Unveiling the Hidden: Exploring Post-Traumatic Growth Hormone Deficiency

In this enlightening podcast episode, Dr. Richard Batson and Dr. Joshua Goldenberg delve into the often-overlooked consequences of traumatic brain injuries, specifically post-traumatic growth hormone deficiency (GHD). Drawing from their extensive research, Dr. Batson provides valuable insights into GHD's symptoms, diagnostic hurdles, and the crucial necessity for specialized testing to enhance the well-being of TBI patients. Together, they navigate through the intricate landscape of GHD, discussing its deceptive symptom overlap with other ailments and its prevalence across all severities of brain injury. They emphasize the significance of precise diagnosis, provocative testing, and the potential involvement of autoimmune responses in GHD development post-TBI. By illustrating the enduring impact of untreated GHD through the 'five B's' - body composition, bone density, blood health, brain function, and overall well-being - they underscore the importance of adhering to established standards of care. 

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Chapters

• 2:00 Understanding Post-Traumatic Growth Hormone Deficiency
• 14:23 Understanding Growth Hormone Deficiency Post-Tbi
• 18:14 Growth Hormone Deficiency in Brain Injury
• 32:02 Challenges in Diagnosing Growth Hormone Deficiency
• 38:34 Unique Approach to Brain Injury Forensics
• 48:19 Growth Hormone Deficiency After Brain Injury
• 1:02:07 Challenges in Growth Hormone Diagnosis

Transcript

Introducer: 0:02

Welcome to the Brain Injury Forensics Podcast presented by Brain Injury Research Solutions, a forensic services and contract research organization. Join Dr.'s Richard Batson and Joshua Goldenberg as they interview nationally and internationally renowned experts and dive into the latest developments in brain injury forensics, applied medical research, state-of-the-art forensic methodologies, gold standard advanced neuroimaging and numerous brain injury related medical topics.

Dr. Goldenberg
 Co-Host  0:37

This is just a reminder before we start that while we are doctors and have advanced training in forensic medical science and forensic epidemiology, and we will be discussing topics that involve medicine and the law, the information in this podcast is not medical, legal or other professional advice, and this podcast is provided for informational and educational purposes only. You should not rely on anything you hear as a substitute for medical care by a physician or other qualified medical professional or legal advice from a licensed attorney. Always consult with your physician or other qualified medical professional for medical advice and an attorney for legal advice. 

Hello everyone and welcome to the Brain Injury Forensics Podcast. This is your hosts, Dr. Goldenberg and Dr. Batson, and today I have Dr. Batson on the line and we are going to talk about post-traumatic growth hormone deficiency. So welcome to another Brain Injury Forensics Podcast.

Dr. Goldenberg
Co-Host: 1:36

Dr Batson, are you ready to go? I'm ready to go. Let's do it. All right, let's do it. So I guess my first question is I mean, there's a lot of nitty gritty with this and a lot of content that I think we're going to get into here, but the first question I have. So my understanding is you've done a lot of your dissertation work around this topic and I was thinking about our conversation today and I guess on a personal level I was just kind of curious like where did your interest in this specific topic? I mean, I know you've been interested in post-concussion and post-TBI sequelae for a while, but where did the fascination in this particular area come from? What led you to focusing on that in your dissertation work?

Dr. Batson:
Co-Host: 2:21

Yeah, it's a really good question. So let me kind of give some framework. So we're talking today about acquired growth hormone deficiency that occurs after traumatic brain injury. This is very different than the growth hormone deficiency most of us think of, which is childhood onset, and maybe we had a friend or something in high school or in grade school or whatever that wasn't growing and then they went to a pediatric endocrinologist and they received growth hormone treatment and they started to grow and they started to develop. In fact I remember a kid like that in my school who was kind of small and then he became the best wrestler and he was kind of kicking everybody's butt afterwards.

But that's not what we're talking about. We're talking about trauma to the brain of any severity, ranging from concussive brain injury all the way up to severe traumatic brain injury. That basically disturbs the function of two particular endocrine structures at the base of the brain the hypothalamus and the pituitary gland, and so we talk about those collectively as the hypothalamic pituitary axis essentially, and it can lead to a number of hormonal deficiencies which we broadly refer to as post-traumatic hypopituitarism. In the context of TBI we'll say traumatic brain injury related hypopituitarism or neuroindifferent dysfunction. So you'll see it in different places in the literature. So that's what we're talking about, and there are seven different possible hormonal aberrations that can occur after a brain injury, and one of them is growth hormone deficiency, which has become my primary area of research. You're correct, I did it. My dissertation work was on the entire set of conditions collectively referred to as post-traumatic hypopituitarism.

4:06

But within that I had a focus on post-traumatic growth hormone deficiency, and one of the reasons is it tends to be under diagnosed and under recognized and it can present with very subtle, sometimes in non-specific, signs and symptoms after brain injury that can be confused with other sequelae or aftermath of the brain injury and so it doesn't get diagnosed. So people can walk around with it for years, sometimes even when they've seen an endocrinologist, they haven't undergone the specialized diagnostic testing they need to confirm the condition.

4:39

And I got interested I was working in brain injury medicine in a multidisciplinary environment and just in the course of seeing hundreds of brain injury patients, people were coming in with hormonal deficits and sometimes they've been treated by a general endocrinologist or an endocrinologist and at that point I just started to dig into the literature in an informal way, made contact at one point with one of the top world's experts in the area, dr Kevin UN, down at Barrow Neurological Institute.

5:15

He was in my area, Seattle at the time, and tried to learn as much as I could about the subject and became pretty fascinated with it, after which I did a very long dissertation I think it was over 200 pages on the subject of post-traumatic hypotetrism with a focus on growth hormone deficiency, and I continued to research that. So I'm a research collaborator with the University of Texas Medical Branch where we continue to research growth hormone abnormalities a little broader than the classical growth hormone deficiency, and we've had clinical trials treating growth hormone deficiency and growth hormone aberrations that don't technically meet the classical definition of growth hormone deficiency with good effect. So that's how I became interested and I just continue to work as a researcher in that environment, as a clinician and, of course, in the medical legal space. We have individuals who have been injured and have open litigation, some of which develop adult onset, acquire post-traumatic growth hormone deficiency and need to be treated, and I'm sought after for consulting in that area because of my dissertation in ongoing research, gotcha.

Dr. Goldenberg
Co-Host: 6:27

Does that make sense? Yeah, it does. Let's drill down a little bit because I want to understand this more and also to kind of keep it on a 30,000-foot view a little bit, because I'm assuming a lot of our listeners are not going to be neuroendocrinologists or focus on this, but in general and this helps because I know very little about this, certainly compared to you but also in general, so I'll help the dear listener by keeping it at this 30,000-foot view. So, basically, what I'm envisioning here is you've got this very delicate brain structure in particular. In particular, you've got this delicate pituitary which is responsible for making all these hormones, and you have this injury to the brain.

7:08

So are we talking about a just to back way up? Are we talking about like a physiologic element, biochemical damage to the pituitary that is leading to this, or is it like downstream effects or Inflammation from the TBI that's then messing with the two? I don't like what are? Is it direct injury that we're talking about here? And and then also like do these, are these structures that can bounce back, or is it just like, like it's just so delicate, it's gone, it's gone?

Dr. Batson
Co-Host: 7:36

Yeah, it's a really good question. And so you've got. You've got basically two endocrine structures. You've got the hypothalamus, above the pituitary it's connected by a stalk and the pituitary gland you can think of them collectively as the master Endocrine glands that are responsible for Stimulating the production and secretion of peripheral hormones like cortisol from the adrenal glands or thyroid hormone from from from the thyroid gland and so forth.

8:02

So, basically those structures are very small and delicate. So the pituitary is about the size. If you've ever seen a garbanzo bean or a chickpea, it's about that size or the tip of a pinky. So it's a very delicate structure. The pituitary in particular sits inside of a hard bony structure called the senoid bone in what's called the Turkish saddle or Celatursika, and what can happen is Due to particularly the coup contra coup injuries or acceleration deceleration injuries, for example in motor vehicle collisions.

