Cushing’s Syndrome Treatments

Posted on January 7, 2026 by MaryO
Medications, Surgery, and Other Treatments for Cushing’s Syndrome

Written by | Reviewed by Daniel J. Toft MD, PhD

Treatment for Cushing’s syndrome depends on what symptoms you’re experiencing as well as the cause of Cushing’s syndrome.

Cushing’s syndrome is caused by an over-exposure to the hormone cortisol. This excessive hormone exposure can come from a tumor that’s over-producing either cortisol or adrenocorticotropic hormone (ACTH—which stimulates the body to make cortisol). It can also come from taking too many corticosteroid medications over a long period of time; corticosteroids mimic the effect of cortisol in the body.

The goal of treatment is to address the over-exposure. This article walks you through the most common treatments for Cushing’s syndrome.

Gradually decreasing corticosteroid medications: If your doctor has identified that the cause of your Cushing’s syndrome is corticosteroid medications, you may be able to manage your Cushing’s syndrome symptoms by reducing the overall amount of corticosteroids you take.

It’s common for some people with certain health conditions—such as arthritis and asthma—to take corticosteroids to help them manage their symptoms. In these cases, your doctor can prescribe non-corticosteroid medications, which will allow you to reduce—or eliminate—your use of corticosteroids.

It’s important to note that you shouldn’t stop taking corticosteroid medications on your own—suddenly stopping these medications could lead to a drop in cortisol levels—and you need a healthy amount of cortisol. When cortisol levels get too low, it can cause a variety of symptoms, such as muscle weakness, fatigue, weight loss, and low blood pressure, which may be life-threatening.

Instead, your doctor will gradually reduce your dose of corticosteroids to allow your body to resume normal production of cortisol.

If for some reason you cannot stop taking corticosteroids, your doctor will monitor your condition very carefully, frequently checking to make sure your blood glucose levels as well as your bone mass levels are normal. Elevated blood glucose levels and low bone density are signs of Cushing’s syndrome.

Surgery to remove a tumor: If it’s a tumor causing Cushing’s syndrome, your doctor may recommend surgery to remove the tumor. The 2 types of tumors that can cause Cushing’s are pituitary tumors (also called pituitary adenomas) and adrenal tumors. However, other tumors in the body (eg, in the lungs or pancreas) can cause Cushing’s syndrome, too.

Pituitary adenomas are benign (non-cancerous), and most adrenal tumors are as well. However, in rare cases, adrenal tumors can be malignant (cancerous). These tumors are called adrenocortical carcinomas, and it’s important to treat them right away.

Surgery for removing a pituitary tumor is a delicate process. It’s typically performed through the nostril, and your surgeon will use tiny specialized tools. The success, or cure, rate of this procedure is more than 80% when performed by a surgeon with extensive experience. If surgery fails or only produces a temporary cure, surgery can be repeated, often with good results.

If you have surgery to remove an adrenal tumor or tumor in your lungs or pancreas, your surgeon will typically remove it through a standard open surgery (through an incision in your stomach or back) or minimally invasive surgery in which small incisions are made and tiny tools are used.

In some cases of adrenal tumors, surgical removal of the adrenal glands may be necessary.

Radiation therapy for tumors: Sometimes your surgeon can’t remove the entire tumor. If that happens, he or she may recommend radiation therapy—a type of treatment that uses high-energy radiation to shrink tumors and/or destroy cancer cells.

Radiation therapy may also be prescribed if you’re not a candidate for surgery due to various reasons, such as location or size of the tumor. Radiation therapy for Cushing’s syndrome is typically given in small doses over a period of 6 weeks or by a technique called stereotactic radiosurgery or gamma-knife radiation.

Stereotactic radiosurgery is a more precise form of radiation. It targets the tumor without damaging healthy tissue.

With gamma-knife radiation, a large dose of radiation is sent to the tumor, and radiation exposure to the healthy surrounding tissues is minimized. Usually one treatment is needed with this type of radiation.

Medications for Cushing’s syndrome: If surgery and/or radiation aren’t effective, medications can be used to regulate cortisol production in the body. However, for people who have severe Cushing’s syndrome symptoms, sometimes medications are used before surgery and radiation treatment. This can help control excessive cortisol production and reduce risks during surgery.

Examples of medications your doctor may prescribe for Cushing’s syndrome are: aminoglutethimide (eg, Cytadren), ketoconazole (eg, Nizoral), metyrapone (eg, Metopirone), and mitotane (eg, Lysodren). Your doctor will let you know what medication—or combination of medications—is right for you.

You may also need to take medication after surgery to remove a pituitary tumor or adrenal tumor. Your doctor will most likely prescribe a cortisol replacement medication. This medication helps provide the proper amount of cortisol in your body. An example of this type of medication is hydrocortisone (a synthetic form of cortisol).

Experiencing the full effects of the medication can take up to a year or longer. But in most cases and under your doctor’s careful supervision, you can slowly reduce your use of cortisol replacement medications because your body will be able to produce normal cortisol levels again on its own. However, in some cases, people who have surgery to remove a tumor that causes Cushing’s syndrome won’t regain normal adrenal function, and they’ll typically need lifelong replacement therapy.2

Treating Cushing’s Syndrome Conclusion
You may need one treatment or a combination of these treatments to effectively treat your Cushing’s syndrome. Your doctor will let you know what treatments for Cushing’s syndrome you’ll need.

From https://www.endocrineweb.com/conditions/cushings-syndrome/cushings-syndrome-treatments

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Clinical Efficacy and Safety of Fluconazole Treatment in Patients with Cushing’s Syndrome

Posted on November 23, 2025 by MaryO

Abstract

Background:

Ketoconazole is effective for treating Cushing’s syndrome (CS) but its use is limited by the risk of hepatotoxicity. Fluconazole, with similar antifungal properties, is being investigated as a potentially safer alternative for managing CS. This study aims to evaluate the efficacy and safety of fluconazole in patients with CS.

Methods:

This retrospective study evaluated a total of 22 patients with CS, including 12 with Cushing’s disease (CD), 3 with adrenal Cushing’s syndrome (ACS), and 7 with ectopic Adrenocorticotropic hormone (ACTH) syndrome. Fluconazole was administered orally, ranging from 112.5 to 450 mg daily, with the duration varying from 2 weeks to over 5 years. The efficacy of fluconazole was assessed by changes in 24-hour urinary free cortisol (24-h UFC) levels. Additionally, hepatic safety was assessed by monitoring changes in alanine aminotransferase (ALT) levels.

Results:

Following fluconazole treatment, 24-h UFC levels significantly decreased from 717.6 ± 1219.4 to 184.1 ± 171.8 µg/day (p = 0.035). ALT levels showed an increase from 38.5 ± 28.4 to 56.5 ± 47.8 U/L, though this change was not statistically significant (p = 0.090). ALT levels exceeding the upper limit of normal range (ULN) were observed in 12 patients (54.5%), with only 4 patients (18.2%) showing ALT levels more than three times the ULN. Out of 10 patients who received treatment for over 1 year, 5 patients (50.0%) experienced a recurrence, with 24-h UFC levels more than 1.5 times the ULN within 3 to 12 months after fluconazole treatment.

Conclusion:

Fluconazole effectively reduces hypercortisolism in patients with CS without significant liver injury, suggesting it as a viable therapeutic option for CS. While some cases have shown treatment escape, more studies are required to confirm the long-term efficacy.

Introduction

Cushing’s syndrome (CS) is a complex endocrine disorder characterized by excessive cortisol production, leading to complications such as insulin-resistant hyperglycemia, muscle weakness (proximal myopathy), osteoporosis, cardiovascular diseases, and neuropsychiatric disorders.1 The primary causes of CS include pituitary ACTH-secreting tumor (Cushing’s disease (CD), adrenal neoplasm (adrenal Cushing’s syndrome (ACS)), or nonpituitary ACTH-secreting tumor (ectopic ACTH syndrome (EAS)). The most common cause is CD. If left untreated, CS patients face a 3.8 to 5-fold increase in mortality compared to the general population.2,3 The first-line treatment for CS involves surgical removal of the offending tumor(s). In CD cases, transsphenoidal pituitary surgery achieves success rates between 65% and 90% for microadenomas. However, complete resection can be challenging, especially with macroadenomas, leading to recurrence or persistent hypercortisolism in approximately 20%–25% of patients.4 Alternative treatments include pituitary stereotactic radiosurgery, which effectively controls cortisol levels over several years but carries potential adverse effects.5,6 For EAS patients, managing hypercortisolism while awaiting definitive treatments like surgery is critical.7 Bilateral adrenalectomy offers immediate control over cortisol excess but necessitates lifelong steroid replacement therapy, impacting the quality of life.8 In addition, some corticotropic pituitary tumors may progress post-surgery, requiring further targeted interventions.9
However, some patients were not candidates for surgery due to factors such as advanced age, personal preference against surgery, or the absence of a definitive culprit lesion. When surgery fails to fully correct hypercortisolism (i.e., when 24-h UFC levels do not decrease or even progressively rise in the weeks to months following surgery, indicating persistence or relapse), pharmacotherapy can be employed to reduce cortisol overproduction and enhance clinical outcomes.10,11 In addition, it could be administered before surgical intervention to reduce perioperative complications.12,13 Various medications are used in the treatment of CS, including adrenal steroidogenesis inhibitors, dopamine agonists, somatostatin analogs, or glucocorticoid receptor antagonist.4,14
Ketoconazole, an imidazole fungicide and adrenal steroidogenesis inhibitor, has long been off-label used as the first-line medication for patients with CS who cannot undergo surgery or for whom surgery is non-curative. It reduces cortisol synthesis by inhibiting the side-chain cleavage enzymes 11β-hydroxylase and 17,20-lyase.10 Effective doses range from 200 to 1200 mg daily, but gradual dose increases may be necessary due to the potential for escape from cortisol inhibition.10,15 Ketoconazole is extensively metabolized in the liver, leading to an increased risk of hepatotoxicity.16 In 2013, the U.S. Food and Drug Administration (FDA) issued warnings about the potentially life-threatening liver toxicity associated with ketoconazole. As a result, ketoconazole is no longer available in many regions.
Fluconazole, another azole antifungal agent, has been explored as an alternative treatment for CS. It inhibits adrenal steroidogenesis through the CYP450 pathway, and the effects have been confirmed in vitro, using primary cultures of human adrenocortical tissues and two adrenocortical carcinoma cell lines. The effects were mainly observed in enzymes 11β-hydroxylase and 17α-hydroxylase, which are key in cortisol synthesis.17 Another study also demonstrated that fluconazole inhibits glucocorticoid production in vitro in the adrenal adenoma cell line Y-1.18 Case reports have also documented adrenal insufficiency in patients with severe comorbidities treated with fluconazole, suggesting its potential for managing hypercortisolism.19,20 Fluconazole is characterized by its small molecular size and low lipophilicity. It is minimally metabolized, with approximately 80% excreted unchanged in the urine.16 This contributes to its lower incidence of adverse effects, particularly liver injury. In a cohort study estimating the risk of clinical acute liver injury among users of oral antifungals (fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine) in the general population from the General Practice Research Database in the United Kingdom, fluconazole was associated with a lower relative risk of acute liver injury compared to other agents.21
Levoketoconazole, the 2S, 4R enantiomer of ketoconazole, provides enhanced enzyme inhibition with greater therapeutic efficacy and fewer side effects compared to ketoconazole.22 The main challenge with using levoketoconazole in the treatment of CS is the limited data from Randomized controlled trials (RCTs). To date, there are only two prospective studies (SONICS and LOGICS) and one systematic review that evaluate the efficacy and safety of levoketoconazole in this context.23–25
Given that existing evidence on fluconazole treatment for CS is primarily limited to case reports, this study aims to evaluate the efficacy and safety of fluconazole in the first relatively large cohort of CS patients.

Patients and methods

Patients

This retrospective study analyzed a total of 22 patients with CS, including 12 cases of CD, 3 cases of ACS, and 7 cases of EAS. For patients who presented with Cushingoid appearance, a 1-mg overnight low-dose dexamethasone suppression test (LDDST) was performed. If the result revealed positive (>1.8 mcg/dL), further surveys were arranged. CS was diagnosed based on 24-h UFC levels (>three times the upper limit of normal range (ULN)), and 2-day LDDST (>1.8 mcg/dL). Once the biochemical diagnosis of CS was confirmed, morning plasma ACTH and cortisol levels were measured to differentiate between ACTH-dependent and ACTH-independent CS. Low ACTH levels (<5 pg/dL) accompanied by elevated cortisol concentrations (>15 mcg/dL) indicated an adrenal origin, consistent with ACTH-independent CS. In such cases, a computed tomography or magnetic resonance imaging scan was performed to evaluate for adrenal masses. If ACTH levels were greater than 5 pg/dL, ACTH-dependent CS was suspected. To identify the source of excessive ACTH secretion—either CD or EAS—further diagnostic testing was conducted, including high-dose dexamethasone suppression test (UFC suppresses >90%, or plasma cortisol suppresses > 50% from baseline, CD is most likely), or corticotropin-releasing hormone (CRH) stimulation test, or desmopressin (DDAVP) stimulation test (ACTH increases >50% and plasma cortisol increases >20% suggests CD), or inferior petrosal sinus sampling (central-to-peripheral ACTH ratio ⩾2 or ⩾3 post CRH or DDAVP suggests CD), or pituitary magnetic resonance imaging (pituitary mass >6 mm suggests CD).1,26 If the patient’s condition allowed, one or more of these tests were performed, and the final diagnosis was made based on a comprehensive interpretation of the combined results.

