Helping others learn more about Cushing’s/Acromegaly

Posted on November 28, 2025 by MaryO

I found this article especially interesting.  This question was asked of a group of endos at an NIH conference a few years ago – if you saw someone on the street who looked like they had symptoms of fill-in-the disease, would you suggest that they see a doctor.  The general answer was no.  No surprise there.

Patients, if you see someone who looks like s/he has Cushing’s, give them a discrete card.

Spread The Word! Cushing’s Pocket Reference

Robin Writes:

This has been a concern of mine for some time. Your post spurred me on to do something I’ve been meaning to do. I’ve designed something you can print that will fit on the business cards you can buy just about anywhere (Wal-mart included). You can also print on stiff paper and cut with a paper cutter or scissors. I’ve done a front and a back.

Cushing's Pocket Reference

Here are the links:

• Front: This card is being presented by a person who cares.
• Back (The same for everyone)

This Topic on the Message Boards

~~~~~~~~~~~~~~~~~~

And now, the article from http://www.guardian.co.uk/lifeandstyle/2009/nov/03/doctor-diagnosis-stranger:

Are doctors ever really off duty?

Which potentially serious symptoms would prompt them to stop and advise a stranger on a bus?

By Lucy Atkins

Bus

Passengers on a London bus. Photograph: David Levene

A Spanish woman of 55, Montse Ventura, recently met the woman she refers to as her “guardian angel” on a bus in Barcelona. The stranger – an endocrinologist – urged Ventura to have tests for acromegaly, a rare disorder involving an excesss of growth hormone, caused by a pituitary gland tumour. How had the doctor made this unsolicited diagnosis on public transport? Apparently the unusual, spade-like shape of Ventura’s hands was a dead giveaway.

But how many off-duty doctors would feel compelled to alert strangers to symptoms they spot? “If I was sitting next to someone on a bus with a melanoma, I’d say something or I wouldn’t sleep at night,” says GP Mary McCullins. “We all have a different threshold for interfering and you don’t want to terrify people, but this is the one thing I’d urge a total stranger to see a doctor about.” So what other symptoms might prompt a doctor to approach someone on the street?

Moon face

Cushing’s syndrome is another rare hormone disorder which can be caused by a non-cancerous tumour in the pituitary gland. “A puffy, rounded ‘moon face’ is one of the classic signs of Cushing’s,” says Dr Steve Field, chair of the Royal College of GPs. “In a social situation, I wouldn’t just say, ‘You’re dangerously ill’ but I’d try to elicit information and encourage them to see a doctor.”

Different-sized pupils

When one pupil is smaller than the other, perhaps with a drooping eyelid, it could be Horner’s syndrome, a condition caused when a lung tumour begins eating into the nerves in the neck. This can be the first obvious sign of the cancer. “I’d encourage someone to get this checked out,” says Dr Simon Smith, consultant in emergency medicine at the Oxford Radcliffe Hospitals Trust. “People often have an inkling that something’s wrong, and you might spur them to get help sooner.”

Clubbing fingers

Some people are born with club-shaped fingers, but if, over time, they become “drumstick-like”, this could signify serious problems such as lung tumours, chronic lung infections or congenital heart disease. “Because it happens gradually, some people disregard clubbing,” says Smith. “But I’d say something because it can be an important symptom in many serious illnesses.”

Lumpy eyelids

Whitish yellowy lumps around the eyelids can be a sign of high cholesterol, a major factor in heart disease. Sometimes you also get a yellow circle around the iris. “I would suggest they got a cholesterol test with these symptoms,” says Smith. “They can do something about it that could save their life.”

Suntan in unlikely places

A person with Addison’s disease, a rare but chronic condition brought about by the failure of the adrenal glands, may develop what looks like a deep tan, even in non sun-exposed areas such as the palms. Other symptoms (tiredness, dizziness) can be non-specific so the condition is often advanced by the time it is diagnosed. Addison’s is treatable with lifelong steroid replacement therapy. “If someone was saying they hadn’t been in the sun but had developed a tan, alarm bells would ring and I’d probably ask how they were feeling,” says McCullins.

Trench mouth

Putrid smelling breath – even if the teeth look perfect – can be a sign of acute necrotising periodontitis. “I’d be able to tell when someone walks through the door,” says dentist Laurie Powell. “But people become accustomed to it and don’t notice.” Untreated, the condition damages the bones and connective tissue in the jaw. It can also be a sign of other diseases such as diabetes or Aids.

Filed under: adrenal, Cushing's, General Health, pituitary, Rare Diseases | Tagged: , , , , , | 2 Comments »

Prospective Assessment of Mood and Quality of Life in Cushing Syndrome Before and After Biochemical Control

Posted on November 27, 2025 by MaryO

Abstract

Context

Cushing’s syndrome (CS) impairs quality of life (QoL) and mood. Prospective real-life data on posttreatment recovery and predictors of improvement are limited.

Objectives

Evaluate changes in QoL, depression, and anxiety in patients with CS, before and after biochemical control, and identify predictors of clinically meaningful improvement.

Design and Setting

Prospective observational study at a tertiary center.

Patients

Sixty-seven patients with endogenous CS (60 pituitary, 7 adrenal) were assessed with active disease and again after achieving biochemical control through surgery and/or medication.

Outcomes

Patient-reported outcomes included CushingQoL, Beck Depression Inventory-II (BDI-II), and State-Trait Anxiety Inventory (STAI).

Results

Mean and longest follow-up was 2.3 and 11.5 years, respectively. Treatment led to improvements in mean scores across all domains (QoL: +18.2 ± 20.9, BDI-II: −6.8 ± 8.6, STAI-State: −9.6 ± 12.5, STAI-Trait: −8.6 ± 12.6; all P < .001). However, a minimal important difference was achieved in 64.6% for QoL, 67.9% for BDI-II, and 53.2% and 52.8% for STAI subscales. After multivariable analysis, QoL improvements were predicted by lower baseline body mass index, pretreatment symptoms ❤ years, postoperative hydrocortisone replacement >6 months, and normal follow-up late-night salivary cortisol (LNSC). Depression improvements were predicted by symptoms ❤ years, normal follow-up LNSC, and surgical treatment. Anxiety improvements were predicted by younger age and >6 months postoperative hydrocortisone. Depression improved more gradually than QoL and anxiety.

