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Workup for Incidental Pituitary Adenoma
MaryO posted a topic in News Items and ResearchEach month, The Clinical Advisor makes one new clinical feature available ahead of print. Don’t forget to take the poll. The results will be published in the next month’s issue. A 35-year-old woman is seen in the outpatient clinic for evaluation of an incidental pituitary macroadenoma. Her medical history is significant for hypertension, diabetes, hyperlipidemia, polycystic ovary syndrome, and obesity. She initially presented to the emergency department (ED) a week ago after an episode of right visual field changes that she described as waviness in her right eye and right hemibody sensory changes without motor deficits. While in the ED, she underwent a full workup for possible stroke, which was negative. Magnetic resonance imaging (MRI) of her brain without contrast revealed a 12-mm pituitary lesion; a repeat MRI with contrast was then ordered (Figure). No serum hormonal panel was available for review from ED records. Figure. Magnetic resonance imaging of the case patient. Left image: sagittal view. Right image: coronal view with contrast. Credit: Melissa Wasilenko, MSN, RN Upon further questioning of her medical history during the clinic visit, the patient notes that a few years ago she was attempting to become pregnant and was evaluated by her gynecologist for amenorrhea. At that time, she reportedly completed an endocrine laboratory workup that showed a slightly elevated prolactin level between 30 and 40 ng/mL (normal level in nonpregnant women, <30 ng/mL). Per the patient, the minimal elevation was not enough to concern the gynecologist and no MRI was ordered at that time. Her gynecologist recommended that she lose weight. Her menses returned to normal with weight loss. With a history of disrupted menstrual cycles, infertility, and patient reported elevated prolactin level, there is high suspicion for endocrine disruption. A complete pituitary panel is ordered again to examine the current hormone function considering the recent MRI findings. This revealed a prolactin of 33.7 ng/ml, and all other hormonal levels were within normal limits. Because the patient reports multiple episodes of visual disturbances and the size of the pituitary adenoma on MRI, a neuro-ophthalmology referral is initiated for visual field testing and to determine if the pituitary macroadenoma is causing mass effect and compressing the optic nerve. The neuro-ophthalmologist found she had no visual field defect from her adenoma on visual field testing and believed that her visual disturbances were probably migraine in nature. Discussion Pituitary gland tumors are usually found incidentally on imaging studies obtained for other reasons or in workup of patients with abnormal endocrine hormone levels (both decreased and increased levels) or with symptoms of mass effect from the lesions.1 These tumors are typically benign in nature; cases with malignancy are extremely rare.1 The exact pathophysiology of pituitary adenomas remains unknown but is thought to be linked to heredity, hormonal influences, and genetic mutations.1 Pituitary tumors are commonly found in adults between the ages of 35 and 60 years of age.2,3 The estimated prevalence of pituitary adenomas varies widely by study and findings are typically based on autopsy and radiology data. Surveillance, Epidemiology, and End Results (SEER) Program data from 2004 to 2018 show an incidence rate of pituitary adenomas and pituitary incidentalomas of 4.28 ± 0.04 and 1.53 ± 0.02 per 100,000 population.4 Pituitary tumors have been found in 14.4% of unselected autopsy cases and 22.5% of radiology tests.1 The SEER data suggest that incidence rates are similar among women and men but are higher among women in early life and higher among males in later life.5 Rates of prolactinomas (prolactin-secreting tumors) and corticotropinomas (adrenocorticotropic hormone-secreting tumors; Cushing disease) are higher in women than men.6 Earlier SEER data showed a significantly higher incidence of pituitary adenomas in Black individuals compared with other racial/ethnic groups; several factors may account for this discrepancy such as the higher stroke rate in this population, which leads to a greater likelihood for brain imaging that detects incident pituitary tumors.5 Incidental findings of pituitary adenoma may be found during workup related to hormonal dysfunction (amenorrhea, galactorrhea, fertility disorders, sexual dysfunction), noticeable vision change, new-onset