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This article is based on reporting that features expert sources. Adrenal Fatigue: Is It Real? More You may have heard of so-called 'adrenal fatigue,' supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money. (GETTY IMAGES) Physicians tend to talk about 'reaching' or 'making' a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as 'perpetrating a diagnosis,' 'misdiagnosis,' 'made-up diagnosis,' 'a fallacy' and 'nonsense.' About 20 years ago, the term "adrenal fatigue" was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue. "The phenomenon emerged from the world of integrative medicine and naturopathic medicine," says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. "It has no scientific basis, and there's no merit to it as a clinical diagnosis." An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for 'adrenal fatigue' among the 331 diagnoses related either to fatigue or adrenal conditions or procedures. In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements "to treat common nonspecific symptoms due to 'adrenal fatigue,' an entity that has not been recognized as a legitimate diagnosis." The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system. Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: "Adrenal fatigue does not exist," according to review authors in the journal BMC Endocrine Disorders. Adrenal Action You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone. Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle. As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis. While some health conditions really do affect the body's cortisol-making ability, adrenal fatigue isn't among them. "There's no evidence to support that adrenal fatigue is an actual medical condition," says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. "There's no stress connection in the sense that someone's adrenal glands will all of a sudden just stop producing cortisol because they're so inundated with emotional stress." If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. "The last thing in the body that's going to fatigue are your adrenal glands," says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. "Adrenal glands are built for stress – that's what they do. Adrenal glands don't fatigue. This is made up – it's a fallacy." The idea of adrenal glands crumbling under stress is "ridiculous," Findling agrees. "In reality, if you take a person and subject them to chronic stress, the adrenal glands don't shut down at all," Findling says. "They keep making cortisol – it's a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don't stop." Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. "Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day," he says. "And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue." Saliva cortisol is a legitimate test that's frequently used in diagnosing Cushing's syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. "What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day," he says. "Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support." Loaded Supplements How do you know what you're actually getting if you buy a dietary supplement marketed for adrenal fatigue or 'adrenal support' use? To find out, researchers purchased 12 such supplements over the counter in the U.S. Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. "These results may highlight potential risks for hidden ingredients in unregulated supplements," the authors concluded. Supplements containing thyroid hormones or steroids can interact with a patient's prescribed medications or have other side effects. "Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times," Vouyiouklis Kellis says. "Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better." Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows' adrenal glands, "can shut off the pituitary," Vouyiouklis Kellis explains. "Because it's signaling to the pituitary like: Hey, you don't need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn't produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol." Some adrenal support products, such as herbal-only supplements, may be harmless. However, they're unlikely to relieve chronic fatigue. Fatigue: No Easy Answers If you're suffering from ongoing fatigue, it's frustrating. And you're not alone. "I have fatigue," Young Jr. says. "Go to the lobby any given day and say, 'Raise your hand if you have fatigue.' Most of the people are going to raise their hands. It's a common human symptom and people would like an easy answer for it. Usually there's not an easy answer. I think 'adrenal fatigue' is attractive because it's like: Aha, here's the answer." There aren't that many causes of endocrine-related fatigue, Young Jr. notes. "Hypothyroidism – when the thyroid gland is not working – is one." Addison's disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated. "In adrenal insufficiency, there is an intrinsic problem in the adrenal gland's inability to produce cortisol," Vouyiouklis Kellis explains. "That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol." Issues can arise even with necessary medications. "For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems," Vouyiouklis Kellis says. "And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol." Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency. Common symptoms of adrenal insufficiency include: Fatigue. Weight loss. Decreased appetite. Salt cravings. Low blood pressure. Abdominal pain. Nausea, vomiting or diarrhea. Muscle weakness. Hyperpigmentation (darkening of the skin). Irritability. Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland. "If the person does not have adrenal insufficiency and they're still fatigued, it's important to get to the bottom of it," Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes. "It's very important to tease out what's going on," Vouyiouklis Kellis emphasizes. "It can be multifactorial – multiple things contributing to the patient's feeling of fatigue." The blood condition anemia – a lack of healthy red blood cells – is another potential cause. "If you are fatigued, do not treat yourself," Vouyiouklis Kellis says. "Please seek a physician or a primary care provider for evaluation, because you don't want to go misdiagnosed or undiagnosed. It's very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first." SOURCES The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines. James Findling, MD Findling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. Mary Vouyiouklis Kellis, MD Vouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic. William F. Young Jr., MD Young Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?
MeganOrrMD, JamesFindlingMD, NathanZwagermanMD, JenniferConnellyMD, KatherineAlbanoMS, JosephBoviMD Show more https://doi.org/10.1016/j.adro.2021.100813Get rights and content Under a Creative Commons license open access Abstract Pituitary carcinoma (PC) is an uncommon intracranial malignancy with a high rate of metastasis, mortality, and inconsistent response to therapy. Because PC is a rare condition (0.1%-0.2% of pituitary tumors), prospective studies and observable data are scarce. Some PC may have an endocrine secretory function and can arise from existing pituitary adenomas. Treatment often includes a combination of surgical resection, radiotherapy, and systemic therapies. Because of the poor treatment response rate and rapid progression, treatment is often palliative. Here we describe a unique, complete amelioration of severe Cushing's disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation with concurrent temozolomide. Summary Pituitary carcinoma is a rare malignancy with high rates of metastases at diagnosis, inconsistent therapeutic response, and high mortality. Treatment includes a combination of surgical resections, radiotherapy, and medications. Because of the poor treatment response rate and rapid progression, treatment is often palliative. This report describes the complete resolution of severe Cushing's disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation and concurrent temozolomide radio-sensitization. Introduction Pituitary adenomas (PA) are a common, benign tumor managed with combinations of surgery, radiotherapy, and medication. While uncommon, there are atypical PA with aggressive behaviors that are refractory to treatment. In rare instances, pituitary tumors can metastasize or spread. These malignant behaving tumors are called pituitary carcinomas (PC). PC is challenging to manage as they metastasize early and have a poor response to treatment. In reported PC cases, malignant transformation of atypical adrenocorticotrophic hormone (ACTH) secreting PA is a common pathogenesis.1 Features of PC include functional ACTH production and resistance to radiation. Because of the aggressive nature and systemic spread, the prognosis is poor with a high mortality rate of 66% at one year.2 Prospective studies and observable data are scarce. Prior reports of treatment include a combination of surgical resection, radiotherapy, and medication with inconsistent responses. Because of the poor treatment response rate and rapid progression, treatment is often palliative. This report describes a complete resolution of severe Cushing disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation with concurrent temozolomide. Case Description A 53-year female presented with complaints of blurry vision, right-sided cranial nerve (CN) III palsy, diffuse edema of her face and extremities, and a 15 lb. weight gain over 2 weeks. Visual field testing revealed bitemporal hemianopsia which prompted imaging. MRI demonstrated a large intracranial sellar mass (4.0 × 4.3 cm) invading the suprasellar cistern and compressing the optic chiasm. ACTH and cortisol were elevated, which combined with radiographic evidence, established a diagnosis of an ACTH-secreting pituitary macroadenoma and Cushing's disease (CD). The patient underwent a transsphenoidal tumor debulking, followed by CyberKnife