Three Cases of Ectopic, Cyclic Cushing Syndrome: A New Square Wave Variant

Posted on November 3, 2025 by MaryO

Abstract

Cyclic Cushing syndrome (CCS) is characterized by unpredictable, intermittent phases of excess cortisol, alternating with periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels. The mechanism is unclear. Due to its rarity and diverse clinical presentation, unpredictable phases, and various etiologies, CCS poses significant diagnostic and management challenges for endocrinologists. The authors describe 3 cases in which each patient’s initial presentation was a life-threatening hypercortisolemic phase that lasted from 4 days to 3 months, followed by spontaneous resolution to prolonged eucortisolemic phases lasting from 10 to 26 months. Further testing indicated an ectopic ACTH-secreting source; however, the locations of the offending tumors were indeterminate. The authors propose the term square wave CCS variant to characterize the unique, prolonged intercyclic phases of hypercortisolemia and eucortisolemia with this subtype that are distinct from conventional CCS characterized by shorter phases of transient hypercortisolemia shifting to periods of eucortisolemia or hypocortisolemia. This uncharacteristic pattern of cyclicity poses diagnostic and therapeutic challenges, thus underscoring the importance of careful diagnostic workup and treatment of these patients.

Keywords: ectopic, cyclic, Cushing syndrome, eucortisolemia, hypercortisolemia

Introduction

Cyclic Cushing syndrome (CCS) is a rare variant of Cushing syndrome (CS) characterized by intermittent episodes of cortisol peaks alternating with variable periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels (troughs) []. These cycles can occur at regular or irregular intervals [], with unpredictable intercyclic phases typically lasting from days to months [, ]. The prevalence of CCS in patients with CS is low, ranging from 8% to 19% []. Several alternative terms (eg, intermittent, variable, periodic, and episodic hypercortisolism) have been proposed to characterize the variable cyclicity of ACTH and cortisol secretion in patients with CCS [].

We describe 3 cases of suspected ectopic ACTH-dependent CS with an indeterminate ACTH source that presented with life-threatening hypercortisolemia lasting from 4 days to 3 months, followed by spontaneous eucortisolemic phases lasting from 10 to 26 months. The term square wave is proposed to describe this unique cyclic pattern to highlight the unpredictability of severe hypercortisolemia followed by spontaneous prolonged eucortisolemic phases, which is distinct from previously described transient regular or irregular cycles with shorter intercyclic phases of CCS that require medical intervention.

Case Presentation

Case 1

A 75-year-old man with atrial fibrillation, bilateral leg edema, 6-month weight loss of 7 pounds (3.2 kg), and generalized muscle weakness was referred for cardiac ablation therapy. However, just before he underwent the procedure, he was found to be profoundly hypokalemic with potassium of 2.9 mEq/L (SI: 2.9 mmol/L) (reference range, 3.6-5.3 mEq/L [SI: 3.6-5.3 mmol/L]) and hyperglycemic, with blood glucose of 498 mg/dL (SI: 27.8 mmol/L) (reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]) and glycated hemoglobin (HbA1c) of 7.4%. He was emergently treated with potassium supplementation and insulin therapy.

Case 2

A 61-year-old woman presented to the emergency department with palpitations, uncontrolled hypertension, weight loss of 20 pounds (9.1 kg) over 2 weeks, new signs of hyperandrogenism (eg, hirsutism, acne, muscle atrophy), lower back pains, easy bruising, and proximal muscle weakness.

Case 3

A 57-year-old woman presented to the emergency department in August 2021 with a 2-month history of facial swelling and generalized muscle weakness. She had reported a similar episode in April 2019 with hypokalemia (potassium, 2.5 mEq/L [SI: 2.5 mmol/L]) that was treated with potassium repletion therapy.

Diagnostic Assessment

Case 1

Further laboratory tests revealed elevated morning (Am) cortisol of 76.8 µg/dL (SI: 2119 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]), Am ACTH of 368 pg/mL (SI: 81 pmol/L) (reference range, 6-50 pg/mL [SI: 1.3-11.0 pmol/L]), and 24-hour urine free cortisol (UFC) of 4223 µg/24 hours (SI: 11 656 nmol/24 hours) (reference range, 1.5-18.1 µg/24 hours [SI: 4-50 nmol/24 hours]) (Table 1). Magnetic resonance imaging (MRI) of the pituitary (Fig. 1) and 68Ga-DOTATATE positron emission tomography (PET) (Table 2) of the chest, pelvis, and abdomen failed to identify the source of ACTH secretion. Inferior petrosal sinus sampling (IPSS) showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source (Table 3).

Table 1.

