CushieBlog

Demographics and baseline characteristics

Demographic variable	n = 67 patients
Age, years
Mean (SD)	42.3 (13.1)
Range	20-75
Sex, n (%)
Female	56 (83.6)
CS subtype, n (%)
CD	60 (89.6)
Adrenal CS	7(10.4)
Race, n (%)
White	50 (74.6)
Black/African American	8 (11.9)
Asian	2 (3.0)
Other/unknown	7 (10.4)
24-hour UFC
Mean (SD)	391.5 (1471) µg/24 hours, 1080 (4060) nmol/24 hours
Median (IQR)	135.0 (82.7-220.0) µg/24 hours, 372 (228-607) nmol/24 hours
Range (min-max)	29-12 346 µg/24 hours, 80-34 053 nmol/24 hours
LNSC, n (%)
Normal	3 (4.5)
Abnormal	59 (88.1)
NA	5 (7.5)
Plasma ACTH
Mean (SD)	70.7 (64.1) pg/mL, 15.6 (14.1) pmol/L
Median (IQR)	56.0 (42.0-83.8) pg/mL, 12.3 (9.2-18.4) pmol/L
Range (min-max)	11-416 pg/mL (2.4-91.5 pmol/L)
Prior recurrence at baseline, n (%)	16 (23.9)
Prior transsphenoidal surgery, n (%)	16 (23.9)
1	9 (13.4)
2	7(10.4)

Abbreviations: CD, Cushing disease; CS, Cushing’s syndrome; IQR, interquartile range; LNSC, late-night salivary cortisol; NA, not available; UFC, urinary free cortisol.

Table 2.

Baseline and follow-up data

	Baseline	Longest follow-up	P-value
BMI (kg/m²)
Mean (SD)	33.2 (7.6)	30.6 (8.5)	<.001
Median (IQR)	31.6 (26.8-37.3)	29.3 (25.3-34.8)
LNSC, n (%)			<.001
Normal	3 (4.5)	30 (44.7)
Abnormal	59 (88.1)	16 (23.8)
NA	5 (7.5)	21 (31.3)
DM, n (%)			<.001
DM	28 (41.8)	13 (19.4)
Pre-DM	15 (22.4)	9 (13.4)
Hypertension, n (%)	55 (82.1)	35 (53.7)	<.001
HbA1C (%)			<.001
Total mean (SD)	6.5 (1.8)	5.7 (0.9)
DM/pre-DM mean (SD)	6.9 (1.8)	6.1 (1.0)
Antidiabetic medications, n (%)	20 (29.9)	(22.4)
1	12 (17.9)	(13.4)
2	1 (1.5)	(3.0)
3	3 (4.5)	(1.5)
Insulin	4 (6.0)	3 (4.5)
Antihypertensive medications, n (%)	34 (50.7)	(37.3)
1	15 (22.4)	(19.4)
2	10 (14.9)	(11.9)
≥3	9 (13.4)	4 (6.0)
Other medications, n (%)
Antidepressants	10 (14.9)	13 (19.4)
Anxiolytics	12 (17.9)	12(17.9)
Pain medications	16 (23.9)	23 (34.3)
Sleep medications	16 (23.9)	21 (31.3)
Treatment at most recent follow-up,^a n (%)
Transsphenoidal surgery		44 (65.7)
Medical therapy		18 (26.9)
Bilateral adrenalectomy		3 (4.5)
Radiation therapy		1 (1.5)
Adrenalectomy (adrenal CS)		7 (10.4)

Abbreviations: BMI, body mass index; CS, Cushing’s syndrome; DM, diabetes mellitus; HbA1c, hemoglobin A1c; IQR, interquartile range; LNSC, late-night salivary cortisol.

^a“n” refers to number of separate baseline-to-follow-up cases.

In total, there were 46 visits in G1, 31 in G2, and 24 in G3. At the most recent follow-up of each case, there were 24 visits in G1, 25 in G2, and 24 in G3.

The mean (range) duration from baseline to most recent follow-up was 28.3 (5-138) months in the overall cohort. The mean (range) follow-up duration since the most recent treatment was 6.3 (4-9) months for G1, 12.7 (10-18) months for G2, and 43.7 (23-120) months for G3. At their final follow-up visit, 44 patients (65.7%) achieved remission after transsphenoidal surgery (TSS), 18 (26.9%) were under medical control, 3 (4.5%) underwent bilateral adrenalectomy (BLA), 1 (1.5%) received radiation therapy (RT), and the 7 (10.4%) patients with adrenal CS underwent unilateral adrenalectomy (Table 2).

The following additional treatments were administered between this study’s baseline visit and longest follow-up: among the 44 patients treated with TSS at their latest follow-up, 1 underwent an additional TSS and 1 received medical therapy prior to TSS. Of the 18 medically managed patients at last follow-up, 8 (44.4%) had previously undergone TSS (3 of whom had 2 TSSs), and 2 of these 8 additionally received at least 1 different medication before switching to the 1 recorded at their last follow-up. Two (11.1%) other patients received 2 sequential medications before the final 1 at follow-up, and 1 (5.6%) patient was on a block-and-replace regimen with hydrocortisone (HC) after 2 TSSs and BLA. The complete treatment journey of patients on medical therapy, before and after entering the study, is shown in Fig. 1. Among the patients who underwent BLA at last follow-up, 1 had 2 prior TSSs, 1 had a sin1 gle prior TSS and received medical therapy and had 2 TSSs and received medical therapy. The patient treated with RT had 2 prior TSSs and received medical therapy.

Figure 1.

Treatment journey of the 18 patients on medical therapy at their longest follow-up. Each row represents the longitudinal treatment course of each patient before and/or after entering the study. Multiple boxes indicating medical therapy within the same patient represent different medications administered over time. Segments outlined in bold represent the follow-up period analyzed in the current cohort, from this’ study baseline to the longest available follow-up.

Abbreviations: CT, clinical trial; Keto, ketoconazole; Levo, levoketoconazole; Mety, metyrapone; Mife, mifepristone; Osilo, osilodrostat; Pasi, pasireotide.

Sixteen patients presented with recurrent disease; an additional 9 patients (13.4%) developed recurrent or persistent disease after surgery. HC replacement was administered at 21 of the longest available follow-up visits [6 due to ongoing hypopituitarism or adrenal insufficiency (AI) and 15 for temporary postoperative AI], with another 9 cases receiving replacement at intermediate follow-up visits.

