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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Osilodrostat Treatment for Adrenal and Ectopic Cushing Syndrome

Posted on May 9, 2025 by MaryO

Integration of Clinical Studies With Case Presentations

Maria Fleseriu, Richard J Auchus, Irina Bancos, Beverly MK Biller
Journal of the Endocrine Society, Volume 9, Issue 4, April 2025, bvaf027
https://doi.org/10.1210/jendso/bvaf027

Abstract

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes.

Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery.

Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease. Nonetheless, reports of its use in patients with ectopic or adrenal Cushing syndrome are increasing. These data highlight the importance of selecting the most appropriate starting dose and titration frequency while monitoring for adverse events, including those related to hypocortisolism and prolongation of the QT interval, to optimize treatment outcomes. Here we use illustrative case studies to discuss practical considerations for the management of patients with ectopic or adrenal Cushing syndrome and review published data on the use of osilodrostat in these patients.

The case studies show that to achieve the goal of reducing cortisol levels in all etiologies of Cushing syndrome, management should be individualized according to each patient’s disease severity, comorbidities, performance status, and response to treatment. This approach to osilodrostat treatment maximizes the benefits of effective cortisol control, leads to improvements in comorbid conditions, and may ameliorate quality of life for patients across all types and severities of Cushing syndrome.

Read the article

 

From https://www.endocrine.org/journals/journal-of-the-endocrine-society/osilodrostat-treatment-for-adrenal-and-ectopic-cushing-syndrome

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Ectopic ACTH-secreting Pheochromocytoma Without Typical Signs of Cushing Syndrome

Posted on May 3, 2025 by MaryO

Abstract

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

Introduction

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

Case report

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

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

 

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

Figure 1

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

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

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

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

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

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

 

Table 1

Histopathological report.

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

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

 

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

Figure 2

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

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

Discussion

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

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

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

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

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

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

Acknowledgements

We thank the radiology department for interpreting the CT.

Conflict of interest

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

Funding

No external funding was received for this study.

Ethical approval

No approval was required.

Consent

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

Guarantor

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

© The Author(s) 2025. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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High Recovery Rate of Adrenal Function After Successful Surgical Treatment of Cushing’s Syndrome

Posted on April 23, 2025 by MaryO

Abstract

Context

Successful first-line treatment of Cushing’s syndrome by resection of the underlying tumor is usually followed by adrenal insufficiency.

Purpose

The aims of this study were to determine the recovery rate and time to recovery of adrenal function after treatment for different forms of endogenous Cushing’s syndrome and to identify factors associated with recovery.

Methods

In this retrospective study of 174 consecutive patients with Cushing’s syndrome, the recovery rate and time to recovery of adrenal function after surgery were assessed.

Results

The 1-year, 2-year and 5-year recovery rates of patients with Cushing’s disease were 37.8, 70.1 and 81.1%, respectively. For patients with adrenal Cushing’s syndrome, the 1-year, 2-year and 5-year recovery rates were higher: 49.3, 86.9 and 91.3%, respectively. Median time to recovery for patients with Cushing’s disease and adrenal Cushing’s syndrome was 13.9 and 12.1 months, respectively. The median time to recovery of adrenal function in patients with Cushing’s disease with and without recurrence was 9.9 versus 14.4 months, respectively. Higher age was associated with a lower probability of recovery of adrenal function: HR 0.83 per decade of age (95% CI 0.70–0.98).

Conclusion

The recovery rate of adrenal function after successful surgery as first-line treatment in patients with Cushing’s syndrome is high. However, it may take several months to years before recovery of adrenal function occurs. In case of early recovery of adrenal function, clinicians should be aware of a possible recurrence of Cushing’s disease.

Introduction

Cushing’s syndrome (CS) is characterized by chronic exposure to an excess of glucocorticosteroids (1). Endogenous hypercortisolism is a rare disorder with an estimated incidence of 0.2–5 patients per million per year (1). CS can cause severe, disabling signs and symptoms and is associated with significantly increased morbidity and mortality. In approximately 70% cases, endogenous CS is caused by an ACTH-producing pituitary adenoma, also known as Cushing’s disease (CD). In 15–25% cases, an ACTH-independent form of CS is caused by a unilateral adrenal adenoma, adrenal carcinoma or bilateral micro- or macronodular hyperplasia (adrenal CS). An ACTH-producing ectopic tumor is a rare cause of CS. First-line treatment of CS is surgical removal of the pituitary, adrenal or ectopic tumor (1, 2).

