165: Why Micronized Progesterone Is Different

If you're considering hormone therapy, there's one detail that deserves more attention: which form of progesterone you're taking. Progesterone and synthetic progestins often get grouped together, but they can act very differently in your body. Micronized progesterone is chemically identical to the progesterone your ovaries make. Micronized simply means the particles are made smaller to help your body absorb it. And that difference matters. In one major trial, it preserved more of estrogen's favorable effect on HDL cholesterol than the synthetic progestin tested. Taken by mouth, it also produces a metabolite that helps calm the brain and may improve sleep. That doesn't mean hormone therapy is risk-free. It means the specific hormone deserves a place in the conversation with your clinician. This is Lecture 165 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Today's topic is micronized progesterone, the form of progesterone that is identical to the hormone a woman's own ovaries make. And I want to, of course, discuss how its metabolic effects compare with those of the synthetic progestins, which have been used for decades in hormone therapies. If you have heard that progesterone raises breast cancer risk or that it blunts some of the cardiometabolic benefits of estrogen, there's a good chance the molecule in those studies was a synthetic progestin, and the evidence for progesterone itself is, thank goodness, considerably more encouraging. If you or someone you care about has been nervous about hormone therapy, I hope this episode, this mini lecture, gives you a clearer and more hopeful picture. As usual with these things, I do not intend to sound like an advocate, but I don't want to shy away from defending what is evident In the science, to see why the molecule matters so much, it helps to start with what progesterone is and where it comes from. Progesterone is a steroid hormone. It's made by the ovaries after ovulation, and later it is by the placenta if the woman is pregnant. In a normal menstrual cycle, it rises during the second half of the cycle after ovulation, specifically when the ruptured follicle has become what's called the corpus luteum. That's why it's called the luteal phase, and that rise converts or matures the lining of the uterus into a tissue that's ready for implantation. Of course, you need the fertilized egg to implant into the wall of the uterus. Progesterone is what allows that to happen. So estrogens are helping grow that lining of the uterus, and then progesterone is helping it kind of convert, if you will, or mature in the proper way. Telling the, the, the tissue, the uterus, hey, you don't need to grow this lining anymore. Now we just need to get it ready for implantation. All of that, that action at the uterus is the reason a progestogen— now I'm using a new, a new word here, progestogen— that's the general term for any compound that acts like progesterone. So that's the justification that it's added whenever estrogen is given to a woman who still has a uterus. Since estrogen alone would stimulate the lining without any restraint. There would be nothing kind of tapping the brakes and telling it that it's time to stop growing. And progesterone does that again by telling it to convert into this more matured version of the lining to get ready for implantation. Because progesterone depends on the corpus luteum, that's that remnant structure after the follicle, after the woman has ovulated. Um, yeah, and so that's the corpus luteum. That's the— what's left when the egg comes out. That, of course, means a woman makes meaningful amounts of progesterone only in cycles in which she actually ovulates. But as she moves through perimenopause and ovulation becomes less frequent, naturally cycles pass with little or no rise in progesterone, even while estrogen levels are still fluctuating and sometimes even running high. Of course, In menopause, ovarian progesterone production falls to very low levels. So menopause reduces both ovarian hormones, and giving progesterone alongside estrogen restores a hormone the body made for decades prior to menopause. As an aside, as the ovaries stop making the sex hormones, the adrenal glands become the primary, albeit much lower, source of these sex hormones. Progesterone receptors are present, of course, in an obvious tissue like the breast, helping the woman get ready for lactation because, after all, it is the hormone of gestation or pregnancy. But you also have progesterone receptors in the brain, in the blood vessels, and bone, and more. So the hormone that accompanies estrogen acts well beyond just the uterus. Clinicians often use the word progesterone for any compound that acts on progesterone receptors, but this does create a lot of confusion because That group includes true progesterone, but also a long list of synthetic progestins, such as medroxyprogesterone acetate, which I'll just refer to as MPA later on. But it also includes some other synthetics like norethindrone and levonorgestrel. Those are quite the names, but these were all designed to last longer in the body. They do bind the progesterone receptor, but their altered structures also allow many of them to bind other receptors. Such as androgen receptors, glucocorticoid receptors, or even both. Now, to say that another way, many of these synthetic progestins also activate the receptors that