Methods

After the approval of the Institutional Review Board at Taipei Veterans General Hospital (IRB No. 2021-04-003CC), we conducted a retrospective study, which was waived for informed consent at Taipei Veterans General Hospital. Sample size calculations were not conducted because this was a retrospective study. We surveyed patients diagnosed with CS (CD, ACS, or EAS) who received fluconazole treatment at Taipei Veterans General Hospital in Taipei, Taiwan, between January 1st, 2015, and August 31st, 2020. Fluconazole was administered orally at doses ranging from 112.5 to 450 mg daily, with treatment durations ranging from 2 weeks to over 5 years (Fluconazole was not administered for other treatment purposes, such as infection). The inclusion criteria consisted of a confirmed diagnosis of CS (whether newly diagnosed, persistent, or recurrent) and a history of fluconazole treatment for CS. The exclusion criteria included patients who were not regularly followed up after fluconazole treatment or who lacked complete 24-h UFC data both before and after treatment with fluconazole.
The following data before initiation of treatment were collected: age, gender, body mass index (BMI), alcohol consumption, history of diabetes mellitus, history of chronic hepatitis, baseline 24-hour urinary free cortisol (24-h UFC) levels (reference range: 20–80 µg/day, measured by chemiluminescent immunoassay), morning serum cortisol, morning adrenocorticotropic hormone (ACTH) levels (measured by chemiluminescent immunoassay), and liver function index (alanine aminotransferase (ALT)). In addition, the history of surgery for pituitary tumor or ectopic lesion resection, as well as any other medical treatments apart from fluconazole, was recorded.
24-Hour UFC levels were monitored every 1 to 3 months after initiating fluconazole treatment. The average values from two 24-h UFC measurements (first and second data points within the first 4 months) were used to assess treatment efficacy. For the evaluation of hepatic safety, the maximum ALT level recorded within 6 months after starting fluconazole treatment was compared to the baseline ALT. In this study, we defined ALT levels exceeding three times the ULN as noteworthy liver injury.

Statistical analysis

Data are presented as mean ± standard deviation (SD) or as numbers (percentage), as appropriate. Due to the small sample sizes in some groups and the non-normal distribution of several variables, nonparametric statistical methods were employed to analyze the relationships between variables. Differences between groups were analyzed using the Pearson Chi-squared test, Student’s t-test, or one-way analysis of variance (ANOVA), as appropriate. A p-value less than 0.05 from the ANOVA was considered statistically significant, indicating that at least one group differed significantly from the others. All statistical analyses were performed using the SPSS software package (version 26; IBM Corporation, Armonk, NY, USA).

Results

The baseline characteristics of the patients are summarized in Table 1. No significant differences were found among the etiologies of CS in terms of age, gender, or history of diabetes (p = 0.271, p = 0.253, and p = 0.667, respectively). Cortisol (8AM), ACTH (8AM), and 24-h UFC levels were significantly higher in the EAS group (p = 0.041, p = 0.005, and p = 0.043, respectively) at diagnosis. BMI was significantly lower in the EAS group compared to the other groups (p = 0.002). Alcohol consumption and history of chronic hepatitis, both common causes of liver injury in Taiwan, showed no significant differences among the groups (p = 0.325 and p = 0.765, respectively). Regarding surgical history, eight patients (66.7%) in the CD group had undergone pituitary surgery, while no patients in the ACS group had a history of surgery. In the EAS group, two patients (28.6%) had undergone surgery: one had an anterior mediastinal tumor removal and left upper lung wedge resection, and the other had a suprasellar tumor resection (p = 0.064).

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Table 1. The baseline characteristics of patients with Cushing’s syndrome.
Characteristics All (n = 22) CD (n = 12) ACS (n = 3) EAS (n = 7) p-Value*
Age (years) 54.5 ± 15.5 49.8 ± 15.3 56.0 ± 12.5 61.9 ± 15.9 0.271
Female, n (%) 17 (77.3) 10 (83.3) 3 (100) 4 (57.1) 0.253
Body mass index (kg/m2) 25.1 ± 4.3 27.4 ± 2.8 27.2 ± 1.3 21.0 ± 3.8 0.002
Cortisol (8AM) (µg/dL) 26.7 ± 18.7 21.5 ± 8.6 14.0 ± 4.0 40.3 ± 26.1 0.041
ACTH (8AM) (pg/mL) 151.9 ± 172.1 98.0 ± 63.1 6.4 ± 0.9 306.5 ± 228.3 0.005
24-h UFC (µg/day) 760.5 ± 1387.8 277.9 ± 125.6 107.6 ± 78.2 1891.2 ± 2155.7 0.043
Alcohol consumption, n (%)a 1 (4.5) 0 (0.0) 0 (0.0) 1 (14.3) 0.325
History of diabetes, n (%) 11 (50.0) 5 (41.7) 2 (66.7) 4 (57.1) 0.667
History of chronic hepatitis, n (%) 2 (9.1) 1 (8.3) 0 (0.0) 1 (14.3) 0.765
Surgery history, n (%)b 10 (45.5) 8 (66.7) 0 (0.0) 2 (28.6) 0.064
Using other medication, n (%) 10 (45.5) 4 (33.3) 0 (0.0) 6 (85.7) 0.020
 Etomidate, n (%) 8 (36.4) 3 (25.0) 0 (0.0) 5 (71.4) 0.047
 Metyrapone, n (%) 1 (4.5) 0 (0.0) 0 (0.0) 1 (14.3) 0.325
 Pasireotide, n (%) 1 (4.5) 1 (8.3) 0 (0.0) 0 (0.0) 0.646
Data are expressed as mean ± SD or number (percentage). 24-h UFC (reference range: 20–80 µg/day)
a
Alcohol consumption was defined as men consume more than two alcoholic equivalents per day, while women consume more than one alcoholic equivalent, with one alcoholic equivalent being 10 g of alcohol.
b
Surgery for pituitary tumor or ectopic lesions.
*
p-Value <0.05 from ANOVA, indicating at least one group differed significantly from the others.
24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; SD, standard deviation.
During fluconazole treatment, significant differences were observed among the three groups concerning the use of additional medications (p = 0.020). In the CD group, three patients (25%) received etomidate and one patient (8.3%) received pasireotide. No patients in the ACS group received other medications. In the EAS group, five patients (71.4%) received etomidate, and one patient (14.3%) received metyrapone. For patients treated with etomidate, the duration was limited to a few days before switching to fluconazole. One patient received concomitant therapy with pasireotide and fluconazole.
Table 2 presents the laboratory results for hormonal parameters and ALT levels before and after fluconazole treatment. Prior to treatment, there were no statistically significant differences among the three groups in terms of serum cortisol (8AM), ACTH (8AM), 24-h UFC, and ALT levels (p = 0.739, p = 0.239, p = 0.157, and p = 0.738, respectively).

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Table 2. The laboratory exams of hormonal parameters and ALT before and after fluconazole treatment.
Variable All (n = 22) CD (n = 12) ACS (n = 3) EAS (n = 7) p-Value
Cortisol (8AM) before fluconazole (µg/dL) 18.3 ± 10.8 17.8 ± 11.6 14.8 ± 3.4 20.6 ± 12.1 0.739
ACTH (8AM) before fluconazole (pg/mL) 104.5 ± 122.2 101.9 ± 64.7 6.4 ± 0.9 150.7 ± 188.4 0.239
ACTH (8AM) after fluconazole treatment (pg/mL)a 75.7 ± 87.0 65.7 ± 44.3 6.8 ± 1.4 122.4 ± 133.4 0.020
24-h UFC before fluconazole (µg/day) 717.6 ± 1219.4 443.1 ± 391.5 139.2 ± 95.7 1436.0 ± 2000.0 0.157
24-h UFC after fluconazole (µg/day)b 184.1 ± 171.8 132.0 ± 117.3 53.3 ± 30.8 321.9 ± 198.8 0.017
Decline percentage (%) of 24-h UFC after fluconazole 39.2% ± 48.2% 50.2% ± 37.4% 55.8% ± 27.3% 13.1% ± 64.4% 0.228
Normalization of 24-h UFC after fluconazole, n (%) 6 (27.3) 4 (33.3) 2 (66.7) 0 (0.0) 0.074
24-h UFC <1.5× ULN after fluconazole, n (%) 10 (45.5) 6 (50.0) 3 (100.0) 1 (14.3) 0.040
ALT before fluconazole (U/L) 38.5 ± 28.4 42.4 ± 32.6 38.0 ± 14.1 30.8 ± 24.2 0.738
ALT after fluconazole (U/L)c 56.5 ± 47.8 76.7 ± 54.3 28.7 ± 12.7 28.8 ± 13.6 0.091
ALT >ULN after fluconazole, n (%)c 12 (54.5) 8 (66.7) 2 (66.7) 2 (28.6) 0.247
ALT >3× ULN after fluconazole, n (%)c 4 (18.2) 4 (33.3) 0 (0.0) 0 (0.0) 0.130
Data are expressed as mean ± SD or number (percentage). ALT (reference range: male: <41 U/L; female: <33 U/L). 24-h UFC (reference range: 20–80 µg/day).
a
The average of first and second ACTH after fluconazole treatment.
b
The average of first and second 24-h UFC after fluconazole treatment.
c
ALT: maximum in following 6 months.
1.
5×, 1.5 times upper limit of normal range; 3×, 3 times upper limit of normal range; 24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; ULN, upper limit of normal range.
Twenty-four-hour UFC levels after fluconazole treatment were monitored over the following months. The average values of the first and second 24-h UFC measurements showed significant declines compared to baseline levels as: decreased from 717.6 ± 1219.4 to 184.1 ± 171.8 µg/day in all patients (p = 0.035), decreased form 443.1 ± 391.5 to 132.0 ± 117.3 µg/day in the CD group (p = 0.009), decreased from 139.2 ± 95.7 to 53.3 ± 30.8 µg/day in the ACS group (p = 0.243), and decreased from 1436.0 ± 2000.0 to 321.9 ± 198.8 µg/day in the EAS group (p = 0.147). The percentage decline in 24-h UFC levels following treatment demonstrated a significant reduction as follows: 39.2% ± 48.2% in all patients, 50.2% ± 37.4% in the CD group, 55.8% ± 27.3% in the ACS group, and 13.1% ± 64.4% in the EAS group (p = 0.228) (Table 2 and Figure 1 illustrate these changes).

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Figure 1. 24-h UFC before and after fluconazole treatment in patients with Cushing’s syndrome.
24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; CD, Cushing’s disease; EAS, ectopic ACTH syndrome.
Normalization of 24-h UFC levels (reference range 20–80 μg/day) was observed in six patients (27.3%) across three groups: four patients (33.3%) in the CD group, two patients (66.7%) in the ACS group, and no patients in the EAS group (p = 0.074). Additionally, 10 cases (45.5%) across 3 groups, 6 cases (50%) in the CD group, 3 cases (100%) in the ACS group, and 1 case (14.3%) in the EAS group showed 24-h UFC less than 1.5 times the ULN (p = 0.040). In this study, 10 patients (45.5%) received fluconazole treatment for more than 1 year. Among these, five patients (50.0%) experienced a recurrence of hypercortisolism, with 24-h UFC levels exceeding 1.5 times the ULN within 3–12 months after treatment with fluconazole.
For hepatic safety assessment, the maximum ALT levels within 6 months of fluconazole treatment were analyzed and are presented in Table 2. Compared to baseline levels, ALT increased from 38.5 ± 28.4 to 56.5 ± 47.8 U/L in all patients (p = 0.090), and increased from 42.4 ± 32.6 to 76.7 ± 54.3 U/L in the CD group (p = 0.047). (Table 2 and Figure 2 illustrate these changes). After fluconazole treatment, 12 cases (54.5%) of all patients, 8 cases (66.7%) in the CD group, 2 cases (66.7%) in the ACS group, and 2 cases (28.6%) in the EAS group revealed ALT levels exceeded the ULN (p = 0.247). Additionally, 4 cases (18.2%) of all patients, 4 cases (33.3%) in the CD group, and no cases in the ACS and EAS groups revealed ALT levels more than three times the ULN (p = 0.130).

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Figure 2. ALT before and after fluconazole treatment in patients with Cushing’s syndrome.
ACS, adrenal Cushing’s syndrome; ALT, Alanine aminotransferase; CD, Cushing’s disease; EAS, ectopic ACTH syndrome.

