Chapters Transcript Prolactinomas: What's New Course: Updates in Endocrinology 2024 So let's start with the prolactinomas and metabolism. So the first thing is, and I'm sure this audience is well aware, prolactin is a hormone that comes from the anterior pituitary, and we are well aware of the effects of prolactin on the breast tissue because it leads to gallacteria. It also suppresses the hypothalamic pituitary gonady axis, leading to hypogonadism. But something that is less well known about prolactin is its effect on energy homeostasis and metabolism. We always talk about hyperfunctioning tumors like acromegaly and Cushing's leading to problems with insulin resistance and weight gain, but not so much with prolactinomas. So this is what we're going to focus for the next few minutes. So why does prolactin have these extra gonadal effects? How does it act outside the pituitary? And to understand that we need to understand a little bit about how the prolactin receptors work. And the prolactin receptors are actually type one cytokine receptors, which are present not just in the pituitary, but interestingly, they're present in all these systemic tissue. So this is this diagram is from an article that we published a couple of years ago looking at the metabolic effects of prolactin, and you can see from this diagram that prolactin receptors can be present in the beta cells of the pancreas, in the heart, in the liver, and also in the adipose tissue. So not just limited to the pituitary but really widespread, and this possibly leads to the direct metabolic effects of prolactin on peripheral tissue. Now of course to treat hyperprolactinemia, we have a great class of medications which is dopamine agonists, and those act through D2 receptors. And interestingly, D2 receptors are not just present in the pituitary tumor, but they are also present in these peripheral tissue. Specifically, the beta cells of the pancreas and also in the adipocytes. So you'll see in the next few slides how use of dopamine agonists can sometimes help with the metabolic dysfunction from hyperprolactinemia. Let's talk a little bit about how prolactinomas can cause obesity, and again, you know, we talk, we think about this with Cushing's and with sometimes with acromegaly, but it's really interesting that now we're talking about prolactinomas and obesity. So the first thing is there's a reduction in the dopaminergic tone, and dopamine is a neurotransmitter that helps with energy regulation. So with reduction in the dopaminergic tone, there's a functional inhibition of um the receptors that lead to dopamine secretion, and hyperprolactinemia is one of the key mechanisms that that happens. Just to kind of remind ourselves, dopamine helps with increasing energy expenditure and it reduces food intake. So anytime you have a reduction in the dopaminergic tone, you're going to have patients with hyperphagia and obesity. This is of course the complex, the very complex neural network of appetite, and this is just a simplified version that I'm showing you here. And you can see here that the oculate nucleus of the hypothalamus really plays a key role in the regulation of appetite. Leptin that comes from the adipose tissue stimulates POM C, which is an appetite suppressing neuron, and it inhibits NPY and AGRP which increase appetite. So overall, leptin suppresses appetite and it prevents obesity. What happens when the prolactin is high? With the high prolactin, there's leptin resistance, and that in turn leads to problems with weight gain and obesity. And of course, I'm sure everyone here is aware of the effects of hyperprolactinemia causing hypogonadism, and hypogonadism is also known to increase body fat mass and it reduces lean body mass. And interestingly, this effect is a little bit more pronounced in men. In fact, there are studies that have looked into testosterone and dihydrotestosterone levels being in the lower quartiles and how the incidence of metabolic syndrome and obesity is almost twofold increased in those patients. So overall, there's an increase, increased in waist circumference, body weight, and BMI and this effect is specifically seen in men with prolactinomas, and there's increase in visual adiposity, which of course can be an independent risk factor for cardiovascular disease. What about prolactinomas and hyperlipidemia? So I showed you on the previous slide that the prolactin receptors are also present in the adipose tissue, but interestingly, the adipose tissue itself also makes prolactin. So at the level of the adipose tissue, prolactin acts as a hormone and also a cytokine, and it leads to hyperplasia and hypertrophy of the adipose tissue. There's reduction in lipoprotein lipase activity leading to increased triglycerides, and there's increased adiponectin, which in turn improves, which in turn um worsens insulin resistance. So all in all, hyperprolactinemia leads to dyslipidemia with increased total cholesterol, increased LDL, increased plasma triglycerides, and a reduction in HDL cholesterol. What about the effects of prolactin secreting tumors on insulin resistance? So of course we know that prolactin is a very important hormone in pregnancy and lactation, and in fact it helps to prevent gestational diabetes in women who are pregnant because it helps with metabolic adaptations of the maternal body. So under the influence of prolactin, there's beta cell expansion. This helps in preventing gestational diabetes. There's increased insulin release with respect to intake of glucose, and there's mild insulin resistance, but this proves to be beneficial because it helps to shunt nutrients to the baby through the placenta. But pathological hyperprolactinemia or