Neuro-endocrinologist Lewis S. Blevins Jr., MD, a specialist in pituitary disorders, breaks down the complexities of hormone levels, with wisdom on how various conditions typically look both in terms of symptoms and test results. He elucidates “normal” results and demonstrates how to interpret test numbers in the context of an individual patient. Includes tips to prevent missing a diagnosis.
uh I was asked to speak about endocrine testing and that's a very broad topic and almost impossible to cover uh in shorter than a few hours. And I thought I would focus on my area of expertise, which is pituitary function tests and relevant clinical correlates. And I'll throw in a few pet piece for good measure, just so that you can understand how I think about some of these disorders and and the evaluation and management of patients with possible pituitary disease. So I want to start by reviewing the hypothalamic pituitary unit and the target glands are involved. As many of you may remember from medical school, the hypothalamus produces releasing hormones that are produced in a cyclical variation uh and circadian variation. They lead to the production of the trophic hormones by the pituitary gland, Which are secreted in a circadian variation. And our pulse a tile with 10 to 12 pulses for each one per day. And then they cause the target glands to produce hormones. And we're talking about the thyroid, the adrenals, gonads and then end organs or tissues that are responsive to growth hormone and two prolactin. This is a general schematic of what we're talking about here. You can see in the top center, the hypothalamus produces another hormones. These are growth hormone releasing hormone prolactin releasing hormone, thyroid trope in releasing hormone cortisol trope in releasing hormone gonadotropin, releasing hormone etcetera. These hormones cause the pituitary gland to produce a number of different hormones shown here. And you can see we have growth hormone prolactin. TSH, 80 th LH and FSH for both women and men. For the gonadotropin the post your pituitary is responsible for the production of vasopressin and oxytocin. Each of these target glands or tissues in turn leads to different effects as a result of the pituitary function. So the liver produces I. G. F. One in response to growth hormone. the breast produces milk in response to prolactin. TSH stimulates the thyroid gland to produce T. Four and T. Three. Ah The leads adrenal production of cortisol and some other hormones which is very important stress hormones for a lot of different reasons. In women the ovaries produce estrogen progesterone. You lied to have the menstrual cycles in general population and in men you have testosterone production and sperm formation as a result of village and FSH production. The best way to think about evaluation of these hormones that you might check in a patient suspected of having say even hypothyroidism, is to understand the path of physiology based interpretation of pituitary and target gland function tests. You need to understand this even if you're checking thyroid functions for patients for example and path a physiologically the hypothalamic Patricia unit can fail, Leading the high papa to tourism and low target gland function. Any pituitary hormone can be secreted in excess, leading the target gland and tissue over activity. Classic example would be acromegaly for example. Uh cushing syndrome. Target glands themselves can fail, leading to low hormone levels but an appropriate response by the hypothalamic pituitary unit. Given the principles of negative feedback for example, uh TSH leads to thyroid hormone production. Thyroid hormone has been measured in the blood by the hypothalamus and the pituitary gland to sort of regulate the production of thyroid hormones. So that's negative feedback where the hormones that are secreted by the target gland negatively impact secretion by the pituitary gland. So the classic thing here would be a patient with primary hypothyroidism due to hashimoto's laryngitis. That T. Four and T three levels are low. The pituitary has an appropriate response. By raising TSH secretion. Target glands can also be autonomous, Leading the low pituitary trophic hormone. Classic example, Graves disease autonomously produce T. Four and T three that suppresses TSH secretion by the pituitary gland. And any one of these main for patio physiological situations of either pituitary overproduction. Pituitary under production, target gland under production or target. And overproduction can be partial or complete. They can be acute or chronic and onset and can depend on the magnitude and breath of the disease state. And they can involve more than one hormone. So what is a normal test result? Almost all normal ranges encompassed the mean and 1.96 standard deviations on either side of the mean for a population. Some of these laboratory tests that we use have been studied in thousands or tens of thousands of people and most of them are are based this way. Some tests, results are normally distributed. Some are skewed. TSH is an example that I'll show you later of a skewed distribution. Uh the 11 of the most important concepts that uh I think that necessary for interpretation of endocrine function tests is to recognize that every single one of us has our own normal range for our endocrine tests. And in most cases we're going to maintain hormone levels that are gonna be regulated within a narrow range for us and we all fit into the population or the realm of the population that is normally distributed. But I'll show you some examples of that and talk about how that's important later. Yeah. The essential thing to keep in mind though is that it's possible to have abnormal levels for an individual, even though levels are in the normal range. This is a classic statistical representation of a normal distribution Where the 95% of the people, those the main plus 1.96 standard deviations on the other side of it are considered normal. That develops the reference range. By definition, 2.5% of people will have a high test result. Those are false positives. 