Ben Bickman (2:39)
Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging before we get started. Just as a reminder, you can listen to both of my podcasts ad free by becoming an insider. Just go to Ben Bickman.com or click on the link at the top of the show. Notes welcome back to the Metabolic Classroom. I'm Ben Bickman, biomedical scientist and professor of cell biology. Today we're tackling a topic that affects millions of men but rarely gets the attention it deserves male menopause. Or as it's sometimes called and perhaps more accurately, andropause. Now I know what you might be thinking Male menopause? Isn't menopause something that only affects women? And you'd be, of course right to question the terminology. The word menopause literally refers to the cessation of menstruation, which obviously does not apply to men. But here's why I still find the term useful, if perhaps still a little confusing. It helps us understand that men experience their own version of hormonal decline with age, just as women do. It's the male equivalent of menopause, not the same thing, and not equal in degree, but a parallel process that does deserve some attention. Just for the sake of the men who are wanting to understand their health a little better. To really appreciate what's happening in men, let's briefly review what happens in women during menopause. This comparison will illuminate why the male experience is fundamentally different but equal in its own way. In women, menopause represents something truly remarkable from a biological standpoint, the complete exhaustion of a finite resource. Here's what I mean. When a female baby is developing in the womb, her ovaries already contain all the eggs she will ever have, somewhere between 1 to 2 million primordial follicles. By the time she reaches puberty, that number has already declined to about 300,000. This isn't because something went wrong, it's simply how the system is designed. The follicles are continuously being activated and lost through a process called atresia or just a programmed death of the follicle. The rate of follicle loss accelerates dramatically as women age. Before age 37, women lose approximately 5% of their remaining follicles each year. But after 37, that rate more than doubles to about 12% annually. This acceleration continues until typically in the late 40s or early 50s, the ovaries are essentially depleted of follicles. When this happens, estrogen production plummets by roughly 90%, because the follicles themselves are the primary source of estrogen in premenopausal women. This dramatic hormonal cliff is why menopause symptoms can be so sudden and pronounced. These are dramatic manifestations, things like hot flashes, mood changes, sleep disturbances, and more. The body is experiencing a rapid hormonal withdrawal. The male experience is quite different in origin and magnitude. Unlike ovaries, which have a finite supply of follicles. And remember, the follicle is so relevant because it's the source of all of these hormones, men's Leydig cells, that's the cells within the testes that are responsible for producing testosterone, actually persist throughout life. It's not a finite resource. Men don't run out of testosterone producing cells. Instead, these cells gradually become less capable at their job. Think of it this way. If female menopause is like a warehouse running out of inventory, male menopause is like a factory that keeps running, but slow less and less of the product each year. The machinery is still there, but it's not working as well as it once did. This gradual decline typically begins around age 30 to 40, with testosterone levels dropping approximately 1% per year. But here's what makes this particularly significant. Free testosterone, the biologically active form that's not bound to proteins in the blood, which inactivates it. It declines even faster at about 1 1/2 to 2% per year. This is partly because levels of sex hormone binding globulin, sometimes just abbreviated as shbg, tend to increase with age, grabbing more of that testosterone and make it unavailable for use. So we have this compounding effect, a reduction in testosterone production. At the same time, we have an increase in testosterone binding. So the sex hormone binding protein is locking up more of the testosterone and thus the free amount, which is, again, as I noted, the biologically active form, is greatly reduced relatively. There's a landmark study called the Massachusetts Male Aging Study, and they found that total Testosterone declined at 1.6% per year, while bioavailable, or the free Testosterone, dropped at 2 to 3% per year. Similarly, the Baltimore Longitudinal Study of Aging confirmed consistent testosterone decline across every decade from the 30s through the 80s. The clinical implications are substantial. By their 60s, approximately 20% of men have clinically low testosterone. By the 70s and 80s, that number rises to about 50%. Yet because this decline happens so gradually, unlike the more abrupt transition that women experience, many men don't realize what's happening until the effects have accumulated significantly. The mechanisms behind the decline are myriad and interesting. So I want to discuss them. Of course, as a cell biologist, I always want to look at the mechanism. So I'd mentioned this earlier. Do Leydig cells actually become less efficient? This is where the metabolic connections become particularly fascinating and where I think we can find some hope for intervention. First, let's talk about mitochondria. Testosterone synthesis is fundamentally a mitochondrial process, the rate limiting step in steroid hormone production, which is all the sex hormones. Actually, it's getting cholesterol, which is the raw material for all sex hormones, testosterone included, into the inner mitochondrial membrane, where it can be converted to a molecule called pregnenolone, which is the precursor to all steroid hormones. Now, there's a little bit of fundamental endocrinology baked into this discussion that I'm kind of assuming, you know, and that might be dangerous on my part