Fertility Docs Uncensored is hosted by Dr. Carrie Bedient from the Fertility Center of Las Vegas, Dr. Susan Hudson from Texas Fertility Center, and Dr. Abby Eblen from Nashville Fertility Center. Featuring Mark Ratner, Scientific Director of Theralogix. In this deep dive into fertility supplements, Mark Ratner helps us decode the science behind NAD and its exciting role in longevity and reproductive health. NAD itself can’t be taken directly—it must be boosted through precursors, which then power SIRTs, a family of seven proteins that regulate cellular health, mitochondrial function, and even egg longevity. Among them, SIRT1 is particularly important for egg rescue and extending reproductive potential. Mark explains how these pathways differ from the effects of coenzyme Q10, yet still play a key role in energy production within the mitochondria. We also explore the latest research on Ovasitol, an inositol supplement important for PCOS management. The new formulation, which includes added milk proteins, may enhance absorption and overall effectiveness. Finally, Mark introduces OvaNAD+, a newly available Theralogix supplement that delivers the right NAD precursor to support SIRT activation, energy production, and reproductive health. This podcast is sponsored by IVF Florida.

Episode Transcript:

Susan Hudson MD (00:01)

Hello everyone, this is Dr. Susan Hudson from Texas Fertility Center with another episode of Fertility Docs Uncensored. I am here with my bright, brave, and boisterous co-hosts, Dr. Carrie Bedient from Fertility Center of Las Vegas, and Dr. Abby Eblen from Nashville Fertility Center. And we are so excited, we love, love, love having Dr. Mark Ratner, who is the Chief Science Officer at TheraLogix.

Carrie Bedient MD (00:16)

Hello

Abby Eblen MD (00:21)

Hi everybody.

Mark Ratner MD (00:32)

Thanks for having me back.

Susan Hudson MD (00:34)

We love having you. We get smarter every time you come on.

Mark Ratner MD (00:38)

Well, I’ll try not to disappoint.

Abby Eblen MD (00:41)

And actually, Mark, we need to thank you too. Thank you so much for reviewing our supplements chapter in our upcoming book. It’s coming out on Tuesday. So yeah, We really appreciate it. By the time everybody hears it, it’ll be out, but We appreciate you working and reviewing all that information for us.

Carrie Bedient MD (00:45)

Yes.

Mark Ratner MD (00:58)

 It was really our pleasure and happy to be able to do that. And maybe ⁓ if it’s out by Tuesday, maybe you’ll have some copies that you can share at ASRM. Okay.

Susan Hudson MD (01:10)

We will.

Abby Eblen MD (01:10)

We’re planning to.

Carrie Bedient MD (01:10)

Absolutely. Absolutely. There’s one with your name on it for sure.

Mark Ratner MD (01:15)

That’d be great. That’d be terrific.

Carrie Bedient MD (01:17)

So You just got back aside from all of the fascinating science, you just got back from Iceland, right? So What was your favorite thing that you did there? 

Mark Ratner MD (01:25)

Yeah, we did.

So Iceland is a really unusual place ⁓ in that it is sort of, ⁓ it’s fire and ice as they say, ⁓ because it’s a volcanic island. In fact, they just, I think about two months ago, they had a pretty bad volcanic eruption there that temporarily shut down the airport and everything. ⁓

And it’s got all of these glaciers. ⁓ And it’s cold most of the year and windy, really windy. ⁓ But, you know, the hiking is great and ⁓ it’s just, it’s a landscape that’s unlike anything you’ve ever seen. It’s just, it’s really beautiful. And Reykjavik, which is the ⁓ capital city, ⁓ is a great place to spend a few days. It is actually also the home to the only, it’s actually the only penis museum in the entire world. Yes, it’s the, yes, no, as a board certified urologist, as a board certified urologist, I had to go, right? So I asked for a discount

Abby Eblen MD (02:37)

Thanks for sharing that with us.

Susan Hudson MD (02:38)

You heard that on Fertility Docs Censored. If you want to go to a penis museum, need to go to Iceland.

Abby Eblen MD (02:44)

There you go, of course, need to check it out.

Mark Ratner MD (02:51)

When I got to the ticket booth, they were like, no, sorry. ⁓ But it’s an interesting place. And the people there are

Abby Eblen MD (02:51)

So did you learn something in the museum? Or as a urologist, did you know?

Mark Ratner MD (03:03)

museum?

Not really. ⁓ But believe it or not, it is the most visited museum in Iceland. Now that may sound like a low bar, okay, but they’ve got some really great you know, they’ve got

Abby Eblen MD (03:14)

Yeah, I believe that.

Susan Hudson MD (03:15)

I am not really surprised about that.

Mark Ratner MD (03:22)

…art museums there and the National Museum of Iceland, which has all the Norse history and the Viking history and stuff. And so there’s a lot of interesting stuff going on there. But this is the number one museum in Iceland. I guess, you know, but it.

Susan Hudson MD (03:40)

What is the food like in Iceland? Is it mainly like… The food. Is it mainly seafood?

Mark Ratner MD (03:43)

The food? Yeah, it’s a lot of fish ⁓ and lamb. They have no beef there. They don’t really grow cows, but lamb is their big thing. ⁓ And of course, because it’s an island with a pretty big fishing industry, ⁓ lots of seafood and fish. ⁓ You can go whale watching there. You can see the Northern Lights there. ⁓ And so we did all of that stuff. It was great.

