had 10 percent shorter penises, even while controlling for the fat tissue that's on the base of the pubic area. [Music] Good morning, friends. Today, I will tell you how being fat during puberty may make you have a smaller penis later in life. This is the first video ever made about this subject. It's based on a paper released this year, so this is exciting stuff. But before we talk about it, please subscribe to the channel if you're not already, like the video, and comment on the video for the sake of the algorithm. Now, let's get started. I want you guys to know how interested I am in this subject. For years and years, I've been suspicious, even before I knew very much about biology, that being fat during puberty somehow affects our growth and development. In particular, I was fat during my puberty, and I was particularly tall for my class until we reached puberty, at which I didn't grow much more, and I noticed other people that were much smaller than me before grew dramatically. Moreover, as I learned more

about endocrinology later in life. I became suspicious that being fat promoted a pro-estrogenic hormonal environment in the body that may inhibit some androgenic signaling. For those that don't know, estrogens are sort of female hormones that in men are mostly derived from our male hormone. The male hormones are called androgens, and they're mostly known for testosterone, although there's also another hormone called dihydrotestosterone, which is made from testosterone and particularly relevant to penile growth. Now, before we move on, we have to briefly talk about how hormones affect penile growth in humans, but we're not going to be comprehensive. In particular, I want you guys to understand how a couple of hormones are all that we need to get good penile growth throughout our lifetimes. And to show you that, I want to review a rodent study. In this rodent study, what the authors did was they intervened on rodents' sexual development by using what's called a gonadotropin-releasing

hormone receptor agonist. Well, that was a mouthful. What is that briefly? I have to describe to you how steroidal hormones signal in our bodies. There are two points that they signal in the brain. One is the hypothalamus, and one is the pituitary. By the way, as a side note, that's why the hypothalamus and pituitary are one of the reasons that they're the most important parts of our brain and our bodies, really. Anyway, the hypothalamus releases gonadotropin-releasing hormone, which the pituitary senses, and in response releases luteinizing hormone and follicle-stimulating hormone. In males, luteinizing hormone tells their gonads to produce testosterone. The gonads are the testicles, whereas follicle-stimulating hormone tells the gonads to proliferate and differentiate sperm, and it tells the gonads to grow in adulthood. Follicle-stimulating hormone (FSH) is at somewhat lower levels than in puberty because, except in pathological circumstances in adulthood, that hormone is mainly

stopping our testicles from atrophying. It's not meant to grow them, whereas in puberty, follicle-stimulating hormone can be much higher. So, in this study, what they did was use an agonist of the gonadotropin-releasing hormone on the pituitary. What does that do? Well, when you agonize that receptor continuously in the pituitary, the pituitary down-regulates that receptor and consequently stops producing luteinizing hormone and follicle-stimulating hormone. So, in this study, what the authors did was essentially induce hypogonadism among rodents. Hypogonadism means small gonads but essentially indicates low testosterone levels, low testicular health, and so on. So, what does this hypogonadism do to the rodents' penile health? Well, one of the things it does is cause fibrotic development in the penis through the overexpression of collagen 1 and collagen 3. This fibrotic development is not actually healthy; it's pathological and can inhibit not only

growth of the penis, but also erectile quality later in life. And this by itself is an interesting side note for those that don't know that when you have hypogonadism, you are more likely to develop scar tissue in your penis and in your testicles acutely, even as an adult. But of course, that's not why I'm telling you about this study. What I wanted to show you in the study that's quite interesting is that the authors compared how testosterone by itself and testosterone with growth hormone and growth hormone by itself affected penile development in these rodents that didn't have working testicles. What did growth hormone do by itself? Well, it normalized collagen 3 overexpression, but it didn't grow the penis without the testosterone. The growth hormone did not cause any recovery of penile size in the rodents, whereas testosterone monotherapy did grow the rodents' penises, but it didn't normalize them. It didn't recover them fully from this intervention. On the other hand, even though these rodents didn't have working testicles

testosterone therapy with growth hormone totally normalized their penile dimensions by adulthood. This appears to be due to growth hormone upregulating the androgen receptor in these rodents, particularly in their penises. Another interesting note, actually, growth hormone treatment attenuated the effects of testosterone replacement therapy on increasing hypogonadism. Well, that was a little complicated. Let me break that down for you. So, essentially, what happens is these rodents have smaller testicles that are not working properly because of the intervention, but testosterone monotherapy makes them even more dependent on this exogenous testosterone level and gives their brains a negative feedback to whatever signal they are producing to their gonads. So, they're gonna shrink even more. Growth hormone treatment inhibited this extra shrinkage that came from the testosterone replacement therapy. And this is quite interesting because I've known some people that say that they don't have much testicular shrinkage from going on steroid cycles, and oftentimes these people also use growth hormone. It may not be coincidental in