stereotactic radiosurgery two months after surgery (treated to 24 Gy, seeTable 2). Pathology revealed an atypical PA, positive for p53 and with a low Ki-67 index. Table 1. Clinical Course Date Condition 24 h urinary cortisol* Late salivary cortisol* Serum morning cortisol* ACTH* Nov 2009 Before 1st debulking surgery 3,192 N/A N/A 635 Feb 2010 Cyberknife 6.9 1.5 9.6 134 May 2014 Redo-Debulking 40.2 5.5 11.8 190.0 August 2017 3 months post RT 20.1 5.5 39.4 240.8 May 2018 1 year post RT 16.0 5.9 12.6 199.8 Feb 2019 1 year and 6 months post RT 2.1 3.6 6.8 111.8 Jan 2020 Post 3rd Debulking N/A N/A 8.4 88.5 ⁎ 24h urinary cortisol (NR:30-310 ug/24h). Late salivary cortisol(NR < 0.13 ug/dL). Serum morning cortisol (NR: 5-25 ug/dL). ACTH (NR <46 pg/dL) GC: glucocorticoids, CS: Cushing syndrome Table 2. CyberKnife Radiation Treatment Plan Cyber Knife Feb 2010 Target/OAR Volume(cm3) Max Dose(cGy) Min Dose(cGy) Mean Dose(cGy) Standard deviation (SD)(cGy) CTV 7 2817 1214 2403 240 PTV 6 2817 1323 2457 204 Brain Stem 34 1023 28 250 160 Left Eye 7 65 16 29 7 LON 2 1069 39 233 223 Optic Chiasm 1 845 194 448 164 Right Eye 7 164 16 31 12 RON 2 1267 48 298 216 After three years in remission, she experienced worsening symptoms associated with cortisol excess. Medical management of cabergoline (D2 receptor agonist) followed by pasireotide (somatostatin analog) was tried without clinical improvement. Imaging demonstrated the mass had recurred with non-congruent intracranial spread. This noncontiguous intracranial growth met the criteria for PC. A second transsphenoidal subtotal resection was performed. Pathology revealed atypical ACTH secreting adenoma with a similarly low Ki-67, but with a new loss of p53 signaling. Despite debulking, she had biochemical persistence of hypercortisolism. Over the next two months, the patient declined rapidly with weakness, and worsening Cushing's symptoms. She was enrolled in a Phase III clinical trial with osilodrostat (11-Beta hydroxylase inhibitor) however, could not tolerate the investigational drug and was taken off. Subsequent MRI showed evidence of progression with gross residual disease and interval growth. She was referred to radiation oncology. She completed a course of image-guided, intensity modulated, radiotherapy (IG-IMRT) with concurrent temodar (TMZ) radiosensitization. TMZ was dosed at 75 mg/m2 per day for 42 days during radiation. Her IG-IMRT plan consisted of a gross tumor volume (GTV); drawn for MR defined gross disease and a clinical target volume (CTV) encompassing gross disease at risk areas of microscopic disease extension (Figure 1). These volumes were then expanded to 2 planning target volumes (PTV). The first, and larger, PTV was created by expanding the CTV to PTV1 and treated to 50.4 Gy in 28 fractions (180 cGy/fraction). The GTV alone was expanded to PTV2 (integrated boost) and was treated to a total dose of 56 Gy in 28 fractions (200 cGy/fraction) (See Table 3). Over the next two years, the patient had a steady decline in ACTH and cortisol levels and experienced a significant improvement in CD symptoms. Amazingly, she developed hypocortisolemia. Following concurrent chemo-RT, her leg strength and ambulation improved, and she endorsed improvements in vision. Surveillance images taken a year and a half after chemo-RT showed stable size and configuration of the residual sella and parasellar lesion with obvious shrinkage of the residual PC compared to prior scans. Download : Download high-res image (798KB) Download : Download full-size image Figure 1. IG-IMRT Planning Images Radiotherapy Planning session MRI T1 weighted images with contrast (March 2017) showing PTV's and prescribed isodose lines. Red lines: 5600 cGy, dose1. Yellow lines: 5040 cGy, dose 2. Orange lines: PTV1. Purple lines: PTV2. Table 3. IG-IMRT Radiation Treatment Plan IG-IMRT May 2017 Target/OAR Volume(cm3) Max Dose(cGy) Min Dose(cGy) Mean Dose(cGy) SD(cGy) EqD2 (cGy) GTV 83 6091 4922 5621 233 CTV 24 6083 5292 5793 102 PTV 1 241 6118 4753 5423 270 PTV 2 51 6118 5074 5779 106 Brain Stem 32 5784 2374 4701 586 4324 CHIASM PRV 5 5640 4881 5266 171 5109 Eye_L 8 3173 537 1355 574 841 Eye_R 7 3680 542 1551 644 990 EyeLens_L 0.1 997 614 765 81 435 EyeLens_R 0.1 830 626 719 41 406 InnerEar_L 0.5 5088 4235 4687 164 4305 InnerEar_R 0.4 5673 4853 5165 112 5175 LacrimalGland_L 0.7 2207 734 1313 382 810 LacrimalGland_R 0.8 2518 1064 1736 340 1137 OpticChiasm 0.8 5367 4881 5177 89 4981 OpticNerve_L 0.5 5325 2742 4723 592 4353 OpticNerve_R 0.6 5327 3149 4799 493 4456 EqD2: Equivalent dose in 2 Gy fractions Two years following concurrent chemo-RT, a new clival nodule was noted on imaging. Biopsy confirmed pituitary carcinoma. This was managed with single fraction Gamma Knife delivering a margin dose of 16 Gy (Figure 2) to the biopsied area of recurrence. She remains in clinical remission with stable tumor appearance on recent imaging (Figure 3). Download : Download high-res image (686KB) Download : Download full-size image Figure 2. Gamma Knife Radiation Therapy Planning