2.5% of people have a low test results. Those are false positives for, say, let's imagine this is T four levels, 2.5% of people going to be normal, but they have an elevated value. 2.5% of people are going to be normal, but they have a low value. And of course, the disease state overlaps the tail ends of these cars. Some people who have disease have normal results, other people gonna have frankly low or frankly high results. This is the the distributions are turned on the side here, but this is a normal distribution in men and women, they're almost the same as you could look at one or the other uh, for TSH levels and normal people without thyroid disease. And you can see that the mean TSH is around 1.2 or 1.5, we think of the normal range is 0.5 to 4.5. Sometimes it goes up to five, but clearly the mean is around one. Um and one important concept to recognize that if someone is supposed to be normal, appear around 4.5, but their TSH is one, there there may be a little bit hyper thyroid on their dose of thyroid oxen. If a person is on fire oxen and has a TSH F four, but they're supposed to be down here at 40.75 They may say, you know, the medicine is just not working. I feel like I'm not enough thyroid hormone and they may be right because you need to find their normal range. Uh this skewed distribution we've known about for about 30 years, but I think that modern approaches are that if you're treating a patient who has primary hypothyroidism with cataracts, and you may want to aim for TSH around 1.2 to 1.52 real to get them at the population. Mean, to give them the benefit of the doubt, rather than saying, well, your TSH is normal. So let's just continue the same dose of medication. So keep in mind this sort of standard deviation, especially, uh when you're looking at patients with thyroid disease who takes Iraq's in this is the distribution of T four and T three levels over here on the, on the right side of the panel. And you can see it's relatively normal distribution of skew here whatsoever. In this particular lab. They looked at the gray bars of the normal ranges and they looked at the fact that in the particular normal range for their lab, a significant portion of people still had a low T. Three, whereas a significant proportion of people had an elevated T. Four higher than the normal sort of 2.5% that you would expect. So keep in mind that even though a normal range is a normal range, you still might have people outside of that that are normal. Over here on the left, the larger curve shows you a group of people in the normal distribution of T. four levels. And of course the frequency of 20 would represent 20 patients. And they took one person out of here and they looked at their normal level. So, repeated tests in the same person, you can determine your very own normal range. Uh so that this person is normal range for T. Four. Uh Sorry about that is down here on the low end of the normal range for the population. So you can imagine if this person had a T. Four appear, there would be hyper thyroid, they would have anxiousness, nervousness, tenuousness, what have you. But if the person up there, say at the 145, we're down here where this other person is, they may have hypothyroidism, symptoms and signs. And this is what I mean by the concept of we all have our own little normal range that fits within the normal range for the population. And we can have a level that is abnormal even though it's within the normal range. So keep in mind that every patient is going to have their own normal range and expected physiological set point. Let's talk about some of these pituitary axis. So we'll first talk about the hypothalamic pituitary thyroid axis and what we call central hypothyroidism and central meaning it's not primary or not peripheral hypothyroidism, the thyroid disease, it's central look resulting from hypothalamic pituitary dysfunction, large number of causes pituitary tumors, cranial friend, Joma radiation to the head, head trauma for example, all sorts of things can cause central hypothyroidism. The problem here is that either it's TRH production by the hypothalamus or TSH production by the pituitary gland or even the inability to get the TRH to the pituitary gland In these patients. You can interpret the results. TSH may be low normal or even slightly high, but what we do know is it's biologically less active than normal. TSH it simply just doesn't work. When you do a blood test to check TSH. You're looking at the TSH for the five seconds. It takes that tube to fill with blood. And it doesn't tell you anything about when you measure TSH immuno immunologically. It doesn't tell you anything about biological activity. Studies have been done that showed that the TSH mass that's created over 24 hours is lower in these patients with pituitary disease and it's not biologically active. Even though you can detect a normal amount of TSH in the blood stream. It doesn't tell you whether it works Or whether there's a normal amount secreted in a 24 hour period. So keep that in mind when you think about results that you're just looking at a small blood biopsy of about five seconds in these patients because they have problems with TSH secretion. Usually the T. Four and T three levels are usually low or low normal. They're not as low as a person with hashimoto's would be because the thyroid has a constituent of ability to produce thyroid hormone even in the absence of TSH. So you may see free T four levels of 40.6 point eight. Rather than, say frankly undetectable as you can see in some people with hashimoto's thyroid itis with severe disease. So usually low or low normal and the TSH can be either low normal or even slightly high. Most of these patients will have mild to moderate symptoms of hypothyroidism and one of my pet peeves is the reflex to TIF the reflex to T. Four. So you check a TSH with the reflex T. Four. They only do the T. Four in the lab. If the patient has an abnormal TSH, about 20% of people with hypothyroidism actually have uh