Ectopic ACTH-secreting Pheochromocytoma Without Typical Signs of Cushing Syndrome

Posted on May 3, 2025 by MaryO

Abstract

This case report describes a 42-year-old female with a rare pheochromocytoma presenting without classic Cushingoid features but with uncontrolled hypertension, type 2 diabetes, and recurrent headaches. Despite the absence of typical signs, biochemical analysis revealed elevated cortisol and ACTH levels, and imaging showed a 6 cm adrenal mass. The patient was stabilized preoperatively with alpha-blockers and metyrapone before undergoing a successful laparoscopic adrenalectomy. Histopathology confirmed pheochromocytoma with aggressive features. Postoperatively, her blood pressure and symptoms improved, and her cortisol levels normalized. This case underscores the diagnostic challenges of ACTH-secreting pheochromocytomas without classic hypercortisolism signs and emphasizes the need for thorough endocrine and imaging assessments. Surgical resection remains the definitive treatment, with long-term follow-up essential to monitor for recurrence. This case contributes to the limited literature on the coexistence of pheochromocytoma and ectopic ACTH secretion.

Introduction

Ectopic ACTH-dependent tumors are rare, comprising approximately 5%–10% of Cushing syndrome cases, and are infrequently associated with pheochromocytomas, making this a unique presentation [1, 2]. Pheochromocytomas, though rare, can present as adrenal incidentalomas, often discovered during imaging for unrelated conditions. They represent 7% of adrenal incidentalomas and pose clinical challenges due to the risk of hormonal hypersecretion, including excess catecholamines and cortisol [1]. This case highlights the coexistence of an ectopic ACTH-producing tumor and pheochromocytoma, a combination rarely reported in the literature [3, 4]. While Cushing syndrome typically arises from adrenal or pituitary sources, ectopic ACTH secretion from pheochromocytomas presents a diagnostic and therapeutic challenge due to its rarity and aggressive potential [4–6]. Early diagnosis is crucial, particularly in cases with comorbidities like hypertension and diabetes, which are common in pheochromocytomas [1, 2]. This case underscores the need for a multidisciplinary approach to managing rare endocrine tumors.

Case report

A 42-year-old female from Mexico City presented with a history of treatment-resistant hypertension and a newly identified adrenal mass. She had no history of alcohol or tobacco use and led a generally healthy lifestyle. She was diagnosed with type 2 diabetes five years before symptoms appeared and developed hypertension five years before hospitalization, managed with valsartan and amlodipine verapamil.

The patient’s hypertension worsened, with blood pressure readings reaching 200/160 mmHg. She presented with asthenia and adynamia, and a CT scan revealed a 4 cm right adrenal mass, confirmed as 4.7 cm on a subsequent scan (Fig. 1). No signs of metastasis were observed. Upon hospital admission, her physical examination revealed a blood pressure of 95/84 mmHg, a heart rate of 95 beats per minute, a respiratory rate of 28 breaths per minute, and a systolic murmur. She exhibited no Cushingoid features.

 

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Figure 1

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Initial laboratory tests showed elevated white blood cells (11 000/mm3), hemoglobin of 12.5 g/dl, and platelet count of 305 000/mm3. Blood chemistry indicated hyperglycemia (132 mg/dl), hyponatremia (129 mEq/l), and hypokalemia (3.4 mEq/l). Cortisol levels were elevated at 31.53 μg/dl, and a 1 mg low-dose dexamethasone suppression test showed cortisol levels of 16.65 μg/dl and 14.63 μg/dl, suggesting ACTH-dependent Cushing syndrome.

ACTH levels were 24 pg/ml, which, while elevated, were not suppressed. However, elevated 24-h urinary metanephrines (9881 μg/24 h) confirmed the presence of pheochromocytoma. The patient’s aldosterone-to-renin ratio was measured, revealing a ratio of 4. The serum aldosterone level was 5 ng/dl (138 pmol/l), while plasma renin activity was recorded at 1.1 ng/ml/h.

Imaging revealed a 4.7 cm right adrenal mass with a density of 36 Hounsfield Units and an absolute washout of 64%, with no signs of malignancy (Fig. 1).

The patient’s hypertension was initially managed with prazosin and metoprolol, but her blood pressure spiked to 200/160 mmHg during a hypertensive crisis, requiring nitroprusside. Surgical intervention was planned after diagnosis was confirmed.

The patient underwent a successful laparoscopic right adrenalectomy. The tumor measured 6 cm, and histopathology confirmed a pheochromocytoma with a PASS score of 4, indicating potential for aggressive behavior (Table 1). Histological and immunohistochemical analysis revealed the tumor’s characteristic organoid pattern (Zellballen) with chromogranin and synaptophysin positivity in principal cells and S100 protein staining in sustentacular cells, consistent with pheochromocytoma (Fig. 2). Postoperatively, her blood pressure stabilized, and symptoms of palpitations and sweating resolved. She has weaned off antihypertensives, and a follow-up dexamethasone suppression test showed a significant reduction in cortisol levels (1.2 μg/dl), indicating successful tumor removal.

 

Table 1

Histopathological report.

HISTOPATHOLOGICAL DIAGNOSIS
Specimen from right adrenalectomy:
Pheochromocytoma measuring 6×6 cm (positive for chromogranin 7, synaptophysin +S100, with sustentacular cells staining positive)

  • Marked nuclear pleomorphism: 1 point
  • Diffuse growth pattern: 2 points
  • Capsular invasion: 1 point
Total: 4 points.
Tumors with a score greater than 4 may exhibit aggressive biological behavior.

 

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Figure 2

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Postoperatively, her course was uneventful, with stable blood pressure without antihypertensives. A follow-up evaluation revealed normal cortisol levels, and 24-h urinary metanephrines returned to normal (312 μg/24 h for metanephrines; 225 μg/24 h for normetanephrines). Repeat imaging showed no residual adrenal mass. At her most recent follow-up, the patient remained asymptomatic with normal laboratory values, and no recurrence has been detected.

Discussion

Ectopic ACTH-secreting pheochromocytomas are rare, accounting for a small percentage of ACTH-dependent Cushing syndrome cases [1, 4–6]. These tumors present diagnostic challenges, mainly when typical signs of Cushing syndrome, such as moon face, abdominal striae, or muscle weakness, are absent [3]. In this case, the patient exhibited only diabetes, uncontrolled hypertension, and recurrent headaches, symptoms that can also be attributed to pheochromocytoma itself [1]. The absence of Cushingoid features delayed the identification of ectopic ACTH secretion, making this case particularly difficult and unusual.

According to Gabi JN et al., most patients with ACTH-secreting pheochromocytomas present with severe hypercortisolism, including rapid weight gain and characteristic facial changes [3]. The absence of such features in this patient highlights the need to consider ectopic ACTH secretion in cases of adrenal masses, even without typical Cushing syndrome symptoms. This case illustrates how subtle presentations can lead to delayed diagnoses, emphasizing the importance of thorough evaluation in patients with adrenal tumors and metabolic abnormalities [1, 3].