Summary of biochemical testing data for the 3 patients with a square wave pattern of cyclic Cushing syndrome

Test, reference range Patient 1 (male, 75 years) Patient 2 (female, 61 years) Patient 3 (female, 57 years)
IP EP IP EP IP EP
AM cortisol 5-23 µg/dL (138-690 nmol/L) 76.8 µg/dL (2119 nmol/L) 14.2 µg/dL (392 nmol/L) 38.4 µg/dL (1060 nmol/L) 17.9 µg/dL (494 nmol/L) 56.8 µg/dL (1568 nmol/L) 14.4 µg/dL (397 nmol/L)
AM ACTH 6-50 pg/mL (1.3-11.0 pmol/L) 368 pg/mL (81 pmol/L) 38.1 pg/mL (8.4 pmol/L) 118 pg/mL (26 pmol/L] 16.5 pg/mL (3.6 pmol/L) 159 pg/mL (35 pmol/L] 39 pg/mL (8.6 pmol/L)
PM cortisol 2.9-17.3 µg/dL (80-477 nmol/L) 57.8 µg/dL (1594 nmol/L) — — — — <0.05 µg/dL (<1.4 nmol/L)
24-h UFC 1.5-18.1 µg/24 hours (4-50 nmol/24 hours) 4223 µg/24 hours (11 656 nmol/24 hours) 10.5 µg/24 hours (29 nmol/24 hours) 52.9 µg/24 hours (146 nmol/24 hours) 13 µg/24 hours (36 nmol/24 hours) 670.5 µg/24 hours (1851 nmol/24 hours) 23 µg/24 hours (63 nmol/24 hours)
Post 1-mg DST cortisol <1.8 ng/dL (<50 nmol/L) 74.6 ng/dL (2059 nmol/L) — 26.9 ng/dL (743 nmol/L) 1.4 ng/dL (<50 nmol/L) 16.7 ng/dL (461 nmol/L) —
Salivary cortisol < 0.09 µg/dL (<2.5 nmol/L) — 0.08 µg/dL (2.2 nmol/L) — 0.04 µg/dL (1.1 nmol/L) — —
S-DHEA 7-162 µg/dL (0.19-4.37 µmol/L) — 63 µg/dL — — — —
Chromogranin A <311 ng/mL* (<311 µg/L) 725 ng/mL (30.6 nmol/L) — — — — —
Lipase 8-78 U/L 40.0 U/L (40.0 U/L) — — — — —
Hemoglobin A1c <5.7% 8.9% 5.9% 9.2% 5.9% — —

International System of Units are included within parentheses.

Dash (–) indicates that no data are available.

* Method dependent.

Abbreviations: ACTH, adrenocorticotropic hormone; AM, morning; DST, dexamethasone suppression test; EP, eucortisolemic phase; IP, initial presentation; PM, afternoon; S-DHEA, serum dehydroepiandrosterone; UFC, urine free cortisol.

Figure 1.

Figure 1.

Case 1. (A) Sagittal and (B) coronal magnetic resonance images demonstrating normal appearance of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.

Table 2.

Imaging workup summary

Case Imaging modalities Interpretation
Case 1 Pituitary MRI, CT chest/abdomen/pelvis, pelvic USG, 68Ga-DOTATATE PET/CT No ectopic ACTH-secreting source identified
Case 2 Pituitary MRI, CT chest/abdomen/pelvis, 68Ga-DOTATATE PET/CT No ectopic ACTH-secreting source identified
Case 3 Pituitary MRI, CT chest/abdomen/pelvis, pelvic USG, 68Ga-DOTATATE PET/CT No ectopic ACTH-secreting source identified

Abbreviations: ACTH, adrenocorticotropic hormone; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; USG, ultrasound.

Table 3.

ACTH levels from inferior petrosal sinus sampling

Variable −5 Minutes 0 Minutes +2 Minutes +5 Minutes +10 Minutes
CASE 1
Right IPS 239 pg/mL (52.6 pmol/L) 221 pg/mL (48.6 pmol/L) 218 pg/mL (48.0 pmol/L) 239 pg/mL (52.6 pmol/L) 217 pg/mL (47.8 pmol/L)
Left IPS 226 pg/mL (49.8 pmol/L) 221 pg/mL (48.6 pmol/L) 216 pg/mL (47.6 pmol/L) 251 pg/mL (55.3 pmol/L) 213 pg/mL (46.9 pmol/L)
Peripheral 225 pg/mL (49.5 pmol/L) 219 pg/mL (48.2 pmol/L) 210 pg/mL (46.2 pmol/L) 217 pg/mL (47.8 pmol/L) 237 pg/mL (52.2 pmol/L)
Right IPS: peripheral ratio 1.06 1.00 1.03 1.10 .92
Left IPS: peripheral ratio 1.00 1.00 1.02 1.15 .89
CASE 2
Right IPS 59 pg/mL (13.0 pmol/L) 79 pg/mL (17.4 pmol/L) 203 pg/mL (44.7 pmol/L) 296 pg/mL (65.2 pmol/L) 374 pg/mL (82.3 pmol/L)
Left IPS 61 pg/mL (13.4 pmol/L) 77 pg/mL (17.0 pmol/L) 196 pg/mL (43.2 pmol/L) 313 pg/mL (68.9 pmol/L) 341 pg/mL (75.1 pmol/L)
Peripheral 62 pg/mL (13.7 pmol/L) 64 pg/mL (14.1 pmol/L) 146 pg/mL (32.2 pmol/L) 235 pg/mL (51.8 pmol/L) 368 pg/mL (81.0 pmol/L)
Right IPS: peripheral ratio .95 1.23 1.39 1.26 1.02
Left IPS: peripheral ratio .98 1.20 1.34 1.33 .93
CASE 3
Right IPS 119 pg/mL (26.1 pmol/L) 121 pg/mL (26.6 pmol/L) 380 pg/mL (83.8 pmol/L) 581 pg/mL (128.0 pmol/L) 232 pg/mL (51.2 pmol/L)
Left IPS 124 pg/mL (27.4 pmol/L) 133 pg/mL (29.3 pmol/L) 358 pg/mL (78.9 pmol/L) 568 pg/mL (125.0 pmol/L) 262 pg/mL (57.7 pmol/L)
Peripheral 113 pg/mL (24.9 pmol/L) 111 pg/mL (24.4 pmol/L) 322 pg/mL (70.9 pmol/L) 527 pg/mL (116.0 pmol/L) 178 pg/mL (39.1 pmol/L)
Right IPS: peripheral ratio 1.04 1.09 1.18 1.10 1.31
Left IPS: peripheral ratio 1.10 1.20 1.13 1.08 1.48

International System of Units are included within parentheses.

