Once-Daily Treatment for Cushing Syndrome May Safely Restore Cortisol Rhythms

Posted on June 13, 2025 by MaryO

Once-daily evening osilodrostat improved cortisol rhythms, sleep, and quality of life in Cushing syndrome without compromising disease control or safety.

 

Once-daily osilodrostat administered in the evening is safe, effective, and restores circadian cortisol rhythms in patients with biochemically controlled Cushing syndrome (CS), according to results published in the Journal of Clinical Endocrinology & Metabolism.

“By achieving lower evening cortisol exposures, this regimen improves sleep quality and overall quality of life. Over the long term, these changes may translate into potential cardiovascular benefits,” wrote corresponding author Andrea M. Isidori, MD, PhD, and colleagues.

A loss of circadian cortisol rhythm is a hallmark of CS and contributes to systemic adverse effects, the authors explained. The prospective pilot study assessed chronotherapy with once-daily osilodrostat and its effect on circadian cortisol profiles in 16 patients with well-controlled CS who transitioned from twice-daily osilodrostat therapy.

Researchers used ultra-high performance liquid chromatography–tandem mass spectrometry on saliva, serum, and urine samples to analyze circadian steroid hormones at baseline, when patients were taking twice-daily osilodrostat, and 60 to 90 days after they switched to a single equivalent daily dose at 19:00 ±1 hour. Investigators also assessed cardiometabolic markers, quality of life, sleep function, and safety outcomes.

At baseline, most patients had mild CS; the mean osilodrostat dose was 4.2 ±1.3 mg.

“Compared to the standard twice-daily regimen, once-daily dosing resulted in significantly reduced late afternoon to early morning cortisol exposure…without altering morning peak levels, reflecting an improved alignment with the natural circadian rhythm of glucocorticoids,” the researchers reported.

With the transition to dosing at 19:00 ±1 hour, salivary cortisol exposure decreased 6.1 ng/mL/h during the afternoon to early morning period, according to the study. Additionally, scores on the CushingQoL questionnaire increased 4.2 points, while scores on the Pittsburgh Sleep Quality Index decreased 1.7 points. The serum steroid precursors 11-deoxycorticosterone and 11-deoxycortisol also decreased.

“Eight patients advancing dosing to 16:00 ±1 hour showed comparable reductions,” the authors wrote, “with phase shifts in acrophase and nadir.”

No patients experienced adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control with the transition. Moreover, blood pressure, lipid profile, and glucose metabolism trended toward improvement.

“These results lay the groundwork for future large-scale, long-term studies to fully explore the potential of chronotherapy approach in the management of CS,” the researchers wrote.

https://www.physiciansweekly.com/once-daily-treatment-for-cushing-syndrome-may-safely-restore-cortisol-rhythms/

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Osilodrostat Treatment of Cushing Syndrome in Real-World Clinical Practice

