Hello, everybody. Thank you very much for inviting me to give this webinar. Today my talk is how to do the workup and diagnosis of the hyperlactean and prolactinoma. I have no conflict of interest for this topic, and I have no direct financial benefit from the research I've been doing. These are the topics I'm going to cover today. The physiology of the prolactin, etiology and workup for the hyperlactean, and then what is a prolactinoma, underlying pathology, and then underlying genetic and management. And then I'm going to touch about the prolactinoma in pregnancy, and then I'm going to touch a little bit about the prolactinoma, malignant prolactinoma. Prolactin is under the dual control. You may see here that dopamine is under the negative control through the D2 receptor. Any disruption of the dopamine pathway from the hypothalamus or pituitary can raise the prolactin. And it is also under the stimulation of the TRH and then VIP, and it also stimulates the prolactin secretion. And these under the dual control, controlling the prolactin secretion from the anterior pituitary. And prolactin is a very parasitized hormone, and half-life is 20 to 50 minutes. It is mainly metabolized by the liver, 75%, and then some degree it's metabolized by the kidney. And it also has effect under the estrogen, and then any disruption of this hypothalamus or pituitary stalk, it can disrupt the dopamine pathway, and it can raise the prolactin. The major function of the prolactin is preparation for the lactation, and then lactation after the pregnancy. You may see that it cause expansion of the ductal and alveolar formation and the secretory differentiation of the alveoli. So when the woman is pregnant, there will be increase in the breast tissue. And then after the delivery, it can start the positive feedback of the suckling and then prolactin secretion, it can start the lactation process. Not only the lactation, we now know that prolactin is important for the bone metabolism, hair cycle, and then some adipose tissue metabolism, and the beta cell. Some, they may have a food intake as well. So because of the limitation of my topic today, I'm not going to cover for the other non-lactation effect of the prolactin in this topic. These are the causes of the high prolactin. Mainly it's a two, a physiologic etiology and pathologic etiology. Physiology is from the pregnancy, lactation, any nipple stimulation, exercise, stress, sex, and then any high protein meal and alcohol consumption can raise the prolactin level. These are the normal physiological stimulation of the prolactin. Pathological, there are three subcategories of pathological, pituitary pathology, non-pituitary pathology, and genetic. Let me start with the pituitary pathology. Prolactinoma, acromegaly, and then any tumor with the stalk effect, and also hypothalamus, pituitary stalk lesion, and then hypophysitis. And the last is the idiopathic. You know, after we cannot find any reason, it can be the idiopathic. And the non-pituitary causes are mainly the primary hypothyroidism, severe liver disease, and then chronic kidney disease, anorexia, malnutrition, any chest wall irritation, heartbeats, neurogenic trauma, and also the surgery. Very rarely, it can cause the atopic prolactin secretion from the renal cell carcinoma, ovarian teratoma. And the last is a genetic cause. Because of inactivation mutation of the prolactin receptor gene, it also can raise, you know, raise the prolactin. These are just example of the, you know, common medicine that can raise the prolactin. The most, you know, notorious is the dopamine receptor blocker, a lot of the antipsychotic medication, and a lot of prokaryotic medications such as glucopramide, metoclopramide, and then tromperidone, and then halbaldol, and the dopamine synthesis inhibitor, methidopa, and then cholinergic agonist, visostigmine. The blood pressure medicine such as verapamil, labiltilol can raise the prolactin. H2 receptor blocker, antihistamine can raise the prolactin as well. Anticonvulsant phenotrile can raise the prolactin. These are the neuroleptic medication. They can cause, you know, high prolactin as well. Especially older generation, halbaldol can raise the prolactin significantly. Opiate and opiate agonist can raise the prolactin. Heroin, methadone, morphine, and currently the newer, you know, antidepressants such as tricyclic antidepressant and SSRI, which are not very new anymore, they can raise the prolactin as well. Even the minor stress such as venipuncture can raise the prolactin up to two to four fold. But usually the level is very mild, less than 60 nanogram per mil. It lasted less than one hour. So after the stress resolve, prolactin level can come down also. Whenever the prolactin level less than five times upper limit or normal, or if there is a concomitant stress as suspected, we always have to repeat the prolactin value or we have to get the cannulated venipuncture level. The woman with the, you know, prolactin, you know, here's a prolactin value. Take a look at it. After this, you know, after they repeated some of the prolactin value normalized, this red column is normalized after the cannulated prolactin. The blue column is, they are not normalized after the cannulation. You may see that if the woman with the menstrual irregularity has a much more, you know, convincing reason for the prolactin remain high. And then any symptom combination can have a remain high as well. But here is, you know, if the patient has no symptoms and after they repeat the prolactin through the cannulation process, cannulated venipuncture, the repeat prolactin level can be normalized. These are the common etiology of high prolactin. This is just a range of the prolactin range and nanogram per mil. And electrotrope macroprolactinoma is a very high level with a thousands. And the microprolactin can be a few hundred. Idiopathic can be a little bit similar range, a little bit on the lower end. The macroprolactinemia, enlarged, you know, macroprolactin molecule, which I'm going to talk about later on, it can also cause, you know, a few hundred. And the drug-induced can have a few hundred. People with acromegaly can have a high prolactin. And the non-functional pituitary adenoma can raise the prolactin as well, but not as much as, you know, other causes. Primary hypothyroidism can raise the prolactin value as well. Here, the most tricky thing is, if it's a macroprolactinoma, it's easy, hundreds of thousands, macroprolactin, a few hundred. But tricky thing is here, from the macroprolactinoma, idiopathic prolactinemia, and then sometimes even the drug-induced, and then they can be hard to differentiate. Sometimes some of the non-functional pituitary adenoma can also be as high as the macroprolactinoma level. If it's a prolactinoma, the tumor size correlate very well with the prolactin value. This is a patient series with the non-prolactinoma. The higher the tumor size, the higher the prolactin level. Stock effect is mainly whatever the, you know, high prolactin with the cellar mass, with the associated diabetes insipidus, central DI, whenever there's a presentation, prolactinoma is less likely. We got to think about the stock compression or dopaminergic neuronal damage by the cellar tumor. Usually it's a dysthelminoma, craniopharyngioma. These tumors can have a significant size, more than two or three centimeters in tumor size, and it can cause a stock compression. It can raise the prolactin. Hypophysitis, any inflammation can raise the prolactin. A metastatic of the primary tumor matched to the pituitary gland can raise the prolactin. Glomerulus infiltration of the hypothalamus, not just sarcoidosis, can raise the prolactin as well. Whenever there is a, you know, mildly elevated prolactin level, and after you give a therapeutic trial with the dopamine agonist, if there is no shrinkage of the tumor, and then they may have a, you know, decline in the prolactin value, and we should consider with the stock effect by the non-functional pituitary edenoma. So you can always, whatever you suspect, you can always try the therapeutic trial with the dopamine agonist, because these dopamine agonists has a very good response rate. And after you try with the dopamine agonist, there will be have a shrinkage of the tumor, and also there will be decline of the prolactin level. If there is no such response, you know, we have to consider, you know, stock effect by the non-functional pituitary edenoma, which I'm going to talk about in the later part of the slides as well. It is a case series of the 64 patients with the histo, immunohistochemically confirmed non-functional pituitary edenoma. 