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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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.).
Vogt-Koyanagi-Harada disease (VKH) is a rare autoimmune disorder, especially in children, requiring long-term corticosteroids. We report a 13-year-old male with VKH who developed iatrogenic Cushing’s syndrome and secondary adrenal insufficiency after prolonged prednisone treatment. Despite adding mycophenolate mofetil, tapering failed due to relapses. He showed weight gain, growth delay, striae, and suppressed cortisol and adrenocorticotropic hormone, confirming hypothalamic-pituitary-adrenal axis suppression. Hydrocortisone was given for stress coverage. A relapse followed steroid discontinuation. This case highlights the risk of endocrine complications in pediatric VKH and emphasizes the importance of early hormonal evaluation and individualized tapering during chronic steroid therapy.
KEYWORDS
Vogt-Koyanagi-syndrome
Cushing syndrome
Adrenal insufficiency
Pediatrics
INTRODUCTION
Vogt-Koyanagi-Harada disease (VKH) is a rare autoimmune disorder that can significantly affect the eyes, skin, and central nervous system (Stern & Nataneli, 2025). Among the various forms of autoimmune uveitis, VKH is particularly notable for its broad clinical spectrum, encompassing ocular, neurologic, and cutaneous manifestations (Herbort & Mochizuki, 2007). In pediatric patients, age-specific considerations become paramount, as prolonged corticosteroid therapy is frequently required to control inflammation but can result in serious endocrine complications. One such complication is iatrogenic Cushing’s syndrome (ICS), which may predispose to secondary adrenal insufficiency (SAI), especially when steroid withdrawal is abrupt or inadequately tapered (Improda et al., 2024; Prete & Bancos, 2021). Despite increasing recognition of pediatric VKH, endocrine consequences of its treatment remain underreported.
We present the case of a 13-year-old male with VKH who displayed overt signs of hypercortisolism and biochemical evidence of adrenal suppression after discontinuing corticosteroids, underscoring the importance of vigilant monitoring and a carefully structured tapering protocol in pediatric patients requiring long-term steroid therapy. Given that many pediatric patients with VKH and steroid-related complications are managed not only by pediatric endocrinologists but also by pediatric providers, including nurse practitioners, this case highlights aspects relevant to a broad clinical audience.
CASE PRESENTATION
A 13-year-old male with a known history of VKH was referred to our clinic for growth and pubertal assessment following significant weight gain and clinical features suggestive of ICS. His perinatal period was uneventful; he was born at term via cesarean section for maternal indications (bicornuate uterus), with a birth weight of 2980 g and a length of 49 cm. Family history was notable for celiac disease in the mother, mixed hypercholesterolemia in the father, vitiligo in the maternal grandfather, and autoimmune diseases (Sjögren’s syndrome and multiple sclerosis) in second-degree maternal relatives.
The patient first presented, at age 11 years and 11 months, with redness, pain, and photophobia of the right eye [Figure 1]. Initial ophthalmological examination revealed panuveitis, with signs of posterior synechiae and optic disc edema. Fluorescein and indocyanine green angiography confirmed bilateral granulomatous involvement. Systemic workup excluded other infectious and autoimmune causes of uveitis. Neurological imaging revealed a non-specific thalamic lesion, classified as a radiological isolated syndrome, with no clinical neurological deficits.
Oral prednisone (25 mg/day) was initiated, along with topical ocular corticosteroids, leading to clinical improvement. The first tapering and discontinuation of prednisone occurred after seven months of therapy. Three months later, a clinical relapse occurred, requiring re-initiation of prednisone and subsequent addition of mycophenolate mofetil as a steroid-sparing agent. Prednisone was then tapered and discontinued again after another seven months of treatment. Over the course of therapy, the patient gained approximately 15 kg and developed progressive cushingoid features [Table 1].
TABLE 1. Clinical and biochemical features of ICS and SAI in the patient
Empty Cell
Clinical Findings
Interpretation
Growth and development
Height: 143.5 cm (3rd percentile); mid-parental height: 171 ± 8 cm
Growth deceleration likely related to chronic glucocorticoid exposure and ICS
Weight and body composition
Weight: 53.3 kg (75th–90th percentile); BMI: 25.8 kg/m²; central obesity
Suggestive of glucocorticoid-induced lipogenesis and altered fat distribution
Skin and soft tissue
Striae rubrae on flanks; mild dorsal fat pad (“buffalo hump”)
Normal glucose metabolism; mild hyperinsulinemia possibly due to steroid exposure
Thyroid function
TSH: 2.32 µU/mL; free T4: 1.59 ng/dL
Euthyroid; no evidence of central or primary thyroid dysfunction
Neurologic imaging
Right thalamic signal abnormality; stable; no neurological deficits
No CNS involvement of VKH; imaging excluded alternative diagnoses
Family history
Autoimmune conditions in maternal relatives; vitiligo in grandfather
Suggests genetic predisposition to autoimmune diseases; relevant to VKH etiology
Therapeutic course
Initial improvement with prednisone; relapses on tapering; mycophenolate added; steroids reintroduced
Demonstrates difficulty in achieving steroid-free remission and the need for steroid-sparing agents
Abbreviations: ACTH, adrenocorticotropic hormone; BMI, body mass index; CNS, central nervous system; HPA, hypothalamic-pituitary-adrenal; ICS, iatrogenic Cushing’s syndrome; SAI, secondary adrenal insufficiency; TSH, thyroid-stimulating hormone; VKH, Vogt-Koyanagi-Harada disease.
