Avascular Necrosis in Patients With Cushing Syndrome

Posted on March 12, 2025 by MaryO

Abstract

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, leading to a range of clinical manifestations including avascular necrosis (AVN), a rare complication of CS. Although AVN is often associated with exogenous glucocorticoid treatment, it can occur in endogenous CS but may be unrecognized because of its rarity and possibly from a subclinical presentation. We describe a case of a 71-year-old male with florid Cushing disease who initially presented with bilateral hip AVN and later developed bilateral shoulder AVN despite achieving biochemical remission following transsphenoidal surgery and adjuvant stereotactic photon radiosurgery. AVN in endogenous CS is underreported, and guidance on routine screening is lacking. Our case underscores the importance of considering AVN in patients with CS, especially in those with persistent or recurrent joint symptoms and markedly elevated cortisol levels. Early detection of AVN is crucial as it can lead to irreversible joint damage and disability if untreated. Screening strategies should be explored to identify high-risk patients who are diagnosed with CS for timely intervention, thereby preventing long-term morbidity associated with AVN.

Introduction

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, either from exogenous glucocorticoids or endogenous sources. In endogenous CS, hypercortisolism may be due to an ACTH-dependent process, most often from a corticotroph adenoma in Cushing disease (CD) or from ectopic ACTH secretion from neuroendocrine tumors or other solid tumors such as small cell lung carcinoma. On the other hand, ACTH-independent CS is mainly driven from adrenal pathology including adrenal adenomas, adrenocortical carcinomas, adrenal hyperplasia, and primary pigmented micronodular disease [1]. The presenting symptoms and signs of CS include hypertension, diabetes mellitus, weight gain, facial plethora, dorsocervical fat pads, muscle weakness, and osteoporosis, most of which may be detected on physical examination or diagnosed biochemically. A less common symptom is avascular necrosis (AVN) of bone tissue [1, 2], which can present with pain or point tenderness of the hip or other joints as well as present subclinically [3].

AVN of the hip results from compromised blood supply to the bone tissue and usually impacts the hips and shoulders. This leads to necrosis of hematopoietic cells, adipocytes, and osteocytes. Subsequently, bone repair processes are activated, with differentiation of mesenchymal cells into osteoblasts to build new bone and hematopoietic stem cells into osteoclasts to remove necrotic tissue. However, because of impaired bone resorption and formation, subchondral fractures eventually occur [4]. Exogenous glucocorticoid treatment is 1 of the most common causes of AVN and may account for up to 38% of atraumatic AVN and is dose dependent [5]. Glucocorticoid treatment is theorized to cause AVN through increased systemic lipids, leading to compromised perfusion to the femoral head resulting from fat emboli or external lipocyte compression, as well as alterations in the inflammatory cytokines resulting in osteoclast activation and osteoblast apoptosis [4, 6]. Compared to exogenous glucocorticoid treatment, AVN caused by endogenous hypercortisolism is not frequently reported nor is it screened for on diagnosis of CS.

We describe a patient who presented with bilateral hip AVN in the context of florid CD. We aim to highlight this presenting feature to heighten awareness for screening for this progressive condition, which can potentially lead to joint damage, loss of mobility, and long-term disability.

Case Presentation

A 71-year-old male with medical history of active tobacco use and obstructive sleep apnea was diagnosed with new-onset hypertension during an annual health visit. He was started on antihypertensive medications (losartan, hydrochlorothiazide, and spironolactone) by his primary care doctor, but the hypertension remained uncontrolled. Over the course of 2 months, the patient developed progressive lower extremity edema and was started on furosemide, which led to hypokalemia and was subsequently discontinued. He clinically deteriorated, with progressive anasarca and dyspnea, and then developed acute left eye ptosis and diplopia and was admitted to the hospital. The patient also endorsed irritability, mood swings, easy bruising, low libido, increased appetite, 30-lb weight gain, and bilateral hip pain.

Diagnostic Assessment

Physical examination was significant for oral candidiasis, dorsocervical fat pad, facial plethora, proximal muscle weakness, and bilateral hip tenderness. Testing confirmed ACTH-dependent CS with elevated 24-hour urine free cortisol of 1116 μg/24 hours (30788.21 nmol/24 hours) and 1171.9 μg/24 hours (32330.38 nmol/24 hours) (normal reference range, 3.5-45 μg/24 hours; 96.56-1241.46 nmol/24 hours) and ACTH of 173 pg/mL (38.06 pmol/L) and 112 pg/mL (24.64 pmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L) on 2 separate occasions. He had hypogonadotropic hypogonadism with total testosterone levels of 41 ng/dL (1.42 nmol/L) (normal reference range, 250-1100 ng/dL; 8.68-38.17 nmol/mL) and suppressed LH and FSH at <0.2 mIU/mL (<0.2 IU/L) (normal reference range, 0.6-12.1; 0.6-12/1.1 IU/L) and 0.2 mIU/mL (<0.2 IU/L) (normal reference range, 1.0-12.0 2 mIU/mL; 1.0-12.0 2 IU/L) respectively, whereas the remaining pituitary hormones were normal, although IGF-1 was low normal at 66 ng/mL (8.65 nmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L). He also had new-onset diabetes mellitus with glycated hemoglobin of 8% (<5.7%) (Table 1). Imaging of the lungs showed a 15-mm solid noncalcified nodule in the posterior right upper lobe concerning for neoplasm. Pituitary magnetic resonance imaging (MRI) revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (Fig. 1). Additionally, pelvis computed tomography (CT) scan demonstrated bilateral avascular necrosis of the capital femoral epiphysis without evidence of fracture or subchondral collapse (Fig. 2A and 2B).

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Figure 1.

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Figure 2.

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Table 1.

Laboratory evaluation of the patient at presentation

Lab Value Reference Range
Conventional units (Système International units)
ACTH 173 pg/mL (38.06 pmol/L) 7.2-63 pg/mL (1.58-13.86 pmol/L)
24-h urine free cortisol 1116 μg/24 h (30,788.21 nmol/24 h) 4.0-55.0 μg/24 h (110.35-1517.34 nmol/24 h)
Total testosterone 41 ng/mL (1.42 nmol/L) 250-1100 ng/mL (8.68-38.17 nmol/L)
Free testosterone 12.3 pg/mL (0.07 nmol/L) 30.0-135.0 pg/mL (0.17-0.79 nmol/L)
LH <0.2 mIU/mL (<0.2 IU/L) 0.6-12.1 mIU/mL (0.6-12.1 IU/L)
FSH 0.2 mIU/mL (0.2 IU/L) 1-12 mIU/mL (1-12 IU/L)
Prolactin 9.6 ng/mL (9.6 μg/L) 3.5-19.4 ng/mL (3.5-19.4 μg/L)
TSH 0.746 mIU/L 0.450-5.330 mIU/L
Free T4 0.66 ng/dL (8.49 pmol/L) 0.61-1.60 ng/dL (7.85-20.59 pmol/L
IGF-1
Z score		 66 ng/mL (8.65 nmol/L)
−0.9		 34-245 ng/mL (4.45-32.09 nmol/L)
−2.0 to +2.0
HbA1c 8.2% <5.7%

Abbreviations: Hb A1c, hemoglobin A1C.

Treatment

Prophylactic treatment was started with subcutaneous heparin for anticoagulation and trimethoprim-sulfamethoxazole for opportunistic infections. Orthopedic evaluation did not recommend acute intervention for the hip AVN. Given the pituitary macroadenoma on imaging and left cranial nerve VI palsy, it was determined that the patient likely had CD, so he underwent transsphenoidal surgery. Surgical pathology confirmed the adenoma was ACTH positive, sparsely granulated, with Ki-67 index of 4%, and without increased mitotic activity (Fig. 3).

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Figure 3.

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Outcome and Follow-up

Due to ongoing hypercortisolism (Table 2) and residual tumor in the left cavernous sinus, the patient underwent adjuvant treatment with stereotactic photon radiosurgery at a dose of 13 Gy targeted to the left cavernous sinus and was started on osilodrostat, an oral, reversible inhibitor of 11β-hydroxylase that drives the final step of cortisol synthesis and aldosterone synthase, which converts 11-deoxycorticosterone to aldosterone [7]. The starting dose of osilodrostat was 2 mg twice per day. As the patient developed nausea, lack of appetite, and malaise with decreasing cortisol levels, osilodrostat was reduced to 1 mg daily, and he was started on hydrocortisone replacement therapy on week 11 postoperatively (Table 3). Ultimately, both osilodrostat and hydrocortisone were discontinued following normalization of cortisol levels. Regarding the rest of the hormonal deficiencies, his total testosterone and IGF-1 levels improved to levels of 483 ng/dL (16.76 nmol/L) and 99 (12.97 nmol/L), respectively, and he did not require hormone replacement therapy. Clinically, the patient improved with resolution of his hypertension and diabetes and achieved a 38-lb weight loss. Additionally, his diplopia improved and his hip pain resolved without any restriction in mobility. However, 1 year postoperatively, the patient developed bilateral shoulder pain. MRI of the shoulders demonstrated subchondral changes in the right humeral head (Fig. 2C) and a linear area of subchondral change involving the left humeral head (Fig. 2D) consistent with AVN, as well as a bilateral high-grade supraspinatus tear and acromioclavicular joint osteoarthritis. He was treated with an intraarticular methylprednisolone 40-mg injection to both shoulders, with subsequent improvement of the pain and joint mobility. He also underwent a coronary artery bypass graft surgery for 3-vessel disease. The patient has otherwise maintained normal urine and salivary cortisol levels off osilodrostat or hydrocortisone, and 1 year after surgery, the ACTH (cosyntropin) stimulation test was normal. The pulmonary nodule has remained stable on serial imaging.

Table 2.

Postoperative cortisol and ACTH levels

Postoperative day
Lab Reference Range Conventional units (Système International units) 1 2 2 3 4 5
Morning cortisol 3.7-19.4 μg/dL (102.08- 535.21 nmol/L) 26 μg/dL (717.29 nmol/L) 21.5 μg/dL (593.14 nmol/L) 6 μg/dL (165.53 nmol/L) 8.1 μg/dL (223.46 nmol/L) 16.4 μg/dL (452.44 nmol/L) 21.5 μg/dL (593.14 nmol/L)
ACTH 7.2-63.3 pg/mL (1.58- 13.93 pmol/L) 72 pg/mL (15.84 pmol/L) 62 pg/mL (13.64 pmol/L)

Table 3.