hyperprolactinemia that comes from prolactinomas doesn't act in such a beneficial way. That causes more postcranial hyperinsulinemia with an exaggerated response on OGTT. Glucose uptake and utilization can be reduced specifically at the level of the skettal tissue, and there is increased hepatic insulin resistance, all in all increasing the incidence of insulin resistance. But interestingly, this is not a new concept. In 1947, Doctor Bernardo Husse received a Nobel Prize in medicine and physiology, essentially looking at the concept of prolactin being a diabetogenic hormone. And what he did was he injected partially pancreatectomized cats and dogs with prolactin, and he saw that those animals were developing glucose urea, high glucose, and symptoms of diabetes, and that's how he concluded that prolactin may be a dibatogenic hormone. So hyperprolactinemia, as we saw, causes insulin resistance, hyperlipidemia, and adiposity. But then we have an excellent class of medications in dopamine agonists which can help to mitigate some of these effects of hyperprolactinemia. And in fact, bromocriptine, which is one of the older dopamine agonists, was approved for type 2 diabetes use in 2009 as a glucose lowering drug. How does this work? So bromocriptine increases the levels of hypothalamic dopamine. You may remember from the first few slides that with hyperprolactinemia there's reduction in dopaminergic tone. So bromocriptine helps to bring that up again. There's also reduction of hepatic glucose production, and together that that reduces the weight, improves glucose tolerance, and also improves insulin sensitivity. This is a really nice review article that was published 10 years ago, and you can see that both romocriptin and Cabergoline really have a beneficial effect on body weight, fasting glucose, and the overall prevalence of metabolic syndrome as well. So in the last few years, because metabolism in prolactinomas has come up in such a big way, there have been lots and lots of studies to look at the effect of dopamine agonists on metabolic parameters in prolactinomas, and here I've just kind of highlighted the important studies that have done so, and I'm going to try and summarize all of these studies in this box here. So the first thing is, most of these studies were retrospective and the baseline Cabergoline dose in these studies was pretty standard to what we use in patients with prolactinomas. So approximately 0.5 mg per week or more. The body weight and BMI of these patients with prolactinomas started improving after approximately 12 months of dopamine agonist therapy. The longest study that I found in the literature was up to 5 years of dopamine agonist therapy, but interestingly, the effect on BMI took approximately 12 months or so. Also, prolactinomas in men can have more fatty tissue, and so the benefit of dopamine agonists was seen more in men compared to women. The LDL and triglyceride also improved only after 6 months of dopamine agonist use. However, some studies of course showed a neutral effect here, and there was significant improvement in the insulin resistance parameters only after 6 to 12 months of therapy. The thing to keep in mind though is that these are not randomized studies. These are smaller retrospective studies, and there was a great deal of heterogeneity in the overall outcome of these studies. This very seminal study was published in 2017. Um, this comes from Doctor Nikki Karawataki's group in the University of Birmingham in the UK, which for the first time showed that men with prolactinoma are at an increased risk of cardiovascular disease compared to women. This was a population-based retrospective open cohort study. You can see that it had a large number of patients, and these were well matched patients compared to risk factors, age, BMI, um, smoking history, and all, uh, risk factors as well. And the primary outcome here was cardiovascular disease, MI cerebrovascular disease or heart failure. And you can see that men had a higher incidence of coronary vascular disease and cardiovascular disease, and this was significant even after covariate adjustments. So this is definitely one of the kind of the more important articles that I wanted to highlight here. So to summarize, hyperprolactinemia causes obesity from those three mechanisms that I spoke about. It also causes hyperlipidemia. It causes insulin resistance, and it has an independent effect as a chronic immune regulator where it increases the amount of high sensitivity CRP and ultimately leads to metabolic syndrome and cardiovascular disease. So why is this important and why should we know about metabolic dysfunction in prolactinomas? This is the guidance which was published from the pituitary Society in September 2023, and if you have not read this article, I strongly urge you to do so. It's a really wonderful piece of work, and I always go back to it whenever I have questions about prolactinomas, and it's a very detailed, nice journal article. So the two recommendations here are that women with well-controlled microprolactinomas entering menopause should undergo a trial of dopamine agonist withdrawal. Unless pregnancy is desired, management of premenopausal women with microprolactinomas can include the option of sex hormone replacement without other interventions. So I can tell you I've definitely done this in my practice and I'm sure many of you have practiced this way, where if a woman is going towards menopause, you tend to have a discussion about stopping dopamine agonists, or if you have a patient with a small microprolactinoma who does not have any symptoms and is not looking to get pregnant, you can even think about withholding dopamine agonist therapy. But