The diagnostic approach for pheochromocytomas includes hormonal assays and imaging [7, 8]. Preoperative management for pheochromocytomas typically includes alpha-blockers to manage catecholamine excess [4, 7, 8]. This patient was managed with prazosin for blood pressure control and metyrapone to suppress cortisol production, consistent with clinical guidelines for managing ACTH-secreting tumors [5, 7, 8]. Despite the absence of Cushingoid features, careful preoperative preparation was essential to prevent complications during surgery.

Surgical resection is the definitive treatment for pheochromocytomas, particularly those secreting ACTH [8]. In this case, the patient underwent a successful laparoscopic adrenalectomy with no intraoperative complications. Histopathology confirmed a pheochromocytoma with marked nuclear pleomorphism and capsular invasion, suggesting potential aggressive behavior. Postoperatively, the patient’s blood pressure normalized, and her diabetes improved, aligning with outcomes reported in similar cases [4, 6]. Cortisol levels also returned to normal, demonstrating the effectiveness of adrenalectomy in resolving hypercortisolism.

A limitation in this case was the delayed recognition of ectopic ACTH secretion due to the absence of typical Cushingoid signs. The literature underscores the importance of considering this diagnosis, even in nonspecific cases [5].

Long-term management of pheochromocytomas, particularly those with aggressive features like capsular invasion, requires close follow-up [5, 7, 8]. Genetic testing should be considered, especially in patients with unusual presentations or family histories of endocrine disorders [1, 5]. Although not performed in this case, genetic testing could have provided further insight into the tumor’s etiology.

Acknowledgements

We thank the radiology department for interpreting the CT.

Conflict of interest

The authors declare no conflicts of interest related to this case report.

Funding

No external funding was received for this study.

Ethical approval

No approval was required.

Consent

Written informed consent was obtained from the patient and her parents to publish this case report and any accompanying images.

Guarantor

Froylan D. Martinez-Sanchez is the guarantor for this publication and accepts full responsibility for the work.

© The Author(s) 2025. Published by Oxford University Press.
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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Adrenal Insufficiency May Be Misdiagnosed as Anxiety

Posted on November 23, 2024 by MaryO

The hormone cortisol is produced by the adrenal glands, so adrenal insufficiency (also called Addison’s disease) is caused when the adrenal glands do not produce cortisol normally. Low cortisol can actually cause anxiety and depression, so some patients may really have anxiety — though doctors need to do further testing and/or evaluation to see that it is caused by their hormone levels, not a mental illness.

“I have adrenal insufficiency, which can cause depression and anxiety as a sign and symptom of low cortisol. After attempting hospitalization for depression, we found that I’d been living on almost undetectable cortisol for at least a year,” Sarah Reilley said. “Now that I’m on hydrocortisone replacement, my depression and anxiety are nearly gone and serve to warn me when my cortisol is dangerously low! I’m really lucky to be alive.”

Read about other conditions that may be misdiagnosed as anxiety here: https://themighty.com/topic/chronic-illness/misdiagnosed-anxiety-symptoms/

Filed under: Addison's disease, adrenal, adrenal crisis | Tagged: , , , , | Leave a comment »

Iatrogenic Cushing Syndrome and Adrenal Suppression Presenting as Perimenopause

Posted on November 12, 2024 by MaryO

JCEM Case Reports, Volume 2, Issue 11, November 2024, luae183, https://doi.org/10.1210/jcemcr/luae183

Abstract

Secondary adrenal insufficiency is a life-threatening condition that may arise in the setting of iatrogenic Cushing syndrome. Intra-articular corticosteroid injections (IACs) are a standard treatment for osteoarthritis, and they carry a high risk of secondary central adrenal suppression (SAI). We present the case of a 43-year-old woman who was referred to reproductive endocrinology for evaluation of abnormal uterine bleeding with a provisional diagnosis of perimenopause. She reported new-onset type 2 diabetes mellitus, abdominal striae, hot flashes, and irregular menses. Laboratory evaluation revealed iatrogenic Cushing syndrome and SAI attributable to prolonged use of therapeutic IACs for osteoarthritis. Treatment included hydrocortisone replacement and discontinuation of IACs followed by hydrocortisone taper over the following 16 months that resulted in the return of endogenous ovarian and adrenal function. This case demonstrates the many hazards of prolonged IAC use, including suppression of ovarian and adrenal function and iatrogenic SAI.

Introduction

Intra-articular corticosteroid injections (IACs) are commonly used for the treatment of symptomatic osteoarthritis [1]. Synovial injections carry the highest risk of secondary central adrenal suppression (SAI) [2-5]. Further, exogenous glucocorticoid administration may also result in secondary Cushing syndrome. Symptoms associated with exogenous glucocorticoid administration vary significantly, and misdiagnosis is common [6, 7]. Here, we present a case of exogenous IAC use resulting in SAI and Cushing syndrome in a 43-year-old woman who was referred for evaluation and treatment of abnormal uterine bleeding with a provisional diagnosis of perimenopause.

Case Presentation

A 43-year-old woman with a past medical history of fibromyalgia, osteoarthritis, bursitis, asthma, gastroesophageal reflux, and diabetes was referred to reproductive endocrinology with a chief complaint of hot flashes for over 2 years and a presumptive diagnosis of perimenopause. Approximately 2 years before the onset of her symptoms, she reported irregular menses, followed by 11 months of amenorrhea, then 3 menstrual intervals with prolonged bleeding lasting 45, 34, and 65 days, respectively. She reported menarche at 11 years old, regular menstrual cycles until the last 2 years, and 4 pregnancies that were spontaneously conceived. She delivered 3 liveborn term children and had one spontaneous miscarriage. Her only complication of pregnancy was gestational hypertension during her last pregnancy that occurred 9 years prior when she was 34 years old.

In addition to menstrual irregularity, she also reported hot flashes, increasing truncal weight gain over the last 5 years, new-onset diabetes mellitus, and hypertension. Eighteen months prior to referral, she had an endometrial biopsy, which demonstrated secretory endometrium without hyperplasia, and cervical cancer screening was negative.

She initially reported the following medications: inhaled fluticasone/propionate + salmeterol 232 mcg + 14 mcg as needed and albuterol 108 mcg as needed. Her daily medications were glimepiride 1 mg, furosemide 20 mg, omeprazole 20 mg, montelukast 10 mg, azelastine hydrochloride 137 mcg, ertugliflozin 5 mg, and tiotropium bromide 2.5 mg. Importantly, she did not report IAC treatments.

Diagnostic Assessment

Initial physical examination showed height of 160 cm, weight of 103.4 kg, body mass index (BMI) of 46 kg/m2, and blood pressure (BP) of 128/80. Physical exam was significant for round facies with plethora, bilateral dorsocervical neck fat pads, and violaceous striae on her abdomen and upper arms (Fig. 1). The patient ambulated with a cane and reported severe bilateral proximal leg atrophy and weakness.

 

Abdominal and upper extremity striae prior to treatment with truncal obesity immediately before (A) and 1 year after initial diagnosis (B).

