A Case Series of Bilateral Inferior Petrosal Sinus Sampling Using Desmopressin for Evaluation of ACTH-Dependent Cushing’s Syndrome in Pediatric Patients

Posted on June 11, 2025 by MaryO

Abstract

Background

Pediatric Cushing Syndrome (CS) is rare and difficult to diagnose, especially when distinguishing ACTH-dependent subtypes. Bilateral inferior petrosal sinus sampling (BIPSS) is an essential but technically challenging procedure for this purpose. Because corticotropin-releasing hormone (CRH), the standard stimulant, has limitations, desmopressin is being explored as an alternative. This study assesses desmopressin-stimulated BIPSS for its diagnostic accuracy and tumor localization in pediatric CS within an Iranian cohort, addressing a gap in pediatric-specific diagnostic strategies and offering insights into the applicability of desmopressin in this context.

Methods

Four pediatric patients with inconclusive pituitary imaging and suspected Cushing’s disease (CD) underwent BIPSS with desmopressin at Taleghani Hospital, Tehran, Iran, between August 2015 and March 2019. Sensitivity of BIPSS for CD diagnosis was assessed, and tumor localization accuracy was evaluated during surgery.

Results

Bilateral IPSS demonstrated a sensitivity of 100% for diagnosing CD in pediatric patients. However, accuracy for tumor lateralization was moderate, with only 50% concordance between BIPSS lateralization and surgical findings. Specifically, two out of four patients had correct lateralization confirmed during surgery, while one patient with left lateralization was consistent with hypophysectomy findings. These discrepancies highlight challenges such as anatomical and drainage variations that can lead to mislocalization.

Conclusion

Desmopressin enhances the sensitivity of BIPSS for diagnosing pediatric CD, presenting as a viable alternative to CRH stimulation. Despite high sensitivity, caution is advised when interpreting BIPSS results for tumor localization. Further research is needed to optimize diagnostic strategies for pediatric CS management.

From https://link.springer.com/article/10.1007/s40200-025-01634-4

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Survival Probabilities in Patients with Ectopic Cushing’s Syndrome

Posted on June 9, 2025 by MaryO

Abstract

Objective

We aimed to estimate 1- and 5-year survival probabilities in patients with different forms of ectopic Cushing’s syndrome (ECS) and identify factors influencing survival.

Methods

In this systematic review and meta-analysis, we searched the online databases PubMed, Scopus and Web of Science up to October 18th, 2023, for studies reporting survival in patients with ECS. Data extraction and risk of bias assessment were performed by three independent investigators. Primary outcome was survival in patients with ECS and secondary outcome was factors influencing survival.

Results

We included 40 studies with a total of 1148 patients. The pooled mean 1-year survival probability for ECS of mixed etiologies was 78% while the mean pooled 5-year survival probability was 47%. The 5-year survival probabilities for patients with pulmonary neuroendocrine neoplasm (NEN) was 81%, occult ECS 66%, thymic NEN 50% and pancreatic NEN 40%. Only eight studies reported factors influencing survival, where total resection of the primary tumor was associated with better overall survival, and unresectable tumors, metastatic disease at diagnosis, severe hypercortisolism, hypokalemia, and new onset diabetes mellitus were associated with worse prognosis.

Conclusion

Survival in ECS varies considerably, mainly due to the underlying origin of the tumor, tumor stage and severity of the hypercortisolism. Further studies analyzing the importance of factors affecting survival are needed.

Accepted manuscripts
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A Second Look at Cushing Disease: Hypercortisolism Recurrence From Another Gland

Posted on June 2, 2025 by MaryO

Abstract

Cushing disease (CD) is the most common form of adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS), whereas unilateral adrenal adenoma is the most common cause of ACTH-independent CS. However, the occurrence of different subtypes of CS in a single individual is very rare.

We present a case of a 44-year-old woman with distant histories of left adrenalectomy for an adrenal adenoma and total thyroidectomy following the diagnosis of papillary thyroid carcinoma.

She was later diagnosed with CD, achieving disease remission after pituitary surgery, but subsequently developed adrenal CS from the remaining right adrenal gland. After discussing the potential advantages and drawbacks of another adrenalectomy to remove her right adrenal gland, the patient declined surgery and opted for medical management. After 7 years of imaging follow-up studies, her right adrenal adenoma has remained stable in size and she is biochemically controlled on low-dose osilodrostat therapy. Our case emphasizes the importance of recognizing the rare occurrence of successfully treated CD followed by the recurrence of CS from a different gland, and the adoption of management strategies tailored to each individual patient’s preferences.

Introduction

Cushing syndrome (CS) arising from either pituitary or adrenal lesions is generally a rare condition, with an estimated prevalence of 10 to 15 cases per million individuals [1]. The majority of cases of endogenous CS are adrenocorticotropin (ACTH) dependent, accounting for 80% to 85% of cases. Among these cases, approximately 75% to 80% are attributed to pituitary corticotroph adenomas [2, 3], whereas ACTH-independent CS constitutes 15% to 20% of cases, with 90% of such cases caused by unilateral adrenal adenomas [4]. Surgery is the preferred first-line treatment option for all cases of CS; however, approximately 20% cases may recur following surgical resection that necessitates second-line treatments, such as medical therapy, adrenalectomy, and radiation therapy [5, 6].

Bilateral adrenalectomy may be considered for some Cushing disease (CD) patients, such as patients with persistent or recurrent disease following pituitary surgery, medication intolerance, nonadherent or unresponsive to medical therapy, or in situations where rapid normalization of life-threatening hypercortisolism is required. However, this procedure carries the risk of development of Nelson syndrome and lifelong use of glucocorticoid and mineralocorticoid replacement therapies [7]. Consequently, the role of bilateral adrenalectomy in patients with CS still remains a subject of debate and medical therapy is increasingly preferred [8]. Additionally, there is accumulating evidence affirming the effectiveness, safety, and tolerability of medical therapies leading to its increased use in the treatment of CS, subsequently allowing a more personalized approach for these patients [9].

We hereby present a case of a patient with distant histories of left adrenalectomy for an adrenal adenoma and total thyroidectomy for papillary thyroid carcinoma, who later developed CD that required transsphenoidal resection. After 6 years of disease remission following her transsphenoidal resection, the patient sought medical guidance for recurrence of her hypercortisolemic symptoms leading to the discovery of a right cortisol-secreting adrenal adenoma and the subsequent diagnosis of adrenal CS.

Case Presentation

A 44-year-old African American woman presented to our clinic in 2017 for worsening headaches, joint and muscle pains, muscle weakness, facial acne, facial roundness, facial plethora, pink abdominal striae, easy skin bruising, hair loss, and weight gain of 7 kg over 6 months. Her past surgical history included a left adrenalectomy for an adrenal adenoma in 2009, transsphenoidal resection of a corticotroph adenoma in 2011, and total thyroidectomy for papillary thyroid carcinoma in 2016. The left adrenalectomy was undertaken due to worsening hypertension and mildly elevated plasma metanephrines and catecholamines; however, the pathology revealed an adrenal cortical adenoma and not pheochromocytoma characteristics, demonstrating clear and eosinophilic cytoplasm, low mitotic activity, no significant atypia, and no vascular invasion, while immunohistochemistry was positive for inhibin, calretinin, and Melan-A. Genetic studies, including multiple endocrine neoplasia (MEN) 1 testing, were performed and were negative. Her past medical history included long-standing type 2 diabetes mellitus, metabolic dysfunction–associated steatohepatitis, and osteoporosis with compression fractures on her lumbar 4 to 5 vertebral bodies of her spine. The patient reported no known family history of endocrine disorders.

