Speaker 1:

Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now let's meet the endocrine experts who will be talking with us today.

Dr. Bauer:

Welcome to the AACE Podcast. I am Dr. Elizabeth or Lissa Bauer as I go by. I'm a practicing endocrinologist at Naval Medical Center in San Diego, and today, we're going to be exploring impulse control disorders in patients with Hyperprolactinemia on a dopamine agonist therapy. My guest is Dr. Nicholas Tritos from Mass General, who was the lead author of a recent review on this topic, which was recently just published in Endocrine Practice. Dr. Tritos, thank you for joining us.

Dr. Nicholas Tritos:

Thank you so much for having me. I would like to thank you and AACE for the kind invitation to this podcast.

Dr. Bauer:

Can you tell us a little bit about yourself and your clinical practice, and then what prompted you to take a closer look at impulse control disorders in these patients?

Dr. Nicholas Tritos:

Yeah, thanks again. So I'm a pituitary endocrinologist and so I have an interest in all pituitary disorders, and of course, Hyperprolactinemia is one of them. My colleague, Dr. Daftari, and I wrote this review article because we think that this is an important issue for patients and their clinicians. This topic has received relatively limited attention in the endocrine literature, so I think that raising awareness of the issue among clinicians and their patients can have a very positive impact on patient care.

Dr. Bauer:

Was there a moment in your clinical work where this first came onto your radar? I'm assuming you treat a lot of prolactinomas. When did this first become an issue that you noticed?

Dr. Nicholas Tritos:

So it's been certainly a number of years since I first realized that this could happen among patients treated with dopamine agonists based on discussions with colleagues and then reading the literature, and certainly impulse control disorders have been recognized among patients with Parkinson's disease on dopamine agonist therapy for many years. However, reports on hyperprolactinemic patients have appeared in the past 15 years or so, initially case reports and then mostly cross-sectional studies. But I think that awareness of the problem in the endocrine community and implementation of systematic evaluation for the development of impulse control disorders is often lacking in practice based on informal discussions with colleagues, and I think this can be partly attributed to the sensitive nature of some of these impulse control disorders, and the patient or the clinician may simply not feel comfortable bringing up the problematic behavior.

Dr. Bauer:

Okay. Well, let's delve into this a little bit more. For our listeners who may not treat prolactinomas, can we first briefly explain, what is Hyperprolactinemia and how do these dopamine agonist treatments work?

Dr. Nicholas Tritos:

Sure, thank you. So hyperprolactinemia is essentially high serum prolactin level. This is a common neuroendocrine problem that affects about four per thousand individuals in the general population, and it can be caused by a variety of etiologies including pituitary tumors that secrete prolactin or other cellar or parasellar mass lesions compressing the pituitary stalk. Also, there are many other causes, medications, systemic conditions such as renal failure or severe liver disease among others. Of course, hyperprolactinemia can be physiologic, for example, during pregnancy or acutely right after exercise or food consumption. That is not a clinical problem but may come up in practice.

So we're going to be talking about patients with pathological hyperprolactinemia who may develop hypogonadism, including women and men, galactorrhea, particularly women, gynecomastia in men, infertility. Some patients may have a neurologic or other endocrine manifestations related to an underlying cellar mass. There are also patients with hyperprolactinemia that can have no symptoms whatsoever, so there's a huge variation in terms of their presentation. When treatment is required, and not everybody needs treatment, but when treatment is required, dopamine agonists are generally first line therapy for patients with hyperprolactinemia and can improve gonadal function and fertility in addition to reducing the size of the prolactin secreting tumor in the majority of patients. So they're actually useful drugs, and usually, typically very well tolerated.

Dr. Bauer:

Okay. And with these drugs as first line, there's the side effects that we're going to talk about, which is what your whole paper is on. What exactly are impulse control disorders and how do they usually present in this patient group?

Dr. Nicholas Tritos:

Right, right, absolutely. So these are behaviors resulting from an inability to resist temptations or urges in a given individual, and these can certainly be harmful not only for the individual but also their families and society in general, depending on their behavior. There's obviously a range. Some examples may include pathological gambling, compulsive shopping, hypersexuality, compulsive eating, punding, but even more rarely, other behaviors that can be quite problematic such as kleptomania or pyromania and others, so there's a huge range of potential behaviors.

