00:00:04.924	00:00:11.635	Hey everyone I wanted to put together a video that answers a lot of the questions we get about hormones.
00:00:10.971	00:00:22.579	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.
00:00:21.771	00:00:32.756	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.
00:00:31.852	00:00:56.564	And basically what I am going to do is talk about how these hormones come, about how they are 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 are also going to chop them up and you can, if you are only interested for example in female sex hormones we will have just a shorter video that covers that, but it will be the exact same content that's shown here.
00:00:55.707	00:01:01.939	So dive in I am going to start with the thyroid system - if for no other reason then I am just going to go head to toe…
00:01:06.459	00:01:10.004	Okay so let's start with the thyroid system.
00:01:09.099	00:01:13.123	I have drawn a little bit of a schematic here.
00:01:12.364	00:01:19.507	It's a bit oversimplified and it's also at the same time a little bit messy, I am going to try to explain it and sense.
00:01:18.555	00:01:21.763	You have the thyroid gland.
00:01:20.859	00:01:32.563	This is the thing that sits in front of your larynx, you can actually feel the thyroid gland and it's shaped as a shield which it gets its name.
00:01:31.707	00:01:55.219	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.
00:01:54.268	00:01:59.203	Now I will come back to the regulation of these in a moment, but let's just go back to the thyroid gland.
00:01:58.299	00:02:04.483	So the thyroid gland makes mostly T4 and a little bit of T3.
00:02:04.060	00:02:06.691	Now where do the 3 and the 4 come from?
00:02:05.787	00:02:07.555	What are they referring to?
00:02:06.652	00:02:11.780	Well they are referring to the number of iodines that are in the molecule.
00:02:10.828	00:02:14.948	So, not surprisingly T4 (thyroxine) has four iodines.
00:02:14.092	00:02:17.012	T3 (triiodothyronine) has three iodines.
00:02:16.683	00:02:18.979	What's the difference between them?
00:02:18.268	00:02:21.668	the difference has to do with their biologic activity.
00:02:21.243	00:02:35.300	when you think of all the things that the thyroid hormone does for example it keeps you warm aids in metabolism controls things like the brittleness of your nails your hair a bowel function all sorts of things.
00:02:34.780	00:02:41.108	of the thyroid promoting functions are controlled by the active version which is T3.
00:02:40.683	00:02:55.171	T4 conversely is the inactive version of the hormone so if you are paying attention to what I just said you will note I just said that basically most of what comes out of the thyroid is T4 which is inactive.
00:02:54.651	00:03:01.795	now it's not entirely clear what the ratio is between these but it's directionally about four or five to one.
00:03:00.939	00:03:16.051	i think it's almost just as easy to imagine that virtually everything the thyroid is producing is T4 so if the thyroid's producing T4 which is inactive it needs to be converted into an active hormone in the body.
00:03:15.675	00:03:20.804	and that's where these enzymes called deiodinases come in.
00:03:19.948	00:03:37.075	and as their name suggests deiodinases 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 deiodinases.
00:03:36.556	00:03:42.500	but the three most relevant are D1 D2 and D3.
00:03:42.123	00:03:45.907	so let's talk for a moment about these three deiodinases.
00:03:45.243	00:03:52.532	D1 and D2 are quite similar in that they both convert T4 into T3 more about that a moment.
00:03:51.723	00:03:56.707	it's just where they do it that's slightly different: D1 is extracellular.
00:03:55.804	00:04:05.539	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.
00:04:04.731	00:04:13.939	but put that aside for a moment and just keep in mind that D1 and D2 both convert T4 into the active hormone T3.
00:04:13.132	00:04:24.067	this is the one that has positive effects of thyroid hormone now D3 is different in that D3 takes T4 and makes something called reverse T3 (rT3).
00:04:23.259	00:04:33.956	reverse T3 is very similar to T3 except for a very important difference which is it doesn't activate the receptor that T3 activates.
00:04:33.052	00:04:37.220	so occupies the receptor without activating it.
00:04:36.747	00:04:42.451	so effect you can think of reverse T3 anti T3.
00:04:41.644	00:04:45.043	it basically blocks the effects of T3.
00:04:44.908	00:04:52.435	it sounds like a very bad idea to have reverse T3 floating around and unfortunately in the modern world it often is.
00:04:51.483	00:04:56.516	it usually is a sign of inflammation illness or things of that nature.
00:04:55.947	00:05:03.091	but I think that the reason it probably exists is to cope with shortage of nutrients.
00:05:02.139	00:05:14.851	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.
00:05:13.947	00:05:27.812	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 how much my thyroid function deteriorated during that period of time.
00:05:26.908	00:05:34.339	and it wasn't just a deterioration in the usual metrics such as TSH and T4.
00:05:33.723	00:05:38.372	it was how much my free T3 and reverse T3 change.
00:05:37.612	00:05:44.324	in fact the ratio of my free T3 to reverse T3 might go from 0.25
00:05:43.755	00:05:48.596	which is pretty normal, to 0.05 or less 
00:05:48.603	00:05:53.252	in just a five to seven day fast.
00:05:52.348	00:06:01.220	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.
00:06:00.651	00:06:25.699	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.
00:06:25.084	00:06:37.172	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?
00:06:36.843	00:06:44.612	Well there must not be much T3 around, because it would be inhibiting TSH.
00:06:44.716	00:06:53.540	If TSH is very very low, you would be getting a lot inhibition from these things, you would be in a hyperthyroid state.
00:06:54.172	00:07:03.283	But the reality of it is, you can sometimes have a normal TSH and still have the symptoms of hypothyroidism.
00:07:02.379	00:07:41.348	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 nonspecific 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?
00:07:40.396	00:07:48.259	And to be clear, hypothyroidism is far more common than hyperthyroidism. I not going to talk about hyperthyroidism.