Diagnostic Assessment

Further testing at this clinic visit revealed elevated 24-hour urine cortisol levels of 49.3 μg/24 hours (135.73 nmol/24 hours) (reference range [RR] <45 μg/24 hours; <124.40 nmol/24 hours), unsuppressed overnight 1-mg dexamethasone suppression test with a postdexamethasone cortisol level of 15.8 µg/dL (435.88 nmol/L) (RR <5 µg/dL; <138 nmol/L), a low dehydroepiandrosterone sulfate level of 14 µg/dL (0.38 µmol/L) (RR: 32-240 µg/dL; 0.86-6.49 µmol/L), and normal 24-hour urine metanephrine levels. These findings, in conjunction with the patient’s clinical symptoms, raised concerns of recurrence of CS, especially considering a recent magnetic resonance imaging scan that had revealed some residual tissue in the sella described as a nonenhancing cystic foci in the left lateral aspect of the pituitary gland (Fig. 1).

Nonenhancing cystic foci in the left lateral aspect of the pituitary gland (A: sagittal view; B: coronal view).

Figure 1.

Nonenhancing cystic foci in the left lateral aspect of the pituitary gland (A: sagittal view; B: coronal view).

Follow-up laboratory testing revealed plasma morning ACTH of less than .1 pg/mL (<23.98 pmol/L) (RR: 7-63 pg/mL; 152.6-1373.4 pmol/L), whereas 24-hour urinary free cortisol and serum morning cortisol levels were within the normal range at 47 mcg/24 hours (129.98 nmol/24 hours) and 14.8 mcg/dL (408.67 nmol/L) (RR <45 μg/24 hours; 124.40 nmol/24 hours). Due to the low plasma morning ACTH level, an abdominal magnetic resonance imaging scan was performed that revealed a right adrenal adenoma measuring 6.3 × 3.5 cm. Additionally, her insulin-like growth factor 1 was elevated at 316 ng/mL (41.28 nmol/L) (RR: 7.44-25.44 nmol/L), while her prolactin levels were normal. Based on her elevated insulin-like growth factor 1 level, an oral glucose tolerance test for growth hormone suppression was performed that ruled out acromegaly, with a nadir growth hormone level of 0.20 ng/mL (0.61 mIU/L) (RR <1 ng/mL; <3.03 mIU/L) [10].

Suspecting recurrence of CS, her serum cortisol and ACTH levels were closely monitored over the course of a year (Table 1). During this period, her 24-hour urinary free cortisol levels were either mildly elevated or within the normal range at 47, 39, and 32 mcg/24 hours (129.74, 107.63, and 88.14 nmol/day, respectively) (RR <45 μg/24 hours; <124.40 nmol/24 hours), prompting further evaluation with late-night salivary cortisol measurements on 4 separate occasions that were consistently elevated at 0.154, 0.218, 0.298, and 0.109 μg/dL (4.24, 6.01, 8.21, and 3.01 nmol/L, respectively) (RR: <0.010-0.090 μg/dL; <0.28-2.48 nmol/L). The persistent suppression of ACTH levels supported the diagnosis of adrenal CS, and an abdominal computed tomography (CT) scan revealed a lipid-rich adenoma that was stable in size measuring 6.6 × 3.5 cm (Fig. 2).

Abdominal computed tomography images demonstrating adrenal adenoma in the right adrenal gland measuring 6.6 × 3.5 cm.

Figure 2.

Abdominal computed tomography images demonstrating adrenal adenoma in the right adrenal gland measuring 6.6 × 3.5 cm.
Table 1.

Comparison of hormonal parameters over time

Hormone tested Initial consult Post adrenal adenoma findingsa Post osilodrostat (1 y)b Reference range
8 Am ACTH <1.1 pg/mL
(<0.24 pmol/L)		 <1.1 pg/mL
(<0.24 pmol/L)		 3.5 pg/mL
(0.76 pmol/L)		 7.2-63.3 pg/mL
(1.6-13.9 pmol/L)
8 Am serum cortisol 14.8 μg/dL
(408.67 nmol/L)		 16.3 μg/dL
(448.1 nmol/L)		 4.2 μg/dL
(115.8 nmol/L)		 6.2-19.4 μg/dL
(171.1-534.41 nmol/L)

Reported in conventional units (SI units).

Abbreviation: ACTH, adrenocorticotropin.

aOne year after initial consult.

bTwo years and 9 months after initial consult.

Treatment

Because our patient was biochemically in remission following her pituitary surgery for CD for 6 years before the current presentation and now has biochemical evidence of recurrence of hypercortisolism due to adrenal CS, treatment options were discussed with the patient, including medical therapy and right adrenalectomy. The patient opted against a right adrenalectomy due to concerns about the need for lifelong hydrocortisone and fludrocortisone, and decided to commence medical therapy. The patient was offered the option to start either ketoconazole or a glucocorticoid receptor antagonist (mifepristone). The patient declined being treated with ketoconazole and mifepristone, as she was concerned about the side-effect profile of liver function test derangements due to her history of metabolic dysfunction–associated steatohepatitis and hypokalemia, respectively. Hence, she decided to start osilodrostat therapy and began a low dose of 1 mg twice daily.

Outcome and Follow-up

Annual follow-up CT imaging studies of the patient’s adrenal gland for the next 7 years after the current presentation have shown stability in the size of her right adrenal adenoma. Her blood pressure is well controlled with a single antihypertensive medication (amlodipine), and her glycated hemoglobin has remained in the nondiabetic range. Additionally, she has been experiencing increased energy levels and improvement in peripheral edema. While on osilodrostat therapy, she continues to be biochemically well controlled and has had only a single episode of adrenal insufficiency. A chronological overview of clinical events is displayed in Fig. 3. Because her morning serum cortisol level was relatively low (5.6 µg/dL [154.5 nmol/L]), her osilodrostat dose was further decreased to 1 mg in the evening in December 2024 and she was educated on the proper timing and administration of rescue oral hydrocortisone therapy of 5 to 10 mg, as needed, whenever she developed symptoms of adrenal insufficiency.

Chronological overview of clinical events.

Figure 3.

Chronological overview of clinical events.

Discussion

While previous reports have documented the coexistence of CD with a solitary adrenal adenoma [9], the unique aspect of our case lies in the development of a right adrenal adenoma after a distant history of surgical resection of a left adrenal adenoma and the achievement of disease remission following transsphenoidal resection of a pituitary corticotroph adenoma [4]. Several molecular studies have been performed to elucidate the pathogenesis of recurrent and refractory endocrine tumors, revealing links to genetic factors. The majority of previously reported cases of pituitary adenomas coexisting with adrenal adenoma are seen in patients with MEN syndromes [11]. The genetic testing for MEN 1 syndrome conducted on our patient yielded negative results. However, while MEN 1 was ruled out in our patient, it is possible that other, yet-unidentified genetic factors may contribute to this pattern of tumor formation, including Carney complex and McCune-Albright syndrome, that can be associated with adrenal adenomas and will need to be tested in our patient. Notably, our patient does not report any family history of endocrine tumor syndromes, and corticotroph adenomas are primarily sporadic monoclonal neoplasms that are rarely found in genetic syndromes [12].