A lot of hiking, you can go hiking on glaciers. It’s a fun trip, and at least from the East Coast, ⁓ it’s a very quick flight. It’s like five hours to get there.

Carrie Bedient MD (04:25)

So I have a random food question about Iceland. It’s an island in a location that is a very inhospitable climate and not a huge amount of sun. How do they get vegetables? Are there just greenhouses everywhere?

Mark Ratner MD (04:28)

Sure. They have really, they have a very, it’s a great question. They have a short growing season, but they managed to do it. And, ⁓ you know, they, ⁓ it’s a very cloud covered, a lot of rain. ⁓ And as somebody said before we went, ⁓ there’s, you know, you worry about the weather. They said, there’s no such thing as bad weather, only bad packing. Okay.

If you bring everything that you might need, you’ll be fine. And we were actually very lucky. We had a bunch of very sunny days and ⁓ it was great. It was a very nice trip, interesting place.

Susan Hudson MD (05:16)

So is this a good place to do like a seven day trip or is it a 10 day or a two week? What’s the happy medium?

Mark Ratner MD (05:23)

I think, yeah, I think, you we were there for like eight days and I think that was sort of perfect. know, Reykjavik itself, you can spend maybe three days there. But then, you know, there’s actually a road that goes around the entire island, which they call the Ring Road. ⁓ And the northern and western, I guess it would be the western ⁓ parts of that road are out in the middle of like nothing. There’s not this very small little towns every few hundred, maybe every few dozen miles. ⁓ And so most people tend to hit the southern coast and you can easily spend two or three days there. ⁓ And then the northeastern coast, which has some really beautiful spots that you you can stay overnight. It’s ⁓ yeah. So I think like eight days, 10 days is probably plenty. 

But, ⁓ and the driving is easy. You know, they, The steering wheel’s on the right, is on the proper side of the car. And they drive, you know, on, ⁓ it’s not like going to England where you’re constantly worried about you know, stepping off the curb and not looking the right way. you know, so. ⁓ And the people are friendly, learned a lot of interesting things. There are no family surnames in Iceland.

There are no family names. ⁓ It’s what they call a patronymic system, ⁓ where you have your first name, and then your second name is the name of your father, followed by either son or -dottir, D-O-T-T-I-R, which means daughter. So Peterson would be Peter’s son. Gunderson is Gunders son.

Gunddottir would be Gunder’s… And so everybody has, there’s no way you can track your family back genealogically using a name ⁓ because there’s no continuity of family names. It was like really interesting things to learn there. mean, it’s a very, they’re very concerned about keeping Iceland pure. So ⁓ you don’t get full citizenship if you don’t follow that naming convention there. It’s really, it’s an interesting place.

Abby Eblen MD (07:57)

So for those people to do 23 and those people that do 23 and me probably got some real big surprises with that system.

Mark Ratner MD (08:03)

And, and, But the the, person who was explaining this to us said that in Iceland, they have actually recorded every birth that took place in Iceland for like the last 1200 years. Crazy since like the middle ages, they’ve been, so you can actually, you don’t even need the family name to track back like you know eight, ten, twelve generations. Yeah, it’s definitely an interesting place.

Carrie Bedient MD (08:35)

Wow.

Susan Hudson MD (08:39)

It’s neat about the naming in Lithuania, there’s something similar that your last name changes. So you have kind of the male version of the last name. But for women, you have a different, I guess it would be suffix if you’re unmarried. And then when you marry and if you change your name, then the suffix to your married name, doesn’t match your husband. It has a suffix that essentially implies that you’re married. It’s very challenging to do things genealogically with the last names when you have that going on. It’s like everything changes all the time. And yeah.

Mark Ratner MD (09:22)

Interesting. But I guess with that system, when you introduce yourself and tell somebody your name, they know kind of like your social situation,

Susan Hudson MD (09:30)

Exactly, you’re either on the market or off the market. At least for women.

All right, well, let’s do a question today. So Our question today is, throughout my secondary infertility journey, I have met with three reproductive endocrinologists. To sum things up, I have a prolactinoma, managed well with medication, and have a left unicornate uterus with a single blocked tube. Every RE has a different opinion. One said I should be happy I had my miracle and wouldn’t recommend further treatment. One said she believes

unicornuates can be great candidates for IVF. One’s opinion was somewhere in the middle. How do I find authentic hope when all three experts have different opinions?

Well, we may add four opinions to this, but I think we’ll probably be somewhere in the same ballpark.

Abby Eblen MD (10:23)

Yeah, I mean, I think people with all kinds of malformations can do just fine. If you talk to general OBGYN, they will tell you they deliver people all the time with bicornuate, unicornuate. So I would not be discouraged. I mean, you know, ideally it would be nice if your uterus was normal shape, but I think you can do fine. You you do have a higher risk of preterm labor and preterm delivery from an incompetent cervix. So for whatever reason, the muscular part of the uterus is not as strong. But, know, as long as your OBGYN knows about that, they can monitor that really closely.

They may even put in a cerclage even before you have a go at it to make sure your cervix is strong enough to hold the pregnancy. And as long as you realize that and recognize that, the cerclage actually works pretty well. And then basically the cerclage, which is really a string that goes around the cervix, it’s just snipped right before about 35 or right around 36 weeks. And then you can go into a natural delivery on your own. So ⁓ I wouldn’t be discouraged. If it were me, I would try and get pregnant.

