Cushing's syndrome, resulting from prolonged exposure to excess glucocorticoids, has a highly variable clinical presentation making it a dificult condition to diagnose.

 

 

 

 

 

 

 

While it is rare, Cushing's syndrome, when present, calls for early and aggressive intervention. What makes it challenging to establish a diagnosis of this condition, is not only it's highly variable clinical presentation but the subtle clinical features that exhibit an overlap in symptoms in individuals with and without the syndrome.

 

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Clinical features and Diagnosis 

Cushing's syndrome has no true pathognomonic signs or symptoms and hence the clinical diagnosis needs to be based on one or more of the findings.

Weight gain emerges as the most common symptom of Cushing's syndrome.Since it is a very widely prevalent condition in people without the syndrome as well it is difficult to establish a diagnosis based on this feature. Other features that can be used to distinguish Cushing’s syndrome more reliably from simple obesity include proximal muscle weakness, easy bruising, and violaceous striae greater than 1 cm wide,striae, acne, flushing, poor wound healing, lower limb edema, fatigue, impaired glucose tolerance, osteoporosis, hyperpigmentation of the skin, mood and memory changes, amenorrhea, hirsutism, decreased sexual drive, or frequent infections.Clinical suspicion in patients with multiple and progressive signs and symptoms suggestive of Cushing’s syndrome should provoke diagnostic testing. Screening may be considered in patients with other features of Cushing’s syndrome, particularly with poorly controlled diabetes or hypertension, or unexplained osteoporosis. Patients with an incidentally discovered adrenal mass should be evaluated.

Clinical manifestations vary widely among patients.A high index of clinical suspicion must be maintained in order to correctly make this diagnosis.

Diagnostic Evaluation

For arriving at a diagnosis for Cushing's syndrome initial laboratory testing is usually directed at confirming excessive glucocorticoid production. Biochemical diagnostic tests to confirm hypercortisolism include salivary and blood serum cortisol testing, 24-hour urinary-free cortisol testing, and low-dose overnight dexamethasone suppression testing.  Amongst these, the  best test for confirming hypercortisolism is the analysis of a 24-hour urine collection for urinary free cortisol excretion. Normal values are less than 90 μg per 24 hours (250 nmol per day). Values more than 300 μg per day (830 nmol per day) are considered diagnostic for Cushing's syndrome. Because of the difficulty in obtaining 24-hour urine collections in many outpatients, some physicians use a l-mg overnight dexamethasone suppression test.

Treatment

The main aim of medical therapy in the management of Cushing’s disease (CD) is to control hypercortisolism when surgery is contraindicated, non-curative or when no tumor is visible on imaging. The treatment focusses on three pathophysiological mechanisms;

1. Central inhibition of adrenocorticotropic hormone (ACTH) secretion
2. Adrenal-directed inhibition of steroidogenesis
3. Glucocorticoid-receptor blockade

Central inhibition of adrenocorticotropic hormone (ACTH) secretion

Somatostatin receptors ligands (SRLs) have anti- secretory and anti- proliferative properties and they act directly at the source of CD i.e corticotroph adenoma. Hypercortisolism suppresses somatostatin receptor (SSTR) type 2 and as first generation SRL’s, such as octreotide and lanreotide, target these receptors. Therefore, they are ineffective as primary medical treatment for Cushing's syndrome. Following are the drugs which have now proven to be an effective alternative for the first generation SRL’s

1. Pasireotide: SSTR, type 5 is the predominant SSTR which is expressed in corticotroph tumors. Pasireotide is a SRL which has 40-times more affinity for SSTR type 5. It suppresses ACTH secretion and cell proliferation. Studies have shown that the use of Pasireotide (600 to 900 µg subcutaneous twice daily) has been successful in reducing the urinary free cortisol(UFC) by almost 50%. Reduction of tumor volume >20% has also been observed on MRI in patients with baseline visible tumors.
2. Cabergoline: It is the most effective dopamine agonist (DA) and can be used as a monotherapy or add-on therapy. A response rate of 30% to 40% at a high mean dose of 3.5 mg/week (0.5 to 7 mg/week), has been reported. However, a lack of long-term response in few patients and concerns about valvulopathy at high doses may hold back the physician from prescribing this drug.
3. Ongoing Clinical Trials: New molecular targets such as retinoic acid receptors, cyclin-dependent kinases and epidermal growth factor receptor (EGFR) have been identified. The drugs that target these molecules are in the different stages of clinical and pre-clinical development.

Adrenal-directed inhibition of steroidogenesis

1. Ketoconazole: It is a variety of imidazole and has been long used off label to treat Cushing's disaese. It acts primarily by reducing glucocorticoid synthesis. It also causes inhibition of androgen synthesis which may cause hypogonadism and gynecomastia in men but useful in women for managing hirsutism. The drug may be tolerated less owing to its effect such as nausea and vomiting.
2. Metyrapone: It has strong cortisol-lowering effects and research shows that approximately 50% of patients will achieve eucortisolism. During the first months of therapy, there may be a compensatory increase in ACTH which might diminish the clinical response initially.
3. Mitotane: This drug has potent adrenolytic effects and is therefore commonly used in adrenocortical cancer. At lower doses, this drug also inhibits steroid biosynthesis. Research predicts that 70% of the patients will achieve normal UFC and about 10% may have sustained remission after discontinuation. Mitotane may cause adrenal insufficiency (AI) and thus, higher doses of hydrocortisone may be needed for replacement.
4. Etomidate: It is an anesthetic drug which is administered parenterally. In CD patients with uncontrolled hypercortisolism, a low, non-hypnotic perfusion dose, can bring cortisol levels in control.

Ongoing clinical trials

• Osilodrostat (LCI699): It is an oral inhibitor of 18-hydroxylase. Hypokalemia is a common side effect associated with the drug. Two phase III trials of this drugs are in progress.
• Levoketoconazole: It is an enantiomer of ketoconazole. It has been found to be a better alternative to ketoconazole in terms of efficacy and side effects.

Glucocorticoid-receptor blockade

• Mifepristone: It is a glucocorticoid-receptor antagonist, which has >10-fold affinity for glucocorticoid-receptor when compared to cortisol and >3 times when compared to dexamethasone.

It blocks the progesterone-receptor and is contraindicated in women who are planning pregnancy.

There would be a transient increase in ACTH in two-thirds of patients without tumor growth correlation. However, patients with macroadenomas should be regularly examined for tumor progression.

In patients on Mifepristone, lab evaluation of the cortisol levels is not reliable and adjustments in the doses should be made based on the clinical evaluation of the patient.

If AI occurs, high doses of dexamethasone(2 to 10 mg daily) is required to deal with the receptor blockade.
 

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References

Kairys N, Schwell A. Cushing Disease. [Updated 2017 Aug 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2017 Jun-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448184/

Kirk LF Jr1, Hash RB, Katner HP, Jones T.Cushing's disease: clinical manifestations and diagnostic evaluation.Am Fam Physician. 2000 Sep 1;62(5):1119-27, 1133-4.