8:33

There can be there can be stretching of the stalk or Disruption, disruption of the blood flow system that brings blood flow as well as hormones to the pituitary. We have some some some fancy words for that, which I won't drop on the reader, but essentially one of the hypotheses is is a vascular hypothesis, which is, after the injury, these tiny little vessels that bring blood and hormones to the pituitary gland are Disrupted or damaged in some way and you get a kind of a schemia or a loss of blood flow and associated oxygen, nutrients and hormones, and so that's the ischemic hypothesis or the loss of, or the vascular Hypothesis.

9:14

What can also happen is pressure effects as well. So you get things like in more severe traumatic brain injuries, get cerebral edema, increased intracranial pressure and that can put downward pressure on to the pituitary gland and then the cells can get damaged that way.

Dr. Goldenberg
Co-Host: 9:29

So there's a number of different. Now, yeah, go ahead. Well, I'm just, I'm just envisioning this little garbanzo bean in surrounded by this hard shell, and so Is that. Is it particularly Sceptible to that pressure? Just because, like there's nowhere for it to? Well, I guess I could hemorrhage out on top. But like is that, or just anywhere in the brain could be, could be damaged by the sort of edema that would result.

Dr. Batson
Co-Host: 9:55

It has to do with the surrounding anatomy generally, with an increase in intracranial pressure there's a downward push on to the pituitary gland, so it gets kind of smashed down and and there's pressure effects on it and it can lead to something called empty cell or partial empty cell. For for some view that Listening that may may know about that. But the other one, that's the more fascinating thing, is a recent mouse model that they did that from Osterstock back in 214, where they, they, they have a paradigm called controlled cortical impact or controlled cortical injury in mice and they, they give a, a, an exact amount of Impact at the Bragma which is at the roughly at the top of the head, a little indentation if you go back two or three inches from your hairline, and this causes selective, isolated growth hormone deficiency.

Dr. Goldenberg
Co-Host: 10:47

Consistently with no other deficiencies.

Dr. Batson
Co-Host: 10:50

And so they figured out really, yeah, yeah, they figured out that there's, that the pressure effects, basically the downward pressure from this point through the ventricular system, which hold the cerebral spinal fluid inside of your brain, puts a downward pressure, and what it does is it? It targets the energy or transfer of force to the bottom part of the hypothalamus, in a select group of cells that are called growth hormone, releasing hormone cells, and it's a little area called the arcuate, new nucleus and the median eminence, and that is the signaling hormone to the pituitary to produce and secrete growth hormone.

Dr. Goldenberg
Co-Host: 11:28

But what they found in that study was there was no damage to the pituitary and there was no damage to the stalk.

Dr. Batson
Co-Host: 11:34

There was no damage to the rest of the hypothalamus, only to this bottom layer of the hypothalamus where the growth hormone releasing hormone cells Basically produce and secrete this signaling hormone. And so that's kind of changed the way we look at it, because it's you know.

11:50

It's that's crazy, yeah, yeah it's pretty, why it's pretty wild, yeah, and so most of the hypotheses before have been focused on the pituitary and saying, oh, it's in this little hard, hard bony structure we call the Turkish set, turkish saddle, inside the sphenoid bone and it must be the pressure effects or disruption of blood flow. And this, this mouse model, and this was concussive brain injury. It wasn't enough to cause gross anatomical Injury of the brain, so it would parallel a simple concussion, a mild, uncomplicated TBI, which we've talked about Perhaps in other podcasts. So not a significant brain injury but leads to a significant efficiency of isolated growth hormone efficiency.

Dr. Goldenberg
Co-Host: 12:30

That isolation pieces is just so fascinating. So, clinically, are you like, do you see that I would imagine that almost always All these Deficiencies go together after a brain injury? But are you clinically, are you seeing this sort of isolated growth hormone deficiency Like relatively commonly?

Dr. Batson
Co-Host: 12:46

Well, it's not clinically what I see. We have 20 plus years of epidemiological research Validating that, and so we have. We have lots and lots of papers on this, peer-reviewed publications, and so so isolated growth hormone deficiency is in fact the most common form of hypopatuiturism. You can get any. You can get any group or cluster if you knock out the entire pituitary. We call it panhypopatuiturism and you get all of the hormonal deficiencies that's.

13:13

That's less common, except in very severe traumatic brain injury I've seen it where the sphenoid bone has been fractured in multiple places and that type of thing. But epidemiologically, when you look at the population literature, isolated growth hormone deficiency is the most common and it's it's been thought it has to do with the location of the growth hormone cells in the pituitary, which sit on the outside of the pituitary, called the lateral wings, and they have a Limited blood supply, whereas other cells inside of the pituitary are more privileged. They're in the center and they also have a posterior blood flow that comes, come is shared with the back, the pituitary gland. So for for many years the leading hypothesis has been the vascular one at the pituitary level.

13:54

It wasn't till Osterstock and the mice model came along that that we thought well, maybe there's something entirely different, and it's not at the pituitary level at all.

14:04

But we don't have a lot of easy ways to research that clinically sure to be able to determine Is it happening, you know, is it happening at the level of a hypothalamus Above the pituitary, where the signaling hormone, growth hormone releasing hormone, is, is not working right, or is it happening at the pituitary level, or is it happening at both? And none of our diagnostic tests that we use, which we'll talk about, easily differentiate between those two areas. There's one that that bypasses the hypothalamus. So technically, if you pass that test and then I did another one that doesn't bypass and failed that, we would assume that it was at the level of the hypothalamus. But from a clinical perspective, differentiating between the two doesn't really matter because the treatment's the same. The treatment is yeah, we're competent human growth hormone, which is essentially synthesized in a lab.

14:52

Yeah, and then given as a night nightly injection and more recently we have a long-acting version that's given as a, as a, as a weekly injection. But essentially, you know the kind of, you know how it's happening. Why it's happening is going to be an area of ongoing Debate, probably, you know, into the into the next decade or so, if not longer, sure, and less, we can create more of these models where, with controlled cortical injury or, have you know tests specifically that help to differentiate, that are deployed more frequently.

Dr. Goldenberg
Co-Host: 15:23

Yeah, and to your point it probably it may not make much pragmatic difference for a patient. I just find it fascinating that you can have this sort of like targeted impact on Growth hormone production in particular. But okay, so let's keep, let's take it out of sort of the, I guess, anatomic issues and circulatory issues here. So you get, you have a concussion, a tbi, mild tbi, some sort of insult to the brain. You can have these isolated or not isolated Impacts on on growth hormone production.

15:51

You know one thing you mentioned in terms of you know your interest isn't that, it was, it's. It was missed a lot, it was misdiagnosed and so like, let's talk about that for a little bit. I know you said that the, the symptomatology, can you know, kind of overlap with other things, so sometimes missed. You know what are, what are your? Is there anything else going on that leads this to be missed? Is it harder to visualize, like from a radiologic perspective? Why is this missed? Is a testing that difficult? I mean it sounds like. If it's such a relatively common thing that can happen and let's talk a little bit about how common this is why is this a misdiagnosis and how long does it take until patients and individuals at least, haven't understanding about what the heck's going on and why.

Dr. Batson
Co-Host: 16:38

Right, right, it's a really good question. So there was about a seven part question. You realize that.

Dr. Goldenberg
Co-Host: 16:43

So let me let me, let me, let me, let me, gonna test your cognitive abilities to go through them.

Dr. Batson
Co-Host: 16:49

Yeah, yeah, and I, and you know, one of the things I think we get we'll get out of the way is sort of the epidemiology or the population data, which is well, how common is this particular disorder? And it ranges greatly within the population literature and again, when we use the word epidemiology we're assuming some people have listened to prior lectures, that's simply the, the study of exposures and outcomes, to keep it very, very simple on a population level.