headaches, or imaging performed for other diagnostic purposes.7 Pituitary Types Pituitary tumor types are differentiated by location, size, and functional status. Pituitary tumors commonly arise from the anterior portion of the gland (adenohypophysis) and rarely from the posterior portion (neurohypophysis).2 Both adenohypophyseal and neurohypophyseal tumors are commonly benign and slow-growing.1 Malignant pituitary tumors account for less than 1% of pituitary lesions and are usually metastases from breast and lung cancers.3 Adenohypophyseal carcinoma is rare, with less than 140 reported cases.2 Pituitary tumors are categorized by the size1,2: Microadenomas (<10 mm) Macroadenomas (>10 mm to 40 mm) Giant adenomas (>40 mm) Pituitary adenomas are further classified as functioning (hormone-secreting) or nonfunctioning (nonsecreting).1,6 If the adenoma is functioning, hormone levels will be found in excess. If the levels are within normal limits, a nonfunctioning pituitary adenoma is suspected. Functioning Tumors Approximately 65% of all pituitary adenomas are functioning tumors.2 Functioning pituitary adenomas present in various ways depending on which hormone is involved and the level of hormone secretion. Prolactinomas are the most common type of functioning adenomas followed by growth hormone-secreting and adrenocorticotropic hormone-secreting pituitary tumors. Adenomas secreting thyrotropin and follicle-stimulating hormone are less commonly found.2 Clinical features of functional pituitary adenomas are outlined in Table 1.2.8 Table 1. Clinical Features and Laboratory Findings of Functioning Pituitary Adenomas Nonfunctioning Tumors Approximately 20% to 30% of pituitary adenomas are nonfunctional.3 These tumors may go undiagnosed for years until the mass of the tumor starts to effect surrounding structures and causing secondary symptoms such as compression of the optic chiasm causing vision impairments. Nonfunctioning pituitary adenomas and prolactinomas (functioning) are the 2 most common types of pituitary adenomas.2,3 The consulting clinician must understand the difference in pathology of these 2 types of lesions, what diagnostic test to order, how to interpret the test results, and which specialty to refer the patient to best on the initial workup findings. Initial Workup Proper baseline workup should be initiated before referring patients with incidental pituitary adenoma to a specialist. The initial workup includes imaging, blood work to determine if the pituitary adenoma is causing hormonal dysfunction, and neuro-ophthalmology referral for visual field testing to determine if the optic nerve/chiasm is impacted. Imaging The most accurate diagnostic modality of pituitary gland pathology is MRI with and without contrast. The MRI should focus on the hypothalamic-pituitary area and include contrasted imaging to evaluate the soft tissue within the intracranial structure.9 The coronal and sagittal views are the best to display the pituitary gland width and height and identify abnormalities.9 The MRI provides a detailed evaluation of the pituitary gland related to adjacent structures within the skull, which helps to detect microalterations of the pituitary gland.10 If a pituitary adenoma is an incidental finding on another imaging modality (such as a computed tomography scan or MRI without contrast), an MRI with and without contrast that focuses on the pituitary gland should be obtained. Pituitary Laboratory Panel A complete pituitary panel workup should be obtained including prolactin, thyrotropin, free thyroxine, cortisol (fasting), adrenocorticotropic hormone, insulinlike growth factor 1, growth hormone, follicle-stimulating hormone, luteinizing hormone, estradiol in women, and total testosterone in males.1 Tests should be completed in the morning while fasting for the most accurate results. For instance, normally cortisol levels drop during fasting unless there is abnormality. Table 2 below shows normal laboratory ranges for a complete pituitary panel. Serum prolactin levels can slightly increase in response to changes in sleep, meals, and exercise; emotional distress; psychiatric medications; and oral estrogens. If the initial prolactin level is borderline high (21-40 ng/mL), the test should be repeated. Normal levels are higher in women than in men. Microadenomas may cause slight elevations in prolactin level (ie, <200 ng/mL), while macroadenomas are likely to cause greater elevations (ie, >200 ng/mL).1 Patients with giant prolactinomas typically present with prolactin levels ranging from 1000 ng/mL to 100,000 ng/mL.11 