Posted on May 23, 2025 by MaryO
Abstract
Context
In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).
Objectives
A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.
Methods
A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.
Results
A total of 42 patients (Cushing disease, n = 34; CS due to adrenal adenoma, n = 5; ectopic adrenocorticotropin syndrome [EAS], n = 3) were included. Starting doses were 2 mg twice daily in 27/42 patients (64.3%), maintenance doses were 2 mg twice daily in 6 of 9 patients (66.7%) attaining them. During osilodrostat treatment, urinary free cortisol (UFC) decreased below the upper limit of normal (ULN) in 14 of 20 patients (70.0%) with pretreatment UFC greater than the ULN. Osilodrostat response was observed across a range of doses (2-20 mg/day). In Cushing disease, median UFC and late-night salivary cortisol decreased from 3.03 and 2.39 × ULN, respectively, to 0.71 and 1.13 × ULN at last assessment in those with available data (n = 17 and 8, respectively). UFC decreased in all patients with adrenal CS or EAS with available data (n = 2 each). There were no unexpected safety signals; the most common adverse events (incidence ≥20%) were fatigue, nausea, and lower-extremity edema. Glucocorticoid withdrawal syndrome and/or adrenal insufficiency were reported in 12 of 42 patients (28.6%) after osilodrostat initiation, resulting in treatment discontinuation in 4.
Conclusion
In routine practice with dosing individualized according to clinical condition, response, and tolerability, osilodrostat was effective and well tolerated regardless of CS etiology and severity.
Cushing disease, ectopic adrenocorticotropin syndrome, adrenal Cushing syndrome, osilodrostat, retrospective, real world
Subject Pituitary and Neuroendocrinology
Issue Section: Clinical Research Article
Endogenous neoplastic Cushing syndrome (CS) is a serious endocrine condition characterized by excessive endogenous cortisol secretion [1, 2]. Untreated, hypercortisolism has serious cardiovascular, metabolic, neuropsychiatric, and infectious consequences, which negatively affect patients’ quality of life [2-4]. The risk of mortality is higher in patients with CS than in the general population, mainly because of greater mortality from cardiovascular and infectious diseases [2-5]. More recently, it has been shown that cancer risk is increased in population cohorts with CS [6, 7].
Most cases of CS are caused by excess secretion of adrenocorticotropin (ACTH) from a pituitary adenoma (Cushing disease), which results in excess cortisol release from the adrenal glands [2, 4]. However, some patients may present with ectopic ACTH syndrome (EAS; also referred synonymously as ectopic CS) or ACTH-independent cortisol excess from adrenal adenomas, adrenocortical cancers, or bilateral nodular adrenal hyperplasia (adrenal CS) [2, 4].
Osilodrostat is a potent oral inhibitor of 11β-hydroxylase, the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex [8]. In phase 3 trials in patients with Cushing disease, osilodrostat was associated with a rapid and sustained reduction in cortisol levels, as well as improvements in cardiovascular and metabolic parameters, the physical manifestations of Cushing disease, and patients’ quality of life [9-13]. The clinical development program for osilodrostat also included a phase 2 study in patients with EAS or adrenal CS, which demonstrated that osilodrostat can lower cortisol regardless of the etiology of CS [14]. Based on these data, osilodrostat was licensed for use in adults with Cushing disease for whom pituitary surgery is not an option or has not been curative (United States) [15] and in adults/patients with endogenous CS (Europe [16]/Japan [17]).
Although prospective clinical trials are essential for demonstrating the efficacy and safety of drug therapies, they entail enrollment of selected patient populations and a tightly controlled research setting [18]. Real-world observational studies, in which the drug is used according to physicians’ clinical practice, provide complementary and helpful information in this context. Previous real-world studies conducted in patients with CS in Europe have shown that osilodrostat reduces cortisol levels and improves comorbidities, with no unexpected safety signals [19-22]. The present study, osIlodrostat reaL-worLd Utilization Study To Retrospectively Assess paTient Experience (ILLUSTRATE), was conducted in multiple clinical practices in the United States to evaluate the dosing, effectiveness, and safety of osilodrostat in patients with CS, irrespective of its etiology.
Materials and Methods
ILLUSTRATE was a retrospective chart-review study of patients in the United States treated with osilodrostat between May 1, 2020, and October 29, 2021. The index date for each patient was defined as the date of the first osilodrostat prescription (between May 1, 2020, and October 29, 2021). Preprescription data were collected from the 12 months before each patient’s index date to provide baseline data for that patient.
Patients were eligible for inclusion if aged 18 years or older, with a diagnosis of endogenous neoplastic CS (due to a pituitary adenoma, adrenal adenoma, or ectopic tumor) and a documented prescription for osilodrostat on or after May 1, 2020. As osilodrostat was approved for Cushing disease in the United States earlier the same year (March 6, 2020) [23], the start date for ILLUSTRATE was selected to avoid inclusion of patients treated with osilodrostat in clinical trials. The study was approved by a central independent review board (Western Institutional Review Board). As the study employed secondary data collection of anonymized patient data, a waiver of consent was granted under the privacy rule of HIPPA (the Health Insurance Portability and Accountability Act).
If available, the following data were extracted from patients’ medical records into an electronic case report form (eCRF): demographic details (age, sex, race, ethnicity); clinical history (date of CS diagnosis, signs and symptoms, prior surgery and/or radiotherapy); duration of disease prior to osilodrostat prescription; other therapies (cortisol-lowering medications, concomitant steroid use or replacement, antihypertensive and antidiabetic medications); laboratory data (urinary free cortisol [UFC], late-night salivary cortisol [LNSC], morning serum cortisol, serum potassium, testosterone [female patients only]); osilodrostat use (starting dose, uptitration, downtitration, duration of treatment); and adverse events (AEs). AEs were selected from a dropdown list that included the following: hypotension, hyperkalemia, hypokalemia, prolonged QT interval on electrocardiogram, lower-extremity edema, dizziness, rash, constipation, fatigue, alopecia, headache, nausea, vomiting, pituitary tumor size, hypertension, hirsutism, acne, irregular menstruation, brain fog or other cognitive changes, insomnia, striae, muscle weakness, depression, anxiety, other emotional changes, arthralgia/myalgia, and sleep changes.
The following variables were derived from the information recorded in the eCRF: time to maintenance dose (maintenance dose was defined as the first dose that was not modified between two consecutive visits, which could include the baseline visit); titration interval (time between osilodrostat dose changes; if patients had multiple dose changes, the average was reported); and proportion of patients on osilodrostat 6 months after the index prescription. In patients who had dose changes after reaching the maintenance dose, the time between these dose changes was included in the calculation of average titration interval.
Investigator-reported events of glucocorticoid withdrawal syndrome (GWS) and adrenal insufficiency (AI) were evaluated by two of the authors (J.L.S.-S. and K.C.D.) and adjudicated according to symptoms and the level of morning serum cortisol, where available. If the symptoms were consistent with GWS and serum cortisol at the time of the event was greater than 10 µg/dL (>276 nmol/L), these cases were classified as GWS. If the symptoms were more severe or cortisol levels were less than or equal to 10 µg/dL (≤276 nmol/L), AI could not be ruled out, and these cases were classified as such. If the investigator recorded GWS and AI in the same patient at the same visit, they were classified as a single event.
Descriptive statistics were used for all variables based on the number of patients with data available for each variable. Laboratory measures were reported as n times the upper limit of normal (ULN). Independent quality assessments were conducted to check content, inconsistencies, and missing fields in the eCRF.
Results
Overall, 42 patients were included in the study: 34 patients with Cushing disease, 5 patients with adrenal CS as a result of adrenal adenoma, and 3 patients with EAS. Two patients with Cushing disease had only a single clinical encounter and were included in the baseline results only. Four patients (9.5%), all with Cushing disease, discontinued osilodrostat during follow-up; in all cases, this was because of GWS or AI.
Baseline Characteristics
Baseline demographics and clinical characteristics are summarized in Table 1. Mean age was 43.7 years, and most patients (76.2%) were female. Mean disease duration before osilodrostat prescription was 57.3 months, and most patients had previously undergone surgery (81.0%) and/or received one or more medical therapies (61.9%). In the subgroup of patients with adrenal CS (n = 5), 2 patients had undergone surgery and 2 patients had expressed a preference not to undergo surgery; in the final patient, information on previous surgery was not recorded in the eCRF. In the overall study population, median UFC, LNSC, and morning serum cortisol levels were 2.54, 2.39, and 1.16 × ULN, respectively. Twelve and 5 patients, respectively, had morning serum cortisol levels and UFC less than the ULN at baseline; of these, 6 (50.0%) and 3 (60.0%), respectively, had received previous medical therapy.
Table 1.Open in new tabBaseline demographic and clinical characteristics (overall and by etiology)
  All patients
(n = 42) Cushing disease (n = 34) Adrenal CS (n = 5)a EAS
(n = 3)b
Mean age (SD), y 43.7 (15.0) 40.8 (13.9) 49.2 (14.0) 66.7 (3.5)
Sex, n (%)
 Female 32 (76.2) 27 (79.4) 2 (40.0) 3 (100)
 Male 10 (23.8) 7 (20.6) 3 (60.0) 0
Race, n (%)
 White 22 (52.4) 17 (50.0) 4 (80.0) 1 (33.3)
 Black or African American 10 (23.8) 8 (23.5) 1 (20.0) 1 (33.3)
 Asian 2 (4.8) 1 (2.9) 0 1 (33.3)
 Multiracial 1 (2.4) 1 (2.9) 0 0
 Unknown 7 (16.7) 7 (20.6) 0 0
Ethnicity, n (%)
 Hispanic, Latino, or Spanish origin
  Yes 8 (19.0) 8 (23.5) 0 0
  No 28 (66.7) 20 (58.8) 5 (100) 3 (100)
 Unknown 6 (14.3) 6 (17.6) 0 0
Mean age at CS diagnosis (SD), y 37.7 (14.8) 34.9 (12.7) 40.0 (14.8) 66.3 (3.1)
Mean duration of disease prior to osilodrostat prescription (SD), mo 57.3 (82.0) 64.8 (86.7) 30.4 (26.6) 1.2 (0.3)
Previous pituitary or adrenal surgery for CS, n (%) 34 (81.0) 32 (94.1) 2 (40.0) 0
Radiotherapy for CS in last 5 y, n (%) 10 (23.8) 10 (29.4) 0 0
Previous medical therapy for CS,c n (%) 26 (61.9) 21 (61.8) 3 (60.0) 2 (66.7)
 Pasireotide 3 (7.1) 3 (8.8) 0 0
 Cabergoline 7 (16.7) 7 (20.6) 0 0
 Ketoconazole 10 (23.8) 8 (23.5) 0 2 (66.7)
 Metyrapone 2 (4.8) 1 (2.9) 1 (20.0) 0
 Mitotane 1 (2.4) 0 1 (20.0) 0
 Mifepristone 6 (14.3) 5 (14.7) 1 (20.0) 0
UFC,d × ULN n = 32 n = 25 n = 4 n = 3
 Mean (SD) 7.67 (14.84) 3.14 (2.98) 13.93 (15.25) 37.03 (36.46)
 Median (min-max) 2.54
(0.09-75.20) 2.28
(0.09-11.17) 13.77
(0.42-27.76) 33.33
(2.57-75.20)
LNSC,d × ULN n = 18 n = 16 n = 1 n = 1
 Mean (SD) 4.80 (8.18) 5.25 (8.59) 0.55 1.82
 Median (min-max) 2.39
(0.44-36.33) 2.78
(0.44-36.33) 0.55 1.82
Morning serum cortisol,d × ULN n = 32 n = 24 n = 5 n = 3
 Mean (SD) 1.23 (0.77) 1.13 (0.42) 1.08 (0.97) 2.33 (1.78)
 Median (min-max) 1.16
(0.19-4.38) 1.18
(0.19-1.88) 0.83
(0.39-2.76) 1.43
(1.17-4.38)
Potassium levels,d mmol/L n = 41 n = 33 n = 5 n = 3
 Mean (SD) 4.1 (0.6) 4.3 (0.5) 3.7 (0.5) 3.6 (0.9)
 Median (min-max) 4.0
(2.6-5.6) 4.2
(3.6-5.6) 3.4
(3.3-4.5) 3.7
(2.6-4.4)
Potassium levels <LLN,e n (%) n = 37
5 (13.5) n = 30
1 (3.3) n = 5
3 (60.0) n = 2
1 (50.0)
Testosterone levels,f × ULN n = 11 n = 9 n = 1 n = 1
 Mean (SD) 1.00 (1.48) 0.96 (1.56) 0.07 2.29
 Median (min-max) 0.36
(0.03-5.02) 0.36
(0.03-5.02) 0.07 2.29
ULNs varied between study centers, ranging from 32 to 64 µg/24 hours (88.3-176.6 nmol/L) for UFC, 0.01 to 0.112 µg/dL (0.28-3.09 nmol/L) for LNSC, 18.4 to 25 µg/dL (507.8-690.0 nmol/L) for morning serum cortisol, and 41 to 100 ng/dL (1.42-3.47 nmol/L) for testosterone (female patients).
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LLN, lower limit of normal; max, maximum; min, minimum; ULN, upper limit of normal.
aAll patients had adrenal adenoma.
bIn 1 patient, the primary tumor could not be located; in the other 2 patients, the location of the ectopic tumor was not recorded.
cReasons for stopping these therapies and switching to osilodrostat were not collected as part of this study.
dNot all patients had values recorded at baseline (see n numbers in each column).
eLLN was not available for all patients with available potassium data.
fFemale patients only.
Osilodrostat Dosing
Information on osilodrostat dosing is summarized in Table 2. The most common starting dose of osilodrostat was 4 mg/day in 28 of 47 patients (66.7%; Fig. 1A), comprising 2 mg twice daily in 27 patients and 4 mg once daily in 1 patient. Some patients with Cushing disease and adrenal CS were initiated on lower doses (1 mg once daily [n = 2] or twice daily [n = 10], or 2 mg once daily [n = 1]).
A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
Figure 1.A, Total osilodrostat daily starting dose* in all patients (n = 42) and B, dose changes postinitiation (by etiology) in patients with at least one clinical encounter after initiating osilodrostat (n = 40). *Osilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
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Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
Table 2.Open in new tabOsilodrostat treatment (overall and by etiology)
  All patients
(n = 42) Cushing disease (n = 34) Adrenal CS (n = 5) EAS
(n = 3)
No. of patients with initial dose information 42 34 5 3
Starting total daily dose, mg
 Mean (SD) 3.4 (1.1) 3.4 (1.1) 3.0 (1.4) 4.0 (0.0)
 Median (min-max) 4 (1-6) 4 (1-6) 4 (1-4) 4 (4-4)
Starting dose schedule, n (%)
 Twice daily 38 (90.5) 31 (91.2) 4 (80.0) 3 (100)
 Once daily 4 (9.5) 3 (8.8) 1 (20.0) 0
Starting dose and schedule, n (%)
 1 mg once daily 2 (4.8) 1 (2.9) 1 (20.0) 0
 1 mg twice daily 10 (23.8) 9 (26.5) 1 (20.0) 0
 2 mg once daily 1 (2.4) 1 (2.9) 0 0
 2 mg twice daily 27 (64.3) 21 (61.8) 3 (60.0) 3 (100)
 3 mg twice daily 1 (2.4) 1 (2.9) 0 0
 4 mg once daily 1 (2.4) 1 (2.9) 0 0
No. of patients with postinitiation clinical encounters 40 32 5 3
Patients who reached maintenance dose by last interaction, n (%) 9 (22.5) 7 (21.9) 1 (20.0) 1 (33.3)
Time to maintenance dose or end of follow-up, wk
 Mean (SD) 34.7 (18.0) 36.7 (19.1) 23.0 (11.7) 33.6 (3.3)
 Median (min-max) 33 (0.7-78.1) 37 (0.7-78.1) 17 (13.0-37.6) 32 (31.3-37.4)
Maintenance dose,a n (%)
 2 mg twice daily 6 (66.7) 4 (57.1) 1 (100) 1 (100)
 4 mg twice daily 2 (22.2) 2 (28.6) 0 0
 10 mg twice daily 1 (11.1) 1 (14.3) 0 0
Patients with dose change, n (%) 25 (62.5) 21 (65.6) 2 (40.0) 2 (66.7)
Titration period in patients with dose change, wk
 Mean (SD) 13.8 (12.4) 14.8 (13.2) 4.9 (3.2) 13.0 (0.0)
 Median (min-max) 11 (2.6-57.0) 11 (4.6-57.0) 5 (2.6-7.1) 13 (13.0-13.0)
Osilodrostat treatment interruption,b n (%) 9 (22.5) 7 (21.9) 1 (20.0) 1 (33.3)
Duration of exposure up to treatment interruption or study end, wk
 Mean (SD) 35.2 (22.0) 36.5 (22.5) 26.8 (26.3) 35.8 (4.5)
 Median (min-max) 35 (0.7-78.1) 38 (0.7-78.1) 14 (4.0-69.7) 37 (30.7-39.3)
Duration of treatment up to study end,c wk
 Mean (SD) 37.0 (20.9) 38.2 (21.5) 29.4 (24.0) 36.0 (4.2)
 Median (min-max) 37 (0.7-78.1) 40 (0.7-78.1) 17 (13.0-69.7) 37 (31.3-39.3)
Patients on osilodrostat for ≥6 mo prior to study end,c,d n (%) 28 (96.6) 23 (95.8) 2 (100) 3 (100)
Duration of therapy prior to study endc in patients with ≥6 mo persistence, wk
 Mean (SD) 47.3 (15.2) 48.5 (15.3) 51.6 (25.6) 36.0 (4.2)
 Median (min-max) 44.9 (28.1-78.1) 45.7 (28.1-78.1) 51.7 (33.6-69.7) 37.4 (31.3-39.3)
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
aIn those who reached a maintenance dose (defined as a dose that was not modified between 2 consecutive visits) by last interaction.
bDefined as a break in osilodrostat treatment for 30 days or longer.
cOr treatment discontinuation (n = 4).
dIn 29 patients with 6 months’ follow-up (n = 24, 2, and 3 for Cushing disease, adrenal CS, and EAS, respectively).
Mean titration interval was 13.8 weeks for all patients (4.9 weeks in patients with adrenal CS, 13.0 weeks in patients with EAS, and 14.8 weeks in patients with Cushing disease). Nine patients (22.5%; 7 patients with Cushing disease and 1 patient each with adrenal CS and EAS) achieved a maintenance dose of osilodrostat (defined as no dose modification between 2 consecutive visits) after a mean (SD) of 34.7 (18.0) weeks. The most common maintenance dose was 2 mg twice daily (see Table 2).
Overall, 25 of 40 patients (62.5%) had their osilodrostat dose adjusted during the study. In most of these cases (n = 20), the dose was increased; 2 patients had a dose decrease and 3 patients had doses both increased and decreased (Fig. 1B). In those who had an osilodrostat dose increase only, most (14/20; 70.0%) had only a single dose increase; in the remaining patients, 4 (20.0%) had 2 dose increases and 2 (10.0%) had 4 dose increases. In those who had dose adjustments, there was no observable pattern between starting and final osilodrostat doses (Table 3). Overall, 9 of 40 patients (22.5%) had osilodrostat treatment temporarily interrupted, which occurred in the first 3 months of treatment in 5 patients, between treatment months 3 and 6 in 2 patients, and after 6 months in 2 patients. Reasons for temporary interruption were hypocortisolism-related AEs, patient undergoing surgery, lack of availability of osilodrostat in the hospital setting, and insurance noncoverage.
Table 3.Open in new tabShift table showing starting and final doses for those patients who had dose adjustments during the study period (n = 26)
Starting dosea Final dose, No. of patients
  1 mg/d 2 mg/d 4 mg/d 5 mg/d 6 mg/d 8 mg/d 10 mg/d 14 mg/d 20 mg/d
Cushing diseaseb
1 mg/d (n = 1)1
2 mg/d (n = 10)811
4 mg/d (n = 11) 1 1 1 4 2 2
Adrenal CS
1 mg/d (n = 1)1
4 mg/d (n = 1)1
EAS
4 mg/d (n = 2)11
Some patients had the same starting and final doses as their doses were increased then decreased during the study.
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome.
aOsilodrostat starting doses were given twice daily in all except 3 patients with Cushing disease (initiated on 1 mg once daily, 2 mg once daily, and 4 mg once daily) and 1 patient with adrenal CS (initiated on 1 mg once daily).
bOne patient had only their osilodrostat starting dose reported.
Mean (SD) duration of follow-up was 37.1 (20.5) weeks, and mean (SD) duration of osilodrostat treatment was 37.0 (20.9) weeks; almost all patients with postinitiation clinical encounters (96.6%) received treatment for 6 months or longer (see Table 2).
Changes in Cortisol Levels During Osilodrostat Treatment
In patients with available assessments, median values for all cortisol parameters decreased during osilodrostat treatment, regardless of CS etiology (Table 4). In the subgroup of patients with Cushing disease, median UFC and morning serum cortisol levels were less than the ULN at the last assessment (0.71 and 0.68 × ULN, respectively), while median LNSC levels were slightly higher than the ULN (1.13 × ULN). In patients with UFC, LNSC, and morning serum cortisol levels greater than the ULN at baseline, 12 of 16, 3 of 8, and 8 of 15, respectively, had levels less than the ULN during osilodrostat treatment (Fig. 2); the final osilodrostat doses in these patients ranged from 1 to 20 mg/day. Neither of the patients who had a final dose of 20 mg/day were receiving concomitant glucocorticoids (ie, they were not being treated with a “block-and-replace” approach). In those with UFC and morning serum cortisol less than the ULN at baseline, levels remained less than the ULN in 1 of 1 and 7 of 8 patients, respectively.
Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.
Figure 2.Changes in A, UFC; B, LNSC; and C, morning serum cortisol in individual patients. *In patient 23, the first and last doses recorded were both 2 mg twice daily; during the follow-up period, 2 changes in dose were recorded the same day on 2 separate occasions.
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Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LNSC, late-night salivary cortisol; NA, not available; UFC, urinary free cortisol; ULN, upper limit of normal.
Table 4.Open in new tabMedian (minimum-maximum) urinary free cortisol, late-night salivary cortisol, and morning serum cortisol levels (overall and by etiology)
  All patients Cushing disease Adrenal CS EAS
UFC, × ULN n = 21 n = 17 n = 2 n = 2
 Baseline 3.73 (0.09-75.20) 3.03 (0.09-11.17) 14.40 (1.03-27.76) 54.27 (33.33-75.20)
 Last assessment 0.71 (0.02-11.82) 0.71 (0.07-4.19) 6.18 (0.53-11.82) 1.44 (0.02-2.86)
LNSC, × ULN n = 8 n = 8 n = 0 n = 0
 Baseline2.39 (1.44-5.89)2.39 (1.44-5.89)
 Last assessment1.13 (0.44-4.44)1.13 (0.44-4.44)
Morning serum cortisol, × ULN n = 30 n = 23 n = 5 n = 2
 Baseline 1.15 (0.19-4.38) 1.16 (0.19-1.88) 0.83 (0.39-2.76) 2.91 (1.43-4.38)
 Last assessment 0.67 (0.02-2.76) 0.68 (0.19-1.87) 0.61 (0.05-2.76) 0.47 (0.02-0.93)
Results are based on patients with both baseline and postosilodrostat prescription data available.
Abbreviations: CS, Cushing syndrome; EAS, ectopic adrenocorticotropin syndrome; LNSC, late-night salivary cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.
The effect of osilodrostat on UFC and morning serum cortisol levels in individual patients with adrenal CS or EAS and available data are shown in Fig. 2A and 2C, respectively. In patients with adrenal CS, UFC levels were reduced in the 2 patients with data available, and morning serum cortisol levels were reduced in 2 of 5 patients with data available. In patients with EAS, there were substantial reductions both in UFC and morning serum cortisol (n = 2).
The time course of cortisol changes and corresponding osilodrostat doses in 2 patients with Cushing disease and 2 patients with EAS are illustrated in Fig. 3.
Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.
Figure 3.Individual osilodrostat dosing, UFC, and serum cortisol levels during the study period in illustrative patients. ULN for UFC was 50 μg/24 hours for patients 11, 4, and 1 and 42 μg/24 hours for patient 2. *ULN for serum cortisol was not provided for this patient, so it was estimated to be approximately 18 µg/dL.
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Abbreviations: BID, twice daily; EAS, ectopic adrenocorticotropin syndrome; UFC, urinary free cortisol; ULN, upper limit of normal.
Safety and Tolerability
Overall, 29 patients (69.0%) had an AE reported. The most common AEs (incidence ≥20%) were fatigue, nausea, and lower-extremity edema (Table 5).
Table 5.Open in new tabAdverse events reported during osilodrostat treatment (overall patient population)a
AE, n (%) n = 42a
Any AE 29 (69.0)
Fatigue 23 (54.8)
Nausea 12 (28.6)
Lower-extremity edema 11 (26.2)
Headache 6 (14.3)
Dizziness 6 (14.3)
Hypokalemia 6 (14.3)
Alopecia 4 (9.5)
Vomiting 3 (7.1)
Hypotension 2 (4.8)
Hyperkalemia 1 (2.4)
Prolonged QT interval on electrocardiogram 1 (2.4)
Abbreviation: AE, adverse event.
aIncludes 2 patients who had no postinitiation interaction before study end.
According to the events reported by the investigators, 13 patients had GWS (n = 3), AI (n = 3), or both (n = 7). Of these, osilodrostat treatment was interrupted in 3 patients, the dose was decreased in 2 patients, and there was no change in dose in 4 patients; in the remaining 4 patients, osilodrostat treatment was discontinued. Glucocorticoid use was reported in 4 patients overall; this included 2 patients in whom AI and/or GWS were reported. The first patient reported to have AI and GWS by the investigator was prescribed hydrocortisone 5 mg twice daily for 2 weeks. The second patient (AI) was also prescribed hydrocortisone at a dose of 20 mg/day (duration not specified).
On author adjudication, using the criteria outlined in “Materials and Methods,” 1 case of AI was reclassified as GWS and 5 cases reported to be both GWS and AI by the investigator were reclassified as AI only. Another case of AI was excluded as the symptoms of AI had started before initiation of osilodrostat; this patient had been treated with pasireotide in the 5 months before starting osilodrostat. Thus, the number of author-adjudicated cases during osilodrostat treatment was 12: 4 for GWS, 6 for AI, and 2 for both (ie, patients experiencing ≥1 distinct episode of GWS and AI).
To illustrate different presentations and management practices of AI and GWS, we describe details regarding individual cases. In 1 patient with GWS, symptoms were dizziness, nausea, and fatigue, with serum cortisol levels remaining above 10 µg/dL (276 nmol/L). The symptoms occurred early in the course of treatment and were managed by reducing the osilodrostat dose. In another patient with GWS, symptoms occurred after prolonged treatment, and osilodrostat was discontinued. In 2 patients with AI, symptoms were also dizziness, nausea, and fatigue, but serum cortisol levels were less than or equal to 10 µg/dL (≤276 nmol/L). In the first patient, osilodrostat was maintained at the same dose; symptoms resolved and cortisol levels increased slightly, to above 10 µg/dL (276 nmol/L). Treatment was interrupted in the second patient, but further information on the symptoms and cortisol levels were unavailable.
In patients with available data at baseline and last assessment (n = 38), median (minimum-maximum) serum potassium levels were 4.0 (2.6-5.6) and 4.3 (3.7-5.5) mmol/L, respectively. In those who were normokalemic at baseline (n = 30), 2 patients had potassium levels less than the lower limit of normal during osilodrostat treatment; in those who were hypokalemic at baseline (n = 4), 3 patients had potassium levels reverting to normal during treatment. In female patients with available data at baseline and last assessment (n = 4), mean testosterone levels were 1.48 × ULN at baseline and 1.52 × ULN at the last posttreatment assessment.
Discussion
This study evaluated the real-world use of osilodrostat in patients in the United States with CS during the period shortly after osilodrostat was approved by the US Food and Drug Administration for the treatment of adults with Cushing disease for whom pituitary surgery is not an option or has not been curative. The results highlight the importance of selecting a starting dose and titration regimen according to each patient’s circumstances, clinical response, and tolerability, as the dose required to normalize cortisol levels varies between patients and does not appear to depend on baseline levels. Most of the patients in the study (n = 34/42 [81.0%]) had Cushing disease, as expected. In this subgroup, most patients (n = 21/34 [61.8%]) were initiated on the approved starting dose of osilodrostat (2 mg twice daily), but many (n = 11/34 [32.4%]) were started on lower doses. All patients with Cushing disease who were initiated on doses lower than 2 mg twice daily required a dose increase during the study. A dose of 2 mg twice daily was also the most common maintenance dose in those with Cushing disease who reached a maintenance dose: a total of 57.1% remained on 2 mg twice daily, while 28.6% and 14.3% were uptitrated to 4 mg twice daily and 10 mg twice daily, respectively. In phase 3 clinical trials of osilodrostat in patients with Cushing disease (LINC 3 and LINC 4), median (interquartile range) average doses at the end of the extension periods were 7.4 (3.5-13.6) mg/day in LINC 3 and 4.6 (3.7-9.2) mg/day in LINC 4 [9, 11]. In the present study, most patients whose dose was uptitrated required only one dose increase. Mean duration of the titration period in patients with Cushing disease, defined as the period between any osilodrostat dose changes, was 14.8 weeks. In LINC 3 and LINC 4, doses were increased according to UFC levels in the first 12 weeks, after which dose adjustments were permitted during the remainder of the 48-week core period based on efficacy and tolerability [10, 12]. In both trials, starting and final osilodrostat doses were lower in Asian patients with Cushing disease than in non-Asian patients, regardless of body mass index, likely because of differences in bioavailability [24].
In the subgroup of patients with Cushing disease, most of those with UFC and morning serum cortisol levels greater than the ULN at baseline had their levels reduced to normal during treatment (12/16 and 8/15, respectively). Some patients had UFC and morning serum cortisol levels less than the ULN when osilodrostat was initiated, presumably reflecting a switch to osilodrostat from another medical therapy (eg, because of tolerability issues). More than 60% of patients had received one or more medical therapies before starting osilodrostat, but the reasons for stopping these therapies were not collected as part of the study. In patients with normal levels at study baseline, levels remained less than the ULN in 1 of 1 patient for UFC and 6 of 8 patients for morning serum cortisol. Median levels of UFC and morning serum cortisol in the subgroup of patients with Cushing disease decreased to within the normal range during osilodrostat treatment. These real-world results are consistent with those from the 48-week core phases of LINC 3 and LINC 4 [10, 12, 13].
The present study also included a small number of patients with adrenal CS (n = 5) and EAS (n = 3). The starting dose was 2 mg twice daily in all patients with EAS; in patients with adrenal CS, the starting dose was 2 mg twice daily (n = 3), 1 mg twice daily (n = 1), and 1 mg once daily (n = 1). Baseline median UFC, which was higher in the adrenal CS and EAS subgroups than in patients with Cushing disease, decreased during osilodrostat treatment but remained above the ULN. Median morning serum cortisol levels decreased from above to within the normal range in patients with EAS and remained within the normal range in patients with adrenal CS. Notably, baseline levels of morning serum cortisol, mean UFC, or LNSC did not necessarily predict the osilodrostat dose needed for biochemical normalization. Again, these results emphasize the need to individualize the starting dose and titration regimen based on each patient’s clinical circumstances and response to treatment. Differences in the pathophysiology of CS subtypes may also influence decisions about osilodrostat titration; for example, unlike in Cushing disease, ACTH rarely rises during inhibition of cortisol synthesis in EAS, and the rise in ACTH is delayed after cortisol normalization in adrenal CS. The results for the adrenal CS and EAS subgroups in the present study should be interpreted with caution given the small number of patients, and data from individual patients are perhaps more illustrative in this context. Individual UFC and morning serum cortisol levels were reduced in all patients with adrenal CS or EAS except for 2 patients (both with adrenal CS), whose morning serum cortisol levels did not change; in one of these patients, morning serum cortisol was within the normal range at baseline. Data on LNSC levels should also be interpreted with caution given the small number of patients with data available for this parameter.
The safety profile of osilodrostat was similar to that observed in clinical trials [10, 12, 14], with no unexpected safety signals. GWS and AI are recognized as potential side effects of osilodrostat based on its mechanism of action, but they can be difficult to differentiate as many of their symptoms overlap [25]. In the present study, there were 12 cases of GWS and/or AI after initiation of osilodrostat (28.6% of patients); this rate is lower than in the LINC 3 clinical trial (54.0% of patients with hypocortisolism-related AEs) [9] and similar to that seen in LINC 4 (27.4%) [11]. In LINC 3 and LINC 4, most hypocortisolism-related AEs were classified by the investigator as AI [11], but further evaluation to differentiate between this and GWS was not possible. For the present study, we were able to evaluate the symptoms and biochemical changes associated with these AEs, and we confirmed that it was often not possible for clinicians to accurately distinguish GWS and AI based on symptoms alone. As GWS and AI may require different management approaches, measurement of serum cortisol levels is essential to help guide the management strategy in these cases. In the present study, most cases of GWS and AI were managed by reducing the dose or temporarily interrupting treatment, which is consistent with the results from LINC 3 and LINC 4 [9-12]; only 4 patients (9.5%) with AI or GWS in the present study had discontinued treatment as a result. Treatment with glucocorticoids was recorded in 2 patients; the timing of treatment indicates that glucocorticoids were used to treat the symptoms of AI/GWS rather than as part of a “block-and-replace” strategy, in which glucocorticoids are administered concomitantly with osilodrostat [21, 26]. Slower dose escalation may reduce the risk of hypocortisolism-related AEs; the longer titration interval in LINC 4 (every 3 weeks) than in LINC 3 (every 2 weeks) may explain the lower incidence of hypocortisolism-related AEs during LINC 4 [10, 12]. Regardless, and as with all steroidogenesis inhibitors, all patients treated with osilodrostat should be monitored regularly and educated on the signs and symptoms of GWS and AI. Case reports have described rare episodes of delayed cortisol reduction during chronic osilodrostat therapy and prolonged AI after its discontinuation, which emphasizes the importance of lifelong, close monitoring of symptoms and serum cortisol levels [27-29].
The results of the present study are consistent with those of previous studies demonstrating the efficacy and safety of osilodrostat in patients with EAS or adrenal CS. In a prospective phase 2 study conducted in Japan, mean UFC levels decreased in all patients and normalized in most following 12 weeks of treatment [14]. In LINC 7, a retrospective study conducted in France, 103 patients with adrenal CS or EAS were followed up retrospectively for up to 36 months; at last assessment, mean UFC was normalized in most patients [30]. Compared with LINC 7, the starting and maintenance doses of osilodrostat were lower in the present study, once again emphasizing the importance of individualizing osilodrostat dosing. In a second real-world study in France, which was conducted in 30 patients with EAS, median UFC decreased significantly following osilodrostat monotherapy (when used both first and second line) and combination therapy with other cortisol-lowering drugs [21]. There were also substantial improvements in hypertension, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of concomitant treatments. Several other case series and case reports have documented effective control of cortisol levels and good tolerability in patients with adrenal CS or EAS [26, 31-38], adding to the body of evidence supporting the use of osilodrostat in patients with CS irrespective of severity and etiology.
Limitations of the present study include the small patient numbers, particularly in the groups with adrenal CS and EAS. As the study was conducted shortly after osilodrostat was approved in the United States for patients with Cushing disease for whom pituitary surgery is not an option or has not been curative, the predominance of patients with Cushing disease was expected, albeit slightly higher (81%) than the overall prevalence of Cushing disease (up to 70%), vs other causes of CS in a clinical setting [2]. Another limitation is that data were extracted retrospectively from patients’ medical records rather than recorded prospectively according to a study protocol; this resulted in many missing data points, especially for laboratory data. Despite these limitations, the results provide invaluable information on the real-world use of osilodrostat in the United States, for which data are currently lacking. The design of the study also allowed adjudication of AI vs GWS events by the authors in some patients as morning cortisol levels were available. In addition, ILLUSTRATE is the only completed multicenter study in the United States to date that evaluates the effect of osilodrostat not only in Cushing disease, but also in adrenal CS and EAS, providing data on the cortisol-lowering effectiveness of osilodrostat across the spectrum of hypercortisolism etiologies.
Conclusions
Results of this real-world study are consistent with those from clinical trials and other real-world studies, showing that osilodrostat was effective and well tolerated in patients with varying etiologies and severities of CS when used by physicians in routine clinical practice. The results also highlight the importance of individualizing the osilodrostat dose and titration regimen according to each patient’s clinical condition, response, and tolerability.
Acknowledgments
We thank all clinicians and patients who participated in the study.
Funding
This work was supported by Recordati Rare Diseases Inc, Bridgewater, New Jersey, United States. AMICULUM provided medical editorial assistance, funded by Recordati Rare Diseases Inc.
Disclosures
M.F. reports grants to her university from Crinetics and Sparrow and occasional scientific consulting fees from Crinetics, Recordati Rare Diseases, Sparrow, and Xeris Pharmaceuticals; she served as a member of the LINC 3 steering committee. R.J.A. reports grants and personal fees from Xeris Pharmaceuticals, Spruce Biosciences, Neurocrine Biosciences, Corcept Therapeutics, Diurnal Ltd, Sparrow Pharmaceuticals, Crinetics Pharmaceuticals, and Recordati Rare Diseases and personal fees from Adrenas Therapeutics, Quest Diagnostics, H Lundbeck A/S, Novo Nordisk, and Besins Pharmaceuticals. W.H. reports grants to his institution from CinCor, Corcept, Crinetics, Spruce, and Ascendis and honoraria from Novo Nordisk, Recordati Rare Diseases, Chiesi, Crinetics, Neurocrine, Camurus, and Spruce. J.L.S.-S. reports research grants from Recordati Rare Diseases and scientific consulting fees from Crinetics, Recordati Rare Diseases, and Corcept. K.C.J.Y. reports grants to his institution from Corcept, Sparrow, Chiesi, and Ascendis and honoraria from Novo Nordisk, Ascendis, Chiesi, Recordati Rare Diseases, Xeris, Crinetics, Camurus, and Neurocrine. K.C.D. and J.P. are employees of Recordati Rare Diseases Inc. E.K.B. was an employee of Recordati Rare Diseases Inc at the time the study was conducted (current affiliation: Inizio Engage, Yardley, Pennsylvania, USA). A.K.D., C.C., and M.S.B. are employees of PHAR, which received funding from Recordati Rare Diseases Inc to conduct the analysis. A.G.I. reports grants to her university from Recordati Rare Disease, Xeris Pharmaceuticals, and Chiesi and occasional consulting fees from Xeris Pharmaceuticals, Crinetics, Camurus, and Chiesi.
Data Availability
Some data sets generated and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
References
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Abbreviations
ACTH
adrenocorticotropin
AE
adverse event
AI
adrenal insufficiency
CS
Cushing syndrome
EAS
ectopic adrenocorticotropin syndrome
eCRF
electronic case report form
GWS
glucocorticoid withdrawal syndrome
ILLUSTRATE
osIlodrostat reaL-worLd Utilization Study To Retrospectively Assess paTient Experience
LLN
lower limit of normal
LNSC
late-night salivary cortisol
UFC
urinary free cortisol
ULN
upper limit of normal
© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
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The Impact of Prolonged High-Concentration Cortisol Exposure on Cognitive Function and Risk Factors: Evidence From Cushing’s Disease Patients

