Progesterone Shots: Are Fertility Doctors Sadists or Just Following the Science?

Progesterone-in-oil shots, also known as PIO shots, are one of the most feared and hated parts of IVF. They are uncomfortable, intimidating, and often leave patients wondering: “Do I really need this, or is my fertility doctor just being cruel?”

In this episode of Taco Bout Fertility Tuesday, Dr. Mark Amols explains why progesterone matters for implantation, how estrogen and progesterone work together to prepare the uterine lining, and why the type of embryo transfer cycle changes everything.

The key question is not simply whether progesterone shots are better than vaginal progesterone. The real question is whether your body is making progesterone on its own.

Dr. Amols breaks down the difference between ovulatory or modified natural frozen embryo transfers and programmed frozen embryo transfers. In an ovulatory cycle, the body forms a corpus luteum and produces progesterone naturally. In a programmed cycle, there is no ovulation, no corpus luteum, and therefore no natural progesterone production — meaning all progesterone support must come from medication.

This episode also reviews the research comparing daily progesterone-in-oil shots, vaginal progesterone alone, and combination protocols using vaginal progesterone plus intermittent PIO injections. The data shows why vaginal progesterone alone may not be enough in programmed frozen embryo transfer cycles and why many clinics still rely on PIO for reliable progesterone support.

Dr. Amols also discusses progesterone blood levels, why levels can be hard to interpret with vaginal progesterone, why clinics may differ in their protocols, and how some patients may be candidates for fewer injections or modified natural cycles.

If you are preparing for an embryo transfer, taking progesterone, or wondering why your clinic recommends PIO shots, this episode will help you understand the science behind the shot — and hopefully hate your doctor a little less.

The bottom line: fertility doctors are not sadists. Progesterone-in-oil may be a literal pain in the butt, but in some embryo transfer cycles, it has an important purpose.

Thanks for tuning in to another episode of 'Taco Bout Fertility Tuesday' with Dr. Mark Amols. If you found this episode insightful, please share it with friends and family who might benefit from our discussion. Remember, your feedback is invaluable to us – leave us a review on Apple Podcasts, Spotify, or your preferred listening platform.

Stay connected with us for updates and fertility tips – follow us on Facebook. For more resources and information, visit our website at www.NewDirectionFertility.com.

Have a question or a topic you'd like us to cover? We'd love to hear from you! Reach out to us at TBFT@NewDirectionFertility.com.

Join us next Tuesday for more discussions on fertility, where we blend medical expertise with a touch of humor to make complex topics accessible and engaging. Until then, keep the conversation going and remember: understanding your fertility is a journey we're on together.

