Kofinas Podcast Series


Getting to the Root Cause of Your Infertility

In this episode, Kristyn and Dr. Kofinas delve into the importance of diagnosing infertility's root cause and navigating treatment options, including the intricate role of the immune system. Join them as they explore women's health with expertise and compassion, dedicated to holistic care.

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[00:00:05] Kristyn Hodgdon

Hi, I'm Kristyn Hodgdon, an IVF mom, proud women's health advocate, and co-founder of Rescripted. Welcome to

From First Period to Last Period, a science-backed health and wellness podcast dedicated to shining a light on all of

the women's health topics that have long been considered taboo. From UTIs to endometriosis, we're amplifying

women's needs and voices because we know there's so much more to the female experience than what happens at the

doctor's office. With From First Period to Last Period, we're doing the legwork on your whole body so you can be the

expert in you. Now, let's dive in.

[00:00:41] Kristyn Hodgdon

Hi everyone, and welcome back to From First Period to Last Period. I'm thrilled to have Doctor Jason Kofinas back on

the podcast. This time, we are going to talk all about why it's so important to find a fertility clinic that is willing to get to

the root cause of your infertility. So welcome back, Doctor Kofinas.

[00:01:02] Jason Kofinas

Thank you, Kristyn. It's great to be back, and I'm excited. This is one of my favorite topics.

[00:01:06] Kristyn Hodgdon

Absolutely. Doctor Kofinas is a reproductive endocrinologist and infertility specialist, in case you missed the last

episode, at the Kofinas Fertility Group in New York City. And what I love about Kofinas is just how you guys really try to

get to the bottom of the issue and really have individualized care for each patient. First things first like, why do you think

it's essential for a fertility clinic to identify that root cause?

[00:01:34] Jason Kofinas

I think it's important to make the point that not everybody necessarily needs an in-depth evaluation, right? A lot of

patients, literally, they'll do an IUI, they'll get pregnant, they'll be on their way, but unfortunately, that doesn't work for

everyone. And it is our philosophy to not get into a situation where we go through the steps, we increase the intensity of

the treatments, and then you get to the point where you've done IVF, and you've done genetic testing on the embryo.

You do a transfer, and the transfer fails, or even worse, you have a miscarriage or a biochemical pregnancy. Then

you're saying, well, now we have to go backwards. And,

[00:02:16] Kristyn Hodgdon


[00:02:16] Jason Kofinas

I think the most common frustration that I see in patients who come to see me, who have failed multiple transfers of

genetically normal embryos, is why wasn't that looked at yet? Or why did I use all these embryos and do the same thing

over and over again? And I see that quite frequently. And it did help guide a little bit of our philosophy as a clinic,

although we've been around since 1987, and we've been doing a lot of what we'll talk about, I'm sure, for a very long

time. But I think the importance of when you first meet a patient understanding what could be happening based on their

medical history, and then formulating the workup and the diagnostic testing from there to figure out what could be

potential pitfalls before they happen is really important.

[00:03:08] Kristyn Hodgdon

Yeah, definitely. And so, what are some of the diagnostic tests that are non-negotiables for you?

[00:03:15] Jason Kofinas

A basic fertility workup, which is not unique to us by any stretch of the imagination, is ovarian reserve testing your

general kind of health, thyroid health, blood counts, electrolyte testing, infectious disease testing in terms of what you're

immune to, I think genetic testing is essential, and I haven't really had any patients in the last few years that have

refused to do that, which is good. And then if you're just coming in, you've been, you're young, you've been trying, but

you haven't really had any testing done, really, the first question is, is the sperm okay? Are the tubes open? Are there

any lesions in the uterus that might be getting in the way? And are you ovulating, and are there enough eggs, right?

That's really the basic workup.

[00:03:58] Kristyn Hodgdon


[00:03:58] Jason Kofinas

So you do all that. But then one of the things that we like to do at the beginning is we like to look for things like polyps.

