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Abstract

Background:

Cushing’s syndrome (CS) is a rare endocrine disorder caused by long-term exposure to excess cortisol and is linked to significant morbidity. Data from multiple centers in Latin America remains limited.

Objectives:

To describe the clinical, diagnostic, and treatment characteristics of patients with CS in a regional Colombian cohort and to assess surgical outcomes in patients with Cushing’s disease (CD) based on neurosurgical expertise.

Design:

Multicenter retrospective cohort study.

Methods:

Medical records from six hospitals in Antioquia, Colombia, were reviewed, including adult patients with biochemically confirmed endogenous CS diagnosed between 2010 and 2024. Data collected included sociodemographic, clinical features, diagnostic tests, etiological classification, treatments, and outcomes. In patients with CD, surgical remission, recurrence, persistence, and postoperative complications were compared based on neurosurgical expertise.

Results:

A total of 130 patients were included; 86.9% were women, with an average age of 50.7 years. The most common presenting features were weight gain (79.2%), moon face (36.9%), and striae (29.2%). CD was the leading cause (74.6%), followed by adrenal CS (17.6%) and ectopic adrenocorticotropic hormone syndrome (1.5%). The most frequently used diagnostic tests were 24-h urinary free cortisol and the 1-mg overnight dexamethasone suppression test, while late-night salivary cortisol and inferior petrosal sinus sampling were less commonly performed. Transsphenoidal surgery in CD achieved an initial remission rate of 63.3%, with no significant differences based on neurosurgical experience. All cases of adrenal CS underwent unilateral adrenalectomy.

Conclusion:

In this Colombian multicenter cohort, the clinical features, etiological distribution, and surgical outcomes in CS and CD were similar to those reported in specialized international centers. These findings highlight the importance of early detection, better access to diagnostic tools, and multidisciplinary care to improve outcomes in this rare disease.

Plain language summary

Analysis of the Cushing’s syndrome registry in Antioquia, Colombia

CS is a rare condition caused by long-term exposure to high cortisol levels. Cortisol is produced by the adrenal glands, but its overproduction can result from different causes: excessive adrenocorticotropic hormone (ACTH) secretion from the pituitary gland (CD), autonomous cortisol production by an adrenal tumor, or produced by tumors located elsewhere in the body (EAS). The condition often develops slowly and can be difficult to recognize because its symptoms—such as weight gain, high blood pressure, diabetes, muscle weakness, and osteoporosis—are also common in other diseases. We conducted a study in six hospitals in Antioquia, Colombia, to gain a deeper understanding of how CS presents, how it is diagnosed, and how it is treated in real-world practice. We reviewed the medical records of 130 adult patients diagnosed between 2010 and 2024. Most patients were women in their 50s, and the most frequent symptoms were weight gain, round face, and purple stretch marks. The most common cause was CD, accounting for about three out of every four cases. For diagnosis, the most commonly used tests were UFC and the ODST. LNSC, despite being highly accurate and widely recommended, was less frequently performed. The main treatment for CD was pituitary surgery, with similar remission rates between highly experienced and less experienced neurosurgeons. In patients with adrenal CS, adrenal surgery was the standard treatment. Our results highlight the importance of early detection, access to accurate diagnostic tests, and specialized surgical care. They also show that outcomes in Antioquia are comparable to those from specialized international centers, despite the challenges of managing a rare and complex disease in our setting.

Keywords

Cushing’s syndrome epidemiology registry surgery

Introduction

Cushing’s syndrome (CS) is a rare endocrine disorder characterized by chronic exposure to elevated cortisol levels in the absence of exogenous glucocorticoids.^1–3 Endogenous CS is classified into adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent forms. Among ACTH-dependent causes, Cushing’s disease (CD) resulting from an ACTH-secreting pituitary adenoma accounts for approximately 80%–90% of cases, while ectopic adrenocorticotropic hormone syndrome (EAS) comprises the remainder and arises from tumors producing ACTH or corticotropin-releasing hormone at non-pituitary sites.^1,2 In adrenal Cushing’s syndrome (ACS), or ACTH-independent CS, cortisol production originates from unilateral adrenal adenomas, carcinomas, or bilateral adrenal hyperplasia.³

The estimated incidence of endogenous CS ranges from 1.2 to 3.2 cases per million individuals per year, with higher prevalence in women and a peak onset between the fourth and sixth decades of life.^4,5 These epidemiological estimates vary across studies due to differences in screening strategies, case ascertainment, diagnostic methods, and health-system characteristics.⁶ As highlighted by systematic evaluations of rare-disease registries, disparities in diagnostic infrastructure and clinical expertise may further influence detection and reported incidence.⁷