Successful first-line treatment by resection of the underlying tumor is usually followed by adrenal insufficiency (AI) due to suppression of the hypothalamic–pituitary–adrenal axis after prolonged exposure to high concentrations of cortisol (3, 4, 5). Theoretically, one would expect that the hypothalamic–pituitary–adrenal axis recovers over time and that the substitution of glucocorticosteroids can slowly be reduced and stopped as long as there is no irreversible damage to the remaining adrenal or pituitary tissue. However, in clinical practice, AI is not always transient. In a subset of patients, this is caused by permanent AI due to perioperative damage to the pituitary gland or irreversible atrophy of the contralateral adrenal gland. In other cases, tapering the dosage of glucocorticosteroids is not possible because this causes worsening of symptoms. Despite the glucocorticoid replacement therapy, patients often experience symptoms resembling AI, such as fatigue, myalgia, arthralgia, depression, anxiety and decreased quality of life, also known as glucocorticoid withdrawal syndrome (GWS) (6). GWS is caused by dependence on supraphysiologic glucocorticoid concentrations after chronic exposure to high concentrations of glucocorticoids, which can complicate and delay the withdrawal of exogenous steroids. As a result, patients and physicians often struggle with a dilemma: on the one hand, lowering the cortisol substitution is necessary to enable functional recovery of the hypothalamic–pituitary–adrenal axis. On the other hand, lowering the substitution therapy often causes worsening of symptoms. In clinical practice, it is not always possible to completely taper the substitution of steroids due to GWS, even in spite of intensive guidance and support by the treating physician, specialized nurse and other healthcare professionals. Moreover, in patients remaining on glucocorticoid replacement, it is not always clear whether the failure to recover from AI is caused by the irreversible damage of the remaining pituitary or adrenal tissue or the failure to overcome the GWS. The time after which adrenal function recovers and substitution therapy can be tapered off varies largely between patients but may take several years (7).

A recent survey among patients with CS highlighted the need of patients for better information about the difficult post-surgical course (8). However, scientific data about this post-operative period, particularly regarding the recovery rate and time to recovery from AI are scarce (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Because of the rarity of CS, most studies are hampered by a limited number of patients. The reported recovery rates of adrenal function after first-line treatment for CS vary widely, between 37 and 93% for CD (9, 10, 11, 12, 13) and between 38 and 93% for overt adrenal CS (10, 12, 14, 15, 16, 17).

The reported duration to recovery of the hypothalamic–pituitary–adrenal axis after CD and adrenal CS also varies widely, between 13 and 25 months after CD (9, 10, 11, 13, 19) and between 11 and 30 months in overt adrenal CS (10, 14, 15, 16, 18, 20).

Factors which influence the recovery rate and the duration to recovery of adrenal function are not entirely clear. A few studies reported a lower chance of recovery and a longer duration to recovery of adrenal function in patients who are younger, have more severe hypercortisolism, and longer duration of symptoms before diagnosis, whereas other studies could not confirm these findings (10, 13, 21). By contrast, other studies reported a higher chance of recovery in younger patients (21). Identification of these factors may help provide patients with more information about the expected post-surgical course.

Therefore, the aims of the present study were to assess the recovery rate and time to recovery of adrenal function after successful first-line treatment in the different subtypes of CS in a large series of consecutive patients treated at a tertiary referral center and to identify factors associated with recovery.

Methods

Patients

The medical records of adult and pediatric patients treated for CS at Radboud University Medical Center, Nijmegen, between 1968 and 2022 were examined retrospectively. This is a tertiary referral hospital where practically all cases of CS from the large surrounding geographic area are managed. All patients with CD, adrenal CS and ectopic CS who were in remission and developed AI after first-line surgical treatment were included. Exclusion criteria were bilateral adrenalectomy as first-line treatment, adrenocortical carcinoma, radiotherapy of the pituitary gland before surgery, pituitary carcinoma and the therapeutic use of corticosteroids for conditions other than AI. Data were collected on age, sex, body mass index (BMI), duration of CS symptoms, comorbidities, the use of medication, biochemical results at diagnosis and during follow-up, preoperative imaging, surgical treatment and histology.

The study was assessed by the Committee for Research with Humans, Arnhem/Nijmegen Region and the need for written approval by individual patients was waived since this study did not fall within the remit of the Medical Research Involving Human Subjects Act (WMO). The study has been reviewed by the ethics committee on the basis of the Dutch Code of conduct for health research, the Dutch Code of conduct for responsible use, the Dutch Personal Data Protection Act and the Medical Treatment Agreement Act. The ethics committee has passed a positive judgment on the study. The procedures were conducted according to the principles of the Declaration of Helsinki.

Diagnostics and definitions

Patients were diagnosed with CS according to the guidelines available at the time, i.e., the presence of signs and symptoms of hypercortisolism in combination with confirmatory biochemical tests, including the 1 mg dexamethasone suppression test (DST), 24-h urine free cortisol (UFC), late-night salivary cortisol concentrations and/or hair cortisol. The cutoff value for adequate cortisol suppression after the DST was <50 nmol/L (22). For UFC, the times upper limit of normal was calculated because several assays with different reference values were used over time.

