51: The Metabolism of Male Infertility with Dr. Ben Bikman

Hello and welcome to the metabolic classroom. I am Professor Ben Bickman, biomedical scientist and professor of cell biology. It is my great pleasure to be a scientist who focuses on metabolic health. And while some topics lend itself quite obviously to discussing metabolic health, like obesity and diabetes, there are others that you don't think of when you think of metabolic health. That includes infertility, and that is what we're discussing. The previous episode explored the relevance of metabolic health in the context of female infertility. And today we're moving to the men because after all, men also can experience problems, albeit entirely different one different ones than seen in females because of course, reproduction involves very different processes across the sexes. Um, but interestingly, despite the differences that the that are obvious in when we discuss infertility in females versus males, they do share a common metabolic core, as happens so often, albeit different parts of metabolic health and manifested differently. All right, now, just by way of establishing some familiarity with this topic. Infertility is a problem that affects a growing number of couples. But 15% ish of couples that are actively trying to have offspring or trying to get pregnant are unable to experience infertility, with men typically accounting for upwards of 30%. In some instances it's even higher than that. These are statistics that of course are kind of difficult to pin down, but it appears that slightly less than half of instances of infertility are because of a problem with the man. Now there are, just like is with females, several hormones that are involved. It's easy to just think of fertility as being a problem of estrogens or androgens, but it is not the case that there are always upstream regulators. There are hormones that are telling that are dictating the levels of androgens and estrogens. And that was a topic that we discussed pretty well as a, as a primer in the previous episode because of the intricate balance, the ebb and the flow and in fact the fairly substantial flow or the increase to be more precise, in some hormones that are coming directly from the brain. In the case of the female ovulatory cycle, in the case of the man, these same hormones are relevant. They just don't have this kind of 10x, you know, really dramatic rise and fall like you see in the females. They're generally just kind of always on, albeit at a lower level. And so two of the brain derived hormones that we discussed last time were follicle stimulating hormone FSH and luteinizing hormone lh. Those same two hormones are relevant in reproduction in men as much as we only often think of them as relevant in women. And indeed the names themselves are born from their supposed singular relevance to female fertility. The fact that we call the hormone follicle stimulating hormone, for example, obviously has relevance to the development of the follicle as we described in the previous episode. And yet same with luteinizing hormone, obviously relevant to the corpus luteum of the the remnant structure after ovulation within the ovary. Despite the naming of these hormones, which are obviously very female centric, they are still relevant in males. Fsh, follicle stimulating hormone and LH luteinizing hormone. Now how are they relevant? Let's just brief review that. Just like I did before with female infertility, I want you to have an appreciation of the the relevance of endocrine signaling or hormones in normal male reproductive function. Because with that background, it helps me as the teacher then go on to explore how things go wrong or to say that all another way. Before you can really appreciate what is going wrong, you need to appreciate what goes right or when it's supposed to work right. So with fsh, FSH stimulates spermatogenesis, which is the multi syllabic word simply referring to the process of the testes producing sperm. So this is relevant not only for the production but also the maturation of sperm cells within the testes. There are two distinct cell types within the testes that have female analogs. In the ovaries testes, it is the Sertoli cells and the LE cells. And this is more function, more a process in the Sertoli cells to facilitate the nourishment and the development of these kind of early sperm cells, what will ultimately become the sperm. But also with fsh, through its actions on the, on a particular set of tubules or these kind of carrying structures that are moving the sperm around. FSH just helps regulate the the structure, maintains the structure of these tubules to allow the sperm to get where it needs to, which is from testes to out in the case of male reproduction. Now, luteinizing hormone is also relevant primarily through its actions on the other cell type of the testes, namely the LE cells. So FSH is primarily acting on Sertoli cells to promote the development of sperm. LH is primarily acting