00:07:47.451	00:07:49.220	I am going to talk about hypothyroidism
00:07:50.187	00:07:56.036	Standard treatment for hypothyroidism is to give T4 (thyroxine).
00:07:55.660	00:08:19.267	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 into T3 via D1 and D2, 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.
00:08:18.363	00:08:38.131	So, for example, if a patient shows up to see you and they have the classic symptoms of hypothyroidism and their TSH elevated, for example, at 6 or 7, you might give them say 75 micrograms of T4 and you might expect to come back and see that TSH at 2 or 3 and them feeling better.
00:08:37.419	00:08:42.451	And many times it works out that way, but unfortunately it doesn't always work out that way.
00:08:41.836	00:08:59.491	And in fact what you see sometimes is that you give a patient T4 (thyroxine) 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.
00:09:00.028	00:09:12.596	But for physiologic reasons, their D1 and D2 are being down-regulated while their D3 is being up-regulated, and they are taking that T4 that you are giving them, and they are just making more and more reverse T3.
00:09:12.316	00:09:55.220	Now, again, a person who's insulin resistant, a person who has low grade inflammation, these are typically things that 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 are basically bypassing this system. All together, you are still getting the feedback that's appropriate, but you bypass the step where the body might erroneously turn the T4 into reverse T3. 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.
00:09:54.268	00:10:17.443	When I was in training, we would give T3 to patients after we did thyroid cancer, and patients could rarely tolerate. 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.
00:10:16.683	00:10:19.028	Now, since that time
00:10:19.275	00:10:22.580	I think T3 has largely fallen out of favor.
00:10:21.964	00:10:31.028	Not many doctors use Cytomel (which is the trade name for T3) because is so rapid in its onset.
00:10:30.172	00:10:35.875	Instead, people are typically using two other formulations.
00:10:35.403	00:10:40.244	The first is compounded control release T3.
00:10:39.436	00:10:46.964	It's the exact same hormone T3 it's just compounded in a way be slowly released.
00:10:46.059	00:10:51.572	This seems to be much more well tolerated, and the doses can be pushed a little bit higher.
00:10:50.716	00:10:59.779	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.
00:10:58.827	00:11:06.980	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.
00:11:06.700	00:11:18.403	There's another way that patients often receive T3, and that's in combination with T4 vis à vis a formulation known as desiccated thyroid.
00:11:17.596	00:11:28.004	Desiccated thyroid is basically whole thyroid gland, and therefore it contains T4, T3, and even some T2, but we are not going to talk about that.
00:11:27.292	00:11:34.340	So the two most common versions of desiccated thyroid are a formulation called Nature Thyroid and Armour Thyroid.
00:11:33.388	00:11:38.659	If you are watching this video and you are interested in this topic you have undoubtedly heard of these things.
00:11:37.707	00:11:41.443	Now, I am not going to get into the religious debates about this stuff.
00:11:40.539	00:11:50.371	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.
00:11:49.899	00:12:15.427	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 giving control release T3. I have interacted with people from all of these schools and all I can say is if you are really interested in treating hypothyroidism, you better know of them because there are some patients in whom one way works and another way doesn't.
00:12:14.475	00:12:22.196	I have had patients who came to me on desiccated formulations, and I thought, you know, I don't really like these desiccated formulations.
00:12:21.244	00:12:30.740	I am going to switch them over to T4 plus control release T3, and I could never get them right, and I ultimately ended up putting them undessicated and getting them right.
00:12:29.836	00:12:47.971	Similarly I get patients that show up undessicated and they sort of feel okay, but they are not quite right, and we get them feeling right in other ways. Now, keep in mind if you are giving desiccated thyroid, and this is kind of the reason why I don't generally like to use it except when it works, you are giving a fixed amount of T4 and T3.
00:12:47.163	00:12:49.316	You don't get to control it.
00:12:48.364	00:13:02.083	The ratio is set and it's something like 1 to 42 or something like that, meaning for every unit of T3 you are giving giving 42 units or micrograms of T4.
00:13:01.227	00:13:13.268	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.
00:13:12.460	00:13:21.331	But again you are here to fix the symptoms more than you are here to fix the numbers, and you ultimately end up using whatever works.
00:13:20.956	00:13:23.971	Finally, a word on half life.
00:13:23.836	00:13:27.908	T4 has a very long half life.
00:13:27.388	00:13:29.875	It's a matter of days.
00:13:29.019	00:13:36.019	And for that reason, a patient shouldn't panic if they miss a day of T4.
00:13:35.259	00:13:41.587	If they forget their dose of T4, okay, just take it the next day, and don't double up.
00:13:41.067	00:13:50.611	Conversely, T3 has a much shorter half life, and therefore you do need to stay on top of your T3 when you give it.
00:13:49.659	00:14:05.875	Now, of course remember the controled-release and the immediate-release T3 also have very different half lives, but what I am referring to is endogenous T3 as well, so there you have it a pretty hopefully simple overview of the thyroid system.
00:14:05.019	00:14:15.283	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.
00:14:14.331	00:14:21.331	And unfortunately, when you go to the doctor's office, a lot of the times that's the only lab they have ordered.
00:14:20.908	00:14:32.131	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.
00:14:31.179	00:14:34.004	I don't always order this blood test.
00:14:33.052	00:14:39.235	So, if the TSH is normal, the T3 and T4 are normal and the patient is asymptomatic,
00:14:38.283	00:14:45.812	I am not looking at their reverse T3 if a patient has symptoms. And you need to investigate them, I think you have to understand all of these.
00:14:44.860	00:15:02.035	And what you are basically doing is using the amounts of T4 or free T4, T3 or free T3, reverse T3 to impute what the action of these deiodinases, and therefore what your treatment strategy, needs to be.
00:15:06.412	00:15:10.292	Okay, next we are going to talk about the adrenal system.
00:15:09.532	00:15:14.131	Personally, I find this to be the most confusing of the systems.
00:15:13.275	00:15:20.035	It's also the one for which we can get virtually no information from a blood test.