81%, majorities are very mildly elevated, 81% has a less than 100 nanogram per mil. And then another case series of 226 histologically confirmed non-functional pituitary edenoma, only three cases has more than 100 nanogram per deciliter. So in that case, it's rule of thumb is whatever you have a tumor less than 100, prolactin level less than 100 of the pituitary tumor, you always think of the non-functional pituitary edenoma. And whatever the prolactin value, more than 250 and higher nanogram and mil and higher, we have to consider the prolactinoma, either the most likely as a microprolactinoma. However, there's a, what is the measurement threshold for the prolactin value for the diagnosis cutoff for diagnostic cutoff for the non-functional pituitary edenoma is still a matter of debate. We have to exclude the macroprolactinemia, it's aggregate of the prolactin with the IgA and IgG, or we have to exclude the hook effect, which is mostly due to the falsely lower or falsely close to normal prolactin value because of the macroprolactinoma. After we exclude those two factors, we can consider the differential diagnosis of the non-functional pituitary edenoma. I'm going to switch my gear to talk about the assay issue since as endocrinology, we rely so much on the assay and that we have to know about the assay interference. And just like any, any other, you know, hormone assay, prolactin also under the, you know, influence of all these assay interference. This is an example of the radio immunoassay and then two antibody specific for the different epitope of prolactin. This is a serum prolactin, this is a capture antibody, that's a radioisotope label antibody. And after the, you know, these antibody bound to the prolactin, they form the sandwich formation. After these, you know, you know, the prolactin molecule, they, you know, wash out, unbound material will be washed out and only bound material with the, you know, left behind with the help of the capture antibody, it will generate the signal. This signal directly correlate to the prolactin value. There's no such kind of stimulation or suppression testing, like the cortisol value for the prolactin. So there is no such a, such benefit of these tests. That's why these stimulation and then suppression of the prolactin has been abandoned. So really immunoradiometric assay or the immunochemilumetric assay, IGMA, and then those are also affected by the hook effect. If you have a very high prolactin, extremely high thousands of prolactin, especially from the macroprolactin NOMA, these high prolactin saturate the both capture antibody and detection antibody. They overwhelm these, these antibody. So you can see that, you know, since they overwhelm these antibody, they don't form the sandwich formation. Then they don't form the sandwich formation. The prolactin may not be high enough corresponding to the pituitary tumor size. Whenever you have a more than three centimeter of the pituitary NOMA with the seemingly normal or the mildly elevated prolactin value, usually it's a less than a couple of hundred, two or 300, we got to consider the hook effect. And also in that case, we'll call the lab and we request a dilutional. Sometimes we have to do the one to a hundred, one to 400, 500, or we may have to use a different assay platform, which does not have a hook effect also. Currently today, assays are very sensitive that they can, you know, eliminate or that such a hook effect has been less and less common, you know, compared to before. Just like any immunometric assay, this prolactin assay has affected by the heterofibe antibody and also the anti-human, anti-mouse antibody. In that case, as these days, we are taking people taking the biotin, such cases can be affected. The assay interferes as well. You can have a falsely positive assay, people using the biotin these days for the hair and nails supplement, and then these biotin, especially if they take it in high concentration, it can affect the prolactin assay, just like the thyroid hormone assay as well. I'm going to talk about the macroprolactin. The one that are clinically active molecules are the free prolactin or the monomeric prolactin. These are active prolactin. They cleave from the pre-prolactin and also they become a free prolactin. When they bound to the, you know, another prolactin, they become a dimeric prolactin. These are clinically inactive. When they bound mostly to the IgG and sometime with the IgA, they become an extremely large, you know, macroprolactin molecule. It is called a big, big prolactin or macroprolactinemia. In such cases, these are, you know, also these two are inactive. In these cases, these can still be the antigenic. They can interact with the antibody from the assay and they're giving you the positive result, but clinically they are not as active as a free prolactin molecule. So these antibodies bound to this, you know, prolactin molecule, either the IgG, which is more common or sometimes IgG, they retain the partial immunoreactivity to the antibody in the immunoassay, but biologically they are less active. So one of the case series, they pointed out that macroprolactinemia can be as common as almost 25% of the cases with the high prolactin. These macroprolactin can co-exist with monomeric prolactin. So a patient can have a both, you know, high monomeric prolactin, which is also called a free prolactin or the macroprolactin. In these cases, they can give you the extremely high prolactin level, but the real, you know, free prolactin may not be that high. The current immunoassay, they cannot differentiate between the monomeric prolactin and macroprolactin. Here, a patient with a high prolactin, and then this is a two-side immunometric assay, this assay can bind to the, you know, monomeric prolactin and the macroprolactin as well, but that's why they can give you the positive result for the both prolactin. In that cases, you can request a polyethylene glycol, and you can call the lab and let them precipitate. After they precipitate, you will see here before the polyethylene glycol, and then the levels are high. And then after the precipitation of the big prolactin or big, big prolactin, they will show you the real value of the high prolactin, which remain high. Sometimes, you know, majority of the, you know, high prolactin before the polyethylene glycol, a majority of them are macroprolactin. In that case, after the precipitation, and the real free prolactin or active prolactin may not be as high as, you know, original before the ethylene glycol method. This is a most likely reason, and it is much more, you know, can have an interference, especially if the patient has a very high gamma globulin. So in that cases, it