Titration of osilodrostat treatment based on cortisol levels

Postoperative week
Lab Reference range Conventional units (Système International units) 8 9 11 13 15 18 22 24
ACTH 7.2-63.3 pg/mL (1.58-13.93 pmol/L) 95.6 pg/mL (21.03 pmol/L) 131 pg/mL (28.82 pmol/L) 58.8 pg/mL (12.94 pmol/L) 79.3 pg/mL (17.45 pmol/L) 79.9 pg/mL (17.58 pmol/L) 73.4 pg/mL (16.15 pmol/L) 62 pg/mL (13.64 pmol/L) 71.5 pg/mL (15.73 pmol/L)
Morning cortisol 3.7-19.4 μg/dL (102.08-535.21 nmol/L) 23.9 μg/dL (659.35 nmol/L) 18.8 μg/dL (518.65 nmol/L) 6.6 μg/dL (182.08 nmol/L) 4.5 μg/dL (124.15 nmol/L) 3.3 μg/dL (91.04 nmol/L) 2.4 μg/dL (66.21) nmol/L 8.2 μg/dL (226.22. nmol/L) 4.1 μg/dL (113.11 nmol/L)
LNSC <0.010-0.090 μg/dL (0.28-2.48 nmol/L) 0.615 μg/dL (16.97 nmol/L) 0.058 μg/dL (1.60 nmol/L) 0.041 μg/dL (1.13 nmol/L) 0.041 μg/dL (1.13 nmol/L)
UFC, 24-h 5-64 μg/24 h (137.94-1765.63 nmol/24 h) 246 μg/24 h (6786.65 nmol/24 h) 226 μg/24 h (6234.89 nmol/24 h) 2 μg/24 h (55.18. nmol/24 h)
Osilodrostat dose 2 mg BID 2 mg BID 2 mg AM
3 mg PM		 2 mg BID 2 mg AM
1 mg PM		 1 mg BID 1 mg daily Oslidrostat discontinued

Abbreviations: BID, twice per day; LNSC, late night salivary cortisol; UFC, urine free cortisol.

Discussion

Our patient exhibited pronounced hypercortisolism secondary to CD, with bilateral hip AVN as 1 of the presenting symptoms. Despite achieving biochemical remission of the disease and resolution of other associated symptoms, the patient was later diagnosed with bilateral shoulder AVN.

AVN caused by endogenous hypercortisolism is seldom documented, and routine screening for it is not typically conducted during the diagnosis of CS. However, AVN has been reported to be a presenting symptom in several case reports or may manifest years after the initial diagnosis [8]. Reported causes of AVN in endogenous CS include pituitary adenomas, adrenal adenomas or carcinomas, adrenal hyperplasia, or neuroendocrine tumors [8‐23] (Table 4), with some cases of AVN associated with severe hypercortisolism [10, 15]. Other risk factors associated with AVN include hip trauma, femoral fractures, hip dislocation, systemic lupus erythematosus in the setting of concomitant corticosteroid treatments, or vasculitis, sickle cell disease, hypercoagulability, Gaucher disease, hyperlipidemia or hypertriglyceridemia, hyperuricemia, hematological malignancies, antiretroviral medications, alcohol use, and exogenous steroid treatment [4]. Our patient had no history of hip trauma or other aforementioned comorbidities. Furthermore, during presentation, his lipid levels were normal, with low-density lipoprotein cholesterol of 89 mg/dL (<130 mg/dL) and triglycerides of 97 mg/dL (<150 mg/dL). Therefore, it is likely that his bilateral hip and shoulder AVN was caused by severe endogenous hypercortisolism.

Table 4.

Published cases of avascular necrosis in patients with endogenous hypercortisolism

First author, year Age (y)/sex Time of diagnosis in relation to CS diagnosis AVN related symptoms Imaging modality Imaging description Diagnosis Treatment
Salazar D, 2021 [15] 38 F 3 y prior to diagnosis Right hip pain MRI
  • Right hip joint effusion and synovitis
  • Flattening of the femoral head-Subcortical edema
 Adrenal adenoma Right hip arthroplasty
Madell SH, 1964 [16] 41 F 1 month before diagnosis Right shoulder pain X-ray
  • Increased density of the right humeral head with spotty areas of radiolucency
  • Early flattening and beginning of fragmentation
 Adrenal adenoma Osteotomy
Anand A, 2022 [21] 47 M Bilateral hip pain MRI
  • Necrosis of bilateral femur heads
 adrenocortical carcinoma
Belmahi N, 2018 [9] 28 F Progressive limping and right hip pain MRI
  • Right femoral head AVN
 Pituitary adenoma Right total hip replacement
Wicks I, 1987 [10] 39 M 18 months before diagnosis Progressive hip pain and stiffens X-ray
Bone scan
  • Lucent and sclerotic regions within flattened femoral heads
  • Some loss of articular cartilage
 Pituitary adenoma Conservative management
Koch C, 1999 [11] 30 F Sudden onset of severe left hip pain MRI
  • Abnormal high intensity signal changes in the bone marrow of the left femoral head
  • Joint effusion
  • Stage 2 AVN
 Pituitary adenoma Immediate core decompression surgery with decongestion of the left femoral head
Premkumar M, 2013 [12] 26 F 2 y after pituitary surgery for Cushing, while on replacement steroid therapy Progressive bilateral hip pain resulting in difficulty in walking MRI
  • Bilateral multiple bony infarcts in the proximal femur and distal femur
  • Femoral head collapse fractures -Stage 2 avascular necrosis
 Pituitary adenoma
Bauddh N, 2022 [13] 24 M 2 y prior to diagnosis Progressive left hip pain and difficulty in walking X-ray
MRI
  • Left femoral head AVN
 Pituitary adenoma Planned for surgery of hip AVN
Joseph A, 2022 [14] 21 F 1 y prior to diagnosis Bilateral hip joint pain X-ray
MRI
  • Ill-defined mixed sclerotic and lytic pattern of the femoral heads
  • Cortical disruption of the round contour
  • Low signal intensity in the subchondral region of the femoral necks on T1-weighted images
 Pituitary adenoma Planned for total hip replacement.
Bisphosphonates.
Pazderska A, 2016 [19] 36 F Right leg pain MRI
  • Bilateral AVN of the femoral heads
  • Left femoral head with early bone fragmentation
 Bilateral primary pigmented micronodular adrenal disease Spontaneous healing of AVN after adrenalectomy.
Papadakis G, 2017 [22] 55 F MRI
PET/CT 68Ga-DOTATATE
  • Bilateral AVN
  • Bone marrow edema extending to the intertrochanteric area
  • Mild subchondral femoral head collapse of the left hip
  • Increased activity in bilateral femoral heads and in the bone marrow consistent with edema
  • Mild left femoral head collapse
 Ectopic ACTH- secreting tumor
Phillips K, 1986 [8] 24 F 4.5 y after diagnosis Right femoral AVN X-ray
  • Flattening and sclerosis of femoral head
 Cushing disease
25 F 4 y after diagnosis Right femoral AVN
  • Subchondral lucency
43 F 8 mo after diagnosis Right humeral AVN
  • Sclerosis and flattening of articular surface of humeral head
61 F 11 y after diagnosis Left femoral AVN and bilateral humeral heads
  • Cortical indistinctness and subchondral lucency
  • Left humeral head flattening and sclerosis
Cerletty J, 1973 [20] 54 M 3 mo before diagnosis Right femoral head fracture X-ray
  • Bilateral subchondral sclerosis of the femoral heads
  • Some narrowing of the joint space on the left
  • Infraction of the margin of the right femoral head
  • Femoral neck fracture.
 Bilateral adrenal cortical hyperplasia Total hip joint arthroplasty
Ha J-S, 2019 [18] 36 F 2 y before diagnosis 2 mo left hip restricted range of motion X-ray
MRI
  • Right femoral head with areas of hyperlucency and surrounding sclerosis
  • Subtle changes in the shape of the articular surface
  • Bilateral femoral head osteonecrosis -Increased amount of joint fluid and bone marrow edema in the left hip
  • Right femoral head necrosis
 Adrenal cortical adenoma Total hip replacement
Takada, J, 2004 [17] 55 F Intense right hip pain and a limp MRI
  • Low-intensity band on T1-weighted images
  • Stage 2 AVN.
 Adrenal adenoma Total hip arthroplasty
Modlinger RS, 1972 [23] 69 F Increased pain of right shoulder X-ray
  • Bilateral shoulders with aseptic necrosis of the humeral heads
 Ectopic ACTH secretion NET form pancreatic tumor

Abbreviations: AVN, avascular necrosis; F, female; M, male; MRI, magnetic resonance imaging; NET, neuroendocrine tumor.

AVN can result in irreversible femoral head collapse, leading to severe limitation in movement, reduced joint functionality, and decreased quality of life [24]. Initially, patients may be asymptomatic or endorse nonspecific pain when presenting with AVN and may not be diagnosed until an advanced stage when they develop more severe pain and disability [25]. In a meta-analysis assessing the prevalence of AVN in patients with systemic lupus erythematosus, including those who received corticosteroid treatment, asymptomatic AVN was detected in 29% of patients and symptomatic disease was noted in 9% [26]. AVN can diagnosed with MRI or CT imaging. Although noncontrast MRI has higher sensitivity and specificity in detecting early stages of the disease, CT is comparable to MRI in more advanced stages. Ancillary imaging modalities include plain radiography, positron emission tomography, and bone scan [27].

Staging of AVN relies on radiologic features and size of lesions. In earlier stages, imaging can be normal (stage 0) or with subtle abnormalities on MRI or bone scan and normal radiography (stage 1). As the disease progresses, structural changes, including cystic and sclerotic changes (stage 2), subchondral collapse (stage 3), flattening of the femoral head (stage 4), joint narrowing and acetabular changes (stage 5), and, finally, advanced degenerative changes (stage 6) can be detected on most imaging modalities.

Management of early stages of AVN includes observation or conservative weight-bearing management, medical therapy with bisphosphonates, anticoagulation therapy, statins, and vasodilators. Invasive procedures such as mesenchymal stem cells implantation, osteotomy, surgical joint decompression, and total hip replacement are reserved for more advanced stages [28]. Indeed, AVN accounts for approximately 10% of total hip replacements in the United States [29]. Staging has prognostic implications for treatment options and disease outcomes. Early-stage disease, when diagnosed and treated, can often regress, and be cured. Conservative measures, medical treatment, biophysical stimulation, extracorporeal shockwave therapy, or core decompression, can prevent femoral head collapse and further hip arthroplasty. On the other hand, late-stage disease, characterized by joint collapse, is irreversible and often requires joint replacement [30].

