Turning labor on and off: the identification of a trigger: Conversation with Dr. Polina Lishko, PhD, part I

One of the big unknowns in pregnancy, and there are many, is what initiates labor. Researchers point to many different possible triggers, and likely it is some combination of signals from the placenta, the fetus and the mother that kick off productive contractions. 

This is a highly sought after bit of information in part because if we knew what initiated labor, maybe, just maybe we could turn it off in teh case of preterm labor. preterm labor is a significant issue in the US. 1 in 10 births are premature. And presently we don't have a successful approach to turning labor off once it's started--which is why my conversation with a researcher today, whose group has identified one of the switches that turns contractions on, is so exciting and inspiring.

To read more about Dr. Lishko's work, you can find her here: https://cellbiology.wustl.edu/people/polina-lishko-phd/

Transcript

One of the big unknowns in pregnancy, and there are many, is what initiates labor researchers point to many different possible triggers and likely it's some combination of signals from placenta, fetus, and the mother that define the start. This is a highly sought after bit of information, in part because if we knew what initiated labor.

Maybe just, maybe we could turn it off. In the case of preterm labor. Preterm labor is a significant issue in the us. One in 10 births are premature, and presently we don't have a successful approach to turning labor off once it's started, which is why my conversation with a researcher today, whose group has identified one of the switches that turns contractions on, is so exciting and inspiring.

Welcome to Making Sense of Pregnancy this show is a [00:01:00] new pregnancy reference. I'm finding and talking with experts doing cutting edge work to better understand what we do and don't know about pregnancy and what you can do to better understand your own experience. Each week I'll be talking to scientists, doctors, and researchers who are trying to uncover the many mysteries that still exist in reproduction, giving you the most current evidence-based way to approach this enormous transition in your life.

I hope it will become your go-to source for how to make your pregnancy better. Please enjoy the first part of my conversation with Dr. Paulina Lisko.

Paulette: today we're lucky to have Dr. Paulina Lisko on the show. She's a professor of cell biology and physiology at Washington University's School of Medicine. Her lab is looking at many things in the reproduction and aging space, and in particular for our discussion today, a possible trigger point for labor at the cellular level.

Is that a, is that a reasonable way to describe this Tier 7.1? 

Dr. Lishko: Yes. Uh, okay. Good.

Paulette: Thank [00:02:00] you. So to date, no one knows what initiates spontaneous labor, but this work, what we're gonna talk about today, gives us some insight into one of the possible mechanisms, right? 

Dr. Lishko: Yes. We definitely getting a better window in what can cause.

Preterm labor. And what is the relation between, , steroid hormones, endogenous regulators that female body produces and the labor, progression. 

So just a note here, we jumped into this conversation with very little runway, but by endogenous regulator, I think what Dr. Lisko is referring to is the Kir R 7.1, ion channel, which I'm about to mention, which is a built-in part of your cells that controls potassium levels, helping the body manage things like electrical signals.

Paulette: Okay, so this is so cool. Do you call it KI 7.1 or does everyone in the lab have a cooler name for it? 

Dr. Lishko: , No. I think it's kind of, it's, uh, depends.

Some people call it [00:03:00] K-I-R-I-R. 

Paulette: Okay. And 

Dr. Lishko: shorten into KI and 7.1. It's like it's mouthful. It stands for inwardly rectifying potasium channels. That's what IR stands for. And it's , name stuck to the founding member of the family of those proteins. And then based on discovery there was sun number 1, 2, 3, 4, and one seven.

Paulette: Okay. So super cool. So we are gonna talk about ion channels here and electricity. . 

But before we dig into the specifics, we can talk about the question that's motivating this research and this finding.

Paulette: Maybe you can set the stage for, what people think initiates labor or what they used to think about progesterone and why that story doesn't entirely make sense for humans.

And , what set you off on this quest? 

Dr. Lishko: Of course, absolutely. So it's kind of a common knowledge that, uh, progesterone, a hormone produced by a female body, and especially it's produced in a large quantity [00:04:00] during pregnancy, during so-called gestational time. The progesterone is absolutely important.

To maintain pregnancy, and that has been known for decades. But how exactly this, , hormone, the steroid works was not clearly known . The main function of progesterone, in addition to stimulate tissue development and growth of the, of the baby and maintain the, health , of the female body is also to keep uterus, which holds the baby right, to keep the uterus quiescent, to prevent contraction of the uterus.

Paulette: So when you say quiescent, another way to say that would be like quiet. So it's not contracting. Yeah, yeah. 

Dr. Lishko: Not contracting. Yeah. And that becomes, as pregnancy progresses, it becomes more and more important task because baby is growing, it becomes heavier. And , uterus is one of the strongest smooth muscles in human body.

