Medic Alert Bracelets

Posted on December 16, 2025 by MaryO

Since the last topic was about Adrenal Insufficiency, it seemed that a great next topic would be about Medic Alert Bracelets.

Many doctors insist that everyone who has had pituitary or adrenal surgery have a bracelet – and some will even tell patients what they should say on them.

While I was still a patient at the NIH (National Institutes of Health) after my pituitary surgery, I was given my first bracelet along with my kit in care of adrenal crisis.  I had to learn to give myself a shot before I could go home.

Now, my endo checks mine at every visit to be sure I’m wearing my bracelet and reads it to be sure it’s still legible and checks to see what the text says.

He feels that the bracelets – and he insists that they LOOK like medic alert bracelets, not disguised as jewelry – are life savers.

I’m not so sure – I read stories on the message boards that people have gone into AI (adrenal insufficiency and no one has ever looked at their bracelet.  That was certainly the case for young Sam.  Her mom had instructions everywhere, none were heeded and the situation rapidly turned disastrous.

…We have dealt with Addison’s for 7 years; but I have handled everything. Apparently the vials of solu-cortef with step-by-step instructions hanging on the bulletin board in the kitchen, medicine cabinet and in every vehicle somehow missed his attention…  (read the whole story at survive the journey: Stars Go Blue)

A Paramedic wrote on the message boards:

I’d like to add a couple things from the perspective of a Paramedic…

A lot of us are not taught about adrenal insufficiency during our education….nor do many of us (if any at all) have a protocol to administer Injectable for AI unless we are able to contact the ER doctor for permission. So…if any of you should have an AI crisis please gently nudge your paramedic to contact the receiving physician for permission to administer the medication. I know this sounds like a lot of responsibility on the part of the patient…but you have to realize that we’re taught to recognize the most common life threats and endocrine disorders (other than diabetes) most usually do not present with life threats (we all know that as cushing’s is more recognized that this will change)…and our protocols cover the most common life threats….so while we may recognize that you are hypotensive and need fluids (IV) and are sweaty, nauseated, decreased level of responsiveness etc…we are not equipped to deal with the actual cause unless you help educate us….

Also…please don’t get angry with us….if we are having problems understanding…just gently insist that a call be made to your doctor or the receiving ED (usually not feasible for us to call your doctor since they do not come to the phone for just anybody but if you have access to them, as many cushies do, it would be great to talk to them)…

Paramedicine is evolving….someday soon, hopefully, our education will include more diagnostic skills…untill just in the past 5 years or so we were NEVER to make a diagnosis at all…just treat the symptoms!!!! So there is hope out there for futher understanding of such a critical problem for those without adrenal (or asleep adrenals) glands….

The medical alert jewerly is a life-saver and we do look for it….

So, the questions for discussion are:

  • Do you have a medical alert bracelet
  • Does your doctor check on it or suggest proper wording.
  • If you have one, has any medical staff read it during a crisis
  • And… what does yours say?

Filed under: adrenal crisis, Cushing's, pituitary | Tagged: , , , , | 15 Comments »

Cushing’s, Cancer and Other Serious Diseases

Posted on December 2, 2025 by MaryO

I was drawn to this blog post because the author mentioned that she had both Cushing’s and cancer, a kind of unusual combination.

1974 to Today: Seal it up
By Experience
I still haven’t heard what the consensus is on my aftercare: Cushing’s and Cancer. I don’t know what I will be expecting to feel like after surgery. My endocrinologist said that I should get sick after the surgery and need some kind of …
1974 to Today – http://1974totoday.blogspot.com/

I don’t usually comment on blog posts but I did on this one because we seem to share so much, disease-wise.

I said

Hi, I was drawn to your blog post because I have a blog with the same name, Cushings & Cancer.

I had my Cushing’s long ago and my cancer (kidney aka renal cell carcinoma) was 3 years ago but I sure know where you’re coming for.

My surgeon contacted my endo for the amounts of steroids during surgery (they came through the IV) then post-op, they kept cutting my dose in half until I was back down to normal.
Generally, you stress-dose after surgery if you feel like you have a flu coming on. Has your endo given you Cortef or another steroid to take for emergencies like this? Sometimes, they will give you an injectible to be faster acting.

Best of luck with the cancer surgery AND your Cushing’s.
MaryO

I sure hope that this isn’t a trend, Cushies getting cancer although I know of a couple others on the boards getting cancer.