All 18 patients on medical therapy at their longest follow-up received adrenal steroidogenesis inhibitors: osilodrostat (8 patients, 44.4%), metyrapone (6 patients, 33.3%), and ketoconazole (4 patients, 22.2%).

Comorbid Conditions

As shown in Table 2, mean body mass index (BMI) at baseline was 33.2 ± 7.6 kg/m². Twenty-eight (41.8%) patients presented with DM, 15 (22.4%) with prediabetes, and 24 (35.8%) without DM. Fifty-five of 67 patients (82.1%) had hypertension at baseline. At the longest follow-up, mean BMI decreased to 30.6 ± 8.5 kg/m² (P < .001), and mean HbA1c decreased to 5.7 ± 0.9% (P < .001). Thirteen patients (19.4%) continued to have DM, and 9 patients (13.4%) had prediabetes. Hypertension was present in 35 patients (53.7%), of whom 25 (71.4%) were receiving at least 1 antihypertensive medication.

LNSC levels remained abnormal in 16 patients (23.8%), although LNSC data were not available for 21 patients (31.3%). Of those, LNSC testing was not considered clinically indicated in some cases, such as patients on HC replacement for postoperative AI (n = 10) or patients with adrenal CS status postadrenalectomy (n = 3). The remaining 8 patients with missing LNSC data were on medical therapy (n = 4) or status post-TSS (n = 4).

Cushing QoL

Sixty-five patients (71 baseline to follow-up case pairs) completed the CushingQoL assessment. In the overall cohort, treatment resulted in significant improvements in mean QoL scores at all follow-up time points: mean change in G1 was 16.6 ± 18.6 (P < .001); G2, 19.1 ± 19.4 (P < .001); and G3, 16.6 ± 27.1 (P = .009) (Table 3, Fig. 2A). For longest available follow-up for each case, overall mean improvement was 18.2 ± 20.9 points (P < .001).

Figure 2.

Score trajectory for (A) Cushing QoL, (B) BDI-II, (C) STAI-State, and (D) STAI-Trait in the overall cohort based on duration of follow-up, including patients with 2 follow-up visits. Significant improvements in mean scores were observed in all assessments and all follow-up time points except in group 3 STAI-State, noted with a gray line. Group 1: 6 months posttreatment, group 2: 12 to 18 months posttreatment, group 3: ≥ 24 months posttreatment.

Abbreviations: BDI-II, Beck Depression Inventory-II; QoL, quality of life; STAI, State-Trait Anxiety Inventory.

Table 3.

Cushing QoL scores at baseline, follow-up visit, and mean score change in each time-based group for total cohort, patients who had TSS and patients on medical therapy

Category	Subgroup	n	Baseline mean	Follow-up visit mean	Mean change	SD (change)	P-value
Total cohort	Longest follow-up	71	42.4	60.6	18.2	20.9	<.001
	Group 1	45	40.6	57.2	16.6	18.6	<.001
	Group 2	30	43.5	62.6	19.1	19.4	<.001
	Group 3	23	41.2	57.9	16.6	27.1	.009
TSS	Longest follow-up	42	40.0	59.9	20.0	18.5	<.001
	Group 1	29	40.2	57.0	16.8	19.1	<.001
	Group 2	21	41.4	61.9	20.4	15.8	<.001
	Group 3	9	29.0	48.7	19.7	24.9	.045
Medical therapy	Longest follow-up	19	46.3	58.4	12.1	26.2	.059
	Group 1	9	44.6	56.7	12.1	18.5	.086
	Group 2	7	40.9	57.1	16.3	31.4	.219
	Group 3	10	56.0	62.0	6.0	27.9	.513

Abbreviations: QoL, quality of life; TSS, transsphenoidal surgery.

In the subanalysis by treatment strategy, 42 patients who completed the Cushing QoL achieved surgical remission and 19 patients were controlled on medical therapy. In the surgical cohort, improvement in scores were noted across all time groups with a mean score increase of 20.0 ± 18.5 points from baseline to the longest available follow-up (P < .001) (Figs. 3A and 4A). Among these patients, 15 had 2 follow-up visits; between them the mean score further increased by 9.6 ± 14.8 points, indicating significant QoL improvement >6 months postsurgery (P = .025). In contrast, patients under medical control at follow-up showed a mean improvement of 12.1 ± 26.2 points from baseline to the longest follow-up, which did not reach statistical significance (n = 19; P = .059) (Table 3, Figs. 3A and 4A).

Figure 3.

Mean score change in total cohort, patients after transsphenoidal surgery, and patients on medical therapy based on duration of follow-up: (A) Cushing QoL, (B) BDI-II, (C) STAI-State, (D) STAI-Trait. Direct comparison between the 2 treatment modalities was performed only in the longest available follow-up visit for each patient. Caps represent SEM. Only P-values ≤ .05 are displayed.

Abbreviations: BDI-II, Beck Depression Inventory-II; QoL, quality of life; STAI, State-Trait Anxiety Inventory.

Figure 4.

Mean scores at baseline and longest follow-up in total cohort, patients after transsphenoidal surgery, and patients on medical therapy for (A) Cushing QoL, (B) BDI-II, (C) STAI-State, (D) STAI-Trait. Caps represent SEM. Asterisks (*) indicate significant change from baseline to follow-up (P ≤ .05) and brackets significant differences between the 2 treatment modalities at the longest follow-up visit (P ≤ .05).

Abbreviations: BDI-II, Beck Depression Inventory-II; QoL, quality of life; STAI, State-Trait Anxiety Inventory.

MID achievement and predictors of improvement

In the overall cohort, CushingQoL MID was achieved in 42 of the 65 patients (64.6%) (Fig. 5). When stratified by follow-up duration, MID achievement rates were 60.8% in G1 (n = 45), 70.0% in G2 (n = 30), and 60.9% (n = 23) in G3.

Figure 5.

MID achievement rates for all patient-reported outcomes at most recent follow-up.

Abbreviations: MID, minimal important difference.

Males (n = 11) improved more than female patients (n = 54) (27.8 ± 13.0 vs 15.5 ± 21.9; P = .020) and achieved the MID more frequently (90.9% vs 59.3%; P = .045). Even though they presented with lower baseline scores compared to females (33.2 ± 16.3 vs 44.3 ± 20.7), that difference was not significant (P = .117).

Score change differed by BMI category, using as cut-off the baseline mean of our cohort (≤33.2 vs >33.2 kg/m²): patients with lower BMI (n = 34) improved considerably more than those with higher BMI (n = 31) (median score change: 26 vs 11; P = .023). Likewise, MID achievement was more common in the low-BMI group (76.5% vs 51.6%; P = .036).

