COVID-19 May Be Severe in Cushing’s Patients

Posted on January 23, 2026 by MaryO

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Low Cortisol Levels Hours After Surgery Predict Long-term Remission in Cushing’s Patients

Posted on January 21, 2026 by MaryO

The level of decline in blood cortisol levels in the immediate period after transsphenoidal surgery for Cushing’s disease may help predict which patients will achieve long-term disease remission.

The study, “Earlier post-operative hypocortisolemia may predict durable remission from Cushing’s Disease” was published in the European Journal of Endocrinology.

Transsphenoidal surgery (TSS) is a minimally invasive procedure for removing pituitary adenomas and is the primary treatment for Cushing’s disease.

But, while 77 to 98 percent of patients achieve remission after TSS, a third of these patients eventually will see their disease returning.

The surgical removal of the pituitary adenoma often leads to a drop in the adrenocorticotropic hormone (ACTH) and cortisol levels (hypocortisolemia).

“In the post-operative setting, failure to achieve hypocortisolemia is thought to reflect the presence of residual tumor cells,” the researchers wrote in the study. “Therefore, serum cortisol has become a well-established biochemical marker of early surgical remission.”

In an attempt to identify patients with a complete tumor resection – and with lower risk of recurrence – researchers examined the rates of serum cortisol decline in the immediate period after surgery.

The study included 257 Cushing’s disease patients who underwent 291 TSS interventions at the National Institutes of Health (NIH), between 2003 and 2016.

After surgery, patients had their cortisol levels measured every six hours until the third day after surgery. Then, patients had their cortisol levels measured every morning until day 10 or were discharged.

Early remission was defined based on nadir serum cortisol levels – the lowest concentration of cortisol, that is usually reached during the night – below 5 μg/dL.

Of 268 unique admissions, 90 percent of patients (241) achieved remission with a post-operative cortisol nadir below 5 μg/dL within 10 postoperative days.

However, recurrence was seen in 9 percent of these patients. For those with a cortisol nadir below 2 μg/dL, the rates of recurrence dropped to 6 percent.

Interestingly, the team found that cortisol levels below 5 μg/dL by 15 hours after surgery or below 2 μg/dL in the first 21 hours may “accurately predict durable remission in the intermediate term.”

“In our cohort, early, profound hypocortisolemia could be used as a clinical prediction tool for durable remission,” the researchers wrote.

“Such a clinical prediction tool may have significant utility in the management of [Cushing’s disease]. Further validation of its accuracy in a multi-centre prospective study with longer-term follow up is warranted,” the study concluded.

From https://cushingsdiseasenews.com/2018/01/18/low-cortisol-levels-after-surgery-may-predict-remission-cushings-disease/

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Transsphenoidal Surgery Leads to Remission in Children with Cushing’s Disease

Posted on January 19, 2026 by MaryO

Transsphenoidal surgery — a minimally invasive surgery for removing pituitary tumors in Cushing’s disease patients — is also effective in children and adolescents with the condition, leading to remission with a low rate of complications, a study reports.

The research, “Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature,” was published in the journal Child’s Nervous System.

Transsphenoidal (through the nose) pituitary surgery is the main treatment option for children with Cushing’s disease. It allows the removal of pituitary adenomas without requiring long-term replacement therapy, but negative effects on growth and puberty have been reported.

In the study, a team from Turkey shared its findings on 10 children and adolescents (7 females) with the condition, who underwent microsurgery (TSMS) or endoscopic surgery (ETSS, which is less invasive) — the two types of transsphenoidal surgery.

At the time of surgery, the patients’ mean age was 14.8 years, and they had been experiencing symptoms for a mean average of 24.2 months. All but one had gained weight, with a mean body mass index of 29.97.

Their symptoms included excessive body hair, high blood pressure, stretch marks, headaches, acne, “moon face,” and the absence of menstruation.

The patients were diagnosed with Cushing’s after their plasma cortisol levels were measured, and there was a lack of cortical level suppression after they took a low-dose suppression treatment. Measurements of their adrenocorticotropic (ACTH) hormone levels then revealed the cause of their disease was likely pituitary tumors.

Magnetic resonance imaging (MRI) scans, however, only enabled tumor localization in seven patients: three with a microadenoma (a tumor smaller than 10 millimeters), and four showed a macroadenoma.