Dr. Bauer:

Do you see impulsivity with language such as saying things that a patient normally wouldn't say on these meds?

Dr. Nicholas Tritos:

I have not encountered that.

Dr. Bauer:

Some patients ask in clinic and I had that question submitted to me, but the language part, like, "Am I saying things that I normally wouldn't say?" When people are on these medications and they're getting the impulse control disorders, how is it different in hyperprolactinemia compared to Parkinson's disease?

Dr. Nicholas Tritos:

Yeah, I'm not sure that we know the answer to that. Of course, patients with Parkinson's disease may have many other manifestations including cognitive dysfunction which may color their behavior. But aside from that, hyperprolactinemic patients tend to be younger and usually have intact cognition, so I'm sure that can affect how these people present, but I don't think the issue has been systematically analyzed.

Dr. Bauer:

And in your paper, you mentioned the wide prevalence range of ICDs being somewhere, I think you said 7.5% to 46%. Why do you think there's such a wide variation, and are we missing cases in practice?

Dr. Nicholas Tritos:

Yeah, I think that's an interesting question and I don't think we really know. It's not entirely clear. I think that the issue is likely underreported in practice, but even in studies, when people have looked for this, as you pointed out, there's a wide range in prevalence. And this could depend on a variety of factors including the test instruments used, the diagnostic criteria used to detect and establish the presence of impulse control disorders, but also potentially differences between study populations, and this may involve genetic differences but also cultural differences I think.

Dr. Bauer:

And what risk factors stood out to you as the most clinically relevant?

Dr. Nicholas Tritos:

So I think the ones that have been more consistently reported in the literature include younger age and male sex. There's also at least one report of genetic polymorphic variations in certain genes that may affect the risk. So to be a little more granular, in several cross-sectional studies, a younger age has been associated with a higher risk of impulse control disorders in general, and also male sex in several, but not all studies has been associated not only with a higher risk of ICDs, impulse control disorders, but also specifically hypersexuality. On the other hand, women, at least in some reports, in some studies, may have a higher risk of compulsive eating or shopping, although this has not been reproduced consistently, so there seems to be some sex-related variation in terms of their presentation.

At least in one report, retrospectively, there were specific polymorphic variations in genes and coding receptors and other proteins involved in neurotransmission, dopamine, serotonin, glutamine or opioid-mediated neurotransmission, that these variations were associated with a higher risk of impulse control disorders. And this needs to be, of course, verified and validated prospectively, but I think it's interesting and hypothesis generating.

Dr. Bauer:

It's fascinating, and it goes into my next question. We talked about the why or who is at risk, but now why does it happen? What is the biology behind it? Can you walk us through the main theories on how these dopamine agonists are triggering these behaviors?

Dr. Nicholas Tritos:

Yes. So this is indeed fascinating, and I should point out that the pathophysiology is not entirely clear. There are experimental and some human data that support the hypothesis that activation of dopamine receptors that are present in the mesocorticolimbic system, which is normally involved in mediating reward motivated behaviors, may result in decreased inhibitory responses to external cues in some patients, and that leads to the development of impulse control disorders. So that's really the overview, but I think it's important to note that this is an area of investigation and we don't really know in detail why some people develop it and others don't, so this is an exciting area for possible research.

Dr. Bauer:

Yeah, definitely. And it seems like cabergoline is more often implicated than bromocriptine. Do we know why?

Dr. Nicholas Tritos:

Yeah, so that's an interesting question. I think this is based on case reports of impulse control disorders in patients. I think this observation does not take into account the denominator, that is the number of patients being treated with each drug, and it is conceivable simply that cabergoline is more commonly used than bromocriptine at the present time, because typically, cabergoline is more efficacious and better tolerated in clinical settings. So this observation was made in case reports. However, in cross-sectional studies, there appears to be no evident difference in risk of developing impulse control disorders between patients treated with bromocriptine versus cabergoline. So I think the issue is not completely settled, but I think at least this is a potential explanation for this observation.