Discussion

To date, our study is the largest retrospective analysis providing the evaluation of the clinical efficacy and safety of fluconazole treatment in patients with CS. The major findings demonstrated that 24-h UFC levels significantly decreased across all groups after fluconazole treatment, with more than 50% reduction in both the CD and ACS groups. However, the EAS group showed only a 13.1% decline in 24-h UFC levels, although with a large interval (SD 64.4%) and small case numbers in this group, indicating greater variability in response and heterogeneity in this group. Regarding hepatic safety, while ALT levels increased after fluconazole treatment, particularly in the CD group, the changes were not statistically significant in other groups. The significant increase in ALT levels (42.4 ± 32.6 to 76.7 ± 54.3 U/L) in the CD group, but mild—less than two times ULN, may also be related to the high variability (large SD). Importantly, there was no severe hepatotoxicity in the study, because only four patients (18.2%) revealed ALT levels more than three times the ULN.
Fluconazole can be administered either intravenously or orally. Several case reports highlight its effectiveness and safety: Teng Chai et al. reported successful long-term treatment of recurrent CD in a 50-year-old woman using fluconazole with cabergoline, resulting in significant clinical and biochemical improvement without adverse effects.27 Zhao et al. reported that fluconazole normalized cortisol levels pre-surgery in a 48-year-old woman with CD and pulmonary cryptococcal infection.28 In another case, fluconazole with low-dose metyrapone normalized cortisol levels for 6 months in a 61-year-old woman with recurrent CD prior to radiotherapy.29 Riedl et al. demonstrated fluconazole’s efficacy and safety in an 83-year-old woman with CS from adrenocortical carcinoma.18 Canteros et al. reported effective cortisol reduction with mild side effects from fluconazole in a 39-year-old woman with EAS, enabling successful bilateral adrenalectomy.30 An 80-year-old woman with CS of unknown origin also showed effective cortisol control with fluconazole.31 Two of these six cases suffered from hepatic dysfunction at fluconazole doses over 400 mg/day; however, liver enzyme levels returned to normal after dosage reduction. A secondary analysis of a dose-adjustment trial for fluconazole in the treatment of invasive mycoses examined 85 patients who received prolonged high-dose treatment. For these cases, 27% experienced clinical symptoms, and 42% exhibited abnormal laboratory results. The common side effects were <5% of anorexia, hair loss, headache, and 12% of eosinophilia. However, these adverse effects did not progress, leading the study to conclude that fluconazole is well tolerated and generally safe.32
Ketoconazole has been used to treat hypercortisolism by inhibiting CYP450 enzymes, specifically 11β-hydroxylase and 17α-hydroxylase, and fluconazole has similar properties.17 Previous studies suggest that fluconazole is less potent in inhibiting glucocorticoid production compared to ketoconazole, with varying effects; however, cortisol reduction with fluconazole use has been confirmed.17,18 Unlike ketoconazole, which is extensively metabolized in the liver and associated with significant hepatotoxicity, fluconazole is minimally metabolized in the liver.16 According to the FDA, the risk of serious liver injury from ketoconazole is higher than with other azole agents.33 In our study of 22 patients, fluconazole was well tolerated, with no significant elevations in liver enzyme levels observed during 6 months of treatment. These findings suggest that fluconazole may represent a safer alternative to ketoconazole for the treatment of CS.
In five studies involving 310 patients with CS treated with an average dose of 673.9 mg/day of ketoconazole over an average of 12.6 months, normalization of urinary free cortisol was achieved in 64.3% of patients (median 50%, range 44.7%–92.9%). However, 23% of initially responsive patients eventually lost biochemical control.34 Another retrospective study of 200 patients with CD receiving ketoconazole at an average dose of 600 mg/day found that 64.7% of patients treated for over 2 years achieved UFC normalization, while 15.4% experienced recurrence, or “escape,” from cortisol control.15 In our study, 10 patients (45.5%) received fluconazole treatment for over 1 year, with 5 of these patients (50%) showing 24-h UFC levels not exceeding 1.5 times the ULN in the following 3–12 months (under control without escape). The long-term control of hypercortisolism with fluconazole appears to be less effective than with ketoconazole. However, this could be attributed to the small sample size in our study.
Table 1 shows baseline morning ACTH levels at diagnosis for all patients before any treatment, highlighting a statistically significant difference. In comparison, Table 2 presents morning ACTH levels prior to fluconazole treatment, where no statistical difference was observed. This is likely due to some patients in the CD and EAS groups having previously undergone surgery or received other medical treatments, which might reduce the tumor burden and the levels of ACTH.
Recent studies suggest that levoketoconazole demonstrates good efficacy and safety in the management of CS.23–25 However, no head-to-head trials have been conducted to compare ketoconazole, levoketoconazole, and fluconazole directly. Therefore, further clinical trials are warranted to provide clearer insights into the comparative efficacy and safety of these therapeutic options in CS.
The limitations of this study include its retrospective design, which lacked comparator groups, and the small sample sizes in the ACS and EAS groups. In addition, patients were treated by different physicians, each using their own clinical judgment, without standardized follow-up protocols, making some data difficult to collect and analyze. The heterogeneity in dosing regimens also posed challenges in assessing the dose-response relationship. Besides, the relationship between the timing and dosages of other medications (etomidate, pasireotide, and metyrapone) and their effects on laboratory findings is challenging to analyze due to the limited number of cases. There were no statistically significant differences in ACTH level changes before and after fluconazole treatment among the three groups. This may be a limitation, as we only monitored the first and second ACTH measurements following fluconazole treatment. Further investigations with longer monitoring of ACTH levels may be necessary. The study’s observation period was approximately 5.5 years, but further investigation is required to confirm the long-term efficacy and safety of fluconazole treatment in CS.

Conclusion

This study demonstrates that fluconazole is effective in treating patients with CS, as evidenced by a significant reduction in 24-h UFC levels. Moreover, fluconazole was generally well tolerated, with a minimal risk of liver injury, suggesting it may be an effective and safe option for managing hypercortisolism in CS.

Acknowledgments

The authors thank the Medical Sciences & Technology Building of Taipei Veterans General Hospital for providing experimental space and facilities.

ORCID iD

Footnotes

Ethics approval and consent to participate This study was approved by the Institutional Review Board at Taipei Veterans General Hospital (IRB No. 2021-04-003CC). Due to the retrospective nature of this study, informed patient consent was waived.

Consent for publication Not applicable.

Author contributions

Tang-Yi Liao: Data curation; Formal analysis; Writing – original draft.
Yi-Chun Lin: Data curation; Writing – review & editing.
Chun-Jui Huang: Data curation; Writing – review & editing.
Chii-Min Hwu: Conceptualization; Data curation.
Liang-Yu Lin: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Writing – review & editing.

Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partly supported by research grants (Grant Nos. V108C-197, V109C-179, V110C-198, V111D62-002-MY3, V112C-183, V113C-094, V114C-116, and V114D77-002-MY3-1) to L.Y.L. from Taipei Veterans General Hospital, Taipei, Taiwan and MOST 111-2314-B-075-040-MY2 to L.Y.L. from National Science and Technology Council, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests The authors declare that there is no conflict of interest.

Availability of data and materials The data and materials generated and analyzed in the study are available from the corresponding author on reasonable request.

References

1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5): 1526–1540.
2. Clayton RN, Raskauskiene D, Reulen RC, et al. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96(3): 632–642.
3. Lindholm J, Juul S, Jørgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86(1): 117–123.
4. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93(7): 2454–2462.
5. Castinetti F, Nagai M, Morange I, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 2009; 94(9): 3400–3407.
6. Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 2011; 96(7): 1992–2003.
7. Porterfield JR, Thompson GB, Young WF Jr, et al. Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 2008; 32(5): 659–677.
8. Findling JW, Raff H. Cushing’s Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006; 91(10): 3746–3753.
9. Assié G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 2007; 92(1): 172–179.
10. Schteingart DE. Drugs in the medical treatment of Cushing’s syndrome. Expert Opin Emerg Drugs 2009; 14(4): 661–671.
11. Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002; 5(2): 77–82.
12. Valassi E, Franz H, Brue T, et al. Preoperative medical treatment in Cushing’s syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN. Eur J Endocrinol 2018; 178(4): 399–409.
13. Varlamov EV, Vila G, Fleseriu M. Perioperative management of a patient with Cushing Disease. J Endocr Soc 2022; 6(3): bvac010.
14. Pivonello R, De Martino MC, De Leo M, et al. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37(1): 135–ix.
15. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 2014; 99(5): 1623–1630.
16. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994; 330(4): 263–272.
17. van der Pas R, Hofland LJ, Hofland J, et al. Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol 2012; 215(3): 403–412.
18. Riedl M, Maier C, Zettinig G, et al. Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur J Endocrinol 2006; 154(4): 519–524.
19. Albert SG, DeLeon MJ, Silverberg AB. Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients. Crit Care Med 2001; 29(3): 668–670.
20. Santhana Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J 2006; 82(971): e23.
21. García Rodríguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48(6): 847–852.
22. Creemers SG, Feelders RA, De Jong FH, et al. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, a new steroidogenesis inhibitor for Cushing’s syndrome treatment. J Clin Endocrinol Metabol 2021; 106: 1618–1630.
23. Fleseriu M, Pivonello R, Elenkova A, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabet Endocrinol 2019; 7: 855–865.
24. Pivonello R, Zacharieva S, Elenkova A, et al. Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 2022; 25: 911–926.
25. Patra S, Dutta D, Nagendra L, et al. Efficacy and safety of levoketoconazole in managing Cushing’s syndrome: a systematic review. Indian J Endocr Metab 2024; 28: 343–349.
26. Sharma ST; AACE Adrenal Scientific Committee. An individualized approach to the evaluation of Cushing Syndrome. Endocr Pract 2017; 23(6): 726–737.
27. Teng Chai S, Haydar Ali Tajuddin A, Wahab NA, et al. Fluconazole as a safe and effective alternative to ketoconazole in controlling hypercortisolism of recurrent Cushing’s disease: a case report. Int J Endocrinol Metab 2018; 16(3): e65233.
28. Zhao Y, Liang W, Cai F, et al. Fluconazole for hypercortisolism in Cushing’s disease: a case report and literature review. Front Endocrinol (Lausanne) 2020; 11: 608886.
29. Burns K, Christie-David D, Gunton JE. Fluconazole in the treatment of Cushing’s disease. Endocrinol Diabetes Metab Case Rep 2016; 2016: 150115.
30. Canteros TM, De Miguel V, Fainstein-Day P. Fluconazole treatment in severe ectopic Cushing syndrome. Endocrinol Diabetes Metab Case Rep 2019; 2019(1): 19-0020.
31. Schwetz V, Aberer F, Stiegler C, et al. Fluconazole and acetazolamide in the treatment of ectopic Cushing’s syndrome with severe metabolic alkalosis. Endocrinol Diabetes Metab Case Rep 2015; 2015:1 50027.
32. Stevens DA, Diaz M, Negroni R, et al. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group. Chemotherapy 1997;43(5):371–377.
33. Greenblatt HK, Greenblatt DJ. Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol 2014; 54(12): 1321–1329.
34. Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing’s disease. Endocr Rev 2015; 36(4): 385–486.

 

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Clinical Efficacy and Safety of Fluconazole Treatment in Patients with Cushing’s Syndrome

Posted on November 11, 2025 by MaryO

Abstract

Background:

Ketoconazole is effective for treating Cushing’s syndrome (CS) but its use is limited by the risk of hepatotoxicity. Fluconazole, with similar antifungal properties, is being investigated as a potentially safer alternative for managing CS. This study aims to evaluate the efficacy and safety of fluconazole in patients with CS.

Methods:

This retrospective study evaluated a total of 22 patients with CS, including 12 with Cushing’s disease (CD), 3 with adrenal Cushing’s syndrome (ACS), and 7 with ectopic Adrenocorticotropic hormone (ACTH) syndrome. Fluconazole was administered orally, ranging from 112.5 to 450 mg daily, with the duration varying from 2 weeks to over 5 years. The efficacy of fluconazole was assessed by changes in 24-hour urinary free cortisol (24-h UFC) levels. Additionally, hepatic safety was assessed by monitoring changes in alanine aminotransferase (ALT) levels.

Results:

Following fluconazole treatment, 24-h UFC levels significantly decreased from 717.6 ± 1219.4 to 184.1 ± 171.8 µg/day (p = 0.035). ALT levels showed an increase from 38.5 ± 28.4 to 56.5 ± 47.8 U/L, though this change was not statistically significant (p = 0.090). ALT levels exceeding the upper limit of normal range (ULN) were observed in 12 patients (54.5%), with only 4 patients (18.2%) showing ALT levels more than three times the ULN. Out of 10 patients who received treatment for over 1 year, 5 patients (50.0%) experienced a recurrence, with 24-h UFC levels more than 1.5 times the ULN within 3 to 12 months after fluconazole treatment.

Conclusion:

Fluconazole effectively reduces hypercortisolism in patients with CS without significant liver injury, suggesting it as a viable therapeutic option for CS. While some cases have shown treatment escape, more studies are required to confirm the long-term efficacy.

Introduction

Cushing’s syndrome (CS) is a complex endocrine disorder characterized by excessive cortisol production, leading to complications such as insulin-resistant hyperglycemia, muscle weakness (proximal myopathy), osteoporosis, cardiovascular diseases, and neuropsychiatric disorders.1 The primary causes of CS include pituitary ACTH-secreting tumor (Cushing’s disease (CD), adrenal neoplasm (adrenal Cushing’s syndrome (ACS)), or nonpituitary ACTH-secreting tumor (ectopic ACTH syndrome (EAS)). The most common cause is CD. If left untreated, CS patients face a 3.8 to 5-fold increase in mortality compared to the general population.2,3 The first-line treatment for CS involves surgical removal of the offending tumor(s). In CD cases, transsphenoidal pituitary surgery achieves success rates between 65% and 90% for microadenomas. However, complete resection can be challenging, especially with macroadenomas, leading to recurrence or persistent hypercortisolism in approximately 20%–25% of patients.4 Alternative treatments include pituitary stereotactic radiosurgery, which effectively controls cortisol levels over several years but carries potential adverse effects.5,6 For EAS patients, managing hypercortisolism while awaiting definitive treatments like surgery is critical.7 Bilateral adrenalectomy offers immediate control over cortisol excess but necessitates lifelong steroid replacement therapy, impacting the quality of life.8 In addition, some corticotropic pituitary tumors may progress post-surgery, requiring further targeted interventions.9
However, some patients were not candidates for surgery due to factors such as advanced age, personal preference against surgery, or the absence of a definitive culprit lesion. When surgery fails to fully correct hypercortisolism (i.e., when 24-h UFC levels do not decrease or even progressively rise in the weeks to months following surgery, indicating persistence or relapse), pharmacotherapy can be employed to reduce cortisol overproduction and enhance clinical outcomes.10,11 In addition, it could be administered before surgical intervention to reduce perioperative complications.12,13 Various medications are used in the treatment of CS, including adrenal steroidogenesis inhibitors, dopamine agonists, somatostatin analogs, or glucocorticoid receptor antagonist.4,14
Ketoconazole, an imidazole fungicide and adrenal steroidogenesis inhibitor, has long been off-label used as the first-line medication for patients with CS who cannot undergo surgery or for whom surgery is non-curative. It reduces cortisol synthesis by inhibiting the side-chain cleavage enzymes 11β-hydroxylase and 17,20-lyase.10 Effective doses range from 200 to 1200 mg daily, but gradual dose increases may be necessary due to the potential for escape from cortisol inhibition.10,15 Ketoconazole is extensively metabolized in the liver, leading to an increased risk of hepatotoxicity.16 In 2013, the U.S. Food and Drug Administration (FDA) issued warnings about the potentially life-threatening liver toxicity associated with ketoconazole. As a result, ketoconazole is no longer available in many regions.
Fluconazole, another azole antifungal agent, has been explored as an alternative treatment for CS. It inhibits adrenal steroidogenesis through the CYP450 pathway, and the effects have been confirmed in vitro, using primary cultures of human adrenocortical tissues and two adrenocortical carcinoma cell lines. The effects were mainly observed in enzymes 11β-hydroxylase and 17α-hydroxylase, which are key in cortisol synthesis.17 Another study also demonstrated that fluconazole inhibits glucocorticoid production in vitro in the adrenal adenoma cell line Y-1.18 Case reports have also documented adrenal insufficiency in patients with severe comorbidities treated with fluconazole, suggesting its potential for managing hypercortisolism.19,20 Fluconazole is characterized by its small molecular size and low lipophilicity. It is minimally metabolized, with approximately 80% excreted unchanged in the urine.16 This contributes to its lower incidence of adverse effects, particularly liver injury. In a cohort study estimating the risk of clinical acute liver injury among users of oral antifungals (fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine) in the general population from the General Practice Research Database in the United Kingdom, fluconazole was associated with a lower relative risk of acute liver injury compared to other agents.21
Levoketoconazole, the 2S, 4R enantiomer of ketoconazole, provides enhanced enzyme inhibition with greater therapeutic efficacy and fewer side effects compared to ketoconazole.22 The main challenge with using levoketoconazole in the treatment of CS is the limited data from Randomized controlled trials (RCTs). To date, there are only two prospective studies (SONICS and LOGICS) and one systematic review that evaluate the efficacy and safety of levoketoconazole in this context.23–25
Given that existing evidence on fluconazole treatment for CS is primarily limited to case reports, this study aims to evaluate the efficacy and safety of fluconazole in the first relatively large cohort of CS patients.

