Cushing Syndrome: Symptoms, Types, Causes and Treatment

Cushing syndrome is a complex endocrine disorder that results from prolonged exposure to excessive levels of cortisol, a hormone produced by the adrenal glands. Recognized for its broad impact on the body and mind, Cushing syndrome significantly affects quality of life and increases mortality risk if left untreated. This article explores the key symptoms, the different types, underlying causes, and modern approaches to treatment—synthesizing evidence from the latest clinical research.

Symptoms of Cushing Syndrome

Cushing syndrome manifests in a variety of ways, impacting nearly every system in the body. Early recognition of its symptoms is crucial for timely intervention and improved outcomes. The syndrome can present with both physical and psychological symptoms, some of which may precede other classical signs, making awareness essential for patients and clinicians alike.

Symptom	Description	Frequency/Impact	Source
Obesity	Central (truncal) weight gain, moon face	Most common, noticeable	1 2 3 11
Skin Changes	Purple striae, easy bruising, acne	Characteristic, variable	1 3 11 12
Muscle Weakness	Proximal muscle atrophy/weakness	Frequent, disabling	1 2 3 12
Hypertension	Elevated blood pressure	Common, serious risk	2 3 11
Psychiatric	Depression, anxiety, cognitive deficits	Often under-recognized	4 5 11
Reproductive	Menstrual changes, impotence	Variable by sex/age	1 3 11

Table 1: Key Symptoms

Physical Manifestations

Central Obesity and Fat Redistribution

• Most individuals with Cushing syndrome develop pronounced central obesity, which may manifest as a “moon face,” “buffalo hump” (fat pad on the upper back), and increased abdominal girth. This fat pattern is distinct from general obesity and is often accompanied by thin limbs 1 2 3 12.

Skin and Hair Changes

• Wide, purple abdominal striae (stretch marks) and easy bruising are hallmark features. The skin may become thin and fragile, with poor wound healing. Acne and excessive hair growth (hirsutism) are also common, especially in women 1 3 11 12.

Musculoskeletal Symptoms

• Cushing syndrome causes muscle weakness, particularly in the proximal muscles of the arms and legs, making everyday tasks challenging. Osteopenia and osteoporosis are frequent, leading to an increased risk of fractures 1 3 11 12.

Cardiovascular and Metabolic Complications

• Hypertension is present in the majority of patients and, together with glucose intolerance or frank diabetes, increases the risk of cardiovascular events 2 3 11 12.

Neuropsychiatric and Cognitive Effects

• Depression is the most prevalent psychiatric manifestation, but anxiety, cognitive impairment, mood swings, and even psychosis can occur. These symptoms may precede other physical signs, leading to misdiagnosis if not carefully considered 4 5 11.

Reproductive and Immune Dysfunction

• Women may experience menstrual irregularities or amenorrhea, while men may report impotence and decreased libido. Immune suppression is also common, increasing susceptibility to infections 1 3 11.

Comorbidities

• Cushing syndrome is associated with a spectrum of comorbidities, including metabolic syndrome, thromboembolic disease, and increased infection risk. Prompt recognition and management of these complications are essential to reduce morbidity and mortality 2 11.

Types of Cushing Syndrome

Understanding the different types of Cushing syndrome is vital for accurate diagnosis and treatment. The syndrome is primarily categorized by the source of cortisol excess—either endogenous (produced by the body) or exogenous (due to medication).

Type	Defining Feature	Relative Frequency	Source
Exogenous	Due to glucocorticoid therapy	Most common overall	1 2 10
Endogenous: ACTH-Dependent	Pituitary or ectopic ACTH production	Majority of endogenous cases	1 7 8 10 13 14 16
Endogenous: ACTH-Independent	Adrenal tumor/hyperplasia	Minority of endogenous cases	1 9 16
Subclinical	Mild/no classic symptoms, adrenal tumors	Increasingly recognized	6

Table 2: Types of Cushing Syndrome

Exogenous (Iatrogenic) Cushing Syndrome

• Most common overall form
• Results from prolonged exposure to high doses of glucocorticoid medications (such as prednisone) prescribed for various conditions, including asthma, autoimmune diseases, and organ transplantation.
• Symptoms and complications mirror those of endogenous forms 1 2 10.

Endogenous Cushing Syndrome

ACTH-Dependent

• Cushing Disease: Caused by a pituitary adenoma secreting excess adrenocorticotropic hormone (ACTH), stimulating the adrenal glands to overproduce cortisol. Accounts for about 70% of endogenous cases 1 8 10 13 14 16.
• Ectopic ACTH Syndrome: ACTH is produced by non-pituitary tumors (often lung or neuroendocrine tumors). Less common but often more severe 7 8 10 13 14 16.

ACTH-Independent

• Adrenal Cushing Syndrome: Due to adrenal adenomas, carcinomas, or hyperplasia leading directly to excess cortisol production, independent of ACTH. These cases make up about 15% of endogenous Cushing syndrome 1 9 16.

Subclinical Cushing Syndrome

• No overt classic symptoms
• Detected incidentally, often during imaging for other reasons (adrenal “incidentalomas”)
• Patients may lack obvious features but still have metabolic complications like hypertension, obesity, and diabetes 6.

Causes of Cushing Syndrome

Identifying the cause of Cushing syndrome is fundamental to selecting the right treatment. The syndrome is characterized by excessive cortisol, which can result from diverse mechanisms.

