Cushing’s Disease | CushieBlog

Postoperative Initiation of Thromboprophylaxis in Patients with Cushing’s Disease (PIT-CD):

Posted on June 28, 2025 by MaryO

Abstract

Background

Pituitary surgical intervention remains the preferred treatment for Cushing’s disease (CD) while postoperative venous thromboembolism (VTE) is a significant risk. Whether to prescribe pharmacological thromboprophylaxis presents a clinical dilemma, balancing the benefit of reducing VTE risk with the potential for increasing hemorrhagic events in these patients. Currently, strong evidence and established protocols for routine pharmacological thromboprophylaxis in this population are lacking. Therefore, a randomized, controlled trial is warranted to determine the efficacy and safety of combined pharmacological and mechanical thromboprophylaxis in reducing postoperative VTE risk in patients with CD.

Methods

This investigator-initiated, multi-center, prospective, randomized, open-label trial with blinded outcome assessment aims to evaluate the efficacy and safety of combined pharmacological and mechanical thromboprophylaxis compared to mechanical thromboprophylaxis alone in postoperative patients with CD. A total of 206 patients diagnosed with CD who will be undergoing transsphenoidal surgery will be randomized in a 1:1 ratio to receive either combined pharmacological and mechanical thromboprophylaxis (intervention) or mechanical thromboprophylaxis only (control). The primary outcome is the risk of VTE within 12 weeks following surgery.

Discussion

This trial represents a significant milestone in evaluating the efficacy of combined pharmacological and mechanical prophylaxis in reducing VTE events in postoperative CD patients.

Trial registration

ClinicalTrials.gov Identifier: NCT04486859, first registered on 22 July 2020.

Peer Review reports

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}	Postoperative Initiation of Thromboprophylaxis in patients with Cushing’s Disease (PIT-CD): a randomized control trial
Trial registration {2a and 2b}	ClinicalTrials.gov Identifier: NCT04486859, first registered on 22 July 2020 WHO Trial Registration Data Set (Supplement)
Protocol version {3}	Date: 1 July 2021, Version 5.0
Funding {4}	The trial is supported by Clinical Research Plan of SHDC (SHDC2020CR2004A).
Author details {5a}	Nidan Qiao, Min He, Zhao Ye, Wei Gong, Zengyi Ma, Yifei Yu, Zhenyu Wu, Lin Lu, Huijuan Zhu, Yong Yao, Zhihong Liao, Haijun Wang, Huiwen Tan, Bowen Cai, Yerong Yu, Ting Lei, Yan Yang, Changzhen Jiang, Xiaofang Yan, Yanying Guo, Yuan Chen, Hongying Ye, Yongfei Wang, Nicholas A. Tritos, Zhaoyun Zhang, Yao Zhao.
Name and contact information for the trial sponsor {5b}	Investigator initiated trial, principal investigators, post-production correspondence: Yao Zhao (YZ), Department of Neurosurgery, Huashan Hospital, Fudan University, 12 mid Wulumuqi Rd, Shanghai 200040, China. Email: zhaoyao@huashan.org.cn Zhaoyun Zhang (ZZ), Department of Endocrinology, Huashan Hospital, Fudan University, 12 mid Wulumuqi Rd, Shanghai 200040, China. Email: zhangzhaoyun@fudan.edu.cn
Role of sponsor {5c}	The trial sponsor holds responsibility for all key elements of the trial’s execution, including its design, data collection, management, analysis, interpretation of results, and reporting. An independent Data Safety Monitoring Board monitors data safety and participant protection to ensure the trial’s integrity and the safety of participants.

Introduction

Background and rationale {6a}

Cushing’s disease (CD) is characterized by hypercortisolism resulting from an adrenocorticotropic hormone-secreting pituitary adenoma [1]. Tumor-directed surgical intervention remains the preferred treatment for this condition. Patients with Cushing’s disease commonly experience a hypercoagulable state due to activation of the coagulation system [2], suppression of anticoagulation and fibrinolytic pathways, and enhanced platelet activation, significantly increasing their risk of venous thromboembolism (VTE). Postoperative VTE risk is further exacerbated by factors such as intravenous medications, blood loss, and prolonged bed rest. Multiple studies report postoperative VTE risks in patients with CD ranging from 3 to 20% [2,3,4,5].

The Endocrine Society and Pituitary Society recommends considering perioperative thromboprophylaxis as a strategy to reduce VTE risk in patients with CD [1, 6]. However, this recommendation was based on a single study that investigated perioperative prophylactic anticoagulation in patients with Cushing’s syndrome [7]. The study was limited by its small sample size, single-center nature, and retrospective design. Crucial details such as the optimal timing for initiation, choice of anticoagulant, and duration of therapy were not established. Recent surveys of European and US centers indicate that thromboprophylaxis protocols are not routinely employed, and there is considerable heterogeneity in prophylactic practices across centers [8, 9].

The primary risk associated with thromboprophylaxis is postoperative hemorrhage. In patients with CD, although the risk of bleeding is significantly lower than after a typical craniotomy, complications such as intrasellar hemorrhage and nasal bleeding may still occur. Due to its retrospective nature, the aforementioned study cannot conclusively determine whether the benefits of thromboprophylaxis outweigh its risks. Consequently, guidelines from hematology and neurosurgical societies have concluded that the current evidence is insufficient to support a standardized VTE prophylaxis regimen for neurosurgical patients [10,11,12]. Nevertheless, both the American Society of Hematology and European guidelines suggest that a combination of pharmacological and mechanical prophylaxis may be justified for higher-risk subgroups [10, 13].

Objectives {7}

Due to conflicting recommendations and lack of a definitive study to determine whether the benefits outweigh the risks regarding the use of pharmacological antithrombotic prophylaxis in patients with CD following pituitary surgery, we initiated this study, called Postoperative Initiation of Thromboprophylaxis in Patients with Cushing’s Disease (PIT-CD). The aim of this study is to evaluate whether the combined use of pharmacological and mechanical prophylaxis reduces VTE events compared to mechanical prophylaxis alone in postoperative CD patients.

Trial design {8}

Our hypothesis was that pharmacological prophylaxis in combination with intermittent pneumatic compression would be superior to intermittent pneumatic compression alone.

The PIT-CD study is an open-label, multicenter, prospective, randomized clinical trial with open-label treatment designed to assess the efficacy of combined pharmacological and mechanical prophylaxis compared to mechanical prophylaxis alone. Patients are randomized in a 1:1 ratio. The patient flow is illustrated in Fig. 1.

Methods: participants, interventions and outcomes

Study setting {9}

This study was initiated in tertiary centers across China with expertise in managing patients with CD. Currently, seven centers (see Supplements) are actively recruiting patients for the study.

Eligibility criteria {10}

Inclusion criteria

Patients are eligible for inclusion if they meet the following criteria:

1.Age between 18 and 65 years (inclusive)
2.Diagnosed with CD and scheduled to undergo transsphenoidal surgery
3.Either newly diagnosed or recurrent disease

A diagnosis of CD is confirmed based on the following criteria:

A.Twenty-four-hour urine free cortisol > upper normal boundary and low-dose dexamethasone suppression test (overnight or over two days): serum cortisol > 1.8 µg/dL
B.8 AM serum adrenocorticotropic hormone > 20 pg/mL
C.High-dose dexamethasone suppression test: serum cortisol or 24-h urine cortisol suppression > 50%
D.Inferior petrosal sinus sampling (IPSS) indicates elevated adrenocorticotropic hormone central gradient consistent with secretion from a central source

Patients are diagnosed with CD if both criteria A and B are met, in addition to either C or D. In patients with tumors smaller than 6 mm on MRI, IPSS indicating a central source is essential.

Exclusion criteria

Patients will be excluded from the study if they meet any of the following criteria:

1.History of VTE before surgery or within 24 h post-surgery
2.Acute bacterial endocarditis
3.Major bleeding events within the previous 6 months
4.Thrombocytopenia
5.Active gastrointestinal ulcers
6.History of stroke
7.High risk of bleeding due to clotting abnormalities
8.Participation in other clinical trials within the last three months
9.Contraindications to rivaroxaban (e.g., renal dysfunction with eGFR < 50 mL/min)
10.Presence of malignant diseases
11.Severe mental or neurological disorders
12.Presence of intracranial vascular abnormalities
13.Contraindications to mechanical prophylactic anticoagulation
14.Pregnancy
15.Any other condition that researchers deem inappropriate for study participation (e.g., oral contraceptive use, history of thrombophilia)

Who will obtain informed consent? {26a}

Patients with CD are provided with detailed information about the clinical trial, including known and foreseeable risks and potential adverse events. Investigators are required to thoroughly explain these details to the patients or their guardians if the patients lack capacity to provide consent. Following a comprehensive explanation and discussion, both the patients or their guardians and the investigators sign and date the informed consent form.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

N/A. Biological specimens are unnecessary in this trial. Participant data was not intended to be included in any other ancillary studies.

Interventions

Explanation for the choice of comparators {6b}

Participants in the control arm of the study will be required to use a limb compression system twice daily, for 30 min each session, from the 2nd to the 7th day post-surgery. The intermittent pneumatic compression devices are the standard of care in the prevention deep vein thrombosis in many literatures [14, 15].

Intervention description {11a}

Participants in the intervention arm of the study will be required to use the same limb compression system, also for 30 min twice daily from the 2nd to the 7th day post-surgery. Additionally, participants will receive subcutaneous injections of low molecular weight heparin (4000 IU) once daily from the 2nd to the 4th day post-surgery. Starting on the 5th day and continuing through the 28th day post-surgery, participants will take oral rivaroxaban tablets (10 mg) once daily.

Criteria for discontinuing or modifying allocated interventions {11b}

Participants have the right to withdraw their consent at any time without providing a reason, thereby terminating their participation in the study. Any withdrawal and the reasons, if known, will be documented. Criteria for premature termination include the following: occurrence of the primary outcome (patients will still be monitored for safety for 12 weeks), failure to meet inclusion criteria, fulfillment of exclusion criteria, or loss of contact.

Strategies to improve adherence to interventions {11c}

Several strategies will be employed to maintain adherence to interventions in this trial. Participants will receive thorough preoperative education on the importance of pharmacological and mechanical prophylaxis in preventing VTE if they are assigned to the intervention arm or the importance of mechanical prophylaxis if they are assigned to the control arm. Detailed instructions on the use of the limb compression system and administration of rivaroxaban will be provided. Pill counts will be performed to document adherence in the intervention group.

Relevant concomitant care permitted or prohibited during the trial {11d}

N/A. Participants in both groups will receive treatment according to the current standard-of-care.

Provisions for post-trial care {30}

Participants experiencing adverse events will be followed until the events are resolved. Other participants will be regularly followed in accordance with clinical routine clinical practice. Participants in the trial are compensated in the event of trial-associated harms.

Outcomes {12}

Primary outcome

The primary outcome of the study is the risk of venous thromboembolism (VTE) within 12 weeks after surgery. VTE is defined as either deep vein thrombosis (DVT) or pulmonary embolism (PE), regardless of whether the cases are symptomatic or asymptomatic.

Secondary outcomes

The secondary outcomes are as follows: (1) risk of DVT within 12 weeks after surgery; (2) risk of PE within 12 weeks after surgery; (3) risk of symptomatic DVT, symptomatic PE, or symptomatic VTE within 12 weeks after surgery; (4) risk of VTE-associated mortality within 12 weeks after surgery; (5) risk of all-cause mortality within 12 weeks after surgery.

“Symptomatic” is defined as the presence of one or more of the following symptoms attributed to VTE: pain or swelling in the affected leg; chest pain, dyspnea, or decreased oxygen saturation.

Safety outcomes

Safety outcomes include the following: (1) major bleeding; (2) minor bleeding; (3) hemorrhage-associated surgery; (4) hemorrhage-associated readmission; (5) coagulation disorders (APTT or INR > 2.5 normal upper boundary); (6) thrombocytopenia; (7) increase in liver function tests.

Major bleeding is defined according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis [16]. This includes fatal bleeding; bleeding that is symptomatic and occurs in a critical area or organ; extrasurgical site bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to transfusion of two or more units of whole blood or red cells; surgical site bleeding that requires a second intervention.

Participant timeline {13}

A schema of all trial procedures and clinical visits is summarized in Table 1.

Table 1 Schedule of enrolment, interventions and assessments

Full size table

Sample size {14}

Our estimates are based on a retrospective study examining the effects of preventive anticoagulation during the perioperative period in Cushing syndrome [7]. This study reported that the risk of postoperative VTE was lower in patients receiving preventive anticoagulants (6%) compared to those who did not (20%). Therefore, we assume that the risk of the primary outcome in the control group is 20%, while in the intervention group it is 5% within 12 weeks. Based on these assumptions, we calculated the required sample size for each group to be is 93 using PASS software, with an alpha level of 0.05 and a power of 0.9. Accounting for an estimated 10% dropout rate, the total number of patients required is 206.