Transcript

>> Dr. Mark Amols: 0:00

Today we talk about one of the most feared portions of IVF and one of the most hated portions, the PIO shot. I'm Dr. Mark Amols, and this is Taco Bout Fertility Tuesday. If you have ever looked at a progesterone-in-oil needle and wondered, is my fertility doctor sadistic, I promise you we're not. We're just following the science. And unfortunately, sometimes the science points directly at your butt. So why is progesterone-in-oil one of the most hated portions of IVF? Well, not because it's dangerous, not because it's complicated, but because it goes into your backside with a needle that looks like it came out of a veterinary clinic. This is the famous IVF butt shot. The shot that turns your spouse into a nurse. The shot that makes Google have one of the common search terms of how to get progesterone without crying. PIO, known as progesterone-in-oil, is this infamous shot. And patients reasonably ask me questions like, well, do I really need it? Or can I use vaginal progesterone? Or potentially, can we just check blood levels? And the answer is kind of maybe, but it depends on the type of embryo transfer you're doing. Is it a frozen embryo transfer or is it a fresh embryo transfer? Or what's called a modified natural FET transfer? And this is the part that most patients are never taught, because the real question is not, are progesterone shots better than vaginal progesterone? The real question is, is your body making any progesterone on its own? That changes everything. Now, let's just start off with a clear disclaimer. Whatever your clinic tells you to do is what you should do. But today we're going to talk about progesterone support for frozen embryo transfer cycles. Specifically, we're going to talk about why progesterone matters, why some patients need progesterone shots versus vaginal progesterone, and why vaginal progesterone alone may not be enough for frozen transfers. And you're just not going to take my opinion for it. We're going to talk about the research. And that's because there is no one-size-fits-all. Different situations require different types of progesterone. It's a bit complicated. Depending if you're doing a natural cycle, modified natural, programmed, that changes what type of progesterone you will do. And if you go out there, you'll find out there are many types of progesterone. There's vaginal progesterone there's injectable progesterone to the muscle. There's even subcutaneous progesterone. There's even creams out there. And at some point, you just want someone to say, well, here's what you need and why. And that's what we're gonna do today. So let's first start with, why does progesterone even matter? Well, progesterone helps prepare the uterus for implantation, specifically the lining. And most focus on things like the thickness of the lining. Saying, my lining was 8 millimeters, or, mine was 9, and my lining looks so beautiful. And, yeah, that's important, but thickness is only part of the story. A thick lining is not automatically a receptive lining. Think of estrogen as the hormone that builds up the lining, but progesterone is the hormone that matures the lining. Think of estrogen as building the house, putting up the walls, and getting the room ready. But progesterone is the one that turns on the light, puts the sheets on the bed, and says, okay, embryo, now we're ready for you. And progesterone doesn't just mature the lining. It also affects the synchronization with the embryo. That timing is critical. If the embryo is at day-five blastocyst. The lining needs to be exposed to progesterone for the right amount of time before transfer. Too little exposure, and the lining may not be ready. Too much exposure, and that window may be off. This is why fertility clinics are so annoyingly specific about the day and time you start the progesterone. It's not because we enjoy making medication calendars that look like NASA launch sequences. It's because the timing matters. Exactly. In the natural menstrual cycle, progesterone comes from the ovary after ovulation. See, what happens is, is the brain sends a hormone FSH down to the ovary, and the follicle starts to grow. When that follicle is growing, it starts producing the hormone estrogen. That estrogen is what goes to the uterine lining and starts building it up. Now, once the follicle releases an egg, what happens is those cells left over from where the egg was in become luteinized and then start making what's called a corpus luteum. And that corpus luteum is what basically is a progesterone factory. But it's only temporarily going to be there, and it plans on being there for the second half of the menstrual cycle. Now, if pregnancy happens, then the pregnancy releases hCG, which looks like the hormone LH that was coming from the pituitary and will keep the corpus luteum making progesterone. It basically rescues it from collapsing, because if you don't get pregnant, that corpus luteum will just collapse and the progesterone levels will drop and you'll get a menses. But in a frozen embryo transfer, you are actually preventing ovulation. Instead, you are building up the lining with estrogen, and then you have to start progesterone. So if you don't ovulate, you don't make a corpus luteum. And if you don't make a corpus luteum, your body is not making progesterone for the transfer. And that means progesterone has to come from medication, all of it. And that's one of the major points of this episode. It's not some of it, but all of the progesterone has to be given. So let's divide embryo transfers into two major categories. Number one will be called ovulatory frozen embryo