triglyceride; mg/dL) 148 104 < 200
LDL (low-density lipoprotein; mg/dL) 138 98 < 130
HDL (high-density lipoprotein; mg/dL) 64 55 30–70
In hospital
Cortisol 8 a.m. fasting (μg/dL) 20.2 14.1 4.3–24.9
ACTH (adrenocorticotropic hormone; pg/mL) < 1 — 7.2–63.3
1 mg Overnight dexamethasone suppression test (μg/dL) 16.5 — < 1.8

3 Methods (Differential Diagnosis, Investigations, and Treatment)

Initially suspected of having exogenous-induced CS, the patient’s prednisolone was on hold for 3 days. Cortisol 8 a.m. fasting level, measured with Electrochemiluminescence (ECL) and adrenocorticotropic hormone (ACTH) test, was 20.2 μg/dL (585.4 nmol/L) and < 1 pg/mL, respectively. Due to the lack of suppression of serum cortisol despite not using oral glucocorticoids, the absence of adrenal insufficiency symptoms, and the fact that the patient’s symptoms remained unchanged during this period, co-occurrence of endogenous CS was suspected.

A 1 mg overnight dexamethasone suppression test was performed to confirm endogenous CS diagnosis, and the results were reported as 16.5 μg/dL (normal range < 1.8 μg/dL). Considering the possibility of an ACTH-independent CS, the patient underwent an abdominopelvic multidetector computed tomography (MDCT) of abdominopelvic with adrenal protocol, which revealed a well-defined lesion with an approximate size of 32.8 × 38.6 mm in the left adrenal gland with a radiodensity of 90 Hounsfield units and a normal right adrenal gland (Figure 2). Moreover, evidence of previous old fractures as multiple callus formation was seen involving the clavicles, sternum, bilateral ribs, ischium, and pelvic bones. Multilevel old stable compression fractures of thoracic and lumbar vertebral bodies were also present. The differential diagnoses were glucocorticoid secretory adrenal tumors, including adrenal cell carcinoma and lipid-poor adenoma. In order to rule out pheochromocytoma, 24-h urine catecholamines were measured, and the results were negative.

Details are in the caption following the image

Abdominopelvic multidetector computed tomography (MDCT) with adrenal protocol showing a well-defined lesion with an approximate size of 32.8 × 38.6 mm in the left adrenal gland; radiodensity 90 HU. (A) Transverse plane. (B) Coronal plane. (C) Sagittal plane.

Finally, the patient underwent left adrenalectomy and corticosteroid replacement therapy due to the suppression of the other adrenal gland. According to the post-operative pathological investigations, immunohistochemistry markers reported as negative chromogranin, positive melan-A and inhibin, less than 3% Ki-67 marker, and lipid-poor adrenal cortical adenoma without invasions were diagnosed (Figure 3).

Details are in the caption following the image

Immunohistochemistry of the adrenal lesion (all panels acquired with a 100× oil-immersion objective; 10× eyepiece; original magnification ×1000). (A) Positive inhibin, (B) Positive Melan-A, (C) Less than 3% Ki-67 marker, and (D) Negative chromogranin.

4 Results (Outcome and Follow-Up)

Within 3 months after the operation, the patient’s corticosteroid was tapered and then discontinued due to the normalization of the cortisone serum test (14.1 μg/dL). Proximal limb weakness and hip pain, which had deprived the patient of the ability to move, gradually improved so that he could walk easily and perform daily activities. The signs and symptoms related to CS, including the patient’s mood, skin signs, and general appearance, returned to normal. The patient has been followed up for 6 months after the surgery. The patient’s BMI decreased to 24 kg/m2, and he stopped his anti-hypertensive medications with a blood pressure of 100/60 mmHg without previously prescribed drugs. So far, the laboratory tests have been within the normal range, and he has no complaints (Table 1).