Conclusion

Although effective treatment improves mood and QoL in CS, clinically meaningful recovery is variable and incomplete for some patients. Our findings highlight the need to limit diagnostic delay and provide comprehensive posttreatment care that includes normalization of cortisol circadian rhythm.

Endogenous Cushing’s syndrome (CS) is a rare disorder characterized by chronic cortisol excess, most commonly due to an ACTH-secreting pituitary tumor [Cushing disease (CD)], followed by a cortisol-secreting adrenal adenoma and ectopic ACTH production due to a nonpituitary tumor (1). CS is associated with multiple comorbidities including diabetes, obesity, hypertension, immune suppression, osteoporosis, and cardiovascular disease, among others (2). Apart from these, patients face a spectrum of neuropsychiatric disturbances including depression, anxiety, mania, sleep disorders, and even psychosis. These comorbidities significantly disturb quality of life (QoL) and may persist long after treatment (3-7).

As with many rare diseases, CS remains incompletely understood, and patients experience impaired disease perception, information gaps, and isolation. In this context, patient-reported outcomes (PROs) have become useful instruments to clarify these gaps and guide patient-centered care. Disease-specific tools (CushingQoL, Tuebingen CD-25) and generic mood scales (Beck Depression Inventory, State-Trait Anxiety Inventory [STAI; including State (STAI-S) and Trait (STAI-T), Hospital Anxiety and Depression Scale] have established impairments in QoL and mood both during active disease and in remission (4, 8-11).

Although improvements are noted with treatment, recovery does not seem to be complete. Studies have reported persistently reduced QoL compared to the general population and the presence of depressive symptoms even 12 months postoperatively (4, 9). Findings regarding anxiety are less consistent: while some studies did not support the increased prevalence of anxiety in patients with active CS compared to the general population (12), others reported higher anxiety traits among patients with CS (during active disease and in remission) (13, 14) with steady improvement at 6- and 12-month follow-up (15). Clinical trials with adrenal steroidogenesis inhibitors or pasireotide demonstrated that effective biochemical control can improve QoL and depression (16-18). However, it is unclear whether these improvements are clinically significant and if patients achieve normal QoL and depression scores.

The role of PROs in assessing recovery during the treatment journey of patients with CS has not been clearly established, and QoL and mood trajectories remain unclear, largely due to small samples, limited follow-up, and cross-sectional designs. Among available prospective studies using PROs in CS, only 3 (2 evaluating pasireotide and 1 osilodrostat) reported the proportion of patients who met the minimal important difference (MID), which is the score change reflecting a clinically meaningful improvement (17-19), while others have only reported statistically significant changes in mean score, an important but possibly less clinically relevant outcome (20-22). Real-world clinical management adds further complexity: postoperative glucocorticoid replacement, potential glucocorticoid-withdrawal symptoms, and 20% to 30% recurrence rates after initial surgical “cure” all suggest that, for many patients, recovery may follow a nonlinear course. To date, no clinical practice prospective study has systematically assessed QoL and mood across multiple timepoints, compared surgical and medical strategies within a single cohort, and limited inclusion to patients who achieved biochemical remission or control for at least 6 months. Therefore, the aims of this study were to evaluate changes in QoL, depression, and anxiety in a clinical practice cohort of patients with CS before and over time after biochemical control, report achievement rates of MID, and identify predictors of clinically meaningful improvement.

Methods

Study Design

This study includes prospective data from patients enrolled in an ongoing observational cohort study, which since 2017 enrolls patients with endogenous CS at Memorial Sloan Kettering Cancer Center (MSKCC) [prior to 2017, enrollment took place at Mount Sinai (2012-2017)]. In this protocol, CS patients being treated at the MSKCC Pituitary and Skull Base Tumor Center are enrolled at any point in their treatment journey and prospectively followed over time after surgical, medical, and/or radiation treatment. At each study visit, a detailed medical history and biochemical and clinical data are collected according to standard of care. Patients also complete validated psychological and QoL assessments.

The current analysis includes a cohort of 67 patients with CS: 60 with pituitary and 7 with adrenal CS. Each patient completed a baseline (active disease) visit and at least 1 follow-up visit after achieving surgical remission or endocrine control due to medical therapy.

From the total of 67 patients, we analyzed 73 distinct baseline-to-follow-up case pairs. Six patients experienced recurrence after surgery or were inadequately controlled while on medical therapy after their initial follow-up visit and underwent a subsequent change in treatment strategy. These instances were treated as separate case pairs when needed, enabling comparison of different treatment approaches. When analyzing for a single follow-up, visits were grouped by time: group 1 (G1): 6 months, group 2 (G2): 12-18 months, and group 3 (G3): 24 or more months posttreatment. Each patient contributed to 1 or multiple groups based on the number of their study visits. For patients with multiple visits receiving different treatments throughout the current study, each follow-up visit was categorized based on time since the most recent intervention to ensure that we assessed outcomes according to the duration of biochemical control. For patients who underwent surgery, the follow-up interval was calculated from the date of surgery; for those on medical therapy, it was calculated from the start of medication. In the subanalysis comparing treatment- or demographic-related score changes, the most recent available follow-up was used in each case. At each visit patients completed at least 1 of the following: Cushing QoL, Beck Depression Inventory-II (BDI-II), or STAI-S and STAI-T.

For multiple follow-up visits during remission or treatment, 28 patients were evaluated. For this subgroup, we examined their whole trajectory over time. We then stratified this subgroup by total follow-up duration (<2 years vs ≥2 years) and assessed for significant differences between these 2 categories where applicable.