First-line treatment consisted of pituitary surgery in patients with CD and unilateral adrenalectomy in patients with ACS. In patients with bilateral macronodular hyperplasia, adrenalectomy of the largest adrenal was performed after carefully outweighing the risks and benefits of surgery together with the patient, taking into account factors such as age, severity of symptoms, comorbidities associated with hypercortisolism (e.g., diabetes mellitus type 2, cardiovascular disease, osteoporosis) and the severity of the hypercortisolism (2).

Peri- and postoperatively, all patients received glucocorticoid stress dosing, which was tapered off within a few days after surgery. Adrenal function was initially evaluated with a postoperative morning fasting cortisol concentration, measured at least 24 h after the last dose of hydrocortisone or cortisone acetate, within 7 days after surgery. If the postoperative morning fasting cortisol was <200 nmol/L, the patient was considered to have AI and glucocorticoid replacement therapy was continued. The starting dose was usually hydrocortisone 30 mg once daily (or an equivalent dose of cortisone acetate in the early years). For children, the dose was weight-based. Afterwards, the dose was slowly tapered off according to the symptoms/well-being of the patient and fasting cortisol values. During follow-up, the dose was usually divided into two or three doses a day.

Remission of CS after treatment was defined as either a morning cortisol of ≤50 nmol/L, adequate cortisol suppression after DST or a late-night salivary cortisol concentration within the reference range. Duration of AI was defined as the time between surgery and discontinuation of glucocorticoid replacement therapy. Complete recovery of adrenal function was assessed by spontaneous fasting cortisol concentration, an insulin tolerance test or a 250 μg ACTH stimulation test after discontinuation of glucocorticoid replacement therapy. In cases where fasting morning cortisol ≥520 nmol/L, adrenal function was considered as completely recovered. For the dynamic tests, assay-dependent cutoff values were used according to the guidelines available at the time. The dynamic tests were not performed routinely in all patients until 1999. In patients for whom no dynamic tests (results) were available, complete recovery of AI was defined as complete discontinuation of replacement therapy. Recurrence of CS was defined as the presence of signs and symptoms of hypercortisolism in combination with confirmatory biochemical tests, including the 1 mg DST, 24-h UFC, late-night salivary cortisol concentrations and/or hair cortisol.

Statistical analysis

Continuous data were expressed as mean ± SD or median + interquartile range (IQR), and categorical data were presented as frequency (n) and percentage (%). We produced Kaplan–Meier curves to determine the unadjusted probability of recovery of adrenal function over time. Patients that tapered off and completely stopped the glucocorticoid replacement therapy were assigned in the survival analyses as having an event (=recovery of adrenal function). The date of the last follow-up visit was assigned in the survival analyses as the last date and patients that were lost to follow-up or developed a recurrence before stopping the glucocorticoid replacement therapy were censored. In order to identify factors associated with recovery of adrenal function, we compared Kaplan Meier curves between several subgroups of patients: CD versus adrenal CS versus ectopic CS, age (at diagnosis) groups of ≤35 versus 36–55 versus ≥56 years old, patients with or without postoperative pituitary deficiencies, patients with or without recurrence of CS during follow-up, patients with or without preoperative medical treatment (PMT), patients operated before versus after 2010 and patients with a low versus slightly higher post-operative morning cortisol (<100 nmol/L versus 100–200 nmol/L), measured within 7 days after surgery. The Kaplan–Meier curves of the subgroups were compared using the two-sided log-rank test. The P-value ≤0.05 was considered statistically significant. The Kaplan–Meier curves provided the 1-year, 2-year and 5-year recovery rates and the median time to recovery of the adrenal gland. We used Cox proportional hazards models to calculate hazard ratios (HRs) with a 95% confidence interval (CI) of the probability of recovery of adrenal function over time in order to identify factors associated with recovery of adrenal function (univariate analyses). Cox proportional hazards models with multivariate analyses were performed to calculate the adjusted HRs with 95% CI. The model of multivariate analysis for the whole group included the variables: etiology of CS, age, sex, BMI, duration of symptoms before diagnosis, UFC and postoperative cortisol 0.10–0.20 versus <0.10 mcmol/L. The model of multivariate analysis for the patients with CD only included the variables: etiology of CD, age, sex, BMI, duration of symptoms before diagnosis, UFC, post-operative cortisol 0.10–0.20 versus <0.10 mcmol/L, PMT, hormonal deficiencies of the anterior pituitary gland other than AI and micro/macroadenoma. A 95% CI not including 1 was considered statistically significant.

All statistical analyses were performed using STATA version 11 (StataCorp, USA).