Patients and methods

Patients

This retrospective study analyzed a total of 22 patients with CS, including 12 cases of CD, 3 cases of ACS, and 7 cases of EAS. For patients who presented with Cushingoid appearance, a 1-mg overnight low-dose dexamethasone suppression test (LDDST) was performed. If the result revealed positive (>1.8 mcg/dL), further surveys were arranged. CS was diagnosed based on 24-h UFC levels (>three times the upper limit of normal range (ULN)), and 2-day LDDST (>1.8 mcg/dL). Once the biochemical diagnosis of CS was confirmed, morning plasma ACTH and cortisol levels were measured to differentiate between ACTH-dependent and ACTH-independent CS. Low ACTH levels (<5 pg/dL) accompanied by elevated cortisol concentrations (>15 mcg/dL) indicated an adrenal origin, consistent with ACTH-independent CS. In such cases, a computed tomography or magnetic resonance imaging scan was performed to evaluate for adrenal masses. If ACTH levels were greater than 5 pg/dL, ACTH-dependent CS was suspected. To identify the source of excessive ACTH secretion—either CD or EAS—further diagnostic testing was conducted, including high-dose dexamethasone suppression test (UFC suppresses >90%, or plasma cortisol suppresses > 50% from baseline, CD is most likely), or corticotropin-releasing hormone (CRH) stimulation test, or desmopressin (DDAVP) stimulation test (ACTH increases >50% and plasma cortisol increases >20% suggests CD), or inferior petrosal sinus sampling (central-to-peripheral ACTH ratio ⩾2 or ⩾3 post CRH or DDAVP suggests CD), or pituitary magnetic resonance imaging (pituitary mass >6 mm suggests CD).1,26 If the patient’s condition allowed, one or more of these tests were performed, and the final diagnosis was made based on a comprehensive interpretation of the combined results.

Methods

After the approval of the Institutional Review Board at Taipei Veterans General Hospital (IRB No. 2021-04-003CC), we conducted a retrospective study, which was waived for informed consent at Taipei Veterans General Hospital. Sample size calculations were not conducted because this was a retrospective study. We surveyed patients diagnosed with CS (CD, ACS, or EAS) who received fluconazole treatment at Taipei Veterans General Hospital in Taipei, Taiwan, between January 1st, 2015, and August 31st, 2020. Fluconazole was administered orally at doses ranging from 112.5 to 450 mg daily, with treatment durations ranging from 2 weeks to over 5 years (Fluconazole was not administered for other treatment purposes, such as infection). The inclusion criteria consisted of a confirmed diagnosis of CS (whether newly diagnosed, persistent, or recurrent) and a history of fluconazole treatment for CS. The exclusion criteria included patients who were not regularly followed up after fluconazole treatment or who lacked complete 24-h UFC data both before and after treatment with fluconazole.
The following data before initiation of treatment were collected: age, gender, body mass index (BMI), alcohol consumption, history of diabetes mellitus, history of chronic hepatitis, baseline 24-hour urinary free cortisol (24-h UFC) levels (reference range: 20–80 µg/day, measured by chemiluminescent immunoassay), morning serum cortisol, morning adrenocorticotropic hormone (ACTH) levels (measured by chemiluminescent immunoassay), and liver function index (alanine aminotransferase (ALT)). In addition, the history of surgery for pituitary tumor or ectopic lesion resection, as well as any other medical treatments apart from fluconazole, was recorded.
24-Hour UFC levels were monitored every 1 to 3 months after initiating fluconazole treatment. The average values from two 24-h UFC measurements (first and second data points within the first 4 months) were used to assess treatment efficacy. For the evaluation of hepatic safety, the maximum ALT level recorded within 6 months after starting fluconazole treatment was compared to the baseline ALT. In this study, we defined ALT levels exceeding three times the ULN as noteworthy liver injury.

Statistical analysis

Data are presented as mean ± standard deviation (SD) or as numbers (percentage), as appropriate. Due to the small sample sizes in some groups and the non-normal distribution of several variables, nonparametric statistical methods were employed to analyze the relationships between variables. Differences between groups were analyzed using the Pearson Chi-squared test, Student’s t-test, or one-way analysis of variance (ANOVA), as appropriate. A p-value less than 0.05 from the ANOVA was considered statistically significant, indicating that at least one group differed significantly from the others. All statistical analyses were performed using the SPSS software package (version 26; IBM Corporation, Armonk, NY, USA).

Results

The baseline characteristics of the patients are summarized in Table 1. No significant differences were found among the etiologies of CS in terms of age, gender, or history of diabetes (p = 0.271, p = 0.253, and p = 0.667, respectively). Cortisol (8AM), ACTH (8AM), and 24-h UFC levels were significantly higher in the EAS group (p = 0.041, p = 0.005, and p = 0.043, respectively) at diagnosis. BMI was significantly lower in the EAS group compared to the other groups (p = 0.002). Alcohol consumption and history of chronic hepatitis, both common causes of liver injury in Taiwan, showed no significant differences among the groups (p = 0.325 and p = 0.765, respectively). Regarding surgical history, eight patients (66.7%) in the CD group had undergone pituitary surgery, while no patients in the ACS group had a history of surgery. In the EAS group, two patients (28.6%) had undergone surgery: one had an anterior mediastinal tumor removal and left upper lung wedge resection, and the other had a suprasellar tumor resection (p = 0.064).
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Table 1. The baseline characteristics of patients with Cushing’s syndrome.
Characteristics All (n = 22) CD (n = 12) ACS (n = 3) EAS (n = 7) p-Value*
Age (years) 54.5 ± 15.5 49.8 ± 15.3 56.0 ± 12.5 61.9 ± 15.9 0.271
Female, n (%) 17 (77.3) 10 (83.3) 3 (100) 4 (57.1) 0.253
Body mass index (kg/m2) 25.1 ± 4.3 27.4 ± 2.8 27.2 ± 1.3 21.0 ± 3.8 0.002
Cortisol (8AM) (µg/dL) 26.7 ± 18.7 21.5 ± 8.6 14.0 ± 4.0 40.3 ± 26.1 0.041
ACTH (8AM) (pg/mL) 151.9 ± 172.1 98.0 ± 63.1 6.4 ± 0.9 306.5 ± 228.3 0.005
24-h UFC (µg/day) 760.5 ± 1387.8 277.9 ± 125.6 107.6 ± 78.2 1891.2 ± 2155.7 0.043
Alcohol consumption, n (%)a 1 (4.5) 0 (0.0) 0 (0.0) 1 (14.3) 0.325
History of diabetes, n (%) 11 (50.0) 5 (41.7) 2 (66.7) 4 (57.1) 0.667
History of chronic hepatitis, n (%) 2 (9.1) 1 (8.3) 0 (0.0) 1 (14.3) 0.765
Surgery history, n (%)b 10 (45.5) 8 (66.7) 0 (0.0) 2 (28.6) 0.064
Using other medication, n (%) 10 (45.5) 4 (33.3) 0 (0.0) 6 (85.7) 0.020
 Etomidate, n (%) 8 (36.4) 3 (25.0) 0 (0.0) 5 (71.4) 0.047
 Metyrapone, n (%) 1 (4.5) 0 (0.0) 0 (0.0) 1 (14.3) 0.325
 Pasireotide, n (%) 1 (4.5) 1 (8.3) 0 (0.0) 0 (0.0) 0.646
Data are expressed as mean ± SD or number (percentage). 24-h UFC (reference range: 20–80 µg/day)
a
Alcohol consumption was defined as men consume more than two alcoholic equivalents per day, while women consume more than one alcoholic equivalent, with one alcoholic equivalent being 10 g of alcohol.
b
Surgery for pituitary tumor or ectopic lesions.
*
p-Value <0.05 from ANOVA, indicating at least one group differed significantly from the others.
24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; SD, standard deviation.
During fluconazole treatment, significant differences were observed among the three groups concerning the use of additional medications (p = 0.020). In the CD group, three patients (25%) received etomidate and one patient (8.3%) received pasireotide. No patients in the ACS group received other medications. In the EAS group, five patients (71.4%) received etomidate, and one patient (14.3%) received metyrapone. For patients treated with etomidate, the duration was limited to a few days before switching to fluconazole. One patient received concomitant therapy with pasireotide and fluconazole.
Table 2 presents the laboratory results for hormonal parameters and ALT levels before and after fluconazole treatment. Prior to treatment, there were no statistically significant differences among the three groups in terms of serum cortisol (8AM), ACTH (8AM), 24-h UFC, and ALT levels (p = 0.739, p = 0.239, p = 0.157, and p = 0.738, respectively).
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Table 2. The laboratory exams of hormonal parameters and ALT before and after fluconazole treatment.
Variable All (n = 22) CD (n = 12) ACS (n = 3) EAS (n = 7) p-Value
Cortisol (8AM) before fluconazole (µg/dL) 18.3 ± 10.8 17.8 ± 11.6 14.8 ± 3.4 20.6 ± 12.1 0.739
ACTH (8AM) before fluconazole (pg/mL) 104.5 ± 122.2 101.9 ± 64.7 6.4 ± 0.9 150.7 ± 188.4 0.239
ACTH (8AM) after fluconazole treatment (pg/mL)a 75.7 ± 87.0 65.7 ± 44.3 6.8 ± 1.4 122.4 ± 133.4 0.020
24-h UFC before fluconazole (µg/day) 717.6 ± 1219.4 443.1 ± 391.5 139.2 ± 95.7 1436.0 ± 2000.0 0.157
24-h UFC after fluconazole (µg/day)b 184.1 ± 171.8 132.0 ± 117.3 53.3 ± 30.8 321.9 ± 198.8 0.017
Decline percentage (%) of 24-h UFC after fluconazole 39.2% ± 48.2% 50.2% ± 37.4% 55.8% ± 27.3% 13.1% ± 64.4% 0.228
Normalization of 24-h UFC after fluconazole, n (%) 6 (27.3) 4 (33.3) 2 (66.7) 0 (0.0) 0.074
24-h UFC <1.5× ULN after fluconazole, n (%) 10 (45.5) 6 (50.0) 3 (100.0) 1 (14.3) 0.040
ALT before fluconazole (U/L) 38.5 ± 28.4 42.4 ± 32.6 38.0 ± 14.1 30.8 ± 24.2 0.738
ALT after fluconazole (U/L)c 56.5 ± 47.8 76.7 ± 54.3 28.7 ± 12.7 28.8 ± 13.6 0.091
ALT >ULN after fluconazole, n (%)c 12 (54.5) 8 (66.7) 2 (66.7) 2 (28.6) 0.247
ALT >3× ULN after fluconazole, n (%)c 4 (18.2) 4 (33.3) 0 (0.0) 0 (0.0) 0.130
Data are expressed as mean ± SD or number (percentage). ALT (reference range: male: <41 U/L; female: <33 U/L). 24-h UFC (reference range: 20–80 µg/day).
a
The average of first and second ACTH after fluconazole treatment.
b
The average of first and second 24-h UFC after fluconazole treatment.
c
ALT: maximum in following 6 months.
1.
5×, 1.5 times upper limit of normal range; 3×, 3 times upper limit of normal range; 24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; ULN, upper limit of normal range.
Twenty-four-hour UFC levels after fluconazole treatment were monitored over the following months. The average values of the first and second 24-h UFC measurements showed significant declines compared to baseline levels as: decreased from 717.6 ± 1219.4 to 184.1 ± 171.8 µg/day in all patients (p = 0.035), decreased form 443.1 ± 391.5 to 132.0 ± 117.3 µg/day in the CD group (p = 0.009), decreased from 139.2 ± 95.7 to 53.3 ± 30.8 µg/day in the ACS group (p = 0.243), and decreased from 1436.0 ± 2000.0 to 321.9 ± 198.8 µg/day in the EAS group (p = 0.147). The percentage decline in 24-h UFC levels following treatment demonstrated a significant reduction as follows: 39.2% ± 48.2% in all patients, 50.2% ± 37.4% in the CD group, 55.8% ± 27.3% in the ACS group, and 13.1% ± 64.4% in the EAS group (p = 0.228) (Table 2 and Figure 1 illustrate these changes).
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Figure 1. 24-h UFC before and after fluconazole treatment in patients with Cushing’s syndrome.
24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; CD, Cushing’s disease; EAS, ectopic ACTH syndrome.
Normalization of 24-h UFC levels (reference range 20–80 μg/day) was observed in six patients (27.3%) across three groups: four patients (33.3%) in the CD group, two patients (66.7%) in the ACS group, and no patients in the EAS group (p = 0.074). Additionally, 10 cases (45.5%) across 3 groups, 6 cases (50%) in the CD group, 3 cases (100%) in the ACS group, and 1 case (14.3%) in the EAS group showed 24-h UFC less than 1.5 times the ULN (p = 0.040). In this study, 10 patients (45.5%) received fluconazole treatment for more than 1 year. Among these, five patients (50.0%) experienced a recurrence of hypercortisolism, with 24-h UFC levels exceeding 1.5 times the ULN within 3–12 months after treatment with fluconazole.
For hepatic safety assessment, the maximum ALT levels within 6 months of fluconazole treatment were analyzed and are presented in Table 2. Compared to baseline levels, ALT increased from 38.5 ± 28.4 to 56.5 ± 47.8 U/L in all patients (p = 0.090), and increased from 42.4 ± 32.6 to 76.7 ± 54.3 U/L in the CD group (p = 0.047). (Table 2 and Figure 2 illustrate these changes). After fluconazole treatment, 12 cases (54.5%) of all patients, 8 cases (66.7%) in the CD group, 2 cases (66.7%) in the ACS group, and 2 cases (28.6%) in the EAS group revealed ALT levels exceeded the ULN (p = 0.247). Additionally, 4 cases (18.2%) of all patients, 4 cases (33.3%) in the CD group, and no cases in the ACS and EAS groups revealed ALT levels more than three times the ULN (p = 0.130).
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Figure 2. ALT before and after fluconazole treatment in patients with Cushing’s syndrome.
ACS, adrenal Cushing’s syndrome; ALT, Alanine aminotransferase; CD, Cushing’s disease; EAS, ectopic ACTH syndrome.