Summary of patient’s clinical signs and biochemical parameters during corticosteroid therapy, including features of ICS and evidence of SAI.
Laboratory testing during steroid tapering attempts revealed HbA1c of 5.9% (41 mmol/mol), fasting glucose of 72 mg/dL, and insulin of 16.9 mcU/mL; morning serum cortisol was markedly reduced (0.5 mcg/dL; ref. 2.4–22.9), raising concerns for SAI. Gonadotropins (follicle-stimulating hormone 4.3 mcU/mL, luteinizing hormone 1.1 mcU/mL) and testosterone (0.03 ng/mL) were consistent with early puberty. Thyroid function (thyroid-stimulating hormone 2.32 mcU/mL, free thyroxine 1.59 ng/dL) and celiac serology were normal. Brain magnetic resonance imaging confirmed a stable right thalamic signal abnormality and minor asymmetry of cerebral arteries, in line with prior findings; cardiac and abdominal ultrasounds were unremarkable.
When first evaluated in our endocrinology clinic (at age 13 years and 6 months), the patient’s height was 143.5 cm (3rd percentile; mid-parental height target: 171 ± 8 cm), and his weight was 53.3 kg (75th–90th percentile), corresponding to a body mass index of 25.8 kg/m². He exhibited central obesity, striae rubrae on the flanks, and a mild dorsal hump. Genital examination showed bilateral testicular volumes of 5–6 mL and pubic hair at Tanner stage I, compatible with early puberty. The remainder of the physical exam was unremarkable.
In light of clinical and biochemical evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, further hormonal testing was performed. Serum cortisol had partially recovered (9.9 mcg/dL; ref. 2.7–18.4) with adrenocorticotropic hormone (ACTH) at 23.1 pg/mL (ref. 7.3–63.3). Hydrocortisone was prescribed for use during stressful events. However, two months after prednisone discontinuation, at age 13 years and 8 months, a clinical relapse of VKH occurred, requiring escalation of mycophenolate mofetil and re-initiation of prednisone therapy.
The patient currently remains under combined rheumatologic, ophthalmologic, and endocrinologic management. Steroids have been successfully tapered and discontinued, but signs of chronic adrenal suppression and cushingoid features persist. Mycophenolate mofetil is ongoing as maintenance immunosuppression, and adrenal function is being closely monitored.
DISCUSSION
VKH is a rare granulomatous autoimmune condition targeting melanocyte-containing tissues, including the uveal tract, meninges, inner ear, and skin. While more frequently diagnosed in adults, pediatric-onset VKH is increasingly recognized and often presents with bilateral panuveitis, optic disc edema, serous retinal detachments, and systemic manifestations such as meningismus, tinnitus, hearing loss, vitiligo, and poliosis (Abu El-Asrar et al., 2021; Reiff, 2020). Early and aggressive immunosuppression is essential to prevent chronic recurrent uveitis and progressive vision loss (Abu El-Asrar et al., 2008).
Systemic corticosteroid therapy—using high-dose oral prednisone or intravenous pulse methylprednisolone—is the first-line treatment for pediatric VKH, and is effective in rapidly controlling intraocular inflammation and achieving favorable visual outcomes when initiated early (Leal et al., 2024; Reiff, 2020). Gradual tapering of corticosteroids over at least six months is critical to minimize recurrence and prevent chronic disease evolution (Ei Ei Lin Oo et al., 2020; Wang et al., 2023). Rapid tapering is associated with higher rates of relapse and chronicity. Nonetheless, corticosteroid monotherapy is often insufficient to prevent long-term recurrence and chronic complications in pediatric VKH (Abu El-Asrar et al., 2021; Park et al., 2022; Sakata et al., 2015). Early addition of immunosuppressive agents—such as mycophenolate mofetil or methotrexate—within three months of disease onset improves long-term control, reduces the risk of chronic recurrent uveitis, and enhances visual outcomes (Ei Ei Lin Oo et al., 2020; Park et al., 2022). Long-term remission rates are higher when immunosuppressive therapy is maintained for several years with sustained inflammation control (Wang et al., 2023).