Patients presenting with recurrent disease at baseline (n = 16) reported better baseline QoL than those with primary disease (n = 49) (51.6 ± 19.5 vs 39.5 ± 20.9; P = .046), and their mean improvement following treatment was smaller (7.2 ± 21.0 vs 21.0 ± 19.8; P = .022). Only 43.8% of recurrent cases achieved the MID compared to 71.4% of primary cases (P = .044).

Patients reporting symptom duration ≥3 years prior to diagnosis (n = 29) were less likely to achieve the MID compared to those with shorter symptom duration (n = 35) (48.3% vs 66.7%; P = .008).

Patients with at least 1 abnormal LNSC (n = 15) value at follow-up were less likely to meet MID compared to those with normal LNSC values (n = 28) (33.3% vs 75.0%; P = .008). Similarly, patients requiring HC replacement (after their first TSS or unilateral adrenalectomy for adrenal CS) for >6 months (n = 22) were more likely to achieve MID than those requiring ≤6 months (n = 30) (81.8% vs 50.0%; P = .019).

MID achievement rates between the TSS and medical-therapy groups differed (71.4% vs 47.4%) but did not reach significance (P = .070).

Baseline 24 hours UFC was inversely correlated with baseline CushingQoL score (ρ = −0.3; P = .035), indicating a relationship between biochemical and symptomatic disease severity.

BDI-II

Fifty-six patients (60 case pairs) were included in this subgroup. In the overall cohort, improvements in BDI-II score were seen at all follow-up time points: mean change in G1 was 4.7 ± 9.2 (P = .004); in G2, 7.7 ± 7.3 (P < .001); and in G3, 7.6 ± 10.6 (P = .008). In the overall cohort, mean improvement from baseline to the longest follow-up was 6.8 ± 8.6 points (P < .001) (Table 4, Fig. 2B). Of note, a significant 7.3-point improvement was noted between follow-up G1 (6 months) and follow-up G2 (12 months) (n = 11, P = .025), indicating continued improvement in depressive symptoms over time after treatment.

Table 4.

BDI-II scores at baseline, follow-up visit, and mean score change in each time-based group for total cohort, patients who had TSS and patients on medical therapy

Category	Subgroup	n	Baseline mean	Follow-up visit mean	Mean change	SD (change)	P-value
Total cohort	Longest follow-up	60	15.7	8.9	6.8	8.6	<.001
	Group 1	37	17.0	12.2	4.7	9.2	.004
	Group 2	26	15.2	7.5	7.7	7.3	<.001
	Group 3	18	15.9	8.3	7.6	10.6	.008
TSS	Longest follow-up	32	17.1	8.2	8.8	8.1	<.001
	Group 1	22	18.6	13.6	5.0	10.9	.043
	Group 2	17	14.7	6.7	8.0	8.1	<.001
	Group 3	6	20.5	8.3	12.2	4.7	.001
Medical therapy	Longest follow-up	18	14.4	11.0	3.4	9.9	.159
	Group 1	8	14.6	11.0	3.6	6.7	.171
	Group 2	6	18.3	10.8	7.5	7.1	.049
	Group 3	9	11.8	8.8	3.0	13.3	.517

Abbreviations: BDI-II, Beck Depression Inventory-II; TSS, transsphenoidal surgery.

Among the 32 patients who underwent TSS, improvements were noted across all follow-up time groups, with mean scores decreasing from 17.1 ± 10.9 to 8.2 ± 7.0 at the longest follow-up (P < .001). In contrast, the 18 patients treated medically did not experience a significant change (P = .159). Improvement following TSS was significantly greater than with medical therapy at longest follow-up for each case (8.8 ± 8.1 vs 3.4 ± 9.9; P = .043) (Figs. 3B and 4B).

MID achievement and improvement predictors

Thirty-eight patients (67.9%) achieved MID by their longest follow-up (Fig. 5). Twenty-nine (51.8%) patients had baseline scores ≥14 points, indicating mild or moderate depression, and 23 (79.3%) of these patients met the MID. By follow-up duration, overall MID achievement rates were 56.8% in G1 (n = 37), 76.9% in G2 (n = 26), and 72.2% in G3 (n = 18).

By treatment approach, MID was met by 75.0% of patients who had TSS (n = 32) and 38.9% of patients on medication (n = 18) (P = .012). All patients who underwent BLA (n = 4) or RT (n = 1) and 5 out of 6 patients treated for adrenal CS achieved MID.

Patients with recurrent and primary disease did not differ in terms of baseline score (P = .267). However, those with recurrent disease were less likely to achieve MID (42.9% vs 76.2%; n = 14 vs 75.6%; n = 42, P = .021).

Symptom duration prior to diagnosis was inversely correlated with BDI-II score change (ρ = −0.33, P = .016). Patients experiencing symptoms for ≥3 years (n = 24) exhibited lower MID achievement rates compared to those with shorter symptom duration (n = 31) (50.0% vs 83.9%; P = .007).

Patients with normal LNSC at follow-up had higher MID achievement rates (81.5%; n = 27 vs 45.5%; n = 11, P = .026).

STAI

STAI-S

Fifty-six patients (60 case pairs) completed the STAI-State questionnaire. All follow-up time groups exhibited improvements, although in G3 the score decrease did not reach significance. In the overall cohort, mean scores declined from 44.8 ± 14.0 to 35.3 ± 11.2 at the longest follow-up (P < .001) (Table 5).

Table 5.

STAI scores at baseline, follow-up visit, and mean score change in total cohort, patients who had TSS and patients on medical therapy

Outcome	Category	Subgroup	n	Baseline mean	Follow-up visit mean	Mean change	SD (change)	P-value
STAI-State	Total cohort	Longest follow-up	60	44.8	35.3	9.6	12.5	<.001
		Group 1	40	45.9	36.6	9.3	12.3	<.001
		Group 2	25	46.2	35.3	10.8	10.8	<.001
		Group 3	17	42.4	36.1	6.3	13.8	.078
	TSS	Longest follow-up	33	44.4	34.3	10.1	12.3	<.001
		Group 1	24	44.4	35.8	8.6	11.9	.002
		Group 2	16	43.7	33.9	9.8	11.9	.005
		Group 3	7	46.0	37.9	8.1	12.1	.126
	Medical therapy	Longest follow-up	17	47.2	37.4	9.8	14.7	.014
		Group 1	9	50.9	37.2	13.7	13.7	.017
		Group 2	5	56.4	39.8	16.6	8.4	.012
		Group 3	8	36.3	34.6	2.0	14.9	.715
STAI-Trait	Total cohort	Longest follow-up	58	46.0	37.3	8.6	12.6	<.001
		Group 1	36	47.9	40.3	7.6	12.0	<.001
		Group 2	26	45.7	36.0	9.6	10.9	<.001
		Group 3	16	46.7	36.9	9.8	13.2	.010
	TSS	Longest follow-up	31	47.5	36.7	10.7	12.2	<.001
		Group 1	22	47.9	40.6	7.3	11.5	.008
		Group 2	16	46.3	35.9	10.4	11.4	.002
		Group 3	6	54.0	37.8	16.2	7.5	.003
	Medical therapy	Longest follow-up	18	45.1	38.8	6.2	13.4	.065
		Group 1	8	49.5	39.8	9.8	14.0	.089
		Group 2	6	47.5	36.2	11.3	10.9	.052
		Group 3	8	39.3	37.5	1.8	12.7	.709

