Progesterone Side Effects & Intolerance: Why You Feel Worse on Progesterone | Dr. Jolene Brighten

0:00Get business done with the new American Express Graphite Business Cash Unlimited card. With unlimited 2 % cash back on all eligible purchases, unlimited 5 % cash back on flights and prepaid hotels booked through American Express Travel Online, and a flexible spending capacity that can grow with your business, you'll have the confidence to keep building. Apply today and earn a welcome offer of$1 ,500 cash back after you spend$50 ,000 in qualifying purchases on your new card within the first six months of card membership. Terms apply. Learn more at go.mx.graphite. ultra running shoes are all about space the space to go further to feel better to do something you never thought possible and this space starts with ultra fit unlike traditional running shoes ultra fit gives toes more room to move naturally so every step is strong balanced and comfortable whatever you're lacing up for stay out there with ultra shop now at ultra running.com that's a-l-t-r-a running.com So you finally got your progesterone prescription to help you start feeling better.

1:04And instead of feeling better, you're actually feeling more anxious, more moody, and that sleep you were promised, you're not getting it. You may have progesterone intolerance. And while we expect progesterone to make us feel calm and relaxed and promote sleep and love life, this is not the reality for everyone. and we do not talk enough about when women struggle with progesterone. And today we're going to get into that in this episode of the Dr. Brighton Show, and I'm going to share insights with you from the research as to why this may happen for some women. So if you're someone who has taken oral micronized progesterone or in the U.S.

1:46what's known as Prometrium and felt worse, this episode's for you. And listen, if you're someone and you're tuning in, you're like, wait a minute, I'm nowhere near this hormone replacement therapy conversation in my life. But maybe you've identified you have PMDD, you've been diagnosed with PMDD, which is a severe, severe form of PMS. Maybe you do have PMS or you're someone who struggles with sleep and mood during your luteal phase. That's the two weeks leading up to your period right after ovulation, then I definitely want you to tune into this episode as well. So stay with me. And if you're new here, hi, welcome to the Dr.

2:28Brighton show. I'm your host, Dr. Jolene Brighton. I'm board certified in naturopathic endocrinology. I'm a nutrition scientist. I am a menopause certified practitioner, and I'm very passionate about helping women understand their hormones, especially when the standard advice and protocols just aren't cutting it. I have been treating women in menopause for over a dozen years and prescribing HRT, and progesterone intolerance is something I have seen quite a lot of. Today, we are going to talk all about how to identify if you have progesterone intolerance and how you may need to change your prescription if you are taking oral micronized progesterone or any form of HRT.

3:14We're actually going to talk about estrogen as well and how that fits in. I'm also going to go over why progesterone intolerance happens, including some fascinating new brain science that just came out this year. This doesn't necessarily explain it for everyone, and we don't have great studies just specifically on progesterone intolerance, but we do have enough information about how progesterone and its metabolite is interacting in the brain, especially in certain populations like those with PMDD that have a worse time with progesterone. So we're going to talk about that, how to know if you might have it, and most importantly, what you can do about it.

3:56Now, before we jump in, if you've already left me a review, thank you so much. And if you haven't, could you take just a quick second to just hit the five stars or leave a little note for me? It helps this podcast get out into the world and support the efforts of myself and my team. And if you're watching this on YouTube, please hit the subscribe button and hang out with me. We do this show twice a week. All right, with that said, let's get into what is progesterone intolerance. Now, we don't have a lot of research and we don't have a formal definition for this, But we do understand that some women don't respond the way we expect them to when they take progesterone.

4:40So progesterone intolerance is when your nervous system, especially your brain, has an exaggerated or paradoxical reaction to progesterone. So this isn't a progesterone deficiency. We're going to talk about how it's also not necessarily about the levels. This is also not a progesterone allergy. And on that note, it's also not in your head. So you should know that things are happening in your head, but you're not making this up. This is a sensitivity in how your brain responds to progesterone or namely allopregnenolone. We'll get into that. And it can show up whether that's progesterone that's coming from an oral capsule or from your body, from your own ovaries.