So, we'll do a saline sonogram. We like to look for things like endometritis, which is inflammation of the uterus. That can

be done at the same time as the saline sonogram. And if you do have the risk, there is that you'll either you're not going

to get pregnant or you're going to have pregnancy loss. And it's so easily treatable that it's really, I don't personally

understand why that's not part of the initial workup. A lot of places, a lot of clinics will look for that after you've failed an

embryo transfer. That's something that we focus on. And then from there, those are the basic things. Now, for a very

long time, we have been focused on blood clotting disorders. We believe, as a clinic, that initial connection between the

embryo and the uterus. The better the connection, the healthier the pregnancy, the bigger the chance the pregnancy

will go to full term, the smaller the chance that the things like preeclampsia or third-trimester complications will occur.

[00:05:09] Kristyn Hodgdon

Do you mean like initial hCG numbers?

[00:05:11] Jason Kofinas

Not just numbers, but just that initial process of the implantation, the process of implantation. You want that to be

optimized, right? We believe that all those little blood vessels in the developing placenta, there really should be as

much of you should really be focusing on keeping those blood vessels from clotting and allowing the proper kind of

exchange of nutrients between the growing fetus and the mother. And getting a healthy placenta in the first trimester

sets the pregnancy up for progressing in a not complicated way, and we believe that. So that's why we look at these

blood clotting disorders as well in our patients, because a lot of times, we'll identify some very common ones that are

very easily treatable and can prevent pregnancy loss and can prevent late third trimester complications.

[00:06:07] Kristyn Hodgdon

Yeah, it seems so obvious, but I have heard a lot of stories, actually, about endometritis being discovered later. And it's

like, why?

[00:06:17] Jason Kofinas

Exactly. Because it's such an easy test. So you have experience. Good. Okay. So you know what I'm talking about


[00:06:22] Kristyn Hodgdon

Yes. And the saline sonogram, in my experience, at least, was pretty straightforward and not painful or anything. So

that wasn't for anyone who might be nervous about it.

[00:06:33] Jason Kofinas

Yeah, it can be a little crampy, and people have different thresholds, but it's not a dangerous test, and it's a very

valuable test, so it's worth going through.

[00:06:42] Kristyn Hodgdon

Yeah, absolutely. So what about unexplained infertility? Because that's such a frustrating diagnosis both at the outset

and also like you've had failed implantation, and you don't know why.

[00:06:56] Jason Kofinas

Yeah, unexplained infertility is one of the most frustrating things that patients can hear. And the statistic is that if you

have been diagnosed with unexplained infertility, most likely 50% of those patients have endometriosis.

[00:07:12] Kristyn Hodgdon

You know, that is so crazy. I actually know someone who just had a hysterectomy, and she's in her 50s, and she has

had like painful periods her whole life, and it wasn't until she literally was getting a hysterectomy that they found that

she has and she had really bad endometriosis.

[00:07:32] Jason Kofinas


[00:07:33] Kristyn Hodgdon

And I know that it takes 7 to 10 years on average to get diagnosed. So what do you typically do to diagnose endo? Do

you do like those tests? Any testing off the bat in unexplained patients?

[00:07:46] Jason Kofinas

It's the gold standard of diagnosis, unfortunately, is a laparoscopy.

[00:07:51] Kristyn Hodgdon


[00:07:51] Jason Kofinas

So it's a surgical procedure. You have to go to sleep, and the camera goes to the belly button, and it's direct

visualization. There are many attempts. Whether they're successful or not is another issue to get less invasive

diagnostic methods. The first step is always an ultrasound. If you see a cyst on the ovary that is very clearly as the

features of an endometriosis cyst or endometrioma, then that's a pretty easy stage three or stage four diagnosis to

make. Sometimes, if the lesions are big enough, you won't see them on ultrasound, but you can see them on MRI. But

a lot of times, the MRI can say, oh, there's no evidence, but in fact, if you go in laparoscopically, you'll find that the

endometriosis. So you really have to look at the patient's history and the patient as a whole to understand who you're

going to be a little bit more aggressive with. If somebody has significant pain with their periods, painful intercourse, and