For the baseline visit, ACTH-dependent pituitary and ACTH-independent adrenal Cushing’s was confirmed according to Endocrine Society guidelines (23). Surgical remission was defined as postoperative serum cortisol <5 μg/dL (<138 nmol/L) and requirement of glucocorticoid replacement, according to the Endocrine Society’s guidelines and the Pituitary Society’s recent consensus statement (24, 25). For patients managed medically, endocrine control was defined as normalization of 24-hour urinary free cortisol (UFC) and based on clinical review and assessment by E.B.G.

The study was approved by the institutional review board at MSKCC. All subjects gave written informed consent before participation.

Outcome Measurements

Cushing QoL

The Cushing QoL is a validated disease-specific questionnaire consisting of 12 questions on a 5-point scale ranging from “always” to “never” (for 10 questions) or “very much” to “not at all” (for 2 questions). Total score ranges from 12 to 60. This is converted to a 0 to 100 scale, with 0 indicating the worst and 100 the best QoL. It evaluates physical and psychological issues and can also be scored through these 2 distinct subscales. MID is defined as an increase of ≥10.1 (26).

BDI-II

The BDI-II is a validated 21-item patient-reported questionnaire. Patients self-rate each item on a scale from 0 to 3 based on how they were feeling during the past 2 weeks. Total score ranges from 0 (best) to 63 (worst); scores from 0 to 13 indicate no or minimal depression; 14 to 19, mild depression; 20 to 28, moderate depression; and 29 to 63, severe depression. MID is defined as a 20% reduction from baseline score (27, 28).

STAI

The STAI is an instrument with 2 subscales: State anxiety (STAI-S), which reflects the present moment, and Trait anxiety (STAI-T), which assesses a stable tendency toward anxiety. Both subscales consist of 20 items scored from 0 to 3. Total scores range from 0 to 60, with higher scores indicating greater anxiety. Prior studies suggest a change of 0.5× SDs—or approximately 5 to 10 points—as a reasonable threshold for MID. In our study, we defined the MID at 7 points, based on observed SD of change at 12.5 for STAI-S and 12.6 for STAI-T (29).

In this study, all score changes from baseline to follow-up were reported as positive values to uniformly represent improvement across measures. For BDI-II and STAI where higher scores indicate worse outcomes, the direction of change was inverted for consistency.

Hormone Assays

Hormone testing was performed at either the MSKCC clinical laboratory or external laboratories (Quest Diagnostics, Labcorp, Mayo Clinic Laboratories). Plasma ACTH was measured using Tosoh immunoassay [RRID:AB_2783633; normal range (NR): 7.4-64.3 pg/mL (1.6-14.2 pmol/L); MSKCC or 6 to 50 pg/mL (1.3-11.0 pmol/L); QuestDiagnostics] or electrochemiluminescence immunoassay [RRID:AB_3678556; NR: 7.2-63.3 pg/mL (1.6-13.9 pmol/L); LabCorp, Mayo Clinic Laboratories]. Serum cortisol was measured via either immunoassay [RRID:AB_2802133; NR: 4-22 µg/dL (110-607 nmol/L); QuestDiagnostics or 7-25 µg/dL (193-690 nmol/L); Mayo Clinic Laboratories], electrochemiluminescence immunoassay [RRID:AB_2802131; NR: 6.2-19.4 µg/dL; (171-535 nmol/L); LabCorp], or liquid chromatography–tandem mass spectrometry [LC-MS/MS; NR: 5-25 µg/dL (138-690 nmol/L)]. UFC was measured using LC-MS/MS [NR: 3.5-45 µg/24 hours (9.7-124 nmol/24 hours); MSKCC, Mayo Clinic Laboratories or 3.0 to 50 µg/24 hours (8.3-138 nmol/24 hours); Quest Diagnostics, LabCorp]. Late-night salivary cortisol (LNSC) was assessed via LC-MS/MS [NR: ≤ 0.09 µg/dL (2.5 nmol/L); QuestDiagnostics, LabCorp or <100 ng/dL (27.6 nmol/L); MSKCC, Mayo Clinic Laboratories]. LNSC values were analyzed categorically (normal vs abnormal), and patients were asked to provide 2 LNSC samples on separate evenings. Abnormal LNSC was defined as at least 1 value above the upper limit of normal for the assigned laboratory.

Comorbidities

Diabetes mellitus (DM) was defined by any of the following: hemoglobin A1c (HbA1c) > 6.4%, fasting blood glucose (FBG) ≥ 126 mg/dL (7.0 mmol/L), or use of at least 1 antidiabetic medication. Pre-DM was defined as HbA1c between 5.7% and 6.4% or FBG between 100 and 125 mg/dL (5.6-6.9 mmol/L). Women taking metformin for polycystic ovary syndrome were classified as nondiabetic only if their HbA1c and FBG values both before metformin initiation and at the time of CS diagnosis remained within the normal range. Hypertension was defined as systolic blood pressure ≥ 130 mmHg, diastolic blood pressure ≥ 80 mmHg, or use of any antihypertensive medication.

Statistical Analysis

Analyses were conducted using IBM SPSS for Windows (version 29.0, IBM Corp.). Data normality was assessed by the Shapiro–Wilk test. Descriptive statistics were used for demographic and clinical characteristics. Normally distributed data were compared by Student’s t-test and nonnormally distributed variables with the Mann–Whitney U-test. Paired T-tests were conducted to study mean changes from baseline to a single follow-up visit. For categorical characteristics and the MID, we calculated the achievement rates and used Pearson’s chi-square for comparisons where applicable. For patients with more than 2 follow-up visits ANOVA (repeated measures) was applied for the trajectory of each measurement over time. To identify predictors of improvement, univariable linear regression models for score change and logistic regression for MID achievement were performed using baseline visit and longest follow-up visit for each patient. Variables with P ≤ .10 or of clinical relevance were then entered into multivariable regression models—again, linear regression for score change and logistic regression for MID achievement—where each predictor was separately evaluated, adjusting for age, sex, and baseline score. Correlation analyses were performed using Pearson or Spearman correlation coefficients for data with normal or abnormal distribution, respectively. Correlation coefficients (r) were interpreted as follows: values between 0.0 and ±0.3: weak, between ±0.3 and ±0.7: moderate, and between ±0.7 and ±1.0: strong relationships. All statistical tests were 2-sided, and results were considered significant with P ≤ .05.