central hypothyroidism. So you're going to miss those people because the TSH can be normal in them. So if you see a patient in the clinic and you really think they have hypothyroidism, you have to know that it could be thyroid disease or pituitary disease. And you should go ahead and check a TSH and a free T. Four if you're ordering the TSH because you suspect hypothyroidism, The TSS with reflects the T. four I think is a useful only in patients who having a routine chemistry study and you don't have a suspicion of hypothyroidism. But if you think of patients hypothyroidism both and I say that because I've seen countless patients over my 32 years of doing pituitary disease Who did not get that T. four level and had they done so, the pituitary disorder would have been diagnosed at a much earlier stage. Another corollary here is do not rely on a TSH as a marker of the adequacy of thorax in replacement. Instead, check a free T. Four and T three levels and aim for the middle of the normal ranges and then fine tune as necessary based on the patient's symptoms. And I say this because we it's our approach to look at T. Four and T. Three, and I do aimed for the middle of the normal range and if a patient feels hyper thyroid, I'll lower the dose. If they feel hypothyroidism, go up a little bit further and get them into the upper part of the normal range. When I was on my training at Hopkins, we used to aim for the three quarters of the way through the normal range to be a an appropriate level. Some people get hypothermic hyper thyroid on that and you have to lower the dosage. Remember TSH is the problem in these pituitary patients and you can't use it as a marker of the adequacy of thorax in. You have to look at the T. Four and T three levels probably 15 times a year. I see patients who I've managed their central hypothyroidism. We co manage the patient with the primary care physician, but the primary care physician sees a low TSH and will lower the dose of Iraq's in after several dose changes. The patient comes to be feeling miserable in states that my primary physician lowered or stopped my thyroid hormone because my TSH was low. Uh So it's important to understand this basic principle of the path of physiology of the disease state and how in this setting, the TSH is not a reliable measure of thyroid hormone. Adequacy. This is a slide. I alluded to this before just to reiterate it because I have the picture, it shows you TSH levels in normal people. Those are the ones that are going high at nighttime where TSH is mostly secreted after 24 hour, 2400 hour. Uh And uh TSH levels are lower during the daytime and the bottom curves that are basically flat. Or the patients who had normal TSH results but had uh central hypothyroidism. And you can do area under the curve to equate to the mass of TSH secreted per unit time. And see that the hypothyroidism patients, even though they had normal TSH results were still um very abnormal in the amount of TSH secured over time. And again, there's a loss of diurnal variation, which I didn't mention. But that's another reason that the TSH doesn't drive the thyroid to work normally and there's also the loss of biological activity. Yeah. When it comes to primary hypothyroidism, this is a situation where the thyroid does not produce adequate amounts of thyroid hormone T four and T three levels are usually lower. Low normal T three levels will often be preserved because it's sort of you ramp up your peripheral conversion of T. Four to T. Three in early stages of hypothyroidism as you can see a normal T. Three but a low T four. But due to the loss of negative feedback, TSH levels are usually high. There's a lot of controversy about what are clinically meaningful degrees of elevation. Some people say a TSH, only over 20 other people say 10. When you look at the fact that the population mean is 1.2, I would propose that if a patient has symptoms of hypothyroidism and a TSH, regardless of the degree of elevation and positive thyroid antibodies, that patient might benefit from thyroid hormone replacement. Usually primary hypothyroidism. We have one or more symptoms of hypothyroidism with or without a goiter depending on whether patient has uh autoimmune thyroid disease. Um One of the things to look for us a scar with the interior neck. It's remarkable in my career the number of people that I've seen who had severe hypothyroidism. And when you ask them about the family history for autoimmune thyroid disease or whether they've had any prior surgery, they say no. But then you see a scar over the neck and then they remember they had a goiter removed. So it's an important physical feature to look for evaluating people who have that high TSH with low T. Four and T. Three when it comes to still in the H. P. T. Axis here. TSH mediated hyperthyroidism. We do see people rarely who have pituitary tumors that secrete uh TSH uh and usually the TSH is inappropriately normal and meaning that it should be low. If thyroid hormone levels are high it's inappropriately normal should be suppressed. That tells you that TSH is the driving factor. Sometimes it's elevated. But in these patients usually have hyperthyroidism and T. Four and T. Three levels are elevated. It's about 1 to 2% of all the pituitary tumors we see in our practice and use it to have classic hypothyroidism and goiter. The reason I presented here is usually it's a it's an astute primary care physician who recognizes wait a minute the TSH is high but the T. Four and T. Three levels are high should refer to an endocrinologist. And many of these patients either have one of 22 conditions, thyroid woman resistance or TSH producing pituitary adenoma. So if you ever see this pattern, just be alerted to the fact that you may be dealing with pituitary tumor I. T. S. H. I. T. Four and T. Three. And then of course there's primary hyperthyroidism that affects the H. P. T. Access. This is autonomous release of thyroid woman from the thyroid gland. T. Four and T. Three are usually elevated. But due to negative feedback the TSH will usually