Case study shows chronic marijuana use associated with hypopituitarism

Posted on January 3, 2026 by MaryO

PHOENIX — Results of a case study presented here at the American Association of Clinical Endocrinologists 22nd Scientific and Clinical Congress demonstrate that smoking marijuana may result in serious endocrine complications.

Hormone feedback cycles

Hormone feedback cycles (Photo credit: Wikipedia)

“We really feel that the evidence to-date shows this is a much more serious health problem than we’ve given credit to,” Pinsker said during a press conference. “Marijuana’s always been laughed off: ‘it’s a kid’s drug; they’ll outgrow it.’ In certain communities, it’s so common that people look at it as if they’re having a glass of beer. I think it’s time that physicians start having their antenna up for all the difficulties that come with this drug.”

The patient presented to the emergency department with dyspnea on exertion, increasing fatigue and loss of libido with no previous radiation exposure or head trauma. He had bibasilar rales, gynecomastia and bilateral atrophied testis.

His hormonal evaluation demonstrated low Luteinizing Hormone (0.2 mIU/mL); FSH (1.8 mIU/mL) and testosterone (22 ng/dL), as well as high prolactin (53.3 ng/mL).

Additionally, the patient had ACTH of 6 pg/mL and cortisol of 6.4 ug/dL at 0 minutes and 9.3 ug/dL at 60 minutes following cosyntropin administration.

Further labs revealed low total T3 (30 ng/dL); high T3 resin reuptake (49%); low total T4 (3.94 ng/dL); normal free T4 (0.97 ng/dL) and low TSH (0.22 uIU/mL). Growth hormone was within normal range (5.0 ng/mL) and IGF-I was low (75 ng/mL; Z-score of -1.3). An MRI revealed a slightly enlarged protuberant pituitary gland, but no identified mass lesion.

After being started on cortisone 25 mg in the morning and 12.5 mg at bedtime, as well as levothyroxine 25 mcg daily, the patient’s fatigue and edema improved significantly, according to the abstract.

In this case, severe hypopituitarism occurred from interference between THC, the psychoactive ingredient in marijuana which has the ability to alter neural transmitters in the hypothalamus, and hypothalamic function.

Additionally, studies show that marijuana impairs the release of gonadotropin-releasing hormone (GnRh), resulting in reduced production of testosterone.

Other symptoms seen with prolonged use include cognitive decline in school children and older people, according to Pinsker. “The public will become more attuned to looking for these things. We’re going to have what we call a surveillance bias and we’re going to start discovering that it’s a lot higher than we gave it credit for, both because of increased use and because we’re going to be looking for it.”

The authors conclude that, as many states consider the legalization of marijuana, more study should be conducted with regard to the effects of chronic use of the drug on the endocrine system.

“Of course this is one case report, but I think it should alert further research that needs to be done, “ said Pinsker. “Something prospectively should be done to map this out more scientifically, but this would be difficult in what, to-date, has been an illegal substance.”

For more information:

Pinsker R. Abstract #825. Presented at: the AACE Annual Scientific and Clinical Congress; May 1-5, 2013; Phoenix.

Disclosure: The authors report no relevant financial disclosures.

 From Healio.com

Filed under: pituitary, Rare Diseases | Tagged: , , , , , , , , , , , , , , , , , , , , | Leave a comment »

Diabetic Ketoacidosis as the First Manifestation of Ectopic Cushing’s Syndrome

Posted on December 9, 2025 by MaryO

Abstract

Diabetic ketoacidosis is an exceptionally rare initial manifestation of ectopic adrenocorticotropic hormone (ACTH) syndrome. A 42-year-old woman with multiple cardiovascular risk factors was admitted to the emergency room with diabetic ketoacidosis. During stabilization, florid Cushing’s syndrome was suspected and confirmed biochemically as ACTH-dependent. Further biochemical and imaging surveys led to the diagnosis of a 25×15 mm nodule in the lingula. Thoracic surgery was performed, and pathology revealed a neuroendocrine tumor positive for ACTH.

We reviewed eight additional cases of diabetic ketoacidosis associated with Cushing’s syndrome from PubMed. Clinicians should bear in mind this etiology of diabetic ketoacidosis based on clinical signs and younger patients with multiple, age-atypical comorbidities. This would permit the expedited targeted stabilization of Cushing’s syndrome and the suitable institution of the diagnostic approach and treatment for this challenging syndrome.

Introduction

Endogenous Cushing’s syndrome (CS) is a rare disease resulting from pathological glucocorticoid excess of neoplastic origin, with an annual incidence of two/three cases per 1.000.000 inhabitants [1]. The severity of CS varies widely from mild to severe and, if left untreated, can be fatal due to the increased risk of cardiovascular events and opportunistic infections. Endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (80%) and -independent (20%) forms. ACTH-dependent CS is further divided into Cushing’s disease (68%) when the pituitary is the source of excess ACTH, or ectopic ACTH syndrome (EAS; 12%) when the cause is a non-pituitary neoplasia of neuroendocrine origin. EAS has an annual incidence of one case per 1.250.000 inhabitants and is more frequent in men [1]. It can be secondary to an aggressive small-cell lung carcinoma (19%), but the majority of cases arise from indolent lesions such as bronchial and thymic (combined: 33%) or pancreatic (12%) neuroendocrine tumors (NET) [1-3]. These indolent lesions usually evolve clinically over 6 to 24 months, whereas carcinomas have a faster onset. Symptoms and signs of excess cortisol in EAS are usually indistinguishable from Cushing’s disease. The most discriminatory signs of CS are plethora, purplish striae, proximal myopathy, and spontaneous ecchymosis. Multiple vascular risk factors, namely, hypertension, diabetes mellitus (DM), dyslipidemia, and obesity (especially central adiposity), occurring in a young patient, should also raise suspicion for CS [2]. Diabetic ketoacidosis (DKA) as the inaugural presentation of CS is very rare [1-3]. We searched through PubMed and reviewed articles in English where this association was reported using keywords such as “Cushing’s syndrome”, “Diabetic ketoacidosis”, “hypercortisolism”, and “Ectopic ACTH syndrome”. CS presenting initially with DKA is, as to this day, limited to eight case reports [4-11]. The clinical recognition of this syndrome as a very rare etiology of DKA is of paramount importance, as it is usually severe and relates to sepsis and several biochemical, hematologic, and hemodynamic derangements that should be addressed expeditiously with targeted drugs [3].

Here, we describe a female patient with florid clinical EAS uncovered upon her admission to the Emergency Room (ER) due to DKA. We searched through PubMed and reviewed articles in English where this association was reported, using keywords such as “Cushing’s syndrome”, “Diabetic ketoacidosis”, “hypercortisolism”, and “Ectopic ACTH syndrome”.

This article was previously presented as a meeting abstract at the 2024 ENDO, The Endocrine Society Annual Meeting on June 3, 2024.

Case Presentation

A 42-year-old woman was admitted in June 2022 to the ER due to severe DKA and hypokalemia (Table 1) and mild coronavirus disease. Physical examination at initial presentation was also remarkable for grade 2 hypertension with hypertensive retinopathy. Florid Cushingoid features, including a “buffalo hump”, plethora, hirsutism, abdominal ecchymosis, and marked proximal limb sarcopenia were noted (Figure 1).