Discussion

To date, our study is the largest retrospective analysis providing the evaluation of the clinical efficacy and safety of fluconazole treatment in patients with CS. The major findings demonstrated that 24-h UFC levels significantly decreased across all groups after fluconazole treatment, with more than 50% reduction in both the CD and ACS groups. However, the EAS group showed only a 13.1% decline in 24-h UFC levels, although with a large interval (SD 64.4%) and small case numbers in this group, indicating greater variability in response and heterogeneity in this group. Regarding hepatic safety, while ALT levels increased after fluconazole treatment, particularly in the CD group, the changes were not statistically significant in other groups. The significant increase in ALT levels (42.4 ± 32.6 to 76.7 ± 54.3 U/L) in the CD group, but mild—less than two times ULN, may also be related to the high variability (large SD). Importantly, there was no severe hepatotoxicity in the study, because only four patients (18.2%) revealed ALT levels more than three times the ULN.
Fluconazole can be administered either intravenously or orally. Several case reports highlight its effectiveness and safety: Teng Chai et al. reported successful long-term treatment of recurrent CD in a 50-year-old woman using fluconazole with cabergoline, resulting in significant clinical and biochemical improvement without adverse effects.27 Zhao et al. reported that fluconazole normalized cortisol levels pre-surgery in a 48-year-old woman with CD and pulmonary cryptococcal infection.28 In another case, fluconazole with low-dose metyrapone normalized cortisol levels for 6 months in a 61-year-old woman with recurrent CD prior to radiotherapy.29 Riedl et al. demonstrated fluconazole’s efficacy and safety in an 83-year-old woman with CS from adrenocortical carcinoma.18 Canteros et al. reported effective cortisol reduction with mild side effects from fluconazole in a 39-year-old woman with EAS, enabling successful bilateral adrenalectomy.30 An 80-year-old woman with CS of unknown origin also showed effective cortisol control with fluconazole.31 Two of these six cases suffered from hepatic dysfunction at fluconazole doses over 400 mg/day; however, liver enzyme levels returned to normal after dosage reduction. A secondary analysis of a dose-adjustment trial for fluconazole in the treatment of invasive mycoses examined 85 patients who received prolonged high-dose treatment. For these cases, 27% experienced clinical symptoms, and 42% exhibited abnormal laboratory results. The common side effects were <5% of anorexia, hair loss, headache, and 12% of eosinophilia. However, these adverse effects did not progress, leading the study to conclude that fluconazole is well tolerated and generally safe.32
Ketoconazole has been used to treat hypercortisolism by inhibiting CYP450 enzymes, specifically 11β-hydroxylase and 17α-hydroxylase, and fluconazole has similar properties.17 Previous studies suggest that fluconazole is less potent in inhibiting glucocorticoid production compared to ketoconazole, with varying effects; however, cortisol reduction with fluconazole use has been confirmed.17,18 Unlike ketoconazole, which is extensively metabolized in the liver and associated with significant hepatotoxicity, fluconazole is minimally metabolized in the liver.16 According to the FDA, the risk of serious liver injury from ketoconazole is higher than with other azole agents.33 In our study of 22 patients, fluconazole was well tolerated, with no significant elevations in liver enzyme levels observed during 6 months of treatment. These findings suggest that fluconazole may represent a safer alternative to ketoconazole for the treatment of CS.
In five studies involving 310 patients with CS treated with an average dose of 673.9 mg/day of ketoconazole over an average of 12.6 months, normalization of urinary free cortisol was achieved in 64.3% of patients (median 50%, range 44.7%–92.9%). However, 23% of initially responsive patients eventually lost biochemical control.34 Another retrospective study of 200 patients with CD receiving ketoconazole at an average dose of 600 mg/day found that 64.7% of patients treated for over 2 years achieved UFC normalization, while 15.4% experienced recurrence, or “escape,” from cortisol control.15 In our study, 10 patients (45.5%) received fluconazole treatment for over 1 year, with 5 of these patients (50%) showing 24-h UFC levels not exceeding 1.5 times the ULN in the following 3–12 months (under control without escape). The long-term control of hypercortisolism with fluconazole appears to be less effective than with ketoconazole. However, this could be attributed to the small sample size in our study.
Table 1 shows baseline morning ACTH levels at diagnosis for all patients before any treatment, highlighting a statistically significant difference. In comparison, Table 2 presents morning ACTH levels prior to fluconazole treatment, where no statistical difference was observed. This is likely due to some patients in the CD and EAS groups having previously undergone surgery or received other medical treatments, which might reduce the tumor burden and the levels of ACTH.
Recent studies suggest that levoketoconazole demonstrates good efficacy and safety in the management of CS.23–25 However, no head-to-head trials have been conducted to compare ketoconazole, levoketoconazole, and fluconazole directly. Therefore, further clinical trials are warranted to provide clearer insights into the comparative efficacy and safety of these therapeutic options in CS.
The limitations of this study include its retrospective design, which lacked comparator groups, and the small sample sizes in the ACS and EAS groups. In addition, patients were treated by different physicians, each using their own clinical judgment, without standardized follow-up protocols, making some data difficult to collect and analyze. The heterogeneity in dosing regimens also posed challenges in assessing the dose-response relationship. Besides, the relationship between the timing and dosages of other medications (etomidate, pasireotide, and metyrapone) and their effects on laboratory findings is challenging to analyze due to the limited number of cases. There were no statistically significant differences in ACTH level changes before and after fluconazole treatment among the three groups. This may be a limitation, as we only monitored the first and second ACTH measurements following fluconazole treatment. Further investigations with longer monitoring of ACTH levels may be necessary. The study’s observation period was approximately 5.5 years, but further investigation is required to confirm the long-term efficacy and safety of fluconazole treatment in CS.

Conclusion

This study demonstrates that fluconazole is effective in treating patients with CS, as evidenced by a significant reduction in 24-h UFC levels. Moreover, fluconazole was generally well tolerated, with a minimal risk of liver injury, suggesting it may be an effective and safe option for managing hypercortisolism in CS.

Acknowledgments

The authors thank the Medical Sciences & Technology Building of Taipei Veterans General Hospital for providing experimental space and facilities.

ORCID iD

Footnotes

Ethics approval and consent to participate This study was approved by the Institutional Review Board at Taipei Veterans General Hospital (IRB No. 2021-04-003CC). Due to the retrospective nature of this study, informed patient consent was waived.

Consent for publication Not applicable.

Author contributions

Tang-Yi Liao: Data curation; Formal analysis; Writing – original draft.
Yi-Chun Lin: Data curation; Writing – review & editing.
Chun-Jui Huang: Data curation; Writing – review & editing.
Chii-Min Hwu: Conceptualization; Data curation.
Liang-Yu Lin: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Writing – review & editing.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partly supported by research grants (Grant Nos. V108C-197, V109C-179, V110C-198, V111D62-002-MY3, V112C-183, V113C-094, V114C-116, and V114D77-002-MY3-1) to L.Y.L. from Taipei Veterans General Hospital, Taipei, Taiwan and MOST 111-2314-B-075-040-MY2 to L.Y.L. from National Science and Technology Council, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests The authors declare that there is no conflict of interest.

Availability of data and materials The data and materials generated and analyzed in the study are available from the corresponding author on reasonable request.

References

1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5): 1526–1540.
2. Clayton RN, Raskauskiene D, Reulen RC, et al. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96(3): 632–642.
3. Lindholm J, Juul S, Jørgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86(1): 117–123.
4. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93(7): 2454–2462.
5. Castinetti F, Nagai M, Morange I, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 2009; 94(9): 3400–3407.
6. Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 2011; 96(7): 1992–2003.
7. Porterfield JR, Thompson GB, Young WF Jr, et al. Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 2008; 32(5): 659–677.
8. Findling JW, Raff H. Cushing’s Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006; 91(10): 3746–3753.
9. Assié G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 2007; 92(1): 172–179.
10. Schteingart DE. Drugs in the medical treatment of Cushing’s syndrome. Expert Opin Emerg Drugs 2009; 14(4): 661–671.
11. Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002; 5(2): 77–82.
12. Valassi E, Franz H, Brue T, et al. Preoperative medical treatment in Cushing’s syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN. Eur J Endocrinol 2018; 178(4): 399–409.
13. Varlamov EV, Vila G, Fleseriu M. Perioperative management of a patient with Cushing Disease. J Endocr Soc 2022; 6(3): bvac010.
14. Pivonello R, De Martino MC, De Leo M, et al. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37(1): 135–ix.
15. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 2014; 99(5): 1623–1630.
16. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994; 330(4): 263–272.
17. van der Pas R, Hofland LJ, Hofland J, et al. Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol 2012; 215(3): 403–412.
18. Riedl M, Maier C, Zettinig G, et al. Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur J Endocrinol 2006; 154(4): 519–524.
19. Albert SG, DeLeon MJ, Silverberg AB. Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients. Crit Care Med 2001; 29(3): 668–670.
20. Santhana Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J 2006; 82(971): e23.
21. García Rodríguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48(6): 847–852.
22. Creemers SG, Feelders RA, De Jong FH, et al. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, a new steroidogenesis inhibitor for Cushing’s syndrome treatment. J Clin Endocrinol Metabol 2021; 106: 1618–1630.
23. Fleseriu M, Pivonello R, Elenkova A, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabet Endocrinol 2019; 7: 855–865.
24. Pivonello R, Zacharieva S, Elenkova A, et al. Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 2022; 25: 911–926.
25. Patra S, Dutta D, Nagendra L, et al. Efficacy and safety of levoketoconazole in managing Cushing’s syndrome: a systematic review. Indian J Endocr Metab 2024; 28: 343–349.
26. Sharma ST; AACE Adrenal Scientific Committee. An individualized approach to the evaluation of Cushing Syndrome. Endocr Pract 2017; 23(6): 726–737.
27. Teng Chai S, Haydar Ali Tajuddin A, Wahab NA, et al. Fluconazole as a safe and effective alternative to ketoconazole in controlling hypercortisolism of recurrent Cushing’s disease: a case report. Int J Endocrinol Metab 2018; 16(3): e65233.
28. Zhao Y, Liang W, Cai F, et al. Fluconazole for hypercortisolism in Cushing’s disease: a case report and literature review. Front Endocrinol (Lausanne) 2020; 11: 608886.
29. Burns K, Christie-David D, Gunton JE. Fluconazole in the treatment of Cushing’s disease. Endocrinol Diabetes Metab Case Rep 2016; 2016: 150115.
30. Canteros TM, De Miguel V, Fainstein-Day P. Fluconazole treatment in severe ectopic Cushing syndrome. Endocrinol Diabetes Metab Case Rep 2019; 2019(1): 19-0020.
31. Schwetz V, Aberer F, Stiegler C, et al. Fluconazole and acetazolamide in the treatment of ectopic Cushing’s syndrome with severe metabolic alkalosis. Endocrinol Diabetes Metab Case Rep 2015; 2015:1 50027.
32. Stevens DA, Diaz M, Negroni R, et al. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group. Chemotherapy 1997;43(5):371–377.
33. Greenblatt HK, Greenblatt DJ. Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol 2014; 54(12): 1321–1329.
34. Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing’s disease. Endocr Rev 2015; 36(4): 385–486.

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Predictors of Cancer in Patients With Endogenous Cushing’s Syndrome

Posted on July 21, 2025 by MaryO

We previously reported an increase in overall cancer risk in patients with endogenous Cushing’s syndrome (CS), mainly during the 10-year period following CS diagnosis.

To identify predictors of cancer in patients with CS, we conducted this retrospective nationwide cohort study of patients with CS, diagnosed between 2000 and 2023 in Israel. The cohort comprised 609 patients with CS (age at diagnosis, 48.1 ± 17.2 years; 65.0% women) and 3,018 age-, sex-, socioeconomic status-, and body mass index-matched controls (1:5 ratio).

