Hormone Replacement Therapy: In Depth

Foreign. Stands for hormone replacement therapy. It's got shortened hrt. But the concept is that you're born with different kinds of cells. So we have somatic cells, which is all the cells you typically think about in your body. And then we have germ cells, which are the cells that allow us to reproduce. They're essentially immortal. So you'll pass on your germ cells, your kids and not so much your somatic cells. And that's through reproduction. And those same organs produce our sex hormones. So we say hrt, it really is kind of a crude term for sex hormone replacement therapy, not regarding to having sex, but regarding to the sex type hormones. So we have many hormones in our body you might even think of like your cortisol level or your thyroid. And hormone replacement therapy, typically in the, in this setting we're referring to testosterone, estrogen and progesterone. And there's a whole slew of other ones, but those are the key ones and we have tons of other hormones beyond that. So what happens is that a man and a woman are both born with organs that can create this hormone replacement therapy. So there's one in our brain, there's actually a couple organs in our brain that stimulate the production of pre hormones that signal our sex organs to make our sex hormones. So the simple one is a man, because we have predominantly testosterone, which is much, much richer in our body than estrogen, although we do make estrogen as well on progesterone. And with a man, he never really goes through a true menopause type thing. We might call it andropause, but over time that testosterone just sort of dwindles down. And the faster it goes down, the more aging symptoms the man will typically have. So a guy will that has a lower testosterone at 40 than other men, will act a little older, won't put muscle on as fast, won't be as fast, won't be as confident, be more tired, maybe some depression, some erectile dysfunction, some decreased energy, falling asleep in the afternoon. And the guy that's 80 years old and still active and playing golf and you know, logging and cutting wood and he seems like he's really good shape. He measures testosterone levels usually like that of a 40 year old guy. So it's higher, but between 20 and 40 it drops, and 40 and 60 it drops. But there's generally not an abrupt change for women. Women have a certain number of eggs they're born with. So men make testosterone and sperm throughout their life. Women have a certain number of eggs and once they run out before they run out. They're kind of grabbing the bottom of the basket and getting perimenopausal. Once they run out, they're not making nearly as much testosterone, estrogen, progesterone and interestingly, a woman has 20 times more testosterone than estrogen. We think about estrogen as being the female hormone and it is more of a feminizing hormone. But men and women have almost the same amount of estrogen and men have 20 times more testosterone than women or at least 10 times more. And women have 20 times more testosterone than they have estrogen. So we both have both of those hormones, but we just have in men we have much more testosterone than estrogen, more like 200 times more testosterone, estrogen in men and more like 20 times more in women. And there's different things that feminize or masculinize men and women besides your hormones. So a woman gets into menopause or perimenopause, her eggs are no longer producing as much of this progesterone, different hormones to, to make her feel like a woman. And once she goes into menopause, ovaries have basically failed. It's whole menopause is defined as having either having your ovaries removed or, or the ovaries stop producing eggs and you don't have a period for a year is the classic definition. When that happens, these testosterone level precipitously drops, estrogen precipitates or drops and progesterone precipitously drop and it's more abrupt. And when we get more we call vasomotor symptoms which would be commonly would be the hot flashes, night sweats, mental fogginess, decreased energy, maybe irritability and you know, hair loss on the scalp and facial hair growth. Bones get thinner, weight starts piling on, skin gets a little bit weaker. And this has led to the idea of using hormone replacement therapy for women. The first one of the first hormones approved for women was testosterone in 1953 or so for breast cancer. But the first time we started using hormone replacement therapy for women was right around that time, maybe a little early. We would use up, use ground up sheep ovaries and women would basically dry them out. It's called desiccating them. And women would eat them and they get symptomatic relief and women get symptomatic relief. And then for then later on came using horse estrogen. And the one that was common was called Premarin. P R E pregnant mare M A R E Horse in urine pregnant mare urine. So the five year old pregnant Mare has got a lot of estrogens that they urinate out, and they would take that and drive it out, and this would become a pill form for women. Now they no longer make Premarin out of horse urine. They take soybeans, and they genetically create the soybeans to reproduce a pregnant mare's urine of estrogen. And there's many different estrogens that have Premarin in a pregnant mare urine. And they do help with menopausal symptoms. So back in the 80s and 90s, let's say