00:15:19.227	00:15:27.331	So, when you think about the thyroid test, when you think about the sex hormones that we are going to talk about later, we can get so much information from blood tests.
00:15:26.668	00:15:31.028	But when it comes to this system, we can't get anything from a blood test.
00:15:30.076	00:15:36.211	So, when people, you know, say hey, I just got a blood test and my cortisol level was high… What does that mean?
00:15:35.307	00:15:38.179	Or my cortisol level was low, what does that mean?
00:15:37.323	00:15:39.427	I say I don't know.
00:15:38.475	00:15:45.235	It doesn't mean anything, because what those tests are measuring are total cortisol.
00:15:44.331	00:15:56.419	And total cortisol, just as we will talk about when we talk about testosterone, is actually kind of unhelpful, because it's all of the cortisol including that which is bound.
00:15:55.467	00:16:05.011	And the majority of cortisol is bound to a carrier protein known as cortisol bindingprotein (CBG) also bound to albumen and other proteins as well.
00:16:04.443	00:16:14.947	So, we really need to understand how much cortisol unbound, what's called free cortisol, and it's this free cortisol that exerts its biologic activity.
00:16:14.524	00:16:24.259	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.
00:16:23.596	00:16:26.371	We use a test called the DUTCH test.
00:16:25.467	00:16:27.908	We have no affiliation with them.
00:16:27.436	00:16:31.652	You can find out anything you want about the DUTCH test online.
00:16:30.748	00:16:33.620	you can probably order directly through them.
00:16:32.812	00:16:35.299	I don't really know, to be honest with you.
00:16:34.395	00:16:39.956	But we order these for our patients when we think there's something worth investigating here.
00:16:39.004	00:16:47.251	We don't do these tests on everybody. The reason we like the DUTCH test is, first of all, it is measuring free cortisol.
00:16:46.923	00:16:50.947	Secondly it's measuring cortisol metabolites.
00:16:49.995	00:16:57.620	And cortisol metabolites are very helpful when it comes to understanding what cortisol production looks like.
00:16:56.716	00:16:59.251	I explain that in a moment.
00:16:58.347	00:17:01.604	Okay, so let's start with the basics.
00:17:00.748	00:17:08.036	you have two adrenal glands one on top each kidney and the adrenal glands produce cortisol.
00:17:07.132	00:17:14.324	If you want to go high enough on the chain you will know that this comes as a precursor via cholesterol.
00:17:13.420	00:17:20.276	So, cholesterol is the precursor that ultimately results in cortisol production just as it does androgens.
00:17:19.516	00:17:20.852	Okay
00:17:21.099	00:17:23.491	Go back to what I said a moment ago.
00:17:22.539	00:17:34.531	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 carry your proteins.
00:17:33.627	00:17:42.500	what we care about how much of that is free, because it's only the free cortisol that does the important job of a glucocorticoid.
00:17:42.892	00:18:04.195	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 how much free cortisol exists, how much free cortisone exists, and equally importantly how much of their metabolites or breakdown products exist.
00:18:03.435	00:18:22.963	So, alpha tetrahydrocortisol, beta tetrahydrocortisol and tetrahydrocortisone. Now, again you can't get these from a blood test, and why they are important is because the sum total of these is how I learn what the total adrenal output is.
00:18:22.923	00:18:28.483	There's a term that you hear thrown around a lot called “adrenal fatigue”.
00:18:27.915	00:18:40.531	The suggestion is that if a person feels lousy, it's because the adrenal gland isn't making enough cortisol, because it's fatigued, and of course these people may indeed have low levels of cortisol.
00:18:39.579	00:18:48.740	They may even have low levels of free cortisol, but it doesn't mean their adrenal glands are fatigued. I would say the answer is in most cases probably not.
00:18:47.884	00:18:59.587	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.
00:18:58.971	00:19:13.556	What might be happening is that they are degrading too much of their cortisol, or turning too much of their cortisol into the inactive cortisone, and instead of maybe converting it back actually, just metabolizing it here.
00:19:13.468	00:19:16.531	So, what regulates all of these things?
00:19:15.579	00:19:26.420	Well, first of all, the regulation of turning cortisol into its metabolites and cortisone into its metabolite is regulated by enzymes called reductases.
00:19:25.468	00:19:37.364	Again I think the names of these enzymes are not really that important, but for the people who really care, 5-alpha reductase, 5-beta reductase, 5-beta reductase. We are going to talk about these later with sex hormones, never mind.
00:19:36.460	00:19:52.147	We 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.
00:19:51.723	00:20:11.635	So, if a person is feeling lousy and their free cortisol is low, and their 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.
00:20:10.779	00:20:17.347	You really need to address the obesity, the insulin resistance, the leptin resistance, the underlying inflammation.
00:20:17.403	00:20:31.604	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.
00:20:30.844	00:20:33.763	So, I always check in my mind things first.
00:20:32.811	00:20:39.571	So, I always look to make sure adrenal output is appropriate and, as I said, it's virtually always appropriate.
00:20:39.579	00:20:43.892	The second thing I am asking is, is the rhythm normal?
00:20:43.036	00:20:47.875	Meaning, do they wake up with a low level of free cortisol?
00:20:49.852	00:20:52.099	Do they wake up about here?
00:20:52.107	00:20:56.564	Do they have a nice rise a couple of hours after waking?
00:20:56.284	00:21:00.500	Does it fall in the afternoon and is it down here at bedtime?
00:21:00.460	00:21:02.948	So, that's about what we want to see.
00:21:02.955	00:21:06.355	If the answer is yes, then we are all done.
00:21:05.451	00:21:10.195	If the answer is no, and let's assume that the person is really low,
00:21:09.387	00:21:22.627	so they wake up here, they stay kind of low, they stay kind of low, they stay kind of low, and they are symptomatic. So they say, boy, I just can't, I just can't get going during the day.
