Cushing’s disease is caused by an ACTH-secreting pituitary adenoma resulting in excess cortisol levels.
For the great majority of patients with Cushing’s disease transsphenoidal tumor removal (via the nose) is the initial treatment of choice. Fortunately, this surgical technique in experienced hands at a Pituitary Center of Excellence has a relatively high rate of success. Notably, there have been major technical advances in endoscopic pituitary surgery over the last two decades that have helped improve surgical success rates, including high-definition endoscopy, surgical navigation techniques and more effective skull base closure methods.
At Pacific Pituitary Disorders Center we have one of the world’s largest experiences in endonasal endoscopic transsphenoidal surgery with over 1600 endonasal surgeries. Our Cushing’s disease surgeons led by Center Director and Neurosurgeon Dr. Daniel Kelly have extensive experience in diagnosing and successfully treating newly diagnosed and recurrent Cushing’s disease.
For those patients who do not achieve remission with surgery, we have highly experienced endocrinologists to provide the latest in medical therapy. Clinical trials are also available using novel medical therapies for patients with persistent Cushing’s disease after prior treatments. For patients with Cushing’s disease that is still uncontrolled after surgery and medical therapy, our radiation oncologists can use focused radiosurgery to help halt the disease and normalize cortisol levels; finally for patients with persistent Cushing’s disease after these treatments, bilateral adrenalectomy is an option, performed by expert endocrine surgeon Dr. Melanie Goldfarb.
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Cushing’s disease is caused by an ACTH-secreting pituitary adenoma, the vast majority of which are benign tumors (not cancerous). This serious endocrinopathy is a subset of Cushing’s syndrome which refers to elevated blood cortisol levels. Cushing’s syndrome results from tumors of the pituitary, adrenal glands or from tumors elsewhere in the body (ectopic ACTH producing tumors). The cause of Cushing’s syndrome is a pituitary adenoma in over 70% of patients.
Most ACTH adenomas are microadenomas. Cushing’s disease is relatively uncommon, affecting 10-15 of every million people each year, and most commonly in adults aged 20-50 years old; women account for over 70% of cases. Given that Cushing’s disease causes so many common problems affecting the general population such as obesity, hypertension and diabetes, it is possible that many patients with Cushing’s disease are undiagnosed for years or perhaps never diagnosed.
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Because excess cortisol has so many effects on different parts of the body and brain, symptoms of Cushing’s disease can present in many different and initially subtle ways. The major types of changes are in body habitus, blood glucose levels, blood pressure, bone and skin integrity, immune system and ability to fight infection, as well as sexual function and psychological state. Unfortunately, the diagnosis of Cushing’s disease is often long delayed.
Body changes including weight gain in the face (moon face), above the collar bone (supraclavicular) and on the back of the neck (buffalo hump) are commonly seen in patients with Cushing’s disease. Skin changes may include easy bruising, with purplish stretch marks (stria) and red cheeks (plethora) as well as excess hair growth (hirsutism) on the face and body. The high cortisol levels also cause weakness, fatigue and muscle wasting. Women may develop menstrual disorders including amenorrhea (absence of menses) and both women and men may develop decreased libido.
Additional serious consequences may include hypertension, diabetes mellitus, osteoporosis and depression. Patients are often diagnosed with Cushing’s disease after several years of symptoms which might include progressive weight gain, new onset hypertension or diabetes and mood changes. Comparison of old and recent photographs will often demonstrate changes in appearance. An Endocrinologist should always supervise the evaluation for Cushing’s disease.
The first step in diagnosing Cushing’s disease is to confirm excessive cortisol secretion which is done by performing a 24-hour urinary free cortisol collection, midnight salivary cortisol test and/or a low-dose dexamethasone suppression test. If blood ACTH levels are elevated or normal, then the source is from either an ACTH-secreting pituitary adenoma or an ectopic (elsewhere in the body) ACTH-producing tumor. A high-dose dexamethasone suppression test and/or petrosal sinus sampling are tests used to distinguish between ectopic ACTH production and pituitary ACTH production (Cushing’s disease). Petrosal sinus sampling should never be performed before the diagnosis of ACTH-dependent Cushing’s syndrome is established.
Once the diagnosis of Cushing’s syndrome is confirmed by hormonal testing, a pituitary MRI can detect an adenoma in 70-80% of cases. Dynamic post-gadolinium MRI is a recent technique that helps diagnose small adenomas that may not be seen on a conventional pituitary MRI. CT scans of the adrenal glands are very useful for determining the presence or absence of an adrenal tumor causing Cushing’s syndrome.
- Endonasal Endoscopic Surgery Surgical removal is the primary means to achieve long term remission in Cushing’s disease; at Pituitary Centers of Excellence, remission rates range from 80-90% for microadenomas and 30-70% for invasive adenomas or macroadenomas; for non-visible adenomas, the surgical success rate ranges from 40-60%. Because of improved visualization, the endonasal endoscopic approach is rapidly becoming the preferred method for removal of most pituitary adenomas, including ACTH-secreting adenomas. Long-term follow-up with 24 hour urinary free cortisol levels every 6 months is essential to monitor for tumor recurrence which can occur in 5 – 10% of patients.
- Medical Therapy In patients who fail to have remission of their Cushing’s disease or syndrome state after surgery, “adrenal-directed” medications can be used such as ketoconazole which inhibits steroid (cortisol) production in the adrenal glands. These are initially effective but have some side effects, and the overall long-term control of Cushing’s disease with these drugs is rather poor.
- Two Relatively New FDA-Approved Medical Therapies For patients with persistent Cushing’s disease after surgery, include Signifor (pasireotide) and Korlym (mifepristone). Both medications have shown moderate success in clinical trials. Pasireotide is an injectable somatostatin receptor ligand with strong affinity for somatostatin receptor 5. In clinical trials, pasireotide reduced urinary free cortisol (UFC) levels in a majority of Cushing’s disease patients. The main side effect is hyperglycemia. Mifepristone, is a glucocorticoid receptor blocker that can result in improvements in symptoms of Cushing’s and blood glucose control. The main side effects are adrenal insufficiency, low blood potassium levels and vaginal bleeding in women.
- Bilateral Adrenalectomy Removal of the adrenal glands was at one time a preferred method for treating Cushing’s disease and lowering cortisol levels. Currently however, this treatment is reserved for patients who have failed prior endonasal transsphenoidal surgery. Although bilateral adrenalectomy has a high success rate in reversing hypercortisolism ranging from 90% to 100%, there is significant risk (25%) of developing Nelson’s syndrome with an aggressive ACTH-secreting adenoma. Prior radiosurgery or radiotherapy to the pituitary gland may reduce the risk and delay onset of Nelson’s syndrome. The average interval between bilateral adrenalectomy and development of Nelson’s syndrome is approximately 5 to 10 years but may be as short as 6 months. Given the long-term risk of Nelson’s syndrome after bilateral adrenalectomy this treatment is generally considered a 2nd or 3rd line therapy.