Speaker 1: From the campus of Harvard Medical School, this is Think Research-- a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan: And I'm Brendan, and we are your hosts. Think Research is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

Speaker 1: And by NCATS, the National Center for Advancing Translational Sciences.

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Brendan: Historically, we have come to understand the importance of nutrition and diet as it relates to better health outcomes. Research shows that eating healthy foods can prevent and reverse disease. For years, how nutrition related to reproductive success and fertility went widely understudied-- now, Dr. Jorge Chavarro's research covers the impact of nutrition on fertility, and the successful outcomes of infertility treatment technologies.

Jorge Chavarro is an Associate Professor of Medicine at Harvard Medical School, and Associate Professor of Nutrition and Epidemiology at the Harvard T.H Chan School of Public Health. Dr. Chavarro is also the principal investigator of Nurses' Health Study 3, Dr. Chavarro, welcome to Think Research. Thank you very much for joining us.

Jorge Chavarro: Thank you for inviting me.

Brendan: So one of the areas you study is nutrition and its impact on fertility-- when you first started doing research though, you were initially interested in nutrition and cancer, how did you change your focus?

Jorge Chavarro: That's correct. So when I first started my research training, the idea was that I was going to be doing cancer prevention research and trying to understand how nutrition might impact cancer-- but it turned out that apparently I'm not that good at coming up with original ideas as it relates to cancer, or at least not at that moment. My doctoral studies advisors remembered that, as a medical student, I had been a research assistant a couple of studies related to fertility, so he suggested that maybe would be a good idea to take look at nutrition and other lifestyle factors related to fertility.

Which, at the moment, I thought was a terrible idea, but something that would be good to get me through the PhD and that then allow me to really focus into something that I thought were interesting, but it ended up being my entire career. So, nearly more than 15 years later, I'm still doing the same, so I guess it was a very good idea and not a terrible idea as I originally thought.

Brendan: And you said you thought it was a terrible idea, was it just because you hadn't thought about that field before? It wasn't something you were interested in?

Jorge Chavarro: Well, it wasn't something I had thought about before, so and-- there was some literature at the time suggesting that body weight was going to be important, right? So we knew that underweight people, underweight women, had a difficult time getting pregnant-- that was well established at the time, and there was emerging literature showing that obesity was equally important, but I didn't think at the time-- and there wasn't much in the literature at all, and definitely not in the medical literature-- suggesting that diet itself, that the composition of diet beyond energy balance, would make any difference.

So what I thought was that I was going to end up writing a series of null papers saying, no, there's nothing here, there's nothing here, there's nothing here, and kind of restating the obvious. But it turned out not to be the case, and it was only when I started reading more into the literature on a few specific conditions, especially on polycystic ovary syndrome-- which is one of the most common causes of infertility as it relates to an ovulation specifically-- that I started realizing that maybe there was something there.

That, given what was known at the time about PCOS, and about the role of insulin sensitivity on PCOS-- that if insulin sensitivity was so important to PCOS, then maybe risk factors for diabetes-- which is also where insulin resistance also very important-- might overlap with risk factors for PCOS.

And with infertility related to an ovulation in women who were PCOS, or who had a phenotype that looked PCOS, but failed to meet the diagnostic criteria-- so that was the initial lead. And then trying to say, OK, maybe there's something there-- maybe we can go kind of down the diabetes route, and see if there's some overlap between risk factors for diabetes and risk factors for infertility, at least as it relates to an ovulation.

And the other thing was I ended up scouring PubMed everywhere. So this was back before you could get a full text PubMed on your office, so I actually had to spend quite a bit of time in the dungeons of Countway library looking for old papers. And it turned out that there had been a few case reports here and there suggesting that some micronutrient deficiencies might be important for fertility, but it never made it past case reports.

So there was really nothing systematic on these nutrient deficiencies, but it was curious that the same nutrient deficiencies kept creeping up over and over again in same case reports. And then I ended up discovering that, even though there was not much of a medical literature in nutrition fertility, there was a lot of veterinary literature on nutrition and fertility-- especially in pigs and in cows.

Because it turns out that it is very, very important to control fertility in animals that are of commercial interests, where it makes a big difference if you have a cow that has four calves or three calves-- that that's a lot of money, and that one calf makes a lot of economic difference. So there was a time a huge, huge literature on nutrition and reproduction in animal reproduction-- and I think, still today, we know more about nutrition in animal reproduction than we know about nutrition in human reproduction.