CD diagnosis was confirmed by surgery and the presence of characteristic pituitary changes. The three patients with no sign of adenoma on their MRIs showed evidence of ACTH-containing adenomas on tissue evaluation.

Eight patients underwent TSMS, and 2 patients had ETSS, with no surgical complications. The patients were considered in remission if they showed clinical adrenal insufficiency and serum cortisol levels under 2.5 μg/dl 48 hours after surgery, or a cortisol level lower than 1.8 μg/dl with a low-dose dexamethasone suppression test at three months post-surgery. Restoration of normal plasma cortisol variation, eased symptoms, and no sign of adenoma in MRI were also requirements for remission.

Eight patients (80%) achieved remission, 4 of them after TSMS. Two patients underwent additional TSMS for remission. Also, 1 patient had ETSS twice after TSMS to gain remission, while another met the criteria after the first endoscopic surgery.

The data further showed that clinical recovery and normalized biochemical parameters were achieved after the initial operation in 5 patients (50%). Three patients (30%) were considered cured after additional operations.

The mean cortisol level decreased to 8.71 μg/dl post-surgery from 23.435 μg/dl pre-surgery. All patients were regularly evaluated in an outpatient clinic, with a mean follow-up period of 11 years.

Two patients showed pituitary insufficiency. Also, 2 had persistent hypocortisolism — too little cortisol — one of whom also had diabetes insipidus, a disorder that causes an imbalance of water in the body. Radiotherapy was not considered in any case.

“Transsphenoidal surgery remains the mainstay therapy for CD [Cushing’s disease] in pediatric patients as well as adults,” the scientists wrote. “It is an effective treatment option with low rate of complications.”

 

From https://cushingsdiseasenews.com/2019/01/15/transsphenoidal-surgery-enables-cushings-disease-remission-pediatric-patients-study/

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , , , , , , , , | Leave a comment »

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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Osilodrostat for Cyclic Cushing’s Disease

Posted on October 24, 2025 by MaryO

Highlights

  • •
    Cyclic Cushing’s syndrome (CCS) is a rare entity with significant comorbidities
  • •
    It is defined by at least 3 peaks of hypercortisolism, 2 troughs of eucortisolism
  • •
    Surgical cure is preferred, and medications are second-line
  • •
    Our case is the first showing successful treatment of native CCS with osilodrostat
  • •
    Osilodrostat showed rapid onset/offset and reversible inhibition of steroidogenesis

Abstract

Background/Objective

Cyclic Cushing’s syndrome is a rare subtype of Cushing’s syndrome with episodes of hypercortisolism, followed by spontaneous remission.

Case Report

Our patient was a 68-year-old male who presented with his third cycle of cyclic Cushing’s disease with facial swelling, buffalo hump, fatigue, proximal muscle weakness, and lower extremity edema. Laboratory tests showed the following: 24-hour urine free cortisol 12030.3 mcg/d (normal <= 60.0 mcg/d), morning adrenocorticotropic hormone (ACTH) 464 pg/mL (normal 6-59 pg/mL), morning serum cortisol 91 mcg/dL (normal 8-25 mcg/dL), and potassium 3.3 mmol/L (normal 3.6-5.3 mmol/L). MRI pituitary without/with contrast showed a partially empty sella. Prior inferior petrosal sinus sampling during the second cycle indicated a potential pituitary source of increased ACTH production, localized or draining to the right side. The patient was treated with osilodrostat with improvement in laboratory values and clinical symptoms by 2-3 weeks. After development of adrenal insufficiency (AI), osilodrostat was rapidly titrated off by 2 months of treatment. Subsequently, labs after 8 days off osilodrostat confirmed clinical remission and reversibility of medication-induced AI.

Discussion

Since hypercortisolism is associated with mortality risk and comorbidities, timely management is a priority. If a surgical cure is not possible, a medication that treats hypercortisolism with rapid onset, reversible inhibition, and minimal side effects would be ideal to address the cyclicity.

Conclusion

Our case is the first to our knowledge demonstrating osilodrostat’s use for native cyclic Cushing’s syndrome treatment and highlighted its reversibility and ability to preserve normal adrenal function.

