Pseudo-Cushing’s syndrome is when symptoms are similar to those of Cushing’s syndrome, but further tests show that the syndrome is not present.
Common causes include consuming too much alcohol, obesity, persistently high blood glucose levels, pregnancy, and depression.
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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.
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.
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 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:
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.
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
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.
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.
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.
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
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
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.
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.
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
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Those “underlying medical conditions” include diabetes and obesity.
Murfreesboro Medical Clinic & SurgiCenter
272 Garrison Drive
Murfreesboro, TN 37129
615-893-4480
Murfreesboro Medical Clinic & SurgiCenter is committed to meeting the needs of Rutherford County’s growing community. In addition to adding two new locations in 2019, MMC will be adding five new doctors to its team of physicians.
The physicians joining MMC this fall are: Christopher Albergo, M.D. (Endocrinology), Lauren Blackwell, D.O. (Pediatrics), C. Brad Bledsoe, M.D. (Dermatology), Britni Caplin, M.D. (ENT), and Brittany Cook, M.D. (Ophthalmology).
“With a national shortage of physicians, it is becoming more and more challenging to find quality physicians to meet the growing healthcare needs of our community,” noted Joey Peay, MMC’s Chief Executive Officer. “For MMC to find five quality physicians to join us in 2019 in addition to the nine that began practicing at MMC in 2018 is truly remarkable! Each of them will be a valuable member of our medical team and a wonderful member of the Murfreesboro community.”
Christopher Albergo, M.D. is a board-certified Endocrinologist skilled in general endocrinology, including Hypothyroid, Parathyroid, Thyroid Cancer, Graves’ Disease, Pituitary disorders, Adrenal disorders, Hypogonadism , PCOS, Obesity, Diabetes and Osteoporosis.
Read about all the new doctors here: https://www.wgnsradio.com/murfreesboro-medical-clinic-surgicenter-is-proud-to-announce-the-addition-of-five-new-physicians-to-its-practice-in-2019–cms-53464
James Findling, MD, is a veteran of the endocrinology field, a clinical practitioner and a Cushing’s syndrome expert. For his efforts in these areas, particularly clinical practice, the Endocrine Society is honoring him with its Outstanding Clinical Practitioner Award at ENDO 2019 in New Orleans.
Findling, who currently serves as director of community endocrinology services and clinical professor of medicine at the Medical College of Wisconsin in Milwaukee, has made his clinical practice a national one as, according to the Endocrine Society, he receives referrals from across the U.S. In addition, he has played an important role in Cushing’s syndrome research, including breakthroughs that the Endocrine Society has incorporated into its own clinical practice guidelines.
In a conversation with Endocrine Today, Findling discussed his serendipitous entrance into endocrinology, his own experience with medical history and his dream of playing golf with Barack Obama.
What was the defining moment that led you to your field?
Findling: In 1977, I was a resident in internal medicine at what was then the Milwaukee County General Hospital, which doesn’t exist anymore. I did an endocrinology rotation, and my attending physician was James Cerletty, MD. Endocrinology was the farthest thing from my mind as something I would be interested in, but I was assigned to do this rotation and it changed my life. I thought, “Oh my goodness. This is fascinating.” Dr. Cerletty was a fabulous teacher and great mentor. The reason I chose endocrinology was because of that 1-month rotation. I had never done it previously, and I just fell in love with it. It was primarily because of this one man, who just died recently. He changed my life.
I was a chemistry major in college, and I enjoyed the pathophysiology and the biochemistry of it. I remember in those days, it was a little bit more complicated and convoluted to assess thyroid function, and it was never something I appreciated or understood. The concepts like T3 resin uptake I didn’t quite understand. Jim Cerletty made me understand how to interpret thyroid function studies, how they were done, how T3 resin uptake was measured, and it made all the difference in the world; a light bulb went off.
What area of research in endocrinology most interests you right now and why?