The clinical presentation of CS is heterogeneous, reflecting the multisystemic effects of chronic cortisol excess. Common manifestations include weight gain, facial rounding, proximal muscle weakness, metabolic syndrome, hypertension, dyslipidemia, hyperglycemia, osteoporosis, and menstrual irregularities.^1,2 Because individual symptoms are nonspecific and frequently overlap with more common conditions such as obesity or type 2 diabetes, diagnostic delays are typical. Combinatorial clinical patterns—rather than isolated findings—substantially increase the likelihood of CS, supporting the need for structured clinical assessment.^8,9

Accurate diagnosis requires biochemical confirmation of cortisol excess through at least two abnormal first-line tests (late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ODST), or urinary free cortisol (UFC)) in accordance with Endocrine Society recommendations and updated consensus statements.^10,11 LNSC demonstrates excellent diagnostic performance, with recent studies using second-generation electrochemiluminescence assays reporting area-under-the-curve values approaching 0.99 and sensitivity/specificity exceeding 95%.¹² However, access to LNSC remains limited in many regions, including parts of Latin America, leading clinicians to rely more heavily on UFC despite known limitations of immunoassay-based measurements, which may suffer from cross-reactivity and preanalytical variability.^13–15 Once hypercortisolism is established, differentiating between ACTH-dependent and ACTH-independent causes requires measurement of plasma ACTH, cross-sectional imaging, and inferior petrosal sinus sampling (IPSS) in selected ACTH-dependent cases, which remains the gold standard for identifying pituitary-driven disease in patients with discordant biochemical or imaging findings.¹⁶

Surgery remains the cornerstone of treatment across CS subtypes. In CD, transsphenoidal surgery is the first-line therapy, with remission rates strongly influenced by the neurosurgeon’s expertise.^17,18 Contemporary series, including those from specialized centers and recent regional studies, report initial remission rates ranging from 60% to 80%.¹⁹ Nonetheless, recurrence may occur in up to one-third of patients, warranting long-term surveillance.²⁰ Medical therapies, including pituitary-directed agents and steroidogenesis inhibitors, and glucocorticoid receptor antagonists, are recommended when surgery is contraindicated or unsuccessful, and recent clinical trials have expanded therapeutic options.²¹ Adrenal CS is primarily treated surgically, most commonly with unilateral adrenalectomy in patients with unilateral adrenal disease, while bilateral adrenalectomy may be required in selected bilateral adrenal disorders or in refractory ACTH-dependent CS.²²

Despite advances in diagnostic tools and surgical techniques, substantial variability persists in clinical outcomes across regions, especially in settings with uneven access to specialized endocrinology and neurosurgery services. Prior Colombian studies in CD have reported remission rates markedly lower than those reported by high-volume international centers.^23,24 These discrepancies highlight the need to better characterize real-world diagnostic and therapeutic practices in Colombia.

To address this gap, the present multicenter study aimed to describe the sociodemographic and clinical features of patients diagnosed with CS in Antioquia between 2010 and 2024 and, in CD specifically, to evaluate surgical outcomes and postoperative complications according to neurosurgical expertise.

Materials and methods

Study design and population

A multicenter longitudinal study was conducted with retrospective data collection from a cohort of patients with CS, using electronic medical records (EMRs) from six hospitals in the department of Antioquia, Colombia: Clínica Las Américas (CLA), Hospital Pablo Tobón Uribe (HPTU), Hospital Universitario San Vicente Fundación (HUSVF), Clínica Somer, and two private outpatient centers (Consulta Externa Rio Plaza and Torre City Médica). All patients aged 18 years or older with a biochemically confirmed diagnosis of endogenous CS between January 1, 2010, and December 31, 2024, were eligible.

The diagnosis of CS required at least two abnormal first-line biochemical screening tests, following the Endocrine Society Clinical Practice Guideline¹⁰ and updated international consensus recommendations.¹¹

Exclusion criteria included:

exogenous glucocorticoid exposure,

lack of accessible medical records,

incomplete essential diagnostic or follow-up information,

alternative diagnoses (e.g., non-functioning pituitary neuroendocrine tumors, congenital adrenal hyperplasia),

and age <18 years.

A convenience sampling strategy was selected because CS is a rare disease.^1,3

Patients were identified using ICD-10 codes E24.0 and E24.9. Four investigators screened EMRs across institutions, extracted data, and entered them into standardized spreadsheets. Subsequently, the investigators held cross-institutional adjudication meetings to: Eliminate duplicate entries using national identification numbers, assign a unique anonymized code to each patient, standardize outcome definitions, verify and complete biochemical and clinical follow-up data. All compiled databases were merged into a de-identified master file.

Diagnostic evaluation

First-line tests included:

ODST,

LNSC,

UFC.

Interpretation adhered to recommended cutoffs.^10,13

Assay methodologies

Biochemical assays were performed in institutionally certified laboratories:

Serum cortisol and plasma ACTH were measured using electrochemiluminescence immunoassays.