Children are especially vulnerable to the adverse effects of prolonged corticosteroid exposure, including growth failure, pubertal delay, obesity, insulin resistance, ICS, and suppression of the HPA axis with subsequent SAI (Bornstein et al., 2016; Messazos & Zacharin, 2016; Santos-Oliveira et al., 2025). ICS results from chronic exposure to supraphysiologic doses of glucocorticoids and may present with weight gain, central obesity, facial rounding, and violaceous striae—many of which were observed in our patient. In children, these manifestations may overlap with common features of puberty or lifestyle-related obesity, making early diagnosis more challenging (Savage & Storr, 2012). SAI is a potentially life-threatening complication that occurs when exogenous glucocorticoids suppress the endogenous production of corticotropin-releasing hormone and ACTH. The risk is highest with longer treatment durations (typically > 12 weeks) and higher cumulative doses, particularly with long-acting steroids such as betamethasone or dexamethasone (Beuschlein et al., 2024).
Our patient presented with markedly reduced morning cortisol levels and low-normal ACTH, consistent with central adrenal suppression. Partial biochemical recovery occurred months after discontinuation, yet persistently suboptimal cortisol levels indicated incomplete restoration of HPA function. These findings align with a meta-analysis by Broersen et al., which showed that although adrenal recovery improves over time, a significant proportion of patients remain functionally insufficient even six months after stopping corticosteroids (Broersen et al., 2015).
To our knowledge, this is among the first reported pediatric cases of VKH complicated by both ICS and SAI. Although the literature contains extensive documentation of glucocorticoid side effects in autoimmune and inflammatory conditions (Arroyo et al., 2023), there remains a notable gap in addressing endocrine sequelae within VKH, particularly in children. Most published pediatric VKH case reports focus on ophthalmologic or immunologic outcomes, with limited attention to longitudinal hormonal monitoring and risk mitigation. VKH is rare in childhood, representing an uncommon cause of uveitis, with pediatric-onset forms accounting for fewer than 10% of all VKH cases (Martin et al., 2010; Yang et al., 2023). Several works have documented its course and treatment (Abu El-Asrar et al., 2008; Albaroudi et al., 2020; Sadhu et al., 2024); none of the reports explicitly addressed endocrine complications, highlighting a major gap in longitudinal follow-up and inter-specialty collaboration in such cases.
The recent 2024 Joint Clinical Guideline from the European Society of Endocrinology and the Endocrine Society offers important insight into the diagnosis and management of glucocorticoid-induced adrenal insufficiency (Beuschlein et al., 2024). Although not providing pediatric-specific recommendations, it emphasizes that children are included among at-risk populations, and that the same diagnostic and tapering principles apply across age groups. It highlights that the risk of SAI depends not only on dose and duration, but also on the glucocorticoid formulation, route of administration, and individual susceptibility. The guideline recommends transitioning from long-acting to short-acting glucocorticoids (e.g., prednisone or hydrocortisone) to facilitate tapering and adrenal recovery. Tapering should begin only after adequate disease control and must proceed gradually—especially once physiologic dose equivalents are reached (4–6 mg/day of prednisone). Morning serum cortisol serves as the initial screening tool for HPA recovery, with levels > 10 µg/dL (> 300 nmol/L) indicating recovery and < 5 µg/dL (< 150 nmol/L) indicating suppression. Importantly, symptoms of glucocorticoid withdrawal (e.g., fatigue, myalgias, mood changes) may mimic adrenal insufficiency and require temporary increases in glucocorticoid dose and a slower taper.
In our case, hydrocortisone was prescribed for use during stress, such as illness or surgery, in accordance with these recommendations. Given his partial biochemical recovery, the patient was also advised to carry steroid warning documentation and to continue close endocrine follow-up. This approach reflects best practice in managing patients transitioning off chronic corticosteroid therapy, particularly in pediatric populations where risks are amplified (Beuschlein et al., 2024).
We strongly advocate for multidisciplinary collaboration in managing complex VKH cases [Figure 2]. Ophthalmologists and rheumatologists should remain alert to endocrine warning signs such as growth deceleration, cushingoid appearance, and fatigue (Santos-Oliveira et al., 2025), while endocrinologists should consider autoimmune or inflammatory etiologies in children with ICS or SAI. Importantly, the early use of steroid-sparing immunosuppressants—as was done with mycophenolate mofetil in our case—can reduce glucocorticoid burden and mitigate downstream complications. Agents such as azathioprine, methotrexate, or mycophenolate have demonstrated efficacy in reducing steroid dependence in pediatric uveitis (Simonini et al., 2013; Sood & Angeles-Han, 2017).
FIGURE 2. Multidisciplinary management plan for pediatric VKH with chronic corticosteroid therapy. Schematic representation of the recommended multidisciplinary team for pediatric patients with VKH requiring prolonged corticosteroid therapy. The model emphasizes collaboration among health professionals for early recognition and management of VKH manifestations.
(abbreviations: CNS, central nervous system; HPA, hypothalamic-pituitary-adrenal; VKH, Vogt-Koyanagi-Harada disease).