Although actual prevalence rates of AVN in endogenous CS is unknown, one should consider screening for AVN in this high-risk population, particularly in patients showing markedly elevated cortisol levels, as in our case. Such an approach would facilitate the early identification of individuals who would benefit from earlier medical or surgical interventions, thereby preventing permanent joint destruction and chronic disability.

Learning Points

  • AVN can be a complication of endogenous hypercortisolism.
  • AVN may present asymptomatically or with nonspecific symptoms such as joint pain.
  • AVN can affect multiple joints, including hips and shoulders, and its early diagnosis relies on MRI or CT imaging.
  • Early detection and intervention for AVN are crucial to prevent irreversible joint damage and disability.
  • Screening for AVN in patients with CS should be considered to enable timely intervention and prevent long-term complications, particularly in patients with hip or shoulder pain and severe hypercortisolism.

Contributors

All authors made individual contributions to authorship. N.T. and O.C. were involved in the diagnosis and management of the patient and manuscript submission. S.B. was involved in the histopathology section and preparation of histology images. T.L. was involved in the interpretation and preparation of the radiology images. A.N.M. was responsible for the patient’s surgery and treatment plan. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

Dr. Odelia Cooper is an Editorial Board member for JCEM Case Reports and played no role in the journal’s evaluation of the manuscript. There are no other disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

  • AVN

    avascular necrosis

  • CD

    Cushing disease

  • CS

    Cushing syndrome

  • CT

    computed tomography

  • MRI

    magnetic resonance imaging

© The Author(s) 2025. 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. See the journal About page for additional terms.

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

Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

Filed under: Clinical trials, Cushing's, pituitary, Rare Diseases, Treatments | 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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Management of Diabetes Mellitus in Acromegaly and Cushing’s Disease with Focus on Pasireotide Therapy

Posted on August 2, 2024 by MaryO

Abstract: Patients suffering from acromegaly and Cushing’s Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts’ consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.

Keywords: acromegaly, Cushing’s disease, pasireotide, hyperglycemia, diabetes mellitus, cardiovascular risk

Introduction

Acromegaly and Cushing’s Disease (CD) are rare but weakening endocrine diseases.

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma, with subsequent excess of insulin-like growth factor (IGF-1).1 CD is characterized by hyperproduction of cortisol due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma.2 Impaired glucose metabolism and the onset of DM are common clinical conditions resulting from these diseases. The worsening of glycemic control might also be caused by treatment with somatostatin receptor analogs, more specifically with pasireotide.

Pasireotide, a second-generation somatostatin receptor ligand (SRLs), is currently used for the treatment of acromegaly and CD.3,4

In the management of acromegaly, long-acting pasireotide is recommended at a starting dose of 40 mg monthly (potentially up-titrated to 60 mg) in patients with poorly controlled or uncontrolled disease after failure with first generation SRLs. Several Randomized Control Trials (RCTs) have shown better outcomes in achieving biochemical control compared to octreotide and lanreotide, both in parallel arms as well as in a cross-over evaluation.5,6 In CD, pasireotide is approved for the treatment of persistent hypercortisolism after a surgical procedure or when surgery is not feasible or refused, at a start dose of 0.6 mg twice daily (potentially up titrated to 0.9 mg twice daily).7,8

Hyperglycemia and Increased Cardiovascular Risk in Acromegaly and CD

Impaired glucose metabolism is one of the comorbidities associated with acromegaly and CD, uniquely linked to the pathophysiology of the diseases. As a matter of fact, in acromegaly, the prevalence of altered basal glucose ranges between 7 and 22%, of altered glucose tolerance between 6 and 45%, and of diabetes between 19 and 56%.9 Additionally, disorders of carbohydrate metabolism occur in 14–74% of the patients among the various forms of hypercortisolism while the prevalence of diabetes varies between 21 and 47%.10

The pathogenesis of insulin resistance (IR) in acromegaly is due to multiple factors: GH exerts its effects both directly by inducing gluconeogenesis, glycogenolysis and lipolysis and promoting IR in the liver and peripheral tissues, as well as indirectly through IGF-1.11 GH stimulates the hydrolysis of triglycerides and the production of free fatty acids from adipose tissue, and this increased synthesis of free fatty acids leads to a decrease in insulin-mediated glucose uptake by inhibiting glucose transporters GLUT-1 and GLUT-4.12,13 Moreover, GH suppresses key insulin signaling pathways involved in stimulating glucose transport in muscle and adipose tissue and inhibiting glucose production in the liver.14

The effects of IR secondary to the excess of GH are initially compensated by the increased secretion of insulin from the pancreatic beta cells, which, however, diminishes over time, favoring the onset of prediabetes and diabetes.15,16 Once the beta cell function is affected, the glucose metabolism disorders persist even after the acromegaly is cured.17 Although physiologically IGF-1 improves glucose homeostasis, the chronic excess of GH in acromegaly that causes IR greatly exceeds the possible beneficial effects of IGF-1 on insulin sensitivity.18

Similar to the excess of GH, hypercortisolism affects carbohydrate metabolism mainly in liver, skeletal muscles, and adipose tissue.19 In the liver, excess glucocorticoids stimulate gluconeogenesis by activating numerous genes involved in the hepatic gluconeogenesis, stimulating lipolysis and proteolysis with increasing substrates for gluconeogenesis, potentiating the action of glucagon and inhibiting glycogenogenesis.20

In the muscle, hypercortisolism induces IR by interfering with different components of the insulin-signaling cascade, as well as by stimulating proteolysis and loss of muscle mass. All this reduces the capacity of the muscle to synthesize glycogen and uptake most of the postprandial glucose from circulation.21

Additionally, hypercortisolism causes an increase in visceral obesity and a relative reduction in peripheral adipose tissue, and this “shift” is closely associated with metabolic syndrome and worsens IR. Moreover, the excess of cortisol influences the synthesis and release of hormones from adipose tissue, mainly adipokines, further contributing to the development of IR.21

Glucocorticoids inhibit the synthesis and secretion of insulin. Also in CD, there is an initial transient phase characterized by the increase in insulin secretion as an adaptive mechanism to IR, but later the chronic exposure to higher levels of cortisol induces pancreatic beta cell apoptosis, loss of beta cell function and the subsequent development of diabetes.20,22

The involvement of the bone system in affecting glucose homeostasis has also been found: in fact, long-term exposure to glucocorticoids causes a reduction in circulating osteocalcin that can increase IR.23

Furthermore, two studies in humans24,25 suggested that secretion of incretins (glucagon-like peptide-1, GLP-1 and glucose dependent insulinotropic peptide, GIP) was unaffected by dexamethasone administration, but their insulinotropic effects of on beta-cells were reduced.

The worsening of glycemic control and the onset of DM are also important limitations in the management of some patients treated with pasireotide.26,27 This topic will be further explored in a subsequent paragraph.

As is well known, hyperglycemia contributes to increasing cardiovascular risk, which is already very high in patients with acromegaly or CD.28,29

Cardiovascular disease is the leading cause of death in 23–50% of patients with acromegaly in different studies.9 Hypertension affects about 33% of the patients, ranging from 11 to 54.7%,30 and it is strongly related with typical cardiac implications of acromegaly as valvulopathy, arrhythmias and cardiomyopathy.

In the large Liege Acromegaly Survey database of 3173 acromegalic patients from 10 European countries,31 left ventricular hypertrophy was present in 15.5% at time of diagnosis. The most common manifestations of cardiopathy are biventricular hypertrophy, diastolic-systolic dysfunction, and valvular regurgitation.32 Certainly, the severity of cardiac disease is correlated with age, duration of acromegaly, GH and IGF-1 levels (both vascular growth factors which stimulate collagen deposition) and long-standing hypertension.33 In the worst cases, hypertrophic cardiopathy can evolve into Left Ventricular Systolic Dysfunction (LVSD), the last stage of cardiac disease, with recurring hospitalizations and very high mortality rates.34 Acromegaly is also associated with sleep apnea (ranging from 45 to 80% of the cases).35

Similarly, in CD cardiovascular disease is the leading cause of death: a retrospective study involving 502 patients (83% in remission) with a median follow-up of 13 years36 demonstrated a standardized mortality ratio (SMR) of 3.3 (95% CI 2.6–4.3) for CV disease, in particular 3.6 (95% CI 2.5–5.1) for ischemic cardiac disease and 3.0 (95% CI 1.4–5.7) for stroke. SMR related cardiovascular disease remained higher also after biochemical remission (2.5, 95% CI 1.8–3.4).36 Cardiovascular remodeling caused by hypercortisolism is frequently irreversible: at 5 years post-remission, coronary artery plaques persisted in 27% of subjects vs 3% of control.37 As a result, the risk for ischemic events remains above that of the general population.38

Hypertension is highly prevalent in patients with hypercortisolism: the majority (80–85%) of patients have hypertension at diagnosis and 9% may have required hospital admission because of the hypertension crisis before the diagnosis of hypercortisolism.39 Also, after remission, hypertension results are highly prevalent, as shown in two different studies (50% and 40%, respectively).40,41 Up to 70% of the patients with active CD present abnormal left ventricular mass parameters, whereas systolic and diastolic function were usually normal. Rarely, patients present dilatative cardiopathy and severe HF.42 Moreover, greater incidence of hypokalemia exposes patients to fatal arrhythmias.

Finally, both obesity and dyslipidemia, frequently occurring in these diseases, do not normalize despite biochemical remission.