testosterone and cortisol activate. Micronized progesterone, by contrast, is chemically identical to the progesterone the ovary makes. The word micronized just refers to the grinding up of these little crystal molecules to a structure That's a very fine particle, and, and then, uh, more of it can get absorbed through the oral route. And that solved some of the poor absorption that, that was found with older oral progesterone, but it leaves the molecule itself intact. It's unchanged. Now, the route of delivery matters because it affects which of progesterone's benefits a woman receives. When micronized progesterone is taken by mouth, it passes through the gut and liver before reaching the circulation. So the blood, and much of each dose is converted along the way. Part of what the liver produces is a molecule called allopregnanolone, a metabolite that reaches the brain and has a calming effect. That's thought to be the basis for some of the sleep benefits that can come from progesterone. The oral capsule is also the form used in nearly every trial that I'm going to mention in this mini lecture, including the studies of lipids and insulin and the uterus and sleep and hot flashes. So it is the form with the deepest body of human evidence behind it. Another way to take it is vaginal progesterone, and that does take a more direct path. Much of it travels from the vagina straight to the uterus, so the lining receives a strong signal while blood levels stay relatively low. And women who find the oral form too sedating— so it makes them a little too sleepy— they'll often tolerate this form better. Also, progesterone creams applied to the skin— that's a different matter entirely. The doses they deliver have not really been shown to protect the uterus in any way. So a cream cannot replace the oral or the vaginal forms when estrogen is part of the regimen. So that is the molecule and how it reaches the body. Next, let's look at the receptors themselves, because this is where the metabolic differences begin. When a molecule binds the glucocorticoid receptor in addition to the progesterone receptor, it will produce some of the metabolic effects of cortisol, that main stress hormone, or what I like to call the metabolic adaptation hormone. MPA, that first of the artificial progestins I mentioned earlier, it does have meaningful and relevant activity here at this cortisol receptor, but natural progesterone is much more selective, and it doesn't. It's just going to focus on its own. All of this matters for metabolism because chronically elevated cortisol, even if it's— or at least cortisol signaling, I should say, even if it's not cortisol itself, like in this case, it does promote insulin resistance. It also favors fat storage around the center or abdominal area of the body, and it can work against the insulin-sensitizing benefits of estradiol, the main of the estrogens. Reviews that have been published with menopausal hormone therapy and diabetes risk have shown this pretty clearly. They've noted that MPA can blunt estradiol's favorable effect on insulin resistance, while progestogens with less of this activity, so that are not activating the cortisol receptors, come closer to the metabolic— to a level of metabolic neutrality, and they don't offset the estrogen's benefits. as, as much. A second group of synthetic progestins, which includes the other ones I mentioned, norethindrone and levonorgestrel— these are derived actually from testosterone, and these compounds carry varying degrees of testosterone-like activity. They tend to lower HDL cholesterol and to counteract the rise in HDL that estrogen produces. And reviews of hormone therapy and diabetes risk generally favor the less androgenic options when the goal is to protect insulin sensitivity. Now, natural progesterone has no meaningful testosterone-like activity, so it avoids all of that. It avoids the cortisol-like effect, and it avoids the testosterone-like effects that come with those synthetic progestins. Now, progesterone also has a receptor interaction that works in its favor. It binds the receptor for aldosterone. That's the— that's an adrenal hormone, so from your adrenal glands, and it tells the kidneys to hold on to sodium, or, or the part of salt, and water. And it blocks that receptor rather than activating it. The result of this is a mild tendency for the kidneys to release sodium and water, which gives progesterone a modest influence on fluid balance and in principle on blood pressure. The other synthetics, the synthetic progestins, don't do this. The estrogen or estrogens, but I'm just going to call it estrogen. The estrogen in these regimes is metabolically helpful in its own right. A big study, the Women's Health Initiative, which is a very large trial conducted in the US, it tested conjugated estrogen, which is a mixture of estrogens actually from the urine of pregnant horses, as opposed to estradiol, which is the main estrogen that a woman's own ovaries make. Women randomized to conjugated estrogen plus MPA, which is one of the synthetic progestins, they were less likely to develop diabetes and their insulin resistance fell during the first year of treatment. That benefit most likely does reflect the estrogen. And because MPA is known to weaken estrogen's effects on insulin, pairing estrogen with a more neutral partner such as micronized progesterone I think is a pretty sensible way to preserve and even amplify as much of the estrogen benefit as possible. Now we can turn to the clinical trials, starting with the question every woman with a uterus needs answered. The first job of micronized progesterone in hormone therapy is to protect the lining of the uterus. And the natural question is whether a molecule this gentle can do that job while leaving estrogen's metabolic effects intact? 