Results

In total, 174 patients were included in the analysis. The assessment of eligibility, the number of patients excluded from this study and the reasons for exclusion are shown in Fig. 1. The baseline characteristics are described in Table 1. The median follow-up was 6.8 years (IQR: 2.2–12.6). In 69.6% (94/135) of all patients who discontinued their glucocorticoid replacement therapy, the recovery of adrenal function was confirmed with a dynamic test or a morning cortisol concentration ≥520 nmol/L.

Figure 1View Full Size
Figure 1
Flowchart showing the assessment for eligibility, the number of patients excluded from the study and the reasons for exclusion.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Table 1Baseline characteristics.

Variable All patients CD Adrenal CS
Participants (n) 174 135 35
Female (%) 135/174 (77.6%) 102/135 (75.6%) 32/35 (91.4%)
Median age at diagnosis (y) 44 (35–55) 43 (32–55) 47 (36–54)
Median BMI at diagnosis (kg/m2) 28.3 (24.7–32.4) 28.6 (24.7–32.9) 28.0 (26.0–31.8)
Median duration of symptoms before diagnosis of CS (years) 3.0 (1.0–5.6) 3.0 (1.0–6.0) 3.5 (1.5–5.6)
Median times upper limit of normal UFC at diagnosis 3.7 (1.9–5.8) 3.9 (2.0–6.4) 2.4 (1.4–4.1)
Median cortisol after DST (nmol/L) 480 (320–630) 460 (290–620) 550 (330–710)
Median salivary cortisol at diagnosis (nmol/L) 8.6 (5.4–15.4) 10.1 (5.9–18.0) 6.1 (4.0–8.9)
Median follow up (years) 6.8 (2.2–12.6) 8.4 (3.0–13.5) 2.2 (1.2–4.7)
Preoperative medical therapy* (n) 120/174 (69%) 106/135 (78.5%) 10/35 (28.6%)
Pituitary microadenoma/macroadenoma/no adenoma detected on MRI scan (n) – 64/27/28** –
Bilateral disease (n) – – 7/35 (20.0%)

CD, Cushing’s disease; CS, Cushing’s syndrome; BMI, body mass index; UFC, 24-h urine free cortisol; DST, 1 mg dexamethasone suppression test. Continuous data are summarized as median and interquartile ranges. Categorical data are presented as frequencies and percentages.

*Cortisol-lowering medication, either metyrapone or ketoconazole.

**Missing data on MRI in 16 patients.

Recovery rates and recovery times of adrenal function

The probability of recovery of AI for CD, adrenal CS and ectopic CS are depicted in Fig. 2. The 1-year, 2-year and 5-year recovery rates of adrenal function for the entire cohort were 40.1, 73.4 and 83.3%, respectively. The median time to recovery of adrenal function was 13.9 months. The 1-year, 2-year and 5-year recovery rates of patients with CD were 37.8, 70.1 and 81.1%, respectively. The median recovery time was 13.9 months for patients with CD. For patients with adrenal CS, the 1-year, 2-year and 5-year recovery rates were higher: 49.3, 86.9 and 91.3%, respectively (two-sided log-rank test: P = 0.14). The median recovery time for patients with adrenal CS was 12.1 months. Seven out of the 35 patients with adrenal Cushing had bilateral disease. The median time to recovery in patients with bilateral disease was 17.5 versus 11.0 months in patients with unilateral disease.

Figure 2View Full Size
Figure 2
Cumulative probability of recovery of adrenal function in CD (n = 135), adrenal CS (n = 35) and ectopic Cushing (n = 4).

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Of the 15 evaluated patients with ectopic CS, only four patients underwent successful resection of the ectopic tumor and were included in our study. All four patients had a neuroendocrine tumor of the lung and recovered from AI. The time to recovery of adrenal function was known in three patients: 5.7, 7.9 and 14.5 months.

Factors associated with recovery of adrenal function

Age at diagnosis

Figure 3 shows the Kaplan–Meier curves of three different age groups (group 1: 0–35 years old, group 2: 36–55 years old and group 3: 56–100 years old). The 1-year recovery rates of patients aged between 0–35, 36–55 and 56–100 years old were 54.6, 37.2 and 31.4%, respectively. The 2-year recovery rates were 79.3, 72.6 and 68.4%, respectively and the 5-years recovery rates were 89.6, 83.8 and 75.1%, respectively. The median times to recovery of adrenal function of patients aged between 0–35, 36–55 and 56–100 years old were 11.2, 13.4 and 17.6 months, respectively. The probability of recovery of AI was higher in young patients (0–35 years old) (two-sided log-rank test: P = 0.05).