CONCLUSION
This case highlights the dual endocrine risks associated with prolonged corticosteroid therapy in pediatric patients with VKH: ICS and SAI. It underscores the importance of routinely monitoring growth, pubertal development, and HPA axis function both during and after steroid treatment.
Given the widespread use of systemic corticosteroids in pediatric inflammatory disorders, proactive endocrine screening, multidisciplinary collaboration, and adherence to guideline-based tapering protocols are essential to ensure effective disease management while minimizing preventable hormonal complications. Further research and the development of pediatric-specific guidelines are warranted to optimize endocrine care in children receiving long-term glucocorticoid therapy.
REPORTING CHECKLIST DISCLOSURE
We are submitting this case report using the CARE checklist.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
FUNDING
The authors did not receive support from any organization for the submitted work.
PATIENT CONSENT
Written informed consent and permission to share this case were obtained from the legal guardians/parents.
ETHICAL STATEMENTS
Please find attached the AIFA regulation regarding observational studies, provided in Italian. For your convenience, we have translated the relevant section (highlighted in light blue, pages 7-8) into English:
“The registration of studies covered by this provision in the Register of Observational Studies (RSO) is mandatory for review by the Ethics Committee, except for the exemptions listed below. This guideline does not apply to the following categories: […] Case reports and case series (typically involving 3-5 patients at most) that do not have a methodological approach qualifying them as clinical studies.”
Our study falls precisely into the category of a case report, rather than a clinical study.
CRediT authorship contribution statement
Roberto Paparella: Writing – original draft, Conceptualization. Irene Bernabei: Writing – original draft. Arianna Bei: Writing – original draft. Cinzia Fiorentini: Resources. Norma Iafrate: Resources. Roberta Lucibello: Resources. Francesca Pastore: Resources. Ida Pucarelli: Writing – review & editing, Supervision, Conceptualization. Luigi Tarani: Writing – review & editing, Supervision.
F. Beuschlein, T. Else, I. Bancos, S. Hahner, O. Hamidi, L. Van Hulsteijn, E.S. Husebye, N. Karavitaki, A. Prete, A. Vaidya, C. Yedinak, O.M. Dekkers
European society of endocrinology and endocrine society joint clinical guideline: diagnosis and therapy of glucocorticoid-induced adrenal insufficiency
A notable proportion of patients with mild hypercortisolism achieved blood pressure (BP) control with low-dose evening metyrapone, without requiring the intensification of antihypertensive therapy. The treatment was particularly beneficial for those with higher baseline systolic BP and was well tolerated, with no adverse events reported.
METHODOLOGY:
This prospective observational study assessed the impact of low-dose evening metyrapone on 24-hour ambulatory BP, glucose metabolism, and the cortisol circadian rhythm in 20 patients with mild hypercortisolism (median age, 70.5 years; 65% women).
Eligible patients had cortisol levels > 1.8 μg/dL after a 1-mg dexamethasone suppression test on at least two separate occasions, fewer than two specific Cushing syndrome‑related symptoms, and either hypertension or impaired glucose metabolism.
Patients received evening metyrapone 250 mg/d, with dose adjustments on the basis of clinical response and cortisol secretion; in 12 patients who showed no signs of hypoadrenalism after week 12, an additional 250-mg afternoon dose was given.
The primary endpoint was BP control, defined as a reduction in mean 24-hour systolic BP of ≥ 5 mm Hg without increasing antihypertensive medication; ambulatory BP monitoring was done at baseline and weeks 12 and 24.
TAKEAWAY:
At 24 weeks, 40% of patients had a clinically significant improvement in BP control without escalation of therapy, with reductions in both daytime and nighttime systolic BP; benefits were more pronounced in those with elevated baseline systolic BP.
Glucometabolic control improved in four patients at 24 weeks; those with poorly controlled type 2 diabetes at baseline achieved the most pronounced glycaemic benefits.
Salivary cortisol levels remained unchanged from baseline; no significant changes in hormonal, metabolic, or anthropometric parameters were observed from baseline, except for testosterone levels in women.
The treatment was well tolerated, with no side effects or reports of adrenal insufficiency.
IN PRACTICE:
“Our findings support the notion that metyrapone may offer clinical benefits in patients with mH [mild hypercortisolism], particularly those with uncontrolled comorbidities. The observed improvements in BP and glycaemic control, despite minimal changes in UFC [urinary free cortisol] levels, underscore the need to re-evaluate traditional therapeutic targets and to adopt a more holistic approach to disease management,” the authors of the study wrote.
SOURCE:
This study was led by Antonio Musolino, University of Milan, Milan, Italy. It was published online on October 16, 2025, in the European Journal of Endocrinology.
LIMITATIONS:
This study was limited by its relatively short treatment duration, potential adherence bias, and an older cohort age, which may have limited generalisability. The sample size, although adequate for the primary endpoint, was limited. The absence of a control group restricted the ability to definitively attribute improvements to metyrapone therapy.
