FDA Declines to Approve Relacorilant for Hypertension Linked to Hypercortisolism

Posted on January 6, 2026 by MaryO

Key takeaways:

  • The FDA issued a complete response letter for relacorilant to treat hypertension tied to hypercortisolism.
  • The investigational drug induced BP reductions for adults with hypertension in the phase 3 GRACE trial.

The FDA has issued a complete response letter for an oral selective glucocorticoid receptor antagonist under investigation for the treatment of hypertension secondary to hypercortisolism, according to an industry press release.

Corcept Therapeutics announced the FDA issued a complete response letter for relacorilant (Corcept Therapeutics). The drug is under investigation for the treatment of endogenous hypercortisolism, ovarian cancer and other disorders, according to the company.

As Healio previously reported, the phase 3 GRACE trial enrolled 152 adults with Cushing’s syndrome plus hypertension, hyperglycemia or both conditions. Participants received relacorilant for 22 weeks during an open-label phase. At 22 weeks, adults who met criteria for hypertension or hyperglycemia control entered a withdrawal phase where they were randomly assigned, 1:1, to continue relacorilant or switch to placebo for 12 weeks.

In the GRACE trial, adults with hypertension had a 7.9 mm Hg decrease in systolic blood pressure and a 5.1 mm Hg decline in diastolic BP at 22 weeks. During the randomized withdrawal phase, adults who remained on relacorilant had no change in systolic and diastolic BP, whereas those receiving placebo had a BP increase from the start of the phase to week 12.

In a press release from Corcept Therapeutics from 2024, the company announced results from the phase 3 GRADIENT trial, a randomized, double-blind, placebo-controlled trial where adults with Cushing’s syndrome caused by an adrenal adenoma or adrenal hyperplasia were randomly assigned, 1:1, to relacorilant or placebo for 22 weeks. According to the press release, the relacorilant group had a 6.6 mm Hg decline in mean systolic BP compared with baseline at 22 weeks. However, there was no significant difference in mean systolic BP change between the relacorilant and placebo groups.

As Healio previously reported, relacorilant was also assessed in a long-term extension study that enrolled adults who completed the GRACE and GRADIENT trials as well as a phase 2 hypercortisolism study. In that trial, relacorilant conferred a 10 mm Hg drop in 24-hour ambulatory systolic BP and a 7.3 mm Hg reduction in 24-hour ambulatory diastolic BP at 24 months.

In the company’s press release announcing receipt of the complete response letter, Corcept Therapeutics said the FDA acknowledged that the GRACE trial met its primary endpoint and that the GRADIENT trial provided “confirmatory evidence.” However, the FDA said it did not view relacorilant offered “a favorable benefit-risk assessment” without more data of its effectiveness, according to the press release.

“We are surprised and disappointed by this outcome,” Joseph K. Belanoff, MD, CEO of Corcept Therapeutics, said in a press release. “Our commitment to patients suffering from the effects of hypercortisolism is unwavering. I am confident we will find a way to get relacorilant to the patients it could help. We will meet with the FDA as soon as possible to discuss the best path forward.”

https://www.healio.com/news/endocrinology/20251231/fda-declines-to-approve-relacorilant-for-hypertension-linked-to-hypercortisolism?utm_source=selligent&utm_medium=email&utm_campaign=20251231ENDO&utm_content=20251231ENDO

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Genetic mutation lowers obesity in Cushing’s syndrome

Posted on January 5, 2026 by MaryO

London E. J Clin Endocrinol Metab. 2013; doi:10.1210/jc.2013-1956.

Among adult patients with Cushing’s syndrome, those with mutations in PRKAR1A, the gene that controls cAMP-dependent protein kinase, are less obese than their counterparts without these mutations, according to a recent study.

The retrospective study evaluated adrenalectomy samples from 51 patients with Cushing’s syndrome, 13 with PRKAR1A mutations and 32 without. Of the 51 patients, 40 were female and 11 were male, and patients ranged in age from 4 to 74 years.

A non-Cushing’s syndrome comparison group consisting of 6 adrenalectomy patients with aldosterone producing adenomas (APAs) was included. Additional comparison groups comprising clinical data from 89 patients with Cushing’s disease and 26 with hyperaldosteronism were also studied.

Researchers recorded the weight, height and BMI of all patients, and measured abdominal subcutaneous adipose tissue (ScAT) and periadrenal adipose tissue (PAT) using computed tomography. PAT was collected and frozen for evaluation; the extracts were assessed for levels of cAMP and protein kinase (PKA) activity, as well as for protein and mRNA expression of subunits of PKA. Diurnal cortisol levels and urine-free cortisol were also measured preoperatively.

The study found that in adults with Cushing’s syndrome, the mean BMI of those with PRKAR1A mutations was lower than that of patients with noPRKAR1A mutations (P<.05), and was not inconsistent with the hyperaldosteronism comparison group.