Patient's-Cushingoid-features
Figure 1: Patient’s Cushingoid features

The patient was transferred to the intensive care unit (ICU). A multimodal treatment plan was initiated, including intravenous insulin (total daily dose: 1.2U/Kg) as per the protocol for DKA, antihypertensives, and prophylactic doses of low-molecular-weight heparin. After resolution of DKA and hydroelectrolytic disturbances, a gasometric follow-up revealed metabolic alkalosis (pH 7.529). The patient was then able to report a six-month history of weight gain, secondary amenorrhea, impaired concentration and memory, ecchymoses, and proximal myopathy with frequent falls and dependency on relatives for daily life activities. No chronic diarrhea or flushing was reported. She also reported a fungal pneumonia, dyslipidemia, and hypertension in the last four months, and a diagnosis of DM treated with metformin two weeks before her admission to the ER. Family history was unremarkable. Biochemical surveys (Table 1) revealed ACTH-dependent hypercortisolism, low thyroid-stimulating hormone (TSH), and hypogonadotropic hypogonadism. High-dose dexamethasone suppression (HDDS) and corticotropin-releasing hormone (CRH) stimulation tests were not suggestive of a pituitary source of ACTH (Table 1). Pituitary magnetic resonance imaging was normal. While waiting for further investigations regarding the source of excess ACTH, the patient was started on 750 mg/day of metyrapone in three divided doses. The patient was started and discharged from the ward with hydrocortisone 10 mg in the morning and 5 mg at midday and in the afternoon. The dose of metyrapone was carefully adjusted during two months according to morning serum cortisol, but was rapidly decreased and stopped due to spontaneous clinical resolution of CS. In the postoperative follow-up (total: 23 months), Cushingoid features (plethora, dorsal fat pad, ecchymosis, central adiposity) continued to disappear, and she regained muscle mass and independence in her daily activities and remission from all glucocorticoid related-comorbidities was maintained (fasting glucose: 91 mg/dL; glycated hemoglobin (HbA1c): 5.8%; low-density lipoprotein (LDL) cholesterol: 138 mg/dL; triglycerides: 80 mg/dL). Twelve months after surgery, the patient was able to discontinue hydrocortisone upon biochemical evidence of restoration of adrenal function (cortisol peak at Synacthen test: 21.1 ug/dL; basal ACTH: 15.6 pg/mL). Her last (23 months after surgery) endocrine surveys (midnight salivary cortisol: 0.14 ug/dL; ACTH: 18 pg/mL) and thoracic CT showed no evidence of disease relapse.

Parameter Presentation 12-month follow-up Reference
Hemoglobin (g/dL) 12.8 – 12-15.5
White blood count (×103/uL) 11.3 – 4.0-11.5
Platelets (×103/uL) 331 – 150-400
Fasting blood glucose (mg/dL) 427 76 74-106
HbA1c (%) 9.6 5.6 <6.5
Serum sodium (mmol/L) 146 – 135-145
Serum potassium (mmol/L) 2.7 – 3.5-5.1
Serum creatinine (mg/dL) 0.32 0.59 0.67-1.17
pH 7.17 – 7.35-7.45
HCO3– (mmol/L) 4.4 – 21-26
Anion gap 35 – 7
IGF-1 (ng/mL) 89.8 – 77-234
FSH (mUI/mL) 0.9 –¥ 3.5-12.5
LH (mUI/mL) <0.1 –¥ 2.4-12.6
Prolactin (ng/mL) 8.8 – 4.0-24.3
TSH (UI/mL) 0.02 0.61 0.35-4.94
Free T4 (ng/dL) 1.26 1.02 0.7-1.48
Midnight salivary cortisol (ug/dL) 25.5 2.4* <7.5
UFC (ug/dL) 1072.5 74.5* <176
Cortisol at 1 mg overnight DST (ug/dL) 25.7 – <1.8
Cortisol, baseline (ug/dL) 30.9 11.4* 5-18
Cortisol after HDDS test (ug/dL) 42.1 – Refer to reference 2
ACTH, baseline (pg/mL) 93.4 22.1* 7.2- 63.3
ACTH, maximum after CRH (pg/mL) 101.8 – Refer to reference 2
Table 1: Biochemical surveys of the patient at baseline and at the 12-month follow-up

* After metyrapone washout

¥ Gonadotropins not repeated due to resumption of regular menses

Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DST, dexamethasone suppression test; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; HDDS, high-dose dexamethasone suppression; IGF-1, insulin-like growth factor type 1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; UFC, urinary free cortisol

She was referred for inferior petrosal sinus sampling (IPSS) but it was postponed for several months due to healthcare strikes. While waiting for IPSS, she performed a thoracic computerized tomography (CT) scan to exclude EAS, which revealed thymic hyperplasia and a 25×15 mm, well-defined nodule in the lingula (Figure 2).

Thoracic-CT-scan-revealed-a-25x15-mm,-well-defined-nodule-in-the-lingula
Figure 2: Thoracic CT scan revealed a 25×15 mm, well-defined nodule in the lingula

A 68Ga-DOTANOC positron emission tomography-computed tomography (PET/CT) was then performed and showed a single uptake in the same lung region (Figure 3).

68Ga-DOTANOC-PET/CT-showing-a-single-uptake-in-the-lingula.
Figure 3: 68Ga-DOTANOC PET/CT showing a single uptake in the lingula.

Abbreviations: PET/CT, positron emission tomography-computed tomography

The patient was referred to thoracic surgery and underwent lingulectomy plus excisional biopsy of the interlobar lymph nodes. Pathology revealed a typical carcinoid/neuroendocrine tumor (NET), grade one (Ki67<2% and <2 mitosis per high-power field (HPF)) without involved lymph nodes, which showed positivity for ACTH (Figure 4).

Immunohistochemistry-findings
Figure 4: Immunohistochemistry findings

a- hematoxylin and eosin x400 magnification, b- synaptophysin x100 magnification, c- chromogranin A x400 magnification, d- ACTH x400 magnification, e- Ki-67 x100 magnification.

The patient was started on hydrocortisone 10 mg in the morning and 5 mg at midday and afternoon, which was discontinued 11 months later due to restoration of adrenal function (cortisol peak at Synacthen test: 21.1 ug/dL; basal ACTH: 15.6 pg/mL). In the postoperative follow-up, Cushingoid features continued to disappear, and she regained muscle mass and independence in her daily activities. Her last CT showed no evidence of disease.

