256 ‒ The endocrine system: exploring thyroid, adrenal, and sex hormones | Peter Attia, M.D.

foreign I wanted to put together a video that answers a lot of the questions we get about hormones now many of our podcasts cover hormones and they cover them in really great detail but a lot of times we kind of skip the basic physiology and frankly even some of the treatment implications so the purpose of this video is to cover four hormone systems the thyroid system the sex hormone system both male and female and the adrenal system and basically what I'm going to do is talk about how these hormones come about how they're regulated what

the feedback Cycles are and then talk a little bit about how we treat deficiencies in these hormones now this will all be available in this video but we're also going to chop them up and you can if you're only interested for example in female sex hormones we'll have just a shorter video that covers that but it will be the exact same content that's shown here so let's dive in and I'm going to start with the thyroid system if for no other reason then I'm just going to go head to toe okay so let's start with

the thyroid system I've drawn a little bit of a schematic here it's a bit oversimplified and it's also at the same time a little bit messy so I'm going to try to explain it and hopefully it makes sense you have the thyroid gland this is the thing that sits in front of uh your larynx you can actually feel the thyroid gland and it's shaped as a shield which is how it gets its name and the thyroid gland is regulated directly via a hormone called TSH so TSH is stimulated from the anterior portion of the pituitary

gland and it tells the thyroid gland to make T4 and T3 and the pituitary gland is regulated Upstream by the hypothalamus which stimulates it via a hormone called trh now I'll come back to the regulation of these in a moment but let's just go back to the thyroid gland so the thyroid gland makes mostly T4 and a little bit of T3 now where do the three and the four come from what are they referring to well they're referring to the number of iodines that are in the molecule so not surprisingly T4 has four iodines T3

has three iodines what's the difference between them the difference has to do with their biologic activity when you think of all the things that the thyroid hormone does for example how it keeps you warm AIDS in metabolism controls things like the brittleness of your nails your hair bowel function all sorts of things all of the thyroid promoting functions are controlled by the active version which is T3 T4 conversely is the inactive version of the hormone so if you're paying attention to what I just said you'll note I just said that basically most of what comes

out of the thyroid is T4 which is inactive now it's not entirely clear what the ratio is between these but it's directionally about four or five to one I think it's almost just as easy to imagine that virtually everything the thyroid is producing is T4 so if the thyroid is producing T4 which is inactive it needs to be converted into an active hormone in the body and that's where these enzymes called D iodinases come in and as their name suggests D iodinases remove one of the iodines from T4 to create T3 which is the active

hormone now the story gets a little bit more complicated because there are different types of diode nases but the three most relevant are D1 D2 and D3 so let's talk for a moment about these three diode nases D1 and D2 are quite similar in that they both convert T4 into T3 more about that in a moment it's just where they do it that's slightly different D1 is extracellular it's on the cell membrane facing outward whereas D2 is on the membrane of the endoplasmic reticulum and it's facing internal to the cytosol but put that aside for

a moment and just keep in mind that D1 and D2 both convert T4 into the active hormone T3 this is the one that has all of the you know positive effects of thyroid hormone now D3 is different in that D3 takes T4 and makes something called reverse T3 reverse T3 is very similar to T3 except for a very important difference which is it doesn't activate the receptor that T3 activates so it occupies the receptor without activating it so in effect you can think of reverse T3 as anti-t3 it basically blocks the effects of T3 now

it sounds like a very bad idea to have reverse T3 floating around and unfortunately in the modern world it often is it usually is a sign of inflammation illness or things of that nature but I think that the reason it probably exists is to cope with shortage of nutrients in other words when nutrients are scarce when you need to slow down metabolism one of the first things that the body does is it increases the production of reverse T3 to block the effects of T3 in fact one of the things I used to notice when I

did frequent fasting because I would fast for say a week at a time and I would always check my blood pre and post is how much my thyroid function deteriorated during that period of time and it wasn't just a deterioration in the usual metrics such as TSH and T4 it was how much my free T3 and reverse T3 changed in fact the ratio of my free T3 to reverse T3 might go from 0.25 which is pretty normal to 0.05 or less in just a five to seven day fast and you know I would say about

half of that was due to the reduction in T3 and the majority of that was due to the increase in Reverse T3 so the body is going to regulate these three enzymes in response to various physiologic circumstances and that's effectively at the cellular level how the body is controlling thyroid function now this creates a bit of a problem when you want to evaluate a patient for their thyroid status because the traditional way to think about a patient's thyroid status is actually just to look at their TSH and on the surface this kind of makes sense

because if everything is working perfectly the TSH should give you the answer if the TSH is very high what must be true well there must not be much T3 around because it would be inhibiting TSH if TSH is very very low you would be getting a lot of inhibition from these things you would be in a hyperthyroid state but the reality of it is you can sometimes have a normal TSH and still have the symptoms of hypothyroidism if for example you have very high amounts of reverse T3 and very low amounts of T3 in other