UFC: immunoassays.

Normal ranges followed manufacturer-specific and laboratory-validated thresholds.

Etiological classification of CS

ACTH measurement

Patients were classified into ACTH-dependent or ACTH-independent CS based on plasma ACTH concentrations and imaging findings.

Imaging

Pituitary MRI for suspected CD.

Adrenal CT/MRI for suspected adrenal CS.

Inferior petrosal sinus sampling

IPSS was performed in ACTH-dependent cases with negative or equivocal MRI findings.

High-dose dexamethasone suppression test

High-dose dexamethasone suppression test (HDDST; 8 mg DST) was used only as an adjunct for differentiating CD from EAS and not as a diagnostic test for CS. Suppression >50% was considered supportive of CD.

Variables collected

We recorded:

Sociodemographic variables

Clinical presentation (signs, symptoms, comorbidities)

Biochemical tests at diagnosis and during follow-up

Anatomical imaging results

Etiology (CD, ACS, EAS, unlocalized ACTH-dependent CS)

Tumor size and characteristics

Initial and subsequent treatments (surgery, medical therapy, radiotherapy, adrenalectomy)

Postoperative complications

Biochemical outcomes over time

A comprehensive variable list appears in Supplemental Table 1.

Exposure variable: Neurosurgical expertise

An expert neurosurgeon was defined as performing ⩾20 transsphenoidal surgeries for CD per year. Non-expert surgeons performed <20 such procedures annually.

Outcomes of surgical management in CD

Initial remission: Defined as the requirement for glucocorticoid replacement therapy, a morning serum cortisol level <2 µg/dL within the first 24 h after surgery, or a morning serum cortisol <5 µg/dL measured within the first postoperative week, according to criteria consistently used across participating centers.

Sustained remission: Absence of biochemical evidence of disease activity for at least 12 months after resection, confirmed by normal UFC, an ODST result <1.8 µg/dL, and LNSC within the reference range.

Recurrence: Biochemical evidence of hypercortisolism (elevated UFC, ODST ⩾1.8 µg/dL, or LNSC above the upper limit of normal (ULN)) after documented at least 12 months of sustained remission, in accordance with published recommendations.²⁰ Time to recurrence was also assessed.

Persistence: Biochemical evidence of hypercortisolism following initial surgery.

Surgical complications: Adverse events related to pituitary surgery were evaluated, including CSF leak, arginine vasopressin (AVP-D), and hypopituitarism.

Biochemical monitoring

UFC, ODST, and LNSC were recorded at 6 and 12 months and at the last available follow-up, consistent with international follow-up recommendations.^10,11

Sample size calculation

Given the retrospective and registry-based design of this study, a formal sample size calculation or a priori power analysis was not performed. CS is a rare disease, with an estimated annual incidence of 1–3 cases per million inhabitants, which makes prospective sample size estimation challenging. Therefore, the study included all consecutive adult patients with biochemically confirmed endogenous CS identified in the participating centers during the study period (2010–2024). This approach is consistent with real-world registry studies of rare endocrine disorders, in which the sample size is determined by case availability rather than predefined statistical assumptions.

Statistical analysis

The Kolmogorov–Smirnov test was used to assess the normality of continuous variables. Variables that did not follow a normal distribution were summarized as medians and interquartile ranges (IQR), whereas normally distributed variables were reported as means and standard deviations (SD). Differences in continuous variables were analyzed using either the independent t test (for normally distributed variables) or the Mann–Whitney U test (for non-normal distributions). For categorical variables, comparisons were made using differences in proportions.

In the subgroup of patients with CD, a stratified analysis was conducted based on the level of neurosurgical expertise. A bivariate logistic regression model was used to compare clinical outcomes and postoperative complications between surgeries performed by expert versus non-expert neurosurgeons. All analyses were performed using the “statistics” package in R software.²⁵

Ethics approval and written informed consent

The study was approved by the Institutional Review Board of the three main centers CLA (number 2024.228), HPTU (number 2024.065), and Clínica Somer (number 2024.81). Only four investigators had access to the EMR systems for data extraction; all other team members worked exclusively with a de-identified dataset.

Results

Study population

A total of 234 patients with a recorded diagnosis of CS were initially identified across the 6 participating institutions. After applying predefined exclusion criteria, 104 patients were excluded: 40 due to exogenous hypercortisolism, 35 because no medical records were retrievable, 10 due to incomplete essential data, 13 with non-functioning pituitary neuroendocrine tumors, 3 with congenital adrenal hyperplasia, and 3 patients younger than 18 years of age. The final cohort consisted of 130 patients included in the descriptive analyses. Etiological classification identified 97 patients (74.6%) with CD, 22 patients (16.9%) with ACS, all of whom had unilateral adrenal adenomas, 2 patients (1.5%) with ectopic ACTH syndrome (EAS) in whom the primary tumor could not be identified, and 9 patients (6.9%) with unlocalized ACTH-dependent CS. Only patients with CD were included in the analyses of pituitary surgical outcomes. The study flow is illustrated in Figure 1.