00:21:22.731	00:21:26.324	I ask the question, well how much cortisone do they have?
00:21:25.468	00:21:29.347	And they might actually have plenty of cortisone.
00:21:28.971	00:21:46.435	Well, in that case what we have to do is flip the way this enzyme is working, because there's enzyme 11-beta HSD that converts cortisol to cortisone and back, but here's what's interesting is the direction of travel is determined by various things.
00:21:45.579	00:21:56.804	So, cortisone gets converted to cortisol preferentially when you have insulin resistance, obesity, inflammation, low thyroid function, leptin resistance.
00:21:56.619	00:22:03.380	The other direction, cortisol being turned into cortisone, is facilitated when you have glucocorticoids.
00:22:02.476	00:22:08.468	So, for example, a patient is taking steroids. Understandably, the body says we don't need any more cortisol,
00:22:07.516	00:22:09.715	Let's turn it to cortisone.
00:22:09.099	00:22:14.324	Hyperthyroidism, progesterone PCOS, and even supplements like curcumin.
00:22:13.900	00:22:28.579	So, what we like to do, 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.
00:22:27.627	00:22:32.900	And frankly one of the most potent things to do is use something like an adrenal support.
00:22:31.948	00:22:39.811	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.
00:22:38.859	00:22:45.907	It's actually kind of a funny story, but high enough amounts of licorice will render a person functionally
00:22:46.731	00:22:49.556	basically high in cortisol.
00:22:48.652	00:22:56.084	So, I remember a story in medical school of a person that showed up looking like they had Cushing's disease.
00:22:55.180	00:23:11.683	Cushing's disease is a condition of excess cortisol production, and nobody could figure out 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.
00:23:10.731	00:23:14.468	And the nephrologist said “hey by the way I noticed you are eating licorice.”
00:23:13.516	00:23:15.428	How much of that do you eat?
00:23:14.476	00:23:17.251	And he's like, oh, you know, about ten packs a day.
00:23:16.299	00:23:24.740	And so, he eating like ten packs of black licorice a day and he was basically shutting off this system and driving his cortisol to the root.
00:23:23.836	00:23:30.884	So, you can actually use that to your advantage, using licorice root if indeed that's part of the problem.
00:23:30.748	00:23:35.971	The other thing we tend to look at is are there ways to suppress this system?
00:23:35.019	00:23:40.051	So, let's say you have a person who wakes up here
00:23:40.299	00:23:47.635	and you know they shoot up to here and then they just stay high and they tell you I am really having a difficult time sleeping.
00:23:47.259	00:23:58.531	In those people I like to use something like phosphatidylserine, which suppresses the cortisol production in the evening and that actually helps facilitate sleep.
00:23:57.579	00:24:04.819	In fact, this is something I use for myself if I am jet lag, or if I need to be doing a big time zone jump.
00:24:03.915	00:24:17.491	So, if I need to go to bed at, say, noon, functionally, right, if I am, you know, putting myself in the time zone of where I am going and it's nighttime there, and it's only noon in my home time zone but I need to go to sleep on the plane,
00:24:16.635	00:24:28.243	one of the most important things I will take is, you know, anywhere from 400 to 600 milligrams of phosphatidylserine, because what that's doing is dropping cortisol.
00:24:27.339	00:24:31.988	By the way, it's not clear what the mechanism of action is, at least to me it's not.
00:24:31.084	00:24:36.932	So, we have looked at this and we can't quite figure out what the mechanism action is, but we see the result.
00:24:36.892	00:24:39.811	So what's the take home here?
00:24:38.907	00:24:53.635	Okay the take home here, it is very difficult, if not impossible, to impute what's going on with adrenal function 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.
00:24:52.875	00:24:56.660	You really do need to see what's going on in total.
00:24:56.284	00:24:57.811	Secondly,
00:24:58.251	00:25:03.188	free cortisol and free cortisone by themselves still don't tell you a total picture.
00:25:02.523	00:25:10.051	You do need to have some sense of what their metabolites are because that's what's actually telling you total adrenal output.
00:25:09.771	00:25:14.132	Next thing you need to understand is the balance of cortisol and cortisone.
00:25:13.228	00:25:15.859	How much do they have each?
00:25:15.579	00:25:17.683	This is inactive,
00:25:16.779	00:25:28.627	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.
00:25:27.723	00:25:30.019	Remember these are one way streets.
00:25:29.067	00:25:36.980	So, once you go down to here, you are not reversing those, you are just slowing those enzymes, but here we can go back and forth between the two.
00:25:36.460	00:25:59.731	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 are 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's truly in distress.
00:25:58.827	00:26:09.140	And obviously, if a person has an addisonian crisis gland, which is what happens when the adrenal gland completely shuts down, and of course that's absolutely something that can happen,
00:26:08.236	00:26:11.299	that happens in the face of an overwhelming infection for example.
00:26:10.395	00:26:27.763	By all means those people need glucocorticoids or they will die. 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.
00:26:26.859	00:26:41.107	Instead what you favor are addressing the underlying issues that are either extracting cortisol into its metabolites turning cortisol into cortisone, and the problem is there are very few pills that fix that.
00:26:40.395	00:26:44.900	A lot of that comes down to this word: we all hate lifestyle management.
00:26:43.948	00:26:54.259	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.
00:26:53.355	00:26:56.276	Anyway I hope that's helpful.
00:27:01.180	00:27:06.211	Okay, so the next system we are going to talk about is the female reproductive system.
00:27:05.788	00:27:11.635	Now this looks pretty complicated, but let me tell you why I am to make it less complicated.
00:27:10.875	00:27:18.932	I think, to understand female sex hormones, the easiest way to do it to understand it during the reproductive cycle.
00:27:18.124	00:27:27.284	In other words, to understand what's happening with women's sex hormones during her menstrual cycle, and during her reproductive years.
00:27:26.380	00:27:34.147	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.