Baseline IPS: P > 2.0; Suggests pituitary (Cushing’s disease).

Post-stim IPS: P > 3.0; Confirms pituitary ACTH source.

Abbreviations: ACTH, adrenocorticotropic hormone; IPS, inferior petrosal sinus.

Case 2

Laboratory tests revealed elevated Am cortisol of 38.4 µg/dL (SI: 1060 nmol/L) and Am ACTH of 118 pg/mL (SI: 26 pmol/L), hypokalemia (potassium, 2.9 mEq/L [SI: 2.9 mmol/L]) and new-onset type 2 diabetes mellitus with a random blood glucose of 489 mg/dL (SI: 27.2 mmol/L) and HbA1c of 9.2% (reference range, < 5.7%) (Table 1). Lumbar spine radiography and spine MRI demonstrated compression fractures of L1 to L4 vertebrae, and pituitary MRI showed a 2-mm hypo-enhancing foci within the midline and to the right of the pituitary gland (Fig. 2).

Figure 2.

Figure 2.

Case 2. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland show 2-mm hypo-enhancing foci (arrows) within the midline and to the right side of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.

Case 3

During the present hospital admission, the patient was hypokalemic (potassium, 2.7 mEq/L [SI: 2.7 mmol/L]) and hypercortisolemic with Am cortisol and Am ACTH levels of 56.8 µg/dL (SI: 1568 nmol/L) and 159 pg/mL (SI: 35 pmol/L), respectively. After 4 days of hospitalization, the patient spontaneously became eucortisolemic with an Am cortisol of 16.8 µg/dL (SI: 464 nmol/L), 24-hour UFC of 670.5 µg/24 hours (SI: 1851 nmol), and late-night salivary cortisol of 0.03 µg/dL (SI: 0.828 nmol/L) with symptom improvement (Table 1). Pituitary MRI revealed a flattened, normal-appearing pituitary gland (Fig. 3).

Figure 3.

Figure 3.

Case 3. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland showing a flattened pituitary gland. No discrete, sizable, differentially enhancing mass is detected within the sella. From Barrow Neurological Institute, Phoenix, Arizona.

Treatment

Case 1

Because of the patient’s worsening clinical condition and severe hypercortisolemia with no identifiable ACTH source, ketoconazole was considered to induce eucortisolemia. While electrocardiography and liver function tests were being measured before starting ketoconazole, the patient’s Am cortisol levels spontaneously normalized to 14.2 µg/dL (SI: 392 nmol/L) with symptomatic improvement.

Case 2

The patient began insulin, spironolactone, and levothyroxine therapy. After 2 days in the hospital, her Am cortisol decreased to 17.9 µg/dL (SI: 494 nmol/L) and remained within the range of 9.4 to 17.9 µg/dL (SI: 259-494 nmol/L). An IPSS performed 3 weeks later showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source. By month 3, her Am cortisol levels consistently remained below 15 µg/dL (SI: 414 nmol/L). Blood pressure was controlled with one antihypertensive agent, and insulin was discontinued due to frequent hypoglycemic episodes.

Case 3

The patient was readmitted 18 months later with worsening muscle weakness, uncontrolled hypertension, hypokalemia (potassium, 2.4 mEq/L [SI: 2.4 mmol/L]), and hypercortisolemia with elevated Am cortisol and Am ACTH levels. 68Ga-DOTATATE PET did not reveal an ectopic ACTH source (Table 2), and IPSS did not reveal any significant ACTH gradient (Table 3). However, computed tomography (CT) of the chest, abdomen, and pelvis revealed a 0.7-cm lung nodule. During this hospitalization, the patient received supportive treatment, including antihypertensive therapy and electrolyte replacement. No pharmacologic intervention was required to control her cortisol levels.

Outcome and Follow-Up

Case 1

Late-night salivary cortisol levels measured were within the normal range (0.08 µg/dL, 0.06 µg/dL, and 0.08 µg/dL [SI: 2.2 nmol/L, 1.7 nmol/L, and 2.2 nmol/L]; reference range, < 0.09 µg/dL [SI: < 2.5 nmol/L]). Because of these biochemical and symptomatic improvements, ketoconazole therapy was deferred. At the most recent outpatient clinic follow-up 26 months after his cortisol levels normalized, the patient remained in remission without recurrence of hypercortisolemic symptoms.

Case 2

The patient remained in biochemical and clinical remission for 15 months until she began experiencing abdominal distention, bilateral leg edema, and facial swelling again. Blood pressure increased at this time, requiring 3 antihypertensive medications. Her Am cortisol levels rose to 29.1 µg/dL (SI: 803 nmol/L), but repeat IPSS showed no ACTH gradient, and 68Ga-DOTATATE PET/CT of the chest, abdomen, and pelvis was unremarkable (Tables 2 and 3). Block-and-replace therapy of osilodrostat and hydrocortisone was initiated to preemptively prevent hypercortisolemic episodes; after 3 months of therapy, she underwent successful bilateral adrenalectomy (BLA).