Results

Study Participants

From a cohort of 226 endogenous CS and silent ACTH tumor patients enrolled in our ongoing MSKCC prospective cohort study, we identified patients who had a baseline visit with active hypercortisolism, who had at least 1 follow-up visit while in surgical remission or medical control, and who had completed at least 1 of the evaluated questionnaires correctly. After excluding patients with silent ACTH tumors, those with missing data, and follow-up visits that did not meet remission criteria, we included 67 patients (56 females, 11 males) with a mean baseline age of 42.3 ± 13.1 years. Among these patients, 60 had CD and 7 had adrenal CS.

Further patient demographic information is shown in Tables 1 and 2.

 
Table 1.

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.

 

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.

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).

 

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.

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).

 

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.

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.

 

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).

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.

 

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

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).

 

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.

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.

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.

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

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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.).

References (35)

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Delirium Induced by Rapid Titration of Osilodrostat in a Patient With Cushing’s Disease

Posted on November 21, 2025 by MaryO

Abstract

Cushing’s disease frequently presents with psychiatric symptoms such as depression, anxiety, and cognitive impairment. Osilodrostat, an 11β-hydroxylase inhibitor, is used for persistent or recurrent cases, but rapid titration may precipitate adrenal insufficiency and psychiatric complications.

We report a woman in her early 40s with a history of major depressive disorder treated with clomipramine. After transsphenoidal surgery for Cushing’s disease, she remained hypercortisolemic, and hydrocortisone replacement was continued postoperatively for safety due to unstable cortisol secretion. Cortisol secretion was unstable, with day-to-day fluctuations. Osilodrostat was initiated at 2 mg/day. Shortly thereafter, urinary free cortisol (UFC) increased, and between days 3 and 5, she developed depressive symptoms, depersonalization, and suicidal ideation. These were judged to be related to cortisol elevation, and osilodrostat was rapidly titrated, reaching 40 mg/day by day 9. Depressive symptoms improved as UFC decreased. However, from day 9, she developed delirium with fluctuating consciousness, disorientation, purposeless hyperactivity, and stereotyped speech, peaking on days 10-12. During this period, blood pressure decreased, accompanied by tachycardia and fever. Infection and metabolic abnormalities were clinically excluded. Symptoms resolved spontaneously by day 14, with amnesia for the episode, and she was discharged on day 20 without recurrence.

This case illustrates a rare clinical course where depressive symptoms during cortisol elevation and delirium during cortisol reduction occurred sequentially in the same patient following rapid osilodrostat titration. The episode suggests that abrupt cortisol fluctuations may induce psychiatric symptoms even under hydrocortisone supplementation. Clinicians should avoid rapid titration and ensure close collaboration between endocrinology and psychiatry when psychiatric symptoms arise during treatment.

Introduction

Cushing’s disease is caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma, leading to chronic hypercortisolism. In addition to physical features such as central obesity, moon face, and hypertension, psychiatric symptoms including depression, anxiety, and cognitive impairment are frequently observed [1-3]. Depression occurs in 40-60% of patients and is associated with increased suicide risk. Anxiety and cognitive impairment are also common, and psychiatric symptoms may even precede the physical manifestations. Thus, psychiatrists may encounter such patients at an early stage, and it is clinically important to consider underlying endocrine disorders [1,3]. The first-line treatment is transsphenoidal surgery, but remission is not always achieved [4].

Osilodrostat, an oral 11β-hydroxylase inhibitor, is primarily used for the treatment of persistent or recurrent Cushing’s disease. By inhibiting cortisol synthesis, it effectively lowers circulating cortisol levels, thereby improving the clinical manifestations of hypercortisolism. The phase III LINC 3 trial demonstrated its efficacy [5], but adverse events such as adrenal insufficiency and psychiatric symptoms have been reported [6-8]. Acute adrenal insufficiency can present with hypotension, tachycardia, fever, and gastrointestinal symptoms, and in severe cases with impaired consciousness or delirium [9]. To minimize these risks, gradual titration in 2-mg increments at intervals of at least two weeks is recommended [6].

For monitoring treatment efficacy, urinary free cortisol (UFC) is widely used as a reliable marker reflecting total cortisol secretion over 24 hours and serves as a standard index of disease activity and treatment response [1,2].

Case Presentation

The patient was a 43-year-old woman with a history of major depressive disorder since her early twenties, treated mainly with clomipramine. Although she experienced recurrent episodes, she was able to continue working as a clinical psychologist, with occasional sick leave. Her past history included papillary thyroid carcinoma treated surgically, followed by hypothyroidism managed with levothyroxine 75 µg/day.

In her thirties, she developed treatment-resistant hypertension. In March 2024, inferior petrosal sinus sampling confirmed Cushing’s disease. In April 2024, she underwent transsphenoidal surgery and started hydrocortisone replacement at 30 mg/day. However, hypercortisolism and elevated ACTH persisted. Cortisol levels showed marked day-to-day fluctuations rather than being consistently elevated, and replacement therapy was continued for safety.

In June 2024, she was admitted to our endocrinology department because of persistent disease activity. Psychiatry was consulted due to her psychiatric history. At admission, she was alert, cooperative, and exhibited neither depressive nor psychotic symptoms. Clomipramine was continued. Physical examination revealed a BMI of 27.5, central obesity, moon face, and violaceous striae. Blood pressure was 155/105 mmHg. Routine chemistry and thyroid function were within normal limits. Endocrinological work-up confirmed persistent hypercortisolism: the 24-hour UFC was markedly elevated (409.2 µg/day; normal < 50 µg/day), midnight serum cortisol was inappropriately high (14.3 µg/dL; normally suppressed at night), and dexamethasone suppression testing failed to suppress morning cortisol (9.7 µg/dL after 0.5 mg dexamethasone). Corticotropin-releasing hormone stimulation testing demonstrated an exaggerated ACTH response (63.6 → 105.0 pg/mL), consistent with pituitary-dependent Cushing’s disease. Postoperative brain MRI showed only expected surgical changes without new lesions.