Figure 1.

Abdominal and upper extremity striae prior to treatment with truncal obesity immediately before (A) and 1 year after initial diagnosis (B).

A laboratory evaluation was recommended but was not initially completed. She was scheduled for a transvaginal ultrasound that required prior authorization; the pelvic ultrasound showed a heterogeneous and thickened anterior uterine wall, suggestive of adenomyosis, with a posterior intramural fibroid measuring 15 × 15 mm and an anterior intramural fibroid measuring 15 × 8 mm. Endometrial lining was thin at 5 mm. Both ovaries were small, without masses or antral follicles. Three-dimensional reconstruction showed a normal uterine cavity with some heterogeneity of the endometrial lining but no discrete masses suggestive of polyps or intracavitary fibroids as the cause of irregular bleeding. Upon additional questioning, she acknowledged receiving bilateral shoulder, hip, and knee injections of triamcinolone 80 mg every 2 to 3 months to each joint for about 5 years. Table 1 shows the initial laboratory evaluation and includes age-appropriate low ovarian reserve as evidenced by anti-Müllerian hormone (AMH), secondary hypothalamic hypogonadism, diabetes mellitus, and central adrenal suppression. Of note, the diabetes mellitus developed after 3 years of IAC use. Additional diagnostic assessment for adrenal insufficiency by synacthen testing was scheduled, however, the patient declined further investigation.

Initial laboratory values at presentation

Result Reference range
Basic metabolic panel
 Sodium 141 mEq/L; 141 mmol/L 135 to 145 mEq/L; 135 to 145 mmol/L
 Potassium 3.7 mEq/L; 3.7 mmol/L 3.7 to 5.2 mEq/L; 3.7 to 5.20 mmol/L
 Chloride 104 mEq/L; 104 mmol/L 96 to 106 mEq/L; 96 to 106 mmol/L
 Carbon dioxide 25 mEq/L; 25 mmol/L 23 to 29 mEq/L; 23 to 29 mmol/L
 Creatinine 0.42 mg/dL; 37.14 µmol/L 0.6 to 1.3 mg/dL; 53 to 114.9 µmol/L
 Urea nitrogen 14 mg/dL; 5 mmol/L 6 to 20 mg/dL; 2.14 to 7.14 mmol/L
Adrenal function
 Cortisol 0.8 µg/dL; 22.07 nmol/L 4-22 µg/dL; 138-635 nmol/L
 ACTH <5 pg/mL; <1 pmol/L 6-50 pg/mL; 5.5-22 pmol/L
 DHEAS 8 mcg/dL; 0.02 µmol/L 15-205 mcg/dL; 1.36-6.78 µmol/L
Endocrine function
 HbA1c 8.5% <5.7%
 Random glucose 124 mg/dL; 6.9 mmol/L 80-100 mg/dL; 4.4-5.5 mmol/L
 TSH 1.74 mIU/L 0.5-5 mIU/L
 tT4 10.5 µg/dL; 135.2 nmol/L 5.0-12.0 µg/dL; 57-148 nmol/L
 Free T4 index 2.6 ng/dL; 33.4 pmol/L 0.7-1.9 ng/dL; 12-30 pmol/L
 tT3 165 ng/dL; 2.5 nmol/L 60-180 ng/dL; 0.9-2.8 nmol/L
 TPO antibody Negative n/a
Ovarian function
 FSH 5.6 IU/L 4.5-21.5 IU/L
 LH 2.9 IU/L 5-25 IU/L
 Progesterone <0.5 ng/mL; 1.6 nmol/L Varies
 Estradiol 21 pg/mL; 77.1 pmol/L Varies
 AMH 1.1 ng/mL; 7.9 pmol/L 1.0-3.0 ng/mL; 2.15-48.91 pmol/L

Abbreviations: ACTH, adrenocorticotropic hormone; AMH, anti-Müllerian hormone; DHEAS, dehydroepiandrosterone sulfate; eGFR, estimated glomerular filtration rate; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1C; LH, luteinizing hormone; TPO antibody, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; tT4, total thyroxine.

Treatment

The patient was immediately started on hydrocortisone 10 mg twice daily for glucocorticoid replacement, which was gradually reduced to 5 mg daily each morning at 16 months. Endocrine function testing was trended over the following months as replacement cortisone therapy was tapered.

Outcome and Follow-Up

Within 6 months of replacement and cessation of IACs, hot flashes ceased, and she reported regular menses. She lost 6.8 kg, her truncal obesity and striae significantly improved (Fig. 1), and she could now ambulate without assistance. Her glycated hemoglobin (HbA1c) level decreased from 8.5% to 6.8%. Fourteen months after her initial diagnosis and cessation of IAC, laboratory studies demonstrated partial recovery of adrenal and ovarian function and improved metabolism, as evidenced by increases in morning cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), and decreased HbA1c. At 16 months, she had a return of ovulatory ovarian function.

Discussion

Cortisol is the main glucocorticoid secreted by human adrenal glands. The secretion pattern is precisely regulated by an integrated limbic-hypothalamic-pituitary (LHP) drive with the physiologic goal of homeostasis [1]. Conditions that result in deviations in glucocorticoid concentrations carry a variety of consequences. Our patient was referred because of a provisional diagnosis of abnormal uterine bleeding and perimenopause, which distracted from recognition of iatrogenic Cushing syndrome and secondary central adrenal suppression. This patient vignette underscores the importance of explicitly asking patients about nonoral medications, as patients may not report their use.

Exogenous administration of long-acting synthetic glucocorticoids may suppress adrenal function via negative feedback at the limbic and hypothalamic levels, which was reflected in this patient by undetectable ACTH and low cortisol levels (Table 1). In addition, excess glucocorticoid levels result in other neuroendocrine concomitants, including suppression of gonadotropin-releasing hormone (GnRH) drive that results in hypothalamic hypogonadism [8, 9], decreased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and anovulation despite AMH levels indicating residual ovarian reserve [10]. The clinical phenotype is variable and reflects individual glucocorticoid receptor sensitivities [9].

Regardless of cause, Cushing syndrome often presents with hallmark features of central obesity, violaceous striae, easy bruising, round facies, and nuchal adiposity with lower limb muscle atrophy and loss of strength [11]. Additionally, glucocorticoid excess causes insulin resistance and metabolic syndrome [8]. Truncal obesity is a common presenting symptom of excess cortisol. Cortisol inhibits metabolic response to insulin centrally and peripherally and increases gluconeogenesis, which together predispose to and cause diabetes [10].

Exogenous use of injectable glucocorticoids carries the highest risk of adrenal suppression when compared to other routes of exogenous steroids [5]. Patients typically report fatigue, malaise, and gastrointestinal complaints. Oligomenorrhea is a common presenting complaint in women, as was the case in our patient. Hyponatremia, water retention, and hypotension may occur in SAI because of endogenous glucocorticoid deficiency. A thorough laboratory evaluation in this patient revealed low LH, FSH, estradiol, and progesterone levels, indicating hypothalamic hypogonadism and not perimenopause/menopause [12] and low levels of cortisol, ACTH, and DHEAS confirmed SIA [10].