Brendan: What was some of the other early research that you did that led you to think that this might be a viable research path?

Jorge Chavarro: Right, so it was really a big bet on polycystic ovary syndrome. The data that we had available at the moment was data from a large prospective cohort study, the Nurses' Health Study 2, that at the time had been filed for a couple of decades. And we had very detailed information on women's diet, but also on whether or not they had tried to become pregnant, and any pregnancies they may have had during the two decades of active follow-up.

And, for the women who had tried unsuccessfully to become pregnant, we had information on whether or not they had sought medical diagnosis and treatment, and-- not surprisingly, the most common self-reported diagnosis of infertility among these women was ovulatory disorder-- most of which we know is, or at least at times, it was polycystic ovary syndrome.

So, obviously there are other underlying causes of infertility, right? So male factor infertility is very common, but we knew that it didn't make any sense to look at male factor infertility as an outcome when all we had was data from the women. Another common underlying cause of infertility is tubal disease obstructed tubes.

But, again, there wasn't any reason to believe that diet had anything to do with tubal disease-- where there's a well-documented pathology involving chronic inflammation, usually secondary to how we can find and treat disease and sexually transmitted infections-- so of the things that we had data on, the one that made the most sense and also happened to be the most common was, infertility due to ovulation disorders.

The interesting thing was that we actually ended up finding quite a bit of nutritional factors associated with infertility related to ovulation disorder. So it turns out that there was indeed quite a bit of overlap between what we knew were nutritional factors that were important for diabetes, and nutritional factors that we found associated to infertility due to ovulation disorders.

And that included the amount and type of carbohydrates that go into diet that overlapped quite well. We also found that associations with the types of fat that you consume, so what we found overlapped quite well with what was known for diabetes, and same thing for different types of protein sources that also overlapped quite well with diabetes-- other things that overlapped with our findings.

So at the time, there was a growing literature that iron intake on iron stores could be a risk factor for diabetes, and we didn't see that, that we actually ended up seeing the opposite-- that iron appeared to be protective-- but that actually aligned with some of the case reports of micronutrient deficiencies.

And the other part that kind of followed up on these case reports that I mentioned earlier was an association with that we found with nutrients involved in the one carb metabolism, most of the folic acid, but also to a lower extent, B12. And the question then was, well, we see all these things associated with infertility deterioration disorders, but to what extent this may also apply to other causes of infertility that are common?

And to what extent this may also apply to couples who are undergoing fertility treatment irregardless of their diagnosis? And that's kind of where our research expanded from that.

Brendan: And so, now, I mean-- so could you bring that up to the present day and where your research is focused on with infertility nutrition?

Jorge Chavarro: Right, so the first big expansion had to do with trying to look at the relation between diet, and semen quality parameters as proxies for male factor infertility, and with male factor infertility itself-- and we do see quite a bit of overlapping risk factors. All of these work was done in collaboration with colleagues at the Mass General Hospital Fertility Center where we are also able to look-- not only at the male partners to look at semen quality, but also at the couples as they were cycling through infertility treatments to see to what extent pretreatment diet might relate to outcomes of infertility treatment with assisted reproductive technologies.

So the big picture is diets that are generally healthy-- so the type of diets that you would recommend for the prevention of heart disease, or that you would prevent before prevention of premature mortality, there is a substantial overlap between those type of diets and the diets that we see associated with better fertility-- whether that is in the setting of assisted reproduction, or whether that refers exclusively to males, or whether that refers exclusive to females as it relates to an ovulation or ovarian reserve measures.

So there are a few things that appear to be particular important to males-- so for example, for males, their intake of omega-3 fatty acids appears to be especially important, much more so than for women, as far as we can tell. And there are a few things that appear to be a lot more important for women than there are for men, so one of them is the one carb metabolism-- so the metabolism folic acid and the nutrients involved in that metabolic pathway appear to be very, very important for ovulation and for early embryo survival.

Early survival really relates to maternal nutrition and the nutritional status of the mom at the time of ovulation, so that that particular part appears to be super, super important for females, but not necessarily for men-- although it's not unimportant. And the omega-3 fatty acid part appears to be super, super important for men, not that it is unimportant for women.

Brendan: I thought it was interesting when we talked previously, when you mentioned how you kind of gave us a really nice history of contraception and how that has affected people's thinking around infertility. And I was wondering if you could touch on that, and why studying nutrition and fertility is so important?

