Cushing’s Syndrome

Cushing’s syndrome is a condition in which the body is exposed to persistently high levels of the hormone cortisol. Cortisol is normally produced in the adrenal cortex and plays a key role in regulating metabolism, immune function, and the stress response. In Cushing’s syndrome, this balance is disrupted, and the elevated cortisol levels cause a wide range of symptoms and complications. Clinically, this condition is highly relevant because it can significantly impair both physical and mental health and increase the risk of several comorbidities¹.

On English, the condition is referred to as “Cushing’s syndrome” or “hypercortisolism.” When caused by excessive production of adrenocorticotropic hormone (ACTH) from the pituitary gland, it is termed “Cushing’s disease.” If the syndrome arises after long-term treatment with corticosteroid medications, it is described as “iatrogenic Cushing’s syndrome” or **“medication-induced Cushing’s syndrome”¹.

Causes and Pathophysiology

Cushing’s syndrome can develop in two main ways:

1. Endogenous hypercortisolism – The body itself produces too much cortisol.

   • Most often due to the pituitary producing excess ACTH, stimulating the adrenal glands to increase cortisol output (Cushing’s disease).

   • Sometimes caused by tumors in other organs producing ACTH (ectopic ACTH production).

   • In rarer cases, an adrenal cortex tumor directly produces excess cortisol.

2. Exogenous hypercortisolism – Long-term use of corticosteroid medications.

   • This is the most common cause, typically seen in patients treated for inflammatory conditions such as asthma or rheumatoid arthritis¹.

Among endogenous cases, pituitary adenomas dominate, accounting for up to 80% of cases. Adrenal tumors and ACTH-producing cancers outside the pituitary are less frequent³.

Risk Factors

The risk of developing Cushing’s syndrome is highest in patients undergoing prolonged corticosteroid therapy, particularly at high doses. Other risk factors include:

• Presence of pituitary or adrenal tumors

• Certain cancers capable of producing ACTH

• Health system–related differences in corticosteroid use

• Age (rare in children and adolescents, more common in adults)

• Gender (more frequent in women than men)¹

Symptoms and Clinical Presentation

Cushing’s syndrome usually develops gradually, often over months or years. The clinical picture is distinctive but can overlap with other conditions. Classic features include:

• Moon face: a rounded, flushed facial appearance

• Buffalo hump: fat accumulation on the back and neck

• Central obesity: pronounced abdominal fat with striae (broad, purplish stretch marks)

• Thin arms and legs due to progressive muscle wasting

• Bone loss leading to kyphosis, back pain, or fragility fractures

Other symptoms include:

• Skin changes: thin, fragile skin, easy bruising, poor wound healing, acne, and excessive hair growth (especially in women)

• Endocrine and reproductive symptoms: menstrual irregularities, absent periods, deepened voice, reduced libido, and in men, impaired sexual function

• Neuropsychiatric symptoms: depression, anxiety, sleep disturbances, and impaired concentration

• Metabolic complications: diabetes mellitus, hypertension, and obesity

• In children: slowed linear growth combined with obesity¹⁴

Complications

If untreated, Cushing’s syndrome can result in severe complications, including:

• Osteoporosis with high fracture risk

• Immunosuppression causing frequent infections and delayed wound healing

• Cardiometabolic disease: type 2 diabetes, hypertension, gastric ulcers, and cardiovascular disease

• Reproductive effects: hirsutism, menstrual disturbances, and breast atrophy in women; reduced fertility and sexual dysfunction in men

• Growth impairment in children (short stature)

• Neuropsychiatric impact: long-term depression, anxiety, or cognitive decline¹³

Diagnosis

• Exogenous Cushing’s syndrome: In patients taking corticosteroid medications, this is almost always the cause, and extensive testing is usually unnecessary.

• Endogenous Cushing’s syndrome: Requires more comprehensive evaluation, since several disorders can mimic the symptoms.

