Global Longitudinal Strain Reduction With Apical Sparing in Cushing Syndrome-Related Heart Failure With Preserved Ejection Fraction (HFpEF): A Case Report

Posted on December 5, 2025 by MaryO

Abstract

We describe a case of a 56-year-old woman with a history of recurrent pituitary adenoma, not well followed, and known comorbidities of coronary artery disease, hypertension, and type 2 diabetes mellitus. She arrived with severely high blood pressure and signs pointing to hypercortisolism. Further evaluation revealed left ventricular hypertrophy, reduced global longitudinal strain, and preserved left ventricular ejection fraction, consistent with heart failure with preserved ejection fraction (HFpEF). Workup for amyloidosis was negative. This case highlights that chronic hypercortisolism may cause pathophysiological changes in the heart, leading to HFpEF, and may induce myocardial fibrosis and impaired myocardial mechanics, producing an echocardiographic pattern that can mimic infiltrative cardiomyopathy. Recognition of this overlap is crucial to avoid misdiagnosis and to ensure timely endocrine and cardiovascular management.

Introduction

Hypercortisolism is defined as a clinical condition resulting from excessive tissue exposure to cortisol or other glucocorticoids. Sustained exposure ultimately leads to Cushing syndrome (CS), a well-established constellation of clinical manifestations arising from chronic endogenous or exogenous cortisol excess [1]. CS is associated with profound metabolic derangements that significantly increase cardiovascular risk, not only during the active phase of the disease but also persisting long after biochemical remission [2,3]. Cardiovascular complications, including premature atherosclerosis, coronary artery disease (CAD), heart failure, and cerebrovascular events, are major contributors to the excess mortality observed in CS compared with the general population [1,3]. Among these complications, arterial hypertension remains the most frequent cardiovascular disorder in patients with Cushing disease (CD) [4].

Although left ventricular (LV) systolic function is generally preserved in patients with CS, several studies have demonstrated that chronic cortisol excess induces structural and functional cardiac alterations, predisposing to major adverse cardiac events and the development of heart failure [5] In the broader context of chronic congestive heart failure, disease progression is tightly coupled with activation of neuroendocrine stress pathways, most notably the hypothalamic-pituitary-adrenal axis, which governs cortisol secretion [6]. Cortisol, a pivotal stress hormone, increases in response to physiological strain, and its sustained elevation contributes to adverse myocardial remodeling.

Heart failure with preserved ejection fraction (HFpEF), a chronic and progressive syndrome, exemplifies the deleterious effects of persistent myocardial stress. While overt heart failure is an uncommon complication of CS, when it does occur, it most often presents with preserved LV ejection fraction (LVEF) or with subclinical LV dysfunction [7]. Prior evidence has also linked CS to LV hypertrophy, diastolic dysfunction, and subtle systolic impairment, with many of these changes demonstrating reversibility upon normalization of cortisol levels [8].

This case is unique as it highlights the interplay between CS and cardiac amyloidosis, emphasizing their overlapping yet distinct echocardiographic features. Global longitudinal strain (GLS), a measure of myocardial deformation, is particularly useful for differentiating these conditions and reveals subtle differences in strain patterns between the two.

Case Presentation

A 56-year-old woman with a significant past medical history of recurrent pituitary macroadenoma, treated with two prior surgical resections, the most recent five years earlier without subsequent follow-up, CAD, long-standing hypertension, and type 2 diabetes mellitus, presented to the emergency department with hypertensive urgency.

On arrival, she presented with a hypertensive crisis, with blood pressure measured at 200/110 mmHg, associated with severe cephalalgia, without syncope, visual changes, or focal neurological deficits. An MRI Brain demonstrated no evidence of acute intracranial hemorrhage or mass effect (Video 1). Initial laboratory testing showed normal complete blood count, renal function, and serum electrolytes. On physical examination, she exhibited characteristic Cushingoid stigmata, including rounded moon facies, central adiposity, and bilateral lower-extremity pitting edema.

