Maria Fleseriu, M.D., a neuroendocrinologist, Professor, Director OHSU Northwest Pituitary Center at Oregon Health & Science University, talks about the important role the pituitary gland.
Interview conducted by Ivanhoe Broadcast News in April 2017.
First of all, the Pituitary gland, what does it control?
Dr. Fleseriu: The pituitary gland is called a master gland. Basically it’s the “boss” of almost every endocrine gland in the body. It’s secreting several hormones including ACTH, growth hormone, prolactin, TSH, gonadotrophs. After secretion, all these hormones will go to their target gland or throughout the body and have profound effects everywhere.
What can go wrong?
Dr. Fleseriu: We can have several pathologies related to the pituitary, for example a pituitary tumor is very frequent with the new imaging systems. Up to one in four patients can have a small abnormality in their pituitary tumor and they don’t even know. That’s called pituitary incidentaloma, if we find it just by chance with new imaging. We can also see patients with pituitary dysfunction meaning the small pituitary tumors or the larger ones for that matter can secrete extra hormones or not enough. One hormone can be too high and then all the other hormones that the pituitary should secrete are low because of the mass effect of the tumor itself. On top of that, when you have a larger tumor, it can grow upward towards the optic nerves and then the patient can present with severe vision loss. Of course, there are some other rare things that can go wrong. Pituitary hemorrhage and then the patients present with acute vision loss and they need emergent surgery. But these are much rarer. Usually they are small pituitary tumors or pituitary dysfunction per se related to traumatic brain injury, autoimmune dysfunction or other type of causes.
Are they common?
Dr. Fleseriu: The pituitary tumors are very common. Patients might have a small pituitary tumor, detected on the MRI, but it doesn’t mean it’s serious in everybody. Yes they are common indeed. We find them very frequently, especially now that the imaging is getting more frequent. Also the MRI machines that we’re using are much better. Since my fellowship, I think we have already changed several types of MRI magnets for example. Overall, we see them more frequently, but it’s also very important that you have the expertise in dealing with these types of tumors. Because though they are frequent overall, their clinical presentation is sometimes nonspecific. There are patients that are missed for years and years, because they didn’t present with very clear-cut symptoms and nobody thought about the possibility of a pituitary tumor. Especially if you have a secreting tumor like an ACTH –secreting tumors, Cushing’s has specific symptoms late in the disease. For growth hormone excess, Acromegaly, for example, the main delay of diagnosis is still ten years. Even new research shows that. In our experience, we have patients that actually had it for way more than that period and nobody even thought about it until the end of their clinical presentation, when they came to an endocrinologist.
What are the consequences of missing a diagnosis for so long?
Dr. Fleseriu: Most of the tumors they grow very, very slowly. If they don’t secrete any hormones, we don’t even know they exist until the patient presents with vision loss. For the hypersecreting tumors, I think the most important one that we shouldn’t miss are the growth-hormone secreting tumors that are causing Acromegaly and the ACTH secreting tumors that are causing Cushing’s. For Acromegaly for example, you were asking about consequences. Even for a small tumor, then the patient doesn’t have vision loss, doesn’t have severe headache, yet because the tumor is very tiny, if the growth hormone secretion is very high from the tumor the patient will have special features. It’s dysmorphia, especially change in facial features, also they can have bone disease; they have increasing hand size, shoe size and also increased risk of cardiovascular disease. Sometimes if it’s not treated and diagnosed late, the patients have increased mortality also. There are serious consequences. For Cushing’s, sometimes we miss the diagnosis because the initial presentations are with co-morbidities that are very frequent in our society. Patients present with facial plethora, diabetes, obesity and hypertension these are very frequent. If somebody doesn’t think about more specific features that will move the diagnosis towards Cushing’s, then that patient will be missed for years and years. Or think about a different disease altogether which will also delay the correct diagnosis. The risk of morbidity, especially cardiovascular disease and mortality for these patients is pretty high. For untreated Cushing’s for example, we have all our data based on studies before treatment for Cushing’s and aggressive treatment for diabetes and lipids , available; older data shows that the morbidity can increase up to four times for Cushing’s that’s not treated; for Acromegaly it’s usually doubled if we don’t treat.