DISCLOSURES:
This study received financial support through an investigator-initiated study grant from ESTEVE (formerly HRA RD). Two authors reported receiving speaker or consultancy fees or honoraria from Corcept Therapeutics.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication
Patients with mild autonomous cortisol secretion (MACS) have similar sleep disturbances as patients with Cushing syndrome, according to results of a study published in the Journal of Clinical Endocrinology & Metabolism.
In both Cushing syndrome and MACS, varying degrees of hypercortisolism can affect circadian cortisol secretion and sleep.
Patients diagnosed with MACS (n=194) or Cushing syndrome (n=154) at the Mayo Clinic in the United States between 2019 and 2025 and healthy control individuals (n=89) recruited between 2019 and 2023 were evaluated for sleep outcomes using the Pittsburgh Sleep Quality Index (PSQI).
The MACS, Cushing syndrome, and control cohorts, of whom 73%, 89%, and 67% were women and 92%, 89%, and 91% were White, respectively, had median ages of 60, 48, and 56 years and a median BMI of 32, 34, and 28 kg/m2, respectively.
For sleep outcomes, all PSQI outcomes were worse among patients with MACS than control individuals (all P <.001). Among patients, more with Cushing syndrome vs MACS had:
Bad sleep quality (75% vs 58%; P <.001);
Sleep duration of less than 5 hours (24% vs 15%; P =.031);
At least 3 days of dysfunction due to daytime sleepiness (70% vs 56%; P =.011); and,
Higher total PSQI scores (mean, 12 vs 11; P =.005).
All outcomes of the Short Form 36 (SF-36) were significantly worse among patients with MACS than control individuals (all P <.001) and worse among patients with Cushing syndrome than MACS (all P £.004), except for the emotional limitation score (P =.002).
Similarly, patients with Cushing syndrome had lower Cushing Quality of Life (CushingQoL) scores than patients with MACS for physical (mean, 23.4 vs 44.9; P <.001), psychosocial (mean, 29.8 vs 46.7; P <.001), and overall (mean, 28.2 vs 46.2; P <.001) scores, respectively.
In Cushing syndrome and MACS, the researchers observed significant correlations between PSQI total scores and SF36 mental (r range, -0.50 to -0.40; both P <.001) and physical (r range, -0.35 to -0.28; both P <.001) component scores and CushingQoL overall (r range, -0.56 to -0.43; both P <.001), physical (r range, -0.57 to -0.38; both P <.001), and psychosocial (r range, -0.49 to -0.38; both P <.001) scores. In only MACS, PSQI was correlated with clinical severity (r, 0.17; P =.020). Among control individuals, PSQI total scores were correlated with SF36 mental (r, -0.29; P =.008) and physical (r, -0.45; P <.001) component scores.
Worse sleep was associated with every 1-kg/m2 increase in BMI among control individuals (b, 0.21; P =.005), inversely related with every 1-year increase in age among patients with Cushing syndrome (b, -0.12; P <.001), and inversely related with every 1-year increase in age (b, -0.08; P =.009) and positively related with every 1-point increase in clinical severity (b, 0.14; P =.044) and with female gender (b, 2.35; P =.002) among patients with MACS.
The major limitation of this study was the lack of objectively measured sleep outcomes.
The study authors concluded, “[W]e found that patients with MACS and [Cushing syndrome] demonstrate similar sleep impairment. Younger age, female sex and higher clinical severity score were associated with worse sleep in patients with MACS, while younger age was the only factor associated with poor sleep in patients with [Cushing syndrome].”
Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Cyclic Cushing syndrome (CCS) is characterized by unpredictable, intermittent phases of excess cortisol, alternating with periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels. The mechanism is unclear. Due to its rarity and diverse clinical presentation, unpredictable phases, and various etiologies, CCS poses significant diagnostic and management challenges for endocrinologists. The authors describe 3 cases in which each patient’s initial presentation was a life-threatening hypercortisolemic phase that lasted from 4 days to 3 months, followed by spontaneous resolution to prolonged eucortisolemic phases lasting from 10 to 26 months. Further testing indicated an ectopic ACTH-secreting source; however, the locations of the offending tumors were indeterminate. The authors propose the term square wave CCS variant to characterize the unique, prolonged intercyclic phases of hypercortisolemia and eucortisolemia with this subtype that are distinct from conventional CCS characterized by shorter phases of transient hypercortisolemia shifting to periods of eucortisolemia or hypocortisolemia. This uncharacteristic pattern of cyclicity poses diagnostic and therapeutic challenges, thus underscoring the importance of careful diagnostic workup and treatment of these patients.
Cyclic Cushing syndrome (CCS) is a rare variant of Cushing syndrome (CS) characterized by intermittent episodes of cortisol peaks alternating with variable periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels (troughs) [1]. These cycles can occur at regular or irregular intervals [2], with unpredictable intercyclic phases typically lasting from days to months [3, 4]. The prevalence of CCS in patients with CS is low, ranging from 8% to 19% [3‐6]. Several alternative terms (eg, intermittent, variable, periodic, and episodic hypercortisolism) have been proposed to characterize the variable cyclicity of ACTH and cortisol secretion in patients with CCS [7].