Mechanisms of Pasireotide-Induced Hyperglycemia

Pasireotide is a multi-receptor targeted SRL, with action on different somatostatin receptors (SSTR). Pasireotide binds with high affinity to SSTR-1, 3 and 5 and lower to SSTR-2 than first generation SSA. More specifically, the affinity for SSTR-5, several times greater than those of octreotide and lanreotide, explains the efficacy of pasireotide: this binding causes the suppression of ACTH and GH, accompanied by tumor volume reduction.43,44

However, this mechanism causes the alteration of glucose metabolism because the binding is not specific to pituitary cells. Stimulation of pancreatic SSTR-5, expressed more in Langerhans islet beta cells than alfa cells (87% vs 44%), suppresses insulin secretion much more than glucagon secretion.45

Pasireotide appears to inhibit the secretion of incretin hormones GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) in health volunteers after oral glucose tolerance test (OGTT),46 even if a recent study showed no differences in incretin levels and their response to mixed meal tolerance test (MMTT) in CD patients,47 suggesting a main role of direct inhibition of beta-cells activity. However, a reduced intra-islet paracrine effect of GLP-1 cannot be excluded whereas an increased IL-6 mediated GLP-1 secretion in CD may disguise pasireotide inhibitory effect.47,48 Furthermore, pasireotide has no effect on hepatic and peripheral insulin sensitivity.46

Pasireotide-induced hyperglycemia is less pronounced following multiple dosing, and it appears even reversible upon discontinuation of the drug,49 as shown in a pharmacokinetic analysis of single-dose administration, in which mean glucose levels increased to 200 mg/dL (11.1 mmol/L) and returned to euglycemia approximately 23 hours later.50

Not all patients treated with pasireotide develop impaired glucose tolerance or DM: the prevalence of these conditions in CD is respectively 21–64% and 20–47%,51 whereas in acromegaly it is 6–45% and 16–65%.9 This suggests that glycemic control prior to the treatment and a preceding DM, could be predictive of the extent of hyperglycemia.

In the PAOLA study6 a fasting blood glucose (FBG) > 100 mg/dL (5.5 mmol/L) at baseline correlated with higher FBG and higher HbA1c during treatment with pasireotide, while patients with acromegaly < 40 years of age were less likely to experience hyperglycemia than older patients.

Moreover, in acromegalic patients, the up-titration to a dose of 60 mg was associated with a 21–36% increased risk of hyperglycemia.52,53 Other factors that could increase the risk of hyperglycemia were a Body Mass Index > 30 kg/m², hypertension and dyslipidemia at baseline.54

Superimposable results were obtained in another Phase III study,55 always performed in subjects with acromegaly: it was reported that up to 45% of patients with baseline FBG between 100 (5.5 mmol/L) and 126 mg/dL (7.0 mmol/L) had FBG levels ≥126 mg/dL (7.0 mmol/L) after 26 months of pasireotide.55

Also, in CD, preexisting DM or impaired glucose tolerance increased the risk of hyperglycemia-related adverse events (AEs) with pasireotide, although severe AEs were not reported.7

A meta-analysis showed a lower frequency of hyperglycemia-related AEs in acromegalic patients treated with pasireotide monthly (57.3–67.0%) in comparison to those who received it twice daily for CD (68.4–73.0%).27 Also, the rate of discontinuation due to hyperglycemia was higher in CD trials (6.0% and 5.3%) than that in acromegaly trials (3.4% and 4.0%).5–7,56 The reasons for these findings are unknown.

On the other hand, it has been acknowledged that other drugs, commonly used for the treatment of acromegaly or CD, may affect glucose metabolism leading to clinical benefits, even during pasireotide therapy. In fact, in acromegalic subjects, cabergoline can improve glucose tolerance,57 whereas pegvisomant reduces fasting glucose levels and improves insulin sensitivity.58,59 Similar results have been highlighted for ketoconazole,60 metyrapone61 and osilodostrat62 in studies involving patients with CD.

Antidiabetic Drugs with Proven Cardiovascular Benefits

The evidence from Cardio Vascular Outcome Trials with GLP-1 RAs and SGLT2-i have revolutionized the management of Type 2 Diabetes Mellitus (T2DM). As reaffirmed in the recent American Diabetes Association-European Association for the Study of Diabetes (ADA-EASD) Consensus, the treatment approach must be holistic and person-centered, with four main areas of interest: glycemic control, weight loss, CV risk reduction and renal protection.63

In a network meta-analysis of 453 trials assessing glucose-lowering medications from nine drug classes, the greatest reductions in HbA1c were seen with GLP-1 RAs.64 Another meta-analysis comparing the effects of glucose-lowering drugs on body weight and blood pressure indicated the greatest efficacy for reducing body weight with GLP-1 RAs, whereas the greatest reduction in blood pressure is seen with the SGLT2-i.65

Among GLP-1 RAs, liraglutide (at a dose of 1.8 mg daily),66 dulaglutide (at a dose 1.5 mg weekly)67 and injectable semaglutide (at a dose of 0.5 and 1 mg weekly)68 reduced the incidence of three point-MACE (Major Adverse Cardiovascular Events) and the progression of CKD (Chronic Kidney Disease) through the reduction of albuminuria.

With regard to SGLT2-i, empagliflozin and canagliflozin reduced the incidence of three point-MACE.69,70 Empagliflozin, dapagliflozin and canagliflozin demonstrated improvement of CKD in trials with specific renal outcomes, and the first two also demonstrated this benefit in patients without T2DM.71–73 Another significant clinical benefit is the reduction of hospitalization for heart failure (HF), demonstrated also in patients without T2DM for empagliflozin and dapagliflozin, both with reduced ejection fraction (HFrEF)74,75 and preserved ejection fraction (HFpEF).76,77

The Current Management of Pasireotide-Induced Hyperglycemia

Several studies, performed with different designs, evaluated the impact of pasireotide on glucose metabolism. The principal results are summarized in Table 1.5–8,78–85

Table 1 Main Studies Regarding the Use of Pasireotide in Acromegaly and in Cushing’s Disease

It’s undeniable that impairment of glucose metabolism occurred: generally, in all studies the number of subjects with diabetes and prediabetes increased, HbA1c levels were higher and anti-hyperglycemic treatments were required. Metformin, DPP-4i and insulin were commonly used to treat hyperglycemia, whereas GLP-1 RAs and SGLT2-i were given only in a small number of cases.

Nevertheless, a recent randomized multicenter study involving 81 patients with acromegaly or CD receiving pasireotide86 and uncontrolled hyperglycemia with metformin or other oral antidiabetic medications (acarbose or sulfonylureas), evaluated the effects of two different regimens of treatment (incretin-based therapy vs insulin). All 38 patients randomized to an incretin-based therapy (acromegaly, n = 26; CD, n =12) received sitagliptin; 28 of them switched to liraglutide. Twelve patients (31.6% [CD, n = 6; acromegaly, n = 6]) randomized to incretin-based therapy received insulin as rescue therapy. The results have shown a trend for better control of HbA1c with incretin-based therapy. Furthermore, in the same study, 109 patients who received pasireotide did not develop hyperglycemia requiring antidiabetic treatment.86 These findings suggest that impaired glucose metabolism or onset of DM during pasireotide therapy are manageable in most patients, without the need for treatment discontinuation.

Accordingly, given the above-mentioned evidence, glycemia should be monitored in all patients treated with pasireotide in order to intercept an initial alteration of glucose metabolism which could be either prediabetes or DM, according to the indications of ADA.87 In patients treated with pasireotide, FBG and HbA1c levels tend to increase during the first 1–3 months of treatment and stabilize thereafter.88

Regarding CD, in 2014, a medical expert recommendation on pasireotide-induced hyperglycemia was published.89 In this, an HbA1c target value less than 7.0–7.5% (53–58 mmol/L) is established, avoiding as much as possible the risk of hypoglycemia. Patients in euglycemia prior to therapy must be monitored: they should self-check FBG and postprandial glucose (PPG) levels during the day, precisely twice in the first week and once weekly later. Instead, patients with prediabetes and DM must be monitored closely (after 1, 2 and 4 weeks), and they should self-check blood glucose values up to six times per day during the first week, and at least four times per day thereafter.26,89

Medical treatment should always include dietary modification and exercise. Metformin is the first line-therapy, unless contraindicated or not tolerated. If glycemic control is not reached or maintained with monotherapy, combination therapy with drugs targeting the incretinic axis is recommended:89 a Phase I study90 in 19 healthy volunteers randomized to pasireotide 600 μg sc bid alone or co-administered with antidiabetic drugs (metformin 500 mg bid, nateglinide 60 mg tid, vildagliptin 50 mg bid and liraglutide 0.6 daily) demonstrated greater effects of vildagliptin and liraglutide in minimizing hyperglycemia.

Therefore, therapy with a DDP-4i is suggested in a first step combination. Only in the case of failure to reach the HbA1c target, the replace of DDP-4i with a GLP-1 RAs is recommended. If pasireotide-induced hyperglycemia remains uncontrolled with combinations containing metformin and DPP-4i or GLP-1 RAs, experts’ recommendations suggest the beginning of basal insulin therapy. If the individual HbA1c targets are not achieved or the postprandial glucose levels remains elevated, prandial insulin can be added.89

Instead, in acromegaly, a very interesting experts’ consensus statement regarding the management of pasireotide-induced hyperglycemia has been recently published.91 It suggests monitoring blood glucose prior to initiation of pasireotide treatment, through the determination of HbA1c or FBG or the execution of OGTT. Patients are divided into three risk categories related to glycemic status: normal glucose tolerance (NGT) patients at low risk, NGT patients at high risk and prediabetic or diabetic patients. In low-risk patients with no worsening of glycemic control, self-measurement of blood glucose (FBG and PPG) once every week is considered sufficient. In high-risk patients who do not have elevated blood glucose levels, weekly self-monitoring (FBG and PPG) is recommended in the first three months. In patients with pre-existing hyperglycemia, daily self-monitoring in recommended with at least one FBG and one PPG, ideally as multiple-point profiles.91 Further, when possible and economically feasible, high-risk patients should temporarily be equipped with continuous glucose monitors (CGMs) to detect elevated blood glucose levels early and determine deviations from the time in range precisely. During treatment with pasireotide, HbA1c measurements should be routinely performed every three months and at least with each IGF-1measurement.91

For the treatment of hyperglycemia, this recent experts’ consensus statement represents an important leap forward from a conceptual point of view. As a matter of fact, glycemic targets are not strictly fixed but an individualized approach for each patient is suggested. Moreover, CV risk is introduced as a factor influencing the choice of antidiabetic drugs.

Obviously, lifestyle intervention (physical activity, healthy sleep, high-quality nutrition) is always suggested. Metformin is indicated as a first-line medication but, considering the high CV risk of acromegalic subjects, GLP-1 RAs with proven CV benefits could also be considered as a first-line treatment. DPP-4i are considered a viable alternative to GLP-1 RAs in case of gastrointestinal side-effects.91

However, studies demonstrated that 10–30% of acromegalic patients show a paradoxical increase in GH (PI-GH) during 75-g OGTT.3 This is probably due to the action of GIP, which is higher in acromegalic patients, particularly in those with hyperglycemia, and that is likely able to increase the secretion of GH.92,93 As is well known, DPP-4i reduce the incretin-degrading enzyme DPP-4 and thus increase the concentration of active incretins, including GIP. Accordingly, a recent study showed that sitagliptin, administered one hour before 75-g OGTT, increase GH in acromegalic patients, especially in those with PI-GH.94 For this reason, acromegalic patients should be carefully monitored for a potential worsening of the underlying disease during treatment with a DPP- 4i.