be suppressed or low. And these patients usually have classic symptoms and signs of hyperthyroidism with other salient features such as if they have Grave's disease. They may have thyroid eye disease goiter. They may have thyroid itis with a painful thyroid gland. They could have a toxic nodule where you feel feel a nodule in the thyroid gland. Or they could have a toxic multi nodule goiter or amiodarone usage. But don't forget exogenous thyroid hormone is a cause. I've probably seen five people in my career who had Munchausen syndrome and we're taking thyroid hormone to cause symptoms in science. And we're being diagnosed by various and sundry clinicians is having thyroid itis or or Graves disease when really they were just taking thyroid woman medication. Occasionally we see people who have a combination. So I have had several patients in my career, two or three that I'm following now who had hypothyroidism due to pituitary disease. So their TSH was not working and they were hypothyroidism and required medication. They had normal T. Four and T three levels and then suddenly their T. Four and T three levels go up. They're not taking extra medication. You stop the medication and you evaluate you find that now they either have Grave's disease and the most recently had a toxic adenoma in her thyroid gland. So we can see patients with pituitary disease, get thyroid disease and present in a different fashion as well. Let's move on to the hypothalamic pituitary adrenal axis and talk a little bit about central adrenal insufficiency and how that differs from primary adrenal insufficiency. So central adrenal insufficiency would be failure of the hypothalamus to produce crh or failure of the pituitary to produce a, see th the bottom line is that you don't produce sufficient amounts of ACDC then that leads to the loss of the traffic. Remember the A. C. T. A chance for doing according to trophic hormone trophic as a growth. So you have lost the trophic stimulation of cortisol secretion. So the adrenals are not maintained. They become sluggish and they don't produce cortisol. Usually the ADM cortisol levels are going to be low but they can also be a little normal. Act ph levels are highly variable because just as in TSH we see patients who have decreased biological activity of their A. C. Th especially if they have the hypothalamic condition where th is not being processed properly from the pomc molecule. Most of these patients since the even though the adrenal glands are normal, they haven't been maintained by A. C. Th so the adrenals are sluggish and patients will usually fail. And a c. Th stimulation test, the traditional A. C. Th stimulation test has about 250 micrograms of a. C. T. H. In it. The test that we use an air clinic as one microgram, it turns out that that's more sensitive for mild disease and determining who requires steroids supplementation. Most of these patients who present with fatigue weight loss or decreased appetite. Sometimes we see hyponatremia a couple times a year because cortisol regulates by suppressing gene transcription. And you can see an s idea it's like picture when you have a cortisol deficiency and adrenal crisis is rare. I had a patient not long ago who developed the flu and was pretty sick and his fiancee came back to visit him and saw that he was passed out on the floor called the paramedics, took him to the hospital and uh they were able to see he was high ponytail and make it led to work up and had a large pituitary tumor and was hypo pituitary. So we can see presentations with adrenal crisis in central hypothyroidism as well. The rain and angiotensin Aldo Austrian system is normal in these patients because it's not affected by the pituitary gland. So there's no hyper colima or volume depletion. But these patients can still have circulatory collapse if their condition is severe enough. Sure, primary adrenal insufficiency is similar and that the ADM cortisol levels will be low. But in these patients a ch is usually elevated because there's no cortisol producing negative feedback. So that's how you differentiate between the two here. The plasma random level is usually elevated in the old Austrian is low because the adrenal glands are involved. Uh And most patients will have a degree of hyper colima and some will have hyponatremia. Usually these patients have hyperpigmentation and the usual symptoms of Addison's such as weight loss, decreased appetite. Uh fatigue. Some some even have psychiatric conditions as well. There are numerous causes including autoimmune disorders. Classic Addison's metastases and renal hemorrhage and filtered of disorders etcetera. Yeah. Still in the HP. A. Access cushing's disease is hyper cortisol is um due to hyper secretion of th Usually we assess these people are looking at the 24 hour urine cortisol. It may be high normal or elevated. Uh The A. C. T. S. Is usually inappropriate, normal or elevated, meaning that if cortisol levels are high you're supposed to turn off A. C. T. H. Uh So that you don't make any more cortisol. That's how the negative feedback works. So if you see an A. C. Th that's high or normal in the setting of an elevator in cortisol that points to a ch being the problem with these patients, we can give decks and methadone to test. You've all probably heard of the dexamethasone suppression test. I won't go into the details but it's a tested an endocrinologist should be doing. You can also check the midnight celebrate cortisol, celebrate cortisol is in equilibrium with serum cortisol. In a in a way to sort of assess for the diurnal variation is to check us celebrate cortisol level at midnight or several times throughout the day. Patients with cushing's usually have elevated cortisol levels at nighttime when most of us are supposed to have low levels. And I'll show you a graphic on that in a moment. Usually patients with cushing's have one or more symptoms and signs of cortisol excess. You all see these patients, they're taking steroids for asthma, steroids for rhinitis, uh, room geologic conditions, skin