5 Discussion

The described case was diagnosed with a cortisol-producing adrenocortical adenoma accompanied by exogenous CS. CS is an uncommon clinical condition caused by prolonged exposure to increased cortisol levels, which can be due to endogenous or exogenous factors [6]. Endogenous CS is infrequent and is classified as ACTH-dependent (80% of cases) or ACTH-independent (20% of cases) [7]. In the ACTH-independent category, adrenal adenoma accounts for 60% of cases and only 12% of cases of endogenous CS [7, 8]. Exogenous CS mainly occurs due to prolonged administration of glucocorticoids, which are used to manage a broad spectrum of diseases such as inflammatory, autoimmune, or neoplastic disorders and are the most common cause of CS worldwide [9]. Multiple factors, including formulation, duration of administration, pharmacokinetics, affinity, and potency of exogenous glucocorticoids, affect the probability of exogenous CS, but all forms of glucocorticoids can induce CS [10].

In the setting of cushingoid clinical features with chronic administration of high-dose glucocorticoids, especially oral prednisolone, the probability of exogenous CS is remarkably high; therefore, CS diagnostic approaches suggest that the first step after confirmation of cortisol excess is ruling out exogenous glucocorticoid administration [7, 8, 10]. Therefore, the possibility of co-occurrence of endogenous CS with iatrogenic CS is extremely low, and the diagnosis requires high clinical suspicion [4].

Differentiating endogenous and exogenous CS based on clinical features can be challenging and far-fetched. However, a few points can help physicians distinguish between these two. First, exogenous CS symptoms tend to be more striking, while endogenous CS appears more gradually. Second, hypertension, hypokalemia, and features of androgen excess, such as acne and hirsutism, are more common in endogenous CS [4, 10]. In addition, endogenous CS should be suspected if the patient’s symptoms continue after corticosteroid discontinuation or if the serum cortisol level is high despite corticosteroid cessation. In our case, the patient had a high cortisol level despite stopping prednisolone for 3 days, and he did not have any symptoms of adrenal insufficiency despite stopping prednisolone suddenly. Consequently, it was suspected that glucocorticoids might come from an endogenous source. Because ACTH was suppressed concurrently with elevated cortisol, non-ACTH-dependent CS was suspected, and MDCT of abdominopelvic confirmed it.

So far, few similar cases of simultaneous endogenous and exogenous CS have been reported. The first case was a 23-year-old woman with juvenile idiopathic arthritis who was administered high doses of triamcinolone for 16 years [4]. The development of cushingoid features that favored endogenous CS, such as hirsutism and acne, strengthened the suspicion of endogenous CS, and a CT scan revealed hypercortisolism with a bulky and nodular left adrenal gland, and a double CS was confirmed [4]. The second case was a 66-year-old woman diagnosed with exogenous CS after consumption of Traditional Chinese medicine (TCM) for a year [5]. The cessation of TCM did not significantly improve her cushingoid features, and she developed additional CS complications, including hypertension, diabetes mellitus, and osteoporotic fractures over the next 8 years. CS workup revealed a right-sided adrenal adenoma, and after the adrenalectomy, her clinical cushingoid features markedly improved [5]. These cases suggest that exogenous and endogenous CS can exist simultaneously in the same person. Although it is very rare, it should be considered in a person who still complains of CS symptoms after corticosteroid cessation. We suggest clinicians evaluate the patients for the disappearance of exogenous CS symptoms after tapering and stopping glucocorticoids. If the symptoms remain, they should be evaluated for endogenous CS.

6 Conclusion

The co-occurrence of an endogenous CS in the setting of an exogenous CS is curious. The diagnosis is based on a high clinical suspicion. Clinicians should evaluate patients for symptom resolution after tapering and discontinuing corticosteroids. Clinical cushingoid features that do not resolve after discontinuing exogenous glucocorticoids and high cortisol levels despite discontinuing corticosteroids should raise clinicians’ suspicion of the co-occurrence of exogenous and endogenous CS.