The use of SGLT2-i is recommended only as second-line treatment for patients with high CV risk and/or renal disease, despite their high prevalence in acromegaly.91 This is justified by the increased risk of diabetic ketoacidosis (DKA), a severe condition related to treatment with SGLT2-i, in acromegalic subjects.95–97 However, patients safely treated with pasireotide and SGLT2-i are reported.98

The addition of insulin may be considered, but it should ideally be used as an adjunct to metformin and at least one other therapeutic agent.

Obviously, in case of poor glycemic control despite treatment with several anti-hyperglycemic drugs, the dose reduction or even the discontinuation of pasireotide should be considered.

A Potential Change of Perspective and Open Issues

Considering the complex cardiovascular profile of patients with acromegaly and CD, a much greater use of GLP-1 RAs and SGLT2-i might be necessary if DM occurs. There are at least three important aspects that support this consideration: glycemic control, cardiovascular protection, and weight loss.

Accordingly, both in acromegaly and CD, the use of GLP-1 RAs contributes to the achievement of these three main goals, providing an important possibility to enhance the quality of life and to decrease the mortality of patients, with evident advantages compared to DDP-4i and insulin.86,91,99 In this regard, co-agonists of GLP-1 and GIP, such as tirzepatide, with their extraordinary impact in terms of HbA1c reduction and weight loss, represent a theoretically intriguing therapeutic option for the future, despite the current lack of data in acromegaly and CD.

SGLT2-i are not included in the expert recommendations for the patients with CD.89 Currently, there is not enough evidence to support their use, even if their impact on cardiorenal risk might be valuable.

The same reasoning could apply to the acromegalic subjects. In particular, the very favorable benefit of SGLT2-i on HF risk could be extremely crucial.

A proposal for an approach to contrasting hyperglycemia, also taking into account the higher cardio-renal risk, in acromegaly and CD is depicted in Figure 1.

Figure 1 Proposal for a new approach to treat hyperglycemia in patients with acromegaly or Cushing’s Disease, with or without pasireotide treatment. The restoration of euglycemia should be achieved with concomitant reduction in terms of weight and cardiovascular risk, improving quality of life and decreasing mortality.

Notes: The choice of anti-hyperglycemic drugs should be driven by high CV risk and not by the concomitant treatment for acromegaly and CD. In patients with dual therapy at baseline (Metformin + SGLT2-i or GLP-1 RAs) and glycemic control not achieved, follow the same indications reported in the figure. Consider DPP-4i in case of intolerance at SGLT2-i and GLP-1 Ras; Consider BASAL INSULIN as first therapy in case of severe glycometabolic state (HbA1c > 10%, FBG > 300 mg/dL, clinical signs of catabolism). In patients with high risk of ketoacidosis and positive anamnesis for recurrent genitourinary infections, SGLT2-i should be avoided.

Potential limits are higher costs and the risk of AEs. It is well known that the most common AEs of GLP-1 RAs are gastrointestinal (nausea, vomiting, and diarrhea) and tend to occur during initiation and dose escalation, diminishing over time.100 Same AEs are noted with pasireotide, even if described as non-severe.

Another AE common to both treatments (pasireotide and GLP-1 RAs) are cholelithiasis and gallbladder disease. Different meta-analysis of RCTs confirmed that GLP1-RAs are associated with an increased risk of cholelithiasis, in the absence of any relevant increase in the risk of pancreatitis and pancreatic cancer.101,102 It is notable that in the study which compared incretin-based and insulin therapy, patients in the latter group had a higher incidence of gallbladder or biliary-related AEs (23.3% vs 13.2%).86

Instead, as reported in the recent consensus about the management of hyperglycemia in acromegaly, a potential limit for the use of SGLT2-i is the risk of DKA, a condition characterized by hyperglycemia, metabolic acidosis and ketosis (pH ≤ 7.3, bicarbonate ≤ 15 mmol/L, anion gap > 12 mmol/L), fortunately rare in acromegaly, considering it concerns only 1% of all cases and it often occurs only in the initial disease manifestation.103 During treatment with SGLT2-i, DKA occurs in the absence of hyperglycemia, and so it also known as euglycemic diabetic ketoacidosis (EuDKA).104 The suggested mechanism behind the EuDKA is the reduction of insulin requirement in patient treated with SGLT2-i due to massive glycosuria, with concomitant increased gluconeogenesis (driven by an increase of glucagon), release of free fatty acid and subsequent propensity to ketone production.105

It is noteworthy that GH and cortisol themselves increase lipolysis, the lipid oxidation rate and so ketone bodies. Moreover, the shift in the insulin/glucagon ratio as observed in pasireotide treatment is thought to be especially prone to this metabolic complication, warranting greater caution.103

It’s essential to consider the higher risk of DKA or EuDKA during treatment with SGLT2-i, but it’s equally necessary to specify that their incidence appears significantly lower compared to that of a fatal cardiovascular event, both in acromegaly and CD. As a matter of fact, a multicenter retrospective study, during 2015–2020, in 9940 persons with T2DM treated with SGLT2-i has shown that the overall prevalence of DKA is around 0.43% (with 0.25% for EuDKA).106 Furthermore, even some real-life evaluations conducted in subjects with Type 1 Diabetes, a clinical condition with a well-known high risk of DKA and in which the use of SGLT2-i is actually contraindicated, have shown similar data: Stougard et al107 have observed an incidence of DKA equal to 0% in patients treated with SGLT2-i whereas Anson et al108 have observed a lower risk of DKA and associated hospitalization in subjects treated with SGLT-2i compared to those treated with GLP-1 RAs (obviously, as an adjunct to insulin therapy).

Additionally, in acromegalic subjects treated with pegvisomant, in monotherapy or in combination with pasireotide, the incidence of the EuDKA should be reduced. In fact, a reciprocal positive interaction could be achieved because SGLT2-i attenuate the hyperglycemic effect by decreased insulin secretion, meanwhile pasireotide in combination with pegvisomant mitigates the hyperglucagonemia induced by SGLT2-i. Also, pegvisomant decreases lipid oxidation via extrahepatic suppression of Growth Hormone Receptor in different tissues.109

Hence, it seems reasonable to encourage the use of SGLT2-i even in acromegalic patients treated with pasireotide, especially in those with well-controlled disease, modest hyperglycemia and undergoing combined treatment with pegvisomant. It should be helpful to advise them to discontinue therapy with SGLT2-i in case of intercurrent illnesses that may cause a reduction in carbohydrates intake and dehydration (eg, infections and gastroenteritis), and to not skip doses in the case of contextual insulin therapy. SGLT2-i should be avoided in patients with poorly controlled disease.

The same considerations could also be applied to patients with poorly controlled CD.

Another potential limit for the use of SGLT2-i, especially in CD patients for the overall increased risk of infection in this disease, is the higher prevalence of genitourinary infections, reported in both clinical trials and real world evidence. These infectious events are usually mild, and their prevalence is related to sex and a prior positive history of genital infections. In fact, the risk appears higher in females, and among them, in those with previous infections.110 Moreover, it is interesting to underline that in the study of McGovern et al110 the use of corticosteroids, a clinical condition similar to CD, higher values of HbA1c were not associated with significant additional infection risk in subjects treated with SGLT2-i.

Therefore, it is good clinical practice to suggest meticulous intimate hygiene to patients treated with SGLT-2i, avoiding the use of this class of drugs in those with positive anamnesis for genitourinary infections, especially for females.

It is also worth noting that neither GLP-1 RAs nor SGLT2-i cause hypoglycemia, another condition that significantly increases cardiovascular risk and mortality, as demonstrated in the ACCORD trial.111

Finally, a recent case report112 showed the positive effect of a combined therapy of GLP-1 RAs and SGLT2-i on pasireotide-induced hyperglycemia in a patient with CD. After the failure of metformin and DPP-4i, multiple daily insulin injections and, after two days, dulaglutide 0.75 mg were initiated. After improvement of glycemic control, 10 mg of empagliflozin was started and insulin discontinued. After 3 months, hypercortisolemia and glucose impairment were well-regulated, and the patient’s health improved overall.112

Despite several limits (not optimal use of insulin, short follow-up, lack of data regarding other parameters), this is an example of a treatment that is not glycemic-centered but focused to prevent and improve hypercortisolemia-related complications.

Needless to say, further investigations are needed to analyze the above-mentioned considerations and to overcome the limited findings available.

Ethics Statement

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution and considerations, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors did not receive support from any organization for the submitted work.

Disclosure

The authors declare that they have no competing interests in this work.

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Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations

Posted on July 31, 2024 by MaryO

Purpose

Early diagnosis and immediate treatment of Cushing’s syndrome (CS) are critical for a better prognosis but remain a challenge. However, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS. This study aimed to clarify the differences in patient-reported and physician-assessed manifestations of signs and symptoms of CS that prevent early diagnosis.

Methods

This single-center retrospective study included 52 patients with CS (16 with Cushing’s disease and 36 with adrenal CS). Upon clinical diagnosis, medical records were used to independently review the patient-reported and physician-assessed manifestations of typical (such as purple striae and proximal myopathy) and nonspecific features (such as hirsutism and hypertension). The correlations and differences between the patient-reported and physician-assessed manifestations were then analyzed.

Results

We observed a positive correlation between the total number of manifestations of nonspecific features reported by patients and those assessed by physicians, but not for typical features. Moreover, manifestations reported by the patients were less frequent than those assessed by physicians for typical features, leading to discrepancies between the two groups. In contrast, there were no differences in most nonspecific features between the patient-reported and physician-assessed manifestations. Notably, the concordance between patient-reported and physician-assessed manifestations of typical features was not associated with urinary free cortisol levels.

Conclusion

Regardless of disease severity, patients often do not complain of the typical features of CS that are crucial for formulating a diagnosis.