Abbreviations: STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

By treatment modality, state anxiety improved in both the TSS group (10.1 ± 12.3; n = 33; P < .001) and patients on medical therapy (9.8 ± 14.7; n = 17; P = .014) (Figs. 3C and 4C).

MID achievement and improvement predictors

Overall, 30 of 56 (53.5%) patients achieved MID in STAI-State at their longest follow-up visit (Fig. 5). By follow-up duration, MID achievement rates were 52.5% in G1 (n = 40), 56.1% in G2 (n = 25), and 64.7% in G3 (n = 17).

A negative correlation was observed between STAI-S score change and baseline age (ρ = −0.3, P = .029). Patients >40 years old at baseline (n = 29), improved less than younger patients (n = 27) [median score change: 5 vs 13 (P = .017)] and were less likely to meet the MID, with results approaching statistical significance (41.4% vs 66.7%, P = .058).

STAI-T

Fifty-three patients (58 case pairs) were evaluated. In the overall cohort, mean score change from baseline to longest follow-up was 8.6 ± 12.6 points (P < .001). In time-based subgroups the following score reductions were noted: G1: 7.6 ± 12.0 (P < .001), G2: 9.6 ± 10.9 (P < .001), G3: 9.8 ± 13.2 (P = .010) (Fig. 2D). Among patients treated with TSS (n = 31), significant improvement was seen in every subgroup. Patients receiving medical therapy (n = 18) showed numerical but not statistically significant improvement (P = .065) (Table 5, Figs. 3D and 4D).

MID achievement and improvement predictors

STAI-Trait MID was achieved by 28 (52.8%) patients at the longest follow-up (Fig. 5). By follow-up duration, MID achievement rates were 44.4% in G1, 53.8% in G2, and 68.8% in G3.

Patients ≤40 years at baseline (n = 26) improved more than those aged >40 years (n = 27), with results approaching significance [median score change: 14 vs 4 (P = .060)].

Patients with ≥2 Follow-up Visits

Twenty-eight patients had multiple follow-up visits; we stratified by follow-up duration (<2 years vs ≥2 years) [Table S1 (30)].

Cushing QoL

Significant improvements were noted in all groups with pairwise comparisons revealing higher scores in both first and second follow-up, with the mean score changing by 14.9 (P = .002) and 21.5 (P < .001) points, respectively, in total cohort.

BDI-II

Although the overall trajectory demonstrated significant improvement, pairwise comparisons showed no significant changes between baseline and first follow-up. Improvement was noted between baseline and the second follow-up visit (P < .001) and between the 2 treated visits (P = .021) (Table 6).

Table 6.

BDI-II mean scores and pairwise comparisons in patients with 2 follow-up visits

Comparison	Mean score A	Mean score B	Mean difference	P-value
Baseline vs follow-up 1	16.9	13.0	4.846	.200
Baseline vs follow-up 2	16.9	7.1	9.731	<.001
Follow-up 1 vs follow-up 2	13.0	7.1	4.885	.021

Abbreviations: BDI-II, Beck Depression Inventory-II.

STAI-S

Overall, the mean score decreased from 45.9 ± 13.0 at baseline to 38.3 ± 12.4 at the first follow-up and to 36.1 ± 10.9 at the second follow-up (P = .005). In cases with follow-up ≥2 years (n = 13), the score trajectory did not change significantly from baseline (P = .187). In contrast, patients with total follow-up <2 years (n = 11) exhibited significant improvement (P = .008).

STAI-T

Overall, the mean score decreased from 49.2 ± 9.0 at baseline to 39.8 ± 11.6 at first follow-up and further to 36.4 ± 10.5 at second follow-up (P < .001). Significant improvement noted from baseline to both follow-up visits in both subgroups (P < .001).

Regression Analyses for Predictors of Change

In all measurements, after controlling for age and sex, baseline score was an independent predictor of greater change (P < .001) (Table 7). Patients with more impaired QoL, or severe depression and anxiety at baseline, had more room for improvement.

Table 7.

Predictors of mean score change from baseline to most recent follow-up of each patient in univariable and multivariable linear regression analysis