on the LE cel case. Its primary action is to promote the production of testosterone, the famous androgen. You'll recall earlier that there are myriad androgens, just like there are estrogens. That's a family of hormone. And testosterone is the poster child of the androgens. Now testosterone itself, as the primary male Sex hormone is very relevant in male fertility. That's not surprising. But I wanted you to appreciate that there are these higher level signals that are dictating what testosterone itself is going to be doing from the testes. That there's these, what we would refer to as a secondary signal coming from the anterior pituitary. And again, that is FSH and lh. Now let's actually go to the testes and then their product here, which is testosterone. So testosterone has a very obvious function. It's simply promoting libido. This does play into the, the sex drive of both sexes. Of course, men having higher levels of testosterone will tend to have a higher sex drive, or just to say that another way, a higher libido. But it's also relevant, very, very relevant in just physical maturation, of course. But this is not a discussion about adolescence, so we don't need to discuss that. But in other words, why little boy begins to look like little man or young man, that is primarily testosterone driven. All right. Now, testosterone also does work in tandem with FSH to support the process of spermatogenesis. So FSH is not doing this or initiating the production of sperm alone. Testosterone is helping. So a product of the testes is helping the testes do what they need to do. This would be an example of autocrine signaling where a cell is producing a hormone. Well, actually in this case it'd be what's it would be more accurately paracrine, because this is testosterone from the leading cell is going right next door and act interacting with the Sertoli cell to promote the production of sperm. Again working in tandem with fsh. Also, independent of the sex drive or the libido, testosterone also plays a part in erection. Of course, erection is obviously relevant in the act of reproduction, but testosterone enhances the production of nitric oxide, which is a key mediator that is necessary for erection. And with all of this as background, let's dive into the pathology or the problem side of things and then discuss how poor metabolic health plays into that. And this is a pretty smooth flow in, in the topic as we move from talking about how testosterone facilitates the production of erections or the actual act of erection via the production of nitric oxide. So let's actually revisit nitric oxide. Nitric oxide is the primary molecule that initiates or that facilitates the erection itself. And it's all about blood flow. Nitric oxide has this, what's called a vasodilatory effect. We talked about vasodilation and vasoconstriction in the blood pressure metabolic classroom topic earlier. But vasodilation is when the blood vessels simply dilate, and that increases blood flow. Wherever you have blood vessels expanding, you have more blood moving into that area. In contrast, if you have blood vessels that are constricted, you would have less blood flow moving into that area, whatever the area may be. In this case, obviously, we're referring to the erection, but this would also have obvious relevance in things just like exercise, where when you are exercising, you do have a local increase in nitric oxide, and the blood flow will increase to the muscle to. To fuel the muscle, to feed the muscle, and to clear away metabolites to enable the muscle to continue to exercise. Well, that's not so different from what's happening with an erection. So you must have an increased production of nitric oxide to induce vasodilation. Insulin has many, many effects in the body, as you have heard me discuss previously. It is unique among its class of hormones, peptides, in that it affects literally every single cell of the body, including the cells that line blood vessels or the endothelium. Endothelial cells will respond to insulin in a way that it will increase its production of nitric oxide. So insulin activates this nitric oxide synthesis, or a specific enzyme that's known as a nitric oxide synthase. So insulin will turn that on the synthesis of nitric oxide. Just as an interesting aside, one of the clinical interventions when someone's having chest pain or an outright heart attack is to give them nitroglycerin under their tongue, a little capsule that gets rapidly dissolved into the bloodstream, which is a precursor then to becoming nitric oxide, inducing vasodilation, opening the blood vessels, in this case of the heart, but everywhere, improving blood flow, helping resolve the immediate infarction. Now, back to the topic here. One of insulin's normal effects is to increase the production of nitric oxide, inducing vasodilation. And again, vasodilation via nitric oxide is essential to normal erectile function. Well, unfortunately, as the endothelium becomes insulin resistant, it