Case 3

On day 5 of hospitalization, her Am cortisol level decreased to 14.4 µg/dL (SI: 397 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]). Her symptoms improved, and she remained well for 11 months before recurrence of muscle weakness, hypokalemia, and hypercortisolemia with an Am cortisol of 58.7 µg/dL (SI: 1620 nmol/L) and Am ACTH of 194 pg/mL (SI: 43 pmol/L). The patient became eucortisolemic without any medical intervention and declined further treatment. She continues with regular outpatient follow-up.

Discussion

Diagnosing CCS poses considerable challenges because of its heterogeneous clinical manifestations, erratic intercyclic duration, frequency of phases, and various etiologies. Patients may experience transient or continuous symptoms with variable degrees of severity []. Our patients presented with severe hypercortisolemia lasting from days to months, followed by an extended period of spontaneous eucortisolemia, lasting from months to years. This unique presentation of cortisol kinetics differs from the classic presentation of CCS, which typically features shorter intercyclic phases [].

We coined the term square wave variant of CCS to characterize this unique feature of prolonged cyclicity of hypercortisolemia shifting spontaneously to eucortisolemia without medical intervention. The term square wave was chosen because the cortisol secretion pattern in these cases resembles a square waveform, with abrupt transitions between prolonged periods of high and low cortisol levels rather than the gradual fluctuations or short irregular peaks seen in typical CCS. This visual and kinetic analogy helps distinguish the pattern observed in our patients from the more classically described forms of CCS.

The absence of a standardized definition of CCS complicates the classification of cases such as ours, which diverge from conventional descriptions in the medical literature [, , ]. Most cases of CCS are associated with pituitary tumors (67%), whereas ectopic ACTH-secreting tumors (17%) and adrenal tumors (11%) are less common [, ]. Our patients had evidence of ectopic CS, of which the ACTH-secreting source was unidentifiable despite extensive imaging. The variability of symptom duration, severity, and timing in our patients implies distinct mechanisms for suppressing or desensitizing adrenal cortisol synthesis during the extended symptom-free periods. Other mechanisms include enhanced effects of specific neurotransmitters, hypothalamic dysregulation, spontaneous tumor hemorrhage, cyclic growth and apoptosis of ACTH-secreting tumor cells, and positive and negative feedback mechanisms []. Another explanation for the prolonged eucortisolemic phase may be due to altered POMC gene expression and defective ACTH secretion from the ectopic tumor []. Over time, the tumor may dedifferentiate or develop a transcriptional or posttranscriptional defect, leading to the secretion of ACTH with a decreased ability to stimulate adrenal cortisol secretion [, ]. Conversely, CCS might also be an exaggerated physiological cyclical variation of ACTH and cortisol secretion [, ]. However, the prolonged eucortisolemic phase observed in our patients argues against this exaggeration theory.

Recent studies have suggested that the anomalous cyclicity of cortisol and ACTH may be influenced by dysregulation of the peripheral clock system in endocrine tumors []. Certain tumors may exhibit aberrant expression of circadian regulators such as CLOCK, PER1, PER2, PER3, and TIMELESS, which can disrupt the physiological rhythmicity of cortisol and ACTH secretion [, ]. For instance, cortisol-secreting adrenal adenomas demonstrate downregulation of PER1, CRY1, and Rev-ERB, whereas adrenocortical carcinomas upregulate CRY1 and PER1 and downregulate BMAL1 and RORα. In patients with CS, clock gene expression in peripheral blood mononuclear cells has been shown to be significantly flattened, contributing to the loss of circadian variation in cortisol levels [].

Surgery is the preferred treatment option for CCS patients, provided the tumor is localizable []. Medical therapy is used when the tumor is undetectable, unresectable, or recurs. Medical therapy can overtreat and induce iatrogenic adrenal insufficiency during the eucortisolemic phases. This risk can be mitigated by the block-and-replace strategy of high-dose steroidogenesis inhibitors to suppress adrenal cortisol production and supplemented with exogenous glucocorticoids []. In patients for whom the ectopic tumor is unidentifiable, the initial tumor resection is ineffective, or if medical management does not adequately control hypercortisolemia, BLA may be considered [].

Although treatment of CCS resembles that of CS, the heterogeneity in the severity and duration of symptoms prohibits the implementation of some conventional treatment strategies. Consequently, long-term medical therapy may not align with the patient’s preferences, especially those whose course of illness is characterized by prolonged eucortisolemia and milder symptoms. Such patients should be educated to monitor symptoms closely during the eucortisolemic phase to recognize the signs and symptoms of hypercortisolism using objective parameters such as self-assessment of weight, blood pressure, and capillary blood glucose. Periodic biochemical monitoring may also be helpful, including standby kits for self-testing of late-night salivary cortisol and 24-hour UFC. If the source of ectopic ACTH secretion continues to elude detection, BLA during the eucortisolemic phase may be considered to prevent future life-threatening hypercortisolemic episodes.

Learning Points

  • Unlike typical CCS, there may be a subset of patients with a distinct square wave variant of CCS marked by severe hypercortisolemia followed by prolonged periods of eucortisolemia.
  • Ectopic ACTH-secreting sources in CCS may be linked to unusually long symptom-free intervals of eucortisolemia and hypocortisolemia between episodes of hypercortisolemia.
  • If possible, CCS management should be individualized to address its cause, with vigilant monitoring during the eucortisolemic phase to detect potential recurrence early.
  • If the source of the ectopic ACTH-secreting tumor is not identifiable, BLA may be considered during the eucortisolemic phase to prevent future life-threatening hypercortisolemic episodes.