can cause you the false deposit result. The most reliable reference method is a gel filtration chromatography method, but it's cumbersome and costly. So you can always start with the polyethylene glycol, especially if the patient has a high prolactin value without the significant clinical symptoms, we should suspect the macroprolactinemia. But not all the macroprolactin molecules are clinically inert. Yes, they are clinically less active than the monomodulate prolactin, but not all of them are really inert. So this is a case series of the macroprolactin. If you take a look at it, and then some of them has no significant symptom. Yes, significant number of the patients, 61 patients, macroprolactin has no symptom. But if you take a look at them, some of them has some of the oligomoria, some of them has a, here is a darker column is a, you know, colectoria, but in order to have a both colectoria and oligomoria only 2%, and that if you have a both symptoms, majorities become monomodulate prolactin. So the symptom presentation of the macroprolactin can be similar to the monomodulate prolactin. So that's why macroprolactin screening should not be restricted only to the asymptomatic patient. So usually you have to do the macroprolactin screening more than the, you know, we should, and then so that we get the much more correct monomodulate prolactin value. The take-home message here is not all the macroprolactin anemia are the, you know, asymptomatic. Some of, yes, majorities are asymptomatic, but sometimes they may have some symptoms as well. And then, this is a workup from the, how to do the workup for the high prolactin. If you have a high prolactin, we always correlate the clinical finding. That's the patient has a clinical feature supported of the prolactinoma, colectoria, reduced libido, infertility, menstrual irregularity, or re-digest function. If they have a clinical symptoms, you can check the prolactin. If the patient has a saliva mask, you can check the prolactin because prolactinoma is the most common functional pituitary tumor. And sometimes you can check the prolactin out of the workup for the hypochondrotropic hypogonadism. That's the most common reason we check the prolactin in our clinic as well, because I see a lot of patients with the low testosterone. And then after you have a prolactin, you have to judge how high the prolactin level is. If the prolactin levels are not very high, usually less than 5% of the upper limit normal, and then without the convincing clinical sign of symptom, you can always repeat the level. And if the patient has a, without the clinical symptoms, and then just isolated high prolactin value, you have to exclude the macro prolactin. If the prolactin levels are less than 200, we have to go and take a look at the proper history, stress, even the phlebotomy and the hypothyroid adrenal insufficiency, liver insufficiency, and then medication. So we have to go through all the medication which can raise that prolactin. Even though the cutoff is somewhere around 200, we have seen that some of the medication, especially with the antipsychotic medication, older generation, they can raise up to a couple of hundred easily. And the last, not the least, is we always have to exclude the pregnancy, which can present as galacturia and then amenorrhea. Any young woman, even at the reproductive, any reproductive age, we have to exclude the pregnancy risk as well. After that, if the prolactin has remained significantly high, more than 200, getting the MRI is quite reasonable. And then depending on the MRI, we can get the very large tumor, which can be the macro prolactin or the micro prolactin. And then sometimes if the tumor is a decent size, two to three centimeter without the significant clinical symptoms, and the only mildly elevated prolactin level, we have to consider about the non-prolactinoma or the non-functional pituitary adenoma. And whenever you have, in these cases, we have to consider about the stock effect as well. I'm going to switch my gear to talk about the pituitary adenoma. Pituitary adenoma is an old term, you know, since 1912, you know, Harvey Khrushchev used the pituitary adenoma. Pituitary society still uses this term. However, WHO and international pathology pituitary club, pituitary pathology club in Paris in 1916, when they gather and they try to change the name and the name, they come up with a pituitary neuroendocrine tumor. So WHO adopted that term and accepted the term. That's why whenever you see this, some of the radiology report and pathology report, you will see the PNET, pituitary neuroendocrine tumor. Clinician wise, clinically, and then most of the clinicians still use a pituitary adenoma, micro adenoma, adenoma, but still you may see that this term, pituitary neuroendocrine tumor has been catching on. So I'm going to tell you the pros and cons of usage of these terms. And then the rationale to use a PNET is it recognize, this term recognize a lack of the predictability of the pituitary tumor. It reflect the potential of the malignant behavior. These tumors are not benign tumor. They are the, in fact, they are neuroendocrine tumor. They extract the neuroendocrine markers, such as CD56, insulin-like protein, synaptophysin, and the chromogranin. They are resistant to conventional, they can be resistant to conventional therapy. Some of them are prognosis, and rarely they can present as a metastasis in the malignancy. Definitely, they behave like invasive tumor or aggressive tumor invading the nearby structure. Sometimes the tendency, they can cause a hemorrhage and necrosis because of the increased growth rate. This is a pituitary society, endocrine society. They still use a term called the pituitary denoma. The rationally, they use this term called the pituitary denoma is that this is a very, autopsy series, very rarely it causes invasiveness, one in 2,000, and much more rare, it can cause malignancy and spread beyond the pituitary gland, one in 100,000. And most of the pituitary tumor do not require biopsy. And then if you take a look at here, according to autopsy series, 10% of the population has a pituitary denoma. It is very common. Only 0.1% can present with a clinical sinus symptoms. And out of these, not all of them got the surgery, less than 50%, 45% to be exact, got the surgery. And then out of them, from the surgery, we have a pathology. A lot of them, majority, they don't have a surgery. We don't know the pathology. Out of them, only small percentage, somewhere around 16%, they have invasiveness or malignancy risk. Majority of these tumors are benign. We presume that a lot of these people who never got the surgery are not significant enough to get the surgery. And then these people who got the surgery might have some indication to get the surgery. And then those who got the surgery, after they take a look at the pathology, not all of them express the neuroendocrine marker. And then these neuroendocrine markers are not the pituitary-sensitive, they're specific. They can express in other endocrine tumors, such as follicular thyroid cancer and adrenal adenoma as well. So that's why a lot of the clinicians from the endocrine society and the endocrine-pituitary society, they still use a term called the pituitary adenoma. But you may come across a PNAT from the pathology report and also from the radiology report as well. This is a pathogenesis of the pituitary tumor. And then majority of the pituitary tumor are null cell. And the significant proportion of, they are not producing any hormone. And then they have a silent corticotrope, silent corticotrope and the silent somatotrope. And they have a variable transcription factor. It