is less capable of producing nitric oxide. So when insulin comes knocking at the endothelium. Insulin. Normally, the endothelium would respond by increasing nitric oxide production. That would be its response to insulin. But of course, that becomes compromised as the endothelium becomes insulin resistant. So in insulin resistant states, the endothelial production of nitric oxide is diminished, leading to compromised blood flow. Not only does it have a systemic effect on increasing blood pressure, but of course, it results in the failure of normal erectile function leading to erectile dysfunction. So that's the general topic that I wanted to discuss. Now, I've taken. I took a long time, admittedly, to get around to it, but erectile dysfunction is the most common form of infertility in men, and now you know why. It is very, very commonly a result of compromised insulin signaling leading to reduced nitric oxide production, leading to failure of vasodilation, thus failure of erectile function, which of course then is giving rise to erectile dysfunction itself. Now, let's move on to a separate topic, but of course all complementary under this broad umbrella of the metabolic origins of infertility in men, which is low T or low testosterone. This is something that has been. Has become fantastically common, at least in advertisements and in clinical focus. There are entire clinics that exist simply to enhance a man's testosterone levels. And you'll hear abundant radio ads discussing or wondering, querying the male listener to determine whether he is low T, using all sorts of vague descriptions. Are you tired? Are you gaining weight? You might be low T. Well, maybe, but it's not because your testosterone is low. It happens to be that the same metabolic variables that are causing you to gain weight and feel lethargic are the same ones that are reducing your ability to produce testosterone. So let's get into that. Now, insulin resistance is significantly associated with decreased testosterone production in the testes, and this is primarily a direct effect on the LE cells which are responsible for testosterone synthesis. Now, let's actually start this part of the conversation, low T, by describing the metabolic effects of testosterone itself. So before we go into how insulin resistance impacts testosterone production leading to low testosterone, I want to just highlight the second part of this, which is how low testosterone, or just how testosterone in general, impacts insulin signaling in the body. Because in so doing, you then begin to see how this starts to create a vicious cycle, which I'll. I will revisit. All right, so first and foremost, with testosterone, Testosterone enhances insulin signaling. It increases the expression of key proteins involved in the insulin signaling pathways, such as the insulin receptor substrate 1, IRS1, which is right at the front of this series of events. When insulin binds to its receptor, the very next thing is the activation of IRS 1. And then the signal will go down actually many, many pathways and split and multiply or amplify, as we say in cell biology. But it also affects the expression of the glucose transporter that is in muscle and fat cells, glute 4. And those. Glute 4 is critical for insulin's action in Tissues like muscle and adipose to pull in the glucose and regulate blood glucose levels. Also, testosterone generally has a lipolytic effect. Testosterone treatment has been shown to decrease fat levels, particularly in the visceral space. That's the we've talked about before, of course, but that is where you, you're storing fat deeper within your abdominal cavity, woven through your intestines and you know, your kidneys, et cetera. Of course, by reducing overall body fat and shrinking fat cells, we have a direct increase or improvement in insulin sensitivity and the risk of Things like type 2 diabetes goes down dramatically. But also you've heard me discuss previously how inflammation is a primary driver of insulin resistance. Testosterone can lower levels of inflammatory markers like C reactive protein. These inflammatory markers are not only linked to reduced insulin sensitivity, they actually are causing the reduction in insulin sensitivity. Thus, by modulating inflammation, testosterone can enhance the body's response to insulin. In other words, improving insulin sensitivity. So again, as I mentioned a moment ago, that paradigm that I just finished describing is talking about how testosterone is affecting insulin signaling or insulin sensitivity and insulin resistance. Now let's kind of go back to the perspective you were expecting, namely how insulin resistance is affecting testosterone. Now that we appreciate how important testosterone is in metabolic function. So first and foremost there is a decreased leading cell testosterone secretion. So the actual amount of testostero coming out of the testes is down. So production is down. Studies have shown that increasing insulin resistance correlates. Correlates, That's