In assessing our patient, we also noted a discrepancy between the overt cushingoid features in our patient and the marginal elevations in 24-hour urine free cortisol levels, underscoring the complexities in diagnosing and characterizing the severity of hypercortisolemic states. While 24-hour urine free cortisol remains an important screening test, its limitations must be acknowledged, including variability in 24-hour cortisol secretion, renal clearance differences, and the potential for episodic hypercortisolism that may not be fully captured in a single 24-hour urine collection measurement [13]. These factors have been substantiated by Petersenn et al [14], who reported significant intrapatient variability in 24-hour urinary free cortisol measurements, with a coefficient of variation of approximately 50%, highlighting the need for multiple sample collections to improve the reliability of assessments. These fluctuations, along with individual differences in cortisol sensitivity and metabolism, may account for the presence of varying phenotypic features that are not correlated with the degree of urinary hypercortisolism [15]. In our patient’s case, her clinical phenotype, imaging data, and the associated comorbidities are more useful in assessing the severity of CS, highlighting the importance of thorough and comprehensive clinical and biochemical assessments for CS patients.

Another aspect contributing to the complexity of our case included the treatment options that we could offer to our patient. She opted to avoid a second adrenalectomy, which has the potential of causing Nelson syndrome [9]. Initially, we offered the patient to start treatment with a steroidogenesis inhibitor such as ketoconazole, which has been used to treat hypercortisolism for more than 30 years with an average remission rate of 71.1% [9]. Another alternative was mifepristone, a glucocorticoid receptor antagonist used in the treatment of hyperglycemic patients with underlying CS [16]. However, our patient decided against being treated with ketoconazole and mifepristone due to the side-effect profiles of liver function test derangements and hypokalemia, respectively. Hence, she was offered osilodrostat treatment, to which she has responded well symptomatically, and her disease currently remains well-controlled in remission.

Because of the effectiveness of osilodrostat, adrenal insufficiency is a side effect that was commonly reported in previous pivotal clinical trials [17, 18]. More recently there have been several publications describing prolonged duration of adrenal insufficiency even after osilodrostat discontinuation that requires close monitoring, a finding that remains mechanistically unclear, especially with its short half-life of approximately 4 hours [19, 20]. Given the emerging reports of prolonged adrenal insufficiency after osilodrostat discontinuation [19, 20], close monitoring of serum cortisol levels and patient education to manage symptoms of adrenal insufficiency are essential for the long-term management of patients on osilodrostat therapy. Finally, eventual recovery of adrenal function has also been recently reported [21], hence clinicians are advised to exercise a low threshold of retesting the adrenal reserve of patients who have discontinued osilodrostat therapy.

Learning Points

  • This case highlights an unusual scenario in which a patient with CS presented with both adrenal and pituitary adenomas following prior surgical resections. Physicians should be aware of the rare occurrence of two different etiologies of CS in the same patient and should consider its possibility in patients with recurrent hypercortisolism.
  • The patient’s hesitation to undergo a second adrenalectomy demonstrates the importance of personalized medicine in individualizing the treatment plan for our patient.
  • Recent reports suggest that prolonged adrenal insufficiency after discontinuation of osilodrostat and the eventual recovery of adrenal function can occur in some patients. Clinicians should be aware of this and ensure close monitoring of adrenal function after discontinuing therapy.

Contributors

All authors made individual contributions to authorship. K.C.J.Y. was involved in the diagnosis and management of this case, manuscript review, and text editing. M.M.-G. was involved in manuscript preparation, writing, and submission. Both authors reviewed and approved the final draft.

Funding

This research did not receive any specific grants from any funding agencies in the public, commercial, or not-for-profit sectors.

Disclosures

None.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the present study.

From https://academic.oup.com/jcemcr/article/3/6/luaf089/8117205?login=false

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Utility of Intraoperative Ultrasound in Identifying Pituitary Adenoma Hidden Behind a Cystic Lesion in Cushing’s Disease

Posted on May 29, 2025 by MaryO

Highlights

  • •
    Intraoperative ultrasound enhances tumor localization during endoscopic pituitary surgery for MRI-negative Cushing’s disease.
  • •
    Our findings support intraoperative US as a valuable adjunct in cases where preoperative imaging fails to reveal a lesion.
  • •
    Further studies are expected to validate the efficacy of intraoperative ultrasound as a useful tool for MRI-negative Cushing’s disease.

Abstract

Cushing’s disease with inconclusive MRI findings presents a significant diagnostic and surgical challenge due to the difficulty in localizing the causative pituitary adenoma. This case report highlights the use of intraoperative ultrasound as an adjunct for tumor detection and successful resection in a Cushing disease patient with hidden adenoma. A 55-year-old female with a history of hypertension, diabetes, and a recent cerebral infarction presented with clinical and biochemical features of Cushing’s disease. Brain MRI revealed a 10 mm non-enhancing cystic lesion in the sella, making it difficult to confirm the underlying pathology. Inferior petrosal sinus sampling suggested a right-sided lesion, leading to an endoscopic endonasal transsphenoidal surgery. Intraoperatively, ultrasound was employed to assess the sellar region, initially identifying a cystic structure consistent with a Rathke’s cleft cyst. Following fluid drainage, ultrasound revealed an iso-echoic lesion with a distinct margin, which was subsequently resected and confirmed as a pituitary adenoma on histopathological examination.
The patient experienced postoperative biochemical remission, with normalization of ACTH levels and resolution of hypertension and diabetes. This case demonstrates that intraoperative ultrasound can be a valuable tool for tumor localization in suspicious MRI-negative Cushing’s disease. By aiding in the identification of adenomas obscured by cystic lesions or surrounding structures, intraoperative ultrasound may improve surgical outcomes. Further studies are warranted to validate its efficacy in routine clinical practice.

Introduction

Cushing’s disease is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, leading to hypercortisolism and significant metabolic disturbances. Magnetic resonance imaging (MRI) is the primary imaging modality for detecting pituitary adenomas; however, in approximately 30–40 % of cases, no visible adenoma is detected, a condition known as MRI-negative Cushing’s disease [1,2]. The absence of a discernible lesion on MRI poses a diagnostic and therapeutic challenge, often necessitating additional testing such as bilateral inferior petrosal sinus sampling (IPSS) to confirm pituitary-dependent Cushing’s syndrome [3]. Given the limitations of imaging, treatment strategies for MRI-negative Cushing’s disease require a multimodal approach.
The first-line treatment for Cushing’s disease, regardless of MRI findings, is transsphenoidal surgery. However, MRI-negative cases are associated with lower remission rates due to the difficulty in localizing the microadenoma intraoperatively [4]. When surgery fails or is not feasible, alternative treatments such as repeat surgery, radiotherapy, bilateral adrenalectomy, or medical therapy are considered [5]. Despite these therapeutic options, long-term disease control remains challenging, highlighting the need for improved diagnostic tools and targeted treatment strategies.
The authors aim to report the use of intraoperative ultrasound in a Cushing disease patient with hidden adenoma, demonstrating its possibility to detect tumors that were not visible on MRI and facilitate successful tumor resection, ultimately leading to remission.

Section snippets

Case report

A 55-year-old female patient was referred from the endocrinology department for evaluation of Cushing’s disease. She had been on medication for hypertension and diabetes for the past seven years. Two months prior, she suffered an acute cerebral infarction, resulting in left-sided hemiparesis.
The endocrinology department diagnosed her with Cushing’s disease based on a dexamethasone suppression test. Brain MRI revealed a 10 mm non-enhancing cystic mass in the right side of the sella. (Fig. 1) Due…

Diagnostic approach for MRI-negative cushing’s disease

Diagnosing MRI-negative Cushing’s disease is particularly challenging due to the absence of a visible pituitary adenoma on standard imaging. A stepwise diagnostic approach is necessary to confirm the presence of ACTH-dependent hypercortisolism, differentiate between pituitary and ectopic sources, and localize the tumor. The initial step involves biochemical confirmation of endogenous hypercortisolism through tests such as the 24-hour urinary free cortisol, and the low-dose dexamethasone…

Conclusion

MRI-negative Cushing’s disease presents significant challenges not only for neurosurgeons but also for endocrinologists. The conventional hypophysectomy is invasive and has a high risk of causing other complications. The present case report showed that intraoperative ultrasound can be used effectively in a Cushing disease patient with hidden adenoma. We hope to derive more definitive conclusions through future case studies.