can present with a mass effect. That's why they can present with a pituitary insufficiency sinus symptoms. The among the functional tumor, prolactinomas are the most common tumor as well. They can be subdivided into the densely granulated, sparsely granulated acetyl filled tumor. According to the transcription factor, the pituitary tumor can be divided into the three group. And then T-PIT group, and then PIT-1 and the SF-1. From the PIT-1 group, which is a somatotrope stem cell, it can be subdivided into three group. Somatotrope, growth hormone producing tumor. Lactotrope, prolactin producing tumor. And thyrotrope, DSH producing tumor. Somatomemotrope can produce both growth hormone and the prolactin secretion as well. Since we know more about these transcription factor from the pituitary pathology, so these prolactinoma and these pituitary tumor can be subdivided according to the immunohistochemistry staining. The lactotrope can be subdivided into three group. Majorities are the sparsely granulated, the lactotrope cell. They have a good prognosis. Densely granulated lactotropes are rare. They can be clinically aggressive. Estrus field stem cell tumor are very rare. It's a mixed prolactin and growth hormone. It's a pluripotent hormone. Depend on how much prolactin lactotrope cell in the tumor, there's a variable degree of the prolactin secretion. They can produce growth hormone and IGF-1. It can rapidly grow into the macrodenoma, and it can be aggressive and lower curative surgical rate as well. And these are the mixed growth hormone and prolactin secretion, prolactin pituitary adenoma. So since they have a similar precursor in transcription factor, pit transcription factor, some are the pure somatotrope adenoma, 80%. They produce a growth hormone, and then hyperlactin is mainly because of the stock effect. Some are mammal somatotrope adenoma. These are monomorphic tumor coming from the one cell line. It produce a both growth hormone and then prolactin coming from the single hormone progenitor cell. It can significantly raise the prolactin, higher remission rate, and the better prognosis. Mixed somatotrope and lactotrope adenoma, they come in from the dimorphous cell line, dimorphous tumor. So if you stain them, they have a two different type of cell line. It can be aggressive, the lowest curative surgical rate as well. Acetyl-5-stem cell tumor, we just covered a little bit. These are a plurihormonous tumor, produce an IGF-1, growth hormone, and then prolactin. And then it can present as acromegaly feature. It can be tumor-wise is pretty aggressive tumor, and then lower surgical cure rate. Most of these are prolactinoma, are the sporadic monoclonal neoplasm. There are some somatic genetic mutation present, but the routine screening is not performed and not recommended. Then this particular prolactin receptor mutation is rare. It can be associated with the increase in prolactinoma proliferation. The mutation in the splicing factor three subunit 1B can present in the 20% of the prolactinoma. When they present, they have a significantly high prolactin value and they can be more aggressive. Sometimes it can be associated with the germline mutation. Luckily, it is very rare. They can present at a young age, associated with the SDHX mutation, which is associated with the adrenal tumor and the BRK1R1A in the max tumor. And then AIP gene mutation, it can be present in the family isolated pituitary edenoma patient or the sporadic cases. Man 1 and then family isolated pituitary edenoma, they can present in the younger age, less than 30, present with the macrodenoma and has a very strong family history of the pituitary edenoma. If it's in man 1 cases, usually they present as a macroprolactinoma, can be more aggressive and they're usually resistant to the dopamine agonist therapy, unlike the isolated sporadic prolactinoma, luckily, which are the most common type. So I'm going to touch about the epidemiology of the prolactinoma. Majority of the cases are in adult. Only the germline mutation type are common in the younger patient, less than 30. And the prevalence is 54 in 100,000. An incident is five cases in 100,000. Women's are three times more common than the men. Before the fifth decade, it's a woman predominant tumor type, five to 10 times more common in the woman than the man. After the menopause, the male and female incident ratios are similar. In the 90% of the women, they present as a microprolactinoma. They usually present with a collectoria, amenorrhea or infertility. In the men, sometimes it can be diagnosis, can be delayed, and then macroprolactin is more common than the woman. So up to, you know, here is, if you take a look at them, woman has, you know, one macroprolactin, there's eight microprolactin. In the men, it's a four macroprolactin, noma, it's a one macroprolactin. So in the men, macroprolactinomas are more common, commonly presented than the female. How do we differentiate, how do we classify the prolactinoma? We can classify according to the size, according to the malignancy and the benign tumor. And if it's a less than one centimeter, microprolactin, good prognosis, it's a low risk of the long-term growth. More than one centimeter, it can be the macroprolactin. These tumor needs a close follow-up. Giant prolactin, it's only 3% of all the prolactin. Usually cutoff is like four centimeter. In cutoff, they may have a significant extracellular extension. And then some of the giant prolactin we pick up in the past might be some of these acidophil stem cell tumor, or some of the particular, you know, subtype of the tumor, since we know more about the prolactin tumor subtype according to the immunohistochemistry staining. These giant prolactinoma can present with a significantly high prolactin value, more than thousands of prolactin level. They may have a concomitant growth hormone production, and they may have a concomitant ACTA production. So they may present with the other, you know, hyperfunctioning feature as well. That there is a some degree responsiveness to the dopamine agonist therapy. They may require the higher than usual dose. Malignant prolactinoma, I'm going to touch about later on. And luckily it is very rare and defined by the metastasis within the CNS or outside of the CNS. This is an example of the giant prolactinoma. You can see that almost entirely infiltrating to the anterior, you know, at the whole, and, you know, pituitary gland, and also invaded into the frontal lobe. These macro giant prolactinoma, they can invade into the surrounding structure, especially the cranial nerve, and then cavernous sinus. They can present with their hearing deficit. They can present with, you know, all these, you know, optic nerve compression. They can present with the cranial nerve palsy as well. How, what are the symptoms of the pituitary prolactinoma? Is it depend on the menstrual cycle, and then depend on the gender and sex. It can vary pre-menstrual woman, pre-menopausal woman. It's a hypogonada, infertility, oligomenorrhea, immunorrhea, colectoria. These are most common. The more you have a patient that has more than one symptoms is a likely chance that they have a prolactinoma. And post-menopausal, they rarely symptomatic, usually become hypogonada, but the patient is post-menopausal, it's hard to tell. And usually they can present like a macro, late with the macro prolactinoma. Men, usually they present with a mass effect because they don't present early on. If there's an early on, they can present with a hypogonadism, low testosterone, gynecomastia, or infertility. And then when they have a mass effect, they can present with a headache, impaired vision. And then if it is