We describe 3 cases of suspected ectopic ACTH-dependent CS with an indeterminate ACTH source that presented with life-threatening hypercortisolemia lasting from 4 days to 3 months, followed by spontaneous eucortisolemic phases lasting from 10 to 26 months. The term square wave is proposed to describe this unique cyclic pattern to highlight the unpredictability of severe hypercortisolemia followed by spontaneous prolonged eucortisolemic phases, which is distinct from previously described transient regular or irregular cycles with shorter intercyclic phases of CCS that require medical intervention.
Case Presentation
Case 1
A 75-year-old man with atrial fibrillation, bilateral leg edema, 6-month weight loss of 7 pounds (3.2 kg), and generalized muscle weakness was referred for cardiac ablation therapy. However, just before he underwent the procedure, he was found to be profoundly hypokalemic with potassium of 2.9 mEq/L (SI: 2.9 mmol/L) (reference range, 3.6-5.3 mEq/L [SI: 3.6-5.3 mmol/L]) and hyperglycemic, with blood glucose of 498 mg/dL (SI: 27.8 mmol/L) (reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]) and glycated hemoglobin (HbA1c) of 7.4%. He was emergently treated with potassium supplementation and insulin therapy.
Case 2
A 61-year-old woman presented to the emergency department with palpitations, uncontrolled hypertension, weight loss of 20 pounds (9.1 kg) over 2 weeks, new signs of hyperandrogenism (eg, hirsutism, acne, muscle atrophy), lower back pains, easy bruising, and proximal muscle weakness.
Case 3
A 57-year-old woman presented to the emergency department in August 2021 with a 2-month history of facial swelling and generalized muscle weakness. She had reported a similar episode in April 2019 with hypokalemia (potassium, 2.5 mEq/L [SI: 2.5 mmol/L]) that was treated with potassium repletion therapy.
Diagnostic Assessment
Case 1
Further laboratory tests revealed elevated morning (Am) cortisol of 76.8 µg/dL (SI: 2119 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]), Am ACTH of 368 pg/mL (SI: 81 pmol/L) (reference range, 6-50 pg/mL [SI: 1.3-11.0 pmol/L]), and 24-hour urine free cortisol (UFC) of 4223 µg/24 hours (SI: 11 656 nmol/24 hours) (reference range, 1.5-18.1 µg/24 hours [SI: 4-50 nmol/24 hours]) (Table 1). Magnetic resonance imaging (MRI) of the pituitary (Fig. 1) and 68Ga-DOTATATE positron emission tomography (PET) (Table 2) of the chest, pelvis, and abdomen failed to identify the source of ACTH secretion. Inferior petrosal sinus sampling (IPSS) showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source (Table 3).
Table 1.
Summary of biochemical testing data for the 3 patients with a square wave pattern of cyclic Cushing syndrome
Case 1. (A) Sagittal and (B) coronal magnetic resonance images demonstrating normal appearance of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.
Laboratory tests revealed elevated Am cortisol of 38.4 µg/dL (SI: 1060 nmol/L) and Am ACTH of 118 pg/mL (SI: 26 pmol/L), hypokalemia (potassium, 2.9 mEq/L [SI: 2.9 mmol/L]) and new-onset type 2 diabetes mellitus with a random blood glucose of 489 mg/dL (SI: 27.2 mmol/L) and HbA1c of 9.2% (reference range, < 5.7%) (Table 1). Lumbar spine radiography and spine MRI demonstrated compression fractures of L1 to L4 vertebrae, and pituitary MRI showed a 2-mm hypo-enhancing foci within the midline and to the right of the pituitary gland (Fig. 2).
Case 2. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland show 2-mm hypo-enhancing foci (arrows) within the midline and to the right side of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.
Case 3
During the present hospital admission, the patient was hypokalemic (potassium, 2.7 mEq/L [SI: 2.7 mmol/L]) and hypercortisolemic with Am cortisol and Am ACTH levels of 56.8 µg/dL (SI: 1568 nmol/L) and 159 pg/mL (SI: 35 pmol/L), respectively. After 4 days of hospitalization, the patient spontaneously became eucortisolemic with an Am cortisol of 16.8 µg/dL (SI: 464 nmol/L), 24-hour UFC of 670.5 µg/24 hours (SI: 1851 nmol), and late-night salivary cortisol of 0.03 µg/dL (SI: 0.828 nmol/L) with symptom improvement (Table 1). Pituitary MRI revealed a flattened, normal-appearing pituitary gland (Fig. 3).
Case 3. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland showing a flattened pituitary gland. No discrete, sizable, differentially enhancing mass is detected within the sella. From Barrow Neurological Institute, Phoenix, Arizona.