Patients were grouped according to the occurrence of any malignancy within 10-years after the diagnosis of CS. Cox proportional hazards models, with death as a competing event, were used to identify predictors of cancer development. Independent predictors of cancer development in patients with CS included age ≥60 years (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73). Baseline urinary-free cortisol levels were not associated with cancer development. Patients with ≥4 CS-associated comorbidities had a higher cancer risk (HR 1.76, 95% CI 1.03–3.02; age- and sex-adjusted). The overall 10-year risk of malignancy was twice as high in patients with CS compared to matched controls, with cancer developing, on average, 5 years earlier in patients with CS (62.3 ± 15.0 vs 67.2 ± 12.3 years). Cancer-related mortality at 10-years was twice as high in deceased patients with CS, compared to deceased controls. In conclusion, age ≥60 years at CS diagnosis, male gender, and adrenal-origin CS are independent predictors of cancer diagnosis within 10-years of initial confirmation of CS.

 

Introduction

Prolonged cortisol exposure may promote cancer development and growth (Mayayo-Peralta et al. 2021, Khadka et al. 2023). Epidemiological research showed that extended glucocorticoids use is associated with elevated overall cancer risk (Oh & Song 2020). Recently, several studies suggested that cortisol levels increase cancer risk in patients with endogenous Cushing’s syndrome (CS). A Danish study found higher rates of cancer at the time of CS diagnosis compared to controls (Dekkers et al. 2013). A Swedish study examined comorbidity rates in patients with CS and identified a nonsignificant trend of increased cancer rates in CS compared to the general population, but was probably underpowered for this relatively rare outcome (Papakokkinou et al. 2020). Our nationwide retrospective matched-cohort study, using the Clalit Health Services (CHS) database in Israel (including 609 patients with CS and 3,018 age-, sex-, socioeconomic status- and body mass index (BMI)-matched controls), observed higher rates of all cancer types in patients with CS, with a hazard ratio (HR) of 1.78 (95% CI 1.44–2.20) (Rudman et al. 2024). Elevated cancer incidence was evident in patients with Cushing’s disease (CD) and in patients with adrenal CS. The overall cancer risk remained elevated during the first 10 years that followed CS diagnosis (Rudman et al. 2024). Similarly, a nationwide cohort study from Taiwan investigated the association between endogenous CS and cancer incidence, and reported a standardized incidence ration of 2.08 (95% CI 1.54–2.75) for cancer in patients with endogenous CS (Wu et al. 2025).
Hypercortisolemia and CS-associated comorbidities could drive malignancy development in patients with CS (Rudman et al. 2024, Wu et al. 2025). While it is known that the incidence of diabetes, obesity and insulin resistance is higher in patients with CS than that of the general population (Pivonello et al. 2016, Fleseriu et al. 2021, Reincke & Fleseriu 2023) – all of which are linked to cancer development (Renehan et al. 2008, Ling et al. 2020) – it remains unclear whether these comorbidities specifically contribute to the risk of malignancy within the CS population.
Thus, the aims of the present study were to identify the baseline predictors of cancer development in CS and to test the hypothesis that cumulative cortisol exposure, measured by urinary-free cortisol (UFC), predicts cancer risk in patients with CS.

Methods

Study design and data collection

We conducted a retrospective matched-cohort study using the electronic health record database of Clalit Health Services (CHS), the largest health maintenance organization (HMO) in Israel with over 4.8 million members. The CHS database includes demographic and clinical data, hospital and outpatient clinic diagnoses, medication dispensation, and all laboratory test results conducted at the HMO’s laboratories. All diagnoses and respective dates were identified using the International Classification of Diseases, tenth revision (ICD-10) codes (Supplementary Table S1 (see section on Supplementary materials given at the end of the article)). Weight and height data, and smoking status, were recorded regularly during visits to primary care clinics and in some specialized clinics. 24 h UFC results were collected and the normal reference range for each kit used. As these tests were performed by several different laboratories and devices (in all cases the bioanalytical method used was an immunoassay test), the results were reported as multiples of the upper limit of normal (×ULN). Data were extracted using the CHS research data-sharing platform, powered by MDClone. Importantly, the diagnoses of chronic medical conditions, recorded at the time of CS diagnosis, were validated: any member of CHS who required chronic treatment for a medical condition (e.g., medication for hypertension or diabetes) could only receive his prescriptions if the primary physician has registered the diagnosis, coded according to the ICD-10, in the computerized system. Mortality data were collected from the hospital’s mortality database, which is updated from the Ministry of Interior’s population registry. Data on cancer-specific mortality were obtained from hospital discharge certificates at the time of the hospitalization that ultimately resulted in the patient’s death. The study protocol, including detailed data collection methods, has been previously published (Rudman et al. 2024).

Ethical approval

The study was approved by the institutional ethics review board of Rabin Medical Center. As data were collected anonymously and in a retrospective manner, a waiver of informed consent was granted.

Patients and outcome measures

The methods we used for patient selection and matched controls selection have been previously published (Rudman et al. 2024), as the current study is based on the same group of patients with CS and controls. After the initial screening, potential cases with ICD-10 diagnosis of CS had to fulfill at least one of the following criteria: i) 24 h UFC ≥4 ×ULN, ii) 24 h UFC ≥3 ×ULN and surgical intervention to remove a pituitary or adrenal adenoma, and iii) 24 h UFC ≥2 ×ULN and metyrapone, ketoconazole, osilodrostat, cabergoline, or pasireotide treatment. All patients with CS and non-suppressed adrenocorticotropic hormone (ACTH) levels who did not receive pituitary-directed therapy and were diagnosed with a malignancy possibly causative of ectopic CS, including small-cell lung carcinoma, bronchial and thymic carcinoids, medullary thyroid carcinoma, neuroendocrine tumors or pheochromocytoma, were suspected of ectopic CS and were excluded from this study (Rudman et al. 2024). Patients diagnosed with adrenocortical carcinoma before or within 5 years of CS diagnosis were excluded.
All identified cases were individually matched in a 1:5 ratio with age-, sex-, socioeconomic status-, and BMI-matched controls from the general population (CHS members who have never been tested for suspected hypercortisolism). The age of the individually matched controls matched the age of cases ±12 months.
The follow-up period began at the time of CS diagnosis for all cases (newly diagnosed patients with CS) and at the exact same day for each individually matched control. It continued until death, termination of CHS membership, or until the date of data collection (June 30, 2023).
The main outcome measure was the first diagnosis of any malignancy following CS diagnosis, excluding non-melanoma skin cancer. Recurrences of known malignancies were also excluded.

Statistical analysis

The statistical analysis was generated using the SAS Software, Version 9.4, SAS Institute Inc., Cary, NC, USA. Continuous variables were presented by the mean ± standard deviation or median (interquartile range (IQR)). Categorical variables were presented by (n, %). Normality of continuous variables was assessed using the Kolmogorov–Smirnov test. The t-test, Mann–Whitney test, and chi-square test were used for comparison of normally distributed, non-normal, and categorical variables, respectively. The Cox proportional hazard model, with death without malignancy treated as a competing risk, was used to calculate both univariate and multivariate HR; the Fine and Gray methodology for dealing with competing risks was used, both in the cumulative incidence plots and in HR calculations. Baseline variables found to be associated with malignancy in the univariate analysis (with a between-group P-value below 0.05) were incorporated into the multivariate model. The appropriateness of the proportional hazard assumption was assessed visually. Two-sided P-values less than 0.05 were considered statistically significant.

Results

Patient characteristics

From January 1, 2000, to June 30, 2023, a total of 609 patients with CS met the study inclusion criteria (65.0% women, mean age at CS diagnosis of 48.1 ± 17.2 years). All cases of CS were matched with up to five controls based on age, sex, socioeconomic status, and BMI, and amounted to a total of 3,018 controls. Baseline characteristics of all 609 patients and 3,018 controls, with subdivisions according to disease source, are shown in Table 1.

Table 1. Baseline characteristics (at diagnosis/time 0) of patients with Cushing’s syndrome (CS) and matched control of all patients with CS, Cushing’s disease (CD), and adrenal CS.

Baseline characteristics, all patients with CS CS (n = 609) Matched controls (n = 3,018) P value CD (n = 251) Matched controls (n = 1,246) P value Adrenal CS (n = 200) Matched controls (n = 991) P value
Age, years, mean (SD) 48.1 (17.2) 47.9 (17.2) 45.7 (17.8) 45.7 (17.8) 51.1 (16.6) 51.0 (16.6)
Sex, no. (%)
 Females 396 (65.0) 1,975 (65.4) 164 (65.3) 818 (65.6) 137 (68.5) 684 (69.0)
 Males 213 (35.0) 1,043 (34.6) 87 (34.7) 428 (34.4) 63 (31.5) 307 (31.0)
Socioeconomic status, no. (%)a
 Low 74 (12.8) 371 (13.0) 34 (14.2) 172 (14.5) 20 (10.5) 99 (10.4)
 Middle 349 (60.6) 1,719 (60.3) 145 (60.7) 713 (60.2) 119 (62.6) 594 (62.9)
 High 153 (26.6) 760 (26.7) 60 (25.1) 300 (25.3) 51 (26.9) 252 (26.7)
Body mass index, Kg/m2, mean (SD)b 30.9 (7.6) 30.0 (6.9) 30.2 (7.4) 29.6 (6.8) 30.8 (7.1) 30.3 (6.3)
Source of hypercortisolism, no. (%)
 Cushing’s disease 251 (41.2)
 Adrenal Cushing’s syndrome 200 (32.8)
 Indeterminatec 158 (25.9)
Smoking status, no. (%)d 0.35 0.77 0.18
 Non-smoker 198 (59.8) 910 (62.6) 87 (64.0) 387 (65.3) 61 (53.0) 327 (60.1)
 Smoker/former smoker 133 (40.2) 544 (37.4) 49 (36.0) 206 (34.7) 54 (47.0) 217 (39.9)
Comorbidities, no. (%)
 Diabetes mellitus 140 (23.0) 396 (13.1) <0.01 55 (21.9) 148 (11.9) <0.01 51 (25.5) 158 (15.9) <0.01
 Hypertension 343 (56.3) 957 (31.7) <0.01 129 (51.4) 338 (27.1) <0.01 129 (64.5) 387 (39.0) <0.01
 Dyslipidemia 258 (42.4) 874 (29.0) <0.01 97 (38.6) 305 (24.5) <0.01 97 (48.5) 339 (34.2) <0.01
 Ischemic heart disease 70 (11.5) 191 (6.3) <0.01 23 (9.2) 67 (5.4) 0.03 25 (12.5) 77 (7.8) 0.04
 Cerebrovascular disease 27 (4.4) 82 (2.7) 0.04 12 (4.8) 35 (2.8) 0.11 10 (5.0) 32 (3.2) 0.21
 Osteoporosis 75 (12.3) 187 (6.2) <0.01 26 (10.4) 57 (4.6) <0.01 28 (14.0) 82 (8.3) 0.02
 Malignancy before CS diagnosis 50 (8.2) 117 (3.9) <0.01 15 (6.0) 48 (3.9) 0.12 20 (10.0) 50 (5.0) 0.01
Cases and controls were individually matched for age, sex, socioeconomic status, and body mass index.
a
Cushing’s syndrome n = 576, controls n = 2,850; Cushing’s disease n = 239, controls n = 1,185; adrenal Cushing’s syndrome n = 190, controls n = 945.
b
Cushing’s syndrome n = 363, controls n = 1,549; Cushing’s disease n = 152, controls n = 644; adrenal Cushing’s syndrome n = 131, controls n = 570.
c
Ectopic ACTH secretion and adrenocortical carcinoma were excluded.
d
Cushing’s syndrome n = 331, controls n = 1,454; Cushing’s disease n = 136, controls n = 593; adrenal Cushing’s syndrome n = 115, controls n = 544.
At baseline, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis were more common among patients with CS (P < 0.01). Smoking rates were similar between the two groups (Table 1). A prior history of malignancy was more prevalent among patients with CS than controls (8.2 vs 3.9%, respectively; P < 0.01) (Table 1).

Predictors of new malignancy in patients with Cushing’s syndrome

Table 2 presents the baseline characteristics of 609 patients with CS, including demographic data, CS etiology, history of malignancy before CS diagnosis, maximal UFC at diagnosis, and CS-associated comorbidities. In a univariate time-to-event analysis of the 10-year cumulative cancer risk, accounting for death as a competing event, we found that age ≥60 years at CS diagnosis, male gender, adrenal-origin CS, hypertension, dyslipidemia, and ischemic heart disease at baseline were all associated with a higher cancer risk. The 10-year cumulative cancer risk, with death as a competing event, stratified by age, sex, and CS etiology is shown in Fig. 1. Prior malignancy, diabetes, and obesity were not associated with an increased risk of malignancy in patients with CS (Table 2). The cohort was divided into three groups based on baseline UFC level (below 5 ×ULN, 5–10 ×ULN, and above 10 ×ULN) with comparison of time to cancer occurrence. Higher UFC levels at the time of CS diagnosis were not associated with cancer development (Table 2 and Fig. 2). In a multivariable Cox regression model (multivariable model 1, Table 2), we found that age ≥60 years at CS diagnosis (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73) were independent predictors of cancer development within 10 years after CS diagnosis. In an additional model (multivariable model 2, Table 2), we observed that patients with ≥4 CS-associated comorbidities at the time of CS diagnosis had a higher risk of cancer (HR 1.76, 95% CI 1.03–3.02), after adjustment for age and sex.

Table 2. Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with Cushing’s syndrome, accounting for death as a competing event.