Author Contributions

Reza Amani-Beni: investigation, methodology, writing – original draft, writing – review and editing. Atiyeh Karimi Shervedani: methodology, writing – original draft. Bahar Darouei: conceptualization, validation, writing – review and editing. Matin Noroozi: methodology, writing – original draft. Maryam Heidarpour: conceptualization, supervision, validation, writing – review and editing.

Acknowledgments

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient to publish this report, including de-identified clinical photographs, in accordance with the journal’s patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that supports the findings of this study are available on request of the corresponding author. The data are not publicly available due to privacy restrictions.

https://onlinelibrary.wiley.com/doi/10.1002/ccr3.71419

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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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Exogenous Cushing Syndrome and Hip Fracture Due to Over-the-Counter Supplement (Artri King)

Posted on August 18, 2023 by MaryO

​

Abstract

The most common cause of Cushing syndrome (CS) is exposure to exogenous glucocorticoids. There is an increasing incidence of adulterated over-the-counter (OTC) supplements containing steroids. We present a case of Artri King (AK)-induced CS in a 40-year-old woman who presented with an intertrochanteric fracture of her right femur. Laboratory testing revealed suppressed cortisol and adrenocorticotropic hormone, which was consistent with suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Following the cessation of the AK supplement, the patient’s HPA axis recovered, and the clinical manifestations of CS improved. This case emphasizes the need for better regulation of OTC supplements and the need for cautious use.

Introduction

Cushing syndrome (CS) is a condition that occurs because of high blood levels of glucocorticoids (GCs). These patients can present with a variety of systemic signs and symptoms, including truncal obesity, easy bruising of the skin, violaceous abdominal striae, resistant hypertension, dysglycemia, as well as osteoporosis. CS can occur because of adrenal etiologies such as adrenal adenoma, adrenal cancer, or adrenal hyperplasia or from an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma or ectopic tumor. However, the most common cause of CS is the exogenous administration of GCs [1]. While exogenous GCs are often medically prescribed for the treatment of inflammatory conditions, some patients may be accidentally exposed to exogenous GCs from over-the-counter (OTC) supplements. We present a case of a young woman who developed exogenous CS and suffered a hip fracture as a result of taking an OTC supplement, Artri King (AK), adulterated with GCs.

Case Presentation

A 40-year-old obese woman presented to the hospital following a fall at home. She reported a snapping noise and sudden right hip pain while trying to stand up, and subsequently fell to the floor. She had noted right-sided hip pain for several days preceding her fall. She was evaluated in the emergency department where computed tomography (CT) imaging of the right lower extremity showed an intertrochanteric fracture of the right femur (Figure 1). The patient underwent open reduction and internal fixation of her right femur. The patient reported an unexplained weight gain of approximately 40 lbs in the preceding five months with a peak weight of 223 lbs (101 kg) and a body mass index (BMI) of 37 kg/m2. The patient denied taking any medications or supplements at the time of hospitalization. The endocrinology team was consulted to evaluate for causes of secondary osteoporosis in this young woman.

A-CT-scan-showing-the-right-intertrochanteric-fracture-of-the-right-femur-(yellow-arrows)
Figure 1: A CT scan showing the right intertrochanteric fracture of the right femur (yellow arrows)

Diagnostic assessment

Her vital signs showed a blood pressure of 142/96 mmHg, heart rate of 68 beats per minute, temperature of 98.1°F (36.7°C), and 98% oxygenation on room air. Physical examination did not reveal abdominal striae or buffalo hump. She did have supraclavicular fat deposition and central obesity. No proximal muscle weakness was present.