transfers. And number two will be considered programmed frozen embryo transfers. Now, ovulatory frozen embryo transfers may be called natural cycles, modified natural cycles, or ovulatory FETs. And because the patient ovulates, that means they're going to form a corpus luteum. And because of that, that means their body is going to make progesterone. Now, many clinics may give supplemental progesterone in these cycles, and the question is, why? Well, partly because we like to give belts and suspenders to protect things. But technically, in this situation, the medication is not necessarily needed because the source of progesterone is the body. So if you're using vaginal progesterone, in this situation, you're more supplementing the progesterone versus giving it all. But in the second one, the programmed frozen embryo transfer, this may be called a medicated cycle or an artificial cycle, but in this type of cycle, we use estrogen to prepare the lining. And since you don't ovulate, we have to add all the progesterone to mature the lining. No ovulation, no corpus luteum, no natural progesterone production. So now it's no longer a supplement. The entire supply chain is coming from the medication. And this is why the route matters more in a programmed cycle than in the modified natural cycle. This is why you cannot compare progesterone strategies until you ask the question. Is the patient ovulating? Because vaginal progesterone in an ovulatory cycle is not the same situation as vaginal progesterone. In a programmed cycle, one is backup, in the other, it's for the whole game. Now, let's talk about the different ways progesterone can be given. There are actually several options. First, there's oral progesterone. And this sounds great. Pills, easy. But pills go through the digestive system and then liver metabolism. And for the embryo transfer support, it's generally not the most reliable option for that. Additionally, it can kind of make people sleepy, sometimes dizzy, which is not really ideal when you're already taking estrogen, tracking, appointments, and emotionally negotiating with your uterus. So, not the first line now. Second, there's progesterone cream. This sounds amazing. Rub some cream on your skin, avoid needles, avoid vaginal discharge, everyone goes home happy. The problem is that transdermal progesterone has not been well supported as reliable luteal support for IVF and frozen embryo transfers. So creams are not usually the main protocol for embryo transfer support. But what about vaginal progesterone? This can be in capsules, tablets, gels, even suppositories. And vaginal progesterone is very commonly used in many parts of fertility, essentially because it's so close to the uterus. The local absorption goes to the uterus without having such a large systemic absorption. This means you get all the benefits without all of the, let's say, side effects from progesterone going through your GI system. Now, one thing that's not fun about it is it can be messy. Usually it will break down in the vagina and the discharge will come out. And many women have to wear pads constantly to prevent it from getting on their clothes. I'm pretty sure if you've ever used it and you're listening to this podcast, you're nodding right now. One of the last ways to get progesterone is intramuscular progesterone, such as PIO progesterone-in-oil. And this is the classic injection. Usually it goes in the upper outer quadrant of the gluteal area. It's progesterone dissolved in oil, injected into the muscle where it can slowly absorb. But there's one thing. It's uncomfortable. It causes things like knots, soreness, bruising, occasionally even reactions to the oil. But it gives a reliable systemic progesterone exposure. And that reliability is the reason it has stuck around, not because doctors are creepy, sadistic people. Although I understand why patients may think that it's because that's where the science leads us. Now, there is a subcutaneous progesterone, but unfortunately it is not allowed in the United States because it has not been approved by the FDA. But it is used in Europe. It eventually may make its way to the USA, but it's not here yet. Whether you are being given a PIO shot or whether you are giving the PIO a shot, let's be honest, PO shots are not fun for anyone. I've seen some people not only get knots, but literally have a hard time walking and usually walk with a limp after getting these shots. And if you're doing these shots for weeks, it gets old fast. So when patients ask, well, can I use vaginal progesterone instead? That's not a lazy question. That's a very reasonable question. And I have no doubt that they maybe have a friend who's using vaginal progesterone. And then in that situation, there are two questions that have to be answered. One, did they ovulate? As we discussed, if they ovulated, now you're only supplementing. So yes, vaginal progesterone is fine. But the second question is, if they didn't ovulate, why are they using vaginal progesterone? And that's where we turn to the science. The study that changed the conversation was one of the most important studies that looked at patients doing programmed frozen embryo transfers. Essentially what they did is they looked at three progesterone strategies. Number one, they looked at a group using daily intramuscular progesterone-in-oil shots. The second group used vaginal progesterone plus PIO shots every third day. And the third group used vaginal progesterone alone. And the question being asked is the same question patients had, can we avoid shots? And the results were very important. The vaginal-only group had a lower live birth rate. The