The Future of Fertility Preservation

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Shubh: Hi, welcome to the Baylor College of Medicine Resonance podcast. I'm one of the sound engineers for today's episode, Shubh Desai. 

Madeline: And I'm Madeline. I'm the writer and host for today's episode. I'm also a third year medical student at Baylor College of Medicine. Today, I had the honor of interviewing Dr. Laura Detti, who's the director of the Reproductive Endocrinology and Infertility - also known as REI -department here at Baylor College of Medicine. So first, a little bit about Dr. Detti. She earned her medical degree at the University of Florence in Italy and completed her OBGYN residency there, as well as at the University of Cincinnati. Dr. Detti completed her fellowship training in Reproductive Endocrinology and Infertility at Wayne State University School of Medicine and has completed research fellowships at Yale University and the University of Virginia. She currently serves as the director of the Reproductive Endocrinology and Infertility Department here at Baylor College of Medicine. 

Shubh: Wow, that's super cool Madeline. How did you get to meet Dr. Detti?

Madeline: So, I met Dr. Detti as a part of my REI elective that I'm doing right now in the department of Ob-Gyn. And before I started the elective, I was looking into her research and was just really fascinated by the work that she does. So, I'm very excited to have her on the podcast today. Now, before we jump to the interview, there are a few background pieces of information that I think will be helpful to mention. So first, infertility is defined by maternal age. So, if patients are younger than 35, it is defined as 1 year of regular unprotected intercourse. In patients that are greater or equal to 35 years of age, it's defined as six months. 
Per the CDC, in heterosexual women aged 15 to 49 years of age, with no prior births, about one in five, (19%) are unable to get pregnant after one year of trying to conceive. Additionally, one in four women in this age group have difficulty getting pregnant or carrying a pregnancy to term. 

Another thing that I think is helpful to discuss before we jump into the podcast is AMH. AMH is a hormone called anti-mullerian hormone, and it's critical to the sexual development of fetuses and can also be used as a reference marker for ovarian reserve. In genetically male fetuses, the testes will produce anti-mullerian hormone, which causes the Mullerian — female — ducts to disappear. The Mullerian duct develops into the ovaries, uterus, cervix, and the upper 1/3 of the vagina. 

Testosterone produced by the testes causes the Wolffian, ducts to remain, which develop into the male reproductive system. In contrast, in the ovaries, AMH also plays a role in follicle development. Every month, several follicles begin to mature and the granulosa cells of the follicle produce AMH.  The AMH inhibits recruitment of follicles from the resting pool in order to select for the dominant follicle. The more developing ovarian follicles a person has, the more AMH can be produced. AMH can be measured in the blood and compared to other patients of the same age to estimate how many follicles are left in the ovaries, a term called ovarian reserve. This marker is used as one factor in guiding fertility treatment as it can help estimate how many oocytes would be extracted in an IVF or oocyte cryopreservation cycle.  So again, I want to welcome Dr. Detti to the podcast. 

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Dr. Detti: Thank you so much Madeline. I'm really honored to be here today with you, and this is a new experience for me, so I'm extremely excited. 

Madeline: So we're excited to have you as well to talk about all the exciting stuff you have going on here at Baylor. So first, can you tell us a little bit about your journey in medicine and what brought you here? 

Dr. Detti: Sure. So, I'm originally from Italy, that's my accent and I came to the U.S. with the prospect of doing research for just a few years. And then I loved the system, the medical system here in the U.S. And so, from just a few years, it became over 25 years and I'm still here. And so I've been having different research interests over time because fundamentally, I am a very curious person. And I always ask why a certain action or outcome happens and why a certain response is also elicited and that has been the push to develop my research interests over time. 
So, my interests have changed from initially assisted reproduction technology but then they shifted towards the uterus and studying the Mullerian anomalies and specifically the uterine septum which has been a niche of mine and then I shifted to studying more the endometrium, and how it can impact success rates in natural pregnancy as well as in IVF. And then again, I went on to early pregnancy and then fertility preservation to find out possible causes of ovarian damage. And also to finding ways to prevent ovarian damage. So, my research has evolved together with my career and with my curiosity of clinical cases that we see every day in the clinic basically. 