Adrenal insufficiency can be a life-threatening condition that requires supplementation with glucocorticoids [10, 13, 14]. A review of patients diagnosed with SAI suggested tapering of hydrocortisone before discontinuing all replacement therapy and revealed most patients recover without the need for exogenous steroids after 2 years from diagnosis [14]. ACTH stimulation testing may indicate the return of adrenal function [14, 15]. Our patient showed increased ACTH, cortisol, and DHEAS at 14 months. Ovulatory ovarian function, indicated by progesterone < 5 ng/mL (< 1.59 nmol/L) (Table 2), returned at 16 months after cessation of IACs. The improvement in adrenal and ovarian function following cessation of IACs and tapering of hydrocortisone replacement therapy was accompanied by decreased HbA1c, weight loss, truncal obesity, and stria, and increased muscle strength scalp hair.

 
Table 2.

Endocrine lab results 7 years prior, at presentation (T0), and over the next 16 months

Analyte Reference range 7 years prior T0 1 month 7 months 13 months 14 months 16 months
DHEAS 15-205 µg/dL; 1.36-6.78 nmol/L — 8 µg/dL; 0.22 nmol/L 5 µg/dL;
0.14 nmol/L		 6 µg/dL;
0.16 nmol/L		 22 µg/dL; 0.59 nmol/L 28 µg/dL; 0.76 nmol/L 24 µg/dL; 0.65 nmol/L
Cortisol 4-22 µg/dL; 138-635 nmol/L — 0.9 µg/dL;
24.83 nmol/L		 5.8 µg/dL;
160.01 nmol/L		 3.0 µg/dL;
82.76 nmol/L		 3.9 µg/dL;
107.59 nmol/L		 11.2 µg/dL;
308.99 nmol/L		 12.6 µg/dL;
347.61 nmol/L
ACTH 6-50 pg/mL; 5.5-22 pmol/L — <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L 11 pg/mL;
2.42 pmol/L		 10 pg/mL;
2.20 pmol/L
HbA1c <5.7% 5.0% 8.5% 8.5% 7.8% 5.8% 5.7% 5.7%
LH 5-25 IU/L — 5.8 IU/L 2.9 IU/L — 3.3 IU/L 5.2 IU/L 5.7 IU/L
FSH 4.5-21.5 IU/L — 6.2 IU/L 5.6 IU/L — 2.0 IU/L 3.5 IU/L 1.3 IU/L
Estradiol Varies — 21 pg/mL;
77.09 pmol/L		 74 pg/mL;
271.65 pmol/L		 — 101 pg/mL;
370.77 pmol/L		 — 121 pg/mL;
444.19 pmol/L
Progesterone Varies — <0.5 ng/mL;<1.59 nmol/L <0.5 ng/mL;<1.59 nmol/L — <0.5 ng/mL;<1.59 nmol/L — 6.6 ng/mL;
20.99 nmol/L

Abbreviations: ACTH, adrenocorticotropic hormone, DHEAS, dehydroepiandrosterone sulfate, FSH, follicle-stimulating hormone, LH, luteinizing hormone, T0, time at presentation.

In conclusion, exogenous glucocorticoids, specifically intra-articular injections, carry the highest potential for iatrogenic Cushing syndrome and secondary adrenal insufficiency. Glucocorticoid excess has a variable presentation that often obscures diagnosis. As this scenario demonstrates, careful physical and laboratory assessment and tapering of hydrocortisone replacement eventually can lead to restoration of adrenal, ovarian, and metabolic function and improved associated symptoms.

Learning Points

  • Exogenous intra-articular glucocorticoid use may suppress adrenal and ovarian function via central suppression of ACTH and GnRH.
  • Cushing syndrome presents with a broad spectrum of signs and symptoms that may be mistaken for individual conditions, such as perimenopause and isolated diabetes mellitus.
  • Exogenous steroid use may lead to Cushing syndrome and subsequent adrenal insufficiency, which is life-threatening.
  • Treatment of adrenal insufficiency with a long-term exogenous glucocorticoid taper allows for subsequent return of adrenal and ovarian function.

Contributors

All authors contributed to authorship. S.L.B. was involved in the diagnosis and management of the patient, and manuscript editing. S.A. was involved in patient follow-up and manuscript development. J.M.G. was responsible for manuscript development and editing. All authors reviewed and approved the final draft.

Funding

None declared.

Disclosures

S.L.B. reports ClearBlue Medical Advisory Board, 2019—present

Emblem Medical Advisory Board, Amazon Services, 2022—present

Medscape, 2023

Myovant, May 2023

Omnicuris, 2023

Sage Therapeutics and Biogen Global Medical, Zuranolone OB/GYN Providers Advisory Board, Dec 2022, March 2023

Member, Board of Trustees, Salem Academy and College, Salem, NC: 2018-present (Gratis)

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Originally data generated and analyzed in this case are reported and included in this article.

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Abbreviations

 

  • ACTH

    adrenocorticotropic hormone

  • AMH

    anti-Müllerian hormone

  • DHEAS

    dehydroepiandrosterone sulfate

  • FSH

    follicle-stimulating hormone

  • HbA1c

    glycated hemoglobin

  • IAC

    intra-articular corticosteroid

  • LH

    luteinizing hormone

  • SAI

    secondary central adrenal suppression

Published by Oxford University Press on behalf of the Endocrine Society 2024.
This work is written by (a) US Government employee(s) and is in the public domain in the US. See the journal About page for additional terms.

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

Cushing’s Syndrome Masquerading as Fibromyalgia: A Case Series

Posted on September 2, 2024 by MaryO

​Abstract

Three young female patients with a history of generalized body pain were diagnosed with fibromyalgia. They visited several specialities which related patients’ symptoms to their previous diagnosis of fibromyalgia and were treated symptomatically. These patients developed a multitude of clinical features including fractures, hypertension, abnormal weight gain, proximal myopathic pain and bruising. They were seen by rheumatologists whose assessment was that their clinical features were not entirely due to fibromyalgia and suspected that patients have a possible underlying endocrine cause. Patients were referred to an endocrinologist for further tests with suspicion of Cushing’s syndrome. Laboratory tests and imaging confirmed a diagnosis of Cushing’s syndrome. Two of them had adrenal adenoma and one had iatrogenic corticosteroid use. These cases emphasize the need for thorough clinical evaluation for patients who are thought to have fibromyalgia. Fibromyalgia is a diagnosis of exclusion.

Introduction

Fibromyalgia is a chronic functional neurosensory disorder characterized by diffuse musculoskeletal pain, fatigue, and insomnia [1]. The exact cause is yet to be understood and the diagnosis relies solely on the patient’s history as physical examination, imaging, and laboratory tests are usually normal making it a diagnosis of exclusion.

Cushing’s syndrome is an endocrine disorder caused by an increase in cortisol level in the body due to either exogenous glucocorticoid administration or endogenous overproduction of cortisol due to adrenal adenoma, pituitary adenoma, or ectopic paraneoplastic foci [2].