fact. GH treatment to adolescence induces testicular growth even when they are not GH deficient, causing their testicles to actually get larger, particularly not just their whole body but in particular their testicles. As I said, I may make a video later on on all the determinants of penile size and how it varies across our lifetime, the growth rate. But for now, all you have to remember is that androgen signaling locally at the penis is the most important determining factor for penile growth and penile development throughout our lifetimes, and it's potentiated by growth hormone and likely IGF-1 signaling. So now that we know that testosterone and growth hormone are that important to our penile development throughout our lives, how does being fat in puberty affect your hormones? First of all, girls who are fat during puberty have earlier puberties pathologically. So whereas boys that are fat during puberty sometimes in some studies have earlier puberties and in other studies they have later puberties, but in both cases they usually enter into and finish from

puberty quickly, and the main study we're going to review today. Teenage boys had 40 to 50 reduced testosterone levels if they were obese compared to their lean friends. 40 to 50 percent. That's half the testosterone levels that lean kids had. Next, how does being fat during puberty affect growth hormone levels? Well, fat teenagers have lower growth hormone levels. In fact, they respond to growth hormone-releasing hormone less than other teenagers. So, in fact, if they're injected with growth hormone-releasing hormone, they don't respond normally. They respond to the hunger hormone ghrelin, which is also an activator of the growth hormone-releasing hormone, better than they do to growth hormone-releasing hormone. But they also don't respond to ghrelin well in terms of growth hormone synthesis. They have lower serum growth hormone levels generally than people who are not obese. In fact, some obese teenagers have such low growth hormone levels that if you looked at their blood work, you would think that they were dwarfs. Obesity harms the growth hormone.

signaling pathways so much that it even blunts the growth hormone response to exercise, and that's dependent on adrenaline, by the way. So, that's through a different mechanism as well. But anything that gets to that growth hormone system doesn't work on these guys. Serum growth hormone levels are inversely associated with adiposity, such that the fatter you get, the less growth hormone you have. On the other hand, serum levels of ghrelin, that hunger hormone that also activates the growth hormone system, are positively associated with adiposity, such that the fatter you are, the higher your serum ghrelin levels are. And this is associated with ghrelin resistance among the obese, which likely explains some form of how their growth hormone systems are impaired. In fact, I'm not the only one who thinks this way. Some academics have also theorized that the way the growth hormone system gets impaired is through the ghrelin resistance and also IGF-1, which we'll talk about in a little bit. Now, a side

note before we leave. Growth hormone growth hormone synthesis in puberty is also affected by steroidal synthesis such that testosterone levels affect growth hormone levels in that causal reaction. Next, igf-1. I just want to touch on this briefly because it's important to mention obese children and obese pubertal adolescents have higher serum igf-1 levels. Igf-1 is a well-known growth factor called insulin-like growth factor 1. Igf-1 rises in response to growth hormone through the growth hormone receptor, but it also acts as a negative feedback for the synthesis of growth hormone. The reason the obese are thought to have higher igf-1 levels is due to insulin signaling because they eat so much. In fact, obese children of all ethnicities have higher serum igf-1 levels, but particularly obese people who are of African descent because those of African descent on average almost always have higher igf-1 levels in studies. Now, I've read some studies before that theorized that pubertal increases in igf-1 signaling due to obesity may

overwhelm the reduction in growth hormone synthesis, but that's not true. Obese children mature to be about five centimeters shorter than they would have been otherwise, and in fact, they're even short compared to their parents, as compared to lean children, compared to their parents. And note that even in the treatment of children who are short, like dwarfs, growth hormone plus igf-1 therapy is always superior to igf-1 therapy by itself. Growth hormone is indeed a growth hormone, and it is necessary for our full development, irrespective of igf-1 levels, even if they're a bit higher. So let's recap what have we learned so far. Well, if you're obese during your puberty, you likely had about half the level of testosterone that you would have had otherwise, and your growth hormone levels may have been so low that people couldn't distinguish you from a dwarf based on your blood work. What would we expect this to do? Well, given that rodent study that we just reviewed, we would