Introduction

Endogenous Cushing’s syndrome (CS) is caused by chronic and excessive glucocorticoid exposure. This occurs primarily due to adrenocorticotropic hormone (ACTH)-producing pituitary tumors (Cushing’s disease; CD) or cortisol-producing adrenal tumors (adrenal Cushing’s syndrome; ACS) [1]—and has a high mortality rate owing to cardiovascular disease, severe infection, and suicide, even when diagnosed and treated appropriately [1, 2]. Moreover, the prognosis is poor if the disease is not adequately treated or remains undiagnosed [2]. Therefore, early diagnosis and immediate intervention are important, as remission of CS due to surgical and pharmacological treatment can reduce the risk of mortality [3, 4].
CS is a rare disease with a prevalence of 57 per million individuals and an annual incidence of 3.2 per million, and its epidemiology is consistent across various regions worldwide [5, 6]. Most symptoms and signs of CS are common in general metabolic disorders, including obesity, hypertension, osteoporosis, and diabetes mellitus [7]. However, CS should be suspected if these symptoms appear as unusual features for their age [1, 8]. Consequently, the identification of CS is challenging and labor-intensive [1, 9, 10]. In fact, recent research revealed that a definitive diagnosis of CD (the most common form of CS), took an average of 3.8 ± 4.8 years from the onset of symptoms, and patients typically consulted 4.6 ± 3.8 medical professionals before this disease was identified [11]. Typical features of CS include symptoms of moon face, central obesity, or buffalo hump [12], which are similar to other symptoms such as primary obesity and therefore can lead to misdiagnosis. Furthermore, although purple striae or thin skin with an increased propensity for bruising are other typical features of CS [12], these attributes are not commonly acknowledged by the general population [1, 9].
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Attempts have been made to diagnose CS early, including the development of scoring systems to estimate the pre-test probability of CS and facial image analysis software to diagnose the specific facial features of CS [13‐15]; however, these have not yet been used widespread or fully and the early diagnosis of CS remains dependent on the experience-based medical skills of the clinical staffs [16].
Additionally, although it is difficult for patients to recognize complex and nonspecific symptoms [17, 18], the significance of patients recognizing their illness has recently been reported for various diseases such as heart failure and malignant carcinoma [19‐21]. It is widely acknowledged that patients’ self-recognition can result in early detection of the disease, reduce its severity and recurrence, and enhance their quality of life [19]. In patients with endocrine diseases, there is increasing focus on issues surrounding self-recognition [22‐24]. For example, a previous study focusing on acromegaly reported a discrepancy between patient-reported and physician-reported manifestations and indicated that resolving this discrepancy could shorten the time to diagnosis [25].
Identifying CS may be challenging for primary care physicians who are yet to specialize. Therefore, endocrinologists with extensive experience in CS have often noticed that patients and these physicians struggle to identify the symptoms of CS; however, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS.
Therefore, this study aimed to investigate the unreported manifestations of CS among individuals referred to non-specialist healthcare providers, including primary care physicians, and to recognize potential challenges with the current diagnosis of CS with the goal of facilitating early detection.
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Materials and methods

Patients, study design, and data collection

This single-center retrospective study was conducted to identify the discrepancies between patient-reported and physician-assessed symptoms and investigate the factors causing these differences.
From September 2004 to December 2022, 199 patients were referred to our department at a tertiary medical institution upon suspicion, evaluation, or follow-up for hypercortisolism. Of these patients, 92 were newly diagnosed with CS (36 with CD, 51 with ACS, and 5 with ectopic ACTH syndrome) based on the diagnostic guidelines [3, 8, 12], with a diagnosis confirmed by pathological evaluation after surgical resection [26]. However, 35 patients were excluded due to a lack of detailed clinical data on the manifestations at diagnosis. Similarly, we excluded individuals diagnosed with ectopic ACTH syndrome because of the lack of comprehensive information on symptoms reported by the patients and primary care physicians due to the rapid progression and severity of this disease. Therefore, 52 patients (16 with CD and 36 with ACS) were enrolled in this study.
Upon clinical diagnosis, the manifestations included in the comprehensive standardized interview at the time of diagnosis and those assessed by the physician through collaborative assessment with multiple board-certified endocrinologists as routine practice were independently reviewed from the medical records. We categorized these manifestations reviewed from the medical records into the following two categories based on the diagnostic guidelines including those of the Japan Endocrine Society: typical features, including moon face, central obesity or buffalo hump, purple striae of ≥1 cm, thin skin and easy bruising, and proximal myopathy; and nonspecific features (shown as atypical in Japan Endocrine Society’s guideline), including hypertension, menstrual abnormalities, acne, hirsutism, peripheral edema, glucose metabolism impairment, osteoporosis, pigmentation (which is not expected in patients with ACS), and mental abnormalities [1, 8, 12]. Central obesity or buffalo hump can also be observed in pseudo CS. However, in this study, features were classified as the same typical feature according to clinical guidelines [12, 27]. We also reviewed the biochemical findings, comorbidities, duration from the initial recognition of CS-related symptoms to diagnosis, and number of medical institutions visited before diagnosis.
The present retrospective study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351). The patients had the option of an opt-out process, and all procedures were part of routine medical care.

Definition of patient-reported and physician-assessed manifestations

In the context of routine clinical care, physicians asked the patients about the presence or absence of manifestations and comorbidities (e.g., hypertension, menstrual abnormalities, glucose metabolism impairment, osteoporosis, and mental abnormalities), which were documented in the medical records. These reports in the medical records were defined as patient-reported manifestations in this study. In contrast, the manifestations and comorbidities of CS were assessed within several weeks after the patient was referred to our department for suspected CS. Additional diagnostic information on comorbidities is provided in the subsequent section. Physician-assessed manifestations were subsequently defined based on these findings.

Comorbidities of Cushing’s syndrome

All comorbidities were diagnosed according to the appropriate guidelines [28‐30]. For example, hypertension was diagnosed if patients were taking oral antihypertensive medication or had more than grade 1 hypertension (≥140/90 mmHg) in a treatment-naïve state [28]. Moreover, glucose metabolism impairment—including diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose—was diagnosed based on the results of blood glucose levels during fasting and after a 75-g oral glucose tolerance test, as well as hemoglobin A1c (HbA1c) levels [29]. Patients taking medications for diabetes mellitus at the time of CS diagnosis were also categorized as having diabetes.
Other comorbidities included mental abnormalities, menstrual abnormalities, and the presence of osteoporosis. Mental abnormalities were defined as the use of anxiolytic medications, sleeping pills, or antidepressants prescribed by experienced psychologists, and menstrual abnormalities were defined as women with irregular menstrual cycles. Furthermore, the presence of osteoporosis was defined as bone mineral density (BMD) of <–2.5 standard deviations (SD) of the T-score of the lumbar vertebrae (L2–L4), femoral neck, or distal radius measured using dual-energy x-ray absorptiometry (DXA; Horizon A DXA System), and/or an experience of a fragility fracture [30]. As per the specifications of the measurement system employed, L1 was not included in the assessment. The Z-score was also employed as a diagnostic reference among young adults. Patients also diagnosed with osteoporosis who were receiving medications for this disease.

Hormone assay

In this study, blood samples were collected after an overnight fast. Subsequently, serum cortisol levels were measured using a chemiluminescent enzyme immunoassay [CLEIA] (TOSOH, Tokyo, Japan, RRID:AB_3099658) or enzyme immunoassay [EIA] (TOSOH, Tokyo, Japan, RRID:AB_3076600). Similarly, plasma ACTH levels were measured using a CLEIA (TOSOH, Tokyo, Japan, RRID:AB_3099657, or Siemens, Tokyo, Japan, RRID:AB_2909441) and EIA (TOSOH, Tokyo, Japan, RRID:AB_2783633). In both methods, the measurements showed good correlation and no conversion was required [31, 32].
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Urinary free cortisol (UFC) levels were also measured using radioimmunoassays (RIA; TFB, Tokyo, Japan, RRID:AB_2894408) or chemiluminescent immunoassays (CLIA; Siemens, Tokyo, Japan, RRID:AB_2893154). Using the following formula, the UFC levels measured by RIA were then corrected to the value measured by CLIA: Y = 0.832X − 4.23 (Y = UFC levels using CLIA, X = UFC levels using RIA) [33].

Statistical analysis

All statistical analyses were performed using SPSS ver. 28.0 software (IBM Corp., Armonk, NY, USA). All continuous variables were analyzed using the Shapiro–Wilk normality test to confirm a normal distribution, whereas Fisher’s exact test was used to analyze categorical data. Between the two groups, differences in normally or non-normally distributed data were compared using the unpaired Student’s t-test or the Mann–Whitney U test, respectively.
Cohen’s kappa coefficient was used to describe the concordance between the patient-reported and physician-assessed manifestations. As previously reported [19, 20, 34], the concordance based on the value of Cohen’s kappa coefficient was rated as follows: 0.00–0.20 for “Slight,” 0.21–0.40 for “Fair,” 0.41–0.60 for “Moderate,” 0.61–0.80 for “Substantial,” and 0.81–1.00 for “Almost Perfect.” For correlation analysis between two variables of non-normally distributed data, we used Spearman’s rank correlation coefficient. Multivariate logistic regression analyses were then performed to investigate variables associated with the discrepancies between patient-reported and physician-assessed manifestations.
The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data, and differences were considered statistically significant when the P value was <0.05.
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Results

Clinical characteristics of the patients

We included 52 patients diagnosed with CS in this study. Their clinical characteristics are presented in Table 1. Notably, this group consisted of 5 males and 47 females, with a mean age of 49.4 ± 15.8 years, median body mass index (BMI) of 23.0 [21.3–28.0] kg/m2, and median UFC level of 272.1 [126.0–435.0] µg/day. Of the CS patients, 16 had CD and 36 had ACS, which is consistent with epidemiological data on CS observed in Asians (including Japanese individuals); however, this differed from epidemiological data from Western countries [35, 36]. Regarding comorbidities, 43 patients were diagnosed with hypertension—of which 34 were prescribed antihypertensive medications—with a mean systolic blood pressure (BP) of 136.4 ± 21.5 mmHg and diastolic BP of 83.5 ± 15.0 mmHg. In addition, 44 patients were diagnosed with glucose metabolism impairment—of which, 20 were prescribed oral hypoglycemic agents and/or insulin—with a median fasting serum glucose level of 99.5 [87.3–116.5] mg/dL and median HbA1c level of 6.3% [5.7–7.4]. Moreover, 29 patients were diagnosed with osteoporosis, of which 4 were prescribed antiosteoporosis medication, with BMD T-score SDs of -1.54 ± 1.39, -1.76 ± 1.12, and -0.50 [-1.53–0.50] for the lumber spine, femoral neck, and distal radius, respectively. Notably, the UFC levels were higher in patients with CD than in those with ACS (412.6 [243.2–1,100.3] vs. 215.3 [114.0–387.8] µg/day); however, there were no significant differences attributed to sex, age, BMI, or the proportion of patients with respect to comorbidities, including hypertension and glucose metabolism impairment, between patients with CD and ACS.