Discussion

Severe CS (SCS) is defined by random serum cortisol above 41 ng/dL and/or a urinary free cortisol (UFC) more than fourfold the upper limit of normal and/or severe hypokalemia (<3.0 mmol/L), along with the recent onset of one or more of the following: sepsis, opportunistic infection, refractory hypokalemia, uncontrolled hypertension, edema, heart failure, gastrointestinal bleeding, glucocorticoid-induced acute psychosis, progressive debilitating myopathy, thromboembolism, uncontrolled hyperglycemia and ketoacidosis [3]. SCS results in high morbidity and mortality, requiring a rapid recognition and targeted therapy of the uncontrolled hypercortisolism [3]. Patients with SCS usually have florid signs, and straightforward clinical suspicion is possible, except in cases of ECS due to small-cell lung carcinoma, where the rapid onset of hypercortisolism and related morbidity precedes the development of clinical stigmata [2,3]. The gasometric parameters in DKA associated with SCS can also provide clues for the presence of CS. The mineralocorticoid effect of excess cortisol leads to metabolic alkalosis through increased hydrogen excretion in the distal nephron, which is masked by metabolic acidosis due to excess β-hydroxybutyrate and acetoacetate [6,12,13]. This mixed acid-basic disorder can be suspected by a ratio of ∆anion gap to ∆HCO3 of higher than one, which is not seen in pure metabolic acidosis. Additionally, after treating the DKA by decreasing ketones through the inhibition of its production by insulin and increased renal excretion with improved renal perfusion, metabolic alkalosis may supervene in gasometric monitoring, as seen in our report and others [6,9]. In rare cases, SCS can also lead to diabetic ketoalkalosis instead of DKA [1]. Several factors may contribute to the predominant alkalosis, namely, decreased hydrogen due to high renal excretion (excess mineralocorticoid effect), intracellular shift (due to severe hypokalemia), gastrointestinal losses (vomiting), and hyperventilation due to pulmonary diseases (as in heavy smokers) [13,14].

The main priorities in managing SCS are to control opportunistic infections, hypokalemia, DM, hypertension, and psychosis, and, importantly, investigations of the etiology of CS should be postponed until clinical stabilization [3]. The control of glucocorticoid-induced complications should encompass therapies to stabilize/reverse the CS induced morbidity (e.g., large-spectrum antibiotics for opportunistic infections; spironolactone for hypokalemia; insulin for DM) followed by targeted treatment of hypercortisolism [3]. Several oral adrenolytic agents are available and have proved their usefulness in SCS, namely, metyrapone (onset: hours; UFC normalization: 83%), ketoconazole/levoketoconazole (onset: days; UFC normalization: 70-81%), osilodrostat (onset: hours; UFC normalization: 82%), and mitotane (onset: days to weeks; UFC normalization: 72-82%). They can be used in monotherapy or in combination therapy, the latter strategy increasing the efficacy with lower doses of drugs and a lower risk of side effects [3,14]. Additionally, as first-line therapy for patients with an unavailable oral route (e.g., glucocorticoid-induced psychosis), or as second-line therapy when other adrenolytic agents have failed to control hypercortisolism, the anesthetic etomidate can be used under multidisciplinary supervision in an ICU, and it is highly effective (~100%) in controlling SCS within hours, in doses that do not induce anesthesia [3]. If medical therapy proves unsuccessful, bilateral adrenalectomy may be considered after careful clinical judgement, as it is highly effective in life-threatening SCS uncontrolled by medical therapy. Nevertheless, all attempts should be made to reduce hypercortisolemia with medical therapy before surgery [3].

DKA, as the inaugural presentation of CS, was previously published in eight case reports [4-11] (Table 2). Briefly, and including our case, almost all reports were severe (77.8%), mainly from EAS (55.6%) or pituitary adenomas (33.3%), and with a female preponderance (77.8%).

Reference Gender Age Florid CS signs Severe CS Etiology of CS Definitive treatment
Uecker JM, et al. [4] Female 43 Yes Yes EAS (duodenal NET) Pancreaticoduodenectomy
Kahara T, et al. [5] Male 53 No No ACTH-independent Adrenalectomy
Weng Y, et al. [6] Female 28 Yes Yes Cushing’s disease (macroadenoma) Transsphenoidal surgery
Catli G, et al. [7] Female 16 Yes Yes Cushing’s disease (microadenoma) Transsphenoidal surgery
Sakuma I, et al. [8] Female 56 Yes Yes EAS (pheochromocytoma) Adrenalectomy
Achary R, et al. [9] Female 48 Yes Yes Cushing’s disease (microadenoma) Transsphenoidal surgery
Cheong H, et al. [10]* Female 22 Unknown Unknown EAS (medullary thyroid carcinoma) None
Shangjian L, et al. [11] Male 46 Unknown Yes EAS (pheochromocytoma) Adrenalectomy
Our case Female 42 Yes Yes EAS (bronchial NET) Thoracic surgery
Table 2: Review of published cases of DKA as the inaugural presentation of CS

*Deceased

Abbreviations: ACTH, adrenocorticotropic hormone; CS, Cushing’s syndrome; EAS, ectopic ACTH syndrome; NET, neuroendocrine tumor

The etiology of CS should be investigated in diagnostic steps. After confirming hypercortisolism (low-dose dexamethasone suppression test, UFC, and/or late-night salivary cortisol) and its ACTH dependence (usually well above 20 pg/mL in EAS), the source of excess ACTH should be pursued. The CRH test is the most accurate dynamic test to distinguish between pituitary and ectopic sources of ACTH, followed by the desmopressin and HDDS tests. The combination of CRH and HDDS tests has an accuracy close to the IPSS, the gold standard to distinguish pituitary from ectopic sources of ACTH. If the investigation approach points to EAS, the most accurate exam to detect a lesion is 68Ga-DOTA-somatostatin analogue PET/CT, followed by 18F-FDG PET and conventional cross-sectional imaging [1-3].

After being discharged from the ward, our patient showed spontaneous resolution of hypercortisolism requiring the withdrawal of metyrapone and all medications to control glucocorticoid-induced morbidity, suggesting cyclic CS. This very rare variant of CS is present when periods of hypercortisolism alternate with periods of normal cortisol secretion, each phase lasting from days to years, which makes this type of CS very challenging to manage. The pituitary is the main source of cyclic CS, followed by EAS and, infrequently, the adrenal gland. The criteria of three peaks and two periods of normal or low cortisol levels needed to diagnose cyclic CS were not seen in the follow-up period of our patient, as after one peak and trough, we found and removed the source of EAS [1].