Baseline characteristics Patients (n = 609) Incident cases of cancer (n = 81) Deaths without cancer (n = 40) Univariate analysis Multivariable model 1* Multivariable model 2 (total no. of CS-associated comorbidities, with age and sex adjustment)
Age <60 years (ref) 444 44 10 – – –
Age ≥60 years 165 37 30 2.47 (1.60–3.82) 1.75 (1.01–2.68) 3.18 (2.09–4.86)
Female (ref) 396 42 23 – – –
Male 213 39 17 1.75 (1.13–2.70) 1.67 (1.04–3.05) 1.60 (1.11–2.29)
Low SESa 74 13 5 1.29 (0.65–2.56)
Medium SESa 349 42 21 0.87 (0.52–1.45)
High SES (ref)a 153 22 13 –
Cushing’s disease (ref)b 251 27 21 – –
Adrenal CSb 200 39 8 1.87 (1.14–3.05) 1.66 (1.01–2.73)
Non-smoker (ref)c 198 25 12 –
Smoker/former smokerc 133 21 12 1.25 (0.70–2.23)
Prior malignancy 50 6 14 0.91 (0.40–2.08)
No prior malignancy (ref) 559 75 26 –
Maximal urinary free cortisold
 <5 × ULN (ref) 231 38 18 –
 5–10 × ULN 135 18 7 0.86 (0.49–1.48)
 ≥10 × ULN 70 10 4 0.89 (0.45–1.78)
CS-associated comorbidities
 Obesitye 176 28 17 1.22 (0.71–2.11)
 No obesity (ref)e 187 24 12 –
 Diabetes mellitus 140 21 14 1.28 (0.78–2.10)
 No diabetes mellitus (ref) 469 60 26 –
 Hypertension 343 59 34 2.23 (1.36–3.65) 1.52 (0.83–2.81)
 No hypertension (ref) 266 22 6 – –
 Dyslipidemia 258 44 29 1.81 (1.17–2.81) 0.97 (0.55–1.72)
 No dyslipidemia (ref) 351 37 11 – –
 Ischemic heart disease 70 19 11 2.70 (1.62–4.51) 1.48 (0.81–2.71)
 No ischemic heart disease (ref) 539 62 29 –
 Stroke 27 3 2 1.07 (0.33–3.49)
 No stroke (ref) 582 78 38 –
 Osteoporosis 75 9 9 0.92 (0.46–1.84)
 No osteoporosis (ref) 534 72 31 –
Total no. of CS-associated comorbiditiesf
 0–1 (ref) 295 27 9 – –
 2–3 205 33 15 2.09 (1.36–3.22) 1.40 (0.87–2.26)
 ≥4 109 21 16 3.76 (2.37–5.97) 1.76 (1.03–3.02)
CS, Cushing’s syndrome; SES, socioeconomic status; ULN, upper limit of normal. Bold indicates statistical significance.
*
Included variables: age, sex, source of hypercortisolism, hypertension, dyslipidemia, and ischemic heart disease.
a
n = 576.
b
Ectopic ACTH secretion and adrenocortical carcinoma were excluded.
c
n = 331.
d
Maximal value of urinary-free cortisol divided by the upper limit of normal of the specific assay, n = 436.
e
n = 363.
f
CS-associated comorbidities include obesity, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis.
Figure 1

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Figure 1. The 10-year cumulative cancer risk, with death as a competing event, among patients with Cushing’s syndrome, according to age at diagnosis (A), sex (B), and Cushing’s syndrome etiology (C). CD, Cushing’s disease; CS, Cushing’s syndrome. A full colour version of this figure is available at https://doi.org/10.1530/ERC-25-0059.

Figure 2

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Figure 2. The 10-year cumulative cancer risk, with death as a competing event, among patients with Cushing’s syndrome, according to the maximal value of UFC divided by the upper limit of normal (ULN) of the specific assay used: UFC <5 × ULN (reference), 5–10 × ULN, and ≥10 × ULN. A full colour version of this figure is available at https://doi.org/10.1530/ERC-25-0059.

Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with CD and adrenal CS are presented in Tables 3 and 4. In the univariate time-to-event analysis of 251 patients with CD, age ≥60 years at CS diagnosis and the presence of dyslipidemia and ischemic heart disease at baseline were associated with higher cancer risk. The multivariable Cox regression model did not identify any significant predicting factors in patients with CD. Tables 3 and 4 also present the univariate analysis for the 10-year cumulative cancer risk in 200 patients with adrenal CS, which showed that age ≥60 years, male gender, and ischemic heart disease were associated with cancer development. In the multivariable model, only age ≥60 years at CS diagnosis (HR 2.66, 95% CI 1.36–5.18) was found to be independently associated with cancer development in patients with adrenal CS (Table 4). UFC levels at the time of CS diagnosis were not associated with new cancer diagnosis in either patients with CD or with adrenal CS (Tables 3 and 4).

Table 3. Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with Cushing’s disease, accounting for death as a competing event.

Cushing’s disease baseline characteristics Patients (n = 251) Incident cases of cancer (n = 27) Deaths without cancer (n = 21) Univariable Multivariable model 1 Multivariable model 2 (total no. of CS-associated comorbidities, with age and sex adjustment)
Age <60 years (ref) 196 16 8 – – –
Age ≥60 years 55 11 13 2.72 (1.27–5.81) 1.83 (0.65–5.18) 3.54 (1.81–6.92)
Female (ref) 164 14 14 – – –
Male 87 13 7 1.79 (0.85–3.80) 1.61 (0.73–3.56) 1.22 (0.68–2.18)
Low SESa 34 5 5 1.29 (0.42–3.99)
Medium SESa 145 13 12 0.81 (0.32–2.00)
High SES (ref)a 60 7 4 –
Non-smoker (ref)b 87 6 6 –
Smoker/former smokerb 49 8 8 2.59 (0.91–7.39)
Prior malignancy 15 26 15 0.66 (0.09–5.13)
No prior malignancy (ref) 236 1 6 –
Maximal urinary-free cortisolc
 <5 × ULN (ref) 133 15 14 –
 5–10 × ULN 70 6 3 0.78 (0.31–2.00)
 ≥10 × ULN 40 6 4 1.48 (0.57–3.79)
CS-associated comorbidities
 Obesityd 69 7 10 0.80 (0.31–2.09)
 No obesity (ref)d 83 10 6 –
 Diabetes mellitus 55 5 6 0.89 (0.34–2.35)
 No diabetes mellitus (ref) 196 22 15 –
 Hypertension 129 17 17 1.67 (0.76–3.64)
 No hypertension (ref) 122 10 4 –
 Dyslipidemia 97 15 13 2.31 (1.08–4.96) 1.64 (0.58–4.61)
 No dyslipidemia (ref) 154 12 8 – –
 Ischemic heart disease 23 5 4 2.71 (1.03–7.08) 1.29 (0.43–3.86)
 No ischemic heart disease (ref) 228 22 17 – –
 Stroke 12 2 1 2.34 (0.53–10.30)
 No stroke (ref) 239 25 20 –
 Osteoporosis 26 24 15 1.14 (0.35–3.66)
 No osteoporosis (ref) 225 3 6 –
Total no. of CS-associated comorbiditiese
 0–1 (ref) 136 11 6 – –
 2–3 74 10 8 2.19 (1.13–4.26) 1.48 (0.72–3.04)
 ≥4 41 6 7 3.69 (1.78–7.66) 1.72 (0.73–4.02)
CS, Cushing’s syndrome; SES, socioeconomic status; ULN, upper limit of normal. Bold indicates statistical significance.
a
n = 239.
b
n = 136.
c
Maximal value of urinary free cortisol divided by the upper limit of normal of the specific assay; n = 243.
d
Cushing’s disease, n = 152.
e
CS-associated comorbidities include obesity, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis.

Table 4. Univariate analysis and multivariable regression models for the 10-year cumulative cancer risk in patients with adrenal Cushing’s syndrome, accounting for death as a competing event.

Adrenal Cushing’s syndrome baseline characteristics Patients with CS at risk (n = 200) Incident cases of cancer (n = 39) Deaths without cancer (n = 8) Univariable Multivariable model 1 Multivariable model 2 (total no. of CS-associated comorbidities, with age and sex adjustment)
Age <60 years (ref) 134 20 1 – – –
Age ≥60 years 66 19 7 2.12 (1.13–3.96) 2.66 (1.36–5.18) 2.70 (1.35–5.42)
Female (ref) 137 17 3 – – –
Male 63 22 5 2.97 (1.58–5.58) 1.81 (0.94–3.51) 3.11 (1.73–5.57)
Low SESa 20 3 0 0.62 (0.17–2.28)
Medium SESa 119 22 3 0.73 (0.36–1.44)
High SES (ref)a 51 13 5 –
Non-smoker (ref)b 61 12 3 –
Smoker/former smokerb 54 10 2 0.86 (0.38–1.99)
Prior malignancy 20 4 2 1.03 (0.38–2.81)
No prior malignancy (ref) 180 35 6 –
Maximal urinary free cortisolc
 <5 × ULN (ref) 98 23 4 –
 5–10 × ULN 65 12 4 0.84 (0.42–1.69)
 ≥10 × ULN 30 4 0 0.53 (0.18–1.52)
CS-associated comorbidities
 Obesityd 64 15 4 1.68 (0.75–3.74)
 No obesity (ref)d 67 10 3 –
 Diabetes mellitus 51 12 3 1.47 (0.75–2.89)
 No diabetes mellitus (ref) 149 27 5 –
 Hypertension 129 29 7 1.73 (0.84–3.58)
 No hypertension (ref) 71 10 1 –
 Dyslipidemia 97 20 7 1.20 (0.65–2.25)
 No dyslipidemia (ref) 103 19 1 –
 Ischemic heart disease 25 10 4 2.65 (1.31–5.34) 1.51 (0.68–3.32)
 No ischemic heart disease (ref) 175 29 4 – –
 Stroke 10 1 1 0.58 (0.08–4.35)
 No stroke (ref) 190 38 7 –
 Osteoporosis 28 2 2 0.32 (0.08–1.33)
 No osteoporosis (ref) 172 37 6 –
Total no. of CS-associated comorbiditiese
 0–1 (ref) 82 14 1 – –
 2–3 76 15 2 1.24 (0.62–2.48) 0.95 (0.44–2.02)
 ≥4 42 10 5 2.46 (1.20–5.05) 1.21 (0.51–2.85)
CS, Cushing’s syndrome; SES, socioeconomic status; ULN, upper limit of normal. Bold indicates statistical significance.
a
n = 190.
b
n = 115.
c
Maximal value of urinary-free cortisol divided by the upper limit of normal of the specific assay; n = 193.
d
n = 131.
e
CS-associated comorbidities include obesity, diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis.

The 10-year cancer risk in patients with Cushing’s syndrome vs controls

In the 10 years following CS diagnosis, 81 (13.3%) patients with CS were diagnosed with cancer and 40 (6.6%) died without malignancy, compared with 206 (6.8%) and 152 (5.0%) controls, respectively. Similar to the previously reported risk for the entire follow-up period (Rudman et al. 2024), the overall 10-year risk of malignancy, calculated with death as a competing event, was twice as high in patients with CS than in matched controls (HR 2.01; 95% CI, 1.55–2.60) (Supplementary Fig. S1).
The mean age of cancer development in patients with CS was 62.3 ± 15.0 years, compared with 67.2 ± 12.3 years in controls (P < 0.01). The risk of cancer across different subgroups (patients with CS vs controls) is shown in Fig. 3 and Table 5. The number of cases for each type of cancer in patients with CS and controls is shown in Supplementary Table S2.
Figure 3

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Figure 3. The 10-year cancer risk in subgroups of the entire cohort (cases vs matched controls). Cases and controls were individually matched for age, sex, socioeconomic status, and body mass index.

Table 5. The 10-year cancer risk in subgroups of the entire cohort (cases vs matched controls).

Subgroup Cushing’s syndrome Individually matched controls HR 95% CI
Patients Incident cases of cancer Deaths Patients Incident cases of cancer Deaths
Age
 <60 444 44 10 2,200 84 30 2.67 1.85–3.85
 ≥60 165 37 30 818 122 122 1.55 1.08–2.24
Sex
 Females 396 42 23 1,975 117 89 1.83 1.29–2.61
 Males 213 39 17 1,043 89 63 2.25 1.54–3.28
Socioeconomic status
 Low 74 13 5 371 14 17 5.03 2.37–10.68
 Middle 349 42 21 1,719 116 90 1.83 1.28–2.60
 High 153 22 13 760 73 36 1.52 0.94–2.45
Smoking status
 Smoker/former smoker 133 21 12 544 46 34 1.84 1.09–3.10
 Non-smoker 198 25 12 910 66 48 1.79 1.13–2.83
Comorbidities
 Obesity 176 28 17 698 45 62 2.52 1.57–4.04
 No obesity 187 24 12 851 70 46 1.58 0.99–2.51
 Diabetes mellitus 140 21 14 396 45 75 1.35 0.80–2.25
 No diabetes mellitus 469 60 26 2,622 161 77 2.13 1.58–2.86
 Hypertension 343 59 34 957 106 126 1.59 1.16–2.19
 No hypertension 266 22 6 2,061 100 26 1.71 1.07–2.72
 Dyslipidemia 258 44 29 874 100 100 1.53 1.07–2.17
 No dyslipidemia 351 37 11 2,144 106 52 2.15 1.47–3.13
 Ischemic heart disease 70 19 11 191 30 49 1.89 1.06–3.35
 No ischemic heart disease 539 62 29 2,827 176 103 1.88 1.41–2.52
 Stroke 27 3 2 82 7 17 1.50 0.39–5.74
 No stroke 582 78 38 2,936 199 135 2.02 1.56–2.63
 Osteoporosis 75 9 9 187 23 32 0.98 0.45–2.10
 No osteoporosis 534 72 31 2,831 183 120 2.15 1.64–2.83
Cases and controls were individually matched for age, sex, socioeconomic status, and body mass index.
Among 487 cases and 2,411 controls with an attainable follow-up period of at least 10 years, 52 patients with CS and 184 controls died (from any cause) during the 10 years that followed CS diagnosis. Eight (15.4%) patients with CS died due to malignancy, compared with 12 (6.5%) patients in the control group (P = 0.04).
During the 10-year follow-up after CS diagnosis, 27 out of 251 patients with CD (10.8%) were diagnosed with malignancy, compared to 71 (5.7%) controls. Among 200 patients with adrenal CS, 39 (19.5%) were diagnosed with cancer, compared to 79 (8.0%) controls. The 10-year risk of overall malignancy was higher in patients with CD (HR 1.92, 95% CI 1.23–3.00) and in patients with adrenal CS (HR 2.63, 95% CI 1.79–3.87), compared to controls (Supplementary Fig. S1). The number of cases for each specific cancer type in patients with CD and adrenal CS and their individually matched controls is elaborated in Supplementary Table S2.