diseases, et cetera. Everybody knows what a cushion with patient looks like. One of my big pet peeves as I've seen patients who've looked cushion would for years and uh they ultimately were finally diagnosed after years of looking cushion. Oid almost by accident. Um, and yet primary care physicians seat cushion with patients all the time. So the the thing is if you're patient looks cushing wide and isn't on steroids and test for cushing's that's that's probably one of the most powerful messages I can give today because I see time and time again. People recognize the patients occasionally, but they don't do anything about it. They just sort of almost like we have some cognitive dissonance against it. And I've seen that even within the Quran ologists who followed patients over time, this is a graph showing the celebrate cortisol profile. And it sort of has this normal diurnal variation where levels are highest when you wake up in the morning and in the afternoon, they're about half to a third of that. And in a bedtime or midnight, they're usually 1/10 of what they are in the morning. And this profile is a sign of normality. If you lose this profile, that uses a sign that a patient has a disease state. Uh, here's one of my patients, a 36 year old woman with cushing's. This lower line. Uh that's teal in color is a normal person. Normal patient that I had showing the celebrate cortisol levels falling from eight am to afternoon too late night. And the other curve is the patient that had cushing's disease due to pituitary tumor, showing that the salary cortisol levels are elevated in the afternoon and at night, but nearly similar to what they were in the morning. So we often use this. The records will profile the screen for cushing's. Um and we'll talk more about that in just a moment. So, this is where I want to talk more about that cushing syndrome due to adrenal disease. Uh This would be the target gland over activity. The most common causes adrenal adenoma, but you can see it with adrenal hyperplasia and a few other disease processes, its autonomous production of cortisol by the adrenal gland due to negative feedback. Your A. C Chiefs levels are usually low or very low. normal. Uh many of these patients have one or more symptoms or signs of cortisol excess. There is now a paper out where this is. A lot of patients with adrenal disease are thought to have hidden hyper cortisol is um meaning it's hidden. It doesn't look like hyper cord of socialism, but they may present with just diabetes mellitus or osteoporosis or even hypertension. And then when they're evaluated carefully there proved to have an adrenal adenoma with autonomous cortisol secretion. Some studies have showed as much as 20% of people will fail the dexamethasone suppression test. Uh in one study, it was even up to 40% of people if they have an adrenal adenoma and you actually bothered to do the work up. So the key message here is if you see a scan of the abdomen where they reported incidentally detected adrenal adenoma on your patients, you should consider doing about chemical work up for evidence of hormone overproduction in these patients because it's the fact that they have many of them have cushing's and other studies that show, you know, how should the hyper old Austrian is um is far more common and what we believed in this subset of patients. So work them up and you'll find some Cushing's patients and some patients with hyper old Austrian is um if you do so, yeah, yeah, let's move to the hypothalamic pituitary testicular axis. Um and talk about central hypogonadism. So this is hypogonadism that's due to impaired LH and FSH secretion by the pituitary gland. And it will lead to low testosterone levels in men, LH and FSH levels are low or low normal. But testosterone levels are low or low normal. I want to talk a little bit about the interpretation of testosterone levels and I saw a patient this morning who had a total testosterone that was low at 195 but his free testosterone was normal three quarters of the way through the normal range. And he had a low sex hormone binding globulin. So sex hormone binding globulin levels can affect the results in normal persons and disease states. Uh sex hormone binding globulin is a major carrier protein of testosterone. It's also carried by albumin and and buy some lipoproteins as well. So that when you look at the total testosterone, you're looking at a combination of testosterone. It's found to several different proteins and that that is free in the circulation. And it's a free testosterone. That's really the business end of the molecules, so to speak, or the business packaging of the molecule where those levels are available to body tissues. So if you have a protein that has elevated your total testosterone is going to be high, but your free testosterone we usually normal. Uh, if you have a protein that's low like sex hormone binding globulin, then your total testosterone is going to be low and your normal will be free. And that was the case with my patient here. Um, it's always useful to know what the tollan free testosterone levels are so that you can use, um if they're, if they're congress with one another, you can use the total to determine your treatment. If they're in congress, then you have to check the free to know whether patients in adequate doses of testosterone, usually the central hypogonadism and men manifest is any one of a multitude of symptoms and signs of hypogonadism, such as weakness, fatigue, depression, hot sweats, erectile dysfunction, diminished libido, impaired ejaculation, etcetera. Another big piece of mind is that so many of my patients who were found to have a pituitary tumor years prior presented to their primary care physicians with impotence or uh some form of diminished libido. And they were either treated with Viagra or testosterone without a work up. And I cautioned against just treating with phosphate ester ace inhibitors for erectile dysfunction and leaving it that um everybody has stress in their life. And a lot of these patients were told that's