Table 1

Clinical characteristics of the patients
Total
CD
ACS
CD vs. ACS P value
Number of men/women
5/47
1/15
4/32
1.00
Age (years)
49.4 ± 15.8
54.3 ± 19.2
47.2 ± 13.8
0.14
BMI (kg/m2)
23.0 [21.3–28.0]
24.7 [22.2–30.0]
22.8 [20.8–26.4]
0.17
Midnight F (µg/dL)
20.1 [16.0–23.5]
20.2 [13.9–24.7]
20.1 [16.9–23.0]
0.97
F after LDDST (μg/dL)
21.2 ± 6.9
24.2 ± 10.1
19.7 ± 4.2
0.11
UFC (μg/day)
272.1 [126.0–435.0]
412.6 [243.2–1,100.3]
215.3 [114.0–387.8]
0.02
Basal ACTH (pg/mL)
2.0 [0.0–53.9]
83.2 [57.4–169.9]
0.0 [0.0–2.1]
<0.01
Systolic BP (mmHg)
136.4 ± 21.5
140.5 ± 20.7
134.6 ± 21.8
0.36
Diastolic BP (mmHg)
83.5 ± 15.0
83.1 ± 14.3
83.6 ± 15.5
0.90
Use of antihypertensive drugs, n (%)
34 (65)
13 (81)
21 (58)
0.13
FSG (mg/dL)
99.5 [87.3–116.5]
110.0 [102.0–142.8]
92.5 [83.3–114.3]
0.01
HbA1c (%)
6.3 [5.7–7.4]
6.8 [5.9–8.6]
6.0 [5.7–7.1]
0.08
Use of OHA and/or insulin, n (%)
20 (38)
9 (56)
11 (31)
0.12
LS BMD T-score (SD)
−1.54 ± 1.39
−1.00 ± 1.38
−1.79 ± 1.35
0.07
LS BMD Z-score (SD)
−0.78 ± 1.37
0.13 ± 1.11
−1.20 ± 1.28
<0.01
FN BMD T-score (SD)
−1.76 ± 1.12
−1.73 ± 1.54
−1.78 ± 0.88
0.92
FN BMD Z-score (SD)
−0.79 ± 1.01
−0.39 ± 1.10
−0.99 ± 0.92
0.10
Radius BMD T-score (SD)
−0.50 [−1.53–0.50]
−0.30 [−2.50–0.40]
−0.60 [−1.30–0.60]
0.79
Radius BMD Z-score (SD)
0.60 [−0.60–1.50]
1.50[−0.60–1.80]
0.50[−0.50–1.00]
0.33
Use of antiosteoporosis drugs, n (%)
4 (8)
1 (6)
3 (8)
1.00
Time to diagnosis (months)
44.0 [13.3–125.3]
43.0 [15.0–128.3]
47.5 [12.5–125.3]
0.87
Number of medical institutions before diagnosis
3.0 [2.0–5.0]
3.0 [2.0–5.0]
3.0 [3.0–5.8]
0.23
The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data
CD Cushing’s disease, ACS adrenal Cushing’s syndrome, BMI body mass index, F cortisol, LDDST low-dose dexamethasone suppression test, UFC urinary free cortisol, ACTH adrenocorticotropic hormone, BP blood pressure, FSG fasting serum glucose, HbA1c hemoglobin A1c, OHA oral hypoglycemic agents, BMD bone mineral density, LS lumber spine, FN femoral neck
The median duration from the patients’ initial recognition of CS-related manifestations to diagnosis was 44.0 [13.3–125.3] months, and it took more than 3 years to diagnose CS in 30 patients (58%). Furthermore, the median number of medical facilities visited by patients before diagnosis was 3.0 [2.0–5.0]; however, there were no significant differences in the duration or number of medical institutions between patients with CD and those with ACS.

Frequency and concordance between patient-reported and physician-assessed CS-related manifestations

Each manifestation reported by a patient or assessed by a physician is shown vertically for individual cases in Fig. 1. Compared with nonspecific features, typical features appeared to not be reported by the patients but were only assessed by the physicians. In addition, compared to nonspecific features, there were fewer cases in which the manifestations reported by the patients were consistent with those assessed by physicians for typical features.

https://static-content.springer.com/image/art%3A10.1007%2Fs12020-024-03935-9/MediaObjects/12020_2024_3935_Fig1_HTML.png

Fig. 1

Consistency between patient-reported and physician-assessed manifestations for each individual case. The consistencies or discrepancies between patient-reported and physician-assessed manifestations are shown. Vertical lines represent manifestations in individual patients. CD Cushing’s disease, ACS adrenal Cushing’s syndrome
Consistent with the impact of these visually distinctive presentations shown in Fig. 1, no correlation was observed in the number of typical features between patient-reported and physician-assessed manifestations (r = –0.20, P = 0.16) (Fig. 2A), whereas a positive correlation was found for nonspecific features (r = 0.62, P < 0.01) (Fig. 2B). Moreover, the total number of patient-reported manifestations of typical features was lower than that of physician-assessed manifestations (1.0 [0.0–2.0] vs. 3.5 [3.0–4.0], P < 0.01), and four of the five typical features were reported less frequently by patients than by physicians, except for proximal myopathy (Table 2A). According to Cohen’s kappa coefficient, the concordance between patient-reported and physician-assessed manifestations was marked as “Fair” to “Slight,” indicating a discrepancy for all typical features. Similarly, the total number of patient-reported manifestations of nonspecific features was also lower than that in physicians (2.5 [2.0–3.0] vs. 4.0 [3.0–5.0], P < 0.01). However, except for glucose metabolism impairment or osteoporosis, there were no differences in the frequencies of nonspecific features between patient-reported and physician-assessed manifestations, and the concordance of the nonspecific features between the patient-reported and physician-assessed manifestations was “Almost perfect” for menstrual abnormality and “Substantial” for mental abnormality and hypertension, whereas that for glucose metabolism impairment and osteoporosis was “Fair.” This suggests that the discrepancy between patient-reported and physician-assessed manifestations was more significant for typical than for nonspecific features. However, no differences in these discrepancies were observed between patients with CD and those with ACS (Table 2B, C).

https://static-content.springer.com/image/art%3A10.1007%2Fs12020-024-03935-9/MediaObjects/12020_2024_3935_Fig2_HTML.png

Fig. 2

Correlation between the total number of patient-reported and physician-assessed manifestations. Correlations between the total number of patient-reported and physician-assessed manifestations are shown for typical (A) and nonspecific features (B). CD is plotted by ×, and ACS is plotted by ○. The Spearman’s rank correlation coefficients and P value are presented. CI confidence interval, CD Cushing’s disease, ACS adrenal Cushing’s syndrome
Table 2

Frequencies of patient-reported and physician-assessed manifestations and their concordance. A. All patients (n = 52). B. Patients with CD (n = 16). C. Patients with ACS (n = 36)
Patient-reported
Physician-assessed
P value of Fisher’s exact test
Concordance with Cohen’s kappa coefficient
A
Typical features
Moon face, n (%)
20 (39)
48 (92)
<0.01
Slight
Central obesity or buffalo hump, n (%)
13 (25)
44 (85)
<0.01
Slight
Purple striae, n (%)
3 (6)
15 (29)
<0.01
Fair
Thin skin and easy bruising, n (%)
15 (29)
43 (83)
<0.01
Slight
Proximal myopathy, n (%)
21 (40)
27 (52)
0.33
Slight
Nonspecific features
Hypertension, n (%)
39 (75)
43 (83)
0.47
Substantial
Menstrual abnormalities, n (%)
11 (21)
11 (21)
1.00
Almost perfect
Acne, n (%)
7 (14)
13 (25)
0.21
Moderate
Hirsutism, n (%)
3 (6)
10 (19)
0.07
Moderate
Peripheral edema, n (%)
24 (46)
28 (54)
0.56
Fair
Glucose metabolism impairment, n (%)
24 (46)
44 (85)
<0.01
Fair
Osteoporosis, n (%)
7 (14)
29 (56)
<0.01
Slight
Pigmentation, n (%)
0 (0)
5 (10)
0.06
–
Mental abnormalities, n (%)
17 (33)
17 (33)
1.00
Substantial
B
Typical features
Moon face, n (%)
6 (38)
14 (88)
0.01
Slight
Central obesity or buffalo hump, n (%)
6 (38)
15 (94)
<0.01
Slight
Purple striae, n (%)
2 (13)
4 (25)
0.56
Moderate
Thin skin and easy bruising, n (%)
4 (25)
13 (81)
0.06
Slight
Proximal myopathy, n (%)
8 (50)
8 (50)
1.00
Slight
Nonspecific features
Hypertension, n (%)
16 (100)
15 (94)
0.78
Slight
Menstrual abnormalities, n (%)
5 (31)
5 (31)
1.00
Almost perfect
Acne, n (%)
1 (6)
3 (19)
0.56
Moderate
Hirsutism, n (%)
2 (13)
4 (25)
0.56
Moderate
Peripheral edema, n (%)
8 (50)
10 (63)
0.56
Slight
Glucose metabolism impairment, n (%)
10 (63)
15 (94)
0.14
Slight
Osteoporosis, n (%)
4 (25)
9 (56)
0.15
Slight
Pigmentation, n (%)
0 (0)
5 (31)
0.14
–
Mental abnormalities, n (%)
5 (31)
6 (38)
0.78
Moderate
C
Typical features
Moon face, n (%)
14 (39)
34 (94)
<0.01
Slight
Central obesity or buffalo hump, n (%)
7 (19)
29 (81)
<0.01
Slight
Purple striae, n (%)
1 (3)
11 (31)
<0.01
Slight
Thin skin and easy bruising, n (%)
11 (31)
30 (83)
<0.01
Slight
Proximal myopathy, n (%)
13 (36)
19 (53)
0.24
Slight
Nonspecific features
Hypertension, n (%)
23 (64)
28 (78)
0.30
Substantial
Menstrual abnormalities, n (%)
6 (17)
6 (17)
1.00
Almost perfect
Acne, n (%)
6 (17)
10 (28)
0.40
Moderate
Hirsutism, n (%)
1 (3)
6 (17)
0.11
Fair
Peripheral edema, n (%)
16 (44)
18 (50)
0.81
Fair
Glucose metabolism impairment, n (%)
14 (39)
29 (81)
<0.01
Fair
Osteoporosis, n (%)
3 (8)
20 (56)
<0.01
Slight
Pigmentation, n (%)
0 (0)
0 (0)
–
–
Mental abnormalities, n (%)
12 (33)
11 (31)
1.00
Almost perfect
The frequencies of patient-reported and physician-assessed manifestations were compared using Fisher’s exact test. The concordance between patient-reported and physician-assessed manifestations was evaluated with Cohen’s kappa coefficient, and its coefficients were defined as follows: 0.00–0.20 for “Slight,” 0.21–0.40 for “Fair,” 0.41–0.60 for “Moderate,” 0.61–0.80 for “Substantial,” and 0.81–1.00 for “Almost perfect”
CD Cushing’s disease, ACS adrenal Cushing’s syndrome
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We performed logistic regression analyses using UFC to investigate whether excess cortisol levels influenced the discrepancy between patient-reported and physician-assessed manifestations. Notably, we observed no association between UFC levels and discrepancies between patient-reported and physician-assessed manifestations in the univariate or multivariate logistic regression analyses adjusted for sex and age (Table 3A). In addition, no association was observed after adjusting for other variables such as BMI and disease duration. Similarly, we found that the serum cortisol levels after the low-dose dexamethasone suppression test (LDDST) were not associated with discrepancies between patient-reported and physician-assessed manifestations (Table 3B). Thus, these disparities were shown to be insignificant when directly related to the severity of CS.