Laboratory tests were pertinent for decreased 25-hydroxy vitamin D, increased parathyroid hormone (PTH), and normal calcium (Table 1). These findings were consistent with secondary hyperparathyroidism due to vitamin D deficiency. Dual-energy X-ray absorptiometry (DEXA) scan revealed osteoporosis (Figures 2, 3 and Tables 2, 3). Further testing showed normal thyroid-stimulating hormone (TSH), estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), thus ruling out hyperthyroidism and primary ovarian insufficiency as possible causes of reduced bone mineral density (Table 1). Random cortisol was checked as hypercortisolism was suspected but it was found to be decreased along with decreased ACTH as well (Table 4). A cosyntropin stimulation test was performed, which showed decreased baseline cortisol with inappropriately decreased cortisol levels at 30 minutes and 60 minutes (Table 5). Given the discordance between the patient’s presentation and the lab results, assay interference was suspected, and further evaluation of the adrenal function was performed. Repeat labs using liquid chromatography-mass spectrometry (LCMS) assay again confirmed persistently low cortisol (Table 4). A 24-hour free urine cortisol was too low to quantify per assay despite the adequate volume. Further evaluation showed overall low adrenal steroids, including deoxycorticosterone, 17-hydroxyprogesterone, androstenedione, 11-deoxycortisol, pregnenolone, dehydroepiandrosterone sulfate, corticosterone, and progesterone.

Lab test Patient’s value Reference range
25-hydroxy vitamin D 12.8 ng/ml 30-100 ng/ml
Parathyroid hormone (PTH) 86.2 pg/ml 10-66 pg/ml
Serum calcium 9.5 ng/dl 8.8-10.5 mg/dl
Thyroid-stimulating hormone (TSH) 2.49 mIU/L 0.36-3.74 mIU/L
Estradiol 57.1 pg/ml 19.8-144.2 pg/ml
Follicle-stimulating hormone (FSH) 5.4 mIU/ml 2.5-10.4 mIU/ml
Luteinizing hormone (LH) 6 mIU/ml 1.9-12.5 mIU/ml
Table 1: Patient’s lab values on admission
Dual-energy-X-ray-absorptiometry-(DEXA)-scan-of-the-femoral-neck-showing-osteopenia
Figure 2: Dual-energy X-ray absorptiometry (DEXA) scan of the femoral neck showing osteopenia
Dual-energy-X-ray-absorptiometry-(DEXA)-scan-of-the-lumbar-spine-showing-osteoporosis
Figure 3: Dual-energy X-ray absorptiometry (DEXA) scan of the lumbar spine showing osteoporosis
Region Area (cm2) Bone mineral content (g) Bone mineral density (g/cm2) T-score Peak reference Z-score Age-matched
Femoral neck 4.76 3.53 0.742 -1.0 87 -0.7 91
Total 33.39 26.14 0.783 -1.3 83 -1.1 85
Table 2: Summary of dual-energy X-ray absorptiometry (DEXA) scan results of the femoral neck
Region Area (cm2) Bone mineral content (g) Bone mineral density (g/cm2) T-score Peak reference Z-score Age-matched
L1 10.79 7.56 0.701 -2.6 71 -2.4 73
L2 11.79 9.06 0.768 -2.4 75 -2.1 77
L3 12.70 9.98 0.786 -2.7 73 -2.4 75
L4 15.57 11.42 0.733 -3.0 69 -2.7 71
Total 50.86 38.03 0.748 -2.7 71 -2.5 73
Table 3: Summary of dual-energy X-ray absorptiometry (DEXA) scan results of the lumbar spine
Lab test Patient’s values while on Artri King Patient’s values four weeks off of Artri King Reference range
Random cortisol (routine assay) <0.64 μg/dL 7.3 μg/dL 5-25 μg/dL
Adrenocorticotropic hormone (ACTH) 1.5 pg/ml 12 pg/ml 7.2-63.3 pg/ml
Random cortisol (using liquid chromatography-mass spectrometry (LCMS) assay) 0.526 μg/dL N/A 5-25 μg/dL
Table 4: Patient’s cortisol and adrenocorticotropic hormone levels before and after stopping Artri King
Cosyntropin stimulation test Patient value Reference range
Baseline cortisol 1.64 μg/dL 5-25 μg/dL
Cortisol after 30 minutes 1.33 μg/dL >18 μg/dL
Cortisol after 60 minutes 6.48 μg/dL >18 μg/dL
Table 5: Results of cosyntropin test while on Artri King