Recruitment {15}

Clinical investigators will receive training on communicating with potential patients and their relatives, documenting screening logs, and other standard operating procedures during the kick-off meeting at each participating center. All centers will recruit patients competitively, and recruitment progress will be monitored to track the process. The estimated recruitment rate is 8 to 10 patients per month, with an expected recruitment period of 2 years.

Assignment of interventions: allocation

Sequence generation {16a}

The randomization procedure is computer- and web-based, and is stratified by age (≤ 35 years old vs. > 35 years old), sex (female vs. male) and disease duration (≤ 2 years vs. > 2 years).

Concealment mechanism {16b}

Participants are randomized using a web-based randomization system (edc.fudan.edu.cn). This system maintains allocation concealment by withholding the randomization code until screening is complete.

Implementation {16c}

Investigators will enroll participants, with the stratified block algorithms generating a random allocation sequence. Participant assignment through the randomization system is not subject to influence by the clinical investigators.

Assignment of interventions: blinding

Who will be blinded {17a}

This is an open-label trial, meaning that both the treating physicians and the participants are aware of the treatment allocation. However, a separate group of clinical outcome assessors (Clinical Event Committee, CEC), who are blinded to the treatment allocation, will determine the clinical outcomes. Similarly, lower limbs ultrasound and pulmonary computed tomography angiography (CTA) assessments will be adjudicated by an Independent Review Committee (IRC) that is blinded to the treatment allocation. Statisticians remain blinded to treatment allocation prior to the final analysis, and the interim analyses will be conducted by a separate team from the one undertaking the final analysis.

Procedure for unblinding if needed {17b}

N/A. The design is open label.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Deep vein thrombosis (DVT) will be assessed using bilateral lower limb ultrasound. Asymptomatic participants will undergo evaluation at prespecified intervals (day 4, day 7, week 4, and week 12 post-intervention), while symptomatic individuals will receive immediate imaging upon presentation of clinical manifestations such as unilateral or bilateral lower extremity edema or pain. Pulmonary embolism (PE) screening will be performed via pulmonary computed tomography angiography (CTA) at day 7 in asymptomatic cases, with expedited assessment triggered by acute symptoms (e.g., chest pain, dyspnea) or radiographic evidence of DVT detected during lower limb ultrasonography. These events will be adjudicated by an Independent Review Committee (IRC). A CEC will be convened to assess other outcomes.

Plans to promote participant retention and complete follow-up {18b}

The initial intervention for participants takes place during the patient’s inpatient stay, during which researchers will provide detailed information about the required procedures. Participants will undergo routine follow-up at 4 weeks and 12 weeks post-surgery, with VTE-related follow-up arranged during these routine visits. Transportation and examination expenses for follow-up visits are reimbursable.

Data of those who discontinue will also be documented.

Data management {19}

Data will be kept, both on paper and in electronic databases, for at least 5 years. Data will be entered by clinical investigators using electronic case report forms (eCRFs) on a web-based platform (http://crip-ec.shdc.org.cn). The investigators will be introduced to the platform and trained in data entry during the initial kick-off meeting before the recruitment of the first study participant. Access to the study database will be restricted to authorized clinical investigators, who will use a personal ID and password to gain entry.

Confidentiality {27}

When adding a new participant to the database, identifying data (e.g., Chinese name) are entered on a form that is printed but not saved on the server. On this form, participants will be represented by a unique ID. The printed form is kept in a locked space accessible only to the principal investigator and may be used to unblind personal data if necessary.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

N/A. There will be no biological specimens collected.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary analysis will be conducted on the full analysis data set, adhering to the intention-to-treat principle, which includes all patients randomized in the study. Generalized linear models (GLMs) with binomial distribution will be employed to analyze primary, secondary, and safety outcomes. Treatment effects for these outcomes will be quantified as risk differences (RDs) with corresponding 95% confidence intervals (CIs). Additionally, odds ratios with 95% confidence intervals will be calculated using a logistic regression model, and hazard ratios with 95% confidence intervals will be calculated using a Cox Proportional model.

Safety analyses will be based on all randomized patients who have received the study treatment. The risk and percentages of adverse events (AEs) and serious adverse events (SAEs) will be summarized by treatment group. Instances of subject death will be summarized and listed. All analyses will be performed using the SAS system, version 9.4.

Interim analyses {21b}

The Data Safety Monitoring Board (DSMB) plans to convene the interim analysis meeting after randomization and 12-week follow-up visits are completed for 103 participants. The significance level for interim analysis (primary outcome) is set at 0.001 according to the Haybittle–Peto boundary principle.

Based on these analyses, the DSMB will advise the steering committee on whether the randomized comparisons in this study have demonstrated a clear benefit of the intervention. If the p-values from the interim analysis for both groups are less than 0.001, recruitment will be halted, and the study will meet the criteria for early termination. If the p-values are greater than or equal to 0.001, recruitment will continue until the planned sample size is achieved, with the final analysis significance level set at 0.049.

Methods for additional analyses (e.g., subgroup analyses) {20b}

For both primary and secondary outcomes, pre-specified subgroup analyses will be conducted based on sex, age, disease duration, and magnitude of urine free cortisol elevation.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The primary analysis will be conducted on the intention-to-treat data set, which includes all randomized patients and is based on the treatment arm to which they were assigned, regardless of the therapy they actually received. A per-protocol analysis will also be performed to account for non-adherence. If appropriate, multiple imputation will be used to address any missing data in the dataset. The prespecified statistical analysis plan (SAP), developed by independent biostatisticians blinded to treatment allocation, will be prospectively registered on ClinicalTrials.gov prior to database lock.

Plans to give access to the full protocol, participant-level data and statistical code {31c}

The trial was prospectively registered in ClinicalTrials.gov with the Identifier NCT04486859. Updates to reflect significant protocol amendments will be submitted. The statistical analysis protocol will also be updated prior to database locking. The datasets and statistical code are available from the corresponding author upon reasonable request.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

The trial steering committee is composed of four Chinese experts and two international experts from outside of China. Investigators in participating centers are required to attend a training course during a kick-off event organized by the principal investigator. Each investigator must confirm that they have been properly introduced to trial-specific procedures. An IRC will adjudicate primary outcomes. An independent CEC will be responsible for ensuring high-quality outcomes and minimizing inconsistencies or bias in the clinical trial data.

Composition of the data monitoring committee, its role and reporting structure {21a}

The Data Safety Monitoring Board (DSMB) consists of three members, including one statistician. The DSMB will regularly receive blinded statistical reports and monitor serious adverse events throughout the trial to assess patient safety and determine if the trial should be terminated prematurely due to safety concerns.

An initial DSMB meeting will be conducted to ensure that DSMB members fully understand the research protocol, review and approve the DSMB charter, assess the monitoring plans for safety and efficacy data, and discuss the statistical methods, including stopping rules. A second DSMB meeting will be conducted to review the interim analysis. The interim analyses and the treatment allocation data will be provided by an independent trial statistician and provided confidentially to the DSMB chairman. An ad hoc DSMB meeting may be convened by either the principal investigators or the DSMB if imminent safety issues arise during the trial.

Adverse event reporting and harms {22}

Adverse events (AEs) and serious adverse events (SAEs) are defined according to the ICH GCP guidelines. All AEs and SAEs reported by study participants or observed by investigators within the study period must be documented in the eCRF and reported to the DSMB. Additionally, SAEs must be reported to the IRB.

Anticipated adverse events, including both major and minor bleeding events (e.g., epistaxis necessitating readmission), as well as coagulation disorders, thrombocytopenia, and elevated liver function tests, will be prospectively monitored in all trial participants. Unanticipated adverse events (not pre-specified in Section {12}) will be captured through spontaneous reporting. All adverse event data will be classified and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to ensure consistency. For reporting, we will disclose all protocol-specified adverse events from Section {12}, alongside any unanticipated events higher than Grade 3.

Frequency and plans for auditing the trial conduct {23}

The trial conduct will be regularly audited to ensure compliance with the study protocol and Good Clinical Practice guidelines. Audits will be conducted by independent monitors from Shanghai Shenkang Hospital Developing Centers. These audits will involve reviewing study documentation, informed consent forms, source data verification, and adherence to the protocol. Audits will also assess data entry accuracy and the overall management of the trial. The frequency of these audits will be determined based on the recruitment rate, safety concerns, and previous audit findings.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Any modifications to the study protocol will require protocol amendments, which will be promptly submitted for approval to the Institutional Review Board. These changes will only be implemented after receiving approval from the Institutional Review Board. Once approved, ClinicalTrials.gov will be updated to reflect any significant changes. If necessary, protocol training to implement the amendments will be provided by the study team to participating centers.

Dissemination plans {31a}

After database closure and data analysis, the trial statistician will prepare a report detailing the main study results. Following this, a meeting of the investigators will be convened to discuss the findings before drafting a scientific manuscript for peer review and publication in a major scientific journal. Additionally, efforts will be made to present the results at key international conferences of neuroendocrine societies.

Discussion

This trial represents a significant milestone in evaluating the efficacy of combined pharmacological and mechanical prophylaxis in reducing VTE events in postoperative CD patients. To date, no similar randomized controlled trials have addressed this specific clinical question.

Transnasal transsphenoidal pituitary tumor resection is the preferred surgical approach for patients with CD. Compared to craniotomy, transsphenoidal surgery has a significantly lower risk of bleeding. The published literature indicates a bleeding risk of 0.02% following transsphenoidal surgery [17], whereas the incidence of intracranial hemorrhage after craniotomy ranges from 1% to 1.5% [18]. Therefore, for clinical practicality and safety, this study will exclusively include patients undergoing transsphenoidal resection.

Early meta-analyses indicated that low molecular weight heparin is generally safer, with a relatively lower bleeding risk compared to rivaroxaban, particularly when used for thrombosis prevention after hip and knee replacement surgeries [19]. However, recent studies have shown that rivaroxaban may have no significant difference in major bleeding and non-major bleeding risks compared to enoxaparin in thromboprophylaxis following non-major orthopedic surgeries of the lower limbs [20]. Given the risk of postoperative bleeding and the potential bleeding side effects of oral medications, LMWH was chosen for initial postoperative treatment because of its relatively lower bleeding risk. As patients prepare for discharge, the more convenient oral medication was selected for ongoing prophylaxis.

Patients who develop early VTE on the first day after surgery or despite anticoagulant use will be included in a further post hoc analysis. This will help identify risk factors for VTE. This analysis will aim to determine why VTE occurred despite anticoagulant use and explore whether specific factors, such as hypertension, diabetes, body mass index, or disease duration, are associated with increased risk. Based on our findings, recommendations may include earlier initiation of prophylaxis, dosage adjustments, or extended duration of treatment for high-risk patients.

Trial status

This protocol is based on trial protocol version 5.0, dated July 1, 2021. The first patient was enrolled in December 2020, and the final patient is expected to be enrolled by the end of 2024. While the original plan anticipated completing recruitment by December 2022, the COVID-19 pandemic significantly impacted many districts and cities in China, leading to lockdowns that have severely delayed the implementation and recruitment for this trial.

Data availability {29}

Data will be made available from the corresponding author upon reasonable request.

Abbreviations

CD:: Cushing’s disease
VTE:: Venous thromboembolism
DVT:: Deep vein thrombosis
PE:: Pulmonary embolism
CEC:: Clinical events committee
IRC:: Independent Review Committee
CTA:: Computed tomography angiography
eCRFs:: Electronic case report forms
AE:: Adverse events
SAE:: Severe adverse events
DSMB:: Data Safety Monitoring Board

References

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From https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-025-08923-6

Filed under: Cushing's, pituitary, Treatments | Tagged: Cushing's Disease, pituitary, post-op, thromboprophylaxis | Leave a comment »

Challenges of Cushing’s Syndrome and Bariatric Surgery

Posted on June 26, 2025 by MaryO

Abstract

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

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

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

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

hypercortisolism, adrenocorticotropic hormone, Cushing syndrome, obesity, bariatric surgery

Subject

Bariatric Surgery

Issue Section:

Case Report

Filed under: Cushing's, pituitary, Treatments | Tagged: bariatric surgery, Cushing's Disease, ketoconazole, liver failure, obesity, Pituitary adenoma, Transsphenoidal surgery | Leave a comment »

A Prospective Trial With Ketoconazole Induction Therapy and Octreotide Maintenance Treatment for Cushing’s Disease

Posted on June 21, 2025 by MaryO

Abstract

Context and Objective

The lack of efficacy of somatostatin receptor subtype 2 (SST2) preferring somatostatin analogs in patients with Cushing’s disease (CD) results from a downregulating effect of hypercortisolism on SST2 expression. Our objective is to evaluate the efficacy of a strategy with sequential treatment of ketoconazole to reduce cortisol levels and potentially restore SST2 expression followed by octreotide as maintenance therapy in patients with CD.