Perimetry Pituitary adenomas may cause ophthalmologic manifestations ranging from impaired visual field to diplopia because of upward displacement of the optic chiasm. The optic chiasm is located above the pituitary gland and a pituitary tumor that grows superiorly can cause compression in this area.12 Optic chiasm compression from a pituitary adenoma commonly causes bitemporal hemianopsia.2 If the tumor volume is promptly reduced by surgical resection or medication (in the case of prolactinomas), initial vision changes due to compression may be reversible.12 Baseline and routine follow-up perimetry are important in patients with pituitary adenoma, as symptoms of optic chiasm compression may go unnoticed by patients as visual field deficits often develop gradually. Also, post-treatment perimetry assessments can be used to compare the initial testing to evaluate reversible visual field deficits. It is recommended that patients with pituitary adenomas (both function and nonfunctiong) receive neuro-ophthalmologic evaluations twice a year to ensure no visual changes have occurred.12 Referral to a Specialist Management of pituitary adenomas requires a multidisciplinary team of specialists including endocrinologists, neurosurgeons, and neuro-ophthalmologists. The type of adenoma governs which specialist patients with incidental adenoma should see first. Patients with functioning pituitary adenomas should be referred to an endocrinologist before a neurosurgeon. The most prevalent functioning adenomas, prolactinoma, are initially treated with dopamine agonist medications.1,6 A patient with prolactinoma would only need to see a neurosurgeon if they have a macroadenoma that is not responsive or only partially responsive to dopamine agonists therapy or is causing vision deficits related to compression of the optic chiasm.2 Patients with nonfunctioning pituitary adenomas should first be referred to a neurosurgeon to discuss surgical options versus observation. The recommended treatment for patients with nonfunctioning adenomas and clinical features of mass effect (ie, visual deficits) is surgery.1,6 If the patient is asymptomatic with no signs of visual field deficits, the neurosurgery team may recommend continued surveillance with serial imaging and serial perimetry screenings.12 The patient in the case was found to have a nonfunctioning pituitary adenoma (prolactin was 33.7 ng/mL). Neuro-ophthalmology did not find any visual field defect upon initial assessment; the patient decided to continue observation with serial imaging (MRI) and serial neuro-ophthalmology assessments. Serial imaging with MRI brain revealed slow but real progression of the pituitary macroadenoma (12 mm initially; 13 mm 6 months later; and 14 mm 1 year from initial MRI findings). Although the patient still did not have any visual field defects per the neuro-ophthalmology reassessments, the documented growth on MRI over a short period of time was enough to make the patient more amendable to surgical resection. The patient underwent trans-sphenoidal resection of the pituitary lesion approximately 16 months after discovery of the tumor. Conclusion A thorough workup including laboratory testing, imaging, and vision field testing is the foundation of an effective referral process for pituitary adenomas and guides which specialist is consulted first. If patients are referred before initial workup is completed, delays in care, unnecessary specialty visits, and increased overall health care costs may occur. Melissa Wasilenko, MSN, RN, is a registered nurse at Lyerly Neurosurgery in Jacksonville, Florida. She is currently pursuing a doctorate in nursing practice with a focus in family medicine at the University of North Florida in Jacksonville. References 1. Russ S, Anastasopoulou C, Shafiq I. Pituitary adenoma. 2021 Jul 18. In: StatPearls. StatPearls Publishing; 2022 Jan–. Updated July 18, 2021. 2. Greenberg MS. Tumors of non-neural origin. In: Handbook of Neurosurgery, 9th ed. Thieme Medical Publishers: 2019; 1655-1755 3. Yeung M, Tahir F. The pathology of the pituitary, parathyroids, thyroid and adrenal glands. Surgery. 2020;38(12):747-757. 4. Watanabe G, Choi SY, Adamson DC. Pituitary incidentalomas in the United States: a national database estimate. World Neurosurg. 2021:S1878-8750(21)01780-0. doi:10.1016/j.wneu.2021.11.079 5. McDowell BD, Wallace RB, Carnahan RM, Chrischilles EA, Lynch CF, Schlechte JA. Demographic differences in incidence for pituitary adenoma. Pituitary. 2011;14(1):23-30. doi:10.1007/s11102-010-0253-4 6. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516-524. doi:10.1001/jama.2016.19699 7. Yao S, Lin P, Vera M, et al. Hormone levels are related to functional compensation in prolactinomas: a resting-state fMRI study. J Neurol Sci. 2020;411:116720. doi:10.1016/j.jns.2020.116720 8. Beck-Peccoz P, Persani L, Lania A. Thyrotropin-secreting pituitary adenoma. In: Feingold KR, Anawalt B, Boyce A, et al, ed. Endotext. MDText.com, Inc.; 2019. 9. Yadav P, Singhal S, Chauhan S, Harit S. MRI evaluation of size and shape of normal pituitary gland: age and sex related changes. J Clin Diagnostic Research. 2017;11(12):1-4. doi:10.7860/JCDR/2017/31034.10933 10. Varrassi M, Cobianchi Bellisari F, Bruno F, et al. High-resolution magnetic resonance imaging at 3T of pituitary gland: advantages and pitfalls. Gland Surg. 2019;8(Suppl 3):S208-S215. doi:10.21037/gs.2019.06.08 11. Shimon I. Giant prolactinomas. Neuroendocrinology. 2019;109(1):51-56. doi:10.1159/000495184 12. Vié AL, Raverot G. Modern neuro-ophthalmological evaluation of patients with pituitary disorders. Best Pract Res Clin Endocrinol Metab. 2019;33(2):101279. doi:10.1016/j.beem.2019.05.003 From the March/April 2022 Issue of Clinical Advisor
Cushing’s Syndrome: A Tale of Frequent Misdiagnosis
MaryO posted a topic in Cushing's BasicsJessica Rotham, National Center for Health Research What is it? Cushing’s syndrome is a condition you probably have never heard of, but for those who have it, the symptoms can be quite scary. Worse still, getting it diagnosed can take a while. Cushing’s syndrome occurs when the tissues of the body are exposed to high levels of cortisol for an extended amount of time. Cortisol is the hormone the body produces to help you in times of stress. It is good to have cortisol at normal levels, but when those levels get too high it causes health problems. Although cortisol is related to stress, there is no evidence that Cushing’s syndrome is directly or indirectly caused by stress. Cushing’s syndrome is considered rare, but that may be because it is under-reported. As a result, we don’t have good estimates for how many people have it, which is why the estimates for the actual number of cases vary so much–from 5 to 28 million people. The most common age group that Cushing’s affects are those 20 to 50 years old. It is thought that obesity, type 2 diabetes, and high blood pressure may increase your risk of developing this syndrome. What causes Cushing’s Syndrome? Cushing’s syndrome is caused by high cortisol levels. Cushing’s disease is a specific form of Cushing’s syndrome. People with Cushing’s disease have high levels of cortisol because they have a non-cancerous (benign) tumor in the pituitary gland. The tumor releases adrenocorticotropin hormone (ACTH), which causes the adrenal glands to produce excessive cortisol. Cushing’s syndrome that is not Cushing’s disease can be also caused by high cortisol levels that result from tumors in other parts of the body. One of the causes is “ectopic ACTH syndrome.” This means that the hormone-releasing tumor is growing in an abnormal place, such as the lungs or elsewhere. The tumors can be benign, but most frequently they are cancerous. Other causes of Cushing’s syndrome are benign tumors on the adrenal gland (adrenal adenomas) and less commonly, cancerous adrenal tumors (adrenocortical carcinomas). Both secrete cortisol, causing cortisol levels to get too high. In some cases, a person can develop Cushing’s syndrome from taking steroid medications, such as prednisone. These drugs, known as corticosteroids, mimic the cortisol produced by the body. People who have Cushing’s syndrome from steroid medications do not develop a tumor. What are the signs and symptoms of Cushing’s Syndrome? The appearance of people with Cushing’s syndrome starts to change as cortisol levels build up. Regardless of what kind of tumor they have or where the tumor is located, people tend to put on weight in the upper body and abdomen, with their arms and legs remaining thin; their face grows rounder (“moon face”); they develop fat around the neck; and purple or pink stretch marks appear on the abdomen, thighs, buttocks or arms. Individuals with the syndrome usually experience one or more of the following symptoms: fatigue, muscle weakness, high glucose levels, anxiety, depression, and high blood pressure. Women are more likely than men to develop Cushing’s syndrome, and when they do they may have excess hair growth, irregular or absent periods, and decreased fertility. Why is Cushing’s Syndrome so frequently misdiagnosed? These symptoms seem distinctive, yet it is often difficult