Latest / Fertility Untamed / Progesterone Explained! Does it ACTUALLY Help you Get Pregnant?
Transcript
- speaker-0: Hello and welcome back to Fertility Untamed season two. So I am here with Dr. Rebecca Mackenzie Proctor, myself, Dr. Sylvia Ross, and and unfortunately Dr. Dev is still waiting for a taxi at the airport. So we're just gonna push on and do a couple of little bonus episodes together. And I thought something that we get a lot of questions about, and we've had a lot of messages through the Instagram page, is about progesterone. And of course, it's a really hot topic for anyone trying to conceive. So we just thought we'd do a bit of a progesterone 101. What is it? Where does it come from? How is it made? How do we use it in infertility? So progesterone is a hormone. I think the name speaks for itself. It's progestation. You know, it's all about becoming and maintaining a pregnancy. It is released by the corpus luteum, which is the cyst which forms on your ovary after ovulation. And it is there to help prepare the endometrium, the lining of the uterus for pregnancy to implant. And also to maintain a pregnancy by maintaining the uterus in a relaxed state. And it's really important in fertility treatment where we know that we need to prepare the endometrium appropriately and keep it at good levels for maintaining pregnancy as well. I guess there's probably quite a lot to talk about. We're going to try and split this into a couple of episodes. This will be a bit of basic information about progesterone, what does it do and what formulations are there and how do we use it in fertility treatment? And then we're going to add on a separate talk luteil phase deficiency, what that means and what we can do about it, because that's just such a hot topic on its own anyway. Rebecca, take me through some of the times that we would we would use progesterone as treatment for a patient seeing us. speaker-1: Depends what kind of progesterone we're talking about here, Sylvia. So there's actually different ways we use progesterone, either orally, into the vagina, intramuscular, or subcut. And depending on what kind of protocol we're using it for, we will use a different version. And so we can use progesterone if we start off at the beginning of the fertility journey. If we're using it in our IVF cycles, we'll often use it to stop the body from ovulating when we're doing a stimulation cycle. And we it's called that's called a P POS cycle. obarian stimulation and it's actually not progesterone priming at all. There speaker-0: Actually makes no sense. speaker-1: you go. Unfortunately we're stuck with the name and the name is quite easy to remember and and catchy to say, but it is not what it actually is doing. The idea is that by having the progesterone there, it stops the body being able to make to mount the LH surge on its own to be able to release the eggs so we can keep on stimulation happening without the body ovulating early. speaker-0: That's right. Because the point of IVF is that we're trying to tell your ovaries, make as many of these eggs mature for us as possible, but please don't lose them. And so that's kind of the break to stop losing them. And the thing I love about it is it replaces an injection. And, you know, for patients who are having a fresh embryo transfer, where we need the lightning of the uterus to be expecting an embryo, we can't use it. But it's amazing for patients such as egg freeze, fertility preservation, where you know you're going to be freezing embryos, like pre implantation genetic testing cycles. It just reduces that treatment burden so nicely. I mean how great. speaker-1: It if you could do a cycle where you had to do one less needle every single day, amazing. Why wouldn't you? Yeah, why wouldn't you? So we do. Yes. and so that would be one of the versions where we use progesterone in an IVF cycle. Then we come to preparing that lining of the endometrium. And that's where things become a little bit more tricky because when we're doing a frozen embryo transfer or a fresh embryo transfer, we need to consider what the lining of the uterus is doing. We also use this in other cycles such as ovulation induction cycles and IUI cycles as well, where there is some evidence that a supporting the luteal phase can be important. And there are other situations too, like miscarriage or threatened miscarriage, and we'll probably go into more details around some of the evidence for that too. So let's just stick to IVF. With IVF, once you've had your eggs collected and you're deciding to make embryos and we're thinking about implantation, we can either use a fresh embryo transfer or a frozen embryo transfer. So fresh would be straight after the egg collection, and so the the embryo hasn't been frozen, and obviously frozen is when we have frozen the embryo after after creation and then we're coming back at another stage. speaker-0: That's right. So fresh will be a few days after air collection by the time it's had time to develop and