Acknowledgments

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

Abbreviations

ACTH
adrenocorticotropic hormone
BLA
bilateral adrenalectomy
CCS
cyclic Cushing syndrome
CS
Cushing syndrome
CT
computed tomography
HbA1c
glycated hemoglobin
IPSS
inferior petrosal sinus sampling
MRI
magnetic resonance imaging
PET
positron emission tomography
UFC
urine free cortisol

Contributor Information

Mercedes Martinez-Gil, Department of Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85012, USA.

Tshibambe N Tshimbombu, Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA.

Yvette Li Yi Ang, Division of Endocrinology, Department of Medicine, National University Hospital, Singapore 119228, Singapore.

Monica C Rodriguez, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.

Kevin C J Yuen, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.

Contributors

All authors contributed substantially to the manuscript. K.C.J.Y. supervised the project, provided content review, and edited the text. M.M.-G. and T.N.T. contributed equally to the preparation, writing, and submission of the manuscript. M.C.R. was responsible for the clinical management of one of the cases. Y.L.Y.A. contributed to the diagnosis, management, and writing of one of the cases. All authors reviewed and approved the final version of the manuscript.

Funding

All authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this manuscript.

Disclosures

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this manuscript.

Informed Patient Consent for Publication

Signed informed consents were obtained directly from the patients.

Data Availability Statement

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

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

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

https://pmc.ncbi.nlm.nih.gov/articles/PMC12559019/

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Using the Desmopressin Stimulation Test to Assess for Residual Tumor in Cushing Disease With Cyclic Hypercortisolism

Posted on October 26, 2025 by MaryO

Abstract

Cushing disease is caused by excess ACTH secretion by a pituitary adenoma leading to hypercortisolism. Cyclic Cushing syndrome, in which periods of cortisol excess are interspersed by periods of normal or low values, poses a challenge to diagnostic testing and postoperative monitoring. We present a 26-year-old woman with cyclic Cushing syndrome who achieved apparent biochemical remission after transsphenoidal resection of an ACTH-producing pituitary tumor, confirmed on pathology. Despite initial clinical improvement, she later experienced recurring symptoms. Biochemical evidence of hypercortisolism was documented, but 1 month later morning serum cortisol was undetectable. A desmopressin stimulation test (DesST) produced a rise in ACTH and cortisol, indicating likely residual tumor tissue. After repeat surgery, pathology again confirmed an ACTH-secreting tumor. Postoperatively, ACTH and cortisol levels were again low, but a repeat DesST was now negative, suggesting successful resection of the residual tumor, and she remains in remission 3 years later. This case describes the unique utility of the DesST to detect a pituitary corticotroph tumor in cyclic Cushing disease during periods of low disease activity. It also highlights the potential role of the DesST in postoperative monitoring.

Cushing disease, cyclic Cushing, desmopressin stimulation test
Issue Section:

Case Report

Introduction

Cushing disease (CD), in which excess ACTH from a pituitary adenoma drives hypercortisolism, causes up to 70% of endogenous Cushing syndrome (CS) [1]. When possible, the first-line treatment for CD is transsphenoidal surgery (TSS) to remove the causative tumor. This leads to remission in approximately 80% of cases, with recurrence rates estimated at 20% [2].

Cyclic CS, in which periods of excess cortisol are interspersed with periods of normal or low cortisol, complicates both the initial diagnosis of CS and the interpretation of post-TSS hormone levels [3]. Basal ACTH and cortisol, and dexamethasone suppression tests performed during a period of low disease activity, can be misleading because they reflect healthy pituitary corticotrophs that are responsive to and suppressed by persistent hypercortisolism [4]. The same mechanism of corticotroph suppression pertains after TSS, so that very low morning plasma ACTH and serum cortisol levels (generally less than 10 pg/mL [SI: 2.2 pmol/L] and 5 µg/dL [SI: 138 nmol/L], respectively), indicate successful tumor resection [5, 6]. However, if postoperative testing occurs during a period of low disease activity in cyclic CS, it may falsely indicate remission.

The desmopressin stimulation test (DesST), in which ACTH and cortisol levels are measured following intravenous administration of 10 µg desmopressin, may help to resolve these problems. Most corticotroph adenomas respond to desmopressin with an increase in ACTH secretion, followed by a cortisol increase [7, 8]. By contrast, most healthy people do not respond. Desmopressin, a synthetic analogue of arginine vasopressin (AVP), is believed to trigger this response by binding to upregulated V3 receptors or ectopically expressed V2 receptors on corticotroph adenomas [9]. Some of the most commonly used response criteria for the DesST, ≥35% and ≥20% increases in ACTH and cortisol, respectively, are based on thresholds that produce high performance for the CRH stimulation test [10]. Currently, however, there is no clear consensus on optimal cutoffs for the DesST [9].

The return of a positive DesST response has been shown to precede the return of hypercortisolism when monitoring for recurrence of CD [11]. By analogy, we postulated that a postoperative DesST might identify residual tumor in a patient with cyclic CS. In this case presentation, we will highlight the utility of the DesST to establish both partial and successful tumor resection in such a patient.