In pediatric patients with adrenal Cushing’s syndrome, the presence of PRKAR1A mutation did not have an impact on mean BMI z-scores. However, in comparison with pediatric patients with pituitary Cushing’s disease, the BMI z-scores were significantly lower in pediatric Cushing’s disease patients with PRKAR1Amutations (P<.05). Patients with Cushing’s syndrome without PRKAR1A mutations had significantly more PAT and ScAT than non-Cushing’s syndrome patients. Additionally, the ratio of basal-to-total (cAMP-triggered) PKA activity was significantly lower in patients with PRKAR1A mutations, suggesting greater proportions of active PKA (P<.005).

“These findings have obvious implications in the establishment of the diagnosis of CS in patients with PRKAR1A mutations: These patients may be leaner than other patients with [Cushing’s syndrome],” the study authors wrote. “Perhaps more importantly, our findings point to the importance of cAMP and or PKA signaling in the regulation of adiposity.”

Disclosures: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B693f94cd-359d-4c52-8e0d-bfd0e4a51d03%7D/genetic-mutation-lowers-obesity-in-cushings-syndrome

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A Second Look at Refractory Edema: Delayed Diagnosis of Paraneoplastic Cushing’s Syndrome in Small Cell Lung Cancer

Posted on January 4, 2026 by MaryO

Abstract

Paraneoplastic Cushing syndrome (PCS) is a rare manifestation of ectopic adrenocorticotropic hormone (ACTH) production, mostly associated with bronchial carcinoid and small cell lung cancer (SCLC). Its clinical manifestations: refractory hypertension, profound hypokalemia, metabolic alkalosis, worsening hyperglycemia, and edema, can easily be misattributed to more common conditions, especially in older adults with multiple comorbidities, leading to diagnostic errors.

We present a case of an 84-year-old man with a history of stage IA non-SCLC treated one year earlier, who developed progressive dyspnea, orthopnea, bilateral extremity edema, severe hypokalemia, metabolic alkalosis, and new-onset hypertension. His symptoms were initially managed as volume overload and diuretic-resistant heart failure in the outpatient setting. During hospitalization, persistent metabolic alkalosis, worsening hyperglycemia, resistant hypertension, and refractory hypokalemia prompted further evaluation. Laboratory studies demonstrated markedly elevated early morning cortisol (102.7 µg/dL) and ACTH (293 pg/mL). Computed tomography (CT) imaging revealed a new right infrahilar mass, extensive mediastinal adenopathy, and bilateral adrenal metastases. Endobronchial ultrasound-guided biopsy confirmed SCLC. The patient was diagnosed with paraneoplastic ACTH-dependent CS and initiated on systemic chemotherapy.

This case highlights several diagnostic vulnerabilities, including anchoring bias, confirmation bias, premature closure, and failure to integrate multiple abnormal findings into a unifying diagnosis. Earlier recognition of the characteristic cluster of hypercortisolism signs-refractory hypokalemia, metabolic alkalosis, resistant hypertension, and hyperglycemia- may have accelerated diagnosis and treatment. Clinicians should maintain a high index of suspicion for PCS in older adults with a history of lung cancer who present with unexplained electrolyte disturbances and rapidly worsening cardiometabolic parameters. Early diagnosis is critical given the high morbidity and mortality associated with untreated paraneoplastic Cushing’s syndrome.

Introduction

Paraneoplastic ACTH-dependent Cushing syndrome (CS) is an uncommon but severe manifestation of ectopic adrenocorticotropic hormone production. Ectopic ACTH syndrome accounts for approximately 6-10% of all cases of endogenous CS [1]. This represents 10-20% of ACTH-dependent forms of Cushing syndrome, which themselves comprise 70-80% of all endogenous CS cases. Lung neuroendocrine tumors account for approximately 25% of cases, followed by small cell lung cancers (SCLC) (20%), with other sources being neuroendocrine tumors of the thymus, pancreas, and medullary thyroid carcinoma [2,3]. Patients typically present with symptoms related to underlying malignancy and rapid onset of severe hypercortisolism characterized by profound hypokalemia, metabolic alkalosis, hyperglycemia, and muscle weakness, often without the classic cushingoid features seen in other forms of CS [4,5].

These abnormalities are often initially attributed to more common conditions, including heart failure, diuretic use, thyroid disease, and worsening chronic diseases such as diabetes mellitus, especially in older adults with multimorbidity. This often leads to diagnostic errors. Diagnostic delays in paraneoplastic Cushing syndrome (PCS) are common and clinically meaningful. Hypercortisolism accelerates tumor progression, increases vulnerability to infection, worsens cardiometabolic dysfunction, and contributes to poor performance status, substantially limiting therapeutic options [6-8]. Prompt recognition requires clinicians to identify the hallmark constellation of metabolic disturbances and consider endocrine etiologies early.

We describe an older adult who presented with cough, dyspnea, edema, severe resistant hypertension, metabolic alkalosis, and electrolyte derangements that were initially attributed to volume overload and chronic lung disease. The diagnostic process ultimately led to the identification of extensive-stage SCLC, which caused ectopic ACTH production. We emphasize the diagnostic errors that contributed to the delayed recognition of this life-threatening syndrome.