For somebody with Acromegaly are their lives often shortened?
Dr. Fleseriu: They might be. Right now, we’re getting better, once we diagnose and the patient has surgery, even if the growth hormone is coming down, but it’s not normal, we’re treating the patient as a whole and we start medication immediately. We have several new medications, on all of them we’ve worked here at the research stage here in our center, too and we are able to decrease the growth hormone to normal. Once we achieve that, the studies show that mortality will go back to general population. If we can’t achieve it or the patient is diagnosed late, I assume that we can say that these patients will have a shortened survival. We’re really trying our best so this is not happening anymore.
What are you most excited about in terms of being able to diagnose and spot and maybe intervene earlier?
Dr. Fleseriu: We’re getting better and I can say I’m very excited about the move towards earlier diagnosis. We are still seeing patients late in the disease. We changed medical school curriculum, clearly we’re making progress. I can’t say we’re really making huge progress though, especially for our earlier diagnoses. Maybe I’m too ambitious with that. On the other hand, I think for treatment we have made huge progress over the last several years, but also if we’re looking decades- wise. These patients, especially with Acromegaly and larger tumors, would have had surgery and then maybe conventional radiation and nothing else was available. For the last twenty years we had one new medication after another for acromegaly. Also the surgery has become much better with the advance of the endoscopy. The neurosurgeon can really see how much tumor is there and also try to excise the most of it. Sometimes it’s not possible, because the tumor grew in the sinus where the carotid is, so we tell the surgeons no, you don’t need to even get there. Then we have the options of medical therapy. I think for growth hormone excess, Acromegaly and for Cushing’s, I’m more excited about the new advances that we have for medical therapy. We have several groups of medications that are targeting a different level and we’re also studying it in combinations. We’re able to actually control the large majority of these patients probably for the last several years, patients that we were never able before that. The first medication for Cushing’s for example, was FDA-approved in 2012. We’re really recent in to this era. For Acromegaly we’re doing more studies, including care with new types of medications as a different mechanism and also different types of delivery. Because it’s not just that we have the medications, but a patient needs to take it and sometimes it’s harder for them because it’s an injection every month for the rest of their life. This is a burden in itself. On top of that, we also know that the quality of life for these patients, especially for Cushing’s, almost never goes back to normal even despite our best treatment. They look good “on paper,” they have perfect biochemical numbers, but their quality of life sometimes is still decreased over time. I think that goes back to what I mentioned earlier, that we need to make more efforts to increase diagnosis with the general population and also with the general practitioners.
What do patients complain about losing in terms of their quality of life?
Dr: Fleseriu: The most frequent changes seen with pituitary….it’s a little bit different from disease to disease. For patients with non-functioning tumors, they are growing and destroying the hormones, but they don’t secrete extra hormones in itself. Most of the changes are related to their loss of hormones and that’s called hypopituitarism. If you lose for example, cortisol and you have adrenal insufficiency, overall you can end up in the hospital more frequently if you are not appropriately replaced for example. For Cushing’s and Acromegaly in general, quality of life is lower, you have to see doctors all the time and the truth is, nobody really likes that. On top of that, there might be changes in memory, concentration, sometimes even depression of course. For Cushing’s, quality of life doesn’t go back to normal sometimes and have many other co-morbidities that need follow up all their life.
The patient we’re going to see this afternoon tell me a little about him.