00:27:33.243	00:27:39.811	Okay, so the first thing is for the sake of simplicity I am going to assume a 28 day cycle.
00:27:38.955	00:27:42.259	I realize of course that is not always the case.
00:27:41.307	00:27:45.619	There are some women who might have a slightly shorter cycle or a longer cycle.
00:27:44.667	00:27:51.907	But for the purpose of illustration let's assume a 28 day cycle, which is about where most women are.
00:27:51.003	00:28:11.299	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 will talk about.
00:28:11.211	00:28:24.067	Then you move into a follicular phase, the purpose of that phase which is really driven by follicle stimulating hormone and estrogen is to ripen the follicle for ovulation.
00:28:23.355	00:28:26.324	Ovulation takes place mid cycle.
00:28:25.468	00:28:30.115	After ovulation we move into the luteal phase.
00:28:29.211	00:28:39.332	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.
00:28:38.380	00:28:59.203	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 are 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 and the cycle begins again.
00:28:58.299	00:29:01.364	So let's talk about how these things work from the beginning.
00:29:00.508	00:29:17.155	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.
00:29:16.299	00:29:26.516	so the follicular phase is really dominated by estrogen and FSH (follicle-stimulating hormone), and of course the purpose of this is to prepare the body for ovulation.
00:29:25.756	00:29:34.867	Now, we are very particular about when we like to do a blood test here, especially when a woman approaching a perimenopausal state.
00:29:33.963	00:29:45.284	So, 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.
00:29:44.380	00:29:55.172	And it's kind of the canary in the coal mine as a woman is getting close to menopause, from a biochemical standpoint, a rising FSH during that phase.
00:29:54.220	00:30:02.564	So, FSH should normally be very low during day three, four, five, which is usually when a woman is still in her period.
00:30:01.804	00:30:09.715	If FSH starts to climb, especially if estradiol is low, you can be pretty sure that she's heading towards menopause.
00:30:08.859	00:30:18.692	In fact, menopause is chemically demonstrated by a high FSH, typically worth of 25, 35, 40, and low estradiol.
00:30:17.740	00:30:25.652	in fact a woman who's been in menopause for many years would easily have FSH level of 50 or higher, and unmeasurable levels estradiol.
00:30:25.372	00:30:31.124	So, again back to this situation here FSH is rising.
00:30:30.220	00:30:33.955	It has a little bit of a peak just before ovulation.
00:30:33.051	00:30:39.763	Estrogen really rises now, so peak estrodial occurs right at or just before ovulation.
00:30:39.099	00:30:50.468	The follicle comes out, and the way it goes, to see, if indeed it's going to be met with a sperm, if so, is it going to attach to the endometrium et cetera?
00:30:49.660	00:30:53.731	Now this is where we enter the second half of the phase, the luteal phase.
00:30:52.779	00:30:55.460	This is dominated by luteinizing hormones.
00:30:54.508	00:31:00.548	So, the purpose of luteinizing hormone is to prepare the endometrium for this implantation.
00:30:59.644	00:31:17.011	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 about here, the endometrial is its finest, right?
00:31:16.107	00:31:22.195	You just shed that lining and it's slowly slowly slowly building up.
00:31:21.243	00:31:36.836	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.
00:31:35.884	00:31:38.612	And again in most cases it's not.
00:31:37.708	00:31:43.316	And so, because it's not pregnant, it begins to rapidly drop that progesterone level.
00:31:42.460	00:31:46.435	Estrogen has also risen for a second peak.
00:31:45.675	00:31:56.516	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 the endometrium at the end of that cycle.
00:31:55.756	00:31:59.107	There are a bunch of things I think I want to say about this.
00:31:58.731	00:32:00.980	The first is that
00:32:01.564	00:32:11.395	You know, any point in time when you get a blood draw on a woman and you are looking at FSH, LH (luteinizing hormone), estradiol and progesterone, you have to sort of know where you are.
00:32:10.539	00:32:14.084	Now, once you do a lot of this you are pretty good at guessing.
00:32:13.324	00:32:26.468	So, it's not rocket science when you are 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.
00:32:25.564	00:32:36.307	But in cases where it gets a little bit more complicated, when women's periods are irregular, when they are approaching perimenopause, it helps to have some sense of what's going on.
00:32:35.355	00:32:43.748	And of course in the case where a woman is not menstruating at all, it tends to be pretty easy because you are going to see very high levels of FSH or LH.
00:32:42.796	00:32:49.028	Now it becomes more complicated when a woman has an IUD, and as a result of that she's not menstruating.
00:32:48.076	00:32:51.619	But I am not going to get those complex situations right now.
00:32:50.667	00:32:55.124	I just kind of want to go over the basics of the hormone system.
00:32:54.412	00:33:01.796	The second thing I want to point out, and this point has been made in my podcast before, I think if you are only coming to this now it's worth understanding
00:33:02.667	00:33:09.907	for many women what's happening between day twenty one and day twenty eight is really profound physiologically.
00:33:09.243	00:33:15.667	So, you know, we talk about this thing called PMS (premenstrual syndrome) and I think any woman who's experienced it knows it's a real thing.
00:33:14.715	00:33:23.203	I certainly can't say I have experienced it but I have to who have I have a real sense of why it's probably happening.
00:33:22.395	00:33:30.692	It's not entirely clear if it's the drop in progesterone that's driving this, but it likely is.
00:33:30.124	00:33:46.147	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.
00:33:45.387	00:34:04.963	So, for women who do experience significant and unwanted side effects of progesterone withdrawal, known as PMS, a very simple and effective way to treat it is with a low dose of progesterone that is administered starting at day twenty one to twenty eight.
00:34:04.155	00:34:06.067	So, how does that work?
00:34:05.163	00:34:16.148	If a woman 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.
00:34:15.244	00:34:19.219	typically this is done about 50 milligrams orally.