Figure 1 illustrates the clinical course in this case. Osilodrostat was initiated at 2 mg/day on day 1. UFC unexpectedly rose thereafter, and between days 3 and 5, she developed depressed mood, depersonalization, and suicidal ideation. These psychiatric symptoms were judged to be associated with increased cortisol secretion. Antidepressant adjustment was not attempted. Instead, priority was given to endocrine control, and osilodrostat was rapidly up-titrated. Although the risk of adrenal insufficiency was considered, treatment was deemed safe under hydrocortisone supplementation. By day 9, the dose of osilodrostat reached 40 mg/day, UFC decreased, and depressive symptoms improved.

Timeline-of-clinical-events-and-interventions-in-the-present-case.
Figure 1: Timeline of clinical events and interventions in the present case.

Panel (A) shows the osilodrostat dosage and 24-hour urinary free cortisol (UFC) levels; panel (B) depicts vital signs (sBP, systolic blood pressure; BT, body temperature); and panel (C) illustrates psychiatric symptoms and the dosages of antipsychotic medications, all plotted against treatment days.

However, from day 9 onward, delirium and psychomotor agitation emerged, peaking on days 10-12. She displayed fluctuating consciousness, global disorientation, impaired attention, purposeless hyperactivity, stereotyped behaviors, and repetitive utterances of meaningless numbers. She wandered barefoot and occasionally shouted fragmented phrases such as “Say you love me.” Anxiety and insomnia were prominent, but hallucinations and self-disturbances were absent.

At that time, her vital signs showed a decline in blood pressure from 155/105 mmHg to 125/59 mmHg, a pulse rate of 110/min, and a temperature of 38.3°C. Electrolytes and glucose were normal, and no inflammatory response or other signs of infection were detected. Because of marked psychomotor agitation, imaging and EEG were not performed. Risperidone and haloperidol were given but were ineffective.

At onset, the delirium was interpreted as a manifestation of hypercortisolism, partly because it occurred during a holiday when comprehensive evaluation was not feasible. Osilodrostat was therefore not reduced. As her symptoms improved spontaneously and she remained stable under hydrocortisone supplementation, the dose was maintained. Since the delirium resolved completely and did not recur, additional imaging or EEG was not performed.

By day 14, delirium had resolved, and the patient reported amnesia for the episode. No recurrence occurred, and she was discharged on day 20 at her and her family’s request. Outpatient follow-up confirmed stable status without recurrence of delirium.

Discussion

This case illustrates an unusual clinical course in which qualitatively distinct psychiatric symptoms appeared sequentially during rapid titration of osilodrostat. The initial depressive phase coincided with a transient rise in UFC and may have been related to unstable cortisol secretion that had already been observed prior to admission. Although not sufficient for a formal diagnosis, such variability is reminiscent of cyclical Cushing’s disease [10], which has also been associated with mood fluctuations [1,3]. Previous studies have demonstrated the link between hypercortisolism and depression [1,3], and our case is consistent with these findings during the early phase of treatment.

In contrast, the subsequent delirium phase was accompanied by hypotension, tachycardia, and fever, resembling adrenal insufficiency. Similar neuropsychiatric manifestations, including delirium and psychosis, have been described in previous reports of adrenal insufficiency [8,9]. However, unlike those cases, where symptoms typically emerged after drug withdrawal, delirium in our patient developed rapidly following dose escalation. This temporal pattern suggests that even transient cortisol reductions may precipitate acute neuropsychiatric symptoms.

Taken together, these observations both align with and extend prior findings linking cortisol dysregulation to psychiatric manifestations. Our case supports previous evidence that hypercortisolism is associated with depressive symptoms [1,3], whereas hypocortisolism predisposes to delirium or psychosis [8,9]. Importantly, it also highlights a dynamic aspect of this relationship: abrupt cortisol fluctuations themselves, regardless of direction, may transiently disrupt neuroendocrine homeostasis and trigger psychiatric symptoms. This interpretation is consistent with reports of cyclical Cushing’s disease showing alternating mood states [10], but it differs in that the fluctuation here was iatrogenic and temporally linked to rapid pharmacologic titration.

Pharmacological factors may have further amplified these effects. Clomipramine and antipsychotics such as haloperidol and risperidone are known to cause confusion or agitation, particularly under hormonal stress. It is therefore plausible that psychotropic drug interactions and cortisol fluctuations acted synergistically to produce the observed neuropsychiatric manifestations.

This report has several limitations. The onset of delirium occurred during a holiday, and severe agitation precluded blood sampling for serum cortisol, ACTH testing, or therapeutic steroid administration. Thus, strict diagnostic criteria for adrenal insufficiency could not be fulfilled. Nonetheless, the clinical presentation, with hypotension, tachycardia, fever, and altered consciousness, was consistent with an adrenal insufficiency-like state. Electrolytes, glucose, and inflammatory markers remained within normal limits, making infection or metabolic causes unlikely. However, structural or neurological contributors could not be completely excluded because imaging and EEG were not performed. Although the clinical picture resembled adrenal insufficiency, true adrenal crisis was unlikely given the normal electrolyte levels, spontaneous recovery, and maintained oral intake. Therefore, this episode may be better characterized as a state of functional adrenal dysregulation rather than frank adrenal insufficiency.

Conclusions

This case highlights a rare course in which depressive symptoms during cortisol elevation and delirium during cortisol reduction occurred sequentially in the same patient following rapid titration of osilodrostat. The episode suggests that even under hydrocortisone supplementation, abrupt cortisol fluctuations can induce psychiatric symptoms. However, because some observations were paradoxical and certain assessments could not be performed during the acute phase, these interpretations should be made with caution. The episode may represent a state of functional adrenal dysregulation rather than distinct phases of hyper- or hypocortisolism.