a long-term tumor, because they don't get the diagnosis in timely manner, they can have a sarcopenia, and then reduced body hair, osteoporosis. Colectoria can be rare. It can, in cases, it can present up to like 20% of the cases but extremely rare in the men to present with a significant colectoria. Here's the most common clinical manifestation. Here's according to case series up to like 10 to 30%, but I think 33% is a little bit too much over of the estimation. And in the women, up to 80% can present with a colectoria. Absence of colectoria does not exclude the high prolactin. Some of the women, they don't present with a colectoria, does not mean that they don't have a prolactinemia or prolactinoma. And then some of the colectoria can be intermittent or spontaneous. Some of them are only upon the expression. At the same time, we have to know about the idiopathic causes. You know, they may have a 50% of the women who had a colectoria, we cannot find any causes. After the repeated walkup, prolactin remain normal. And it is very important to differentiate the breast milk or the other discharges and the rule for the other breast pathology. And the patient with a Dr. Atasia can present with a breast milk discharge as well. And any chest wall irritation, trauma, traumatic lesion to the chest wall, such as burn, heart disaster, and the recent surgical scar can raise the prolactin. Sometimes, you know, it can cause some colectoria upon expression as well. Depending on the size of the tumor, especially the macroprolactinoma, it can present with a mass effect and it can present with a hormonal deficiency. The prevalence and clinicals can be less well-defined and then except with the hypogonadal. So it's a central hypogonadalism or hypothalamus, you know, hypogonadotropic hypogonadalism. These gonadal function assessment can be done at the time of diagnosis. And then six months after the normalization of prolactin level, then a lot of the women, they recover the gonadal function more than the men. And then it's hard to tell. Usually we have to evaluate. In the pituitary function recovery, they can present with associated pituitary deficiency, but these function can recover, depend on the tumor size, based on how many hormone deficiency they have, and then how much response to the treatment, and then what is the underlying prolactin value and what is the underlying tumor size. Sometimes they can present only after the surgery or the radiation therapy. It can cause, you know, hypopituitarism because of the surgery and radiation therapy. Medication therapy is a mainstream treatment. Carboxylin is a preferred. It's a once or twice a week. We start with a very low dose, 0.25 to 0.5 milligram weekly. We can go up the maintenance dose to 3.5 milligrams. Sometimes, you know, you may up for the two milligram per week, depend on the size of the tumor, depend on the prolactin value, depend on the response. Bromocryptine, you have to use it twice a day. It is less and less, you know, popular now since carboxylin has been getting cheaper than before. Neparglyte and then quinacrylate, we are not using that often. And then currently, carboxylin has been the mainstay and the preferred treatment as well. The most common side effect is the GI side effect, nausea, vomiting, diarrhea, post-hypertension, mental fogginess. It can cause a nasal stuffiness and depression, renal phenomenon, alcohol intolerance, and then it can cause a constipation. In that case, whenever you notice a side effect, you always start with a low dose and you let them take with the food or let them take with the bedtime. Sometimes these dopamine agonists can be so effective that it can cause apoplexy in the macroprolactinoma because of the aggressive and then extensive shrinkage. You will even need the surgery to repair this kind of prolactin, dopamine agonist-induced apoplexy, and then it can cause a CSF rhinorrhea. So the patient can present with a runny nose. In such cases, you got to do the beta-2 transferring to check whether it's coming from the CSF fluid or it's coming from just a runny nose. And then this can happen, you know, especially in the patient with a significantly, you know, macroprolactin, high, big macroprolactinoma who is very responsive to the dopamine agonist therapy. These prolactinoma or the pituitary tumors, it can be graded according to the tumor size. You know, here is, we use Knopf's classification and how much, whether they are well-maintained to the, well-confined to the cellar. You know, it's a cellar tarsica area. It's a grade zero. And then if it's gradually infiltrate to the cavernous sinus, it can become a grade one. There's imaginary line cut off here. It's go beyond, it can go become a stage three, grade three. And then it is a grossly invaded into the, you know, cavernous sinus, you know, outside of the cavernous sinus, it can cause a grade four tumor. These invasion are very important to decide which patient would get more benefit from the surgery. Currently in the, you know, surgery has been more and more popular compared to before. Until recently, dopamine agonist is a mainstay of treatment. We use dopamine agonist for the microprolactinoma, macroprolactinoma, they respond well. And then dopamine agonist is a mainstay of treatment. Now, the trend has been changing, especially with the latest pituitary society guideline. And if the tumor is confined to the, you know, cellar area, then they can still respond to the surgery. So these are the guideline. So if it's a microprolactin, not zero. If they're not zero, you have to differentiate if the patient's a premenopausal or postmenopausal. If it's postmenopausal, without the symptom, we can observe this premenopausal, we got to take a look at it. It's a hypogonadal or eugonadal. If it's eugonadal, if the patient is menstruating well, you can still observe. If it's hypogonadal, you can give a hormonal replacement therapy. And here, we can consider the surgery in the following situation with the microprolactin. So this is a change from the previous guideline that surgery can be considered in the microprolactin, especially if you have a good pituitary surgeon. Which patient would get benefit from the surgery? It's the patient with a rapid visual loss and the patient with a young age. So the rapid visual loss is less likely with the microprolactin. If the patient with a mixed growth hormone and prolactin secretion. So in such cases, they may not respond very well to the dopamine agonist therapy from the mixed tumor classification. And also they can be quite invasive and they can go aggressive as well. So in such cases, instead of giving the trial of the trial with the dopamine agonist therapy, surgery should be considered. Patient with a psychiatric disorder, dopamine agonist therapy may not be appropriate. And also if the tumor has a NOPS3 and higher, we can consider dopamine agonist therapy as a first-line agent, especially in the male sex and then especially in the children because they don't respond very well to the surgery. And then here, some of these microprolactin, you can consider the dopamine agonist therapy as a first-line agent in the children and the male patient as well. If the NOPS1, you can consider the surgery, especially if the patient has fulfilled all the criteria as well. But the most important is your surgery should have a patient with this center for the excellence if you have a good surgeon. What about the second-line agent? If the patient's a recurrence, if you have a pituitary tumor center for the center for excellence, you should do the surgery. And then if there's a recurrence, if the pituitary center for excellence is not available, you