Disease Remission and Surgical Outcomes of Endoscopic Transsphenoidal Surgery for Cushing Disease: A Single Center Experience

Posted on February 1, 2026 by MaryO

Introduction

Transsphenoidal surgery is the primary treatment for patients with Cushing disease (CD). This study assessed the surgical and endocrinologic outcomes of patients with CD following endoscopic pituitary surgery using strict biochemical criteria to guide surveillance in patients not achieving early remission.

Methods

The medical records of all patients with CD who underwent endoscopic transsphenoidal surgery at a single institution between 2004 and 2025 were reviewed. Remission was defined as a fasting serum cortisol level <50 nmol/L (1.8 μg/dL) either basal or after 1 mg dexamethasone.

Results

A total of 125 patients were diagnosed with CD and had a primary endoscopic transsphenoidal surgery during the study period (median age 48 years [range: 14–79 years; M:F 93:32). Fifty-seven patients (45.6%) had a microadenoma, 41 (32.8%) had a macroadenoma, and 26 (20.8%) had no demonstrable focal lesion on pituitary magnetic resonance imaging (MRI) (MRI-negative CD). The median length of follow-up was 3.1 years (range: 1 month to 16.7 years). Initial remission rates 3 months after surgery were: 72.0% for patients with MRI-negative CD, 77.2% for microadenomas, and 48.7% for macroadenomas. Age, male sex, MRI-negative, and single operation were predictors of remission. Patients who achieved remission at 3 months were significantly more likely to be in remission at last follow-up after accounting for patient and tumor characteristics. The 5-year recurrence rate following remission was 6.9%.

Conclusion

Endoscopic transsphenoidal surgery is an effective first-line treatment for patients with CD but a significant minority will relapse. Close biochemical surveillance of patients who fail to achieve remission may support the use of early adjuvant radiotherapy.

Key words

Cushing disease
Endoscopic transsphenoidal surgery
Remission

Abbreviations

CD

Cushing’s Disease
CSF

Cerebrospinal fluid
DI

Diabetes insipidus
MRI

Magnetic Resonance Imaging

Introduction

Cushing disease (CD) is a rare endocrine disease caused by the circulation of excess cortisol due to hypersecretion of adrenocorticotrophic hormone from a pituitary adenoma. The annual incidence of CD is estimated to be between 1.2 and 2.4 million cases per year1, 2, 3 although it may be higher in selected patient populations such as those with poorly controlled diabetes and young patients with osteoporosis or hypertension.4 Untreated CD is associated with a very poor prognosis and a significantly reduced 5-year survival mandating prompt and effective treatment.5 Nevertheless, long-term management of patients with CD remains challenging.
In most cases of CD, the pituitary adenoma is benign and excellent remission rates have been reported with surgical treatment.6, 7, 8 Comparable remission rates of around 80% have been reported with both microscopic and endoscopic transsphenoidal pituitary surgery,7,8 however the basal serum cortisol level used to define remission varies significantly in the literature (50–138 nmol/L). Several previous studies have also excluded macroadenomas and invasive tumors from longitudinal analysis. As such, there is a paucity of long-term clinical data for an unselected population undergoing endoscopic transsphenoidal pituitary surgery for CD. Furthermore, there is little evidence concerning the optimal management of patients who fail to enter complete biochemical remission (basal serum cortisol level <50 nmol/L [1.8 μg/dL]) following their initial surgical treatment.
The aim of this study was to assess the treatment pathway and long-term outcomes of consecutive patients treated at a regional treatment center over a 20-year period. All surgical cases were performed using a purely endoscopic approach and we evaluated the impact surgical experience on clinical outcomes. We assessed biochemical remission rates immediately following surgery (within 2 weeks of surgery), at 3 months and at the patient’s most recent follow-up appointment and analyzed predictors of successful remission in our patient group. For those who did not achieve biochemical remission, we detail the treatment course of patients placed under surveillance and those who underwent adjuvant therapy. In doing so, we illustrate a complete picture of the surgical outcomes and subsequent management of an unselected population that may be encountered during the treatment of patients with CD at a dedicated regional center.

Methods

Study Population

We analyzed the medical records of all patients diagnosed with CD who underwent primary surgical treatment at King’s College Hospital, London, between January 2004 and January 2025. Patients were identified from our prospective pituitary multidisciplinary database and cross-referenced with data from the hospital’s clinical coding department and operative database.

Preoperative Investigations

Serum cortisol was measured by chemiluminescent assay (Siemens ADVIA Centaur XP) with a sensitivity of 0.0362 nmol/L. A diagnosis of Cushing syndrome was confirmed by a serum cortisol measurement of >50 nmol/L after administering a 1-mg low-dose dexamethasone suppression test. Additional 24-hour urinary free cortisol measurements (>50 μg/24 hours), late night salivary cortisol measurements (>4 nmol/L), plasma adrenocorticotrophic hormone levels (pg/mL), and 48-hour 2-mg low-dose dexamethasone suppression tests were performed as required. All patients with confirmed Cushing syndrome underwent magnetic resonance imaging (MRI) of the pituitary gland and in equivocal cases patients also underwent corticotrophin-releasing hormone stimulation, high-dose dexamethasone suppression test, and/or inferior petrosal sinus sampling before proceeding to surgery.

Surgical Procedure

Surgery was performed via an endoscopic transnasal transsphenoidal approach in all study patients as described by Jho9 and Cappabianca.10 Image guidance was used in patients with complex or atypical sinus or vascular anatomy, those with very small microadenomas, and in patients undergoing repeat surgery. Complete hypophysectomy (sellar clearance) was performed for patients with MRI-negative Cushing disease. The histological pseudocapsular technique was employed to permit wide exposure of the sella, pituitary, and parasellar region.11,12 If a cerebrospinal fluid (CSF) leak was identified intraoperatively, an autologous adipose tissue graft was positioned in the pituitary fossa and sphenoid sinus and in selected cases a vascularized naso-septal flap was also positioned over the defect.