Figure 1.

Flowchart of patient selection for the Antioquia multicenter Cushing’s syndrome registry, showing the initial screened population, exclusion criteria, and final study sample.

Clinical characteristics at presentation

Among the 130 patients, 86.9% were women, with a mean age of 50.7 years (SD: 15.04). The majority of patients were diagnosed at two tertiary referral centers (CLA and HPTU), representing 83.8% of cases. Regarding health insurance status, 53.9% were affiliated with the contributory system, 32.3% with the subsidized regime, and 13.8% had private insurance. Most patients (65.4%) resided in urban areas. The mean body mass index was 29.3 kg/m² (SD: 6.9). The median diagnostic delay was 1.00 year (IQR: 0–3). Sociodemographic and clinical features are summarized in Table 1.

Table 1.

Sociodemographic and clinical characteristics at diagnosis of patients with Cushing’s syndrome.

Variable	Total N = 130
Female	113 (86.9%)
Age, years (mean ± SD)	50.7 ± 15.04
Healthcare center
CLA	32 (24.6%)
HPTU	30 (23.1%)
HUSVF	19 (14.6%)
Clínica SOMER	3 (2.3%)
Private centers	18 (13.8%)
Combinations of centers	28 (21.5%)
Health insurance
Contributory	70 (53.9%)
Subsidized	42 (32.3%)
Private	18 (13.8%)
Place of residence
Rural	45 (34.6%)
Urban	85 (65.4%)
Body mass index, kg/m² (mean ± SD)	29.3 ± 6.9
Time from symptom onset to diagnosis, years (median (IQR))	1 (0–3)

Sociodemographic data, baseline clinical characteristics, and diagnostic delay of patients included in the Antioquia multicenter Cushing’s syndrome registry. Data are presented as mean (SD), median (IQR), or n (%), as appropriate.

BMI, body mass index; CLA, Clínica Las Américas; HPTU, Hospital Pablo Tobón Uribe; HUSVF, Hospital San Vicente Fundación; IQR, interquartile range; SD, standard deviation.

The most frequent presenting symptom was weight gain (79.2%), while the most common physical signs were moon facies (36.9%) and striae (29.2%; Figure 2). Comorbidities were highly prevalent: hypertension in 66.2%, obesity in 61.5%, dyslipidemia in 46.9%, T2DM in 39.2%, osteoporosis in 26.2%, and obstructive sleep apnea syndrome in 14.6%. Hypokalemia was documented in 14.6% of patients, occurring in both patients with EAS and being less frequent in ACS and CD. Cardiovascular events were observed in 13 patients (10%), including thromboembolic disease (4.6%), coronary artery disease (3.8%), and cerebrovascular disease (3.1%). Three patients experienced more than one type of vascular event.

Figure 2.

Prevalence of clinical signs and symptoms at diagnosis in the cohort of patients with Cushing’s syndrome. Percentages correspond to the proportion of patients presenting each symptom at diagnosis.

Diagnosis of CS

Diagnostic evaluation included both biochemical tests and imaging. UFC was documented in 72.3% of patients, with a median level 2 times above the ULN (IQR: 1–3). LNSC was recorded in 13.1% of patients, with elevated levels in 76.5% of them. The ODST was performed in 60%, and 97.4% demonstrating cortisol values >1.8 µg/dL. The HDDST was available in 36.2% of cases, and showed >50% cortisol suppression in 74.4% of tested patients, exclusively among those later classified as CD. Detailed biochemical results are presented in Table 2.

Table 2.

Diagnostic tests performed according to the Cushing’s syndrome subtype.

Test type	TotalN = 130		CDN = 97		ACSN = 22		EASN = 2
Test type	Measured percentage	Altered result^a	Measured percentage	Altered result^a	Measured percentage	Altered result^a	Measured percentage	Altered result^a
UFC, median ULN (IQR)	72.3	31.9%	75.3	30.1%	50	27.3%	100%	100%
	2 (1–3)		2 (1–3)		2 (1–5)		29 (NA)
ODST	60	97.4%	58.8	96.5%	43.5	100%	100	100%
LNSC	13.1	76.5%	10.3	80%	17.4	100%	50	100%
HDDST	36.2	74.4%	38.1	78.4%	8.7	0%	100	0%
IPSS	38.5		44.3		4.3		0
ACTH,median (IQR)	48.1 (25.2–88)		56 (33.2–88.5)		5 (3.15–5)		97 (96–98)

Frequency and results of biochemical and localization tests used for the diagnosis of Cushing’s syndrome, stratified by etiological subtype. Data are shown as percentages of patients tested and of those with abnormal results.