Case Presentation

A 26-year-old woman developed irregular menses, hair loss, facial rounding, a dorsocervical fat pad, and wide violaceous abdominal striae, accompanied by an unexplained 30-pound weight gain over 3 months. Over the same period, she also noted worsening of longstanding fatigue, anxiety, depression, and acne. Eventually, 1 year after these symptoms started, she was diagnosed with CS based on elevated midnight serum cortisol (24.5 µg/dL [SI: 675 nmol/L], reference range [RR]: <7.5 µg/dL [<207 nmol/L]), 24-hour urine free cortisol (UFC) (337 µg/day [SI: 931 nmol/day], RR: 3.5-45 µg/day [SI: 9.7-124 nmol/day]), and failure to suppress serum cortisol during a 48-hour low-dose dexamethasone suppression test (48-hour cortisol: 26.7 µg/dL [SI: 736 nmol/L], RR: <1.8 µg/dL [SI: <50 nmol/L]). ACTH was not suppressed and pituitary magnetic resonance imaging (MRI) revealed a right-sided 7 mm microadenoma. Bilateral inferior petrosal sinus sampling showed a high central-to-peripheral ACTH ratio, indicative of CD.

Because of surgical delays related to the COVID-19 pandemic, she was started on a block-and-replace regimen of metyrapone and hydrocortisone (HC) before undergoing TSS 6 months later, removing a tumor located in the right superior posterior portion of the pituitary. Pathology confirmed a pituitary tumor with diffuse positivity for ACTH, rare positivity for GH and prolactin, and low mitotic activity (Ki67 index <3%). Morning serum cortisol dropped to 1.2 µg/dL (SI: 33 nmol/L) (RR: 3.7-19.4 µg/dL [SI: 102-535 nmol/L]) on postoperative day 4, at which point physiologic HC replacement was started. HC was eventually tapered and stopped 8 months later, when morning serum cortisol had recovered. Postoperatively, her acne and menstrual irregularities resolved while hair loss continued and her weight stabilized without any significant reduction.

Later, she again developed worsening anxiety and a severely depressed mood to the point where she could barely function at her job. Because of these worsening symptoms, repeat testing was performed 10 months after surgery, confirming return of hypercortisolism: midnight serum cortisol 20.5 µg/dL (SI: 565 nmol/L), UFC 82 µg/day (SI: 227 nmol/day). A small lesion was seen on pituitary MRI, thought to represent postoperative changes or a residual adenoma.

Diagnostic Assessment

The patient presented to our institution for a second opinion. A pituitary MRI was unchanged from the month prior. Unexpectedly, laboratory values now showed undetectable bedtime salivary (<50 ng/dL [SI: 1.4 nmol/L], RR: <100 ng/dL [SI: <2.8 nmol/L]) and morning serum cortisol (<1 µg/dL [SI: <27.6 nmol/L]), and low-normal ACTH (11.9 pg/mL [SI: 2.6 pmol/L], RR: 5.0-46.0 pg/mL [SI: 1.1-10.1 pmol/L]), and UFC (5.6 µg/day [SI: 15.5 nmol/day]). She did not have clinical symptoms of adrenal insufficiency. These results, indicative of secondary adrenal insufficiency, were in stark contrast to the hypercortisolism confirmed 1 month earlier, raising suspicion for apoplexy of residual tumor tissue or cyclic CS. Upon further questioning, the patient reported previous waxing and waning of acne severity, but no clear cyclicity of other symptoms. She felt that it was not possible for her to assess emotional or cognitive variability apart from that caused by the COVID-19 pandemic. Three weeks later, she underwent a DesST, during which baseline cortisol and ACTH were 3.1 µg/dL (SI: 86 nmol/L) and 34.1 pg/mL (SI: 7.5 pmol/L), respectively. After desmopressin, ACTH increased +111% at +15/30 minutes and cortisol increased +172% at +30/45 minutes (Fig. 1). This positive response was interpreted as confirming the presence of residual tumor tissue.

ACTH and cortisol responses during the desmopressin stimulation test (DesST) before and after the patient's second transsphenoidal surgery. Plasma ACTH (A) and serum cortisol (B) levels were measured twice at baseline before and 15, 30, 45, and 60 minutes after intravenous administration of 10 µg desmopressin. Circles and squares represent the values from tests performed before and after surgery, respectively. The presence of a response (despite a low baseline cortisol level) in the preoperative test was considered to represent residual corticotroph tumor tissue; the postoperative loss of response to desmopressin was thought to represent successful resection of residual tumor.

Figure 1.

ACTH and cortisol responses during the desmopressin stimulation test (DesST) before and after the patient’s second transsphenoidal surgery. Plasma ACTH (A) and serum cortisol (B) levels were measured twice at baseline before and 15, 30, 45, and 60 minutes after intravenous administration of 10 µg desmopressin. Circles and squares represent the values from tests performed before and after surgery, respectively. The presence of a response (despite a low baseline cortisol level) in the preoperative test was considered to represent residual corticotroph tumor tissue; the postoperative loss of response to desmopressin was thought to represent successful resection of residual tumor.