She was commenced on intensive antihypertensive therapy, including spironolactone, clonidine, telmisartan, carvedilol, amlodipine, and intravenous furosemide (20 mg, subsequently escalated to 40 mg). Given her clinical appearance and history of pituitary disease, an endocrine evaluation was undertaken. An overnight dexamethasone suppression test revealed an unsuppressed morning cortisol of 360 nmol/L, consistent with hypercortisolism.

Cardiac assessment supported a diagnosis of HFpEF. Transthoracic echocardiography demonstrated preserved left ventricular ejection fraction (60%), impaired GLS (-10%), and mild concentric left ventricular hypertrophy (Figure 1; Video 2).

Transthoracic-echocardiography-demonstrating-reduced-global-longitudinal-strain-(-10%)-consistent-with-preserved-EF-(60%)
Figure 1: Transthoracic echocardiography demonstrating reduced global longitudinal strain (-10%) consistent with preserved EF (60%)

EF: Ejection Fraction

Workup for alternative causes of HFpEF, including renal impairment and infiltrative cardiomyopathy, was unremarkable; both serum and urine protein electrophoresis with immunofixation excluded amyloidosis.

Magnetic resonance imaging of the pituitary revealed recurrence of the macroadenoma. The patient was referred to neurosurgery for consideration of repeat resection, and glucocorticoid-sparing medical therapy was initiated. During hospitalization, her blood pressure was gradually stabilized, diuretic therapy improved signs of congestion, and her functional status returned to near baseline with restored mobility (Video 3).

Discussion

Epidemiology and clinical significance

CD is a severe endocrine disorder characterized by chronic exposure to excess glucocorticoids. Patients with CD have a two- to fivefold higher mortality compared with the general population, predominantly due to cardiovascular complications [4]. Chronic hypercortisolism is associated with systemic hypertension, left ventricular hypertrophy (LVH), diastolic dysfunction, and accelerated atherosclerosis, increasing the risk of myocardial ischemia and heart failure. While these cardiovascular manifestations are common, the development of isolated dilated cardiomyopathy (DCM) in the absence of other major comorbidities is rare but clinically noteworthy [9].

Pathophysiology of cardiac involvement

Chronic glucocorticoid excess contributes to cardiovascular remodeling via multiple mechanisms. Persistent hypertension and metabolic disturbances promote LVH and diastolic dysfunction. Additionally, glucocorticoid excess induces endothelial dysfunction, insulin resistance, and myocardial fibrosis, impairing ventricular compliance and predisposing to HFpEF [1,6]. Advanced echocardiographic techniques, such as GLS, can detect subclinical systolic dysfunction before overt reductions in LVEF [6]. In our patient, preserved LVEF (60%) coupled with markedly reduced GLS (-10%) and concentric LVH was consistent with HFpEF secondary to chronic cortisol excess, further supported by clinical signs of volume overload such as edema and severe hypertension [7].

Apical sparing and mimicking amyloidosis

An important observation in this case was relative apical sparing despite markedly reduced GLS, a strain pattern classically associated with cardiac amyloidosis [10]. Although infiltrative disease was excluded (negative serum and urine protein electrophoresis with immunofixation), this overlap illustrates how hypercortisolism-induced remodeling can phenocopy amyloidosis on imaging. Recent work has shown that hypercortisolism, beyond metabolic derangements, impairs myocardial mechanics and contractile efficiency [11]. Thus, patients with atypical strain findings should undergo careful endocrine evaluation to avoid misdiagnosis. Ultimately, the recognition that hypercortisolism may produce amyloid-like echocardiographic signatures has both diagnostic and management implications. It broadens the differential diagnosis of HFpEF and stresses the need for a multidisciplinary approach involving endocrinology and cardiology to prevent misdiagnosis and ensure tailored therapy.

Dilated cardiomyopathy in CS

Although uncommon, DCM with severe LV systolic dysfunction has been described in CS. Frustaci et al. reported eight cases of hypercortisolism due to adrenal adenoma among 473 patients with DCM (1.7%), all presenting with LVEF <30% and symptomatic heart failure. Endomyocardial biopsy revealed cardiomyocyte hypertrophy, interstitial fibrosis, and myofibrillolysis, distinct from idiopathic DCM and valvular disease controls. Follow-up biopsies in three patients one year post-adrenalectomy demonstrated substantial regression of these changes, highlighting the reversibility of glucocorticoid-induced myocardial injury [12].