for those with Cushing’s syndrome to get an accurate diagnosis. Why? While Cushing’s is relatively rare, the signs and symptoms are common to many other diseases. For instance, females with excess hair growth, irregular or absent periods, decreased fertility, and high glucose levels could have polycystic ovarian syndrome, a disease that affects many more women than Cushing’s. Also, people with metabolism problems (metabolic syndrome), who are at higher than average risk for diabetes and heart disease, also tend to have abdominal fat, high glucose levels and high blood pressure. Problems in testing for Cushing’s When Cushing’s syndrome is suspected, a test is given to measure cortisol in the urine. This test measures the amount of free or unbound cortisol filtered by the kidneys and then released over a 24 hour period through the urine. Since the amount of urinary free cortisol (UFC) can vary a lot from one test to another—even in people who don’t have Cushing’s—experts recommend that the test be repeated 3 times. A diagnosis of Cushing’s is given when a person’s UFC level is 4 times the upper limit of normal. One study found this test to be highly accurate, with a sensitivity of 95% (meaning that 95% of people who have the disease will be correctly diagnosed by this test) and a specificity of 98% (meaning that 98% of people who do not have the disease will have a test score confirming that). However, a more 2010 study estimated the sensitivity as only between 45%-71%, but with 100% specificity. This means that the test is very accurate at telling people who don’t have Cushing’s that they don’t have it, but not so good at identifying the people who really do have Cushing’s. The authors that have analyzed these studies advise that patients use the UFC test together with other tests to confirm the diagnosis, but not as the initial screening test. Other common tests that may be used to diagnose Cushing’s syndrome are: 1) the midnight plasma cortisol and late-night salivary cortisol measurements, and 2) the low-dose dexamethasone suppression test (LDDST). The first test measures the amount of cortisol levels in the blood and saliva at night. For most people, their cortisol levels drop at night, but people with Cushing’s syndrome have cortisol levels that remain high all night. In the LDDST, dexamethasone is given to stop the production of ACTH. Since ACTH produces cortisol, people who don’t have Cushing’s syndrome will get lower cortisol levels in the blood and urine. If after giving dexamethasone, the person’s cortisol levels remain high, then they are diagnosed with Cushing’s. Even when these tests, alone or in combination, are used to diagnose Cushing’s, they don’t explain the cause. They also don’t distinguish between Cushing’s syndrome, and something called pseudo-Cushing state. Pseudo-Cushing state Some people have an abnormal amount of cortisol that is caused by something unrelated to Cushing’s syndrome such as polycystic ovarian syndrome, depression, pregnancy, and obesity. This is called pseudo-Cushing state. Their high levels of cortisol and resulting Cushing-like symptoms can be reversed by treating whatever disease is causing the abnormal cortisol levels. In their study, Dr. Giacomo Tirabassi and colleagues recommend using the desmopressin (DDAVP) test to differentiate between pseudo-Cushing state and Cushing’s. The DDAVP test is especially helpful in people who, after being given dexamethasone to stop cortisol production, continue to have moderate levels of urinary free cortisol (UFC) and midnight serum cortisol. An additional test that is often used to determine if one has pseudo-Cushing state or Cushing’s syndrome is the dexamethasone-corticotropin-releasing hormone (CRH) test. Patients are injected with a hormone that causes cortisol to be produced while also being given another hormone to stop cortisol from being produced. This combination of hormones should make the patient have low cortisol levels, and this is what happens in people with pseudo-Cushing state. People with Cushing’s syndrome, however, will still have high levels of cortisol after being given this combination of hormones. How can Cushing’s be treated? Perhaps because Cushing’s is rare or under-diagnosed, few treatments are available. There are several medications that are typically the first line of treatment. None of the medications can cure Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails. The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and remove the tumor. Radiation may also be used instead of surgery to shrink the