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What All Endocrinologists Should Know about Cushing disease

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Enhanced awareness of the broad range of presentations can help shorten time to diagnosis.

By Lewis Blevins, MD

A rare endocrine disorder, Cushing syndrome results in a variety of symptoms and physical abnormalities that manifest due to excessive amounts of cortisol or hypercortisolism. This steroid hormone is essential for regulating the metabolism of glucose and modulating stress response. Too much cortisol can result in complications such as osteoporosis, hypertension, type 2 diabetes, frequent or unusual infections, and a loss of muscle mass and strength. Cushing syndrome most commonly affects adults between the ages of 25 to 40 and can have both endogenous and exogenous causes.

Cushing disease, first described by Harvey Cushing, MD, in 1932, is responsible for about 70% of all endogenous Cushing syndrome.2 It is due to excess adrenocorticotropin hormone (ACTH) produced by a benign pituitary tumor that in turn causes the adrenal glands to make excess cortisol. In the United States, the incidence of pituitary ACTH-dependent Cushing disease is 6.2 to 7.6 per million person-years.

Early diagnosis is crucial to minimize complications. Yet because the signs and symptoms of Cushing syndrome overlap with common conditions like metabolic syndrome, obesity, osteoporosis, and depression, it can take years for patients to receive the correct diagnosis. According to a recent meta-analysis, people with Cushing syndrome wait a mean of 34 months (range 30-38 months) before receiving a definite diagnosis.4 The report found that waiting time largely depends on the specific disease subtype: those with pituitary ACTH-dependent Cushing disease have the longest mean wait to diagnosis—38 months (range 33-43 months). Patients with ectopic Cushing syndrome have a mean waiting time of 14 months (range 11-17 months) according to the study.

The duration of hypercortisolism is the main factor for determining the degree of morbidity and mortality, making it crucial to establish the diagnosis as early as possible.5 It is not unusual to see patients suffer for as many as 5 years before diagnosis. Here are three factors that endocrinologists can keep in mind to help identify and treat patients with Cushing disease sooner, thereby improving outcomes and quality of life.

1Many patients do not have a textbook presentation of Cushing disease.If physicians are only looking for the classic clinical features, they will miss patients with milder forms of the disease. Most patients present with one or more components of Cushing; not necessarily all of them. A patient may only have osteoporosis, diabetes, or hypertension plus obesity, for example, but lack other classic features like proximal muscle weakness, easy bruising, thinning of the skin, etc.

Most of the patients I see who are hypercortisolemic do not have the full syndrome. Endocrinologists should be aware of patients presenting with milder forms of the disease who have subtle features and not focus solely on those with overt or classic Cushing syndrome. About 5% of patients with newly diagnosed type 2 diabetes will have hypercortisolism.6 Physicians may see a patient with diabetes and treat only that disorder without considering the possibility of there being a hormonal cause.

This means endocrinologists must be looking for Cushing’s syndrome more broadly. The obvious patients are those who have severe, long-term undiagnosed hypercortisolism or those with shorter-term explosive hypercortisolism. Patients often present with non-classical forms of hypercortisolism that should be diagnosed earlier.

An increasing number of patients with hypercortisolism due to adrenal diseases have been recognized over the past couple of decades as a result of intensive evaluation of patients with incidentally detected adrenocortical adenomas.

2. Although the literature discusses diagnostic testing and cutoffs, be aware that the research settings where those tests have been developed do not always apply to clinical settings. Physicians must use more than one diagnostic test and clinical intuition, which comes from taking a patient history and doing a physical examination to interpret the results.

As physicians, we can sometimes overlook evaluating the entire patient. Because not all patients with hypercortisolism have classic features, we need to keep our eyes wide open and maintain firm grounding in the differential diagnosis. By shortening the time to diagnosis of Cushing disease, we can help alleviate the long-term suffering of our patients.

3. Medical management of Cushing disease has progressed. Surgery continues to be the first line-option for these patients; however, medical management is playing a larger role as new therapies become available. One example is osilodrostat (Isturisa; Recordati Rare Diseases Inc.), the only FDA-approved cortisol synthesis inhibitor for Cushing disease. In clinical studies, the oral agent demonstrated normalization of cortisol in a majority of patients as well as improvement in multiple clinical features of the disease with a manageable safety profile.7 Isturisa has various dosing options to tailor management as needed for an individual patient. The choice of medical treatment for Cushing disease is a decision based on individual patient factors such as the severity of disease and the associated manifestations.

Accurate and early identification of Cushing disease is critical for effective management and optimal prognosis—patients diagnosed earlier in the disease’s course are more likely to have better mental health and health-related quality of life in the long term. Endocrinologists and primary care providers should be aware that medical management is within reach and can be considered as first-line therapy after surgery in most patients with mild-to-moderate disease.

Lewis Blevins, MD, is a neuro-endocrinologist specializing in evaluating and managing pituitary and hypothalamus disorders, including acromegaly, prolactinoma and other pituitary tumors, diabetes insipidus, hypopituitarism and growth hormone deficiencies. He is medical director of the California Center for Pituitary Disorders at UCSF Medical Center.  Dr Blevins has no relevant disclosures. 


  1. National Organization for Rare Disorders. Cushing syndrome. https://rarediseases.org/rare-diseases/cushing-syndrome/. Accessed July 20, 2021.
  2. Carpenter PC. Diagnostic evaluation of Cushing’s syndrome. Endocrinol Metab Clin North Am. 1988; 17:445.
  3. 3 Broder MS, Neary MP, Chang E, et al. Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients <65 years old in the United States. Pituitary. 2015;18:283-289. doi: 10.1007/s11102-014-0569-6.
  4. 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):e12–e22. https://doi.org/10.1210/clinem/dgz136.
  5. Javanmard P, Duan D, Geer EB, et al. Mortality in patients with endogenous Cushing’s syndrome. Endocrinol Metab Clin North Am.2018;47(2):313-333. doi: 10.1016/j.ecl.2018.02.005.
  6. Steffensen C, Dekkers OM, Lyhne J, et al. Hypercortisolism in newly diagnosed type 2 diabetes: a prospective study of 384 newly diagnosed patients. Horm Metab Res.2019;51(1):62-68. doi: 10.1055/a-0809-3647.
  7. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748-761. doi: 10.1016/S2213-8587(20)30240-0.