Carrie Bedient MD (11:22)

I think the biggest thing for you is that you’ve already been there, done that. You already have a baby. And unless that kid was two pounds and born at 29 weeks, I think that you’ve got a decent chance of it happening again. You know, If you didn’t have that history, I think the very wide range of advice is very reasonable because there are some patients with unicornuate, unicornuate uterus that don’t get very far. They do have preterm deliveries. They do have to use a surrogate. They can’t get pregnant, all of those things. But you have a track record. And so look back at your own pregnancy history. And if you delivered somewhere in the 20 week, early 30 weeks, maybe you want to think twice. But if you made it reasonably close to term with a decent sized baby that’s five, six, seven pounds or more, I think it’s reasonable for you to go for it because you’ve been there, done that.

Susan Hudson MD (12:16)

I agree with Carrie. I would say that I would be more in favor of if you’re going down the path of fertility treatment, doing something like IVF where we can intentionally put back one embryo and not where you’re taking letrozole or Clomid where you may ovulate multiple follicles at the same time, because it is a high risk pregnancy. We all acknowledge that. The last thing any of us want to do is have two babies in a very small apartment. Okay.

Susan Hudson MD (12:45)

And so IVF gives us the luxury of only having a 1% risk of that little embryo splitting. So that’s kind of the only thing I would add, but I would say you have a proven uterus. Yes, not everything goes exactly the same, but I feel a lot more warm and fuzzy than on a unicornuate uterus that hasn’t been successful.

Carrie Bedient MD (13:09)

Exactly, exactly. Good luck. I hope it works well.

Susan Hudson MD (13:13)

Yes. All right. So we’re going to jump in and talk about some new and exciting supplements, some of which that we haven’t talked about at all, and some of which that may have some new little additions on to them. So let’s let’s jump into NAD. Mark, what is NAD?

Mark Ratner MD (13:34)

So NAD is actually ⁓ a derivative of niacin, vitamin B3. NAD stands for nicotinamide adenine dinucleotide. Don’t worry about that. It’s basically, it’s not a new compound. It’s not something recently discovered. It’s been around, scientists discovered it more than 100 years ago.

So what is new about NAD and really when I say new, talking about maybe just starting about 20 years ago. ⁓ It’s incredibly important role in each of our cells has been more and more ⁓ well understood. ⁓ And the key about NAD is that it is present in every one of our cells in the body. ⁓

And it comes in two forms. One form is called NAD+, and the other form is called NADH. One form is oxidized, and the other form is reduced. So we call that a redox pair. And the two switch back and forth in our cells all the time. And NAD serves two basic functions in our cells.

One function is in energy production. And it’s actually the NADH version, the reduced version, is really critical for mitochondrial energy production. The oxidized version, NAD +, that version of NAD, that form of NAD, activates certain enzymes in our cells.

And so the energy function of NAD ⁓ has been shown to be critical for egg quality. And the enzyme activation version, the NAD+ version is really critical for activating a class of enzyme called sirtuins. ⁓

So sirtuins were just discovered 20 years ago. And they were first discovered in yeast. And what they discovered was something called SIR2, S-I-R-2. SIR stands for silent information regulator. So they discovered this enzyme in yeast. And what they discovered was that if they could crank up the amount of SIR2 enzyme in yeast, the yeast would live 30%, 40 % longer.

So they said, wow, this is a longevity enzyme. This is an enzyme that allows organisms to live longer. ⁓

And it turns out that SIR2, which was this version that they found in yeast, it’s the ancestral version of the sirtuin enzymes that are present in our cells. And so there are actually seven different sirtuins, and we call them SIRT, S-I-R-T-1, S-I-R-T-2, SIRT1, SIRT2, SIRT3, up through SIRT7. Those enzymes basically, from an evolutionary perspective, they descended down from that original yeast

enzyme. What they discovered though was that you needed NAD+ for those SIRT enzymes to be activated and they said okay well if we can increase SIRT enzyme activity and we can increase NAD activity and make yeast live longer let’s try other organisms and so the next thing they tried was roundworms.

and the yeast lived 30 % longer and the roundworms lived about 20 % longer. And so then they said, okay, let’s try something a little bit more complicated than worms. And so they went to fruit flies and the fruit flies lived about 10 % longer. you know, It seemed to be the more complicated the organism got, the less lifespan benefit there was. Then they finally went to mice and the mice didn’t live any longer. But what they did discover was that the mice stayed healthier longer. So they had this concept that we now think about, you know, there’s lifespan, meaning how long are you going to live? But now the concept that a lot of the focus is on is what we call healthspan, ⁓ meaning staying healthier longer. Okay. ⁓ And so they have now done a number of clinical trials in people where they’re increasing NAD using supplements. They can increase NAD. ⁓ And of course, to try and prove longevity benefit in a person, you know, that would be many, many years of study, right?

But they are showing real significant benefits in terms of health span. It reduces inflammation. it increases. So they studied people who had peripheral artery disease, know, bad circulation in their legs and had problems walking. And they took these people and they randomized, they either get a placebo or an NAD supplement. And the people who got the, in a blinded study, and the people who got the NAD supplement could walk much further after six weeks of treatment than the people who got the So it increases energy production. ⁓

Abby Eblen MD (19:25)

What dose mark were they on?

Do you remember what dose?