Keywords

Osilodrostat
cyclic Cushing’s disease
cyclic Cushing’s syndrome

Introduction

Cyclic Cushing’s syndrome is a rare entity that represents a clinical challenge. It is defined by at least 3 peaks of biochemical hypercortisolism, which is clinically symptomatic in the majority though rarely asymptomatic, and 2 troughs with normalized cortisol production that can last from days to years.1 The phenomenon can arise from any potential source of Cushing’s syndrome, including pituitary (54%), ectopic (26%), adrenal (11%), and unclassified (9%) sources.1 Intermittent hypercortisolism can also occur after pituitary surgery for Cushing’s disease.2
The cyclicity interferes with a straightforward diagnosis. It can lead to paradoxical results from biochemical testing and inferior petrosal sinus sampling (IPSS),3 making determination of therapeutic outcomes more complicated.3 The goal of cyclic Cushing’s syndrome management, as in all types of Cushing’s syndrome, is early diagnosis and intervention to reduce the length of hypercortisolism.4 A surgical cure is preferred, as Cushing’s syndrome is associated with a five-fold increased standardized mortality risk.4 Cardiovascular, metabolic, bone, and cognitive comorbidities may persist despite remission and must be aggressively managed.4,5 For patients in whom surgical management is not possible or has not led to remission, medical therapy has a crucial role. We describe the first case to our knowledge of native cyclic Cushing’s syndrome treated successfully with osilodrostat. A case of exogenous cyclic ACTH-independent Cushing’s syndrome from pembrolizumab, with cyclicity attributed to the infusions, also demonstrated successful treatment with osilodrostat.6

Case Report

The patient was a 68-year-old male with hypertension, hyperlipidemia, and rheumatoid arthritis with a history of cyclical episodes of weight gain and facial swelling, occurring spontaneously without steroid treatments. The initial episode occurred at age 62 for 5 months, and returned at age 64 with facial swelling, buffalo hump, fatigue, proximal muscle weakness, sleep disturbances, and lower extremity edema. Laboratory tests showed the following (Table 1): 24-hour urine free cortisol >245 mcg/d (normal 11-84 mcg/d), morning adrenocorticotropic hormone (ACTH) 528.0 pg/mL (normal 7.2-63.3 pg/mL) and morning serum cortisol 91.7 mcg/dL (confirmed on dilution; normal 6.2-19.4 mcg/dL). Laboratory tests were also notable for a mildly low potassium level, low prolactin, low testosterone, and normal thyroid hormone, insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S) levels. MRI pituitary without/with contrast showed no sellar and suprasellar masses. A prior CT abdomen/pelvis with contrast at age 62 noted unremarkable adrenal glands. The patient was referred for inferior petrosal sinus sampling (IPSS) (Table 2), which indicated a potential pituitary source of increased ACTH production, localized or draining to the right side. The central to peripheral gradient was >2 in the first pre-stimulation sample and >3 in all samples after providing 10mcg of desmopressin (DDAVP). There was a >1.4/1 gradient between the right and left sides, suggesting a potential pituitary source draining to the right side (Table 2). The inferior petrosal sinuses were normal and of similar size. Cushing’s symptoms receded spontaneously in 5 months, and the patient did not follow up until recurrence at age 67.