Treatment

She was started on teriparatide as well as vitamin D and calcium supplementation for the treatment of osteoporosis. Based on the aforementioned testing and the apparent symptoms of hypercortisolism, the patient was questioned again about the potential intake of steroids. She then recalled that she had been taking AK, an OTC supplement promoted for joint pain and arthritis. She reported that she had been taking two tablets of the supplement three times a day intermittently for the past three years. The patient neglected to bring it to the medical team’s attention before because she was under the impression that it was a multivitamin and did not have implications on her diagnosis. She was asked to stop the supplement and was educated about potential adrenal insufficiency symptoms and GC withdrawal.

Outcome and follow up

Repeat labs after four weeks off AK showed improved cortisol and ACTH levels indicating recovery of her hypothalamic-pituitary-adrenal (HPA) axis (Table 4). She lost 25 lbs in this time span with lifestyle modification. She continues teriparatide for osteoporosis, and monitoring of her bone mineral density is planned.

Discussion

This patient initially presented with a pathological fracture of her right femoral head. Given her young age, causes of secondary osteoporosis, including CS, were explored. The prevalence of osteoporosis in CS patients is 50% [2]. The effects of GC on bone health have been well studied. The major mechanism by which GC affects bone mineral density is by impairment of bone formation. GCs increase osteoblast and osteocyte apoptosis and decrease osteoblast function through their catabolic effects, which result in a dramatic decrease in bone formation rate. A prolonged lifespan of osteoclasts is observed with GC. A decrease in bone formation markers such as P1NP and osteocalcin has been observed in patients treated with GC [3]. Long-term GC use is associated with increased risk for fractures with a reported global prevalence of fractures of 30-50%. The risk for vertebral fractures is even higher, particularly in the thoracic and lumbar vertebrae. Interestingly, the risk for fracture with GC use peaks early in the course of treatment, often as early as three months into treatment, and declines rapidly after GC discontinuation [4]. An increased fracture risk has been described even with relatively low doses of GC (2.5-7.5 mg of prednisone or other equivalently dosed GC) and even with short-term use of under 30 days [5].

Our patient’s initial labs confirmed adrenal suppression despite our initial suspicion of CS, given her ongoing weight gain, central obesity, and osteoporosis. However, no obvious source of exogenous GC was identified. In most cases, the source of exogenous GC is easily identified through medication reconciliation; however, in our case, the patient was inadvertently exposed to steroids from an unregulated supplement, AK. The supplement’s ingredients were listed as glucosamine, chondroitin, collagen, vitamin C, curcumin, methylsulfonylmethane, nettle, and omega-3 fatty acids, with no mention of any steroid components. In a letter to the editor of the Internal Medicine magazine, several doctors published their concerns about a recent increase in CS cases associated with the use of AK and other similarly unregulated products [6]. Based on our literature search, three similar cases were published [7,8]. The reported cases developed CS after taking Artri King for several months, but none of them presented with a fracture.

A warning by the U.S. Food & Drug Administration (FDA) was issued on April 20, 2022, indicating that FDA laboratory testing of this supplement confirmed the presence of undeclared drug ingredients, including dexamethasone, methocarbamol, and diclofenac. The FDA, however, was unable to confirm the exact amount of dexamethasone that these supplements contained [9]. Adverse events, including liver toxicity and death, were reported by the FDA.

One study revealed that between 2007 and 2016, the FDA had issued more than 700 warnings about the sale of dietary supplements that contained unlisted and potentially dangerous ingredients. The majority of these supplements included those marketed for sexual enhancement, weight loss, or muscle building [10]. This case highlights the risks of undisclosed ingredients in OTC supplements.