It's extremely strong and it must [00:05:00] become even stronger to sustain the weight of the baby. But, the tendency of the. Muscles like uterus, if they experience mechanical pressure, they tend to contract. And as the baby grows more, there is more pressure, so there's more stimulation to contract. So that means, especially at the third trimester.

The uterus really needs additional stimuli to, to be kept quiescent right? And that's why progesterone level increases through the pregnancy and in most of the mammals, right? The onset of labor happens when this level of progesterone, which usually increases just dramatically drops. So this huge drop in progesterone.

Coordinates onset of the labor in most of the mammals except for humans. Primates. 

 As I understand it in humans, labor [00:06:00] starts even when the level of progesterone is high, and that level doesn't tank until after the placenta is delivered, but that's not how it works for other mammals.

Dr. Lishko: Yes, correct. So in humans, in primates, placenta, during pregnancy is the main producer of progesterone. , Before the pregnancy, progesterone is produced by the ovary and as the cycle, as it goes through menstrual cycle, there is a stages where progesterone is produced and there is stage of progesterone goes down towards the next cycle.

. So during, , normal menstrual stages, the progesterone level fluctuates as, egg ovulates and leaves follicle. This place where egg used to be turns into structure called, , Corpus luteum , which is the main production of progesterone by ovary during normal cyclic.

And they're the same in humans, mice. And . But when the pregnancy triggers all the first, , [00:07:00] trimester already still produces progesterone. The corpus luteum still produce progesterone 

Paulette: before you have a placenta. 

Dr. Lishko: No, placenta is already growing. Right, but, but it's 

Paulette: not functional at the level that it has to be to take over.

It's 

Dr. Lishko: not yet the main. Yeah, progesterone producer. But starting from the week, 12 weeks of, , starting from the second trimester, placenta takes over entirely. And in humans ov don't participate in major progesterone delivery. Now, this is job for placenta, however, in, , rodent, in other animals, particularly in mice, placenta is actually not the main producer of progesterone.

It's still ovaries So always in mice take care of the progesterone production throughout the pregnancy. 

Paulette: Okay? Okay. 

Dr. Lishko: And that level of progesterone drops significantly, as onset of labor, happens in rodents But in primates, , in humans, progesterone [00:08:00] does not drop before the labor , the estrogen goes up.

That has been known as this big, puzzle, and it was known as functional withdrawal of progesterone. So the hormone is still there, but somehow it doesn't signal anymore, so. What triggers onset of labor in humans and primates was still not clear because progesterone level doesn't drop. They're still on, but estrogen clears up.

Paulette: In this story, just to repeat some of what you said. , Progesterone is what's keeping the uterus quiet, despite the size of the growing fetus is putting more pressure on this giant muscle. And, and as pregnancy comes to an end. In other mammals, progesterone drops. And so that kind of blanket that you have over the uterus, keeping it quiet is removed.

But in human pregnancy, that is not the case. Progesterone is made at the same or higher level, but somehow it's not keeping the uterus [00:09:00] quiet anymore. And we think maybe that's because estrogen is jacked up really high around delivery. 

Dr. Lishko: Right. 

Paulette: Okay. 

Dr. Lishko: Correct. You nailed it. 

Paulette: So we need to explain how functional withdrawal. Functional withdrawal works. Yeah. 

Dr. Lishko: Yeah. So, and, , that functional withdrawal phenomenon, was really puzzling and that what part of our work answers. How exactly that happens. And what are the key molecules, key regulatory mechanism in the uterus, which helps maintain its quiescent side, , calm state and how it can go wrong.

Right. So this work is centered on the protein called ion channels. And ion channels are basically gates in this. Plasma membrane of the cell, which allowed ions charged particles such as calcium, potasium, sodium [00:10:00] to go inside the cell or going out. And as those charge particles, ions flow, in or out, they generate electrical currents and we, we are bioelectrical beings.

We run on bioelectricity. It's not just our brain. Our whole body generates bioelectricity. Every single cell does, and so does uterus. Uterus is very powerful. Muscle, which contracts, which can generate action potentials generate electrical. Sparks just like our brain, and it relies heavily on those ion channels to keep certain charge electrical charge, right?

So in a quiescent state, in a calm state, it's charged so-called negatively , it's called hyperpolarization. So the negative charge allows us to be more silent, but when we become more positively charged. It stimulates influx of calcium and that triggers [00:11:00] construction. So the ION channel study is a potasium channel that the channel, which requires to keep uterus, , negatively charged and to keep it quiescent, because what this channel does is KIR 7.1.