Patients and Design

Fourteen adult patients with CD were prospectively enrolled. Patients started with ketoconazole. Once cortisol levels were normalized, octreotide was initiated. After 2 months of combination therapy, patients were maintained on octreotide monotherapy until the end of the study period (9 months). Treatment success was defined by normalization of urinary free cortisol (UFC) levels.

Results

Ketoconazole was able to normalize UFC levels in 11 (79%) patients. Octreotide effectively sustained normal levels of UFC in 3 patients (27%) (responders). Four patients (36%) showed a partial response. The remaining 4 (36%) patients developed hypercortisolism as soon as ketoconazole was stopped (nonresponders). Octreotide responders had lower UFC levels at baseline when compared to partial responders and nonresponders (1.40 ± 0.07 vs 2.05 ± 0.20 UNL, P = 0.083). SST2 mRNA was highly expressed in adenomas of 2 responder patients (0.803 and 0.216 copies per hprt).

Conclusion

Sequential treatment with ketoconazole to lower cortisol levels followed by octreotide to maintain biochemical remission according to UFC may be effective in a subset of patients with mild CD, suggesting that cortisol-mediated suppression of SST2 expression is a reversible process.

Cushing’s disease, ketoconazole, octreotide, somatostatin receptor, cortisol

Subject

Pituitary and Neuroendocrinology

Issue Section:

Clinical Research Article

Transsphenoidal adenomectomy is the first-line treatment of Cushing’s disease (CD) [1-3]. Medical therapy can be used as an adjunctive preoperative treatment or in persistent or recurrent disease [2, 4, 5]. Pharmacological treatment of CD can be divided into 3 approaches: pituitary-directed therapy, steroids synthesis inhibitors, and glucocorticoid receptor antagonists [4]. Because of limited efficacy and side effects, a combination of drugs is often necessary to achieve biochemical control [2, 5-8].

Steroid synthesis inhibitors are often used as a first-line medical treatment modality. Ketoconazole and metyrapone can normalize cortisol production in about 50% to 60% of patients, whereas the recently introduced steroidogenic enzyme inhibitor osilodrostat has an efficacy of up to 80% [9-11]. Pharmacotherapy targeting the corticotroph tumor itself may be a more rational approach since it exerts effects at the cause of the disease [2, 5, 12]. The most commonly used drugs in this category are cabergoline, a dopamine agonist, and pasireotide, a second-generation somatostatin analog [2, 3, 13]. Cabergoline inhibits ACTH secretion through agonism of the dopamine type 2 receptor, expressed in the majority of corticotroph tumors [14, 15]. However, cabergoline is able to normalize the cortisol secretion in less than half the patients, and a substantial number of patients escape from treatment [4, 8, 16, 17]. Several small studies show promising effects of cabergoline combined with ketoconazole [7, 8]. Pasireotide exhibits high-affinity binding to somatostatin receptor subtype (SST) 5, which is the SST expressed at the highest level in corticotroph pituitary adenomas. Pasireotide shows moderate efficacy in normalizing cortisol levels in a subset of patients with mild to moderate hypercortisolism, with hyperglycemia as an important side effect [13, 18, 19].

Octreotide, a somatostatin analog with high binding affinity to SST2, was shown to lower ACTH production in patients with corticotroph tumor progression following bilateral adrenalectomy but was unsuccessful in patients with active CD [20, 21]. Table 1 provides an overview of the clinical studies using octreotide in CD. Tumoral pituitary corticotroph cells express about 5 to 10 times higher SST5 compared to SST2, which may explain the reduced efficacy of octreotide compared to pasireotide in inhibiting ACTH secretion in primary cultures of human corticotroph tumors as well as in vivo [13, 28]. This is explained by selective suppressive effects of high cortisol concentrations in active CD on SST2 expression, resulting in an absent treatment response to octreotide [13, 29, 30]. Hence, it may be hypothesized that normalizing or lowering cortisol levels in patients with CD can result in a reciprocal increase in SST2 expression by corticotroph tumor cells. Under such conditions, the use of octreotide could play a potential role in CD management based on its safer toxicity profile compared to pasireotide [31].

Table 1.

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Literature review: octreotide treatment in patients with Cushing’s disease

Study	n	Maximal octreotide dose	Response criteria	Full response	Partial response	No response	Maximal treatment duration
Invitti et al, 1990 [22]	3	1200 µg/day	UFC		1	2	49 days
Lamberts et al, 1989 [20]	3	100 µg (single injection)	Serum cortisol			3	Trial 12 hours
Arregger et al, 2012 [21]	2	Oct-lar (20 mg/month)	UFC			2	4 months
Woodhouse et al, 1993 [23]	4	100-500 µg (every 8 hours)	Serum cortisol			4	Trial 24-72 hours
El-Shafie et al, 2015 [24]	6	100 µg (every 8 hours)	Serum cortisol			6	Trial 72 hours
Ambrosi et al, 1990 [25]	4	100 µg (single injection)	Serum cortisol			4	Trial 7 hours (CRH stimulus)
Stalla et al, 1994 [26]	5	100 µg (30 and 180 minutes)	serum cortisol			5	Trial 400 minutes (CRH stimulus)
Vignati et al, 1996 [27]	3	100 µg (single injection)/300 µg/day	Serum cortisol/UFC		1	2	Trial 8 hours/75 days
Total	30			0	2 (7%)	28

Abbreviation: Oct-lar, long acting repeatable octreotide; UFC, urinary free cortisol.

We previously demonstrated that in corticotroph adenomas obtained from CD patients who were in biochemical remission before surgery, induced by medical treatment, SST2 mRNA expression was significantly higher compared to corticotroph tumor tissue from patients with hypercortisolism at the time of operation [32]. In fact, SST2 mRNA levels in adenomas from these normocortisolemic patients were comparable to those of GH-producing adenomas, which are usually responsive to SST2-preferring somatostatin analogs [32]. In this pilot study, we, therefore, aim to evaluate the clinical efficacy of a sequential regimen with ketoconazole induction therapy to reduce cortisol levels in CD and potentially restore SST2 expression at the level of the corticotroph adenoma, followed by octreotide treatment to reduce ACTH secretion.

Methods

Study Population

Adult patients with recently diagnosed treatment-naïve CD or with persistent or recurrent hypercortisolism after transsphenoidal surgery were eligible for enrollment. Patients already on medical treatment for CD were included only after a drug washout period of 4 weeks and following confirmation of hypercortisolism. Exclusion criteria included elevated liver enzymes, renal insufficiency, history of pituitary radiotherapy, symptomatic cholelithiasis, and pregnancy.

The study protocol was approved by the ethical committees of the participating centers. All patients gave their written informed consent. The trial was registered by the Dutch Trial Register (nr. NL37105.078.11).

Diagnostic Workup of CD

Upon clinical evidence of CD, the diagnosis was biochemically established by elevated 24-h urinary free cortisol (UFC) concentrations (3 samples), failure in suppressing plasma cortisol after 1 mg of dexamethasone, and increased midnight saliva cortisol levels. ACTH dependency was defined on the basis of normal to high ACTH plasma levels. Additionally, plasma cortisol diurnal rhythm was assessed with measurement at 9 Am, 5 Pm, 10 Pm, and midnight. Once a diagnosis of ACTH-dependent hypercortisolism was confirmed, magnetic resonance imaging was performed to detect a pituitary tumor. In the absence of a lesion, or a lesion of less than 6 mm, bilateral inferior petrosal sinus sampling was performed to confirm central ACTH overproduction.

Drug Regimen Protocol

After inclusion, patients were followed monthly for up to 9 months. All patients started with ketoconazole; the initial dose depended on the severity of hypercortisolism, with 600 mg per day for mild hypercortisolism [UFC ≤ 1.5 times the upper limit of normal (ULN)] and 800 mg per day for a higher level of hypercortisolism (UFC >1.5 times the ULN). (Fig. 1). If necessary, the dose of ketoconazole could be uptitrated to 1200 mg per day after 2 months to achieve biochemical remission according to UFC excretion. Once UFC levels were normalized, long acting repeatable (LAR) octreotide treatment was initiated at a dose of 20 mg every 4 weeks. If UFC concentrations remained normal after 2 months of combined therapy (ketoconazole plus octreotide), ketoconazole was discontinued and patients were maintained on octreotide monotherapy until the end of the study period. If the UFC level (mean of 2 samples) was increased above the ULN, the octreotide dose was increased from 20 to 30 mg every 4 weeks. This may have occurred earlier, while octreotide was still combined with ketoconazole, or later, on octreotide monotherapy.

Figure 1.

Study protocol. If UFC excretion (mean of 2 collections) increases again (above the ULN) under octreotide/ketoconazole combination therapy or octreotide monotherapy (20 mg every 4 weeks), the octreotide dosage will be increased to 30 mg every 4 weeks.

Abbreviations: CAB, cabergoline; UFC, urinary free cortisol.; ULN, upper limit of normal.

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Response to octreotide was defined as the maintenance of normal UFC levels after ketoconazole discontinuation until the end of the study period, while partial response was defined as normal UFC levels maintained for at least 1 month after ketoconazole discontinuation and/or a >50% decrease of UFC levels at the last follow-up visit compared to the baseline value. Lack of response to octreotide was defined by the inability of octreotide to maintain normal UFC levels after discontinuation of ketoconazole. In this respect, a persistently elevated UFC concentration for 2 consecutive months was considered as treatment failure, after which the study protocol was terminated earlier, before the study period of 9 months. In case of biochemical remission, octreotide monotherapy was maintained until the end of the study period of 9 months, after which octreotide could be continued or replaced by another treatment modality.

In case ketoconazole therapy for 3 months failed to control cortisol production, a different treatment regimen was introduced. Cabergoline instead of octreotide was added to ketoconazole in an attempt to achieve biochemical control. Cabergoline, starting at 0.5 mg every other day, was gradually increased up to 1 and eventually 2 mg every other day, as needed, and ketoconazole was gradually reduced from 1200 to 400 mg per day within 4 weeks. If successful, this combination treatment (ketoconazole and cabergoline) was maintained until the end of the study period.

Side-effects Monitoring

Between the visits, patients were contacted by telephone for monitoring of adverse events. At each visit, laboratory evaluation was performed of pituitary function, hematology, blood chemistry, liver enzymes and renal function, hemoglobin A1c, glucose, and insulin levels.

During treatment with ketoconazole, concentrations of liver enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, and gamma glutamyl transferase) were regularly measured. In case of an increase in liver enzymes (>4x ULN), the ketoconazole dose was decreased by 50%. If dose reduction did not lead to normalization of liver enzyme concentrations, ketoconazole was stopped with termination of the study. If relative adrenal insufficiency developed with steroid withdrawal complaints, the cortisol-lowering medication was stopped and eventually restarted at a lower dose. In case of absolute adrenal insufficiency hydrocortisone replacement therapy was started in addition to interruption of study medication. Electrocardiography was performed at baseline and at follow-up visits.

Assessment of Treatment Efficacy

Twenty-four-hour urinary cortisol excretion (2 collections) was measured at each monthly visit. Plasma cortisol diurnal rhythm (CDR) was assessed at baseline and at 3, 6, and 9 months. Recovery of CDR was defined by a serum cortisol concentration at midnight of less than 67% of that at 0900 hours (Pm/am ratio >0.67) [33]. Biochemical remission was defined as normalization of UFC concentrations, ie, the mean of 2 collections below the ULN.

Assessment of Clinical Parameters

Physical examination including measurement of blood pressure, heart rate, weight, height, body mass index, and waist circumference was performed at baseline and assessed monthly. Additionally, a routine laboratory examination, including full blood count, electrolytes, creatinine, blood urea nitrogen, liver enzymes, lipase, amylase, bilirubin, glucose, insulin, and glycosylated hemoglobin, was conducted at each visit.

Quantitative PCR

Eleven patients underwent surgery after the study period. In 4 patients, sufficient corticotroph pituitary adenoma tissue was available to assess SST2 mRNA expression. To assess the purity of the samples, GH mRNA relative to pro-opiomelanocortin (POMC) mRNA was calculated. Only samples with a GH/POMC ratio less than 10% for normal pituitary tissue were used in this analysis [34].

Quantitative PCR was performed following a protocol as previously described [35]. Briefly, poly A⁺ mRNA was isolated from corticotroph adenoma cells using oligo (dT)₂₅ dynabeads (Invitrogen, Breda, The Netherlands). Subsequently, 23 µL H₂O was added for elution, and 10 µL of poly A mRNA was used to synthesize cDNA using a commercial RevertAid First Strand cDNA synthesis kit (Thermo Scientific, Breda, The Netherlands). The assay for RT-qPCR was performed using Taqman Universal PCR mastermix (Applied Biosystems, Breda, The Netherlands) supplemented with sst2 forward and reverse primers and probes. (Supplementary Table S1) [36]. The expression of SST2 mRNA was determined relative to the hypoxanthine phosphoribosyltransferase (HPRT) housekeeping gene.