infertility, they have an over 80% chance of having endometriosis. Forget about all the testing and all that. That is a

statistic that is very clear. If somebody doesn't have any symptoms, so that's silent endometriosis. That's a very difficult

diagnosis to make. And it takes a little bit of a leap of faith from both the physician and the patient, in the sense that if I

see someone who has had, you know, multiple failed transfers or is young and is not getting good results from their

trials, there is a possibility that endometriosis has been missed. And in those cases, even if symptoms are not there, I

will very often recommend doing a diagnostic laparoscopy at that point. Obviously, the important thing is that when we

do a diagnostic laparoscopy, we find it. We are able to treat it right then and there, and it turns into an operative

laparoscopy. But I think clinical suspicion is still the best kind of tool that we have. Tests like Receptiva, for example,

that are basically an endometrial biopsy, and they look for a specific marker. I've had patients that the test was

negative, but I suspected it enough that I went in, and sure enough, they had it. And I've had patients that were positive

who did not have endometriosis, so it's not a perfect test. And it's appealing because it's not surgery, but at the same

time, it's really not as accurate as we would like it to be. Also, the treatment modalities that the test recommends might

not necessarily be some that I agree with. I find that endometriosis has multiple camps, and I'm in the camp that you

really need to resect all the lesions and get rid of the disease in order to have optimal treatment.

[00:10:37] Kristyn Hodgdon

Versus Depo Lupron?

[00:10:39] Jason Kofinas


[00:10:40] Kristyn Hodgdon

Yeah. And you guys have your own minimally invasive gynecological surgery center, right?

[00:10:46] Jason Kofinas

Oh, yeah. So we have basically, it's Article 28, which is a specific type of license in New York in order to run a surgery

center that can do more complex cases. And we actually built that center with ovarian tissue cryopreservation in mind.

So, it is built for that purpose, but we also do all our stage four endometriosis cases there. We do all of our

myomectomies, many myomectomies that we do that would really typically be done in the hospital. And I find that our

patients see the experience is more pleasant and the healing process a little bit better than staying in the hospital for

two, three days. Yeah, we have this center. We definitely utilize it and we do focus a lot on this particular kind of

surgical concept of treating infertility patients. And it served us well because a lot of patients who, even patients who

had failed IVF multiple times in other centers, there are cases that we have been able to operate on them, and they get

pregnant naturally.

[00:11:47] Kristyn Hodgdon

Yeah, that's amazing.

[00:11:50] Jason Kofinas


[00:11:51] Kristyn Hodgdon

How common is it to have PCOS and endometriosis?

[00:11:55] Jason Kofinas

Yeah, there is an association between PCOS and endometriosis. I don't know why, but I've noticed it looking at charts

from other doctors who've seen patients. A lot of doctors that do endometriosis surgery have noticed that the literature

has mentioned it. And definitely, if there's PCOS and pelvic pain, you have to consider it. You cannot ignore it.

[00:12:19] Kristyn Hodgdon

What about without pelvic pain?

[00:12:20] Jason Kofinas

That's a tougher one, right? Because one of the features of PCOS is that the quality of the eggs sometimes is not so

good, right? And we think maybe it has something to do with insulin, or maybe it has something to do with the hormonal

milieu within the follicles. But also, if there is underlying endometriosis that's not being diagnosed, perhaps it has

something to do with that. Yeah, and if you have a PCOS patient that you tried everything and you're not getting good

quality embryos or you're not getting plantation and they have no endometriosis symptoms, at that point, what else are

you going to do except look for that one factor that you haven't really looked for?

[00:12:56] Kristyn Hodgdon

Yeah, it's definitely nerve-wracking thinking about a laparoscopy when you don't have any symptoms, but the only way

you can really know is if you go in there, right?