Madeline: That's wonderful. Thank you so much for sharing that. It's really cool to hear about how your research affects your clinical interest in practice and vice versa. So could you tell us a little bit more about how research has affected the way that you practice in the clinic?

Dr. Detti: Sure! So when we do research, we typically come to outcomes and depending on what the results are, I typically shift my way of practicing trying to facilitate a positive outcome versus trying to prevent a negative outcome. And so, the research has taught me to think outside of the box and always expect things that might happen, and also how to troubleshoot those possible adverse outcomes that might come.

Madeline: Wonderful. And I understand you are relatively new to Baylor College of Medicine and you’re now the director of the REI Department, could you tell us a little bit about what specifically brought you to Baylor? 

Dr. Detti: Yes, so I'm extremely excited to be here at Baylor now. I think, I believe, I've been around in the United States for conferences, and also for work, and I believe that Baylor is one of the few true academic and research institutions in this country. And I'm excited about the opportunities that are here for networking and meeting these exceptional people that do research here. And that devote their life to making other people's lives better. 

Madeline: That's wonderful. And I know as a student I've also appreciated being in the medical center and getting to see the collaboration between different specialties and different people in the science and medicine.

Dr. Detti: It's very exciting. 

Madeline: Yes. Yes, I agree.
So, I want to talk about two projects more specifically that you've been involved in. First, there's a project on ultrasound measurements for early pregnancy loss that was investigating different markers, like gestational sac measurements, yolk sac diameter, crown rump length, and all of this was in order to help predict first trimester pregnancy loss. So, could you tell us a little bit more about this project and how you investigated this and what you found? 

Dr. Detti: Yes. So as I told you before, I'm very curious and I use ultrasound in my daily practice. And so what I, what I noted by doing ultrasound in very early pregnancies — we're talking about five to eight weeks gestation — you can actually see some changes in pregnancies that then they just end in a miscarriage or an early pregnancy loss. And so that curiosity of understanding a little more led me to try and research possible changes that could lead to the pregnancy loss and  in a certain way — to not prevent because unfortunately we cannot prevent the pregnancy loss that early when it wants to happen, but at least to prepare the patient and set a follow-up. A plan with the patient that makes her feel really cared for at this difficult time of her life. 

Madeline: Absolutely, and I know working in the fertility and infertility spaces, a lot of these patients are really hopeful, you know, that these pregnancies will continue and it can be quite devastating when they don't work out

Dr. Detti: Right

Madeline: So, that's really interesting that you're able to use these parameters to better counsel patients and help them have a little bit of an idea, what the odds are of this pregnancy continuing. And could you talk a little bit more about specific findings that you found in the project about the yolk sac and gestational sac measurements? 

Dr. Detti: Yes. I've always been fascinated by the yolk sac because in the beginning I really didn't know what it was there for. And many people still believe that the yolk sac just gives some nutrition to the early embryo. In reality, the yolk sac provides to the embryo two vital cell types. One is actually the oogonia or the spermatogonia. So, the, Germ stem cells, and then the other one is the red blood cells. They both derived from the yolk sac, and they start developing and just a few dozens of cells than they  work their way through the inside of the embryo and then they start replicating and producing these two amazing cell lines. And so the yolk sac, and what I found is that it can increase in size, especially when there is a genetic abnormality in the embryo, like a Trisomy 22 or Trisomy 16, that can cause an increase in size of the yolk sac. So, when you notice it at 5 weeks gestation, when the pregnancy still on going there, heart rate is there. But then again you just start preparing the patient and plan for the follow-up. And the other one is the gestational sac size. That also can predict when a pregnancy is going to a good end versus not.