Patients may present with central obesity, easily bruised skin, purple abdominal striae, osteoporosis and pathological fractures, secondary hypertension, hyperglycemia, fatigue, and proximal muscle weakness.

We herein report three cases of patients who had diffuse muscle pain and were misdiagnosed as fibromyalgia without ruling out endocrinological causes such as Cushing’s syndrome which they were found to have.

Case Presentation

Case report 1

A 38-year-old Egyptian female with a history of fibromyalgia presented to the urgent care in November 2020 with right little toe pain and swelling after hitting it against the wall. She had a fracture of the distal phalanx of the fifth toe (Figure 1) and was managed conservatively.

X-ray-of-right-foot-showed-fracture-at-the-distal-phalanx-of-fifth-toe-with-suspected-intra-articular-extension
Figure 1: X-ray of right foot showed fracture at the distal phalanx of fifth toe with suspected intra-articular extension

In January 2022, she presented to her gynaecologist with headache, body swelling and was found to be hypertensive (156/105mmHg). She was referred to cardiology for management of hypertension, who recommended keeping a blood pressure (BP) diary with one-week follow-up as her BP was high on one occasion only.

In May 2022, she visited an internist because of easy bruising for six years in both lower limbs and history of bleeding following dental procedure. She was also complaining of gaining weight (15 kg over seven months). Investigations including coagulation profile, serum electrolyte, blood glucose, liver enzymes, and autoimmune antibodies were ordered, and they were normal. Patient was reassured and was diagnosed as purpura simplex.

In September 2022, she had a visit to the cardiologist after she was diagnosed with hypertension in Egypt and was on ramipril (2.5mg) and torsemide (10mg). The cardiologist continued ramipril and discontinued torsemide. The cardiologist referred her to internal medicine because of her history of fibromyalgia, and review of her prescribed medications from Egypt which included duloxetine, hydroxychloroquine (HCQ), and melatonin.

She had multiple visits to internists between September 2022 and March 2023 with complaints of body swelling, generalized joint stiffness, hip pain, proximal myopathic pain when lifting arms or standing up with oral ulcers and small reddish-purple spots just beneath the skin’s surface most likely purpura simplex. Laboratory tests were ordered, and they showed she had low serum potassium and positive antinuclear antibody (ANA) titer (DFS-70 pattern). Also, she had negative rheumatoid factor (RF), extractable nuclear antigen (ENA) panel, antineutrophil cytoplasmic antibodies (ANCA) and anti-cyclic citrullinated peptide (CCP) with normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). She was given potassium supplements and magnesium. During her visits she was prescribed various medications for fibromyalgia including duloxetine, amitriptyline, and tramadol. She also developed back pain and her MRI of sacroiliac joints showed signs of left-sided linear sacrum fracture, crescentic subchondral edema in the right femoral head suggestive of avascular necrosis (AVN) and narrowing of L5/S1 intervertebral disc space with degenerative changes (Figure 2).

MRI-sacroiliac-joints-showed-left-sided-linear-sacrum-fracture
Figure 2: MRI sacroiliac joints showed left-sided linear sacrum fracture

She then visited an orthopedic surgeon in April 2023 with back and right hip pain. The orthopedic doctor thought that her symptoms and signs were not entirely consistent with fibromyalgia, and she was referred to rheumatology for further review.

On rheumatology review she gave a history of whole-body pain, back pain, severe right hip pain, two fractures (left foot and sacrum), hypertension, hypokalaemia, amenorrhea for 18 months, weight gain (of 15 kg over seven months) and skin bruising. Laboratory tests showed negative autoimmune tests, low serum potassium, high alkaline phosphatase (ALP), normal parathyroid hormone (PTH), Mg, vitamin D and calcium. She was referred to internal medicine for low serum potassium, with suspicion of adrenocortical excess.

Her internist suspected Cushing’s syndrome as her physical examination showed that she was obese with florid purple striae on the trunk and arms in addition to proximal muscle weakness . He then ordered investigations that showed low adrenocorticotropic hormone (ACTH) using electrochemiluminescence immunoassay (ECLIA) of <1 pg/mL (normal range 7.2-63.3 pg/mL), and high serum cortisol using chemiluminescence microparticles immunoassay (CMIA) at 5 pm of 604.03 nmol/L (normal range 79.0-478 nmol/L). Her cortisol before 10 am that was collected at 9:02 am was 623.91 nmol/L (normal range 101-536 nmol/L). In view of these values, she was referred to the endocrinologist. Serum aldosterone, renin, and their ratio were all normal. 24-hour urinary cortisol was inconclusive because of low volume of urine. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin, metanephrines and normetanephrines were normal. It was planned to do overnight dexamethasone suppression tests (ODST), but patient travelled to Egypt.

CT abdomen showed a 3.2×2×3 cm well-defined lesion arising from the junction between the arms of the right adrenal gland showing inhomogeneous density with inhomogeneous enhancement after IV contrast administration with delayed washout, the maximum enhancement after the IV contrast administration at the portal phase about 55 Hounsfield units (HU) indicating a right adrenal adenoma (Figure 3). CT sacrum showed fragmented fracture inferior ramus of right pubic bone associated with callus formation and significant fragmented fracture lateral part of superior ramus of right pubic bone associated with callus formation (Figure 4). MRI hips showed avascular necrosis of the right femur head (stage II according to Ficat and Arlet classification) (Figure 5), which was treated with core decompression surgery.

CT-adrenal-showed-a-3.2×2×3-cm-well-defined-inhomogeneous-density-lesion-arising-from-the-junction-between-the-arms-of-the-right-adrenal-gland-consistent-with-adrenal-adenoma
Figure 3: CT adrenal showed a 3.2×2×3 cm well-defined inhomogeneous density lesion arising from the junction between the arms of the right adrenal gland consistent with adrenal adenoma
CT-pelvis-showed-fragmented-fracture-at-the-inferior-and-superior-ramus-of-right-pubic-bone-associated-with-callus-formation.-Subcortical-ill-defined-lytic-area-is-noted-at-the-right-humeral-head-surrounded-with-sclerotic-reaction-could-be-due-to-avascular-necrosis-(AVN)
Figure 4: CT pelvis showed fragmented fracture at the inferior and superior ramus of right pubic bone associated with callus formation. Subcortical ill-defined lytic area is noted at the right humeral head surrounded with sclerotic reaction could be due to avascular necrosis (AVN)
MRI-of-the-pelvis-showed-subcortical-geographic-area-at-the-right-femoral-head-with-inhomogeneous-signal-intensity-(edematous-and-sclerotic-changes)-mostly-due-to-avascular-necrosis-(stage-II-according-to-Ficat-and-Arlet-classification)
Figure 5: MRI of the pelvis showed subcortical geographic area at the right femoral head with inhomogeneous signal intensity (edematous and sclerotic changes) mostly due to avascular necrosis (stage II according to Ficat and Arlet classification)

She had the surgery to remove the adrenal adenoma in Egypt and histopathology confirmed the diagnosis. She was then started on corticosteroids as she had low serum cortisone levels after her surgery. Currently she is also taking duloxetine and calcium/vitamin D. She developed a fracture at the right femoral neck after a fall and had hip replacement in Egypt (Figure 6).