and become strong enough for transfer in the lab. And frozen is often the next month or after. speaker-1: And so typically when you're doing a fresh transfer, we are starting progesterone treatment usually on the day of egg collec collection or the day after. speaker-0: Yeah, anywhere up to three days after usually is, I think, thought to be best in terms of the evidence. If you'd wait too long it's it's not as good. And that's because although you've made these lovely follicles, they haven't ruptured or or ovulated on their own and so there's been disruption of the cells by the simple fact that we've put a needle into them. speaker-1: And I think that's that's of the misnomers I get all the time. Patients say, well, I've got all these lovely Scorpus Letium. Why do you have to give me more progesterone? But that's exactly the reason, is that we actually disrupt the architecture and the signaling pathways within the ovaries. So, yes, we're for a fresh embryo transfer, we're gonna be starting the progesterone within those three days after the collection and continuing up into a positive pregnancy test and then on within the throughout until a certain time in the pr time in the pregnancy. And that's variable depending on clinicians. And evidence countrywide, and we can also talk about that later. Regarding the doses for these transfers, what do you do, Sylvia? speaker-0: I definitely personalise and I think it depends on which brand and which formulation you're using and obviously which type of progesterone. So the most common thing that we use is vaginal pessary, so a tablet that goes into the vagina and essentially you absorb the the substrate or the medication and then the rest of it comes out as this awful discharge that everyone hates. we get a lot of complaints about it. Unfortunately there's that option or injections, so there's no there's no great option here. In terms of dosing, I typically will dose based on what I'm using. So if they're using a vaginal pissery, it might be something like two hundred milligrams two or three times a day for just a basic transfer where you've done a had an ovulation prior. but if someone's on a cycle where they're using or what we call an HRT or or a manufactured cycle where they're not having an ovulation prior to transfer, I'll typically use a higher dose in those patients because they won't have their own endogenous progesterone. speaker-1: do you measure the progesterone in a fresh cycle? W when would you measure progesterone in a fresh cycle potentially? If they were planning for a fresh cycle? speaker-0: progesterone can be measured prior to the egg collection because if it's really high, that will tell you that the endometrium is getting ready for an embryo before the embryo is going to be ready for the endometrium, and that would be a time where you might use that to say, actually let's freeze instead and we'll give you a better chance of pregnancy by giving it a rest and starting again. speaker-1: That segues really nicely to a discussion around that. That actually the role of progesterone and the endometrium is so important. Yes. Its job is to change the cells, cellular structure, and the communication between the endometrium and the embryo. And they actually talk to each other almost and signal to each other. And this progesterone helps that process happen. So the timing of it is really important. And so we need to make sure that we haven't started it too early the progesterone too early, or the uterus lining hasn't been exposed to progesterone too early. So if you see patients or if you are a patient yourself who has had your cycle cancelled for a fresh transfer, that might be the reason why is that we don't want to put your embryo at risk of not having the right signaling between the uterus lining and the embryo itself to be able to have good implantation. speaker-0: I what you're talking about is the window of implantation, which is this the short time where the uterus is going to accept an embryo. So it has to be ready for it. And that's that's why conception's hard and timing's important, because it's not unfortunately, as sex ed taught us, that you can just get pregnant at any time doing whatever. It's actually really hard. And you've got this sort of couple of days window where we don't know exactly the length of that time, but in that time there's a time where the the endometrium has got these pinipods out, these little receptors saying, I'm ready to accept this embryo, and they'll disappear. And at that point you won't be able to fall pregnant, whether it's through IVF or naturally. So it it is important with the timing. And I think that that sort of leads on nicely to, you know, making sure that if you're using progesterone, even just in your own natural or ovulation induction type cycles, that you're not just starting it because you think you might have ovulated or 'cause someone's told you start it on a certain day. It's very clear that it needs to be after ovulation. speaker-1: No, I've some patients recently actually who've come and see me who are just taking progesterone. And I'm like, gosh, okay, you gotta be really careful. This that might be the reason why you weren't actually getting pregnant because you've started at the wrong time. speaker-0: Let's not forget progesterone is one of our biggest medications for contraception. If you get it wrong, you're literally doing the exact opposite thing of what you want, It's so complicated. speaker-1: That's so funny in medicine, I think sometimes we silo things so easily. you'll silo things, contraceptive bucket, and then you might not be thinking about c conception bucket. Well actually contraception and conception are kind of opposites of each other, like the yin and the yang. And so we actually, you know, should really be looking at both sides of things if you're a a GP out there. Really think about that. speaker-0: That's right, that's right. And I guess one of the other things that we sometimes see is people coming in being told they've got a low progesterone. And we'll go through that in more detail in the next episode. But I guess just something to say about that is that's actually very difficult to say. Progesterone is pulsatile. It's released from the corpus luteum in pulses. And so you could measure it here or you can measure it here and you're gonna get different levels. And so just being treated based on a blood test is typically not appropriate either. speaker-1: Absolutely. And again though, we must remember that that is for people who have got their own ovulation production. So if you're on a frozen embryo transfer cycle that's using fully medicated, then the progesterone that's going to be in the blood is actually what your body's metabolizing and what's there. Which brings me nicely to the next step. So we sort of talked about the ovarian stimulation cycle, we talked about the fresh embryo transfer, and we've briefly kind of touched a bit about the frozen embryo transfer. But with a frozen embryo transfer, we are using one of the embryos that's been made previously, and we have to then get the lining of the uterus ready to be able to have the implantation at the right time. And there are lots of different ways of doing this. So we can either do use a full natural cycle, which is just letting your body see how it develops a follicle, ovulate on its own, and put the embryo back in the right timing. That is quite often a nightmare for patients and doctors alike because we've got to do lots of blood tests, lots of scans to try to find the exact pinpoint. A lot of people now use something called a modified natural cycle. which is when you will try to get the body to ovulate or develop a follicle of its own, such as with like an ovulation induction, with letrazole, for instance. And then when the follicle is big enough and ready to go, we s get it to ovulate, trigger and then we can time transfer after that. speaker-0: Because we're telling the we're just basically mimicking what the body would do in a natural situation. And people often don't get that this is the whole point. So we know that when you ovulate, you know, there's just if you're trying to conceive naturally, there's about twenty four hours in which that egg will be there, ready to meet with a sperm, create an embryo. And then it takes a few days for it to travel down the tube and implant within the uterus. So we're trying to get to that point where it's expecting that embryo to have come through and implant. speaker-1: And so that's a that's how we can time things so easily. So it while we when we're monitoring these cycles, we're monitoring for the thickness of the uterus and we're also monitoring for that follicle to be developed. If once it's ready to go and we've prepared the endometrium, we will then start the progesterone, usually five days or roundabout before the embryo transfer occurs. Moving on to the next stage, it would be the fully hormonal medicated cycles. And this is when you'll be taking medicine from the very beginning, usually estrogen to get the lining thick. when the lining's thick and we've got the timing right, we will start the progesterone. And this is where the probably the biggest body of evidence is around testing of levels and what we should be doing. So ta talk me through a bit about that, Sylvia. speaker-0: Well, I think I guess first to say, as I said, it's i it it's still tricky to test and even in these situations we know that the uterine level may not be the same as the blood level. So we've just got to keep that in mind as well. We're clever but not always as clever as the body. What we like to do is to test for the progesterone level on the day of embryo transfer. 