Case Presentation

An 84-year-old man with a history of pre-diabetes, chronic obstructive pulmonary disease (COPD), a former smoker, and previously treated stage IA non-SCLC (left lower lobe, treated with Stereotactic Body Radiation Therapy) presented with cough, progressive shortness of breath, orthopnea, and bilateral lower extremity edema. Two weeks prior, outpatient clinicians treated his worsening edema and dyspnea with loop diuretics, and he was also started on nifedipine and losartan for hypertension.

In the emergency department, vital signs revealed blood pressure 216/98 mmHg, heart rate 104 beats/min, and respiratory rate 23 breaths/min. Physical examination demonstrated bilateral pedal edema extending to the mid-shins and bilateral upper extremity edema. Lung examination revealed no wheezing or crackles. The abdomen was obese but without palpable masses.

Initial laboratory evaluation showed mild thrombocytopenia (114 × 103/µL), creatinine 1.10 mg/dL, potassium 2.9 mmol/L, bicarbonate 43 mmol/L, chloride 88 mmol/L, glucose 240 mg/dL, unremarkable liver function test, and elevated B-type natriuretic peptide (BNP) of 198 pg/mL. Arterial blood gas demonstrated pH 7.58 and PaCO₂ 42 mmHg, indicating primary metabolic alkalosis. Urinalysis was significant for glucosuria, otherwise unremarkable. Chest X-ray showed bibasilar atelectasis without evidence of pulmonary edema. He was admitted for decompensated heart failure. Pertinent admission laboratory findings are summarized in Table 1.

Test Result Range
Hemoglobin 16.4 g/dL 13.8-17.2 g/dL
White cell count 9.7 × 103/µL 4.0-10.50 × 103/µL
Platelet 114 × 103/µL 130-400 × 103/µL
Sodium 142 mmol/L 133-145 mmol/L
Potassium 2.9 mmol/L 3.3-5.1 mmol/L
Chloride 88 mmol/L 98-108 mmol/L
Bicarbonate 43 mmol/L 22-32 mmol/L
Creatinine 1.10 mg/dL 0.50-1.20 mg/dL
BNP 198.8 pg/mL 10.0-100.0 pg/mL
Albumin 3.7 g/dL 3.0-5.0 g/dL
Glucose 240 mg/dL 70-100 mg/dL
Serum cortisol 102.7 µg/dL 6.7-22.6 µg/dL
Plasma ACTH 293 pg/mL 6-50 pg/mL
Urine chloride 73 mmol/L
Urine potassium 38 mmol/L
Table 1: Summary of relevant laboratory findings at presentation

Metabolic alkalosis, renal potassium wasting, hyperglycemia, elevated cortisol, and ACTH suggested an ACTH-dependent Cushing’s syndrome.

BNPL: brain natriuretic peptide; ACTH: adrenocorticotropic hormone

Despite diuresis with IV furosemide, he continued to demonstrate metabolic alkalosis and worsening hypokalemia (nadir 2.8 mmol/L), requiring repeated potassium supplementation. Hyperglycemia persisted with capillary blood glucose 170-300 mg/dL, requiring escalating insulin doses. Blood pressures remained elevated despite escalation of losartan and nifedipine. Echocardiogram on day 2 of admission was unremarkable with an ejection fraction of 55-60% and normal diastolic function. Doppler ultrasound of the lower and upper extremities did not reveal deep vein thrombosis.

On hospital day 3, diagnosis was reassessed, and differentials were broadened to include endocrine causes of hypertension with metabolic alkalosis. Urine electrolytes revealed high urine chloride (73 mmol/L) and potassium (38 mmol/L), suggestive of potassium wasting from possible mineralocorticoid excess. Subsequent testing revealed markedly elevated serum cortisol (102.7 µg/dL) and plasma ACTH (293 pg/mL), suggesting an ACTH-dependent process. Given his significant history of smoking and treated NSCLC, a CT chest/abdomen/pelvis was done, which showed a new right infrahilar mass, mediastinal lymphadenopathy, and nodular fullness of both adrenal glands concerning for metastatic disease (Figures 1–6).

Axial-CT-chest-showing-an-enlarged-right-paratracheal-lymph-node.
Figure 1: Axial CT chest showing an enlarged right paratracheal lymph node.

Axial image demonstrates a right paratracheal lymph node measuring 14.8 mm in short axis, concerning for malignant nodal involvement.

Non-contrast-axial-CT-chest-showing-a-dominant-right-paratracheal-lymph-node
Figure 2: Non-contrast axial CT chest showing a dominant right paratracheal lymph node

A right paratracheal lymph node measuring 16.2 × 16.5 mm is demonstrated, further supporting malignant mediastinal involvement in small cell lung cancer.