17:15

So we look at lots of people that have had traumatic brain injury and then we say how, how often did they develop growth hormone deficiency or other hormonal deficiencies? And that gives us what we call prevalence data. And so the prevalence data is is is wide ranging and some of it has to do with, you know, different tests that are used, different diagnostic tests that have different diagnostic cut point thresholds, different severities of TBI. But the first systematic review that I'm aware of that came out in 2007,. Across all all severities of TBI mild, moderate, severe was 12% for growth hormone deficiency 12% across all TBI severities.

17:56

Severities yeah.

Dr. Goldenberg
 Co-Host: 17:57

Wow, so that that's surprisingly high and you don't see. It's also interesting that you don't see, like for seizures, for example, like the more severe, you see this dramatic step up in risk, you know, as you go from mild, moderate to severe TBI, but we don't see this with growth hormone. That's interesting.

Dr. Batson
Co-Host: 18:13

Yeah, now now the other. The other really high quality systematic review was Lossier, published in both 2012 and 2014,. And growth hormone deficiency was higher than that, was 16, I wanna say 16.6%, and I think the range was anywhere from seven to 28. So that was the confidence interval. So it could be as high as almost 30% in Lossier's systematic review.

Dr. Goldenberg
Co-Host: 18:38

And what I like about.

Dr. Batson
Co-Host: 18:39

Lossier's work is they controlled for risk of bias and was low risk of bias. So that's really a higher quality study than Schneider study, and then later on, silva in 2015 published sort of one of the first studies on mild traumatic brain injury related growth hormone deficiency in uncomplicated mild TBI. We've talked about the difference, but a lot of the older studies that give prevalence data on mild TBI include complicated and uncomplicated and that's probably beyond this lecture to get into that.

19:12

People can look it up if they don't know the difference but essentially complicated mild TBI's there's greater bio-mechanical forces and so we would expect it to be higher if you include cohorts of complicated mild TBI. But Silva's paper came out to about 10% for mild TBI, about 21% for all severities of TBI. And then there's, of course, our data from our group, which we are presenting as a poster abstract this year and then publishing hopefully by the end of 2024. And I think we've got the largest cohort of mild TBI that we know of between our facilities and that's an uncomplicated mild TBI, simple concussion, and it's come back at about 18%, with the following caveat you need to have had post concussion symptoms, what we sort of call PCS or post concussion syndrome, classically.

20:09

But you need to have ongoing chronic post concussion symptoms at 12 months or greater. And then you go to an endocrine specialty center, right, and then it comes back at around 18%, which is roughly one in five. Now that's a selected population, right. That's high, yeah. And people that are recovering from concussion and move on and some do, that's not so that's not gonna represent the exact prevalence across an entire population of people who got a concussion, but anybody that has chronic symptoms and does is not recovering. Roughly a one in five chance of having growth hormone efficiency using strict, widely accepted diagnostic cut points, according to the American Association of Clinical Endocrinologists in American College.

Dr. Goldenberg
Co-Host: 20:54

So you're like blowing my mind that it's this common, right? So basically, yeah, if you get a concussion and most people recover pretty well, you're great, awesome move on. Many people don't. And you're saying if you had a concussion or other brain injury and you're not recovering well, your data and other data is suggesting like up to one in five of those folks may have this really significant neuroendocrine disorder, which is really surprisingly high to me, even from like concussion, like one in 10, that's a high number. So I guess I've got a zillion questions. But to break it down a little bit and parse it like, if it's that common, I guess my first question is why is it so frequently missed as far as diagnosis Like that? I guess that's the first thing. Is it just hard to diagnose? Is that the thing?

Dr. Batson
 Co-Host: 21:42

Well, yeah, I wanna talk about that, but I wanna also talk about a couple other things as a setup.

21:48

Okay, so the setup is you can have delayed onset growth hormone deficiency, and that's why we accepted within the scientific community involved in this type of research, and we're not sure why it could be a slow ischemia, meaning you lose blood flow and it takes a while for the cells to lose their function.

22:06

So that's one hypothesis. There's also an emerging autoimmune hypothesis, and so there's been research, particularly out of the Istanbul group, on in boxers and martial artists in particular, but using anti-hypothalamic and anti-patuitary antibodies, which are tend to be much higher in those with confirmed growth hormone deficiency and hypopatuitarism. And so what we think is happening there is that, as you know, autoimmune diseases take a while to evolve and take hold, and so that it may be, in fact, that the immune system is launching an attack on the pituitary and that could be due to sort of leaky. There's structures around the pituitary that are immunoperative, relaged, particularly the hypothalamus, and you've got a. It's separated by a sort of a diaphragm-like structure and surrounded by cerebral spinal fluid, and as there's stress of that particular area, we may get sort of a leaky, leaking sort of like a blood-brain barrier leak, whereby the-.

Dr. Goldenberg
Co-Host: 23:07

Yeah, leaky brain, I've heard it called yeah, yeah, exactly.

Dr. Batson
Co-Host: 23:11

And so at that point then, the body develops it sees it as an invader, if you will, and recognizes it as something different from the human body, and then creates antibodies against it, which then attack the hypothalamus and or pituitary.

Dr. Goldenberg
 Co-Host: 23:25

So that's an evolving that's amazing, yeah, and that's.

Dr. Batson
Co-Host: 23:28

You know there's ongoing research in that area, so that could be. But what we know from population data is it can be. You know there's a delayed onset in a fair number of individuals, meaning you test them at three months or six months and they're negative, and then at 12 months they're positive. Now people recover as well, and so you can have people that are positive at three to six months and they recover by 12 months, or they're positive at 12 months and they recover a little bit later, and we don't really have a good way of predicting that in terms of prognosis. So it's just a matter of there's some level of surveillance and endocrinology around it, meaning if we tested somebody at six months and that's no longer recommended and they were positive, we would do surveillance before we would treat them with growth hormone because they have the chance of recovering at 12 months or 18 months, and so they're recommend but they could also be negative but then develop it after six months.

24:24

Yeah, yeah, and the Turkish group actually published data showing of late cases, as late as five years. So there were individuals who were normally three years and then abnormal at five years. And we have another condition called She-Han syndrome, where that's well-recognized.

24:40

She-Han syndrome is a postpartum pituitary necrosis that happens in females who hemorrhage during or after birth and the pituitary gland loses blood flow as a result of shock, essentially, and hemorrhagic shock, and the pituitary is already enlarged during pregnancy and essentially they have all these interesting delayed hormonal deficiencies far, far out that are fairly well studied, and so we already have a parallel model to understand that it's plausible that you could have late, late onset growth hormone deficiency, which means here's the problem you go to an endocrinologist who's reading the guidelines and says, okay, I'm gonna wait until 12 months to test you, and they test you at 365 days and say you don't have it, and then a year or two later you do.

25:34

So it used to be thought that we're just gonna test you once and around the year mark, or, if you come in later than a year, 18 months, and then if you're negative, you're done for life, and that's not a good idea. So it's a good idea to. For those of us that are in the research and know the literature, the science does not suggest that that's necessarily the best clinical approach, and so if somebody's not getting better and the way we usually approach, it is okay. You're negative at 12 months and you got all this other white noise that we'll talk about in concussion of non-specific symptoms, and you're treating all the other stuff, but then there's still stuff that doesn't get better, where you may wanna retest them again at two years or three years, and so that's the approach that we use clinically.

Dr. Goldenberg
Co-Host: 26:19

I mean that is so fascinating. Oh my gosh, so that's so fascinating. So first of all I find the autoimmune hypothesis fascinating because, as you know, my clinical area of expertise is small intestinal bacterial overgrowth and irritable bowel syndrome. And the post-infectious hypothesis, like post-infectious IBS, is like a well-described phenomenon where you have some insult, some foodborne illness. You kick it out, like the insult's done, your brain recovers, right, but you create these antibodies and then six months, 12 months later you start developing these IBS like symptoms. So I just find that absolutely fascinating. It's the same idea leaky gut, leaky brain, like there's a parallel, there's a parallel idea there. Anyway, absolutely fascinating.