Images Gamma Knife Planning session MRI T1 weighted images with contrast (May 2020) showing GTV and prescribed isodose line. Red lines: 1600 cGy prescribed dose. Blue lines: GTV. Download : Download high-res image (469KB) Download : Download full-size image Figure 3. Follow-up Imaging Follow up MRI imaging (Jan 2021) showing stable tumor appearance at 8 months post-GK, and 46 months post-IGMRT with TMZ. Discussion Over a ten-year history of persistent symptoms and aggressive tumor behavior, this patient's diagnosis evolved from an atypical ACTH secreting pituitary macroadenoma to an invasive ACTH secreting pituitary carcinoma (PC) that was managed by fractionated imaged-guided intensity modulated radiotherapy (IG-IMRT) with concurrent temozolomide (TMZ). Approximately two years post-IG-IMRT, ACTH/cortisol labs had declined, and the lesion was reduced radiographically. Remarkably, she developed hypocortisolemia mandating hydrocortisone replacement therapy despite an elevated plasma ACTH. It is postulated that the remission of Cushing's disease was likely related to chemo-radiotherapy-induced alterations in the post-translation processing of proopiomelanocortin (POMC) with the production of biologically inactive ACTH and significant decreases in cortisol biosynthesis.4 To date, the patient endorses substantial strength, visual, and cognitive improvement. The mainstay of PC treatment begins with surgical transsphenoidal resection, followed by radiotherapy for residual tumor growth, and adjuvant medical treatment. Studies show in the case of atypical PA that progress to PC, early and aggressive treatment provides the longest survival.3 Surgical resection is the initial intervention to avoid morbidity and mortality related to mass effect of these large aggressive tumors, however, it is rarely complete.3 As a result, the residual disease progresses, and multiple surgeries may be performed after a recurrence of disease. Primary pituitary tumors that present with metastases at diagnosis are termed PC. If no metastases are present, histological evaluation can aid in the management of the tumor.3 Tumors with a high mitotic index, high Ki-67 index >3%, and/or p53 immunoreactivity are termed atypical PA for their aggressive growth and tendency to recur after resection.3 In both PC and atypical PA guidelines, evidence of post-surgical growth is treated with radiation therapy. In general, radiotherapy provides a modest benefit of local tumor control, especially when administered before distant metastases arise in atypical PA with malignant potential.3 Focal stereotactic treatment has shown mostly palliative benefit with little prognostic improvement.3 Finally, medical therapy is used to combat tumor growth and hypersecretory function. Non-chemotherapy biotherapy includes somatostatin analogs, particularly in the case of GH and TSH-producing tumors, with variable tumor reduction and a limited period of control. Chemotherapy agents such as doxorubicin, cisplatin, and etoposide-based chemotherapy have been implicated in the treatment of PC.3 Responses are variable and not widely replicated, but observational studies indicated prolonged survival in cases of distant metastases, and in aggressive atypical PA before malignant transformation.1-3 One report demonstrated significant regression of an ACTH-secreting PC and distant metastases induced with cisplatin and etoposide, two cytotoxic platinum-based chemotherapy drugs.4 These agents have variable CNS penetrance, unlike TMZ, but have potential benefit in cases of PC with high mitotic indices. Without prospective, randomized studies, significant conclusions on the benefits of chemotherapeutic agents have yet to be made. Current guidelines for PC that demonstrate progression after primary tumor debulking and radiotherapy include further surgery (alpha), focused radiotherapy (beta), chemotherapy (gamma), and treatment with radionuclides (delta).3 In this case, a complex PC/recurrent atypical PA had a stable positive response to combined fractionated IG-IMRT and TMZ, demonstrating radiological decrease in tumor volume, clinical improvement, and endocrine remission status post 1 year and 8 months. The lasting results of a combined therapy approach in treating PC have been illustrated in other literature examples. In a similar case, an ACTH secreting PC was treated with a course of concurrent radiotherapy, TMZ, and bevacizumab, an anti-VEGF monoclonal antibody.5 The multimodality course was implemented six weeks post-resection. At eight weeks, the resolution of a distant metastasis helped established a positive outcome. The patient followed up this course with a year of adjuvant TMZ. Five years post treatment, there has been no evidence of recurrent disease on imaging or with ACTH monitoring.5 Another report found that an aggressive, functional ACTH-producing pituitary adenoma was managed with concurrent TMZ and radiotherapy after failing maximal conventional therapy. As in the presented PC case, this PA was recurrent after