Diagnostic steps include:

1. Hormone measurements

   • Cortisol levels in blood, urine, or saliva

   • Late-night salivary cortisol: in Cushing’s syndrome, levels remain elevated instead of dropping normally

2. Dynamic endocrine tests

   • Suppression or stimulation tests to assess cortisol regulation

3. Imaging

   • MRI or CT scans of the pituitary or adrenal glands

   • In select cases, inferior petrosal sinus sampling to identify the source of ACTH overproduction

This thorough evaluation is crucial to determine the underlying cause and guide treatment¹.

Treatment and Medical Management

The goal of therapy is to normalize cortisol levels and treat the underlying cause:

• Exogenous Cushing’s syndrome

  • Gradual tapering of corticosteroid medications under medical supervision

  • Avoid abrupt withdrawal due to adrenal suppression; temporary hormone replacement may be necessary until recovery

• Endogenous Cushing’s syndrome

  • Surgery is first-line when the cause is a pituitary adenoma, adrenal tumor, or ectopic ACTH-producing tumor

  • Postoperatively, temporary cortisol replacement may be needed while the hypothalamic-pituitary-adrenal (HPA) axis recovers

  • If surgery is unsuccessful:

    • Radiotherapy for pituitary adenomas

    • Medications that inhibit cortisol synthesis (e.g., ketoconazole, metyrapone, mitotane)

• Management of comorbidities

  • Hypertension, diabetes, osteoporosis, and psychological conditions must be addressed concurrently³⁵

Physiotherapy

Physiotherapists most frequently encounter patients with medication-induced Cushing’s syndrome, i.e. after long-term corticosteroid therapy. It is essential to assess muscle strength, bone density, functional capacity, and fall risk.

Goals of physiotherapy:

• Prevent loss of muscle mass and bone tissue

• Improve balance and coordination

• Reduce fall risk

Recommended interventions:

• Weight-bearing strength training (e.g., squats, push-ups, or light resistance training) to maintain muscle mass and bone health

• Aerobic exercise (brisk walking, cycling, swimming) to counteract weight gain and improve overall fitness⁶

• Fall-prevention education: remove loose rugs, ensure proper lighting, and adapt the home environment for safety

• Skin and wound care: high cortisol levels impair wound healing. Patients should be educated in wound hygiene and infection prevention—clean wounds promptly, apply an antibacterial agent, and use sterile dressings⁶

  
  

Prognosis and Course

With appropriate treatment, many patients can recover fully, but residual symptoms and complications may persist for months or even years. People tapering off corticosteroids may require months to regain normal hormonal balance and may still have reduced muscle strength or bone density.

The risk of relapse depends on whether the underlying cause (especially tumors) can be completely eliminated. Untreated Cushing’s syndrome can be life-threatening due to complications such as infections, cardiovascular disease, and severe diabetes. Early diagnosis and close follow-up are crucial for the best possible long-term outcomes¹.

Differential Diagnosis

Several conditions can mimic Cushing’s syndrome, including:

• Obesity

• Polycystic ovary syndrome (PCOS)

• Depression

• Chronic alcohol misuse

Other disorders that trigger prolonged stress responses or hormonal disturbances may also present with a similar picture. Comprehensive clinical evaluation and specific hormonal tests are essential to distinguish Cushing’s syndrome from these conditions.

Sources

1. Goodman CC, Snyder KS. Differential Diagnosis for Physical Therapists: Screening for Referral. Philadelphia: W.B. Saunders Company; 2006: 473–475.

2. Goodman CC, Fuller KS. Pathology: Implications for the Physical Therapist. 3rd ed. St. Louis: Saunders Elsevier; 2009: 481–483.

3. Chaudhry HS, Singh G. Cushing Syndrome. StatPearls [Internet]. 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470218/

4. Beers MH, Porter RS, Jones TV, Kaplan JL, Berkwits M. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station: Merck Research Laboratories; 2006: 1212–1214.

5. Mayo Clinic. Cushing Syndrome – Diagnosis and Treatment. Available from: https://www.mayoclinic.org/diseases-conditions/cushing-syndrome/diagnosis-treatment/drc-20351314

6. Rea C. Cushing's Syndrome. Yahoo Health. Updated April 29, 2008. Available from: http://health.yahoo.com/hormone-living/cushing-s-syndrome-home-treatment/healthwise--hw71687.html