Conclusions

In the context of DKA, florid Cushing signs and multiple vascular risk factors occurring in a young patient should raise suspicion for Cushing’s Syndrome. The severity of this syndrome varies widely from mild to severe and, if left untreated, can be fatal due to the increased risk of cardiovascular events and opportunistic infections. Diabetic ketoacidosis precipitated by an endogenous excess of glucocorticoid is usually associated with severe Cushing’s syndrome and more frequently with EAS, which can have an abrupt onset. Prompt recognition and targeted stabilization of severe Cushing’s syndrome are crucial and should precede a definitive etiologic investigation.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  2. Hayes AR, Grossman AB: Distinguishing Cushing’s disease from the ectopic ACTH syndrome: needles in a haystack or hiding in plain sight?. J Neuroendocrinol. 2022, 34:e13137. 10.1111/jne.13137
  3. Alexandraki KI, Grossman AB: Therapeutic strategies for the treatment of severe Cushing’s syndrome. Drugs. 2016, 76:447-58. 10.1007/s40265-016-0539-6
  4. Uecker JM, Janzow MT: A case of Cushing syndrome secondary to ectopic adrenocorticotropic hormone producing carcinoid of the duodenum. Am Surg. 2005, 71:445-6.
  5. Kahara T, Seto C, Uchiyama A, et al.: Preclinical Cushing’s syndrome resulting from adrenal black adenoma diagnosed with diabetic ketoacidosis. Endocr J. 2007, 54:543-51. 10.1507/endocrj.k06-071
  6. Weng YM, Chang MW, Weng CS: Pituitary apoplexy associated with cortisol-induced hyperglycemia and acute delirium. Am J Emerg Med. 2008, 26:1068.e1-3. 10.1016/j.ajem.2008.03.023
  7. Catli G, Abaci A, Tanrisever O, Kocyigit C, Sule Can P, Dundar BN: An unusual presentation of pediatric Cushing disease: diabetic ketoacidosis. AACE Clinical Case Reports. 2015, 1:53-8. 10.4158/EP14284.CR
  8. Sakuma I, Higuchi S, Fujimoto M, et al.: Cushing syndrome due to ACTH-secreting pheochromocytoma, aggravated by glucocorticoid-driven positive-feedback loop. J Clin Endocrinol Metab. 2016, 101:841-6. 10.1210/jc.2015-2855
  9. Acharya R, Kabadi UM: Case of diabetic ketoacidosis as an initial presentation of Cushing’s syndrome. Endocrinol Diabetes Metab Case Rep. 2017, 2017:10.1530/EDM-16-0123
  10. Cheong H, Koo HL: Medullary thyroid carcinoma with diabetic ketoacidosis: an autopsy case report and literature review. Forensic Sci Med Pathol. 2021, 17:711-4. 10.1007/s12024-021-00407-8
  11. Li S, Guo X, Wang H, Suo N, Mi X, Jiang S: Ectopic adrenocorticotropic hormone-secreting pheochromocytoma with severe metabolic disturbances: a case report. Int J Surg Case Rep. 2024, 116:109341. 10.1016/j.ijscr.2024.109341
  12. Kraut JA, Madias NE: Serum anion gap. Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007, 2:162-74. 10.2215/CJN.03020906
  13. Uwaifo G, Varughese AG: ODP245 Syndrome of diabetic ketoalkalosis due to severe hypercortisolemia: a case series. J Endocr Soc. 2022, 6:A334. 10.1210/jendso/bvac150.693
  14. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A: Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015, 100:2807-31. 10.1210/jc.2015-1818

From https://www.cureus.com/articles/426071-diabetic-ketoacidosis-as-the-first-manifestation-of-ectopic-cushings-syndrome#!/

Filed under: Cushing's, Rare Diseases, symptoms | Tagged: , , , , | Leave a comment »

Clinical Efficacy and Safety of Fluconazole Treatment in Patients with Cushing’s Syndrome

Posted on November 11, 2025 by MaryO

Abstract

Background:

Ketoconazole is effective for treating Cushing’s syndrome (CS) but its use is limited by the risk of hepatotoxicity. Fluconazole, with similar antifungal properties, is being investigated as a potentially safer alternative for managing CS. This study aims to evaluate the efficacy and safety of fluconazole in patients with CS.

Methods:

This retrospective study evaluated a total of 22 patients with CS, including 12 with Cushing’s disease (CD), 3 with adrenal Cushing’s syndrome (ACS), and 7 with ectopic Adrenocorticotropic hormone (ACTH) syndrome. Fluconazole was administered orally, ranging from 112.5 to 450 mg daily, with the duration varying from 2 weeks to over 5 years. The efficacy of fluconazole was assessed by changes in 24-hour urinary free cortisol (24-h UFC) levels. Additionally, hepatic safety was assessed by monitoring changes in alanine aminotransferase (ALT) levels.

Results:

Following fluconazole treatment, 24-h UFC levels significantly decreased from 717.6 ± 1219.4 to 184.1 ± 171.8 µg/day (p = 0.035). ALT levels showed an increase from 38.5 ± 28.4 to 56.5 ± 47.8 U/L, though this change was not statistically significant (p = 0.090). ALT levels exceeding the upper limit of normal range (ULN) were observed in 12 patients (54.5%), with only 4 patients (18.2%) showing ALT levels more than three times the ULN. Out of 10 patients who received treatment for over 1 year, 5 patients (50.0%) experienced a recurrence, with 24-h UFC levels more than 1.5 times the ULN within 3 to 12 months after fluconazole treatment.

Conclusion:

Fluconazole effectively reduces hypercortisolism in patients with CS without significant liver injury, suggesting it as a viable therapeutic option for CS. While some cases have shown treatment escape, more studies are required to confirm the long-term efficacy.

Introduction

Cushing’s syndrome (CS) is a complex endocrine disorder characterized by excessive cortisol production, leading to complications such as insulin-resistant hyperglycemia, muscle weakness (proximal myopathy), osteoporosis, cardiovascular diseases, and neuropsychiatric disorders.1 The primary causes of CS include pituitary ACTH-secreting tumor (Cushing’s disease (CD), adrenal neoplasm (adrenal Cushing’s syndrome (ACS)), or nonpituitary ACTH-secreting tumor (ectopic ACTH syndrome (EAS)). The most common cause is CD. If left untreated, CS patients face a 3.8 to 5-fold increase in mortality compared to the general population.2,3 The first-line treatment for CS involves surgical removal of the offending tumor(s). In CD cases, transsphenoidal pituitary surgery achieves success rates between 65% and 90% for microadenomas. However, complete resection can be challenging, especially with macroadenomas, leading to recurrence or persistent hypercortisolism in approximately 20%–25% of patients.4 Alternative treatments include pituitary stereotactic radiosurgery, which effectively controls cortisol levels over several years but carries potential adverse effects.5,6 For EAS patients, managing hypercortisolism while awaiting definitive treatments like surgery is critical.7 Bilateral adrenalectomy offers immediate control over cortisol excess but necessitates lifelong steroid replacement therapy, impacting the quality of life.8 In addition, some corticotropic pituitary tumors may progress post-surgery, requiring further targeted interventions.9
However, some patients were not candidates for surgery due to factors such as advanced age, personal preference against surgery, or the absence of a definitive culprit lesion. When surgery fails to fully correct hypercortisolism (i.e., when 24-h UFC levels do not decrease or even progressively rise in the weeks to months following surgery, indicating persistence or relapse), pharmacotherapy can be employed to reduce cortisol overproduction and enhance clinical outcomes.10,11 In addition, it could be administered before surgical intervention to reduce perioperative complications.12,13 Various medications are used in the treatment of CS, including adrenal steroidogenesis inhibitors, dopamine agonists, somatostatin analogs, or glucocorticoid receptor antagonist.4,14
Ketoconazole, an imidazole fungicide and adrenal steroidogenesis inhibitor, has long been off-label used as the first-line medication for patients with CS who cannot undergo surgery or for whom surgery is non-curative. It reduces cortisol synthesis by inhibiting the side-chain cleavage enzymes 11β-hydroxylase and 17,20-lyase.10 Effective doses range from 200 to 1200 mg daily, but gradual dose increases may be necessary due to the potential for escape from cortisol inhibition.10,15 Ketoconazole is extensively metabolized in the liver, leading to an increased risk of hepatotoxicity.16 In 2013, the U.S. Food and Drug Administration (FDA) issued warnings about the potentially life-threatening liver toxicity associated with ketoconazole. As a result, ketoconazole is no longer available in many regions.
Fluconazole, another azole antifungal agent, has been explored as an alternative treatment for CS. It inhibits adrenal steroidogenesis through the CYP450 pathway, and the effects have been confirmed in vitro, using primary cultures of human adrenocortical tissues and two adrenocortical carcinoma cell lines. The effects were mainly observed in enzymes 11β-hydroxylase and 17α-hydroxylase, which are key in cortisol synthesis.17 Another study also demonstrated that fluconazole inhibits glucocorticoid production in vitro in the adrenal adenoma cell line Y-1.18 Case reports have also documented adrenal insufficiency in patients with severe comorbidities treated with fluconazole, suggesting its potential for managing hypercortisolism.19,20 Fluconazole is characterized by its small molecular size and low lipophilicity. It is minimally metabolized, with approximately 80% excreted unchanged in the urine.16 This contributes to its lower incidence of adverse effects, particularly liver injury. In a cohort study estimating the risk of clinical acute liver injury among users of oral antifungals (fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine) in the general population from the General Practice Research Database in the United Kingdom, fluconazole was associated with a lower relative risk of acute liver injury compared to other agents.21
Levoketoconazole, the 2S, 4R enantiomer of ketoconazole, provides enhanced enzyme inhibition with greater therapeutic efficacy and fewer side effects compared to ketoconazole.22 The main challenge with using levoketoconazole in the treatment of CS is the limited data from Randomized controlled trials (RCTs). To date, there are only two prospective studies (SONICS and LOGICS) and one systematic review that evaluate the efficacy and safety of levoketoconazole in this context.23–25
Given that existing evidence on fluconazole treatment for CS is primarily limited to case reports, this study aims to evaluate the efficacy and safety of fluconazole in the first relatively large cohort of CS patients.

