Diagnosing and treating Cushingâ€™s syndrome is sometimes just as difficult as it was 70 years ago.
For as long as it has been described, Cushingâ€™s syndrome has presented physicians with a problem. Harvey Cushing first described it in 1932, and the diagnosis, differential diagnosis and treatment of Cushingâ€™s have remained a major challenge for endocrinologists ever since.
Though uncommon, it is difficult to consider Cushingâ€™s syndrome a rare occurrence. New research has shown Cushingâ€™s syndrome to have a substantially higher prevalence than previously thought. Unexpected endogenous hypercortisolism may occur in 0.5% to 1% of patients with hypertension, 2% to 3% with poorly controlled diabetes, 6% to 9% with incidental adrenal masses and 11% with osteoporosis and vertebral fractures.
â€œWe are gaining an appreciation that Cushingâ€™s is more common than it was once believed to be,â€ said Mary Ruppe, MD, endocrinologist at the University of Texas Health Science Center at Houston, and program committee chair of the Women in Endocrinology organization. â€œThis fact points to the need for data regarding the value of the different diagnostic approaches and for data regarding treatment/outcomes in populations with Cushingâ€™s.â€
As most of the characteristics of Cushingâ€™s are common in the general population, including obesity, depression and hypertension, it is extremely difficult for endocrinologists to decide on who should be screened for the disorder. A recent clinical review by Hershel Raff, PhD, and James W. Findling, MD, noted that as the number of patients in these high-risk groups continues to increase, the need for a sensitive and specific diagnostic test for Cushingâ€™s syndrome has become paramount.
The three most commonly performed diagnostic studies for Cushingâ€™s syndrome â€” urine-free cortisol, low-dose dexamethasone suppression test and the nocturnal salivary cortisol â€” are also not without hurdles. All three have been shown to produce false positives and false negatives.
Approximately 80% of patients with Cushingâ€™s syndrome have an adrenocorticotropic-secreting neoplasm from a pituitary tumor (Cushingâ€™s disease) or a nonpituitary neoplasm, and the treatment of Cushingâ€™s disease remains challenging for both endocrinologists and neurosurgeons as well. Transsphenoidal surgery is currently the standard treatment of choice in patients, but achieving surgical remission has been difficult as well.
â€œCushingâ€™s syndrome is a very rare but important diagnosis for the patient and endocrinologist. Confirming the diagnosis may be challenging, and before embarking on a costly set of tests, the endocrinologist should be reasonably assured that the patient indeed requires diagnostic exclusion by rigorous screening methods,â€ said Shlomo Melmed, MD, senior vice president of Academic Affairs at Cedars Sinai Medical Center, Los Angeles, and an Endocrine Today editorial board member
With more than 7.5 decades of research since Dr. Cushingâ€™s discovery, what are the best methods of diagnosis and treatment for Cushingâ€™s syndrome? Endocrine Today talked with leading researchers in the field to uncover the current trends in Cushingâ€™s syndrome treatment.
Laurence Katznelson, MD, associate professor of medicine and neurosurgery at Stanford University, and medical director of the pituitary program at Stanford Hospital and Clinics, explained to Endocrine Today the difficulty of deciding who should be screened for Cushingâ€™s syndrome. For instance, although the syndrome is associated with multiple comorbidities, including obesity, hypertension and depression, endocrinologists should be prepared to delve a little deeper into the symptoms to see if they warrant a screening test.
â€œThe presence of Cushingâ€™s syndrome should be considered if these medical conditions are present, though diagnostic testing should be performed only in subjects who have signs favoring Cushingâ€™s, such as demonstration of objective proximal weakness, spontaneous ecchymoses and violaceous striae,â€ Katznelson said.
â€œFor example, central obesity with supraclavicular and dorsicervical fat pads would favor a diagnosis of Cushingâ€™s syndrome, in contrast to the presence of generalized obesity,â€ he said.
Raff and Findling noted in a recent clinical review that endogenous cortisol excess also leads to fairly specific catabolic effects â€” including the thinning of the skin with easy bruising, abdominal striae, poor wound healing, immune suppression, rib fractures, hirsutism in women, acne and muscle wasting leading to proximal muscle weakness.
â€œThere is no clear guideline,â€ said Roberto Salvatori, MD, associate professor of medicine in the division of endocrinology at Johns Hopkins University School of Medicine. â€œYou need to keep your mind open.â€
â€œSometimes Cushingâ€™s is obvious. Sometimes, when it is mild, it may not be diagnosed for many years. One must screen a lot of patients to find one with Cushingâ€™s. However, anytime a physician thinks about the possibility of a patient having the disease, work-up should be initiated,â€ he said.