Postoperative Investigations and Follow-up

Our postoperative protocol included endocrinologic assessment in the early postoperative period, within 72 hours of surgery, and again within the first 2 weeks following surgery. The patient’s initial treatment strategy was defined as any surgical management within 30 days of the patient’s first surgical procedure. If a postoperative CSF leak was suspected, samples of fluid were sent for confirmatory testing of β-2-transferrin. Management of the CSF leak was determined by its severity and included observation alone, insertion of a lumbar drain and a period of bed rest, and surgical repair. Postoperative diabetes insipidus was defined as patients with polyuria requiring ongoing desmopressin therapy 6 months after surgery.
Long-term biochemical assessment of cortisol status was performed on an annual basis, or more frequently depending on the patient’s individual status. A routine postoperative MRI scan was also performed 3 months postoperatively. Remission was defined as an early morning serum cortisol of <50 nmol/L (1.8 μg/dL) requiring substitutive therapy at 3 months postoperatively. Patients who failed to enter remission were considered for further pituitary surgery, radiotherapy, medical treatment, and/or bilateral adrenalectomy. Recurrence was defined as the re-emergence of clinical features of cortisol excess supported by biochemical evidence of cortisol excess as described above. Persistent disease was defined as such was defined as a postoperative basal cortisol(s) > 50 nmol/.

Data Collection

We reviewed the biochemical, radiologic, medical, and surgical records of all study patients. The following data were collected: demographic features, preoperative endocrinologic measurements, radiologic MRI features of the tumor (including tumor visibility on MRI and size), procedural complications (including CSF leak, meningitis, diabetes insipidus [DI], hematoma, visual complications, or new cranial nerve deficits), postoperative endocrinologic assessments, and any further treatments performed.

Statistical Analysis

Categorical data are summarized using frequencies and percentages and continuous data are described using means, standard deviations, medians, and ranges. Associations between categorical variables were assessed using Fisher’s Exact test. Multivariable logistic regression models were performed in which remission statuses at (i) 3 months and (ii) last follow-up were used as outcome variables. The list of predictors of each outcome included patient characteristics (sex, age), tumor category, number of operations performed, and the presence of postoperational complications, which were decided a priori. Subgroup analyses were also performed based on tumor category—microadenomas, macroadenomas, and MRI-negative CD.
Data were collated in Microsoft Excel (Microsoft, Redmond, WA). All statistical analyses were performed using R software version 4.2.1 (R Foundation for Statistical Computing, 2022; r-project.org). P-values less than 0.05 were considered statistically significant.

Ethics Statement

This study was approved by King’s College Hospital’s research committee without the need for informed consent. The study was conducted in accordance with the ethics standards of the institution’s research committee and with the 1964 Helsinki declaration and its later amendments.

Results

Baseline Characteristics

A total of 125 patients including 93 (74.4%) female patients and 32 (25.6%) male patients were diagnosed with CD and had primary endoscopic transsphenoidal surgery during the study period. The median age was 48 years (range: 14–79 years). Fifty-seven patients (45.6%) had a microadenoma, 41 (32.8%) had a macroadenoma, and 26 (20.8%) had no demonstrable focal lesion on pituitary MRI (MRI-negative CD). The median length of follow-up was 3.1 years (range: 1 month to 16.7 years). Of the 125 patients included in our study, 88 patients (70.4%) had a single operation during their initial treatment strategy. Thirty-seven patients (29.6%) had more than 1 operation; 4 patients (3.2%) had 3 operations during the study period. A summary of the baseline characteristics of our patients can be found in Table 1.

Table 1. Baseline Characteristics of the Study Population

Number of Patients 125
Patient variables
 Age Median 48 (range: 14–79) years
 Male 32 (25.6%)
Pituitary characteristics
 Microadenoma 57 (45.6%)
 Macroadenoma 41 (32.8%)
 No focal lesion on pituitary MRI (MRI-negative Cushing’ disease) 26 (20.8%)
Operative variables
 Single operation 88 (70.4%)
 More than 1 operation 33 (26.4%)
 3 operations 4 (3.2%)

Perioperative Complications

Forty patients (32.0%) had a complication following their surgery (Table 2). The overall complication rate for patients undergoing a single procedure was 23.9% (21 of 88) and was significantly lower than the complication rate in patients who had multiple operations: 51.3% (19 of 37) (P = 0.002). The complication rates for different tumor types were not significantly different: microadenoma 33.3% (19 of 57), macroadenoma 36.6% (15 of 41), MRI-negative CD 23.1% (6 of 26) (P = 0.274). There was a significant difference between complications in the second period; Period 1: 8.7% (2 of 23) and Period 2: 37.3% (38 of 102) (P = 0.008).