Findling: Pituitary-adrenal disorders. How I got interested in that, it’s kind of an interesting story in itself. After I did the month with Dr. Cerletty, I got interested in endocrinology, and 6 months later, I was in a general medical clinic seeing a woman with obesity, hypertension and diabetes. I went in and said to the attending physician at the time, “Well, maybe she has Cushing’s syndrome,” and I got kind of reamed out. “That’s rare. Nobody has that. It’s a stupid thing to think about.” He was trying to embarrass me and it upset me. I said, “How do you know she doesn’t have Cushing’s if you don’t do the testing?”
So, I started looking into it and realized nobody knows. Maybe some of these people with obesity and hypertension do have Cushing’s syndrome, but the testing was cumbersome and stupid and didn’t make any sense to me. About that time there was an article in The New England Journal of Medicine about pituitary surgery for Cushing’s disease from UCSF. I read that and said, “That’s where I’m going. I’m going there to learn about Cushing’s.” I applied and, fortunately, I got in and the rest is history. It’s because some attending physician embarrassed me by saying, “That’s stupid. Nobody could have Cushing’s syndrome,” and I’ve spent the rest of my life trying to figure that out. It’s been my passion for the last 40 years.
What advice would you offer a student in medical school today?
Findling: You need to find something that you’re passionate about in medicine. For many young people, that requires specialization into a relatively focused area so that they can develop a higher level of expertise. For some, that may be a more general area, and for some it may be based on location. For example, they might like to be a family physician in a small town where they can do a great deal of good. Either way, you must find something that you’re passionate about within our field, because if you’re not, you’re going to be unhappy. This is hard work and you’re going to spend many hours doing this, so you better find something you enjoy doing, whatever it is. There are so many different aspects from psychiatry to surgery to hospitals. There are so many different things you can do, but you have to find something that you like.
I hear a lot about work-life balance, and I understand that particularly in young physicians, this is a critically important part of being a doctor. The problem is if you’re going to be a physician, there’s going to be a lot of work. Half of your time or more is going to be working. You better enjoy that part of it because if you don’t enjoy the work part of it, you’re not going to enjoy the life part of it.
Have you ever been fortunate enough to witness or to have been part of medical history in the making?
Findling: I was lucky to go to University of California, San Francisco. Shortly after I got there, there were several people cloning the growth hormone gene and the insulin gene. The foundation of Genentech and the idea of making growth hormone was just fermenting at UCSF when I was there. In one of the labs was Herb Boyer, PhD, who was one of the first people to clone growth hormone, and he was on the cover of Time magazine. The head of the metabolic research unit and my boss was John Baxter, MD, who was president of the Endocrine Society years ago. There is now a prize named after him; he was on the cover of The New York Times magazine. So, here I am at UCSF and somebody in the lab down the hall is on the cover of Time magazine and my boss was on the cover of The New York Times magazine, so it was an exciting time to be at UCSF in the late ’70s and early ’80s.
Another defining moment in my career from a research perspective was when I was a fellow, I had to do a project. We were seeing a lot of patients with Cushing’s — of course, that’s why I went there — and in those days we had no good imaging. There were no CT scans, no MRI, there was no way to image the pituitary gland to find out whether there was a tumor. By the late ’70s it became obvious that some patients with Cushing’s syndrome didn’t have pituitary tumors. They had tumors in their lungs and other places, and there was no good way of sorting these patients from the pituitary patients.
My mentor at UCSF, Blake Tyrrell, MD, had the idea of sampling from the jugular vein to see if there was a gradient across the pituitary. I took the project up because I didn’t think this is going to be helpful due to there being too much venous admixture in the jugular vein from other sources of cerebral venous drainage. We went into the radiology suite to do the first patient. As I was sampling blood from the peripheral veins, the interventional radiologist, David Norman, MD, says, “Would you like to sample the inferior petrosal sinus?” I said, “Why not? It sounds like a good idea to me.” That turned out to be helpful. We then studied several patients, and it eventually went to publication. Now everybody acknowledges it is necessary, maybe not in all patients with Cushing’s, but in many patients with Cushing’s to separate pituitary from nonpituitary Cushing’s syndrome.
