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Cushing's Syndrome

With symptoms similar to other conditions, the path to diagnosis can be challenging.

A rare, but serious condition

Diagnosis of Cushing’s syndrome (CS) is often delayed because it can take years after onset for noticeable signs and symptoms to appear.1,2

  • Average age at diagnosis is 30-60 years3

  • 3-4x more common in women3,4

  • 3.5-5x higher mortality risk than the general population, if not treated properly5,a

aMortality rates vary depending on disease etiology.

Endogenous CS is often caused by a tumor that secretes excess cortisol3

CS can be classified by subtype, based on the source of hypercortisolism4

Illustration of male body highlighting the pituitary gland, the lungs, and adrenal glands

ACTH-dependent1

Cushing's disease

A benign pituitary adenoma that secretes ACTH.4

Ectopic ACTH (EAS)1

Most commonly a lung, mediastinal, pancreas, or medullary thyroid neuroendocrine tumor that secretes ACTH4

ACTH-independent1

Adrenal adenoma

Unilateral, cortisol-producing, benign adenomas located on the adrenal cortex4

Adrenocortical carcinoma

Unilateral malignant neoplasms on the adrenal cortex4

Adrenal hyperplasia

Refers to bilateral adrenal hyperplasia, which is characterized by macronodules or micronodules affecting both adrenal glands, leading to an increase in cortisol secretion4

Reincke M, Fleseriu M. JAMA. 2023;330(2):170-181. Originally published by, adapted and used with permission from American Medical Association.

ACTH, adrenocorticotropic hormone.

In some cases, hypercortisolism is easily recognizable4,6
Overt signs and symptoms of hypercortisolism4,6
Dorsocervical fat pad, moon face, thin skin, central obesity, purple striae, osteopenia/osteoporosis, easy bruising, and muscle weakness
In others, hypercortisolism is easily misdiagnosed4,6
Nonspecific signs and symptoms of hypercortisolism4,6
Anxiety/depression, sleep disturbances, facial plethora, acne, hirsutism, hypertension, dyslipidemia, diabetes, kidney stones, menstrual irregularities, decreased libido

The clinical presentation of CS can vary by etiology7

  • CS can manifest in a variety of ways, based on the severity and duration of hypercortisolism.6
  • Patients with Cushing’s disease may present with distinct CS features, but may also have symptoms of common conditions.8
  • Patients with ectopic CS may present with severe and rapidly developing metabolic signs.6

    Anorexia Myopathy Glucose intolerance Skin hyperpigmentation Hypokalemia Peripheral edema
  • Patients with adrenal carcinomas may have rapid onset of symptoms and show signs of virilization due to secretion of androgens in addition to cortisol.6,9
    Abdominal pain Palpable Tumor Mass Hirsutism Acne Oligomenorrhea
  • Patients with adrenal adenomas may have mild to severe symptoms based on the level of cortisol or aldosterone secretion.10
  • Patients with adrenal hyperplasia can experience a range of symptoms, from mild in macronodular disease to severe in micronodular disease.11

CS diagnosis can often be delayed for years due to these variations in CS presentation1

The mean time to diagnosis for CS is reported as 34 months, but can vary by subtype:12


  • Ectopic CS: 14 months
  • ACTH-independent CS: 30 months
  • Cushing’s disease: 38 months

Hypercortisolism exposure poses risks

In fact, the longer the duration of hypercortisolism exposure, the greater the mortality risk.13,14 Even transient exposure to excess cortisol is associated with increased mortality.14 Therefore, evaluating and treating the long-term negative effects of chronic hypercortisolism may be important to reduce morbidity, improve quality of life, and reduce the long-term mortality associated with Cushing’s syndrome.15

Uncontrolled chronic hypercortisolism also leads to elevated risks of multi-system morbidity and mortality.16 Patients with chronic, uncontrolled hypercortisolism have an approximately 3.5 to 5 times higher mortality risk compared to the general population.5 While the risk of all-cause morbidity and mortality decreases with remission, it is not entirely eliminated.17

The clinical presentation of CS can also overlap with other common conditions18

Due to hypercortisolism, CS is associated with comorbidities and complications that negatively impact quality of life and survival3,19

Comorbidities and Complications of CS3,6,18,19

Man holding head with two hands
Anxiety or depression
Blood droplet
Type 2 diabetes
Blood pressure pump with heart symbol
Hypertension
Restricted blood flow
Hyperlipidemia
Insulin testing
Insulin resistance
Scale indicating high weight
Obesity
Fluid build up
Peripheral edema
Multiple bacteria
Infections
Female reproductive system
Menstrual irregularities
Blood cells
Hypercoagula-bility
Sleepy man
Insomnia or fatigue
Bone with density loss
Osteoporosis

Normalizing cortisol levels may help address comorbidities and complications related to Cushing’s syndrome.