just your work or your financial stress at your marriage, take this medicine, you'll be better. Uh and then years later they start losing vision due to timber pressing on the visual pathways found to have high papa, to tourism due to pituitary adenoma. So the best way to get an early diagnosis for a number of these men is to not just give biography analysis or testosterone, but to give those things and do a work up to figure out is it primary or secondary hypogonadism, Secondary being the central and then if it looks like central getting an MRI to check the pituitary gland. The difference here. Primary hypogonadism is impaired testicular production of testosterone due to a testicular problem. So the testosterone levels will be low and the LH and FSH levels will be high. Whereas there inappropriately low or normal in a patient with central hypogonadism, these patients have the typical symptoms and signs of testosterone deficiency that are already mentioned. Some of the common causes or climb, felter, testicular injury, radiation, and chemotherapy etcetera. Mhm. So believe it or not, you can have central hyper gannett is um we have patients occasionally who have FSH and LH producing pituitary adenomas that dr total and free testosterone levels to be high. And many of these patients will come in and they'll have a history of aggression, hypersexuality. Uh, pituitary tumor mass effects due to the size of the tumor. We had a recent 70 some year old man who had fathered about three kids since his late sixties and had a very high sexual appetite and a young wife. And uh, I was very disappointed when we found that he had a pituitary tumor. And that's why he was so fertile. And his biggest concern was that he was not going to be able to father any more Children. But we told him that things would return to normal and he probably should still be okay if his wife desired additional kids. But we see things like this all the time and it's more common to see men with the LH and FSH producing tumors than it is for women. But again, this is a situation where in a high testosterone state, your LH and FSH should be suppressed If you had a man who had hypogonadism and gave him testosterone and excessive amounts his LH and FSH should fall. These people have high testosterone but have elevated LH and FSH. The hypothalamic pituitary ovarian axis is much more complex uh, than the hypothalamic pituitary testicular axis. There's all sorts of interesting feedback loops involving some proteins that I won't mention today. But in a patient who has impaired LH and FSH secretion, it leads to ovarian dysfunction. And I use that term broadly because it means a lot of things. Uh, LH and FSH levels will be low or low normal for age. We usually will check an estradiol level and find that low or low normal. But the most important clinical correlate is are there any problems? Any symptoms of hypogonadism, such as hot flashes or flesh? Is a memory a irregular menses or some people only have infertility. So the most important question sometimes is, what are the menses doing if it's a reproductive aged woman? Uh, Um, and sometimes if someone has irregular bleeding, we can check a 21 day progesterone level to confirm that there are ovulating to sort of separate out those who might have chronic and ovulation. But usually if I see a patient with pituitary disease or pituitary tumor, if she is having normal menses, I won't check LH and FSH or estradiol. But if a woman is having irregular Menzies or a Maria, then you can check the LH, FSH and estradiol. If you see a low estrogen ill and even a low progesterone in someone with normal LH and FSH and no menses, they may have a pituitary problem. Um, And one of another, one of my pet peeves, as I have seen so many women of reproductive age with abnormal Menzies, uh, told by their physicians, especially their gynecologists, will all of my patients have abnormal Menzies uh and they're left un evaluated and their problems not been defined. And many of them have prolactin, omagh's or other types of pituitary tumors that were the culprit in the first place, primary hypogonadism and women. The classic situation here is menopause or premature menopause where you have ovarian failure if you have a genetic condition that leads to premature menopause or autoimmune destruction of the ovaries or surgery and the pelvis for some reason. Usually these ladies will have a low estradiol. The LH and FSH levels will be elevated as they are in menopause due to the lack of negative feedback of estradiol. Uh One thing that's very interesting about patients and menopause is that the LH levels are high and that can cause androgen production by the post menopausal ovary because the the colonial cells persist and they make androgens which when the follicles were present were converted by the follicles to estrogen's. So the post menopausal ovary does make androgens and sometimes you'll see hyperandrogenism in postmenopausal women. So we often will look at post menopausal women in their testosterone levels just to determine whether or not they have that intact pituitary ovarian unit. Yeah. Growth hormone excess is sort of a central growth hormone problem Where you have acromegaly. This is due to growth hormone and hyper secretion by pituitary tumor. About 1% of patients have a neuro into consumer in the pancreas that causes acromegaly. Growth hormone levels may be normal. But again, the mass of it's created over time is usually elevated. Uh I. G. F. One by the liver is usually elevated. It's easy to get the f one of the growth hormone levels if you suspect acromegaly and you can make a diagnosis based on those results. You may remember from your training that we talked about an oral glucose suppression test, but that's rarely used. It can confirm a diagnosis of mild cases. Um uh And of course this is sort of manifest as actual growth and other symptoms of acromegaly. Most of my patients with Acromegaly have about an 8-10 year history of symptoms and signs of their disease process before they're actually