Outcome	Parameter	Univariable analysis			Multivariable analysis
		Estimate	SE	P-value	Estimate	SE	P-value
Cushing QoL score change	Baseline score	−0.50	0.11	<.001	−0.47	0.11	<.001
	Baseline age	−0.05	0.20	.797	−0.04	0.19	.825
	Male sex	12.11	6.83	.081	7.49	6.68	.267
	Baseline age ≤40 (vs >40)	−3.43	5.23	.515	−4.90	4.89	.321
	Normal LNSC (vs abnormal)	−19.98	6.4	.004	−19.39	5.26	.001
	HC replacement >6 months (vs ≤6 months)	10.06	5.90	.095	12.35	4.96	.016
	Primary disease at baseline (vs recurrent)	−13.19	5.86	.028	−6.63	5.60	.241
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	−8.72	5.1	.095	−6.53	4.71	.171
	Symptom duration ❤ years (vs ≥3 years)	−4.60	5.25	.384	−4.55	4.70	.337
	Treatment (TSS vs medical therapy)	−7.87	5.8	.185	−4.23	5.41	.473
BDI-II score change	Baseline score	0.57	0.09	<.001	0.58	0.09	<.001
	Baseline age	−0.08	0.09	.402	0.02	0.08	.797
	Male sex	−0.59	3.07	.848	0.80	2.53	.752
	Baseline age ≤40 (vs >40)	−3.96	4.82	.429	−0.52	2.02	.800
	Normal LNSC (vs abnormal)	−3.01	3.06	.332	−3.27	1.87	.090
	HC replacement >6 months (vs ≤6 months)	0.06	2.577	.980	2.33	1.90	.226
	Primary disease at baseline (vs recurrent)	−4.76	2.63	.076	−2.66	2.17	.224
	Baseline BMI ≤33.2 kg/m² vs >33.2 kg/m²	−3.79	2.29	.104	−1.41	1.90	.462
	Symptom duration ❤ years (vs ≥3 years)	−5.61	2.23	.015	−3.49	1.78	.055
	Treatment (TSS vs medical therapy)	−5.46	2.60	.041	−3.94	2.02	.057
STAI-State score change	Baseline score	0.57	0.09	<.001	0.56	0.09	<.001
	Baseline age	−0.22	0.13	.104	−0.11	0.12	.338
	Male sex	−5.70	4.37	.197	−4.39	3.69	.239
	Baseline age ≤40 (vs >40)	−5.94	3.30	.078	−3.75	2.73	.175
	Normal LNSC (vs abnormal)	−2.15	3.95	.589	−4.47	2.89	.131
	HC replacement >6 months (vs ≤6 months)	0.72	3.45	.836	4.42	2.81	.123
	Primary disease at baseline (vs recurrent)	2.41	3.91	.743	2.14	2.91	.465
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	−2.36	3.38	.488	−0.93	2.56	.716
	Symptom duration ❤ years (vs ≥3 years)	−5.67	3.33	.095	−3.26	2.46	.192
	Treatment (TSS vs medical therapy)	−1.50	3.91	.970	−2.77	2.97	.355
STAI-Trait score change	Baseline score	0.58	0.11	<.001	0.56	0.12	<.001
	Baseline age	−0.20	0.13	.128	−0.07	0.11	.562
	Male sex	−3.09	4.57	.502	−0.83	4.13	.841
	Baseline age ≤40 (vs >40)	−5.45	3.36	.111	−2.55	3.03	.405
	Normal LNSC (vs abnormal)	−6.52	4.23	.133	−6.74	3.44	.059
	HC replacement >6 months (vs ≤6 months)	4.63	3.52	.195	7.11	2.87	.018
	Primary disease at baseline (vs recurrent)	−2.07	3.90	.597	−0.34	3.42	.921
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	−4.95	3.38	.150	−2.59	3.00	.393
	Symptom duration ❤ years (vs ≥3 years)	−5.78	3.37	.093	−4.35	2.80	.127
	Treatment (TSS vs medical therapy)	−4.49	3.74	.236	−3.39	3.11	.281

Each predictor in multivariable analysis was separately evaluated, adjusting for baseline age, sex, and baseline score. In models exploring baseline age <40 years as a categorical variable, continuous baseline age was not included in the multivariable model. Statistically significant results (P ≤ .05) are indicated in bold.

Abbreviations: BDI-II, Beck Depression Inventory-II; BMI, body mass index; HC, hydrocortisone; LNSC, late-night salivary cortisol; QoL, quality of life; STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

Cushing QoL

Normal LNSC at follow-up and >6 months of postoperative HC replacement were predictors of QoL score improvement and MID achievement even after adjustment for baseline score, age, and sex. Lower baseline BMI and male sex, although significant in univariable analysis, were no longer significant in the multivariable linear model. However, a BMI < 33.2 kg/m² (P = .034) and symptom duration ❤ years prior to diagnosis (P = .005) remained statistically significant predictors of reaching the MID in the multivariable logistic model (Table 8, Fig. 6). To determine if treatment modality modified the effect of LNSC, we built a model including baseline QoL score, age, sex, follow-up LNSC, and treatment type (TSS vs medical therapy). In this multivariable model, normal LNSC remained a significant predictor of improvement (P = .023).

Figure 6.

MID achievement predictors after multivariable analysis for (A) Cushing QoL, (B) BDI-II, (C) STAI-State. Each predictor was analyzed in a separate logistic regression model after adjustment for baseline score, age, and sex. Predictors for trait anxiety are not shown, as a longer duration of postoperative HC replacement was a significant predictor only in the linear multivariable regression model.

Abbreviations: BDI-II, Beck Depression Inventory-II; HC, hydrocortisone; LNSC, late-night salivary cortisol; QoL, quality of life; STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

Table 8.

https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgaf598/8307075?login=false

Predictors of MID achievement from baseline to most recent follow-up of each patient in univariable and multivariable logistic regression models

Outcome	Parameter	Univariable analysis			Multivariable analysis
		Estimate	SE	P-value	Estimate	SE	P-value
Cushing QoL MID achievement	Baseline score	0.94	0.02	<.001	0.94	0.02	<.001
	Baseline age	1.01	0.02	.548	1.02	0.03	.410
	Male sex	6.89	1.09	.076	3.82	1.16	.249
	Baseline age ≤40 (vs >40)	1.01	0.52	.987	1.27	0.62	.704
	Normal LNSC (vs abnormal)	6.00	0.70	.011	22.82	1.17	.007
	HC replacement >6 months (vs ≤6 months)	4.50	0.66	.023	14.49	0.99	.007
	Primary disease at baseline (vs recurrent)	3.21	0.60	.050	1.78	0.68	.400
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	3.05	0.54	.039	4.33	0.69	.034
	Symptom duration ❤ years (vs ≥3 years)	4.29	0.56	.010	9.07	0.78	.005
	Treatment (TSS vs medical therapy)	2.79	0.57	.074	2.36	0.68	.209
BDI-II MID achievement	Baseline score	1.08	0.04	.064	1.08	0.04	.042
	Baseline age	1.02	0.02	.510	1.01	0.03	.613
	Male sex	5.28	1.10	.130	5.76	1.14	.126
	Baseline age ≤40 (vs >40)	1.11	0.57	.854	1.05	0.63	.937
	Normal LNSC (vs abnormal)	5.28	0.78	.033	14.86	1.25	.030
	HC replacement >6 months (vs ≤6 months)	2.00	0.65	.288	2.32	0.71	.236
	Primary disease at baseline (vs recurrent)	4.27	0.65	.026	2.67	0.71	.165
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	1.94	0.58	.255	1.55	0.66	.504
	Symptom duration < 3 years (vs ≥3 years)	5.20	0.64	.010	5.74	0.70	.012
	Treatment (TSS vs medical therapy)	4.71	0.63	.014	4.19	0.69	.039
STAI-State MID achievement	Baseline score	1.17	0.04	<.001	1.19	0.05	<.001
	Baseline age	0.97	0.02	.241	0.96	0.03	.261
	Male sex	1.95	0.71	.347	3.17	1.00	.249
	Baseline age ≤40 (vs >40)	2.83	0.56	.061	5.87	0.89	.048
	Normal LNSC (vs abnormal)	2.02	0.73	.337	2.41	1.04	.396
	HC replacement >6 months (vs ≤6 months)	0.94	0.59	.943	2.66	0.97	.313
	Primary disease at baseline (vs recurrent)	1.21	0.62	.757	2.15	0.92	.408
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	2.05	0.54	.189	1.57	0.82	.584
	Symptom duration < 3 years (vs ≥3 years)	1.39	0.55	.52	0.98	0.77	.980
	Treatment (TSS vs medical therapy)	1.95	0.62	.279	1.44	0.78	.634
STAI-Trait MID achievement	Baseline score	1.17	0.05	<.001	1.17	0.05	<.001
	Baseline age	0.98	0.02	.295	0.97	0.03	.342
	Male sex	2.33	0.75	.257	4.16	1.02	.161
	Baseline age ≤40 (vs >40)	2.12	0.56	.175	2.32	0.76	.265
	Normal LNSC (vs abnormal)	1.78	0.71	.416	1.48	0.96	.686
	HC replacement >6 months (vs ≤6 months)	1.58	0.60	.450	4.21	0.95	.130
	Primary disease at baseline (vs recurrent)	2.45	0.61	.138	2.06	0.90	.421
	Baseline BMI ≤33.2 kg/m² (vs >33.2 kg/m²)	1.98	0.54	.202	1.11	0.79	.891
	Symptom duration < 3 years (vs ≥3 years)	1.09	0.53	.866	0.99	0.71	.984
	Treatment (TSS vs medical therapy)	1.39	0.60	.585	1.18	0.82	.839

