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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Challenges of Cushing’s Syndrome and Bariatric Surgery

Posted on June 26, 2025 by MaryO

Abstract

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

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

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

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

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Cardiometabolic Complications After Cushing’s Disease Remission

Posted on April 30, 2025 by MaryO

Abstract

Background and aim

Cushing’s disease (CD) is associated with phenotypic traits and comorbidities that may persist after the normalization of cortisol levels. Medical therapy is usually given in recurrent or persistent CD after transsphenoidal surgery. We aimed to investigate the impact of long-term normalization of daily cortisol secretion on clinical picture and cardiometabolic comorbidities, comparing surgical remission to medical treatment.

Methods

Monocentric retrospective study, two- and five-years observation. Sixty CD patients, with sustained normal 24-h urinary free cortisol (UFC) levels, divided group 1 (surgical remission, n = 36) and group 2 (medical remission, n = 24).

Results

Patients were different after achieving eucortisolism with surgery or medical treatment. Phenotypic traits: round face, dorsocervical fat pad, and bruisability persisted more prominently in the group 2, however abdominal obesity and muscle weakness persisted in both groups, especially in those patients with increased late-night salivary cortisol (LNSC). Hypertension: greater improvement was observed in group 1 (-31% vs. -5%, p = 0.04). Diabetes: less prevalent in group 1 after 2 years (2/36 vs. 9/24, p = 0.002), with a corresponding reduction in glucose-lowering treatments and persistence of impaired LNSC in diabetic patients (p < 0.001). Dyslipidemia: remained widespread in both groups, with minimal improvement over time (-22% in surgical and − 6% in medical cohort).

Conclusions

Surgical remission leads to faster and sustained improvements in clinical phenotype. However, obesity, arterial hypertension, and dyslipidemia do not completely revert in five years, especially during medical treatment. Most comorbidities persist despite UFC normalization, due to impaired LNSC: the recovery of cortisol rhythms confirms the remission of hypercortisolism.

Introduction

Cushing’s disease (CD) is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, resulting in persistent endogenous hypercortisolism. The cortisol excess leads to a typical clinical picture: round face, facial plethora, buffalo hump, cutaneous striae rubrae, easy bruising, proximal myopathy, weight gain with visceral obesity, hirsutism and acne [1,2,3]. Moreover, several comorbidities are cortisol-related: metabolic syndrome (visceral obesity, arterial hypertension, glucose intolerance or diabetes, and dyslipidemia), acquired thrombophilia, osteoporosis or vertebral fractures, immunological impairments with increased infection susceptibility, and psychiatric disorders [4]. The sum of physical changes and comorbidities leads to a reduced life expectancy and a worsening of the quality of life [5]. Pituitary trans-sphenoidal surgery (TSS) is the first-choice CD treatment [1]. Despite high remission rates (up to 90% in referral centers) [6], the risk of recurrence varies from 10 to 47% [7], especially in series with long-term follow-up. If surgery fails or is not feasible, cortisol excess can be managed with medical therapy. Not rarely, patients on cortisol-lowering therapy experience fluctuations of their cortisol levels, making outcome evaluations difficult and hardly standardized. The goals of CD treatment are to normalize cortisol levels, and to reduce the burden of comorbidities. The most used biochemical marker in clinical practice is urinary free cortisol (UFC), which estimates the cumulative daily secretion of cortisol, but does not offer information about cortisol rhythm [8].

In this study we compared two groups of CD patients with sustained normalization of 24-h UFC due either to post-surgical or medical cortisol-lowering therapy remission. The aim of the study was to analyze the impact of long-term normalization of hypercortisolism in terms of UFC, achieved with surgical or medical treatment, on endocrine parameters, cortisol-related clinical picture and comorbidities, in a five-years observation period of patients with CD.

Materials and methods

Subjects

Sixty CD patients were enrolled (75% female); the median age at diagnosis was 41 years (interquartile range [IQR] 32–52), followed at the Endocrinology Unit of Padua University Hospital from 2000 to 2021. This observational study was conducted in accordance with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines [9]. The study, following the guidelines in the Declaration of Helsinki, was approved by the ethics committee of Padova University Hospital (PITACORA, protocol No. AOP3318, ethics committee registration 5938-AO-24), and all patients gave informed consent. All data are included in the Repository of the University of Padova [10].

The first normalized UFC is considered as the starting point of observation at follow-up (two or five years). The cohort was divided into two cohorts: group 1 achieved CD remission after surgery, and group 2 achieved long-term eucortisolism during medical therapy. The inclusion criterion was 24-h UFC levels (mean of two collections) below the upper limit of normality during the observational period. Postoperative long-term adrenal insufficiency requiring substitutive glucocorticoid treatment (with hydrocortisone or cortisone acetate tablets) 12 months after surgery or new-onset hypopituitarism were considered exclusion criteria. The group 1 was made of 36 patients (69% female) in remission after successful TSS. The second group consisted of 24 patients (83% female) on long-term medical treatment for CD persistence (n = 17) or relapse (n = 4) after surgery and three patients in primary medical therapy for poor surgical eligibility, as shown in Fig. 1. Within group 2, nine patients underwent previous radiotherapy without efficacy, at least 5 years before reaching adequate biochemical control with medical treatment; none developed hypopituitarism. 14/24 patients (58%) were treated with a monotherapy and 11/24 (46%) with combined therapies during the observation period. Details on medical therapies are shown in Table 1. In particular, 3 patients were treated with metyrapone + pasireotide s.c., 1 with metyrapone + ketoconazole, 2 with ketoconazole and cabergoline, 1 with metyrapone + cabergoline, 1 with metyrapone + ketoconazole + cabergoline, 1 with metyrapone + ketoconazole + pasireotide s.c., 1 with metyrapone + ketoconazole + pasireotide s.c. + cabergoline. Metyrapone and ketoconazole were administered two/three times a day, pasireotide s.c. twice daily and cabergoline once daily in the evening.

Fig. 1
figure 1

Treatment and outcome of the described cohort. Light gray box indicates those patients in group 1 (surgical remission, n = 36), dark gray box indicates the patients in group 2 that achieved normalization of UFC with medical therapy (n = 24, either primary or after surgical failure)

Table 1 Cortisol-lowering drugs, dose, and time in treatment of subjects treated with a single and combined lines of therapy

All 60 patients completed at least 2 years of follow-up; a long-term 5-years evaluation was available in 43 patients of the original cohort (32 after surgery and 11 with medical therapy). Baseline characteristics of the two cohorts are reported in Table 2.

Table 2 Baseline characteristics of the two groups and previous treatment modalities

Data collection and study design

Two researchers retrieved clinical and biochemical data independently from the local digital medical records. We considered as baseline visit the clinical and endocrine evaluation performed with active hypercortisolism. Therefore, the baseline visit consists in the pre-surgical evaluation in group 1, and in the post-surgical confirmation of active hypercortisolism in those in medical treatment (or diagnosis in case of primary treatment, group 2).