Conclusions

In conclusion, we recommend that a thorough reconciliation of medication and supplements be obtained for all patients with CS. Supplements should be stopped and HPA axis testing should be repeated in patients with suspected exogenous GC exposure, even if steroids are not declared in the ingredients. It is also important to monitor such patients for adrenal insufficiency due to GC withdrawal and consider GC tapering if necessary. Our patient showed improvement in cortisol levels with no overt symptoms of adrenal insufficiency without the need for GC therapy. This case demonstrates the first case of AK-induced CS resulting in a pathological fracture. Given the increased use and availability of OTC supplements, this case highlights on the importance of detailed history-taking and the role of supplements in causing CS. This case also stresses the need for further education and counseling of our patients as well as tighter control on the manufacturing and sale of these supplements.

References

  1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK: Cushing’s syndrome. Lancet. 2015, 386:913-27. 10.1016/S0140-6736(14)61375-1
  2. Mancini T, Doga M, Mazziotti G, Giustina A: Cushing’s syndrome and bone. Pituitary. 2004, 7:249-52. 10.1007/s11102-005-1051-2
  3. Briot K, Roux 😄 Glucocorticoid-induced osteoporosis. RMD Open. 2015, 1:e000014. 10.1136/rmdopen-2014-000014
  4. Canalis E, Mazziotti G, Giustina A, Bilezikian JP: Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007, 18:1319-28. 10.1007/s00198-007-0394-0
  5. Waljee AK, Rogers MA, Lin P, et al.: Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017, 357:j1415. 10.1136/bmj.j1415
  6. Del Carpio-Orantes L, Quintín Barrat-Hernández A, Salas-González A: Iatrogenic Cushing syndrome due to fallacious herbal supplements. The case of Ortiga Ajo Rey and Artri King. Med Int Mex. 2021, 37:599-602.
  7. Patel R, Sherf S, Lai NB, Yu R: Exogenous Cushing syndrome caused by a “Herbal” supplement. AACE Clin Case Rep. 2022, 8:239-42. 10.1016/j.aace.2022.08.001
  8. Mikhail N, Kurator K, Martey E, Gaitonde A, Cabrera C, Balingit P: Iatrogenic Cushing’s syndrome caused by adulteration of a health product with dexamethasone. JSM Clin Case Rep. 2022, 3:
  9. U.S. Food and Drug Administration. Public notification: Artri King contains hidden drug ingredients. (2022). Accessed: February 25, 2023: https://www.fda.gov/drugs/medication-health-fraud/public-notification-artri-king-contains-hidden-drug-ingredients.
  10. Tucker J, Fischer T, Upjohn L, Mazzera D, Kumar M: Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings. JAMA Netw Open. 2018, 1:e183337. 10.1001/jamanetworkopen.2018.3337

From https://www.cureus.com/articles/153927-exogenous-cushing-syndrome-and-hip-fracture-due-to-over-the-counter-supplement-artri-king#!/

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Exogenous Cushing’s syndrome due to a Chinese herbalist’s prescription of ointment containing dexamethasone

Posted on April 21, 2017 by MaryO

BMJ Case Reports 2017; doi:10.1136/bcr-2016-218721

Summary

Eczema in children is a chronic disabling condition. The impact of this condition on the lives of families is often underestimated by conventional physicians. As a consequence parents may investigate complementary treatment options. Close monitoring by a paediatrician is essential, considering that a variety of adverse effects can occur during the use of complementary treatment.

We present a 5-year-old girl with eczema. She visited a Chinese herbalist who prescribed an ointment. The parents noticed that the eczema resolved fast, itching decreased and she was finally sleeping well. However, her behaviour changed and appetite increased. Undetectable levels of serum cortisol were found, which was indicative of exogenous Cushing’s syndrome. Analysis of the ointment revealed the presence of dexamethasone.