Jorge Chavarro: Right, so I think that fertility in general usually gets relegated to kind of a niche area that doesn't have that much of public health relevance, so it's definitely clinically relevant for addressing the reproductive needs of people.

So I like the way that a colleague once described it at an infertility meeting, I was like, well, one of the problems is that people think of infertility as the plastic surgery of gynecology-- so it's one of these things that was nice, but maybe not necessary. So that is a common perception, but I think that once you start thinking about why should we care about fertility from a big picture perspective, you have to go back and start thinking about what are becoming the most common cause of infertility in our society today, right?

So, increasingly, the most common cause of infertility in the United States is women receiving a diagnosis of diminished ovarian reserve meaning that their ovarian reserve is low, and they are unable to get pregnant because of their low ovarian reserve which we know goes down with age.

And the typical story of a professional couple that they've gone through college, they've gone through graduate school, they've put a lot of time and effort into their professional careers-- and, somewhere in their 30s or mid 30s or so, they said hey, maybe we should have children, and they figure out that they can't.

And the reason this story is so common is because, with the introduction of effective contraception in the second half of the 20th century-- along with improvements in child mortality rate that had been going on throughout the 20th century-- we really changed the culture expectations of women's lives.

So it was no longer the case that women couldn't necessarily plan long term for their education under professional development because at any moment they might become pregnant, and then may have to switch responsibilities to family and child caretaking responsibilities.

It really allowed entire generations of women to say, no, I can decide whether or not to have children, and if I want to have children, this is when I'm going to have children. And over time, slowly since the 1960s, what this has resulted in a slow shift in when couples decide that they want to have children for the first time.

And what we're facing right now is that throughout the Western world, especially in North America, many parts of East Asia, and Western Europe, what we're encountering is that entire populations of people are deciding to delay childbearing into their mid 30s when ovarian reserve starts going down very, very dramatically.

So we find ourselves, really, in a conflict between basic ovarian biology, right? That's how human ovaries work-- and the societal expectations for reproductive choices that are in place because of contraception. Now, I don't think anybody wants to go back to a world without effective contraception to shift back the age distribution of when people try to get pregnant.

So I think that we need to figure out what are going to be the population-wide and society-wide solutions that allow women to continue having these educational, and professional, and personal development that effective contraception has allowed-- without having to pay the penalty of greater risk of infertility, and greater difficulty conceiving, and having to rethink or completely abandon their reproductive choices.

Brendan: And so, you think that changes in nutrition could help people, could help women, overcome some of that difficulty?

Jorge Chavarro: Right, so, yeah. So that's the underlying impetus of our research, so I think that there's definitely a role for nutrition and lifestyle factors in preventing some types of infertility, many of them related to ovulation disorders. Not only to that, but I do think that one of the many things that have been underlooked in infertility is the fact that is primary prevention-- so almost all the attention on infertility is exclusively on treatment.

And with the exception of probably thinking about primary prevention of infertility as it relates to prevention of tubal disease by secondary to prevention of sexually transmitted infections, but very few people have put serious thought on what the primary prevention for fertility might look like.

So I think it's similar to the transition on thinking about heart disease as something that you treat from something that you can prevent, and if it happens, then you treat it. So that transition happened a few decades ago, that transition hasn't happened for infertility and for thinking about human reproduction in general, and I think it's important that we think about that.

And second, inevitably, just like is the case for heart disease, you may be able to prevent some cases of infertility, but you're not going to be able to prevent all of them. And it is equally important to know that, when people do require treatment, that we have all the arsenal at our disposal to improve treatment outcomes.

And that involves, not only improving technology, but on my end of research-- what might be some lifestyle factors and nutritional factors that could serve as adjuvants to whatever treatment technologies happen to be available at any one time to improve success rates. And in both areas-- in both identifying what might be things that could help prevent infertility to begin with, and secondly, in identifying things what might make infertility treatment more successful, we have found that nutrition can play an important role.

Brendan: I wanted to ask you about the Nurses' Health Study 3 that you're the principal investigator for. You mentioned earlier that, when you were doing research, you took a lot of data from Nurses' Health Study II. I think most people listening know about the Nurses' Health Study, but if you could give a little bit of background, and tell us about it and why it's important and what you're hoping to learn?

Jorge Chavarro: Right, so like you said-- so like the name implies, Nurses' Health Study 3 is the third iteration of Nurses' Health Study, so the original Nurses' Health Study was started in 1976. And the reason this study was funded was because, at the time, it wasn't clear whether or not oral contraceptives-- which had been recently introduced into the US market broadly, right?