words if your T4 is being preferentially shunted into reverse T3 instead of T3 you might feel like you have the symptoms of hypothyroidism you could be cold your metabolism might be slow you'd have difficulty sleeping if it were really extreme your nails might even get brittle you'd be constipated these sorts of unfortunately non-specific symptoms which make it difficult to make such a diagnosis at times so where does this matter when it comes to how we treat hypothyroidism and to be clear hypothyroidism is far more common than hype or thyroidism I'm not going to talk about

hyper thyroidism I'm going to talk about hypo the standard treatment for hypothyroidism is to give T4 we give a synthetic version of this hormone the inactive thyroid hormone and we do that with the knowledge that most patients will convert that T4 via D1 and D2 into T3 the T3 will go on to have all the biologic effects and it will also suppress trh and TSH and the body will come back into line so for example if a patient shows up to see you and they have the classic symptoms of hypothyroidism and their TSH is elevated

for example it's six or seven you might give them say 75 micrograms of T4 and you might expect to come back and see that TSH at two or three and them feeling better and many times it works out that way but unfortunately it doesn't always work out that way and in fact what you see sometimes is that you give a patient T4 and they start to feel worse and sometimes their TSH actually improves and the reason it improves is T4 does have some inhibition of TSH not as much as T3 but some but what if

for physiologic reasons their D1 and D2 are being down regulated while their D3 is being upregulated and they're taking that T4 that you're giving them and they're just making more and more reverse T3 now again a person who's insulin resistant a person who has low grade inflammation these are typically things that we we might see drive that state and that patient even though their TSH improves doesn't necessarily feel better and for those patients it might make more sense to actually give them T3 because if you give T3 you're basically bypassing this system all together you're

still getting the feedback that's appropriate but you bypass the step where the body might erroneously turn the T4 into reverse T3 now there's a bit of a problem in giving T3 because the regular version of T3 a drug called cytomel is a very difficult drug for patients to tolerate when I was in training we would give T3 to patients after we did thyroidectomies on them for thyroid cancer and patients could rarely tolerate it we had to give it to them because we would immediately take all of their thyroid out in one moment and they needed

a big dose of T4 but a hefty dose of T3 to get them over the hump and oftentimes they would feel pretty lousy from that now since that time uh I think T3 has largely fallen out of favor not many doctors use cytomel which is the trade name for T3 because it is so rapid in its onset instead people are typically using two other formulations the first is a compounded control release T3 so it's the exact same hormone T3 but it's just compounded in a way to be slowly released this seems to be much more

well tolerated and the doses can be pushed a little bit higher a typical dose might be anywhere from 10 to 25 or even 30 micrograms of control release T3 and that seems to last a patient throughout the day of course they have to take this generally in the morning to make sure that it's out of their system by evening or at least it's reduced in potency there's another way that patients often receive T3 and that's in combination with T4 vis-a-vis a formulation known as desiccated thyroid now desiccated thyroid is basically whole thyroid gland and therefore

it contains T4 T3 and even some T2 but we're not going to talk about that so the two most common versions of desiccated thyroid are a formulation called naturethroid and armor thyroid so if you're watching this video and you're interested in this topic you've undoubtedly heard of these things now I'm not going to get into the religious debates about this stuff there are really competing schools of thought and there are some people that believe that the only thing that should ever be given to any patient with hypothyroidism is a desiccated formulation similarly there are other

people who think all of that desiccated stuff is total crap and it should never be given and we should only be giving T4 or we should only be giving T4 with a little bit of T3 or you should only be given control release T3 I interacted with people from all of these schools and all I can say is if you're really interested in treating hypothyroidism you better know all of them because there are some patients in whom one way works and another way doesn't I've had patients who came to me on desiccated formulations and I

thought you know I don't really like these desiccated formulations I'm going to switch them over to T4 plus control release T3 and I could never get them right and I ultimately end up putting them on desiccated and getting them right similarly I get patients that show up undesicated and they sort of feel okay but they're not quite right and we get them feeling right in other ways now keep in mind if you're giving desiccated thyroid and this is kind of the reason why I don't generally like to use it except when it works you're giving

a fixed amount of T4 and T3 you don't get to control it the ratio is set and it's something like one two four point two or something like that meaning for every unit of T3 you're giving you're giving 4.2 units or micrograms of T4 and again for some patients that's just right but there are other patients who need more or less of one or the other and that's why I tend to use T4 and T3 separately but again you're here to fix the symptoms more than you're here to fix the numbers and you'll ultimately end

up using whatever works finally a word third on half-life T4 has a very long Half-Life it's a matter of days and for that reason a patient shouldn't Panic if they miss a day of T4 so if they forget their dose of T4 it's okay just take it the next day and don't double up conversely T3 has a much shorter Half-Life and therefore you do need to stay on top of your T3 when you give it now of course remember the control release in the immediate release T3 also have very different half-lives but what I'm referring