I suppose Cushing’s doesn’t make us any more immune to other diseases but it seems like it should.

Haven’t we already “done our time”?

OTOH, I have a friend with a serious cancer (aren’t they all?)  who recently learned that she has a second, unrelated, cancer.  Makes you wonder sometimes.

What other diseases have you had in addition to your Cushing’s?

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Co-Occurrence of Endogenous and Exogenous Cushing’s Syndromes: Does “Double Cushing Syndrome” Really Exist? A Case Report

Posted on December 1, 2025 by MaryO

ABSTRACT

Double Cushing syndrome exists: exogenous steroid use can mask concurrent adrenal hypercortisolism. When symptoms persist and cortisol remains high after tapering or stopping prescribed glucocorticoids, an endogenous source is likely. Early recognition with ACTH testing, dexamethasone suppression, and adrenal imaging reduces misdiagnosis, favors timely surgery, and supports safe tapering.

1 Introduction

Cushing syndrome (CS) is a non-physiological increase in plasma glucocorticoids [1]. In most cases, the source of increased plasma glucocorticoids is caused by exogenous steroid administration, which is quite common, and about 1% of the world population is on long-term (more than 3 months) oral glucocorticoids [1, 2]. On the contrary, endogenous overproduction of glucocorticoids is rare, and annually, only two to eight per million people are diagnosed with endogenous CS [3]. The simultaneous occurrence of endogenous and exogenous CS is an exceptionally uncommon phenomenon. This dual manifestation has been reported in a few case reports, highlighting its rarity and the complex diagnostic and therapeutic challenges it poses [4, 5]. Therefore, in this study, we discuss a patient who presented with cushingoid features and was simultaneously diagnosed with both endogenous and exogenous CS or, as it is called, double CS.

2 Case Presentation

The patient was a 46-year-old male with a history of new-onset hypertension and recurrent deep vein thrombosis (DVT) who was referred to our endocrinology clinic with a chief complaint of hip pain and weakness of the lower limbs. In the past 3 years, the patient had been receiving 50 mg/day of oral prednisolone and inhalation powder of Umeclidinium and Vilanterol (62.5/25 μg/dose) because of respiratory complications that started after Coronavirus Disease 2019 (COVID-19) vaccination. After 3 months of corticosteroid treatment, he experienced DVT for the first time when he was started on rivaroxaban. However, while he was on treatment, the second DVT occurred 1 month before his referral, and therefore, rivaroxaban was changed to warfarin 5 mg/day.

The patient also mentioned weight gain with his body mass index (BMI) rising from 26 to 31 kg/m2, progressive weakness of proximal muscles, easy bruising, decreased libido, mood changes with mostly euphoric mood, and irritability during the last 2 years. Moreover, multiple osteoporotic fractures of ribs, clavicle, sternum, and lumbar vertebrae were added to his symptoms in the past 5 months. At that time, he underwent bone densitometry, which revealed osteopenia of the left hip with a Z-score of −1.3 and severe osteoporosis of total lumbar spine with a T-score of −3.9. He started taking calcium and vitamin D3 supplements and received a single injection of 750 μg/3 mL teriparatide 30 days before his referral to our center.

Two months ago, the patient gradually reduced the dosage of prednisolone by tapering the dose to 12.5 mg/day. However, a month later, the hip pain and muscle weakness worsened to such an extent that the patient was unable to walk. Due to his signs and symptoms, the patient was referred to our center for further evaluation of CS. The patient also mentioned a history of nephrolithiasis, new-onset hypertension, and lower limb edema, for which he was started on eplerenone 25 mg and furosemide 20 mg tablets once daily. In his family history, the patient’s mother had type 2 diabetes mellitus, and his two sisters had a history of nephrolithiasis. The patient did not mention any history of allergies to medications or foods. He was addicted to opium and had 15 pack-years of smoking, but he did not mention alcohol consumption.

Upon admission, the patient presented with a blood pressure of 150/83 mmHg, heart rate of 74 bpm, respiratory rate of 20/min, temperature of 36.5°C, oxygen saturation of 93%, and BMI of 31 kg/m2. He was sitting in a wheelchair due to weakness and severe pain in the hip. On physical examination, the patient showed the features of CS, including moon face, buffalo hump, central obesity, facial plethora, thin and brittle skin, acne, and purple stretch marks (striae) on the flanks (Figure 1). Proximal muscle weakness in the lower limbs with a muscle force grade of 4/5 and 3+ edema was also observed. Laboratory investigations are shown in Table 1.