An altered result was defined as a ULC 3 times the ULN, for ODST, the percentage of patients with a result greater than 1.8 μg/dL, for LNSC, the percentage of patients with a result greater than the ULN, and for HDDST, a suppression greater than 50%.

ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; HDDST, high-dose dexamethasone suppression test; IPSS, inferior petrosal sinus catheterization; IQR, interquartile range; LNSC, late-night salivary cortisol; NA, not applicable; ODST, 1-mg overnight dexamethasone suppression test; UFC, urinary free cortisol; ULN, upper limit of normal.

ACTH levels varied according to etiology: Median ACTH values were 56 pg/mL (IQR: 33.2–88.3) in CD, 5.00 pg/mL (IQR: 3.12–5.00) in ACS, 97.0 pg/mL (IQR: 96.0–98.0) in EAS, and 47.6 pg/mL (IQR: 34.7–71.0) in cases with indeterminate etiology.

In patients with CD, pituitary MRI revealed a median tumor size was 7.5 mm (IQR: 5.5–13.5), with 22.7% classified as macroadenomas. IPSS was performed in 38.5% of CD cases, with a median adenoma diameter of 5 mm (IQR: 3.4–7.5). In ACS, the median tumor size was 29 mm (IQR: 24–40).

Biochemical monitoring

At 6 months after initial treatment, UFC was available in 28 patients (21.5%), with a median of 1× ULN (IQR: 0–1). ODST was performed in 35 patients (26.9%), of whom 51.4% had results >1.8 µg/dL. LNSC was recorded in 7 patients (5.9%), with 42.8% above the ULN. At the last available follow-up, UFC was available in 44 patients (25.4%), with a median of 1× ULN (IQR: 0.55–1.10). The ODST was recorded in 25 patients (19.2%), with values >1.8 µg/dL in 10 patients (48%). LNSC was available in 10 patients (7.7%), with 8 (80%) showing elevated levels (Supplemental Table 1).

Treatment

Transsphenoidal pituitary surgery was the first-line treatment in 79 patients with CD (81.4%). Among these, 44 surgeries were performed by an expert neurosurgeon, 22 by a non-expert, and in 13 cases the neurosurgeon’s expertise was not reported. Patients operated on by expert neurosurgeons had larger tumors (median 9.4 mm, IQR: 6.65–16.5), and a higher proportion of macroadenomas (29.5%) compared with those treated by non-expert surgeons (median 7.1 mm, IQR 5.5–8.9; macroadenomas 21%).

In all patients with ACS, unilateral adrenalectomy was performed; in one of them, medical management with ketoconazole was used before surgery. Bilateral adrenalectomy was performed in one patient with EAS and one patient with unlocalized ACTH-dependent CS. Medical therapy was commonly administered in cases of persistent or recurrent disease. Treatments included ketoconazole, cabergoline, pasireotide, osilodrostat, mitotane, or combination regimens. Medical therapy was most frequently used in CD (11.3%), followed by unlocalized ACTH-dependent CS and EAS. Among the 17 patients who received medical therapy as first-line management, treatment outcomes varied according to etiology. The patient with adrenal CS initially treated with ketoconazole and subsequently underwent unilateral adrenalectomy and achieved biochemical remission after surgery. Among patients with ectopic or unlocalized ACTH-dependent CS, none achieved biochemical control with medical therapy alone. In CD, 11 patients received medical therapy as initial treatment; of these, 5 ultimately underwent transsphenoidal surgery and 3 received radiotherapy. At the last available biochemical follow-up, only 3 of the 11 patients had achieved biochemical control. Because the present study was designed primarily as a surgical outcomes analysis, follow-up time was defined from the time of surgery when applicable. Consequently, remission status for medically treated patients was based on the last available biochemical assessment rather than on standardized longitudinal efficacy analyses. Radiotherapy was used in nine patients with CD (10.2%) and in one patient with unlocalized disease, primarily for persistent or recurrent hypercortisolism. Details of adjunctive treatments are summarized in Supplemental Table 2.

Surgical outcomes and complications in CD according to neurosurgeon expertise

One surgical team met the criteria for expertise, performing 80–100 transsphenoidal surgeries annually, while non-expert centers performed 4–10 pituitary surgeries per year. The overall initial remission rate following pituitary surgery was 63.3%, with higher remission in microadenomas (68.3%) than macroadenomas (56%).

When stratified by neurosurgical expertise, no statistically significant differences were observed in initial remission (odds ratio (OR): 1.42; 95% CI: 0.47–4.24). Prolonged remission rates were 45% in both groups. No significant differences were observed between groups in recurrence (OR: 2.1; 95% CI: 0.57–8.99), persistence (OR: 0.83; 95% CI: 0.29–2.32), or remission at last biochemical follow-up (OR: 1.49; 95% CI: 0.51–4.37).