5:27So for a lot of women, when progesterone goes up, it is going to promote this sleepy feeling, this calming effect. But for others, and this may be you, that's probably why you're here, the same rise sets off more of like panic or panic attacks, insomnia, mood swings, even feelings of rage sometimes. So I realize as I say allopregnatalone and I allude to that, we should talk about where do you get progesterone from? There's only two places that you get progesterone. You either make it or you take it in the form of progesterone. Progestin is not the same as progesterone and we're going to get into more of that.

6:11But if you have tried the pill, the patch, the ring, the implant, the depo shot, the IUD, and you had mood symptoms or you felt terrible, that is not progesterone. That is not progesterone intolerance. That is a progestin issue. And we know that progestin comes with side effects. Yes, yes, any of us who have taken it. But we also know from the research that progestin-based contraceptives are very much associated with adverse mood changes. So if you have adverse mood symptoms when you are using birth control, that's progestin, not progesterone. So that doesn't necessarily mean you won't be able to take progesterone.

6:56Now, when it comes to progesterone intolerance, the nervous system driven symptoms we see, I've talked about insomnia or disturbed sleep. Yes. Panic attacks, racing thoughts, feeling anxious, your mood is running away with you. So maybe you'll have crying spells. Maybe you'll feel rage. You feel really irritable. If you are feeling physically restless, like you can't settle in your own skin, that can also be a sign of progesterone intolerance. Now, if it is your natural cycling progesterone, we're going to see that it tends to get worse about five, seven days after your period. And then, so let me explain this.

7:40You ovulate, You then form a structure in your ovaries called the corpus luteum. That releases progesterone. That spikes five to seven days after ovulation. Then the roller coaster comes back down. So usually in that five to seven days and then coming down is when women really feel they're worse. But if you're on oral micronized progesterone, that could just be every single time that you're taking it. Now, I want to talk a little bit more about progesterone and progestins because researchers get this wrong, doctors get this wrong, prescribers get this wrong. People often are saying progesterone when they mean progestogens, progesterone when it should be progestin.

8:31They are different structures all together. Progesterone gets metabolized to allopregnenolone, stimulates the GABA receptor in the brain, makes you feel really good. Okay? That's the way it should flow. Progestins do not get metabolized to allopregnenolone, cannot interact with the receptors, the GABA receptors in the same way, and they can be really problematic in your system. We're going to talk about how they act in your body, but I just think it's really important that we recognize that even like the progesterone only pill is not progesterone. It's progestin. The difference matters, not just on the chemical structure level, but how they interact with your system level.

9:15Now we don't just make progesterone from the corpus luteum post ovulation. We also make it in pregnancy. So we've got our ovary only via ovulation can you make progesterone. This is why when you stop ovulating in perimenopause as regularly or it's weaker, you don't get that progesterone. And in pregnancy, it's initially the corpus lydium, which is kind of crazy and cool and awesome that like this little tiny baby structure can do all of that. And then when you get into the second trimester, it flips over and the placenta starts to take over. Now compared to progestin, progestin is the synthetic compound that was designed to mimic some of progesterone's effects.

9:54Mostly it was made to prevent pregnancy by stopping anything from implanting in the uterine lining by keeping it thin and also thickening the cervical mucus so that sperm cannot pass. I want you to keep in mind that when it comes to the breast cancer risk and everyone being afraid of like hormone replacement therapy is going to cause breast cancer, it's progestins that really seem to be implicated in that. So I want you to understand if you hear that progesterone might raise breast cancer risk, it's progestin. So that's another part of where like even the media gets it wrong and people get nervous.

10:36Now, progesterone binds to progesterone receptors. That makes sense, right? And it interacts with your nervous system, your immune system. It's anti-inflammatory. It's great for your bones, your brain. And again, it should help reduce anxiety. It should help with sleep. It also can help with histamine, and it can also help your thyroid hormone in doing its job. So a lot of roles for progesterone. Progestins, depending on the formula, can bind not only to progesterone receptors, but also to androgen receptors and even cortisol receptors in some cases, and that can create side effects that natural progesterone does not.

11:17Some progestins have a strong androgenic effect. So that means testosterone and acne and oily skin and hair growth. So those excess androgen symptoms that we see in PCOS. And then others can have anti-androgenic effects. So drosperinone, that's in certain birth control pills, that can help with lowering acne risk. So your skin might look better. but sometimes your mood might get worse and you could have electrolyte imbalances. So when it comes to medications, we always want to weigh the risk versus benefit for you. Now that you understand a bit about that, I had told you about the allopregnenolone pathway or aloe.

