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Fertility specialist Oluyemisi Famuyiwa discusses her article “Uterine aging in IVF: Why the ‘soil’ matters as much as the seed.” Oluyemisi explains that while clinicians often focus on egg quality, the aging of the uterus itself is a frequently overlooked factor in implantation failure. She explores clinical data showing that even with chromosomally perfect embryos, success rates decline as the endometrium loses its resilience due to cellular senescence and weakened progesterone signaling. The conversation challenges the standard “seed and soil” analogy by revealing that normal ultrasound thickness does not guarantee a receptive environment for pregnancy. Oluyemisi advocates for a precision medicine approach that scrutinizes the uterine environment as rigorously as the embryo to refine hope for patients. Discover how acknowledging the biological history of the uterus can transform unexplained failure into actionable data.

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today we welcome back Oluyemisi Famuyiwa. Today’s KevinMD article is “Uterine aging and IVF: why the soil matters as much as the seed.” Yemi, welcome back to the show.

Oluyemisi Famuyiwa: Thank you. Thank you. Thank you for having me.

Kevin Pho: All right, what is this latest article about?

Oluyemisi Famuyiwa: So today I wanted to focus on one thing we don’t always talk about, which is uterine aging. The first thing we talk about when it comes to fertility is the eggs getting old. Everybody is told that your eggs are ticking away. But nobody understands that the uterus also ages as well. That is a newer topic that we are discussing.

Kevin Pho: All right. Why is the uterus ignored?

Oluyemisi Famuyiwa: Isn’t that something? I think most of the time in the past we have always focused on it must be the egg. There is something wrong with the egg. But there have been studies where they looked at women who used donor eggs to conceive. Conceivably those eggs are from younger women. But they found out if they use younger eggs and implanted them, if it was in an older patient versus a younger person, there was a difference in pregnancy rate. So the age of the uterus matters just as much as the age of the egg. We are just now working on that. All that science is just now coming out.

Kevin Pho: So give us a basic physiology review in terms of the role of the uterine wall. Just tell us what it is in the normal reproductive cycle.

Oluyemisi Famuyiwa: Yes. So what we are finding out is the lining of the uterus is thinner in older women, so the chances of them successfully implanting are lower.

Also, the ability of the lining to convert from a regular early follicular phase lining cell to a decidualized cell changes. We call it decidual, where the cells become puffy and fat to create a rich carpet or lining where the embryos can implant. That ability to convert changes. You see structural issues in the blood vessels feeding the lining as well as the type of cells that you see.

So in a sense, what is happening is it is creating a very unfavorable environment for implantation to occur. Now we know that there are two reasons why this happens. One is the epigenetics that is being changed. They call it epigenetic drift, which gets worse with age. The other is senescent cells. Let me talk about the epigenetic drift first, and then we will talk about the senescent cells.

If you will, think of it as a software problem and a hardware problem. Your hardware is your uterus. The DNA in the uterus doesn’t change. It is the same from woman to woman, young or old. That is the DNA. What is different is the software that runs the computer that runs the uterus. The software gets corrupted. When you are replicating the software over and over, because the lining changes and sheds, each renewal of that lining corrupts that software. That corruption is called epigenetic drift, so it is not working as well.

The other issue is with age and with stress and environment, you build up what are called senescent cells. Think of them like zombie cells. There are cells, especially in the stroma, that are supposed to be converted to decidualized cells ready for implantation. What happens is these cells lose their ability to decidualize. But they don’t go quietly and die off into the night. They just stick around. They are not dying away, they are not converting, but they start to produce a toxic cloud. They start to produce this inflammatory environment that is also killing off adjacent cells, if you will.

An analogy of it is thinking of the uterus like you’ve got a quiet nursery. You are singing nursery rhymes with maybe a quiet light in the background, ready for a baby. Then you’ve got the senescent cells that are like they come in with a construction jackhammer and they just jiggy up the uterus with loud music blaring. A baby is not going to hang out in there. They turn the environment from being receptive to being inflammatory and unaccommodating.

Kevin Pho: Tell us about some of the factors that make the uterus and the uterus lining less accommodating using your analogy.

Oluyemisi Famuyiwa: Yeah, so using that analogy, what happens is the first thing is your so-called epigenetic drift. They have done research where they found out if the epigenome presents the receptor in a favorable way, that genetic material is read. It is like you have a cookbook. Your epigenome says: “OK, read chapter A, read lines 1, 2, and 3.” All the chapters are there, but the epigenome decides which chapter is read.

As you get older, these changes, like methylation and histone formation, can decide: “Well, you are not reading this chapter today.” So you may have everything ready, but you can’t access the information. Think of it like progesterone, for instance. Progesterone converts the spindle cells to decidual cells. That is its job. It goes into the DNA and says: “Time to change guys.”