Table 2. Procedural Complications Encountered in Our Series

Complication N (%)
Any complication 40 (32.0%)
Persistent diabetes insipidus 18 (14.4%)
Cerebrospinal fluid leak 17 (13.6%)
Meningitis 2 (1.6%)
Ventriculitis 1 (0.8%)
Bleeding/haematoma 4 (3.2%)
Visual deterioration 2 (1.6%)
Death 3 (2.4%)
Eighteen patients (14.4%) developed persistent DI following surgery (requiring treatment for more than 6 months which we considered as a complication). Separately, in 12 patients (9.6%) the DI was transient and resolved spontaneously within 6 months of surgery, and 34 patients (27.2%) recovered from transient DI before discharge.
A confirmed postoperative CSF leak occurred in 17 patients (13.6%) and was significantly higher in patients who had multiple procedures; the CSF leak rate was 16.2% (6 of 37) in patients who had multiple procedures versus 12.5% (11 of 88) in those who only had a single procedure (P = 0.004). The type of tumor did not affect the CSF leak rate (P = 0.737). In 3 (2.4%) patients, the leak settled with observation alone. Three (2.4%) patients were managed with only a lumbar drain and 11 (8.8%) patients underwent surgical repair either as an executive decision or after failed lumbar drain. There were 2 (1.6%) cases with new cranial nerve deficits following surgery presenting with visual deterioration and a partial sixth nerve palsy. Two patients developed meningitis (1.6%), 1 (0.8%) developed ventriculitis. Four patients (3.2%) developed postoperative bleeding or hematoma requiring surgical attention.
Three (2.4%) patients died in the immediate perioperative period. One (0.8%) patient developed acute respiratory failure and suffered a cardiac arrest. Significant intraoperative bleeding was encountered in the other 2 cases (1.6%); 1 (0.8%) subsequently died of acute cardiorespiratory instability and the other (0.8%) died because of multiorgan failure following a prolonged stay on the intensive care unit.

Disease Remission

The overall remission rate 2 weeks following surgery was 59.0% (72 of 122), increasing to 60.7% (74 of 122) at 3 months. The remission rate 3 months following surgery was 72.0% (18 of 25) for patients with MRI-negative CD, 77.2% (44 of 57) for microadenomas, and 48.7% (19/39) for macroadenomas. Following adjuvant treatment and further surgery, the overall remission rate at last follow up was 68.0% (85 of 125).
Age, patient sex, tumor category and the number of operations were significant predictors of remission at three months. Age (adjusted odds ratio [aOR]: 1.04, 95% CI: 1.01–1.07, P = 0.009), male sex (aOR: 4.15, 95% CI: 1.64–10.53, P = 0.003), MRI-negative CD (aOR: 2.25, 95% CI: 1.24–4.07, P = 0.008), and single operation (aOR: 3.87, 95% CI: 1.56–9.61, P = 0.004), were predictors of remission at 3 months (Table 3).

Table 3. Multivariable Logistic Regression for Predictors of Remission at Last Follow-up

Outcome Predictor Multivariable Analysis
Adjusted OR (95% CI) P Value
Remission at 3 months Age 1.04 (95%CI: 1.01–1.07) 0.009
Sex† 3.31 (95%CI: 1.31–8.40) 0.011
MRI-negative Cushing disease‡ 1.88 (95%CI: 1.06–3.35) 0.031
Single operation§ 3.87 (95%CI: 1.56–9.61) 0.004
Remission at last follow-up Age 1.00 (95%CI: 0.97–1.04) 0.904
Sex† 2.92 (95%CI: 0.89–9.62) 0.003
MRI-negative Cushing disease‡ 1.84 (95%CI: 0.89–3.79) 0.008
Single operation§ 1.24 (95%CI: 0.36–4.24) 0.730
Remission at 3 months∗ 27.0 (95%CI: 8.47–83.33) <0.001
∗
No remission is used as the reference group.
†
Female is used as the reference group.
‡
Microadenoma is used as the reference group.
§
Multiple operation is used as the reference group.
Additionally, patients were more likely to be in remission at last follow-up if they had achieved remission at 3 months, compared with those who had not (aOR: 31.25, 95% CI: 11.2–90.9, P < 0.001). On multivariable analysis, this remained significant (aOR: 27.0, 95% CI: 8.47–83.33, P < 0.001).
Of the 72 patients who entered remission following surgery, 5 patients (6.9%) had relapsed at their last follow-up. Further intervention was performed/planned in all patients exhibiting recurrence, including repeat surgery and radiotherapy. Four of the 5 recurrences (80.0%) happened within the first 5 years.

Growth Hormone Replacement Therapy

In total, 48.0% (60 of 125) and 40.8% (51 of 125) patients required growth hormone replacement therapy at three months and at last endocrine follow up. Nine (15.0%) patients who initially needed growth hormone replacement, no longer required it at last endocrine follow-up.

Secondary Intervention

Patients with persistent disease are very likely to require a secondary intervention within a short time after initial surgery. The rate of secondary endoscopic transsphenoidal surgery was more common in patients with persistent disease (22 of 53, 41.5%) than those in initial remission (15 of 72, 20.8%) (aOR: 3.52, 95% CI: 1.48–8.38, P = 0.004). The ongoing management of patients with active disease with was tailored to the patient and included medical therapy with metyrapone, chemotherapy (temozolamide), bilateral adrenalectomy, and radiotherapy; either alone or in combination.

DISCUSSION

In one of the largest modern series in the literature, we reviewed the treatment pathway and long-term outcomes of consecutive patients treated for CD at a single regional treatment center over a 20-year period. Several previous studies have examined the surgical outcomes of patients undergoing microscopic surgery and a recent meta-analysis compared the early clinical outcomes of patients undergoing endoscopic surgery.7 However, there remains little evidence concerning the optimal long-term management of CD patients who do not immediately enter remission following surgery. Given the potential complications of CD and the challenges in managing recurrent disease, our center considers treating any patient with a cortisol of >50 nmol/L (1.8 μg/dL).