surgical, medical, and radiotherapy interventions. It rapidly progressed biochemically, radiologically, and clinically. After initiating the combined concurrent TMZ and radiation, a rapid biochemical response was observed with cortisol normalization and regression of intracranial tumor volume on MRI at 3 and 6 months. The TMZ therapy was stopped after the sixth cycle, and at twenty-two months out from treatment, the patient continues to have stable tumor volume and biochemical remission. Although the patient did not have metastasis necessary for classification of PC, the recurrent clinical course and aggressive functional nature of the tumor demonstrate the lasting positive outcome of a combined modality approach on tumor growth and endocrine remission.6 In presenting this case, fractionated IG-IMRT with TMZ was effective in achieving stable endocrine remission and partial tumor regression for several years’ duration. The recurrent clival PA is ACTH non-secreting after IG-IMRT and concurrent TMZ which has improved the patient's clinical condition. Although this mass recurred after treatment, it is quite remarkable that her tumor has remained hormonally nonfunctional, and the patient continues to have a resolution of CD symptoms. Limited clinical information exists on successful treatment options for PC. Recurrence, metastasis, and mortality are high after exhausting conventional treatment. The alternative combined therapeutic approach of current TMZ and radiation has shown rare, and lasting effects in this patient. These findings may further support the use of combined fractionated radiotherapy with concurrent TMZ treating in patients with ACTH-secreting PC who fail standard surgical and medical interventions. References 1 Joehlin-Price, A. S., Hardesty, D. A., Arnold, C. A., Kirschner, L. S., Prevedello, D. M., & Lehman, N. L. (2017). Case report: ACTH-secreting pituitary carcinoma metastatic to the liver in a patient with a history of atypical pituitary adenoma and Cushing's disease. Diagnostic Pathology, 12(1), 1–8. https://doi.org/10.1186/s13000-017-0624-5 2 Borba, C. G., Batista, R. L., Musolino, N. R. de C., Machado, V. C., Alcantara, A. E. E., Silva, G. O. da, … Cunha Neto, M. B. C. da. (2015). Progression of an Invasive ACTH Pituitary Macroadenoma with Cushing's Disease to Pituitary Carcinoma. Case Reports in Oncological Medicine, 2015(Cd), 1–4. https://doi.org/10.1155/2015/810367 3 Kaltsas, G. A., Nomikos, P., Kontogeorgos, G., Buchfelder, M., & Grossman, A. B. (2005). Clinical review: Diagnosis and management of pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism, 90(5), 3089–3099. https://doi.org/10.1210/jc.2004-2231 4 Cornell, R.F., Kelly, D. F., Bordo, G., Corroll, T. B., Duong, H. T., Kim, J., Takasumi, Y., Thomas, J. P., Wong, Y. L., & Findling, J. W. (2013). Chemotherapy-Induced Regression of an Adrenocorticotropin-Secreting Pituitary Carcinoma Accompanied by Secondary Adrenal Insufficiency. Case Reports in Endocrinology, 2013;2013:675298 https://doi.org/10.1155/2013/675298 5 Touma, W., Hoostal, S., Peterson, R. A., Wiernik, A., SantaCruz, K. S., & Lou, E. (2017). Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. Journal of Clinical Neuroscience, 41, 75–77. https://doi.org/10.1016/j.jocn.2017.02.052 6 Misir Krpan, A., Dusek, T., Rakusic, Z., Solak, M., Kraljevic, I., Bisof, V., … Kastelan, D. (2017). A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma. Case Reports in Endocrinology, 2017, 1–5. https://doi.org/10.1155/2017/2419590 Funding: None Disclosures: Dr. Findling reports grants, personal fees and other from Novartis, personal fees and other from Corcept Therapeutics, personal fees from Recordati, outside the submitted work. Research data are stored in an institutional repository and will be shared upon request to the corresponding author. © 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. From https://www.sciencedirect.com/science/article/pii/S2452109421001718
Personal Stories: From my bio: (At the NIH in October 1987) The MRI still showed nothing, so they did a Petrosal Sinus Sampling Test. That scared me more than the prospect of surgery. (This test carries the risk of stroke and uncontrollable bleeding from the incision points.) Catheters were fed from my groin area to my pituitary gland and dye was injected. I could watch the whole procedure on monitors. I could not move during this test or for several hours afterwards to prevent uncontrollable bleeding from a major artery. The test did show where the tumor probably was located. Also done were more sophisticated dexamethasone suppression tests where drugs were administered by IV and blood was drawn every hour (they put a heplock in my arm so they don't have to keep sticking me). I got to go home for a weekend and then went back for the surgery... _____ From Karen's Story: https://cushingsbios.com/2016/11/18/doc-karen-pituitary-and-bla-bio/ At that time, there was evidence of a pit tumor but it wasn’t showing up on an MRI. So, I had my IPSS scheduled. An IPSS stands