expect the low growth hormone levels to cause a lower androgen receptor expression, so you'd have less androgen receptors in your body for testosterone and dihydrotestosterone in particular to bind to and activate penile growth. But you also have half the level of androgens, so there's a lot less androgenic signaling in general. Next, if being obese during puberty does indeed halt penile growth, what are the mechanisms that might be at play other than this testosterone effect and the growth hormone effect? Well, first of all, many of you know that testosterone aromatizes, gets converted by an enzyme called aromatase into estrogen in men. In fact, peripheral aromatization of testosterone is responsible for about 80 percent of our estradiol. Aromatase expression is particularly high in adipose tissue, that is, fat tissue, which might explain why obese young men have higher estrogen levels than non-obese young men. In fact, as a person gets fatter, their steroidogenesis is inhibited due to their adiposity, but the

interesting thing is that their estradiol levels, the estrogen, reduces less than their testosterone, the result being that their estrogen over testosterone ratio increases. They become more estrogenic and less androgenic as a ratio, but testosterone doesn't just get converted to estrogen in fat. In fact, it gets converted to that directly in our testicles. You see, all of the somatic cells and germ cells in our testicles have aromatase activity. Moreover, local expression of estrogen in our testicles directly inhibits their activity without even affecting our brain. It directly inhibits the activity of the testicles, but estrogen also inhibits activity in the brain, both at the hypothalamus and at the pituitary. So, estrogen levels basically tell your whole body to stop producing steroids, to stop producing your most important steroid, testosterone. As a result, you end up with less estrogen because of less conversion to testosterone, but the ratio changes. To see how powerful this is, consider the common example of obese people going on aromatase inhibitors. Aromatase

inhibitors that inhibit the expression of that enzyme aromatase totally normalize testosterone levels in the obese. But what else could be reducing penile growth during puberty if someone's obese? Well, even hyperglycemia, having high blood sugar all the time, can inhibit the activity of gonadotropin-releasing hormone neurons in the hypothalamus. And hyperglycemia down-regulates gonadotropin-releasing hormone genes, caspectin genes, the kispeptin receptor, which we could talk about in another video. Kispeptin is a separate issue, and the leptin receptor, which we'll talk about in a little bit next. If you're fat during puberty, you're likely insulin resistant, and that's a huge problem for this whole steroidogenesis cascade. The gonadotropin-releasing hormone neurons of the hypothalamus have insulin receptors, and when insulin agonizes those insulin receptors, it releases gonadotropin-releasing hormone. But when you develop resistance to the

insulin at the insulin receptor. Insulin can no longer do its job, and that's how gonadotropin-releasing neurons from the hypothalamus react to insulin resistance. They've stopped producing as much gonadotropin-releasing hormone, causing, in the end, less luteinizing hormone and less follicle-stimulating hormone. Remember, at the hypothalamus, we have the gonadotropin-releasing hormone neurons. Those neurons have insulin receptors. When insulin agonizes those receptors, there's resultant signaling through the MAPK pathway. And as you develop insulin resistance, the gonadotropin-releasing hormone neurons in the hypothalamus also become resistant to insulin, and that insulin signaling apparently is necessary for their full activity. So when young men aged 18 to 25, insulin resistance is highly correlated with low testosterone levels. What's worse is that the androgen receptor is needed to promote some anti-insulin resistance pathways, or pathways in the body that protect us from insulin resistance, such that having lower

testosterone levels actually predispose you to insulin resistance. That's a positive feedback loop. Insulin resistance makes you have low testosterone levels, and low testosterone levels make you insulin resistant, and it keeps going on and on. Next, most of you have heard of the hormone leptin. Leptin was the first hunger hormone, a satiety hormone sort of discovered in that family. Leptin is one of the hormones that tells us we're satiated and we don't need to eat more. Obese people tend to be leptin resistant at the receptor, where they have high leptin levels in their serum, but they don't feel it. Leptin, by the way, is primarily produced by what's called white adipose tissue. That's normal fat that's not thermally active, such that the more white adipose tissue you have, the more leptin levels you have, irrespective of your eating. But also, these people are eating a lot, so they have very high leptin levels. What does leptin have to do with steroidogenesis? Well, there are

some mutations in the leptin receptor that on their own, even without higher serum levels of leptin, cause hypogonadism. Because of these genetic studies, it's thought that leptin signaling, or leptin sensitivity at the very least, is necessary for good steroidogenesis in the human. Consequently, it's thought that leptin resistance down-regulates the synthesis of gonadotropin-releasing hormone at the hypothalamus, inhibiting the whole process from the very beginning. Well, there's another beginning, kispeptin, but we'll talk about that later. But leptin hurts the system in many other ways. So, for example, leptin weakens the blood-testes barrier and gets into the testes and may have a local anti-steroidogenesis effect in the testes. In fact, blood leptin levels are correlated to semen leptin levels and inversely associated with our testosterone levels, such that when the leptin level rises, the testosterone level declines. But there's more leptin.