2 large trials were created to answer this question. The first is the Postmenopausal Estrogen-Progestin Interventions trial, known as PEPI or PEPI. This involved 875 healthy postmenopausal women for 3 years, and it tested micronized progesterone side by side with a synthetic option. Estrogen raises HDL cholesterol, And low HDL is one of the hallmarks of insulin resistance. So this is a useful marker, albeit a surrogate of metabolic health. On estrogen alone, HDL rose by about 5.5 milligrams per deciliter. When micronized progesterone was added, HDL still rose. So women kept most of what estrogen was offering. However, when the estrogen was taken with MPA, the synthetic progestin, It erased most of that benefit. Fasting insulin and glucose also fell slightly on hormone therapy compared with placebo, and the regimen with micronized progesterone performed as well as the others. So Peppy also looked directly at the uterus. So, so far we would see that the micronized progesterone was helping the benefits of the estrogen remain intact, unlike the synthetic ones. So back to the uterus then, when estrogen is given alone, It keeps stimulating the lining of the uterus, which can cause it to overgrow. That overgrowth is called endometrial hyperplasia, and certain forms of it may progress. It may keep growing until it becomes a cancer. Among the women in PEPI who had a uterus, estrogen alone led to some overgrowth, and in a large share of the women, and including some of that overgrowth became a more worrisome, considered a precancerous form. That was about 1 in 8 women. But women who took estrogen with micronized progesterone for 12 days each month had rates similar to women on the placebo. So micronized progesterone protected the uterus effectively while also preserving much of estrogen's benefits when it came to blood lipid changes like higher HDL. Now, that wasn't the only study. The second trial, called Replenish, tested a newer and simpler way to make— to take micronized progesterone. The traditional approach is to take progesterone for part of each month, which usually brings a monthly bleed just like a period. So the woman is essentially just having a normal menstrual cycle. In Replenish, women instead took a single daily capsule that combined estradiol with a lower dose of micronized progesterone, either 50 or 100 milligrams. And the trial followed more than 1,800 postmenopausal women for a year. The capsule reduced hot flashes compared with placebo most strongly at the higher doses. In the 12 months, there were no cases of endometrial hyperplasia because the progesterone was taken every day. Most women had no bleeding at all by the end of the year. Replenish— that study also tracked the metabolic side. Compared with placebo, the daily capsule produced no clinically meaningful changes in blood lipids, blood glucose, or clotting factors over the full year. For a woman who wants relief from hot flashes and also protecting her uterus, that means the combination did its work while leaving her metabolic markers steady. Together, the two trials show that micronized progesterone does its essential job at the uterus, whether it is taken for part of each month or every day at a lower dose, and that it does so working without working. It's not working against a woman's metabolic health. Now, I'd mentioned earlier the brain, so let's shift back to that. So let's go from the uterus, move back to the brain, but in a little more detail, because you'll recall that micronized progesterone can offer something there that the synthetic progestins don't. Part of each oral dose is converted into allopregnanolone. That's a progesterone metabolite that actually strengthens the action of GABA, G-A-B-A. That's the brain's main, uh, calming signal. This is why oral micronized progesterone taken at bedtime helps many, many women fall asleep. In a meta-analysis of randomized trials, most of them in postmenopausal women, It shortened the time it took to fall asleep, and most of the individual trials found that women rated their sleep as better. Synthetic progestins do not appear to generate these calming metabolites in any clinic— clinically useful amount. Now, sleep is relevant here. I think that's why I'm bringing it up, because anytime you're talking about metabolic health, it is appropriate to look at sleep, because sleep loss can impair insulin sensitivity. In a randomized crossover trial in postmenopausal women, 4 nights of sleep restricted— of sleep restriction that was about 60% of their normal sleep— it reduced insulin sensitivity by roughly 12 to 20%, and it lowered the body's ability to burn fat. A hormone already used to protect the uterus that also improves sleep through its own metabolic signaling, its own metabolite I think it's fair to say that it can support metabolic health along a second path, that indirect path of better sleep, since better sleep favors better insulin sensitivity the following day. Micronized progesterone also relieves the symptom that brings most women to hormone therapy in