for Inferior Petrosal Sinus Sampling. It is done because 60 % of Cushing’s based pituitary tumors are so small that they do not show up on an MRI. Non Cushing’s experts do not know this so they often blow patients off, even after the labs show a high level of ACTH in the brain through blood work. An overproduction of the hormone ACTH from the pituitary communicates to the adrenal glands to overproduce cortisol. Well, the IPSS procedure is where they put catheters up through your groin through your body up into your head to draw samples to basically see which side of your pituitary the extra hormone is coming from, thus indicating where the tumor is. U of C is the only place in IL that does it. ... I was scheduled to get an IPSS at U of C on June 28th, 2011 to locate the tumor. Two days after the IPSS, I began having spontaneous blackouts and ended up in the hospital for 6 days. The docs out here had no clue what was happening and I was having between 4-7 blackouts a day! My life was in danger and they were not helping me! We don’t know why, but the IPSS triggered something! But, no one wanted to be accountable so they told me the passing out, which I was not doing before, was all in my head being triggered by psychological issues. They did run many tests. But, they were all the wrong tests. I say all the time; it’s like going into Subway and ordering a turkey sandwich and giving them money and getting a tuna sandwich. You would be mad! What if they told you, “We gave you a sandwich!” Even if they were to give you a dozen sandwiches; if it wasn’t turkey, it wouldn’t be the right one. This is how I feel about these tests that they ran and said were all “normal”. The doctors kept telling us that they ran all of these tests so they could cover themselves. Yet, they were not looking at the right things, even though, I (the patient) kept telling them that this was an endocrine issue and had something to do with my tumor! Well, guess how good God is?!!!! ... Fast forward, I ended up in the hospital with these blackouts after my IPSS. The doctors, including MY local endocrinologist told me there was no medical evidence for my blackouts. In fact, he told the entire treatment team that he even doubted if I even had a tumor! However, this is the same man who referred me for the IPSS in the first place! I was literally dying and no one was helping me! We reached out to Dr. Ludlam in Seattle and told him of the situation. He told me he knew exactly what was going on. For some reason, there was a change in my brain tumor activity that happened after my IPSS. No one, to this day, has been able to answer the question as to whether the IPSS caused the change in tumor activity. The tumor, for some reason, began shutting itself on and off. When it would shut off, my cortisol would drop and would put me in a state of adrenal insufficiency, causing these blackouts! Dr. Ludlam said as soon as we were discharged, we needed to fly out to Seattle so that he could help me! The hospital discharged me in worse condition then when I came in. I had a blackout an hour after discharge! But get this…The DAY the hospital sent me home saying that I did not have a pit tumor, my IPSS results were waiting for me! EVIDENCE OF TUMOR ON THE LEFT SIDE OF MY PITUITARY GLAND!!! _____ From Kirsty: https://cushingsbios.com/2013/06/25/kirsty-kirstymnz-ectopic-adrenal-bio/ The hardest of all these was what they call a petrusal vein sampling (this is where they insert a catheter into the groin through the femoral vein which goes up to the base of the brain to look at the pituitary, they do this while awake – I could actually feel them moving around in my head.) This test concluded that my Cushing’s was being caused by a tumor somewhere other than the pituitary (this only happens in 1% of cases, and there is about a 1 in 10 million chance of getting it). The question now was “where is the tumor?” _____ Find other bios with which mention this test at https://cushingsbios.com/tag/ipss/ __________ This topic on these message boards: https://cushings.invisionzone.com/forum/54-css-ct-ipss-ivp-mri-np-59-scan-octreoscan-pss-sonogram-ultrasound/ __________ Thoughts from Dr. James Findling: https://cushieblogger.com/2019/03/24/cushings-syndrome-expert-a-standout-in-clinical-practice/ 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. __________ Official information Patient information from Canterbury Health Limited Endocrine Services INFERIOR PETROSAL SINUS SAMPLING WITH CRH STIMULATION Introduction You have been diagnosed with Cushing's syndrome which results from excessive production of the hormone cortisol, made by the adrenal glands. In your case, the adrenal glands are being driven by excessive amounts of another hormone called ACTH. This test is to determine where that ACTH is coming from. Constant high levels of ACTH are usually caused by a tumor. Approximately 80% of cases are tumors of the pituitary gland while the remainder may occur in the lung, pancreas and other sites (known as "ectopic" sites). This