But the epigenome changes so that the progesterone may be there, but the DNA can no longer respond. A lot of women think: “I’ll just take more progesterone. I just need to up my progesterone. Please check my progesterone level.” Yeah, the progesterone is just fine, but the uterus is now deaf to the progesterone. It is not going to respond to that.

Now, if you also have the senescent cells that we talked about, the inflammatory cells that create this abnormal environment, you have to find a way to tone them down. You have to take down these so-called senescent cells. You don’t want to get rid of all of them because you need some level of inflammation for implantation to occur. But you need to tone down these abnormal cells, these zombie cells, such that the uterus can now hear the progesterone coming by. So there is a lot of fascinating research going on with that.

Kevin Pho: So how can we measure how healthy the uterine wall is? You mentioned in your article that ultrasounds measure endometrial thickness, but that is not really an accurate measure of how receptive the uterus is.

Oluyemisi Famuyiwa: Right. So that is an area of fascinating ongoing research. We don’t have it yet. There were several things that came out. In the past, they talked about the endometrial receptivity assay, which now is not as accurate as we once thought.

So the new research, and this is pure research, is asking if we can measure the age of the uterus in an epigenetic fashion. Most people know about the Horvath aging clock. You go do your DNA methylation and they can tell you what your biological age is. That doesn’t work for the uterus. Why? The uterus regenerates.

So what do you measure? Think about it. If you were to measure a tree and it grows new leaves every time the weather changes, you can’t just go sample a brand new leaf and say: “Oh, this tree is only two weeks old.” The lining changes so frequently, so you can’t use that old clock that we have used everywhere else.

They are now coming up with newer clocks that take account for the cells’ regular transformation. One of these is called the Zane Clock. So far that has been done in animal studies, not in humans yet. The long story of it is it is very difficult to measure in humans. But if we could measure the age of the uterus, if we could now target some of the senescent cells with either agents that can get rid of them or make them inactive, I think that would be the wave of future research that is going to be possible. In which case, the uterus will never age again because we can write patches to fix the software of the epigenome.

Kevin Pho: So it sounds like we are making the reasons why eggs fail to implant more objective with more data. Whereas before we just didn’t know why some eggs implant or not, now we have more data to make it more objective.

Oluyemisi Famuyiwa: Exactly, yes. So patients come to see me and they say: “Well, I am 52 years old and I don’t understand why I am not getting pregnant. I may use a 24- or 25-year-old donor egg.” But your uterus is 52. So that may account for the severe discrepancy between the pregnancy rate in a younger uterus versus an older uterus. Until we can reverse the aging on the uterus, that stark difference is going to remain.

Kevin Pho: So what are some things women can do to maintain the soil analogy, maintaining the health and making the uterus as receptive as possible? Is there anything women can do?

Oluyemisi Famuyiwa: So a lot of what we have right now are some supplements that they call senolytics or senostatics, like quercetin if you will, that you can use. But ultimately what I usually guide my patients to is to try to live an anti-inflammatory life so that we don’t create more of these senescent cells. Try to reduce your oxidative stress with your diet and with your environment. That is the little we can do right now until we know more about the science.

Kevin Pho: So tell us about some of the things moving forward. You mentioned that this is an area of emerging research. What do we have to look forward to?

Oluyemisi Famuyiwa: I think going forward I really would love to see the age where we can actually say: “Let’s clock the uterus scientifically.” Then maybe: “OK, now we know the age of the uterus. Maybe there is a specific senolytic or senostatic that can be applied to the uterus.” Then we remeasure it and see if we have successfully reversed it in this uterus. And would that translate into an improved success rate? We don’t know yet.

Kevin Pho: So tell us what you are doing now in the office when you talk to families in terms of maintaining how receptive the uterus is. How do you counsel patients?

Oluyemisi Famuyiwa: So for now, what I counsel them is like I said, lifestyle. But also we are looking for things that are obvious. We have to pick the low-hanging fruit. Do you have a fibroid that can be removed? Do you have endometriosis? Is it affecting your uterus? Do we need to suppress that so that the inflammation from that goes down before we talk about implantation? Do you have a defect in your uterus such as an isthmocele from a C-section? Because that can store fluid. That can also raise the inflammation in the uterus. So little things like that we can look for and try to fix.

Kevin Pho: We are talking to Oluyemisi Famuyiwa, fertility specialist. Today’s KevinMD article is “Uterine aging and IVF: why the soil matters as much as the seed.” Yemi, let’s end with some take-home messages that you want to leave with the KevinMD audience.

Oluyemisi Famuyiwa: Thank you. The take-home message is the uterus factor is real. When you go to see your doctor, you can ask questions and have them evaluate your uterus, especially when you are not getting pregnant. You want to look at not just the eggs, but also the uterus.

Kevin Pho: Yemi, as always, thank you so much for sharing your perspective and insight. Thanks again for coming back on the show.

Oluyemisi Famuyiwa: Thank you so much for having me.