Although not assessed in our patient, prior studies have implicated atrogin-1 in CS-related myocardial remodeling. At the molecular level, upregulation of atrogin-1, an E3 ubiquitin ligase expressed in skeletal, smooth, and cardiac muscle, was observed in CS-associated DCM compared with idiopathic DCM and controls [13]. Atrogin-1, implicated in skeletal muscle atrophy and sarcopenia, facilitates proteasomal degradation of intracellular proteins. Its overexpression in cardiomyocytes contributes to glucocorticoid-mediated myocardial remodeling. Importantly, atrogin-1 expression declined significantly following surgical correction of cortisol excess, paralleling improvements in cardiac structure and function. This reversibility mirrors recovery seen in glucocorticoid-induced skeletal myopathy and underscores the unique potential for cardiac recovery in CS-related DCM [9].

Clinical implications and differential diagnosis

This case underscores the multisystem burden of endogenous hypercortisolism, with particular cardiovascular susceptibility [1,6]. Chronic cortisol excess should be considered in the differential diagnosis of HFpEF, particularly when conventional risk factors coexist with systemic features such as central obesity, moon facies, and proximal myopathy [8]. Secondary causes of HFpEF, including cardiac amyloidosis, were excluded, supporting hypercortisolism as the primary etiology. Recognizing CS as a reversible contributor to myocardial dysfunction has important clinical implications, as timely endocrine intervention can improve cardiac function, lower blood pressure, and potentially prevent progression to irreversible myocardial remodeling.

Left ventricular hypertrophy and structural remodeling

Electrocardiographic and echocardiographic studies have characterized the cardiac phenotype in patients with CS. In a cohort of 12 consecutive patients, most had concomitant hypertension (11/12) and diabetes mellitus (7/12). Preoperative ECGs commonly demonstrated high-voltage QRS complexes (10 patients) and T-wave inversions (7 patients), indicative of LV strain. Echocardiography revealed LVH in nine patients, all exhibiting asymmetric septal hypertrophy. Interventricular septal thickness ranged from 16 to 32 mm, with septal-to-posterior wall ratios from 1.33 to 2.67. Compared with essential hypertension or primary aldosteronism, CS patients exhibited more pronounced LVH and a higher prevalence of asymmetric septal hypertrophy, suggesting a unique glucocorticoid-mediated remodeling pattern [13].

Postoperative follow-up in nine patients demonstrated normalization of ECG abnormalities, decreased septal thickness, and resolution of asymmetric septal hypertrophy in all but one patient, highlighting the partial reversibility of LVH following correction of hypercortisolism. The pronounced septal thickening relative to the posterior wall implies that excessive cortisol exposure, beyond hemodynamic effects of hypertension, contributes significantly to myocardial remodeling [13].

Impact of disease duration on concentric remodeling

Fallo et al. evaluated 18 patients with CS compared with 18 matched controls, adjusting for sex, age, body size, blood pressure, and duration of hypertension. Eleven participants in each group were hypertensive. Echocardiography revealed elevated relative wall thickness (RWT >0.45) in 11 patients with CS (five normotensive, six hypertensive) versus two hypertensive controls. Left ventricular mass index was abnormal in three CS patients and in four hypertensive controls, while systolic function was preserved in all participants [14].

No correlation was observed between RWT and either blood pressure or urinary cortisol levels in patients with CS. Instead, RWT correlated significantly with disease duration, indicating that prolonged exposure to glucocorticoid excess, rather than hormone levels or hemodynamic load, is the primary determinant of concentric LV remodeling. Postoperative echocardiography showed normalization of RWT in five of six patients previously affected, reinforcing the concept of reversible myocardial structural changes following correction of hypercortisolism [14].