to is endogenous T3 as well so there you have it a pretty hopefully simple overview of the thyroid system I guess one of the takeaways from this is that it's a little more complicated than you might be led to believe if your doctor is only looking at your TSH and unfortunately when you go to the doctor's office a lot of the times that's the only lab they've ordered I prefer to order not just the TSH but the free T4 the free T3 and the reverse T3 if I have any concerns about hypothyroidism I don't always

order this blood test so if the TSH is normal the T3 T4 are normal and the patient is asymptomatic I'm not looking at their reverse T3 but if a patient has symptoms and you need to investigate them I think you have to understand all of these and what you're basically doing is using the amounts of T4 or free T4 T3 or free T3 reverse T3 to impute what the action is of these diodonases and their for what your treatment strategy needs to be okay next we're going to talk about the adrenal system personally I find

this to be the most confusing of the systems it's also the one for which we can get virtually no information from a blood test so when you think about the thyroid test when you think about the sex hormones that we're going to talk about later we can get so much information from blood tests when it comes to this system we can't get anything from a blood test so when people you know say hey I just got a blood test and my cortisol level was high what does that mean or my cortisol level was low what

does that mean I say I don't know it doesn't mean anything because what those tests are measuring are total cortisol and total cortisol just as we'll talk about when we talk about testosterone is actually kind of unhelpful because it's all of the cortisol including that which is bound and the majority of cortisol is bound to a carrier protein known as cortisol binding protein it's also bound to albumin and other proteins as well so we really need to understand how much cortisol is Unbound what's called free cortisol and it's this free cortisol that exerts its biologic

activity now the really two main ways that you can do that one is through a saliva test and the other is through a urine test I prefer the urine test and we use a test called The Dutch test we have no affiliation with them you can find out anything you want about the the Dutch test online you can probably order directly through them I I don't really know to be honest with you but we order these for our patients when we think there's something worth investigating here we don't do these tests on everybody the reason

we like the Dutch test is first of all it is measuring free cortisol secondly it's measuring cortisol metabolites and cortisol metabolites are very helpful when it comes to understanding what cortisol production looks like I'll explain that in a moment okay so let's start with the basics you have two adrenal glands one on top of each kidney and the adrenal glands produce cortisol if you want to go high enough on the Chain you'll know that this comes as a precursor via cholesterol so cholesterol is the precursor that ultimately results in cortisol production just as it does

androgens okay go back to what I said a moment ago if you go and get a blood test for cortisol all it's doing you is telling you the total amount of this you have in your system but understanding that most of that is bound to carrier proteins what we care about is how much of that is free because it's only the free cortisol that does the important job of a glucocorticoid so what we do when we take a look at a Dutch test is over time typically four times over 24 hours we get a snapshot

of how much free cortisol exists how much free cortisone exists and equally importantly how much of their metabolites or breakdown products exist so Alpha tetrahydrocortisol Beta tetrahydrocortisol And tetrahydrocortisone now again you can't get these from a blood test and why they're important is because the sum total of these is how I learn what the total adrenal output is there's a term that you hear thrown around a lot called adrenal fatigue the suggestion is that if a person feels lousy it's because their adrenal gland isn't making enough cortisol because it's fatigued and of course these people

may indeed have low levels of cortisol they may even have low levels of free cortisol but doesn't mean their adrenal glands are fatigued I would say the answer is in most cases probably not in fact in most of those patients if you look at the total metabolized amount of cortisol and cortisone you would in fact see that they have ample amounts of production what might be happening is that they are degrading too much of their cortisol and or turning too much of their cortisol into the inactive Cortisone and instead of maybe converting it back actually

just metabolizing it here so what regulates all of these things well first of all the regulation of turning cortisol into its metabolites and cortisone into its metabolite is regulated by enzymes called reductases again I think the names of these enzymes are not really that important but for the you know people who really care five Alpha reductase five beta reductase five beta reductase we're going to talk about these later with sex hormones never mind they basically have some enzymes that will turn cortisol into these and cortisone into this and inflammation obesity and factors that are generally

associated with poor health accelerate that conversion so if a person is feeling lousy and their free cortisol is low and they're free cortisone is low and yet they have ample amounts of these you really need to reverse the factors that are driving these things here you really need to address the Obesity the insulin resistance the leptin resistance the underlying inflammation a far more common problem frankly is in people who have very high or very low levels of free cortisol and they may have symptoms associated with those things and then you have to look at what's

going on with their cortisone so I always check in my mind these things first so I always look to make sure adrenal output is appropriate and as I said it's virtually always appropriate the second thing I'm asking is is the Rhythm normal meaning do they have do they wake up with a low level of free cortisol so do they wake up about here do they have a nice rise a couple hours after waking does it fall in the afternoon and is it down here at bedtime so that's about what we want to see now if