Details are in the caption following the image

De-identified clinical photographs illustrating the Cushingoid phenotype. (A) Overall habitus with marked central (truncal) adiposity. (B) Rounded plethoric face (“moon facies”). (C) Relatively slender distal extremities compared with truncal obesity. (D) Dorsocervical fat pad (“buffalo hump”). (E) Upper thoracic/supraclavicular fat accumulation. (F) Protuberant abdomen with wide violaceous striae.
TABLE 1. Laboratory findings of case report.
Laboratory test Patient value (in-hospital) Patient value (follow-up) Reference range
On admission
Hemoglobin (g/dL) 16.6 13.6 13.5–17.5
Hematocrit (%) 49.5 42.1 42–52
WBC (white blood cells; 103/μL) 11.8 7.1 4.0–11.0
PLT (platelet count; 103/μL) 286 294 150–450
BUN (blood urea nitrogen; mg/dL) 10 11 7–18
Cr (creatinine; mg/dL) 0.9 0.9 0.7–1.3
ALP (alkaline phosphatase; IU/L) 1016 129 44–147
AST (aspartate aminotransferase; IU/L) 48 30 < 31
ALT (alanine transaminase; IU/L) 88 21 < 31
CRP (C-reactive protein; mg/dL) 31 3 < 5
ESR (erythrocyte sedimentation rate; mm/h) 63 24 < 15
Sodium (mEq/L) 148 141 136–145
Potassium (mEq/L) 4.8 4.3 3.5–5
FBS (fasting blood glucose; mg/dL) 97 89 80–100
TC (total cholesterol; mg/dL) 267 182 < 200
TG (triglyceride; mg/dL) 148 104 < 200
LDL (low-density lipoprotein; mg/dL) 138 98 < 130
HDL (high-density lipoprotein; mg/dL) 64 55 30–70
In hospital
Cortisol 8 a.m. fasting (μg/dL) 20.2 14.1 4.3–24.9
ACTH (adrenocorticotropic hormone; pg/mL) < 1 — 7.2–63.3
1 mg Overnight dexamethasone suppression test (μg/dL) 16.5 — < 1.8

3 Methods (Differential Diagnosis, Investigations, and Treatment)

Initially suspected of having exogenous-induced CS, the patient’s prednisolone was on hold for 3 days. Cortisol 8 a.m. fasting level, measured with Electrochemiluminescence (ECL) and adrenocorticotropic hormone (ACTH) test, was 20.2 μg/dL (585.4 nmol/L) and < 1 pg/mL, respectively. Due to the lack of suppression of serum cortisol despite not using oral glucocorticoids, the absence of adrenal insufficiency symptoms, and the fact that the patient’s symptoms remained unchanged during this period, co-occurrence of endogenous CS was suspected.

A 1 mg overnight dexamethasone suppression test was performed to confirm endogenous CS diagnosis, and the results were reported as 16.5 μg/dL (normal range < 1.8 μg/dL). Considering the possibility of an ACTH-independent CS, the patient underwent an abdominopelvic multidetector computed tomography (MDCT) of abdominopelvic with adrenal protocol, which revealed a well-defined lesion with an approximate size of 32.8 × 38.6 mm in the left adrenal gland with a radiodensity of 90 Hounsfield units and a normal right adrenal gland (Figure 2). Moreover, evidence of previous old fractures as multiple callus formation was seen involving the clavicles, sternum, bilateral ribs, ischium, and pelvic bones. Multilevel old stable compression fractures of thoracic and lumbar vertebral bodies were also present. The differential diagnoses were glucocorticoid secretory adrenal tumors, including adrenal cell carcinoma and lipid-poor adenoma. In order to rule out pheochromocytoma, 24-h urine catecholamines were measured, and the results were negative.

Details are in the caption following the image

Abdominopelvic multidetector computed tomography (MDCT) with adrenal protocol showing a well-defined lesion with an approximate size of 32.8 × 38.6 mm in the left adrenal gland; radiodensity 90 HU. (A) Transverse plane. (B) Coronal plane. (C) Sagittal plane.