Hydrocortisone substitution and subsequently a reduction schedule were implemented, after which endogenous cortisol production recovered after 4 months. Physicians should be aware that unregistered herbal medicine can contain potent drugs such as glucocorticoids.

Read more at http://casereports.bmj.com/content/2017/bcr-2016-218721.short?rss=1

 

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Cushing’s Syndrome and Skin Problems

Posted on August 22, 2016 by MaryO

By Afsaneh Khetrapal, BSc (Hons)

Cushing’s Syndrome (sometimes called hypercortisolism) is a hormonal disease caused by an abnormally high level of the hormone cortisol in the body. This may arise because of an endogenous or exogenous source of cortisol. Endogenous causes include the elevated production of cortisol by the adrenal glands, while exogenous causes include the excessive use of cortisol or other similar steroid (glucocorticoid) hormones over a prolonged period of time.

The adrenal glands are situated just above each kidney, and form part of the endocrine system. They have numerous functions such as the production of hormones called catecholamines, which includes epinephrine and norepinephrine. Interestingly, the outer layer (cortex) of the adrenal glands has the distinct responsibility of producing cortisol. This hormone is best known for its crucial role in the bodily response to stress.

At physiologically appropriate levels, cortisol is vital in maintaining normal sleep-wake cycles, and acts to increase blood sugar levels. It suppresses the immune system, regulates the effect of insulin on the metabolism of fats, proteins, and carbohydrates, and help with the homeostasis of water in the body.

Exogenous corticosteroids can also lead to Cushing’s syndrome, when they are used as a form of long-term treatment for various medical conditions. In fact, the long-term use of steroid medication is the most common reason for the development of Cushing’s syndrome.

Prednisolone is the most commonly prescribed steroid medicine. It belongs to a class of medicine that is sometimes used to treat conditions such as certain forms of arthritis and cancer. Other uses include the rapid and effective reduction of inflammation in conditions such as asthma and multiple sclerosis (MS), as well as the treatment of autoimmune conditions such as lupus erythematosus, and rheumatoid arthritis.

Overall, Cushing’s syndrome is quite uncommon and affects approximately 1 in 50,000 people. Most of them are adults between the ages of 20 and 50.  Women are 3 times more commonly affected than men. Additionally, patients who are obese, or those who have type 2 diabetes with poorly controlled blood sugar and blood pressure show a greater predisposition to the disorder.

Symptoms of Cushing’s syndrome

There are numerous symptoms associated with Cushing’s syndrome, which range from muscle weakness, hypertension, curvature of the spine (kyphosis), osteoporosis, and depression, to fatigue Specific symptoms which pertain to the skin are as follows:

  • Thinning of the skin and other mucous membranes: the skin becomes dry and bruises easily. Cortisol causes the breakdown of some dermal proteins along with the weakening of small blood vessels. In fact, the skin may become so weak as to develop a shiny, paper-thin quality which allows it to be torn easily.
  • Increased susceptibility of skin to infections
  • Poor wound healing  of bruises, cuts, and scratches
  • Spots appear on the upper body, that is, on the face, chest or shoulders
  • Darkened skin which is seen on the neck
  • Wide, red-purple streaks (at least half an inch wide) called striae which are most common on the sides of the torso, the lower abdomen, thighs, buttocks, arms, and breasts, or in areas of weight gain. The accumulation of fat caused by Cushing’s syndrome stretches the skin which is already thin and weakened due to cortisol action, causing it to hemorrhage and stretch permanently, healing by fibrosis.
  • Acne: this can develop in patients of all ages.
  • Swollen ankles: this is caused by the accumulation of fluid, called edema.
  • Hyperhidrosis (excessive sweating)

Reviewed by Dr Liji Thomas, MD

From http://www.news-medical.net/health/Cushings-Syndrome-and-Skin-Problems.aspx

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