Patients and methods

Patients

This retrospective study analyzed a total of 22 patients with CS, including 12 cases of CD, 3 cases of ACS, and 7 cases of EAS. For patients who presented with Cushingoid appearance, a 1-mg overnight low-dose dexamethasone suppression test (LDDST) was performed. If the result revealed positive (>1.8 mcg/dL), further surveys were arranged. CS was diagnosed based on 24-h UFC levels (>three times the upper limit of normal range (ULN)), and 2-day LDDST (>1.8 mcg/dL). Once the biochemical diagnosis of CS was confirmed, morning plasma ACTH and cortisol levels were measured to differentiate between ACTH-dependent and ACTH-independent CS. Low ACTH levels (<5 pg/dL) accompanied by elevated cortisol concentrations (>15 mcg/dL) indicated an adrenal origin, consistent with ACTH-independent CS. In such cases, a computed tomography or magnetic resonance imaging scan was performed to evaluate for adrenal masses. If ACTH levels were greater than 5 pg/dL, ACTH-dependent CS was suspected. To identify the source of excessive ACTH secretion—either CD or EAS—further diagnostic testing was conducted, including high-dose dexamethasone suppression test (UFC suppresses >90%, or plasma cortisol suppresses > 50% from baseline, CD is most likely), or corticotropin-releasing hormone (CRH) stimulation test, or desmopressin (DDAVP) stimulation test (ACTH increases >50% and plasma cortisol increases >20% suggests CD), or inferior petrosal sinus sampling (central-to-peripheral ACTH ratio ⩾2 or ⩾3 post CRH or DDAVP suggests CD), or pituitary magnetic resonance imaging (pituitary mass >6 mm suggests CD).1,26 If the patient’s condition allowed, one or more of these tests were performed, and the final diagnosis was made based on a comprehensive interpretation of the combined results.

Methods

After the approval of the Institutional Review Board at Taipei Veterans General Hospital (IRB No. 2021-04-003CC), we conducted a retrospective study, which was waived for informed consent at Taipei Veterans General Hospital. Sample size calculations were not conducted because this was a retrospective study. We surveyed patients diagnosed with CS (CD, ACS, or EAS) who received fluconazole treatment at Taipei Veterans General Hospital in Taipei, Taiwan, between January 1st, 2015, and August 31st, 2020. Fluconazole was administered orally at doses ranging from 112.5 to 450 mg daily, with treatment durations ranging from 2 weeks to over 5 years (Fluconazole was not administered for other treatment purposes, such as infection). The inclusion criteria consisted of a confirmed diagnosis of CS (whether newly diagnosed, persistent, or recurrent) and a history of fluconazole treatment for CS. The exclusion criteria included patients who were not regularly followed up after fluconazole treatment or who lacked complete 24-h UFC data both before and after treatment with fluconazole.
The following data before initiation of treatment were collected: age, gender, body mass index (BMI), alcohol consumption, history of diabetes mellitus, history of chronic hepatitis, baseline 24-hour urinary free cortisol (24-h UFC) levels (reference range: 20–80 µg/day, measured by chemiluminescent immunoassay), morning serum cortisol, morning adrenocorticotropic hormone (ACTH) levels (measured by chemiluminescent immunoassay), and liver function index (alanine aminotransferase (ALT)). In addition, the history of surgery for pituitary tumor or ectopic lesion resection, as well as any other medical treatments apart from fluconazole, was recorded.
24-Hour UFC levels were monitored every 1 to 3 months after initiating fluconazole treatment. The average values from two 24-h UFC measurements (first and second data points within the first 4 months) were used to assess treatment efficacy. For the evaluation of hepatic safety, the maximum ALT level recorded within 6 months after starting fluconazole treatment was compared to the baseline ALT. In this study, we defined ALT levels exceeding three times the ULN as noteworthy liver injury.

Statistical analysis

Data are presented as mean ± standard deviation (SD) or as numbers (percentage), as appropriate. Due to the small sample sizes in some groups and the non-normal distribution of several variables, nonparametric statistical methods were employed to analyze the relationships between variables. Differences between groups were analyzed using the Pearson Chi-squared test, Student’s t-test, or one-way analysis of variance (ANOVA), as appropriate. A p-value less than 0.05 from the ANOVA was considered statistically significant, indicating that at least one group differed significantly from the others. All statistical analyses were performed using the SPSS software package (version 26; IBM Corporation, Armonk, NY, USA).

Results

The baseline characteristics of the patients are summarized in Table 1. No significant differences were found among the etiologies of CS in terms of age, gender, or history of diabetes (p = 0.271, p = 0.253, and p = 0.667, respectively). Cortisol (8AM), ACTH (8AM), and 24-h UFC levels were significantly higher in the EAS group (p = 0.041, p = 0.005, and p = 0.043, respectively) at diagnosis. BMI was significantly lower in the EAS group compared to the other groups (p = 0.002). Alcohol consumption and history of chronic hepatitis, both common causes of liver injury in Taiwan, showed no significant differences among the groups (p = 0.325 and p = 0.765, respectively). Regarding surgical history, eight patients (66.7%) in the CD group had undergone pituitary surgery, while no patients in the ACS group had a history of surgery. In the EAS group, two patients (28.6%) had undergone surgery: one had an anterior mediastinal tumor removal and left upper lung wedge resection, and the other had a suprasellar tumor resection (p = 0.064).
Open in Viewer