Mark Ratner MD (19:30)

⁓ Of that study, I don’t. I don’t. But the interesting thing is how do you supplement NAD? In other words, if your goal is to increase NAD levels in the cell, do you just take NAD? Well, the answer is, what’s that?

Susan Hudson MD (19:45)

Or do you have to take a precursor?

Mark Ratner MD (19:50)

That’s exactly it. You’ve got to take a precursor. You can’t take NAD itself because number one, you won’t absorb it very well from your stomach and number two, even the small amount that might get absorbed, can’t get into, can’t get through the cell membranes and into the target tissues. Now, that doesn’t mean there aren’t companies out there.

⁓ that are, Well, there’s two things. There are clinics around the country where you can go in and you lay down and they stick an IV in your arm and they’ll give you NAD intravenously. There’s even a company that’ll sell you a kit. You can give yourself an injection at home with NAD. So this is hot stuff and they advertise it as anti-aging and lifespan, et cetera, et cetera. The data on that stuff is pretty shaky. ⁓

You don’t have to take an intravenously or intramuscularly. You can take a supplement that is a precursor. And there’s basically two different precursors that work. One is called NMN, which stands for nicotinamide mononucleotide. The problem with NMN is that the FDA has stopped sales of that in the United States.

Not because it’s unsafe, not because it doesn’t work, but because of there are these regulations that if a company has already filed to make this into a drug and they’re doing clinical trials for drug development, it’s not allowed to be sold as a supplement. So NMN is basically off the market.

Susan Hudson MD (21:27)

Okay, I’m like remembering something from a prior episode where we were talking about something about the differences in a supplement versus a pharmaceutical. Yeah, can you refresh my memory about why that’s an important ⁓

Mark Ratner MD (21:30)

Yeah? A drug? Uh-huh.

Sure. Yeah, so it’s a strange regulatory kind of environment. The FDA considers a product that is claiming to treat disease or prevent disease a drug, no matter what that product might contain. The best example I can give you is that we make a cranberry product for UTI risk reduction. It’s essentially a cranberry extract powder. right? But we’ve now had that product used in multiple clinical trials, but, and two of them sponsored by the NIH, when those clinical trials get underway, the FDA has to approve the use of that cranberry powder as an investigational new drug. And we say, wait, it’s just cranberry powder. They don’t care. It’s the claim that you’re making about its effect that makes it either a drug or not a drug. And so that’s why on a supplement bottle, ⁓ you’ll always see this little print, what we call the FDA disclaimer. And it says something along the lines of, this product has not been approved by the FDA. It is not intended to treat, prevent, or cure any disease. And that’s basically saying, we’re not claiming this is a drug.

And So a company has essentially filed what’s called an investigational new drug application for NMN with the FDA, and they did that many years, several years ago. And once that happens, it shuts off any opportunity to sell it as a supplement. So that’s why NMN is not really ⁓ available in the United States. The other precursor is called nicotinamide riboside, we just say NR for short. nicotinamide riboside. Both of those are safely taken as a supplement and the body in our cells, convert that into NAD very efficiently. ⁓ And so it works well. ⁓ So the interesting thing about NAD in terms of fertility is that number one, they’re looking to improve egg quality in the short term, okay, over the course of several months prior to an attempted conception, whether it’s through IVF or IUI or timed intercourse, whatever it might be. ⁓ If you can increase cellular NAD, ⁓ you’re potentially gonna improve egg quality in the short term.

But the other thing is that by increasing NAD levels, we improve sirtuin activity. All right, so here’s where the sirtuins come in. And this is really so interesting. Every month, and I’m not telling you guys anything that you didn’t have to learn years and years ago, okay, but for the people who are listening, every month, okay, as everybody knows, a woman is born with all of her eggs in a sort dormant state in her ovaries. right? And the best estimate is that’s about two million eggs. okay? A lifetime supply. And that, those eggs, those dormant, sort of sleeping eggs, those are in the bank, so to speak. That’s kind of what everybody would consider the ovarian reserve. That’s kind of what’s sitting there. And then every month during a woman’s reproductive years, a thousand, roughly a thousand of those dormant follicles activate. And then those thousand over the course of 12 months, roughly, they gradually change. They gradually mature into much into antral follicles. They mature into basically more complete follicles until finally at the end of that 12 month process, one follicle is left, the dominant follicle. And that’s the follicle that ovulates 12 months later and releases the egg. What happens to the other 999? They basically degenerate and they become what we say, atretic. Okay. And so if that happens every month during a woman’s reproductive years, that’s roughly four to five hundred times. Okay. Right. Okay. ⁓ And if you figure a thousand each month, although it’s sort of starts to decline as a woman gets older, it’s not a full thousand, but let’s say it was a full thousand. That’s a half a million of those, what we call primordial follicles, those dominant, I’m sorry, those dormant sleeping follicles that are sitting there waiting to be activated. That’s half a million. A thousand a month times 500 months, right? So what happens to the other 1.5 million? We started with 2 million. right? What happens with the other half a million?

They basically become atretic. They degenerate over the course of time. right? So once those dominant, those dormant follicles activate and they start to mature, the maturation process is under the control of FSH, the hormone that everybody’s familiar with in terms of ⁓ both men and women, FSH helps the egg and the sperm develop. ⁓ But It turns out that what controls the activation, going from a dormant follicle to an active primordial follicle to what we call a primary activated follicle, that thousand, that change over every month, that’s controlled by SIRT 1, sirtuin 1.

