From the Guidelines
Cushing's syndrome, characterized by excess cortisol levels, has severe effects on morbidity, mortality, and quality of life, including weight gain, hypertension, diabetes, and mood disturbances, and requires prompt treatment to prevent serious complications. The effects of Cushing's syndrome can be managed with medical therapies, such as metyrapone or ketoconazole, to reduce the cortisol burden, as recommended by the consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence 1.
Symptoms and Diagnosis
The symptoms of Cushing's syndrome include weight gain with central obesity, moon face, buffalo hump, purple striae, thin skin, easy bruising, muscle weakness, hypertension, diabetes, and mood disturbances. Diagnosis involves measuring cortisol levels through 24-hour urinary free cortisol, late-night salivary cortisol, overnight dexamethasone suppression test, and determining the source through ACTH levels, imaging studies, and possibly inferior petrosal sinus sampling.
Treatment
Treatment depends on the cause: surgical removal of tumors (transsphenoidal surgery for pituitary adenomas, adrenalectomy for adrenal tumors), radiation therapy, or medications like ketoconazole (400-1200 mg/day), metyrapone (250-750 mg every 4 hours), or mifeprone (300-1200 mg/day) to block cortisol production or effects 1. The use of metyrapone and ketoconazole should be limited to short-term treatment due to their adverse effects, such as hirsutism, dizziness, arthralgia, fatigue, hypokalaemia, and nausea, and the risk of hyperandrogenism and advanced bone age in children.
Complications
Chronic hypercortisolism can lead to serious complications, including cardiovascular disease, osteoporosis, and increased mortality, as highlighted in the scientific statement from the American Heart Association on resistant hypertension 1. Prompt treatment is crucial to prevent these complications and improve quality of life. The optimal antihypertensive regimen in patients with Cushing's syndrome remains to be adequately described, but adequate diuretic therapy, such as spironolactone or eplerenone, is likely a sensible strategy to block the mineralocorticoid actions of excess cortisol.
Management
The management of Cushing's syndrome requires a multidisciplinary approach, including endocrinologists, surgeons, and radiologists, to provide individualized treatment and prevent long-term complications. The goal of treatment is to normalize cortisol levels, control symptoms, and improve quality of life, while minimizing the risk of adverse effects and complications.
From the Research
Effects of Cushing's Syndrome
The effects of Cushing's syndrome, a condition characterized by excess cortisol levels, can be severe and life-threatening if left untreated 2, 3, 4, 5, 6.
Morbidity and Mortality
Untreated Cushing's syndrome results in substantial morbidity and mortality, making timely and effective treatment crucial 2.
Treatment Options
Treatment options for Cushing's syndrome include tumor-directed surgery, adrenally directed medical therapies, and other interventions such as radiotherapy and bilateral adrenalectomy 2, 3, 4, 5, 6.
Adrenally Directed Medical Therapies
Adrenally directed medical therapies, including ketoconazole, metyrapone, osilodrostat, mitotane, and etomidate, play a crucial role in managing Cushing's syndrome, particularly in patients with persistent or recurrent hypercortisolism postoperatively or those who cannot undergo tumor-directed surgery 2, 3, 4, 5, 6.
- These medications inhibit one or several enzymes involved in adrenal steroidogenesis.
- They differ in their mechanism of action, time course of pharmacologic effect, safety and tolerability, potential for drug-drug interactions, and route of administration.
- Careful dose titration and patient monitoring are necessary to ensure safety and effectiveness while avoiding hypoadrenalism.
Severe Hypercortisolism
In cases of severe hypercortisolism, urgent therapeutic measures must be taken, and etiological investigation may be postponed until the patient is stabilized 4.
- Adrenal steroidogenesis inhibitors, such as etomidate, ketoconazole, and metyrapone, are commonly used as first-line treatment for severe hypercortisolemia due to their rapid action and good efficacy and safety profile.
- Other medications, such as mifepristone, may also be used, but their use is limited due to difficulties in monitoring efficacy and safety.
Key Considerations
Key considerations in the management of Cushing's syndrome include:
- The need for careful patient monitoring and instruction to ensure treatment goals are met while minimizing adverse effects.
- The importance of timely and effective treatment to prevent substantial morbidity and mortality.
- The role of adrenally directed medical therapies in managing Cushing's syndrome, particularly in patients with persistent or recurrent hypercortisolism postoperatively or those who cannot undergo tumor-directed surgery.