Each predictor in multivariable analysis was separately evaluated, adjusting for baseline age, sex and baseline score. In models exploring baseline age <40 years as a categorical variable, continuous baseline age was not included in the multivariable model. Statistically significant results (P ≤ .05) are indicated in bold.

Abbreviations: BDI-II, Beck Depression Inventory-II; BMI, body mass index; HC, hydrocortisone; LNSC, late-night salivary cortisol; MID, minimal important difference; QoL, quality of life; STAI, State-Trait Anxiety Inventory; TSS, transsphenoidal surgery.

BDI-II

Symptom duration ❤ years (P = .012), normal LNSC at follow-up (P = .030), and TSS (P = .039) instead of medical therapy (for CD) were statistically significant predictors of MID achievement in the multivariable logistic models even after adjusting for age, sex, and baseline score (Table 8, Fig. 6).

STAI-S

In the multivariable logistic model adjusted for sex and baseline score, age <40 predicted higher odds of MID achievement (P = .041) (Table 8, Fig. 6).

STAI-T

After adjustments for sex and baseline score, age group <40 was no longer a predictor of improvement. Although nonsignificant in univariable screening, duration of postoperative HC replacement >6 months emerged as a significant predictor of score change, though not MID achievement, after adjusting for age, sex, and baseline score (Tables 7 and 8).

Discussion

In a clinical practice cohort of patients with CS followed prospectively before and over time up to 11.5 years after surgical remission and/or biochemical control from medical treatment, we identified significant improvements in mean QoL, depression, and anxiety scores in the overall cohort, but only half of patients achieved clinically meaningful improvements in anxiety, as assessed by MID, and about two-thirds of the cohort achieved clinically meaningful improvements in QoL and depression at their most recent follow-up. When assessed by treatment strategy, surgery resulted in statistically significant improvements in all 3 measures, whereas medical therapy resulted in statistically significant improvements in state anxiety but not QoL or depression. These findings may be impacted by the smaller cohort size of the medically treated patients and more complex treatment journeys in the medically vs surgically treated patients. Overall, in this cohort of treated, biochemically controlled patients, several predictors of improvements were identified, including age, baseline BMI, duration of symptoms prior to treatment, duration of HC requirement after surgery, and LNSC normalization with treatment.

PRO studies in CS have shown that patients with CS are at risk for mood disorders and impaired QoL at diagnosis and that improvement posttreatment is often partial, delayed, or inconsistent, even after biochemical remission (3-12). The most recent prospective study confirmed persistent deficits in QoL and depressive symptoms up to 1 year postsurgery, with mean BDI-II scores remaining in the clinically significant range (9). As for anxiety, a prospective study reported high baseline anxiety in patients with CD, and, although it improved after surgery, a proportion continued to experience anxiety up to 1 year posttreatment (14). Neuroimaging supports a biological basis for these symptoms, with brain abnormalities (hippocampal atrophy, cortical thinning, white matter damage) seen after biochemical cure possibly explaining the long-term emotional and cognitive deficits in some patients (12, 15). As for previously reported predictors of improvement, male sex, lower BMI at follow-up (4, 31, 32), LNSC normalization (17), and shorter duration of cortisol exposure (32, 33) emerged as independent predictors of better QoL. Persistent hormone deficits or arginine vasopressin deficiency were related to worse depression (9) while increased age and male sex predicted less anxiety (31). While some studies suggest that hypopituitarism and HC replacement are associated with poorer outcomes (11, 34), others found no significant difference (35). Limitations of these studies include the cross-sectional design (4, 31-36), small cohort sizes (9), and lack of long-term follow-up >12 months (37), especially in the setting of clinical trials (17).

In our study, QoL, depression, and anxiety improved following treatment, but the patterns varied by domain and follow-up duration.

As for QoL, interestingly, patients with recurrent disease showed better baseline QoL scores than those with primary disease, possibly due to posttreatment surveillance, resulting in earlier diagnosis at recurrence vs initial presentation. Although patients on medical therapy showed a trend toward improvement with treatment, results did not reach significance, potentially due to sample size or the increased (better) baseline scores in patients with recurrent disease and thus those receiving medical treatment. Most patients on medical therapy had persistent or recurrent disease and have experienced longer, more complex treatment journeys (as depicted in Fig. 1) compared to those in surgical remission, which also may impact QoL and mood outcomes. Notably, in patients with 2 follow-up visits, QoL continued to significantly improve 6 months posttreatment in those treated surgically but not in the total cohort.

Multivariable analysis revealed several predictors of QoL improvement after treatment. LNSC normalization was independently associated with approximately 20 times higher odds of achieving the MID, indicating the clinical importance of recovery of cortisol circadian rhythm for treated CS patients and the need for further work to identify medical therapies and regimens that can facilitate this. Postoperative HC replacement for more than 6 months after surgery (indicating a longer hypothalamic-pituitary-adrenal axis recovery) was also associated with greater QoL improvement. This finding complements prior work showing an association between duration of postoperative HC replacement and long-term remission (38, 39). Lower baseline BMI and shorter symptom duration were predictive of MID achievement, though not of mean score change.