We considered clinical and biochemical outcomes during routine follow-up at two- and five-years in each group, starting from surgical remission or the beginning of a stable normalization of UFC under medical therapy. CD diagnosis was based on at least two parameters among 24-h UFC above the upper normal limit (ULN, at least two collections), unsuppressed cortisol levels (> 50 nmol/L) after 1 mg overnight dexamethasone test (1 mg-DST) or late-night salivary cortisol (LNSC) > ULN (at least two samples). In all subjects, CD diagnosis was considered in case of normal-high ACTH levels, positive response to dynamic tests (corticotropin-releasing hormone or desmopressin test, high-dose dexamethasone test), and, two cases, with petrosal sinus sampling (BIPSS) [11]. Long-term remission after TSS was defined through normal UFC, combined with serum cortisol levels < 50 nmol/L in the first month after surgery and need of glucocorticoid replacement therapy. A relapse of CD was defined as the reappearance of the typical signs and symptoms of CD associated with the alteration of at least two first-line screening tests. Presence/absence of clinical signs of CD (round face, facial rubor, buffalo hump, bruising, cutaneous red striae, acne, hirsutism and oligo/amenorrhea in females) were evaluated during outpatient visits by expert endocrinologists. The presence of hirsutism in females was measured according to the Ferriman–Gallwey score > 8 (extent of hair growth in 9 locations was rated 0–4). Proximal muscle strength was diagnosed if patients were not able to stand up from a low seated position with anteriorly extended arms. Bodyweight, body mass index (BMI), waist and hip circumference, systolic (SBP), and diastolic blood pressure (DBP) were assessed with calibrated tools. Overweight was diagnosed in patients with BMI 25–30 kg/m2, obesity with BMI > 30 kg/m2. Visceral obesity was diagnosed as waist circumference ≥ 94 cm in men and ≥ 80 cm in women, or with a waist/hip ratio (WHR) ≥ 1 according to International Diabetes Federation criteria. Arterial hypertension was diagnosed for SBP above 140 mm Hg and/or DBP above 90 mm Hg and/or in patients on antihypertensive drugs. Diabetes mellitus (DM) was diagnosed according to American Diabetes Association criteria or when patients were taking antidiabetic medication. Dyslipidemia was diagnosed when low-density lipoprotein (LDL) calculated cholesterol was ≥ 100 mg/dL and hypertriglyceridemia when triglycerides were ≥ 150 mg/dL or when patients were on lipid-lowering medication. The presence of carotid vascular disease (CVD) has been assessed by supra-aortic vessels duplex ultrasound. Cushing’s cardiomyopathy (CCM) was diagnosed by doppler echocardiography with evidence of impaired relaxation and left ventricular filling pattern. The medical history was checked for cardiovascular disease (acute coronary syndrome, ACS) in all cases. A shortened activated partial thromboplastin time (aPTT < 29 s) defined pro-thrombotic status.

Assays

All biochemical analyses were carried out in an ISO15189:2012-accredited clinical laboratory [12], cortisol levels have been measured in urine or saliva with a mass-spectrometry home-made validated method. UFC was determined by a home-brew liquid chromatography-mass spectrometry (LC-MS/MS) method (intra-assay/interassay coefficient of variation [CV] < 6%/< 8%) since 2011 [13], previously by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%). The patients were instructed to discard the first morning urine void and to collect all urine for the next 24 h, so that the morning urine void on the second day was the final collection. The sample was kept refrigerated from collection time until it was analyzed: normal range for UFC is 16–168 nmol/24 h.

Salivary cortisol was measured by a radio-immunometric assay (Radim, intra-assay/interassay CV < 3%/< 9%) until 2014 [14], after then by LC-MS/MS method (intra-assay/interassay CV < 6%/< 8% [15]). In order to prevent food or blood contamination, samples were collected at least 30 min after subjects had eaten, brushed their teeth, smoked or assumed liquorice; undertaken using Salivette® devices containing a cotton swab with or without citric acid (Sarstedt, Nümbrecht, Germany). The sample was stored at − 80 °C, before analyses [15].

The 1-mg DST test was performed orally assuming 1 mg of dexamethasone between 11 P.M. and midnight, sampling serum cortisol the next morning at 8 A.M. Serum dexamethasone levels, routinely evaluated since 2017, were adequate in all cases [16]. Serum cortisol (RRID: AB_2810257) and ACTH (RRID: AB_2783635) were determined by immune-chemiluminescence assay (Immulite 2000, Siemens Healthcare). Dynamic second-line tests and BIPSS were performed according to international standards.

Statistical analysis

Data were analyzed using SPSS Software for Windows, version 24.0 (SPSS Inc). Data are reported as medians and interquartile range or as percentages. The comparison between continuous variables was performed by non-parametric Wilcoxon test or Mann–Whitney test, as appropriate. The comparison between categorical variables was performed by the χ2 test. The correlation between continuous variables was performed by linear regression analysis. The level of significance for the overall difference between the groups was tested with one-way ANOVA. A p value < 0.05 was considered statistically significant.

Results

Endocrine evaluation

At baseline the two groups were similar for morning serum/salivary cortisol, LNSC, cortisol after 1 mg DST and morning ACTH levels (Table 3); UFC levels were higher in the surgical cohort (p < 0.001). Endocrine parameters were not influenced by sex and BMI. At baseline, all patients had impaired salivary cortisol rhythm with increased LNSC and inadequate cortisol suppression after 1-mg DST. At two years the recovery of salivary cortisol rhythm was observed in 97% of patients after surgery and 50% of patients during medical therapy. The only patient who did not show recovery of cortisol rhythm in the surgical cohort had LNSC of 5.4 nmol/L (range 0.5–2.6 nmol/L), with adequate cortisol suppression after 1-mg DST and sustained normal UFC: it was considered a false-positive due to residual minor depression state.

Table 3 Biochemical pattern at baseline and during the follow-up

Adequate cortisol suppression after 1-mg DST (both with normal UFC and LNSC) was observed in 34 out of 36 patients (94%) in the surgical cohort; the two patients who did not show complete cortisol suppression after 1-mg DST had cortisol levels of 60 and 119 nmol/l, respectively. On the contrary, as per selection criteria, none of the patients in group 2 presented suppressed cortisol after 1-mg DST.

At 5 years follow-up, all cases in the surgical cohort had suppressed cortisol after 1-mg DST and normal salivary cortisol rhythm, whereas in group 2 9% had suppressed cortisol after 1-mg DST and 36% recovered salivary cortisol rhythm. At 5 years, UFC and salivary cortisol levels (either morning or late night) were similar in the two groups, while the median value of serum cortisol after 1-mg DST remained not adequately suppressed (median 75 nmol/L, from 18 to 257 nmol/L) during medical therapy (See Table 3). In group 2, patients on combined therapy had higher UFC (102 vs. 76 nmol/24h p = 0.03) and LNSC (2.4 vs. 1.9 p = 0.05) at 5 years, compared to patients on monotherapy.

Hirsutism, abdominal obesity, round face and facial rubor were prevalent in group 1 at baseline. On the contrary, the abdominal obesity, facial rubor and easy bruising were most commonly found in the medical cohort. The prevalence of facial rubor, buffalo hump and bruisability was higher after medical than surgical remission after 2 years of eucortisolism; at 5 years the prevalence of buffalo hump and bruisability was higher in patients under drug therapy as well (Table 4; Fig. 2). Higher levels of UFC at baseline were observed in all patients with proximal myopathy (p < 0.001).