Sensitivity analyses

Due to possible bias in individuals with a genetic predisposition to cancer, and in patients at increased risk due to prior cancer treatment, we excluded all patients with prior history of cancer (50 cases and 117 controls). Following this exclusion, patients with CS still exhibited a higher 10-year cancer risk (HR 2.12, 95% CI 1.62–2.77).
Patients with adrenal cancer diagnosed before or within 5 years of CS diagnosis were excluded from the study. However, as it is possible that adrenal cancer was either not recorded properly or unrecognized at the time of CS diagnosis, we performed an analysis of the risk of malignancy excluding all adrenal cancer cases and found no change in the 10-year risk of overall cancer (HR 1.92, 95% CI 1.48–2.50).
The diagnosis of CS patients in the study included an ICD-10 coding of the diagnosis and laboratory evidence of hypercortisolism (and test date) in all cases. However, because in many cases the diagnostic and treatment process are lengthy, there is a possibility of information bias caused by patients included in the database who were diagnosed before the time period included in the study. Therefore, we performed a sensitivity analysis excluding the first year of the study, without any change in the 10-year risk of malignancy among CS patients (HR 1.98, 95% CI 1.51–2.58).

Discussion

Patients with CS have higher morbidity and mortality (Gadelha et al. 2023, Loughrey et al. 2024), and it has been recently established that CS is associated with an increased cancer risk (Rudman et al. 2024, Wu et al. 2025). However, predictors of a new cancer diagnosis have not been studied. In this nationwide retrospective study, the 10-year cancer risk in 609 patients with CS was twice as high as in 3,018 matched controls. Importantly, the 10-year risk was notably higher in patients with CD (HR 1.92, 95% CI 1.23–3.00) and in those with adrenal CS (HR 2.63, 95% CI 1.79–3.87), compared to controls. Furthermore, the risk of cancer was higher in patients with CS, regardless of age and sex. On average, cancer development in patients with CS occurred at an age that was 5 years younger than that of controls who developed cancer (62.3 ± 15.0 vs 67.2 ± 12.3 years, respectively).
Our study is the first to identify predictors of new cancer diagnosis in patients with CS. A multivariate regression model showed that age ≥60 years at CS diagnosis (HR 1.75, 95% CI 1.01–2.68), male gender (HR 1.67, 95% CI 1.04–3.05), and adrenal-origin CS (HR 1.66, 95% CI 1.01–2.73) were identified as independent predictors of cancer development within 10 years. In addition, we found that patients with ≥4 CS-associated comorbidities at the time of CS diagnosis had an increased risk of cancer (HR 1.76, 95% CI 1.03–3.02; adjusted for age and sex). Interestingly, diabetes and obesity were not associated with malignancy development in patients with CS. Importantly, we found no association between UFC levels at the time of CS diagnosis and cancer development rates.
CS most commonly affects young women, a population not inherently at high risk for malignancy, with the exception of breast cancer (National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program, December 2024. https://seer.cancer.gov/statfacts/html/aya.html). Our study demonstrates that young patients and female patients with CS are at an increased risk of cancer, as compared with matched controls from the general population. However, within the group of patients with CS, we found age and sex disparities in malignancy risk: men and elderly patients (over 60 years of age) showed a higher cancer risk (Table 2). Advanced age is a universal risk factor for cancer (Campisi 2013), and patients with CS are no exception. Previous studies found that male patients with CS are more susceptible to metabolic derangements than female patients (Liu et al. 2015, Broersen et al. 2019), a difference that likely results from gender disparity in response to glucocorticoid receptor activation (Bourke et al. 2012).
In addition, our study found that CS of adrenal origin is associated with a higher risk of malignancy, as compared with CD, after adjustment for age, sex, and significant CS-related comorbidities. Notably, patients with a history of adrenal cancer or ectopic CS were excluded. This finding is difficult to explain, since most studies have found that patients with CD present with higher UFC levels (Berr et al. 2015, Rubinstein et al. 2019, Schernthaner-Reiter et al. 2019) and a longer delay in diagnosis (Rubinstein et al. 2019, Schernthaner-Reiter et al. 2019) compared to those with adrenal CS. One potential explanation for this observation is that adrenal adenomas may be linked to a higher incidence of malignancy, as studies have shown that cancer mortality is increased with autonomic cortisol secretion, with malignancy being the most common cause of death in patients with mild autonomous cortisol secretion (Patrova et al. 2017, Deutschbein et al. 2022). Another conceivable explanation stems from previous research that reported higher rates of non-adrenal malignancies in patients with bilateral adrenal tumors and autonomous cortisol secretion (Kawate et al. 2014), suggesting a possible genetic predisposition in patients with adrenal adenoma that may contribute to the development of overall cancer.
Interestingly, in our study, patients with adrenal CS had a history of malignancy at a higher rate than their individually matched controls at the time of CS diagnosis (Table 1). In contrast, no difference in the rate of malignancy was found between patients with CD and controls. Although it is possible that a prior history of malignancy contributed to the higher risk of cancer observed in patients with adrenal CS, we did not find that a prior malignancy predicted subsequent cancer risk in this population when we analyzed our cohort of patients with adrenal CS (Table 4).
In this study, we found no association between the cumulative exposure to excess glucocorticoids (measured as UFC levels) and the development of malignancy (Fig. 2), but we did identify an association between the total number of CS-related comorbidities and cancer risk (adjusted for age and sex) (Table 2). Previous studies have similarly shown no correlation between the degree of hypercortisolism and the presence of CS-related comorbidities in patients with CS (Schernthaner-Reiter et al. 2019), including diabetes and obesity (Giordano et al. 2014, Bavaresco et al. 2024). Those findings support the hypothesis that individual sensitivity to glucocorticoids varies across tissues, such that UFC levels do not always correlate with symptom burden or comorbidities. Patients who are more sensitive to excess cortisol may experience a broader range of CS-associated comorbidities. Several genetic mutations and alterations have already been identified as causes of variation in cortisol sensitivity, including the genes encoding the human glucocorticoid receptor (NR3C1) (Chrousos et al. 1982, Riebold et al. 2015, Laulhé et al. 2024), the chaperone protein that regulates proper folding of the glucocorticoid receptor (HSP90) (Riebold et al. 2015), and the nuclear protein that modulates glucocorticoid receptor actions (NR2C2) (Zhang et al. 2016). In addition, mutations in glucocorticoid response elements (Vandevyver et al. 2013), variations in RNA-binding to the glucocorticoid receptor (Lammer et al. 2023), and epigenetic changes (Paes et al. 2024) may also play a role in inter-individual differences in response to cortisol excess.
In the univariate model we have performed, the total number of CS-related comorbidities was associated with cancer development, and the risk of malignancy increased with the number of comorbidities. However, after adjustment for age and sex, the HR was significantly moderated (mainly due to a strong correlation between age and comorbidity) but remained graded. We find this observation to support the concept that cancer is a CS-associated comorbidity, and suggest that patients with CS (especially older men with adrenal CS) suffering from multiple disease-related comorbidities require closer follow-up and a rigorous age-adjusted cancer screening, in accordance with guidelines for the general population.
We have previously reported an increased risk of genitourinary, thyroid, and gynecological cancers in patients with CS (Rudman et al. 2024). A Taiwanese national cohort study reported that liver (27.7%), kidney (16.7%), and lung (13.0%) cancers were the most common cancers among patients with CS (Wu et al. 2025). Despite the small absolute number of cases in each cancer type in this study, we found that the incidence in patients with CS was higher across all cancer groups, except for malignant melanoma. One might think that patients with CS underwent more imaging and laboratory tests, and therefore more cases of low-risk cancers (e.g., clinically insignificant prostate or thyroid cancer) were diagnosed in patients with CS than in controls. However, as we have shown, the overall 10-year malignancy-associated mortality was twice as high in patients with CS compared to controls, indicating that malignancies in this group were clinically significant.
Surgery for CS, especially for CD, improves some but not all comorbidities (Dekkers et al. 2013, Terzolo et al. 2014, Papakokkinou et al. 2020, Puglisi et al. 2024). Improvement of comorbidities with medical therapy have been noted in several clinical trials (Fleseriu et al. 2012, 2022, Petersenn et al. 2017); however, there are no prospectively collected data on the risk of cancer in these patients treated long-term. A retrospective study examining the course of several CS-related comorbidities showed that the risk of cancer in patients with CS who did not achieve remission was higher compared to the risk of cancer for patients in remission, yet these analyses did not reach statistical significance, partly due to the limited sample size (Papakokkinou et al. 2020).
In order to successfully identify predictors of cancer in patients with CS, this research of an uncommon outcome (malignancy) in patients with a rare disease (CS) required a long-term follow-up of a large, population-representative cohort, paired with well-matched control group. Matching for socioeconomic status is another strength of this study, as its impact on morbidity has recently been demonstrated in several studies (Ebbehoj et al. 2022, Claudel & Verma 2024).
However, this study has limitations. Missing data prevented us from determining the specific CS etiology in some patients. Correct classification of all cases with an indeterminate diagnosis (as either CD or adrenal CS) would have allowed us to improve the power of subgroup analysis of patients with CD and adrenal CS; however, we had very strict criteria for determining the etiology of CS. Not all data regarding socioeconomic status, BMI, and smoking status were available. In addition, the impact of hypopituitarism and overreplacement of glucocorticoids in patients with CD could not be assessed.
Since the control group was drawn from the general population, ascertainment bias cannot be ruled out, as it is likely that patients with CS underwent more physician-initiated imaging and laboratory tests, and therefore more cases of cancer could have been diagnosed in patients with CS than in controls. However, we consider this bias to be unlikely for most cases of aggressive cancer, especially given our long follow-up period.
While this nationwide study includes a relatively large sample size, we acknowledge that it is likely that our current sample size was not sufficiently powered to detect risk predictors that are only modestly associated with malignancy risk. The small sample size of subgroups and the low frequency of the outcome in these subgroups meant we were unable to predict malignancy in patients with CD or adrenal CS, nor could we estimate the risk of specific malignancies. Moreover, we could not account for certain factors that may influence the risk of malignancy, such as family history of malignancy, duration of exposure to elevated cortisol levels, and the presence of genetic syndromes that predispose individuals to both CS and certain malignancies (e.g., multiple endocrine neoplasia type 1) (Hernández-Ramírez & Stratakis 2018). Finally, the lack of systematic prospective assessment of comorbidities is an important limitation and should raise the standards for future clinical care of these patients and collecting data in new registries. While patients receiving treatment for a particular comorbidity were successfully identified, those without treatment were not systemically recorded, which may have led to underreporting. Such is the case with osteoporosis: only patients who received treatment or whose treating physician decided to send them for a bone density scan were diagnosed, while others without such evaluations were assumed to be free of osteoporosis.
In conclusion, this large nationwide retrospective matched-cohort study found that the risk of cancer was consistently higher in patients with CS, regardless of age or sex, and on average, cancer development occurred 5 years earlier in patients with CS than in controls. The multivariate regression model we developed identified age ≥60 years at CS diagnosis, male gender, and CS of adrenal-origin as independent predictors of malignancy during the 10 years following CS diagnosis. Importantly, we found no association between UFC levels at CS diagnosis and cancer development rates. However, patients with ≥4 CS-associated comorbidities at CS diagnosis were more likely to develop cancer, after adjusting for age and sex. Given previous studies that identified overall cancer as a CS-related comorbidity and as one of the leading causes of death in this population, the results of the current study will help identify patients at high risk of malignancy, emphasize the importance of timely screening tests, in accordance with guidelines for the general population, and highlight the need for larger international cohorts to establish specific cancer screening recommendations for patients with CS.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/ERC-25-0059.

Declaration of interest

Yaron Rudman, Genady Drozdinsky, Hiba Masr-Iraqi, Tzippy Shochat, and Shiri Kushnir do not have any financial or personal relationships with other people or organizations to disclose. Maria Fleseriu has been a PI with research funding to the university from Crinetics and Sparrow and has received occasional scientific fees for scientific consulting and advisory boards from Crinetics, Recordati, Sparrow and Xeris. Ilan Shimon has been an investigator for Xeris Biopharma and has received occasional scientific fees for scientific consulting and advisory boards from Medison, CTS pharma, and Neopharm. Amit Akirov has received occasional scientific fees for scientific consulting and advisory boards from Medison, CTS pharma, and Neopharm.

Funding

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

Data availability

The data that support the findings of this study are available from Clalit Health Services. Restrictions apply to the availability of these data, which were used under license for this study. Deidentified individual participant-level data sharing will be considered by the corresponding author of this study, with the permission of Clalit Health Services. All applicants will be asked to sign a data access agreement. All requests will be assessed as to whether data sharing is appropriate, based on the scientific rigor of the proposal.

References

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Challenges of Cushing’s Syndrome and Bariatric Surgery

Posted on June 26, 2025 by MaryO

Abstract

Cushing’s disease (CD), caused by an adrenocorticotropic hormone-secreting pituitary adenoma, is challenging to diagnose, especially in obese patients post-bariatric surgery.

This report discusses a misdiagnosed case of CD in a 42-year-old obese male with hypertension. CD was suspected only after surgery, confirmed by magnetic resonance imaging (MRI) showing a pituitary macroadenoma.

Despite transsphenoidal surgery and ketoconazole therapy, the patient suffered liver failure and died.

Among 20 CD reviewed cases in the literature, 65% were misdiagnosed. MRI and immunohistochemistry confirmed tumors, with 55% achieving remission post-surgery. Screening for CD before bariatric surgery may prevent mismanagement and complications.

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

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