As for depression, patients with 2 follow-ups had a distinct pattern: no significant change between baseline and first follow-up but significant improvement between the 2 follow-up visits. This suggests that depression may take longer to improve, with more evident change >6 months after biochemical control, which contrasts prior work suggesting that anxiety takes longer than depression to improve (14). The delayed trajectory could reflect the structural brain changes seen in CS even in remission, which are partially reversible (12, 40). Our data showed that symptom duration > 3 years prior to diagnosis reduced MID achievement, consistent with the literature linking diagnostic delay to persistent depression (33). A normal follow-up LNSC was associated with approximately 15 times higher odds of achieving the MID after adjustment, again emphasizing the need to attempt LNSC normalization while on medical therapy (9, 17).

As for anxiety, to date, no prospective study has assessed anxiety longitudinally using STAI, the gold standard for measuring and differentiating between trait and state anxiety (29). Our results confirm that anxiety improves after treatment; however, state and trait show different patterns. State anxiety was the only domain overall to improve significantly in the medical therapy group, while trait anxiety showed only a trend. Although age <40 predicted greater anxiety improvements in both, this remained significant only for state anxiety after adjustment in the logistic model. Trait anxiety improvements were predicted by longer postoperative HC replacement in the linear multivariable model, again suggesting that a shorter recovery time of the HPA axis may be an early indicator for identifying patients who require a closer follow-up. A normal LNSC at follow-up approached significance in the multivariable linear model, suggesting the importance of circadian rhythm recovery in trait anxiety improvement as well.

Across all measures, we found no baseline or outcome differences between pituitary and adrenal CS or between those on or off HC replacement at their last follow-up. Of note, our cohort was predominantly CD patients, and the small number of adrenal CS patients may limit the ability to detect a difference in the 2 cohorts.

Overall, discrepancies between mean change and MID achievement, as reflected in the linear and logistic models, respectively, highlight the importance of reporting both metrics when available, as they may capture different but clinically useful predictors.

We also observed differences between score change and MID achievement across different time groups within the same questionnaire. In STAI-State, G2 (12-18 months since most recent treatment) had greater score reductions than G3 (24 months or more posttreatment)—though change in G3 was nearly significant. However, a higher proportion of patients in G3 achieved MID. Looking at our data, G3 had the highest SD of mean change, indicating greater heterogeneity in treatment response, likely due to broader range of follow-up duration or higher medical therapy rates among patients: 45.5% (n = 10) in G3 vs 22.6% (n = 6) in G2% and 20% (n = 8) in G1. This variability in state anxiety is reflected in the subgroup of patients with 2 follow-up visits: those followed for >2 years showed no significant improvement, while those with <2 years did. Differential responses to long-term medical therapy, higher rates of loss to follow-up among postsurgical patients, or the negative impact of time on state anxiety symptoms may explain this. For BDI-II we used a percentage-based MID, which likely contributed to greater alignment with mean changes, and accounted for individual variability and baseline severity, factors especially relevant when applying generic tools in disease-specific contexts.

Of note, in the cohort overall, the mean follow-up score was within the normal range for depression (<14 for BDI-II) and anxiety (<40 for STAI) (41). This is an encouraging finding that, on average, patients with treated CS may have rates of depression and anxiety that are not clinically significant. Nevertheless, as shown in Table 2, rates of antidepressant, anxiolytic, pain, and sleep medication use did not decrease with treatment but instead were stable or increased numerically, although they were not statistically significant. Similarly, case-control studies have reported higher depression and anxiety levels in patients with CS in remission when compared to healthy controls, even if the mean scores were within the normal range for both groups (15, 42). Whether this difference is clinically significant still remains inconclusive. Taken together, these results emphasize the importance of multidisciplinary pituitary centers that integrate formal psychological services, including psychiatric care and social work support, to monitor and promote long-term mental health in this population.

Inclusion of both surgically and medically treated patients may be considered a limitation to the study, since it introduces heterogeneity in the cohort. However, including patients undergoing a range of treatments allows for analysis of CS cohorts as seen in a real-world practice rather than a controlled clinical trial setting, thus providing clinically valuable information. Another limitation of the study is the use of clinically available, rather than centralized, hormone assays, again introducing variability in our data. As this cohort included patients treated at our center, their endocrine testing followed standard of care, which did not include sending samples to a centralized laboratory. The use of antidepressants in a minority of patients could potentially affect depression scores. However, this is an unavoidable reality in patients with CS, and their use was stable over time (14.9% at baseline vs 19.4% at follow-up, P = .49). Given our prospective study design, which captured each patient’s change relative to their own baseline, and adjustment for baseline scores in multivariable models, any confounding is likely limited.

Despite these limitations, our data contribute to the literature as the largest clinical practice cohort to date that prospectively characterizes QoL and mood disturbances in CS patients, before and over time after achieving biochemical control. By incorporating 3 longitudinal time points, we identified that the greatest improvements occur within the first 6 months for QoL and anxiety, while depression improves more gradually beyond that point. Another strength of our approach is the use of score change and MID as outcomes when exploring potential predictors of improvement and not remission score per se, enabling more precise tracking of each patient’s progress and supporting an individualized approach by accounting for baseline severity.

In summary, this prospective analysis of mood and Qol in a clinical practice cohort of patients with CS showed that effective treatment of hypercortisolism improves depression, anxiety, and QoL, but one-third to one-half of patients do not experience clinically meaningful improvements in these measures. We identified predictors of improvement that highlight the need for early detection of CS and treatment strategies that allow for recovery of cortisol circadian rhythm. Psychological recovery in CS is heterogeneous, domain-specific, and not always aligned with biochemical normalization. Our findings support a model of care that extends beyond endocrine remission, integrating psychosocial follow-up and individualized treatment.

Acknowledgments

We would like to thank the people with Cushing’s syndrome who contributed their valuable time to this research.

Funding

This research was funded by the National Institutes of Health/National Cancer Institute Support Grant P30 CA008748.