the answer is yes then we're all done if the answer is no and let's assume that the person is really low so they wake up here they stay kind of low they stay kind of low they stay kind of low and they're symptomatic so they say boy I just can't I just can't get going during the day then I ask the question well how much cortisone do they have and they might actually have plenty of cortisone well in that case what we have to do is flip the way this enzyme is working because there's an

enzyme 11 beta hsd that converts cortisol to Cortisone and back but here's what's interesting is the the direction of travel is determined by various things so cortisone gets converted to cortisol preferentially when you have insulin resistance obesity inflammation low thyroid function leptin resistance the other direction cortisol being turned into cortisone is uh facilitated when you have glucocorticoids so for example if a patient is taking steroids understandably the body says we don't need any more cortisol let's turn it into cortisone hyperthyroidism progesterone PCOS and even supplements like curcumin so what we like to do and what

I think is one of the most potent things to do in the patient who doesn't have enough of this has plenty of this looks like this and is symptomatic is try to address these issues and frankly one of the most potent things to do is use something like an adrenal support So adrenal support is a supplement that's usually made up of a number of things the most potent of which by the way is licorice root it's actually kind of a funny story but high enough amounts of licorice will render a person functionally uh basically high

in cortisol so I remember a story in medical school of a person that showed up looking like they had Cushing's disease so Cushing's disease is a is a condition of excess cortisol production and nobody could figure out how it was happening until the nephrologist who was involved in this patient's care noticed that the patient was constantly eating licorice while seeing him and the nephrologist said hey by the way I noticed you're eating licorice how much of that do you eat and he's like oh you know about 10 packs a day and so he's eating like

10 packs of black licorice a day and he was basically shutting off this system and driving his cortisol through the roof so you can actually use that to your advantage using licorice root if indeed that's part of the problem the other thing we tend to look at is are there ways to suppress this system so let's say you have a person who wakes up here and um you know they shoot up to here and then they just stay high and they tell you I'm really having a difficult time sleeping so in those people I like

to use something like phosphatidylserine which suppresses the cortisol production in the evening and that actually helps facilitate sleep in fact this is something I use for myself if I'm jet lagged or if I need to be doing a big time zone jump so if I need to go to bed at say noon functionally right if I'm you know putting myself in the time zone of where I'm going and it's night time there and it's only noon in my home time zone but I need to go to sleep on the plane one of the most important

things I'll take is you know anywhere from 400 to 600 milligrams of phosphatidylserine because what that's doing is dropping the um dropping the cortisol by the way it's not clear what the mechanism of action is at least to me it's not so we've looked at this and we we can't quite figure out what the mechanism of action is but we see the result so what's the take home here okay the take home here is very difficult if not impossible to impute what's going on with adrenal function by looking at a blood test because it's looking

at total cortisol and if that weren't bad enough it's just one snapshot in time you really do need to see what's going on in total secondly took free cortisol and free cortisone by themselves still don't tell you a total picture you do need to have some sense of what their metabolites are because that's what's actually telling you total adrenal output next thing you need to understand is the balance of cortisol and cortisone how much do they have of each this is inactive so we think about this at least I think about this as kind of

a repository for which I can put excess cortisol if I don't need it if not down here and where I can draw cortisol if I do need it remember these are one-way streets so once you go down to here you're not reversing those you're just slowing those enzymes but here we can go back and forth between the two okay I hope you can probably see why I find this to be the most complicated system out there and in large part It's Complicated because when a person has low free cortisol and they're symptomatic you really do

not want to give them hydrocortisone or prednisone or any glucocorticoid replacement you would only Reserve such treatment for a person who is truly in distress and obviously if a person has an addisonian crisis which is what happens when the adrenal gland completely shuts down and of course that is absolutely something that can happen that happens in the face of an overwhelming infection for example by all means those people need glucocorticoids or they will die but for the average person who's walking around kind of dragging feeling like blah and indeed they have low free cortisol I

certainly wouldn't favor using glucocorticoids as a treatment for that instead what you favor are addressing the underlying issues that are either extracting cortisol into its metabolites or turning cortisol into Cortisone and the problem is there are very few pills that fix that a lot of that comes down to this word we all hate lifestyle management but unfortunately that is the key again licorice Roots probably one of the best things you can use there and of course in the flip side you can use other sort of adrenal supports as well anyway I hope that's helpful okay

so the next system we're going to talk about is the female reproductive system now this looks pretty complicated but let me tell you why I'm going to make it less complicated uh I think to understand female sex hormones the easiest way to do it is to understand it during the reproductive cycle in other words to understand what's happening uh with women's sex hormones during her menstrual cycle and during her reproductive years so this looks a heck of a lot more simple when you look at it in a woman who's outside of menopause but let's start