[00:13:07] Jason Kofinas

That's right. It's a very hard thing to swallow if you're a patient, and especially if you're a patient who's nervous about

anesthesia or surgery in general. But I think whenever a decision is made to undergo something as drastic as a surgical

procedure just for diagnosis, you really have to look at the benefit-risk ratio. What are the actual risks to the patient from

the most severe risks, but permanent damage to organs versus like just the risk to the ovarian reserve? And then you

have to compare that to if you find this condition and you treat it and you get them to their end goal, that's obviously a

tremendous benefit. So, that balancing act is a tough one, and I deal with that every day, right? So it's not easy, even

from my point of view. I struggle sometimes to figure out what is the right thing to do? What do we, as a clinic and under

the direction of Doctor George Kofinas, who's been doing this a long time, we have all managed to almost form this

second sense where we're able to really understand who needs this.

[00:14:14] Kristyn Hodgdon

Yeah, absolutely. I wanted to talk a little bit about reproductive immunology too, just because I feel like immune, A,

autoimmune diseases are on the rise among women, and I have Hashimoto's, which is a thyroid disease. And I just

think there's not enough research out there yet, but it has to impact fertility somehow.

[00:14:39] Jason Kofinas

Okay. So, let's talk about the immune system. So essentially, you need the immune system to have an attachment and

to get pregnant. And you can't, if you had a completely suppressed immune system, you will have a difficult time getting

pregnant. If you have an overactive immune system and now you have all this kind of inflammation and the byproducts

of inflammation, now you're at risk of rejecting a pregnancy. So there is a fine line, a balance between over-immune,

activity, and under that is this sweet spot where the immune system's working for you versus the gets you. We know

and understand this right. So, the natural killer cell, for example, is a very important reproductive cell that helps to

remodel the lining and allow implantation to occur. If you have too much of that cell, that's where kind of biochemicals

come from, for example, or even first-trimester pregnancy loss. So controlling the percentage of these cells that are

active has been a way that we, as a clinic, have been able to help patients with recurrent pregnancy loss or even these

recurrent biochemical pregnancies, which are difficult to explain. So, yes, we strongly believe that the immune system

plays a major role. To your point, the research is lacking, right? And it is getting better. And I think it's becoming more

accepted. A lot of what we do doesn't have robust randomized controlled trials at all, and we have a lot of internal data

that we are collecting and trying to put together into a paper published. But we have a lot of internal data that shows if

somebody has an elevated immune response, specifically a reproductive response in their blood. So we'll do a blood

test. It doesn't necessarily mean that they're going to have that same response in the uterus at the time of implantation.

[00:16:42] Kristyn Hodgdon

And what blood test is that?

[00:16:43] Jason Kofinas

It's basically, you're testing for natural killer cells, so that you're testing for cytokines which come from T cells, and it's

basically called a reproductive immunophenotype, essentially. So we used to do that pretty much exclusively without

any further testing because that's really all we've had. And as things have progressed, they were understanding what's

going on in the uterus and how implantation is a unique kind of time period, and what happens after implantation has its

own kind of parameters and what that looks like. We started to understand that if just because the blood is showing

suppression, i.e. we need to suppress, you can over-suppress and keep people from implanting. So you need to be

very careful when you're doing immune therapy, or you're looking at the immune system that you focus your therapies

on two time intervals around implantation. And then what happens after implantation?

[00:17:44] Kristyn Hodgdon

Okay. And that treatment, what does that look like?

[00:17:47] Jason Kofinas

Which one? The for the over immune activity?

[00:17:51] Kristyn Hodgdon


[00:17:52] Jason Kofinas

It depends, right? So, if you have elevations in certain cell types, one of the very common therapies that we'll use is a

medication called tacrolimus. And tacrolimus, a lot of endometriosis patients have elevations in their cytokines. And

tacrolimus is being used to treat those and treat T cell reactivity. And just as a kind of a point of reference, tacrolimus is

used in kidney transplant patients who prevent rejection of the kidney, and of course, they use it at a much higher dose.

And you're going to say that can't be safe in pregnancy. And if I told you that some of the most robust, pregnancy-safe

data exists on tacrolimus because these patients get pregnant and they can't stop the medication. So we have a lot of

data. So it is, in fact, a very safe medication in pregnancy. And it's really used to prevent pregnancy loss secondary to

excessive inflammation. So that's one another big one that everyone talks about is intralipids.