as a teacher. The steroid hormones are their own class of hormones separate from any others, where they're all built on a steroid nucleus or a cholesterol molecule that's been modified. So all sex hormones start with cholesterol, and you have to get the cholesterol into the mitochondria. This transport depends on proteins called star, S, T, A, R, that stands for steroidogenic acute regulatory protein, and also another one called tspo, which is a translocator protein. Both of these decline with age. Research that was published in the FASEB journal just a few years ago demonstrated something interesting. They found declining tspo, that's the translocator protein, that these decline in the TSPO levels are associated with deteriorating mitochondrial structure, specifically the cristae. These are the inner foldings of the mitochondria where so much of the cell's energy production happens. You know, if you think of something like the electron transport system, all of that's located on that, on the crystal, these, the inner mitochondrial membrane. When the architecture or the structure of the mitochondria is compromised or shifted, it falls apart. So does the cell's capacity to make testosterone. But here's something that I find particularly interesting. They also showed the same study that promoting mitochondrial Fusion essentially helping the mitochondria maintain a long, connected, reticular or stringy structure. Remember, the word mitochondria is derived from the Greek word for thread, which is mitos. Mitochondria are long, stringy things woven through the cell. They found that when they could really promote a metabolic milieu of greater mitochondrial fusion, they could restore testosterone production even in older Leydig cells. Remember, the Leydig cells are the testosterone producing cells of the testes, the male gonads. This suggests that the decline is not inevitable. It's potentially reversible if we can support mitochondrial health. Indeed, this touches on some of my own work from my lab, where we've published before that ceramides, a very highly active lipid or a type of fat within the cell, can mediate forced mitochondrial fission. And we found one final point before I kind of revisit this. Chronically elevated insulin is a key signal for mitochondrial fission or ceramides production. So basically, we found increased ceramides would force the mitochondria to pull apart. That's the fission aspect of it. And when you have forced the pulling apart. This touches back on this paper from the fastib journal in 2022. If you're forcing mitochondrial to be in a fission state, you're reducing their ability to make testosterone. Now, I mentioned insulin because in my study, that same paper, we found that elevated insulin is a stimulus for ceramides. Now, there are other stimuli as well, like inflammation, but I of course want to talk about insulin because I don't talk about it enough. So by now you surely know that insulin resistance is central to virtually every chronic disease. But the connection to testosterone is both quite direct, but very often overlooked. There was a very good study published in 2005 that examined men across a spectrum of insulin sensitivity. What they found was striking. There was a strong correlation between insulin sensitivity and testosterone response to various stimuli. In other words, the more insulin resistant a man was, the less testosterone his Leydig cells could produce when they were stimulated. What makes this finding so important is that this effect bypassed the pituitary gland. So it wasn't the brain that was sending weaker signals to the testes. It was the leading cells themselves that were less capable of responding to the signals coming from the brain. This is a direct effect of insulin resistance on testosterone production at the gonad level. Now, how might this work mechanistically? In 2013, there was work that identified a key player, a protein called DAX1. Under normal circumstances, insulin helps regulate steroidogenic enzyme expression. But in insulin Resistant states. Chronically elevated insulin leads to upregulation of DAX1, which suppresses the very enzymes needed to make testosterone. It's a metabolic vicious cycle. Insulin resistance impairs testosterone production, and low testosterone itself promotes further metabolic dysfunction. And this brings us to perhaps the most insidious mechanism of all, the role of body fat in testosterone decline. Fat tissue is not just passive energy storage, as it's so often considered. Our body fat is active in both metabolism, yes, but also endocrinology. And one of its activities is particularly problematic for men's hormonal health. Adipose tissue contains an enzyme called aromatase. This enzyme is fascinating because it converts testosterone into estradiol, that's the primary female sex hormone. Now, again, just to confirm, men have estradiol. So even even though I'm calling it the primary female sex hormone, men have estradiol. And estradiol, as I have stated abundantly in the past, is the main estrogen. So even though I have been using the word estrogen throughout this, at least the beginning part of the discussion, there is no single hormone called estrogen. It's the estrogens, which is a small group of the predominant female sex hormones, and estradiol is the main one. So very often people say estrogen and they actually mean estradiol. But to put a fine point on this, all estradiol in men and women came from testosterone. And it's through this process of the enzyme aromatase. In men, approximately 85% of circulating estradiol, or I'll just say estrogen, comes from this peripheral conversion. So what I'm describing, that can happen in the fat cell that is the majority source of estradiol in men. So this is what I just said is peripheral conversion. So in other words, the main source of estradiol in men, and this is important in men's health. Men need estrogen for normal, healthy function. It's from the testes producing a lot of testosterone, and then peripheral tissues like adipose tissue converting it into estradiol or the main estrogen.