Remission

A postoperative cortisol of <50nmol/L is a good predictor of remission but not a guarantee and patients should be advised accordingly. The most conclusive finding of our study was that patients who achieved remission at 3 months were 3 times as likely to still be in remission at their last follow-up, having accounted patient and tumor characteristics. The overall initial 3-month remission rate for patients in our series was 60.7% and is comparable to other studies that have used a similarly low early morning serum cortisol level of <50 nmol/L (1.8 μg/dL) to define remission.13, 14, 15 Despite this, patients achieving early remission remain at risk of relapse with a 5-year recurrence rate of 6.9%. In addition, those with persistent disease are very likely to require a secondary intervention within a short time after initial surgery.
Using an early morning serum cortisol level of 50 nmol/L(1.8 μg/dL). to define remission enabled us to label a subgroup of patients with moderately lowered cortisol levels (50–150 nmol/L [1.8–5.4 μg/dL]) that were placed under close surveillance. It has been demonstrated that patients with postoperative cortisol of 55–137nmol/L (equivalent to 2–5.4 μg/dL) have a higher risk of late recurrence.12 We considered patients with a cortisol of greater than 150 nmol/L to be candidates for early secondary intervention without delay.
Radiotherapy, delivered by conventional external beam radiotherapy or via stereotactic radiosurgery, is typically used as a second-line treatment in CD patients after failure of initial or repeat pituitary surgery.8 In other centers, patients with similar moderately lowered cortisol level would have been labeled as being in remission and would not have been offered adjuvant radiotherapy. However, by closely observing the biochemical trends of these patients in the months following surgery we were able to offer further intervention at an earlier stage, thus avoiding the potentially harmful sequelae of untreated CD. In future work, it would be helpful to compare the long-term clinical outcomes of patients with moderately lowered serum cortisol levels who received early adjuvant therapy with patients who had similar biochemical results but did not receive adjuvant treatment.
Finally, we observed a statistically and clinically significant association between patient sex and tumor type on remission—a finding not previously reported. The underlying reasons for this result are unclear but further work should examine if, and how, the biology and histologic characteristics of adenomas changes with sex and age.9,16, 17, 18

Complications

Previous studies elected not to report the overall complication rate, hence at first sight, our overall complication rate of 32.0% may appear high even though the rate of individual specific complications are similar to those previously reported (Table 2).7, 8,15, 19 Postoperative complications were significantly higher in patients who underwent more procedures.
The overall perioperative mortality rate of 2.4% (n = 3) observed in this series is comparable with other published studies.7,8 One patient developed acute respiratory failure in the early postoperative period and died on day 3 following surgery. In the other cases significant intracavernous and intracranial bleeding was encountered and controlled; one patient subsequently developed acute cardiorespiratory instability and died on day 5; the other developed multiorgan failure and died following a prolonged stay on the intensive care unit. Following an internal review of these deaths we lowered our threshold for giving preoperative medical treatment such as ketoconazole or metyrapone in potential high-risk cases, particularly in those patients presenting with more severe clinical features at diagnosis. Preoperative medical treatment improves the quality of the tissues and increases the patient’s physiological reserve in preparation for surgery.14 In the ERCUSYN study, patients with severe clinical features who were treated preoperatively experienced comparable outcomes to those patients with milder features who were not treated with medical treatment before surgery. This justifies our approach to treat the more severe cases medically in the first instance. Nevertheless, preoperative medical treatment may confound the interpretation of early postoperative serum cortisol levels so close monitoring of these patients is required in the first few months following surgery.14 Since this change in practice, no deaths have occurred in patients undergoing surgery for CD at our unit.

Limitations

CD is a rare disease, and this study offers one of the larger modern series with practical illustrations of multidisciplinary practice at a tertiary pituitary center. Despite its size, this study did confirm that patients who achieved remission at 3 months were more likely to be in remission at the last follow-up. Patient and tumor characteristics were also important factors to consider. This study is nonetheless limited by lack of data on residual tumors found in postoperative MRIs. As such, we were unable to investigate further on the subgroup of patients without biochemical remission who had residual tumors. Furthermore, we do not fully know the proportion of MRI-negative patients who harbored an adenoma on histopathology, which may have skewed our findings. Further multi-institutional research is required to determine if patients with moderately lowered serum cortisol levels who receive early adjuvant radiotherapy have improved long-term clinical outcomes.

Conclusions

Despite good initial remission rates following endoscopic transsphenoidal surgery, this study demonstrated significant recurrence of CD. Nevertheless, patients who achieved initial biochemical remission (serum cortisol <50 nmol/L [1.8 μg/dL]) at 3 months were significantly more likely to achieve long-term biochemical remission. Selected patients with moderately lowered serum cortisol (serum cortisol 50–150 nmol/L [1.8–5.4 μg/dL]) responded well to early adjuvant radiotherapy but further research is required to determine their long-term clinical outcomes.

CRediT authorship contribution statement

Jonathan Shapey: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. Keng Siang Lee: Data curation, Formal analysis, Visualization, Writing – original draft. Vanitha Karunakaran: Formal analysis, Visualization, Writing – review & editing. Mohamed Okasha: Data curation, Writing – review & editing. Proma Dey: Data curation. Sabina Pate: Data curation. Mariusz T. Grzeda: Formal analysis, Writing – review & editing. Jackie Gilbert: Data curation, Writing – review & editing. Paul V. Carroll: Data curation, Writing – review & editing. Benjamin Whitelaw: Data curation, Writing – review & editing. Konstantinos Barkas: Data

curation, Writing – review & editing. Eleni Maratos: Data curation, Writing – review & editing. Sinan Barazi: Data curation, Writing – review & editing. Simon Aylwin: Data curation, Methodology, Supervision, Writing – original draft, Writing – review & editing. Nick WM. Thomas: Conceptualization, Data curation, Methodology, Supervision, Writing – review & editing.

References

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Identification Of Potential Markers For Cushing’s Disease

Posted on January 27, 2026 by MaryO

Endocr Pract. 2016 Jan 20. [Epub ahead of print]

Broder MS1, Chang E1, Cherepanov D1, Neary MP2, Ludlam WH2.