And in order for sirtuin-1 to work, it needs NAD to be present. And so the more sirtuin-1 is present in the cells, the fewer primordial follicles activate each month. If the sirtuin levels are low, more and more follicles get activated. So if you can increase sirtuin levels, and this has been shown ⁓ in mouse models really, really thoroughly. Increasing sirtuin levels, increasing NAD levels slows the recruitment of primordial follicles into primary follicles.

And so you’re keeping more eggs in the bank.

Susan Hudson MD (28:50)

So are you suggesting that taking this precursor can extend the reproductive lifetime?

Mark Ratner MD (29:07)

It’s been very, very convincingly shown in five different studies over the last five years in mice. Now you might say, okay, well, mice and people aren’t necessarily the same, right? Why is the mouse a good model here for this type of work? Well, there’s a couple of reasons. The first is, number one, mice only live two years. okay? And I know it’s a…

It’s a short, brutal life, especially in a lab. But they can start reproducing at eight weeks. Just like women, they are born with primordial follicles, a fixed number of eggs in their ovary. Their ovarian reserve, the number of eggs that remain decline throughout their life.

By eight months to 12 months, mouse eggs have the same chromosomal abnormalities, aneuploidy, ⁓ as human eggs do. And by 18 months of age in mice, the ovarian reserve is completely ⁓ gone and they’re not ovulating anymore. So there are some very distinct parallels ⁓ in terms, and it’s a terrific model to use because unlike a woman where you’re going to have to say treat somebody for five or six years to see whether or not you’re actually slowing in a significant way the loss of ovarian reserve and extending reproductive health span. ⁓ In mice you can tell that much more quickly. Now, go ahead, I’m sorry.

Susan Hudson MD (30:58)

I have so many questions and let me just ask a few of them and then you can go, like you can just like keep on talking. Okay, so one of the questions is, so I’ve had a couple of patients who are like, should I be taking NAD? So is this something that if you’re about to hop right into fertility treatment now, it probably isn’t going to have an effect because you know, what’s…

Do you need to start taking this when you’re 25 because I’m not wanting to reproduce until I’m 35 or 40? Like How does the timing in humans and in the fertility landscape where I want to be pregnant yesterday, how does it fit in?

Mark Ratner MD (31:37)

Excellent questions. So the first human study was just presented in Paris in June at ESHRE at the European, the big European fertility meeting. ⁓ It was an abstract. I’m not going to tell you it was a great abstract.

It was a, it was, it left you scratching your head about certain questions. They didn’t even disclose the dose, okay, ⁓ or the absolute duration that they had used. It was a retrospective study with 50 women, ⁓ actually under 35 years of age, all had diminished ovarian reserve. ⁓ I think they had to have an AMH under one and maybe an antral follicle count under five, and they were all given either, there was a control group or a group that took NMN, the precursor, this was done ⁓ overseas. And so they had a doubling of fertilization rates and a doubling of clinical pregnancy rates ⁓ in the group that took NMN. Okay, now this was an abstract. Hopefully, if this gets published in Human Reproduction, they’ll have someThey’ll have some more details. The problem, here’s the problem with, you so the obvious question is, do we need to wait for prospective placebo controlled human studies to be published before we say this science is exciting, it’s safe, and it holds great promise, and we should start thinking about using it. So the challenge here is that,

because these are supplements, because this is a supplement. By the way, I should have mentioned, the product that we’ve launched is not only the precursor of NAD nicotinamide riboside, but it also has terastilbene, which increases SIRT-1 levels. So that’s the combination. ⁓ If you look at what happened in, like say, the CoQ10, sort of the evolution of that science, Coenzyme Q10.

It was 15 years ago, the first studies that got published were mouse studies. And they specifically looked at aneuploidy, abnormal chromosome ⁓ development in eggs. And they showed clear benefit in mice. then started, ⁓ Casper up in Toronto started a human study. And he tried for two years. He had four sites enrolling patients. ⁓

And after two years, they had to close the because they couldn’t enroll patients. They couldn’t enroll couples. If you try to do a supplement study in the fertility world ⁓ against placebo, where the supplement is something you can basically purchase without a prescription, no one wants to enroll.

Susan Hudson MD (34:49)

Because everybody just wants to go buy it and be on it.

Mark Ratner MD (34:52)

If you give them informed consent, you say here’s the consent, you can either get placebo, 50 % chance you’re gonna get a sugar pill, or 50 % chance you’re gonna get this product that we think might help you conceive and succeed in your treatment. And by the way, this is not prescription. You can buy this on Amazon, okay? ⁓ Goodbye. okay. Yeah, so it took…10 years for there to be studies done with CoQ10 in women going through fertility treatment. There are now six of them that are placebo-controlled studies, all done in China.