Likewise, complication rates did not differ significantly (OR: 0.94; 95% CI: 0.42–3.38), nor did specific complications such as CSF leaks (OR: 0.27; 95% CI: 0.01–2.19), AVP-D (OR: 0.38; 95% CI: 0.08–1.57), or hypopituitarism (OR: 1.57; 95% CI: 0.43–6.57). These findings are detailed in Table 3.

Table 3.

Surgical outcomes and postoperative complications in Cushing’s disease according to neurosurgeon experience.

Outcome evaluated	Non-expert surgeonN = 22	Expert surgeonN = 44	OR	95% CI	p Value
Clinical outcomes
Initial postoperative remission	13 (59.1%)	30 (68.2%)	1.42	0.47–4.24	0.251
Prolonged postoperative remission	10 (45.4%)	20 (45.5%)	1.14	0.35–3.64	0.675
Recurrence	4 (18.2%)	13 (29.5%)	2.1	0.57–8.99	0.311
Persistence	12 (54.5%)	22 (50%)	0.83	0.29–2.32	0.728
Remission at last follow-up	10 (45.5%)	23 (52.3%)	1.49	0.51–4.37	0.858
Post-surgical complications
Any complications	6 (27.3%)	12 (27.3%)	0.94	0.35–2.52	0.763
CSF leak	3 (13.6%)	1 (2.3%)	0.27	0.01–2.19	0.467
AVP-D	4 (18.2%)	3 (6.8%)	0.38	0.08–1.57	0.166
Hypopituitarism	2 (9.1%)	8 (18.2%)	1.88	0.53–7.62	0.504

Comparison of surgical remission rates, recurrence, persistence, and postoperative complications in patients with Cushing’s disease undergoing transsphenoidal surgery, stratified by neurosurgical expertise. Data are presented as n (%), OR, and 95% CI.

AVP, arginine vasopressin; CI, confidence interval; CSF, cerebrospinal fluid; OR, odds ratio.

Among patients with information on recurrence or persistence management, those treated by non-expert surgeons underwent reoperation in 13.6%, received medical therapy in 18.2%, or combination therapy in 18.2%. In the expert group, management included medical treatment in 25%, surgery in 15.9%, radiotherapy in 2.3%, and combined approaches in 9.1% (Supplemental Table 3).

Discussion

Because CS is rare, most available evidence on its diagnosis and management comes from hospital- and clinic-based registries rather than true population-based cohorts.⁷ This multicenter study describes the sociodemographic and clinical characteristics, diagnostic work-up, and treatment outcomes of patients with CS in a Colombian population. The main findings were: (1) sociodemographic characteristics of this cohort were similar to those described in other international registries; (2) CD was the most frequent CS subtype; (3) LNSC and IPSS were underutilized, yet LNSC and the ODST had the highest proportion of positive results at diagnosis; and (4) remission and complication rates after transsphenoidal surgery for CD were similar between expert and non-expert neurosurgeons, although the study was not powered to detect modest differences.

Sociodemographic and clinical features in CS patients from Antioquia

Patients were identified from both public and private healthcare centers. Most were women in their fifth or sixth decade of life. Although age at diagnosis varies globally, many registries report an average between 40 and 55 years,^4,5,26 similar to Colombian studies.^23,24,27,28 The prevalence of weight gain, moon facies, and cutaneous striae aligns with prior registries.^24,26 Hypertension, obesity, dyslipidemia, and T2DM were highly frequent. These cardiometabolic comorbidities are consistent with international and regional reports,^{23,24,26–30} reflecting delayed diagnosis, the prolonged cortisol exposure, and underscoring the importance of multidisciplinary management that includes screening and treatment of comorbidities beyond cortisol control.^31–35

The relatively short reported diagnostic delay may reflect early detection; however, other plausible explanations include recall or reporting bias. Despite the high prevalence of typical signs and symptoms, such features are often dismissed or misattributed until they become more pronounced or occur in combination.⁸ For example, obesity alone is unlikely to trigger suspicion of CS, but when combined with specific features—such as adrenal incidentalomas (OR 2.4), metabolic syndrome (OR 2.7), osteoporosis (OR 3.8), myopathy (OR 6), or the simultaneous presence of three or more symptoms (OR 18)—the probability of a CS diagnosis increases significantly.⁹

Etiological subtypes of CS

CD was the most common etiology in nearly three-quarters of patients, consistent with the ERCUSYN registry,²⁶ national studies,^31,36 and the work by Abreu-Lomba et al.²⁴ in Cali, Colombia, where CD accounted for 82% of CS cases. EAS was the least frequent subtype, occurring in less than 5% of cases. Unlike studies focused exclusively on one subtype,^{20,29,30,37,38–40} our study characterized all three major subtypes (CD, ACS, and EAS).