Figure 3View Full Size
Figure 3
Cumulative probability of recovery of adrenal function by age groups.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Recurrence after primary treatment

In total, 17.8% patients with CD (24/135) had developed a recurrence during follow-up. Figure 4 shows the Kaplan–Meier curves with the probability of recovery of AI of the groups with and without recurrence during follow-up in patients with CD. The probability of recovery of AI was higher in patients with a recurrence (two-sided log-rank test: P-value = 0.02). In patients with a recurrence, the 1-, 2- and 5-year recovery rates of AI were 60.9, 78.3 and 87.0%, respectively. In patients without a recurrence, the 1-, 2- and 5-years recovery rates of AI were 32.6, 68.3 and 79.7%, respectively. The median time to recovery of adrenal function in patients with CD with and without recurrence was 9.9 versus 14.4 months, respectively.

Figure 4View Full Size
Figure 4
Cumulative probability of recovery of adrenal function by recurrence during follow-up in patients with CD.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

There was only one patient with adrenal CS with a recurrence. This was a patient with bilateral macronodular hyperplasia. During the first surgery, the largest adrenal was removed. However, 3 years later, the contralateral adrenal was also removed because of the recurrence of CS.

Hypopituitarism after pituitary surgery

In patients with CD, we performed a sub-analysis based on the presence of anterior pituitary deficiencies after pituitary surgery for CD, besides AI. Antidiuretic hormone (ADH) deficiency was not included in this analysis. As expected after pituitary surgery and in line with the literature, temporary ADH deficiency occurred in a substantial part of the patients after surgery (23). Therefore, only central hypothyroidism, hypogonadotropic hypogonadism and growth hormone deficiency were taken into account (Fig. 5). The probability of recovery of AI was lower in patients with one or more pituitary deficiencies versus patients with intact pituitary function after surgery (two-sided log-rank test: P-value = 0.05). In patients with anterior pituitary deficiencies, the 1-, 2- and 5-years recovery rates of AI were 35.6, 60.4 and 67.6%, respectively. In patients without anterior pituitary deficiencies, the 1-, 2- and 5-years recovery rates of AI were 39.2, 76.0 and 89.1%, respectively. The median time to recovery of adrenal function in patients with CD with and without anterior pituitary deficiencies was 15.9 versus 13.4 months, respectively. Figure 6 shows the Kaplan–Meier curves by the number of hormonal deficiencies of the anterior pituitary gland, other than AI. Although statistical significance was not reached, there is a trend showing that the more postoperative hormonal deficiencies present, the lower the probability of recovery of AI is (two-sided log-rank test: P-value = 0.15).

Figure 5View Full Size
Figure 5
Kaplan–Meier curve by the presence/absence of hormonal deficiencies of the anterior pituitary gland (other than AI) after surgery in patients with CD.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Figure 6View Full Size
Figure 6
Kaplan–Meier curve by the number of hormonal deficiencies of the anterior pituitary gland after surgery in patients with CD.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Preoperative cortisol-lowering medical therapy, year of surgery and fasting cortisol concentration at the initial postoperative evaluation

Sub-analyses regarding patients who received PMT versus patients without PMT did not show any difference in the probability of recovery. In patients without PMT, the 1-, 2- and 5-years recovery rates of AI were 42.6, 77.6 and 85.2%, respectively. In patients with PMT, the 1-, 2- and 5-years recovery rates of AI were 41.6, 73.7 and 82.3%, respectively. The median time to recovery of adrenal function in patients without PMT and with PMT was 14.1 versus 13.5 months, respectively.

Sub-analyses regarding patients operated on before versus after 2010, regarding the results of the 1 mg dexamethasone suppression test at diagnosis and regarding patients with a low versus slightly higher postoperative morning cortisol within 7 days after surgery (<100 versus 100–200 nmol/L) also did not show any difference in the probability of recovery of adrenal function.

Table 2 shows HRs of univariate and multivariate Cox regression analyses. Adrenal CS and ectopic CS were associated with a higher probability of recovery of AI in comparison with patients with CS. Higher age was associated with a lower probability of recovery of AI.

Table 2Uni- and multivariate Cox regression analyses.

Variable Univariate Cox regression Multivariate Cox regression
HR 95% CI P value HR 95% CI P value
Etiology of CS (CD/adrenal CS/ectopic) 1.44 1.00–2.08 0.05 1.76 1.11–2.80 0.02
Etiology of CS (CD/adrenal CS) 1.42 0.91–2.22 0.12
Age (decades) 0.81 0.71–0.93 0.002 0.83 0.70–0.98 0.03
Sex (male/female) 1.02 0.68–1.55 0.92 0.74 0.46–1.20 0.22
BMI (kg/m2) 1.00 0.97–1.02 0.81 1.01 0.97–1.05 0.61
Duration of symptoms before diagnosis (years) 0.95 0.90–1.01 0.08 0.95 0.89–1.01 0.09
UFC (ULN) 1.03 0.99–1.07 0.15 1.01 0.97–1.05 0.57
Post-operative cortisol 0.10–0.20 versus <0.10 mcmol/L 0.92 0.56–1.50 0.73 1.16 0.58–2.30 0.67
In patients with CD only
PMT (no/yes) 1.23 0.75–2.02 0.40 1.26 0.53–3.02 0.60
Hormonal deficiencies of the anterior pituitary gland, other than AI (no/yes) 0.65 0.43–0.99 0.05 0.67 0.40–1.11 0.12
Micro/macroadenoma 1.13 0.70–1.83 0.62 1.42 0.79–2.52 0.24