Posted on May 7, 2025 by MaryO

Abstract

Background

Prolonged high-concentration cortisol exposure may impair cognitive function, but its mechanisms and risk factors remain unclear in humans.

Objective

Using Cushing’s disease patients as a model, this study explores these effects and develops a predictive model to aid in managing high-risk patients.

Methods

This single-center retrospective study included 107 Cushing’s disease patients (January 2020–January 2024) at the First Medical Center of the PLA General Hospital. Cognitive function, assessed using the Montreal Cognitive Assessment, revealed 58 patients with cognitive impairment and 49 with normal cognitive function. Patients were divided into training (n = 53) and validation cohorts (n = 54) for constructing and validating the predictive model. Risk factors were identified via univariate analysis and least absolute shrinkage and selection operator regression, and a nomogram prediction model was developed. Performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).

Results

Cortisol AM/PM ratio, 8 a.m. cortisol concentration, body mass index, and fasting plasma glucose were significant risk factors for cognitive impairment. The nomogram demonstrated strong predictive ability, with ROC values of 0.80 (training) and 0.91 (validation). DCA indicated superior clinical utility compared to treating all or no patients.

Conclusions

This study confirms the significant impact of prolonged high cortisol exposure on cognitive function and identifies key risk factors. The nomogram model offers robust performance, providing a valuable tool for managing Cushing’s disease patients’ cognitive health and informing strategies for other cortisol-related disorders.