Opinions varied when Endocrine Today asked researchers which of the three tests for Cushingâ€™s syndrome was most reliable.
â€œNo test is 100% sensitive or specific,â€ Salvatori said. â€œI always use two, sometimes three, screening tests.â€ However, Salvatori noted he feels the night-time salivary cortisol test is the most reliable and easy to obtain.
Raff and Findling described the measurement of free cortisol in a 24-hour urine collection as being long considered the gold standard for the diagnosis of endogenous hypercortisolism. The test relies on the concept that as daily production of cortisol is increased, the free cortisol filtered and not reabsorbed or metabolized in the kidneys will be increased. They noted that current research has shown that many patients with mild Cushingâ€™s syndrome do not have elevations of urine-free cortisol, â€œmaking it a poor screening test for this condition.â€
The low-dose dexamethasone suppression test relies on the concept that the correct dose of dexamethasone will suppress ACTH, and cortisol will release in normal patients while patients with corticotroph adenomas will not suppress below a specified cut off. Raff and Findling noted that because of the significant variability of the biological behavior of corticotroph adenomas, research has shown that neither the overnight 1-mg dexamethasone suppression test nor the two-day low-dose dexamethasone suppression test appears to be reliable using the standard cutoffs for serum cortisol.
According to Raff and Findling, there is no diagnostic test used in the evaluation of Cushingâ€™s syndrome that performs better than the late night/midnight salivary cortisol method. The concept is based on the fact that patients with mild Cushingâ€™s syndrome fail to decrease cortisol secretion to its nadir at night. However, they still acknowledged that many factors, such as stress, sleep disturbances and psycho-neuroendocrine may falsely elevate nocturnal cortisol secretion.
â€œBecause each of these tests has associated false positives and negatives, a combination of these tests is often necessary for a valid diagnosis,â€ Katznelson said. â€œIn the end, these tests need to be considered in the context of a history and physical examination that favors this diagnosis.â€
Lynette Nieman, MD, associate director of the Intramural Endocrinology Training Program at the NIH, agreed. â€œOf the three recommended tests, each is useful in certain conditions,â€ she said. â€œI try to stress that the testing should be individualized since some tests are likely to be falsely positive in some situations, eg, a woman on birth control pills is likely to have a high corticosteriod-binding globulin, which might elevate serum cortisol.â€
Ruppe said the choice between the tests should be based on patient characteristics that will allow for adequate collection of each sample. â€œFor instance, the use of a late-night salivary cortisol measurement would be suboptimal in an individual who works the third shift and may not have an intact circadian rhythm, or the choice of a 24-hour urinary free cortisol may be suboptimal in an individual with urinary frequency or urinary incontinence.â€
Ruppe also noted that one possible improvement would be to improve standardization of the assays across different labs. â€œSince there is no standardization, the quality of the performance of the assay can vary across different facilities and centers,â€ she said.
Petrosol sinus sampling
Another controversial topic in the field is whether or not the inferior petrosol sinus should be sampled for an ACTH gradient to distinguish between Cushingâ€™s disease and occult ectopic ACTH syndrome.
The invasive procedure has proven to be relatively safe when performed by experienced radiologists, but not all medical centers have the capability.
A woman with mild hypercortisolism, a normal or slightly elevated plasma ACTH and normokalemia has an approximately 95% likelihood of having Cushingâ€™s disease before any differential diagnostic testing is performed, according to Raff and Findling. In contrast, a male patient with prodigious hypercortisolism of rapid onset, hypokalemia and marked elevations of plasma ACTH may be more likely to have an occult ectopic ACTH-secreting tumor.
About half of patients with ACTH-secreting microadenomas are estimated to have a normal pituitary MRI. In such situations, it is important to perform further testing, particularly an inferior petrosal sinus catheterization, to discern the presence of an ectopic ACTH-producing lesion, according to Katznelson.
â€œSome people would say that every patient should have it because it is the one best test for the differential diagnosis of ACTH-dependent Cushingâ€™s syndrome,â€ Nieman said. â€œHowever, patients in whom data strongly suggest Cushingâ€™s disease might forego it.â€
â€œIn a young woman with an MRI with a definitive adenoma and high-dose dexamethasone test showing less than 60% suppression, it is reasonable to proceed with surgery,â€ Salvatori said. â€œBut even the International Prostate Symptom Score is not 100% sensitive or specific.â€ Raff said that he disagrees with the high-dose dexamethasone test.