Dr. Bauer:

Yeah, it's like you read my mind. I was wondering that exact thing. It's like we use cabergoline so much more. Is that just the reason why? And is there a consistent relationship with the dose or the duration of therapy on these dopamine agonists?

Dr. Nicholas Tritos:

So the simple answer is no. Impulse control disorders have developed after quite variable periods of treatment in case reports ranging between a few months to up to 14 years, so it's a huge variation. In cross-sectional studies, there has been no evident association between treatment duration or even the dose of dopamine agonist therapy and the risk of developing impulse control disorders. We had previously reported an association between higher cabergoline dose and higher impulsivity, which was assessed using a computer-based task in a pilot study. But in a clinical setting, in the clinical world, this has not been verified.

Dr. Bauer:

And if we're not sure if one drug has higher risk than the other, does it make sense to even switch between the two? If a patient has an impulse control disorder on, say, cabergoline, would you switch to bromocriptine?

Dr. Nicholas Tritos:

Yeah, that's an interesting question, and I don't think we have an answer to this based on real evidence. I think from practical perspective, if the behavior was mild and not really serious in terms of its potential implications, I might try to do that in some cases. However, I think it's worth pointing out that there are case reports of patients who were on one drug, had an impulse control disorder, then switched to another drug and then the previous behavior subsided but they developed a new impulse control disorder on the second drug. So unfortunately, they were not immune from developing a problematic behavior on the other drug either. So I think I would be very cautious, especially if a patient has a serious impulse control disorder that could have significant repercussions for the patient or the family. In that case, I would not do that, but if it's a mild impulse control disorder, I might try to do that.

Dr. Bauer:

And so catching these issues early is going to be really important and what is going to make the difference for our patients. So are there early warning signs you recommend clinicians to watch for?

Dr. Nicholas Tritos:

I think patient education and proactive monitoring and screening is key, and involving the family if possible would be desirable. So I think clinicians may wish to inquire about compulsive behaviors that represent failure to resist urges and are uncharacteristic of the patient at its clinic visit, and more optimally, even consider administering test instruments at clinic visits that are aimed at detecting impulse control disorders to all patients on dopamine agonist therapy.

And as I mentioned, family members may notice behaviors that are compulsive and that are very atypical and uncharacteristic of the patients such as gambling or compulsive shopping and so on, so I think ideally, I often have family members come to join the patient at the clinic visit. Of course, one has to be mindful and respectful of privacy laws, but nonetheless, if the family member is present at the clinic visit, that's an ideal setting so the issue can be discussed openly in the presence of the patient so that the patient and the family can be informed of the risk of developing these behaviors, and then the family can be enlisted to help bring the patient back to the medical attention sooner if such concerning behaviors do emerge.

Dr. Bauer:

And I remember when I first read your paper, I had not heard of half of these screening tools that you described. Which ones do you use in your clinic and which ones would you recommend? If you have a busy clinic and you're going to recommend one to a busy endocrinologist or practicing provider, which one would you recommend?

Dr. Nicholas Tritos:

Yes, thank you. That's an interesting question. So there are many test instruments that have been validated in general in patients with impulse control disorders, but I should mention that none of them have specifically been validated in hyperprolactinemic patients, and some of these instruments have been validated, for example, in patients with Parkinson's disease. The one that personally, I like using more often is the QUIP-RS, and this is a self-report instrument that was actually designed for patients with Parkinson's disease but can easily be used in a patient with hyperprolactinemia, although not specifically validated, at the moment at least. And it uses a Likert-type scale. The patient can quickly fill out this instrument within maybe five minutes or so. It can be quickly self-administered in the office, even in the waiting room while the patient is waiting. So I think I like this because of the simplicity and ease of administration.

There are several others of course. There's, for example, the MIEDI, M-I-E-D-I. That's a structured interview. That requires a little more time for the clinician to become familiar and administer it, so I think the QUIP-RS is easier to use and effective. There's also, I mentioned the BIS-11 or Barrett scale. That's a self-report instrument of impulsivity. That's an excellent research tool, and the responses to this test correlate with impulse control disorders. It does not directly assess the problematic behaviors. Like I said, it's very useful in research. And there are many others available, but personally, the QUIP-RS I would recommend using. It can be easily obtainable. It's free to download from the internet and can easily be used within a few minutes, self-administered by the patient.