even before then, in the 70s, we were giving women Premarin for menopause. Poisoned were great. They felt better. Hot sweat's gone, gaining less weight, more energy. But lo and behold, women were getting some ovarian cancer. And about 15% of women on Premarin by itself would eventually get ovarian. I'm sorry, uterine cancer. I said ovarian made a mistake. Uterine cancer. And uterine cancer is a cancer of the womb or the uterus. And it's typically one of the much more survivable cancers, but it's a cancer nonetheless due to a hysterectomy. And then we discover, well, you can't give estrogen by itself. You've got to add progesterone to it. Now, progesterone is the yin to the yang of estrogen. So progesterone suppresses overgrowth of the uterus, but also works in the brain, the bones, the heart, and different organs. So we did that, went from Premarin to Premarin plus progesterone. The big trial called the PEPI trial, 30 years ago, maybe more than that. And they found that women on premarin and progesterone, they had their uterus still or women on permarin, only if they didn't have a uterus. Out survived women who took nothing, they lived longer, lived healthier, and a lot less cardiovascular disease. So estrogen was held to be cardiac protective. Well, then along came the concept. Let's study what happens if. Should we just put every single woman who's in menopause, regardless of age, on permarin? And not only that, can we make a synthetic form of progesterone that would theoretically enrich drug companies? And this is, you know, we basically, research is either done by National Institutes of Health, which is altruistic, through the government, or by big Pharma, which is to make profits through new drugs. So progesterone had been used, and out came this class of drugs called progestins. Progestins or a synthetic form of progesterone to protect the uterus from estrogen. And the classic one was Provera. And in fact it did, you know, cut down uterine cancer arguably maybe be better than progesterone. So the standard of care became to use Premarin for women that had hysterectomies. In other words, a uterus removed and women had a uterus were in menopause. Permarin and Provera in a large study called the Women's Health Initiative Trial. Whi many doctors in my field feel that was the biggest disservice study in women's health and history, what they did is they put women who had been in menopause 5, 10, 20, 30 years that were on nothing, had no symptoms. They put them on synthetic estrogen and a synthetic progestin. Even though we had other options. It made sense because this was what doctors were thinking they should be doing. And before the study was finished, they paused it because they saw a statistically significant, very small increase, but a statistically significant of breast cancer and heart disease, depending on what we were looking at. So women on Premarin alone had slight increased risk of heart disease and women on Premarin and Provera had a slight increased risk of breast cancer. It wasn't really expected that to happen that way, but the that's what we saw is about 8, 100 or 1%. So increased risk. This led to doctors abandoning using hormone replacement for women tell them they were going to get breast cancer and heart disease. And what we didn't understand back then in 2002 and 2004, because it was publicized in the USA Today in the Wall Street Journal was that there was a timing concept. We weren't taking women who were 80 years old who had never been on anything and putting them on Premarin and progesterone. We're putting it on it at menopause. Well, they looked at the group of women that were put on Premarin and Probera or Premarin alone within 10 years of menopause, they actually had a 40% reduction in cardiovascular disease, substantial reduction in all cause mortality. In other words, they were less likely to die, 40% less heart attacks. And this has led to why I talked about the biggest mistake or misdeed we did for women's health in modern history is that we misread a study that was intended to answer one question and said, well, you can't do this anymore. So, so women left this or put on antidepressants, antipsychotics left to suffer with it, when in reality they would have had less heart attacks. And if you calculate that out back in the 90s, this was the number one prescribed drug in America. It's not anymore how many deaths occurred because we misread the studies and it became a political hot potato. All of a sudden, hormones caused breast cancer and hormones cause heart disease, which was nothing further from the truth. But cardiovascular disease is markedly protected by estrogen. Estrogen is very cardiac protective. We just misread the data. The other thing is, could we use something other than synthetic drugs? That's another question. So kind of simultaneous with that, there was other studies because Americans were unique in using America. We're in love with big pharma. And if something is generic and safe versus something that's expensive and unknown, we'll buy the expensive and unknown. So we were jumping into the newest stuff. Whereas in Europe, they're more likely to use something called estradiol, which is not, not a horse urine estrogen, but it's actually human estrogen. And they're using testosterone and they're using progesterone. And we see by looking at the European data, depending on what we're looking at is these things are