Fast Facts: Issues at Hand
Currently, transsphenoidal surgery is the primary treatment of Cushingâ€™s disease associated with an ACTH-secreting pituitary tumor. According to recent studies, remission rates after transsphenoidal pituitary microsurgery range from 42% to 86%.
Raff told Endocrine Today that the most important treatment recommendation that an endocrinologist makes to a patient with Cushingâ€™s disease is referral to a neurosurgeon with extensive experience.
â€œReferral to a neurosurgeon who is highly experienced in this procedure is critical,â€ Katznelson agreed. He noted that there have been studies demonstrating that both the degree of tumor bulk resection and rates of biochemical remission are increased for all types of pituitary tumors when the surgery is performed by a neurosurgeon with extensive experience in endonasal pituitary surgery.
â€œIn Cushingâ€™s disease, this is especially true,â€ Katznelson said. â€œBecause the tumors in this disorder are often small, if not microscopic, the surgical strategy may require dissection through the gland. In inexperienced hands, this may result in higher rates of hypopituitarism and lower rates of biochemical cure,â€ Katznelson said.
â€œThere is no doubt that the surgeonâ€™s experience influences the success rate,â€ Nieman said.
Constantine Stratakis, MD, with the National Institute of Child Health and Human Development, said he agreed, and stressed the importance of confirmation of diagnosis of Cushingâ€™s syndrome prior to a referral to a neurosurgeon.
â€œThere is nothing worse than an inexperienced surgeon operating on a patient with Cushingâ€™s or a surgeon operating on a patient who does not have a firm diagnosis of Cushingâ€™s syndrome,â€ Stratakis said.
â€œSurgery offers a reasonable chance for cure in the hands of an experienced neurosurgeon,â€ said Amir Hamrahian, MD, a staff physician at the Endocrinology Institute at the Cleveland Clinic. â€œWe are currently involved in two studies looking at new medications for medical treatment of patients with Cushingâ€™s syndrome. However, surgery is still the best initial approach for those not cured,â€ Hamrahian said.
â€œMedications are the future for patients with inoperable, recurrent Cushingâ€™s syndrome,â€ Stratakis said, referring to pasireotide (SOM230), a somatostatin analog.
He was part of a study in 2006 examining the in vitro effects of SOM230 on cell proliferation in human corticotroph tumors. Researchers found SOM230 significantly suppressed cell proliferation and ACTH secretion in primary cultures of human corticotroph tumors. They concluded that SOM230 may have a role in the medical therapy of Cushingâ€™s disease. Raff said he believes that clinical trials in patients with Cushingâ€™s disease who used SOM230 were not particularly successful. Anne Klibanski, MD, director of the neuroendocrine clinical center at Massachusetts General Hospital and primary investigator of the study, commented that in vitro studies play a critical role in assessing novel targeted pituitary tumor therapies. It is only in rigorous clinical trials that the overall efficacy and risks of such therapies can be established, she suggested.
Constantine Stratakis, MD
â€œMicrosurgical improvements will also be significant, but the major problem right now is the number of patients who are left untreated with recurrent disease,â€ Stratakis said. â€œFor them, there are very few options other than irradiation, so innovative medical treatments with molecularly designed compounds or targeted to specific receptors and/or functions of the pituitary are the most important advances that I see coming in the near future,â€ Stratakis said.
According to James Liu, MD, assistant professor of neurologic surgery at Northwestern University Feinberg School of Medicine in Evanston, Ill., the future appears bright in the battle against Cushingâ€™s.
â€œTechnical advances in surgery including endoscopic pituitary surgery and pseudocapsular dissection can improve surgical outcomes,â€ Liu said.
Katznelson said he hopes the future will bring improved diagnostic strategies important for detecting true Cushingâ€™s syndrome in the presence of multiple comorbidities. He noted that the ongoing research studies involving innovative medical therapeutic strategies that target the corticotroph adenoma itself, or block the effects of cortisol in the periphery, should bring new treatment options in the future.
â€œThese studies will hopefully lead to novel medical options for this syndrome,â€ Katznelson said. â€œThere have been significant advances in surgery, particularly with the development of minimally invasive, endoscopic surgery that has resulted in both improved biochemical outcomes and patient tolerability.â€ â€“ by Angelo Milone
For more information:
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* Batista DL, Zhang X, Gejman R, et al. The effects of SOM230 on cell proliferation and ACTH secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab.2006;91:4482-4488.
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