Conclusions

CS represents a rare but clinically important etiology of heart failure with preserved ejection fraction and, less commonly, dilated cardiomyopathy. Chronic hypercortisolism promotes systemic hypertension, LVH, diastolic dysfunction, myocardial fibrosis, and remodeling that may mimic infiltrative cardiomyopathies such as amyloidosis on echocardiography. GLS with apical sparing, although typically associated with amyloidosis, may also occur in cortisol-induced cardiomyopathy. Advanced imaging, including GLS, can detect subclinical myocardial impairment before overt systolic dysfunction develops. Notably, cardiac structural and functional abnormalities may partially or completely reverse following normalization of cortisol levels, highlighting the importance of early recognition and timely endocrine intervention. Clinicians should maintain a high index of suspicion for hypercortisolism in patients presenting with unexplained LVH, HFpEF, or atypical DCM, particularly when systemic features of CS are present. Future studies are needed to better characterize strain patterns in endocrine cardiomyopathies and to refine imaging-based algorithms for early detection.

References

  1. Uwaifo GI, Hura DE: Hypercortisolism. StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL); 2024.
  2. De Leo M, Pivonello R, Auriemma RS, et al.: Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology. 2010, 92 Suppl 1:50-4. 10.1159/000318566
  3. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jørgensen JO: Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med. 2012, 23:278-82. 10.1016/j.ejim.2011.10.013
  4. Uzie Bło-Życzkowska B, Krzesinński P, Witek P, Zielinński G, Jurek A, Gielerak G, Skrobowski A: Cushing’s disease: subclinical left ventricular systolic and diastolic dysfunction revealed by speckle tracking echocardiography and tissue Doppler imaging. Front Endocrinol (Lausanne). 2017, 8:222. 10.3389/fendo.2017.00222
  5. Brosolo G, Catena C, Da Porto A, Bulfone L, Vacca A, Verheyen ND, Sechi LA: Differences in regulation of cortisol secretion contribute to left ventricular abnormalities in patients with essential hypertension. Hypertension. 2022, 79:1435-44. 10.1161/HYPERTENSIONAHA.122.19472
  6. Gladden JD, Linke WA, Redfield MM: Heart failure with preserved ejection fraction. Pflugers Arch. 2014, 466:1037-53. 10.1007/s00424-014-1480-8
  7. Owan TE, Redfield MM: Epidemiology of diastolic heart failure. Prog Cardiovasc Dis. 2005, 47:320-32. 10.1016/j.pcad.2005.02.010
  8. Pereira AM, Delgado V, Romijn JA, Smit JW, Bax JJ, Feelders RA: Cardiac dysfunction is reversed upon successful treatment of Cushing’s syndrome. Eur J Endocrinol. 2010, 162:331-40. 10.1530/EJE-09-0621
  9. Gill A, Dean N, Al-Agha R: Cushing’s, dilated cardiomyopathy and stroke: case report and literature review. Can J Gen Intern Med. 2016, 11:46-9.
  10. Klein AL, Oh J, Miller FA, Seward JB, Tajik AJ: Two-dimensional and Doppler echocardiographic assessment of infiltrative cardiomyopathy. J Am Soc Echocardiogr. 1988, 1:48-59. 10.1016/s0894-7317(88)80063-4
  11. Sahiti F, Detomas M, Cejka V, et al.: The impact of hypercortisolism beyond metabolic syndrome on left ventricular performance: a myocardial work analysis. Cardiovasc Diabetol. 2025, 24:132. 10.1186/s12933-025-02680-1
  12. Frustaci A, Letizia C, Verardo R, Grande C, Calvieri C, Russo MA, Chimenti C: Atrogin-1 pathway activation in Cushing syndrome cardiomyopathy. J Am Coll Cardiol. 2016, 67:116-7. 10.1016/j.jacc.2015.10.040
  13. Sugihara N, Shimizu M, Kita Y, et al.: Cardiac characteristics and postoperative courses in Cushing’s syndrome. Am J Cardiol. 1992, 1:1475-80.
  14. Fallo F, Budano S, Sonino N, Muiesan ML, Agabiti-Rosei E, Boscaro M: Left ventricular structural characteristics in Cushing’s syndrome. J Hum Hypertens. 1994, 8:509-13.