CRediT authorship contribution statement

Min Ho Lee: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Tae-Kyu Lee: Writing – review & editing, Conceptualization.

Ethics approval

The study was approved by the appropriate institutional research ethics committee and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent was obtained from the patient included in this study.

Declaration of competing interest

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

References (28)

More at https://www.sciencedirect.com/science/article/abs/pii/S0967586825002516

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Changes in Clinical Features of Adrenal Cushing Syndrome

Posted on May 28, 2025 by MaryO

Abstract

Adrenal Cushing syndrome (CS) has been rarely studied in recent years in Japan. This study aimed to investigate clinical characteristics and their changes over time in patients with adrenal CS. We analyzed 101 patients with adrenal CS caused by adenoma, dividing them into two groups based on diagnosis period: December 2011–November 2016 (later group, n = 50) and August 2005–November 2011 (earlier group, n = 51). Differences between the groups and comparisons with previous reports were assessed. Patients with subclinical CS were excluded. Adrenal incidentalomas were the most frequent reason for CS diagnosis (34%). Most patients exhibited few specific cushingoid features (2.5 ± 1.3), with moon faces and central obesity being the most common. Compared to earlier reports, specific cushingoid features were less frequent; nonetheless, no significant differences were observed between the earlier and later groups. All patients had midnight and post-dexamethasone suppression test serum cortisol levels exceeding 5 μg/dL. No significant differences were found between the groups regarding non-specific symptoms, endocrinological findings related to cortisol secretion, cardiometabolic commodities or infections, except for glucose intolerance and bone complications. The prevalence of metabolic disorders other than glucose intolerance and osteoporosis fluctuated over time. Sixteen patients developed cardiovascular diseases or severe infections. In conclusion, adrenal CS became less florid in the 2000s, showed no improvement in the following years, and remained associated with a high complication rate. Further research is needed to establish an early detection model for CS.

Plain language summary

Our study found that one-sixth of patients with adrenal Cushing syndrome continued to develop severe complications in this century despite their specific cushingoid features being less pronounced than in the past. Notably, the findings provide clinical insights that may aid in earlier disease diagnosis.

Keywords: adrenal Cushing syndrome; clinical features; diagnosis; national registry; Japan

Introduction

Chronic exposure to excess glucocorticoids leads to Cushing syndrome (CS), with hypercortisolism causing a range of symptoms, signs and comorbidities, including arterial hypertension, diabetes mellitus, osteoporosis, severe infections and cardiovascular disease, all of which contribute to increased mortality (1, 2, 3, 4, 5). CS also negatively impacts quality of life and cognitive function, leading to worsening socioeconomic conditions; moreover, some of these effects persist even after remission (6, 7). Early diagnosis is therefore essential to reducing morbidity and mortality. A recent study (8) suggests that florid CS has become less common than previously reported, yet the time from symptom onset to diagnosis remains as long as 4 years (9, 10). A similar trend toward an increase in less florid CS is expected in Japan. However, to our knowledge, no nationwide epidemiological survey of adrenal CS has been conducted in Japan in recent decades.

The number of adrenal incidentalomas (AIs) detected through abdominal imaging has been increasing (11, 12), potentially aiding in the early diagnosis of adrenal CS. However, in most studies from other countries, adrenal CS accounts for a smaller proportion of all CS cases compared to Japan (20–47 vs >50%, respectively), despite a rise in incidence in recent reports (10, 13, 14, 15, 16). Consequently, there is limited evidence regarding diagnostic clues, clinical presentation, endocrinological findings and disease progression in a large cohort of patients with adrenal CS caused by adenomas in this century. This study aimed to examine the clinical phenotype, comorbidities and biochemical characteristics of Japanese patients with adrenal CS due to adenomas in the 2000s and to identify differences from previously reported findings.

Materials and methods

Study design and participants

This retrospective observational study was part of the Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan (ACPA-J) study, which involved 10 referral centers (17, 18, 19). The ACPA-J was established to develop a disease registry and cohort for patients with subclinical adrenal CS, adrenal CS, primary macronodular adrenal hyperplasia or adrenocortical carcinoma. The study group collected clinical, biochemical, radiological and pathological data at enrollment to generate new evidence and inform clinical guidelines. Data were obtained from patients aged 20–90 years who were diagnosed with CS due to an adrenal adenoma between August 2005 and November 2016. The dataset used in this study were validated in March 2019. The study protocol was approved by the Ethics Committee of the National Center for Global Health and Medicine (Approval No.: NCGM-S-004259) and the ethics committees of the participating centers. This study adhered to the clinical research guidelines of the Ministry of Health, Labour and Welfare, Japan (MHLWJ) and the principles of the Declaration of Helsinki. Informed consent was obtained through an opt-out option available on the websites of each referral center.

In the ACPA-J study, adrenal diseases, including CS, were initially diagnosed by attending physicians. Patients with iatrogenic CS or CS caused by primary macronodular adrenal hyperplasia or adrenocortical carcinoma were excluded. Of the 106 patients diagnosed with adrenal CS due to adenomas, five were excluded for the following reasons: baseline plasma adrenocorticotropic hormone (ACTH) ≥10 pg/mL (n = 1) or significant missing data related to the hypothalamic-pituitary-adrenal axis (n = 4). None of the patients met the criteria for subclinical CS according to the Japan Endocrine Society clinical practice guidelines (20). Except for three cases, adrenal adenomas were pathologically confirmed through surgical specimens. In patients who did not undergo surgery, a tumor was classified as an adenoma if it appeared round or oval, hypodense (i.e., ≤10 Hounsfield units), homogeneous and well-defined on computed tomography (12). As a result, the final analysis included 101 patients with adrenal CS due to adrenal adenomas (Fig. 1).

Figure 1View Full Size
Figure 1

Flowchart of patient selection. ACTH, adrenocorticotropic hormone; UFC, urinary free cortisol.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0684

The diagnosis of adrenal CS was validated based on the diagnostic criteria established by the Research on Intractable Diseases, Research Committee on Disorders of Adrenal Hormones from the MHLWJ in 2016 (21). These criteria included a combination of the following: the presence of specific and non-specific cushingoid features, confirmation of cortisol hypersecretion through elevated morning serum cortisol levels (generally ≥20 μg/dL) and/or high 24 h urinary free cortisol (UFC; typically more than four times the upper limit of normal (ULN) for the assay used at each center), disruption of the circadian rhythm in serum cortisol levels (serum cortisol at 21:00–23:00 h ≥5 μg/dL), suppression of ACTH secretion (morning plasma ACTH <10 pg/mL and/or a blunted response to corticotropin-releasing hormone (CRH) stimulation, defined as either an increase of <1.5 times the baseline ACTH or peak ACTH <10 pg/mL), failure to suppress serum cortisol levels (≥5 μg/dL) after the standard overnight 1 mg and/or 8 mg dexamethasone suppression test (DST), and the presence of an adrenal tumor on imaging.