Madeline: And the trisomies that you mentioned for our listeners at home that may not know as much, those are common causes of miscarriages, correct?

Dr. Detti: That is correct. 

Madeline: Okay. 

Dr, Detti: Maybe you possibly know the trisomy 21, which is the most well, known of all, which is Down syndrome. That is actually the only Trisomy that is compatible with life. 

Madeline: In another part of the- and five weeks, that’s very early, that's typically earlier than most people would get their first ultrasound to confirm a pregnancy, correct?

Dr. Detti: Correct. So that's the earliest that you can see the embryo inside the gestational sac. 

Madeline: Okay. So we're talking really early on. Okay, so does this have any implications for changing recommendations about when people who are pregnant should seek out their first ultrasound? 

Dr. Detti: So not necessarily, I mean I wouldn't be so ambitious to say that we should change and gestational time when we do the first ultrasound, it can happen, especially in the area of infertility because we, we see the patients from the transfer of the embryo when there are three weeks pregnant and then on, but it would be important. Possibly to have a patient come into the office when they're about the six or seven weeks gestation, I would say. Because at that time, it would be, it would be very nice to identify the pregnancies that are unfortunately destined to fail.

Madeline: And you mentioned when we do embryo transfers, the patients being at three weeks of gestation, can you explain a little bit for our listeners at home? What exactly that means and how that dating is done? 

Dr. Detti: Yes. So we follow nature in the IVF lab, just like just like everywhere else and the normal timing for an embryo to implant inside the uterus is 21 days or so, about seven days after ovulation. That's when the blastocyst will attach to the endometrium. And so when we consider that for the gestational age calculation, we always consider the last menstrual period. Which on a day 21 would be three weeks before. So, when do an embryo transfer we do it at exactly that that time and we prepare the endometrium for being an endometrium like 21 day of the menstrual cycle and so that's why when we do the embryo transfer that fashion if she conceives a she's already three weeks pregnant.

Madeline: Fascinating! And I think just so interesting the way that in REI you're trying to time not only the blastocyst and that side of things to be developed to a certain level, but also making sure that the endometrium and that the patient is optimized for the best outcome. 

Dr. Detti: Exactly, you want to synchronize the two parts so that something good happens. 

Madeline: Exactly, exactly. A lot of scans and a lot of looking at lab values to make sure that everything is perfect to give the patient the best chance. 
So these findings seem really important for counseling patients. And for going through with expectant management and learning how to prepare the patient for these outcomes that may not be as pleasant. What are some other areas of research in this? And this topic that you think are interesting to dive deeper into?

Dr. Detti: My interest has been mostly in the fertility, preservation field, and trying to preserve the ovarian function for longer in women and, and also trying to protect the ovarian function, when women are exposed to gonadotoxic treatments, and for gonnadotoxic treatments, that can be either aggressive surgery, or it could also be — and more often — It is chemotherapy. So treatment to battle cancer to battle adult immune conditions, sickle cell disease, and other hematologic conditions, for which, we do good to the patient on one side, but then their fertility is actually compromised.

Madeline: Absolutely, so patients that are undergoing cancer treatment or having treatment for another disease, that can be life-threatening. Obviously, it is very important. But also, having an opportunity to give them maximum options in the future in regards to their fertility is important to consider as well. So, tell me a little bit about the research that you've been doing in this area.

Dr. Detti: So my research has been translational, which means it's been on the animals and also on cell lines so far, but trying to find a way to protect the ovary during chemotherapy and also after ovarian tissue transplant. I tried to employ AMH. You mentioned it before very nicely, what AMH is. And what many people don't understand is that anti-mullerian hormone is actually an inhibitory hormone that regulates the ovulation and the also the development of the ovarian follicles in such a way that it protects the ovarian reserve of follicles. And so by using AMH, we can actually protect the ovarian follicles and ovarian reserve during chemotherapy and also during other stages of follicular development. And so, this animal studies and basic research studies have shown that. AMH indeed can decrease cellular function to the point that the granulosa cells, which are the main responder to AMH. So, they are the producers of AMH but they're also the main target of the AMH hormone. They can become completely quiescent and for quiescent, I mean They returned to the pre-pubertal stage. Basically, when there they're not functioning and they're just in the ovaries but they're not facilitating any follicular development. 