can try the dopamine agonist therapy and also inadequate remission. They don't really shrink. You have to, even after the surgery, so you can do the dopamine agonist therapy. They're already taking the dopamine agonist therapy. You can consider the surgery and then you can try the increased dose as well if they've already taken it, if the surgery is not available. If the patient cannot tolerate the dopamine agonist therapy, you can always consider the surgery if the surgery is not the option for your patient. And then you can switch to the different dopamine agonist. Again, this is the highly recommended if you have a pituitary center for the excellence and then surgery should be the first-line agent. So you can consider as a second-line agent in some of the cases as well. How do you decide the response to the therapy? And most of the dopamine agonist therapy are quite effective and the 90%, they respond very well. How do the response is? So they take a look at that within the first six months of the treatment therapy, the tumor size will shrink and then prolactin will reduce. And then if you have a first six months, they respond well. They respond, you can see that this tumor will respond. If they don't respond in the first three to six months of the therapy, most likely that tumor will not respond in the future. So prolactin level normalized very quickly and the tumor volume will shrink more than 25% after the three months of the dopamine agonist therapy. In that case, you can predict that this tumor will respond to the long-term therapy. What is the long-term here is more than 15 months. So usually it's that you can take a look at that these are the dictator for the long-term therapy. It's a low pre-treatment prolactin value, smaller tumor size, and then prolactin normalized with the low dopamine agonist dosage. Here is a gabagolin less than two milligram per week. It's a cutoff. So they require the lesser dopamine agonist dosage and the smaller tumor and the lower prolactin level, they respond much more to the long-term treatment. What are the resistant to the dopamine agonist therapy? And the resistant intolerance are the two different terms. So there's a particular definition for the resistant to the dopamine agonist therapy. Only 15% of the prolactinoma are resistant to the dopamine agonist therapy because of the lack of the normalization of the prolactin level or the lack of the tumor reduction in size. Here is at least they should reduce more than 30%. You know, if they reduce more than 50%, even better. And then they give at least a trial of the six-month therapy and then with the decent standard dose, here is a two milligram per week of the cabagolin and the bromocryptin up to 10 milligram per day. And then after they try them for the six month, if they don't respond in terms of the prolactin level or in terms of the tumor size, the patient may have a dopamine resistant prolactinoma. And the man has a much more high chance of the resistant than the female. And after the trial of the maximally tolerated dose of the dopamine agonist therapy, if the prolactin has not normalized, you can label them as a refractory and then you can refer them to the surgery. Now, more and more literature are coming out that people who got this dopamine agonist therapy before the surgery, the surgery success rate is relatively lower compared to those who never got the dopamine agonist therapy. That's why if you have a good surgeon, if you think the patient would qualify for the surgery in terms of the invasion and knobs criteria, you should send the patient to the surgery as a first-line agent. If the tumor is invaded into the cavernous sinus or the very last tumor, then the surgery success rate is also low as well. So how to define the aggressiveness is a progressively increase in tumor size despite of the maximally tolerated dose of the dopamine agonist therapy. Invasiveness and aggressiveness are also not the same. Invasiveness is much more of the imaging and pathological feature of the invasion into the nearby structures. And then that's why it is very important to evaluate the markers of the esdrophage stem cells, the cancer tumor, and then you have to take a look at the co-secretion of the growth hormone, because whenever there's a co-secretion of the growth hormone and pituitary prolactinoma, these cases, they don't respond well and they are much more aggressive from the pathology slides I just discussed. Mechanisms are resistant. We don't know very well all these mechanisms are resistant. They also have a normal D2 receptor binding. There's no receptor mutation, but they do notice a reduction in the receptor messenger RNA expression. And then they also notice a D2 receptor isoform ratio as well, and they believe that it might have an intracellular signal transduction, some alteration also. They believe the D2 receptor gene polymorphism among those patient with the dopamine agonist resistant prolactinoma. Exact mechanism, not very well known. After the dopamine withdrawal, the remission, global remission rate from the meta-analysis is 21%. And then you have a higher remission if it is a microprolactinoma. If you take a look at it, after years of dopamine agonist therapy, only 21% is a higher prolactinoma. And then longer duration has a much more high rate of remission, and the carbagulin has a much more higher remission than the bromocryptin as well. And then you can always consider the withdrawal of the dopamine agonist therapy after the patient went through the menopause or pregnancy. And then because there is a higher chance of resolution of the electrotrope group. And when the prolactin is normalized or no tumor group, according to the MRI, after two years of treatment duration, you can always consider the trial of the dopamine agonist withdrawal. If you don't have a good pituitary surgeon, or if you happen to work in this area, there is no center for the pituitary excellence, center for the pituitary surgery excellence. And then you can still use medical therapy as a first-line agent. And then here are the indication for the surgery from the older endocrine society guideline. But still, a lot of them still remain true. Pituitary apoplexy, you need the surgery. Optic chiasm compression, you need the surgery. Medically non-responsive therapy, you need the surgery. People cannot tolerate, especially the psychiatric patient, you need the surgery. Dopamine-resistant tumor, you need the surgery. Women who are seeking the infertility, even though they have a micro-adenoma, you can consider the surgery. And then CF of leakage, after or during the dopamine agonist therapy, you need the surgery. These surgical indications still stand true for any area, even after the trial of the medical therapy. And then surgery is a first line nowadays because of the advancement in neuroscopic technology and the higher remission rate and the lesser complication, especially with the smaller tumor. And then compared to the larger tumor, if it's a macroprolactinoma, and it should be the well-circumscribed, and then it should be the NOBS grade zero and one, they try to push it to the NOBS two as well. And especially in the woman, you should always consider the surgery as a first line if you have access to the good pituitary surgeon. But Italian Society for the Endocrinologist, they goes that every patient should offer for the pituitary surgery if the tumor is readily resectable. Here is if the tumor is readily resectable, if you have access to the surgery, any patient should offer for the pituitary surgery. The reason surgery become a first line is that it's a higher remission rate. And then in the surgery, compared