X-ray-of-the-right-hip-joint-showed-signs-of-right-hip-joint-replacement
Figure 6: X-ray of the right hip joint showed signs of right hip joint replacement

Case report 2

A 47-year-old Bangladesh female presented with a complex array of symptoms initially suggestive of fibromyalgia. The patient reported chronic widespread muscle and joint pain, with identification of approximately eight tender points during examination. These symptoms, coupled with fatigue, were initially thought to be fibromyalgia due to their nonspecific nature. Subsequently, the patient started to have multiple bone fractures. In total she had six fractures over one year including fractures of the superior and inferior pubic ramus on the left side, right metatarsal bone fracture, fracture of the left proximal shaft of the fifth metatarsal, fractures of the shafts of the third and fourth left metatarsal. She has been reviewed by multiple physicians. A deeper look at her medical history revealed that despite the absence of overt Cushingoid features, she has several medical problems, including newly diagnosed hypertension and type 2 diabetes mellitus (hemoglobin A1C (HbA1C) 7.3%), raising the possibility of an underlying endocrine disorder. Psychiatric concerns involve a history of anxiety, insomnia, and major depressive disorder, with medication adjustments made independently. In addition, the patient reported irregular menstrual cycles, further complicating the clinical picture. Subtle signs such as unexplained central weight gain and telangiectasia prompted further endocrine evaluation.

Elevated morning cortisol levels and non-suppressed cortisol on an overnight 1 mg dexamethasone suppression test with high am cortisol, low am ACTH, ODST showed non-suppressed cortisol >400, and >500 on two occasions, and 24-hour urine free cortisol is high = 483 nmol (28-138). Adrenal CT without contrast revealed a well-defined heterogeneous isodense-to-hypodense lesion in the left adrenal gland, measuring 3.2 x 2.4 cm with a density of 16 HU, indicative of an adrenal adenoma. Imaging also identified old fractures of the left 10th rib and transverse processes of L1 and L4, which were previously undocumented and suggested underlying bone fragility.

The combination of subtle endocrine symptoms, nonspecific musculoskeletal pain, and psychological components initially led to a misdiagnosis of fibromyalgia. However further endocrine investigation confirmed Cushing’s syndrome due to an adrenal adenoma (Figure 7).

CT-adrenal-showed-a-3.2-x-2.4-cm-well-defined-hypodense-lesion-in-left-adrenal-gland
Figure 7: CT adrenal showed a 3.2 x 2.4 cm well-defined hypodense lesion in left adrenal gland

The patient underwent successful laparoscopic removal of the left adrenal adenoma. Post-operatively, the patient developed adrenal insufficiency, necessitating a carefully managed hydrocortisone tapering regimen. Management of diabetes, hypertension, and psychiatric symptoms continued, with adjustments anticipated in response to changes in endocrine status post-adrenectomy. The patient was started on calcium and vitamin D supplementation to address the secondary osteoporosis.

Case report 3

A 35-year-old Emirati woman with a medical history of hypothyroidism, asthma, obstructive sleep apnea, scoliosis, secondary degenerative lumbosacral changes from a previous accident, and migraines sought consultation at the Department of Rheumatology.

She reported a two-year history of polyarthralgia, proximal muscle weakness, profound fatigue, and peripheral edema. BP was 148/88. Physical examination revealed a round face, dorsocervical fat pad, central obesity, and puffy hands and feet.

Laboratories revealed hemoglobin (Hb) 13 g/l, creatinine kinase (CK) normal, while CRP was high (7 mg/l). Weakly positive anti-NOR 90 antibodies were found and noted to have unclear etiology with no clinical manifestation of scleroderma. Vitamin D deficiency was corrected (level: 47 nmol/L, normal range 50-150 nmol/L), and hypothyroidism medication was adjusted (TSH 7.7 IU/L, T4 9, normal range 12-22).

Despite extensive evaluations, including bilateral hands and feet X-rays, MRI of the hand, PET scan and laboratory assessments, the etiology of her symptoms remained elusive. Following a provisional diagnosis of fibromyalgia, the patient was managed symptomatically with medications, including pregabalin, amitriptyline, and duloxetine for one year. However, her symptoms persisted.

Further investigations revealed low serum cortisol levels: a morning cortisol level of 20 nmol/l (64-536), ACTH <0.3 pg/ml (1.6-13.9), and a 24-hour urine cortisol level of 11 nmol (28-138 nmol). Dual-energy X-ray absorptiometry (DEXA) scan demonstrated low bone mineral density with highest value at the lumbar sites (L2-L4), with a T-score of -2.4. Upon detailed review, it was noted that the individual had a history of frequent injections in both sacroiliac and lumbar facet joints, as well as trigger point injections ranging from 80-120 mg, administered every two to three months over a period of two years. Given the overall picture, with adequate adrenal response to synacthen test (the synacthen test results were as follows: baseline ACTH level was 1.2 pmol/L, rising to 0.8 pmol/L at 30 minutes and 0.4 pmol/L at 60 minutes; corresponding cortisol levels were 52 nmol/L at baseline, increasing to 433 nmol/L at 30 minutes and 472 nmol/L at 60 minutes), this was correlated with the diagnosis of iatrogenic Cushing’s syndrome.

A summary of the cases is in Table 1, and the timeline of the cases is in Table 2.

Case Age Gender BMI Steroid (Exogenous vs Endogenous) HTN DM Hyperlipidemia Psychiatric symptoms Fracture Abnormal Test Results Treatment
Case 1 38 F 31.4 Endogenous- adrenal adenoma Yes No  No No Four fractures Low potassium, low ACTH (<1pg/mL), high serum cortisol (604.03 nmol/L) Adrenal adenoma surgical resection
Case 2 48 F 26 Endogenous- adrenal adenoma Yes Yes  Yes Depression on Rx Six fractures Low ACTH (<0.3 pmol/L), high serum cortisol (1104 nmol/L), 24-hour urine free cortisol is high = 483 nmol (28-138) Adrenal adenoma surgical resection
Case 3 35 F 38 Exogenous Yes No No Depression and anxiety on Rx – Low serum cortisol 20 nmol/l (64-536), low ACTH <0.3 pg/ml (1.6-13.9), 24-hour urine cortisol 11 nmol (28-138). Refrain from injection
Table 1: Summary of patients with Cushing syndrome who presented with fibromyalgia

F: female, HTN: Hypertension, DM: Diabetes Mellitus, Rx: Treatment, ACTH: Adrenocorticotropic hormone

Case Timeline of clinical features Final diagnosis date
Case 1 Bruises, myalgia, body pain since 2016; headache, body swelling since 2020; hypertension since 2021; hip pain since Jan 2022; fractured toe in Nov 2022; fracture of pubic rami discovered incidentally in April 2023; avascular necrosis of right hip in April 2023 May 2023 she was diagnosed with Cushing syndrome due to adrenal adenoma
Case 2 Widespread muscle and joint pain in 2017; hypertension and type 2 diabetes mellitus in 2019; multiple fractures in 2020-2021; anxiety, insomnia, and major depressive illness in 2020; menstrual irregularities in July 2021 November 2021 she was diagnosed with Cushing syndrome due to adrenal adenoma
Case 3 Polyarthralgia, proximal muscle weakness, profound fatigue, and peripheral oedema in 2021-2023; depression and anxiety in 2022; hypertension in 2023; low bone mineral density in 2023 June 2023 exogenous Cushing syndrome
Table 2: Timeline of the three cases

Discussion

Fibromyalgia is a multifactorial painful body disorder with several hypotheses regarding its etiology and pathophysiology such as increased pain sensitivity, neuroendocrine axis dysregulation, hypermobile joints, poor physical fitness, as well as genetic predisposition and environmental triggers [3].