Introduction

Chronic stress and prolonged pressure increasingly pose significant burdens on individual health and social systems, particularly on a global scale. Their impact on cognitive function, mental health, and physical well-being cannot be ignored.1 Long-term stress responses and sustained exposure to pressure not only elevate the risk of multiple diseases but also result in considerable socioeconomic burdens. According to the World Health Organization (WHO), approximately 300 million people worldwide suffer from depression, with stress and emotional disorders being critical contributing factors.2 This phenomenon may be associated with prolonged exposure to high concentrations of cortisol induced by chronic stress.3 Such long-term elevated cortisol exposure is thought to exert adverse effects on multiple systems, including the nervous system, leading to anxiety, depression, and cognitive impairment. While the roles of anxiety and depression have been well established,4 the specific impact on cognitive function remains unclear.
Research suggests that abnormally elevated cortisol levels significantly affect brain structure and function. The hippocampus, a key target highly sensitive to cortisol and central to learning and memory, is particularly affected. High cortisol exerts its effects through glucocorticoid receptors and mineralocorticoid receptors in the hippocampus, mediating neurophysiological responses. Prolonged activation may lead to neuronal damage, reduced neuroplasticity, and cognitive impairment.5,6 Additionally, brain regions such as the prefrontal cortex and amygdala are also impacted, potentially causing attentional deficits, impaired executive function, and emotional regulation disturbances.7 Furthermore, abnormal diurnal cortisol rhythms are closely linked to neuroinflammation, oxidative stress, and cerebrovascular lesions.8,9 These mechanisms may interact synergistically to exacerbate cognitive impairment. While animal studies provide substantial evidence for cortisol’s effects on cognitive function, human studies face ethical constraints and experimental limitations. The lack of models for long-term stress and pressure in humans, coupled with challenges in conducting long-term follow-ups, highlights the need for suitable research subjects.
Cushing’s disease is an endocrine disorder caused by excess adrenocorticotropic hormone (ACTH) secretion by anterior pituitary adenomas, leading to abnormally elevated cortisol levels.10 The unique pathological features of Cushing’s disease offer a natural model for studying the effects of prolonged high cortisol exposure on human cognitive function. Patients with Cushing’s disease often experience cognitive impairments, with clinical manifestations including memory decline, attention deficits, and impaired executive function.11–13 However, the specific mechanisms and risk factors underlying these impairments remain unclear.
Against this backdrop, this study uses Cushing’s disease patients as subjects to systematically evaluate the impact of prolonged high cortisol exposure on cognitive function and analyze associated risk factors. Additionally, we develop a nomogram prediction model aimed at improving the identification of high-risk patients, providing a reference for clinical interventions, and offering new perspectives and evidence for the cognitive management and research of cortisol-related disorders.

Methods

Study subjects

This study is a single-center retrospective study that included 107 patients diagnosed with Cushing’s disease at the First Medical Center of the PLA General Hospital between January 2017 and January 2024. Inclusion criteria were as follows: (i) meeting the WHO diagnostic criteria for Cushing’s disease; (ii) disease duration >3 months; (iii) no prior surgical treatment; (iv) complete laboratory and imaging data; (v) no other neurological or psychiatric disorders that could cause cognitive impairment (e.g., dementia, depression, stroke). Exclusion criteria included: (i) disease duration ❤ months; (ii) prior surgical treatment; (iii) missing critical baseline or laboratory data; (iv) severe visual or hearing impairments that could affect cognitive testing results. A total of 107 patients were included in the study, among whom 58 had cognitive impairment and 49 exhibited mild cognitive decline. Cognitive function was classified as follows: Montreal Cognitive Assessment (MoCA) score ≤26 was defined as cognitive impairment, 27–29 as mild cognitive decline, and 30 as normal cognitive function.

Study design

A random allocation method was used to divide all patients into a training cohort (n = 53) and a validation cohort (n = 54) at a 5:5 ratio. The training cohort was used for variable selection and predictive model development, while the validation cohort was used for performance evaluation of the model. The study was approved by the hospital ethics committee (approval number: [S2021-677-01]).

Clinical data collection

Clinical characteristics and laboratory data of patients were obtained from the hospital’s electronic medical record system and included the following: (i) Demographic and clinical characteristics: age, sex, disease duration, years of education, body mass index (BMI), systolic blood pressure, and diastolic blood pressure; (ii) Laboratory indicators: fasting plasma glucose (FPG), 24-h urinary free cortisol, serum cortisol concentrations (0 a.m., 8 a.m., 4 p.m.), ACTH concentrations (0 a.m., 8 a.m., 4 p.m.), total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, cortisol AM/PM ratio (CORT AM/PM), and results of low-dose dexamethasone suppression tests and high-dose dexamethasone suppression tests; (iii) Cognitive function assessment: conducted using the MoCA scale.

Statistical analysis and model development

Categorical variables were expressed as numbers (%), and continuous variables as mean ± standard deviation (SD) or median (interquartile range, IQR). Intergroup comparisons were performed using the chi-square test or Fisher’s exact test for categorical variables. A nomogram was constructed to predict the risk factors for cognitive impairment in patients exposed to prolonged high cortisol levels. Significant clinical features associated with cognitive function were identified through univariate analysis and least absolute shrinkage and selection operator (LASSO) regression analysis.
Based on the final results, a novel nomogram was developed, incorporating all independent prognostic factors to predict the presence or absence of cognitive impairment in individuals exposed to prolonged high cortisol levels. The performance of the nomogram was evaluated using the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), calibration curves, and decision curve analysis (DCA). The C-index was calculated using 1,000 bootstrap samples to assess the internal validity of the model. Each patient’s total score was calculated using the nomogram approach.
Statistical analysis was performed using R programming language and version 4.2.3 of the R environment (http://cran.r-project.org). The main R packages used in this study included gtsummary (version 1.7.0), survival (version 3.5-3), RMS (version 6.3-0), time ROC (version 0.4), and ggplot2 (version 3.4.0).

Results

Patient characteristics

A total of 107 patients with Cushing’s disease were included in this study. MoCA scores revealed that all patients exhibited either cognitive decline or impairment. Among them, 58 patients (54.2%) were classified into the cognitive impairment group, and 49 patients (45.8%) were categorized into the cognitive decline group. Significant differences were observed in demographic characteristics and clinical indicators between the two groups. Detailed information is presented in Table 1.
Table 1. General characteristics of patients.
Variables Total (n = 107) 0 (n = 49) 1 (n = 58) p
sex, n (%) 1
1 10 (9) 5 (10) 5 (9)
2 97 (91) 44 (90) 53 (91)
age, Mean ± SD 41.22 ± 11.19 39.16 ± 11.21 42.97 ± 10.96 0.08
Education y, Median (Q1,Q3) 12 (8, 16) 12 (8, 16) 12 (8.25, 15) 0.835
BMI, Mean ± SD 27.01 ± 3.46 25.49 ± 2.25 28.29 ± 3.79 <0.001
Illness duration, Median (Q1,Q3) 26 (12, 48) 24 (12, 48) 33 (12, 48) 0.6
COR-0am, Mean ± SD 565.86 ± 207.53 513.69 ± 185.87 609.94 ± 216.06 0.015
COR-8am, Mean ± SD 725.63 ± 259.03 612.26 ± 197.79 821.41 ± 267.29 <0.001
COR-4pm, Median (Q1,Q3) 619.19 (491.14, 744.17) 598.3 (472.49, 678.18) 650.43 (503.34, 803.88) 0.109
ACTH0am, Median (Q1,Q3) 12.4 (9.02, 18.4) 11 (8.46, 17.2) 13.95 (9.57, 19.51) 0.114
ACTH8am, Median (Q1,Q3) 15.2 (11.1, 23.5) 13.3 (10.6, 19.4) 17.4 (13.33, 26.27) 0.027
ACTH4pm, Median (Q1,Q3) 15.9 (10.45, 22.75) 13.6 (10.4, 22.6) 16.6 (10.95, 25.15) 0.275
UFC, Median (Q1,Q3) 1644.9 (1146.2, 2501.75) 1483 (1092.3, 2020.6) 1931 (1168.85, 2793.02) 0.131
LDDST-ACTH, Median (Q1,Q3) 16.9 (9.31, 21.15) 16.1 (8.35, 20.6) 17.25 (10.12, 21.17) 0.555
LDDST-CORT, Median (Q1,Q3) 532.95 (390.46, 787.61) 501.63 (360.4, 792.18) 568.37 (398.76, 781.7) 0.606
LDDST-UFC, Median (Q1,Q3) 1050.8 (531.9, 2077.2) 880.6 (454.4, 2419.9) 1200 (580.62, 2010.23) 0.589
HDDST-ACTH, Median (Q1,Q3) 8.81 (5.2, 15.7) 8.48 (4.91, 16.6) 9.12 (5.42, 14.45) 0.837
HDDST-CORT, Median (Q1,Q3) 222.3 (62.41, 354.31) 222.3 (61.7, 348.84) 217.56 (76.25, 356.78) 0.662
HDDST-UFC, Median (Q1,Q3) 336.9 (130.9, 870.86) 281.2 (128.4, 791.7) 391.4 (140.25, 923.43) 0.488
SBP, Mean ± SD 159.09 ± 26.08 157.76 ± 26.67 160.22 ± 25.75 0.629
DBP, Median (Q1,Q3) 105 (92, 116.5) 105 (90, 119) 102.5 (94.5, 114) 0.927
TC, Median (Q1,Q3) 5.13 (4.46, 6.17) 4.92 (4.47, 5.72) 5.24 (4.44, 6.31) 0.386
TG, Median (Q1,Q3) 1.42 (0.99, 2.04) 1.39 (0.99, 2.41) 1.42 (0.99, 1.97) 0.861
ALT, Median (Q1,Q3) 23 (17.55, 33.7) 20.7 (15.8, 33) 23.85 (18.45, 34.3) 0.35
AST, Median (Q1,Q3) 15.2 (13, 18.5) 14.1 (12.7, 18.5) 16.35 (13.62, 18.45) 0.184
GGT, Median (Q1,Q3) 27.6 (21.75, 44.25) 26.7 (22.6, 45.9) 28.95 (21.32, 41.9) 0.913
FPG, Median (Q1,Q3) 7.62 (5.43, 9.66) 5.7 (4.83, 7.49) 8.95 (7.05, 10) <0.001
CORT AM/PM, Median (Q1,Q3) 1.19 (0.99, 1.34) 1.05 (0.88, 1.2) 1.25 (1.15, 1.4) <0.001
ACTH: adrenocorticotropic hormone; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI, body mass index; COR/CORT: cortisol; DBP: diastolic blood pressure; FPG: fasting plasma glucose; GGT: gamma-glutamyl transferase; HDDST: high-dose dexamethasone suppression tests; LDDST: low-dose dexamethasone suppression tests; SBP: systolic blood pressure; TC: total cholesterol; TG: triglycerides; UFC: urinary free cortisol.

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Model development

In the modeling cohort, LASSO regression analysis was used for variable selection. The regression coefficient path diagram and cross-validation curve are shown in Figure 1A and 1B. To ensure a good model fit, the λ corresponding to the minimum mean squared error was chosen through cross-validation. Four variables were identified through LASSO regression analysis: CORT AM/PM, COR-8am, FPG, and BMI. These variables were ultimately deemed risk factors for cognitive impairment associated with prolonged high cortisol exposure. Based on these four significant variables, a nomogram was developed to predict cognitive impairment under prolonged high cortisol exposure, and the model was visualized using a nomogram (Figure 2).
Figure 1. LASSO Cox regression model construction. (A) LASSO coefficient of 27 features. (B) Selection of tuning parameter (k) for the LASSO model.

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Figure 2. Nomogram predicting cognitive impairment in patients with prolonged high cortisol exposure.

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Model performance and validation

To comprehensively evaluate the model’s performance, multiple metrics were employed to verify its accuracy, stability, and clinical utility, including the concordance index (C-index), AUC, calibration curves, and DCA. The AUC values for the training cohort (Figure 3A) and the internal validation cohort (Figure 3B) were 0.80 and 0.91, respectively. These results indicate that the nomogram model effectively distinguishes patients with cognitive impairment in different sample datasets and demonstrates strong predictive accuracy. Calibration curves showed a high level of agreement between the predicted and actual probabilities of cognitive impairment in both the training cohort (Figure 4A) and the validation cohort (Figure 4B), further confirming the model’s stability and utility.
Figure 3. The ROC curve of the predictive model for cognitive impairment in patients with prolonged high cortisol exposure. (A) Derivation cohort. (B) Validation cohort.