all very cardiac protective and breast cancer protective. Large study done in America looking at testosterone with women with menopause is there's anywhere between a 30 and a 70% reduction in breast cancer using testosterone with or without estrogen. And again, we picked Premarin because it was easy to get. But as I told you, there's 20 times more testosterone than there is estrogen in a woman. What about testosterone? Well, testosterone improves all symptoms of menopause, reduces breast cancer by somewhere between 30 and 70%, helps with weight maintenance, helps with bone density, helps with mental, mental fog. It helps the hot flash and night sweats, probably to some degree cardiac protective or cardiac neutral. Estrogen is very cardiac protective. So now if we imagine using testosterone as a primary hormone that you're making when you were at 30, a little bit of estrogen, 1 20th as much, and progesterone for protection of organs, we've got the trifecta of reducing breast cancer cardiovascularities, uterine cancer and improving vasomorph symptoms and improving all cause mortality. And it appears that longevity is extended by somewhere around three years of healthier of a longer lifespan, healthy lifespan. So three years times what, you know, 170 million women in America. That's pretty, pretty profound. So this has led to more modern understanding, temporaneous understanding that hormone replacement therapy, we thought in the 2002 and 2004, that's when the studies were published that there's a risk, but it's really a risk associated with putting women who had been in menopause more than 10 years on aggressive synthetic steroids versus doing hormone replacement therapy. So that's in women. How about men? So men don't have menopause, they have something. Andropause is really not probably a true medical diagnosis. But I mean some. The European considered consensus that there is a male menopause. The testosterone replacement therapy was approved in the 50s as well. And testosterone placement therapy had not the same trajectory as female HRT, but something similar where studies came out and we reacted. So testosterone improved in the 50s for men that had one of three conditions. They had an extra female chromosome, they had brain damage, so their brain could not give the signal to the testicles, make hormones or they had a testicle injury and they had low testosterone. And the testosterone was not just low but extremely low. So in the 1920s they measured a bunch of people, a bunch of men between say 18 and 95. And they said, okay, the bottom 2%, top 2% are abnormal. Everybody else is normal. Probably, you know, it's different now. These were heavier than we were then. And that would presume only 5% of people have abnormal testosterone level from 18 to 95. That became the level with those certain conditions that became FDA approved for men with low testosterone due those conditions. And the way it's established by insurance companies and by say who's going to pay for this is that you've got to check it twice before 10:30 in the morning, two consecutive days, got to be low, like 285 or something. And then insurance will pay to get you from 285 to say 290, which would be considered normal. So that's sort of that. I think one of the things that's so sort of impaired, testosterone replacement therapy is not going to be free from your insurance company. And the second thing that happened is that the in the 90s, testosterone replacement therapy appeared to have great benefits for men. They were having less fat, they had better muscle mass, they had better libido, better energy, they felt better, they weren't as depressed. And these creams for testosterone came out. Initially we've been using pellets or injections and creams came out that probably don't work as well. But again, it was an opportunity for big pharma to make some money. And the Abbey Pharmaceutical company started advertising a Do you have low T campaign? Low T was a big commercial made by the pharmacy companies. Well, the FDA sued them and they said, wait a year, brother. We did not approve testosterone for low T. We approved it for low T due to brain injury, testicle injury, extra female chromosome, therefore US $150 million. You can't advertise this anymore. Knock this off. And they did. And this led to doctors stopping prescribing it because they thought they were restricted by the fda, which are not. The FDA regulates manufacturers, not physicians. And it kind of led to a pullback and insurance being really loose with covering testosterone replacement therapy. And as a result, about 12, 13% of men were on testosterone prior to that time. Now it's about 3%. And so much many less men are treated, even though it has probably better mortality outcomes than testosterone and estrogen in women. Large study done at the VA University St. Louis published in 2016, looked at 80, I think 83 or 86,000 men that were on the average age 66 over six years. So 80,000 men plus over six years, which is a massive study, we call that, you know, basically 500 million person years. And they looked at men with low testosterone diagnosed in a laboratory, and if they were treated or not treated, they had a third group of partially treated. What they found was men that were treated with testosterone were half as likely to die in the next six years than the men that were treated half in 2013. The FDA came out and said, not