Fibromyalgia and Cushing’s syndrome are distinct medical conditions, but they can share some common symptoms such as fatigue, muscle weakness, mood changes, sleep disturbances, and memory deficits. Because of the multiple symptoms that are present in both, a patient could be misdiagnosed with fibromyalgia instead of Cushing’s syndrome if proper history-taking, physical examination and relevant investigation are not pursued. Fibromyalgia is a diagnosis of exclusion, so effort should be made to look for any possible cause of the patient’s symptoms before making a diagnosis of fibromyalgia. According to the American College of Rheumatology, a patient must satisfy these three conditions to be diagnosed with fibromyalgia: widespread pain index (WPI) ≥7 and symptom severity (SS) scale score ≥5 or WPI 3-6 and SS scale score ≥9, symptoms have been present at a similar level for at least three months, and the patient does not have a disorder that would otherwise explain the pain [4].

According to the 2008 Endocrine Society guidelines, Cushing syndrome’s diagnosis is made by lab tests that show consistently high production of cortisol using 24-hour urine free cortisol level, low-dose (1mg) dexamethasone suppression test, or late-night salivary or serum cortisol [5].

A literature review was performed using PubMed and Google Scholar databases. Search terms included “fibromyalgia” and “Cushing’s syndrome” to which five results were shown. Out of the five results, only one case report had slight relevance to our two cases which was about a 39-year-old woman previously diagnosed with Cushing’s disease who developed fibromyalgia [1]. Unlike our cases, she was already diagnosed with Cushing’s disease. Several cases of iatrogenic Cushing’s syndrome are widely recognized [6-10]. Although intra-articular corticosteroid injections are uncommon causes, they are becoming increasingly recognized especially in patients who have received multiple or relatively high doses [11-13].

Our patients saw different physicians from various specialties and had multiple hospital visits over two to three years. They were originally diagnosed with fibromyalgia. Despite a multitude of other symptoms and signs such as fractures, weight gain, amenorrhea, easy bruising, and hypertension, the initial diagnosis of fibromyalgia was carried forward by multiple physicians without proper re-evaluation, resulting in only symptomatic treatment. These cases highlight the importance of thorough clinical evaluation and a holistic approach to patients who present with fibromyalgia symptoms even if a previous diagnosis of fibromyalgia has been made.

Conclusions

These cases underscore the challenges in differentiating Cushing’s syndrome from other conditions, particularly when presenting with nonspecific symptoms similar to fibromyalgia. Heightened clinical suspicion, thorough evaluation, and consideration of medication histories are essential. A high index of suspicion, combined with targeted radiological and biochemical testing, is crucial for accurate diagnosis and effective management.

References

  1. Ohara N, Katada S, Yamada T, et al.: Fibromyalgia in a patient with Cushing’s disease accompanied by central hypothyroidism. Intern Med. 2016, 55:3185-90. 10.2169/internalmedicine.55.5926
  2. Sharma ST, Nieman LK, Feelders RA: Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015, 7:281-93. 10.2147/CLEP.S44336
  3. Coles ML, Weissmann R, Uziel Y: Juvenile primary fibromyalgia syndrome: epidemiology, etiology, pathogenesis, clinical manifestations and diagnosis. Pediatr Rheumatol Online J. 2021, 19:22. 10.1186/s12969-021-00493-6
  4. Wolfe F, Clauw DJ, Fitzcharles MA, et al.: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010, 62:600-10. 10.1002/acr.20140
  5. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  6. Psomadakis C, Tweddell R, Lewis F: Too much of a good thing? Iatrogenic Cushing syndrome secondary to excessive topical steroid use in lichen sclerosus. Clin Exp Dermatol. 2023, 48:429-30. 10.1093/ced/llac097
  7. Jones W, Chastain CA, Wright PW: Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide. Pharmacotherapy. 2014, 34:e116-9. 10.1002/phar.1432
  8. Fredman R, Tenenhaus M: Cushing’s syndrome after intralesional triamcinolone acetonide: a systematic review of the literature and multinational survey. Burns. 2013, 39:549-57. 10.1016/j.burns.2012.09.020
  9. Sadarangani S, Berg ML, Mauck W, Rizza S: Iatrogenic cushing syndrome secondary to ritonavir-epidural triamcinolone interaction: an illustrative case and review. Interdiscip Perspect Infect Dis. 2014, 2014:849432. 10.1155/2014/849432
  10. Sukhumthammarat W, Putthapiban P, Sriphrapradang 😄 Local injection of triamcinolone acetonide: a forgotten aetiology of Cushing’s syndrome. J Clin Diagn Res. 2017, 11:OR01-2. 10.7860/JCDR/2017/27238.10091
  11. Tan JW, Majumdar SK: Development and resolution of secondary adrenal insufficiency after an intra-articular steroid injection. Case Rep Endocrinol. 2022, 2022:4798466. 10.1155/2022/4798466
  12. Alidoost M, Conte GA, Agarwal K, Carson MP, Lann D, Marchesani 😧 Iatrogenic Cushing’s syndrome following intra-articular triamcinolone injection in an HIV-infected patient on cobicistat presenting as a pulmonary embolism: case report and literature review. Int Med Case Rep J. 2020, 13:229-35. 10.2147/IMCRJ.S254461
  13. Kumar S, Singh RJ, Reed AM, Lteif AN: Cushing’s syndrome after intra-articular and intradermal administration of triamcinolone acetonide in three pediatric patients. Pediatrics. 2004, 113:1820-4. 10.1542/peds.113.6.1820

 

From https://www.cureus.com/articles/264073-cushings-syndrome-masquerading-as-fibromyalgia-a-case-series#!/

​

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

Insights on Diagnosing and Managing Cushing’s Syndrome

Posted on August 18, 2024 by MaryO

Cushing’s syndrome, or endogenous hypercortisolemia, is a rare condition that both general practice clinicians and endocrinologists should be prepared to diagnose and treat. Including both the pituitary and adrenal forms of the disease, the Endocrine Society estimates that the disorder affects 10 to 15 people per million every year in the United States. It is more common in women and occurs most often in people between the ages of 20 and 50.