27:00

Now the other thing is diagnostically I can now understand, based on your setup, why this can be missed, right. So you have a brain injury, you get concussion, you have all these amorphous symptoms. You know everyone's trying to work you up and figure out what's going on and this they're not getting better. And as part of the workup, you know you do growth hormone testing, whatever, and comes back negative. And now you just I see diagnostically the cognitive bias there. We try to sort of talk about some of these diagnostic biases. You just kind of hang your hat on that negative diagnosis and you say well, these sort of amorphous, generalized symptoms must be from something else. And I can see how it wouldn't. It would be the rare, impressive clinician unless they were a neuroendocrinologist and was very aware of this that would go back to the drawing board and retest six months, 12 months later, right, so that that from a clinical perspective, that really fits for me as to why this can be missed so often yeah, and let's reinforce that and break that down and augment that.

Dr. Batson
Co-Host: 28:02

So you know, the first principle is fog of concussion, meaning when you've had a concussion and you're not getting better, there's a lot of white noise. There's many different symptoms that overlap and could be due to different causes, and so that's what we call non-specific symptoms.

28:16

It's a chest pain right it'd be a heart attack, could be gastroesophageal reflux, except could be pleuritis. But you take any any kind of symptom in medicine where you've got symptom expression but you're not sure what the cause is, because there are diverse possible causes, fatigue being probably the best example of a non-specific symptom that could be just about anything. And so you've got these non-specific symptoms that you're not necessarily going to link to growth hormone deficiency.

28:42

Now some of the other deficiencies are, have some more specific symptoms than growth hormone deficiency and they're not totally specific. But you know, when a when a male completely loses his libido and erectile, this erectile function, you start to really suspect testosterone deficiency of pituitary origin, which is one of the deficiencies. Second most common deficiency in males is to lose testosterone um, so that that's a little bit more specific when you get sort of the classical erectile dysfunction, loss of sex drive, that kind of thing.

Dr. Goldenberg
Co-Host: 29:15

I could see that being worked up pretty, pretty straightforwardly.

Dr. Batson
Co-Host: 29:18

Yeah, right, but with growth hormone deficiency we'll talk about some of the symptoms of untreated growth hormone deficiency and it. You know you're not going to see it right away. And there's some. There's some objective things you know, like loss of bone mineral density, changes in cardiovascular function and other objective parameters that evolve slowly over time. So you're not going to catch those. You're going to catch those quickly. So we have sort of the fog of concussion or the white noise surrounding the concussion. That's number one. Number two is most of most primary care doctors are not familiar with hypopatuitorism, much less post-traumatic growth hormone deficiency.

29:53

So it's rare to even get a referral to, into an endocrinology or endocrine specific practice. And then there is the moving, the evolution of the disease, meaning delayed onset or resolution, or you know, you're positive, negative and and so forth at different points in time. So not even if you do make it to an endocrinologist and they do run one of the approved diagnostic tests and we'll talk about that in a minute you might have a negative finding meaning you don't have it. You pass the test and you move on and you never, it's never evaluated.

30:30

Now there's a bigger problem inside of endocrinology that all listeners need to be aware of, and I'm hoping this podcast won't be not just for litigators but also for the general public, I think because there's a lot to learn about this, which is diagnosing growth hormone deficiency, is a little more complex than some of the other deficiencies, and I want to explain that because it's one of the reasons why growth hormone deficiency is overlooked, even in endocrinology practices. So when we're talking about some of the deficiencies, like testosterone, central hypothyroidism, which is again hypothalamic, pituitary basal thyroid adrenal insufficiency is is is another one, but it also requires some advanced testing. But a number of the deficiencies can be diagnosed off of simple what we call basal lab work.

Dr. Goldenberg
Co-Host: 31:21

So this is static lab work that's done under normal physiologic conditions you go to lab core, you get a blood draw, you get your answer to the thing yeah, most, most, most commonly in the morning, ideally around 8 am, and that's what that's routine lab work in any clinical setting growth hormone deficiency cannot be diagnosed off of that routine lab work in the vast majority of cases, and central adrenal insufficiency, which is a life-threatening form of hypopituitarism, generally cannot either.

Dr. Batson
Co-Host: 31:52

It can if it's. If the cortisol is very, very low, it can be. We'll cover that in a different podcast and we more broadly broadly cover the different variants, but with growth hormones. So the problem is growth hormone is we have to talk about what's called growth hormone secretary dynamics, so secretary being? How's it secreted? What's the pattern of secretion?

32:13

It's secreted about 10 times a day, on average in pulses, and the half life of growth hormone is only 20 minutes. So now divide 24 hours by 10 roughly. So the problem is you cannot run a basal or static lab tests on growth hormone and have it mean anything, because you could be catching it at the peak or you could be catching it at the trough. So so that's important because there are some you know providers that maybe don't have training in endocrinology and I think well intended that that hear about this condition.

Dr. Goldenberg
Co-Host: 32:44

I didn't know that. That's fascinating, so pulses throughout the day. That's so interesting.

Dr. Batson
Co-Host: 32:48

Yeah, yeah the pulses throughout the day, particularly the largest pulses at night during deep sleep, and so shortly after going into deep sleep you get a huge release of growth hormone that goes down a little bit with age over time but but essentially released in pulses, and so it's like weight, it's like waves coming in. You know, at the ocean where you get a big, you get a swell, and then the end of you get a trough, and so if you're doing the lab work on the swell, it looks high. If you're doing the lab work on the trough, it looks low and it's it's meaningless, so there's no way to diagnose growth, you know true clinical growth hormone deficiency office you don't know what you're looking at.

Dr. Goldenberg
Co-Host: 33:22

Yeah, yeah, so in the research setting.

Dr. Batson
Co-Host: 33:24

You know they'll do samples every 30 minutes for 24 hours and there's lots of other fancy things that are done when you're studying growth hormone secretary dynamics. But when you're when you're doing it clinically, you have to do what's called a provocative test or a stimulation test we also call it dynamic testing and so what you're doing is you're you're altering the physiologic conditions, usually through the injection of a pharmaceutical that then stimulates the pituitary gland to secrete growth hormone, and so common agents that we use are insulin. So the most the gold standard test is called the insulin tolerance test, and insulin is given to cause hypoglycemia and in that at that time the pituitary reacts and produces large amounts of growth hormone, and then it's captured through repeat blood draws over the course of anywhere from two to four hours, depending on the tests that you're doing so, so let me track with you here.

Dr. Goldenberg
Co-Host: 34:17

So you're, you're basically, you're basically like flooding the system, you're getting a response that's so much higher than the baseline swells of the ocean that that, that maximum is what you're looking at to see like the, the peak sort of yeah, yeah, you're, you're looking at the maximum.

Dr. Batson
Co-Host: 34:36

And another, another word for it is a challenge test, which I like, that I like that word. They used to call it challenge testing in different challenge tests. And and it's nice because you're challenging the pituitary you're asking the question if I give you a stimulus, can you produce growth hormone at the same level as normal controls, right?

Dr. Goldenberg
Co-Host: 34:54

and we have those normal controls.

Dr. Batson
Co-Host: 34:55

And then we have people that are known to have birth hormone deficiency, that have had surgeries or severe tumors, and that's your cohort of your disease population. And then you look at those two populations and then diagnostic cut points are created that are imperfect but they capture the vast majority of cases we'll talk about the imperfection of it.

Dr. Goldenberg
Co-Host: 35:14

So that's how we deal with the pulsing, okay, so that makes sense. So that's very, very clever. And yeah, say, diagnose it, and it's just. I'm imagining it's just challenging to do this sort of testing, like there are only special facilities that will even do it. Is that part of the issue? Or you just have to know to order it, or it can't be ordered.

Dr. Batson
Co-Host: 35:31

It has to be done generally in an endocrine specialty practice, so you'd have to refer to an endocrinologist or other endocrine health care provider. There's some really good endocrine nurses now on doctors of nursing that are working in endocrinology. So there's, you know, somebody that's well trained in endocrinology and in dynamic testing and knows how to interpret the testing, because even there's, you know the guidelines are pretty clear on on heuristics for interpreting tests, but there's some subtleties there as well when you go into the research side of it so the you know the analogy I give my patients is making margaritas, right.