Immunohistochemistry

From 4 patients, representative adenoma tissue was available for immunohistochemistry (IHC). IHC was performed on 4-µm thick whole slide sections from formalin-fixed paraffin-embedded tissue blocks, on a validated and accredited automated slide stainer (Benchmark ULTRA System, VENTANA Medical Systems, Tucson, AZ, USA) according to the manufacturer’s instructions. Briefly, following deparaffinization and heat-induced antigen retrieval, the tissue samples were incubated with rabbit anti-SST2A antibody (Biotrend; NB-49-015-1ML, dilution 1:25) for 32 minutes at 37°C, followed by Optiview detection (#760-500 and #760-700, Ventana). Counterstain was done by hematoxylin II for 12 minutes and a blue coloring reagent for 8 minutes. Each tissue slide contained a fragment of formalin-fixed paraffin-embedded pancreatic tissue as an on-slide positive control. A semiquantitative immunoreactivity scoring system (IRS) was used by 2 independent investigators to assess SST2 immunostaining. IRS is based on 2 scales: first, the fraction of positive-stained cells > 80%, 51% to 80%, 10% to 50%, <10% and 0 and second, the intensity of immunostaining as strong, moderate, weak, and negative. The product of these 2 factors was used to calculate the IRS final score (range from 0 to 12) [37].

Statistical Analysis

Given the proof-of-concept nature of the present study, no formal statistical power and sample size calculations were performed. Patients were grouped according to the level of response to treatment in responders, partial responders, and nonresponders. For statistical comparisons, partial responders and nonresponders were grouped together and compared to responders.

Continuous variables are expressed as mean ± SEM. Categorical variables are expressed as counts and percentages. For comparisons between groups, Student’s t-test was used. For paired comparisons (baseline vs follow-up), paired t-test was used. Statistical significance was set at P < .05. GraphPad Prism version 5.01 was used for statistical analysis.

Results

Study Population

Sixteen patients with CD were prospectively enrolled, of whom 14 started the study protocol. One patient withdrew at baseline, and 1 patient was excluded because of pseudo-Cushing’s syndrome due to a psychiatric disorder. The mean age was 48.6 years; 64% (n = 9) were female; 86% (n = 12) were newly diagnosed and naïve in treatment; and 71% (n = 10) presented with mild hypercortisolism, defined as a UFC level <2 times the ULN, at baseline. The average treatment duration in this study was 6 months. Hypertension was the most common comorbidity (93%), followed by diabetes mellitus (50%) and dyslipidemia (43%). The majority of patients (79%, n = 11) exhibited a flattened cortisol rhythm with persistently high levels of plasma cortisol throughout the day (Table 2).

Table 2.

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Baseline demographic and clinical characteristics of the study population

Characteristics	Population (n = 14)
Female sex, no. (%)	9 (64.28)
Age at study, mean (median), years	48.64 (48)
Status of CD, no. (%)
Newly diagnosed	12 (86)
Persistent	1 (7.1)
Recurrent	1 (7.1)
UFC level, times ULN, mean (median)	1.84 (1.76)
ACTH, mean, pg/mL	10.23 ± 6.8
Severity of CD, no. (%)^a
Mild	10 (71.42)
Moderate	4 (28.57)
Severe	0 (0)
Disturbed circadian diurnal rhythm, no. (%)^b	11 (78.6)
Months of study completed, mean (median)	6.43 (7)
MRI, no. (%)
Nonvisible adenomas	3 (21)
Microadenomas	9 (64)
Macroadenomas	2 (14)
Comorbidities, no. (%)
Diabetes	7 (50)
Hypertension	13 (92.85)
Heart/vascular disease	3 (21.42)
Dyslipidemia	6 (42.85)
Obesity	5 (35.71)

Abbreviations: CD, Cushing’s disease; MRI, magnetic resonance imaging; UFC, urinary free cortisol; ULN, upper limit of normal.

^aMild hypercortisolism was defined as UFC level less than 2 times the ULN, moderate hypercortisolism as UFC level between 2 and 5 times the ULN, and severe hypercortisolism as UFC level above 5 times the ULN.

^bDisturbed circadian diurnal rhythm was defined as serum cortisol concentration at 2400 hours/serum cortisol concentration at 0900 hours (Pm/am ratio) above 0.67 [33].

Ketoconazole Treatment

All patients started treatment with ketoconazole monotherapy at a dose of 600 to 800 mg per day depending on baseline UFC level. In 11 patients (79%), normal values of UFC were achieved after 1 or 2 months of treatment. One patient developed symptoms of hypocortisolism with nausea, vomiting, and dizziness. Ketoconazole was discontinued and restarted a week later with a lower dose (200 mg/day), also resulting in normal UFC levels. Another patient discontinued the treatment in the first week because of clinical intolerance. A transient increase in liver enzymes was observed in 5 patients (39%), but no patient had to stop the study protocol because of liver toxicity. Most patients who achieved normal values of UFC (n = 11 out of 14; 79%) lost weight (mean weight loss = 7 ± 4.6 kg) during ketoconazole treatment. No abnormalities were found on electrocardiography during treatment with ketoconazole and octreotide mono- or combination therapy.

According to the study protocol, octreotide (20 mg every 28 days) was added to ketoconazole in the 11 patients who achieved normal cortisoluria. With the combination treatment, 9 patients (82%) sustained normal UFC levels. In 2 patients with recurrent hypercortisolism, increasing the dose of octreotide from 20 to 30 mg/4 weeks normalized UFC levels. Ketoconazole treatment was then stopped, and all patients continued octreotide (20 or 30 mg per month) monotherapy.

Octreotide Treatment

Octreotide monotherapy maintained normal levels of UFC in 3 patients (27%) (responders, Fig 2A). Four (36%) other patients showed a partial response to octreotide (Fig. 2B shows the responses in the individual patients). In 3 of these patients, normal UFC levels were sustained for 1 or 2 months following discontinuation of ketoconazole, and in the other partial responder, the UFC levels at the last follow-up visit had decreased by 57% compared to the baseline levels. The remaining 4 patients developed hypercortisolism as soon as ketoconazole was stopped (nonresponders, Fig. 2C). Responders to octreotide monotherapy had lower UFC levels at baseline when compared to partial responders and nonresponders, with a trend to statistical significance (P = .083) (Table 3). No differences were observed between the 2 groups (responders vs partial responders and nonresponders) related to age, sex, number of comorbidities, and baseline and follow-up cortisol diurnal rhythm (Table 3).

Figure 2.

Levels of UFC under sequential KTC and Octr treatment. (A) Octr responders (n = 3, patients 7, 8, 13). All patients started treatment with KTC monotherapy at a dose of 600 mg per day. Subsequently, Octr (20 mg every 28 days) was added to the treatment regimen. After 2 months of combined therapy, KTC was discontinued. In 2 cases, this led to a gradual increase in UFC levels requiring a higher dose of Octr (30 mg/month). All 3 patients then remained in remission under Octr monotherapy. (B) Octr partial responders (n = 4, patients 5, 10, 14, and 16). The patients followed different treatment schedules. Patient 5 started with KTC monotherapy followed by 1 month of combined treatment (KTC + Octr) and subsequent Octr monotherapy. Under Octr treatment, the patient was in remission for 2 months. Patient 10 started with KTC monotherapy, followed by 3 months of combined treatment (KTC + Octr) because of an escape of the treatment requiring an increase in the dose of Octr from 20 to 30 mg/month and subsequently went on Octr 30 mg/month monotherapy. Under Octr treatment, the patient was in remission for 2 months. Patient 14 started with KTC monotherapy, achieving remission of the disease in the second month, followed by 2 months of combined treatment (KTC + Octr) and subsequent Octr monotherapy. Under Octr treatment, the patient was in remission for 1 month. The last patient (no. 16) started with KTC monotherapy, achieving a normal cortisol level, followed by combined treatment and subsequent Octr monotherapy. UFC levels at follow-up had decreased by 57% compared to baseline. (C) Octr nonresponders (n = 4, patients 2, 4, 12, and 15). All patients started treatment with KTC monotherapy at a dose of 600 to 800 mg per day. Subsequently, Octr was added to the treatment for 2 months. KTC was discontinued in the third month, which led to a gradual increase in UFC levels. Despite the increased dose of Octr (30 mg/month), all patients failed to maintain disease remission. Data represent mean ± SEM.

Abbreviations: KTC, ketoconazole; Octr, octreotide; UFC, urinary free cortisol (24 hours).

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Table 3.

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Clinical characteristics of responder compared to partial/nonresponder patients

Characteristics	Responders	Partial/nonresponders	P-value
No. of patients	3	8
Age (years) (mean ± SEM)	39.67 ± 6.88	52 ± 4.30	.163
Number of comborbidities (mean ± SEM)	2.33 ± 0.33	2.38 ± 0.57	.967
Initial UFC (mean ± SEM)	1.40 ± 0.07	2.05 ± 0.20	.083
Baseline CDR, Pm/am ratio (mean ± SEM)	0.85 ± 0.14	0.91 ± 0.10	.752
Follow-up CDR, Pm/am ratio (mean ± SEM)	0.61 ± 0.17	0.81 ± 0.11	.43

Abbreviations: CDR, circadian diurnal rhythm; UFC, urinary free cortisol.

Responders

Individual patient numbers in brackets refer to the patient numbers in Figs. 2 and 3 and Supplementary Table S1 [36]. In 2 (patients 8 and 13) of the 3 responders, UFC levels gradually increased after discontinuation of ketoconazole treatment, requiring an increase in the octreotide dose from 20 to 30 mg that ultimately induced sustained normalization of UFC levels (Fig. 2A). Overall, among responders, the mean UFC levels at baseline was 1.40 ± 0.07 times the ULN and 0.62 ± 0.19 times the ULN at follow-up at the end of the study period (P = .09). Regarding the CDR, 2 patients (no. 7 and 13) at baseline exhibited disturbed CDR, and in 1 patient (no. 8), it was slightly altered. Full recovery of the CDR at follow-up was observed in 2 patients (no. 7 and 8), including the 1 (no. 8) with discrete alteration, while in another (patient 13), there was a partial recovery. On average, patients exhibited a numerically lower cortisol Pm/am ratio at follow-up as compared to baseline (baseline Pm/am ratios 0.86 ± 0.14 and 0.62 ± 0.09 at follow-up, P = .15). In terms of clinical features of CD, 2 (no. 7 and 13) of the 3 patients showed improvement in weight, waist circumference, and systolic and diastolic blood pressure during the treatment period, with the remaining patient (no. 8) showing a worsening of these parameters (Supplementary Table S2) [36].

Figure 3.

mRNA expression level of SST2 in corticotroph tumors. SST2 mRNA expression in responder (n = 2), partial responder (n = 1), and nonresponder (n = 1). SST2 mRNA expression level in somatotroph tumors (filled bar) was included for comparison (n = 10; ratio over HPRT, mean ± SEM: 0.27 ± 0.08), as published previously by our group using a similar protocol [32].

Abbreviations: HPRT, hypoxanthine phosphoribosyltransferase; non-resp, nonresponder; partial resp, partial responder; pt, patient.

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Partial Responders

Among the 4 patients (patients 5, 10, 14, and 16) with a partial response to octreotide monotherapy, UFC levels were sustained for 1 to 2 months in 3 patients with a gradual increase after ketoconazole discontinuation (Fig. 2B). In another patient, UFC levels at follow-up had decreased by at least 50% compared to baseline, albeit still at abnormal levels (Fig. 2B, patient 16). For all 4 patients, the mean UFC at baseline was 2.32 ± 0.33 and 2.18 ± 0.34 times the ULN at follow-up at the end of the study period (P = .83). No significant change in CDR was observed, with a plasma cortisol Pm/am ratio of 0.99 ± 0.14 at baseline compared to 0.94 ± 0.07 at follow-up. Three out of 4 partial responders (patients 5, 14, and 16) showed improvement in weight and waist circumference at follow-up. Blood pressure control improved in 2 patients (no. 14 and 16). In 1 patient (no. 5), blood pressure was normal at baseline and remained unchanged throughout the study period. One partial responder (patient 10) showed worsening of all these clinical parameters (Supplementary Table S2) [36].

Nonresponders

In the nonresponder group, UFC increased in all 4 patients (no. 2, 4, 12, and 15) immediately after ketoconazole discontinuation despite increased doses of octreotide up to 30 mg/month (Fig. 2C). In 3 (patients 2, 4, and 15) out of 4 nonresponders, UFC levels were unchanged during follow-up compared to baseline. In 1 patient (no. 12), the UFC level at follow-up was doubled compared to baseline. The cortisol Pm/am ratio did not improve during treatment (P = .20). Three (patients 2, 4, and 12) of 4 nonresponders lost weight at follow-up. Blood pressure remained unchanged in all 4 patients (Supplementary Table S2) [36].