the question though arises as to what about the risk of metabolic dysfunction in these patients, which clearly is an effect of hyperprolactinemia. And um I think based on the beneficial metabolic impact of dopamine agonists we should perhaps be rethinking our approach specifically in postmenopausal women where we know that the lack of estrogen causes an increased risk of cardiovascular disease and perhaps we should be rethinking our approach in prolactinomas in men because as I just showed you, there is increased risk of obesity, metabolic syndrome, and perhaps even cardiovascular disease. So for now, I think we need larger prospective studies to look into this question, but it's not unreasonable to at least have this discussion with your patients, make sure you're explaining the pros and cons of both these approaches, specifically when you're trying to withhold dopamine agonist therapy. We'll move on to the next section, which is uh prolactinoma in bone. And uh this is a very simplified cartoon of how prolactin acts at the level of the bone. The traditional paradigm is that prolactin causes hypogonadism, and hypogonadism leads to bone loss. But it was interesting to see that prolactin also has receptors in the bone cells itself. So prolactin has receptors in the osteoblasts in the osteoclasts, and it causes increased bone turnover and reduction in bone formation. In fact, there are studies that have looked into increased markers of bone turno or like NTX and reduction in osteo cancer in patients with prolactinomas. The skeletal site, which is most commonly affected in prolactinomas is the lumbar spine, and that's because it's mostly made of tubercular bone, and we know that tubercular bone is affected in hyperprolactinemia and also in hypogonadicine. So these are two very large cross-sectional studies that were done in 2011, um, in a group from Italy. And uh you can see here that in the pre-menopausal women. Women with amenorrhea had higher risk of fractures compared to controls, and that effect was really exaggerated in postmenopausal women, where they had really an extensive risk of fractures compared to controls and also compared to pre-menopausal women. But I, what I really want to draw your attention to is what happened in men with prolactinomas. So if you look at this cross-sectional study on the right side, this was done in 34 patients. More than 35% of these patients had a vertebral fracture in this particular study. And interestingly, it was not just the patients who had low testosterone that had an increased risk of fracture, but it was also the patients with normal testosterone levels that had an increased risk of fracture. So this talks about the independent effects of prolactin on the bone. This is all sex hormone independent, not just coming from hypogonadism, but also because of the direct effect of prolactin on the bone cells. So what do we know about the effect of dopamine agonist on bone diseases? We know that patients who are untreated have a higher risk of fractures compared to those who are on treatment. Treatment with dopamine agonists improves bone turnover markers likely secondary to improvement of gonadal function, but this is a little more controversial. And the two main risk factors which really lead to bone impairment and hyperprolactinemia are the duration of disease, so long-lasting hyperprolactinemia, and in men, there's definitely an increased prevalence of vertebral fractures as compared to women. So you saw that both for cardiovascular disease and also for hyperprolactinemia in bone, I have highlighted that men can perhaps be more predisposed than women. Why do we think this is? And unfortunately we don't have the exact mechanism for why this happens, but of course we have some hypotheses. So the first thing is women with microprolactin women are diagnosed very early in life and they usually have microprolactinomas or small tumors. Their symptoms of infertility, galloptera, irregular menstrual cycles are very easily picked up, and so they are only in diagnosis with smaller tumors. Men, on the other hand, have symptoms of erectile dysfunction and reduction in libido, and these may be ignored by some men, and they have a median lag in diagnosis of approximately 10 years compared to that in women. So there is a lack of diagnosis, which means a prolonged duration of disease, which, as I just showed you is a risk factor both for cardiovascular dysfunction and also for bone disease. They tend to have larger, more invasive tumors. In fact, the WHO reclassified caractinomas in men as high risk category back in 2017. And interestingly, even after you fix the prolactin, 50% of men continue to continue to be hypogonadral, and of course they can have more compressive hypopituitarism as well. So perhaps this is one of the main reasons that men have more cardiovascular disease, perhaps more spinal disease as well. So the current recommendations from the 2023 guidelines is to do a baseline bone density in all patients with prolactinomas with suspected long standing, which is defined as greater than 6 months of hypogonadism or with other risk factors for osteoporosis. But I'll bring forth the two main points that I did for cardiovascular diseases were what about our patients who are undergoing menopause or approaching menopause, and what about the younger patients who are asymptomatic and not desiring pregnancy? Should we be withholding or withdrawing dopamine agonists in those patients? And the current guidance has not taken bone disease as one of the indications or as one of the risk factors for therapeutic decision making when they think about dopamine agonists, um, and of course again we need more prospective