Dr. Bauer:

And then to use these, do you get a baseline on the patient before you start the dopamine agonist so that you have something to compare it to, or do we just start it after?

Dr. Nicholas Tritos:

Yes, indeed. I think that's ideal, to have a baseline for comparison. There's also, with every test instrument, there's always an issue of learning how much the experience with the previous test could affect your responses to the subsequent test, but patients with hyperprolactinemia are not seen very often. They may be seen every several months or sometimes less often, so I think that's less likely to be an issue. One question is how often would you screen these patients? And I don't think we really know the answer to that. I think it's prudent to screen patients at each clinic visit, including patients who have been on therapy for a number of years since case reports have suggested that impulse control disorders may emerge after years on dopamine agonist therapy, so I wouldn't give up on evaluating patients who have been on medication for a number of years.

Personally, I have seen some patients develop some behaviors within a few months, so there's a huge range. Certainly, I would have a very low threshold to screen everybody systematically or at least ask them, but I do like, again, using the test instrument in the office setting. Even when the patient is in the waiting room, it can easily be administered.

Dr. Bauer:

And then counseling on the medicine is going to be incredibly important, and so hearing from you, the expert, could we hear an example of how you counsel on the possible side effects of a dopamine agonist? Do you have a 30 second elevator speech on the medicine?

Dr. Nicholas Tritos:

Yeah. So I think it is important to have a candid discussion with patients as well as family members to alert them to the possibility of this developing on dopamine agonist therapy. So I would tell them that some patients take to this medication, although typically, they tolerate the medication well, and of course, I would walk them through other more common adverse effects such as nausea and orthostasis. But again, when reviewing the possibility of impulse control disorders, I would say that there are occasionally people who may develop irresistible urge to do certain things. They cannot control themselves or resist the urge to do certain things such as shop or gamble or eat compulsively, and the issue is that this is uncharacteristic of them and they cannot control it. They cannot help stopping doing something like that. So I would ask patients to report any unusual behaviors that are new and uncharacteristic of them and give them some examples of such behaviors, like I said, such as shopping, gambling, spending, and others.

Dr. Bauer:

And then walk us through, if you were to have a patient on a dopamine agonist, on say a moderate dose, not a high dose but not also the lowest dose, and they had impulsive control disorder, say gambling, what would be your next step? Would you start with decreasing medicine dose or would you switch? Walk us through how you would think about that.

Dr. Nicholas Tritos:

Yeah, so that's an interesting question, and the evidence of course is either anecdotal or comes from case reports so we don't really have a systematic evaluation of this issue. In our unit in my practice, we generally recommend stopping the dopamine agonist if problematic behaviors develop. I think the exception can be if one has milder manifestations that are not severe. For example, I would consider gambling to be potentially serious because it can have serious repercussions for the patient and the family, so in that case, I would rather stop the medication and of course seek alternative treatments. But if someone has milder, for example, there are impulse control disorders that are relatively mild, for example, banding, sorting and putting together, stacking objects and things of that nature that are rather harmless. In that case, I think you can try to cut back on the dose and see if that helps. But if someone develops more serious manifestations such as gambling or spending or other behaviors that are very problematic and dangerous for the patient and the family and even society, I would rather stop the medication and then pursue alternatives.

Dr. Bauer:

And after stopping or lowering the dose, how long does it usually take to see those ICDs decrease or go away?

Dr. Nicholas Tritos:

So again, that has not been systematically evaluated, but based on the case reports and anecdotal experience, ICDs appear to resolve within about three months after the drug is discontinued in all patients, so it may take a while, and that's also important to recognize. And as I mentioned, in some case reports, a dose reduction may result in resolution of ICDs, although how often this latter strategy might be effective is unclear. We don't really know that.

Dr. Bauer:

And beyond medication changes, what is the role with psychiatric interventions? Do you refer to mental health to help with this, especially in those where taking them off the medication may have other clinical implications to their tumor burden?