tumor. In patients whose Cushing’s is caused by ectopic ACTH syndrome, all cancerous cells need to be wiped out through surgery, chemotherapy, radiation or a variety of other methods, depending on the location of the tumor. Surgery is also recommended for adrenal tumors. If Cushing’s syndrome is being caused by corticosteroid (steroid medications) usage, the treatment is to stop or lower your dosage. Medications to control Cushing’s (before treatment or if treatment fails) According to a 2014 study in the Journal of Clinical Endocrinology and Metabolism, almost no new treatment options have been introduced in the last decade. Researchers and doctors have focused most of their efforts on improving existing treatments aimed at curing Cushing’s. Unfortunately, medications used to control Cushing’s prior to treatment and when treatment fails are not very effective. Many of the medications approved by the FDA for Cushing’s syndrome and Cushing’s disease, such as pasireotide, metyrapone, and mitotane, have not been extensively studied. The research presented to the FDA by the makers of these three drugs did not even make clear what an optimal dose was. In another 2014 study, published in Clinical Epidemiology, researchers examined these three same drugs, along with ten others, and found that only pasireotide had moderate evidence to support its approval. The other drugs, many of which are not FDA approved for Cushing’s patients, had little or no available evidence to show that they work. They can be sold, however, because the FDA has approved them for other diseases. Unfortunately, that means that neither the FDA nor anyone else has proven the drugs are safe or effective for Cushing patients. Pasireotide, the one medication with moderate evidence supporting its approval, caused hyperglycemia (high blood sugar) in 75% of patients who participated in the main study for the medication’s approval for Cushing’s. As a result of developing hyperglycemia, almost half (46%) of the participants had to go on blood-sugar lowering medications. The drug was approved by the FDA for Cushing’s anyway because of the lack of other effective treatments. Other treatments used for Cushing’s have other risks. Ketoconazole, believed to be the most commonly prescribed medications for Cushing’s syndrome, has a black box warning due to its effect on the liver that can lead to a liver transplant or death. Other side effects include: headache, nausea, irregular periods, impotence, and decreased libido. Metyrapone can cause acne, hirsutism, and hypertension. Mitotane can cause neurological and gastrointestinal symptoms such as dizziness, nausea, and diarrhea and can cause an abortion in pregnant women. So, what should you do if you suspect you have Cushing’s Syndrome? Cushing’s syndrome is a serious disease that needs to be treated, but there are treatment options available for you if you are diagnosed with the disease. If the symptoms in this article sound familiar, it’s time for you to go see your doctor. Make an appointment with your general practitioner, and explain your symptoms to him or her. You will most likely be referred to an endocrinologist, who will be able to better understand your symptoms and recommend an appropriate course of action. All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff. Nieman, Lynette K. Epidemiology and clinical manifestations of Cushing’s syndrome, 2014. UpToDate: Wolters Kluwer Health Cushing’s syndrome/ disease, 2013. American Association of Neurological Surgeons. http://www.aans.org/Patient Information/Conditions and Treatments/Cushings Disease.aspx Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Newell-Price, John, Peter Trainer, Michael Besser and Ashley Grossman. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states, 1998. Endocrine Reviews: Endocrine Society Carroll, TB and JW Findling. The diagnosis of Cushing’s syndrome, 2010. Reviews in Endocrinology and Metabolic Disorders: Springer Ifedayo, AO and AF Olufemi. Urinary free cortisol in the diagnosis of Cushing’s syndrome: How useful?, 2013. Nigerian Journal of Clinical Practice: Medknow. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society. Galdelha, Monica R. and Leonardo Vieira Neto. Efficacy of medical treatment in Cushing’s disease: a systematic review, 2014. Clinical Endocrinology: John Wiley & Sons. Adler, Gail. Cushing syndrome treatment & management, 2014. MedScape: WebMD. Adapted from https://www.center4research.org/cushings-syndrome-frequent-misdiagnosis/?fbclid=IwAR1lfJPilmaTl1BhR-Esi69eU7Xjm3RlO4f8lmFBIviCtHHXmVoyRxOlJqE