Axial-non-contrast-CT-chest-demonstrating-residual-treated-left-lower-lobe-lesion
Figure 3: Axial non-contrast CT chest demonstrating residual treated left lower lobe lesion

A spiculated nodule in the left lower lobe measuring 9.2 mm (AP) × 8.5 mm (transverse) on image 60, slightly decreased from the prior measurement of 9.3 × 10.6 mm, corresponding to the site of previously treated squamous cell carcinoma.

Axial-non-contrast-CT-chest-showing-markedly-enlarged-subcarinal-lymph-node
Figure 4: Axial non-contrast CT chest showing markedly enlarged subcarinal lymph node

A dominant subcarinal lymph node measuring 24 × 34 mm, highly suspicious for malignant mediastinal involvement.

Axial-non-contrast-CT-chest-showing-right-infrahilar-mass-like-fullness
Figure 5: Axial non-contrast CT chest showing right infrahilar mass-like fullness

Soft tissue density in the right lower lobe infrahilar region measuring up to 25 mm in transverse diameter, concerning for primary malignant involvement.

Non-contrast-CT-demonstrating-bilateral-adrenal-metastases
Figure 6: Non-contrast CT demonstrating bilateral adrenal metastases

Nodular enlargement of both adrenal glands has progressed compared with prior imaging: the left adrenal lateral limb measures 14 mm (previously 9.2 mm) and the right adrenal body measures 12.4 mm (previously 7 mm). Multiple benign hepatic cysts are also visualized (red arrows).

Bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration of the subcarinal (station 7) and right hilar (station 10R) lymph nodes revealed small cell carcinoma. He was diagnosed with extensive-stage SCLC with adrenal metastases and paraneoplastic ACTH-dependent Cushing syndrome. Systemic chemotherapy with carboplatin, etoposide, and atezolizumab was initiated.

Discussion

PCS caused by ectopic ACTH secretion is associated with significantly higher morbidity and mortality than other forms of hypercortisolism. Patients experience universal acute complications and have markedly shortened survival, with median survival reported as low as 3-4 months in those with SCLC [7-9]. Early mortality is common, with most deaths occurring within weeks to months of diagnosis and frequently driven by opportunistic infections, thromboembolic events, and severe metabolic derangements [6,7]. Hypercortisolism itself impairs the ability to deliver effective cancer therapy, increasing the risk of treatment-related complications and reducing chemotherapy response rates [6]. Ectopic ACTH production is therefore considered the most lethal etiology of Cushing syndrome, with tumor progression and infection being the predominant causes of death.

Diagnostic error is the failure to establish an accurate and timely explanation of the patient’s health problem(s) or communicate that explanation to the patient [10]. Diagnostic errors remain a significant contributor to patient harm, with estimates suggesting they affect 5-25% of patients [11,12]. These errors often arise not from knowledge deficits but from cognitive heuristics that clinicians rely on to navigate diagnostic uncertainty. While heuristics are essential for efficiency, they can predispose clinicians to systematic errors, especially when used uncritically or in complex cases [13,14]. Three cognitive pitfalls are particularly relevant in diagnostic error: anchoring bias (fixating early on a diagnosis and failing to adjust as new data emerge), premature closure (ceasing further diagnostic inquiry once an initial label is applied), and diagnostic momentum (the inertia created as more clinicians accept and act upon an early diagnostic impression) [15,16]. These processes can perpetuate incorrect diagnoses and delay definitive care.

For our patient, the initial clinical presentation of dyspnea, orthopnea, bilateral edema, and markedly elevated blood pressure in this older adult reasonably prompted consideration of several common cardiopulmonary and renal conditions. Acute decompensated heart failure was an early working diagnosis given his orthopnea, lower extremity edema, and elevated BNP. However, this diagnosis became less convincing as objective data accumulated. The patient had no pulmonary edema on chest imaging and preserved left ventricular systolic and diastolic function on echocardiography. Additionally, the severity of metabolic alkalosis and hypokalemia was disproportionate to the degree of diuretic exposure and volume status. These discrepancies argued against heart failure as a unifying diagnosis.

A COPD exacerbation was also considered due to the patient’s chronic lung disease and dyspnea. Yet he had no wheezing, no infectious symptoms, and no significant gas-exchange abnormality. His arterial blood gas (ABG) demonstrated metabolic alkalosis without primary respiratory acidosis. Moreover, his dyspnea improved early in the hospitalization, while the metabolic disturbances worsened, further making COPD a less likely diagnostic consideration. Renal causes of edema and hypertension, including nephrotic syndrome and intrinsic kidney disease, were evaluated. The patient had normal albumin and creatinine, and no significant proteinuria or hematuria on urinalysis, findings that could not explain his systemic edema. Similarly, acute or chronic kidney disease could not account for the combination of profound hypokalemia, metabolic alkalosis, and high urine chloride, which instead suggested an active mineralocorticoid process with renal wasting.