36:05

So if you, everybody's made margaritas, hopefully. If you haven't go out and make one this week, if you, don't drink, that's fine. If you've had a brain injury, make a virgin margarita so what you do when you're making a margarita.

36:15

Generally you, you know you go on monday, you buy a bag of limes right and then you take it out, you throw the limes on a counter in a bowl and then throughout the week you're looking at those limes and the vast majority are green. They look pretty good. You have some brown ones you know the brown ones right away you're going to throw out they're not going to give good juice.

36:32

If they do, it's going to be rotten. That's kind of like an abnormal pituitary on MRI, right? So you look at the MRI and you can see the pituitaries it damaged. The vast majority of brain injuries, particularly mild traumatic brain injury, have normal, normal radiology. They're normal limes and so well, because it's microscopic damage to the pituitary. Remember, we're talking autoimmune antibodies, we're talking vascular hypotheses. We're talking little tiny cells inside a tiny region of the hypothalamus that are damaged. That you're not going to see. On neuro imaging, so, but you have normal neuro imaging a lot. So diagnosing it has nothing to do with radiology. You can see. If you have radiology on board, you can. You can find abnormalities in some cases, but it's confirmatory, it's not. It's not diagnostic. The diagnosis is biochemical after a challenge test.

37:23

And so now you got this bucket of limes over there, or this, this it's not a bucket, it's a. What is it? It's a, it's a bowl of limes. Thank you, you got a bowl of limes, they're all green. But everybody knows the experience of going over and grabbing a lime. That's really hard, right, even though it looks like the other limes. And then you cut it and hardly any juice comes out. And so when you, when you squeeze it, you're trying to get the juice out. That's like a challenge test for the pituitary. That's what we're doing. So the hand squeezing the lime is a pharmaceutical agent. It could be insulin, it could be glucagon. There's a newer one that's FDA clear that we just lost, actually called macy marylin or macrolin, that you'll hear about. In in europe they use arginine, which is amino acid IV, plus growth hormone releasing hormone. So arginine, gh, rh is another test using europe that we don't have access to here. But any of these are stimulation or challenge tests that basically you're trying to make margarita. Essentially, squeeze those limes and challenge it gotcha okay.

Dr. Goldenberg
 Co-Host: 38:22

So that now I really understand why it's so challenging to make this diagnosis, despite how common it seems to be.

Introducer: 38:34

If you'd like to learn more about our unique approach to brain injury forensics, email us directly at info at braininjuryresearchsolutions.com, or learn more on our website, www.braininjuryresearchsolutions.com. There you can sign up for webinars, explore featured papers and learn about the team. Enjoy the podcast. Don't forget to rate us and review us on Apple Podcast to help spread the word.

Dr. Goldenberg
Co-Host: 39:17

Let's back up for a second because you're right, we got sort of ahead of ourselves. Can we just go through the symptoms like how this presents? I know we talked about it broadly, but let's just name them out for the listener.

Dr. Batson
 Co-Host: 39:29

Yeah, that's fine the way that I like to keep it simple, because if you look at the aftermath, what we call sequelae of untreated growth hormone deficiency- as it evolves over many years.

39:43

It's actually a very, very serious condition. But I teach the five B's and I just try to come up with a way of teaching my patients something they can easily remember. So the five B's are body, bone, blood, brain and being for well-being, and so body stands for body composition and physical performance. And so it's worked similar to testosterone in that growth hormone is lipolytic, it breaks down fat and it builds skeletal muscle and lean muscle mass. And so when you have untreated growth hormone deficiency, you lose lean muscle mass and you get a total fat mass increase and particularly what we call visceral adiposity, which is essentially fat that develops in the midsection, behind the muscles, which is associated with increased cardiovascular disease and death, so that kind of what we call central obesity or central adiposity. And then you get reduced physical performance as well.

40:42

So exercise tolerance goes down and that's been measured in exercise physiology labs with things like VO2 max, and so a common complaint is somebody that's lost. Especially we'll get guys in the military or whatever who were the top of their game. Sometimes I've worked with police officers as well, and they were really fit and they had a lot of stamina and they say I've got about half my stamina. I don't recover. I've gained weight and central fat mass. I don't know why I'm still working out or trying to, but I can't gain. I've lost lean muscle mass.

Dr. Goldenberg
 Co-Host: 41:13

I can't gain it back and their testosterone is normal right, Because there's a lot of crossover between testosterone and growth hormone.

Dr. Batson
 Co-Host: 41:19

They're both anabolic hormones which build the body essentially, and so they fall into that anabolic category.

41:26

So you could have already replaced testosterone but have growth hormone efficiency and you're only getting you're only 50% of the way of achieving normal hormonal status and getting back to your well-being in terms of body comp and physical performance. So that's the B for body. And then the other one, bone, is easy. So you lose bone mineral density. So everybody's heard of, probably, osteoporosis in the elderly, and we think of that as a female disease that happens after menopause. Well, you need growth hormone and it's sister hormone, insulin, like growth factor, one which is secreted from the liver and is under the control of growth hormone, to maintain bone mineral density.

42:05

So within a couple years of growth hormone efficiency, you start losing bone mineral density and over a number of years you can develop either osteopenia or osteoporosis, and that puts you at increased risk of fragility fracture, which is a low trauma fracture that happens falling from a height or lifting too much, that type of thing and you're particularly susceptible in the heads of the femoral neck and then the lower spine and wrists are particularly susceptible.

Dr. Goldenberg
Co-Host: 42:35

The fragility fractures and fragility.

Dr. Batson
Co-Host: 42:37

Fractures as we age are associated with increased disability and early death.

Dr. Goldenberg
Co-Host: 42:41

So you don't want to have osteoporosis?

Dr. Batson
Co-Host: 42:44

I tell the story of a guy that was 16 when he had a head injury and he was never well since, and I think I saw him in his early 30s, maybe 17 years later, and he had the growth hormone deficiency and testosterone deficiency and he had severe osteoporosis and spine. He was 230 pounds and worked out. I told him stop squatting and doing dead lifts until we regenerate your spine. So he changed his exercise program.

43:08

But he had been on all sorts of neuropsychiatric meds for years for depression and anxiety and all these non-specific symptoms and with marginal effect.

43:18

I mean, he was gliding along okay and getting by in life, but he needed the growth hormone, he needed the testosterone. So that's kind of a story of bone mineral density issues. And of course, if females lose estrogen at the same time and they're moving into perimenopause or menopause and they get a head injury and they develop growth hormone deficiency, now you've got a compounding of effects. So you're magnifying the effects of losing estrogen and growth hormone at the same time and that can really accelerate the osteoporosis. So that covers bone. So we did body comp or body bone. What I just used is a broad one to talk about the heart, so you can remember the cardiovascular effects of growth hormone deficiency or vast.

44:06

And so the literature shows increased cardiovascular and cerebral vascular death with reduced life expectancy, and that's probably the one that everybody kind of remembers. But they've done studies where you can look at arterial plaque in the carotid and from oral arteries and you get increased plaque and you get increased carotid intima media thickness. And if you don't know what that is, you can look it up. But it's a marker essentially of cardiovascular integrity. In the carotid arteries you get increased carotid artery stiffness, which is also associated with increased risk of thrombosis or breaking off a clot going to your brain and causing a stroke or having a heart attack. And then the heart has four chambers and the final chamber that pumps out all the blood in circulation is called the left ventricle and it's smooth muscle and actually the myocardium there is supported by growth hormone and you can get reduced left ventricular mass and you lose the efficiency of the pump, essentially weakens your heart and then something called ejection fraction goes down and on and on. So that's the heart for blood.

45:24

But I also use the blood to talk about metabolic complications. So you get worse cholesterol, you get worse triglycerides, you get lower HDL the good stuff and worse, ldl and total cholesterol. The bad stuff increased insulin resistance as well, so you increase risk of diabetes. So that's everything around blood. And then you've got brain and the brain.

