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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Risk Comparison and Assessment Model of Deep Vein Thrombosis in Patients with Pituitary Adenomas After Surgery

Posted on October 22, 2025 by MaryO

Abstract

Background

Deep vein thrombosis (DVT), a major component of venous thromboembolism (VTE), is a common postoperative complication. Its occurrence after pituitary adenoma surgery is influenced by multiple factors.

Methods

This retrospective study analyzed 1440 pituitary adenoma cases treated at Beijing Tiantan Hospital (2018–2023). The incidence of postoperative DVT was recorded, and logistic regression was used to identify associated risk factors. Differences across pituitary adenoma subtypes were compared. Additionally, Regression and machine learning models were developed to predict DVT.

Results

Among 397 patients who underwent postoperative lower limb ultrasound, 104 (7.2 %) developed DVT. Significant risk factors included advanced age, higher body mass index (BMI), intravenous cannulation, prolonged hospital stay, shorter preoperative activated partial thromboplastin time (APTT), longer thrombin time (TT), elevated platelet count, and higher postoperative D-dimer levels. Patients with Cushing’s disease exhibited a significantly higher DVT incidence, potentially related to decreased pre- and postoperative APTT and PT/INR values. Conversely, patients with prolactin-secreting adenomas had a lower DVT incidence, possibly due to younger age and higher postoperative PT values. A support vector machine (SVM) model showed strong predictive performance (AUC: 0.82; accuracy: 86.08 %; specificity: 96.72 %).

Conclusion

DVT incidence varies by pituitary adenoma subtype. Machine learning enhances predictive models for postoperative DVT in pituitary adenoma patients.

Introduction

Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism, is a common cardiovascular disorder. It typically presents with clinical symptoms such as lower limb swelling, chest pain, tachypnea, and, in severe cases, may result in fatal outcomes [1]. The development of VTE is influenced by three factors known as the Virchow triad: altered venous blood flow, endothelial or vessel wall damage, and hypercoagulability [2]. Surgical procedures can increase the risk of VTE, particularly DVT in the lower extremities, due to intraoperative injuries and postoperative hemodynamic changes [[3], [4], [5]]. In the absence of anticoagulant prophylaxis, the incidence of VTE following brain tumor surgery ranges from 3 % to 30 % [[6], [7], [8]]. Although pituitary adenomas are commonly considered benign cranial tumors, emerging evidence suggests that patients undergoing resection of pituitary adenomas may have a higher risk of postoperative VTE compared to those with other sellar or parasellar tumors such as craniopharyngiomas, meningiomas, or chordomas [9].
This disparity may be attributed to the unique hormone secretion functions of pituitary adenomas, as well as dysregulation of water and electrolyte balance—following surgery. Despite this, the risk factors contributing to the development of postoperative VTE in pituitary adenomas have not been extensively explored. Limited studies have identified a particularly elevated VTE risk in patients with Cushing’s disease, a hormone-secreting subtype of pituitary adenoma [10]. Given the relatively high incidence of postoperative DVT in this population, the present study aims to systematically investigate risk factors associated with lower extremity DVT after pituitary adenoma surgery. Furthermore, we seek to compare thrombotic risk across different clinical subtypes of pituitary adenomas and to construct a tailored risk prediction model to guide perioperative thromboprophylaxis in affected patients.

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A Preliminary Model to Tailor Osilodrostat In Patients With Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s syndrome

Posted on October 10, 2025 by MaryO

Abstract

Over the past 10 years, osilodrostat has become one of the most commonly used steroidogenesis inhibitors in patients with Cushing’s syndrome. The starting dose is usually determined based on the product characteristics, the prescriber’s experience, and cortisol levels. However, no study has attempted to determine whether there was a dose–response relationship between osilodrostat and cortisol reduction. In this study, we developed a preliminary kinetic–pharmacodynamic model to tailor osilodrostat in patients with Adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. We first analyzed the decrease in cortisol 48 hours after initiation or dose change of osilodrostat in 18 patients. Simulations were then performed for different doses of osilodrostat to evaluate the variation in cortisol concentrations. Our results report the first dose–response relationship between osilodrostat dose and cortisol levels, which should be helpful in identifying the optimal dosing regimen in patients with Cushing’s syndrome and in individualizing treatment to approximate a nychthemeral rhythm.

osilodrostat, Cushing’s syndrome, Cushing’s disease, cortisol, adrenal insufficiency
Issue Section:

Brief Report

Significance

The current preliminary study is a first step in trying to better understand the effect of osilodrostat on cortisol, which should help determine the optimal dose for each patient.