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Figure 4. Calibration curves of the nomogram. (A) Derivation cohort. (B) Validation cohort.

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To assess the clinical utility of the model, DCA was performed (Figure 5). The results demonstrated that the clinical benefit of using the model to predict cognitive impairment was significantly higher than strategies of treating all patients or treating none (Figure 5). This finding suggests that the nomogram model provides substantial net benefit in clinical decision-making, effectively aiding clinicians in identifying high-risk patients and implementing appropriate interventions.
Figure 5. DCA curves of the nomogram in the training cohort and test cohort.

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Discussion

This study used patients with Cushing’s disease as a model to investigate the effects of prolonged high-concentration cortisol exposure on human cognitive function. The findings revealed that individuals exposed to long-term high cortisol levels generally experienced cognitive decline, with the CORT AM/PM, COR-8am, BMI, and FPG identified as major risk factors for cognitive impairment. Additionally, the developed nomogram model demonstrated excellent predictive performance in both the training (AUC = 0.80) and validation (AUC = 0.91) cohorts, highlighting its strong discriminative ability and clinical utility. These findings provide a foundation for mechanistic research and clinical management of prolonged high cortisol exposure.
BMI, FPG, CORT AM/PM, and COR-8am, as risk factors, are closely related to cortisol levels and its effects on the nervous system. Increased BMI was identified as an independent risk factor for cognitive impairment, likely due to chronic inflammation and oxidative stress caused by metabolic disorders.14–16 Obesity and elevated cortisol levels may form a vicious cycle, further exacerbating damage to the nervous system. Studies have shown that reduced cerebral blood flow and neuronal damage in obese individuals are directly linked to cognitive impairment,17 underscoring the importance of monitoring metabolic status in Cushing’s disease patients. High blood glucose was another critical risk factor, potentially affecting cognitive function through various mechanisms: prolonged hyperglycemia can lead to cerebrovascular damage and impaired blood supply to the brain;18 it may also directly harm neurons through oxidative stress and inflammatory responses.19 Moreover, chronic hyperglycemia alters insulin signaling pathways, disrupting glucose metabolism in the brain and further aggravating cognitive decline.20 Additionally, the study showed that disrupted cortisol circadian rhythms (elevated CORT AM/PM) and increased morning cortisol peaks (COR-8am) were closely associated with cognitive impairment. Circadian rhythm disruption may accelerate hippocampal atrophy and prefrontal cortex dysfunction by affecting the regulation of the hypothalamic-pituitary-adrenal (HPA) axis.21 Excessive morning cortisol peaks may exacerbate neuroinflammation and synaptic dysfunction,22 a finding also supported by previous animal studies.
Cushing’s disease serves as an effective model for studying high cortisol states induced by chronic stress, given the high similarity in pathophysiological mechanisms between the two. Cushing’s disease results from tumor-induced HPA axis hyperactivation, causing sustained cortisol overproduction,23 while chronic stress similarly activates the HPA axis, maintaining cortisol at persistently high levels. Although the etiology of Cushing’s disease is endogenous and pathological, whereas high cortisol in chronic stress is environmentally induced, both share similar features such as metabolic disturbances (e.g., insulin resistance, central obesity), immunosuppression (e.g., increased infection susceptibility), osteoporosis, and psychological disorders (e.g., anxiety and depression).24 Therefore, Cushing’s disease provides an effective model for studying metabolic, immune, and neurological changes in high cortisol states, offering experimental evidence for understanding chronic stress-related disorders and developing intervention strategies.
The results of this study align with previous animal experiments. For instance, animal studies have shown that prolonged cortisol exposure leads to hippocampal atrophy and neuronal damage, impairing cognitive function.25 This study provides supportive evidence in human samples. Furthermore, prior research has found that disrupted cortisol circadian rhythms are often associated with executive function decline in patients with depression,26 consistent with our findings that CORT AM/PM is significantly associated with cognitive impairment in Cushing’s disease patients. Unlike earlier studies focusing primarily on cortisol’s direct neurotoxic effects, this study integrated metabolic indicators (e.g., BMI, FPG) to comprehensively analyze the interaction between cortisol and metabolic disturbances, expanding the understanding of mechanisms underlying cortisol-induced cognitive impairment.
Moreover, unlike previous research that was predominantly based on animal models, this study systematically analyzed data from 107 Cushing’s disease patients, further validating these mechanisms in humans. The construction of the nomogram model significantly enhanced predictive accuracy, providing a practical tool for clinical application.
Despite providing important evidence for the impact of prolonged high cortisol exposure on cognitive function, this study has limitations. First, as a single-center retrospective study with a limited sample size, the results may lack generalizability and require prospective validation. Although Cushing’s disease serves as a model for high cortisol exposure, further validation in populations experiencing chronic stress or prolonged pressure is needed. Second, the lack of long-term follow-up data prevents evaluation of the effects of surgical treatment or other interventions on cognitive function. Third, this study did not consider the impact of sex hormones on cortisol levels and cognitive function. Sex hormones (such as estrogen and testosterone) may regulate cortisol and influence the central nervous system.

Conclusion

This study, using patients with Cushing’s disease as a model, explored the impact of prolonged high-concentration cortisol exposure on human cognitive function. The findings revealed that individuals with prolonged high cortisol exposure commonly experience cognitive decline, with CORT AM/PM, COR-8am, BMI, and FPG identified as major risk factors for cognitive impairment. The nomogram model developed based on these risk factors demonstrated excellent predictive performance and clinical applicability in both the training and validation cohorts, providing an effective tool for the early identification of high-risk patients. These results not only confirmed the significant impact of prolonged high cortisol exposure on the central nervous system but also highlighted the critical role of metabolic factors in this process, emphasizing the multifactorial mechanisms of cognitive impairment. These findings offer a scientific basis for managing the cognitive health of Cushing’s disease patients and provide important insights for prevention and treatment strategies for other cortisol-related conditions, such as chronic stress and metabolic syndrome.

Acknowledgments

We thank the patient for granting permission to publish this information. We appreciate all the team members who have shown concern and provided treatment advice for this patient the Chinese People’s Liberation Army (PLA) General Hospital.

Ethical considerations

This study was approved by the Ethics Committee of the Chinese PLA General Hospital (Approval No. [S2021-67701]).

Consent to participate

All participants provided written informed consent prior to inclusion in the study.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant Nos. 82001798 to Xinguang Yu; Grant Nos. 81871087 to Yanyang Zhang) and the Young Talent Project of Chinese PLA General Hospital (Grant Nos. 20230403 to Yanyang Zhang).

ORCID iDs

Data availability statement

Data are available from the corresponding authors on reasonable request.

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Cardiometabolic Complications After Cushing’s Disease Remission

Posted on April 30, 2025 by MaryO

Abstract

Background and aim

Cushing’s disease (CD) is associated with phenotypic traits and comorbidities that may persist after the normalization of cortisol levels. Medical therapy is usually given in recurrent or persistent CD after transsphenoidal surgery. We aimed to investigate the impact of long-term normalization of daily cortisol secretion on clinical picture and cardiometabolic comorbidities, comparing surgical remission to medical treatment.

Methods

Monocentric retrospective study, two- and five-years observation. Sixty CD patients, with sustained normal 24-h urinary free cortisol (UFC) levels, divided group 1 (surgical remission, n = 36) and group 2 (medical remission, n = 24).

Results

Patients were different after achieving eucortisolism with surgery or medical treatment. Phenotypic traits: round face, dorsocervical fat pad, and bruisability persisted more prominently in the group 2, however abdominal obesity and muscle weakness persisted in both groups, especially in those patients with increased late-night salivary cortisol (LNSC). Hypertension: greater improvement was observed in group 1 (-31% vs. -5%, p = 0.04). Diabetes: less prevalent in group 1 after 2 years (2/36 vs. 9/24, p = 0.002), with a corresponding reduction in glucose-lowering treatments and persistence of impaired LNSC in diabetic patients (p < 0.001). Dyslipidemia: remained widespread in both groups, with minimal improvement over time (-22% in surgical and − 6% in medical cohort).

Conclusions

Surgical remission leads to faster and sustained improvements in clinical phenotype. However, obesity, arterial hypertension, and dyslipidemia do not completely revert in five years, especially during medical treatment. Most comorbidities persist despite UFC normalization, due to impaired LNSC: the recovery of cortisol rhythms confirms the remission of hypercortisolism.

Introduction

Cushing’s disease (CD) is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, resulting in persistent endogenous hypercortisolism. The cortisol excess leads to a typical clinical picture: round face, facial plethora, buffalo hump, cutaneous striae rubrae, easy bruising, proximal myopathy, weight gain with visceral obesity, hirsutism and acne [1,2,3]. Moreover, several comorbidities are cortisol-related: metabolic syndrome (visceral obesity, arterial hypertension, glucose intolerance or diabetes, and dyslipidemia), acquired thrombophilia, osteoporosis or vertebral fractures, immunological impairments with increased infection susceptibility, and psychiatric disorders [4]. The sum of physical changes and comorbidities leads to a reduced life expectancy and a worsening of the quality of life [5]. Pituitary trans-sphenoidal surgery (TSS) is the first-choice CD treatment [1]. Despite high remission rates (up to 90% in referral centers) [6], the risk of recurrence varies from 10 to 47% [7], especially in series with long-term follow-up. If surgery fails or is not feasible, cortisol excess can be managed with medical therapy. Not rarely, patients on cortisol-lowering therapy experience fluctuations of their cortisol levels, making outcome evaluations difficult and hardly standardized. The goals of CD treatment are to normalize cortisol levels, and to reduce the burden of comorbidities. The most used biochemical marker in clinical practice is urinary free cortisol (UFC), which estimates the cumulative daily secretion of cortisol, but does not offer information about cortisol rhythm [8].

In this study we compared two groups of CD patients with sustained normalization of 24-h UFC due either to post-surgical or medical cortisol-lowering therapy remission. The aim of the study was to analyze the impact of long-term normalization of hypercortisolism in terms of UFC, achieved with surgical or medical treatment, on endocrine parameters, cortisol-related clinical picture and comorbidities, in a five-years observation period of patients with CD.

Materials and methods

Subjects

Sixty CD patients were enrolled (75% female); the median age at diagnosis was 41 years (interquartile range [IQR] 32–52), followed at the Endocrinology Unit of Padua University Hospital from 2000 to 2021. This observational study was conducted in accordance with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines [9]. The study, following the guidelines in the Declaration of Helsinki, was approved by the ethics committee of Padova University Hospital (PITACORA, protocol No. AOP3318, ethics committee registration 5938-AO-24), and all patients gave informed consent. All data are included in the Repository of the University of Padova [10].