45:47

There's a whole set of neurocognitive and neuropsychiatric effects, so you can get attention deficits, memory impairment, depression, anxiety, irritability social isolation, that type of thing, and a greater time, more difficulty dealing with pain, increased kind of somatization where you're more fixated on pain complaints and physical complaints and that kind of thing. So there's a whole set of neuropsychiatric effects as well. That's the brain. So the final B is for being, or well-being, and that's where we get into quality of life, and so of course, our team is doing probably the most updated systematic review on the topic of growth hormone replacement, quality life right now.

46:31

I think we've got an online lecture on that as well that people can look at, but diminished quality of life is a big one, and that also includes the social isolation as well. And then you treat all of that.

46:44

And my experience clinically the data shows people get better across all those areas. Generally speaking, there's debate on the neurocognitive benefits of growth hormone and if you look closely at the studies which I did in my dissertation work, a lot of it has to do with the dose Meaning. When you give low doses of growth hormone you don't see a big effect size statistically on improving the neuropsychiatric. But when you give larger doses and optimize the growth hormone, you do, and so you'll get people saying that, yeah, I don't think it does much for the brain, not true? You just need to look at the studies and see what the dose is. So our practice clinically is to optimize growth hormone, not just to give a tiny amount of it, which is that's another problem. So even if you do get in, see an endocrinologist, get the diagnosis, not every endocrinologist may optimize your growth hormone.

47:35

I've seen them give only 0.2 milligrams. I had a guy this is a severe TBI that I was consulting legally on and couldn't treat him and then I referred him to an endocrinologist colleague and I found that he was only on 0.2 milligrams for two years and generally we titrate up by 0.1 or 0.2 milligrams every two months. So we would have had him anywhere from kind of a sweet spot of 0.6 to 1.0 milligramsa day, which is where we find the best effects, and that's there's concordance between that and the studies on improved cognition as well, using standardized neuropsychological testing, meaning you test them before and after, you get them performed on and you actually see objective changes in neuropsychological functioning on gold standard tests of cognition.

48:19

So that gives you an overview of all the stuff that can go wrong and why it needs to be treated right. Compelling reasons to treat the condition, not to just leave it alone.

Dr. Goldenberg
Co-Host: 48:28

Well, and I just to underline that I mean I think pretty much everything you described is like I mean I'm just envisioning a patient, right Like you had a concussion a while ago and then you know he's getting older and you know he's working out, but you know he doesn't really see the gains and he's got, he's getting some fat buildup and his energy is a little bit low and maybe he's not thinking as straight but he's depressed anyway and you know it's kind of like life's kind of beaten down on him but all that it's just so easy for I would imagine for an individual and their doctors to be like you get an older man, you know you're not exercising as much as possible and like, yeah, if you're like an elite warrior or a police officer or something like that and you're working out all the time and you're not seeing those gains, that's you know. Maybe that's more obvious, but for most humans walking around on earth, I feel like you know it's just like ah, yeah, just kind of feeling a little low and you know life's kind of rough and gaining some weight in my cholesterol is up right, like that's just the classic story for so many people on earth, and so I can see how it's not going to raise flags, especially if there's a lag time from the concussion and not a strong correlation in time with that stuff, right, so like that is not shocking. You know, and you know it might be years later, to your point, that they're seeing cardiovascular. But again you would describe the cardiovascular issues to their high cholesterol. You described that to oh, your lifestyle is probably down because you know you're gaining weight as well.

49:54

Like I can see how, diagnostically, that's just a really hard call. And to your point as well, it's like okay, well, these are all fixable things, it sounds like, if you dial it in properly and you're watching the dose. So I don't know what would you. I'm just kind of keeping an eye on the time here. I know we're coming to the end, but you know what would you say to folks that have had a concussion? You know, it just seems to me like this is something that needs, like everyone just needs to be checking Cause. It's just. I mean, I've seen patients describing these sorts of things and you know you make these assumptions diagnostically and you're not going to necessarily connect it to a concussion they had three years ago.

Dr. Batson
Co-Host: 50:35

Yeah, Well, let's be clear what the guidelines say, meaning consensus guidelines. So so, in 2015, the American Association of Clinical Endocrinologists and the American College of Endocrinology one of our big organizations the other one is Endocrine Society.

50:50

they published a clinical state review on this very topic and they said if you've had a moderate or severe TBI, under all conditions it's the standard standard of care for you to see an endocrinologist to be tested period, and if you've had a mild TBI in your symptomatic you should also be tested. So the answer is, if you've had a mild TBI and if you're still symptomatic, you know, at 12 months, then you should see an endocrinologist or other skilled endocrine provider and you should be tested for growth hormone deficiency and hypopetuitism.

51:23

That was actually on hypopetuitism, not just growth hormone deficiency, but growth hormone deficiency being the leading deficiency is obviously part of what needs to be tested for.

Dr. Goldenberg
Co-Host: 51:31

So, period that's it.

Dr. Batson
Co-Host: 51:33

That's the standard of care. If that's not happening, you're falling below the standard of care in conventional endocrinology period.

Dr. Goldenberg
Co-Host: 51:39

So you have a brain injury, you need to get tested, unless it's a mild brain injury, in which case, if you're symptomatic, is it just once? Is it after a certain amount of time, like you were mentioning? You know missing it if you just do the single test.

Dr. Batson
Co-Host: 51:55

Yeah, I mean at least test once. I mean you might come back positive and then you caught the diagnosis and you get a treatment that can be really life changing.

52:04

But if you come back negative at 12 months and you still feel like crap at two years or three years. If you've got an endocrinologist that's willing to do it, test again and see if you're positive, then so you can always approach it that way and I think that's the most rigorous way to do it clinically. So that would be the advice right, and that's the same for litigators as well.

52:27

I think I was lecturing a couple of years ago at one of the big conferences and one of the litigators said well, I don't wanna test for it because you know, let's say, four out of five times it comes back negative right and meaning you've got negative results.

Dr. Goldenberg
Co-Host: 52:41

Well, that's a great thing.

Dr. Batson
Co-Host: 52:42

That means you don't have that and your chronic post-concussion symptoms are something due to something else.

52:47

And I had a debate with the attorney about that and I said you know that absolutely makes no sense and part of the attorney's job is also, in my opinion, help their client get better. And so if there's a life-changing treatment where you've got an 18% chance of having it, and of course you're gonna test for it, but understand that if you're preventing your client from getting that testing because you think there's gonna be a negative finding, you're actually going against standards of care and endocrinology. That's not good.

53:13

So that's, something on the litigation side, because I know this is a forensics podcast, but this has been more directed at people with potential growth hormone deficiency in the broader TBI community. So step one is yes, I've had 12 months of persistent post-concussion symptoms and I had my ultramatic brain injury or worse. Get see an endocrinologist and get tested. Now here's the next caveat If you see an endocrinologist or endocrine provider, what they will do is they will run a screening test called insulin-like growth factor one, igf one, and so IGF one is a hormone that's under control of growth hormone.

53:51

It's produced in different tissues throughout the body, but abundantly in the liver, and so growth hormone stimulates. Growth hormone is the strongest stimulus of IGF one.

54:02

So IGF one is a proxy hormone for growth hormone secretion. So if your IGF one tanks then most certainly it's highly probably have growth hormone deficiency. But IGF is also under control of other factors. So it can be within the normal reference range and you can still have growth hormone deficiency. So if it's really really low it's very specific for growth hormone deficiency. But if it's normal it's not sensitive Meaning you might still have it. So when in doubt run the actual diagnostic testing, don't rely on the IGF one screening test.

Dr. Goldenberg
Co-Host: 54:35

Now I'm gonna get a little bit more detailed with this.

Dr. Batson
Co-Host: 54:39

The clinical algorithm that's published within the AAC guidelines is if you've had a brain injury and if you're symptomatic and you suspect growth hormone deficiency, and then you run the IGF one screening test and your level comes back below 0.0 Z score or standard deviations. And that represents the middle of the reference range, roughly of the cohort, the mean of the healthy cohort. Then go ahead and run the diagnostic test Meaning but if you come back, above 0.0, we're not gonna run the diagnostic test.