That was kind of a defining moment in terms of my research career because it was complete serendipity. I had never even heard of this vessel before. I went to the library to get a bunch of books to try to figure out what the venous drainage of the pituitary gland looked like. That was not easy to find. That was the defining moment of my research career as a postdoctoral fellow in endocrinology at UCSF. I was blessed because there were so many people smarter than me that it was a big help and an inspiration.
What do you think will have the greatest influence on your field in the next 10 years?
Findling: Most people would say genetics. The genetic diagnosis of so many disorders and the connection of disorders because of germline mutations or somatic mutations in tumors is just exploding. Whether you talk about pheochromocytomas, pituitary tumors in Cushing’s disease or adrenal tumors, you can go on and on and on.
Genetics wasn’t even on the radar screen when I was in training, so I feel a little bit lost because I’m behind the eight ball in terms of trying to keep up with that. Nobody was talking about that back in 1979, and I wish I understood it a lot better than I do. If I was going to think that there’s going to be anything that’s going to change the future of endocrinology it’s that, and not just for diagnosis but its potential applications for therapy.
What are your hobbies/interests outside of practicing medicine?
Findling: I’m an avid golfer. I live in Wisconsin, so right now it’s only 4° — so not too much golfing going on. I golf in the summer about once a week. I have a nice group of people I play with, and its one of my passions.
I run a lot. Not in 4° weather, but when the weather’s nice I run a lot and my goal is to run a half marathon this year. I’ve done one in the past, but it’s been many years since I’ve run one. I still enjoy running. Fortunately, my hips and knees and ankles and feet are capable of withstanding it. I don’t run very far. Maybe 8 to 10 miles per week.
I enjoy gardening. My wife and I, she loves flowers and I love vegetables, so we have a nice garden we put up every spring. So that’s another passion I have. We also love live theater, so we go to a lot of theater here in Milwaukee and all over Wisconsin.
Whom do you most admire and what would you ask that person if you had 5 minutes him/her?
Findling: The person I’d most like to meet is President Barack Obama. He’s one person I have a lot of admiration for. I would tell him I want more than 5 minutes. I’d want to play golf with him. I think his skill level is about the same as mine, so we’d have a competitive game. We’d probably do a lot of trash talking along the way.
I would ask him, “How did you stay so calm and have so much grace with all the criticism he got from so many people?” Some criticism is always a little bit justified, but a lot of it was so unjustified. How did he stay so calm and not raise his voice? Sometimes when you’re getting a lot of criticism and people are saying negative things about you, how do you stay professional and graceful? It’s not easy to do.
What was the last book you read , and what did you think of it?
Findling: The last one I finished was American Dervish. It’s a novel by Ayad Akhtar, who grew up in the suburbs of Milwaukee. His parents are from Pakistan, and he grew up as a Muslim. This young man is going to be a force in American literature.
This particular book is the story of a young Pakistani-American boy growing up in the American Midwest and a growing up story with the struggle of identity and religion. It’s a fascinating read.
In fact, Akhtar has won a Pulitzer Prize for one of his plays called Disgraced. He’s just had a play on Broadway that was nominated for a Tony Award called Junk, which the Milwaukee Repertory Theater just performed here. My wife and I saw it recently and it was entertaining
Much of what he’s written is regarding Muslims and the struggles they have living in the United States. If you haven’t seen one of his plays or read any of his stuff, I think he’s going to be a real force. He’s still a young man and he’s creative and provocative. This book, as I understand it, he’s going to make it into a play, and I wouldn’t be surprised if someday it might even be a movie. It’s an interesting perspective and I enjoyed it.
Kenz asked:
I got my lab work done.
I have all the symptoms of cushing’s Disease, from the buffalo hump and obesity to the easy bruising and the muscle weakness.
My cortisol levels came back normal, and I haven’t gotten the results of my ACTH yet.
Has anyone had normal cortisol levels come back and still had cushing’s Disease?
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