Dr. Fleseriu: I have known this patient for almost ten years. He presented with severe Acromegaly, I can say mostly due to a very delayed diagnosis. He had several clinical features already: increasing hand size, shoe size, he already had many specific facial and body features due to long standing growth hormone excess. Clearly he already had also many, many co-morbidities. Notably, he had a large pituitary tumor, maybe few years earlier was much smaller and he could have been cured … the fact that the tumor was so large and extending into both his carotid arteries, a remission was not possible. We knew that from the beginning. We recommended transpendoidal surgery to prevent further vision loss, the patient had a good resection and most of the tumor was out (that usually we expect). We always want for these patients an expert pituitary surgeon, because the surgery might seem easy for some, but you need to do a lot of them to actually to be able to get better results. If it’s a large tumor, we know from the beginning that surgery won’t be enough but it’s necessary. Then we started the patient on medical therapy and we changed medications around until we found one that really worked for him. In between, he had a lot of other problems, some of them might have been related to a long standing Acromegaly, including a blood cancer diagnosis, that we actually found. We know that growth hormone excess probably doesn’t cause cancer per se, but if you have gross hormone excess the cancer is clearly not doing better, because growth hormone excess will actually increase the chances of the cells dividing. I am pleased to say, that on medication he never needed radiation, and yes, he’s seeing us once a month for medication injection, but he is doing great otherwise.
Is the medication that’s often used for both of these issues expensive? Is that one of the problems with patient compliance?
Dr. Fleseriu: Yes and yes. That’s one of the problems, that all of these medications, especially because most of them are new, are indeed expensive. Also especially for Acromegaly, everything that we have available right now is injectable. They are injected once a month, we’re trying to expand and sometimes we can move to every six weeks. We did research with implants, with other types of injections will maybe expand to even more months and even have more studies now with an oral medication. We are making some progress, but for right now for Acromegaly, all medications are injectable and expensive. For Cushing’s, everything that we have FDA approved right now is also expensive, both pills and injections. We are also using other medications that are FDA-approved for other indications, but not Cushing’s. Some of these have been used to treat Cushing’s for 40 years both in Europe and here. We’re also doing several clinical studies with new medications, so my hope is that soon we will have more medications available. One, need to be able to control all patients and, two, to decrease the adverse effects, because as you know everything in life has some adverse effects, but for medications it’s even more important to avoid them as much as possible. Furthermore, with more medications available the cost will probably come down or that’s my hope.
Where we are in the continuum in terms of understanding pituitary and what can go wrong? Do we still have a long way to go or not?
Dr. Fleseriu: I’m an optimist and the glass is half full, but for our understanding about pituitary tumors, I have to say that we’re not where we should be. Clearly, our understanding of physiology of the hormones it’s good, but exactly what is causing these pituitary tumors we still don’t know. We know in some genetic causes, but we’re far from understanding. This is a question I get all the time; the patient is asking, “is it something that I did that made me have a tumor?” Unless it’s a familial one, that we know is genetic, we still don’t all of the mechanisms involved in pituitary tumors. We’re getting better with treatment, as I mentioned earlier, but we’re not where we should be with that one either. I’m hoping that over the next ten years we’re going to know way more. If you ask me again in ten years I would tell you way more about that.
What is the known most common cause of a problem going wrong with the pituitary? Is it a trauma?
Dr. Fleseriu: No, the most common cause of problems related to the pituitary is its function per se, dysfunction caused by a tumor or due to the surgery for a tumor or the radiation. This is the most common. Out of the pituitary tumors, the most common ones are not the one we talked earlier, those are though more severe. The most common pituitary tumors are actually prolactin secreting tumors, that once we diagnose, for the large majority we have medication that we’re able to control prolactin and patients do not need surgery. There are some good news overall, we made big progress but there are a lot of things that we don’t know yet. For example, several years ago we didn’t even know that opioid use can affect pituitary and right now it’s a major issue. It’s actually inducing pituitary dysfunction, and in some cases severe pituitary dysfunction. In a few years, we’ll probably have an epidemic of pituitary dysfunction due to opioid use for example. Trauma with brain injury, this is also new; over the last ten years, we know that after a concussion you can have pituitary dysfunction; sometimes it’s recovering at one year, but sometimes it still persists. There are a lot of things that we find out over time and is an exciting time to do research.
The common incidence of pituitary problem tumors in the general population?