with this okay so the first thing is for the sake of Simplicity I'm going to assume a 28 day cycle I realize of course that is not always the case there are some women who might have a slightly shorter cycle or a longer cycle but for the purpose of illustration let's assume a 28-day cycle which is about where most women are the cycle is divided into two phases technically three because there's a menstrual phase here but let's just acknowledge that the menstrual phase which starts at day zero that's the first day of bleeding even if

it's just spotting and it's not a heavy period That's day zero that's the shedding of the endometrial lining which we'll talk about then you move into a follicular phase and the purpose of that phase which is really driven by follicle stimulating hormonal and estrogen is to ripen the follicle for ovulation ovulation takes place mid-cycle after ovulation we move into the luteal phase the luteal phase is dominated by luteinizing hormone and progesterone and the purpose of the luteal phase is to prepare the endometrial lining for implantation of course this is something that doesn't occur most of

the time that only occurs during pregnancy and therefore when the body realizes hey we're not pregnant the endometrial lining gets shed and that's what results in this crashing progesterone level and that is the shedding of the Linings of course what is the period which brings us back to here in the cycle begins again so let's talk about how these things work from the beginning so follicle stimulating hormone along with luteinizing hormone are secreted from the pituitary gland the same place that makes TSH that we talked about in the thyroid system and again the purpose of

follicle stimulating hormone is to get the follicle ready for ovulation so the follicular phase is really dominated by estrogen and FSH and of course the purpose of this is to prepare the body for ovulation now we're very particular about when we like to do a blood test here especially when a woman is approaching a perimenopausal state so as a woman is getting closer and closer to menopause we will really be monitoring the level of FSH and estradiol in about day three four or five and the kind of the canary in the coal mine as a

woman is getting close to menopause from a biochemical standpoint is a rising FSH during that phase so FSH should normally be very low during day three four five which is usually when a woman is still in her period if FSA starts to climb especially if estradiol is low you can be pretty sure that she's heading towards menopause in fact menopause is you know chemically uh demonstrated by a high FSH typically north of 25 35 40 and lowest crude oil in fact a woman who's been in menopause for many years would easily have an FSH level

of 50 or higher and unmeasurable levels of estradiol so again back to this situation here FSH is rising it has a little bit of a peak just before ovulation estrogen really Rises now so Peak estradiol occurs right at or just before ovulation the follicle comes out and away it goes to see if indeed uh it's going to be met with a sperm and if so is it going to attach to the endometrium Etc now this is where we enter the second half of the phase the luteal phase this is dominated by luteinizing hormones so the

purpose of luteinizing hormone is to prepare the endometrium for this implantation now what I haven't drawn here because it's just too complicated is what the thickness is of the endometrial lining as we go from here to here so of course just as a woman is finishing her period so call it about here the endometrium is at its thinnest right you just shed that lining and it slowly slowly slowly building up and of course at about day 14 it really starts to build up that lining because it's preparing again for that implantation progesterone is rising again

rising and by about day 21 when progesterone Peaks the body figures out if it's pregnant or not and again in most cases it's not and so because it's not pregnant it begins to rapidly drop that progesterone level estrogen has also risen for a second Peak so this is the absolute peak of estrogen but this is a second Peak and both of these hormones come crashing down and the body begins to shed that endometrium at the end of that cycle so there are a bunch of things I think I want to say about this the first

is that um you know any point in time when you get a blood draw on a woman and you are looking at FSH LH estradiol and progesterone you have to sort of know where you are now once you do a lot of this you're pretty good at guessing so it's not rocket science when you're drawing a woman's levels and you see that she has a sky-high luteinizing hormone and estradiol to figure out that you probably drew the blood right around the time that she was ovulating but in cases where it gets a little bit more

complicated when women's periods are irregular when they're becoming a pro when they're approaching perimenopause it helps to have some sense of what's going on and of course in the case where a woman is not menstruating at all it tends to be pretty easy because you're going to see very high levels of FSH or LH now it becomes more complicated when a woman has an IUD and as a result of that she's not menstruating but I'm not going to get into those complex situations right now I just kind of want to go over the basics of

the hormone system the second thing I want to point out and this point has been made in my podcast before but I think if you're only coming to this now it's worth understanding um yeah for many women what's happening between between day 21 and day 28 is really profound physiologically so I you know we talk about this thing called PMs and I think any woman who's experienced it knows it's a real thing I certainly can't say I've experienced it but I've spoken to enough women who have that um I have a real sense of why

it's probably happening now it's not entirely clear if it's the drop in progesterone that's driving this but it likely is I don't know how well this has been investigated but we certainly suspect that there are Central receptors for progesterone and that in a susceptible woman when progesterone levels are withdrawn so quickly that can easily result in mood alterations so for women who do experience significant uh and unwanted side effects of progesterone withdrawal known as you know PMS a very simple and effective way to treat it is with a low dose of progesterone that is administered