So this is about only a decade after oral contraceptives are widely available, and back then you could only get prescriptions if you were a married woman, and so forth. But at the time, it was suspected, but it wasn't clear whether oral contraceptives were risk factors for breast cancer, that was the big question, that was why the study was funded-- it was essentially a breast cancer study.

Then there was the Nurses' Health Study 2 which started in 1989-- again, it was mostly a study driven by trying to identify risk factors for breast cancer. So since 1976, the data on oral contraceptives and breast cancer had been consolidating, but now you have an entire different generation who had access to hormonal contraception earlier in their life. So it wasn't clear that what was learned from the Nurses' Health Study could apply to an entire new generation of women who had been exposed to oral contraceptives earlier, so that was how those two studies started.

By the time I got involved, they had they had morphed into multipurpose research studies that allowed investigators to address a large number of hypotheses. Throughout the years, they have mostly served as studies of cancer, but they have supported research on a wide variety of research area.

So, for example, some of the first human data showing that trans fats were important risk factors for cardiovascular disease came from the Nurses' Health studies. So by time I got involved and there was the possibility of not thinking of a third Nurse's Health Study, there were two lines of interest. One was, again, to breast cancer investigators who by that time there was a lot of interest on earlier life exposures.

So it became increasingly important and increasing fear that whatever happens to that exposures, environmental, and nutritional, or other types of exposures, before a woman's first pregnancy are super, super important for breast cancer risk. And now again we have a completely new generation of women who are delaying childbearing and, therefore, have a much longer period of time to accumulate these exposures that might be important for breast cancer many decades down the line.

And at the same time, my personal interest in reproduction and on fertility we realized that, even though the Nurses' Health Study 2 had been quite useful for studying fertility and starting some pregnancy related events, the study wasn't really designed to address these things.

So I wanted to have an opportunity to have a new study where we could really think of how to best capture reproductive outcomes, and that's what we have been doing in Nurses' Health Study III. So currently we have two major sources funding our grants from the National Heart, Lung, and Blood Institute where we receive funding to serve as research infrastructure for work aimed at identifying how reproductive events, and so reproductive milestones-- as well as intergenerational exposures, and exposures that vary throughout a woman's life course can have an impact on cardiovascular disease and cardiovascular disease risk factors, so it's more of a longer term perspective.

From the National Institute of Environmental Health Sciences from which we receive infrastructure funding to look to identify environmental determinants of a wide variety of health outcomes primarily concentrating on female reproductive health.

Brendan: And, what stage are you at with the study now and how long is it going to run?

Jorge Chavarro: So it may--

Brendan: It's a very long term study, right?

Jorge Chavarro: Right, right. So for example, Nurses' Health Study 1 that started in 1976 is still going, so if participants who are alive are still being followed up, same thing with Nurses' Health Study 2. So with Nurses' Health Study 3 we made a couple of different decisions that Nurses 1 and Nurses 2-- so Nurses 1 and Nurses 2 were essentially brought in a single goal of, OK, we're going to send invitation letters to everybody, and whoever responds is part of the cohort.

With Nurses 3, we have decided to keep it as an open cohort meaning that we're letting anybody enroll at any time, and what we have created is essentially a participant-centered study timeline where the questionnaires that you see at any one time depend on when did you join the study, and also depending on specific life circumstances, right?

To be able to capture pregnancy in a lot of detail, to be able to capture specific life events in a lot of detail. So, so far, we've recruited close to 50,000 women, and any nurse in the United States or Canada who is interested in joining is more than welcome to go-- I'll put the free advertisement there.

So all they need to do is go to www.nhs3.org and it'll have instructions on how to join the study. So we, at the moment, we do not have any plans to cap enrollment at any point. So however many nurses want to join, they're more than welcome to join the study. And as far as until when are we going to continue, I would say that as long as there's funding-- as long as NIH is interested in funding our work, we'll continue working on this study.

And if the original Nurses' Health Study are any indication, I think will be the following these women for the next few decades.

Brendan: Great, well-- Dr. Chavarro, thank you very much for joining us. It was a pleasure to have this conversation with you.

Jorge Chavarro: Thank you for having me. It was a pleasure being here.

Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes, and help us spread the word about the amazing research taking place across the Harvard community.

Speaker 1: To learn more about the guests on this episode, visit our website catalyst.harvard.edu/thinkresearch.

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