From https://www.cureus.com/articles/413845-global-longitudinal-strain-reduction-with-apical-sparing-in-cushing-syndrome-related-heart-failure-with-preserved-ejection-fraction-hfpef-a-case-report?score_article=true#!/

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Helping others learn more about Cushing’s/Acromegaly

Posted on November 28, 2025 by MaryO

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

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

Spread The Word! Cushing’s Pocket Reference

Robin Writes:

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

Cushing's Pocket Reference

Here are the links:

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

This Topic on the Message Boards

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

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

Are doctors ever really off duty?

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

By Lucy Atkins

Bus

Passengers on a London bus. Photograph: David Levene

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

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

Moon face

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

Different-sized pupils

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

Clubbing fingers

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

Lumpy eyelids

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

Suntan in unlikely places

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

Trench mouth

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

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

Posted on November 25, 2025 by MaryO

Abstract

Objective

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

Methods

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

Results

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

Conclusion

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

Introduction

Patients with endogenous Cushing syndrome (CS), including those with Cushing disease (CD), have a mortality rate that is 3 times higher than the general population.1, 2, 3, 4, 5 This increased mortality is primarily attributed to cardiovascular conditions (acute myocardial infarction, stroke, congestive heart failure, and venous thromboembolic [VTE] events), hyperglycemia, and infections.4
It is well-established that endogenous CS is intrinsically associated with VTE events,6, 7, 8, 9, 10, 11 independent of surgical procedures and metabolic disturbances. Previous studies have reported significant rates of VTE events in patients with CS, ranging from 2.6% to 18.2% (predominantly deep vein thrombosis [DVT] and pulmonary embolism [PE]),6, 7, 8, 9, 10, 11, 12 which is approximately 10 times higher than general population (DVT 0.53 to 1.62 per 1000 person-years and PE 0.39 to 1.15 per 1000 person-years).13
The pathophysiological mechanism underlying hypercortisolism as a thrombogenic condition is not fully understood. However, it is primarily attributed to the genomic action of cortisol, which leads to the upregulation of mRNA transcription for hemostatic factors, resulting in the activation of the coagulation cascade and impaired fibrinolytic capacity.6,14 Altered hemostatic parameters are observed even when compared to high-risk groups, such as those with metabolic syndrome.15, 16, 17 The studies reported increased levels of factor VIII, factor IX, von Willebrand factor, and fibrinogen; a shortened activated partial thromboplastin time (APTT); and elevated levels of factors that reduce fibrinolysis, such as plasminogen activator inhibitor-1, thrombin-activatable fibrinolysis inhibitor, and alpha-2-antiplasmin. Some studies also describe an increase in anticoagulant factors, such as protein C, protein S, and antithrombin III, likely through a compensatory mechanism.18
VTE prevalence in CD varies widely across studies, likely due to differences in populations, CS etiologies, inclusion of other events (eg, stroke), and timing (preoperative vs postoperative).6, 7, 8, 9, 10, 11, 12
These factors, along with variability in evaluated hemostatic parameters and use of thromboprophylaxis, hinder consensus on prophylaxis.18, 19, 20
The present study aimed to identify the prevalence and risk profile of VTE events in a large cohort of patients with CD.

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Section snippets

Patients, Controls, and Study Design

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

Description of Patients and Controls

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

Discussion

Strategies for preventing VTE events in CS have been researched in several reference centers.6,9,10,17,19
European surveys reported a VTE incidence of 14.6 per 1000 person-years in CS, about 10 times higher than in the general population. In patients on prophylaxis, the incidence dropped to 10.2 versus 25.6 in those without. Events were more common with greater disease severity, but the diversity of CS types and retrospective designs has limited standardized strategies.6
A Pituitary Society

Data Availability Statement

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

Statement of Ethics

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

Consent to Participate Statement

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

Disclosure

The authors have no conflicts of interest to disclose.