Introduction

Cushing’s syndrome is a rare condition in which increased cortisol levels lead to a wide range of comorbidities and increased mortality. Surgery is usually regarded as the first-line and most effective treatment.1 In some cases, cortisol-lowering drugs are necessary, mainly after failed surgery.2,3 Among several steroidogenesis inhibitors such as ketoconazole and metyrapone,4,5 osilodrostat, which acts through inhibition of 11β-hydroxylase, is now being considered an effective drug in controlling cortisol hypersecretion. Initially designed as a CYP11B2 inhibitor, the study by Ménard et al.6 involving both animal models and healthy human subjects showed that osilodrostat reduced cortisol levels from a dose of 1 mg/day, while lower doses exerted an anti-aldosterone effect. Since then, several clinical trials and retrospective studies emphasized its efficacy in all etiologies of Cushing’s syndrome.7-9 While the usual recommended starting dose is 2 mg twice a day, precise studies on the short-term effect of osilodrostat on plasma cortisol are lacking. These data could, however, be of interest to tailor the treatment. Moreover, baseline urinary free cortisol (UFC) level is not able to predict response to osilodrostat.10 Taking advantage of serial cortisol measurements performed in inpatient clinics in our center at the time osilodrostat became available, we developed a pharmacokinetic (PK)/pharmacodynamic model of plasma cortisol variation as a function of osilodrostat dose in patients with Adrenocorticotropin-hormone (ACTH)-dependent Cushing’s syndrome.

Patients and methods

Clinical data and hormonal measurements

We retrospectively included patients with ACTH-dependent Cushing’s syndrome, who had serial measurements of plasma cortisol (every 4 hours for 24 hours) before and after the first osilodrostat dose between 2019 and 2024. These measurements were part of our standard of care approach when osilodrostat became available in our tertiary expert center as a thorough evaluation of the efficacy and tolerance of a new drug. The initial dose ranged from 2 to 15 mg/day, depending on the severity of hypercortisolism. Subsequently, osilodrostat dose was gradually adjusted based on the successive cortisol measurements described above. Sex, age at diagnosis, and etiologies were recorded, as well as plasma cortisol measurements 48 hours after the initiation or any change in the osilodrostat dose and time elapsed since change of dose and last administration were recorded. All plasma cortisol measurements were performed with the same Elecsys II Cortisol, Cobas (Roche Diagnostics) assay in the hormonal laboratory of our center; cross-reactivity with 11-deoxycortisol is 4.9%. According to our institutional policy, this retrospective study did not require specific signed informed consent from patients as the data collected were anonymized. It was thus approved by the Ethics Committee of Assistance Publique—Hopitaux de Marseille (RGPD PADS reference RUXXX2). The current study complies with the Declaration of Helsinki.

Pharmacokinetics and statistical analysis

The pharmacodynamic parameters of osilodrostat on cortisol concentrations were analyzed using a kinetic–pharmacodynamic (PD) model in the software Nonlinear Mixed Effects Modeling version 7.4 (NONMEM Icon Development Solutions, Ellicott City, MD, United States). PK analysis from a previously published study6 was used to predict plasma concentration in our patients. The PK parameters were described in the article, and mean concentration values were obtained by digitizing the graph of osilodrostat vs time using the software WebPlotDigitizer version 4.2.11 With these data, a one-compartment population PK model was used to predict osilodrostat concentrations for different dosing regimens. Direct and indirect relationship between osilodrostat-predicted concentration and variation of cortisol concentrations were evaluated to consider a delay. The variation of cortisol concentrations was calculated with reference to a session without treatment. Several functions were tested to describe the relationship such as linear and sigmoidal. Model selection and evaluation were done by the likelihood ratio test (objective function), goodness-of-fit plots (observed vs predicted variation of cortisol concentrations, observed vs individual predictions, normalized prediction distribution errors vs time and variation of cortisol predictions), bootstrap, and visual predictive checks. Graphical analysis was performed with the R software version 4.4.012 using the ggplot2 package.13 Simulations were performed for different doses of osilodrostat to evaluate the variation on cortisol concentrations using the package rxode2.14

