16th Annual Patient Day
Your Mother Should Know, Your Doctor Should Know Better!
Patient Day - March 2, 2025
Einhorn Auditorium
Lenox Hill Hospital, New York City
Scientific Director
Dan Martin, MD
Program Director
Tamer Seckin, MD
Alright, I'm excited to introduce our next speaker, Stephanie Bush. She is a fifth year MD PhD candidate at the Donald and Barbara Zucker School of Medicine at Hofstra Northwell, where her PhD work focuses on immune cell functions within the endometrium. She has received a bachelor of science in biochemistry with honors in research from the University of Rochester, and has conducted research at the University of Rochester, university of Washington, Fred Hutchinson Cancer Research Center, and the Feinsteins Institute for Medical Research. She plans to integrate her scientific research and experience with her clinical training to provide cutting edge translational solutions to her future patients. As a physician scientist, please welcome Stephanie Bush.
Hi everyone. Thank you for the introduction. My name is Stephanie Bush again. I'm a fifth year MD PhD candidate at the Zucker School of Medicine. And my PhD work focuses on examining the interactions between immune cells of the endometrium and non-immune cells of the endometrium, particularly how that relates to fertility and endometriosis associated infertility. So first, I know you've learned about infertility already today, so I'm sorry if this is a bit redundant, but let's look at the broad definition of what is infertility. So infertility is generally defined as the inability to achieve a pregnancy after a period of usually 12 months of intentionally trying to conceive that time period is variable depending on some other factors that may be present, but usually defined as 12 months. And this is a major problem for reproductive health because it affects a large number of people. Oops, 13% of women and 10% of men.
And while I'm talking about female infertility today, it is important to note that male factor infertility contributes to 50% of infertility cases. So it's important to understand both aspects of fertility and how it relates to infertility. And while there are fertility treatments available, oftentimes these treatments are inaccessible or expensive. I'm glad we were having that conversation earlier. And infertility just as an experience, contributes a significant amount of stress to those experiencing it both emotionally, financially and physically for undergoing treatments. So it's important that we understand the root causes of infertility so we can develop better, less invasive, more accessible, less expensive treatments that can be implemented potentially earlier along in the treatment process. So in order to do that, we need to understand what are the root causes of infertility? Well, a lot of things, there are a lot of things that contribute to infertility as you can see here.
And I will be talking about two of these today, which is the immunologic component and endometriosis as a component of infertility. But an individual couple's infertility may be caused by one or a combination of any of these things. So I'll be talking about just these two for today. So let's look into what is the association between endometriosis and infertility. So we know that endometriosis is associated with infertility in that 30 to 50% of women with endometriosis experience fertility challenges. On the flip side of all couples presenting with infertility for infertility treatment, endometriosis is identified in a third of those couples. So it's both a large factor of how much does endometriosis contribute to an individual's infertility as well as broadly as a whole. Endometriosis is a major contributor to fertility challenges for couples, but we don't exactly know what the mechanism of this endometriosis associated infertility is.
There are some things that we know, some things that we don't know. So let's dive into that. So for endometriosis associated infertility, what we have on the left here are some clinical implications. So kind of macroscopic level things that we know about endometriosis associated infertility and on the right are some more microscopic things that are being investigated in research right now, including the areas of my work, particularly in immune cell dysfunction within the endometrium. And it is important to remember that these challenges can be overcome by fertility treatments. So if an individual is experiencing infertility with endometriosis, there are treatment options available. But again, our goal is to make better, more accessible, less invasive treatments. So in order to do that, we need to understand the endometrium as a whole. So the endometrium, as we know, is the inner lining of the uterus and it's a very dynamic tissue.
There are a lot of different cells that live in the endometrium and have specialized functions at different times of the menstrual cycle. And my work focuses on understanding these different kinds of cells and what they're doing throughout the normal menstrual cycle and how that may be contributing to fertility or infertility. So the endometrium again is that inner lining of the uterus that builds up and breaks down every month leading to the shedding of the endometrium in the menstrual effluent, more colloquially known as period blood. And within the endometrium the different cells that we have are immune cells, which are the cells that we know to fight infections, mediate inflammation, and assist in wound healing. There are lots of different kinds of immune cells that live in the endometrium. I focus specifically on ones called uterine natural killer cells. So these ones right here, that's what I'll be talking about today.
But remember that there are a lot of different kinds of immune cells within the endometrium, and then there are also non-immune cells. So these are other cell types that you can think of as more structural cells, cells that perform specialized functions specific to the uterus. And these may be cell types like vascular cells, like cells that line the blood vessels, structural fibroblasts that create kind of tissue structure for other cells to grab onto as well as epithelial cells that line the glands. And so of the non-immune cells, I focus mostly on what you'll hear me refer to as stromal cells. So I look at these uterine natural killer cells and these stromal cells and the interaction between all of these different cell types as what allows for the normal function of the endometrium as well as for allowing endometrial receptivity and successful embryo implantation. So how do we study this?