Maybe they have a better compliant patient. I don’t know, maybe the patient population in China is just way more ⁓ willing to go along and happy to just get treated for nothing. It’s almost impossible to do these studies in the United States. ⁓ And to do that kind of a study ⁓ is very expensive. And typically, you’re gonna either have to have government funding, which these days is not an easy thing, especially in this new age of, what’s it called? ⁓ Restorative reproductive. Yeah, yeah. Anyway, so the point here is this, we think this is safe. ⁓ There is ⁓ good mechanistic evidence, there’s a very firm foundation of understanding the science as to how these ⁓ interventions potentially work. And by the way, you know, again, comparing mice and men. okay. ⁓

Those seven sirtuins are exactly the same in mice as they are in people. ⁓ And they serve exactly the same function. It’s interesting, each of these seven sirtuins ⁓ plays different biological roles. And the role that each of them plays is determined by its location in the cell, whether it’s in the nucleus or the cytoplasm or the mitochondria, what its enzymatic action is and then what its target ⁓ molecules are. And so these seven sirtuins are, they’re considered the master regulators of cellular metabolism. The 7 sirtuins are essentially from an evolutionary perspective, they all are descended from that original ⁓ ancestral version. But SIRT1 is by far the best studied and it’s the one that has the most action and importance in ovarian function. know, The interesting thing, I’m going to mention one last thing. You might say, well, okay, if increasing SIRT1 levels in the ovary reduces the number of primordial follicles that get recruited each month. So let’s say instead of a thousand, it’s only 800. Okay. Yes, you’re keeping more in reserve. Okay. But what about the fact that you only start with 800? Are you still going to get to ovulation, You know, 12 months later. And the really cool thing is that what SIRT-1 does, besides slowing recruitment, of those primordial follicles is that it increases the responsiveness of granulosa cells to FSH. so, you know, instead of, and so Basically what happens is as those primary follicles start to mature over the course of 12 months, leading up to that final dominant follicle, ⁓ SIRT1 increases that ⁓ efficiency.

It increases the receptivity of granulosa cells, the cells that surround the egg in the follicle ⁓ to the effects of FSH. So where does this fit in? Go ahead, go ahead, go ahead.

Susan Hudson MD (39:31)

I have two questions.

I love these episodes. Oh my goodness. It’s like everything I want to know. Okay, so My first question is, and of course you can only comment in mice, but when you’re having this supplement and you’re saving up eggs for later, are those eggs for later acting as if they are younger than what they are at that point in time? So, you know, I’ve been doing this and I’m a, five week or I’m a five month old mouse and in at month 10 are they acting younger?

Mark Ratner MD (40:12)

Yes, so I can tell you about the mouse studies. okay? And again, it’s only been the one human study, but in the mouse studies, what they basically have done is they’ve started treating and they’ve used both NMN and NR in the mouse studies. okay? They’ve started treatment anywhere from eight to 10 months of age, which would be analogous to a woman ⁓ in her mid-30s to maybe 40ish in terms of reproductive ovarian reserve and the risk of ⁓ egg aneuploidy. What they’ve consistently seen is that the mice after four months of treatment, actually one of the studies treated for as long as only four weeks in mice. ⁓

A couple of the others did four months. But at the end of treatment, you basically ended up with mice that had ⁓ the same amount of ⁓ aneuploidy as a three-month-old mouse. okay? And by 18 months, they were still ovulating. okay? So it essentially extended…The authors call it rescued. It rescued ovarian aging. Now, is this something that we would think is as reliable as egg freezing? Probably not. Can we say for a woman who’s really concerned about preserving her options for the future, there’s no question that vitrifying her eggs, freezing those eggs at this point is gonna do the job, right? But we also know that it’s only a minority of women who come in for consultation that end up proceeding. right? ⁓ And so I think earlier you said, is this something that a woman who’s maybe 32 or 33 and decides against freezing her eggs could use as a fallback option, potentially, potentially.

Susan Hudson MD (42:17)

So my next question is, and I know you’re probably not gonna wanna answer this one, but my question is, all of our patients are on vitamin overload. They come in with their giant Ziploc baggie of 4 million things, and we’re all big CoQ10 believers a lot because of you, quite frankly. ⁓

But if they’re like, okay, I’m either going to do CoQ10 or I’m going to do the NAD supplement. What are your thoughts?

Mark Ratner MD (42:53)

I think they’re both important for energy production ⁓ in the mitochondria in the egg.

They both work by helping the electron transfer chain, but they work in different parts. And so they don’t overlap. They sort of complement each other to some degree. ⁓

And I think we’re very far away from a study that will say, let’s try one or the other or the combination. ⁓ But from a mechanistic perspective, because we understand where they function in that process of energy production and they function in different places, ⁓ there are some very clear similarities that you’re pointing out. CoQ10 levels decline as we get older.

NAD and sirtuin levels decline in the cells as we get older. They’ve even figured out why NAD levels decline as much as they do, and this is not mouse study. This is human data. NAD, as I mentioned, it’s important for activating certain enzymes in the cells. Sirtuins are the ones we just finished talking about. NAD actually has to be there to activate the sirtuins. But there’s another enzyme which is really critical in our bodies, is called CD38. And CD38 triggers many of the most important immune responses in our body. As we get older and our cells age, ⁓ there’s more and more inflammatory response that gets triggered. And that requires increased CD38 activity.

As CD38 activity goes up, NAD level goes down because the activation of CD38 by NAD consumes the NAD. So the primary driver of NAD decline in our cells is this enzyme called CD38, which as we get older, just gobbles up the NAD. NAD levels in a person who’s 60 or 70 are like a third of what they were in the cells compared to when that person would say 25 or 30. That’s why no one’s going to do a study anytime soon that shows whether NAD makes us live longer. That’s a real roll of the dice for people who think that they’re going to use it as an anti-aging. But whether or not it can improve health span and ovarian health span, I think is a much better bet.