Table 4 Two- and five-years changes in clinical phenotype from baseline in group 1 and group 2
Fig. 2

figure 2

Signs and symptoms of hypercortisolism at baseline (grey bars), two-years (orange bars) and five-years (blue bars) follow up after surgical (TSS) or medical remission (MED)

Arterial hypertension

Arterial hypertension (AH) was the most frequent comorbidity in both groups at baseline, with similar distribution in the two groups (Table 5). The prevalence of AH decreased after two years in both groups, especially in the surgical cohort (64% vs. 44% in group 2, p < 0.001; 75% vs. 71% p = 0.003), with no further improvement after five years. Overall, hypertensive patients were older at diagnosis (45yrs vs. 31y; p < 0.001) and with larger BMI (29 vs. 25 kg/m2; p = 0.03). Median UFC, morning salivary cortisol and LNSC, and 1-mg DST were not different in patients with/without AH at baseline and at 2 years. SBP and DBP values were similar in the two cohorts and were not correlated to UFC, LNSC or 1-mg DST throughout the follow-up. At 2 years, hypertensive patients had higher levels of morning salivary cortisol and LNSC with impaired rhythm (respectively 10.4 vs. 6 nmol/L, p = 0.01 and 3.2 vs. 1 nmol/l, p = 0.007). SBP and DBP values did not change during the five-years observation time in both groups; however, the number of anti-hypertensive drugs was higher in group 2 than in group 1 (p = 0.007). Overall patients treated with metyrapone showed higher values of DBP at 2 years (mean 89.4 vs. 81.7 mmHg, p = 0.01), the prevalence of AH did not differ from patients with other medical treatments.

Table 5 Two- and five-years changes in cardio-metabolic cortisol-related comorbidities of CD from baseline in group 1 and group 2

Glucose metabolism

DM prevalence at baseline did not show a correlation with BMI and age at CD diagnosis. DM prevalence was similar in group 1 and 2 after two and five years of follow-up. The follow-up analysis of DM was performed excluding patients in pasireotide, since its known impact in glucose metabolism. In both groups, median UFC, morning salivary and LNSC, and 1-mg DST were similar in patients with/without DM at baseline. At 5 years, patients with diabetes had higher levels of morning salivary cortisol and LNSC with impaired cortisol rhythm (respectively 15 vs. 7 nmol/L, p < 0.001 and 5.4 vs. 1.5 nmol/l, p < 0.001). None of the explored hormonal parameters was correlated with HbA1c levels in both groups at any time point considered. The number of antidiabetic drugs was higher after medical than surgical remission (Table 5).

As expected, patients treated with pasireotide had higher incidence of newly onset DM at 2- and 5 years (p = 0.02 and p = 0.05 respectively) and required more antidiabetic drugs at 2- and 5 years (p = 0.002, p = 0.05) or insulin units at 5 years (p = 0.03). HbA1c levels during pasireotide were higher than patients treated with other drugs (55.6 vs. 38 nmol/l, p = 0.002), requiring a higher number of antidiabetic drugs (p = 0.008). Patients on combined therapy with pasireotide had higher rates of DM at 2- and 5 years (p < 0.001 and p = 0.01) and used more antidiabetic drugs at 2- and 5 years (p = 0.004, p = 0.01) than those on monotherapy.

Lipid metabolism

The prevalence of dyslipidemia was similar in the two groups at baseline and after two years, and higher in the medical remission cohort after five years (p = 0.01). Overall, dyslipidemic patients were older at diagnosis (46y vs. 36y; p = 0.006) and had higher BMI (30 vs. 25 kg/m2; p < 0.001). There was no correlation between hormone parameters and LDL or triglycerides levels. Lipid profile was similar between patients treated with different drugs.

Vascular disease and coagulative profile

There was no difference between the two groups, at baseline, in the prevalence of carotid vascular disease, history of ACS, and CCM; at 5 years, in both groups, no patient had a worsening of a previously diagnosed stenosis, or novel diagnosis of CVD, ACS and CCM.

The median aPTT value at baseline was in the pro-thrombotic range in both groups (25s), without sex and BMI differences. No correlation was observed between aPTT and UFC, LNSC and 1-mg DST levels. Patients who manifested easy bruising, had shorter aPTT at 2- and 5 years (median 24 vs. 27s, p = 0.03). aPTT does not increase within both groups at 2- and 5-years and aPTT was shorter during medical therapy compared to surgical remission both after 2 and 5 years (22.5s vs. 27s, p = 0.02 at 2y and 23.5s vs. 27.9s, p = 0.02 at 5y).

Discussion

The impact of CD remission on clinical picture and hypercortisolism-related comorbidities is still controversial. The current knowledge suggests that long-term CD surgical remission is associated with increased metabolic and vascular damage, not only if compared to active disease, but also even after long-term normalization of cortisol secretion [17]. If CD recurs after successful TSS, or if surgery fails/is not feasible, cortisol excess can be treated with medical therapy. Likewise, long-term studies (> 2 years) on the clinical effects of medical therapy on CD are lacking. Some prospective registry studies have been published [1], only one retrospective study on long-term use of ketoconazole described a multicentric cohort of CD patients without a control group [18].

In our study, we enrolled 60 patients with CD diagnosed and treated in a single tertiary care center, with sustained and long-term (2 and 5 years) UFC normalization after surgery or during medical therapy. As expected, UFC levels at baseline were different in the two groups, due to the distinct starting point of medical history: a patient with persistent-recurrent CD after pituitary surgery presents with lower UFC than the new diagnosis. After surgical remission, patients achieved the recovery of salivary cortisol rhythm and the complete suppression of cortisol after 1-mg DST (investigated after substitutive glucocorticoid treatment discontinuation) in almost all cases. On the contrary, if eucortisolism is achieved with long-term medical therapy the recovery of salivary cortisol rhythm was observed only in half of patients and only few of them showed cortisol suppression after 1-mg DST within the 5 years observation time. Patients who were more resistant to the recovery of cortisol rhythm were more likely to receive combined treatment, even if no treatment is superior to others in normalizing salivary cortisol rhythm, in line with previous reports [1, 18, 19].

Within 2 years, patients in the surgical remission group showed a marked improvement of all phenotypic traits common at CD diagnosis compared to those in medical therapy. As observed also in other series of CD patients in remission [20], abdominal obesity persisted more than other clinical features over time, leading to an impaired body composition especially in the medically treated group [21]. Considering hyperandrogenism, acne improvement was more relevant at 2 and 5-years of follow up, probably due to a differential effect of ACTH-dependent adrenal androgens compared to hirsutism.

The impaired cortisol rhythm was a predictor of the long-lasting of most CD phenotypic features, as round face, buffalo hump, facial rubor, abdominal obesity, proximal myopathy and bruisability. A more severe clinical phenotype at baseline can explain a reduced control of hypercortisolism in monotherapy, requiring drug combination, and signs or symptoms are likely to persist despite the normalization of UFC [22]. In this study, no medication outperformed the others in terms of recovery from the CD phenotype.

The aetiology of hypertension and dyslipidemia is known to be heterogeneous, since both are influenced also by age at diagnosis and BMI, causing low rates of remission after UFC normalization [23, 24]. Arterial hypertension showed a decreasing trend with the best response within 2 years after UFC normalization only after surgical remission. Patients with disrupted salivary cortisol rhythm were more likely to remain hypertensive during the 5 years follow-up. Likewise, DM persistence during follow up correlates to impaired salivary cortisol rhythm and not with UFC. This finding is in contrast with the observations of Schernthaner-Reiter et al. [25]. on CD remission, and, on the contrary, supports data described by Guarnotta et al. [22]. Newell-Price et al.. recently found that when UFC and LSNC are both normal in patients treated with pasireotide, the rise in HbA1c levels is less evident than in patients with normal UFC but uncontrolled LNSC [26]. This observation underlines the importance of the impaired cortisol rhythm in the glucose impairment pathogenesis in CD. During the 5 years observation time, a worsening of previously diagnosed cardiovascular conditions, or novel acute vascular events, was not observed in both groups. This finding suggested that normalized UFC and intensive treatment of cardio-metabolic CD comorbidities play a fundamental role in reducing cardiovascular mortality [27]. A minor impact of CD therapy was observed in dyslipidemia, which persisted in both groups, with minimal improvement over time (−22% in surgical and − 6% in medical cohort). The criterion of 100 mg/dL LDL cut-off identifies a moderate CV risk reflecting the main focus of the study: the assessment of cardiometabolic complication after CD remission, assuming that they present a lower cardiovascular risk compared to patients with overt hypercortisolism.