Finally, the patient underwent left adrenalectomy and corticosteroid replacement therapy due to the suppression of the other adrenal gland. According to the post-operative pathological investigations, immunohistochemistry markers reported as negative chromogranin, positive melan-A and inhibin, less than 3% Ki-67 marker, and lipid-poor adrenal cortical adenoma without invasions were diagnosed (Figure 3).

Details are in the caption following the image

Immunohistochemistry of the adrenal lesion (all panels acquired with a 100× oil-immersion objective; 10× eyepiece; original magnification ×1000). (A) Positive inhibin, (B) Positive Melan-A, (C) Less than 3% Ki-67 marker, and (D) Negative chromogranin.

4 Results (Outcome and Follow-Up)

Within 3 months after the operation, the patient’s corticosteroid was tapered and then discontinued due to the normalization of the cortisone serum test (14.1 μg/dL). Proximal limb weakness and hip pain, which had deprived the patient of the ability to move, gradually improved so that he could walk easily and perform daily activities. The signs and symptoms related to CS, including the patient’s mood, skin signs, and general appearance, returned to normal. The patient has been followed up for 6 months after the surgery. The patient’s BMI decreased to 24 kg/m2, and he stopped his anti-hypertensive medications with a blood pressure of 100/60 mmHg without previously prescribed drugs. So far, the laboratory tests have been within the normal range, and he has no complaints (Table 1).

5 Discussion

The described case was diagnosed with a cortisol-producing adrenocortical adenoma accompanied by exogenous CS. CS is an uncommon clinical condition caused by prolonged exposure to increased cortisol levels, which can be due to endogenous or exogenous factors [6]. Endogenous CS is infrequent and is classified as ACTH-dependent (80% of cases) or ACTH-independent (20% of cases) [7]. In the ACTH-independent category, adrenal adenoma accounts for 60% of cases and only 12% of cases of endogenous CS [7, 8]. Exogenous CS mainly occurs due to prolonged administration of glucocorticoids, which are used to manage a broad spectrum of diseases such as inflammatory, autoimmune, or neoplastic disorders and are the most common cause of CS worldwide [9]. Multiple factors, including formulation, duration of administration, pharmacokinetics, affinity, and potency of exogenous glucocorticoids, affect the probability of exogenous CS, but all forms of glucocorticoids can induce CS [10].

In the setting of cushingoid clinical features with chronic administration of high-dose glucocorticoids, especially oral prednisolone, the probability of exogenous CS is remarkably high; therefore, CS diagnostic approaches suggest that the first step after confirmation of cortisol excess is ruling out exogenous glucocorticoid administration [7, 8, 10]. Therefore, the possibility of co-occurrence of endogenous CS with iatrogenic CS is extremely low, and the diagnosis requires high clinical suspicion [4].

Differentiating endogenous and exogenous CS based on clinical features can be challenging and far-fetched. However, a few points can help physicians distinguish between these two. First, exogenous CS symptoms tend to be more striking, while endogenous CS appears more gradually. Second, hypertension, hypokalemia, and features of androgen excess, such as acne and hirsutism, are more common in endogenous CS [4, 10]. In addition, endogenous CS should be suspected if the patient’s symptoms continue after corticosteroid discontinuation or if the serum cortisol level is high despite corticosteroid cessation. In our case, the patient had a high cortisol level despite stopping prednisolone for 3 days, and he did not have any symptoms of adrenal insufficiency despite stopping prednisolone suddenly. Consequently, it was suspected that glucocorticoids might come from an endogenous source. Because ACTH was suppressed concurrently with elevated cortisol, non-ACTH-dependent CS was suspected, and MDCT of abdominopelvic confirmed it.

So far, few similar cases of simultaneous endogenous and exogenous CS have been reported. The first case was a 23-year-old woman with juvenile idiopathic arthritis who was administered high doses of triamcinolone for 16 years [4]. The development of cushingoid features that favored endogenous CS, such as hirsutism and acne, strengthened the suspicion of endogenous CS, and a CT scan revealed hypercortisolism with a bulky and nodular left adrenal gland, and a double CS was confirmed [4]. The second case was a 66-year-old woman diagnosed with exogenous CS after consumption of Traditional Chinese medicine (TCM) for a year [5]. The cessation of TCM did not significantly improve her cushingoid features, and she developed additional CS complications, including hypertension, diabetes mellitus, and osteoporotic fractures over the next 8 years. CS workup revealed a right-sided adrenal adenoma, and after the adrenalectomy, her clinical cushingoid features markedly improved [5]. These cases suggest that exogenous and endogenous CS can exist simultaneously in the same person. Although it is very rare, it should be considered in a person who still complains of CS symptoms after corticosteroid cessation. We suggest clinicians evaluate the patients for the disappearance of exogenous CS symptoms after tapering and stopping glucocorticoids. If the symptoms remain, they should be evaluated for endogenous CS.