How am I studying this? My work is a part of the ROSE study, which is the research outsmarts endometriosis study, which is a nationwide clinical trial that collects menstrual effluent samples from patients diagnosed with endo, symptomatic with endo and unaffected by endo. And so we collect these menstrual effluent samples and this study has been going on for a number of years already and we've had a number of key findings. So from this study, we've already been able to associate an impairment in an endometrial differentiation process of those non-immune cells within the endometrium of patients diagnosed with endometriosis. We've been able to identify increased inflammation in another population of those non-immune cells. And what I am particularly interested in is a reduction in the number of those uterine natural killer cells or nnk cells, which is an immune cell population in the endometrium. And that's what I'm particularly interested in.
And so what we're seeing here is a little bit of that data. So this is some of the data that I work with. We don't need to go into everything that's on these graphs here, but what has been shown is that in the menstrual effluent samples of participants unaffected by endo and diagnosed with endo, we see a reduction in the number and the function of these UNK cells in the menstrual effluent of patients who have been diagnosed with endometriosis. And so this is what's called single cell RNA sequencing data. It gives us information about every single cell that we collect from these samples, and it gives us information about what they are and what they're doing. And so that's how we've been able to associate that these NK cells, one of these immune cell populations in the endometrium is both lower in number and lower inactivity in patients with endometriosis.
So what does that mean? Why do we care about that? In order to understand that, we need to know what do u nnk cells do? And that's a great question because it's not particularly known exactly what these cells do in the first place. So if they're missing or defective, we don't fully understand what impacts that may have. What we do know though is that U nnk cells associate with a number of different cells within the endometrium, mostly associated with non-immune cells, and they have some functions to maintain normal endometrial balance, including clearing infections, clearing out debris, and facilitating embryo implantation. We know this because nnk cell depletion, if a person has or a mouse model with no nnk cells has an increase in miscarriages and lower vessel formation in placenta. So we know that the presence of U nnk cells is really important for achieving and maintaining a successful healthy pregnancy.
But this has been challenged by these cells are very difficult to obtain. Obviously the endometrium is not a very accessible tissue. It's typically studied by biopsies which are small and painful and typically not something that people have done. So this is where my work comes in. My work has been to develop a method to isolate those UN K cells from the menstrual effluent, expand them out in the lab, and then use them for functional analysis. So my work in my PhD has allowed us to look at these immune cells from a new source, which is menstrual effluent, which is non-invasive and much easier to collect than something like a biopsy. And so this is some of my work showing that this is just a workflow of what I do. And then this is a fluorescence based identification method to make sure that yes, I am looking at the cells that I want to be looking at how they grow over time as well as what they look like under a microscope.
This is what I see in the lab when I'm working with these cells. And then some of the data that I have so far is showing that when these NK cells are in association with these non-immune stromal cells that I mentioned, they exhibit a property to assist in endometrial remodeling. So there's a structural change here when the NK cells are in contact with the stromal cells during that differentiation process that I mentioned earlier of these non-immune cells that occurs every menstrual cycle. So while that differentiation is occurring, the presence of nnk cells is mediating changes within that tissue architecture that may allow for endometrial receptivity. And so as a whole, what does that mean for patients in general and for patients with endometriosis? So kind of the workflow and the schematic that we work with in research is that in these non-immune cells here, as they differentiate in the endometrium to go from kind of a resting state to a very active state that promotes a growth factor release to assist in supporting an embryo if one is present, that differentiation process also recruits these nnk cells and activates them to perform a number of different functions.
But what we know in endometriosis is that there is an impairment in this process. So what my work has been focusing on is within this impairment that may lead to then an impairment in the UN K cell recruitment inactivation, which then may lead to an impairment in that endometrial remodeling process that we saw. And that may lead to some of the challenges that we know for women with endometriosis in terms of preparing the endometrium for successful implantation and supporting an early pregnancy. So that's some of the work that I've been doing in the lab. And again, these challenges can be overcome by current fertility treatments, but those options may not be available or accessible to everybody who wants them. And it's important to understand what exactly is going on in the endometrium during the time of implantation for successful pregnancies so we can develop better, more affordable and accessible fertility treatments. So if you're interested in the ROSE study, this is an ongoing study. Anybody can participate. We enroll patients who have been diagnosed with endo, who are symptomatic of endo and unaffected people, so anybody can participate. It's a great way to contribute if you are interested. And this is just the interest, the interest form here if you would like more information about the study. So thank you so much for everybody's time. These are the people that have supported my journey in my work and my research. And I think I have time for maybe one question.