This case offers two clinical lessons. First, osilodrostat should be titrated gradually according to established guidelines. Second, if psychiatric symptoms arise during treatment, they are best managed through close collaboration between endocrinology and psychiatry.

References

  1. Pivonello R, Simeoli C, De Martino MC, et al.: Neuropsychiatric disorders in Cushing’s syndrome. Front Neurosci. 2015, 9:129. 10.3389/fnins.2015.00129
  2. Sharma ST, Nieman LK, Feelders RA: Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015, 7:281-93. 10.2147/CLEP.S44336
  3. Sonino N, Fava GA, Raffi AR, Boscaro M, Fallo F: Clinical correlates of major depression in Cushing’s disease. Psychopathology. 1998, 31:302-6. 10.1159/000029054
  4. Fleseriu M, Auchus R, Bancos I, et al.: Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021, 9:847-75. 10.1016/S2213-8587(21)00235-7
  5. Pivonello R, Fleseriy M, Newell-Price J, et al.: Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase 3 study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020, 8:748-61. 10.1016/S2213-8587(20)30240-0
  6. U.S. Food and Drug Administration. Osilodrostat prescribing information. (2020). Accessed: October 18, 2025: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212801s000lbl.pdf.
  7. Gadelha M, Bex M, Feelders RA, et al.: Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022, 107:e2882-95. 10.1210/clinem/dgac178
  8. Ekladios C, Khoury J, Mehr S, Feghali K: Osilodrostat-induced adrenal insufficiency in a patient with Cushing’s disease. Clin Case Rep. 2022, 10:e6607. 10.1002/ccr3.6607
  9. Arlt W: Society for Endocrinology endocrine emergency guidance: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr Connect. 2016, 5:G1-3. 10.1530/EC-16-0054
  10. Meinardi JR, Wolffenbuttel BH, Dullaart RP: Cyclic Cushing’s syndrome: a clinical challenge. Eur J Endocrinol. 2007, 157:245-54. 10.1530/EJE-07-0262

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Rapid Endocrine Remission After ZAP-X Gyroscopic Radiosurgery for Cushing’s Disease

Posted on November 19, 2025 by MaryO

Abstract

Cushing’s disease is a rare but potentially life-threatening disorder caused by excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma. Although transsphenoidal surgery remains the first-line treatment, radiotherapy (RT) can provide effective local and hormonal control in patients with persistent or recurrent disease; however, endocrine remission typically occurs only after several months or even years. To our knowledge, we report the first documented case of an exceptionally rapid hormonal remission following gyroscopic stereotactic radiosurgery (SRS) using the self-shielding ZAP-X system (ZAP Surgical Inc., San Carlos, CA, USA) in a patient with recurrent Cushing’s disease. The patient received a single-fraction dose of 25 Gy prescribed to the 57% isodose line. Remarkably, ACTH and cortisol levels normalized within one month after SRS, accompanied by a striking improvement in clinical symptoms and no treatment-related toxicity. This case highlights the potential of the ZAP-X gyroscopic radiosurgery platform to achieve rapid biochemical control in ACTH-secreting pituitary adenomas and suggests that the unique dose distribution characteristics of this novel technology may contribute to accelerated endocrine responses.

Introduction

Cushing’s disease stems from an excess production of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, leading to elevated cortisol levels and symptoms resembling Cushing’s syndrome [1]. Untreated or inadequately managed hypercortisolism is associated with substantial morbidity and elevated mortality rates for patients with Cushing’s syndrome. While transsphenoidal surgery is frequently considered the preferred initial treatment approach, radiotherapy (RT) can also be contemplated, either as a standalone option for patients ineligible for surgery or as part of a multidisciplinary approach in instances where an adequate response is not attained following surgery. Conventional fractionated RT (CFRT), fractionated stereotactic radiosurgery (F-SRS), and stereotactic radiosurgery (SRS) have all been employed in the treatment of Cushing’s disease, yielding comparable disease control rates ranging from 46% to 100% [2-4]. However, unlike surgery, the response to RT may require time to manifest, and in certain instances, this duration can extend over months or years [4]. Sheehan et al. [5] indicated that the cure rate after RT in patients with Cushing’s disease was 34% in the first year, increasing to 78% by the fifth year. Although CyberKnife (Accuray Inc., Sunnyvale, CA, USA), Gamma Knife (Elekta AB, Stockholm, Sweden), and Linear Accelerator (LINAC)-based systems are all available for F-SRS and SRS, technological advancements are increasing the options. We have integrated the relatively new vault-free, frameless, gyroscopic radiosurgery system, ZAP-X (ZAP Surgical Inc., San Carlos, CA, USA), into our department and have begun using it for cranial F-SRS and SRS treatments [6,7]. To our knowledge, this report introduces the initial case of a patient diagnosed with Cushing’s disease who underwent gyroscopic SRS with the ZAP-X system, experiencing an unexpectedly rapid endocrine response following SRS.

Case Presentation

A 48-year-old female with an unremarkable medical history except for hyperlipidemia underwent investigation in 2018 due to symptoms and findings consistent with Cushing’s syndrome, leading to the detection of hypercortisolism. Her 24-hour urinary free cortisol and ACTH levels were 75 µg/day and 32 pg/mL, respectively. Serum cortisol remained unsuppressed following the 1 mg dexamethasone suppression test (DST), measuring 15.7 mcg/dL. On the magnetic resonance imaging (MRI) of the pituitary gland, a 4.5×3 mm microadenoma was detected in the left half of the adenohypophysis. Following the referral to the neurosurgery department, the patient underwent tumor resection via transsphenoidal endoscopic surgery in December 2018. The pathology resulted in a corticotroph pituitary adenoma. All her symptoms and signs related to Cushing’s disease resolved after surgery, and postoperative MRI showed no residual tumor. The patient was placed under observation without additional treatment. During follow-up visits, the patient remained asymptomatic for approximately five years.