Results

Of the patients who were prescribed osilodrostat at least once between 2019 and 2024, 18 were presenting ACTH-dependent Cushing’s syndrome, 12 women (66.6%) and 6 men (33.3%). Mean age was 53.2 ± 15 years. The cause of Cushing’s syndrome was Cushing’s disease in 16 patients (88.9%), ectopic ACTH secretion in 1 patient (5.6%), and ACTH-dependent hypercortisolism of uncertain diagnosis in 1 patient (5.6%). Clinical characteristics are presented in Table 1. It should be noted that none of the patients included were Asian.

 

 

Table 1.

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Clinical characteristics of patients with all included patients and differentiated according to gender.

All patientsa Women Men
Age at diagnosis 53.2 ± 15 54 ± 17.2 51.5 ± 10.5
Weight 81.7 ± 13.7 79.5 ± 12.7 86.2 ± 15.6
% of CD 88.9 83.3 100
ULN of 24 hour UFC 4.4 ± 8.3 5.5 ± 10.3 2.5 ± 1.8
Osilodrostat starting dose 3.3 ± 2.2 3.7 ± 2.4 2.5 ± 1.4
Cortisol before osilodrostat intake 422.9 ± 159.2 414.7 ± 176.6 439.4 ± 130.7
Cortisol 4 hour after osilodrostat 404 ± 165.6 408.2 ± 200.1 395.5 ± 70.8

 

Abbreviations: CD, Cushing’s disease; ULN, upper limit range; UFC, urinary free cortisol.

aOf note, none of the included patients were Asian.

In their article, Ménard et al.6 showed that the dose–exposure relationship was not strictly proportional. A one-compartment model was enhanced by increasing the relative bioavailability with the dose and was estimated that the dose resulting in a 50% increase in bioavailability was 1.06 mg. The PK parameters derived from Ménard et al.6 were fixed and used to predict osilodrostat concentration in our patients. A direct relationship between the predicted osilodrostat concentrations and variation of cortisol concentrations (%) gave a better fit than an indirect model. The drug effect was modeled with the following sigmoidal function (Eq. 1);

(1)

where Imax is the maximal inhibition and IC50 is the apparent half-maximal inhibitory concentration.

The estimated PD parameters were IC50 and Imax. Their values as well as the relative standard errors (RSE%) and the corresponding bootstrap IC50 are shown in Table 2. Final parameters were used to simulate n = 500 profiles following a single dose of osilodrostat.

 

 

 

Table 2.

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Pharmacodynamic parameters of osilodrostat’s effects on the variation of cortisol concentrations.

Parameters Unit Estimation RSE% Bootstrap
0.025 0.975
KA (fixed)a 1/hour 4.03 — — —
CL/F (fixed)a L/hour 18.3 — — —
V/F (fixed)a L 125 — —
Imax % 44.5 18.7 12.51 90.9
IC50 mg/L 0.011 37.4 0.0001 0.10
Interindividual variability (ω)
 Imax 0.40 30.9 0.003 1.86
 IC50 3.78 41.0 0.003 9.22
Residual unexplained variability (σ)
 Additive % 23.8 12.2 18.2 29.9

 

Abbreviations: CL/F, apparent clearance; IC50, osilodrostat concentration associated with half the maximal inhibition of the cortisol variation; Imax, maximum inhibitory effect of osilodrostat on the variation of cortisol; KA, first-order absorption rate constant; RSE, relative standard error; V/F, apparent volume of distribution.