Susan Hudson MD (45:48)

So I know we’ve talked a lot about NAD. There’s one additional thing I’d really like us to talk about. At Theralogix, we’ve had Ovasitol available for a long time now. ⁓ It’s a great product for women who have PCOS or are anovulatory, ⁓ who have ⁓ metabolic issues like glucose intolerance.

Mark Ratner MD (45:54)

Sure.

Susan Hudson MD (46:15)

But I noticed recently that you have a new product and I was curious what’s the difference between kind of Ovasitol version one versus what you now have as well.

Mark Ratner MD (46:27)

Sure, okay. So the newest product, the newer version is called Ovasitol Plus. okay? And the primary plus is a component that was added, which is called alpha-lactalbumin. okay? It’s a milk protein. okay? And the purpose of adding that is that somewhere about 30, 35 % of women who take inositols, which is what ovasitol is. It’s a combination of myoinositol and D-chiroinositol. But about 30, 35 % of women, roughly a third, have problems absorbing it. When we first learned about this, it was sort of surprising because it’s a sugar alcohol. It’s a fairly simple molecule. And you would think, well, it just gets absorbed easily from the GI tract. But it turns out, no, inositols require what we call active transport to be absorbed from the GI tract. But about a third of women don’t absorb it that well.

Susan Hudson MD (47:31)

How can we tell who absorbs it and who doesn’t?

Mark Ratner MD (47:34)

⁓ Well, non-responders, a significant percentage of women who are non-responders, who take inositols and don’t seem to have much benefit, that may be the group that is not absorbing it as well. They’ve done these studies looking at blood levels. It’s not just a guess, it’s not just saying, hey, ⁓ the basic study that used ⁓ alpha-lactalbumin, and I’m going to I’m gonna make up some numbers just to kind of show you the example. I don’t remember the exact numbers, but let’s say they started with 100 women who were anovulatory and they all got inositols, plain inositols, and about 65 of them responded and started ovulating. That’s a typical percentage that you might see for women with PCOS. They then took the 35 that had not and they gave them inositols with alpha-lactalbumin. And of those 35 initial non-responders, about two thirds of them now responded. ⁓ So the addition of alpha-lactalbumin enhances absorption of the inositols. Whether it’s an all or none thing or whether every woman who takes it with alpha-lactalbumin is gonna get somewhat better absorption, that’s not been determined. Yeah, Abby.

Abby (48:58)

I have a different but sort of related question. so, Carrie and Susan and I have all had the experience where like a patient doesn’t absorb estrogen the way she should. And so, We always say, take the pill and put it in your vagina. And I just had a patient the other day that looked at me like I had three heads and she’s like, but it’s a pill. And I’m like, I know, put it in your vagina. It’s a mucous membrane. So, you know, it’s interesting, I think, which is great. You talk a lot about being worried about absorption, know, with gummy vitamins and, you know, and I think that’s really a critical thing because you may take all these very expensive vitamins or not expensive vitamins and just not absorb them. So to my point, to my question, it is, these, can vitamin pills be used vaginally? Can that pill be used vaginally? Because in women, you know, a lot of times we get better absorption vaginally than we do through the stomach.

Mark Ratner MD (49:50)

Yeah, I think the answer has to be it depends. Okay, first of all, ⁓ ovasitol is a powder that gets mixed with water, right? And, you know, this is an interesting getting back to these FDA kind of regulatory things. ⁓ A supplement company.

Right. If a supplement is sold as you’re not allowed to call a supplement a sublingual supplement. It cannot be absorbed through a mucosal membrane. It can only be absorbed from the stomach or intestines. GI has to be ingested, not absorbed. So technically that wouldn’t be a supplement, there are plenty of like, so for instance, melatonin, which has terrific benefits in terms of egg quality and fertility. That’s a whole other episode though. ⁓ But melatonin can easily be taken sublingually. It’ll be absorbed really well. I think it depends on the actual molecule. Some are going to go through mucous membranes better than others. ⁓

And I mean, look, know, nicotine, they put nicotine in patches that go on the gut. They’ve done testosterone, ⁓ know, buccal testosterone patches. So I think it depends.

Susan Hudson MD (51:16)

So I have another question. ⁓ When it comes to, I have a lot of my patients that they, I’ve used the ovasitol supplement to help them get pregnant. Most of them, as long as they’re tolerating it and they’re happy with it, I encourage them to continue it through pregnancy, theoretically to help improve glucose metabolism and those types of things, maybe decreasing their risk of gestational diabetes and those types of complications. Can the Ovasitol Plus also be used during pregnancy.

Mark Ratner MD (51:49)

Thank you for asking that question. The answer is no. It should not be. And we make this very clear in all of the materials that come with Ovasitol Plus. Ovasitol Plus has three additional components. The first I’ve already mentioned, which is the alpha lactalbumin, just a milk protein, okay, which is totally safe. It’s basically just a component that’s found in milk. okay. The other two components are vitamin D, a little bit of extra vitamin D, which can’t hurt, but the third one is chromium.

And the reason that we’ve included chromium is because it is an insulin sensitizer. Really, really good science to show the benefits of chromium as improving insulin function and reducing insulin resistance. ⁓

Problem is, we have 200 micrograms of chromium in a daily dose of Ovasitol plus. And there are no studies that have looked, there are plenty of studies showing 30 micrograms, 50 micrograms totally safe during pregnancy. There are no studies that show whether 200 micrograms is safe or not. It may well be, but we don’t know.