6 Conclusion

The co-occurrence of an endogenous CS in the setting of an exogenous CS is curious. The diagnosis is based on a high clinical suspicion. Clinicians should evaluate patients for symptom resolution after tapering and discontinuing corticosteroids. Clinical cushingoid features that do not resolve after discontinuing exogenous glucocorticoids and high cortisol levels despite discontinuing corticosteroids should raise clinicians’ suspicion of the co-occurrence of exogenous and endogenous CS.

Author Contributions

Reza Amani-Beni: investigation, methodology, writing – original draft, writing – review and editing. Atiyeh Karimi Shervedani: methodology, writing – original draft. Bahar Darouei: conceptualization, validation, writing – review and editing. Matin Noroozi: methodology, writing – original draft. Maryam Heidarpour: conceptualization, supervision, validation, writing – review and editing.

Acknowledgments

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient to publish this report, including de-identified clinical photographs, in accordance with the journal’s patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that supports the findings of this study are available on request of the corresponding author. The data are not publicly available due to privacy restrictions.

https://onlinelibrary.wiley.com/doi/10.1002/ccr3.71419

Filed under: adrenal, Cushing's, symptoms | Tagged: , , , , , , , , , , | Leave a comment »

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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The Outcome of Abnormal Glucose Metabolism and Its Clinical Features in Patients With Cushing’s Disease After Curative Surgery

Posted on July 27, 2025 by MaryO

Abstract

Objective

To investigate the outcomes of abnormal glucose metabolism and its clinical characteristics in patients with Cushing’s disease (CD) who achieved biochemical remission after surgery.

Methods

Patients diagnosed with CD who achieved biochemical remission and underwent regular follow-up after surgery were enrolled. Pre- and postoperative clinical data were collected and analyzed.

Result

151CD patients were included, of whom 80 (53 %) had preoperative abnormal glucose metabolism, including 56 with diabetes mellitus (DM) and 24 with impaired glucose regulation (IGR). At one year after surgery, 57 patients exhibited improved glucose metabolism, accompanied by a significant reduction in the homeostasis model assessment of insulin resistance (HOMA-IR). Improvements were mainly observed at 3 and 6 months after surgery. At one-year after surgery, there were 20 patients with diabetes and 16 with IGR. Compared to those with NGT, these individuals exhibited a higher prevalence of hypertension, hyperlipidemia, fatty liver, and abnormal bone metabolism.

Conclusion

CD patients demonstrated a high incidence of abnormal glucose metabolism. Notably, approximately two-thirds demonstrated improved glucose metabolism one year after curative surgery, with the greatest improvements observed at 3- to 6-month postoperative follow-up.

Introduction

Cushing’s disease (CD) is characterized by excessive endogenous cortisol production caused by pituitary adrenocorticotropic hormone adenoma and is the main cause of Cushing’s syndrome (CS). Surgical resection of the tumor is the preferred treatment. Prolonged exposure to hypercortisolism increases the risk of metabolic abnormalities, including obesity, hypertension, glucose and lipid abnormalities, osteoporosis, etc. Additionally, it significantly elevates the risk of infection, thrombosis, and hypokalemia. Abnormal glucose metabolism is a common complication of CS, with an incidence ranging from 13.1 % to 47 %[1], and diabetes is an independent risk factor for mortality in CD patients[2].
Previous clinical studies have found that metabolic abnormalities such as diabetes, hypertension, and hyperlipidemia improve in CS patients who achieve biochemical remission after surgical treatment. However, the concept of improvement in glucose metabolism, the incidence of improvement, and its related factors are inconsistent in various reports. Previous studies primarily assessed the outcome of glucose metabolism based on plasma glucose results at a single fixed follow-up time after surgery. The lack of regular follow-up data makes it difficult to clearly understand the trend of postoperative plasma glucose changes, and there are no clinical data on when glucose metabolism begins to improve or change. Therefore, this study retrospectively analyzed the follow-up data of patients with Cushing’s disease in our hospital before and after surgery, and monitored the changes in glucose metabolism, to explore the characteristics and clinical features of such changes in patients with Cushing’s disease who achieved remission from CD following surgery..