Madeline: That's fascinating. So, we're able to turn back the hands of time in a way and pause the oocytes.

Dr. Detti: I like to call it the Fountain of Youth. I don't know if we will get to that point though.

Madeline: But that's certainly very exciting!
Do we know the mechanism behind why putting these follicles in an active state preserves them throughout chemotoxic treatment?

Dr. Detti: Oh yes. So what you have to think is that the every female, mammal female, is born with a fixed number of eggs. In the human, the peak number of eggs in the ovary is about 6 to 7 million and that happens at 20 weeks gestation. So when we're still inside our mothers’ wombs, and then we only lose all those eggs due to apoptosis which is a different kind of necrosis. But during reproductive life, what we know is that for each egg, that is actually ovulated with each menstrual cycle, we know that about another thousand are lost to this apoptotic process. So, if we can find a way to keep that thousand of follicles that will go into apoptosis and eggs containing the follicles. Then we could reverse that that mechanism and keep the follicles inside the ovaries for a longer time. 

Madeline: That's fascinating. And that the implications for this research are really amazing and thinking about what we could do in the clinic potentially, many many years from now with AMH is very cool. 

Dr. Detti: I think it is. And we're trying to further develop this venue and see if we can find doses and other little tricks to make it more efficient. Now, one thing that has to be said though is that AMH is not approved to be used in the human by the FDA yet. And so, it's only for animal studies. 

Madeline: Okay. And is there any is there any progress that the FDA is making towards maybe looking at approving it, or is it still in the very early stages? 

Dr. Detti: Unfortunately, it’s in the early stages because AMH is a large dimeric protein hormone and it's very difficult to produce it in a large-scale maintaining low cost and keeping all the characteristics of that hormone to be active on its own receptor. So, we're at the beginning still, but the future is promising. 

Madeline: Certainly it sounds that way. This is what a wonderful conversation. Thank you so much for joining us today. I want to wrap up with a couple more questions, more generally about things that you're excited about in REI research and things that are up and coming at Baylor specifically. 

Dr. Detti: Yes, yes. So we're trying to remodel our division of REI. And we would like to make it a little more efficient for medical treatment and patient care mostly. Also, we would like to become more of a reference clinic for more complex, REI cases. Baylor, as you know, is one of the world renowned places for genetics. And so, we pride ourselves in taking care of all these difficult genetic cases that might present to us. And of course, we would like to expand the more the fertility preservation because we're placed in this very unique location at Baylor with Texas Children's on one side, MD Anderson on the other. So, we have plenty of good things to happen for the institutions and for Baylor.

Madeline:  And certainly there's a large need for patients who maybe are seeking care at TCH, for genetic conditions or seeking care at MD Anderson for cancer treatment. There’s so much need for fertility preservation discussions and talking through options with these patients. So, I think that the REI department at Baylor is in a wonderful place to be able to help these patients. 

Dr. Detti: We were certainly very lucky. And I feel again very honored and excited to be here. 

Madeline: Well, thank you again and then my last question for you is, could you tell us a little bit about what you're working on in the lab right now? And maybe future directions for your personal research? 

Dr. Detti: Oh yes. So we spoke about the AMH and not being approved by FDA. So, what we're working on right now is a new molecule that could mimic the effects of AMH on the ovary and on the granulosa cells. But without having all the difficulties in production of AMH on a large scale. So that's to come hopefully in the next future. 

Madeline: Oh wow! We will have to have you back for a second episode to talk about that next time.

Dr. Detti: I would be delighted to do that. 

Madeline: Well, thank you again Dr. Detti, and thank you for listening to Resonance. 

Dr. Detti: Well, thank you.

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