Our findings are consistent with those reported by Attri et al.,¹⁹ who analyzed a similar cohort including patients with CD and EAS and described EAS as a less frequent but clinically more severe subtype. In both cohorts, CD was the predominant etiology, while EAS accounted for a small proportion of cases. Importantly, Attri et al. reported a higher prevalence of hypokalemia among patients with EAS, identifying it as a marker of more severe hypercortisolism and a useful clue for etiological differentiation. Similarly, hypokalemia was documented in 14.6% of patients in our study and was present in both EAS cases, supporting its clinical relevance as a red flag for ectopic ACTH secretion.

Diagnostic test utilization in Antioquia

While UFC and the ODST were widely used, LNSC was performed in only a minority of patients despite robust evidence demonstrating its superior diagnostic accuracy.^12,41 The limited availability of salivary cortisol testing in Colombia has likely constrained its implementation, consistent with observations from other middle-income settings.

Despite the widespread use of LC-MS/MS for UFC quantification in high-income countries,^42,43 many Colombian labs still rely on immunoassays, which may lack specificity due to cross-reactivity.^15,44 These analytical considerations underscore the need to strengthen access to LNSC and improve the standardization of UFC methodology across institutions.

Approximately 6% of cases remained etiologically unlocalized, reflecting the diagnostic complexity inherent to ACTH-dependent CS in real-world practice, especially in contexts with limited access to IPSS—the gold standard for confirming CD when imaging is inconclusive.¹⁶

The HDDST demonstrated >50% cortisol suppression in 74.4% of CD patients, consistent with historical suppression rates of 60%–70%. No suppression was seen in ACS or EAS, supporting its use as a secondary differentiating tool, not as a diagnostic test for CS. Modern guidelines emphasize that HDDST cannot replace IPSS but may add value when IPSS is unavailable or contraindicated.^13,16

Surgical outcomes in CD patients in Antioquia

Transsphenoidal resection was the initial treatment in most CD patients, with an overall initial remission rate of 63.3%. This is notable given that transsphenoidal surgery is the standard first-line treatment for CD.^{20,25,28–30,34,36,37,38}

The overall initial remission rate of 63.3% after transsphenoidal surgery aligns with international series reporting remission between 60% and 90%, depending on tumor size, surgeon experience, and outcome definitions.^{19,20,25,28,29,38,45,46} In Latin America, remission rates vary widely: 69% in the Argentine national registry³⁶ and 38%–41% in Colombian single-center reports.^23,24

Variability in surgical outcomes has been linked to surgeon volume. Honegger and Grimm¹⁷ found that performing ⩾10 surgeries annually resulted in remission rates >70%. Although expert surgeons are known to achieve higher remission rates,¹⁷ our study did not detect significant differences between expert and non-expert groups. Importantly, however, the small sample size limited the statistical power. Furthermore, expert surgeons in our cohort treated a higher proportion of macroadenomas, consistent with referral of more complex cases, which may attenuate apparent outcome differences.¹⁸ Other factors influencing remission include patient age and tumor size. The ERCUSYN registry found lower remission in older patients (52% in ⩾65 years vs 65% in younger adults).²⁵ This may reflect referral of more complex cases⁴⁰ and explains why expert-operated cases had similar outcomes despite being higher risk. Moreover, variations in outcome definitions may affect cross-study comparisons. In our study, outcomes were determined through a rigorous consensus process, potentially leading to underestimation if documentation was incomplete.

Among patients who achieved initial remission with non-expert surgery, recurrence-free survival reached 48 months, aligning with international reports.^20,25,34,47 Recurrence rates among expert-operated patients (29%) are consistent with estimates of 15%–30%, emphasizing the need for lifelong surveillance.^20,24,47

Complication rates—including CSF leak and AVP deficiency—were comparable to those reported by high-volume centers.^38,47 Hypopituitarism appeared more frequent in the expert group, likely reflecting the greater surgical complexity of macroadenomas and invasive lesions.⁴⁸ Our findings emphasize the role of surgical expertise but also highlight that long-term follow-up and outcome definitions significantly influence results. UK²⁰ and Iranian²⁹ registries show that surgical variability reflects institutional factors and disease complexity. Johnston et al.¹⁸ found CSF leak and AVP-D rates of 7.3% and 8.2%, respectively, in high-volume centers. In our expert cohort, rates were 2.3% and 6.8%, respectively—comparable to centers performing ⩾25 transsphenoidal surgeries per year.¹⁷ The higher prevalence of hypopituitarism among expert-operated cases may be related to larger tumor size, greater surgical extent, or referral of more complex cases.⁴⁷

Although surgical remission is often achievable, medical therapy, radiotherapy, and bilateral adrenalectomy remain essential in patients who are inoperable or do not achieve remission.^{22,25,35,48–54} Among these, medical therapy was the most commonly used strategy in our cohort. However, because this subanalysis was focused on surgical outcomes, efficacy analyses of medical therapy were descriptive and based on the last available biochemical follow-up. These findings should be interpreted within the context of a surgically focused subanalysis.