starting at day 21-28 so how does that work so again if a woman who has a fairly regular cycle she'll know when she ovulates and she'll know about a week after ovulation to take a low dose of progesterone typically this is done at about 50 milligrams orally that's just taken for seven days until she has her period and what it does is it completely blunts this effect so this effect is still happening but her total levels of progesterone are not nearly as dramatic in the reduction and this tends to ameliorate symptoms so what's the drawback

of that approach well from a physiologic perspective none the biggest drawback is just the logistics of having to remember that seven days out of every 28 you have to take progesterone this is an entirely safe thing to do and I've used this with the number of women in the past it seems to work very well alternatively women can stretch that out and take progesterone for the entire 14 days following their follicular pardon me following their ovulation and of course they can take oral contraceptives throughout but again now that's creating a whole new set of issues

around oral contraceptives which many women simply don't want to do so I just point that out to say one I think when you look at a graph like this hopefully you get an appreciation for what a profound level of uh withdrawal a woman is experiencing during the end of the ludial phase and secondly that there are lots of hormonal ways to address that now the other hormone I haven't drawn on here is testosterone I haven't drawn it for two reasons the first is it doesn't change that much during the cycle it changes a little bit

I've read a number of different studies that have looked at it most of them suggest a peak testosterone about here when you have Peak estradiol but the fluctuation is so minor that I don't think it adds any value to this secondly if I were to draw testosterone to scale on this graph you'd have to look at the ceiling that's how much more testosterone on a woman has in her body than estrogen yes I just said that it sounds very counter-intuitive but it's true a woman has even at Peak estradiol level which is during ovulation a

woman has five to ten times more testosterone in her body than she does estradiol it's just that it's not changing all that much it is unfortunately going away when she enters menopause which is what I want to talk about next so as a woman leaves her reproductive years what's happening well her body is less able to make estradiol and progesterone and as estradiol and progesterone production go down just as testosterone production goes down in a male although it happens far less abruptly for the pituitary gland senses this because there's a negative feedback loop and it

says I want more so it starts making more FSH and more LH and of course the higher those go initially the body responds and you'll see a period where the cycle does continue sometimes it spreads out it gets a little bit longer but the body is able to compensate until of course it isn't so when a woman is in menopause what you'll see is no estrogen no progesterone very high LH very high FSH and so when we initiate hormone replacement therapy and by the way we never want to wait until a woman is in that

state where she has Flat Line estradiol Flatline progesterone Sky High FSH Sky High LH we want to do it long before that we want to do it as she's transitioning from this into that and that could be literally a year or two years prior to that state and what we're doing is we're giving her enough estradiol that her FSH usually ends up hovering around 20 to 30. again that's still a pretty high level of FSH um meaning that's still got the brain thinking I want more estradiol but you don't need to give maximum amounts of

estradiol we're simply trying to control the vasomotor symptoms so the hot flashes the night sweats the vaginal symptoms atrophy dryness and perhaps most importantly cardiovascular risk factors and Bone risk factors so estrogen being the most important hormone both in men and women as it regulates uh sending the signal of tension on the bone into bone building via osteoblasts so in summary that's the look at the female endocrine system again it's much more complicated than the male endocrine system sex endocrine system because of both the cyclic nature of it and the abruptness with which it goes

away um but again I think it's something that everyone needs to understand because if you're a woman you should understand this and frankly if you know a woman and you care about a woman you should understand this and it certainly would hopefully give empathy to um women who are struggling during that last portion of their luteal phase again men don't have an equivalent of this we don't have a scenario whereby we're having a tenfold reduction in a major sex hormone that occurs over the course of a week so I think it's understandable why that can

pose issues for some women so in summary I think you can see that the female sex hormones are a little bit more complicated than what you're going to see in a moment which is the male equivalent um but I think it's also actually a more interesting system um by understanding how this works you have a sense of whether a woman is typically getting closer to menopause which is generally one of our considerations as we're looking at these hormone levels and as a woman is entering that perimenopausal period you want to be especially attentive to the

time in which you draw again day three four five become the most important blood draws as a woman is becoming perimenopausal because it's that FSH level at day three four and five that becomes your Canary in the coal mine if that level starts creeping up and it's over 10 11 12 even though she's not in menopause I'm going to tell her she's probably getting close and that's when we start to have our discussion about what hormone replacement therapy looks like okay this brings us to the final hormone system we'll talk about today which is the

male sex hormone system um this system I think is a little bit simpler than the female system but it still has its nuances so let's kind of go back to a very similar pattern we saw with the thyroid system which is Upstream regulation at the hypothalamus vis-a-vis GnRH gonadotropin releasing hormone that tells the pituitary to secrete LH and FSH again if you just watched me go over the female system you'll realize we have the exact same thing happening there I just didn't draw all of this because we had so many other complicated things to talk