Measurements

The collected data included patient demographics such as age at diagnosis, sex, body mass index (BMI) and the reason for diagnosing CS. Specific cushingoid features recorded were moon face, dorsocervical or subclavian fat pad, central obesity, easy bruising, thin skin, muscle weakness, purple striae and facial plethora. Non-specific cushingoid features included acne, virilism or hirsutism in women, psychiatric disorders, menstrual irregularity and leg edema. Biochemical and hormonal profiles were assessed, including hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), morning and midnight serum cortisol, serum cortisol after the 1 mg or 8 mg DST, plasma ACTH before and after CRH stimulation, 24 h UFC and plasma dehydroepiandrosterone sulfate (DHEA-S). Comorbidities examined included hypertension, impaired glucose tolerance, dyslipidemia, obesity, bone fracture, osteoporosis, venous thromboembolism, cerebral infarction, cerebral hemorrhage, angina pectoris, myocardial infarction, heart failure, pneumonia, sepsis, deep abscess and other infections. Adrenal tumor diameter was assessed using imaging. To systematically assess various measurements, including specific and non-specific cushingoid features in patients with adrenal CS, we predefined survey items before initiating the study. We did not predefine the period for the major adverse cardiovascular and cerebrovascular events (MACCEs) and serious infections. The diseases were registered only if attending physicians determined they were associated with hypercortisolism. Missing data were excluded from the analysis. UFC and serum cortisol levels were partially expressed as multiples of the ULN or lower limit of normal (LLN) due to changes in assay methods. Further details on assay methods are provided in the supplementary data (see section on Supplementary materials given at the end of the article).

Hypertension was defined as a blood pressure of ≥140/90 mmHg or the use of antihypertensive medication (22). Due to inconsistencies in registration data, prediabetes and type 2 diabetes have been classified together under impaired glucose tolerance. Impaired glucose tolerance was defined as a fasting plasma glucose level of ≥110 mg/dL, a 2 h plasma glucose level of ≥140 mg/dL after a 75 g oral glucose load, an HbA1c level of ≥6.2% or current antidiabetic therapy (23). Dyslipidemia was defined by LDL-C levels ≥140 mg/dL, HDL-C levels <40 mg/dL, TG levels ≥150 mg/dL or the use of lipid-lowering therapy (24). Obesity was classified as a BMI ≥25 kg/m2, following the criteria of the Japan Society for the Study of Obesity (25). Osteoporosis was diagnosed based on a T-score ≤−2.5 standard deviation (SD) on dual-energy X-ray absorptiometry, in accordance with World Health Organization criteria (26). The presence of other symptoms, signs or comorbidities beyond the listed conditions was determined by the attending physicians based on medical records. The prevalence of MACCEs was also calculated. The CRH loading test is used to assess ACTH suppression in patients with suspected ACTH-independent hypercortisolism (20). A normal ACTH response to CRH stimulation was defined as plasma ACTH levels exceeding 10 pg/mL and increasing by more than 50% from baseline.

Classification of participants according to the date of diagnosis

The primary objective of this study was to examine temporal changes in the clinical presentation of adrenal CS, necessitating classification based on the date of diagnosis. We also sought to clarify recent trends in CS diagnosis. The most recent diagnosis among study participants was recorded in November 2016. To analyze changes in clinical presentation over 10 years, we classified patients into two groups: those diagnosed within 5 years of the most recent case (i.e., December 2011–November 2016, later group; n = 50) or those diagnosed earlier (i.e., August 2005–November 2011, earlier group; n = 51).

Changes in the clinical pictures over time

To examine changes in the clinical picture over time, we compared the prevalence of symptoms, signs and comorbidities in this study with findings from a nationwide survey conducted by the Research on Intractable Diseases, Research Committee on Disorders of Adrenal Hormones under the MHLWJ in 1997 (16) and data from traditional reports compiled by Rosset et al. (8). The nationwide survey was conducted in 1997 and 1998 using questionnaires sent to 4,060 departments. It included 737 patients with CS, covering adrenal CS caused by adenoma and bilateral hyperplasia, pituitary CS and ectopic ACTH syndrome, with adrenal CS accounting for 47.1% of cases. While the later research did not provide details on patient numbers, study duration or data collection methods, the data sources were clearly stated.

Statistical analysis

Statistical analyses were conducted using SPSS (version 26.0; IBM Corp., USA) or EZR (Saitama Medical Center, Jichi Medical University, Japan) (27). Results are expressed as means ± SDs and frequencies (positive/total observations) unless otherwise specified. Data distributions were assessed using the Kolmogorov–Smirnov test. Quantitative variables were compared between groups using the Student’s t-test, while the categorical variables were analyzed using the χ 2 test or Fisher’s exact test. We used a single-sample binomial test to compare our variable frequencies with those in previous studies (8). Statistical significance was defined as a P-value of <0.05.

Results

Clinical characteristics

This study included 101 patients with adrenal CS, with a higher prevalence in women than men. The average age of participants was 46.9 ± 13.3 years, with only 20% aged over 60 (Table 1). Notably, AIs were the most frequent finding leading to a CS diagnosis, followed by hypertension. Specific cushingoid features, such as moon face and muscle weakness, prompted diagnosis in approximately 15% of cases. The mean maximum diameter of the adenomas was approximately 3 cm. More than 90% of patients (94/101) had adrenal adenomas >2 cm. Bilateral adenomas were observed in nearly 20% of the study population. No significant differences were observed between the earlier and later groups regarding age, sex distribution, diagnostic triggers (except fractures), adenoma size or the prevalence of bilateral adenomas.

Table 1Clinical characteristics of patients with Cushing syndrome.

All patients with Cushing syndrome Earlier group Later group P-value
n = 101 n = 51 n = 50
Age, years 46.9 (13.3) 45.9 (13.3) 47.8 (13.4) 0.459
20–39/40–59/>60, n (%) 30/50/20 (30.0%/50.0%/20.0%) 19/21/10 (38.0%/42.0%/20.0%) 11/29/10 (22.0%/58.0%/20.0%) 0.181
Female, n (%) 90/100 (90.0%) 45/50 (90.0%) 45/50 (90.0%) 0.999
BMI, kg/m2 24.6 (4.3) 24.9 (4.3) 24.4 (4.2) 0.545
Reasons leading to Cushing syndrome diagnosis
 Incidentaloma, n (%) 34/101 (33.7%) 17/51 (33.3%) 17/50 (34.0%) 0.999
 Hypertension, n (%) 30/101 (29.7%) 16/51 (31.4%) 14/50 (28.0%) 0.828
 Moon face, n (%) 11/101 (10.9%) 8/51 (15.7%) 3/50 (6.0%) 0.2
 Weight gain, n (%) 10/101 (9.9%) 4/51 (7.8%) 6/50 (12.0%) 0.525
 Edema, n (%) 10/101 (9.9%) 5/51 (9.8%) 5/50 (10.0%) 0.999
 Fracture, n (%) 8/101 (7.9%) 1/51 (2.0%) 7/50 (14.0%) 0.031
 Muscle weakness, n (%) 4/101 (4.0%) 3/51 (5.9%) 1/50 (2.0%) 0.617
Bilateral adrenal tumors, n (%) 17/101 (16.8%) 11/51 (21.6%) 6/50 (12.0%) 0.308
Maximum diameter of tumor (mm) 28.4 (7.6) 27.2 (7.2) 29.6 (7.9) 0.111
≥20 mm, n (%) 94 (94.0%) 47 (92.2%) 47 (95.9%) 0.678

Data are presented as mean (SD) or number of patients (%). Patients were categorized into two groups based on their diagnosis date: within 5 years of the most recent case (December 2011–November 2016, later group) or earlier (August 2005–November 2011, earlier group).

P-values were calculated using Student’s t-test. Proportions between the before and after groups were compared using the X 2 or Fisher’s exact tests.