only want you to not advertising low T, we want you to label testosterone saying it causes heart attacks. We think it causes heart attacks. And they based it, based on one study that was since retracted, that suggests the testosterone caused heart disease. There was nothing further from the truth. There were over 120 studies, 127 studies published prior to that time showing testosterone was cardiac protective. One study came out, contradicted it. FDA got all over it. That study was retracted. That black box is still there, still there. And some doctors actually believe it because they just believe it. They're detailed to use other drugs. So what do we use instead? We got metformin for diabetes, these GLP1 agonists. We have antidepressants, erectile dysfunction pills, all for things that might be related to low testosterone, even like CPAP machines for sleep apnea from being obese. So now we're seeing back in 2025 and I'm recording this is that now doctors are becoming more aware of studies, more aware of the safety of testosterone, the benefits for it for men, and maybe some of the BS that's gone on to lead to people being afraid of it again. There's a lot of money to be made in managing disease, very little money to be made in curing it. I really think about hrt. Sexual HRT is regenerative. You've lost your ovaries or your testicles ability to make testosterone. Your brain's ability to tell the testicles, make testosterone and you start degenerating quickly. We look at what happens with men with low T, they get more aggressive prostate cancer, they have more heart disease, they have more obesity, they have more frailty, they have more fractures. And we restore that. All those things go down. Now, the testosterone does not protect against prostate cancer, nor does it cause it. But men with low testosterone have the most aggressive prostate cancer. I just want to rephrase that. Testosterone replacement does not cause prostate cancer, but it's not protective either is protective. Cardiac disease, bone demineralization, obesity. Large studies following men over a decade found that testosterone strongly favors leanness over obesity. Now when we see men go on testosterone replacement therapy, let's say a guy's 30 pounds overweight and he's not working out and got a little pot belly, he goes on TRT or testosterone replacement therapy. Over years, weight maybe stay neutral, but he may have gained 8 pounds of muscle and bone and lean mass and lost 8 pounds of fat. He'll mostly feels better, but over a decade his fat mass would typically decrease and tempt him. Forbid he starts exercising. He'll even see that work out better. And guys will more likely exercise when taking TRT because they actually feel up to it. They see the gains. So that's kind of an overview of the history. I've written books on both of these subjects and kind of go into every organ, how these hormone replacement affects different organ systems. We started doing this back in 2003 when the first study from the WH Women's Health Initiative came out, because all of a sudden women were left with no options. The term bioidentical hormones basically just means we're actually using human based hormones. They're not truly natural. They're made in the lab, typically from soybeans or Mexican yams or the products we use to make these things from. But they are indistinguishable from human hormones, Whereas Premarin is indistinguishable from a horse's urine. The estrogen of horse's urine, Provera, which is the progesterone analog, is not in this thing. I mean, it's totally distinguishable from actual progesterone. Now there's analogs to testosterone for certain things. This has nothing to do with normal male trt. There's different drugs that are designed for bodybuilders or for certain rare conditions. That's not part of the normal hormone placement therapy men for sexual hormone replacement therapy. It's mostly for men. It's testosterone. We don't need estrogen in men. We don't need to add it. They'll make plenty. And they don't need progesterone. Typically, they might want to take something to keep their testicles producing testosterone. That's kind of controversial at best. Some men notice when they take TRT that their testicles shrink a little bit. Most men really don't see it or it's not significant. And you could take something that stimulates your body to continue to make sperm and testosterone. And for women, when they go on testosterone, estrogen, progesterone, that's usually, usually it. They still might need to check their other stuff, but other things aren't needed. In reality, these are the things that be taken for the rest of your life, if you so choose. It proves that this protection is long living. Now, somebody that's been in menopause 20 years, there's no known benefit to testosterone replacement therapy for a woman in menopause 20 years and has never been on anything or any hormone replacement therapy would be unknown. I wouldn't say pro or con for men. There's not a particular age. As men get older, they're more likely to have low T. And it's really easy to check. And the one question would be what level predicts which men will benefit? And there's a consensus statement published in the Mayo Clinic Proceedings. It's a consensus journal. And this states basically this. There is no blood test or no blood level that will predict which men will benefit from testosterone replacement therapy. So