about so luteinizing hormone and follicle stimulating hormone are speaking to the testes and yes I realize as I drew this I didn't need to draw two of them that was a bit gratuitous but nevertheless the testes have different cells in them uh certulli cells and latings lading cells the testes make testosterone now there's a little more complexity to this that I will come back to in a moment but let's just start with the fact that the testes are making testosterone we should also point out that testosterone is mostly bound so just as I discussed with

cortisol most cortisol is bound so is most testosterone it's primarily bound to two hormones sex hormone binding globulin or shbg and albumin but a relatively small amount and it depends on how much albumin and shpg you have remains free so we call that free or Unbound testosterone and it's anywhere from one to three percent of the total testosterone now there are two things that are siphoning testosterone away that are very important the first is five Alpha reductase which is the same enzyme we talked about back when we were going over cortisol it's siphoning off some

of that testosterone to make dihydrotestosterone now not huge amounts sort of you know a couple of percent but dihydrotestosterone is a very important sex hormone in fact it has anywhere from two to ten some studies would suggest even higher uh potency 2 to 10 x potency for the Androgen receptor than testosterone so I'm going to talk about the Androgen receptor in a minute but I just want you to keep in mind that DHT has a much higher binding affinity for the Androgen receptor than testosterone does the other thing that is siphoning off testosterone is the

aromatase enzymes that are converting testosterone into estradiol yes that's the very same estrogen that women have as well and estrogen turns out to be a very important hormone for men I think this is something that hasn't been always appreciated but we Now understand that of course estrogen is important in the male for mood for body composition for bone mineral density so I'll talk about this in a moment but things that suppress estrogen have to be considered judiciously because of the negative side effects of having low estrogen okay not surprisingly there is a feedback loop so

the feedback loop works as follows testosterone levels as they rise will inhibit both the hypothalamus and the pituitary which slows down GnRH and LH and FSH this is actually much more complicated than I've drawn it here and I realize that there's going to be some purist out there who says oh my God you forgot to mention this yeah so it turns out that the hypothalamus does not have an overwhelming number of Androgen receptors so this is not happening directly but rather indirectly so testosterone is inhibiting a slightly different neuron that is then speaking to the

hypothalamus but I think for the purpose of this discussion this is sufficient the other thing to point out is that estrogen also inhibits luteinizing hormone secretion via the pituitary so this becomes really important when we talk about certain drugs that are used to replace testosterone or to increase testosterone okay so let's just summarize what we've learned so far in the normal functioning system GnRH tells the pituitary to make LH and FSH they tell the testes to make testosterone small amounts of that are siphoned off to make DHT and even smaller amounts I.E less than one

percent are siphoned off to make estrogen and the system is in perfect balance now how much of that testosterone is actually exerting its biologic effect on the Androgen receptor well it turns out very little is because as I said you have this thing over here sh BG plus albumin and it's soaking up most of the testosterone so that really the free testosterone which is the biologically active represents only about one to three percent of total testosterone but the good news is that's all you need the stuff's pretty darn potent so testosterone binds to an androgen

receptor DHT also binds to an androgen receptor it just does so in a way more potent fashion and this happens inside the nucleus of a cell and that's what affects transcription okay now we're going to talk about a subject that is way more complicated than I think it's being led then people are being led to believe it is and that's testosterone replacement therapy it's not as simple as looking at the total testosterone or even the free testosterone and determining if a person has low testosterone or low T and the reason for that is when you

are measuring total testosterone you don't really know what the free T is the free T is a calculated lab value so they don't really measure free tea by most lab assays they measure total testosterone they measure shbg and albumin and they calculate free tea but let's assume that the calculation is fairly accurate and even if you don't rely on a lab to do that calculation there are calculators online that can do that for you so let's say you now know the free T and we'll talk about what some ranges are in a moment the question

becomes is the patient's low level because let's just say they're at the 30th percentile for what their level is does that explain their symptoms well it's not entirely clear because what we don't know is what's happening here so we don't know how many Androgen receptors a person has and therefore we don't know how saturated their Androgen receptors are with either testosterone or dihydrotestosterone so we have to sometimes treat these things empirically meaning we're treating symptoms but we're using numbers as a guide to do so so the most common symptoms of actual low testosterone of Androgen

deficiency in no particular order because they're going to vary significantly by men would be low libido erectile dysfunction low mood difficulty putting on muscle mass and insulin resistance those are the big ones that I see now there are others to be sure but those are really the big ones and we know from clinical trials that when you give a group of insulin resistant men testosterone their insulin resistance improves we know that if you give men testosterone and you provide them with a training stimulus muscle mass increases strength increases body composition improves which means adipose tissue

goes down we know that mood improves we know that a whole bunch of factors move in the right direction but despite all of that I'm still pretty cautious when giving testosterone because I think it is an overused hormone I think too many people are being given testosterone and they probably don't need it because they're just being treated on their total testosterone level without necessarily considering these other factors such as free testosterone and of course without understanding these things which none of us can outside of a lab so we have to really treat based on symptoms

now what are the treatment options um there are broadly speaking two ways to think about this the first is a direct way to do it which is giving testosterone and this can be done in many formats uh the most common formats would be topical testosterone or injectable testosterone but there's also an intranasal formulation there are pellets that can provide sort of a slow release over a period of months and then there are indirect ways to give testosterone which are basically tricks that mimic these hormones so uh the first of these is something called HCG and