Ketoconazole-Cabergoline Combination Treatment

Finally, in 2 patients with baseline UFC levels of 2.31 and 1.55 ULN, hypercortisolism could not be controlled with ketoconazole monotherapy. The addition of cabergoline did not result in a normalization of UFC. Patients remained uncontrolled during the study period, and an alternative treatment modality was implemented.

In Vitro Studies

Corticotroph tumor tissue was available for the assessment of SST2 mRNA in 4 patients: 2 responders (patients 8 and 13), 1 partial responder (patient 5), and 1 nonresponder (patient 15) (Fig. 3) who underwent transsphenoidal surgery after the trial. Of these, all but 1 patient had normalized UFC levels before surgery. The nonresponder (patient 15) had slightly elevated UFC (1.22 times the ULN). SST2 mRNA expression was highest in the tissue of the 2 responder patients (patient 8, relative expression 0.803 and patient 13, 0.216 normalized to hprt). It is important to highlight that these SST2 mRNA expression values (0.803 and 0.216) were comparable to SST2 expression in GH-secreting tumors (mean of 0.27 ± 0.30, normalized to hprt, n = 10) as we have previously published [32]. Corticotroph tumor tissue of the partial responder (patient 5) also expressed SST2, albeit at a lower level than the 2 responder patients (0.146 normalized to hprt). SST2 expression was low in corticotroph tumor tissue of the nonresponder (0.08 normalized to hprt).

Paraffin-embedded tissue was available for IHC in 4 patients, of which 1 was a responder (patient 7), 2 were partial responders (patients 5 and 10), and 1 was a nonresponder (patient 15). Both mRNA and protein expression were available and assessed for 2 patients who were a partial responder (patient 5) and a nonresponder (patient 15). Before surgery, UFC levels were slightly elevated in 1 partial responder (patient 10) and the nonresponder (patient 15; UFC 1.17 and 1.22 times the ULN, respectively) but normal in the other patients. The IRS for SST2 was higher in the responder compared to the nonresponder patient (IRS 4 and 0, respectively) (Fig. 4). One partial responder (patient 5) had a high IRS for SST2 (IRS 8) with more than 80% of the adenoma cells staining positive for SST2. The second partial responder (patient 10) had no adenoma cells staining positive for SST2 (IRS 0). This patient had slightly elevated UFC levels prior to surgery (described earlier).

Figure 4.

Representative immunohistochemistry of SST2 in corticotroph tumors. Representative photomicrographs of SST2 immunohistochemical staining in formalin-fixed paraffin-embedded tissue sections of 4 corticotroph adenomas of patients included in this study. (A) Adenoma patient 7 (responder) (IRS 4); (B) adenoma patient 5 (partial responder) (IRS 8); (C) adenoma patient 10 (partial responder) (IRS 0); (D) adenoma patient 15 (nonresponder) (IRS 0). (E) Positive control SST2 staining in human pancreatic islets. In most corticotroph adenomas, small blood vessels were SST2 positive (see arrows in panel D).

Abbreviation: IRS, immunoreactivity scoring system.

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Discussion

Selective downregulation of SST2 expression in corticotroph tumor cells by high cortisol levels is thought to impair the efficacy of SST2 preferring somatostatin analogs in the treatment of CD [29, 30]. The transcriptional regulation of SST2 is modulated by glucocorticoids (GC), as it was demonstrated that GC inhibits SST2 promoter activity through GC-responsive elements, resulting in a decrease in SST2 expression [29]. Because this process may be reversible, we examined in a prospective pilot study whether lowering cortisol production with ketoconazole can enhance inhibition of ACTH secretion via subsequent treatment with octreotide in patients with CD. The existing literature of clinical studies using octreotide in CD consisted of case reports (Table 1). This is the first prospective study to evaluate the clinical efficacy of octreotide in CD. Our data may indicate that the sequential strategy treatment with ketoconazole and octreotide can induce sustained biochemical remission in a subset of patients with mild CD.

Several in vivo and in vitro studies provide evidence that SST2 expression in corticotroph tumor cells can recover after suppression of cortisol production or antagonizing cortisol action [27, 33, 38, 39]. As mentioned, we previously demonstrated that SST2 expression is higher in corticotroph tumors of patients operated under controlled cortisol production compared to those of patients with hypercortisolism at the time of operation [32]. However, SST2 expression was only significantly higher at the mRNA level but not at the protein level. Evidence that SST2 expression can also increase at the protein level was provided by case descriptions of 2 patients with ectopic ACTH syndrome [38]. In both patients, the source of ectopic ACTH production was initially occult with negative somatostatin receptor scintigraphy. However, after treatment with mifepristone, antagonizing the effects of cortisol at a tissue level, somatostatin receptor scintigraphy could identify a neuroendocrine lung tumor in both patients, indicating SST2 protein expression. This was recently confirmed by similar observations in 2 patients with an ACTH-producing neuroendocrine lung tumor [39]. In addition, in vitro studies with the selective GC receptor antagonist relacorilant demonstrated the reversal of GC-induced downregulation of SST2 expression in the AtT20 corticotroph tumor cell line [39]. Finally, indirect evidence comes from an older preliminary study in which a further decrease in UFC levels was observed in 4 ketoconazole-treated patients after the addition of octreotide. The ketoconazole dose could subsequently be reduced in 3 patients [27].

The sequential treatment with ketoconazole and octreotide in the present study led to a partial or complete response in 7 out of 11 patients, with 3 of them exhibiting sustained biochemical remission throughout the follow-up period. At the first stage, ketoconazole monotherapy led to normal UFC levels in 79% of the cases. This efficacy is higher compared to previous studies that reported an efficacy of approximately 50% to 60% and can be explained by the fact that the majority of patients had mild hypercortisolism [11, 40-43]. Additionally, the clinical benefit of controlling cortisol secretion was evident with the observed weight loss in most responders to ketoconazole.

Subsequently, the combined therapy (ketoconazole and octreotide) was able to maintain biochemical remission according to UFC levels. No additive effect was observed with add-on treatment during a period of 2 months of combined ketoconazole-octreotide therapy. Following this stage, ketoconazole was stopped, and treatment was continued with octreotide monotherapy that was able to maintain normal UFC levels in 3 (27%) patients. Since the majority of reported cases using octreotide for CD treatment showed failure to induce biochemical remission, as summarized in Table 1, these results suggest that, in a subset of patients, ketoconazole-induced biochemical remission may have indeed led to upregulation of SST2 with subsequent effectiveness of octreotide.

This is supported by the observed dose dependency in the response to octreotide in both the ketoconazole-octreotide combination phase and the octreotide monotherapy phase. In 2 patients treated with ketoconazole and octreotide, UFC levels increased above the ULN after initial normalization but returned to normal values after a dose increase of octreotide. In 2 of the 3 responders to octreotide monotherapy, an increased dose of octreotide was required, and effective, after an initial increase in UFC levels was observed following ketoconazole discontinuation. Of note, given the size of the present study, a starting dose of octreotide cannot be defined based on our data. A previous study showed that ketoconazole can inhibit ACTH secretion in rat corticotroph cells in vitro; therefore, central effects of ketoconazole in vivo cannot be fully excluded [44]. However, sustained normal UFC levels under octreotide monotherapy in 1 responder patient and the dose-dependent response to octreotide in 2 other responders suggest that a central residual effect of ketoconazole is unlikely to explain the response to octreotide.

Interestingly, among the 3 patients considered as responders based on the UFC levels, clinical improvement was observed in 2 patients in terms of weight loss, waist circumference, and blood pressure control. Notably, the small sample size and limited follow-up reduce our ability to assess the long-term clinical impact of the ketoconazole-octreotide sequential strategy.

A common feature of the 3 patients in whom the strategy was most effective is that they had mildly elevated UFC levels at baseline as compared to patients in whom the strategy failed. This is similar to what was observed in studies with another somatostatin analog, pasireotide, which has been shown to be more effective in patients with less severe hypercortisolism [18, 19]. It is important to acknowledge that octreotide has a safer side-effect profile as compared to pasireotide, which is known to induce or worsen hyperglycemia via inhibition of incretin release. Octreotide could, therefore, be a potentially interesting option to maintain remission in (mild) CD after induction therapy with a steroid synthesis inhibitor [31].

When analyzing the 4 nonresponders and 4 partial responders in the trial, in whom, despite ketoconazole effectively reducing cortisol secretion, octreotide monotherapy was unable to maintain normocortisolism, the reasons for a failed response remain speculative. It is possible that because of more severe baseline hypercortisolism in these patients, as compared to the responders, a longer duration of biochemical remission is necessary in order to restore SST2 expression to adequate levels. Alternatively, corticotroph tumors in these cases may not express an adequate amount of SST2, regardless of the cortisolemic state.

Expression of SST2, defined by either immunohistochemical or mRNA level, is positively correlated with octreotide efficacy in GH-secreting tumors [45, 46]. Accordingly, the 2 responder patients to octreotide in whom cortisol levels were normalized before surgery had higher SST2 mRNA expression compared to partial/nonresponder patients, and these SST2 mRNA expression levels were comparable to the levels in somatotroph tumors [32]. The strategy of lowering cortisol levels to increase SST2 expression may have contributed to octreotide efficacy in these patients. Accordingly, an intermediate level of SST2 mRNA was found in the partial responder, whereas the nonresponder patient had a low level of SST2 mRNA. Regarding SST2 protein expression, a responder patient had an intermediate level of SST2, which may explain the efficacy of octreotide treatment. Consistently, the nonresponder patient to octreotide had no SST2 expression as determined by IHC, which may be explained by preoperative hypercortisolism with concomitant effects on SST2 expression level (mRNA and protein). The partial responders had contradictory results, 1 with high and the other with no SST2 expression by IHC. The partial responder with no SST2 protein expression also had high cortisol levels, which may have contributed to this negative result.

The present study needs to be analyzed in light of its inherent limitations. The single-arm design and small sample size, ie, 14 patients with 3 full responders to octreotide, only permits a descriptive analysis without more robust statistics. This is an important limitation, even considering that, given the rarity of CD, the existing literature consists mostly of case reports. Additionally, the period of 9 months of follow-up limited our ability to more thoroughly appreciate the potential clinical benefits associated with the reduction of UFC levels observed with the sequential treatment strategy tested in this trial. The protocol included ACTH measurements every 3 months, so the impact of octreotide treatment on ACTH secretion was not evaluated in the present study. Finally, in corticotroph tumors, only in selected cases sufficient appropriate tissue was available for mRNA and protein analysis. Generally, adenoma tissue pieces in CD are (very) small, representing a challenge to obtaining enough tissue for molecular studies. This is a well-known problem with respect to in vitro studies with corticotroph adenomas.

In conclusion, a treatment strategy consisting of sequential treatment with ketoconazole to lower cortisol levels, followed by octreotide to maintain biochemical remission, may be effective in a subset of patients with mild CD. Additional studies with longer follow-up are warranted to confirm the long-term efficacy of this strategy for the medical treatment of CD.

Funding

The authors received no financial support for this manuscript.

Disclosures

R.A.F. received speakers fees and research grants from Recordati and Corcept.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Clinical Trial Information

Dutch Trial Register nr. NL37105.078.11.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

From https://academic.oup.com/jes/article/9/7/bvaf089/8142193?login=false

Filed under: Cushing's, Treatments | Tagged: Cushing's Disease, ketoconazole, octreotide, pasireotide | Leave a comment »

The Impact of Prolonged High-Concentration Cortisol Exposure on Cognitive Function and Risk Factors: Evidence From Cushing’s Disease Patients

Posted on May 7, 2025 by MaryO

Abstract

Background

Prolonged high-concentration cortisol exposure may impair cognitive function, but its mechanisms and risk factors remain unclear in humans.

Objective

Using Cushing’s disease patients as a model, this study explores these effects and develops a predictive model to aid in managing high-risk patients.

Methods

This single-center retrospective study included 107 Cushing’s disease patients (January 2020–January 2024) at the First Medical Center of the PLA General Hospital. Cognitive function, assessed using the Montreal Cognitive Assessment, revealed 58 patients with cognitive impairment and 49 with normal cognitive function. Patients were divided into training (n = 53) and validation cohorts (n = 54) for constructing and validating the predictive model. Risk factors were identified via univariate analysis and least absolute shrinkage and selection operator regression, and a nomogram prediction model was developed. Performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).

Results

Cortisol AM/PM ratio, 8 a.m. cortisol concentration, body mass index, and fasting plasma glucose were significant risk factors for cognitive impairment. The nomogram demonstrated strong predictive ability, with ROC values of 0.80 (training) and 0.91 (validation). DCA indicated superior clinical utility compared to treating all or no patients.

Conclusions

This study confirms the significant impact of prolonged high cortisol exposure on cognitive function and identifies key risk factors. The nomogram model offers robust performance, providing a valuable tool for managing Cushing’s disease patients’ cognitive health and informing strategies for other cortisol-related disorders.