Strengths and limitations

This is the first multicenter Latin American study to include patients with all three major CS subtypes. These data allow for deeper analyses of test performance, population characteristics, and outcomes in EAS and ACS. Outcomes were determined through investigator consensus and cross-center data review, strengthening reliability. However, retrospective design introduces inherent sources of bias, and the rarity of CS makes prospective studies and a priori sample size estimation challenging. Consequently, no formal power analysis was performed, and the sample size was determined by case availability over the study period. As a result, some subgroup analyses—particularly those comparing outcomes according to neurosurgical expertise or etiological subtype—may have been underpowered to detect modest differences. In addition, incomplete documentation regarding surgical teams reduced the sample size for certain subgroup analyses, and missing biochemical follow-up data may have led to underestimation of remission rates. Finally, although postoperative hypopituitarism was recorded as a global outcome, detailed information on individual pituitary hormone deficiencies was not consistently available, precluding a more granular analysis of specific postoperative endocrine deficits.

Conclusion

The heterogeneity in clinical presentation and treatment response highlights the need for standardized protocols to facilitate early identification, accurate diagnosis, and optimal management. While international comparisons show similarities in epidemiology and etiology, disparities in test access can affect outcomes. Despite varying levels of neurosurgical expertise, remission rates in Antioquia were comparable to international centers of excellence. These real-world data provide a framework for improving diagnostic pathways and optimizing multidisciplinary management of CS in Latin America. The results reinforce the value of strengthening population registries in rare diseases like CS to improve care quality and inform locally adapted, evidence-based strategies.

Supplemental Material

sj-docx-1-tae-10.1177_20420188261434078 – Supplemental material for Clinical characteristics, diagnosis, and treatment of Cushing’s syndrome: analysis of a multicenter registry in Antioquia, Colombia

Supplemental material, sj-docx-1-tae-10.1177_20420188261434078 for Clinical characteristics, diagnosis, and treatment of Cushing’s syndrome: analysis of a multicenter registry in Antioquia, Colombia by Wilfredo Antonio Rivera-Martínez, María Johana Ramírez Castaño, Stefanía Cruz Calderón, Néstor Andrés Díaz Posada, Johnayro Gutiérrez Restrepo, Alejandro Román-González, Natalia Aristizábal Henao, Pablo Alberto Castaño Ceballos, Catalina Isabel Tobón Ospina, Jorge Hernando Donado Gómez, Néstor López Pompey and Carlos Esteban Builes-Montaño in Therapeutic Advances in Endocrinology and Metabolism

Footnotes

Acknowledgements

The authors would like to express their sincere gratitude to all the patients whose clinical information made this study possible, as well as to the multidisciplinary healthcare teams at each participating center for their invaluable contributions to the diagnosis, treatment, and follow-up of patients with Cushing’s syndrome. Their commitment and collaboration were essential to the development of this multicenter study.

Declarations

ORCID iDs

Wilfredo Antonio Rivera-Martínez

Stefanía Cruz Calderón

Néstor Andrés Díaz Posada

Alejandro Román-González

Natalia Aristizábal Henao

Jorge Hernando Donado Gómez

Néstor López Pompey

Carlos Esteban Builes-Montaño

Supplemental material

Supplemental material for this article is available online.

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Clinical characteristics,diagnosis,and treatment of Cushing’s syndrome: analysis of a multicenter registry in Antioquia,Colombia

Abstract

Background:

Objectives:

Design:

Methods:

Results:

Conclusion:

Plain language summary

Keywords

Introduction

Materials and methods

Study design and population

Diagnostic evaluation

Assay methodologies

Etiological classification of CS

ACTH measurement

Imaging

Inferior petrosal sinus sampling

High-dose dexamethasone suppression test

Variables collected

Exposure variable: Neurosurgical expertise

Outcomes of surgical management in CD

Biochemical monitoring

Sample size calculation

Statistical analysis

Ethics approval and written informed consent

Results

Study population

Clinical characteristics at presentation

Diagnosis of CS

Biochemical monitoring

Treatment

Surgical outcomes and complications in CD according to neurosurgeon expertise

Discussion

Sociodemographic and clinical features in CS patients from Antioquia

Etiological subtypes of CS

Diagnostic test utilization in Antioquia

Surgical outcomes in CD patients in Antioquia

Strengths and limitations

Conclusion

Supplemental Material

sj-docx-1-tae-10.1177_20420188261434078 – Supplemental material for Clinical characteristics, diagnosis, and treatment of Cushing’s syndrome: analysis of a multicenter registry in Antioquia, Colombia

Footnotes

Acknowledgements

Declarations

ORCID iDs

Supplemental material

References