BMI, body mass index.

Specific and non-specific cushingoid features

Most patients with CS exhibited a limited number of specific features (mean ± SD, 2.5 ± 1.3) (Table 2). Nearly 40% of patients had two or fewer specific cushingoid features, while only 5% had five or more. The most frequently observed feature was moon face, followed by central obesity with a dorsocervical or subclavian fat pad, easy bruising or thin skin, facial plethora and muscle weakness or purple striae. The two most common features were present in over 50% of patients. Non-specific cushingoid features, including menstrual irregularity, acne, psychiatric disorders, hirsutism, virilization in women and edema, were observed in fewer than 25% of cases. The mean number of non-specific features was approximately one (0.6 ± 0.7). No significant differences in symptoms and signs of CS were found between the earlier and later groups.

Table 2Presence of specific and non-specific cushingoid features.

All patients with Cushing syndrome Earlier group Later group P-value
Cushingoid appearance, n (%) 99/101 (98.0%) 51/51 (100%) 48/50 (96.0%) 0.243
Specific features
 (1) moon face, n (%) 85/101 (84.2%) 41/51 (80.4%) 44/50 (88.0%) 0.439
 (2) central obesity, n (%) 60/101 (59.4%) 32/51 (62.7%) 28/50 (56.0%) 0.626
 (3) easy bruising or thin skin, n (%) 45/101 (44.6%) 19/51 (37.3%) 26/50 (52.0%) 0.163
 (4) facial plethora, n (%) 25/101 (24.8%) 10/51 (19.6%) 15/50 (30.0%) 0.327
 (5) muscle weakness, n (%) 21/101 (20.8%) 10/51 (19.6%) 11/50 (22.0%) 0.959
 (6) purple striae, n (%) 21/101 (20.8%) 14/51 (27.5%) 7/50 (14.0%) 0.156
Non-specific features
 (7) menstrual irregularity, n (%) 20/79 (25.3%) 10/37 (27.0%) 10/42 (23.8%) 0.945
 (8) acne, n (%) 15/101 (14.9%) 8/51 (15.7%) 7/50 (14.0%) 0.999
 (9) psychiatric disorders, n (%) 13/101 (12.9%) 7/51 (13.7%) 6/50 (12.0%) 0.999
 (10) hirsutism or virilization in female, n (%) 9/85 (10.6%) 6/41 (14.6%) 3/44 (6.8%) 0.303
 (11) leg edema, n (%) 4/101 (4.0%) 4/51 (7.8%) 0/50 (0.0%) 0.118
Number of items
In specific features ((1)–(6)), mean (SD) 2.5 (1.3) 2.5 (1.2) 2.6 (1.4) 0.562
In non-specific features ((7)–(11)), mean (SD) 0.6 (0.7) 0.7 (0.8) 0.5 (0.7) 0.258

Data are presented as mean (SD) or number of patients (frequency). Patients were categorized into two groups based on their diagnosis date: within 5 years of the most recent case (December 2011–November 2016, later group) or earlier (August 2005–November 2011, earlier group).

P-values were calculated using Student’s t-test. Proportions between the before and after groups were compared using the X 2 or Fisher’s exact tests.

Endocrinological findings

Serum cortisol levels after the 1 mg or 8 mg DST and midnight serum cortisol levels exceeded 5.0 μg/dL in all participants who underwent these tests (Table 3). In addition, all patients had markedly low baseline plasma ACTH levels. More than 50% of patients had morning serum cortisol levels below the ULN, while over 25% had UFC levels below this threshold (Fig. 2). Absolute serum cortisol concentrations (μg/dL) following the 8 mg DST were higher in the earlier group than in the latter group. However, when expressed as multiples of the LLN, there was no difference between groups, suggesting that this discrepancy was due to variations in assay methods. In contrast, baseline plasma ACTH levels were higher in the earlier group than in the latter group. Other parameters related to the hypothalamic-pituitary-adrenal axis, such as morning, midnight and post-DST serum cortisol levels, UFC levels, serum DHEA-S levels and plasma ACTH levels after CRH stimulation, were comparable between groups. The CRH stimulation test was performed in about 33% of participants. All but one patient had peak plasma ACTH levels below 10 pg/mL after CRH loading.

Table 3Endocrinological findings.

All patients with Cushing syndrome Earlier group Later group P-value
n = 101 n = 51 n = 50
Morning serum cortisol levels (n = 100) μg/dL 17.7 (5.7) 18.4 (4.8) 17.0 (6.5) 0.232
× the ULN times 0.90 (0.3) 0.96 (0.3) 0.88 (0.4) 0.264
Midnight serum cortisol levels (n = 97) μg/dL 17.6 (5.3) 18.6 (4.7) 16.7 (5.8) 0.088
≥5 μg/dL n (%) 97/97 (100%) 48/48 (100%) 49/49 (100%) N/A
× the lower limit of normal times 3.2 (1.3) 3.2 (1.3) 3.2 (1.3) 0.846
Plasma ACTH levels in the morning (n = 100) pg/mL 1.9 (1.7) 2.6 (2.0) 1.2 (0.9) <0.001
<10 pg/mL n (%) 100/100 (100%) 50/50 (100%) 50/50 (100%) N/A
DHEA-S (n = 97) μg/dL 40.7 (50.6) 35.2 (34.3) 45.8 (61.8) 0.313
Urinary free cortisol (n = 91) mg/24 h 283.1 (329.8) 279.8 (273.2) 285.8 (372.5) 0.932
× the ULN times 3.5 (4.1) 3.5 (3.4) 3.6 (4.6) 0.928
Serum cortisol levels after 1 mg DST (n = 96) μg/dL 18.6 (5.4) 19.3 (4.4) 17.9 (6.2) 0.202
≥5 μg/dL n (%) 96/96 (100%) 48/48 (100%) 48/48 (100%) N/A
× the LLN times 3.4 (1.4) 3.3 (1.3) 3.5 (1.4) 0.566
Serum cortisol levels after 8 mg DST (n = 71) μg/dL 18.6 (5.2) 19.9 (5.2) 17.0 (5.0) 0.017
≥5 μg/dL n (%) 71/71 (100%) 38/38 (100%) 33/33 (100%) N/A
× the LLN times 3.4 (1.3) 3.5 (1.5) 3.4 (1.2) 0.775
Peak plasma ACTH value after CRH stimulation test (n = 36) pg/mL 3.4 (3.4) 3.9 (1.5) 2.9 (4.3) 0.413

Data are presented as mean (SD) or number of patients (%). Patients were categorized into two groups based on their diagnosis date: within 5 years of the most recent case (Dec 2011–Nov 2016, later group) or earlier (Aug 2005–Nov 2011, earlier group).

P-values were calculated using Student’s t-test. Proportions between the before and after groups were compared using the X 2 or Fisher’s exact tests.

ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DHEA-S, dehydroepiandrosterone sulfate; DST, dexamethasone suppression test; N/A, not available; LLN, lower limit of normal; ULN, upper limit of normal.

Figure 2View Full Size
Figure 2

Distribution of the ratio of morning serum (left) cortisol and (right) urinary free cortisol levels to the upper limit of normal (ULN).

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0684

Comorbidities

Among cardiometabolic conditions, hypertension was the most prevalent comorbidity (79.2%), followed by dyslipidemia, bone disorders, obesity and glucose intolerance (Table 4). The incidence of venous thromboembolism was 4.2%. Apart from all fractures or osteoporosis, no significant differences in complication rates were observed between the groups. Table 5 presents the frequency of MACCEs and severe infections among participants. Thirteen MACCEs (10.9%), including cerebral infarction or hemorrhage, angina pectoris, myocardial infarction and heart failure, were reported in 11 patients. In addition, six patients (6.0%) developed severe infections, such as pneumonia, sepsis or deep abscesses. Overall, 16 (15.8%) patients experienced serious illnesses. The prevalence of these conditions did not differ significantly between the earlier and later groups.