00:34:18.556	00:34:26.179	That's just taken for seven days, until she has her period, and what it does is it completely blunts this effect.
00:34:25.228	00:34:34.244	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.
00:34:33.291	00:34:35.972	So is there a drawback to that approach?
00:34:35.164	00:34:45.907	Well, from a physiologic perspective known, the biggest drawback is just the logistics of having to remember 7 days out of every 28 you have to take progesterone.
00:34:44.956	00:34:51.668	This is an entirely safe thing to do, and I have used this with a number of women in the past, it seems to work very well.
00:34:50.764	00:35:05.108	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.
00:35:04.347	00:35:11.972	But again, now, that's creating a whole new set of issues around oral contraceptives which many women simply don't want to do.
00:35:11.115	00:35:29.251	So I just point that out to say one I think when you look at a graph like this hopefully you get appreciation for what a profound level of withdrawal a woman experiencing during the end of the luteal phase, and secondly that there are lots of hormonal ways to address that.
00:35:28.396	00:35:32.708	Now, the other hormone I haven't drawn is testosterone.
00:35:31.900	00:35:34.867	i haven't drawn it for two reasons.
00:35:34.204	00:35:40.052	The first, it doesn't change that much during the cycle.
00:35:39.148	00:35:44.947	It changes a little bit, I have read a number of different studies that have looked at it.
00:35:44.235	00:35:54.692	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.
00:35:54.076	00:36:00.884	Secondly, if I were to draw testosterone to scale on this graph you'd have to look at the ceiling.
00:36:00.268	00:36:07.268	That's how much more testosterone a woman has in her body than estrogen, yes I just said that.
00:36:06.315	00:36:09.715	It sounds very counterintuitive but it's true.
00:36:09.148	00:36:22.052	A woman, 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.
00:36:21.148	00:36:24.260	It's just that it's not changing all that much.
00:36:23.356	00:36:36.164	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?
00:36:35.643	00:36:42.307	Well, her body is less able to make estradiol and progesterone.
00:36:41.403	00:36:57.139	And as estradiol and progesterone production go down, just as testosterone production goes down in a male - although it happens far less abruptly - the pituitary gland senses this because there's a negative feedback loop and it says “I want more.”
00:36:56.764	00:37:01.652	So, it starts making more FSH and more LH.
00:37:01.083	00:37:15.043	And of course the higher those go, initially the body responds and you will 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.
00:37:14.284	00:37:25.315	So, when a woman is in menopause, what you will see is no estrogen no progesterone, very high LH and very high FSH.
00:37:24.652	00:37:40.820	And so, when we initiate hormone replacement therapy - and by the way we never want to wait until a woman in that state where she has flatline estradiol flatline progesterone sky high FSH sky high LH, we want to do it long before that.
00:37:39.963	00:37:45.139	We want to do it as she's transitioning from this into that.
00:37:44.284	00:37:49.268	And that could be literally a year or two years prior to that state.
00:37:48.364	00:38:06.260	And what we are doing is we are giving her enough estradiol that her FSH usually ends up hovering around 20 to 30 again, that's still a pretty high level FSH, meaning that's still got the brain thinking…
00:38:05.356	00:38:09.764	“I want more estradiol,” but you don't need to give maximum amounts of estradiol.
00:38:08.811	00:38:11.155	We are simply trying
00:38:11.500	00:38:24.980	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…
00:38:24.123	00:38:36.452	So, estrogen being the most important hormone both in men and women, it regulates sending the signal of tension on the bone into bone building via osteoblasts.
00:38:35.692	00:38:36.835	So,
00:38:37.228	00:38:41.635	in summary that's the look at the female endocrine system.
00:38:41.260	00:38:50.275	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.
00:38:50.188	00:39:00.307	Again I think it's something that everyone needs to understand, because if you are a woman you should understand this, and frankly if you know a woman and you care about a woman you should understand this.
00:38:59.356	00:39:08.708	And it certainly would hopefully give empathy to women who are struggling during that last portion of their luteal phase.
00:39:07.804	00:39:12.307	Again, men don't have equivalent of this.
00:39:11.403	00:39:20.659	We don't have a scenario whereby we are having a tenfold reduction in a major sex hormone that occurs over the course of a week.
00:39:19.996	00:39:25.268	I think it's understandable why that can pose issues for some women.
00:39:25.179	00:39:33.476	So, in summary, I think you can see that the female sex hormones are a little bit more complicated than what you are going to see in a moment, which is the male equivalent.
00:39:33.052	00:40:07.603	But I think it's also actually a more interesting system. 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 are looking at these hormone levels, and, as a woman entering that perimenopausal period, you want to be especially attentive to the time in which you draw. Again, day 3, 4, 5 become the most important blood draws as a woman is becoming perimenopausal, because it's that FSH level at day 3, 4 and 5 that becomes your canary in the coal mine.
00:40:06.748	00:40:20.132	If that level starts creeping up and it's over 10, 11, 12, even though she's not in menopause, I am 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.
00:40:24.844	00:40:28.820	Okay, this brings us to the final hormone system
00:40:27.867	00:40:31.652	we will talk about today, which is the male sex hormone system.
00:40:32.188	00:40:37.556	This system, I think, is a little bit simpler than the female system, but it still its nuances.
00:40:36.748	00:40:53.443	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 à vis GnRH (gonadotropin-releasing hormone) that tells the pituitary to secrete LH (luteinizing hormone).
00:40:52.492	00:40:58.820	Again, if you just watched me go over the female system, you will realize we have the exact same thing happening there.
00:40:57.867	00:41:03.523	I just didn't draw of this because we had so many other complicated things to talk about.
00:41:02.668	00:41:12.692	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.
00:41:11.739	00:41:16.916	That was a bit gratuitous, but nevertheless the testes have different cells in them.
00:41:16.539	00:41:21.907	Sertoli cells and Leydig cells. The testes make testosterone.