Dr. Nicholas Tritos:

Yes, that's obviously an important question because I think it's important to point out that especially people with larger tumors, if they have macroprolactinoma, they are at certainly higher risk for tumor progression and are more likely to require other treatments if they stop a dopamine agonist therapy. So I think ideally, this should be addressed in a multidisciplinary setting. In our unit, we certainly have that option where you have physicians from different specialties, not endocrinology, neurosurgery, psychiatry, who can be available to opine on the patient. A psychiatric consultation, certainly one should have a low threshold to request, and that can be helpful if a patient has particularly worrisome symptoms or the behavior does not promptly resolve after stopping the drug.

There is very limited data about use of pharmacotherapy such as SRIs or cognitive behavior therapy in these cases, and I think that's an area where more research is needed. If one stops the dopamine agonist therapy, then one needs to consider alternative treatments in many cases. For example, this could be pituitary surgery for patients with larger tumors, radiation therapy in some cases. For patients with smaller tumors that are not causing mass effect and are less likely to progress, one may need other treatments such as sex steroid replacement to manage hypogonadism or pursue fertility therapies if that's of interest to the patient.

Dr. Bauer:

I find it so fascinating how some people can have these intense manifestations and that others have no symptoms at all. Have you ever seen in your clinical practice or in your review, have you seen cases where the impulse control disorders resolve without stopping the dopamine agonist?

Dr. Nicholas Tritos:

I have not seen that, but again, we don't advise our patients to stay on therapy if they report these behaviors. Like I said, if it's a very mild impulse control disorder, one can certainly try to reduce the dose to see if it's effective, but for the more problematic ones, we typically advise the patient to stop it, so we don't really know that answer.

Dr. Bauer:

Makes sense. And from a research perspective, what do you think is the biggest unanswered question in this field?

Dr. Nicholas Tritos:

I think one thing that we could all use is a better prediction model for the development of impulse control disorders in hyperpolyconemic patients based on ideally prospectively collected data. And one can envision using pharmacogenomics, multiomics and artificial intelligence approaches to refine our ability to risk stratify patients and develop models that can predict the development of impulse control disorders on therapy. Understanding the pathophysiology better at a fundamental level can also lead potentially to preventive strategies that can work, approaches of mitigation that are more effective. And as I mentioned earlier, the test instruments used to detect these conditions have been validated in other populations, not specifically in hyperpolyconemic patients, so that also could be very useful to do. And finally, other medical therapies such as SSRIs or cognitive behavioral therapy, we need to understand how effective these approaches really are in this context, so there's a lot to do.

Dr. Bauer:

In other words, we have a long way to go to really understand these disorders. Are there any studies that you know of that are underway right now that could change how we approach this?

Dr. Nicholas Tritos:

Yeah. So without going into specifics, there are certainly a number of prospective studies that are trying to address some of these issues and may provide some more light, but they will take time, I'm sure.

Dr. Bauer:

And finally, if our listeners remember just one takeaway from this conversation, what do you think it should be?

Dr. Nicholas Tritos:

Yes. So thank you. Clinicians will need to consider the possibility of impulse control disorders developing over time in practically every patient with hyperprolactinemia treated with dopamine agonists and proactively screen them, including patients on long-term therapy. The other important message, take-home message is that drug discontinuation after these conditions developed will likely result in resolution of symptoms, even though the time interval for that to happen extends up to several months. So I think to me, above all, this issue serves as a lesson and a reminder that even typically well-tolerated medications can have potentially serious adverse effects, and that to me highlights the importance that clinicians have to be vigilant at all times to assure patient safety.

Dr. Bauer:

I think my big takeaway was if you don't look for it, you may not find it. It doesn't mean it's not there, especially with that range of there's seven to 46% of people who have it. So Dr. Tritos, thank you so much for joining us and sharing your insights on this important and often overlooked aspect of dopamine agonist therapy, and to our listeners, you can find the full review in Endocrine Practice. Until next time, I'm Elizabeth Bauer and this has been the AACE Podcast.

Dr. Nicholas Tritos:

Thank you very much for having me.

Speaker 1:

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