Primary hyperaldosteronism was a strong possibility, particularly given the combination of hypertension, hypokalemia, and metabolic alkalosis. However, the patient’s severe hyperglycemia, thrombocytopenia, new constitutional swelling of the upper extremities, and rapid symptom evolution were atypical for isolated hyperaldosteronism. Additionally, bilateral adrenal fullness seen on CT imaging was more consistent with adrenal metastases than with aldosterone-producing adenomas or hyperplasia. The degree of metabolic derangements also exceeded that typically observed in primary hyperaldosteronism, prompting evaluation for cortisol excess.

CS emerged as a unifying explanation for the multisystem abnormalities. The biochemical pattern, including severe metabolic alkalosis, renal potassium wasting, hyperglycemia, and resistant hypertension, is characteristic of activation of glucocorticoid and mineralocorticoid receptors. Markedly elevated cortisol and ACTH levels confirmed ACTH-dependent hypercortisolism. In older adults, pituitary Cushing disease typically evolves more slowly and is rarely associated with such profound hypokalemia [17,18]. Therefore, ectopic ACTH secretion became the leading diagnosis. The patient’s imaging, showing a new right infrahilar mass, progressive mediastinal lymphadenopathy, and bilateral adrenal enlargement, provided a clear source, later confirmed as extensive-stage SCLC.

This diagnostic trajectory illustrates how complex presentations can lead clinicians toward more common conditions, even when early clues point elsewhere. Several cognitive and system-level factors contributed to the delayed recognition of hypercortisolism. Anchoring on heart failure, a condition that fit parts of the patient’s presentation, discouraged re-examination of the initial differential when laboratory data did not fully align. Metabolic abnormalities were at first treated as isolated issues rather than components of a broader endocrine disorder. The patient’s prior non-SCLC had been in remission, which may have reduced the perceived likelihood of malignancy-related pathology, despite the well-known risk of second primary lung cancers and transformation events in older adults with smoking histories. Older adults with a history of smoking who have survived cancer face a substantially elevated risk of developing second primary lung cancers, with the risk persisting for decades after smoking cessation. Among lung cancer survivors, the 10-year cumulative incidence of a second primary lung cancer is approximately 8-15%, which is considerably higher than rates observed in general lung cancer screening populations [19,20].

The availability of more familiar explanations for dyspnea, edema, and hypertension, such as heart failure, may have overshadowed the classical biochemical signature of hypercortisolism. Recognition of ectopic ACTH production requires integrating disparate clinical findings into one physiological pathway. When evaluated collectively rather than individually, these abnormalities strongly suggest cortisol excess long before imaging or biopsy results are available.

Earlier consideration of endocrine etiologies could have expedited diagnosis, reduced unnecessary diuresis, and allowed earlier initiation of appropriate oncologic therapy. PCS from SCLC is associated with rapid clinical decline, impaired immunity, and decreased tolerance to chemotherapy. Prompt recognition may therefore improve both morbidity and the feasibility of cancer-directed treatment. This case reinforces the importance of revisiting and broadening the differential diagnoses when expected clinical improvement does not occur, particularly in older adults with prior malignancy and new multisystem derangements. Incorporating metacognitive strategies, actively questioning initial assumptions, seeking disconfirming evidence, and engaging in reflective practice can mitigate such errors [13].

Conclusions

This case emphasizes the importance of considering paraneoplastic ACTH-dependent CS in older adults presenting with unexplained hypokalemia, metabolic alkalosis, hyperglycemia, and resistant hypertension, particularly in patients with a history of lung cancer. Diagnostic error arose from anchoring on cardiopulmonary etiologies and failure to synthesize metabolic abnormalities into a unifying diagnosis. Early recognition of hypercortisolism is essential, as untreated ectopic ACTH production rapidly worsens morbidity and limits therapeutic efficacy in SCLC.