if you're a man and you have symptoms of low T and you can go online and do something called an atom questionnaire and your symptoms are there, you can get a blood test done. But the way you determine is, you know, take testosterone replacement therapy if you have. If your doctor agrees with you and see if you feel better. If you do, that's your level and what level you need to bring it up to. Again, it's a, it's a, it's a, it's kind of a guessing game. So we don't check a lot of post labs for testosterone because there's not a level that predicts where you'll feel the best. This is basically where you feel the best. Typically it's going to be in the upper limits of normal because your body makes little binding enzymes to bind up testosterone. So if your level is, let's say 300 to 1100 would be normal. When you take exogenous testosterone for man, there's only a certain amount that'll be free. There's not a good way to measure it. Is this a calculation? So we might want to run up to, you know, thousand to thirteen hundred and see where he feels the best for women. We check labs sometimes freaks them out because you got to be about two times, maybe three times normal physiologic levels. Because women make a lot of sex hormone binding globulin to bind it up. So there's not a lot of good monitoring with blood work. I think people do it and they're sort of just creating a lot of unnecessary anxiety. You know, imagine if you had high blood pressure and you're taking lisinopril, very common blood medicine for blood pressure. Would you measure a lisinopril level or the blood pressure? We would measure the blood pressure. Now you can measure lisinopril level but it wouldn't be too relevant because you don't know what level is going to give you a blood pressure. But you can do a blood pressure cuff for a woman that's got hot flashes, night sweat, she's gaining weight, meno fogginess, she's depressed and she feels better. That's her proper level. So how is hormone replacement therapy done? Conventionally you're using a drug that is put on the skin through a patch or a pill. That is the most common method in our practice. We're doing testosterone, estrogen and progesterone. There's not a great testosterone patch or pill women. So we use a pellet and it's about the size of a piece of rice. And we numb the skin up using your buttocks like where your pockets at. We put a little nick in the skin and slide the pellet in there. And since we're already putting a pellet testosterone, we then choose to use a pellet of estrogen. Although estrogen patch would be fine. It's just that's going to be way more cost effective and easy to use. The estrogen pellet, no skin reaction, glue and then the progesterone needs to be taken orally. Typically at night. There's not a pellet for test for progesterone. So why do we use the pellet? Because the testosterone being the mother hormone, it's not suitable for injections. Women or creams or pills. So pellet is the most suitable method. This is done typically every three months. It can be done the rest of your life. The incision is so small, you generally only see the mark. For men. How is testosterone supplied? It's typically injection cream or a pellet. Now, I would say creams are out. These do not give a therapeutic level. They're not going to be as cardiac protective. They're certainly cardiac neutral. They don't benefit the heart and they don't worsen the heart. But they're not as protective as the pellets or injections are. And the pellets injection. Now these. This is a personal choice. The pellets cost more, but we get a lot of patients wanting pellets because they like the fact of coming in twice a year to get it done. And a lot of guys don't want to give themselves shots. So if you don't give yourself shots, pellet's a good option. If you're okay with shots, you'll save some money. And you got to do that like every week. Some people do it twice a week. It's actually indicated to do once a month, which is way too, I mean, way too infrequent, but it's once a week. And the dose is basically based on your weight. And with men, we would check a blood count because sometimes some men will get an elevated red blood cell count. Their blood can get too thick. That's about one out of 20 men. If you're that guy, he's got to go donate blood every eight weeks or so. At the Red Cross, women don't seem to have that effect. So it's done as a pellet. Typically for men, powder, injectable women, a pellet plus a tablet for the progesterone. Men is every five months, sometimes every six months. Women is every three months. There's a lot of variations that you might even hear about using this thing called troches or a sublingual. We don't really do that. Too inconsistent absorption. Familiar with it. But it's. This is not our cup of tea. A good question is, when do I consider hormone replacement therapy? Again, we're talking about sex hormones, testosterone, estrogen, progesterone. It's highly variable discussion you have with your medical provider. But it's principally based on developing symptoms. There is no benefit to taking hormone replacement therapy when you don't have any symptoms. So when we talked about the cardiac protection, the breast cancer protection, when you're already making your own stuff, you've Got that protection. So youth is the best cure for disease. Okay, so if we have youth, let's say you're 30 years old and you know your