The first normalized UFC is considered as the starting point of observation at follow-up (two or five years). The cohort was divided into two cohorts: group 1 achieved CD remission after surgery, and group 2 achieved long-term eucortisolism during medical therapy. The inclusion criterion was 24-h UFC levels (mean of two collections) below the upper limit of normality during the observational period. Postoperative long-term adrenal insufficiency requiring substitutive glucocorticoid treatment (with hydrocortisone or cortisone acetate tablets) 12 months after surgery or new-onset hypopituitarism were considered exclusion criteria. The group 1 was made of 36 patients (69% female) in remission after successful TSS. The second group consisted of 24 patients (83% female) on long-term medical treatment for CD persistence (n = 17) or relapse (n = 4) after surgery and three patients in primary medical therapy for poor surgical eligibility, as shown in Fig. 1. Within group 2, nine patients underwent previous radiotherapy without efficacy, at least 5 years before reaching adequate biochemical control with medical treatment; none developed hypopituitarism. 14/24 patients (58%) were treated with a monotherapy and 11/24 (46%) with combined therapies during the observation period. Details on medical therapies are shown in Table 1. In particular, 3 patients were treated with metyrapone + pasireotide s.c., 1 with metyrapone + ketoconazole, 2 with ketoconazole and cabergoline, 1 with metyrapone + cabergoline, 1 with metyrapone + ketoconazole + cabergoline, 1 with metyrapone + ketoconazole + pasireotide s.c., 1 with metyrapone + ketoconazole + pasireotide s.c. + cabergoline. Metyrapone and ketoconazole were administered two/three times a day, pasireotide s.c. twice daily and cabergoline once daily in the evening.

Fig. 1
figure 1

Treatment and outcome of the described cohort. Light gray box indicates those patients in group 1 (surgical remission, n = 36), dark gray box indicates the patients in group 2 that achieved normalization of UFC with medical therapy (n = 24, either primary or after surgical failure)

Table 1 Cortisol-lowering drugs, dose, and time in treatment of subjects treated with a single and combined lines of therapy

All 60 patients completed at least 2 years of follow-up; a long-term 5-years evaluation was available in 43 patients of the original cohort (32 after surgery and 11 with medical therapy). Baseline characteristics of the two cohorts are reported in Table 2.

Table 2 Baseline characteristics of the two groups and previous treatment modalities

Data collection and study design

Two researchers retrieved clinical and biochemical data independently from the local digital medical records. We considered as baseline visit the clinical and endocrine evaluation performed with active hypercortisolism. Therefore, the baseline visit consists in the pre-surgical evaluation in group 1, and in the post-surgical confirmation of active hypercortisolism in those in medical treatment (or diagnosis in case of primary treatment, group 2).

We considered clinical and biochemical outcomes during routine follow-up at two- and five-years in each group, starting from surgical remission or the beginning of a stable normalization of UFC under medical therapy. CD diagnosis was based on at least two parameters among 24-h UFC above the upper normal limit (ULN, at least two collections), unsuppressed cortisol levels (> 50 nmol/L) after 1 mg overnight dexamethasone test (1 mg-DST) or late-night salivary cortisol (LNSC) > ULN (at least two samples). In all subjects, CD diagnosis was considered in case of normal-high ACTH levels, positive response to dynamic tests (corticotropin-releasing hormone or desmopressin test, high-dose dexamethasone test), and, two cases, with petrosal sinus sampling (BIPSS) [11]. Long-term remission after TSS was defined through normal UFC, combined with serum cortisol levels < 50 nmol/L in the first month after surgery and need of glucocorticoid replacement therapy. A relapse of CD was defined as the reappearance of the typical signs and symptoms of CD associated with the alteration of at least two first-line screening tests. Presence/absence of clinical signs of CD (round face, facial rubor, buffalo hump, bruising, cutaneous red striae, acne, hirsutism and oligo/amenorrhea in females) were evaluated during outpatient visits by expert endocrinologists. The presence of hirsutism in females was measured according to the Ferriman–Gallwey score > 8 (extent of hair growth in 9 locations was rated 0–4). Proximal muscle strength was diagnosed if patients were not able to stand up from a low seated position with anteriorly extended arms. Bodyweight, body mass index (BMI), waist and hip circumference, systolic (SBP), and diastolic blood pressure (DBP) were assessed with calibrated tools. Overweight was diagnosed in patients with BMI 25–30 kg/m2, obesity with BMI > 30 kg/m2. Visceral obesity was diagnosed as waist circumference ≥ 94 cm in men and ≥ 80 cm in women, or with a waist/hip ratio (WHR) ≥ 1 according to International Diabetes Federation criteria. Arterial hypertension was diagnosed for SBP above 140 mm Hg and/or DBP above 90 mm Hg and/or in patients on antihypertensive drugs. Diabetes mellitus (DM) was diagnosed according to American Diabetes Association criteria or when patients were taking antidiabetic medication. Dyslipidemia was diagnosed when low-density lipoprotein (LDL) calculated cholesterol was ≥ 100 mg/dL and hypertriglyceridemia when triglycerides were ≥ 150 mg/dL or when patients were on lipid-lowering medication. The presence of carotid vascular disease (CVD) has been assessed by supra-aortic vessels duplex ultrasound. Cushing’s cardiomyopathy (CCM) was diagnosed by doppler echocardiography with evidence of impaired relaxation and left ventricular filling pattern. The medical history was checked for cardiovascular disease (acute coronary syndrome, ACS) in all cases. A shortened activated partial thromboplastin time (aPTT < 29 s) defined pro-thrombotic status.

Assays

All biochemical analyses were carried out in an ISO15189:2012-accredited clinical laboratory [12], cortisol levels have been measured in urine or saliva with a mass-spectrometry home-made validated method. UFC was determined by a home-brew liquid chromatography-mass spectrometry (LC-MS/MS) method (intra-assay/interassay coefficient of variation [CV] < 6%/< 8%) since 2011 [13], previously by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%). The patients were instructed to discard the first morning urine void and to collect all urine for the next 24 h, so that the morning urine void on the second day was the final collection. The sample was kept refrigerated from collection time until it was analyzed: normal range for UFC is 16–168 nmol/24 h.

Salivary cortisol was measured by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%) until 2014 [14], after then by LC-MS/MS method (intra-assay/interassay CV < 6%/< 8% [15]). In order to prevent food or blood contamination, samples were collected at least 30 min after subjects had eaten, brushed their teeth, smoked or assumed liquorice; undertaken using Salivette® devices containing a cotton swab with or without citric acid (Sarstedt, Nümbrecht, Germany). The sample was stored at − 80 °C, before analyses [15].

The 1-mg DST test was performed orally assuming 1 mg of dexamethasone between 11 P.M. and midnight, sampling serum cortisol the next morning at 8 A.M. Serum dexamethasone levels, routinely evaluated since 2017, were adequate in all cases [16]. Serum cortisol (RRID: AB_2810257) and ACTH (RRID: AB_2783635) were determined by immune-chemiluminescence assay (Immulite 2000, Siemens Healthcare). Dynamic second-line tests and BIPSS were performed according to international standards.

Statistical analysis

Data were analyzed using SPSS Software for Windows, version 24.0 (SPSS Inc). Data are reported as medians and interquartile range or as percentages. The comparison between continuous variables was performed by non-parametric Wilcoxon test or Mann–Whitney test, as appropriate. The comparison between categorical variables was performed by the χ2 test. The correlation between continuous variables was performed by linear regression analysis. The level of significance for the overall difference between the groups was tested with one-way ANOVA. A p value < 0.05 was considered statistically significant.

Results

Endocrine evaluation

At baseline the two groups were similar for morning serum/salivary cortisol, LNSC, cortisol after 1 mg DST and morning ACTH levels (Table 3); UFC levels were higher in the surgical cohort (p < 0.001). Endocrine parameters were not influenced by sex and BMI. At baseline, all patients had impaired salivary cortisol rhythm with increased LNSC and inadequate cortisol suppression after 1-mg DST. At two years the recovery of salivary cortisol rhythm was observed in 97% of patients after surgery and 50% of patients during medical therapy. The only patient who did not show recovery of cortisol rhythm in the surgical cohort had LNSC of 5.4 nmol/L (range 0.5–2.6 nmol/L), with adequate cortisol suppression after 1-mg DST and sustained normal UFC: it was considered a false-positive due to residual minor depression state.

Table 3 Biochemical pattern at baseline and during the follow-up

Adequate cortisol suppression after 1-mg DST (both with normal UFC and LNSC) was observed in 34 out of 36 patients (94%) in the surgical cohort; the two patients who did not show complete cortisol suppression after 1-mg DST had cortisol levels of 60 and 119 nmol/l, respectively. On the contrary, as per selection criteria, none of the patients in group 2 presented suppressed cortisol after 1-mg DST.

At 5 years follow-up, all cases in the surgical cohort had suppressed cortisol after 1-mg DST and normal salivary cortisol rhythm, whereas in group 2 9% had suppressed cortisol after 1-mg DST and 36% recovered salivary cortisol rhythm. At 5 years, UFC and salivary cortisol levels (either morning or late night) were similar in the two groups, while the median value of serum cortisol after 1-mg DST remained not adequately suppressed (median 75 nmol/L, from 18 to 257 nmol/L) during medical therapy (See Table 3). In group 2, patients on combined therapy had higher UFC (102 vs. 76 nmol/24h p = 0.03) and LNSC (2.4 vs. 1.9 p = 0.05) at 5 years, compared to patients on monotherapy.

Hirsutism, abdominal obesity, round face and facial rubor were prevalent in group 1 at baseline. On the contrary, the abdominal obesity, facial rubor and easy bruising were most commonly found in the medical cohort. The prevalence of facial rubor, buffalo hump and bruisability was higher after medical than surgical remission after 2 years of eucortisolism; at 5 years the prevalence of buffalo hump and bruisability was higher in patients under drug therapy as well (Table 4; Fig. 2). Higher levels of UFC at baseline were observed in all patients with proximal myopathy (p < 0.001).

Table 4 Two- and five-years changes in clinical phenotype from baseline in group 1 and group 2
Fig. 2

figure 2

Signs and symptoms of hypercortisolism at baseline (grey bars), two-years (orange bars) and five-years (blue bars) follow up after surgical (TSS) or medical remission (MED)

Arterial hypertension

Arterial hypertension (AH) was the most frequent comorbidity in both groups at baseline, with similar distribution in the two groups (Table 5). The prevalence of AH decreased after two years in both groups, especially in the surgical cohort (64% vs. 44% in group 2, p < 0.001; 75% vs. 71% p = 0.003), with no further improvement after five years. Overall, hypertensive patients were older at diagnosis (45yrs vs. 31y; p < 0.001) and with larger BMI (29 vs. 25 kg/m2; p = 0.03). Median UFC, morning salivary cortisol and LNSC, and 1-mg DST were not different in patients with/without AH at baseline and at 2 years. SBP and DBP values were similar in the two cohorts and were not correlated to UFC, LNSC or 1-mg DST throughout the follow-up. At 2 years, hypertensive patients had higher levels of morning salivary cortisol and LNSC with impaired rhythm (respectively 10.4 vs. 6 nmol/L, p = 0.01 and 3.2 vs. 1 nmol/l, p = 0.007). SBP and DBP values did not change during the five-years observation time in both groups; however, the number of anti-hypertensive drugs was higher in group 2 than in group 1 (p = 0.007). Overall patients treated with metyrapone showed higher values of DBP at 2 years (mean 89.4 vs. 81.7 mmHg, p = 0.01), the prevalence of AH did not differ from patients with other medical treatments.

