Clinical efficacy and safety of fluconazole treatment in patients with Cushing’s syndrome

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.

Keywords

Cushing’s syndrome efficacy fluconazole

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).

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)

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.

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).

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).

The average of first and second ACTH after fluconazole treatment.

The average of first and second 24-h UFC after fluconazole treatment.

ALT: maximum in following 6 months.

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).

Figure 1.

24-h UFC before and after fluconazole treatment in patients with Cushing’s 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).

Figure 2.

ALT before and after fluconazole treatment in patients with Cushing’s 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.

Footnotes

Acknowledgements

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

Declarations

ORCID iD

Liang-Yu Lin

References

Nieman

Biller

Findling

, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5): 1526–1540.

Clayton

Raskauskiene

Reulen

, 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.

Lindholm

Juul

Jørgensen

, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86(1): 117–123.

Biller

Grossman

Stewart

, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93(7): 2454–2462.

Castinetti

Nagai

Morange

, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 2009; 94(9): 3400–3407.

Loeffler

Shih

HA.

Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 2011; 96(7): 1992–2003.

Porterfield

Thompson

Young

Jr , et al. Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 2008; 32(5): 659–677.

Findling

Raff

Cushing’s Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006; 91(10): 3746–3753.

Assié

Bahurel

Coste

, 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

Franz

Brue

, 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

Vila

Fleseriu

Perioperative management of a patient with Cushing Disease. J Endocr Soc 2022; 6(3): bvac010.

14.

Pivonello

De Martino

De Leo

, et al. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37(1): 135–ix.

15.

Castinetti

Guignat

Giraud

, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 2014; 99(5): 1623–1630.

16.

Como

Dismukes

WE.

Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994; 330(4): 263–272.

17.

van der Pas

Hofland

, et al. Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol 2012; 215(3): 403–412.

18.

Riedl

Maier

Zettinig

, 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

DeLeon

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

Cobbs

. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J 2006; 82(971): e23.

21.

García Rodríguez

Duque

Castellsague

, 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

Feelders

De Jong

, 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

Pivonello

Elenkova

, 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

Zacharieva

Elenkova

, 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

Dutta

Nagendra

, 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

; AACE Adrenal Scientific Committee. An individualized approach to the evaluation of Cushing Syndrome. Endocr Pract 2017; 23(6): 726–737.

27.

Teng Chai

Haydar Ali Tajuddin

Wahab

, 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

Liang

Cai

, et al. Fluconazole for hypercortisolism in Cushing’s disease: a case report and literature review. Front Endocrinol (Lausanne) 2020; 11: 608886.

29.

Burns

Christie-David

Gunton

JE.

Fluconazole in the treatment of Cushing’s disease. Endocrinol Diabetes Metab Case Rep 2016; 2016: 150115.

30.

Canteros

De Miguel

Fainstein-Day

Fluconazole treatment in severe ectopic Cushing syndrome. Endocrinol Diabetes Metab Case Rep 2019; 2019(1): 19-0020.

31.

Schwetz

Aberer

Stiegler

, 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

Diaz

Negroni

, et al. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group. Chemotherapy 1997;43(5):371–377.

33.

Greenblatt

DJ.

Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol 2014; 54(12): 1321–1329.

34.

Pivonello

De Leo

Cozzolino

, et al. The treatment of Cushing’s disease. Endocr Rev 2015; 36(4): 385–486.