Table 1. The baseline characteristics of patients with Cushing’s syndrome.
Characteristics All (n = 22) CD (n = 12) ACS (n = 3) EAS (n = 7) p-Value*
Age (years) 54.5 ± 15.5 49.8 ± 15.3 56.0 ± 12.5 61.9 ± 15.9 0.271
Female, n (%) 17 (77.3) 10 (83.3) 3 (100) 4 (57.1) 0.253
Body mass index (kg/m2) 25.1 ± 4.3 27.4 ± 2.8 27.2 ± 1.3 21.0 ± 3.8 0.002
Cortisol (8AM) (µg/dL) 26.7 ± 18.7 21.5 ± 8.6 14.0 ± 4.0 40.3 ± 26.1 0.041
ACTH (8AM) (pg/mL) 151.9 ± 172.1 98.0 ± 63.1 6.4 ± 0.9 306.5 ± 228.3 0.005
24-h UFC (µg/day) 760.5 ± 1387.8 277.9 ± 125.6 107.6 ± 78.2 1891.2 ± 2155.7 0.043
Alcohol consumption, n (%)a 1 (4.5) 0 (0.0) 0 (0.0) 1 (14.3) 0.325
History of diabetes, n (%) 11 (50.0) 5 (41.7) 2 (66.7) 4 (57.1) 0.667
History of chronic hepatitis, n (%) 2 (9.1) 1 (8.3) 0 (0.0) 1 (14.3) 0.765
Surgery history, n (%)b 10 (45.5) 8 (66.7) 0 (0.0) 2 (28.6) 0.064
Using other medication, n (%) 10 (45.5) 4 (33.3) 0 (0.0) 6 (85.7) 0.020
 Etomidate, n (%) 8 (36.4) 3 (25.0) 0 (0.0) 5 (71.4) 0.047
 Metyrapone, n (%) 1 (4.5) 0 (0.0) 0 (0.0) 1 (14.3) 0.325
 Pasireotide, n (%) 1 (4.5) 1 (8.3) 0 (0.0) 0 (0.0) 0.646
Data are expressed as mean ± SD or number (percentage). 24-h UFC (reference range: 20–80 µg/day)
a
Alcohol consumption was defined as men consume more than two alcoholic equivalents per day, while women consume more than one alcoholic equivalent, with one alcoholic equivalent being 10 g of alcohol.
b
Surgery for pituitary tumor or ectopic lesions.
*
p-Value <0.05 from ANOVA, indicating at least one group differed significantly from the others.
24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; SD, standard deviation.
During fluconazole treatment, significant differences were observed among the three groups concerning the use of additional medications (p = 0.020). In the CD group, three patients (25%) received etomidate and one patient (8.3%) received pasireotide. No patients in the ACS group received other medications. In the EAS group, five patients (71.4%) received etomidate, and one patient (14.3%) received metyrapone. For patients treated with etomidate, the duration was limited to a few days before switching to fluconazole. One patient received concomitant therapy with pasireotide and fluconazole.
Table 2 presents the laboratory results for hormonal parameters and ALT levels before and after fluconazole treatment. Prior to treatment, there were no statistically significant differences among the three groups in terms of serum cortisol (8AM), ACTH (8AM), 24-h UFC, and ALT levels (p = 0.739, p = 0.239, p = 0.157, and p = 0.738, respectively).
Open in Viewer

Table 2. The laboratory exams of hormonal parameters and ALT before and after fluconazole treatment.
Variable All (n = 22) CD (n = 12) ACS (n = 3) EAS (n = 7) p-Value
Cortisol (8AM) before fluconazole (µg/dL) 18.3 ± 10.8 17.8 ± 11.6 14.8 ± 3.4 20.6 ± 12.1 0.739
ACTH (8AM) before fluconazole (pg/mL) 104.5 ± 122.2 101.9 ± 64.7 6.4 ± 0.9 150.7 ± 188.4 0.239
ACTH (8AM) after fluconazole treatment (pg/mL)a 75.7 ± 87.0 65.7 ± 44.3 6.8 ± 1.4 122.4 ± 133.4 0.020
24-h UFC before fluconazole (µg/day) 717.6 ± 1219.4 443.1 ± 391.5 139.2 ± 95.7 1436.0 ± 2000.0 0.157
24-h UFC after fluconazole (µg/day)b 184.1 ± 171.8 132.0 ± 117.3 53.3 ± 30.8 321.9 ± 198.8 0.017
Decline percentage (%) of 24-h UFC after fluconazole 39.2% ± 48.2% 50.2% ± 37.4% 55.8% ± 27.3% 13.1% ± 64.4% 0.228
Normalization of 24-h UFC after fluconazole, n (%) 6 (27.3) 4 (33.3) 2 (66.7) 0 (0.0) 0.074
24-h UFC <1.5× ULN after fluconazole, n (%) 10 (45.5) 6 (50.0) 3 (100.0) 1 (14.3) 0.040
ALT before fluconazole (U/L) 38.5 ± 28.4 42.4 ± 32.6 38.0 ± 14.1 30.8 ± 24.2 0.738
ALT after fluconazole (U/L)c 56.5 ± 47.8 76.7 ± 54.3 28.7 ± 12.7 28.8 ± 13.6 0.091
ALT >ULN after fluconazole, n (%)c 12 (54.5) 8 (66.7) 2 (66.7) 2 (28.6) 0.247
ALT >3× ULN after fluconazole, n (%)c 4 (18.2) 4 (33.3) 0 (0.0) 0 (0.0) 0.130
Data are expressed as mean ± SD or number (percentage). ALT (reference range: male: <41 U/L; female: <33 U/L). 24-h UFC (reference range: 20–80 µg/day).
a
The average of first and second ACTH after fluconazole treatment.
b
The average of first and second 24-h UFC after fluconazole treatment.
c
ALT: maximum in following 6 months.
1.
5×, 1.5 times upper limit of normal range; 3×, 3 times upper limit of normal range; 24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; CD, Cushing’s disease; EAS, ectopic ACTH syndrome; ULN, upper limit of normal range.
Twenty-four-hour UFC levels after fluconazole treatment were monitored over the following months. The average values of the first and second 24-h UFC measurements showed significant declines compared to baseline levels as: decreased from 717.6 ± 1219.4 to 184.1 ± 171.8 µg/day in all patients (p = 0.035), decreased form 443.1 ± 391.5 to 132.0 ± 117.3 µg/day in the CD group (p = 0.009), decreased from 139.2 ± 95.7 to 53.3 ± 30.8 µg/day in the ACS group (p = 0.243), and decreased from 1436.0 ± 2000.0 to 321.9 ± 198.8 µg/day in the EAS group (p = 0.147). The percentage decline in 24-h UFC levels following treatment demonstrated a significant reduction as follows: 39.2% ± 48.2% in all patients, 50.2% ± 37.4% in the CD group, 55.8% ± 27.3% in the ACS group, and 13.1% ± 64.4% in the EAS group (p = 0.228) (Table 2 and Figure 1 illustrate these changes).
Open in Viewer

Figure 1. 24-h UFC before and after fluconazole treatment in patients with Cushing’s syndrome.
24-h UFC, 24-hour urinary free cortisol; ACS, adrenal Cushing’s syndrome; CD, Cushing’s disease; EAS, ectopic ACTH syndrome.
Normalization of 24-h UFC levels (reference range 20–80 μg/day) was observed in six patients (27.3%) across three groups: four patients (33.3%) in the CD group, two patients (66.7%) in the ACS group, and no patients in the EAS group (p = 0.074). Additionally, 10 cases (45.5%) across 3 groups, 6 cases (50%) in the CD group, 3 cases (100%) in the ACS group, and 1 case (14.3%) in the EAS group showed 24-h UFC less than 1.5 times the ULN (p = 0.040). In this study, 10 patients (45.5%) received fluconazole treatment for more than 1 year. Among these, five patients (50.0%) experienced a recurrence of hypercortisolism, with 24-h UFC levels exceeding 1.5 times the ULN within 3–12 months after treatment with fluconazole.
For hepatic safety assessment, the maximum ALT levels within 6 months of fluconazole treatment were analyzed and are presented in Table 2. Compared to baseline levels, ALT increased from 38.5 ± 28.4 to 56.5 ± 47.8 U/L in all patients (p = 0.090), and increased from 42.4 ± 32.6 to 76.7 ± 54.3 U/L in the CD group (p = 0.047). (Table 2 and Figure 2 illustrate these changes). After fluconazole treatment, 12 cases (54.5%) of all patients, 8 cases (66.7%) in the CD group, 2 cases (66.7%) in the ACS group, and 2 cases (28.6%) in the EAS group revealed ALT levels exceeded the ULN (p = 0.247). Additionally, 4 cases (18.2%) of all patients, 4 cases (33.3%) in the CD group, and no cases in the ACS and EAS groups revealed ALT levels more than three times the ULN (p = 0.130).
Open in Viewer