studies here, but at this. Point you might want to think pretty strongly about perhaps continuing dopamine agonists in your postmenopausal women, especially if they have underlying risk factors or previous fractures, and perhaps you would want to treat men with prolactinomas a little bit more aggressively. So let's move on to prolactinoma in surgery now and um I'm gonna go from touting dopamine agonist and how wonderful these class of medications are all the way to the other extreme which is surgery. And uh first off, to start with, these are the main indications of surgery in prolactinomas. I'm not going to go over details of each of these indications, but I wanted to highlight that these are the three main ones, which is dopamine agonist resistant prolactinomas, dopamine agonist intolerance, and patient preference is really coming up to be a leading indication as well. From the September 2023 guidance, we now know that in NOS grade 0 and grade 1 prolactinomas, you can actually offer dopamine agonists as first line therapy alongside. Uh, excuse me, you can offer surgery as first line therapy alongside dopamine agonists. So, um, this is, this is the exact guidance surgical resection of microprolactinomas and well circumscribed macrop prolactinomas, NOS grade 0 and 1, and you can discuss surgery alongside dopamine agonist as a first line treatment option in this particular subgroup of patients. Keep in mind that if you have a patient with no grade 2 or more, you probably want to treat with dopamine agonists to start with. Um, for those of you who are not familiar with the NOSS grading, I just wanted to quickly remind you. So that basically looks at paracellar extension of the pituitary adenoma towards the cavernous sinus. And we have these three definitive lines, the medial tangent line, which goes from the supraclinoid ICA to the intra-cavernous ICA. We have the in carotid line right in the middle, and then the lateral tangent line. So NORS classification is very important because it helps the surgeons decide what the degree of camera sinus invasion is and how much of the tumor can be successfully and safely removed. So nos grade 0 tumors are the ones that are medial to this medial tangent line we spoke about. No grade one tumors are in between the medial tangent line and the intercarotid line. And the NOS grade 2 and 3 tumors are more invasive, and NOS grade 4, of course, completely encapsulates the ICA. So again, grade 0 and grade 1 are good surgical candidates. Grade 2 and over, you probably want to start with dopamine agonists to start with. These are the several studies that have been done in the last few years, um, on surgery for prolactinomas and of course, this is the guidance from 2023 and here I've tried to summarize a lot of that data comparing dopamine agonists to surgery. So the first thing is, what about biochemical control? And you can see here that both with medications and with surgery, the effects are pretty comparable. So with dopamine agonists, it's approximately 91% or so with smaller tumors, and surgery leads to a biochemical remission in 75 to 93%, and this of course depends on the surgical expertise and so on. But with macroadenomas you can see that the dopamine agonists actually fared pretty well, 77% biochemical remission, but surgery perhaps not so much, so 40 to 70%, and there was a recent guidance which showed that it could be as low as 60% as well. So you may want to think about macroadenomas and perhaps first line dopamine agonist therapy. And what about recurrence? I am sure that everyone in this audience agrees that whenever you stop or withdraw dopamine agonist therapy, you have to look very, very closely for recurrence, and that's because the risk of recurrence post dopamine agonist withdrawal is really high. It's 60 to 80%. So we should really never tell our patients to not come back for follow-up because that prolactin needs to be checked usually every 3 months, 6 months, and then annually to make sure that hyperprolactinemia is not coming back. And that rate is approximately 10 to 25% in 5 years with surgery. Of course pituitary centers of excellence are key. You want to send these patients to really high volume centers and to surgeons who've done many, many of these cases. This is a review article which I thought was a really excellent representation of what I was saying, which is if you have a center doing more. More than 6 surgeries per year. The rates of remission are greater than 90%, but as soon as you drop that to less than 2 per year, the rates of remission go down to 77%. So this really talks about how important continuous surgical experiences. This is a meta-analysis that we published at NYU in a few years, a few years ago, and uh here we looked at more than 3000 patients, 35 studies that we included, and we concluded that macroadenomas with extracellular extension and cavernous sinus invasions had a lower post-op remission rate. And female gender and absence of pre-op dopamine agonist also gave a higher postop permission, although this effect was not significant in detailed sensitivity analysis. So what are the predictors of surgical remission? How do we know that this is a good candidate and that the candidate is possibly going to do well post-surgery? So again, as you can see from this cartoon, well enclosed medial prolactinomas are probably good candidates of remission of surgical remission, 87% or so as opposed to ones that are closer to the cavernous sinus. Absence of cavernous sinus invasion is important. Prolactin level is greater than 200. Tend to have a poor surgical outcome, independent of tumor size. And immediately after surgery, day one or day two, you usually want the