Introduction

Chronic stress and prolonged pressure increasingly pose significant burdens on individual health and social systems, particularly on a global scale. Their impact on cognitive function, mental health, and physical well-being cannot be ignored.¹ Long-term stress responses and sustained exposure to pressure not only elevate the risk of multiple diseases but also result in considerable socioeconomic burdens. According to the World Health Organization (WHO), approximately 300 million people worldwide suffer from depression, with stress and emotional disorders being critical contributing factors.² This phenomenon may be associated with prolonged exposure to high concentrations of cortisol induced by chronic stress.³ Such long-term elevated cortisol exposure is thought to exert adverse effects on multiple systems, including the nervous system, leading to anxiety, depression, and cognitive impairment. While the roles of anxiety and depression have been well established,⁴ the specific impact on cognitive function remains unclear.

Research suggests that abnormally elevated cortisol levels significantly affect brain structure and function. The hippocampus, a key target highly sensitive to cortisol and central to learning and memory, is particularly affected. High cortisol exerts its effects through glucocorticoid receptors and mineralocorticoid receptors in the hippocampus, mediating neurophysiological responses. Prolonged activation may lead to neuronal damage, reduced neuroplasticity, and cognitive impairment.^5,6 Additionally, brain regions such as the prefrontal cortex and amygdala are also impacted, potentially causing attentional deficits, impaired executive function, and emotional regulation disturbances.⁷ Furthermore, abnormal diurnal cortisol rhythms are closely linked to neuroinflammation, oxidative stress, and cerebrovascular lesions.^8,9 These mechanisms may interact synergistically to exacerbate cognitive impairment. While animal studies provide substantial evidence for cortisol’s effects on cognitive function, human studies face ethical constraints and experimental limitations. The lack of models for long-term stress and pressure in humans, coupled with challenges in conducting long-term follow-ups, highlights the need for suitable research subjects.

Cushing’s disease is an endocrine disorder caused by excess adrenocorticotropic hormone (ACTH) secretion by anterior pituitary adenomas, leading to abnormally elevated cortisol levels.¹⁰ The unique pathological features of Cushing’s disease offer a natural model for studying the effects of prolonged high cortisol exposure on human cognitive function. Patients with Cushing’s disease often experience cognitive impairments, with clinical manifestations including memory decline, attention deficits, and impaired executive function.^11–13 However, the specific mechanisms and risk factors underlying these impairments remain unclear.

Against this backdrop, this study uses Cushing’s disease patients as subjects to systematically evaluate the impact of prolonged high cortisol exposure on cognitive function and analyze associated risk factors. Additionally, we develop a nomogram prediction model aimed at improving the identification of high-risk patients, providing a reference for clinical interventions, and offering new perspectives and evidence for the cognitive management and research of cortisol-related disorders.

Methods

Study subjects

This study is a single-center retrospective study that included 107 patients diagnosed with Cushing’s disease at the First Medical Center of the PLA General Hospital between January 2017 and January 2024. Inclusion criteria were as follows: (i) meeting the WHO diagnostic criteria for Cushing’s disease; (ii) disease duration >3 months; (iii) no prior surgical treatment; (iv) complete laboratory and imaging data; (v) no other neurological or psychiatric disorders that could cause cognitive impairment (e.g., dementia, depression, stroke). Exclusion criteria included: (i) disease duration ❤ months; (ii) prior surgical treatment; (iii) missing critical baseline or laboratory data; (iv) severe visual or hearing impairments that could affect cognitive testing results. A total of 107 patients were included in the study, among whom 58 had cognitive impairment and 49 exhibited mild cognitive decline. Cognitive function was classified as follows: Montreal Cognitive Assessment (MoCA) score ≤26 was defined as cognitive impairment, 27–29 as mild cognitive decline, and 30 as normal cognitive function.

Study design

A random allocation method was used to divide all patients into a training cohort (n = 53) and a validation cohort (n = 54) at a 5:5 ratio. The training cohort was used for variable selection and predictive model development, while the validation cohort was used for performance evaluation of the model. The study was approved by the hospital ethics committee (approval number: [S2021-677-01]).

Clinical data collection

Clinical characteristics and laboratory data of patients were obtained from the hospital’s electronic medical record system and included the following: (i) Demographic and clinical characteristics: age, sex, disease duration, years of education, body mass index (BMI), systolic blood pressure, and diastolic blood pressure; (ii) Laboratory indicators: fasting plasma glucose (FPG), 24-h urinary free cortisol, serum cortisol concentrations (0 a.m., 8 a.m., 4 p.m.), ACTH concentrations (0 a.m., 8 a.m., 4 p.m.), total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, cortisol AM/PM ratio (CORT AM/PM), and results of low-dose dexamethasone suppression tests and high-dose dexamethasone suppression tests; (iii) Cognitive function assessment: conducted using the MoCA scale.

Statistical analysis and model development

Categorical variables were expressed as numbers (%), and continuous variables as mean ± standard deviation (SD) or median (interquartile range, IQR). Intergroup comparisons were performed using the chi-square test or Fisher’s exact test for categorical variables. A nomogram was constructed to predict the risk factors for cognitive impairment in patients exposed to prolonged high cortisol levels. Significant clinical features associated with cognitive function were identified through univariate analysis and least absolute shrinkage and selection operator (LASSO) regression analysis.

Based on the final results, a novel nomogram was developed, incorporating all independent prognostic factors to predict the presence or absence of cognitive impairment in individuals exposed to prolonged high cortisol levels. The performance of the nomogram was evaluated using the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), calibration curves, and decision curve analysis (DCA). The C-index was calculated using 1,000 bootstrap samples to assess the internal validity of the model. Each patient’s total score was calculated using the nomogram approach.

Statistical analysis was performed using R programming language and version 4.2.3 of the R environment (http://cran.r-project.org). The main R packages used in this study included gtsummary (version 1.7.0), survival (version 3.5-3), RMS (version 6.3-0), time ROC (version 0.4), and ggplot2 (version 3.4.0).

Results

Patient characteristics

A total of 107 patients with Cushing’s disease were included in this study. MoCA scores revealed that all patients exhibited either cognitive decline or impairment. Among them, 58 patients (54.2%) were classified into the cognitive impairment group, and 49 patients (45.8%) were categorized into the cognitive decline group. Significant differences were observed in demographic characteristics and clinical indicators between the two groups. Detailed information is presented in Table 1.

Table 1. General characteristics of patients.

Variables	Total (n = 107)	0 (n = 49)	1 (n = 58)	p
sex, n (%)				1
1	10 (9)	5 (10)	5 (9)
2	97 (91)	44 (90)	53 (91)
age, Mean ± SD	41.22 ± 11.19	39.16 ± 11.21	42.97 ± 10.96	0.08
Education y, Median (Q1,Q3)	12 (8, 16)	12 (8, 16)	12 (8.25, 15)	0.835
BMI, Mean ± SD	27.01 ± 3.46	25.49 ± 2.25	28.29 ± 3.79	<0.001
Illness duration, Median (Q1,Q3)	26 (12, 48)	24 (12, 48)	33 (12, 48)	0.6
COR-0am, Mean ± SD	565.86 ± 207.53	513.69 ± 185.87	609.94 ± 216.06	0.015
COR-8am, Mean ± SD	725.63 ± 259.03	612.26 ± 197.79	821.41 ± 267.29	<0.001
COR-4pm, Median (Q1,Q3)	619.19 (491.14, 744.17)	598.3 (472.49, 678.18)	650.43 (503.34, 803.88)	0.109
ACTH0am, Median (Q1,Q3)	12.4 (9.02, 18.4)	11 (8.46, 17.2)	13.95 (9.57, 19.51)	0.114
ACTH8am, Median (Q1,Q3)	15.2 (11.1, 23.5)	13.3 (10.6, 19.4)	17.4 (13.33, 26.27)	0.027
ACTH4pm, Median (Q1,Q3)	15.9 (10.45, 22.75)	13.6 (10.4, 22.6)	16.6 (10.95, 25.15)	0.275
UFC, Median (Q1,Q3)	1644.9 (1146.2, 2501.75)	1483 (1092.3, 2020.6)	1931 (1168.85, 2793.02)	0.131
LDDST-ACTH, Median (Q1,Q3)	16.9 (9.31, 21.15)	16.1 (8.35, 20.6)	17.25 (10.12, 21.17)	0.555
LDDST-CORT, Median (Q1,Q3)	532.95 (390.46, 787.61)	501.63 (360.4, 792.18)	568.37 (398.76, 781.7)	0.606
LDDST-UFC, Median (Q1,Q3)	1050.8 (531.9, 2077.2)	880.6 (454.4, 2419.9)	1200 (580.62, 2010.23)	0.589
HDDST-ACTH, Median (Q1,Q3)	8.81 (5.2, 15.7)	8.48 (4.91, 16.6)	9.12 (5.42, 14.45)	0.837
HDDST-CORT, Median (Q1,Q3)	222.3 (62.41, 354.31)	222.3 (61.7, 348.84)	217.56 (76.25, 356.78)	0.662
HDDST-UFC, Median (Q1,Q3)	336.9 (130.9, 870.86)	281.2 (128.4, 791.7)	391.4 (140.25, 923.43)	0.488
SBP, Mean ± SD	159.09 ± 26.08	157.76 ± 26.67	160.22 ± 25.75	0.629
DBP, Median (Q1,Q3)	105 (92, 116.5)	105 (90, 119)	102.5 (94.5, 114)	0.927
TC, Median (Q1,Q3)	5.13 (4.46, 6.17)	4.92 (4.47, 5.72)	5.24 (4.44, 6.31)	0.386
TG, Median (Q1,Q3)	1.42 (0.99, 2.04)	1.39 (0.99, 2.41)	1.42 (0.99, 1.97)	0.861
ALT, Median (Q1,Q3)	23 (17.55, 33.7)	20.7 (15.8, 33)	23.85 (18.45, 34.3)	0.35
AST, Median (Q1,Q3)	15.2 (13, 18.5)	14.1 (12.7, 18.5)	16.35 (13.62, 18.45)	0.184
GGT, Median (Q1,Q3)	27.6 (21.75, 44.25)	26.7 (22.6, 45.9)	28.95 (21.32, 41.9)	0.913
FPG, Median (Q1,Q3)	7.62 (5.43, 9.66)	5.7 (4.83, 7.49)	8.95 (7.05, 10)	<0.001
CORT AM/PM, Median (Q1,Q3)	1.19 (0.99, 1.34)	1.05 (0.88, 1.2)	1.25 (1.15, 1.4)	<0.001

ACTH: adrenocorticotropic hormone; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BMI, body mass index; COR/CORT: cortisol; DBP: diastolic blood pressure; FPG: fasting plasma glucose; GGT: gamma-glutamyl transferase; HDDST: high-dose dexamethasone suppression tests; LDDST: low-dose dexamethasone suppression tests; SBP: systolic blood pressure; TC: total cholesterol; TG: triglycerides; UFC: urinary free cortisol.

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Model development

In the modeling cohort, LASSO regression analysis was used for variable selection. The regression coefficient path diagram and cross-validation curve are shown in Figure 1A and 1B. To ensure a good model fit, the λ corresponding to the minimum mean squared error was chosen through cross-validation. Four variables were identified through LASSO regression analysis: CORT AM/PM, COR-8am, FPG, and BMI. These variables were ultimately deemed risk factors for cognitive impairment associated with prolonged high cortisol exposure. Based on these four significant variables, a nomogram was developed to predict cognitive impairment under prolonged high cortisol exposure, and the model was visualized using a nomogram (Figure 2).

Figure 1. LASSO Cox regression model construction. (A) LASSO coefficient of 27 features. (B) Selection of tuning parameter (k) for the LASSO model.

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Figure 2. Nomogram predicting cognitive impairment in patients with prolonged high cortisol exposure.

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Model performance and validation

To comprehensively evaluate the model’s performance, multiple metrics were employed to verify its accuracy, stability, and clinical utility, including the concordance index (C-index), AUC, calibration curves, and DCA. The AUC values for the training cohort (Figure 3A) and the internal validation cohort (Figure 3B) were 0.80 and 0.91, respectively. These results indicate that the nomogram model effectively distinguishes patients with cognitive impairment in different sample datasets and demonstrates strong predictive accuracy. Calibration curves showed a high level of agreement between the predicted and actual probabilities of cognitive impairment in both the training cohort (Figure 4A) and the validation cohort (Figure 4B), further confirming the model’s stability and utility.

Figure 3. The ROC curve of the predictive model for cognitive impairment in patients with prolonged high cortisol exposure. (A) Derivation cohort. (B) Validation cohort.

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Figure 4. Calibration curves of the nomogram. (A) Derivation cohort. (B) Validation cohort.

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To assess the clinical utility of the model, DCA was performed (Figure 5). The results demonstrated that the clinical benefit of using the model to predict cognitive impairment was significantly higher than strategies of treating all patients or treating none (Figure 5). This finding suggests that the nomogram model provides substantial net benefit in clinical decision-making, effectively aiding clinicians in identifying high-risk patients and implementing appropriate interventions.