Table 1. Labs at time of onset of cyclical episodes

Empty Cell Labs at age 64 y/o (2nd episode) Labs at age 67 y/o (3rd episode)
24hr urine free cortisol level >245 mcg/24hr (normal 11-85 mcg/24hr) 12030.3 mcg/d (normal <= 60.0 mcg/d)
24hr urine creatinine 1495 mg/24hr (normal 1000-2000mg/24hr) 1868 mg/day (normal 800-2100 mg/day)
Morning ACTH 528.0 pg/mL (normal 7.2-63.3 pg/mL) 464 pg/mL (normal 6-59 pg/mL),
Morning cortisol 91.7 mcg/dL (normal 6.2-19.4 mcg/dL) 91 mcg/dL (normal 8-25 mcg/dL)
Thyroid-stimulating hormone level (TSH) 0.452 mcIU/mL (normal 0.450-4.500 mcIU/mL) 0.08 mcIU/mL (normal 0.3-4.7 mcIU/mL)
Free thyroxine (free T4) 1.34 ng/dL (normal 0.82-1.77 ng/dL) 1.30 ng/dL (normal 0.8-1.7 ng/dL)
Prolactin <1.0 ng/mL (normal 3.0-15.2 ng/mL) 8.05 ng/mL (normal 3.5-19.4 ng/mL)
Insulin-like growth factor-1 (IGF-1) 148 ng/mL (normal 64-240 ng/mL) 128 ng/mL (normal 41-279 ng/mL)_
Testosterone panel Total 66 ng/dL(11AM)
(normal 264-916 ng/dL)
Free 9.6 pg/mL (11AM)
(normal 6.6-18.1 pg/mL)		 Total 107 ng/dL (8:30AM)
(normal 300-720 ng/dL)
Bioavailable 61 ng/mL (8:30AM)
(normal 131-682 ng/mL)
Follicle-Stimulation Hormone (FSH) 3.6 mIU/mL (normal 1.6-9 mIU/mL)
Luteinizing Hormone (LH) 1.6 mIU/mL (normal 2-12 mIU/mL)
Dehydroepiandrosterone sulfate (DHEA-S) 153 mcg/dL (normal 48.9-344.2 mcg/dL)
Potassium level 3.2 mmol/L (normal 3.4-4.8 mmol/L) 3.3 mmol/L (normal 3.6-5.3 mmol/L)
Creatinine level 0.92 mg/dL (normal 0.7-1.2 mg/dL) 0.89 mg/dL (normal 0.6-1.3 mg/dL)

Table 2. Inferior Petrosal Sinus Sampling (IPSS)

Empty Cell Time Right IPS
ACTH level (normal 6-59 pg/mL)		 Left IPS
ACTH level (normal 6-59 pg/mL)		 Inferior Vena Cava ACTH level (normal 6-59 pg/mL) Serum Cortisol (normal 8-25 mcg/dL)
Baseline 1 08:25 AM 32 23 14 7
Baseline 2 08:27 AM 19 16 13 7
Desmopressin (DDAVP) 08:30 AM
Post 2 min 08:32 AM 150 34 15
Post 5 min 08:35 AM 123 32 18
Post 10 min 08:40 AM 49 26 17
Post 15 min 08:45 AM 124 31 17
Post 30 min 09:00 AM 107 28 13
*These results may indicate a pituitary source for increased ACTH production, localized or draining to the right side. There is a Central:Peripheral gradient of >2 (right IPS) in the first pre-stimulation samples and >3 in all post-desmopressin (DDAVP) 10mcg samples. If due to an adenoma, it might drain into the right given the presence of a significant (greater than 1.4/1) gradient between right and left. The inferior petrosal sinuses were of similar size and normal. These results must take into account the patient’s clinical scenario, and there are false positives and possible overlap with normal results.
*Abbreviation: min = minutes
During the third and most recent cycle of Cushing’s syndrome, laboratory tests after 1 month of symptom development showed the following (Table 1): 24-hour urine free cortisol 12030.3 mcg/d (normal <= 60.0 mcg/d), morning ACTH 464 pg/mL (normal 6-59 pg/mL), morning serum cortisol 91 mcg/dL (normal 8-25 mcg/dL), potassium level 3.3 mmol/L (normal 3.6-5.3 mmol/L), and mild leukocytosis and erythrocytosis. Repeat MRI pituitary without/with contrast showed a partially empty sella and no pituitary mass (Figure 1).

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Figure 1. MRI pituitary without/with contrast at the time of the third cyclical episode of Cushing’s disease. The MRI showed a partially empty sella with no evidence of a pituitary mass. Left) Coronal view. Right) Sagittal view.