00:41:21.052	00:41:29.923	Now, there's a little more complexity to this, that I will come back to a moment, but let's just start with the fact that the testes are making testosterone.
00:41:29.547	00:41:34.724	We should also point out that testosterone is mostly bound.
00:41:33.820	00:41:40.820	So, just as I discussed with cortisol, most cortisol is bound, so is most testosterone.
00:41:39.916	00:41:47.780	It's primarily bound to two hormones, sex hormone binding globulin or SHBG, and albumin.
00:41:47.500	00:41:58.291	But a relatively small amount, and it depends how much albumin SHBG you have, remains free, so we call that free or unbound testosterone.
00:41:57.387	00:42:08.755	And it's anywhere from 1 to 3 percent of the total testosterone. Now, there are two things that are siphoning testosterone away that are very important.
00:42:08.284	00:42:18.931	The first is 5-alpha reductase, the same enzyme we talked about back when we were going over cortisol. It's siphoning off of that testosterone to make dihydrotestosterone.
00:42:17.980	00:42:25.268	Now, not huge amounts, sort of, you know, a couple of percent but dihydrotestosterone is a very important sex hormone.
00:42:24.364	00:42:36.500	In fact, it has anywhere from 2 to 10… Some studies would suggest even higher potency, 2 to 10 x potency for the androgen receptor than testosterone.
00:42:35.547	00:42:46.099	So, I am going to talk about the androgen receptor in a minute, but I just want you to keep in that DHT (dihydrotestosterone) has a much higher binding affinity for the androgen receptor than testosterone does.
00:42:45.628	00:42:53.972	The other thing that is siphoning off testosterone is the aromatase enzymes that are converting testosterone into estradiol.
00:42:53.115	00:42:57.715	Yes, that's the very same estrogen that women have as well.
00:42:56.764	00:43:00.884	And estrogen turns out to be a very important hormone for men.
00:42:59.980	00:43:12.068	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.
00:43:11.403	00:43:25.603	I will 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.
00:43:24.748	00:43:46.820	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, I have drawn it here, and I realize that there's going to be some purists out who says oh my god you forgot to mention this!
00:43:46.012	00:43:57.619	Yeah, so it turns out that the hypothalamus does not have overwhelming number of androgyne receptors, so this is not happening directly but rather indirectly.
00:43:56.715	00:44:03.476	Testosterone is inhibiting a slightly different neuron that is then speaking to the hypothalamus.
00:44:02.572	00:44:07.027	But I think for the purpose of this discussion this is sufficient.
00:44:06.748	00:44:14.132	The only thing to point out is that estrogen also inhibits luteinizing hormone secretion via the pituitary.
00:44:13.563	00:44:29.539	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 have learned so far in the normal functioning system.
00:44:29.211	00:44:33.284	GnRH tells the pituitary to make LH and FSH.
00:44:32.331	00:44:35.300	They tell the testes to make testosterone.
00:44:34.588	00:44:38.036	Small amounts of that are siphoned off to make DHT (dihydrotestosterone).
00:44:37.132	00:44:39.668	And even smaller amounts
00:44:38.764	00:44:44.947	i.e. less than one percent are siphoned off to make estrogen, and the system in perfect balance.
00:44:44.139	00:44:50.900	Now, how much of that testosterone is actually exerting its biologic effect on the androgen receptor?
00:44:50.043	00:44:58.579	Well, it turns out very little is, because I said you have this thing over here, SHBG (sex hormone binding globulin) 
00:44:58.923	00:45:00.931	plus albumin
00:45:03.675	00:45:14.036	and it's soaking up most of the testosterone, so that really the free testosterone, which is the biologically active
00:45:14.235	00:45:20.516	represents only about one to three percent of total testosterone.
00:45:19.612	00:45:22.148	But the good news is that's all you need.
00:45:21.244	00:45:24.019	This stuff's pretty darn potent.
00:45:23.500	00:45:32.708	Testosterone binds to an androgen receptor, DHT also binds to an androgen receptor.
00:45:31.900	00:45:41.731	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.
00:45:40.827	00:45:42.884	Okay.
00:45:43.083	00:45:52.291	Now, we are going to talk about a subject that is way more complicated than I think people are being led to believe it is, and that's testosterone replacement therapy.
00:45:53.596	00:46:04.436	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”.
00:46:04.108	00:46:13.507	And the reason for that is when you are measuring total testosterone you don't really know what the free T is.
00:46:12.652	00:46:16.579	The free T is a calculated lab value.
00:46:16.204	00:46:21.668	So they don't really measure free T by most lab assays.
00:46:20.956	00:46:22.675	They measure
00:46:22.876	00:46:28.003	total testosterone, they measure SHBG and albumen and they calculate free T.
00:46:27.628	00:46:31.219	But let's assume that the calculation is fairly accurate.
00:46:30.315	00:46:34.867	And, even if you don't rely on a lab to do that calculation,
00:46:33.963	00:46:37.123	There are calculators online that can do that for you.
00:46:36.172	00:46:41.876	So let's say you now know the free T, and we will talk about what some ranges are in a moment.
00:46:41.164	00:46:45.956	The question becomes: is the patient's low level?
00:46:45.052	00:46:52.675	Because, let's just say, they are at the thirtieth percentile for what their level is, does that explain their symptoms?
00:46:51.916	00:46:57.043	Well, it's not entirely clear because what we don't know is what's happening here.
00:46:56.764	00:47:18.260	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 are treating symptoms but we are using numbers as a guide to do so.
00:47:17.596	00:47:37.507	So, the most common symptoms, of actual low testosterone, of androgen deficiency, in no particular order because they are going to vary significantly by men, would be low libido, erectile dysfunction, low mood, difficulty putting on muscle mass, and insulin resistance.
00:47:36.940	00:47:39.235	Those are the big ones that I see.
00:47:38.331	00:47:43.123	Now, there are others, to be sure, but those are really the big ones.