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Treatment

Two weeks after the positive DesST, on admission for repeat TSS, morning serum cortisol had risen to 15.2 µg/dL (SI: 419 nmol/L). After resection of residual tissue within the anteroinferior and right lateral aspect of the gland, pathology again confirmed a focus of ACTH-positive tumor. By postoperative day 3, morning serum cortisol was again undetectable with an unchanged plasma ACTH of 12.1 pg/mL (SI: 2.7 pmol/L). Because of the difficulty in distinguishing a satisfactory postoperative biochemical response from a period of low disease activity in cyclic CS, a second DesST was performed. This time the test was negative, with ACTH increasing by only 8%, whereas cortisol remained undetectable throughout (Fig. 1). This drastic change in response to desmopressin was believed to represent successful resection of residual tumor tissue. She was discharged on physiologic HC replacement and daily desmopressin after developing postoperative AVP deficiency.

Outcome and Follow-up

The AVP deficiency resolved over 6 months, whereas HC was stopped after 8 months, following a normal insulin tolerance test. The patient lost 20 pounds in the first 9 months after her second surgery, before gradually losing an additional 40 pounds over the following 3 years, reaching her baseline weight. The facial rounding and dorsocervical fat pad resolved, and acne improved. Three years after her second surgery, biochemical remission was maintained but she continued to experience hair loss, reduced taste and smell, and fluctuating severity of her preexisting fatigue, anxiety, and depression.

Discussion

Of note, our patient’s initial evaluation and surgery took place at an expert pituitary center in the United Kingdom, whereas the second evaluation was performed in the United States. This case shows some regional differences in testing protocols; for example, the 48-hour dexamethasone suppression and insulin tolerance tests are used more often in the United Kingdom. However, both surgical procedures were performed by high-volume pituitary surgeons, which is crucial to maximize the probability of remission [2].

While previous reports have described the role of the DesST in CD diagnosis [9], our case highlights its unique utility during periods of low disease activity in cyclic CD. Other tests for the diagnosis or etiology of CS rely on ongoing disease activity and require ongoing tumoral secretion of ACTH accompanied by suppression of healthy corticotrophs. Importantly, most healthy corticotrophs do not exhibit a significant response to desmopressin [7, 9]. In our patient, the diagnosis of CD was confirmed based on previous surgical pathology. Although documented recurrent hypercortisolism and CS symptoms were highly suspicious, the presence of residual disease was questioned due to the lack of ongoing hypercortisolism. In this context, the clearly positive response to DesST provided supportive evidence for pursuing a second TSS. The subsequent postoperative loss of response to desmopressin was interpreted as representing successful resection of all residual tumor tissue, which was supported by enduring remission of most symptoms 3 years after surgery. Biochemical postoperative assessments are based on trends in ACTH and cortisol. Typically, both hormones plummet after successful removal of an ACTH-producing tumor, since healthy corticotrophs remain suppressed because of longstanding hypercortisolism. Corticotrophs take at least 6 months to recover; earlier normalization of ACTH and cortisol raises concern for residual tumor tissue [12].

Postoperative hormonal trends may be different in 2 settings that were both relevant to our patient: preoperative medical therapy to restore eucortisolism and cyclic CS. In both scenarios, recent hypercortisolism may have been mild or absent, potentially allowing for a swift recovery of healthy corticotrophs. Postoperative ACTH and cortisol levels may be normal, making it difficult to establish a biochemical cure. In this setting, the usual screening tests for hypercortisolism (UFC, bedtime cortisol, low-dose dexamethasone suppression test) are useful to determine whether excessive ACTH secretion persists.

However, these postoperative screening tests for hypercortisolism may not be reliable in cyclic CS since low or normal ACTH and cortisol levels can reflect either remission or low disease activity. The DesST may be particularly useful in this situation to identify residual disease or confirm successful tumor resection. For this test to be useful, however, it is important to obtain a preoperative DesST to establish a baseline because a minority of tumors causing CD do not respond to desmopressin [9].

Learning Points

  • Most healthy pituitary corticotrophs and tumors causing ectopic ACTH syndrome do not exhibit a response during the desmopressin stimulation test (DesST), making it useful for Cushing disease (CD) diagnosis.

  • The DesST may be particularly useful during periods of low disease activity in cyclic Cushing syndrome, as other dynamic tests used to diagnose CD may be uninterpretable in this setting.

  • Postoperatively, the DesST may be useful to confirm successful tumor resection and to monitor for CD recurrence. It is, however, important to obtain a preoperative DesST to establish whether the causative tumor is responsive to desmopressin.

Contributors

All authors made individual contributions to authorship. B.M.B., L.K.N., and H.E. were involved in the writing and submission of the manuscript. W.D., R.M., L.K.N., and H.E. were involved in the diagnosis and management of this patient. All authors reviewed and approved the final draft.

Funding

This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

Disclosures

B.M.B., W.D., R.M., and H.E. have nothing to disclose. L.K.N. receives royalties from UpToDate.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Published by Oxford University Press on behalf of the Endocrine Society 2025.
This work is written by (a) US Government employee(s) and is in the public domain in the US. See the journal About page for additional terms.

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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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BIPSS Diagnostic Method May Cause False Positive in Some Cases of Cyclic Cushing’s Syndrome

Posted on January 3, 2020 by MaryO

A diagnostic technique called bilateral inferior petrosal sinus sampling (BIPSS), which measures the levels of the adrenocorticotropic hormone (ACTH) produced by the pituitary gland, should only be used to diagnose cyclic Cushing’s syndrome patients during periods of cortisol excess, a case report shows.

When it is used during a spontaneous remission period of cycling Cushing’s syndrome, this kind of sampling can lead to false results, the researchers found.