11:58Maybe I should just call it that. It's a lot easier. So your natural progesterone or the bioidentical one you take is converted into a neurosteroid called allopregnenolone or aloe. Now that can have a calming effect through the GABA receptors in the brain. Progestins don't convert to aloe, and this means that you're going to miss out on progesterone's natural sleep and mood-supporting benefits. And in some women, progestins have been shown to be associated with worsening mood, worsening depression, and worsening anxiety. In fact, research shows that certain progestins can increase the risk of depression, especially in adolescents and in women who are starting hormonal contraception for the first time.

12:46So this is just to illustrate they work differently in the brain as well. Now, progesterone is essential for a healthy luteal phase. It also is important if you want to get pregnant for supporting implantation, successful pregnancy, and it can help with reducing PMS symptoms. Progestins are found in contraceptives that often stop ovulation and suppress your natural hormone rhythms, which means you don't get any progesterone. And that's very effective for preventing pregnancy, but it's also meaning that you lose the cyclical progesterone benefits like bone protection and anti-inflammatory effects and helping with histamine.

13:28So when it comes to progestin contraceptives, there are the combination ones like you'll find in the pill. Then there is the mini pill, which only sometimes shuts down ovulation altogether. There's the IUDs. They don't always shut down ovulation. So it's not always clear cut that you will absolutely shut down ovulation. The combination ones, yes. However, with an IUD, some women stop ovulating, some women don't. But the reality is that these progestins can bind more strongly to your progesterone receptors. So even if you are making your progesterone, you may not feel those benefits. Now, within the United States, I said that there's Prometrium.

14:12So Prometrium is the micronized progesterone. unless you're getting compounded, this is the only type of progesterone that's bioidentical. The progestins, those are not interchangeable with progesterone. If the goal is to help with the luteal phase, to help you get pregnant, and to help with perimenopause symptoms, quite frankly, progesterone is going to be a lot better. We want bioidentical progesterone. So if your doctor gives you something, says it's progesterone, if it's not Prometrium or it's not, it doesn't say it's, there's generics, bioidentical progesterone, oral micronized progesterone, it may be a progestin.

14:57Okay, now that we've had the progestin talk, let's talk about who is most susceptible to progesterone intolerance. Again, I'm talking about bioidentical progesterone. So we know that certain groups of women are more likely to experience progesterone intolerance like those with PMDD, which is premenstrual dysphoric disorder. I should have said that before. Sorry about that. I said PMDD as if everybody knew it at the start of this episode. Other women that we see are susceptible are those who fall under the neurodivergent umbrella. So we see a lot more research with ADHD and autism. We see less research around those with tics or OCD or other forms of neurodivergence, but we do understand that in neurodivergence, your brain works a bit differently.

15:55Now, women in perimenopause, when their hormone fluctuations get more erratic and we try to come in with progesterone, they can sometimes be susceptible to progesterone intolerance. And women who have a history, maybe you haven't been diagnosed with PMDD, but you've had some really significant mood swings. You have not felt well in your luteal phase. You may also be someone who is at risk for this. Those are some of the clues. Get business done with the new American Express Graphite Business Cash Unlimited card. With unlimited 2 % cash back on all eligible purchases, unlimited 5 % cash back on flights and prepaid hotels booked through American Express Travel Online, and a flexible spending capacity that can grow with your business, you'll have the confidence to keep building.

16:43Apply today and earn a welcome offer of$1 ,500 cash back after you spend$50 ,000 in qualifying purchases on your new card within the first six months of card membership. Terms apply. Learn more at go.pamex.com. So if you're someone who's your symptoms reliably worsen like 7 to 10 days before your period, and then they go away once you start your period, like within a couple of days, that can be a sign that you have progesterone intolerance. If you've taken progesterone and you're like, I went crazy, that's literally the words that women will use. And if you can see me, I'm doing air quotes of went crazy because that's how women feel.