Author information

Abstract

OBJECTIVE:

Cushing’s disease (CD) causes a wide variety of nonspecific symptoms, which may result in delayed diagnosis. It may be possible to uncover unusual combinations of otherwise common symptoms using ICD-9-CM codes. Our aim was to identify and evaluate dyads of clinical symptoms or conditions associated with CD.

METHODS:

We conducted a matched case-control study using a commercial healthcare insurance claims database, designed to compare the relative risk (RR) of individual conditions and dyad combinations of conditions among patients with CD versus matched non-CD controls.

RESULTS:

With expert endocrinologist input, we isolated 10 key conditions (localized adiposity, hirsutism, facial plethora, polycystic ovary syndrome, abnormal weight gain, hypokalemia, deep venous thrombosis, muscle weakness, female balding, osteoporosis) with RR varying from 5.1 for osteoporosis to 27.8 for hirsutism. The RR of dyads of these conditions ranged from 4.1 for psychiatric disorders/serious infections to 128.0 for hirsutism/fatigue in patients with vs. without CD. Construction of uncommon dyads resulted in further increases in RR beyond single condition analyses, such as osteoporosis alone had RR of 5.3, which increased to 8.3 with serious infections and to 52.0 with obesity.

CONCLUSION:

This study demonstrated that RR of any one of 10 key conditions selected by expert opinion was ≥5 times greater in CD compared to non-CD, and nearly all dyads had RR≥5. An uncommon dyad of osteoporosis and obesity had an RR of 52.0. If clinicians consider the diagnosis of CD when the highest-risk conditions are seen, identification of this rare disease may improve.

KEYWORDS:

Cushing’s disease; delay in diagnosis; disease markers; insurance claims; relative risk

PMID:
26789346
[PubMed – as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/26789346

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Cushing’s Syndrome Subtype Affects Postoperative Time to Adrenal Recovery

Posted on January 25, 2026 by MaryO

Berr CM. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2014-3632.

January 16, 2015

In patients undergoing curative surgical tumor resection for Cushing’s syndrome, the time to recovery of adrenal function is contingent upon the underlying etiology of the disease, according to recent findings.

In the retrospective study, researchers reviewed case records of 230 patients with Cushing’s syndrome. All patients were seen at a tertiary care center in Munich between 1983 and 2014, whose cases were documented in the German Cushing’s Registry. Patients were divided into three subgroups of Cushing’s syndrome: Cushing’s disease, adrenal Cushing’s syndrome and ectopic Cushing’s syndrome.

After applying various exclusion criteria, the researchers identified 91 patients of the three subgroups who were undergoing curative surgery at the hospital. The patients were followed for a median of 6 years. The researchers defined adrenal insufficiency as the need for hydrocortisone replacement therapy, and collected this information from patient records and laboratory results.

The duration of adrenal insufficiency was calculated as the interval between successful surgery and the completion of hydrocortisone replacement therapy. Cushing’s syndrome recurrence was defined as biochemical and clinical signs of hypercortisolism.

The researchers found a significant difference between Cushing’s syndrome subtypes in the likelihood of regaining adrenal function within 5 years of follow-up: The probability was 82% in ectopic Cushing’s syndrome, 58% in Cushing’s disease and 38% in adrenal Cushing’s syndrome (P=.001). Among the 52 participants who recovered adrenal function, the median type to recovery also differed between subtypes and was 0.6 years in ectopic Cushing’s syndrome, 1.4 years in Cushing’s disease and 2.5 years in adrenal Cushing’s syndrome (P=.002).

An association also was found between younger age and adrenal recovery in the Cushing’s disease participants (P=.012).

This association was independent of sex, BMI, symptom duration, basal adrenocorticotropic hormone and cortisol levels. No association was seen between adrenal recovery and length of hypercortisolism or postoperative glucocorticoid replacement dosage.

“It is the main finding of this series that the median duration of tertiary adrenal insufficiency was dependent on the etiology of [Cushing’s syndrome]: It was shortest in the ectopic [Cushing’s syndrome], intermediate in [Cushing’s disease] and longest in adrenal [Cushing’s syndrome] caused by unilateral cortisol producing adenoma,” the researchers wrote. “The significant difference to [Cushing’s disease] is an unexpected finding since by biochemical means cortisol excess is generally less severe in adrenal [Cushing’s syndrome]. If confirmed by others, our data have clinical impact for the follow-up of patients after curative surgery: Patients should be informed that adrenocortical function may remain impaired in benign conditions such as cortisol-producing adenoma.”

Disclosure: The study was funded in part by the Else Kröner-Fresenius Stiftung.

The original article is here: Healio

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COVID-19 May Be Severe in Cushing’s Patients

Posted on January 23, 2026 by MaryO

A young healthcare worker who contracted COVID-19 shortly after being diagnosed with Cushing’s disease was detailed in a case report from Japan.

While the woman was successfully treated for both conditions, Cushing’s may worsen a COVID-19 infection. Prompt treatment and multidisciplinary care is required for Cushing’s patients who get COVID-19, its researchers said.

The report, “Successful management of a patient with active Cushing’s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia,” was published in Endocrine Journal.

Cushing’s disease is caused by a tumor on the pituitary gland, which results in abnormally high levels of the stress hormone cortisol (hypercortisolism). Since COVID-19 is still a fairly new disease, and Cushing’s is rare, there is scant data on how COVID-19 tends to affect Cushing’s patients.

In the report, researchers described the case of a 27-year-old Japanese female healthcare worker with active Cushing’s disease who contracted COVID-19.

The patient had a six-year-long history of amenorrhea (missed periods) and dyslipidemia (abnormal fat levels in the body). She had also experienced weight gain, a rounding face, and acne.