00:47:42.364	00:48:00.164	And we know from clinical trials that when you give a group 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.
00:47:59.835	00:48:02.083	We know that mood improves.
00:48:01.179	00:48:13.748	We know that a whole bunch of factors move in the right direction, but despite of that I am still pretty cautious when giving testosterone, because I think it an overused hormone.
00:48:12.844	00:48:30.164	I think too many people are being given testosterone, and they probably don't need it, because they are 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.
00:48:29.260	00:48:33.380	So we have to really treat based on symptoms.
00:48:32.523	00:48:35.059	Now, what are the treatment options?
00:48:35.788	00:48:39.715	There are, broadly speaking, two ways to think about this.
00:48:38.860	00:48:43.603	The first is a direct way to do it, which is giving testosterone,
00:48:42.652	00:48:45.907	and this can be done in many formats.
00:48:45.867	00:48:52.387	The most common formats would be topical testosterone or injectable testosterone.
00:48:51.436	00:48:54.403	But there's also intranasal formulation.
00:48:53.596	00:49:06.500	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.
00:49:05.596	00:49:13.603	The first of these is something called hCG (human chorionic gonadotropin), and hCG is a mimetic of luteinizing hormone.
00:49:12.748	00:49:22.628	So, injection of hCG will tell the body to make testosterone, just as you were giving luteinizing hormone.
00:49:23.068	00:49:28.291	There is also a synthetic FSH it's far more expensive and it's virtually never used.
00:49:27.628	00:49:57.668	So, the typical use case for synthetic FSH 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 -
00:49:56.715	00:50:00.403	so we should make sure we never lose sight of that.
00:50:01.228	00:50:08.516	The other way to do this is to give a drug that has become very popular, called CLOMID.
00:50:07.612	00:50:15.331	CLOMID, or clomifene, is a drug that has been used historically by women using it for fertility purposes.
00:50:14.476	00:50:27.860	And what CLOMID is doing is effectively tricking the brain via stimulation of GnRH, by blocking the estrogen receptor,
00:50:28.108	00:50:42.356	to make more LH and FSH. Now, the reason I am 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
00:50:41.452	00:50:44.516	and that turns out to be a negative thing.
00:50:43.804	00:50:52.052	It turns out we want the feedback of estrogen in the brain because it has many beneficial effects on mood.
00:50:51.291	00:51:19.556	And there are some men who, actually, when they are on clone, even though their testosterone levels soar, don't feel any better. We wonder if, in fact, that's because of clone, so not every man. There are some men that are on clone and feel great on it, but 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.
00:51:18.652	00:51:21.907	This is a very potent feedback loop.
00:51:22.251	00:51:29.684	When you give testosterone these hormones will go up. Now, they go up depending on a number of factors.
00:51:29.307	00:51:33.572	5 alpha reductase has quite a strong genetic component.
00:51:32.668	00:51:40.244	So, some men are very strong 5 alpha reductase producers, and they are going to make a lot of DHT (dihydrotestosterone).
00:51:39.387	00:51:45.092	By the way, this is responsible for one of the side effects of testosterone which is hair loss.
00:51:44.380	00:51:56.804	So, a lot of hair loss is driven by DHT and the androgen receptor, and therefore if you are susceptible to that and you give testosterone and you make more DHT, you are going to accelerate hair loss.
00:51:56.715	00:52:17.827	Similarly, aromatase activity varies genetically, but 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.
00:52:17.596	00:52:21.619	Are there side effects of having too much estradiol?
00:52:20.764	00:52:31.652	Yes, there are, at some point estradiol levels can become counterproductive, and of course if they get very high - although I have never seen a case of this in ten years of prescribing
00:52:30.844	00:52:36.692	testosterone - we can see gynecomastia, so that's when a man will develop breast tissue.
00:52:35.884	00:52:45.572	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.
00:52:45.195	00:52:53.923	But if estradiol levels do get a little too high, they can be managed with a drug that blocks that conversion.
00:52:53.547	00:52:56.516	The drug is known as Anastrozole.
00:52:55.851	00:53:03.523	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.
00:53:02.619	00:53:12.403	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.
00:53:11.500	00:53:30.980	So we will typically not use Anastrozole, unless the estradiol level 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,
00:53:30.315	00:53:39.427	i.e. free testosterone needs to be relatively low, at least below the fiftieth percentile, and there needs to be, more importantly, a symptomatic case for it.
00:53:38.572	00:53:48.260	If both of those conditions are met, and of course the patient understands the risks and benefits, we would give treatment for a period of eight to twelve weeks.
00:53:47.452	00:53:57.956	We would determine that we have fixed the biochemical issue, so they go from being at, say the thirtieth percentile, to being at the eightieth percentile, and then we assess the symptoms.
00:53:57.052	00:54:00.452	And sometimes the man says I don't feel any better.
00:53:59.835	00:54:03.907	So, you have fixed the number but you haven't fixed the symptoms.
00:54:03.003	00:54:09.764	And with very few exceptions, at that point, I would say it doesn't make sense to continue this, we should stop doing it.
00:54:09.099	00:54:13.795	Now, one exception to that would be if you were doing it for bone health.
00:54:12.891	00:54:21.380	So, if a man has osteopenia and he has low estradiol and low testosterone, we don't really care about symptoms at that point.
00:54:20.476	00:54:33.139	We want his testosterone high, we want 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.
00:54:32.331	00:54:44.228	But for most men we care about the symptoms more than we care about the numbers. 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?
00:54:43.275	00:54:45.235	Oftentimes they don't.
00:54:44.380	00:54:47.635	And again I can't answer what's going on there.
00:54:46.684	00:54:59.204	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 that they have in the first place. Right, so there you have it…
00:54:58.396	00:55:04.195	That's sort of the quick overview of the male sex hormone system.
00:55:03.820	00:55:11.780	I think this system has its own nuances and complexities vis à vis how to make the diagnosis, and then of course how to treat it.
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