diagnosed. And um the longest I can remember now is the patients become a good friend of mine. He's about 25 to 30 years of symptoms and science before he was actually diagnosed. Um And the the things that these patients usually present with our sleep apnea, diabetes, hypertension growth of their hands and their feet. Uh Those are probably the predominant ones. Uh Sometimes they have spacing of the teeth and often dentists of the first ones to to diagnose it uh in their patients because they see the spacing between the teeth to the radio and longitudinal growth of the mandible. Uh My feeling is that everybody will sleep at me. I should get an I. G. F. One level uh to evaluate for the disease process. And certainly anyone who says they had to change the ring size of the shoes so as to get that I. G. F. One level as well. We need to do something to try to enhance the recognition and diagnosis this disease process because it can lead to early uh morbidity and mortality and patients who can have miserable lives before they die soon if it's not treated soon enough. And I've certainly had many people die of this disease process due to a delay in diagnosis. So think about it. If you see a patient who looks like andre the giant or any one of the NBA basketball players who had acromegaly or the jaws character from the bond films. Think about acromegaly and try to diagnose those patients sooner rather than later, we can also have a central failure of growth hormone that's called growth hormone deficiency. Uh This is due to impaired growth hormone secretion as a result of hypothalamic pituitary disease. I. G. F one levels are usually low normal or frankly low. Research has shown their I. G. F. One that was only about 75% accurate. And the only way to really know whether the patient has growth hormone deficiency is to confirm with a glue keegan stimulation test, where we try to stimulate growth hormone production, The 75% accuracy is that a number of people who have normal. Just going back to that graphic on the T. four levels. People who are supposed to be in the high part of the normal range of I. G. F. One. If they're in the low part, They have growth hormone deficiency with that uh leading to be in the low part but still have a normal test result. And that's why the test is only 75% accurate because some people are still normal but have the disease. So the stimulation test is required to confirm the diagnosis. Many of our patients with growth hormone deficiency have fatigue, poor exercise capacity, altered body composition, with weight gain and loss of uh lean mass and muscle strength etcetera. Some have brain fog, osteopenia and hypercholesterolemia, higher risk for heart disease and stroke and early mortality. As a result of these things, most of these symptoms probably sound like half the patients I saw today, even though the growth hormone levels are okay, either on treatment or not. Um, and many of you would probably say, well, that's half the patients that's on my clinic today as well. And the point to make here is that growth hormone deficiency, like many of these endocrine deficiency states, and even some of the excess states are very common symptoms. Uh, how many have you had? A patient said they had fatigue and you didn't sort of understand the cause, but some of them actually are going to have a hormone deficiency state that needs attention. So just be aware of the fact that the endocrine system is, is often one of the less obvious contributors to some of the symptoms and signs that patients present with. The next one we'll talk about is the prolactin and I like to call the prolactin target tissues. Um because largely it's the breast to produce the milk production. But prolactin is more broad than that. It's probably it has something to do with weight management and it may have something to do with their function of our immune system as well. It's a hormone that's uh that's sort of mysterious and we're learning a lot about it over time. If you see a patient with hyper prolactin anemia. So the classic situation be a woman has irregular menses Raymond area, you check the prolactin. Maybe she has galactic area, you check the prolactin. So if it's elevated, you usually think about prolactin producing pituitary tumors that we called prolactin, oma, hypothalamic and pituitary stalk disease, pregnancy. Oral contraceptive use psychiatric medicines etcetera. Usually they have galatasary and ovarian dysfunction. And the reason they get the ovarian dysfunction is that prolactin itself inhibits the uh sick licit e of gonadotropin releasing hormone from the hypothalamus, which leads to intelligent infestation, impaired secretion, which leads to ovarian problems. So you get anything from infertility to aim honoria. And some patients can have premature menopause. And because the gonadotropin have been suppressed by the prolactin, they will have normal LH and FSH prolactin levels are usually greater than 20. Uh Proactive numbers have a prolactin level at any any level, but the macro adenomas and apologized for them a spelling, There are often with prolactin levels greater than 200. Uh Some of the other causes like a stock effect problem or pregnancy or birth control pills, usually there under 150. Uh and in many cases we have to do delusion or sensitive radio usa to detect these patients. There is a disorder called macro proactive anemia where people can have elevated prolactin. But the free prolactin is normal and these patients usually have antibodies against the prolactin level. It's not unusual and I just mentioned it to sort of indicate that these patients can be rather complex and indifferent consultations usually required. Mhm. We do see hippo prolactin Neemia. This is in women with known pituitary disorders. The most common When is she hand syndrome? Where a woman has a either hypotension or hemorrhage at the time of childbirth. And then the history is that they can't breastfeed afterwards and develop fatigue and lassitude and ultimately found to be hypo pituitary. They have a low prolactin. Uh