Plasma hypercoagulability, with shortened aPTT, was found in all patients with active hypercortisolism. In the 5 years observation time, this parameter showed latency in increasing in both groups and in none achieved normality (> 28s). As previously observed in other studies, no correlation is observed between aPTT and any of the explored hormonal parameters [22, 28]. At 2- and 5 years, instead, shorter aPTT was observed during medical treatment than after surgical remission cohort. In both groups a shorter aPTT was associated with bruisability, which is related to impaired LNSC, strengthening the role of the impaired cortisol rhythm as a major driver of hypercoagulability. Also, Ferrante et al.. observed the long latency of plasma hypercoagulability, persisting for years after biochemical remission of CD: in that series thrombophilia appeared to be reversible within 5 years [29], while in our cohort the recovery takes longer.

Additionally, sexual differences characterize patients with patients with Cushing’s syndrome and hypogonadism in hypercortisolism is known to further increase the cardiovascular risk [30, 31]. However, it was not an interfering factor in our study population since hypopituitarism was considered an exclusion criterion, no case of new-onset hypogonadism was reported (even in male patients treated with ketoconazole), and the menopause transition in six women during the observation was not considered relevant.

The limits of the present study are its retrospective design, the variability of concomitant treatments, the heterogenous combinations of medical therapy used in clinical practice, the presence of treatment-specific adverse events that mimic the effects of hypercortisolism (such as pasireotide-induced DM and hypertension with metyrapone), the unpredictable effect of previous treatments, including radiotherapy. We considered UFC and LNSC as markers of hypercortisolism remission; nonetheless we acknowledge that both of them present some limitations, especially during medical treatment. The former considers the whole cortisol secretion during the day, and albeit UFC normalization is the main outcome of all trials for medical treatment [32, 33] it does not detect mild hypercortisolism. On the other hand, a normal LNSC does not fully reflect a normal circadian rhythm: only high cortisol levels in the morning with a decline in the night are able to restore clock-related activities [34].

Its strengths are the complete patient characterization in a single tertiary care center, the comparative study design, and the standardized protocols for diagnosis and long-term follow-up. In particular, samples have been processed within a single laboratory with accurate methods (LC-MS for urinary and salivary steroids), and all endocrine aspects of hypercortisolism were considered (overall daily cortisol production by UFC, circadian cortisol rhythm, and the recovery of the hypothalamic-pituitary axis by 1-mg DST overnight test).

To conclude, despite UFC normalization in both groups during follow-up, surgical remission results in more rapid and relevant improvements in CD phenotype and comorbidities. During medical therapy the UFC levels can be higher than after surgery, although in the normal range, and the normalization of LNSC is not always achieved: both conditions suggests that stricter criteria should be considered to define eucortisolism in patients with CD under medical treatment. Conditions such as obesity, hypertension, dyslipidemia, and hypercoagulability are not completely reversible in a 5-year observation time even in the surgical remission group. This observation underlines that all the comorbidities, independently of the normalization of UFC, must be intensively treated. Moreover, UFC normalization should not be considered the only biochemical goal to be reached, since the persistence of comorbidities seems to be more related to an impaired cortisol rhythm rather than to the cortisol secretory burden.

References

  1. Fleseriu M et al (2021) Consensus on diagnosis and management of Cushing’s disease: a guideline update, Dec. 01, Elsevier Ltd. https://doi.org/10.1016/S2213-8587(21)00235-7

  2. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M Cushing’s syndrome. Dec 09 2023 Elsevier B V https://doi.org/10.1016/S0140-6736(23)01961-X

  3. Ceccato F et al (2024) Clinical and biochemical data for the diagnosis of endogenous hypercortisolism: the ‘cushingomic’ approach. J Clin Endocrinol Metab Jul. https://doi.org/10.1210/clinem/dgae517

    Article Google Scholar

  4. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A (2016) Complications of Cushing’s syndrome: state of the Art. Lancet Publishing Group. https://doi.org/10.1016/S2213-8587(16)00086-3

    Article Google Scholar

  5. Clayton RN et al (2016) Mortality in patients with Cushing’s disease more than 10 years after remission: A multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol 4(7):569–576. https://doi.org/10.1016/S2213-8587(16)30005-5

    Article PubMed Google Scholar

  6. Pivonello R, De Leo M, Cozzolino A, Colao A (2015) The treatment of Cushing’s disease. Endocr Soc. https://doi.org/10.1210/er.2013-1048

    Article Google Scholar

  7. Petersenn S et al (2015) Outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: Systematic review assessing criteria used to define remission and recurrence. BioScientifica Ltd. https://doi.org/10.1530/EJE-14-0883

    Article Google Scholar

  8. Broersen LHA, Jha M, Biermasz NR, Pereira AM, Dekkers OM (2018) Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary 21(6):631–641. https://doi.org/10.1007/s11102-018-0897-z

    Article CAS PubMed PubMed Central Google Scholar

  9. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP (2008) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 61(4): 344–349. https://doi.org/10.1016/j.jclinepi.2007.11.008

  10. Ceccato F (2024) The burden Of Cushing’s disease cardiometabolic comorbidities: comparison between surgical remission and long-term eucortisolism with medical treatment. Repository of the University of Padova. https://doi.org/10.25430/researchdata.cab.unipd.it.00001350

  11. Barbot M et al (2016) Second-line tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome. Pituitary 19(5):488–495. https://doi.org/10.1007/s11102-016-0729-y

    Article CAS PubMed Google Scholar

  12. ISO 15189:2012 Medical laboratories — Requirements for quality and competence. Published 2022. Accessed October 10 (2023) https://www.iso.org/standard/56115.html

  13. Ceccato F et al (2014) The diagnostic performance of urinary free cortisol is better than the cortisol: cortisone ratio in detecting de Novo Cushing’s syndrome: the use of a LC-MS/MS method in routine clinical practice. Eur J Endocrinol 171(1):1–7. https://doi.org/10.1530/EJE-14-0061

    Article CAS PubMed Google Scholar

  14. Ceccato F et al (2012) Assessment of glucocorticoid therapy with salivary cortisol in secondary adrenal insufficiency. Eur J Endocrinol 167(6):769–776. https://doi.org/10.1530/EJE-12-0534

    Article CAS PubMed Google Scholar

  15. Antonelli G, Ceccato F, Artusi C, Marinova M, Plebani M (2015) Salivary cortisol and cortisone by LC-MS/MS: Validation, reference intervals and diagnostic accuracy in Cushing’s syndrome. Clinica Chimica Acta 451:247–251. https://doi.org/10.1016/j.cca.2015.10.004