Filed under: Clinical trials, Cushing's, pituitary, symptoms | Tagged: depression, diabetes, hypertension, immune suppression, medication, mood, obesity, osteoporosis, post-op, surgery | Leave a comment »

Prevalence and Associated Risk Factors for Venous Thromboembolism in a Large Cohort of Patients With Cushing Disease

Posted on November 25, 2025 by MaryO

Abstract

Objective

Endogenous Cushing syndrome is associated with an intrinsic hypercoagulable state and an increased risk of venous thromboembolism (VTE). This study aimed to determine the prevalence and risk factors for VTE in a large cohort of patients with Cushing disease (CD).

Methods

A retrospective study was conducted at a tertiary care center, including 408 patients diagnosed with CD. Clinical, laboratory, hormonal, imaging, and outcome data were analyzed and compared based on the occurrence of VTE events. A control group of 323 patients with clinically nonfunctioning pituitary adenomas, all macroadenomas, who underwent similar surgical procedures, was used for comparison.

Results

VTE events were observed in 35 patients with CD (8.6%) and in 1 patient from the nonfunctioning pituitary adenoma group (0.3%; P < .001). The slight majority of VTE events (54%) occurred in the preoperative period. Logistic regression analysis identified obesity, mood disorders, supraclavicular fossa fullness, leukopenia or leukocytosis, elevated cortisol levels (both serum and 24-hour urinary cortisol), and the presence of postoperative complications (such as infections, cerebrospinal fluid leak, and vasopressin deficiency) as significant risk factors for VTE.

Conclusion

The findings of this study confirm a high prevalence of VTE events in patients with CD, irrespective of the surgical period. Risk factors associated with a higher likelihood of VTE include obesity, severity of hypercortisolism, and the occurrence of postoperative complications. In this patient population, thromboprophylaxis should be considered.

Introduction

Patients with endogenous Cushing syndrome (CS), including those with Cushing disease (CD), have a mortality rate that is 3 times higher than the general population.1, 2, 3, 4, 5 This increased mortality is primarily attributed to cardiovascular conditions (acute myocardial infarction, stroke, congestive heart failure, and venous thromboembolic [VTE] events), hyperglycemia, and infections.⁴

It is well-established that endogenous CS is intrinsically associated with VTE events,6, 7, 8, 9, 10, 11 independent of surgical procedures and metabolic disturbances. Previous studies have reported significant rates of VTE events in patients with CS, ranging from 2.6% to 18.2% (predominantly deep vein thrombosis [DVT] and pulmonary embolism [PE]),6, 7, 8, 9, 10, 11, 12 which is approximately 10 times higher than general population (DVT 0.53 to 1.62 per 1000 person-years and PE 0.39 to 1.15 per 1000 person-years).¹³

The pathophysiological mechanism underlying hypercortisolism as a thrombogenic condition is not fully understood. However, it is primarily attributed to the genomic action of cortisol, which leads to the upregulation of mRNA transcription for hemostatic factors, resulting in the activation of the coagulation cascade and impaired fibrinolytic capacity.⁶^,¹⁴ Altered hemostatic parameters are observed even when compared to high-risk groups, such as those with metabolic syndrome.15, 16, 17 The studies reported increased levels of factor VIII, factor IX, von Willebrand factor, and fibrinogen; a shortened activated partial thromboplastin time (APTT); and elevated levels of factors that reduce fibrinolysis, such as plasminogen activator inhibitor-1, thrombin-activatable fibrinolysis inhibitor, and alpha-2-antiplasmin. Some studies also describe an increase in anticoagulant factors, such as protein C, protein S, and antithrombin III, likely through a compensatory mechanism.¹⁸

VTE prevalence in CD varies widely across studies, likely due to differences in populations, CS etiologies, inclusion of other events (eg, stroke), and timing (preoperative vs postoperative).6, 7, 8, 9, 10, 11, 12

These factors, along with variability in evaluated hemostatic parameters and use of thromboprophylaxis, hinder consensus on prophylaxis.18, 19, 20

The present study aimed to identify the prevalence and risk profile of VTE events in a large cohort of patients with CD.

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Section snippets

Patients, Controls, and Study Design

A retrospective observational cohort study was conducted at a single center, including 408 patients with CD who were evaluated between 1990 and 2020. Inclusion criteria consisted of patients with a confirmed CD, defined by pituitary adenoma with immunohistochemistry positive, remission after neurosurgery, a central-to-peripheral ACTH gradient in inferior petrosal sinus sampling (IPSS), macroadenoma, or Nelson syndrome after adrenalectomy. Exclusion criteria included lack of CD confirmation,

Description of Patients and Controls

A total of 408 patients with CD were included in the study, with a predominance of females (n = 324, 79%). The median age was 32 years (range: 8-71). Most patients presented with microadenomas (n = 207, 50.7%), while 27.0% (n = 110) had pituitary macroadenomas (≥10 mm on magnetic resonance imaging [MRI]; mean diameter 17.0 ± 9.1 mm, range 10-64 mm), including 4 giant tumors (≥4 cm). Ninety-one patients (22.3%) exhibited no visible or undefined lesions on sellar MRI. IPSS was performed in 152

Discussion

Strategies for preventing VTE events in CS have been researched in several reference centers.⁶^,⁹^,¹⁰^,¹⁷^,¹⁹

European surveys reported a VTE incidence of 14.6 per 1000 person-years in CS, about 10 times higher than in the general population. In patients on prophylaxis, the incidence dropped to 10.2 versus 25.6 in those without. Events were more common with greater disease severity, but the diversity of CS types and retrospective designs has limited standardized strategies.⁶

A Pituitary Society

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Statement of Ethics

All procedures performed in this study that involved human participants were in accordance with the Ethical Standards of the Institutional National Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Ethical and Research Committees of the University of Sao Paulo Medical School approved the study, number 44044320.4.0000.0068.

Consent to Participate Statement

All participants or their legal guardians signed a written informed consent form.

Disclosure

The authors have no conflicts of interest to disclose.

Author Contributions

All authors contributed to the study conception/design and realization (A.J.G.P., R.L.B., M.B.C.C.-N., V.A.S.C., G.O.S., M.C.B.V.F., I.N.N., A.G., and M.C.M.). The first draft of the manuscript was written by A.J.G.P. and M.C.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript (A.J.G.P., R.L.B., M.B.C.C.-N., V.A.S.C., G.O.S., M.C.B.V.F., I.N.N., A.G., and M.C.M.).

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From https://www.sciencedirect.com/science/article/abs/pii/S1530891X25012534

Filed under: Cushing's, pituitary, symptoms | Tagged: macroadenomas, pituitary, venous thromboembolism (VTE) | Leave a comment »

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)

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).

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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).

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).

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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

Liang-Yu Lin https://orcid.org/0000-0003-0334-790X

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.

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