testosterone is doing great, your estrogen for a woman is doing great. Adding to it can only cause side effects because you're going to have testosterone, estrogen excess once you start becoming symptomatic. So let's talk about women. So women during perimenopause, they're still making plenty of estrogen, their testosterone is typically dropping off and their progesterone is getting erratic. So a lot of times you'll see women in their late 40s and they're perimenopausal, which means they're still having periods. They might be erratic, but they're having symptoms of menopause. Hot flashes, night sweats, mental fogginess, weight gain. And those women, we may do a trial of testosterone with or without progesterone, we will not add estrogen. That'll cause tumor, too much uterine bleeding. So the, that's when we would consider it based on the patient's symptoms and the discussion with the patient. Now, once a woman's in menopause and she's not had a period for a year, then the threshold is really lower because you're not really testing it. You're going to say, okay, if you're symptomatic and you want to have a better quality of life, have these, understand the risk benefit that we've discussed, then it's appropriate to initiate therapy. Now, for men, it's a much more mixed bag because a lot of guys want to go on testosterone to look like the Hulk. And that's not going to happen with physiologic testosterone replacement therapy. So if a guy's got a testosterone level that's normal and he goes on testosterone placement, it's still going to be normal and his balls are going to shrink or his balls are not going to produce testosterone anymore because he's got enough. Now, these bodybuilders that get really big, they're taking 5, 10, 15 times the dose of testosterone, which is got its own inherent safety issues, which are considerable. So I'm not talking about that whatsoever. We don't practice that. So I'm not, I'm sure it can be done in some ways, let's say quasi safely, but that's not our practice or my expertise. There's no benefit for a man that has a normal testosterone has no symptoms. However, once a guy starts getting symptoms of low testosterone, he might start talking to his doctor. His medical provider about trying testosterone replacement therapy. Again, there's not a perfect lab level. I'll tell you when you might experience benefit. But there is a. Definitely a but. So if a man is on testosterone replacement, typically his likelihood of fathering a child would, would reduce. Because your testicles make sperm and testosterone, what is the incidence of that? Kind of unknown. What is the incidence of men that go on testosterone five years, stop it and try to get pregnant? It's considered to be pretty high likelihood. However, if you're a young man without a family and you do have low testosterone been worked up, we, you know, it's idiopathic, there's not a known cause, it's reasonable to donate sperm at a sperm bank should you fail to resume spermatic spent production after starting testosterone or ceasing it. And for the most part, though, when our practice doesn't see a lot of young men, we, if we have a young man with low testosterone, we usually have them go get worked up by an endocrine specialist, make sure you have a tumor in his brain or something like that. Typically we're seeing men in their 40s, 50s, 60s, maybe 70s that have low testosterone for no cause other than age. And again, that's not the FDA indication. The FDA says, nope, it's only for brain disorder, extra female chromosome testicle disorder. But most men taking testosterone placement have none of those. And their level is not severely low, it's just low. And he's going to have more diabetes, more obesity, more, less muscle mass, a little bit more erectile dysfunction, less sexual interest, less energy, more depression. So the age range is pretty much the same, men and women, you know, late 40s, 50s, 60s, younger people with hormone symptoms really are not going to fall into that typical sex hormone replacement. They're going to need to be worked up for many other conditions. Because when we're 50 and your period. Stop. A horse is a horse is a horse. It's a, it's menopause. When you're 20, in your period. Stop. There's something going on, we gotta figure out what it is. And it's not natural. You didn't run out of eggs. So the younger people should be worked up by an endocrine specialist. Once that's been done, they can see a hormone specialist, a hormone replacement specialist. And again, the difference between endocrinologist and a hormone replacement specialist. The endocrinologist deals with all endocrine realities and really deal with some of what we call the zebras, the rare conditions. And there's only a few of them. And they can't see all the people that are in America that have basically 100% have hormone deficiencies. Deficiencies. And your general doctor, your family practitioner, your nurse practitioner, they can be hormone specialists. They might not be, but they can be. So you're going to see a lot of generalists that are hormone specialists, and they are hormone specialists, but specific for menopause and antipause related to sex hormone decline. Whereas an endocrinologist, really, that's not their. That's not their cup of tea. They're going to be looking more for things like diabetes and rare endocrine disorders, and then they might pass you off to a hormone specialist.