    Article CAS Google Scholar

  16. Ceccato F et al (2020) Dexamethasone measurement during low-dose suppression test for suspected hypercortisolism: threshold development with and validation. J Endocrinol Invest 43(8):1105–1113. https://doi.org/10.1007/s40618-020-01197-6

    Article CAS PubMed Google Scholar

  17. Pivonello R, Faggiano A, Lombardi G, Colao A (2005) The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. W.B. Saunders. https://doi.org/10.1016/j.ecl.2005.01.010

    Book Google Scholar

  18. Castinetti F et al (2014) Ketoconazole in Cushing’s disease: is it worth a try. J Clin Endocrinol Metab 99(5):1623–1630. https://doi.org/10.1210/jc.2013-3628

    Article CAS PubMed Google Scholar

  19. Barbot M et al (2014) Combination therapy for Cushing’s disease: Effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole? Pituitary 17(2):109–117. https://doi.org/10.1007/s11102-013-0475-3

    Article CAS PubMed Google Scholar

  20. Colao A et al (1999) Persistence of Increased Cardiovascular Risk in Patients with Cushing’s Disease after Five Years of Successful Cure,., [Online]. Available: https://academic.oup.com/jcem/article/84/8/2664/2864186

  21. Ceccato F et al (2017) Sep., Body Composition is Different after Surgical or Pharmacological Remission of Cushing’s Syndrome: A Prospective DXA Study, Hormone and Metabolic Research, vol. 49, no. 9, pp. 660–666. https://doi.org/10.1055/s-0043-115008

  22. Guarnotta V et al (2017) The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome. Endocrine 55(2):564–572. https://doi.org/10.1007/s12020-016-0914-9

    Article CAS PubMed Google Scholar

  23. Giordano R et al (2011) Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different aetiologies during active disease and 1 year after remission. Clin Endocrinol (Oxf) 75(3):354–360. https://doi.org/10.1111/j.1365-2265.2011.04055.x

    Article CAS PubMed Google Scholar

  24. Jha S, Sinaii N, McGlotten RN, Nieman LK (2020) Remission of hypertension after surgical cure of Cushing’s syndrome. Clin Endocrinol (Oxf), 92(20): 124–130. https://doi.org/10.1111/cen.14129

  25. Schernthaner-Reiter MH et al (2019) Factors predicting long-term comorbidities in patients with Cushing’s syndrome in remission. Endocrine 64(1):157–168. https://doi.org/10.1007/s12020-018-1819-6

    Article CAS PubMed Google Scholar

  26. Newell-Price J et al (2020) Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease. Eur J Endocrinol 182(2):207–217. https://doi.org/10.1530/EJE-19-0695

    Article CAS PubMed Google Scholar

  27. Mondin A et al (2023) Complications and mortality of Cushing’s disease: report on data collected over a 20-year period at a referral centre. Pituitary 26(5):551–560. https://doi.org/10.1007/s11102-023-01343-2

    Article PubMed PubMed Central Google Scholar

  28. Barbot M et al (2018) Effects of pasireotide treatment on coagulative profile: a prospective study in patients with Cushing’s disease. Endocrine 62(1):207–214. https://doi.org/10.1007/s12020-018-1669-2

    Article CAS PubMed Google Scholar

  29. Ferrante E et al (2022) Evaluation of procoagulant imbalance in Cushing’s syndrome after short- and long-term remission of disease. J Endocrinol Invest 45(1):9–16. https://doi.org/10.1007/s40618-021-01605-5

    Article CAS PubMed Google Scholar

  30. Zilio M, Barbot M, Ceccato F, Camozzi V, Bilora F, Casonato A, Frigo AC, Albiger N, Daidone V, Mazzai L, Mantero F, Scaroni C (2014) Diagnosis and complications of Cushing’s disease: gender-related differences. Clin Endocrinol (Oxf) 80(3):403–410. https://doi.org/10.1111/cen.12299

    Article CAS PubMed Google Scholar

  31. Detomas M, Deutschbein T, Tamburello M, Chifu I, Kimpel O, Sbiera S, Kroiss M, Fassnacht M, Altieri B (2024) Erythropoiesis in Cushing syndrome: sex-related and subtype-specific differences. Results from a monocentric study. J Endocrinol Invest 47(1):101–113. https://doi.org/10.1007/s40618-023-02128-x

    Article CAS PubMed Google Scholar

  32. Fleseriu M et al (2019) Long-term efficacy and safety of once-monthly pasireotide in Cushing’s disease: A Phase III extension study. Clin Endocrinol (Oxf) 91(6):776–785. https://doi.org/10.1111/cen.14081

    Article CAS PubMed Google Scholar

  33. Ceccato F et al (2018) Metyrapone treatment in Cushing’s syndrome: a real-life study. Endocrine 62(3):701–711. https://doi.org/10.1007/s12020-018-1675-4

    Article CAS PubMed Google Scholar

  34. Minnetti M, Hasenmajer V, Pofi R, Venneri MA, Alexandraki KI, Isidori AM (2020) Fixing the broken clock in adrenal disorders: Focus on glucocorticoids and chronotherapy. BioScientifica Ltd. https://doi.org/10.1530/JOE-20-0066

    Article Google Scholar

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Funding

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All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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Authors and Affiliations

  1. Department of Medicine-DIMED, University of Padova, Padova, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

  2. Endocrinology Unit, Department of Medicine DIMED, University Hospital of Padova, Via Ospedale Civile, 105, Padova, 35128, Italy

    Irene Tizianel, Laura Lizzul, Alessandro Mondin, Giacomo Voltan, Pierluigi Mazzeo, Carla Scaroni, Mattia Barbot & Filippo Ceccato

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Correspondence to Filippo Ceccato.

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Tizianel, I., Lizzul, L., Mondin, A. et al. Cardiometabolic complications after Cushing’s disease remission. J Endocrinol Invest (2025). https://doi.org/10.1007/s40618-025-02572-x

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Avascular Necrosis in Patients With Cushing Syndrome

Posted on March 12, 2025 by MaryO

Abstract

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, leading to a range of clinical manifestations including avascular necrosis (AVN), a rare complication of CS. Although AVN is often associated with exogenous glucocorticoid treatment, it can occur in endogenous CS but may be unrecognized because of its rarity and possibly from a subclinical presentation. We describe a case of a 71-year-old male with florid Cushing disease who initially presented with bilateral hip AVN and later developed bilateral shoulder AVN despite achieving biochemical remission following transsphenoidal surgery and adjuvant stereotactic photon radiosurgery. AVN in endogenous CS is underreported, and guidance on routine screening is lacking. Our case underscores the importance of considering AVN in patients with CS, especially in those with persistent or recurrent joint symptoms and markedly elevated cortisol levels. Early detection of AVN is crucial as it can lead to irreversible joint damage and disability if untreated. Screening strategies should be explored to identify high-risk patients who are diagnosed with CS for timely intervention, thereby preventing long-term morbidity associated with AVN.

Introduction

Cushing syndrome (CS) results from prolonged exposure to excess glucocorticoids, either from exogenous glucocorticoids or endogenous sources. In endogenous CS, hypercortisolism may be due to an ACTH-dependent process, most often from a corticotroph adenoma in Cushing disease (CD) or from ectopic ACTH secretion from neuroendocrine tumors or other solid tumors such as small cell lung carcinoma. On the other hand, ACTH-independent CS is mainly driven from adrenal pathology including adrenal adenomas, adrenocortical carcinomas, adrenal hyperplasia, and primary pigmented micronodular disease [1]. The presenting symptoms and signs of CS include hypertension, diabetes mellitus, weight gain, facial plethora, dorsocervical fat pads, muscle weakness, and osteoporosis, most of which may be detected on physical examination or diagnosed biochemically. A less common symptom is avascular necrosis (AVN) of bone tissue [1, 2], which can present with pain or point tenderness of the hip or other joints as well as present subclinically [3].