to the medical therapy alone, up to almost 60%, and then cost-effective because it doesn't need the long-term dopamine therapy, trial and error as well. And the microprolactinoma has a higher remission rate compared to the macroprolactin and the very low risk of complication and no mortality. And then if the tumor is big, they have a lower remission. If the tumor has a higher prolactin value, has a lower remission rate. And especially if the patient has a NOPS criteria is higher and the male sex has a lower remission rate. So it's changed our understanding. In the past, we try to think the smaller tumor, we should consider the medical therapy and the larger tumor, we should consider the surgery. It should be other way around now is if you have a smaller tumor, surgery should be considered as a first line because of the cost-effectiveness and because of the higher remission rate. How do you follow these patients after the dopamine agonist therapy in terms of the MRI? Macroprolactinoma every three to six months after the treatment initiation. If the patient is partially responsive or if the patient has a dose close to the optic chiasm, we can do the, you know, every three years annually and the less often, you know, after the three years time. It is a microprolactinoma. We had to do, you know, after one year, we don't need the frequent, you know, imaging. And then whenever we consider the withdrawing of therapy, and if the patient has a treatment responsive micro and macroprolactinoma, if the tumor shrink and the response are very well in terms of the tumor size and prolactin value and the prolactin beyond MRI beyond one year, not necessarily unless patient has a persistently high prolactin. So whenever the prolactin is normalized and then there is evidence of the tumor shrinkage, you may not need the annual MRI even for the macroprolactinoma. How do you follow up for the, you know, other therapy, you know, after the dopamine agonist therapy? And if it is a microprolactinoma after 12 months, you do the MRI annually, you can do the monitor the adverse side effect and then you can follow up annually and then whether you can stop the medical therapy or not. Every three to 12 months, every three to 12 months, you have to check the level. And then every three to six months, you see whether the hypogonadism symptoms resolved. If not, you have to consider the starting the hormone replacement therapy or the sex hormone. And anytime if there's a new symptoms develop or the pituitary dysfunction or the prolactin rise, you can always get the, you know, follow up MRI as well to assess the growth of the tumor. So after the surgery, three to six months, you can do the surgery to get the baseline of the tumor mass. And also after the six months, you check the adverse side effect and then recovery of the pituitary function. And then every three to 12 months, you monitor the prolactin level. Again, the same thing with the three to six months, you check the hypogonadism symptoms with the labs. And anytime whenever there's a tumor dysfunction, pituitary dysfunction or the increase in prolactin, you can do the follow up MRI. So I'm going to switch my gear for the prolactinoma in the pregnancy. And this dopamine agonist therapy is so effective that you have to start the mechanical contraception in any woman during the reproductive age to confirm the efficacy of the dopamine agonist therapy and also to establish the menstrual cycle. Sometimes the woman can conceive even before the recurrence of the menstrual cycle. So if it's a micro prolactinoma, you stop the dopamine agonist therapy to avoid the exposure of the fetus as soon as the woman is pregnant. That mean a woman can get pregnant, that mean your dopamine agonist therapy is quite successful. The most likely the tumor shrink and then during the pregnancy, we do the very conservative monitoring, no checking the prolactin because pregnancy itself can raise the prolactin significantly high. Lactation can raise the prolactin high. And then the MRI is not needed. Only when we do the MRI without contrast, whenever we suspect the tumor growth, headache, blurred vision, in that case we have to do the MRI. If you see the tumor growth, which is very rare during the pregnancy, and then we can always reintroduce the dopamine agonist therapy. This is a case series, series of meta-analysis, all these cases with the tumor growth during the pregnancy. You can take a look at it. Micro prolactinoma has a very small amount of tumor growth in general. Micro prolactin has a much more higher, more than 10 times higher than the micro prolactin, but even the micro prolactin, after they got the treatment, and then the risk of the growth reduced significantly. So when somebody who got the treatment for the micro prolactin during the pregnancy, chances are the regrowth of the tumor is less likely because even though there was a concern because of surge in prolactin and the estrogen during the pregnancy as well. So if it's a very large micro prolactinoma, if you have concern for the regrowth during the pregnancy, so maintenance of the dopamine agonist therapy at the least effective dose is reasonable. And then because it does not have much of the teratogenic effect for the fetus, and then both carbacolid and bromocloprin are very safe. Carbacolid is preferred. And then you have to follow up closely for such patient as you have to do the visual assessment frequently. And then if they're taking this dopamine agonist therapy, breastfeeding can be affected, but there is no contradiction for the breastfeeding. And then breastfeeding itself does not cause a tumor growth. And then you can always wean off the dopamine agonist therapy if the patient try to do the breastfeeding after the baby is delivered, because the dopamine agonist therapy can interfere with the breastfeeding. And the micro prolactinoma, before they even plan for the pregnancy as a pre-pregnancy counseling, you always confirm the dopamine agonist treatment, responsiveness, and try to see what the tumor size, try to see what the prolactin level. If you suspect that the tumor is resistant to therapy or the refractory to the treatment, you have to offer the surgery before the pregnancy because there is a risk of the tumor enlargement. So that's why if the large tumor in the woman who are planning to have a pregnancy, prophylactic surgery is a quite reasonable, even it's a dopamine agonist responsive tumor. There was a concern for the valvular heart disease, use of the dopamine agonist, especially in the Parkinson's disease because of the FDA warning, and then how often we are to monitor the echo. The literature is not very strong. It's a mainly weak recommendation. Dopamine agonist can stimulate the serotonin receptor in the valvular valve of the heart, and it mediate the mitogenesis and the fibroblast proliferation. The rule of thumb is that you always try to get at least one echocardiogram to check the baseline, and then the higher dopamine agonist dosage, you may need every two, three years lower, which is two milligram. It's a cut off here with the carboglycine, and every five years without symptoms, or the annually if the patient has symptoms. Symptom here is a heart failure exacerbation, which is very rare, or the detection of murmur because of the echocardiogram. Bone health. This prolactinoma can affect the hypogonadism. That's why it can cause osteoporosis, osteopenia, mainly affecting the men, majorities are male, and the only small proportion are the premenopausal female, and after the female become a menopause, it can precipitate the postmenopausal osteoporosis. Interestingly, it can affect the trabecular bone