prolactin to drop to 5 to 10 nanograms per mL. That tells you that there's been a good surgical resection. Pre-op use of dopamine agonists is debatable, and I think we need larger studies to really kind of conclude what we should be doing with dopamine agonist prior to surgery. So I'm going to conclude with 3 quick cases, um, which I think really highlight the importance of the role of surgery in prolactinomas. This is case one. It's a 40 year old female, these are my clinic patients. It's a 40 year old female who presented with amenorrhea and infertility. Dopamine agonist intolerance patient preference. She wanted the tumor taken out, and you can see here that the tumor is nicely localized. It's central. There's no cavernous sinus invasion. The prolactin is 100, so remember it really should be less than 200 ideally pre-op. So it was 100 and it improved to less than 6 after surgery, and you can see that her pituitary looks nice and normal. Case 2, this is a young female who came in with amenorrhea. She had a dopamine agonist resistant prolactinoma, but she also had MEN1 syndrome, and we know that 50% of MEN1 cases can have some degree of dopamine agonist resistance. And again, she had a really nice response well localized tumor, central location, and the prolactin went from 400s to 20s. But this guy was not so lucky, so he came in with uh headaches and uh blurry vision, really a giant prolactinoma as you can see from this particular slide. So we did not send him for surgery. We started him on Cabergoline and we had to ramp up doses pretty quickly to get to get him to good biochemical response. And as you can see from this image, he also had very, very good radiological response. You can see the supercellar extension of the tumor really improving in these radiological images, and this happened within 2 years, so really, really responded well. So in summary, for prolactinomas and metabolism, I think we should be aware that prolactin does cause obesity, metabolic syndrome, perhaps an increased risk of cardiovascular dysfunction. Dopamine agonist treatment may induce weight loss, improved metabolic profile, and insulin resistance, and I think we may want to moving forward, consider metabolic dysfunction in decision making, specifically when we're trying to withdraw dopamine agonist therapy or if we are debating starting it. Prolactinoma in bone disease. Prolactin likely plays an independent role separate from gonadal status. The duration of hypercolactinemia and male gender end up being independent risk factors for bone impairment. And again, I think we need to consider bone disease in decision making about dopamine agonists. And the last thing of course is the role of surgery, and we are so excited that now we can indeed offer surgery as first line in some of these tumors. Pituitary centers of excellence are key, and repeat surgery is curative, but only in less than 50% of the cases, you may want to consider adding dopamine agonists in those patients. So thank you so much for your attention and I'm happy to take any questions. 00, sure, sure, sure. Good morning everybody. My name is Richard Fillers. I'm gonna moderate the Q&A session for this wonderful presentation by Nei. Thank you so much. Can I ask one question? Um, you mentioned nonvertebral vertebral fractures. Is there any data on non-vertebral fractures or hip fractures? Yeah, great, great question. So, you know, they actually did not look at that mostly because of the cortical bone being predominant, um, or at least 50% more predominant. So they have not looked at hip fractures. Um, there was one small study that looked at radial fractures and they found that there was no significance. So it was all the studies have been done on vertebral fractures. So one question, uh, online, uh, in a post, uh, menopausal femur with a history of traumatic brain injury, with the pituitary transaction with anterior, uh, hyperpituitarism and hyperpoinemia, which you treat this patient with dopamine agonists. Sorry, I can put it down. OK, OK, thank you so much, Richard. So in a postmenopausal female with a history of TBI with pituitary transaction, with anterior pituitary hypopituitarism and hyperprolactinemia, prolactin in the 200s, would you treat with dopamine agonists? So, so this is getting to um a topic that I did not touch upon, which is um non-prolactinoma hyperprolactinemia. And you know, most of the studies have been done in patients with CKD, in patients with PCOS and hyperprolactidemia as causes of increased prolactin, but I didn't really see any independent studies on, on traumatic brain injury, which is the question here. I will say though, Cabergoline is just overall a low risk drug, so I think if we were to start it and see what the response is, that would definitely be reasonable. There's another question which is asking about vaginal cabergoline for people who cannot tolerate PO. And there was a study that was just published in pituitary, 2 years ago which looked at vaginal cabergoline, intranasal cabergoline in patients who don't have good tolerance to PO cabergoline. And unfortunately, the effect on the tumor reduction was just not significant enough. So if you have a patient with a big tumor, you're better off sending that patient for surgery. What about patients with hyperprolactinemia with no detectable mass? You should still be treating if you have a high suspicion for hyperprolactinemia. And um yeah, and then just some good feedback. So thank you again for um all your attention and um very happy to introduce the next speaker. Thank you. Published March 22, 2024 Created by Related Presenters Nidhi Agrawal, MD View full profile
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