55:14

A terrible, terrible heuristic. And the reason it's not a good heuristic is because we're publishing on this as well and presenting, and we recently published a poster abstract on it where we researched all of this. But and this is widely known with an endocrinology, the assays vary for IGF one, meaning they're very different across commercial platforms, and we actually compared five different commercial platforms.

55:39

Which means you could run five different IGF one assays and you could have a. Four out of five could be above zero and one could be below. And if you'd run any of those other assays, you never get the diagnostic test. And I'm not gonna go into evaluating the different commercial assays. People can do that with me privately, but we are publishing on that.

Dr. Goldenberg
 Co-Host: 56:01

And we can maybe do a different podcast on IGF.

Dr. Batson
Co-Host: 56:03

One assays and why that's important. So the bottom line is you know if you go to an endocrinologist and they run an assay that tends to run higher and then they say, oh, you're above the mean meaning, you're above 0.0, or you're above the midpoint of the reference not the midpoint, but the mean of the reference range we're just not gonna run the diagnostic test, whereas if you'd run a different assay you would have gotten the diagnostic test. So really, we test people if they're anywhere near and around that and we use.

56:29

We've also tested the different assays, so we use a very specific IGF one assay that tends to be more sensitive, meaning if you do have growth hormone deficiency, it falls below 0.0 or almost 100% of the time. So we're not so worried if we even if we did follow that algorithm that we would not diagnostic test and then we would miss the diagnosis.

56:53

So to me, unless you've got a researcher endocrinologist who's part of this and originally, like a handful of endocrine researchers in the country that are doing specific work around IGF, that I know probably our group, which is, I think, five.

57:06

Then you just you don't know if you have growth hormone deficiency until you've been through one of the approved diagnostic tests. Right now in the United States there's only two left. We've got the glucagon stimulation test, which is now the easiest one to run and most states endocrinologists will run that, and that's an outpatient test that's very safe. And then you've got the insulin tolerance test, which is the gold standard, but it needs to be done in a quasi hospital setting with a crash car because you're inducing hypoglycemia and very few endocrinologists do that still, but you have senior endocrinologists that do that and you have to go to specialty facilities to do that. For example, like Barrow Neurological Institute is excellent with the medical director there, dr Kevin Uyen, who's part of our research group and was one of my main mentors in this area, so they still run the insulin tolerance test, but it's very hard to find.

57:58

But that is the gold standard test against which all other tests were developed, but the front line one that you could probably get in any state is glucagon stimulation test. So then you get into even more complex issues, which is the glucagon test is not perfect and it depends on body mass index, and so you have different cut points for different body mass index, and that's a different topic. So we can have a critical appraisal with the glucagon stimulation test podcast for people that have been through it and told that they don't have it, generally speaking. So if you have a body mass index below 25, your cut point is three, which means when you stimulate the growth hormone if it's below three, you get a diagnosis, but if you have a BMI above 30, the cut point becomes one.

58:46

So, and then between 25 and 30, it's equivocal, and you've got to do some clinical decision making. Well, you can still be above one, like at two, and below three, and it's, the test is not confirmatory, but it didn't really exclude it. And now you run the gold standard test and you fail it.

59:03

So sometimes you need two dynamic tests, Dr Goldenberg, not just one. And that's where the clinical acumen comes in. It's like well, you had a borderline result on the frontline outpatient test, but we need to run a second test because we're not sure. That rarely ever happens. It's very, very uncommon that that's happening in clinical endocrinology practices, so you can see how difficult it is. You've got the barrier of referral from primary care based on knowledge of the condition. Then you have to get into an endocrine specialty clinic, Then you have to pass fail the screening test so that you actually get the diagnostic test.

59:37

And then you've got to have somebody that can interpret the diagnostic test with a certain level of clinical acumen to make sure it's on what's called false negative, meaning the tests using the heuristics or the kind of commonplace algorithms, decision making trees. It's misunderstood by saying well, you don't have it. Well, you might have it, it just didn't confirm it. So you see how difficult it can be to get the diagnosis.

Dr. Goldenberg
Co-Host: 1:00:03

Yeah, I think we've come full circle. I mean, from starting off about an hour ago talking about how much this is missed, I think I now have a very full understanding and listen, there's a very full understanding about why all the different issues involved and why it would be important to have a real expert look at this carefully and make sure you're not just getting tested once, you're not just getting the screening test. You're doing the right screening test, you're doing the right diagnostic test. The cup points are right, the weight's the right way, you're maybe testing again if it's negative initially. So I can kind of see a lot of these challenges and this all makes a lot more sense now.

Dr. Batson
Co-Host: 1:00:42

One more thing, Dr Gilmour, I wanna mention because this is critical at the end, we're talking about barriers to diagnosis of growth hormone deficiency, which we all know is a serious condition.

1:00:52

Now, another barrier that I see is coming sort of out of the alternative medical or CAM environment, complementary alternative medicine environment, but also C I, h I guess we call it complementary and integrative health environment, and so because hormones have been taken into that particular practice, you can see, sometimes people with growth hormone deficiency may go to a provider that's prescribing what we call Socraticogs, and Socraticogs are things that stimulate growth hormone secretion in normal people, so it can work, for example, in aging and that type of thing, and so common Socraticogs that people may have heard of. Ceramorellin is a common one, epamorellin is another one, and then people will use these combinations of amino acids like L-Arginine, orthanine, l-tyrazine, an herb called L'Micuna Purians, which has L-Dopa, which is a precursor to dopamine. So all of those things can stimulate some level of growth hormone secretion if the pituitary is working, if the pituitary is working. But if the pituitary is not working properly, they will not work.

1:02:07

And now you're interfering because people think they're getting a growth hormone treatment and they're not. And the problem is if you just follow up once with an IGF1 test. Igf1 is very equal anyway, so you need to do a number. So someone might take a Socraticog and their next IGF1 level is higher than their previous one. You need to do a distribution about five to 10 tests over time to be able to see if it's a true finding, because there's some degree of variance within the lab assay.

Dr. Goldenberg
 Co-Host 1:02:34

So you might have growth hormone deficiency, take a Socraticog.

Dr. Batson
Co-Host: 1:02:36

You're getting better because you're taking other hormones as well, like Testosterone. And then you think that you're approving your growth hormone and you're not, and that's important because growth hormone and IGF1 have different receptors throughout the entire body. So you need the direct growth hormone stimulation and you need the IGF1 stimulation, but you gotta have both. So that's another barrier If someone is getting treated and they think that they're using something that's naturally stimulating their pituitary and it's not actually doing that.

Dr. Goldenberg
Co-Host: 1:03:09

Now if they pass a challenge?

Dr. Batson
Co-Host: 1:03:11

test and they have a normally functioning pituitary and they wanna use something like that, that's fine. I mean, there's OTC stuff like Arginine.

1:03:19

Now, that being said, L-Arginine was used as an amino acid, as an intravenous, as a stimulation test, and even as an intravenous preparation. It's a weak stimulus of growth hormone, and so taking it orally as a supplement is even weaker, and so the real way to test these Socraticogs would be to do a dynamic test, meaning you take it and then you measure growth hormone multiple times to see if it's actually stimulating it. Because IGF1 by itself, unless you really measure it over and over rigorously, it's hard to know whether you're getting optimal effects from the Socraticogs, even when you have supposedly normal growth hormone secretion and the pituitary is able to do that so that's the final barrier to diagnosis of growth hormone deficiency.

1:04:09

So the bottom lines if you wanna be rigorous, you get a diagnostic test done 

Dr. Goldenberg
Co-Host: 1:04:16

You're saying that the final so you're saying that the final challenge is, if someone comes in taking this stuff, that it could inappropriately modify the levels. Why would that be a challenge for the diagnosis?

Dr. Batson
Co-Host: 1:04:29

Well, no, it's not. My concern is this. My concern is somebody goes to a CAM provider, for example, anti-aging medicine, et cetera, and they get a treatment for the other stuff, which is great. Their testosterone is low. They got some testosterone XYZ.