Table 4Comorbidities in patients with Cushing syndrome.

All patients with Cushing syndrome Earlier group Later group P-value
n = 101 n = 51 n = 50
Cardiometabolic
 Hypertension, n (%) 80/101 (79.2%) 42/51 (82.4%) 38/50 (76.0%) 0.588
 Dyslipidemia, n (%) 61/99 (61.6%) 32/50 (64.0%) 29/49 (59.2%) 0.775
 Obesity (BMI ≥25 kg/m2), n (%) 39/96 (40.6%) 23/48 (47.9%) 16/48 (33.3%) 0.212
 Impaired glucose tolerance, n (%) 33/101 (32.7%) 17/51 (33.3%) 16/50 (32.0%) 1
Bone
 All fractures, n (%) 25/93 (26.9%) 9/45 (20.0%) 16/48 (33.3%) 0.224
 Osteoporosis, n (%) 42/90 (46.7%) 17/42 (40.5%) 25/48 (52.1%) 0.374
 All fractures or osteoporosis, n (%) 48/101 (47.5%) 18/51 (35.3%) 30/50 (60.0%) 0.017
Coagulopathy
 Venous thromboembolism, n (%) 4/96 (4.2%) 3/50 (6.0%) 1/46 (2.2%) 0.670

Patients were categorized into two groups based on their diagnosis date: within 5 years of the most recent case (December 2011–November 2016, later group) or earlier (August 2005–November 2011, earlier group). BMI, body mass index.

Table 5Number of cardiovascular disease and infection events.

All patients with Cushing syndrome Earlier group Later group P-value
n = 101 n = 51 n = 50
MACCEs, n (%) 11/101 (10.9%) 6/51 (11.8%) 5/50 (10%) 1
 Cerebral infarction, n (%) 2/101 (2.0%) 1/51 (2.0%) 1/50 (2.0%) 1
 Cerebral hemorrhage, n (%) 0/101 (0%) 0/51 (0%) 0/50 (0%) N/A
 Angina pectoris, n (%) 2/101 (2.0%) 2/51 (3.9%) 0/50 (0%) 0.484
 Myocardial infarction, n (%) 2/101 (2.0%) 1/51 (2.0%) 1/50 (2.0%) 1
 Heart failure, n (%) 7/101 (6.9%) 4/51 (7.8%) 3/50 (6.0%) 1
Severe infection, n (%) 6/101 (6.0%) 4/51 (7.8%) 2/50 (4.1%) 0.678
 Pneumonia, n (%) 2/101 (2.0%) 1/51 (2.0%) 1/50 (2.0%) 1
 Deep abscess, n (%) 2/101 (2.0%) 1/51 (2.0%) 1/50 (2.0%) 1
 Sepsis, n (%) 1/101 (1.0%) 1/51 (2.0%) 0/50 (0%) 1
 Other infections, n (%) 1/101 (1.0%) 1/51 (2.0%) 0/50 (0%) 1

Patients were categorized into two groups based on their diagnosis date: within 5 years of the most recent case (December 2011–November 2016, later group) or earlier (August 2005–November 2011, earlier group). MACCEs, major adverse cardiovascular and cerebrovascular events; N/A, not available.

Changes in the clinical presentation over time

To assess temporal changes in the clinical presentation, we compared the prevalence of symptoms, signs and comorbidities in this study with data from a nationwide survey conducted by the MHLWJ in 1997 (16) and traditional reports compiled by Rosset et al. (8) (Supplementary Table 1). The frequency of specific cushingoid features, except for moon face, and non-specific cushingoid features, such as diabetes mellitus, menstrual irregularities, obesity and dyslipidemia, was significantly lower in our cohort compared with previous reports. The trends in hypertension, depression and osteoporosis varied by region. In addition, significant differences in the prevalence of easy bruising, hypertension and osteoporosis were observed between the earlier and later groups.

Discussion

This multicenter study in Japan demonstrated that fully developed adrenal CS has been identified less frequently in the twenty-first century compared with the previous century, and clinical outcomes did not improve during the 2000s. One possible reason for the increased detection of less florid CS is the higher likelihood of encountering AIs, as AIs discovery led to CS diagnosis in approximately 33% of the study cohort. Similar trends have been observed in West and North Africa (10, 14, 15, 16). In addition, Braun et al. (28) reported that the presence of AIs independently increased the likelihood of a CS diagnosis. However, the incidence of AIs far exceeds that of CS (11, 12). Given that the Endocrine Society’s practice guidelines for CS (29) advise against widespread testing for all suspected cases, additional information is needed to enhance the pretest probability for detecting CS. In this study, only one patient (1/100, 1%) was male with an adrenal tumor smaller than 2.0 cm (7/101, 6.0%), suggesting that clinical evaluation can significantly reduce the likelihood of CS.

To assess the impact of AIs on early CS detection, we categorized adrenal CS patients into two groups based on whether their diagnosis resulted from AIs (n = 34) or not (n = 67). The mean number of specific cushingoid features was comparable between the two groups (2.3 ± 1.4 vs 2.7 ± 1.2, P = 0.119, data not shown). Similar trends were observed in non-specific cushingoid features, endocrinological findings, comorbidities and MAACEs. Conversely, when categorized based on having fewer than two specific cushingoid features (n = 21) versus two or more (n = 80), the detection rate of AIs tended to be higher, and serum cortisol levels at midnight or after a 1 mg DST were lower in those with fewer features than in those with more pronounced features (52.4 vs 28.7%, P = 0.067; 15.4 ± 4.4 μg/dL vs 18.2 ± 5.4 μg/dL, P = 0.031; and 16.3 ± 5.0 μg/dL vs 19.1 ± 5.3 μg/dL, P = 0.03, respectively, data not shown). Furthermore, the Cochran–Armitage test indicated that the trend across the diagnosis rate of CS leading to AIs rose with an increasing number of positive findings of specific cushingoid features (P = 0.035, data not shown). These findings suggest that while AIs may aid in identifying patients with less florid CS, they are unlikely to contribute to earlier diagnosis.

Cushingoid features can be categorized as specific or non-specific. Specific features help differentiate patients with severe CS from those without CS or those with cardiometabolic disorders or AIs with mild autonomous cortisol secretion (30). In this study, a moon face was observed in over 80% of participants, making it the most prevalent specific cushingoid feature. This suggests that a moon face may appear early and/or serve as the first distinct sign in most CS cases. Therefore, when evaluating patients at risk for CS, physicians should compare past and current photographs to facilitate early diagnosis. The development of advanced facial recognition software capable of detecting facial changes over time could further aid in preventing missed diagnoses of CS (31, 32). In addition, central obesity, defined by a dorsocervical and/or subclavian fat pad, was present in over 50% of CS cases, whereas obesity based on BMI criteria was observed in approximately 40% (24). The rising global prevalence of overweight and obesity complicates the diagnosis of CS. However, general obesity may negatively impact CS prediction (33). Our findings suggest that body shape, fat distribution – including the presence of a distinct fad pad – and facial contour are more relevant than body weight in distinguishing CS from general obesity. This distinction may help reduce unnecessary testing for CS.