Figure 2. ALT before and after fluconazole treatment in patients with Cushing’s syndrome.
ACS, adrenal Cushing’s syndrome; ALT, Alanine aminotransferase; CD, Cushing’s disease; EAS, ectopic ACTH syndrome.

Discussion

To date, our study is the largest retrospective analysis providing the evaluation of the clinical efficacy and safety of fluconazole treatment in patients with CS. The major findings demonstrated that 24-h UFC levels significantly decreased across all groups after fluconazole treatment, with more than 50% reduction in both the CD and ACS groups. However, the EAS group showed only a 13.1% decline in 24-h UFC levels, although with a large interval (SD 64.4%) and small case numbers in this group, indicating greater variability in response and heterogeneity in this group. Regarding hepatic safety, while ALT levels increased after fluconazole treatment, particularly in the CD group, the changes were not statistically significant in other groups. The significant increase in ALT levels (42.4 ± 32.6 to 76.7 ± 54.3 U/L) in the CD group, but mild—less than two times ULN, may also be related to the high variability (large SD). Importantly, there was no severe hepatotoxicity in the study, because only four patients (18.2%) revealed ALT levels more than three times the ULN.
Fluconazole can be administered either intravenously or orally. Several case reports highlight its effectiveness and safety: Teng Chai et al. reported successful long-term treatment of recurrent CD in a 50-year-old woman using fluconazole with cabergoline, resulting in significant clinical and biochemical improvement without adverse effects.27 Zhao et al. reported that fluconazole normalized cortisol levels pre-surgery in a 48-year-old woman with CD and pulmonary cryptococcal infection.28 In another case, fluconazole with low-dose metyrapone normalized cortisol levels for 6 months in a 61-year-old woman with recurrent CD prior to radiotherapy.29 Riedl et al. demonstrated fluconazole’s efficacy and safety in an 83-year-old woman with CS from adrenocortical carcinoma.18 Canteros et al. reported effective cortisol reduction with mild side effects from fluconazole in a 39-year-old woman with EAS, enabling successful bilateral adrenalectomy.30 An 80-year-old woman with CS of unknown origin also showed effective cortisol control with fluconazole.31 Two of these six cases suffered from hepatic dysfunction at fluconazole doses over 400 mg/day; however, liver enzyme levels returned to normal after dosage reduction. A secondary analysis of a dose-adjustment trial for fluconazole in the treatment of invasive mycoses examined 85 patients who received prolonged high-dose treatment. For these cases, 27% experienced clinical symptoms, and 42% exhibited abnormal laboratory results. The common side effects were <5% of anorexia, hair loss, headache, and 12% of eosinophilia. However, these adverse effects did not progress, leading the study to conclude that fluconazole is well tolerated and generally safe.32
Ketoconazole has been used to treat hypercortisolism by inhibiting CYP450 enzymes, specifically 11β-hydroxylase and 17α-hydroxylase, and fluconazole has similar properties.17 Previous studies suggest that fluconazole is less potent in inhibiting glucocorticoid production compared to ketoconazole, with varying effects; however, cortisol reduction with fluconazole use has been confirmed.17,18 Unlike ketoconazole, which is extensively metabolized in the liver and associated with significant hepatotoxicity, fluconazole is minimally metabolized in the liver.16 According to the FDA, the risk of serious liver injury from ketoconazole is higher than with other azole agents.33 In our study of 22 patients, fluconazole was well tolerated, with no significant elevations in liver enzyme levels observed during 6 months of treatment. These findings suggest that fluconazole may represent a safer alternative to ketoconazole for the treatment of CS.
In five studies involving 310 patients with CS treated with an average dose of 673.9 mg/day of ketoconazole over an average of 12.6 months, normalization of urinary free cortisol was achieved in 64.3% of patients (median 50%, range 44.7%–92.9%). However, 23% of initially responsive patients eventually lost biochemical control.34 Another retrospective study of 200 patients with CD receiving ketoconazole at an average dose of 600 mg/day found that 64.7% of patients treated for over 2 years achieved UFC normalization, while 15.4% experienced recurrence, or “escape,” from cortisol control.15 In our study, 10 patients (45.5%) received fluconazole treatment for over 1 year, with 5 of these patients (50%) showing 24-h UFC levels not exceeding 1.5 times the ULN in the following 3–12 months (under control without escape). The long-term control of hypercortisolism with fluconazole appears to be less effective than with ketoconazole. However, this could be attributed to the small sample size in our study.
Table 1 shows baseline morning ACTH levels at diagnosis for all patients before any treatment, highlighting a statistically significant difference. In comparison, Table 2 presents morning ACTH levels prior to fluconazole treatment, where no statistical difference was observed. This is likely due to some patients in the CD and EAS groups having previously undergone surgery or received other medical treatments, which might reduce the tumor burden and the levels of ACTH.
Recent studies suggest that levoketoconazole demonstrates good efficacy and safety in the management of CS.23–25 However, no head-to-head trials have been conducted to compare ketoconazole, levoketoconazole, and fluconazole directly. Therefore, further clinical trials are warranted to provide clearer insights into the comparative efficacy and safety of these therapeutic options in CS.
The limitations of this study include its retrospective design, which lacked comparator groups, and the small sample sizes in the ACS and EAS groups. In addition, patients were treated by different physicians, each using their own clinical judgment, without standardized follow-up protocols, making some data difficult to collect and analyze. The heterogeneity in dosing regimens also posed challenges in assessing the dose-response relationship. Besides, the relationship between the timing and dosages of other medications (etomidate, pasireotide, and metyrapone) and their effects on laboratory findings is challenging to analyze due to the limited number of cases. There were no statistically significant differences in ACTH level changes before and after fluconazole treatment among the three groups. This may be a limitation, as we only monitored the first and second ACTH measurements following fluconazole treatment. Further investigations with longer monitoring of ACTH levels may be necessary. The study’s observation period was approximately 5.5 years, but further investigation is required to confirm the long-term efficacy and safety of fluconazole treatment in CS.

Conclusion

This study demonstrates that fluconazole is effective in treating patients with CS, as evidenced by a significant reduction in 24-h UFC levels. Moreover, fluconazole was generally well tolerated, with a minimal risk of liver injury, suggesting it may be an effective and safe option for managing hypercortisolism in CS.

Acknowledgments

The authors thank the Medical Sciences & Technology Building of Taipei Veterans General Hospital for providing experimental space and facilities.