Treatment
Case 1
Because of the patient’s worsening clinical condition and severe hypercortisolemia with no identifiable ACTH source, ketoconazole was considered to induce eucortisolemia. While electrocardiography and liver function tests were being measured before starting ketoconazole, the patient’s Am cortisol levels spontaneously normalized to 14.2 µg/dL (SI: 392 nmol/L) with symptomatic improvement.
Case 2
The patient began insulin, spironolactone, and levothyroxine therapy. After 2 days in the hospital, her Am cortisol decreased to 17.9 µg/dL (SI: 494 nmol/L) and remained within the range of 9.4 to 17.9 µg/dL (SI: 259-494 nmol/L). An IPSS performed 3 weeks later showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source. By month 3, her Am cortisol levels consistently remained below 15 µg/dL (SI: 414 nmol/L). Blood pressure was controlled with one antihypertensive agent, and insulin was discontinued due to frequent hypoglycemic episodes.
Case 3
The patient was readmitted 18 months later with worsening muscle weakness, uncontrolled hypertension, hypokalemia (potassium, 2.4 mEq/L [SI: 2.4 mmol/L]), and hypercortisolemia with elevated Am cortisol and Am ACTH levels. 68Ga-DOTATATE PET did not reveal an ectopic ACTH source (Table 2), and IPSS did not reveal any significant ACTH gradient (Table 3). However, computed tomography (CT) of the chest, abdomen, and pelvis revealed a 0.7-cm lung nodule. During this hospitalization, the patient received supportive treatment, including antihypertensive therapy and electrolyte replacement. No pharmacologic intervention was required to control her cortisol levels.
Outcome and Follow-Up
Case 1
Late-night salivary cortisol levels measured were within the normal range (0.08 µg/dL, 0.06 µg/dL, and 0.08 µg/dL [SI: 2.2 nmol/L, 1.7 nmol/L, and 2.2 nmol/L]; reference range, < 0.09 µg/dL [SI: < 2.5 nmol/L]). Because of these biochemical and symptomatic improvements, ketoconazole therapy was deferred. At the most recent outpatient clinic follow-up 26 months after his cortisol levels normalized, the patient remained in remission without recurrence of hypercortisolemic symptoms.
Case 2
The patient remained in biochemical and clinical remission for 15 months until she began experiencing abdominal distention, bilateral leg edema, and facial swelling again. Blood pressure increased at this time, requiring 3 antihypertensive medications. Her Am cortisol levels rose to 29.1 µg/dL (SI: 803 nmol/L), but repeat IPSS showed no ACTH gradient, and 68Ga-DOTATATE PET/CT of the chest, abdomen, and pelvis was unremarkable (Tables 2 and 3). Block-and-replace therapy of osilodrostat and hydrocortisone was initiated to preemptively prevent hypercortisolemic episodes; after 3 months of therapy, she underwent successful bilateral adrenalectomy (BLA).
Case 3
On day 5 of hospitalization, her Am cortisol level decreased to 14.4 µg/dL (SI: 397 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]). Her symptoms improved, and she remained well for 11 months before recurrence of muscle weakness, hypokalemia, and hypercortisolemia with an Am cortisol of 58.7 µg/dL (SI: 1620 nmol/L) and Am ACTH of 194 pg/mL (SI: 43 pmol/L). The patient became eucortisolemic without any medical intervention and declined further treatment. She continues with regular outpatient follow-up.
Discussion
Diagnosing CCS poses considerable challenges because of its heterogeneous clinical manifestations, erratic intercyclic duration, frequency of phases, and various etiologies. Patients may experience transient or continuous symptoms with variable degrees of severity [1]. Our patients presented with severe hypercortisolemia lasting from days to months, followed by an extended period of spontaneous eucortisolemia, lasting from months to years. This unique presentation of cortisol kinetics differs from the classic presentation of CCS, which typically features shorter intercyclic phases [2].
We coined the term square wave variant of CCS to characterize this unique feature of prolonged cyclicity of hypercortisolemia shifting spontaneously to eucortisolemia without medical intervention. The term square wave was chosen because the cortisol secretion pattern in these cases resembles a square waveform, with abrupt transitions between prolonged periods of high and low cortisol levels rather than the gradual fluctuations or short irregular peaks seen in typical CCS. This visual and kinetic analogy helps distinguish the pattern observed in our patients from the more classically described forms of CCS.