 

aAdapted from Ménard et al.6

The effects on plasma cortisol variation are depicted in Figure 1. Cortisol concentration declines during the first hour after taking osilodrostat, from 24% for a 1 mg dose to over 42% for a 20 mg dose. Thereafter, from the first hour onward, cortisol increases progressively, with loss of treatment efficacy occurring around the 10th-15th hour for 1 and 2 mg, while for doses above 5 mg, a moderate effect persists over the following hours. Figure 2 shows the variation in cortisol concentration for a 2 mg dose, with median decrease in cortisol variation of 31%, ranging from 0% to 67.5%, with, as mentioned above, a maximum effect 1 hour after osilodrostat intake, and a progressive increase in cortisol levels, mainly during the 12 hours following treatment. The same analysis for 10 mg revealed a median reduction in cortisol of 38%, ranging from 5% to 80%. Figure 3 describes the relationship between osilodrostat concentration and cortisol variation, showing that the maximum effect corresponds to the maximum concentration and that a decrease in osilodrostat concentration results in an increase in cortisol level.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

Figure 1.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

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Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

Figure 2.

Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

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Relation between osilodrostat concentration and cortisol variation.

Figure 3.

Relation between osilodrostat concentration and cortisol variation.

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Discussion

To the best of our knowledge, this is the first study that attempts to define a dose/efficacy relationship between osilodrostat dose and the variation of plasma cortisol. First, our results suggest that the effect of osilodrostat appears immediately after the peak of concentration, 1 hour after treatment intake, which highlights the parallel evolution of osilodrostat and cortisol concentrations. This is unusual, as typically effect peak takes few hours, following concentration peak.15 The relationship between osilodrostat concentration and the effect on cortisol is not linear but sigmoidal with a rapid increase in concentrations producing a rapid significant effect, leading to a maximal effect. Because elimination is a slower process than absorption, the effect’s decline will also be slower: this means that efficiency remains stable during the first 5 hours, with a further progressive increase of cortisol and a loss of efficiency around 10-15 hours after intake. This confirms the need for two intakes per day, with one early in the morning and the other 12 hours later in the evening. In addition, even if our simulation suggests a wide interindividual variability, we were able to determine the impact of different doses of osilodrostat on the percent decrease in plasma cortisol levels. For instance, 20 mg osilodrostat leads to an estimated 42% decrease in cortisol concentration. Interestingly, Ferrari et al.16 recently showed that patients controlled with two doses of osilodrostat for at least 1 month had the same efficacy with a single intake (combing both doses) at 4 or 7 Pm. This is quite surprising and will need to be evaluated in future studies: our preliminary model could give more precise information on this point.

Cushing’s syndrome is also characterized by a loss of circadian rhythm leading to increased comorbidities such as diabetes, hypertension, and cardiovascular disease.17,18 This is why 24 hour UFC can only be considered an imperfect marker of glucocorticoid overexposure even though it is an easy-to-use marker, as exemplified by its use in all the clinical trials performed on cortisol-lowering drugs.7,8,10,19 Predicting the efficacy of osilodrostat on plasma cortisol might be helpful to tailor the treatment as a titrating approach. Of note, some studies suggested that there might be an inpatient variability of cortisol secretion in Cushing’s syndrome,20 and this might account for a bias in our results. However, none of our patients had cyclical Cushing’s syndrome. Moreover, 12 patients in our cohort had at least two cortisol cycles (every 4 hours during the day) before starting treatment. A comparison of these two cycles using Student’s t-test showed no significant difference (P = .7), indicating no obvious spontaneous variability. Our preliminary report gives interesting insights into the maximal efficacy expected for a single dose of osilodrostat, thus defining the initial dosage needed to rapidly control hypercortisolism, as opposed to the dose currently recommended by the manufacturer (2 mg twice daily). Thus, our results could help define an optimal dose in the morning, but also in the evening, with the aim of re-establishing a circadian profile. This will, however, have to be confirmed on an interventional study focusing on comorbidities, quality of life and their potential improvements while using this PK model.