It allows potassium ions to leave the cell, and potasium ions charge positively and as they leave the cell. The cell, the uterus become negatively charge. And as long as this channel is active, as long as K so active and allows potassium to leave the cell, the uterus will still will stay quiet. When this channel is blocked or it's absent or is dysfunctional, then , the positive charge starts to accumulate and the uterus has ability to become more contractile, starts to contract.

Paulette: Let me repeat to you just to, , level set where we are here. So. The uterus is a muscle, like other muscles. Mm-hmm. And muscles run on . [00:12:00] Bioelectricity. And the way that's generated is that there are positive and negative charges flowing in and out of the cell.

And it's this change in voltage that is making a current, and one thing that we're focused on is this potassium channel, which keeps the cell too negative to, contract yeah. So, so that's keeping the uterus quiet. So that is one form of control. 

Dr. Lishko: Exactly. 

Paulette: That, that is related or unrelated to progesterone?

Dr. Lishko: Oh, it's very much related because one of the discovery we made that progesterone directly activates this channel. 

Paulette: Okay. 

Dr. Lishko: So that's a target, that's progesterone target. So, okay. Yeah. So, , canonically steroid hormones such as progesterone, estrogen, testosterone, and so on, canonically, they sought to act.

Through the, so-called genomic pathway, they have to go inside the cell, they have to bind to their receptors. In the target inside [00:13:00] the cell, and then the whole complexus goes to nucleus and trigger expression of the genes and making more proteins. This whole pathway takes hours, days, and that's absolutely required for the cell division, for the growth of the tissue.

You know, like when people kind of pump the muscle and grow big muscle, that's what , testosterone does, but this is a canonical genomic pathway. This is not what we studied. This is not, what is it? Here in this particular regulatory pathway, progesterone directly binds to the channel, the KIR7.1 and keeps it active.

So it's more direct, so-called non genomic pathway, which is much less studied. And we are one of the, , few groups, who directly, study this regulation in non genomic direct. Play and what we found that this potassium channel is directly [00:14:00] activated by progesterone. So as long as progesterone is present, this channel is open and it's active, and it keeps the cell negatively charged, relax, calm, and everything is great.

But when estrogen comes and high concentration of estrogen. Which is physiologically relevant. That's what happened during one set of labor, that concentration of estrogen, antagonizes effect of progesterone. It basically kicks progesterone from the channel and then the channel becomes dysfunctional, doesn't work anymore.

So the cell becomes, the uterus become positively charged and starts to contract. 

Paulette: So there's a lot of literature trying to use. Well, lemme back up once. Yeah. , Do we think preterm labor is initiated in the same ways that spontaneous term labor is initiated? Are these two different, processes or they're the same, just at a different time?

Dr. Lishko: So preterm [00:15:00] labor, , there are multiple triggers of the preterm lead, right? Yeah. 

Paulette: Yeah. 

Dr. Lishko: And, it can start at any stage at a very early stage that would be called miscarriage, right. Like first, second trimester probably. But when we are getting into third trimester, it's already called preterm labor.

Sometimes this border is kind of fluid between second and third trimester. And trigger of preterm labor often kind of canonically recognized is, , inflammation, 

Paulette: right? 

Dr. Lishko: The local inflammation. Which can be triggered by placenta insufficiency or some, infection or, , rhesus factor incompatibility that can trigger a lot of, , cases of preterm labor, but also insufficient level of progesterone that has been widely recognized that if the placenta is a human, placenta doesn't produce enough progesterone.

That can cause premature , delivery and premature labor. [00:16:00] And that was not particularly clear how exactly. I think now we know that's likely through this potassium channel, which would be, and as a previous work from also the same university I am right now in and from the Washington University. In St. Louis, the work from SAR group actually showed on mice that this mutation channel KIR7.1

If you genetically, manipulate mice in a way that during the pregnancy you decrease the level of KIR7.1 in the uterus, the uterus starts to contract this crazy and, , that can trigger preterm labor. 

Paulette: So this is my question, there are many different paths to preterm labor.

Yes, but the KIR channel underlies all of them. 

Dr. Lishko: So it's one of the important, regulator. There are other, , potasium channel, calcium channel because it's electrically active organs, right? So, there are multiple players and if one of the [00:17:00] players goes wrong, the preterm labor can happen. But the progesterone pathway.

Through. 

Paulette: Okay. 

Dr. Lishko: So the connection between steroid hormones, leads to this specific relationship 

Paulette: So it seems like the literature on using, progesterone to stop preterm labor is patchy,

And what I mean by patchy is that administering progesterone to women with preterm contractions works for some groups and doesn't work for others. It kind of depends what brought you to preterm labor.

Paulette:  . And does your investigation of the KIR Channel help explain why it works in some instances and not in others?