a limitation with a decline in leading cell testosterone secretion. And this appears to be independent of anything LH is trying to do. Lh? Luteinizing hormone coming from the anterior pituitary. So this suggests that there is a direct effect of insulin resistance at the level of the testes, where the insulin resistance is somehow comprom the leading cell's ability to produce testosterone in response to whatever the stimulating signal would be. Lh most commonly also it is the overall what's called steroidogenic pathway. Now what is that? That's a big word. Stero, steroidogenic. You can hear within that the word steroid and genic or genesis. So this is referring to the simple production of the steroid hormones or the overall activation of that steroid pathway. Very, very. All sex hormones come from cholesterol. Cholesterol is converted into what was referred to as the steroid nucleus. And this then becomes the literal backbone that all of the so called steroid hormones are built on. Now that is the obvious steroid hormones like the sex hormones. But it's also Less obvious steroid hormones like aldosterone or, you know, which is a hormone that's involved in body water and salt or electrolyte regulation. So it's not just sex hormone we're talking about when we discuss the steroidogenic pathway, but insulin resistance can lead to disregulation of various pathways, signaling pathways within the leading cells that are essential for testosterone production, essentially compromising the entire process there within the testes. All right, now, as I mentioned then, as we look at how insulin resistance can affect testosterone production, we now can appreciate this vic vicious cycle where insulin resistance is resulting in reduced testosterone production, and reduced testosterone production is in turn resulting in increased insulin resistance, which in turn is compromising testosterone production. And we continue to feed forward or we have this vicious cycle that just keeps feeding on itself. Now, till up until this point, I've discussed the reduced. With regards to testosterone, we discussed reduced testosterone production. But to add insult to injury, the problems, the hits don't stop there. It's not only with insulin resistance, a case of reduced testosterone production, but also there is an increased testosterone conversion, or in other words, to be more precise, there is aromatization. Aromatization is the. The term that refers to converting testosterone into estrogens. So this is a normal process that happens in men. Men have estrogen levels, most especially estradiol, the poster child of the estrogens. What testosterone is to the androgens, estradiol is to the estrogens. So that's a normal process that happens in men and women. Men generally have relatively low levels of aromatization. So the testes aren't as interested in converting a lot of the testosterone into estrogens. It relatively wants to keep much more testosterone or androgens than estrogens. So there's very little activity of the aromatase enzyme, which is the name of the enzyme that's actually converting the testosterone into estrogens. Unfortunately, as a quirk of physiology, fat cells have the ability to express aromatase, particularly as they get bigger, and particularly abdominal fat, which men generally have more of within the, you know, as a comparison across the two sexes. So men generally have more abdominal fat. Abdominal fat generally expresses more levels of aromatase compared to fat cells stored anywhere else. So let me just make sure you really get that. As men store ever more fat, particularly in their abdominal area, the fat begins to act more and more like ovaries. Ovaries are quite aggressive in their aromatization of testosterone, converting it from testosterone into estrogens, thereby reducing testosterone and increasing estrogens. But again, As a quirk of physiology, men begin to start to mimic that overall endocrine or hormone profile. Not because his testes are turning into ovaries, but because his fat cells are kind of acting like the ovaries are. So there's this higher amount of aromatase which is leading to this higher degree of aromatization, converting testosterone into estrogens, resulting in reduced testosterone in the man, which of course is going to facilitate weight gain. It's going to facilitate just insulin resistance, compromising erectile function, compromising sperm production, compromising libido. All of this as a result of how. How he's. How he's storing fat and having too much fat. But then speaking of how he's storing fat, he can actually start to literally store fat in a more female or prototypical female pattern as his estrogen levels are starting to get higher. You'll recall from previous discussions, sex hormones largely dictate where we store fat, not how much fat we store. That's primarily insulin's effect, but the sex hormones will dictate where we store fat. And as his fat is increasing the amount of estrogens relative to