17:22If you are not feeling calm when you take your progesterone or your progesterone rises and instead you start feeling like kind of amped up, overstimulated, emotionally unstable, if that's you, your next step is to track your cycle and your symptoms. Even just two months of good tracking can give you and your provider some clear insight. And this goes to, as I said, if you're cycling, but even if you're not cycling, maybe you're cycling progesterone or you are taking continuous progesterone, track your symptoms. We want to be able to correlate what happens to you and your symptoms when you take X amount of progesterone.

18:06That is really insightful. And as we're going to talk later in this episode, I'm going to go over like different dosages of progesterone and what you can be trying because this can take some fine tuning. You know, a lot of people are going to go on HRT and, you know, so if you've been with me in other episodes, then you know, I usually start women with progesterone because I'm seeing them early enough in perimenopause. But if we're starting them on estrogen HRT, we're going to be bringing on progesterone as well, especially if there's a uterus. you know, when women jumpstart on that, because it is like a jumpstart, right?

18:41Especially taking 200 milligrams, they are sometimes like, they're like, oh, I feel pretty good. And then they miss a dose and they feel awful and they go back on and they're like, oh, I'm still not feeling well. So we're going to talk about the nuance of like what can happen with dosing and different strategies that you can talk to your provider about trying. Now, a lot of the research that I look to in understanding progesterone intolerance comes from those with PMDD because PMDD women, they sometimes do feel better if you give them progesterone, but it is during the progesterone phase of their cycle that they feel their worst.

19:20So when we look at the research, there was a new study that just came out and what it showed us is that the main metabolite of progesterone, aloe or allopregnantolone. I feel like I don't want to just call it aloe because I'm like, are we all on the same page with that? Anyhow, it's supposed to enhance the activity of the GABA receptors. And then that is supposed to calm the brain. GABA system's the brake system. But in some women, allopregnantolone's effects are flipping. So instead of pressing the brake pedal, it's almost like it's slamming on the gas and it's leading to anxiety and agitation and trouble sleeping.

20:01And so the study that just came out this year, I'll link in the show notes, it was on PMDD and this has a lot of overlap with progesterone intolerance. And what it found is that in the luteal phase when progesterone is naturally higher, these women had a lower expression of the gamma subunit of the GABA receptor. That's kind of a mouthful to say, but basically one of the GABA receptors was down-regulated. So you might be like, well, what does that even matter? So this particular subunit is a key site where allopregnenolone is supposed to dock and do its calming work. And so if it's not there, allopregnenolone can't do its job.

20:48So even if your progesterone levels are fine, this is why I'm like, it's not like all about the levels all the time and you're metabolizing it just fine, you might not be able to use it. Now, even more striking in this study is that women who had a lower subunit of the GABA receptor expression, they had higher amygdala activation when they looked at emotional faces. So the amygdala is the brain's emotional center. And in these women, it's firing more strongly, meaning they're more reactive, more overwhelmed. They're much more sensitive to the environmental inputs that may mean that they're in danger.

21:30And so what we can see is that HPA access, the stress system from the brain to the adrenal glands, can be getting activated. And what's really interesting is that when I piece this together, so I'm currently working on a new book and something that I've been reading a lot about is just HPA access regulation and dysregulation at different phases of our life. And what's interesting is that if in puberty, your HPA access is more dysregulated, more reactive, you are at higher risk for having depression. And if you have depression, you are at higher risk of having heightening symptoms during the luteal phase, this phase that we're talking about that's a high progesterone phase in your cycle.

22:22So putting that all together, some women with PMDD, they have a lower expression of the GABA receptors where allopregnenolone, the metabolite of progesterone, is supposed to dock, tell them chill, be cool, be calm, go to sleep. Okay, less receptors to do that work. And a heightened amygdala getting stressed by looking at, like having this emotional reaction just by looking at other people's faces. And what does this all tell us? That progesterone intolerance isn't just a hormone story, a hormone problem. It's a brain adaptation problem. And so for some women, the nervous system can't recalibrate the GABA receptors when the hormones are shifting.

23:13And these are big shifts happening in your cycle. And so this is leaving them more emotionally reactive right when alopregnenolone should be calming things down. So it's like, are you intolerant to progesterone? Is that the best thing that we could be calling it? or is it that you're insensitive to progesterone? We need more research to know exactly what is going on. Now, other studies have also pointed to there might be receptor hypersensitivity. So even when you have normal progesterone levels, they feel too high to your body. You also might be someone who's a rapid metabolizer. And so you're taking your progesterone and you're pushing allopregnenolone really high, too hard, too fast, and then dropping too fast.