After transferring to a new workplace, the woman visited a new gynecologist, who checked her hormonal status. Abnormal findings prompted a visit to the endocrinology department.

Clinical examination revealed features indicative of Cushing’s syndrome, such as a round face with acne, central obesity, and buffalo hump. Laboratory testing confirmed hypercortisolism, and MRI revealed a tumor in the patient’s pituitary gland.

She was scheduled for surgery to remove the tumor, and treated with metyrapone, a medication that can decrease cortisol production in the body. Shortly thereafter, she had close contact with a patient she was helping to care for, who was infected with COVID-19 but not yet diagnosed.

A few days later, the woman experienced a fever, nausea, and headache. These persisted for a few days, and then she started having difficulty breathing. Imaging of her lungs revealed a fluid buildup (pneumonia), and a test for SARS-CoV-2 — the virus that causes COVID-19 — came back positive.

A week after symptoms developed, the patient required supplemental oxygen. Her condition worsened 10 days later, and laboratory tests were indicative of increased inflammation.

To control the patient’s Cushing’s disease, she was treated with increasing doses of metyrapone and similar medications to decrease cortisol production; she was also administered cortisol — this “block and replace” approach aims to maintain cortisol levels within the normal range.

The patient experienced metyrapone side effects that included stomach upset, nausea, dizziness, swelling, increased acne, and hypokalemia (low potassium levels).

She was given antiviral therapies (e.g., favipiravir) to help manage the COVID-19. Additional medications to prevent opportunistic fungal infections were also administered.

From the next day onward, her symptoms eased, and the woman was eventually discharged from the hospital. A month after being discharged, she tested negative for SARS-CoV-2.

Surgery for the pituitary tumor was then again possible. Appropriate safeguards were put in place to protect the medical team caring for her from infection, during and after the surgery.

The patient didn’t have any noteworthy complications from the surgery, and her cortisol levels soon dropped to within normal limits. She was considered to be in remission.

Although broad conclusions cannot be reliably drawn from a single case, the researchers suggested that the patient’s underlying Cushing’s disease may have made her more susceptible to severe pneumonia due to COVID-19.

“Since hypercortisolism due to active Cushing’s disease may enhance the severity of COVID-19 infection, it is necessary to provide appropriate, multidisciplinary and prompt treatment,” the researchers wrote.

From https://cushingsdiseasenews.com/2021/01/15/covid-19-may-be-severe-cushings-patients-case-report-suggests/?cn-reloaded=1

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Insulin Resistance Unveiled: Cushing’s Disease in a Patient with Type 1 Diabetes Mellitus and Worsening Glycemic Control

Posted on January 22, 2026 by MaryO

Highlights

  • Coexistence of hypercortisolism secondary to ACTH-producing pituitary adenoma and type 1 diabetes mellitus.
  • Presentation of Cushing’s disease in individuals with type 1 diabetes mellitus.
  • Automated insulin delivery utilization in type 1 diabetes with comorbid refractory hypercortisolism.

ABSTRACT

Background/Objective

Type 1 diabetes mellitus is an autoimmune disease often characterized by endogenous insulin deficiency and often sensitivity to endogenous insulin administration. Cushing’s disease, though rare, should be considered as a cause of insulin resistance and increased insulin requirements in individuals with type 1 diabetes mellitus.

Case Presentation

A 21-year-old female with type 1 diabetes mellitus presented with steadily increasing insulin requirements via her hybrid closed-loop insulin pump. She subsequently developed hypertension, weight gain, violaceous striae, and cystic acne. Laboratory evaluation revealed unsuppressed cortisol of 16.6 μg/dL after a 1-mg dexamethasone suppression test, with a simultaneous adrenocorticotropin hormone level of 73.3 pg/mL. Pituitary MRI showed a 1.9 cm sellar mass with local invasion. She underwent transsphenoidal hypophysectomy. Postoperative cortisol was 8.9 μg/dL after intraoperative dexamethasone exposure. Residual hypercortisolism was confirmed, necessitating gamma knife radiation and pharmacologic treatment with a steroidogenesis inhibitor.

Discussion

We present a case of Cushing’s disease due to a corticotropin-secreting pituitary macroadenoma in a young woman with type 1 diabetes. Her initial presentation included rising insulin requirements, followed by overt hypercortisolism. Despite surgery, persistent hypercortisolism required further intervention with gamma knife radiation and osilodrostat. She experienced reductions in both weight and insulin needs, with normalization of cortisol levels on maintenance osilodrostat.

Conclusion

Cushing’s syndrome should be considered in the differential diagnosis of patients with type 1 diabetes and increasing insulin requirements. This case underscores the importance of regular review of automated insulin delivery data and consideration of endocrine causes of insulin resistance and increased insulin requirements in those with type 1 diabetes.

KEY WORDS

Type 1 Diabetes Mellitus
T1DM
Cushing’s disease
Insulin resistance
Insulin pump
Total Daily Dose
TDD