Author Contributions

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

References (35)

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

Posted on November 21, 2025 by MaryO

Abstract

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

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

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

Introduction

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

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

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

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

Conclusions

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

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

References

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

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

Posted on November 19, 2025 by MaryO

Abstract

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

Introduction

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

Case Presentation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

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

Conclusions

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

References

  1. Lonser RR, Nieman L, Oldfield EH: Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017, 126:404-17. 10.3171/2016.1.JNS152119
  2. Estrada J, Boronat M, Mielgo M, et al.: The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med. 1997, 336:172-7. 10.1056/NEJM199701163360303
  3. Minniti G, Osti M, Jaffrain-Rea ML, Esposito V, Cantore G, Maurizi Enrici R: Long-term follow-up results of postoperative radiation therapy for Cushing’s disease. J Neurooncol. 2007, 84:79-84. 10.1007/s11060-007-9344-0
  4. Hughes JD, Young WF, Chang AY, et al.: Radiosurgical management of patients with persistent or recurrent Cushing disease after prior transsphenoidal surgery: a management algorithm based on a 25-year experience. Neurosurgery. 2020, 86:557-64. 10.1093/neuros/nyz159
  5. Sheehan J, Kondziolka 😧 Results of gamma knife surgery for Cushing’s disease. J Neurosurg. 2013, 119:1642.
  6. Weidlich GA, Bodduluri M, Achkire Y, Lee C, Adler JR Jr: Characterization of a novel 3 megavolt linear accelerator for dedicated intracranial stereotactic radiosurgery. Cureus. 2019, 11:e4275. 10.7759/cureus.4275
  7. Ehret F, Kohlhase N, Eftimova D, et al.: Self-shielding gyroscopic radiosurgery: a prospective experience and analysis of the first 100 patients. Cureus. 2024, 16:e56035. 10.7759/cureus.56035
  8. Daly AF, Beckers A: The epidemiology of pituitary adenomas. Endocrinol Metab Clin North Am. 2020, 49:347-55. 10.1016/j.ecl.2020.04.002
  9. Mathieu D, Kotecha R, Sahgal A, et al.: Stereotactic radiosurgery for secretory pituitary adenomas: systematic review and International Stereotactic Radiosurgery Society practice recommendations. J Neurosurg. 2022, 136:801-12. 10.3171/2021.2.JNS204440
  10. Minniti G, Osti MF, Niyazi M: Target delineation and optimal radiosurgical dose for pituitary tumors. Radiat Oncol. 2016, 11:135. 10.1186/s13014-016-0710-y
  11. Kotecha R, Sahgal A, Rubens M, et al.: Stereotactic radiosurgery for non-functioning pituitary adenomas: meta-analysis and International Stereotactic Radiosurgery Society practice opinion. Neuro Oncol. 2020, 22:318-32. 10.1093/neuonc/noz225
  12. Paddick I: A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg. 2000, 93 Suppl 3:219-22. 10.3171/jns.2000.93.supplement
  13. Timmerman R: A story of hypofractionation and the table on the wall. Int J Radiat Oncol Biol Phys. 2022, 112:4-21. 10.1016/j.ijrobp.2021.09.027
  14. Johnson MD, Woodburn CJ, Vance ML: Quality of life in patients with a pituitary adenoma. Pituitary. 2003, 6:81-7. 10.1023/b:pitu.0000004798.27230.ed
  15. Manetti L, Deutschbein T, Schopohl J, et al.: Long-term safety and efficacy of subcutaneous pasireotide in patients with Cushing’s disease: interim results from a long-term real-world evidence study. Pituitary. 2019, 22:542-51. 10.1007/s11102-019-00984-6
  16. Owen D, Siva S, Salama JK, Daly M, Kruser TJ, Giuliani M: Some like it hot: the value of dose and hot spots in lung stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2023, 117:1-5. 10.1016/j.ijrobp.2023.03.056
  17. Abraham C, Garsa A, Badiyan SN, et al.: Internal dose escalation is associated with increased local control for non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiosurgery (SRS). Adv Radiat Oncol. 2018, 3:146-53. 10.1016/j.adro.2017.11.003

 

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

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