24:02And then as I was saying, there's also that cortisol dysregulation piece where chronic stress will prime your nervous system to overreact to hormonal changes. So I just want you to understand that it is complicated. There are a lot of things going on. And the answer is not always just give more progesterone. So I have actually seen a lot of women be told, just take more progesterone. You have PMS, you have PMDD, just take more progesterone. And to be clear, that is life-changing for some women. For some women, it's like the best thing that ever happened to them. And for others, it's overwhelmed in their brain and they don't feel better.

24:46And so this is where we have to believe patients, listen to patients, because they're definitely guiding us in where we need more research and more information. Okay, so let's talk about dosing progesterone. I've been talking a lot in the context of just a natural cycle and having that luteal phase, but if we live long enough, which is the goal, which is why I have this podcast, I give you all this information, we will lose a luteal phase because we will be in menopause. So let's talk about how do we first approach progesterone in perimenopause because because I told you, I start with progesterone if I'm seeing someone early enough.

25:24If we're already to the phase where estrogen's going and we're having hot flashes and brain fog, we're not feeling great, sure, sure, sure. I'm not going to deny anybody estrogen. But if you're like 42 and you're like, well, my cycles are still regular, maybe they're a little bit shorter, but I have anxiety like two days before my period and my periods are getting really heavy and clotty and we start to get all these low progesterone symptoms, you can't sleep, we're going to start with progesterone. And I start with oral micronized progesterone. Most clinicians are going to start with typically 100 to 200 milligrams of oral micronized progesterone at night because it can make you groggy.

26:05Some go as high as 300 milligrams. That's something that you see comes up in a lot in PCOS protocols. But in perimenopause, if you're still cycling, It's typically going to be 200 milligrams for about two weeks of your cycle. But there's a caveat. If you feel worse on it than you do off of it, we will have to change things. So typically why we're cycling progesterone in early perimenopause is because you still have a cycle and you are meant to have all that wonderful estrogen bathing your brain in the follicular phase. And we don't want to mess with that. We don't want to oppose that. And we don't want to confuse the body.

26:50So if we know when you ovulate, we'll start you on it post-ovulation, so the day after ovulation, and then continue that until typically when your period comes. So we say two weeks, but it might be like 12 days. Oftentimes, what a provider will do is they'll take your cycle and they'll split it in half and say, this is about when ovulation would be. Let's continue the progesterone during this time. And that should help. Periods get easier because when you don't have enough progesterone, because even if you ovulate, the corpus luteum can be weak. It doesn't give you what you need in your progesterone.

27:25And though your periods can become heavier, you can have more clots, you can have more cramps sometimes, especially problematic if you have a history of endometriosis or adenomyosis. So with that, we want to have that progesterone coming in and opposing things to make it easier. Now, I did say there's a caveat, right? Because there should be. Because in bio-individualized medicine, there should always be a, if this doesn't work, what else can we do? Because it doesn't always work. Things don't always work in the typical fashion, right? So if you're feeling worse when you're on it, you're on progesterone, taking oral micronized progesterone, you're like, I just feel awful.

28:04All the things we described before. That's when we start looking at doing something like maybe 100 milligrams continuously. We may even go lower to 50 milligrams continuously. Again, I don't want to block out estrogen. I still want estrogen to do her thing, but you may need to stay continuous. This works really well in PMDD as well, by the way. So the reason why this improves symptoms is because you have a steady dose of allopregnenolone throughout the month, and that appears to be more favorable for the GABA receptors. Um, as my friend, Dr. Sarah Hill, who's a brilliant researcher explains it.

28:44She's like, your brain builds GABA receptors and then allopregnenolone drops. And then suddenly they're like, I'm naked. Uh, you're no, I'm totally naked here. Um, and just as awkward as it would be, like if you were out in a crowd and suddenly found yourself naked, that's like the brain being like, what do we do here? Um, anyhow, I just think that's a great analogy because what is happening in the luteal phase is that as those progesterone levels are rising, the brain is adapting and making all these GABA receptors. And then when you get to like a few days before your period, that progesterone drops.