The main limitation of this proof-of-concept study is the large CI. This may be due to the relatively low number of patients and the fact that cortisol was measured every 4 hours instead of every hour, but also to the large variability in efficacy between subjects. Due to the number of patients included in the analysis, it was not possible to investigate further if a covariate, such as the gender, may explain these differences between individuals. It is important to highlight that although our model predicts cortisol levels 1 hour post intake as the most reliable predictor of future efficacy, cortisol measurements were taken every 4 hours. Thus, this finding should be confirmed in prospective studies with more frequent cortisol measurements, particularly 1 hour after osilodrostat administration. While the kinetic–pharmacodynamic approach used in this study can present with some inherent limitations, this type of approach is regularly used to define the modalities of use for a medication in a new indication. A nonlinear mixed-effects modeling allows the use of data from the routine clinical follow-up of patients. This method is thus effective and particularly well-suited for sparse data. Finally, a larger study could include closer measurements of cortisol. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is the best method for avoiding cross-reactivity with steroid precursors and could be used for these measurements. However, we used the Elecsys Cortisol II Immunoassay, which shows <5% cross-reactivity with 11-deoxycortisol; thus, our results are credible.

In conclusion, we designed a kinetic–pharmacodynamic model to adapt osilodrostat in patients with ACTH-dependent Cushing’s syndrome. Our model shows that cortisol level 1 hour after treatment is the best indicator of future efficacy. Moreover, depending on the initial cortisol level and the goal to be achieved, different doses should be prescribed. Despite wide inter-patient variability, we believe our model provides insight into the minimal dose necessary to decrease cortisol levels and the maximal efficacy expected for a given dose. Thus, it should help physicians tailor the treatment to reach maximal efficacy in the shortest possible time. The next step will be to analyze whether this percent decrease remains stable on a long-term basis or becomes more important with time, as suggested by some clinical cases showing delayed adrenal insufficiency on stable doses of osilodrostat.21

Authors’ contributions

Cecilia Piazzola (Conceptualization [equal], Formal analysis [equal], Writing—original draft [equal]), Frederic Castinetti (Conceptualization [equal], Formal analysis [equal], Writing—review & editing [equal]), Katharina von Fabeck (Conceptualization [equal], Writing—review & editing [equal]), and Nicolas Simon (Conceptualization [equal], Methodology [equal], Supervision [equal], Validation [equal], Writing—original draft [equal], Writing—review & editing [equal])

Funding

This work received an unrestricted educational grant from Recordati Rare Diseases.

To see the references and the original article, please go here: https://academic.oup.com/ejendo/article/193/4/K11/8255719?login=false

 

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Changing face of Cushing’s Disease Over Three Decades in Pituitary Center

Posted on October 1, 2025 by MaryO

Abstract

Objective

Cushing Disease (CD) presents with typical clinical findings, even though, there is a wide spectrum of manifestations. Over the years, the sings and symptoms of Cushing’s syndrome (CS) have become more subtle and atypical forms of CS have emerged. In this study, we aimed to investigate the changes in the clinical presentation of CD in recent years.

Materials and methods

In this study, CD patients followed by our center were examined. A total of 258 patients with CD were included in the study. The clinical findings at the time of presentation, laboratory and imaging findings, treatment modalities and remission status in the first year after treatment were evaluated.

Results

The mean age of the patients included in the study was 41.3 ±13.28 years. CD patients diagnosed between 2013 and 2023 were older than those diagnosed between 1990 and 2012 (p < 0.001). There was no difference between the groups in terms of gender. Moon face, purple striae, hirsutism, and menstrual irregularities were statistically significantly less frequent in the last 10 years than in previous years (p < 0.001; p = 0.004; p < 0.001; p < 0.001, respectively). In addition, patients who applied after 2013 had lower baseline cortisol and adrenocorticotropic hormone (ACTH) levels, and a smaller median size of the pituitary adenoma. Limitations of the study include its retrospective design and the subjectivity of clinical data.

Conclusion

As the clinical presentation of Cushing’s disease changes over time, waiting for the typical Cushing’s clinic can delay diagnosis. It is important that clinicians take this into account when they suspect CD.

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