PMT, preoperative medical treatment; HR, hazard ratio; CI, confidence interval; CS, Cushing’s syndrome; CD, Cushing’s disease; BMI, body mass index; UFC (ULN), times upper limit 24-h urine free cortisol; AI, adrenal insufficiency. The model of multivariate analysis for the whole group included the variables: etiology of CD, age, sex, BMI, duration of symptoms before diagnosis, UFC and postoperative cortisol 0.10–0.20 versus <0.10 mcmol/L. The model of multivariate analysis for the patients with CD only included the variables: etiology of CD, age, sex, BMI, duration of symptoms before diagnosis, UFC, postoperative cortisol 0.10–0.20 versus <0.10 mcmol/L, preoperative medical treatment, hormonal deficiencies of the anterior pituitary gland other than AI and micro/macroadenoma.

Discussion

In this study, we investigated the recovery rate of adrenal function and time to recovery after first-line treatment in patients with CS. The main finding is that the recovery rates of adrenal function are high. However, it may take several months to years before recovery of adrenal function occurs.

Patients with adrenal CS had higher recovery rates than patients with CD. This can be explained by the fact that the cortisol excess is generally less severe in adrenal CS and the fact that one adrenal gland remains completely intact after unilateral adrenalectomy. By contrast, patients who undergo pituitary surgery are at risk of developing new pituitary hormone deficiencies, including corticotrope deficiency, due to permanent structural damage to the pituitary gland. Our finding that patients with additional pituitary deficiencies after surgery for CD had lower recovery rates of adrenal function supports this hypothesis.

The recovery rates of adrenal function in CD, as well as in adrenal CS, are higher than what was reported in some previous studies (10, 11, 12), but are similar to other reports (13, 15, 17, 18). As shown in Table 3, it is difficult to compare previous studies because they all differ in design, study population and inclusion and exclusion criteria. For example, Berr et al. and Klose et al. used a different cutoff value of postoperative cortisol (<100 nmol/L) than we did (<200 nmol/L) to define initial AI shortly after surgery. However, only 25 patients in our cohort had a postoperative morning cortisol between 100 and 200 nmol/L and sub-analysis of patients with a morning cortisol <100 nmol/L versus patients with a morning cortisol between 100 and 200 nmol/L did not show any difference in recovery rate or time. Another difference between studies is the strategy for tapering off and stopping glucocorticoids in the postoperative period. In our study, patients started with 30 mg hydrocortisone per day after surgery. One might expect that a higher dose of hydrocortisone leads to a longer time to recovery of adrenal function. However, there are no data or evidence-based guidelines regarding the best strategy for tapering off and stopping glucocorticoids in the postoperative period.

Table 3Overview of previous studies regarding recovery of adrenal function after surgery in patients with CS.

Author n, etiology Recovery rate AI Time to recovery, years Follow up years Definition of AI/remission Substitution therapy (start doses) Recurrence rate (CD)
Alexandraki, 2013 (8) 131 CD 49/81 (60.5%) during follow up Median 1.5 years Minimum 6 years, mean 15.9 ± 6 years Postoperative cortisol ≤50 nmol/L Prednisolone 5 + 2 mg or HC 20 mg in divided doses 22.7% (microadenoma) 33.3% macroadenoma
Berr, 2015 (9) 5-year: Median: Mean 8.2 years Morning cortisol ≤100 nmol/L HC 40–50 mg/day
54 CD CD: 58% CD: 1.4 years CD: 7.0 years
26 ACS ACS: 38% ACS: 2.5 years ACS: 8.5 years
11 ECS ECS: 82% ECS: 0.6 years ECS: 13.5 years
Serban, 2019 (12) 61 CD 5-year: Median 1.6 years Minimum 3 years, median 6 years Morning cortisol ❤ μg/dL or cortisol after 250 μg synacthen test <18 μg/dL Cortisone acetate 25 mg, divided in 2–3 doses 16.4%
Persistent remission: 55.8% 2.1 years
Recurrence: 100% 1.0 years
Ciric 2012 (10) 86 CD 59.3% during follow up Mean 1.1 years Minimum 0.5 years, mean 5.7 years Drop in immediate postoperative cortisol, range <0.5–5.3 µg/dL and symptoms No specific unified algorithm 9.7%
Klose, 2004 (11) 2-year: Median: Post-operative cortisol <100 nmol/L and/or UFC <50 nmoL/24h Hydrocortisone 20–30 mg/day
18 CD CD: 67% CD: 2 years CD: 22.2%
14 ACS ACS: 79% ACS: 2 years ACS: 0%
Prete, 2017 (18) Median: Minimum 2 years Postoperative morning serum cortisol <5 μg/dL/138 nmol/L Hydrocortisone 20–30 mg/day in divided in 2–3 doses Patients with recurrence were excluded
15 CD CD: 1.3 years CD: median 5.8 years
31 ACS ACS: 0.8 years ACS: Median 4.0 years
 14 overt ACS Overt ACS: 1.5 years
 17 subclinical ACS Subclinical ACS: 0.5 years
Hurtado, 2018 (14) 81 ACS 87.8% during follow up Median ACS: 0.4 years Median ACS: 1.2 years Postoperative morning (day 1) serum cortisol <10 μg/dL/276 nmol/L or hemodynamic instability or received perioperative GC due to anticipated AI after unilateral adrenalectomy Prednisone or hydrocortisone, median hydrocortisone-equivalent dose 40 mg/day
 27 severe CS Severe: 1.0 years Severe: 1.0 years
 24 moderate CS Moderate: 0.2 years Moderate: 1.0 years
 30 MACE MACE: 0.2 years MACE: 1.5 years
Dalmazi, 2014 review on adrenal function after adrenalectomy for subclinical CS, 28 studies (17) ACS: 376 overt ACS 141 subclinical ACS Overt ACS: 93.4% subclinical ACS: 97.9% Mean overt ACS: 0.9 years subclinical ACS 0.5 years