really doesn't like the steroidogenesis pathway. Let's talk about two more issues. First of all, leptin directly inhibits our antioxidant defense system and is associated in human serum. Leptin levels are associated with inflammation. It's not thought to be just because those people with high leptin levels happen to be obese. Instead, it's actually weakening our ability to deal with oxidative stress in our bodies. As such, leptin resistance is thought to play a causal role in some forms of chronic inflammation. And it still gets worse. Leptin also raises aromatase expression in fat, and particularly in breast tissue. It plays a causal role in obesity-induced gynecomastia. It even stimulates the growth of mammary epithelial cells directly without the estrogen receptor. So, it potentiates estrogen signaling in the development of gynecomastia and directly causes gynecomastia as well. Finally, for good measure, how else could being fat during puberty make you have lower testosterone levels and a smaller penis later in life?

inflammation. As those that watch my channel often will know, there is a robust relationship between inflammation and lower testosterone levels. The higher your inflammation is, the less you will synthesize gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone, and the lower your testosterone level will be. Before we talk about the amazing paper that I really want to talk about today, let's quickly review the mechanisms I mentioned. I mentioned five mechanisms that could cause you, if you're obese during puberty, to have a smaller penis later in life. These are mechanisms I thought of myself. The first is having higher estrogen levels and a higher estrogen-to-androgen ratio. The second is being hyperglycemic. The third is being insulin-resistant. The fourth is being leptin-resistant. And the final one is inflammation. So how does being fat during puberty affect penile growth? Well, again, before I say that, I want to say one more thing. It's just an interesting subject. There's a study done on toddlers, following them from three months old to

three years old. Even in those years, in the toddler years, body mass index was inversely associated with testosterone levels, such that even in toddlers, the fat toddlers have smaller penises. So, this really starts quite early, although I admit that this major effect might be seen because in the first three years of life, the first six months, the mini-puberty that I talked about in my voice video is disproportionately large out of the whole lifetime. For those that didn't see my voice video, when we're born, for the first six months of our life, we have very high steroidogenesis, testosterone, and estrogen levels, somewhat similar to in puberty, but then it declines and doesn't rise again that high until puberty. And finally, now let's talk about the amazing study from this year, an Italian cross-sectional 2021 study. This study covered newborns to the age of 20, and it had 1,130 participants, all pediatric patients of a certain pediatric clinic in Italy. This study recorded the testosterone levels, the weights, and the stretched flaccid length.

of the penises of these 1130 youths. By the way, as a side note, the stretched flaccid length is the most reliable way to measure a penis's length consistently across time and across people and is usually used in these studies. So, what did the authors learn in this study? Well, they learned three interesting things. The first is that the obese children entered into puberty later and went through puberty quicker than the non-obese children. In all of the cases, the obese children had lower testosterone levels than the average children their age that weren't obese. And finally, the obese children had 10 percent shorter penises, even while controlling for the fat tissue that's on the base of the pubic area. This 10 decrease was consistent across the age groups and was statistically significant. So, there you have it. Being obese during puberty makes you, on average, five centimeters shorter than what you would have been otherwise and makes you have a penis that's ten percent shorter than what it would have been otherwise. And by the way, I have another hunch. I believe

that being obese during puberty should affect the circumference of the penis even more than the length of the penis because of its effect on blood flow. Anyway, guys, what's the long and short of it all? Well, first of all, we talked about how testosterone and growth hormone cause penile development through our lifetimes. We also talked about five mechanisms by which being fat during puberty could cause you to have a smaller penis later in life, and that coincides with the five-centimeter average reduction in height. So, if you have children or relatives that are young that you care about, let them know if they're fat during their development, they'll be shorter and less masculine for the rest of their lives. Anyway, guys, thank you so much for bearing with me. I hope to see you again this afternoon. [Music] You

This Made Your Penis Smaller

This Made Your Penis Smaller