The patient was started on osilodrostat 2mg twice daily. By week 2 of treatment, the morning cortisol level improved to 9.5 mcg/dL (8-25 mcg/dL) and potassium level normalized, though facial and body swelling persisted. Significant improvement in symptoms and fatigue were noted by week 3 of treatment with the following labs: morning ACTH 145 pg/mL (normal 6-59 pg/mL), morning serum cortisol 5.4 mcg/dL (8-25 mcg/dL), and 24-hour urine free cortisol 7 mcg/d (normal 5-64 mcg/d). The osilodrostat dose was decreased to 1mg twice daily, then 1mg daily, and stopped by 2 months of treatment after development of adrenal insufficiency (AI), which was confirmed on laboratory results (Table 3), along with corresponding symptoms of nausea, abdominal pain, low appetite, and fatigue. By that time, the facial and body swelling had also resolved. Potassium levels remained normal throughout treatment. After eight days off osilodrostat, laboratory tests showed the following: Noon ACTH 67 pg/mL (normal 6-59 pg/mL), noon serum cortisol 7.24 mcg/dL (normal 8-25 mcg/dL), and 24-hour urine free cortisol 26.2 mcg/d (normal <=60.0 mcg/d). Nearly 3 months off osilodrostat, the patient had an 11 AM ACTH of 68.9 pg/mL (normal 7.2-63.3 pg/mL) and 11AM serum cortisol level of 11.0 ug/dL (6.2-19.4 ug/dL). The clinical course is summarized in Table 3 and Figure 2. A DOTATATE-PET scan was discussed, though the patient wished to reconsider in the future given clinical response.

Table 3. Labs during treatment (Tx) with osilodrostat

Empty Cell 1 month before Tx Week 2 on Tx Week 3 on Tx Week 7 on Tx Week 9 on Tx – Tx stopped Week 1 off Tx Month 3 off Tx
Treatment with osilodrostat None On 2mg BID since Week 0 of Tx Advised to decrease to 1mg BID but patient did not decrease dose. Decreased to 1mg BID Decreased to 1mg daily after serum lab resulted. Then discontinued Tx after 24hr UFC resulted in several days. None None
ACTH level (pg/mL) 464 145 126 135 67 68.9
Cortisol level (mcg/dL) 91
8:32AM		 9.5
7:04AM		 5.4
7:11AM		 3.04
11:56AM		 4.9
11:26AM		 7.24
12:14PM		 11
11:08AM
24hr urine free cortisol (UFC) level (mcg/day) 12030.3 7 14 26.2
*Normal reference ranges depending on assays:
ACTH: 6-59 pg/mL or 7.2-63.3 pg/mL
Serum morning cortisol: 8-25 mcg/dL or 6.2-19.4 mcg/dL
24hr urine free cortisol: <=60.0 mcg/day or 5-64 mcg/day
*Acronyms: Tx = treatment; BID = twice daily; UFC = urine free cortisol, ACTH = adrenocorticotropic hormone

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Figure 2. Trends of 24hr urine cortisol levels and serum cortisol levels with osilodrostat treatment (Tx)