Cause Type	Mechanism/Source	Typical Example	Source
Exogenous	Medication-induced	Long-term steroid therapy	1 2 10
Pituitary	ACTH-producing adenoma	Cushing disease	1 3 8 10 13 14 16
Ectopic	ACTH from non-pituitary tumor	Small cell lung cancer	7 8 10 13 14 16
Adrenal	Autonomous cortisol secretion	Adrenal adenoma/carcinoma	1 9 10 16

Table 3: Causes of Cushing Syndrome

Exogenous Glucocorticoid Exposure

• The most frequent cause of Cushing syndrome is the therapeutic use of glucocorticoids. The body’s own production of cortisol is suppressed, but the external supply leads to classic syndrome features 1 2 10.

Pituitary Causes (Cushing Disease)

• A benign pituitary adenoma overproduces ACTH, which in turn overstimulates the adrenal glands 1 3 8 10 13 14 16.
• Genetic and molecular alterations, particularly in the cAMP-PKA pathway, are increasingly implicated in these tumors 9.

Ectopic ACTH Production

• Certain tumors outside the pituitary (notably small cell lung carcinoma and neuroendocrine tumors) can secrete ACTH or related peptides, causing rapid-onset and severe hypercortisolism 7 8 10 13 14 16.

Adrenal Tumors

• Autonomous cortisol production can arise from:
  • Adenomas (benign tumors)
  • Carcinomas (malignant tumors)
  • Adrenal hyperplasia (overgrowth of adrenal tissue)
• Some genetic mutations have been linked to familial forms, especially with bilateral adrenal hyperplasia 9.

Subclinical and Incidental Causes

• With the increased use of imaging, adrenal tumors secreting small amounts of cortisol are more frequently detected. These cases often lack classical stigmata but can still contribute to metabolic and cardiovascular risk 6.

Treatment of Cushing Syndrome

Treating Cushing syndrome is both challenging and crucial, aiming to normalize cortisol levels, resolve symptoms, and prevent life-threatening complications. The approach depends on the underlying cause, the patient’s health, and the presence of comorbidities.

Approach	Primary Target/Use	Typical Indication	Source
Surgery	Remove tumor (pituitary, adrenal, ectopic)	First-line for most cases	1 8 13 14 15 16
Medical	Inhibit cortisol production/activity	Inoperable/refractory cases	13 15 16 17
Radiation	Pituitary tumors	After failed surgery	13 14 15
Adjuvant	Manage comorbidities (e.g. HTN, DM)	All patients	11 13 15

Table 4: Treatment Approaches

Surgical Management

• First-line therapy for most cases
  • Pituitary Tumors (Cushing Disease): Transsphenoidal surgery to remove the tumor, with high remission rates 1 8 13 14 15 16.
  • Adrenal Tumors: Laparoscopic or open adrenalectomy for benign and malignant tumors 13 15 16.
  • Ectopic ACTH Tumors: Surgery to remove the ACTH-producing tumor when identified 13 14 16.
• Bilateral adrenalectomy may be considered for refractory or unidentifiable sources of cortisol excess but causes lifelong adrenal insufficiency 13 14 15.

Medical Therapy

• Indications: For inoperable cases, as a bridge to surgery, or for persistent/recurrent disease 13 15 16 17.
• Medications include:
  • Steroidogenesis Inhibitors: Ketoconazole (most used), metyrapone, mitotane, and newer agents reduce cortisol synthesis 15 16 17.
  • Glucocorticoid Receptor Antagonists: Mifepristone is effective, especially in those with diabetes or glucose intolerance 15.
  • Pituitary-Directed Agents: Cabergoline (dopamine agonist), pasireotide (somatostatin analog), effective in select pituitary cases 15.

Radiation Therapy

• Used for pituitary tumors that cannot be fully resected or recur after surgery 13 14 15.
• Stereotactic radiosurgery or conventional radiotherapy can control disease but may cause hypopituitarism 15.

Management of Comorbidities

• Hypertension, diabetes, dyslipidemia, osteoporosis, and psychiatric symptoms require targeted treatment alongside efforts to control cortisol 11 13 15.
• Psychiatric monitoring and psychological support should be integrated throughout all phases of care 4 5 11.

Special Considerations

• Subclinical Cushing Syndrome: The decision for adrenalectomy versus conservative management should be individualized, weighing risks (especially in older or asymptomatic patients) 6.
• Postoperative Care: Patients may require temporary or lifelong steroid replacement, depending on the extent of surgery and recovery of adrenal function 6 13 15.

Conclusion

Cushing syndrome is a potentially life-threatening condition that requires a high index of suspicion, especially given the overlap of its symptoms with more common disorders. Rapid diagnosis and tailored therapy are crucial for reducing complications and improving patient outcomes.

Key Takeaways:

• Cushing syndrome presents with a wide array of physical and psychological symptoms, including central obesity, skin changes, muscle weakness, hypertension, and psychiatric disturbances 1 2 3 4 5 11.
• It is classified as exogenous (most common, due to medications) or endogenous (ACTH-dependent and ACTH-independent), with rare subclinical forms increasingly diagnosed 1 2 6 8 9 10.
• Causes include pituitary adenomas (Cushing disease), ectopic ACTH production, adrenal tumors, and chronic glucocorticoid therapy 1 3 7 8 9 10 13 14 16.
• The cornerstone of treatment is surgical removal of the causative tumor. Medical therapy, radiation, and management of comorbidities play key roles for inoperable or recurrent cases 13 14 15 16 17.
• Multidisciplinary care, including psychiatric and metabolic support, is essential for optimal patient quality of life and long-term survival 4 5 11 13 15.

With ongoing advances in diagnosis and therapy, the prognosis for patients with Cushing syndrome continues to improve, provided that the condition is recognized and treated promptly.