Risk of VTE, AMI, Stroke, and Heart Failure in Patients With CS

Chronic exposure to excess cortisol increases risk for all-cause morbidity and mortality20

Lungs

VTE

~8.4X Higher Risk

Heart

Heart
Failure

~6.8X Higher Risk

Brain

Stroke

~5.0X Higher Risk

Heart rate monitor

AMI

~2.2X Higher Risk

Mortality was twice as high in CS patients compared with controls.21

Model adjusted for age and sex. Hazard ratios presented are for a 3-year period before CS diagnosis.

AMI, acute myocardial infarction; VTE, venous thromboembolism.

Untangling the effects of excess cortisol in Cushing’s syndrome

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REFERENCES: 1. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7. 2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605-1617. doi:10.1016/S0140-6736(06)68699-6. 3. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611-629. doi:10.1016/S2213-8587(16)00086-3. 4. Reincke M, Fleseriu M. Cushing syndrome: a review. JAMA. 2023;330(2):170-181. doi:10.1001/jama.2023.11305. 5. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary. 2016;19(6):643-653. doi:10.1007/s11102-016-0742-1. 6. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015;173(4):M33-M38. doi:10.1530/EJE-15-0464. 7. Juszczak A, Morris D, Grossman A. Cushing’s syndrome. Endotext. Accessed November 11, 2024. https://www.ncbi.nlm.nih.gov/books/NBK279088. 8. Pivonello R, De Martino MC, De Leo M, Simeoli C, Colao A. Cushing’s disease: the burden of illness. Endocrine. 2017;56(1):10-18. doi:10.1007/s12020-016-0984-8. 9. Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocortical carcinoma with hypercortisolism. Endocrinol Metab Clin North Am. 2018;47(2):395-407. doi:10.1016/j.ecl.2018.02.003. 10. Mahmood E, Loughner CL, Anastasopoulou C. Adrenal adenoma. StatPearls. StatPearls Publishing; 2024. Accessed December 3, 2024. https://www.ncbi.nlm.nih.gov/books/NBK539906. 11. Chevalier B, Vantyghem MC, Espiard S. Bilateral adrenal hyperplasia: pathogenesis and treatment. Biomedicines. 2021;9(10):1397. doi:10.3390/biomedicines9101397. 12. Rubinstein G, Osswald A, Hoster E, et al. Time to diagnosis in Cushing’s syndrome: A meta-analysis based on 5367 patients. J Clin Endocrinol Metab. 2020;105(3):dgz136. doi:10.1210/clinem/dgz136. 13. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326. doi:10.1530/EJE-11-1095. 14. Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab. 2007 Mar;92(3):976-81. doi: 10.1210/jc.2006-2112. 15. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. doi: 10.1210/jc.2015-1818. 16. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing’s syndrome. Lancet. 2015;386(9996):913-927. doi: 10.1016/S0140-6736(14)61375-1. 17. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015 Aug;36(4):385-486. doi: 10.1210/er.2013-1048. 18. Nieman LK, Biller BMK, 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. doi:10.1210/jc.2008-0125. 19. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing’s syndrome. Lancet. 2023;402(10418):2237-2252. doi:10.1016/S0140-6736(23)01961-X. 20. Dekkers OM, Horváth-Puhó E, Jørgensen JOL, et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98(6):2277-2284. doi: 10.1210/jc.2012-3582. 21. van Haalen FM, Broersen LHA, Jorgensen JO, Pereira AM, Dekkers OM. Management of endocrine disease: Mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol. 2015;172(4):R143-R149. doi: 10.1530/EJE-14-0556.