Discussion

Cyclic Cushing’s syndrome is a rare subtype of Cushing’s and occurs in both ACTH-dependent and ACTH-independent cases.3,7 Cyclicity has been attributed to hypothalamic dysfunction exaggerating a normal variant of hormonal cyclicity, a dysregulated positive feedback mechanism followed by negative feedback, intra-tumoral bleeding, and ACTH-secretion from neuroendocrine tumors (ex carcinoid tumors, pheochromocytomas).7,8,9,10
Potentially curative pituitary surgery or unilateral adrenalectomy are the treatments of choice.4 For example, cases of cyclic Cushing’s in primary pigmented nodular adrenocortical disease have demonstrated cure in some patients with unilateral adrenalectomy.11 In florid Cushing’s syndrome that is not amenable or responsive to other treatments, bilateral adrenalectomy could be lifesaving, though risks significant comorbidities including Nelson’s syndrome.4,12 Pituitary radiotherapy/radiosurgery are treatment options, though risks progressive anterior pituitary dysfunction.4 Medical therapy can play an important role as a bridge to surgery or radiation, with recurrence, for poor surgical candidates, or when there is no identifiable source as in our patient.13 Cyclic Cushing’s syndrome, moreover, has a higher recurrence rate (63%) and lower remission rate (25%), compared to classic Cushing’s syndrome.8
Medical treatments of cyclic Cushing’s syndrome include steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, and osilodrostat), adrenolytic agents (mitotane), glucocorticoid receptor blockers (mifepristone), and pituitary tumor-directed agents (pasireotide, cabergoline, and temozolomide).8,14,15 Treatment goal is normalization of 24-hour urine cortisol levels and morning serum cortisol levels, though block-and-replace regimens occasionally are used.13,14 A block-and-replace regimen with osilodrostat and dexamethasone was used in the case of exogenous cyclic Cushing’s from pembrolizumab, given need for the immunotherapy;6 however, this regimen would hinder assessment of remission in native cyclic Cushing’s.
As our patient had cyclic Cushing’s disease, pituitary tumor-directed medications could be used for treatment. Pasireotide and cabergoline, however, are limited by a significant percentage of non-responders, along with risk of hyperglycemia for pasireotide.15 We considered mifepristone, which is a competitive antagonist at the glucocorticoid receptor and progesterone receptor; however, mifepristone is limited by the inability to directly monitor cortisol response on labs, in addition to the risk of AI and mineralocorticoid side effects with overtreatment.16
Steroidogenesis inhibitors block one or more enzymes in the production of cortisol, with potential risk of AI. The new steroidogenesis inhibitor osilodrostat, like metyrapone, selectively inhibits CYP11B1 and CYP11B2, which are involved in the final steps of cortisol and aldosterone synthesis, respectively.13,14 Ketoconazole and levoketoconazole, on the other hand, block most enzymes in the adrenal steroidogenesis pathway, including CYP11B1 and CYP11B2, and are limited by their inhibition of CYP7A (with associated hepatotoxicity) and strong inhibition of cytochrome p450 CYP3A4 (leading to many drug-drug interactions, decreased testosterone production, and QTc prolongation).14
Osilodrostat and metyrapone do not affect CYP7A and less potently inhibit CYP3A4.13 However, they can lead to increased deoxycorticosterone levels, with associated risks of hypokalemia, hypertension, and edema, and increased androgen production (with metyrapone thus being considered second-line in women).13,14,17
Osilodrostat, compared to metyrapone and ketoconazole, has a higher potency in CYP11B1 and CYP11B2 inhibition and a longer half-life, with stronger effects in lowering cortisol levels, allowance of less frequent (twice daily) dosing, and possibly less side effects.13,14,17,18 Compared to metyrapone, studies have suggested osilodrostat leads to a lesser rise in 11-deoxycortisol levels and less hyperandrogenic effects.13,14 Osilodrostat is also rapidly absorbed with sustained efficacy up to 6.7 years.17,18 Though rare cases of prolonged AI following discontinuation exist, osilodrostat (like other steroidogenesis inhibitors) is generally considered a reversible inhibitor.19 Reversible inhibition of cortisol synthesis is particularly appealing to treatment of cyclic Cushing’s syndrome as patients will not suffer from prolonged AI after episodes subside.
We thus considered osilodrostat an attractive treatment of cyclic Cushing’s syndrome. In our patient, osilodrostat was efficacious and well-tolerated, consistent with the literature,17 with clinical effects within 2-3 weeks without significant mineralocorticoid side effects. Differentiation of AI as a side effect of osilodrostat or from remission of the cyclical episode is crucial. Our patient was carefully tapered off osilodrostat after developing AI, and reversal of AI and osilodrostat inhibition were clearly demonstrated after 8 days off osilodrostat. Off treatment, the patient demonstrated neither prolonged AI nor clinical hypercortisolism, confirming remission of cyclic Cushing’s.

Conclusion

We present the first case to our knowledge demonstrating successful treatment of cyclic Cushing’s syndrome with osilodrostat. Osilodrostat showed rapid and safe control of hypercortisolism and importantly exhibited quick reversible inhibition of steroidogenesis upon discontinuation, a virtue in cyclic Cushing’s syndrome management.

References

Cited by (0)

The authors declare the following:
This paper did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All authors do not have any conflicts of interests regarding the manuscript.
Run Yu, MD, PhD runyu@mednet.ucla.edu
Clinical Relevance
Osilodrostat is a new steroidogenesis inhibitor. Our case demonstrates the first successful treatment of native cyclic Cushing’s syndrome with osilodrostat, which showed rapid onset/offset, clinical safety, and reversible inhibition of steroidogenesis and medication-induced adrenal insufficiency. Osilodrostat’s preservation of underlying adrenal function is key when the cyclic Cushing’s episode spontaneously remits.

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