Introduction

Cushing’s syndrome occurs as the result of prolonged elevation in plasma cortisol which can lead to adverse effects including insulin resistance, hyperglycemia, hypertension, weight gain, immunosuppression, and neurocognitive changes. Cushing’s syndrome can occur due to exogenous exposure to corticosteroids or endogenous cortisol hypersecretion. The most common etiology of endogenous hypercortisolism is Cushing’s disease secondary to a corticotrophin-secreting pituitary tumor. In 90% of cases of Cushing’s disease, patients present with pituitary microadenomas, with only 10% of patients presenting with pituitary tumors >1 cm1.
Type 1 diabetes mellitus is an autoimmune condition characterized by T-cell mediated destruction of pancreatic beta cells with ultimate inability to produce insulin and subsequent insulin dependence2. Over the last decade, there has been significant advancement in diabetes management strategies and insulin delivery with creation of hybrid closed-loop insulin pump technology used in conjunction with continuous glucose monitoring systems to provide automated insulin delivery. Within the field of endocrinology, this has required a shift in both the interpretation of glycemic data, insulin utilization data, as well as a pivot to approaching titration of insulin pump settings. Assessment of total daily basal and total daily dose (TDD) in automated mode is of utmost importance when utilizing automated insulin delivery as the amount of insulin utilized can vary significantly in comparison to fixed quantities seen with use of manual mode in an insulin pump2,3.
Type 1 diabetes mellitus is typically characterized by relative insulin sensitivity, particularly early in the disease course. Patients can develop insulin resistance over time, particularly in the setting of comorbid obesity. However, we present a case of a young woman with type 1 diabetes mellitus presenting with steadily increasing insulin requirements followed by development of overt Cushing’s secondary to corticotropin-secreting pituitary macroadenoma. She was utilizing a hybrid-closed loop insulin pump technology with insulin pump download indicating diminished glycemic control despite a steady increase in total daily insulin requirements. This is only the third reported case of Cushing’s disease in a person living with type 1 diabetes mellitus4,5.

Case Presentation

A 21-year-old female with a history of type 1 diabetes diagnosed at age 11 in the context of admission for diabetic ketoacidosis initially presented to adult endocrinology for routine outpatient diabetes management. Type 1 Diabetes Mellitus was managed with automated hybrid-closed loop insulin pump technology (Tandem T-slim X:2 with Dexcom G6 continuous glucose monitoring system). Her hemoglobin A1c was 6.2% with a review of her continuous glucose monitoring system indicating time in range of 73% with 21% of blood glucose levels >180 mg/dL. At that time, she reported concerns regarding high insulin requirements despite an active lifestyle as she was running out of insulin for use in pump early. She was noted to have significant prandial insulin requirements with insulin to carbohydrate ratio of 1 unit for every 3.0-4.5 carbohydrates, raising concern for insulin resistance. Over the next 16 months, she had weight gain of 15.8 kg with elevation in blood pressure and worsening hyperglycemia. Review of her insulin pump downloads indicated a steady increase in her total daily insulin requirements of close to 30%, coupled with reduced time in range and increase in HbA1c.
On repeat physical examination, the development of cystic acne, trace pitting pedal edema, and purple violaceous striae on the abdomen, hips, and thighs were observed. She was also noted to have a new elevation of blood pressure to 162/101 mm Hg. She declined exposure to exogenous corticosteroids (including oral, topical or intra-articular formulations). Based on clinical examination and changes in insulin requirements, the decision was made to evaluate for hypercortisolism. Laboratory evaluation at that time revealed unsuppressed 08:00 AM cortisol level of 16.6 ug/dL after 1 mg of dexamethasone the evening prior. Dexamethasone level was confirmed to be more than adequate at 418 ng/dL (reference range for 8:00 AM level following 1 mg dexamethasone previous evening: 140-295 ng/dL). A simultaneous ACTH level was elevated at 73.3 pg/mL (reference range: 7.2-63.3 pg/mL). She was also noted to have midnight salivary cortisol levels of 0.646, 0.290, and 0.350 ug/dL on three consecutive evenings (reference range <0.010-0.090 ug/dL).
She then underwent MRI pituitary with and without gadolinium enhancement which revealed 1.8 x 1.9 cm enhancing sellar mass with invasion of the right cavernous sinus, extension around the right internal carotid artery, as well as posteriorly down the dorsal aspect of the clivus (Figures 1 and 2). As both hypercortisolism as well as type 1 diabetes mellitus have been implicated as etiologies for lower bone density with subsequent increased risk of osteoporosis later in life, bone densometry was also obtained for this patient. She was found to have low bone mineral density for her age with Z-score of the lumbar spine of -3.2, Z-score of the femoral neck of -2.3, and Z-score of the total hip of -2.8.

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Figure 1. MRI pituitary coronal image revealing sellar mass with invasion of the right cavernous sinus, extension around the right internal carotid artery.

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Figure 2. MRI pituitary sagittal image revealing 1.8 x 1.9 cm sellar mass.

She was evaluated by neurosurgery and underwent endoscopic trans-sphenoidal resection of pituitary macroadenoma. Pathology revealed immunoreactivity for neuroendocrine marker INSM1 (Insulinoma-associated protein 1) and adrenocorticotropic hormone. The lesion was negative for immunoreactivity for prolactin, growth hormone, thyroid-stimulating hormone, follicle-stimulating hormone, and beta-luteinizing hormone.
The cortisol level was 8.9 ug/dL on post-operative day 1. It is notable that she had received 10 mg of intravenous Dexamethasone intraoperatively, raising concern for residual tumor. On post-operative day 3, cortisol level was 4.1 mcg/dL with ACTH level of 94.5 pg/mL. Repeat random cortisol level was 16.3 mcg/dL with simultaneous ACTH level of 63.3 pg/mL. Upon being discharged home, a repeat 24-hour urinary free cortisol was obtained in the outpatient setting and found to be elevated at 464 ug/24 hours (reference range: 6-42 ug/24 hours), consistent with refractory hypercortisolism (Table 1, Figure 4). She was then initiated on osilodrostat, a steroidogenesis inhibitor approved by the FDA in 2020 for use in refractory Cushing’s disease after pituitary surgery. Osilodrostat works via inhibition of 11β-hydroxylase and aldosterone synthase to inhibit the production of cortisol and aldosterone6,7. She underwent ongoing up titration to a maintenance dose of osilodrostat 7 mg twice daily with additional insulin pump titrations over a 2-year duration. Urinary free cortisol was monitored as this is the gold standard for monitoring refractory Cushing’s and the preferred modality for monitoring cortisol levels in individuals on osilodrostat. Final repeat 24-hour urine free cortisol level normalized to 35 ug/24 hours and TDD of insulin via automatic insulin delivery system was lower than time of diagnosis of pituitary Cushing’s at 96 units per day despite having had a roughly 27 kg weight gain (Table 1, Figure 4).