The study, “A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome,” was published in BMC Endocrine Disorders.

Cushing’s syndrome is caused by abnormally high levels of the hormone cortisol. This is most often the result of a tumor on the pituitary gland that produces too much ACTH, which tells the adrenal glands to increase cortisol secretion.

However, the disease may also occur due to adrenal tumors or tumors elsewhere in the body that also produce excess ACTH — referred to as ectopic Cushing’s syndrome.

Because treatment strategies differ, doctors need to determine the root cause of the condition before deciding which treatment to choose.

BIPSS can be useful in this regard. It is considered a gold standard diagnostic tool to determine whether ACTH is being produced and released by the pituitary gland or by an ectopic tumor.

However, in people with cycling Cushing’s syndrome, this technique might not be foolproof.

Researchers reported the case of a 43-year-old woman who had rapidly cycling Cushing’s syndrome, meaning she had periods of excess cortisol with Cushing’s syndrome symptoms — low potassium, high blood pressure, and weight gain — followed by normal cortisol levels where symptoms resolved spontaneously.

In general, the length of each period can vary anywhere from a few hours to several months; in the case of this woman, they alternated relatively rapidly — over the course of weeks.

After conducting a series of blood tests and physical exams, researchers suspected of Cushing’s syndrome caused by an ACTH-producing tumor.

The patient eventually was diagnosed with ectopic Cushing’s disease, but a BIPSS sampling performed during a spontaneous remission period led to an initial false diagnosis of pituitary Cushing’s. As a result, the woman underwent an unnecessary exploratory pituitary surgery that revealed no tumor on the pituitary.

Additional imaging studies then identified a few metastatic lesions, some of which were removed surgically, as the likely source of ACTH. However, the primary tumor still hasn’t been definitively identified. At the time of publication, the patient was still being treated for Cushing’s-related symptoms and receiving chemotherapy.

There is still a question of why the initial BIPSS result was a false positive. The researchers think that the likely explanation is that BIPSS was performed during an “off phase,” when cortisol levels were comparatively low. In fact, a later BIPSS performed during a period of high cortisol levels showed no evidence of ACTH excess in the pituitary.

This case “demonstrates the importance of performing diagnostic tests only during the phases of active cortisol secretion, as soon as first symptoms appear,” the researchers concluded.

From https://cushingsdiseasenews.com/2020/01/02/cushings-syndrome-case-study-shows-drawback-in-bipss-method/

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Patient Develops Cyclic Cushing’s Syndrome Due to Lung Neuroendocrine Tumor

Posted on January 26, 2019 by MaryO

Tumors located outside the pituitary gland that produce the adrenocorticotropic hormone (ACTH) may cause, on rare occasions, cyclic Cushing’s syndrome — when cortisol levels show substantial fluctuations over time.

That finding, based on the case of a patient with ACTH-secreting lung cancer,  is found in the study, “Cyclic Cushing’s syndrome caused by neuroendocrine tumor: a case report,” which was published in Endocrine Journal.

Cushing’s syndrome is characterized by too much cortisol, either due to adrenal tumors that produce cortisol in excess, or because too much ACTH in circulation — resulting from ACTH-producing tumors — act on the adrenal glands to synthesize cortisol.

Cyclic Cushing’s syndrome (CCS) is a rare type of Cushing’s in which cortisol production is not steadily increased. Instead, it cyclically fluctuates, from periods with excessive cortisol production interspersed with periods of normal levels.

The fluctuations in cortisol levels over time pose difficulties for a definite diagnosis. Moreover, the precise mechanism underlying the periodic peaks of cortisol peaks are unknown.

Investigators now reported the case of a 37-year-old man admitted to the hospital due to repeated attacks of dizziness, weakness, and high cortisol levels for two weeks.

Repeated tests measuring the levels of cortisol in the blood and a 24-hour urine free cortisol (24 hUFC) assay confirmed a cyclic fluctuation of cortisol, with levels peaking three times and dropping twice (the standard rule for diagnosing CSC).

Upon hospitalization, he further developed high blood pressure and weight gain.

The patient underwent computed tomography (CT) scans, which revealed the presence of an ACTH-secreting tumor in the lungs, the likely cause of the patient’s Cushing’s symptoms. These type of tumors are called neuroendocrine tumors because they are able to release hormones into the blood in response to signals from the nervous system.

Additional scans detected tumors in the adrenal and pituitary glands, but further analysis revealed they were non-functioning tumors, i.e., as their name indicates, they didn’t release excessive ACTH. The thyroid gland also was positive for a tumor.

The patient underwent resection surgery to remove the tumor located in the lungs and nearby lymph nodes. After the surgery, the levels of cortisol in the blood and urine returned to normal, confirming the tumor as the source of the CSC.

The patient also received surgery to remove his thyroid tumor.

An analysis of the patient’s genomic DNA revealed a novel mutation in the PDE11A gene, which is linked to a rare form of ACTH-independent Cushing’s syndrome called primary pigmented nodular adrenocortical disease (PPNAD) type 2.

Whether the patient developed PPNAD, however, and the contribution of a potential PPNAD diagnosis to the CCS, requires further investigation. “To explore pathogenicity of the genetic mutation, we will still plan for a follow-up visit to this patient,” researchers wrote.

From https://cushingsdiseasenews.com/2019/01/24/patient-develops-cyclic-cushings-syndrome-due-to-lung-neuroendocrine-tumor/

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