AVN of the hip results from compromised blood supply to the bone tissue and usually impacts the hips and shoulders. This leads to necrosis of hematopoietic cells, adipocytes, and osteocytes. Subsequently, bone repair processes are activated, with differentiation of mesenchymal cells into osteoblasts to build new bone and hematopoietic stem cells into osteoclasts to remove necrotic tissue. However, because of impaired bone resorption and formation, subchondral fractures eventually occur [4]. Exogenous glucocorticoid treatment is 1 of the most common causes of AVN and may account for up to 38% of atraumatic AVN and is dose dependent [5]. Glucocorticoid treatment is theorized to cause AVN through increased systemic lipids, leading to compromised perfusion to the femoral head resulting from fat emboli or external lipocyte compression, as well as alterations in the inflammatory cytokines resulting in osteoclast activation and osteoblast apoptosis [4, 6]. Compared to exogenous glucocorticoid treatment, AVN caused by endogenous hypercortisolism is not frequently reported nor is it screened for on diagnosis of CS.

We describe a patient who presented with bilateral hip AVN in the context of florid CD. We aim to highlight this presenting feature to heighten awareness for screening for this progressive condition, which can potentially lead to joint damage, loss of mobility, and long-term disability.

Case Presentation

A 71-year-old male with medical history of active tobacco use and obstructive sleep apnea was diagnosed with new-onset hypertension during an annual health visit. He was started on antihypertensive medications (losartan, hydrochlorothiazide, and spironolactone) by his primary care doctor, but the hypertension remained uncontrolled. Over the course of 2 months, the patient developed progressive lower extremity edema and was started on furosemide, which led to hypokalemia and was subsequently discontinued. He clinically deteriorated, with progressive anasarca and dyspnea, and then developed acute left eye ptosis and diplopia and was admitted to the hospital. The patient also endorsed irritability, mood swings, easy bruising, low libido, increased appetite, 30-lb weight gain, and bilateral hip pain.

Diagnostic Assessment

Physical examination was significant for oral candidiasis, dorsocervical fat pad, facial plethora, proximal muscle weakness, and bilateral hip tenderness. Testing confirmed ACTH-dependent CS with elevated 24-hour urine free cortisol of 1116 μg/24 hours (30788.21 nmol/24 hours) and 1171.9 μg/24 hours (32330.38 nmol/24 hours) (normal reference range, 3.5-45 μg/24 hours; 96.56-1241.46 nmol/24 hours) and ACTH of 173 pg/mL (38.06 pmol/L) and 112 pg/mL (24.64 pmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L) on 2 separate occasions. He had hypogonadotropic hypogonadism with total testosterone levels of 41 ng/dL (1.42 nmol/L) (normal reference range, 250-1100 ng/dL; 8.68-38.17 nmol/mL) and suppressed LH and FSH at <0.2 mIU/mL (<0.2 IU/L) (normal reference range, 0.6-12.1; 0.6-12/1.1 IU/L) and 0.2 mIU/mL (<0.2 IU/L) (normal reference range, 1.0-12.0 2 mIU/mL; 1.0-12.0 2 IU/L) respectively, whereas the remaining pituitary hormones were normal, although IGF-1 was low normal at 66 ng/mL (8.65 nmol/L) (normal reference range, 7.2-63 pg/mL; 1.58-13.86 pmol/L). He also had new-onset diabetes mellitus with glycated hemoglobin of 8% (<5.7%) (Table 1). Imaging of the lungs showed a 15-mm solid noncalcified nodule in the posterior right upper lobe concerning for neoplasm. Pituitary magnetic resonance imaging (MRI) revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (Fig. 1). Additionally, pelvis computed tomography (CT) scan demonstrated bilateral avascular necrosis of the capital femoral epiphysis without evidence of fracture or subchondral collapse (Fig. 2A and 2B).

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Figure 1.

Pituitary magnetic resonance imaging (MRI) with gadolinium, using T1-weighted, turbo spin-echo revealed sequence revealed a 16 × 20 × 16 mm macroadenoma invading the left cavernous sinus (white arrow).

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Figure 2.

Coronal inversion recovery image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (A). Axial proton density with fat saturation image bilateral hips demonstrates geographic lesions bilateral femoral heads with serpentine borders consistent with bilateral femoral head bone infarcts. No subchondral collapse or arthritic changes identified (B). Coronal T1 image of the right shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (C). Coronal T1 image of the left shoulder demonstrates geographic lesion medial humeral head with serpentine border consistent with bone infarct. No subchondral collapse or arthritic changes identified (D) (white arrows).

Table 1.

Laboratory evaluation of the patient at presentation

Lab Value Reference Range
Conventional units (Système International units)
ACTH 173 pg/mL (38.06 pmol/L) 7.2-63 pg/mL (1.58-13.86 pmol/L)
24-h urine free cortisol 1116 μg/24 h (30,788.21 nmol/24 h) 4.0-55.0 μg/24 h (110.35-1517.34 nmol/24 h)
Total testosterone 41 ng/mL (1.42 nmol/L) 250-1100 ng/mL (8.68-38.17 nmol/L)
Free testosterone 12.3 pg/mL (0.07 nmol/L) 30.0-135.0 pg/mL (0.17-0.79 nmol/L)
LH <0.2 mIU/mL (<0.2 IU/L) 0.6-12.1 mIU/mL (0.6-12.1 IU/L)
FSH 0.2 mIU/mL (0.2 IU/L) 1-12 mIU/mL (1-12 IU/L)
Prolactin 9.6 ng/mL (9.6 μg/L) 3.5-19.4 ng/mL (3.5-19.4 μg/L)
TSH 0.746 mIU/L 0.450-5.330 mIU/L
Free T4 0.66 ng/dL (8.49 pmol/L) 0.61-1.60 ng/dL (7.85-20.59 pmol/L
IGF-1
Z score		 66 ng/mL (8.65 nmol/L)
−0.9		 34-245 ng/mL (4.45-32.09 nmol/L)
−2.0 to +2.0
HbA1c 8.2% <5.7%

Abbreviations: Hb A1c, hemoglobin A1C.

Treatment

Prophylactic treatment was started with subcutaneous heparin for anticoagulation and trimethoprim-sulfamethoxazole for opportunistic infections. Orthopedic evaluation did not recommend acute intervention for the hip AVN. Given the pituitary macroadenoma on imaging and left cranial nerve VI palsy, it was determined that the patient likely had CD, so he underwent transsphenoidal surgery. Surgical pathology confirmed the adenoma was ACTH positive, sparsely granulated, with Ki-67 index of 4%, and without increased mitotic activity (Fig. 3).

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Figure 3.

Hematoxylin and eosin (A) and adrenocorticotropic hormone (B) stained sections show oval nuclei with “salt and pepper” chromatin and granular, ACTH-positive cytoplasm. Original magnification 250×.