Even though Cushing’s remains a rare disease, cortisol recently made waves at the American Diabetes Association 84th Scientific Session. A highlight of the meeting was the initial presentation of data from the CATALYST trial, which assessed the prevalence of hypercortisolism in patients with difficult-to-control type 2 diabetes (A1c 7.5+).

CATALYST is a prospective, Phase 4 study with two parts. In the prevalence phase, 24% of 1,055 enrolled patients had hypercortisolism, defined as an overnight dexamethasone suppression test (ODST) value greater than 1.8 µg/dL and dexamethasone levels greater than 140 µg/dL. Results of CATALYST’s randomized treatment phase are expected in late 2024.

Elena Christofides, MD, FACE, founder of Endocrinology Associates, Inc., in Columbus, OH, believes the CATALYST results will be a wake-up call for both physicians and patients seeking to advocate for their own health. “This means that nearly 1 in 4 patients with type 2 diabetes have some other underlying hormonal/endocrine dysfunction as the reason for their diabetes, or significant contribution to their diabetes, and they should all be screened,” she said. “All providers need to get comfortable with diagnosing and treating hypercortisolemia, and you need to do it quickly because patients are going to pay attention as well.”

In Dr. Christofides’ experience, patients who suspect they have a hormonal issue may start with their primary care provider or they may self-refer to an endocrinologist. “A lot of Cushing’s patients are getting diagnosed and treated in primary care, which is completely appropriate. But I’ve also met endocrinologists who are uncomfortable diagnosing and managing Cushing’s because it is so rare,” she said. “The important thing is that the physician is comfortable with Cushing’s or is willing to put in the work get comfortable with it.”

According to Dr. Christofides, the widespread popular belief that “adrenal fatigue” is causing millions of Americans to feel sick, tired, and debilitated may be creating barriers to care for people who may actually have Cushing’s. “As physicians, we know that adrenal fatigue doesn’t exist, but we should still be receptive to seeing patients who raise that as a concern,” said Dr. Christofides. “We need to acknowledsalige their lived experience as being very real and it can be any number of diseases causing very real symptoms. If we don’t see these patients, real cases of hypercortisolemia could be left undiagnosed and untreated.”

Dr. Christofides, who also serves as a MedCentral Editor-at-Large, said she reminds colleagues that overnight dexamethasone suppression test (ODST) should always be the first test when you suspect Cushing’s. “While technically a screening test, the ODST can almost be considered diagnostic, depending on how abnormal the result is,” she noted. “But I always recommend that you do the ODST, the ACTH, a.m. cortisol, and the DHEAS levels at the same time because it allows you to differentiate more quickly between pituitary and adrenal problems.”

Dr. Christofides does see a place for 24-hour urine collection and salivary cortisol testing at times when diagnosing and monitoring patients with Cushing’s. “The 24-hour urine is only positive in ACTH-driven Cushing’s, so an abnormal result can help you identify the source, but too many physicians erroneously believe you can’t have Cushing’s if the 24-hour urine is normal,” she explained. “Surgeons tend to want this test before they operate and it’s a good benchmark for resolution of pituitary disease.” She reserves salivary cortisol testing for cases when the patient’s ODST is negative, but she suspects Cushing’s may be either nascent or cyclical.

Surgical resection has long been considered first-line treatment in both the pituitary and adrenal forms of Cushing’s. For example, data shared from Massachusetts General Hospital showed that nearly 90% of patients with microadenomas did not relapse within a 30-year period. A recent study found an overall recurrence rate of about 25% within a 10-year period. When reoperation is necessary, remission is achieved in up to 80% of patients.

As new medications for Cushing’s syndrome have become available, Dr. Christofides said she favors medical intervention prior to surgery. “The best part about medical therapy is you can easily stop it if you’re wrong,” she noted. “I would argue that every patient with confirmed Cushing’s deserves nonsurgical medical management prior to a consideration of surgery to improve their comorbidities and surgical risk management, and give time to have a proper informed consent discussion.”

In general, medications to treat Cushing’s disease rely on either cortisol production blockade or receptor blockade, said Dr. Christofides. Medications that directly limit cortisol production include ketoconazole, osilodrostat (Isturisa), mitotane (Lysodren), levoketoconazole (Recorlev), and metyrapone (Metopirone). Mifepristone (Korlym, Mifeprex) is approved for people with Cushing’s who also have type 2 diabetes to block the effects of cortisol. Mifepristone does not lower the amount of cortisol the body makes but limits its effects. Pasireotide (Signifor) lowers the amount of ACTH from the tumor. Cabergoline is sometimes used off-label in the US for the same purpose.

Following surgery, people with Cushing’s need replacement steroids until their adrenal function resumes, when replacement steroids must be tapered. But Dr. Christofides said she believes that all physicians who prescribe steroids should have a clear understanding of when and how to taper patients off steroids.

“Steroid dosing for therapeutic purposes is cumulative in terms of body exposure and the risk of needing to taper. A single 2-week dose of steroids in a year does not require a taper,” she said. “It’s patients who are getting repeated doses of more than 10 mg of prednisone equivalent per day for 2 or more weeks multiple times per year who are at risk of adrenal failure without tapering.”

Physicians often underestimate how long a safe, comfortable taper can take, per Dr. Christofides. “It takes 6 to 9 months for the adrenals to wake up so if you’re using high-dose steroids more frequently, that will cause the patient to need more steroids more frequently,” she explained. “If you’re treating an illness that responds to steroids and you stop them without tapering, the patient’s disease will flare, and then a month from then to 6 weeks from then you’ll be giving them steroids again, engendering a dependence on steroids by doing so.”

When developing a steroid taper plan for postoperative individuals with Cushing’s (and others), Dr. Christofides suggests basing it on the fact that 5 mg of prednisone or its equivalent is the physiologic dose. “Reduce the dose by 5 mg per month until you get to the last 5 mg, and then you’re going to reduce it by 1 mg monthly until done,” she said. “If a patient has difficulty during that last phase, consider a switch to hydrocortisone because a 1 mg reduction of hydrocortisone at a time may be easier to tolerate.”

Prednisone, hydrocortisone, and the other steroids have different half-lives, so you’ll need to plan accordingly, adds Dr. Christofides. “If you do a slower taper using hydrocortisone, the patient might feel worse than with prednisone unless you prescribe it BID.” She suggests thinking of the daily prednisone equivalent of hydrocortisone as 30 mg to allow for divided dosing, rather than the straight 20 mg/day conversion often used.

What happens after a patient’s Cushing’s has been successfully treated? Cushing’s is a chronic disease, even in remission, Dr. Christofides emphasized. “Once you have achieved remission, my general follow-up is to schedule visits every 6 months to a year with scans and labs, always with the instruction if the patient feels symptomatic, they should come in sooner,” she said.

More on Cushing’s diagnosis and therapies.

https://www.medcentral.com/endocrinology/cushings-syndrome-a-clinical-update

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