In September 2023, the patient presented with complaints of proximal muscle weakness, irregular menstruation, and Cushingoid appearance. Upon evaluation, hypercortisolism was detected once again. On the pituitary MRI, no residual or recurrent lesion was observed. Subsequently, the patient underwent a second transsphenoidal surgery, but the pathology result did not reveal tissue consistent with a pituitary adenoma. In January 2024, upon initial presentation to our center, the patient’s ACTH level was 29.8 pg/mL, 24-hour urinary free cortisol was 442 µg/day, and serum cortisol following a 1 mg DST was 19 mcg/dL. The levels of the remaining anterior pituitary hormones were within normal ranges. The patient, who continued to exhibit symptoms consistent with Cushing’s syndrome, underwent another pituitary MRI. At this point, it was discovered that there was a recurrent lesion measuring 2×1 mm on the left half of the adenohypophysis. Pasireotide (0.6 mg once daily) was initiated for persistent hypercortisolism but was discontinued due to frequent diarrhea and a widespread allergic skin reaction. The patient was then evaluated by the multidisciplinary neuro-oncology tumor board at our hospital, which recommended RT as the next step. SRS was selected as the RT technique due to the tumor’s small size and its lack of proximity to critical structures such as the optic chiasm. A simulation computed tomography (CT) scan with a 1 mm axial slice thickness was conducted with the patient in the supine position. Intravenous contrast and a thermoplastic mask were utilized to ensure better visualization and precise immobilization. Gross tumor volume (GTV) was delineated as the macroscopic tumor volume according to the MRI, which was performed a few days before SRS. A planning target volume (PTV) was not generated for this case. The prescription dose was 2500 cGy in a single fraction to the 57% isodose (Figure 1). Dose-volume histogram (DVH) was presented in Figure 2. The SRS plan was generated with the integrated ZAP-X treatment planning software (version 1.8.58.12369), and detailed parameters of the plan were presented in Table 1.

Dose-distribution-of-the-gyroscopic-stereotactic-radiosurgery-plan-for-pituitary-adenoma
Figure 1: Dose distribution of the gyroscopic stereotactic radiosurgery plan for pituitary adenoma

The image shows the three-dimensional dose distribution generated using the ZAP-X system (ZAP Surgical Inc., San Carlos, CA, USA). The prescription dose of 25 Gy to the 57% isodose line is illustrated. A: planning computed tomography (CT) scan showing the isodose distribution around the target; B: planning magnetic resonance imaging (MRI) fused with CT for target delineation.

Dose-volume-histogram-(DVH)-of-the-gyroscopic-stereotactic-radiosurgery-plan
Figure 2: Dose-volume histogram (DVH) of the gyroscopic stereotactic radiosurgery plan

The DVH demonstrates a steep dose fall-off beyond the target margins, with minimal exposure to the optic nerves, optic chiasm, and brainstem, confirming optimal dose conformity and effective sparing of organs at risk. Within the gross tumor volume (GTV), the dose distribution is intentionally inhomogeneous, with a hot spot centrally located to ensure adequate tumor coverage and biological effectiveness.

Parameters Values
Volume (GTV) 0.13 cm3
Prescription dose & isodose 2500 cGy & 57.6%
Coverage 95.68%
Homogeneity index 1.74
New conformity index 1.48
Gradient index 3.58
GTV Dmean 3249 cGy
GTV Dmax 4340 cGy
GTV Dmin 2364 cGy
Optic chiasm (Dmax) 452 cGy
Left optic nerve (Dmax) 480 cGy
Right optic nerve (Dmax) 212 cGy
Brainstem (Dmax) 233 cGy
Number of beams 128
Number of isocenters 3
Monitor units 16.121
Collimator thicknesses 4 & 4 & 5 mm
Treatment delivery time 33 min
Table 1: Detailed parameters of the gyroscopic radiosurgery plan

Dmax: maximum dose; Dmean: mean dose; Dmin: minimum dose; GTV: gross tumor volume; mm: millimeter; min: minute

The treatment was well tolerated, and a marked biochemical response was observed one month after SRS, with ACTH and 24-hour urinary free cortisol levels decreasing to 14.2 pg/mL and 116 µg/day, respectively. Serum cortisol following a 1 mg DST was suppressed to 1.6 µg/dL. Concurrently, there was a noticeable improvement in the clinical signs and symptoms of Cushing’s disease. The patient was subsequently followed with regular clinical assessments at three-month intervals for one year. Throughout the follow-up period, ACTH, 24-hour urinary free cortisol, and post-DST serum cortisol levels remained near-normal (Figure 3). Levels of other anterior pituitary hormones were within normal limits. The patient’s biochemical parameters, including ACTH, urinary free cortisol, and serum cortisol levels before and after SRS, are summarized in Table 2. At the three-month post-SRS MRI, the lesion was found to be radiologically stable. However, the patient reported a subjective improvement in proximal muscle weakness beginning one month after treatment. No SRS-related toxicity was observed during the follow-up period, and partial regression of the Cushingoid phenotype was documented (Figure 4).

Temporal-changes-in-hormonal-parameters-following-gyroscopic-stereotactic-radiosurgery
Figure 3: Temporal changes in hormonal parameters following gyroscopic stereotactic radiosurgery

A: adrenocorticotropic hormone (ACTH) levels showed a rapid decline within the first month after treatment, remaining suppressed throughout follow-up; B: twenty-four-hour urinary free cortisol (UFC) demonstrated a similar sharp reduction after radiosurgery, indicating early biochemical response; C: serum cortisol levels after dexamethasone suppression normalized by the first month and remained within the physiological range during subsequent evaluations, consistent with sustained hormonal remission.