Dr. Lishko: Absolutely. So the situation is preterm labor, as I said, because there are multiple causes, right? There are subpopulation of, pregnant, , patients which have low concentration of progesterone, and they're more likely. To, uh, the preterm labor or the [00:18:00] pregnancy, , complication could be caused because of , this channel the KIR7.1 is not active, but also a population of, , patients of pregnant, , patients who have like inflammatory pathway, right?

Infection who have normal progesterone level. The preterm labor causes is likely 'cause of a different cause, right? If you put everything together, everything in the kitchen sink, then you don't have a statistic, right? 

Paulette: Yeah. 

Dr. Lishko: But then another important factor to consider that, for example, progesterone effect on this channel is, has so-called high on off rate.

So progesterone binds very quickly, opens this channel, but also can be washed out also very easily. So it's kind of a dynamic. So as long as progesterone present is great, as long as it's removed from the body, everything goes back to dysfunction. That's why, , progesterone injection has been recognized for many years, decades, , as a factor required to prevent return [00:19:00] labor.

, But they were given very frequently and. It's now understood why? Because as long progesterone is bioidentical ob, it's a natural molecule. The body metabolizes, the body destroys very quickly. So it needs to be supplemented, , at relatively high quantity. , However, if there would be a compound which would keep this channel active in a, sustain a longer time than progesterone, that compound would be more beneficial.

This compound, this compounds actually existed. It's exists and has been used, for decade to prevent preterm labor until FDA put from the market last year. So this compound is, , called , McKinna. That's, oh, 

Paulette: that's the 17, 

Dr. Lishko: 17 hydroxy progesterone compound. Yeah. 

Paulette: Yeah, yeah. 

Dr. Lishko: , And, , it was believed the exact mechanism, how this component works was not clear.[00:20:00] 

It was believed to act through the classical genomic pathway, and, it went, , all the way, through the clinical trials it was approved. Then the larger meta study, they looked at 10,000 patients and they didn't found particular benefits because they just probably pulled everything together again. 

Paulette: Yeah, yeah.

Dr. Lishko: But what we show , in that work, that this, kinna 17 hydro actually has much slower off rate. It binds to the, to KIR and it keeps this channel. Open for much longer time, which might explain beneficial effect of this compound, in order to sustain activity of the channel for longer time.

Paulette: So you wouldn't need a progesterone shot every day? 

Dr. Lishko: Exactly. Right. Yeah. Inject once per, you know, a few days, once a week. So that explains because it a more, , careful elite design compound. 

Paulette: This, this is such a [00:21:00] cool finding ' for many reasons. But, I interviewed, , Matthew Hoffman, I don't know if you know him.

, A couple months ago he worked with colleagues, but a giant international trial of using aspirin really early in pregnancy. 

 During my conversation with Dr. Lisko, I couldn't remember what the sample was, but I looked it up and that study sample was a large, diverse group of women who were pregnant for the first time and were only carrying one fetus.

Paulette: It had a dramatic effect on preterm delivery.

But he was saying we can't figure out why it didn't help everyone. But you may have the answer because there are these other pathways and Exactly. To be, to be more effective, we'll have to sort out what is driving preterm labor for each person who shows up with preterm labor.

Dr. Lishko: Exactly because, such a simple test as probably hormonal test is to take some blood draw and look at the progesterone level would be already very helpful because in humans, progesterones produced by placenta and of course it doesn't produce enough, it'll show up, , in [00:22:00] a simple blood test.

And those cohort of, , pregnant patient would benefit perhaps from. Well, unfortunately, FDA a pulled from the market in February, so it's not the real, I mean, that's, 

Paulette: it's a little surprising to me that you just group all the preterm labor people together. Since you know that there are all these different paths to preterm labor, that's some silver bullet you're looking for.

That could turn 'em all off. Right? That's, yeah. 

Dr. Lishko: Yeah. It's, it's sad is right now, except for progesterone, there's no intervention. 

Paulette: Yeah. 

Dr. Lishko: And this huge amount of, population which essentially underserved. There there's no available effective treatment. 

Paulette: I am gonna stop my conversation with Dr. Lisko here, With the state of nature around obstetrics care for preterm labor and this new finding about these potassium ion channels, what they do.

Keeping the uterus quiet by keeping uterine myocytes the muscle cells. Two [00:23:00] negative to fire and how they can explain exactly what's happening. When we say that there's a quote, functional withdrawal of progesterone, maybe we'll adapt the name of that phenomenon to be more specific. Something like estrogen blockade or, or something like that.

This substitute name is clearly a work in progress. . Bear with me. Thanks for listening. If you like this episode, please share it with friends. Join us next week while I'll continue my conversation with Dr. Lisko, and we talk about how knowledge about these specific ion channels has shed light on other mysteries in the field.