Table 5 Two- and five-years changes in cardio-metabolic cortisol-related comorbidities of CD from baseline in group 1 and group 2

Glucose metabolism

DM prevalence at baseline did not show a correlation with BMI and age at CD diagnosis. DM prevalence was similar in group 1 and 2 after two and five years of follow-up. The follow-up analysis of DM was performed excluding patients in pasireotide, since its known impact in glucose metabolism. In both groups, median UFC, morning salivary and LNSC, and 1-mg DST were similar in patients with/without DM at baseline. At 5 years, patients with diabetes had higher levels of morning salivary cortisol and LNSC with impaired cortisol rhythm (respectively 15 vs. 7 nmol/L, p < 0.001 and 5.4 vs. 1.5 nmol/l, p < 0.001). None of the explored hormonal parameters was correlated with HbA1c levels in both groups at any time point considered. The number of antidiabetic drugs was higher after medical than surgical remission (Table 5).

As expected, patients treated with pasireotide had higher incidence of newly onset DM at 2- and 5 years (p = 0.02 and p = 0.05 respectively) and required more antidiabetic drugs at 2- and 5 years (p = 0.002, p = 0.05) or insulin units at 5 years (p = 0.03). HbA1c levels during pasireotide were higher than patients treated with other drugs (55.6 vs. 38 nmol/l, p = 0.002), requiring a higher number of antidiabetic drugs (p = 0.008). Patients on combined therapy with pasireotide had higher rates of DM at 2- and 5 years (p < 0.001 and p = 0.01) and used more antidiabetic drugs at 2- and 5 years (p = 0.004, p = 0.01) than those on monotherapy.

Lipid metabolism

The prevalence of dyslipidemia was similar in the two groups at baseline and after two years, and higher in the medical remission cohort after five years (p = 0.01). Overall, dyslipidemic patients were older at diagnosis (46y vs. 36y; p = 0.006) and had higher BMI (30 vs. 25 kg/m2; p < 0.001). There was no correlation between hormone parameters and LDL or triglycerides levels. Lipid profile was similar between patients treated with different drugs.

Vascular disease and coagulative profile

There was no difference between the two groups, at baseline, in the prevalence of carotid vascular disease, history of ACS, and CCM; at 5 years, in both groups, no patient had a worsening of a previously diagnosed stenosis, or novel diagnosis of CVD, ACS and CCM.

The median aPTT value at baseline was in the pro-thrombotic range in both groups (25s), without sex and BMI differences. No correlation was observed between aPTT and UFC, LNSC and 1-mg DST levels. Patients who manifested easy bruising, had shorter aPTT at 2- and 5 years (median 24 vs. 27s, p = 0.03). aPTT does not increase within both groups at 2- and 5-years and aPTT was shorter during medical therapy compared to surgical remission both after 2 and 5 years (22.5s vs. 27s, p = 0.02 at 2y and 23.5s vs. 27.9s, p = 0.02 at 5y).

Discussion

The impact of CD remission on clinical picture and hypercortisolism-related comorbidities is still controversial. The current knowledge suggests that long-term CD surgical remission is associated with increased metabolic and vascular damage, not only if compared to active disease, but also even after long-term normalization of cortisol secretion [17]. If CD recurs after successful TSS, or if surgery fails/is not feasible, cortisol excess can be treated with medical therapy. Likewise, long-term studies (> 2 years) on the clinical effects of medical therapy on CD are lacking. Some prospective registry studies have been published [1], only one retrospective study on long-term use of ketoconazole described a multicentric cohort of CD patients without a control group [18].

In our study, we enrolled 60 patients with CD diagnosed and treated in a single tertiary care center, with sustained and long-term (2 and 5 years) UFC normalization after surgery or during medical therapy. As expected, UFC levels at baseline were different in the two groups, due to the distinct starting point of medical history: a patient with persistent-recurrent CD after pituitary surgery presents with lower UFC than the new diagnosis. After surgical remission, patients achieved the recovery of salivary cortisol rhythm and the complete suppression of cortisol after 1-mg DST (investigated after substitutive glucocorticoid treatment discontinuation) in almost all cases. On the contrary, if eucortisolism is achieved with long-term medical therapy the recovery of salivary cortisol rhythm was observed only in half of patients and only few of them showed cortisol suppression after 1-mg DST within the 5 years observation time. Patients who were more resistant to the recovery of cortisol rhythm were more likely to receive combined treatment, even if no treatment is superior to others in normalizing salivary cortisol rhythm, in line with previous reports [1, 18, 19].

Within 2 years, patients in the surgical remission group showed a marked improvement of all phenotypic traits common at CD diagnosis compared to those in medical therapy. As observed also in other series of CD patients in remission [20], abdominal obesity persisted more than other clinical features over time, leading to an impaired body composition especially in the medically treated group [21]. Considering hyperandrogenism, acne improvement was more relevant at 2 and 5-years of follow up, probably due to a differential effect of ACTH-dependent adrenal androgens compared to hirsutism.

The impaired cortisol rhythm was a predictor of the long-lasting of most CD phenotypic features, as round face, buffalo hump, facial rubor, abdominal obesity, proximal myopathy and bruisability. A more severe clinical phenotype at baseline can explain a reduced control of hypercortisolism in monotherapy, requiring drug combination, and signs or symptoms are likely to persist despite the normalization of UFC [22]. In this study, no medication outperformed the others in terms of recovery from the CD phenotype.

The aetiology of hypertension and dyslipidemia is known to be heterogeneous, since both are influenced also by age at diagnosis and BMI, causing low rates of remission after UFC normalization [23, 24]. Arterial hypertension showed a decreasing trend with the best response within 2 years after UFC normalization only after surgical remission. Patients with disrupted salivary cortisol rhythm were more likely to remain hypertensive during the 5 years follow-up. Likewise, DM persistence during follow up correlates to impaired salivary cortisol rhythm and not with UFC. This finding is in contrast with the observations of Schernthaner-Reiter et al. [25]. on CD remission, and, on the contrary, supports data described by Guarnotta et al. [22]. Newell-Price et al.. recently found that when UFC and LSNC are both normal in patients treated with pasireotide, the rise in HbA1c levels is less evident than in patients with normal UFC but uncontrolled LNSC [26]. This observation underlines the importance of the impaired cortisol rhythm in the glucose impairment pathogenesis in CD. During the 5 years observation time, a worsening of previously diagnosed cardiovascular conditions, or novel acute vascular events, was not observed in both groups. This finding suggested that normalized UFC and intensive treatment of cardio-metabolic CD comorbidities play a fundamental role in reducing cardiovascular mortality [27]. A minor impact of CD therapy was observed in dyslipidemia, which persisted in both groups, with minimal improvement over time (−22% in surgical and − 6% in medical cohort). The criterion of 100 mg/dL LDL cut-off identifies a moderate CV risk reflecting the main focus of the study: the assessment of cardiometabolic complication after CD remission, assuming that they present a lower cardiovascular risk compared to patients with overt hypercortisolism.

Plasma hypercoagulability, with shortened aPTT, was found in all patients with active hypercortisolism. In the 5 years observation time, this parameter showed latency in increasing in both groups and in none achieved normality (> 28s). As previously observed in other studies, no correlation is observed between aPTT and any of the explored hormonal parameters [22, 28]. At 2- and 5 years, instead, shorter aPTT was observed during medical treatment than after surgical remission cohort. In both groups a shorter aPTT was associated with bruisability, which is related to impaired LNSC, strengthening the role of the impaired cortisol rhythm as a major driver of hypercoagulability. Also, Ferrante et al.. observed the long latency of plasma hypercoagulability, persisting for years after biochemical remission of CD: in that series thrombophilia appeared to be reversible within 5 years [29], while in our cohort the recovery takes longer.

Additionally, sexual differences characterize patients with patients with Cushing’s syndrome and hypogonadism in hypercortisolism is known to further increase the cardiovascular risk [30, 31]. However, it was not an interfering factor in our study population since hypopituitarism was considered an exclusion criterion, no case of new-onset hypogonadism was reported (even in male patients treated with ketoconazole), and the menopause transition in six women during the observation was not considered relevant.

The limits of the present study are its retrospective design, the variability of concomitant treatments, the heterogenous combinations of medical therapy used in clinical practice, the presence of treatment-specific adverse events that mimic the effects of hypercortisolism (such as pasireotide-induced DM and hypertension with metyrapone), the unpredictable effect of previous treatments, including radiotherapy. We considered UFC and LNSC as markers of hypercortisolism remission; nonetheless we acknowledge that both of them present some limitations, especially during medical treatment. The former considers the whole cortisol secretion during the day, and albeit UFC normalization is the main outcome of all trials for medical treatment [32, 33] it does not detect mild hypercortisolism. On the other hand, a normal LNSC does not fully reflect a normal circadian rhythm: only high cortisol levels in the morning with a decline in the night are able to restore clock-related activities [34].

Its strengths are the complete patient characterization in a single tertiary care center, the comparative study design, and the standardized protocols for diagnosis and long-term follow-up. In particular, samples have been processed within a single laboratory with accurate methods (LC-MS for urinary and salivary steroids), and all endocrine aspects of hypercortisolism were considered (overall daily cortisol production by UFC, circadian cortisol rhythm, and the recovery of the hypothalamic-pituitary axis by 1-mg DST overnight test).

To conclude, despite UFC normalization in both groups during follow-up, surgical remission results in more rapid and relevant improvements in CD phenotype and comorbidities. During medical therapy the UFC levels can be higher than after surgery, although in the normal range, and the normalization of LNSC is not always achieved: both conditions suggests that stricter criteria should be considered to define eucortisolism in patients with CD under medical treatment. Conditions such as obesity, hypertension, dyslipidemia, and hypercoagulability are not completely reversible in a 5-year observation time even in the surgical remission group. This observation underlines that all the comorbidities, independently of the normalization of UFC, must be intensively treated. Moreover, UFC normalization should not be considered the only biochemical goal to be reached, since the persistence of comorbidities seems to be more related to an impaired cortisol rhythm rather than to the cortisol secretory burden.

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Funding

Open access funding provided by Università degli Studi di Padova within the CRUI-CARE Agreement.

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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Authors and Affiliations

  1. Department of Medicine-DIMED, University of Padova, Padova, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

  2. Endocrinology Unit, Department of Medicine DIMED, University Hospital of Padova, Via Ospedale Civile, 105, Padova, 35128, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

Corresponding author

Correspondence to Filippo Ceccato.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants involved in the study.

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Tizianel, I., Lizzul, L., Mondin, A. et al. Cardiometabolic complications after Cushing’s disease remission. J Endocrinol Invest (2025). https://doi.org/10.1007/s40618-025-02572-x

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Ectopic CRH/ACTH-Co-Secreting Neuroendocrine Tumors Leading to Cushing’s Disease

Posted on March 17, 2025 by MaryO

Abstract

Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing’s syndrome, a condition with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, contributing to this syndrome. This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of these tumors. Emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and necessitates tailored therapeutic strategies. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area.

We report the case of a 53-year-old female patient who presented with severe Cushing’s syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial indications pointing towards pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated atypically located tumor in the upper lobe of the left lung, adjacent to the mediastinum. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of the presence of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates the expression of ACTH via binding to CRH-R1. This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors impacting cortisol production, such as CRH production and other contributing neuroendocrine mechanisms.

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