'Cause there are a few studies now that show that if that level's low when you're doing a transfer, you can rescue it by adding more progesterone and that will increase your chance of having a pregnancy if that is a healthy embryo. speaker-1: I think that's a really key point to one of the big changes in medicine in the last even four to five years is that the thought of rescuing a cycle rather cancelling a cycle has become the focus. Yes. And that now we've got really good ways of trying to bring that up. And sometimes P patients are on a really high concoction and dosage of progesterone to get them to that phase. What are some of the things that might be causing someone not to be able to have the adequate level of progesterone? speaker-0: Look, there's lots of different medical reasons, for example, and particularly with when it comes to, natural natural cycles. But obviously also in the in the IVF setting, people who have a body weight which is too low or too high, we can struggle with those patients. people who have their own ovulation disorders obviously are not going to have normal progesterone levels when we want them to. and other endocrinological disorders, so things like problems with the thyroid, problems with prolactin. It it's very complex, and it's not one of these things that you would necessarily expect to to know the answer for the individual patient. You sometimes do have to do the testing and and work it out. speaker-1: And frustratingly, sometimes it's different in different cycles. That's right. As well. And so metabolism's another thing. That how do patients metabolize the progesterone? and sometimes that's when I'll change the root of progesterone. So either if it's vaginally, I'll try subcartonin. oral progesterone is not available in Australia, but is available in some parts of New Zealand. speaker-0: Yeah, not for this use, yeah. speaker-1: But there are some progesterone there, like to fasten is used orally, which is an an interesting area of medicine. too. and in America there's lots of different progesterones as well and it's actually really big study hopefully coming out soon called Nat Pro which will talk to us a lot about the progesterone that we're using and which is going to be the most beneficial. speaker-0: And I'm often asked by patients around intramuscular progesterone injections because that's what they use in America. We don't have that here. It's not what we use. and there's you know, intramuscular is pretty horrible if you're doing it every day and there's you can get things like abscesses from it. so I don't think it's better. I I'm not sure why they've always stuck with it. Probably to ask someone in America. speaker-1: Yes, well I'm really looking forward to a study which shows head to head with the intramuscular and the subcut. Because I think patients do not enjoy subcut, but that they I see some amazing results when they actually get that in there. And they just might be someone who hasn't been able to process the progesterone properly or metabolises it too quickly. speaker-0: So I guess one of the things which is important is to talk about even just the different brand names and how the dosing can seem different and you know that can that can be hard to to work out when you're a patient who's maybe done different treatment in different places and tried all sorts of different things. one of them that we hadn't talked about is crinone as well, which is another that's a gel. That's that's one which is still vaginal, but it's only once a day. and then you've got nutrogestin, oropro and cyclogest, which are the pisseries, so the tablets that you put inside the vagina. They come in different formulations and different dosages. per pessary, so they might be a hundred, two hundred, four hundred milligrams. So you've you've got to be careful around that when you make sure that you're following your instructions correctly. And also the time of day that you have it. It's not as precise as with the injections for IVF, which is good. You know, the timing doesn't have to be quite as perfect. for example, people on uterjestin are often on it three times a day and they think, I've got to take it to work and do it at lunchtime. You don't, you can actually do morning, dinner time and bedtime if you want, which is much friendlier as well. And then we've talked a little bit about prolietex. Maybe tell us about Rebecca. speaker-1: So Polytex is subcutaneous injection and often it's 25 milligrams once a day is the standard dosing, but sometimes we'll increase it to twice a day. There's little evidence about that, but there's. Some anecdotal studies have shown that actually it does have an improved level of progesterone for people. Again, it can be a little uncomfortable. and it's in Australia it's not funded for this purpose. and so it can be a little bit of a cost burden to patients too. I think what's really important to realise going back to the vaginal preparations is it there's been no study to say that one preparation is better than the others. That's right. So they all have got a similar efficacy. And it's more about the patient's preference, about what they find easier. And some patients sort of say to me they didn't like the whichever one they were given because it caused vaginal irritation