References

  1. Reincke M, Fleseriu M: Cushing syndrome: A review. JAMA. 2023, 330:170-81.
  2. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M: Cushing’s syndrome. Lancet. 2023, 402:2237-52. 10.1016/S0140-6736(23)01961-X
  3. Pelosof LC, Gerber DE: Paraneoplastic syndromes: An approach to diagnosis and treatment. Mayo Clin Proc. 2010, 85:838-54. 10.4065/mcp.2010.0099
  4. Haugen BR, Alexander EK, Bible KC, et al.: 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016, 26:2016. 10.1089/thy.2015.0020
  5. NCCN Guidelines Version 2.2026 Small – Google Scholar [Internet]. (2025). Accessed: October 7, 2025: https://scholar.google.com/scholar.
  6. Ost DE, Jim Yeung SC, Tanoue LT, Gould MK: Clinical and organizational factors in the initial evaluation of patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013, 143:e121S-41S. 10.1378/chest.12-2352
  7. Schernthaner-Reiter MH, Siess C, Micko A, et al.: Acute and life-threatening complications in Cushing syndrome: Prevalence, predictors, and mortality. J Clin Endocrinol Metab. 2021, 106:e2035-46. 10.1210/clinem/dgab058
  8. Shepherd FA, Laskey J, Evans WK, Goss PE, Johansen E, Khamsi F: Cushing’s syndrome associated with ectopic corticotropin production and small-cell lung cancer. J Clin Oncol. 1992, 10:21-7. 10.1200/JCO.1992.10.1.21
  9. Al-Toubah T, Pelle E, Hallanger-Johnson J, Haider M, Strosberg J: ACTH-secreting pancreatic neuroendocrine neoplasms: A case-series. J Neuroendocrinol. 2023, 35:e13336. 10.1111/jne.13336
  10. Measure Dx: A Resource To Identify, Analyze, and Learn From Diagnostic Safety Events. (2022). Accessed: October 7, 2025: https://www.ahrq.gov/diagnostic-safety/tools/measure-dx.html.
  11. Singh H, Meyer AN, Thomas EJ: The frequency of diagnostic errors in outpatient care: Estimations from three large observational studies involving US adult populations. BMJ Qual Saf. 2014, 23:727-31. 10.1136/bmjqs-2013-002627
  12. Auerbach AD, Lee TM, Hubbard CC, et al.: Diagnostic errors in hospitalized adults who died or were transferred to intensive care. JAMA Intern Med. 2024, 184:164-73.
  13. Croskerry P: The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003, 78:775-80. 10.1097/00001888-200308000-00003
  14. Gigerenzer G, Gaissmaier W: Heuristic decision making. Annu Rev Psychol. 2011, 62:451-82. 10.1146/annurev-psych-120709-145346
  15. Watari T, Tokuda Y, Amano Y, Onigata K, Kanda H: Cognitive bias and diagnostic errors among physicians in Japan: A self-reflection survey. Int J Environ Res Public Health. 2022, 19:4645. 10.3390/ijerph19084645
  16. Ogdie AR, Reilly JB, Pang WG, Keddem S, Barg FK, Von Feldt JM, Myers JS: Seen through their eyes: Residents’ reflections on the cognitive and contextual components of diagnostic errors in medicine. Acad Med. 2012, 87:1361-7. 10.1097/ACM.0b013e31826742c9
  17. Paleń-Tytko JE, Przybylik-Mazurek EM, Rzepka EJ, Pach DM, Sowa-Staszczak AS, Gilis-Januszewska A, Hubalewska-Dydejczyk AB: Ectopic ACTH syndrome of different origin-Diagnostic approach and clinical outcome. Experience of one Clinical Centre. PLoS One. 2020, 15:e0242679. 10.1371/journal.pone.0242679
  18. Melmed S: Pituitary-tumor endocrinopathies. N Engl J Med. 2020, 382:937-50. 10.1056/NEJMra1810772
  19. Adams SJ, Stone E, Baldwin DR, Vliegenthart R, Lee P, Fintelmann FJ: Lung cancer screening. Lancet. 2023, 401:390-408. 10.1016/S0140-6736(22)01694-4
  20. Takemura C, Yoshida T, Yoshida Y, et al.: Unveiling the molecular and clinical risk landscape of second primary lung cancer in resected non-small cell lung cancer. Lung Cancer. 2025, 208:108750. 10.1016/j.lungcan.2025.108750

https://www.cureus.com/articles/448285-a-second-look-at-refractory-edema-delayed-diagnosis-of-paraneoplastic-cushings-syndrome-in-small-cell-lung-cancer#!/

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The Effect of Hypercortisolism Treatment on Dyslipidemia in Cushing Syndrome

Posted on January 2, 2026 by MaryO

Abstract

Introduction

Cushing syndrome (CS) is a clinical condition caused by increased plasma cortisol levels and characterized by high cardiovascular mortality. Among the metabolic effects of CS and its treatment, glycaemic disturbances have been investigated in depth, while data on dyslipidemia is still lacking.

Objectives

Our study aims at evaluating the effects of CS treatment on serum lipid levels.

Materials and methods

A literature search was conducted using PubMed, Scopus, and EMBASE databases to investigate the effects of CS treatment on serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG). Before-after analysis and subgroup analysis were performed.

Results

Twenty-nine observational or interventional studies (51.7% of good quality) were included in the quantitative analysis. Treatment of CS led to clinically and statistically significant decrease in serum TC (MD -26.49; 95% CI: -29.95, -23.04; p < 0.00001), LDL-c (MD -18.44; 95% CI: -21.30, -15.57; p < 0.00001), and TG levels (MD -17.77; 95% CI: -22.70, -12.84; p < 0.00001), with no significant changes in HDL-c levels (MD -2.34; 95% CI: -6.96, 2.28; p= 0.32). Subgroup analysis showed greater decrease in TC levels in subjects with adrenal hypercortisolism, in those treated with steroidogenesis inhibitors and in those with treatment duration equal or longer than 12 months. In addition, CS treatment significantly decreased blood glucose (BG) levels, body mass index (BMI), waist circumference (WC), and insulin resistance index.

Conclusion

Our study demonstrate a significant improvement in serum lipid levels after treatment of CS. Since the cardiovascular complications of hypercortisolism depend on several factors, further studies are needed to determine whether this directly translates into an adequate reduction in the risk of major cardiovascular events.