earlier than the cortical bone. So it can affect the spine, then the hip. So you can do the screening bone density if the patient is qualified for the screening age, they can do screening a little bit early on if they are close to the screening age. If they're like 60s and older, you have to screen them. If they're high prolactin for the long duration, or if the patient does not recover the hypogonadism sinus symptom, or if the patient's additional risk factors such as bed bound or has smoking and alcoholism. And these bone density improvement is strongly linked to the hypogonadism recovery than the prolactin normalization. So the point is that the prolactin can normalize, the patient can still suffer from the osteoporosis, osteopenia because of the hypogonadism. So that's why you have to treat the hypogonadism after the prolactin normalized. You're gonna assess the hypogonadism three to six months after the prolactin is normalized. And then if the patient needs a treatment for the osteoporosis, treat them. Screen the osteo bone density at the appropriate screening age if there's additional risk factor as well. How do the mental health? And so definitely it is a tricky situation. Dopamine agonist therapy can exacerbate the neuropsychotic sinus symptoms such as mood changes, compulsive buying, gambling, aggressive aggression, and hypersexuality. And then whenever the high prolactin level is more than 10 times upper limit of normal, then you suspect the prolactin normal and then you have to do the MRI. We do the MRI of the pituitary gland much more frequently in the patient with the mental health. Sometimes it's hard to tease out if it's coming from the macroprolactinoma or the just incidental pituitary micro-adenoma, which is associated and then which can have a associated medication-induced hyperlactin. In such cases, you can work with the psychiatric team and the change of the prolactin sparing antipsychotic such as Aribiprazole, but it's hard. Sometimes the patient really need the stronger antipsychotic medication and you have no way to withdraw these antipsychotic medication as well. If it's a drug-induced hyperlactin, a few months or a few weeks after the withdrawal of the antipsychiatric medication on any medication, and especially the opioid agonist and opioid, you may see the prolactin level will be normalized or reduced significantly. Is the micro-prolactinoma or the micro-adenoma, because sometimes it's hard to tease out which one is which, we can monitor without the treatment. And then if there's a hypogonaditis sinus symptom, you need to supplement the sex hormone. It's a team, multidisciplinary team approach with endocrinology, psychiatry, and neurosurgeon as well. So my last topic is the pituitary carcinoma. Luckily, it is a very rare, only 4% of all the pituitary tumor, pituitary recurrent, all these pituitary adenoma, and they can recur. Recurrence timeline is very vague, 0.4 to 37 years after the surgery. But that means you have to wait for years after the surgery. That's why you really don't discharge these patients. You follow them for every one year, every two years. Majority of the recurrence happen in the men. And the most of the pituitary carcinoma are producing the letharotrope pituitary carcinoma. Then these are second most. And then the most common pituitary carcinomas are the ACTH-producing pituitary carcinoma, corticotrope pituitary carcinoma. Letharotrope carcinomas are the second most common type. These are poor prognosis and the limited survival. Every survivor is less than four years. They can present with metastasis within the CNS, outside of CNS. It's very challenging to get early diagnosis. And then because they can even present as aggressive pituitary tumor or the invasive pituitary tumor initially. So hard to tease out which one become a pituitary carcinoma from the invasive prolactinoma. The malignant transformation can may take years to become clinically apparent. And then that's why there's no typical histological feature, even after you do the surgery. And then there's nothing you can tell. They may have some Ki-65 and 67 index. There's increased mitotic and P53 expression. And these are not like slammed down black and white. And the patient with the early radiological evidence of invasion nearby structure, they can predict the prognosis. There's no single histopathological marker reliably predict which tumor become invasive or which tumor become malignant tumor as well. That's why it is very hard to differentiate the carcinoma versus a adenoma in the early phase. So these malignant tumor, surgery is the mainstay of treatment. You can get the adjuvant radiation therapy. Temozolomide acrylating agent can be used as a first line chemotherapy as well. Usually you can evaluate after the three cycle and then drug resistant can occur after the couple of cycle as well. Adjuvant radiation therapy is reserved for the people who failed the medical therapy, temozolomide and also surgical therapy. These radiation therapy can normalize the prolactin level up to 70%. They control the tumor group. In order to see the full effect, it may take up to 20 years. And then side effects are hypopituitarism of common and the rarely they can cause a cranial damage and the secondary tumor formation. And then sometimes it can cause a severe vascular death or the stroke as well. All these malignant prolactinoma, we can always give a TKI and we can have give a VEGF monoclonal antibody. We can give NTOL inhibitor. We can give the estrogen receptor modulator. We can use Lutathera, which is a radioactive isotope, you know, Lutetium-177. And last not the least, you can always try the immune checkpoint inhibitor, but literature is still evolving since the case are so rare. And then sometimes it's hard to tell whether the tumor itself is a nature, nature of the tumor itself or the response to the therapy as well. So I'm going to close my talk by giving you the take-home message. It is very important to differentiate the pathological causes of the high prolactin and the physiologic causes. We got to know these challenges about the prolactin assay, such as assay interference, hook effect, stock effect, and the macroprolactin. And also some of the stock effect of the non-functional pituitary denoma. Medical therapy is still the main treatment in the most of the area where the pituitary center is not available or the good pituitary surgeon is not easily accessible. But if you have a center for the excellent, for the pituitary surgery, or if you have access to the good pituitary surgeon, you can try the surgery for the smaller tumor and then confine the tumor with the NOPS1 and even the 2 because of the lower recurrence and the cost-effective. And then these are, you know, more and more surgery is a failover with advancement in the pituitary surgery. An echo and the MRI monitoring, routine monitoring is not necessary. You're going to use your judgment according to the patient responsiveness and then remission. And the conservative management during the pregnancy, just monitoring. And the last, not the least, that we should not forget about the bone health as well, that these pituitary, especially the longstanding, you know, hypogonadal patient with the prolactinoma, they can suffer from the osteoporosis and fracture as well. So I'm going to close my talk with the slides. And if you have any question, feel free to email me. Thank you very much for the Endocrine Society and thank you very much for your attention. Have a nice day. Bye-bye.

prolactin

hyperprolactinemia

prolactinomas

dopamine

TRH

lactation

bone metabolism

dopamine agonists

cabergoline

bromocriptine

pituitary tumors