Consistent with previous studies (33, 34), cardiometabolic conditions such as metabolic syndrome and bone comorbidities (i.e., osteoporosis and fractures) were frequently observed in patients with CS. However, as noted earlier, the prevalence of AIs with mild cortisol hypersecretion is significantly higher than that of CS, and non-specific cortisol-related cardiometabolic comorbidities are also common in AIs (34). Because these conditions are prevalent in the general population, broad screening has not been endorsed, as some non-specific features (e.g., hypertension, obesity and glucose intolerance) are more likely to indicate non-CS (35). Therefore, as recommended by clinical guidelines (29), additional factors – such as comorbidities that develop atypically with age, worsen over time or appear sequentially – should be considered before initiating screening. Moreover, in this study, 19 MACCEs or severe infections requiring hospitalization were reported in 16 patients (15.8%). This underscores the fact that, even in the 2000s, delays in diagnosing adrenal CS persist, necessitating improvements to reduce complications. Similarly, Rubinstein et al. (10) found no evidence of earlier CS diagnosis in patients treated after 2000 compared to studies conducted before 2000.

Our study revealed four notable findings in the endocrinological data. First, we confirm that CS should not be ruled out even if morning serum cortisol levels are normal, as this was observed in 66% of our patients. Endocrinologists must inform general practitioners to prevent missed diagnoses of CS. Second, post-1 mg DST serum cortisol levels in our cohort were much higher than the 1.8 μg/dL (50 nmol/L) cutoff recommended by the Endocrine Society Practical Guideline (29), consistently exceeding 5.0 μg/dL (138 nmol/L). Ceccato et al. (33) suggested a new threshold of 7.1 μg/dL (196 nmol/L) to distinguish CS from AIs without CS and 2.4 μg/dL (66 nmol/L) to differentiate CS from non-CS. We considered adjusting DST cutoffs based on the patient’s circumstances (e.g., the presence or absence of AIs or specific cushingoid features). Recent guidelines state that cortisol autonomy exists on a biological continuum, without a distinct separation between nonfunctioning and functioning adenomas with varying degrees of cortisol excess (12). Any post-DST cortisol cutoff value generally demonstrates poor accuracy in predicting prevalent comorbidities in patients with AIs. However, this finding applies to patients without overt CS, as the risk of developing CS is very low in the absence of clinical signs at the initial assessment. Furthermore, adrenal adenomas associated with overt CS have shown a distinct mutation profile compared to those with mild autonomous cortisol secretion (36). These results suggest that the two types of adenomas should be distinguished. Our data indicate that if serum cortisol levels after DST are significantly higher than the current cutoff value (i.e., 1.8 μg/dL), physicians should carefully assess patients for specific cushingoid features. A large-scale nationwide study in Japan, including adrenal CS, AIs with autonomous cortisol secretion, and non-CS, is needed to determine the optimal serum cortisol level cutoff after a DST for diagnosing adrenal CS in the Japanese population.

Third, normal UFC levels were found in 25% of participants despite elevated serum cortisol levels after the DST or at midnight in all patients. Several factors such as urinary volume, adherence to proper urine collection, day-to-day variability, and the number of measurements can affect UFC levels (37). To assess the impact of renal function on these results, we analyzed the estimated glomerular filtration rate (eGFR) in patients with normal UFC levels. The mean UFC levels were lower in patients with an eGFR <60 mL/min/m2 (n = 22) than in those with an eGFR ≥60 mL/min/m2 (n = 68) (1.0 ± 0.8 × ULN vs 4.0 ± 4.3 × ULN, P = 0.016), suggesting that renal impairment partially contributed to the discrepancies. Unfortunately, other factors affecting the results were not available in our data. Finally, all but one patient (97.3%) had peak plasma ACTH levels <10 pg/mL after CRH stimulation. This test may yield pseudo-positive results, as the exceptional patient had five specific cushingoid features along with typical autonomous cortisol secretion in CS (e.g., serum cortisol levels at midnight and after 1 mg DST near 20 μg/dL). Thus, the CRH stimulation test may not provide additional information for most patients with adrenal CS exhibiting clear ACTH suppression.

This study has several limitations, primarily due to its retrospective, cross-sectional design. First, selection bias may have occurred due to differences in data handling across participating centers, endocrine tests related to CS, or assay methods for CS-related comorbidities. Second, there were varying numbers of patients available for each measurement. Third, the absence of a predefined diagnostic protocol for CS and its comorbidities may have contributed to inconsistencies in diagnosis. Fourth, comparisons were challenging due to the wide variability in assay methods. Fifth, a 5-year period may be insufficient to evaluate changes in the clinical presentation of CS over time. Finally, as the study was conducted solely in Japan and primarily referenced Japanese CS and/or subclinical CS clinical guidelines (20, 21), its findings may not be generalizable. However, a key strength of this study is its involvement of multiple centers and a larger sample size compared to previous studies.

In conclusion, cases of adrenal CS in the 2000s were less florid than in previous decades although no further clinical improvement was observed during this century. A new model for the early detection of CS is necessary, as the prevalence of CS-related complications remains high. To reduce the time to diagnosis of adrenal CS, it is important to avoid overlooking moon face and central obesity with dorsocervical and/or subclavian fat pad, assess morning ACTH and serum cortisol after a DST with higher cutoff values than those recommended by the Endocrine Society, use abdominal computed tomography, and consider tumor size and patient sex when evaluating patients with suspected CS. Additional studies are needed to create a more effective diagnostic method for earlier identification of CS.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0684.

Declaration of interest

The authors declare that there are no conflicts of interest that could be perceived as affecting the impartiality of the research presented.

Funding

This research was supported by the National Center for Global Health and Medicine, Japan (grant numbers 21A1015, 24A1004), the MHLWJ (grant number Nanbyo-Ippan-23FC1041) and AMED, Japan (grant numbers JP17ek010922, JP20ek0109352).

Author contribution statement

Takuyuki Katabami (conceptualization (lead), methodology (lead), validation (equal), visualization (lead), writing–original draft (lead), writing–review and editing (equal)), Shiko Asai (data curation (lead), formal analysis (lead), investigation (equal), software (equal), visualization (equal), writing–review and editing (equal)), Ren Matsuba (data curation (equal), formal analysis (lead), investigation (equal), software (equal), visualization (equal), writing–review and editing (equal)), Masakatsu Sone (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Shoichiro Izawa (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Takamasa Ichijo (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Mika Tsuiki (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Shintaro Okamura (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Takanobu Yoshimoto (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Michio Otsuki (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Yoshiyu Takeda (data curation (equal), investigation (supporting), writing–review and editing (supporting)), Mitsuhide Naruse (data curation (equal), project administration (equal), supervision (lead), validation (lead), writing–review and editing (lead)), Akiyo Tanabe (data curation (equal), funding acquisition (lead), project administration (equal), resource (lead), supervision (lead), validation (lead), writing–review and editing (lead)), ACPA-J Study Group (data curation (equal), investigation (supporting), writing–review and editing (supporting)).

Data availability

The data supporting this article cannot be shared publicly due to restrictions imposed by the authors’ institutes. Data can be made available upon reasonable request to the corresponding author.

Acknowledgments

We acknowledge the contributions of the ACPA-J Study Group members, including Daisuke Taura (Kyoto University), Mukai Kosuke (Osaka University), Shigeatsu Hashimoto (Fukushima Medical University Aizu Medical Center), Masanori Murakami (Tokyo Medical and Dental University), Norio Wada (Sapporo City General Hospital), Mai Asano (Kyoto Prefectural University), Yutaka Takahashi (Nara Medical University), Hidenori Fukuoka (Nara Medical University) and Tomoko Suzuki (International University of Health and Welfare).

References

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