testosterone, he can start to store fat in prototypical female areas, including on the chest and on the hips and butt area. So making him start to, albeit more subtle than a woman, but have him start storing fat in a bit more of a female pattern. This is usually most obvious in having what's looking like he's, you know, growing breast tissue. He's not growing breast tissue. He doesn't have like, mam. Functioning mammary glands. He just has a lot of fat there. All right, I've painted a sober picture. But as I like to do, I want to end this with. With a happy ending. As much as the story has seemed like a bit of a sobering, scary one, the solution, it's at its simplest in the man who struggles with infertility. Now, of course, there can be myriad causes of infertility, and I never mean to imply in this case or any, that the only cause of the problem is a metabolic problem. Maybe I should have led with that, that that there are instances of infertility in men where it has nothing to do with metabolic health. So please understand that. But having said that, as a metabolic scientist, I'm only focusing on the metabolic aspect. I believe I'm justified in doing that, not only because of my expertise, and so I want to talk about the topic that I'm an expert on, but also simply because of statistics, where I would strongly submit most instances of Infertility in men. The reason infertility is climbing in the, in men and women is not because of some mutation within the species that is resulting in this sterility or mounting infertility. It, it is a, it is at its core a metabolic problem. I feel very strongly about that and I'm sure you don't need any convincing if you've joined me here. All right, now, at its simplest then, assuming that the infertility in the man is a result of poor metabolic health, what can be done? The most powerful strategy is one that will lower insulin and shrink fat cells. Anything that will do that is going to help. I really want to make that clear. Anything that is going to reduce or shrink fat cells especially is going to improve insulin sensitivity and, and in this case result in lower aromatase action and ultimately his testosterone will climb, sperm production will improve, and generally infertility will be resolved or at least vastly improved. So let's just highlight very briefly some strategies. Some of these are redundant, of course. There's no surprise in what I'm going to say here, but I'm just presenting them now in the context of infertility in men. No surprise that diet impacts hormones and thus it impacts sperm quality. Now, this is where there's a little bit of a conflict, but for me it's a bit of an amusing one and I think you'll agree. I wanted to emphasize that any strategy that shrinks fat cells will improve fertility in men by improving insulin sensitivity and metabolic health. That could, heaven forbid, a plant based, low fat, kind of vegetarian based diet. Those diets can, if you take someone who's on a standard American diet, high calories, high carbs, and put them onto a plant based diet, they're generally experiencing some degree of starvation or, you know, chronic fasting, to be a little more precise. They're chronically undernourished and thus fat cells will shrink. Now, I have strong thoughts on the long term feasibility of such strategy, but you've heard it from me. I want to make sure I've disclosed it very frankly. You can adopt, basically. I'll say it this way, anything that takes you off the standard American diet is going to improve your insulin sensitivity. And I want that statement to have some impact on you because that can help you reconcile how someone could eat nothing but potatoes, which is pure starch, basically, and improve their insulin sensitivity while they're also just eating a lot than they were before. And frankly, depending on how you prepared the potato, there might not be the substantial glucose and insulin spike that you Expect. But anyway, anything that takes you off the standard American diet, either cutting calories and cutting carbs, which is what they always do, is going to shrink fat cells. Now, in the context of male fertility, it's actually not that clear, despite what I said a moment ago. Anything you do to lower insulin and shrink fat cells is going to improve it, unless it's a low fat or vegetarian diet. Because there the results get a little mixed. There are studies like Vukovich in 2009 or Ataman A T T a M A N in 2012. There are studies to show that if you take a man and put him on a low fat or plant based diet, two things are going to happen. His testosterone will go down and his sperm quality will go down. That's why I sometimes joke, and I do mean it to be a joke, that veganism is a self correcting problem because its adherence generally won't be able to reproduce and so the ideology will stop with that generation. Now I know that's a bit of a bold statement, I do actually mean to offer it tongue in cheek, but I hope it still has some impact on you as you think