[00:18:52] Kristyn Hodgdon


[00:18:53] Jason Kofinas

You've heard of it. Intralipids, the're infusions. They're soy-based batting falsified. The point is that in vitro, they were

shown to decrease natural killer cell percentages. So you could actually send your blood, and if you have an elevated

natural killer cell percentage, they treat it with insulin, and they see how much drops. So, you know, if the treatment's

that good, right? So that if you have elevated natural killer cells, then you would use the Intralipids to decrease those

natural killer cells to a more acceptable level.

[00:19:26] Kristyn Hodgdon


[00:19:28] Jason Kofinas

So that's another one. And then a very common treatment is steroids, right? So, prednisone is an extremely robust

suppressor of natural killer cell activity. I have noticed that prednisone, if you have, if you're using it around the time of

the plantation and you don't have an obvious need for suppression at the time of implantation, you can ... the

implantation process by overusing the prednisone. So, the timing of the prednisone is really important as well.

[00:19:58] Kristyn Hodgdon

Interesting. That's very interesting. So much of this is so outside of the box. And in the best way possible, it, when you

have all the information, you can actually ask your healthcare team and try to make. And then once you have all the

information, you can make the best educated decision for yourself. But if you don't know about any of this, it's really

hard to know what you don't know, like we said before. For the NK cells or like autoimmune tests, like to ask for that,

would someone just, it was just a blood test?

[00:20:32] Jason Kofinas

Like cautioning people, you're a run-of-the-mill kind of fertility center that doesn't deal with this. They're either going to

dismiss you or if you get the blood test, they'll probably order the wrong one, and if the result comes back, they won't

know what to do with it.

[00:20:45] Kristyn Hodgdon


[00:20:46] Jason Kofinas

So if they're, and unfortunately, discussing this with your fertility doctor is not going to get anywhere, then you go on the

internet, which is not exactly the best thing in the world either. And you start to get all these kinds of different things, and

you can go down this rabbit hole, which is not necessarily where you want to be if there's a concern, right, so concerns

for immune issues would be something like recurrent implantation failure, multiple biochemicals with genetically tested

embryos or pregnancy loss of genetically normal either pregnancies or embryos. In that case, you seek out care from a

doctor who either deals with this and understands it. The field of reproductive immunology has also expanded. There

are doctors who literally only do reproductive immunology.

[00:21:36] Kristyn Hodgdon


[00:21:36] Jason Kofinas

They are trained in a specific kind of unofficial fellowship. And then, they consult with the fertility doctors. And of course,

your fertility doctor needs to be willing to listen to this individual and or incorporate the treatments that they're


[00:21:53] Kristyn Hodgdon

And I think. A lot of people just knowing that cost is such a barrier to care for so many people, like adding on the

reproductive immunology is definitely daunting. So the fact that if a clinic is willing to do it in house, it's such it's so


[00:22:11] Jason Kofinas

Oh yeah, I've heard some incredibly high consultation fees just to get on the books for Reproductive Immunologist, and

we're doing it every day for our patients just to increase their chances and increase the successes, obviously. So that, I

found very interesting, and I'm sure this is experimental. So insurance is not going to cover it, so it's all out of pocket

and it could be thousands of dollars.

[00:22:32] Kristyn Hodgdon

Yeah. So I guess, it's just like how do you even I don't know, as someone who's gone through field implantation, it's just

so tough to know. Is it the embryos? Is it my body? Is, do I go down that route? Has it just been bad luck? It's, especially

when you've had a successful pregnancy in the past, all you can do is check the boxes and.

[00:22:57] Jason Kofinas

My recommendation for someone like you, or someone who might be going through what you're going through, is to

organize your thoughts, and your, and the direction that you're going in. And to your point, check off the boxes, but

make sure that the correct boxes are being checked off and have a strategy with your doctor that makes sense.