Outcome and Follow-up

Due to ongoing hypercortisolism (Table 2) and residual tumor in the left cavernous sinus, the patient underwent adjuvant treatment with stereotactic photon radiosurgery at a dose of 13 Gy targeted to the left cavernous sinus and was started on osilodrostat, an oral, reversible inhibitor of 11β-hydroxylase that drives the final step of cortisol synthesis and aldosterone synthase, which converts 11-deoxycorticosterone to aldosterone [7]. The starting dose of osilodrostat was 2 mg twice per day. As the patient developed nausea, lack of appetite, and malaise with decreasing cortisol levels, osilodrostat was reduced to 1 mg daily, and he was started on hydrocortisone replacement therapy on week 11 postoperatively (Table 3). Ultimately, both osilodrostat and hydrocortisone were discontinued following normalization of cortisol levels. Regarding the rest of the hormonal deficiencies, his total testosterone and IGF-1 levels improved to levels of 483 ng/dL (16.76 nmol/L) and 99 (12.97 nmol/L), respectively, and he did not require hormone replacement therapy. Clinically, the patient improved with resolution of his hypertension and diabetes and achieved a 38-lb weight loss. Additionally, his diplopia improved and his hip pain resolved without any restriction in mobility. However, 1 year postoperatively, the patient developed bilateral shoulder pain. MRI of the shoulders demonstrated subchondral changes in the right humeral head (Fig. 2C) and a linear area of subchondral change involving the left humeral head (Fig. 2D) consistent with AVN, as well as a bilateral high-grade supraspinatus tear and acromioclavicular joint osteoarthritis. He was treated with an intraarticular methylprednisolone 40-mg injection to both shoulders, with subsequent improvement of the pain and joint mobility. He also underwent a coronary artery bypass graft surgery for 3-vessel disease. The patient has otherwise maintained normal urine and salivary cortisol levels off osilodrostat or hydrocortisone, and 1 year after surgery, the ACTH (cosyntropin) stimulation test was normal. The pulmonary nodule has remained stable on serial imaging.

Table 2.

Postoperative cortisol and ACTH levels

Postoperative day
Lab Reference Range Conventional units (Système International units) 1 2 2 3 4 5
Morning cortisol 3.7-19.4 μg/dL (102.08- 535.21 nmol/L) 26 μg/dL (717.29 nmol/L) 21.5 μg/dL (593.14 nmol/L) 6 μg/dL (165.53 nmol/L) 8.1 μg/dL (223.46 nmol/L) 16.4 μg/dL (452.44 nmol/L) 21.5 μg/dL (593.14 nmol/L)
ACTH 7.2-63.3 pg/mL (1.58- 13.93 pmol/L) 72 pg/mL (15.84 pmol/L) 62 pg/mL (13.64 pmol/L)

Table 3.

Titration of osilodrostat treatment based on cortisol levels

Postoperative week
Lab Reference range Conventional units (Système International units) 8 9 11 13 15 18 22 24
ACTH 7.2-63.3 pg/mL (1.58-13.93 pmol/L) 95.6 pg/mL (21.03 pmol/L) 131 pg/mL (28.82 pmol/L) 58.8 pg/mL (12.94 pmol/L) 79.3 pg/mL (17.45 pmol/L) 79.9 pg/mL (17.58 pmol/L) 73.4 pg/mL (16.15 pmol/L) 62 pg/mL (13.64 pmol/L) 71.5 pg/mL (15.73 pmol/L)
Morning cortisol 3.7-19.4 μg/dL (102.08-535.21 nmol/L) 23.9 μg/dL (659.35 nmol/L) 18.8 μg/dL (518.65 nmol/L) 6.6 μg/dL (182.08 nmol/L) 4.5 μg/dL (124.15 nmol/L) 3.3 μg/dL (91.04 nmol/L) 2.4 μg/dL (66.21) nmol/L 8.2 μg/dL (226.22. nmol/L) 4.1 μg/dL (113.11 nmol/L)
LNSC <0.010-0.090 μg/dL (0.28-2.48 nmol/L) 0.615 μg/dL (16.97 nmol/L) 0.058 μg/dL (1.60 nmol/L) 0.041 μg/dL (1.13 nmol/L) 0.041 μg/dL (1.13 nmol/L)
UFC, 24-h 5-64 μg/24 h (137.94-1765.63 nmol/24 h) 246 μg/24 h (6786.65 nmol/24 h) 226 μg/24 h (6234.89 nmol/24 h) 2 μg/24 h (55.18. nmol/24 h)
Osilodrostat dose 2 mg BID 2 mg BID 2 mg AM
3 mg PM		 2 mg BID 2 mg AM
1 mg PM		 1 mg BID 1 mg daily Oslidrostat discontinued

Abbreviations: BID, twice per day; LNSC, late night salivary cortisol; UFC, urine free cortisol.

Discussion

Our patient exhibited pronounced hypercortisolism secondary to CD, with bilateral hip AVN as 1 of the presenting symptoms. Despite achieving biochemical remission of the disease and resolution of other associated symptoms, the patient was later diagnosed with bilateral shoulder AVN.

AVN caused by endogenous hypercortisolism is seldom documented, and routine screening for it is not typically conducted during the diagnosis of CS. However, AVN has been reported to be a presenting symptom in several case reports or may manifest years after the initial diagnosis [8]. Reported causes of AVN in endogenous CS include pituitary adenomas, adrenal adenomas or carcinomas, adrenal hyperplasia, or neuroendocrine tumors [8‐23] (Table 4), with some cases of AVN associated with severe hypercortisolism [10, 15]. Other risk factors associated with AVN include hip trauma, femoral fractures, hip dislocation, systemic lupus erythematosus in the setting of concomitant corticosteroid treatments, or vasculitis, sickle cell disease, hypercoagulability, Gaucher disease, hyperlipidemia or hypertriglyceridemia, hyperuricemia, hematological malignancies, antiretroviral medications, alcohol use, and exogenous steroid treatment [4]. Our patient had no history of hip trauma or other aforementioned comorbidities. Furthermore, during presentation, his lipid levels were normal, with low-density lipoprotein cholesterol of 89 mg/dL (<130 mg/dL) and triglycerides of 97 mg/dL (<150 mg/dL). Therefore, it is likely that his bilateral hip and shoulder AVN was caused by severe endogenous hypercortisolism.

Table 4.

Published cases of avascular necrosis in patients with endogenous hypercortisolism