Table 1. Weight trends as well as TDD of insulin listed along with glycemic parameters from automated insulin dosing system Tandem T-slim X:2 with automated mode utilizing Decom G6 CGM. 24-hour urine cortisol collection data included to highlight degree of hypercortisolism. Treatments denoted by asterisk in table include

Date Weight (kg) Total daily insulin dose (units/day) HbA1c (%) Time in range (%) Urine cortisol (mcg/24 hours); RR 6-42 mcg/24 hours
03/2021 72.7 99.25 6.2 73
06/2021 74.5 109.56 6.6 73
12/2021 80.0 117.17 6.9 62
05/2022 88.5 126.84 6.9 57
11/2022∗ – – – –
12/2022 93.8 124.15 7.0 61 464
01/2023∗∗ – – – –
02/2023 35
06/2023∗∗∗ – – – –
06/2023 100.4 122.76 7.0 54
07/2023 137
12/2023 100.9 130.34 6.8 48 48
08/2024 106 125 6.9 58 76
02/2025 100 96 5.8 76 42
∗
Transsphenoidal resection.
∗∗
Osilodrostat initiated.
∗∗∗
Gamma knife radiosurgery.

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Figure 3. MRI pituitary coronal image revealing right eccentric heterogenous enhancing sellar mass which is decreased in size. Redemonstrated residual tissue around the right carotid artery.

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Figure 4. Graphical representation of weight (kg), total daily dose of insulin (units per day), and 24-hour urine cortisol measurements (mcg/24 hours).

Due to ongoing hypercortisolism, repeat MRI pituitary with and without gadolinium enhancement was obtained and revealed residual disease in the right sella with right cavernous sinus involvement and extending posteriorly along the dorsal aspect of the clivus (Figure 3). She had subsequent consultation with neurosurgery at which time the decision made to proceed with single-fraction gamma knife stereotactic radiosurgery. She received additional treatment of gamma knife radiosurgery with dose of 18 Gy to target residual pituitary disease.

Discussion

We present, to our knowledge, the third reported case of Cushing’s disease due to a corticotropin-secreting pituitary adenoma in an individual with type 1 diabetes. Prolonged hypercortisolism, as seen in this case, is associated with obesity, hypertension, decreased bone density, insulin resistance, and decreased glucose control. Hypercortisolism is most commonly caused by chronic exogenous corticosteroid exposure however, endogenous hypercortisolemia should be considered as a potential etiology of worsening glycemia and insulin resistance in individuals with diabetes mellitus.
The coexistence of Cushing’s disease secondary to a corticotropin-secreting pituitary macroadenoma in an individualwith type 1 diabetes mellitus is exceedingly rare. Furthermore, only 10% of pituitary Cushing’s cases present with macroadenomas at the time of diagnosis. Several studies indicate that smaller lesions at the time of diagnosis and earlier diagnosis of Cushing’s disease are associated with reduced risk of disease recurrence6,7,8. In this case, a young female presented with a macroadenoma at the time of diagnosis and had residual post-operative hypercortisolism requiring gamma knife radiation and pharmacologic intervention with osilodrostat, a steroidogenesis inhibitor approved by the FDA in 2020 for use in refractory Cushing’s disease after pituitary surgery. Osilodrostat works via inhibition of 11β-hydroxylase and aldosterone synthase to inhibit the production of cortisol and aldosterone9,10. Of the two other reported cases of comorbid type 1 diabetes and Cushing’s disease, one individual presented with a macroadenoma at the time of diagnosis. This case occurred in a pediatric male with type 1 diabetes mellitus who was ultimately admitted to the hospital with worsening headaches in the setting of pituitary apoplexy. Prior to hospitalization, this individual showed numerous clinical stigmata of hypercortisolism.
Other contributors to increased insulin resistance, such as obesity, infection, stress, and concurrent glucocorticoids, should also be considered in the differential diagnosis when evaluating etiologies for unexplained changes in glycemic control. However, this case emphasizes the importance of considering the possibility of comorbid Cushing’s disease in persons with type 1 diabetes mellitus. This is imperative to mitigate the consequences of prolonged hypercortisolism and to potentially aid in earlier diagnosis. In this case, declining glucose control and increasing insulin requirements were noted prior to other overt clinical findings of hypercortisolism. Thus, this case also underscores the importance of steadfast evaluation of insulin dose requirements for individuals using continuous insulin infusion devices (particularly hybrid closed-loop automated insulin delivery [AID] systems). With growing emphasis on the review and utilization of the one-page ambulatory glucose profile, it is important to also review insulin pump settings and insulin delivery for those utilizing these systems as automated insulin delivery profile for total daily dose can change and should be reviewed at each visit.

Conclusion

In closing, this case emphasizes the importance of considering secondary endocrine disorders in those living with diabetes mellitus who experience sudden or unexplained changes in glycemic control and insulin requirements. Although rare, coexistence of type 1 diabetes and Cushing’s disease can occur. Prompt recognition and treatment of the underlying Cushing’s disease can lead to significant improvements in insulin sensitivity and glycemic outcomes. This report reinforces the need for multidisciplinary management of vigilant monitoring in patients with coexisting endocrine pathologies, particularly when advanced diabetes technologies are in use. Ultimately, it highlights the critical role of clinical suspicion and timely intervention in optimizing outcomes for complex endocrine cases.

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References

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