about this. So a man can be losing weight, but as he leaves animal based nutrition behind, he is leaving his chances of fertility behind as well. So it's not quite as clear cut as I implied at the outset of this bit of the conversation. Now let's talk about just low carb. It's difficult to really find well controlled studies that look at say low carb, which calorie for calorie is going to elicit superior improvements in insulin sensitivity as a, as compared to a low fat high carb diet. But there was a study published Wilson et Al in 2017 that looked at resistance trained athletes. So these are guys who lifted weights that followed either a ketogenic diet or a traditional western or standard American diet. But they're being more accurate than me. We should call it a western diet. It found that lean body mass increased in both. So all the people who say you can't gain lean body mass with a ketogenic diet, that is not true. This study directly refutes that they gained the same amount as those eating the standard diet. But the ketogenic diet group showed a significant increase in total cholesterol, sorry, total testosterone levels compared to the western diet group, suggesting that if, if a primary outcome is just purely based on testosterone levels, this study suggests that reducing carbs has a more powerful effect. But just to put a fine point on that part of the conversation, if you improve Insulin sensitivity, you are improving metabolic health. One of the things I don't like about this aggressive promoting of. Of low T if you will as a, as a thing is that it is a thing people, men can have lower than ideal levels of testosterone. But rather than just going in and beating the testosterone to death with say like testosterone replacement therapy, wonder why the man has low testosterone. It's not some fundamental defect within the testes. Again it's not like the species is evolving within a generation to become suddenly infertile. In this case reflected by a reduction in testosterone. No, there's ask yourself what is the underlying cause? Overwhelmingly it's going to be that the man is insulin resistant and he has high amount of fat, a high amount of aromatase within his high amount of body fat. All right, now let's leave diet behind because anything that improves insulin sensitivity generally, especially low carb, is going to improve infertility. But then second is medication, generally an insulin sensitizing medication. And I'm emphasizing that a medication that actually improves insulin sensitivity, which many so called metabolic drugs do not, many anti diabetic drugs do not actually improve insulin sensitivity. They'll just regulate the blood glucose levels in some instances by making the insulin resistance worse ultimately. But using insulin sensitizing drugs like metformin has been shown and is in is currently being explored as a potential intervention for male infertility. All right. Now lastly, exercise of course I just feel compelled to mention it. Resistance exercise in particular has been suggested to improve markers of male reproduction and performance through anti inflammatory and antioxidant mechanisms. I, I will just insert my own addition to this. I increasingly feel very strongly, although I've said this for years now, that if you minute for minute, if you have to pick an exercise aerobic or resistance default to resistance every time particularly and pardon me for being a little personal now, the older I'm getting and the more I have to fight to keep my muscle mass. That's where I'm devoting my time more and more in, in doing whatever I can to keep my muscle mass. Muscle mass not how quickly can you run five miles is the better predictor of, of longevity and this inverse indicator of mortality. So I don't. It's less important to me as I age that I can run five miles very quickly than it is how well I can move my body. And that's generally going to be influenced more by muscle mass rather than cardiorespiratory fitness. And I'm thinking admittedly very long term but just based on the studies that look at the variables that tend to correlate with longevity. Few things correlate better than muscle mass, so focus on that. All right, that's it. No other thoughts are coming to my mind as we wrap up this topic. I hope now you have a deeper appreciation of the relevance or the endocrinology of male infertility or just male reproductive function generally. And then in the context of infertility, insulin matters as much as we only look at it as a metabolic hormone. You can't really appreciate reproduction without appreciating metabolic function. After all, the organism or the body does not want to commit to reproduction if it doesn't deem itself metabolically fit. It would basically be saying, hey, let's get this in order first and then we can worry about reproduction. So get metabolic health in order before worrying about reproduction. Well, that's it for now. Until next time. Remember, more knowledge, better health. I'll see you then.