Table 3

Logistic regression analyses of the discrepancies between the patient-reported and physician-assessed manifestations. A. Variables associated with UFC levels. B. Variables associated with serum cortisol levels after the LDDST
Univariate
Multivariate 1 (sex- and age-adjusted)
Multivariate 2 (BMI-adjusted)
Multivariate 3 (disease duration-adjusted)
A
Moon face
1.000 (0.999–1.001)
1.000 (0.999–1.001)
1.000 (0.998–1.002)
1.000 (0.999–1.001)
Proximal myopathy
1.000 (0.999–1.001)
1.000 (0.999–1.001)
1.000 (0.998–1.001)
1.000 (0.998–1.001)
Thin skin and easy bruising
1.000 (0.998–1.001)
1.000 (0.999–1.001)
1.000 (0.999–1.001)
1.000 (0.998–1.001)
Central obesity or buffalo hump
1.001 (1.000–1.003)
1.001 (1.000–1.003)
1.001 (1.000–1.003)
1.001 (1.000–1.003)
Purple striae
1.000 (0.999–1.002)
1.000 (0.998–1.002)
1.001 (0.999–1.003)
1.000 (0.999–1.002)
B
Moon face
0.998 (0.919–1.084)
0.999 (0.919–1.086)
1.000 (0.920–1.088)
0.997 (0.918–1.082)
Proximal myopathy
1.007 (0.925–1.097)
1.007 (0.924–1.097)
1.007 (0.925–1.097)
1.006 (0.924–1.096)
Thin skin and easy bruising
1.022 (0.939–1.112)
1.018 (0.934–1.109)
1.023 (0.940–1.113)
1.019 (0.937–1.109)
Central obesity or buffalo hump
0.979 (0.890–1.078)
0.978 (0.865–1.105)
0.981 (0.875–1.099)
0.978 (0.887–1.078)
Purple striae
0.998 (0.919–1.084)
0.999 (0.919–1.086)
1.000 (0.920–1.088)
0.997 (0.918–1.082)
The results are presented as odds ratios (95% confidence intervals)
UFC urinary free cortisol, BMI Body Mass Index, LDDST low-dose dexamethasone suppression test

Discussion

In the present study, we highlight the challenges associated with the diagnosis of CS—a condition resulting from excessive glucocorticoid exposure—and elucidate the divergence between patient-reported and physician-assessed manifestations. Thus, this study may aid in the early detection of CS by identifying symptoms that patients are unable to recognize based on the disparities between patient-reported and physician-assessed manifestations of CS.
In this study, the number of patient-reported manifestations of both typical and nonspecific features was lower than that of physician-assessed manifestations, suggesting that CS symptoms may have been overlooked by relying solely on patient reports. Additionally, analysis of the concordance between patient-reported and physician-assessed manifestations revealed a tendency for these manifestations to be inconsistent for both typical and nonspecific features, with a tendency to be more significant for typical features. Furthermore, the UFC and serum cortisol levels after the LDDST, which represent the severity of CS, were not associated with the concordance of manifestations between patients and physicians, suggesting that even in cases of severe CS, patients may not recognize their symptoms. These findings imply that typical features, which are essential for diagnosing CS, may be difficult for patients to recognize and poorly identified or conveyed to patients by non-specialist physicians, who are typically the first to interact with individuals with CS. The importance of educating healthcare providers such as primary care physicians, family physicians and gynecologists for early diagnosis of CS should be highlighted.
According to a previous report on the diagnostic history of 176 patients with CD, 83% of the patients visited their family physician for manifestations such as weight gain and hypertension, while 46% visited a gynecologist for menstrual abnormalities before the diagnosis of CD [11]. Thus, the typical features of CS were not recognized. The examination may reveal nonspecific features. However, individuals who are non-specialists may not recognize these features as indications of CS. Therefore, patients are often unaware of the potential complications associated with CS. This is consistent with the results of our study, in which patient-reported and physician-assessed manifestations were more consistent for hypertension and menstrual abnormalities than for other manifestations such as typical features, glucose metabolism impairment, and osteoporosis. This makes diagnosis challenging as non-specialist physicians and, more prominently, patients may not recognize the full range of symptoms associated with CS, especially the typical features with high diagnostic value. In addition, older patients diagnosed with CS present with a lower BMI and waist circumference than younger patients [37], and they typically do not exhibit symptoms commonly associated with CS such as skin alterations, depression, hair loss, hirsutism, and reduced libido. These findings may further complicate the diagnosis of CS in elderly patients.
By evaluating only the patient-reported manifestations, it appears that manifestations such as peripheral edema and proximal myopathy were more common. Possibly, these symptoms were not considered features of CS by physicians, in comparison to the degree of symptoms experienced by the patients. However, this may not necessarily imply diminishing the significance of the patient’s signs and symptoms, as these manifestations can be considered as the unidentified complaints and may result in a postponement of the diagnosis of CS. Patients may be experiencing symptoms that physicians do not perceive, indicating the importance of interview and physical examination. Further investigation is needed to elucidate underlying factors.
Considering the rarity of CS, it is crucial to suspect and diagnose the condition based on clinical symptoms and perform the appropriate screening tests without over- or under-screening [7]. Although CS screening in patients with diabetes mellitus and hypertension has been reported to lead to a diagnosis in only 0–0.7% and 0.1–0.5% of these patients, respectively [38‐41], it is ineffective in terms of false positives and cost [9]. Therefore, patients with typical features that are highly specific for CS, such as purple striae, easy bruising, and proximal myopathy [1, 8, 12], as well as those with obesity, diabetes mellitus, or hypertension in combination with these features, should be screened for CS [7, 27]. However, our results suggest that these symptoms are unlikely to be self-recognized. Therefore, the appropriate screening measures must be implemented to establish an early and effective diagnosis of CS.
In these situations, it is crucial for physicians to utilize their knowledge and experience to suspect CS based on symptoms such as typical features [10]. It has been reported that years of clinical experience in endocrine practice can contribute to the estimation of the pre-test probability of CS [16]. In contrast, non-specialists are less likely to encounter patients with CS in their lifetime, which can make it difficult to properly suspect CS [9]. From this perspective, it is of utmost importance that family physicians and general internists are knowledgeable regarding the manifestations that require screening for CS, as early diagnosis of this uncommon and severe condition is crucial [11]. Therefore, it is important for physicians who routinely treat patients presenting with common symptoms such as obesity, diabetes mellitus, and hypertension to meticulously interview and observe for any indicators of CS, even if the patient does not recognize them. Failure to adopt an appropriate tone in these situations may cause the disease to become undetectable.
In rare disorders such as CS, in addition to enhancing public recognition of the disease, the appropriate sharing of information and provision of specialized care in clinical practice remain important issues [42]. Early identification of such rare diseases can be achieved by promoting an understanding of the disease and its symptoms among family, friends, and patients who may be the first to recognize the signs and symptoms in an individual. In fact, in a questionnaire survey of 340 patients with CS across 30 countries, the diagnosis of CS was made in 5.6% of cases by the patients themselves and in 0.9% by their family or friends [43]. In the present study, we found that it took more than 3 years to diagnose CS in 58% of the cases. If CS and its symptoms are popularized among the public, the typical features of CS could be more readily reported to physicians and the time to diagnosis might be shorter. Furthermore, a primary care physician who is well-educated and knowledgeable is crucial in ensuring that the concerns of such individuals are not overlooked.
This study has some limitations. First, this single-center retrospective study included a relatively small sample size with few male patients. Second, CD and ACS have different pathologies; therefore, the frequencies of several CS-related manifestations will differ depending on their subtypes [3, 44]. However, in this study, there was no difference in the discrepancies between patient-reported and physician-assessed manifestations in patients with CD or ACS. Nonetheless, it is crucial that comprehensive research is conducted in larger patient populations with a focus on employing methods that accurately reflect the pathophysiology of CD and ACS. Third, patient reports may be inaccurate in terms of onset and duration because they depend on the patient’s memory. Fourth, the endocrinologists who examined the patients differed, which may have affected the presence or absence of physician-assessed manifestations. Finally, this study investigated the differences between the manifestations reported by patients and those assessed by endocrinologists, although the evaluations conducted by primary care physicians, which are crucial for the early detection of CS, were not available. Future research is needed to investigate the differences in recognizing manifestations between non-specialist physicians and endocrinologists with extensive experience in CS and to examine the changes before and after education for these non-specialists to determine if they can lead to earlier diagnosis of CS.
In conclusion, endocrinologists have been shown to be aware of CS-related symptoms, especially typical features, whereas patients do not recognize these manifestations, even when the disease is severe. Therefore, the key to the early diagnosis and treatment of CS is a more proactive approach of questioning and examining patients suspected of having the disease.

Acknowledgements

We thank all the physicians and medical assistants who were involved in this study. We are grateful to all the laboratory members for their excellent discussions and fruitful suggestions. We also thank Editage (www.​editage.​jp) for English language editing.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Ethics approval

This study conformed to the Declaration of Helsinki guidelines and was approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351).
Informed consent was obtained from all the participants using an opt-out approach.
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