or bit of bleed spotting. And the most common one I see is actually crinone causing this funny, weird, spotty kind of discharge like it's they almost describe it but like vaginal bleeding. And it's most common with crino and it's almost like chalky stuff that comes out. And so I think that's that's actually quite normal. So if you're experiencing in that, it's normal. But if you're experiencing heavy bleeding, let someone know. But just being aware that there's everybody can be little bit different with their experience of the vaginal pisseries. speaker-0: What other side effects do you have people report with the progesterone? speaker-1: progesterone is a very relaxant hormone. So a lot of people feel really tired with the progesterone and actually even in early pregnancy you'll see that we've put these people on progesterone till nine to twelve weeks sometimes and they're just exhausted and they're like as soon as progesterone finishes they're Hallelujah. And it is a real thing. And progesterone it is a sedative hormone. It actually acts on the GABA receptors in the brain as well. If you get if you're getting levels in the blood, that's gonna get to the brain and it can make you feel really tired, lethargic. So sometimes you can get breast breast swelling, funnily enough, it has the same symptoms as pregnancy. So it can be really frustrating for some people who are who have had their embryo transfer and they are using the progesterone and like, my god, I feel really pregnant and they get a negative pregnancy test. And that's something we do see 'cause it really mimics the early pregnancy symptoms. speaker-0: And on that same vein with the relaxation, it also relaxes the bowel. So it's not uncommon for people to complain of constipation that time. So obviously you want to manage that as much as you can with dietary things and if not, get a bit of extra help. speaker-1: Let's just quickly slide across to non-ART management. So things like ovulation induction and IUI. What are your thoughts around usage of progesterone in those situations? speaker-0: Yeah, I think that the usage of progesterone i it can be personalised. It doesn't necessarily have to be used with ovulation induction. if you've got a patient who's doing basic ovulation induction where they're having letrozole or clomophene, they're ovulating sort of on their own without a trigger after that, then they they may not need it unless there's other clinical indication. If you are triggering people or if you're doing intraudine semination, it would be more standard to use progesterone in my in my practice anyway. and that's and that's because again, like with the IVF, but slightly different, the process of ovulation is different than than just your body doing it on its own. And sometimes it's happening, you know, earlier at the follicle size than what it would have happened on its own. and just giving that extra bit of support can be really useful. Is that similar to what you do? speaker-1: That's exactly similar to what I do. And I often will use progesterone even in sometimes in natural cycles for people. not because of a luteophase deficit, which we'll talk about in another episode, but sometimes just to give them a little bit of support, whether or not it's placebo versus actual benefit is yet to be seen. The biggest difficulty I have this, and I want to warn anyone out there that's doing this, is that you sometimes see a higher rate of biochemical pregnancies because you are saving pregnancies that might not have normally implanted. speaker-0: Yes, and and I think that this is a really important point because although we know that your natural progesterone is coming initially from the corpus luteum, that ovulation cyst, when there's a pregnancy, it will produce HCG, the same hormone that we measure on a pregnancy test. HCG acts on the same receptors as LH, the one which has given us the surge and told your body to make progesterone, and it will start the production of progesterone as well. Now when that's not a healthy pregnancy and it's not going to continue to a healthy baby, then those levels are probably lower. But we may be, as you say, rescuing again something that was never actually going to continue. speaker-1: Exactly. And I sometimes see this when when I'm reviewing patients who have got low progesterones, it's always going in back of my mind thinking, is this a sign that the embryo isn't good anyway? Yes. Is it is it actually an embryo problem? And am I saving something that's not going to be good? Or am I saving something that could be good? And I think it's the always that could be good is why we keep saving. But it remembering that actually the physiological reason behind this. Yes. speaker-0: Is it the producer in a league? Yeah. speaker-1: Yes. Or the embryo. So I mean we could talk and talk about protesterone, it's a really, really big topic. speaker-0: So I guess the other thing that I wanted to talk about with you, Rebecca, on this whole progesterone