Dr. Fleseriu: On MRI imaging and in autopsy studies up to one in four or five people have something on the MRI that might be a tumor. That’s what we know. Now, most of them are not clinically significant. There’s no exact study to say how many, especially in the U.S. are actually clinical significant. There are studies done in Europe, but you can see they have a different homogenous population, so they might have more familial tumors with genetic causes. At least one in a thousand people has a clinically significant pituitary adenoma. Patients may have headaches or they got in to a car accident, they have a CT, they have a tumor, so per medical definition this is pituitary incidentaloma. For that particular patient though, it is more than an incidental finding: they have a pituitary tumor that they have to see the doctor for, and also they can have some pituitary dysfunction. But even if they don’t have dysfunction, they will need repeat imaging. It’s the stress that this is inducing on the patient until they know more. Sometimes they don’t even know what the pituitary tumor can do or the fact that, that pituitary tumor just needs to be followed and it’s nothing to worry about. Unless they see somebody that’s an expert in pituitary disease, patients might all go undiagnosed from hormonal dysfunction. Or they can just disregard the fact that they need continued follow up.
What is your program at OHSU are you focusing on, what are you most excited about?
Dr. Fleseriu: We are an expert center in pituitary disease for all the pituitary diseases. And the pilot program that we have developed now for more than a decade that I’m most excited about is the multidisciplinary approach. We have neuroendocrinologist, we have neurosurgeons experts and we are seeing over five hundred patients per year and they are coming from all over the country not just from Oregon, way far beyond Oregon or the surrounding states. But we also have experts in pituitary disease from neuropathology, neuroradiology, neuroopthalmology that we all work together and discuss each patient that we’re seeing. We also have nurse practitioners, physician assistant that are seeing these patients before and after surgery. One of our nurse practitioners for example has a doctorate in quality of life issues in patients with pituitary disorders. We communicate with patients at a distance all the time, especially when they have surgery and require closer follow-up. We talk to them on the phone; we see them very frequently after that to make sure they have the desired outcomes. And then we send them back to their local providers, we have patients that even if they live far away, they are flying in to see them once a year. And it establishes a nice relationship, we know everything about them. From a research point of view, I’m most excited – and I am a neuroendocrinologist, you should see the surgeon, who is actually more excited about it. Improvement in surgery, endoscopy and how much tumor they can take out now from different areas is amazing. I’m also very excited about the new medications that we have available in clinic and are under clinical investigations, especially for Acromegaly and Cushing’s. We see patients for second opinion, third opinion, fourth opinion for these particular diseases both for Acromegaly and Cushing’s. Definitely, that’s what keeps me up at night, but is also comforting to see their disease constantly improving!
With the patient we’re seeing in a little while didn’t have your expertise and hadn’t been seen, was he diagnosed before he got to you?
Dr. Fleseriu: No.
What would you say the consequences would be today if you had been treating him or knowing him for ten years?
Dr. Fleseriu: For this particular patient, as his disease was so severe that we can definitely say he would have had severe heart disease or even would have died if he wasn’t diagnosed. Now, that doesn’t mean that another endocrinologist probably could have diagnosed him, but his initial surgeon that looked at his thyroid and nobody else at that time even noticed, that he might have Acromegaly. He was sent to us for a pituitary tumor that was incidentally diagnosed on a CT. This goes back to “incidentally.” It’s not really incidental, you know, to patients. However, we also have to reassure the general population that if you have a small pituitary tumor that was incidentally found, that doesn’t mean it has to be severe. It just has to be worked up and have the proper follow up. We have for few years guidelines at the Endocrine Society level (that’s a society all endocrinologists around the world) for Acromegaly, Cushing’s, prolactinomas and pituitary incidentalomas. Also recently, new guidelines for hypopituitarism (actually I was the Chair for these guidelines) have been published to help navigate the data available regarding ideal doses of hormonal replacement. Each patient is different and guidelines are just that, guidelines, but having uniform clinical guidelines for diagnosis and follow-up of pituitary patients is important and hopefully will improve outcomes.
END OF INTERVIEW
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