[00:23:18] Kristyn Hodgdon


[00:23:18] Jason Kofinas

A strategy that I want you to come up with it, you then have a roadmap, and you do all the testing that's required, and

you don't go off on tangents or start going backwards. So again, this goes back to the root cause issue. Know kind of

which direction you're going in and keep moving forward, so that way you're not in a situation where you find yourself

throwing your hands up in the air and saying, I think I've done everything or have I? Then we go searching for all these

random things, right? So I think that's really a good point that you make. And I think that because it's so frustrating what

you're going through and what many others are going through because it's not normal to fail that many transfers, right?

Something is going on, and you do need a methodology to follow that's going to at least attempt to give you that


[00:24:09] Kristyn Hodgdon

Exactly. And it can be easy to say, want to get to the finish line and be rushing the process. And I don't know if I want to

repeat those tests, but in a way it's you're better off doing it beforehand because you don't want to wish that you had.

[00:24:25] Jason Kofinas

Yeah. That's correct. That is correct.

[00:24:28] Kristyn Hodgdon

Exactly. As a sort of last question, I always like to ask, what would you rescript about the way people think about their

infertility, their clinic, and whether they're asking the right questions or their clinic is asking the right questions of them?

[00:24:45] Jason Kofinas

Oh, that's a that's a great question. For some reason and I'm not the only one who has noticed this, we all talk amongst

ourselves. For some reason, the amount of transfers or amount of retrievals that it takes to reach a live birth, it's not

going in the right direction. In fact, people are requiring quite a few more transfers than you would think.

[00:25:09] Kristyn Hodgdon

As opposed to a few years ago or?

[00:25:11] Jason Kofinas

Yeah, we even we'd have noticed that our kind of what could also be patient population. But we have noticed that it

takes a little bit, maybe two transfers or three transfers, especially as you're getting older. And in those cases, I'll see

patients, they had a failed transfer one transfer, and they'll come to see me, and I'll put you're starting over here one

failed transfer, okay? If you have 5 or 4, I understand, but give your clinic a chance because it's not easy to move your

embryos. It's not easy to go through everything again. And so that would be one of my main comments to patients

would be, okay, if you're not feeling that your clinic is offering you reason or really paying attention and just doing the

same thing over and over again, maybe it's time for a change. But if the clinic is being proactive, is trying different

things, it really can become a little bit daunting to move clinics as well. So just understand that everyone's feeling the

same thing, every clinic is having the same experience. The amount of transfers, and the amount of retrievals, it's

changed a little bit from a few years ago, and you would think, how does that make any sense? We're supposed to be

doing better and better, right? And my answer to that is the medicine and the science in our field has stagnated. We

don't have major developments like we did a few years ago, for example, genetic testing of embryos. That was huge.

Or when we started culturing embryos to blastocyst and not using all weekday three embryos. That was a major

advancement when we were vitrifying our flash freezing versus slow freezing major advancement. There haven't been

any like that in years. And sure, there's the artificial intelligence movement. And what does that mean for embryo

selection? And sure, there are genetic screening methods of embryos that could potentially offer a little more insight

into the whole genome of the embryo. But those are not ready yet. And again, it's been years since significant

achievements have been made. So I think that's part of it.

[00:27:15] Kristyn Hodgdon

Yeah, I hope the next one is more people adopting the immunology approach, just knowing that so many women

struggle with autoimmune issues. And it is, if it is taking more time to get to a positive pregnancy test, it just feels like it

needs to be looked into more.

[00:27:34] Jason Kofinas

I agree, and I hope so. I'm rooting for that, absolutely.

[00:27:38] Kristyn Hodgdon

This was wonderful, Dr. Kofinas. I think, I am so in awe of how thorough you are at the Kofinas Fertility Group, and I've

been taking notes over here. I appreciate your time as always, and talk to you soon. Thank you so much.

[00:27:53] Jason Kofinas

Thank you, Kristyn, for your time. I enjoyed our conversation and hope to talk to you soon.

[00:28:01] Kristyn Hodgdon

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