CD, Cushing’s disease; ACS, adrenal Cushing’s syndrome; ECS, ectopic Cushing’s syndrome; AI, adrenal insufficiency; Subclin: subclinical; MACE, mild autonomous cortisol excess.

One might also hypothesize that the studies reporting high recurrence rates are related to higher recovery rates in CD patients. In our study, the recurrence rate was 17.8%, which is in line with previous studies (9, 13, 24). The establishment of recovery of adrenal function in patients with a recurrence later on is a difficult matter: despite the exclusion of patients with immediate obvious persistent disease in our study, recovery of glucocorticoid secretion in patients who developed a recurrence later on could be an early manifestation of recurrence instead of true recovery of physiological adrenal function. A striking finding in this study, in line with the aforementioned hypothesis, was the considerably higher 1-year recovery rate and the shorter time to recovery of patients with a recurrence in comparison to patients without a recurrence. Recovery of adrenal function is more rapid in patients with recurrences (13, 25). These findings imply that in case of an early recovery of adrenal function, clinicians should be aware of a possible recurrence of CD.

Another difference between studies is the inclusion or exclusion of patients with mild autonomous cortisol secretion (MACS), formerly known as subclinical CS. Previous studies have shown that patients with subclinical CS have a higher probability of recovery and a shorter duration of AI (14, 15, 16, 18). In our study, only two patients were diagnosed with subclinical CS (in this study characterized as inadequate suppression after DST in combination with values of UFC within the reference range) and therefore subgroup analysis was not possible.

In the present study, a rather high number of patients received PMT in comparison to other studies. In our institution, it was common practice to start PMT 3 months before pituitary surgery in patients with CD with the aim to improve hemostasis and other Cushing-related comorbidities, although the benefit of PMT has not yet been well established by randomized controlled trials. At the liberty of the treating physician, the dose of ketoconazole or metyrapone was titrated with the aim to normalize the 24-h UFC excretion. The doses needed to achieve normal 24-h UFC and the time to normalization of 24-h UFC varied between patients.

One could hypothesize that lowering cortisol levels during the weeks to months before surgery may result in a faster recovery of adrenal function. However, this was not the case in this study.

Overall, the present study shows a high recovery rate of adrenal function after treatment for CS. The time until recovery is partly dependent on the strategy and success of tapering off of glucocorticoids replacement and therefore may be very long because of GWS. These are meaningful findings. Tapering glucocorticoid substitution in parallel with the recovery of cortisol secretion after surgery for CS is often a challenging and lengthy trajectory for both patients and physicians. The lack of standardization of the follow-up and of the tapering protocols, the need for constant shared decision-making and personalized support for patients, particularly of those who are also confronted with severe associated comorbidities and unpredictable withdrawal symptoms, may discourage patients and physicians from proceeding in this endeavor. Given the rarity of the disease, knowledge on this topic is scarce. Previous, mainly smaller studies reported a wide range of recovery rates of adrenal function after first-line treatment for CS (varying between 37 and 93% for CD, and for overt adrenal CS between 38 and 93%) (10, 11, 12, 13, 15, 17, 18). The rather low percentages of recovery of adrenal function in some of these previous studies could discourage patients and physicians to persevere the attempt to taper off hydrocortisone. Our findings in a large cohort of patients with CS, including a sizable subgroup of patients with CD, allow us to deepen the multivariate analysis to uncover factors that are associated with a better chance of recovery. The data indicate that in this real-life setting, despite the long time to achieve recovery, the recovery rates are high and while this occurs for most of the patients within 1–2 years after treatment, recovery is still possible even after a longer follow-up. Moreover, this study showed that the recovery rate is higher in patients with adrenal CS versus CD, in younger patients and in patients with CD with preserved pituitary function after pituitary surgery. These findings are very important for clinical practice. They highlight the importance of continuing to taper off the glucocorticoids, if necessary slowly and steadily, in the years after surgery. They also help us better inform the patients beforehand and to improve the management and the expectations of both patients and physicians to motivate them to persevere in tapering of the glucocorticosteroids while considering the factors such as those identified to influence the chance of recovery during their personalized counseling and guidance of the patients in this often very difficult and lengthy period.