test relies on the fact that if the source of your high ACTH is the pituitary gland blood levels taken from very near the gland will be higher than the blood level in an arm vein. Pituitary gland tumors are often tiny and can't be seen even with the most modern scanners. This test will help your endocrinologist to know with almost 100% certainty whether the pituitary gland is the source or if a search is needed elsewhere (for example in the lungs or abdomen). This guides treatment, for example the recommendation for Pituitary surgery. Procedure You are allowed water only from midnight the night before (nothing else to eat or drink). You will be given a light sedative, but will be awake during the procedure. You will be taken to the Radiology Department where the procedure will take place. The radiologist will place some local anesthetic into the groin on each side over the main vein that drains blood from each leg. Then a fine bore catheter will be passed up the vein, past the heart and into the major vein in the neck (the jugular vein). From there it is passed into a smaller vein that drains blood directly from the pituitary gland, known as the inferior petrosal sinus. The procedure is repeated for the other side. X-ray screening guides the radiologist to know where the catheters are positioned. A small butterfly needle is inserted into an arm vein. Once the catheters are in place, blood samples will be taken from the right and left petrosal sinus, and an arm vein at exactly the same time. After two baseline samples, a hormone called CRH is injected into the arm vein. This increases ACTH when a pituitary gland tumor is present, but has no effect on ectopic ACTH production. Further blood samples are taken for another 10 to 15 minutes, then the catheters are withdrawn. Pressure is applied to the groins to minimize bruising. Often sampling is continued from the arm vein only, for a total of 90 minutes. You will have to remain lying on your back for at least 2 hours afterwards. Risks This procedure is very safe when performed by an experienced radiologist. Rarely, there have been reports of people having a stroke at the time of this procedure but this was related to a catheter of faulty design which is now no longer used. Bruising, which is common in Cushing's syndrome, may occur after the catheters are pulled out. Some people notice flushing of the face after the CRH and rarely it can result in a fall in blood pressure. From: http://www.pituitarycenter.com/html/article1.html INFERIOR PETROSAL SINUS SAMPLING Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive. The inferior petrosal sinus sampling procedure is performed in the radiology department. With the patient on the angiography table both groin regions are partially shaved, sterilized, and a local anesthetic is injected into the skin to provide pain relief. A tiny incision is made within the skin and a needle is inserted to puncture the femoral vein which drains blood from the leg. A small catheter is then inserted into the vein and flushed with an intravenous solution. Longer catheters are passed into the shorter catheters and advanced through the large veins traversing the torso into the neck and then into the base of the skull. Thereafter, a microcatheter is advanced through each of these larger guiding catheters and threaded into the inferior petrosal sinuses which lie along the internal aspect of the skull base and drain blood from the pituitary gland. Once these microcatheters have been positioned, contrast dye is injected and X-rays are taken to verify their position in the inferior petrosal sinuses. Next, blood samples are collected from both catheters in the inferior petrosal sinuses and from a peripheral (usually arm) vein. Thereafter, corticotropin-releasing hormone is administered through the peripheral vein. Repeat blood samples are drawn 2, 5, and 10 minutes after the injection. Additional X-rays are taken to confirm that the catheters were not dislodged from their site during the sampling procedure. Thereafter, the catheters are removed and direct pressure is applied to the groin region to decrease the likelihood of bruising. Patients are observed for 4 hours following the procedure to ensure that no bleeding from the femoral vein puncture sites will occur. Normal non-strenuous activity may be resumed 48 hours after the procedure. Sedatives and pain relievers may be administered during the procedure as necessary. A blood thinner might be used depending on the patient's anatomy and the clinical suspicion of developing a blood clot. If a blood thinner is used, this may be counteracted with medication at the conclusion of the procedure to ensure that normal blood clotting resumes while removing the catheters. Overall, the inferior petrosal sinus sampling procedure involves minimal discomfort. The risks of the procedure are small. X-rays are used but the radiation doses are minimized. Infection is controlled by using sterile technique. Some patients might have an unexpected allergic reaction to the dye used during the study. A bruise may develop within the groin. Although rare, blood clots have developed in the groin veins following this procedure. Again, steps are taken to minimize the likelihood of each and every one of these complications. ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source. ___ From: http://www.mc.vanderbilt.edu/pituitarycenter/html/article1.html Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive. The inferior petrosal sinus sampling procedure is performed in the radiology department. With the patient on the angiography table both groin regions are partially shaved, sterilized, and a local anesthetic is injected into the skin to provide pain relief. A tiny incision is made within the skin and a needle is inserted to puncture the femoral vein which drains blood from the leg. A small catheter is then inserted into the vein and flushed with an intravenous solution. Longer catheters are passed into the shorter catheters and advanced through the large veins traversing the torso into the neck and then into the base of the skull. Thereafter, a microcatheter is advanced through each of these larger guiding catheters and threaded into the inferior petrosal sinuses which lie along the internal aspect of the skull base and drain blood from the pituitary gland. Once these microcatheters have been positioned, contrast dye is injected and X-rays are taken to verify their position in the inferior petrosal sinuses. Next, blood samples are collected from both catheters in the inferior petrosal sinuses and from a peripheral (usually arm) vein. Thereafter, corticotropin-releasing hormone is administered through the peripheral vein. Repeat blood samples are drawn 2, 5, and 10 minutes after the injection. Additional X-rays are taken to confirm that the catheters were not dislodged from their site during the sampling procedure. Thereafter, the catheters are removed and direct pressure is applied to the groin region to decrease the likelihood of bruising. Patients are observed for 4 hours following the procedure to ensure that no bleeding from the femoral vein puncture sites will occur. Normal non-strenuous activity may be resumed 48 hours after the procedure. Sedatives and pain relievers may be administered during the procedure as necessary. A blood thinner might be used depending on the patient's anatomy and the clinical suspicion of developing a blood clot. If a blood thinner is used, this may be counteracted with medication at the conclusion of the procedure to ensure that normal blood clotting resumes while removing the catheters. Overall, the inferior petrosal sinus sampling procedure involves minimal discomfort. The risks of the procedure are small. X-rays are used but the radiation doses are minimized. Infection is controlled by using sterile technique. Some patients might have an unexpected allergic reaction to the dye used during the study. A bruise may develop within the groin. Although rare, blood clots have developed in the groin veins following this procedure. Again, steps are taken to minimize the likelihood of each and every one of these complications. ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source. ___ From https://www.uclahealth.org/radiology/interventional-neuroradiology/inferior-petrosal-sinus-sampling The IPSS test is done in some patients to identify if there is too much ACTH is causing the excess production of cortisol, and where it is coming from. How do we do an IPSS procedure? Typically under general anesthesia, we place small tubes (catheters) into the femoral veins (the main vein draining the legs) at the level of the groin. From there, under X-ray guidance, we navigate those catheters to the main veins which drain the Pituitary gland. These are the inferior petrosal sinuses (right and left). We then draw samples from those veins and the main vein of the abdomen and test those samples for ACTH. We also take timed samples after giving a dose of medication which would normally stimulate the production of ACTH to improve the sensitivity of the test. When we get the results, the different levels of ACTH may help the endocrinologist determine where the tumor is located that is causing the adrenal gland to produce the excess cortisol. If it is from the Pituitary gland, any difference between the right and left samples may help the surgeon determine the surgical plan to remove the tumor yet preserve the normal Pituitary gland. Example of testing results: Time Right IPS Left IPS Inf Vena Cava Cortisol Baseline 1 09:32 40 pg/ml 17 18 25 mcg/dl Baseline 2 09:34 45 18 15 24 DDAVP inj 09:38 Post 2min 09:40 72 21 18 Post 5min 09:43 157 20 19 Post 10min 09:48 161 30 25 Post 15min 09:53 162 33 26 Post 30min 10:08 124 32 29 30 This example shows elevation of ACTH in the right inferior petrosal sinus, likely indicating a tumor in the right side of the pituitary gland causing Cushing’s Disease. Picture of contrast injection of the inferior petrosal sinuses: Tips of the catheters in the inferior petrosal sinuses.