HCG is a memetic of luteinizing hormone so an injection of HCG will tell the body to make testosterone just as you were giving luteinizing hormone there is also a synthetic FSH it's far more expensive and it's virtually never used so the typical use case for synthetic FSH is in men who have been on testosterone replacement therapy for many years who have now lost the ability to make testosterone because if you are given enough exogenous testosterone you will shut down the capacity to make testosterone in very short order and within a year two years you will

permanently lose that ability minus some Herculean doses of synthetic LH and synthetic FSH so we should make sure we never lose sight of that the other way to do this is to give a drug that has become very popular called Clomid Clomid or clomiphene is a drug that has been used historically by women using it for fertility purposes and what Clomid is doing is effectively tricking the brain via stimulation of GnRH by blocking the estrogen receptor to make more LH and FSH now the reason I'm not a fan of Clomid there are several reasons but

one of the most important reasons is that it blocks the effect of estrogen in the brain and that turns out to be a negative thing turns out we want the feedback of estrogen in the brain because it has many beneficial effects for mood and there are some men who actually when they're on Clomid even though their testosterone levels soar don't feel any better we wonder if in fact that's because of Clomid so not every man there are some men that are on Clomid that feel great on it but there are some who don't alternatively you

give testosterone and when you give testosterone you have to be mindful of the fact that your LH and FSH are going to go to zero because your body is going to stop making testosterone this is a very potent feedback loop when you give testosterone these hormones will go up now they go up depending on a number of factors 5-alpha reductase has quite a strong genetic component so some men are very strong 5-alpha reductase producers and they're going to make a lot of DHT by the way this is responsible for one of the side effects of

testosterone which is hair loss so a lot of hair loss is driven by DHT and the Androgen receptor and therefore if you're susceptible to that and you give five if you give testosterone and you make more DHT you're going to accelerate hair loss similarly aromatase activity varies genetically but it also varies by factors such as insulin resistance obesity and factors like that and therefore the more adipose tissue you have typically the more aromatase you have so a person who's overweight is going to make more estradiol all things equal from a given amount of testosterone than

a person who is lean are there side effects of having too much estradiol yes there are at some point estradiol levels can become counterproductive and of course if they get very high although I've never seen a case of this in 10 years of prescribing testosterone we can see gynecomastia so that's when a man will develop breast tissue again these are typically things that are only seen in people who are using excessive amounts of testosterone usually not under the care of a doctor unfortunately but if estradiol levels do get a little too high they can be

managed with a drug that blocks that conversion the drug is known as Anastrozole again I personally am not a big fan of using it because I find you really don't need to use it in most men in fact it's nice to have the estradiol levels go up because you want it for bone health you want it for mood you want it for all of those other reasons so we will typically not use Anastrozole unless the estradiol level is in excess of 50 55 or even 60 unless we are seeing symptoms that we would attribute to

that my general philosophy on testosterone replacement is that there has to be a biochemical case for it I.E free testosterone needs to be relatively low at least below the 50th percentile and there needs to be more importantly a symptomatic case for it if both of those conditions are met and of course the patient understands the risks and benefits we would give trt for a period of 8 to 12 weeks we would determine that we've fixed the biochemical issue so they go from being at say the 30th percentile to being at the 80th percentile and then

we assess the symptoms and sometimes the man says I don't feel any better so you fix the number but you haven't fixed the symptoms and with very few exceptions at that point I would say it doesn't make sense to continue this we should stop doing it now one exception to that would be if you were doing it for bone health so if a man has osteopenia and he has low estradiol and low testosterone we don't really care about symptoms at that point we want his testosterone High we want his estradiol High because those are going

to be two of the most important steps we can take in combination with heavy training to increase or minimum maintain his bone mineral density but for most men we care about the symptoms more than we care about the numbers and if we don't fix the symptoms we don't we take it off and we also watch hey do your symptoms get worse when we remove the testosterone oftentimes they don't and again I can't answer what's going on there I suspect that these might be men who have either low amounts of estrogen receptors or their estrogen receptors

are just highly saturated with a little bit of testosterone they have in the first place all right so there you have it that's uh sort of the quick overview of the male sex hormone system again I think this system has its own nuances and complexities vis-a-vis how to make the diagnosis and then of course how to treat it thank you for listening to this week's episode of the drive if you're interested in diving deeper into any topics we discuss we've created a membership program that allows us to bring you more in-depth exclusive content without relying

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