Parameter Unit Reference Range At Initial Diagnosis (2018) Recurrence (Jan 2024, before SRS) 1 Month After SRS 3 Months After SRS 6 Months After SRS 12 Months After SRS
ACTH pg/mL 7.2 – 63.3 32 29.8 14.2 11.0 12.5 15.0
24-hour UFC µg/day 20 – 90 75 442 116 65 55 45
Serum cortisol after 1 mg DST µg/dL < 1.8 (suppressed) 15.7 19.0 1.6 9.0 2.5 3.0
Table 2: Summary of laboratory findings before and after gyroscopic stereotactic radiosurgery

ACTH: adrenocorticotropic hormone; UFC: urinary free cortisol; DST: dexamethasone suppression test; SRS: stereotactic radiosurgery

Facial-appearance-before-and-after-gyroscopic-stereotactic-radiosurgery-(SRS)
Figure 4: Facial appearance before and after gyroscopic stereotactic radiosurgery (SRS)

The images illustrate the patient’s appearance at the time of initial diagnosis (A), before SRS (B), and after the procedure (C).

Discussion

To our knowledge, we report a rapid endocrine response observed in the first patient with Cushing’s disease treated using the ZAP-X gyroscopic radiosurgery system. Despite the patient having a significantly high 24-hour urinary free cortisol level before SRS, there was a considerable decrease within a short period after SRS.

Both surgical and medical treatments, along with RT, are viable approaches for managing pituitary adenomas. Approximately 70% of pituitary adenomas are associated with syndromes characterized by excessive hormone secretion, with the most common types producing prolactin, growth hormone, and ACTH [8]. Unlike non-secreting adenomas, the treatment goal for secreting adenomas extends beyond local tumor control to include the management of endocrinopathies. Although transsphenoidal surgery is commonly regarded as the first-line treatment, RT may also be considered, either as a primary modality in patients who are not surgical candidates or as part of a multimodal strategy when surgical outcomes are suboptimal. CFRT, F-SRS, and SRS have all been employed in treating patients with Cushing’s disease, yielding comparable disease control rates [9]. CFRT may be preferred, particularly for larger tumors or those located near organs at risk (OAR). In appropriately selected cases, advanced techniques such as F-SRS and SRS can shorten treatment duration and enable dose escalation within the tumor while providing a rapid dose fall-off outside the target volume. While RT can effectively control local tumor growth, its success in addressing endocrinopathies is typically more limited. In a systematic review, the rates of local tumor control and endocrine control for Cushing’s disease were reported as 92% and 48%, respectively [9]. Additionally, the radiation doses required for tumor control and endocrine response vary from each other [10]. While SRS doses ranging from 12 to 20 Gy typically achieve adequate local tumor control, especially in non-secreting adenomas, it has been observed that endocrine response rates improve at marginal doses around 30 Gy [11,12]. However, administering high doses can be challenging due to the presence of OAR, such as the optic apparatus, which is located in close proximity to the target volumes. It is recommended that the volume of the OAR receiving a dose of 8 Gy for the optic apparatus in SRS plans should be <0.2 cm³, and the volume receiving a dose of 10 Gy should be <0.035 cm³ [13]. Therefore, modern SRS platforms, which enable the delivery of high doses within the target volume while ensuring steep dose fall-off beyond it, offer the potential to widen the therapeutic window. In our patient, the ZAP-X gyroscopic SRS system enabled the delivery of 2500 cGy to the GTV at the 57% isodose line, while maintaining doses to OAR below recommended thresholds. Additionally, intratumoral hotspots allowed for the desired dose inhomogeneity, aligning with the core principles of SRS.

It is important to note that many patients with secreting pituitary adenomas suffer from symptoms caused by excessive hormone secretion, significantly impacting their quality of life and requiring consideration in treatment decisions [14]. In cases where patients experience severe symptoms due to elevated hormone levels, surgery may be prioritized, although various medical treatments are also viable options to consider. Pasireotide, a somatostatin analogue with multireceptor targeting, serves as an effective treatment for patients with persistent or recurring hypercortisolism post-surgery or when surgery isn’t viable. However, its tolerability is debatable due to various adverse effects such as hyperglycemia and diarrhea [15]. In our patient, despite initiating pasireotide due to persistently elevated hormone levels post-surgery, it was discontinued within less than two weeks due to intolerable adverse effects.

The biological effect of SRS on hormonal hypersecretion is believed to unfold gradually, and in some cases, this process may span months or even years. Sheehan et al. [5] reported outcomes for patients with Cushing’s disease, revealing a response rate of 34% at one year, 54% at two years, 72% at three years, and 78% at five years following SRS. In our patient, a significant decrease in 24-hour urinary free cortisol level was observed within only one month after SRS. To the best of our knowledge, this represents the most rapid endocrine response after SRS reported to date. It is important to consider, however, that the rapid hormonal normalization observed in our case may have been influenced by prior medical and surgical interventions. The patient underwent two transsphenoidal surgeries and briefly received pasireotide before radiosurgery, which could have altered tumor biology or hormonal responsiveness. Nevertheless, the close temporal relationship between ZAP-X treatment and biochemical remission strongly suggests a causal association. Potential factors contributing to this rapid endocrine response may include the administration of an effective radiation dose, such as 2500 cGy, utilization of a precise SRS technique like gyroscopic radiosurgery, and the presence of hotspots within the tumor, reaching up to 4000 cGy in a single fraction. During RT, the presence of hotspots within target volumes has been shown to be associated with increased local control for various tumor types [16,17]. Therefore, while it may not be directly attributable to hotspots, it seems possible that the underlying mechanism of the rapid endocrine response observed in our patient could be related to them. However, the short follow-up duration is the main limitation of this report.

Conclusions

To our knowledge, we report the first case of a refractory ACTH-secreting pituitary adenoma successfully treated using the vault-free ZAP-X gyroscopic SRS system. This case demonstrates that the unique design of the ZAP-X platform enables the safe delivery of a highly effective dose to the target while minimizing exposure to surrounding structures. In patients with Cushing’s disease, SRS can achieve rapid endocrine remission, although prospective studies are warranted to define the optimal dose and treatment parameters.

References

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From https://www.cureus.com/articles/430830-rapid-endocrine-remission-after-zap-x-gyroscopic-radiosurgery-for-cushings-disease-a-case-report?score_article=true#!/

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