Figure 5. DCA curves of the nomogram in the training cohort and test cohort.

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Discussion

This study used patients with Cushing’s disease as a model to investigate the effects of prolonged high-concentration cortisol exposure on human cognitive function. The findings revealed that individuals exposed to long-term high cortisol levels generally experienced cognitive decline, with the CORT AM/PM, COR-8am, BMI, and FPG identified as major risk factors for cognitive impairment. Additionally, the developed nomogram model demonstrated excellent predictive performance in both the training (AUC = 0.80) and validation (AUC = 0.91) cohorts, highlighting its strong discriminative ability and clinical utility. These findings provide a foundation for mechanistic research and clinical management of prolonged high cortisol exposure.

BMI, FPG, CORT AM/PM, and COR-8am, as risk factors, are closely related to cortisol levels and its effects on the nervous system. Increased BMI was identified as an independent risk factor for cognitive impairment, likely due to chronic inflammation and oxidative stress caused by metabolic disorders.^14–16 Obesity and elevated cortisol levels may form a vicious cycle, further exacerbating damage to the nervous system. Studies have shown that reduced cerebral blood flow and neuronal damage in obese individuals are directly linked to cognitive impairment,¹⁷ underscoring the importance of monitoring metabolic status in Cushing’s disease patients. High blood glucose was another critical risk factor, potentially affecting cognitive function through various mechanisms: prolonged hyperglycemia can lead to cerebrovascular damage and impaired blood supply to the brain;¹⁸ it may also directly harm neurons through oxidative stress and inflammatory responses.¹⁹ Moreover, chronic hyperglycemia alters insulin signaling pathways, disrupting glucose metabolism in the brain and further aggravating cognitive decline.²⁰ Additionally, the study showed that disrupted cortisol circadian rhythms (elevated CORT AM/PM) and increased morning cortisol peaks (COR-8am) were closely associated with cognitive impairment. Circadian rhythm disruption may accelerate hippocampal atrophy and prefrontal cortex dysfunction by affecting the regulation of the hypothalamic-pituitary-adrenal (HPA) axis.²¹ Excessive morning cortisol peaks may exacerbate neuroinflammation and synaptic dysfunction,²² a finding also supported by previous animal studies.

Cushing’s disease serves as an effective model for studying high cortisol states induced by chronic stress, given the high similarity in pathophysiological mechanisms between the two. Cushing’s disease results from tumor-induced HPA axis hyperactivation, causing sustained cortisol overproduction,²³ while chronic stress similarly activates the HPA axis, maintaining cortisol at persistently high levels. Although the etiology of Cushing’s disease is endogenous and pathological, whereas high cortisol in chronic stress is environmentally induced, both share similar features such as metabolic disturbances (e.g., insulin resistance, central obesity), immunosuppression (e.g., increased infection susceptibility), osteoporosis, and psychological disorders (e.g., anxiety and depression).²⁴ Therefore, Cushing’s disease provides an effective model for studying metabolic, immune, and neurological changes in high cortisol states, offering experimental evidence for understanding chronic stress-related disorders and developing intervention strategies.

The results of this study align with previous animal experiments. For instance, animal studies have shown that prolonged cortisol exposure leads to hippocampal atrophy and neuronal damage, impairing cognitive function.²⁵ This study provides supportive evidence in human samples. Furthermore, prior research has found that disrupted cortisol circadian rhythms are often associated with executive function decline in patients with depression,²⁶ consistent with our findings that CORT AM/PM is significantly associated with cognitive impairment in Cushing’s disease patients. Unlike earlier studies focusing primarily on cortisol’s direct neurotoxic effects, this study integrated metabolic indicators (e.g., BMI, FPG) to comprehensively analyze the interaction between cortisol and metabolic disturbances, expanding the understanding of mechanisms underlying cortisol-induced cognitive impairment.

Moreover, unlike previous research that was predominantly based on animal models, this study systematically analyzed data from 107 Cushing’s disease patients, further validating these mechanisms in humans. The construction of the nomogram model significantly enhanced predictive accuracy, providing a practical tool for clinical application.

Despite providing important evidence for the impact of prolonged high cortisol exposure on cognitive function, this study has limitations. First, as a single-center retrospective study with a limited sample size, the results may lack generalizability and require prospective validation. Although Cushing’s disease serves as a model for high cortisol exposure, further validation in populations experiencing chronic stress or prolonged pressure is needed. Second, the lack of long-term follow-up data prevents evaluation of the effects of surgical treatment or other interventions on cognitive function. Third, this study did not consider the impact of sex hormones on cortisol levels and cognitive function. Sex hormones (such as estrogen and testosterone) may regulate cortisol and influence the central nervous system.

Conclusion

This study, using patients with Cushing’s disease as a model, explored the impact of prolonged high-concentration cortisol exposure on human cognitive function. The findings revealed that individuals with prolonged high cortisol exposure commonly experience cognitive decline, with CORT AM/PM, COR-8am, BMI, and FPG identified as major risk factors for cognitive impairment. The nomogram model developed based on these risk factors demonstrated excellent predictive performance and clinical applicability in both the training and validation cohorts, providing an effective tool for the early identification of high-risk patients. These results not only confirmed the significant impact of prolonged high cortisol exposure on the central nervous system but also highlighted the critical role of metabolic factors in this process, emphasizing the multifactorial mechanisms of cognitive impairment. These findings offer a scientific basis for managing the cognitive health of Cushing’s disease patients and provide important insights for prevention and treatment strategies for other cortisol-related conditions, such as chronic stress and metabolic syndrome.

Acknowledgments

We thank the patient for granting permission to publish this information. We appreciate all the team members who have shown concern and provided treatment advice for this patient the Chinese People’s Liberation Army (PLA) General Hospital.

Ethical considerations

This study was approved by the Ethics Committee of the Chinese PLA General Hospital (Approval No. [S2021-67701]).

Consent to participate

All participants provided written informed consent prior to inclusion in the study.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (Grant Nos. 82001798 to Xinguang Yu; Grant Nos. 81871087 to Yanyang Zhang) and the Young Talent Project of Chinese PLA General Hospital (Grant Nos. 20230403 to Yanyang Zhang).

ORCID iDs

Yuxiang Sun https://orcid.org/0009-0001-9533-5334

Shiyu Feng https://orcid.org/0000-0002-2267-4386

Data availability statement

Data are available from the corresponding authors on reasonable request.

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From https://journals.sagepub.com/doi/full/10.1177/25424823251338161

Filed under: Cushing's, pituitary, symptoms | Tagged: cognitive impairment, cortisol, Cushing's Disease, stress | Leave a comment »

Treatment-Resistant Cushing Disease and Acromegaly in a Young Woman: A Case Of Functional Pituitary Macroadenoma

Posted on March 14, 2025 by MaryO

Abstract

Cushing disease and acromegaly are common endocrine disorders caused by excessive cortisol and growth hormone production, respectively. Both conditions can co-occur due to functioning pituitary adenomas, which are typically benign pituitary gland tumors. This report discusses a 30-year-old woman with hyperpituitarism leading to treatment-resistant Cushing disease and acromegaly caused by a functional pituitary macroadenoma.

A 30-year-old woman presented with a history of excessive weight gain, facial puffiness, fatigue, persistent headaches, and visual disturbances. Clinical examination revealed features consistent with Cushing disease and acromegaly, including a moon face, central obesity, and large hands and feet—the ophthalmologic evaluation identified bitemporal hemianopia, suggesting optic chiasm compression. Laboratory results showed elevated ACTH, IGF-1, and prolactin levels, alongside confirmed hypercortisolism. The patient also had secondary diabetes mellitus and galactorrhea—initial treatment with octreotide provided limited benefit, with persistent hormone elevations and insufficient symptom control. The patient underwent endonasal endoscopic transsphenoidal resection of the pituitary macroadenoma, leading to marked symptomatic and hormonal improvements. This underscores the diagnostic challenge and treatment complexity of such cases. Early diagnosis is critical for optimizing outcomes in patients with hyperpituitarism and mitigating complications. This case highlights the importance of multidisciplinary management and the necessity of long-term follow-up to monitor for recurrence and ensure sustained remission.

Introduction

Pituitary adenomas are benign tumors arising from the pituitary gland, often referred to as the “master gland” due to its central role in regulating key physiological processes such as growth, metabolism, and reproduction [1,2]. These tumors are classified by size into microadenomas (<10 mm) and macroadenomas (≥10 mm) and by hormonal activity into functioning and nonfunctioning adenomas. Functioning adenomas actively secrete hormones, leading to distinct syndromes such as prolactinomas, acromegaly (from growth hormone overproduction), and Cushing disease (from excess ACTH). In contrast, nonfunctioning adenomas do not secrete hormones but may cause symptoms due to mass effects, such as visual disturbances or hypopituitarism [[3], [4], [5]].

The simultaneous occurrence of Cushing disease and acromegaly is rare and presents a significant diagnostic and therapeutic challenge. Both conditions stem from hyperpituitarism, typically due to a functional pituitary adenoma [6,7]. Cushing disease results from ACTH hypersecretion, causing excessive cortisol production and features such as central obesity, hypertension, hyperglycemia, and muscle weakness [[8], [9], [10]]. Prolonged cortisol exposure can lead to severe complications, including cardiovascular diseases and osteoporosis. Acromegaly, on the other hand, arises from growth hormone overproduction, leading to elevated IGF-1 levels and characteristic features such as enlarged extremities, facial changes, and systemic complications like insulin resistance and joint abnormalities [[11], [12], [13]].

The coexistence of Cushing disease and acromegaly within the same affected person is extraordinarily rare, making this particular case record particularly noteworthy [14,15].

The simultaneous presentation of these 2 endocrine problems in a young lady because of a hormonally functioning pituitary macroadenoma presents a unique scientific venture [16,17]. The pituitary macroadenoma, defined as a tumor more than 10 mm in diameter, can compress adjoining structures within the sella turcica and enlarge into surrounding areas, leading to signs and symptoms with complications, visible disturbances, and hyperpituitarism. In this case, the patient presented with both Cushing disease and acromegaly, at the same time symptoms as a result of the mass impact of the macroadenoma.

The case of a 30-year-old female with hyperpituitarism, characterized with the aid of drug-resistant Cushing disease and acromegaly, highlights the complexities intricately associated with the analysis and control of a couple of endocrine issues bobbing up from a single pituitary macroadenoma. Her medical presentation changed into one marked by a history of noticeable weight gain, facial puffiness, fatigue, chronic complications, and visual disturbances. A thorough physical exam found traits consistent with each Cushing disorder and acromegaly, which include a moon face, vital weight problems, and enlarged arms and toes. The ophthalmologic exam confirmed bitemporal hemianopia, indicative of optic chiasm compression with the aid of the pituitary macroadenoma. Early recognition and multidisciplinary management are essential to mitigate the significant morbidity associated with these conditions. This case report highlights a rare instance of concurrent Cushing disease and acromegaly due to a functional pituitary macroadenoma, underscoring the importance of timely diagnosis and treatment.

Case presentation

This case of a 30-year-old female highlights the complexities of diagnosing and managing a functional pituitary macroadenoma presenting with overlapping features of Cushing disease and acromegaly, along with secondary diabetes mellitus.

The patient demonstrated classic signs of hypercortisolism, including central obesity with a “moon face” and “buffalo hump,” skin thinning, easy bruising, and muscle weakness. Cortisol’s catabolic effects were evident in her limb wasting and truncal obesity. Metabolic complications included hypertension and secondary diabetes mellitus, supported by elevated random blood sugar (22 mmol/L) and postprandial blood sugar levels (27 mmol/L). Laboratory findings showed significantly elevated ACTH levels (670 pg/mL; normal: 10–60 pg/mL) and increased morning urine cortisol levels.

The patient also exhibited hallmark features of acromegaly, including enlarged hands and feet, necessitating larger shoe and glove sizes, and distinct facial changes such as mandibular prognathism, frontal bossing, and nasal broadening. Soft tissue swelling and fatigue were also noted, alongside joint pain likely resulting from cartilage and bone overgrowth. Her IGF-1 levels were markedly elevated (798 ng/mL; normal: 100–300 ng/mL).

Hyperprolactinemia (643 ng/mL; normal: 5–25 ng/mL) caused galactorrhea, likely resulting from tumor compression of the pituitary stalk or direct prolactin secretion. Diabetes mellitus, secondary to insulin resistance driven by excess cortisol and growth hormone, further complicated her clinical picture (Table 1).

Table 1. Markedly elevated hormone levels preoperatively and their postoperative normalization.