two groups that included PIO shots did better and the miscarriage rate was higher in the vaginal-only group. In summary, the vaginal progesterone alone group had a live birth rate of about 27%, while the combination group had a 46% live birth rate and the daily injection group had a 44% live birth rate. Miscarriage was 50% with vaginal-only progesterone compared with 26 in the combination group and 33% in the daily intramuscular group. So the take-home is programmed frozen embryo transfers with vaginal progesterone alone did not perform as well as the protocols that included PIO shots. Now, that doesn't mean that vaginal progesterone was bad. That does not mean that every patient in every transfer cycle needed PIO. What it does mean is that if you are in a programmed FET cycle, you should not use progesterone alone because it's riskier due to the lower live birth rate and the higher rate of, miscarriages. And that's why doctors shouldn't just say, you need PIO. They should explain, you're not ovulating. You didn't make a corpus luteum, so your body is not making progesterone. This medication is the entire support system for your lining. Then it makes more sense for patients. They're still not going to like the shots. They're still going to be a pain in the butt, literally. But at least there's some science behind it. Now, it is important to understand that in this study, it wasn't like vaginal progesterone never worked. It did work. It just had a lower live birth rate and a higher miscarriage rate. And when it comes to cycles where you ovulate, it's perfectly fine. It's only in programmed frozen embryo transfers where there's a danger zone. Another interesting thing about this study is that it showed that vaginal progesterone plus PIO every third day performed similarly to the daily PIO shot group. That means there may be a middle ground. Not zero shots, but maybe fewer shots. Even at our clinic, where we have used daily shots for many, many years and have very good rates, we have now slowly allowed patients to transition to taking shots every other day and even stop shots later on in the pregnancy once they are pregnant. So why doesn't every clinic just switch right away? Well, because they have high pregnancy rates with the way they do it. So just because something worked in one study doesn't mean that they feel comfortable yet making that transition. And just like us, we make it slowly. As I mentioned earlier, there is no wrong or right. However your clinic does it is the way they do it and definitely follow them. Now, what about progesterone levels? Why can't we just follow those? Well, if you're taking progesterone systemically, such as with injectables, we have a predictable progesterone level that we're going to expect from, and we can follow that. But when it comes to things like vaginal progesterone, as I talked about locally, it's going to be absorbed by the uterus, but systemically it will not be. And in that situation, you can't follow the blood levels as well. So unlike hCG levels where we expect them to double. You can't do that with progesterone if you're not taking it systemically. And the good news is they've studied this. They actually had animals where they took endometrial biopsies and verified the progesterone levels are appropriate at the uterus. But in the blood levels, it's not going to be as high because, again, it's not absorbed systemically as well. And that's one of the hard parts about using vaginal progesterone injections. At the same time, when those progesterone levels go a little bit lower, even though we understand the science, we get nervous, patients get nervous, and then we say, go back to the shots. Technically, if you are using vaginal progesterone with injections, and I'm talking about injections every few days, you probably shouldn't even be checking progesterone levels because you're not getting a real sense of the progesterone at the uterus. So what's the final takeaway? Well, the bottom line is progesterone is essential for implantation in early pregnancy. But the type of progesterone matters, depending on the type of embryo transfer. The question that you need to ask is, did I ovulate? And if you did, then that means you are supplementing the progesterone. If you didn't, then that means you are giving all of the progesterone. And now you know that the science shows that vaginal progesterone in a programmed cycle leads to lower live birth rate and higher miscarriage rate. So the reason doctors use PIO is not because fertility doctors are sadists, but because it's reliable progesterone support, and that's what matters. And the good news is there are some protocols that don't require daily progesterone injections. And if you don't think you can do the shots, then talk to your clinic about modified natural cycles. Now, it's important to understand not every doctor feels comfortable doing these. So don't be upset if your clinic doesn't do it. They're doing what they know is best and what they know how to do. In the end, everyone is going towards the same goal to help you get pregnant, stay pregnant, and have a live birth of that beautiful child. If you might be taking progesterone or you know someone who's going to be taking progesterone, this podcast may help them understand why they're taking progesterone. So they don't hate their doctor, think their doctors are being mean. As always. If you like this podcast, please tell your friends about it. Give us a five-star review on your favorite platform that you listen to this podcast on, but most of all keep coming back. I look forward to talking again next week on Taco Bout Fertility Tuesday.