In our institution, it is common practice to counsel and provide guidance intensively to patients in this difficult period, both by the treating physician and a specialized nurse, as we consider this coordinated guidance of utmost importance. Moreover, all patients are provided with contact details so that they can reach to us for advice 24 h a day, either by phone or by secure email throughout this process. When indicated, patients are referred to other healthcare professionals such as psychologists, physical therapists, social workers and other specialists.

One important strength of our study is the large size of our single-center cohort, considering the rarity of the disease. This has also allowed us to do subgroup analyses and assess factors associated with recovery from postoperative AI. The limitations include the retrospective character of this study and the fact that patients were included over a long period of time (1968 to 2022) during which diagnostic tools and management protocols for CS have somewhat changed over this period of time. We have tried to mitigate the limitations that are inevitable with a retrospective study by being thorough and extensive in the quality and amount of data that we were able to collect. In addition to that, the diagnostic assessment and the treatment of the patients followed very strict and uniform protocols in conformity with the internationally recognized clinical guidelines available at the time. On the other hand, the fact that this represents a real-life study renders the results more relatable for clinical practitioners and strengthens its impact.

We collected data from medical records regarding the duration of CS-related signs and symptoms before diagnosis, as mentioned by the patient during history taking. We are well aware that these data are rather subjective and dependent on the accuracy of the recollection of the patient. However, this is the only way to assess the duration of symptoms before diagnosis. In our opinion, these data still could be very valuable.

In conclusion, our study shows that the large majority of patients with CS recover their adrenal function after first-line surgical treatment, even though the time to recovery may take several months to years. Informing patients beforehand and providing support, encouragement and guidance in this process is therefore paramount. Herewith, one could consider factors such as the age of the patient, the etiology of CS and the presence of additional pituitary deficiencies after pituitary surgery. In case of an early recovery of adrenal function, clinicians should be aware of a possible recurrence of CD. Future studies should establish the optimal postoperative management for CS to improve the chance for success of recovery of adrenal function.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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

Impact of Remission Status in Endogenous Cushing’s Syndrome on Cancer Incidence

Posted on March 4, 2025 by MaryO

Abstract

Objective
Endogenous Cushing’s syndrome (CS) has been linked with an increased risk of cancer. We aimed to evaluate the association between cancer risk and disease remission post-surgery in adrenal CS and Cushing’s disease (CD).
Design
A nationwide retrospective matched-cohort study of patients with CS diagnosed between 2000-2023 in Israel, using Clalit Health Services’ database. Methods Patients with CS were matched 1:5 with controls by age, sex, socioeconomic status, and BMI. Remission status post-surgery was assessed within two years after the diagnosis of CS. The outcome measured was time to first diagnosis of malignancy, at least three years post-CS diagnosis, excluding those who died or developed cancer earlier. Malignancy risk, stratified by remission status, was evaluated using Cox proportional hazards with death as a competing event.
Results
The cohort comprised 388 cases and 1,862 controls [mean age at diagnosis, 47.4±16.8 years; 1,534 (68.2%) women]. Among patients with CD, those who did not achieve remission within 2 years post diagnosis (n=69) had a higher risk of malignancy compared to those who achieved remission (n=99) (HR 3.89, 95% CI 1.41-10.75). Cancer risk in patients with CD who achieved remission was similar to that of the controls (HR 0.58, 95% CI 0.23-1.47). In patients with adrenal CS, the risk of cancer was comparable between those who did not achieve early remission (n=39) and those who did (n=113) (HR 1.68, 95% CI 0.83-3.40).
Conclusion
Though cancer risk is higher in both CD and adrenal CS, we have shown that achieving surgical remission within 2 years may attenuate cancer risk in patients with CD, but not in those with adrenal CS.

Filed under: Cancer, Clinical trials, Cushing's | Tagged: , , , , , | Leave a comment »

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