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On Becoming Empowered

Posted on January 1, 2026 by MaryO

This is kind of a “cheat” post since it’s a compilation of other posts, web pages, message board posts and some original thoughts.  

For all of my early life, I was the good, compliant, patient.  I took whatever pills the doctor prescribed, did whatever tests h/she (most always a he) wrote for.  Believed that whatever he said was the absolute truth.  He had been to med school.  He knew what was wrong with me even though he didn’t live in my body 24/7 and experience what I did.

I know a lot of people are still like this.  Their doctor is like a god to them.  He can do no wrong – even if they don’t feel any better after treatment, even if they feel worse.  “But the doctor said…”

Anyway, I digress.

All this changed for me in 1983.

At first I noticed I’d stopped having my periods and, of course, I thought I was pregnant. I went to my Gynecologist who had no explanation. Lots of women lose their periods for a variety of reasons so no one thought that this was really significant.

Then I got really tired, overly tired. I would take my son to a half hour Choir rehearsal and could not stay awake for the whole time. I would lie down in the back of the van, set an alarm and sleep for the 30 minutes.

A whole raft of other symptoms started appearing – I grew a beard (Hirsuitism), gained weight even though I was on Weight Watchers and working out at the gym nearly every day, lost my period, everything hurt, got what is called a “moon face” and a “buffalo hump” on the back of my neck. I also got stretch marks. I was very depressed but it’s hard to say if that was because of the hormone imbalance or because I felt so bad and no one would listen to me.

I came across a little article in the Ladies Home Journal magazine which said “If you have these symptoms…ask your doctor about Cushing’s”. After that, I started reading everything I could on Cushing’s and asking my doctors. Due to all my reading at the library and medical books I bought, I was sure I had Cushing’s but no one would believe me. Doctors would say that Cushing’s Disease is too rare, that I was making this up and that I couldn’t have it.

I asked doctors for three years – PCP, gynecologist, neurologist, podiatrist – all said the now-famous refrain.  It’s too rare.  You couldn’t have Cushing’s.  I kept persisting in my reading, making copies of library texts even when I didn’t understand them, keeping notes.  I just knew that someone, somewhere would “discover” that I had Cushing’s.

My husband was on the doctors’ sides.  He was sure it was all in my mind (as opposed to all in my head!) and he told me to just think “happy thoughts” and it would all go away.

A Neurologist gave me Xanax. Since he couldn’t see my tumor with his Magnetic Resonance Imaging (MRI) machine there was “no possibility” that it existed. Boy was he wrong!

Later in 1986 I started bruising incredibly easily. I could touch my skin and get a bruise. On New Year’s Day of 1987 I started bleeding under the skin. My husband made circles around the outside perimeter each hour with a marker, like the rings of a tree. When I went to my Internist the next day he was shocked at the size. He now thought I had a blood disorder so he sent me to a Hematologist/Oncologist.

Fortunately, the Hematologist/Oncologist ran a twenty-four hour urine test and really looked at me. Both he and his partner recognized that I had Cushing’s. Of course, he was sure that he did the diagnosis.  No matter that I had been pursuing this with other doctors for 3 years.

It was not yet determined if it was Cushing’s Disease (Pituitary) or Syndrome (Adrenal). However, he couldn’t help me any further so the Hematologist referred me to an Endocrinologist.

The Endocrinologist, of course, didn’t trust the other tests I had had done so I was back to square one. He ran his own multitude of tests. He had to draw blood at certain times like 9 AM. and 5 PM. There was a dexamethasone suppression test where I took a pill at 10 p.m. and gave blood at 9 am the next day. I collected gallons of urine in BIG boxes (Fun in the fridge!). Those were from 6 a.m. to 6 a.m. to be delivered to his office by 9 a.m. same day. I was always worried that I’d be stopped in rush hour and the police would ask about what was in that big container. I think I did those for a week. He also did standard neurological tests and asked lots of questions.

When the endo confirmed that I had Cushing’s in 1987 he sent me to a local hospital where they repeated all those same tests for another week and decided that it was not my adrenal gland (Cushing’s Syndrome) creating the problem. The doctors and nurses had no idea what to do with me, so they put me on the brain cancer ward.

When I left this hospital after a week, we didn’t know any more than we had before.

As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection. I chose NIH – closest and free. After I was interviewed by the Doctors there, I got a letter that I had been accepted into the clinical trial. The first time I was there was for 6 weeks as an inpatient. More of the same tests.

There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with. While I was at NIH, I was gaining about a pound a day!