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Section snippets

Subjects

This study enrolled hospitalized patients with Cushing’s disease at Huashan Hospital, Fudan University from January 2014 to February 2020. Inclusion criteria were as follows: (1) Age ≥ 18 years; (2) diagnosis of Cushing’s disease according to the 2021 Consensus on the Diagnosis and Management of Cushing’s Disease, confirmed by pathology[3]; (3) biochemical remission after transsphenoidal surgery; (4) complete preoperative data and regular follow-up visits (including visits at 1, 3, 6, and

Patients’ baseline characteristics

A total of 168 patients with CD were admitted to Huashan Hospital from 2014 to 2020 with pathological diagnosis and regular postoperative follow-up; however, 17 patients were excluded due to no biochemical remission after surgery or relapse during follow-up (Fig. 1). Ultimately, 151 patients (32 males and 119 females) were included in this study. The baseline characteristics of the included patients were shown in Table 1. There were 80 cases (53 %) complicated with abnormal glucose metabolism

Discussion

CD was a rare disease often associated with abnormal glucose metabolism. Based on medical history and OGTT screening, we found that over half (53 %) of CD patients exhibited abnormal glucose metabolism before surgery, with 37.1 % being diagnosed with diabetes. Previous studies have shown that the prevalence of diabetes in CS patients ranged from 13.1 % to 47 %, and most reports falling between 35 % and 45 %, which is consistent with our findings [1,12,13]. However, it should be noted that CD

Author contributions

Q.C. analyzed the data and wrote the manuscript. Q.C., Y.L., X.L., Q.S., W.S., and H.Z. collected the data. Y.L., Z.Z., M.H., S.Z., and H.Y. recruited patients. J.Z., Y.S., and S.Z. conducted the study design and revised the manuscript. All authors read and approved the final manuscript.

CRediT authorship contribution statement

Qiaoli Cui: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yujia Li: Writing – original draft, Investigation, Formal analysis, Data curation. Xiaoyu Liu: Investigation, Formal analysis, Data curation. Quanya Sun: Investigation, Data curation. Wanwan Sun: Investigation, Formal analysis, Data curation. Min He: Project administration, Investigation. Jie Zhang: Writing – review & editing, Supervision, Funding

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We are indebted to the patients who participated in this study and all the doctors who contributed to the diagnosis and treatment of these patients. This work was supported by grants from the Multidisciplinary Diagnosis and Treatment (MDT) demonstration project in research hospitals (Shanghai Medical College, Fudan University, NO: DGF501069/017), National Science and Technology Major Project (NO: 2023ZD0506800，2023ZD0506802), 2023 Ningbo International Cooperation Program (NO: 2023H024).

References (16)

  • R.N. Clayton et al.

    Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study

    Lancet Diabetes Endocrinol

    (2016)
  • M. Fleseriu et al.

    Consensus on diagnosis and management of Cushing’s disease: a guideline update

    Lancet Diabetes Endocrinol

    (2021)
  • C. Scaroni et al.

    Glucose Metabolism Abnormalities in Cushing Syndrome: from Molecular Basis to Clinical Management

    Endocr Rev

    (2017)
  • C. Dai et al.

    Surgical outcome of transsphenoidal surgery in Cushing’s disease: a case series of 1106 patients from a single center over 30 years

    Endocrine

    (2022)
  • E. Valassi et al.

    Delayed remission after transsphenoidal surgery in patients with Cushing’s disease

    J Clin Endocrinol Metab

    (2010)
  • X. He et al.

    Glucocorticoid Withdrawal Syndrome following treatment of endogenous Cushing Syndrome

    (2022)
  • E.V. Varlamov et al.

    Perioperative Management of a Patient with Cushing Disease

    J Endocr Soc

    (2022)
  • Q. Cui et al.

    The recovery time of hypothalamic-pituitary-adrenal axis after curative surgery in Cushing’s disease and its related factor

    Endocrine

    (2023)
There are more references available in the full text version of this article.

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