topic is yes, we've done everything we can to get this person pregnant or maybe they've conceived on their own. We we love seeing that too. But how do they stay pregnant and what is the role of progesterone there? speaker-1: So Ziby already explained in terms of the physiology of it and the relationship with the the placenta and H C G, once they are pregnant, then we wanna make sure that predesterone level is continuing to increase throughout the throughout the pregnancy. if someone how long do we continue that going for? Is usually between nine weeks and twelve weeks. Yes. speaker-0: So look, I think we've covered well the use of progesterone in trying to conceive. And another place that we see people asking about whether progesterone will be helpful for them are people who have experienced pregnancy loss already, particularly those with recurrent pregnancy loss. And I know there's been a couple of pretty big studies on this. Rebecca, maybe talk us through, you know, which patients would you use it for who are pregnant? where is the evidence and what do you do? speaker-1: It's actually a really good question because there have been two major trials which we've learned about a lot in our studies, and one is the PR PRISM trial and one was the Promise trial. But before I go into those, I also want to say that the guidelines worldwide aren't consistent here anymore. So from these two studies I'm going to talk about, they have sp clear recommendations. And now we have conflicting advice from the some of the international guidelines saying that we should use producerone in a way that is against these two trials. So I'll just gonna briefly explain them very shortly. There are two trials. One is called the Promise trial and one is called the PRISM trial. And they're both looking at recurrent pregnancy loss. Now, the promise trial is looking at those that have just experienced a loss or that meets the recurrent pregnancy loss criteria, which is other two or three pregnancy losses consecutively. And then the PRISM trial is looking at those who've had bleeding in pregnancy. So it's like threatened miscarriage. And in the promise trial, it said showed that progesterone had no benefit at all in terms of increasing the chance of live birth. speaker-0: And a future print. speaker-1: pregnancy future pregnancies. And then the Prism trial showed that if you've had bleeding and you've had more than two pregnancy losses, that if you use progesterone in a future pregnancy you're imp and you have bleeding in that pregnancy, you may have an improvement in in life birth outcomes. That's right. speaker-0: They're saying don't use it routinely if someone's had multiple pregnancy losses, but if they then get bleeding, it could be helpful. Now, I I mean I think that's you know, that's important, that's where the literature stands. But if you're seeing a woman in front of you who's had a number of pregnancy losses and they want to start it straight away, I mean it's pretty low harm. What would you do? I speaker-1: Start us right away. that's the thing about guidelines is our guidelines. And I think this is now where some of the bigger guideline groups are having a lot more room for data-driven recommendations and patient-driven recommendations. So when we get together as clinicians in rooms and when we are there for some of the ANZREI guidelines, you see the discussions of what do we do in clinical practice and what is the data saying. And sometimes we have to use our clinical judgment to make the right calls, but we have the guidelines there to back us up. and also to help direct us where we need to be going. Or if those that don't know, then they should be following guidelines. speaker-0: Because it seems a bit unfair, someone's sitting there saying, Well, why do we have to wait to have bleeding to be able to do something about it? No one wants to experience bleeding in an early pregnancy, particularly when you've had multiple losses before. It's so triggering. So I I'm the same. I I think for some patients I'm quite happy to to do it anyway, as long as they're very aware that it's not strictly evidence based in that setting. speaker-1: And when we just say before limited harm, is there a harm in having too much progesterone? speaker-0: there's cost and horrible discharge. That's probably speaker-1: That's considered harm, pre considering but actually having a really too high a progesterone has never been shown to cause fetal abnormalities or cause any other problems that we know of. So we can we can be really reassured that it's safe to use in the pregnancy and that using too much of it's not gonna be any more than just a expensive discharge. speaker-0: Whoa, what a great place to rip up. speaker-1: Great place to end I love the use of the word discharge in pregnancy. Goodness gracious. So it's been absolute pleasure talking with you this afternoon, Dr. Ross. And we will bring you back another episode shortly. Thank you so much for tuning in and we'll be back soon.