ORCID iD

Footnotes

Ethics approval and consent to participate This study was approved by the Institutional Review Board at Taipei Veterans General Hospital (IRB No. 2021-04-003CC). Due to the retrospective nature of this study, informed patient consent was waived.

Consent for publication Not applicable.

Author contributions

Tang-Yi Liao: Data curation; Formal analysis; Writing – original draft.
Yi-Chun Lin: Data curation; Writing – review & editing.
Chun-Jui Huang: Data curation; Writing – review & editing.
Chii-Min Hwu: Conceptualization; Data curation.
Liang-Yu Lin: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Writing – review & editing.
Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partly supported by research grants (Grant Nos. V108C-197, V109C-179, V110C-198, V111D62-002-MY3, V112C-183, V113C-094, V114C-116, and V114D77-002-MY3-1) to L.Y.L. from Taipei Veterans General Hospital, Taipei, Taiwan and MOST 111-2314-B-075-040-MY2 to L.Y.L. from National Science and Technology Council, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests The authors declare that there is no conflict of interest.

Availability of data and materials The data and materials generated and analyzed in the study are available from the corresponding author on reasonable request.

References

1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5): 1526–1540.
2. Clayton RN, Raskauskiene D, Reulen RC, et al. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96(3): 632–642.
3. Lindholm J, Juul S, Jørgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001; 86(1): 117–123.
4. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93(7): 2454–2462.
5. Castinetti F, Nagai M, Morange I, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab 2009; 94(9): 3400–3407.
6. Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 2011; 96(7): 1992–2003.
7. Porterfield JR, Thompson GB, Young WF Jr, et al. Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 2008; 32(5): 659–677.
8. Findling JW, Raff H. Cushing’s Syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006; 91(10): 3746–3753.
9. Assié G, Bahurel H, Coste J, et al. Corticotroph tumor progression after adrenalectomy in Cushing’s disease: a reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab 2007; 92(1): 172–179.
10. Schteingart DE. Drugs in the medical treatment of Cushing’s syndrome. Expert Opin Emerg Drugs 2009; 14(4): 661–671.
11. Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002; 5(2): 77–82.
12. Valassi E, Franz H, Brue T, et al. Preoperative medical treatment in Cushing’s syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN. Eur J Endocrinol 2018; 178(4): 399–409.
13. Varlamov EV, Vila G, Fleseriu M. Perioperative management of a patient with Cushing Disease. J Endocr Soc 2022; 6(3): bvac010.
14. Pivonello R, De Martino MC, De Leo M, et al. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37(1): 135–ix.
15. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 2014; 99(5): 1623–1630.
16. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994; 330(4): 263–272.
17. van der Pas R, Hofland LJ, Hofland J, et al. Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol 2012; 215(3): 403–412.
18. Riedl M, Maier C, Zettinig G, et al. Long term control of hypercortisolism with fluconazole: case report and in vitro studies. Eur J Endocrinol 2006; 154(4): 519–524.
19. Albert SG, DeLeon MJ, Silverberg AB. Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients. Crit Care Med 2001; 29(3): 668–670.
20. Santhana Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J 2006; 82(971): e23.
21. García Rodríguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48(6): 847–852.
22. Creemers SG, Feelders RA, De Jong FH, et al. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, a new steroidogenesis inhibitor for Cushing’s syndrome treatment. J Clin Endocrinol Metabol 2021; 106: 1618–1630.
23. Fleseriu M, Pivonello R, Elenkova A, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabet Endocrinol 2019; 7: 855–865.
24. Pivonello R, Zacharieva S, Elenkova A, et al. Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 2022; 25: 911–926.
25. Patra S, Dutta D, Nagendra L, et al. Efficacy and safety of levoketoconazole in managing Cushing’s syndrome: a systematic review. Indian J Endocr Metab 2024; 28: 343–349.
26. Sharma ST; AACE Adrenal Scientific Committee. An individualized approach to the evaluation of Cushing Syndrome. Endocr Pract 2017; 23(6): 726–737.
27. Teng Chai S, Haydar Ali Tajuddin A, Wahab NA, et al. Fluconazole as a safe and effective alternative to ketoconazole in controlling hypercortisolism of recurrent Cushing’s disease: a case report. Int J Endocrinol Metab 2018; 16(3): e65233.
28. Zhao Y, Liang W, Cai F, et al. Fluconazole for hypercortisolism in Cushing’s disease: a case report and literature review. Front Endocrinol (Lausanne) 2020; 11: 608886.
29. Burns K, Christie-David D, Gunton JE. Fluconazole in the treatment of Cushing’s disease. Endocrinol Diabetes Metab Case Rep 2016; 2016: 150115.
30. Canteros TM, De Miguel V, Fainstein-Day P. Fluconazole treatment in severe ectopic Cushing syndrome. Endocrinol Diabetes Metab Case Rep 2019; 2019(1): 19-0020.
31. Schwetz V, Aberer F, Stiegler C, et al. Fluconazole and acetazolamide in the treatment of ectopic Cushing’s syndrome with severe metabolic alkalosis. Endocrinol Diabetes Metab Case Rep 2015; 2015:1 50027.
32. Stevens DA, Diaz M, Negroni R, et al. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group. Chemotherapy 1997;43(5):371–377.
33. Greenblatt HK, Greenblatt DJ. Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol 2014; 54(12): 1321–1329.
34. Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing’s disease. Endocr Rev 2015; 36(4): 385–486.

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

Crinetics Pharma’s Promising Study on CRN04894 for Cushing’s Syndrome: A Potential Game-Changer?

Posted on November 1, 2025 by MaryO

Crinetics Pharmaceuticals is conducting a study titled ‘A Phase 1b/2a Open-label Multiple-ascending Dose Exploratory Study of CRN04894 in ACTH-dependent Cushing’s Syndrome.’ This study aims to evaluate the safety, tolerability, and pharmacokinetics of CRN04894, an ACTH receptor antagonist, in treating Cushing’s Syndrome, a condition characterized by excessive cortisol production. The study’s significance lies in its potential to offer a new treatment avenue for patients with Cushing’s disease or Ectopic ACTH Syndrome.

The intervention being tested is a drug named atumelnant, which is an orally active agent designed to block the action of ACTH at its receptor. This intervention is administered in tablet form and is intended to manage the symptoms of ACTH-dependent Cushing’s Syndrome.

The study employs an interventional design with a sequential model, featuring multiple ascending doses over 10 to 14 days. It is open-label, meaning there is no masking, and its primary purpose is treatment-focused, aiming to assess the drug’s effects on participants.

The study began on March 27, 2023, and is currently recruiting participants. The last update was submitted on April 8, 2025. These dates are crucial as they indicate the study’s progress and ongoing nature, which is essential for stakeholders tracking its development.

This clinical update could influence Crinetics Pharma’s stock performance positively by showcasing their commitment to advancing treatment options for Cushing’s Syndrome. Investors may view this as a promising development, potentially enhancing market sentiment. The study’s progress should be monitored alongside competitors in the endocrinology space to gauge its broader industry impact.

https://www.tipranks.com/news/company-announcements/crinetics-pharmas-promising-study-on-crn04894-for-cushings-syndrome-a-potential-game-changer

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

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.

Open in new tabDownload slide

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.

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

« Previous Page — Next Page »