Hormone	Patient’s level (Preoperative)	Postoperative levels	Normal reference value
ACTH	670 pg/mL	90 pg/mL	10–60 pg/mL
IGF-1	798 ng/mL	280 ng/mL	100–300 ng/mL (age-dependent)
Prolactin	643 ng/mL	42 ng/mL	5–25 ng/mL
Morning Urine Cortisol	Elevated	Normal	<50 mcg/24 h
Random Blood Sugar	22 mmol/L	6.5 mmol/L	4.0–7.8 mmol/L
2-Hour Postprandial Blood Sugar	27 mmol/L	7.0 mmol/L	<7.8 mmol/L
TSH (Thyroid-Stimulating Hormone)	0.8 mIU/L	1.2 mIU/L	0.5–5.0 mIU/L
FT3 (Free Triiodothyronine)	4.5 pmol/L	4.0 pmol/L	3.5–7.7 pmol/L
FT4 (Free Thyroxine)	15 pmol/L	16 pmol/L	12–22 pmol/L

Secondary diabetes mellitus is a common trouble in sufferers with Cushing disease and acromegaly, stemming from the insulin resistance brought about by persistent hypercortisolism and hypersecretion of GH. This patient’s multiplied blood sugar also reflects tremendous impairment in glucose metabolism. Polyuria, polydipsia, and unexplained weight loss are classic signs of diabetes that could have been found in her clinical history but are frequently overshadowed by the traits of the more distinguished functions of her endocrine disorders. The affected person additionally experienced galactorrhea, an odd milk discharge from the breasts, that’s on account of her expanded prolactin levels (643 ng/mL, ordinary range: 2-29 ng/mL). Hyperprolactinemia inside the context of a pituitary macroadenoma can result from the tumor’s direct secretion of prolactin or from the stalk effect, where the tumor compresses the pituitary stalk, disrupting dopamine inhibition of prolactin secretion.

MRI was the primary imaging modality, revealing a large pituitary macroadenoma centered within the sella turcica and extending suprasellar. The tumor demonstrated homogeneous postcontrast enhancement and exerted mass effects, including optic chiasm compression correlating with bitemporal hemianopia. Other modalities, such as CT, were not considered due to MRI’s superior resolution for pituitary evaluation.

The MRI scans of the patient reveal a large, well-defined pituitary macroadenoma centered within the sella turcica, exhibiting significant suprasellar extension. On sagittal T1-weighted postcontrast imaging (Fig. 1), the lesion demonstrates homogeneous enhancement with clear, well-defined borders, expanding superiorly into the suprasellar region. Coronal T2-weighted images (Fig. 2) further delineate this suprasellar extension, with the mass exerting mass effect on adjacent structures.

Additional sagittal T1-weighted postcontrast imaging (Fig. 3) confirms the uniform enhancement of the macroadenoma, filling the sella turcica and extending upward. Coronal T2-weighted MRI (Fig. 4) reveals the lesion as hyperintense, extending into the suprasellar region and displacing the optic chiasm. The imaging highlights the well-defined borders of the mass and the potential mass effect on adjacent structures.

Axial T2-weighted MRI images (Fig. 5) depict a hyperintense lesion in the basal ganglia and thalamus, appearing as a bright, well-defined signal. This finding suggests a potential coexisting pathology affecting deep brain structures, which may or may not be related to the primary pituitary lesion. The characteristics and location of the pituitary macroadenoma correspond with the patient’s clinical presentation of bitemporal hemianopia, likely caused by compression of the optic chiasm.

The overall imaging features, including homogeneous enhancement, well-defined borders, and suprasellar extension, are hallmark characteristics of pituitary macroadenomas. The potential lateral extension toward the cavernous sinus warrants further evaluation, while the hyperintense lesion in the basal ganglia and thalamus may indicate secondary effects or unrelated CNS pathology.

The imaging findings collectively support the diagnosis of a large, functioning pituitary macroadenoma, exceeding 10 mm in diameter. The mass’s size and anatomical impact align with the patient’s clinical presentation, which includes headaches, visual field deficits, and hormonal imbalances. The documented compression of the optic chiasm and possible involvement of the cavernous sinus provide a radiological explanation for the patient’s visual symptoms and hormonal disruptions. This MRI assessment substantiates the diagnosis of a pituitary macroadenoma with significant suprasellar extension and compression effects, consistent with the patient’s symptomatology and clinical findings.

The conglomeration of her clinical presentations, elevated hormone levels, and MRI findings of a big suprasellar mass pretty suggestive of a pituitary macroadenoma showed the analysis of a functioning pituitary adenoma. The preliminary treatment control with octreotide, a somatostatin analog, aimed to control both acromegaly and Cushing disorder by inhibiting GH and ACTH secretion. However, the suboptimal reaction highlighted the undertaking of achieving hormone manipulation in sufferers with massive, competitive adenomas.

Given the patient’s persistent symptoms and the insufficient biochemical response to medical therapy, surgical intervention was considered imperative. The patient underwent endonasal endoscopic transsphenoidal resection of the pituitary gland, a minimally invasive surgical approach targeting the tumor via the nasal passages. This approach was preferred over traditional craniotomy due to its demonstrated efficacy in reducing tumor size and lowering elevated hormone levels with fewer complications, reduced morbidity, shorter hospital stays, and faster recovery times. Additionally, the endoscopic technique offers superior visualization of the surgical field, which aids in precise tumor resection and preservation of normal pituitary tissue.

During the surgery, the tumor was noted to be soft and well-circumscribed, with no significant adherence to adjacent structures such as the cavernous sinus or optic chiasm. This facilitated a complete resection of the tumor, minimizing the risk of residual disease. There were no notable intraoperative complications, such as cerebrospinal fluid leakage or significant bleeding, underscoring the safety and efficacy of the chosen approach. Postoperatively, the patient demonstrated marked clinical improvement in her symptoms, accompanied by a significant reduction in hormone levels to within normal reference ranges. This confirmed the diagnosis and highlighted the effectiveness of the surgical intervention. Specifically, there was a substantial decrease in ACTH, IGF-1, and prolactin levels, leading to clinical remission of Cushing disease and acromegaly.

In the postoperative period, the patient did not require immediate hormone replacement therapy, as her endocrine functions remained stable. However, long-term monitoring is planned to assess for potential hormone deficiencies, disease recurrence, or other complications. The follow-up plan includes regular clinical evaluations, hormonal assays, and periodic imaging studies to ensure sustained remission and to promptly address any residual or recurrent tumor growth. This case highlights the crucial role of surgical intervention in managing functional pituitary macroadenomas, particularly when medical therapy fails. The successful outcome underscores the importance of a multidisciplinary approach and the need for lifelong surveillance to optimize long-term outcomes for such patients. This case scenario also underscores the complexities interwoven in diagnosing and coping with hyperpituitarism because of a pituitary macroadenoma, emphasizing the warrant for a complete and multidisciplinary approach. Early recognition of symptoms, correct diagnostic workup, and timely endocrine disorders.

Discussion

The case of this 30-year-old woman with concurrent refractory Cushing disease and acromegaly due to a functional pituitary macroadenoma highlights the challenges inherent in diagnosing and managing multiple endocrine disorders. Recognizing overlapping clinical features was central to reaching the diagnosis. Classic symptoms of Cushing disease, such as a moon face and central obesity, coupled with acromegalic features, including enlarged extremities, underscored the complexity of the case. The presence of bitemporal hemianopia further pointed to a large pituitary mass compressing the optic chiasm, necessitating imaging studies for confirmation. This case underscores the need for clinicians to remain vigilant when evaluating overlapping endocrine features to avoid delays in diagnosis and treatment [[18], [19], [20]].

Laboratory evaluations were pivotal, revealing markedly elevated ACTH, IGF-1, and prolactin levels, in addition to evidence of hypercortisolism and secondary diabetes mellitus. These findings highlighted the intricate interplay of hypersecreted pituitary hormones and the systemic consequences of unregulated hormone production. MRI findings of a large suprasellar pituitary tumor were instrumental in confirming the diagnosis of a functional macroadenoma and guided subsequent treatment decisions.

The patient’s suboptimal response to octreotide therapy underscored the limitations of medical treatments in addressing aggressive, hormone-secreting pituitary macroadenomas. While somatostatin analogs are effective in many cases of acromegaly and can provide symptomatic relief, their efficacy is limited in patients with large adenomas and significant hormonal hypersecretion. This case highlights the necessity of early consideration of definitive surgical intervention when medical therapy fails to achieve adequate biochemical control [[21], [22], [23]].

Endonasal endoscopic transsphenoidal surgery was selected for this patient due to its minimally invasive approach, superior visualization of the sellar region, and lower complication rates compared to traditional craniotomy. Intraoperatively, the tumor’s soft consistency and lack of adherence to adjacent structures facilitated a complete resection. Notably, the absence of significant complications, such as cerebrospinal fluid leakage or vascular injury, reflected the safety and precision of this surgical approach [[24], [25], [26]].

Postoperatively, the patient experienced substantial improvement in symptoms, with normalization of ACTH, IGF-1, and prolactin levels. This outcome underscores the efficacy of surgical intervention in achieving hormonal remission and alleviating symptoms in patients with functional macroadenomas. The resolution of her secondary diabetes mellitus and galactorrhea further reinforced the success of treatment [[27], [28], [29]].

Managing such complex endocrine disorders necessitates a multidisciplinary approach, with endocrinologists, radiologists, and neurosurgeons collaborating to ensure accurate diagnosis and effective treatment planning. Radiologists play a critical role in identifying and characterizing pituitary tumors, while endocrinologists monitor hormonal responses and guide perioperative management [[30], [31], [32]]. Neurosurgeons provide expertise in resecting these challenging lesions and optimizing patient outcomes.

The prognosis for patients undergoing surgical resection of functional pituitary macroadenomas is generally favorable when hormonal remission is achieved. However, long-term follow-up is critical to monitor for potential disease recurrence and manage any residual hormone deficiencies. Lifelong surveillance, including periodic hormonal assays and imaging studies, is recommended. Although the patient did not require immediate hormone replacement therapy, ongoing assessment of endocrine function remains essential to address emerging deficiencies promptly [[33], [34], [35], [36]].

This case exemplifies the importance of integrating current evidence-based practices into patient care. Recent guidelines and studies emphasize the role of endoscopic surgery as the preferred approach for resecting pituitary tumors due to its high success rates and reduced morbidity compared to older techniques.

Conclusion

This case highlights the pivotal role of surgical intervention in managing hormone-resistant pituitary macroadenomas underscoring the role of a multidisciplinary approach involving endocrinology, radiology, and neurosurgery, demonstrating its effectiveness in resolving hormonal overproduction and alleviating symptoms. Long-term follow-up is indispensable to monitor for recurrence, address emerging complications, and ensure sustained remission, reinforcing the need for vigilance and specialized endocrine care in managing these complex disorders.

Patient consent

Written informed consent for publication of this case report was obtained from the patient(s). The patient(s) were provided with sufficient information regarding the nature of the publication, including the details to be disclosed and potential implications. The patient(s) have confirmed their understanding and voluntarily agreed to the publication of this case report.

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: Competing Interests: 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.

From https://www.sciencedirect.com/science/article/pii/S1930043325000147?viaihub

Filed under: Cushing's, pituitary, Rare Diseases | Tagged: Acromegaly, Cushing's Disease, pituitary | Leave a comment »

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Postoperative Initiation of Thromboprophylaxis in Patients with Cushing’s Disease (PIT-CD):

Abstract

Background

Methods

Discussion

Trial registration

Administrative information

Introduction

Background and rationale {6a}

Objectives {7}

Trial design {8}

Methods: participants, interventions and outcomes

Study setting {9}

Eligibility criteria {10}

Inclusion criteria

Exclusion criteria

Who will obtain informed consent? {26a}

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Interventions

Explanation for the choice of comparators {6b}

Intervention description {11a}

Criteria for discontinuing or modifying allocated interventions {11b}

Strategies to improve adherence to interventions {11c}

Relevant concomitant care permitted or prohibited during the trial {11d}

Provisions for post-trial care {30}

Outcomes {12}

Primary outcome

Secondary outcomes

Safety outcomes

Participant timeline {13}

Sample size {14}

Recruitment {15}

Assignment of interventions: allocation

Sequence generation {16a}

Concealment mechanism {16b}

Implementation {16c}

Assignment of interventions: blinding

Who will be blinded {17a}

Procedure for unblinding if needed {17b}

Data collection and management

Plans for assessment and collection of outcomes {18a}

Plans to promote participant retention and complete follow-up {18b}

Data management {19}

Confidentiality {27}

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

Interim analyses {21b}

Methods for additional analyses (e.g., subgroup analyses) {20b}

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Plans to give access to the full protocol, participant-level data and statistical code {31c}

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

Composition of the data monitoring committee, its role and reporting structure {21a}

Adverse event reporting and harms {22}

Frequency and plans for auditing the trial conduct {23}

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Dissemination plans {31a}

Discussion

Trial status

Data availability {29}

Abbreviations

References

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Challenges of Cushing’s Syndrome and Bariatric Surgery

Abstract

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A Prospective Trial With Ketoconazole Induction Therapy and Octreotide Maintenance Treatment for Cushing’s Disease

Abstract

Methods

Study Population

Diagnostic Workup of CD