First author, year Age (y)/sex Time of diagnosis in relation to CS diagnosis AVN related symptoms Imaging modality Imaging description Diagnosis Treatment
Salazar D, 2021 [15] 38 F 3 y prior to diagnosis Right hip pain MRI
  • Right hip joint effusion and synovitis
  • Flattening of the femoral head-Subcortical edema
 Adrenal adenoma Right hip arthroplasty
Madell SH, 1964 [16] 41 F 1 month before diagnosis Right shoulder pain X-ray
  • Increased density of the right humeral head with spotty areas of radiolucency
  • Early flattening and beginning of fragmentation
 Adrenal adenoma Osteotomy
Anand A, 2022 [21] 47 M Bilateral hip pain MRI
  • Necrosis of bilateral femur heads
 adrenocortical carcinoma
Belmahi N, 2018 [9] 28 F Progressive limping and right hip pain MRI
  • Right femoral head AVN
 Pituitary adenoma Right total hip replacement
Wicks I, 1987 [10] 39 M 18 months before diagnosis Progressive hip pain and stiffens X-ray
Bone scan
  • Lucent and sclerotic regions within flattened femoral heads
  • Some loss of articular cartilage
 Pituitary adenoma Conservative management
Koch C, 1999 [11] 30 F Sudden onset of severe left hip pain MRI
  • Abnormal high intensity signal changes in the bone marrow of the left femoral head
  • Joint effusion
  • Stage 2 AVN
 Pituitary adenoma Immediate core decompression surgery with decongestion of the left femoral head
Premkumar M, 2013 [12] 26 F 2 y after pituitary surgery for Cushing, while on replacement steroid therapy Progressive bilateral hip pain resulting in difficulty in walking MRI
  • Bilateral multiple bony infarcts in the proximal femur and distal femur
  • Femoral head collapse fractures -Stage 2 avascular necrosis
 Pituitary adenoma
Bauddh N, 2022 [13] 24 M 2 y prior to diagnosis Progressive left hip pain and difficulty in walking X-ray
MRI
  • Left femoral head AVN
 Pituitary adenoma Planned for surgery of hip AVN
Joseph A, 2022 [14] 21 F 1 y prior to diagnosis Bilateral hip joint pain X-ray
MRI
  • Ill-defined mixed sclerotic and lytic pattern of the femoral heads
  • Cortical disruption of the round contour
  • Low signal intensity in the subchondral region of the femoral necks on T1-weighted images
 Pituitary adenoma Planned for total hip replacement.
Bisphosphonates.
Pazderska A, 2016 [19] 36 F Right leg pain MRI
  • Bilateral AVN of the femoral heads
  • Left femoral head with early bone fragmentation
 Bilateral primary pigmented micronodular adrenal disease Spontaneous healing of AVN after adrenalectomy.
Papadakis G, 2017 [22] 55 F MRI
PET/CT 68Ga-DOTATATE
  • Bilateral AVN
  • Bone marrow edema extending to the intertrochanteric area
  • Mild subchondral femoral head collapse of the left hip
  • Increased activity in bilateral femoral heads and in the bone marrow consistent with edema
  • Mild left femoral head collapse
 Ectopic ACTH- secreting tumor
Phillips K, 1986 [8] 24 F 4.5 y after diagnosis Right femoral AVN X-ray
  • Flattening and sclerosis of femoral head
 Cushing disease
25 F 4 y after diagnosis Right femoral AVN
  • Subchondral lucency
43 F 8 mo after diagnosis Right humeral AVN
  • Sclerosis and flattening of articular surface of humeral head
61 F 11 y after diagnosis Left femoral AVN and bilateral humeral heads
  • Cortical indistinctness and subchondral lucency
  • Left humeral head flattening and sclerosis
Cerletty J, 1973 [20] 54 M 3 mo before diagnosis Right femoral head fracture X-ray
  • Bilateral subchondral sclerosis of the femoral heads
  • Some narrowing of the joint space on the left
  • Infraction of the margin of the right femoral head
  • Femoral neck fracture.
 Bilateral adrenal cortical hyperplasia Total hip joint arthroplasty
Ha J-S, 2019 [18] 36 F 2 y before diagnosis 2 mo left hip restricted range of motion X-ray
MRI
  • Right femoral head with areas of hyperlucency and surrounding sclerosis
  • Subtle changes in the shape of the articular surface
  • Bilateral femoral head osteonecrosis -Increased amount of joint fluid and bone marrow edema in the left hip
  • Right femoral head necrosis
 Adrenal cortical adenoma Total hip replacement
Takada, J, 2004 [17] 55 F Intense right hip pain and a limp MRI
  • Low-intensity band on T1-weighted images
  • Stage 2 AVN.
 Adrenal adenoma Total hip arthroplasty
Modlinger RS, 1972 [23] 69 F Increased pain of right shoulder X-ray
  • Bilateral shoulders with aseptic necrosis of the humeral heads
 Ectopic ACTH secretion NET form pancreatic tumor

Abbreviations: AVN, avascular necrosis; F, female; M, male; MRI, magnetic resonance imaging; NET, neuroendocrine tumor.

AVN can result in irreversible femoral head collapse, leading to severe limitation in movement, reduced joint functionality, and decreased quality of life [24]. Initially, patients may be asymptomatic or endorse nonspecific pain when presenting with AVN and may not be diagnosed until an advanced stage when they develop more severe pain and disability [25]. In a meta-analysis assessing the prevalence of AVN in patients with systemic lupus erythematosus, including those who received corticosteroid treatment, asymptomatic AVN was detected in 29% of patients and symptomatic disease was noted in 9% [26]. AVN can diagnosed with MRI or CT imaging. Although noncontrast MRI has higher sensitivity and specificity in detecting early stages of the disease, CT is comparable to MRI in more advanced stages. Ancillary imaging modalities include plain radiography, positron emission tomography, and bone scan [27].

Staging of AVN relies on radiologic features and size of lesions. In earlier stages, imaging can be normal (stage 0) or with subtle abnormalities on MRI or bone scan and normal radiography (stage 1). As the disease progresses, structural changes, including cystic and sclerotic changes (stage 2), subchondral collapse (stage 3), flattening of the femoral head (stage 4), joint narrowing and acetabular changes (stage 5), and, finally, advanced degenerative changes (stage 6) can be detected on most imaging modalities.

Management of early stages of AVN includes observation or conservative weight-bearing management, medical therapy with bisphosphonates, anticoagulation therapy, statins, and vasodilators. Invasive procedures such as mesenchymal stem cells implantation, osteotomy, surgical joint decompression, and total hip replacement are reserved for more advanced stages [28]. Indeed, AVN accounts for approximately 10% of total hip replacements in the United States [29]. Staging has prognostic implications for treatment options and disease outcomes. Early-stage disease, when diagnosed and treated, can often regress, and be cured. Conservative measures, medical treatment, biophysical stimulation, extracorporeal shockwave therapy, or core decompression, can prevent femoral head collapse and further hip arthroplasty. On the other hand, late-stage disease, characterized by joint collapse, is irreversible and often requires joint replacement [30].

Although actual prevalence rates of AVN in endogenous CS is unknown, one should consider screening for AVN in this high-risk population, particularly in patients showing markedly elevated cortisol levels, as in our case. Such an approach would facilitate the early identification of individuals who would benefit from earlier medical or surgical interventions, thereby preventing permanent joint destruction and chronic disability.

Learning Points

  • AVN can be a complication of endogenous hypercortisolism.
  • AVN may present asymptomatically or with nonspecific symptoms such as joint pain.
  • AVN can affect multiple joints, including hips and shoulders, and its early diagnosis relies on MRI or CT imaging.
  • Early detection and intervention for AVN are crucial to prevent irreversible joint damage and disability.
  • Screening for AVN in patients with CS should be considered to enable timely intervention and prevent long-term complications, particularly in patients with hip or shoulder pain and severe hypercortisolism.

Contributors

All authors made individual contributions to authorship. N.T. and O.C. were involved in the diagnosis and management of the patient and manuscript submission. S.B. was involved in the histopathology section and preparation of histology images. T.L. was involved in the interpretation and preparation of the radiology images. A.N.M. was responsible for the patient’s surgery and treatment plan. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

Dr. Odelia Cooper is an Editorial Board member for JCEM Case Reports and played no role in the journal’s evaluation of the manuscript. There are no other disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

  • AVN

    avascular necrosis

  • CD

    Cushing disease

  • CS

    Cushing syndrome

  • CT

    computed tomography

  • MRI

    magnetic resonance imaging

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

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Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

Filed under: Clinical trials, Cushing's, pituitary, Rare Diseases, Treatments | Tagged: , , , | Leave a comment »

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