The MRI still showed nothing, so they did a Petrosal Sinus Sampling Test. That scared me more than the prospect of surgery. (This test carries the risk of stroke and uncontrollable bleeding from the incision points.) Catheters were fed from my groin area to my pituitary gland and dye was injected. I could watch the whole procedure on monitors. I could not move during this test or for several hours afterwards to prevent uncontrolable bleeding from a major artery. The test did show where the tumor probably was located. Also done were more sophisticated dexamethasone suppression tests where drugs were administered by IV and blood was drawn every hour (they put a heplock in my arm so they don’t have to keep sticking me). I got to go home for a weekend and then went back for the surgery – the Transsphenoidal Resection. I fully expected to die during surgery (and didn’t care if I did) so I signed my will and wrote last letters to those I wanted to say goodbye to. During the time I was home just before surgery, a college classmate of mine (I didn’t know her) did die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until a couple months later!

November 3, 1987, the surgeon, Dr. Ed Oldfield, cut the gum above my front teeth under my upper lip so there is no scar. He used tiny tools and microscopes. My tumor was removed successfully. In some cases (not mine) the surgeon uses a plug of fat from the abdomen to help seal the cut. Afterwards, I was in intensive care overnight and went to a neurology ward for a few days until I could walk without being dizzy. I had some major headaches for a day or two but they gave me drugs (morphine) for those. Also, I had cotton plugs in my nostrils. It was a big day when they came out. I had diabetes insipidus (DI) for a little while, but that went away by itself – thank goodness!

I had to use a foam product called “Toothies” to brush my teeth without hitting the incision. Before they let me go home, I had to learn to give myself an injection in my thigh. They sent me home with a supply of injectible cortisone in case my level ever fell too low (it didn’t). I was weaned gradually off cortisone pills (scary). I now take no medications. I had to get a Medic Alert bracelet. I will always need to tell medical staff when I have any kind of procedure – the effects of my excess cortisone will remain forever.

I went back to the NIH for several follow-up visits of a week each where they did all the blood and urine testing again. After a few years NIH set me free. Now I go to my “outside” endocrinologist every year for the dexamethasone suppression test, 24-hour urine and regular blood testing.

As I get further away from my surgery, I have less and less chance that my tumor will grow back. I have never lost all the weight I gained and I still have the hair on my chin but most of my other symptoms are gone. I am still and always tired and need a nap most days. I do not, however, still need to take whole days off just to sleep.

I consider myself very lucky that I was treated before I got as bad as some of the others on my floor at NIH but think it is crazy that these symptoms are not taken seriously by doctors.

My story goes on and if you’re interested some is on this blog and some is here:

Forbes Magazine | MaryO’s bio | Cushing’s and Cancer Blog | Cushing’s Awareness Day Testimonial Archive |

Because of this experience in getting a Cushing’s diagnosis – and later, a prescription for growth hormone – I was concerned that there were probably other people not being diagnosed with Cushing’s. When I searched online for Cushing’s, all the sites that came up were for dogs and horses with Cushing’s.  Not what I was looking for!

In July of 2000, I was talking with my dear friend Alice, who ran a wonderful menopause site, Power Surge, wondering why there weren’t many support groups online (OR off!) for Cushing’s.  This thought percolated through my mind for a few hours and I realized that maybe this was my calling.  Maybe I should be the one to start a network of support for other “Cushies” to help them empower themselves.

I wanted to educate others about the awful disease that took doctors years of my life to diagnose and treat – even after I gave them the information to diagnose me.  I didn’t want anyone else to suffer for years like I did.  I wanted doctors to pay more attention to Cushing’s disease.

The first website (http://www.cushings-help.com) went “live” July 21, 2000.  It was just a single page of information. The message boards began September 30, 2000 with a simple message board which then led to a larger one, and a larger.  Today, in 2010, we have over 7 thousand members.  Some “rare disease”!

The message boards are stillactive and we have weekly online text chats, weekly live interviews, local meetings, conferences, email newsletters, a clothing exchange, a Cushing’s Awareness Day Forum, podcasts, phone support and much more. Because I wanted to spread the word to others not on “the boards” we have extended out to social networking sites – twitter groups, facebook groups, twines, friendfeeds, newsletters, websites, chat groups, multiply.com, and much, much more.

People are becoming more empowered and participating in their own diagnoses, testing and treatment.  This have changed a lot since 1983!

When I had my Cushing’s over 40 years ago (AARRGGHH!), I never thought that I would meet another Cushing’s patient in real life or online. Back then, I’d never even been aware that there was anything like an “online”. I’m so glad that people struggling with Cushing’s today don’t have to suffer anymore thinking that they’re the only one who deals with this.

Because of my work on the websites – and, believe me it is a ton of work! – I have had the honor of meeting over a hundred other Cushies personally at local meetings, conferences, at NIH (the National Institutes of Health in Bethesda, MD where I had my final diagnosis and surgery). It occurred to me once that this is probably more than most endocrinologists will ever see in their entire career. I’ve also talked to countless others on the phone. Amazing for a “rare” disease!

I don’t know what pushed me in 1983, how I got the confidence and self-empowerment to challenge these doctors and their non-diagnoses over the years.  I’m glad that I didn’t suffer any longer than I did and I’m glad that I have a role in helping others to find the medical help that they need.

What do *YOU* think?  How are you becoming empowered?

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