and uh the prolactin is usually under 10 in these patients, and I mentioned it here just to cover the whole gamut of uh of the hypothalamic pituitary target Gland axes. So my final comments then are the proper interpretation of pituitary function test is based on a sound understanding of normal physiology and the path of physiology of the various disease states. And I teach this to my residence and uh and co faculty. I wanted to share it today because I think if you can understand the four things that I started with beforehand, such as the pituitary could fail or produce too much hormone or the target gland can fail or produce too much hormone. It's easy to interpret these tests, but you have to check the target gland and the pituitary hormones to be able to interpret them. You can't just check the the pituitary hormones and our neurosurgery residents were in the habit of just checking the pituitary hormones and pituitary patients, but you have to know what the target lands are doing as well in response to what those pituitary hormone levels are. Also want to emphasize that a normal test result for one may not be normal for another and just keep in mind this concept of the fact that someone could still be abnormal in the normal range. Um I gave this talk intentionally to uh with the different axes to compartmentalize so that you think about pituitary axis, adrenal axis going to addle access because I think it's a lot easier to compartmentalize your symptoms that you're asking your patient for the history and also think about your physical exam in these compartments and also to make sure you order all of the proper laboratory studies. So when I go through my history with my patients, I asked my thyroid review of systems and my adrenal review, then my growth hormone review and so on. Just so that I keep it compartmentalized and I order appropriate tests based on the history and physical or more likely than not. If I know they have pituitary disease, I'll get the whole panel of tests just to be able to provide a global understanding of what's going on with their disease process. And the next thing I want to say where there's smoke, there's probably a fire with more smoke. So in other words, if you see erectile dysfunction, that's the smoke, uh, figure out what the fire is. Is this erectile dysfunction due to testicular failure? That might be a pituitary tumor. And the more smoke is that the patient may have other hormone deficits. And uh, you know, astute clinician would consider the differential diagnosis or everyone was in medical school, we were taught what's the differential diagnosis work through that and then arrive at whether you need to do additional studies and then develop your treatment plan. But I see so many times now people just sort of blow the smoke away with Cialis or testosterone or telling a woman that her menses are irregular or well. Yeah, you've got diabetes mellitus forgetting the fact that 5% of new type two diabetes mellitus patients have cushing's, for example. So think about this and I used to smoke thing because I was having a conversation the other day with a patient about the fires we had last year and we're hopeful that we won't see that today. But where there's smoke, there's probably a fire with more smoke and just practice this medicine than this man than this manner. And I think you'll diagnose patients much sooner than the usual, uh, that we see in our practice with pituitary diseases. And the last thing is that this stuff is all confusing. You know, it took me years to learn this and to understand it and legions of patients to really develop my suspiciousness and learning the caveats about the interpretation of the test results and the disease states, etcetera. So it can be confusing. So call for assistance when necessary. So that's about it. This is our team at California center for particular disorders at UCSF. I'm a neuro endocrinologist, Sandy Kanwar Mini oggi Tarun arora and filthy at this office of the surgeons who work with me. Sandeep is the surgical director and our principal surgeon. But they all play an important role. Tirana's in marin uh uh Phil does a lot of our skull base surgery. Many issues are probably second busiest surgeon and he's our scholar in the group. He's a tremendous investigator and an excellent surgeon as well. But it's not just us that we interface with physicians in so many different specialties and we consider their colleagues in these arenas to also be part of our pituitary centers of people in neuro radiology, neuropathology, radiation, oncology, neuro ophthalmology, even your of anesthesia and oncology for otolaryngology. Rather I also like to give credit to a nursing staff, administrative staff and a neurosurgery residents because they are all vital to us performing our role in managing these complex patients with these multifaceted disorders. And this is a slide that sort of reiterates my name, my email, my personal cell phone number and how to call to refer patients to our center. And I want to uh emphasize that we do telemedicine and we're doing consultations across state lines as well. Uh in fact I haven't seen a patient lives since october and I see about 45 to 50 patients, so we can be a telemedicine until we feel that it's probably safe to get back to the office full time. What we have found is that since most of our patients have outside the Bay Area, that many never liked to come To the city because of the hassles with traffic and taking time off from work. And some if they live far enough away you have to stay in a hotel. So patients love telling medicine now everybody wants to get their visits and our productivity is actually at 50% throughout the whole year of covid because people are finding it reasonable to have a video visit versus traveling to san Francisco. Uh And we're always available, feel free to write me with any particular questions that you might have about your patients um for a curbside or if you'd like a real consult or telemedicine visit, we're happy to arrange for those as well.