the first place. In a large study, 300 milligrams of oral micronized progesterone taken at bedtime with no estrogen at all Reduced the frequency and severity of hot flashes and night sweats more than placebo over 12 weeks. Night sweats are among the most common reasons menopausal sleep is broken. So this effect and the sleep effect reinforce each other, and a woman who takes progesterone at bedtime may benefit from both of them at once. All right. With the benefits laid out, it is worth turning to safety since that is usually the first thing women ask about. Micronized progesterone has proven reassuring when studied on its own. In a 3-month randomized trial in healthy early postmenopausal women, oral micronized progesterone without estrogen left blood vessel function, weight, waist circumference, blood pressure, inflammation, and clotting markers unchanged relative to placebo. Now, blood clots That's a very relevant part of this conversation. It's one of the most important safety concerns in hormone therapy, and here too, micronized progesterone compares well. A French study of women aged 45 to 70 found that estrogen taken by mouth was associated with roughly a fourfold higher risk of blood clots in the veins, while estrogen delivered through the skin wasn't. Micronized progesterone showed no association with clot risk, whereas a class of synthetic progestins widely used in France was associated with roughly a fourfold higher risk. The difference by route makes some physiological sense because estrogen taken by mouth passes through the liver first and stimulates the, the production of clotting proteins there, while estrogen absorbed through the skin Largely avoids that first pass through the liver. These findings suggest that transdermal estrogen paired with micronized progesterone is among the best, perhaps, combinations with respect to clotting. Breast cancer is the concern that most often keeps women away from hormone therapy, and the progestogen appears to matter here as well. One of the most informative sources is the French E3. N cohort, and it followed about 80,000 postmenopausal women for an average of about 8 years. Over that time, women using estrogen combined with progesterone had no increase in invasive breast cancer risk compared with women who had never used hormone therapy at all, while women using estrogen combined with synthetic progestins had about a 70% higher risk. A later meta-analysis that pooled all of the available studies reached the same conclusion, finding Lower breast cancer risk with progesterone than with synthetic progestins. Altogether, the evidence consistently favors micronized progesterone over MPA and the more androgenic progestins—the other ones I mentioned. Whether this question is focused on insulin or uterus or sleep or safety, micronized progesterone always seems to be coming out on top. Now there are a few things worth knowing as you think this through. Most of these advantages show up when micronized progesterone is. Paired with estrogen in place of a synthetic progestin. So its value is best understood as that of a good partner to estrogen. Now finally, let's bring all of this back to insulin, a topic I can never step away from. The reason the companion molecule matters so much for insulin comes down to what estrogen does in the first place. Estradiol, that main estrogen, acts mainly through estrogen receptor alpha, and it has been shown to support insulin signaling in skeletal muscle. It also does the same in liver, helping manage liver glucose output, and it favors fat storage in the subcutaneous space, so under the skin rather than around the organs in that visceral space. When estrogen falls at menopause, those benefits weaken. Which is why women commonly see a shift toward abdominal fat. They're going to see their insulin coming up. They're going to become more insulin resistant in this transition to menopause. Estrogen therapy restores much of that support, and the progestogen given alongside it helps keep it balanced on the side of benefits. This is why analyses of diabetes incidence generally look favorable for regimens that contain estrogen, especially when therapy begins near menopause. Many synthetic progestins push against that effect through that cortisol-like activity and that testosterone-like activity, or both, while progesterone, identical to the ovarian hormone, lets the benefits come through. HDL is one measurable readout of that partnership, and sleep is another, since oral micronized progesterone improves sleep onset, and good sleep protects insulin sensitivity in everyone, most especially postmenopausal women. So micronized progesterone brings metabolic advantages to hormone therapy. It is the same molecule the ovary makes. It preserves estrogen's benefits with blood lipids far better than the synthetic progestins, and it does so while protecting the uterus from that estrogen-driven overgrowth. It also avoids the cortisol-like activity of some of the synthetic progestins, and it supports restful sleep, relieves night sweats, through actions that synthetic progestins do not really provide. For any woman considering hormone therapy, choosing micronized progesterone to protect the uterus is a metabolically favorable action, and I think it makes sense to focus on that one alongside the estrogen. I hope you found the mini lecture helpful. Class dismissed. Until next time, more knowledge, Better health.