The absence of a standardized definition of CCS complicates the classification of cases such as ours, which diverge from conventional descriptions in the medical literature [3, 4, 8]. Most cases of CCS are associated with pituitary tumors (67%), whereas ectopic ACTH-secreting tumors (17%) and adrenal tumors (11%) are less common [7, 9]. Our patients had evidence of ectopic CS, of which the ACTH-secreting source was unidentifiable despite extensive imaging. The variability of symptom duration, severity, and timing in our patients implies distinct mechanisms for suppressing or desensitizing adrenal cortisol synthesis during the extended symptom-free periods. Other mechanisms include enhanced effects of specific neurotransmitters, hypothalamic dysregulation, spontaneous tumor hemorrhage, cyclic growth and apoptosis of ACTH-secreting tumor cells, and positive and negative feedback mechanisms [7]. Another explanation for the prolonged eucortisolemic phase may be due to altered POMC gene expression and defective ACTH secretion from the ectopic tumor [10‐13]. Over time, the tumor may dedifferentiate or develop a transcriptional or posttranscriptional defect, leading to the secretion of ACTH with a decreased ability to stimulate adrenal cortisol secretion [14, 15]. Conversely, CCS might also be an exaggerated physiological cyclical variation of ACTH and cortisol secretion [14, 15]. However, the prolonged eucortisolemic phase observed in our patients argues against this exaggeration theory.
Recent studies have suggested that the anomalous cyclicity of cortisol and ACTH may be influenced by dysregulation of the peripheral clock system in endocrine tumors [16]. Certain tumors may exhibit aberrant expression of circadian regulators such as CLOCK, PER1, PER2, PER3, and TIMELESS, which can disrupt the physiological rhythmicity of cortisol and ACTH secretion [16, 17]. For instance, cortisol-secreting adrenal adenomas demonstrate downregulation of PER1, CRY1, and Rev-ERB, whereas adrenocortical carcinomas upregulate CRY1 and PER1 and downregulate BMAL1 and RORα. In patients with CS, clock gene expression in peripheral blood mononuclear cells has been shown to be significantly flattened, contributing to the loss of circadian variation in cortisol levels [16].
Surgery is the preferred treatment option for CCS patients, provided the tumor is localizable [18]. Medical therapy is used when the tumor is undetectable, unresectable, or recurs. Medical therapy can overtreat and induce iatrogenic adrenal insufficiency during the eucortisolemic phases. This risk can be mitigated by the block-and-replace strategy of high-dose steroidogenesis inhibitors to suppress adrenal cortisol production and supplemented with exogenous glucocorticoids [10]. In patients for whom the ectopic tumor is unidentifiable, the initial tumor resection is ineffective, or if medical management does not adequately control hypercortisolemia, BLA may be considered [19].
Although treatment of CCS resembles that of CS, the heterogeneity in the severity and duration of symptoms prohibits the implementation of some conventional treatment strategies. Consequently, long-term medical therapy may not align with the patient’s preferences, especially those whose course of illness is characterized by prolonged eucortisolemia and milder symptoms. Such patients should be educated to monitor symptoms closely during the eucortisolemic phase to recognize the signs and symptoms of hypercortisolism using objective parameters such as self-assessment of weight, blood pressure, and capillary blood glucose. Periodic biochemical monitoring may also be helpful, including standby kits for self-testing of late-night salivary cortisol and 24-hour UFC. If the source of ectopic ACTH secretion continues to elude detection, BLA during the eucortisolemic phase may be considered to prevent future life-threatening hypercortisolemic episodes.
Learning Points
Unlike typical CCS, there may be a subset of patients with a distinct square wave variant of CCS marked by severe hypercortisolemia followed by prolonged periods of eucortisolemia.
Ectopic ACTH-secreting sources in CCS may be linked to unusually long symptom-free intervals of eucortisolemia and hypocortisolemia between episodes of hypercortisolemia.
If possible, CCS management should be individualized to address its cause, with vigilant monitoring during the eucortisolemic phase to detect potential recurrence early.
If the source of the ectopic ACTH-secreting tumor is not identifiable, BLA may be considered during the eucortisolemic phase to prevent future life-threatening hypercortisolemic episodes.
Acknowledgments
We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.
Abbreviations
ACTH
adrenocorticotropic hormone
BLA
bilateral adrenalectomy
CCS
cyclic Cushing syndrome
CS
Cushing syndrome
CT
computed tomography
HbA1c
glycated hemoglobin
IPSS
inferior petrosal sinus sampling
MRI
magnetic resonance imaging
PET
positron emission tomography
UFC
urine free cortisol
Contributor Information
Mercedes Martinez-Gil, Department of Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85012, USA.
Tshibambe N Tshimbombu, Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA.
Yvette Li Yi Ang, Division of Endocrinology, Department of Medicine, National University Hospital, Singapore 119228, Singapore.
Monica C Rodriguez, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.
Kevin C J Yuen, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.
Contributors
All authors contributed substantially to the manuscript. K.C.J.Y. supervised the project, provided content review, and edited the text. M.M.-G. and T.N.T. contributed equally to the preparation, writing, and submission of the manuscript. M.C.R. was responsible for the clinical management of one of the cases. Y.L.Y.A. contributed to the diagnosis, management, and writing of one of the cases. All authors reviewed and approved the final version of the manuscript.
Funding
All authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this manuscript.
Disclosures
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this manuscript.
Informed Patient Consent for Publication
Signed informed consents were obtained directly from the patients.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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