And so to err on the side of caution, we basically say, ⁓ if you’re trying to deal with metabolic issues, weight, hair, skin issues ⁓ that the PCOS is creating, this is a terrific option. If you’re trying to conceive, there’s no danger if you stay on it for a week or two once you’re pregnant. But once you confirm a pregnancy, ⁓ switch to regular Ovasitol. And the benefit of regular Ovasitol, of inositols during pregnancy, ⁓ particularly for women with PCOS, is…I think pretty well established. There was actually just a new meta-analysis released this week, ⁓ eight different studies ⁓ showing that it reduces the risk of gestational diabetes by about 50%. ⁓ And so although, and we follow the literature really closely, JAMA, the Journal of the American Medical Association, just published a study two weeks ago that had been done, I think, England, ⁓ maybe England or the Netherlands, I forget, where they enrolled women prospectively with PCOS, okay, and then kept them on it, either inositols or placebo, kept them on it throughout their pregnancy and found no difference in the risk of gestational diabetes.

But again, the devil’s in the details. If you look at the inclusion criteria for that study, the average at the time of entry into the study, the average HbA1c in both arms of the study was 5.1. Okay. I would kill for a 5.1, okay, I would kill for it. So, and the average BMI.

Okay, so I guess the point is that if these were women with PCOS and they were they were enrolled using Rotterdam criteria, okay, but they clearly were not the classic phenotype. ⁓

Susan Hudson MD (55:13)

We don’t really have that in the South.

Abby (55:15)

Yeah, that’s not really.

Carrie Bedient MD (55:16)

It was not a thing.

Abby (55:29)

No, not at all.

Mark Ratner MD (55:32)

What was the risk of insulin resistance in these women? They never measured that. They never measured insulin resistance or insulin sensitivity. ⁓ I think the answer to the question probably is that the higher your BMI, the greater your risk of gestational diabetes, the more potential benefit. ⁓ I think overall, given how many studies have now been published, ⁓ it’s safe to stay on inositols during pregnancy, but not in ovasitol plus. We do want you to switch back.

Susan Hudson MD (56:08)

Oh my goodness, Mark. I get smarter every time we talk. You’re just amazing.

Carrie Bedient MD (56:10)

Very nice.

Abby (56:11)

Perfect.

Mark Ratner MD (56:14)

I’m happy I can be of service. ⁓ Yeah, and so listen, I’ll just mention real quickly, Ovinad +, O-V-A-N-A-D +, is the name of our product, is, it’s nicotinamide riboside ⁓ plus terasteel beam, the goal being to increase NAD levels and SIRT-1 levels. And we think it has potential benefit both short term, in terms of improving egg quality.

⁓ A woman who’s going to do egg freezing might want to start taking that two or three months prior to doing the egg freeze. ⁓ And potentially as a fallback option for a woman who, for whatever reason, decides she can’t or doesn’t want to do an egg freeze. ⁓ This might be a way of slowing ⁓ the loss of ovarian reserve. Last thing I’ll tell you, we are planning a clinical trial. And we are gonna be looking at ⁓ women with diminished ovarian reserve, but not pathologic. In other words, over the age of say 38, ⁓ we’re still working at our inclusion criteria and we’re gonna be looking at ⁓ AMH levels after six months of treatment, placebo versus our product looking at both AMH levels and antral follicle count.

Susan Hudson MD (57:37)

Wonderful. Keep all of us in mind when you’re developing your study.

Carrie Bedient MD (57:40)

Yeah.

Mark Ratner MD (57:43)

Yeah, well, ⁓ we’re trying to make our way through some FDA regulatory questions. ⁓ Because if it’s women trying to conceive, OK, this gets back to what’s a drug versus what’s a supplement. If you tell the if the IRB, you know, the group that’s going to tell you, yes, you can do the study.

If the IRB says, well, you’re treating women with infertility, therefore the FDA needs to bless this study. OK? So now we’re looking at maybe we can enroll women in that age range who say, not trying to conceive. OK? But we’re working through that.

Susan Hudson MD (58:23)

Well, thank you so much, Mark, for joining us. Again, he is Dr. Mark Ratner, the Chief Science Officer from Theralogix. All of the products that we talked about today are available on theralogix.com. But we love having you and we’re always blessed every time you make a presence on Fertility Docs Uncensored.

Abby (58:25)

Thank you.

Mark Ratner MD (58:26)

Thank you for having me.

I’ll see you guys soon.

Susan Hudson MD (58:48)

Absolutely. And to our audience, thank you so much for listening and subscribe to Apple Podcast to have next Tuesday’s episode pop up automatically for you. And be sure to subscribe to YouTube. That really helps us spread reliable information and help as many people as possible.

Mark Ratner MD (58:50)

Bye bye.

Carrie Bedient MD (59:04)

Visit fertilitydocsuncensored.com to submit questions and sign up for our email list. Pick up your copy of the IVF Blueprint today at Amazon, Barnes & Noble, or your favorite bookstore. Check out our Instagram or TikTok for quick hits of fertility tips between episodes.

Abby (59:19)

And as always, this podcast is intended for entertainment and it’s not a substitute for medical advice from your own physician. Subscribe, sign up for our emails and we’ll talk to you soon.

Susan Hudson MD (59:30)

Bye!

Carrie Bedient MD (59:30)

Bye!

Mark Ratner MD (59:32)

Hey, quick question for you guys. If you’re interested, is funny, we did this last year or the year before. ⁓