1:04:50

We'll talk about central adrenal insufficiency another time because it's life-threatening and it needs to be diagnosed. It's not one you want to miss, but they're given seromerellin or epomerellin or another secretogog, which the way the secretogogs work is. They stimulate predominantly the hypothalamus, possibly the pituitary, to secrete growth hormone. But the equipment has to be working. Oh, I see, right, so the equipment's broken. You can't send a radio signal to a radio that's broken and have anything come out, so you're basically sending a radio signal to a receiver that doesn't work. And so what happens is people are taking these preparations that are secretogogs instead of the recombinant growth hormone which they really need, which is the downstream hormone, so to speak. I mean, it's made in the pituitary but ultimately it works throughout circulation on all sorts of different tissues in the body, the ones we talked about. So now they're taking a natural supplement or a off-label. You've got to get a prescription for things like seromerellin and epomerellin, but they're taking an off-label secretogog and the radio's not working. And so now they've actually they're walking around for the next decade.

Dr. Goldenberg
Co-Host: 1:06:04

So it won't work.

Dr. Batson
Co-Host: 1:06:05

Yeah, it won't work. It will not work. And how do we know that? We know that because of Macy Morellin.

Dr. Goldenberg
Co-Host: 1:06:10

So this is a great story.

Dr. Batson
Co-Host: 1:06:12

So there's a compound. So one of the strongest signals for growth hormone is a protein called ghrelin, and ghrelin is produced predominantly in the stomach, a little bit in the small intestine, a little bit in the brain a little bit in the pancreas that goes to the hypothalamus and stimulates growth hormone and releasing hormone, and then it also, which then stimulates the pituitary to release growth hormone.

Dr. Goldenberg
Co-Host: 1:06:40

So it's a signaling hormone.

Dr. Batson
Co-Host: 1:06:41

So Ghrelin being the strongest stimulus of growth hormone. The pharmaceutical industry created something called ghrelin mimetics and these are molecules that are almost identical to ghrelin that do the same thing to the pituitary.

1:06:56

So if you look up, ghrelin mimetics, you'll find things like seromerellin and epomerellin, and these have become very popular in sort of anti-aging or age management medicine. For, you know, natural age related declines in growth hormone secretion that's a different topic. We're not even covering that, and whether that's prudent or not prudent not the topic today. We're talking about using these when you've had a brain injury and your pituitary is not working. It will not work, and here's why the strongest secretion known to man is called macymerellin. And so back in 216, and it was proved in 218 by the FDA we wanted another easy to use growth hormone challenge test that would be like the insulin tolerance test, and it was validated against the insulin tolerance test. That wouldn't require, you know, an quasi-in hospital setting. So macy was it.

1:07:49

And so they said we're going to find the strongest secretion on earth and it's given an extremely high dose. So 64 milligrams. So the average kind of anti-aging dose of seromerellin is 200 micrograms, so about a fifth of a milligram. So now do the math 64 times 5. That's how much stronger it is. We're roughly what 3,600 something, excuse me, 360 plus times in strength. Okay, got it. So people fail this test, meaning you give them a massive dose of agri-alumimetic and their growth hormone doesn't go up. So we know from that test that there's no way we're going to give us a credit card like seromerellin or ebomerellin or some amino acids and they're going to get any kind of significant secretion of growth hormone, because we've had that gold standard macy merellin test and all of the what we call pharmacokinetics around growth hormone secretion very, very well studied. So that's what I'm talking about. Does that make sense? Dr Goldenberg, that's a barrier If you're taking one of these things and then you're not and you think you're okay but you're not getting the diagnostic test done.

Dr. Goldenberg
Co-Host: 1:09:00

Got it. Okay, I think I'm with you. Now it sounds like and I just wanted to end with this it sounds like there are ways to stimulate, like a working growth hormone mechanism, but if you have this TBI related damage, it ain't going to work, type of thing.

Dr. Batson
Co-Host: 1:09:19

Bingo.

Dr. Goldenberg
Co-Host: 1:09:20

And there might be some misunderstanding with that. And so it sounds like you're suggesting that the replacement is, and the treatment is, recombinant growth hormone. Is that something that is like a lifelong thing, like if you've got Hashimoto's you're taking thyroid meds forever? Is that something? Can this resolve? I know you mentioned it can kind of resolve spontaneously, but when people are on these medications, are they on them for a life? Is it something you just kind of watch forever type of thing?

Dr. Batson
Co-Host: 1:09:46

Many of them are on for life the majority. However, it's up to the patient, and so you got to be off.

1:09:52

We generally recommend 60 days off of growth hormone before we retest through one of the diagnostic tests. So you can put them on for a couple of years and then take them off for 60 days and see if the axis is recovered. So, because growth hormone can be helpful in the brain injury recovery process. So if somebody gets a diagnosis 12 months and goes on growth hormone and they feel like heck of a lot better for a year or two year, then take them off of it and see if the axis is recovered. That's legitimate, you can do that.

Dr. Goldenberg
Co-Host: 1:10:20

So that can happen, so the axis can come back, if it can come back, okay, I've seen it come back.

Dr. Batson
Co-Host: 1:10:26

I've seen it come back. I've seen it three years after a positive diagnosis at one.

Dr. Goldenberg
Co-Host: 1:10:31

Okay. Well, that's good news for the listener. I think that's really good it's good news for the listener, yeah.

1:10:36

So we've got specific medications that need to be done. We've got a lot of issues with diagnosis. This is a challenging diagnosis to make, but it's very common, outstanding Okay. Well, thank you so much for that really, really excellent lecture on this. We can we might circle back to this later. I think there's all sorts of different avenues here we could explore, but thanks for a really excellent survey of some of those, particularly around the challenges of diagnosis. That makes so much sense, the way you laid that out, and now it's very clear to me why you could have a very common thing that's just missed all the darn time. So, yeah, very good. Well, thanks again for the lecture and Absolutely.

1:11:15

We'll talk to you next time. Any last minute words for the listener or you feel like we got? We got it covered.

Dr. Batson
Co-Host: 1:11:20

I think we got it covered. If listeners want to make comments, we'll post this podcast. If there's additional questions, just feel free to think our email will be on there. Feel free to email us and we'll we'll do what we can to share, share our knowledge and experience with you in a way that can hopefully help you, your family members, as well as litigators who might be involved with post-traumatic growth hormone deficiency in the legal setting as well.

Dr. Goldenberg
Co-Host: 1:11:44

So appreciate everybody, and that's all I got for today, perfect, and Dr Batson, send us the that guideline you were talking about as far as like the testing workup, and we'll put that in our show notes for the listeners as well. All right, thanks everybody for listening. Yeah.

Dr. Batson
Co-Host: 1:11:59

And one last thing Dr Goldberg, I know we're going to be doing a. We're going to be doing a lecture in a couple of weeks for the research group on dynamic testing, I think. And how do you diagnose growth hormone deficiency? So we can make that publicly available for those that want to get a deeper take, a deeper dive into it, and that'll be a that'll be for an academic group of doctors and training PhDs, you know, epidemiology MPHs and so forth that are working on the actual research in this area. So if people want a more technical approach although today was fairly technical that should be available within about three to four weeks as well.

Dr. Goldenberg
Co-Host: 1:12:32

Perfect, and we'll link to that as well Once that comes out. We'll do a retrospective linking there too for the listeners. So excellent. Thank you everyone for listening and we'll see you in a couple of weeks.

Introducer: 1:12:47

Thank you for listening to the Brain Injury Forensics podcast with doctors bats and in Goldberg, brought to you by Brain Injury Research Solutions. If you'd like to learn more about our unique approach to brain injury forensics, email us directly at info at braininjuryresearchsolutions.com, or learn more on our website, www.braininjuryresearchsolutions.com. There you can sign up for webinars, explore featured papers and learn about the team. Enjoy the podcast. Don't forget to rate us and review us on Apple Podcast to help spread the word.