Reproductive Health Center, Tucson, Arizona

Hutchison’s Huddle: Unexplained Infertility

You and your partner have done all the tests. You’ve changed your diet, starting taking more vitamins, improved your health–but you still aren’t getting pregnant. What is going on?

When we still can’t find any cause of infertility, the diagnosis that is sometimes given is “Unexplained Infertility.” Thankfully, there is still a lot we can do to help couples build their families. To explain more about the process and potential treatment options, Dr. Scot Hutchison went on Facebook Live for a Hutchison’s Huddle talking all about Unexplained Infertility.

Find Dr. Hutchison’s entire Huddle on Facebook, YouTube, or below!


Hello, Hi! This is Dr. Scot Hutchison here in Tucson, Arizona for another Hutchison’s Huddle and today it’s about unexplained infertility! So it’s a very sizeable proportion of the patient population who are trying to have children, and we’ll just talk about that for a few minutes now. 

When we talk about unexplained infertility, we mean where we’ve done an evaluation to try to figure out all the possible causes, and we still can’t find anything. So for example, the standard fertility evaluation is usually comprised of, like a, now we do to these televisits, so basically, I will talk with you in a format like this, either on a video feed or on the telephone, and either is perfectly fine, I would say about 40% of patients prefer the televisit and 60%, just on the telephone and either one is perfectly fine. But we basically get the history. So you fill out a history form and that lets us know about any other medical problems: regularity or lack thereof of menstrual cycles, prior fertility for example, and then you can get a pretty good idea from that about what’s going on. But then we also do a physical exam and you know, check people’s thyroid, check your abdomen, do a quick pelvic exam and ultrasound to look for things like uterine fibroids or uterine polyps, for example. Then there’s a test called the hysterosalpingogram, or HSG, which looks at the fallopian tubes. And then we do a semen analysis because, obviously, that’s a big proportion of things that’s, you know, pushing 50% of the men now have issues with sperm production. And then we do laboratory testing to look at other things like subtle decreases in thyroid function, high prolactin level, egg reserve testing. We make sure people aren’t anemic, that they have decent lipids and check them for German measles immunity and chickenpox immunity. And then we do the serum STD testing as well. 

And then if we can’t really find anything at that point, then you say, ok, that’s unexplained infertility, if you’ve been trying to get pregnant for–you know, and we usually initiate those evaluations at about a year of trying to get pregnant if people are under 35 and about six months if it’s over 35. So but certainly, you know, pretty much, you get into your 30s, you can do whatever you want to do. If you want to be evaluated sooner than that, then I think that that’s okay. Certainly, being evaluated earlier sometimes lets us get the supplements like the CoQ10 and the prenatals and the vitamin D, the things that we’ve covered on these Huddles so many times, but you can look back on what we recommend, we can get those going for people earlier. 

But anyway, most I would say the majority of so-called unexplained infertility is really endometriosis that just hasn’t been diagnosed. And it used to be that we used to do laparoscopies right out of the gate on practically everybody. And then time kind of went by and it turned out that you know, if you go in there and you do laparoscopy and you remove a bunch of endometriosis, it improves the chance of pregnancy a little bit but it’s really pretty modest. It’s only, give or take, about half a percent per month spread out over about a three year period of time and that’s probably the best data on it and that was not a randomized perfect trial or anything. So anyway, laparoscopy now is reserved for people who have really severe either pelvic pain or dysmenorrhea. So bad, bad cramping, and that pretty much precludes them from going to work. And so a lot of patients have not had that laparoscopy. But there may be other subtle findings that we can kind of say, Hey, that looks like endometriosis and that they have maybe free fluid in their pelvis on the ultrasound or you see the uterus being tilted backwards, or what’s called retroverted, retroflexed, which is a common finding with endometriosis. Sometimes you never see any of that. And I’ll even have patients who will say I want to do a laparoscopy because I want to just I want to know whether I’ve got endometriosis or something else, like pelvic adhesions that are that are interfering, these scar tissue bands–you can you can Google pictures of those–that can interfere with picking up eggs and we’ll do laparoscopy on them and not find a thing. And then those couples really are in that truly unexplained infertility range. And not just from endometriosis. 

So the treatment, however, is the same. And it really revolves around two main things–we used to do more things, but it turned out that the things in the middle really didn’t matter very much, it didn’t add anything and just cost more money and created more complications like triplets. But on the one hand, for the unexplained infertility patient, you can do what’s called Superovulation with insemination. And that’s where you have the person take a pill form fertility drug like Letrozole or Clomiphene for a period of five to 10 days, depending on the situation, and then you look with ultrasound and try to time putting the sperm up in the uterus to when you think that they’re going to ovulate or just before they ovulate. And the chance of pregnancy with that is about 10% per cycle, give or take, the younger you are, the higher it is–may it may edge up into the some years we’ll see 12 to 15%. As you get into the certainly into the later 30s, you’re going to see it drop down around into the 8% range. Twin risk with it, regardless, is about 5 to 7%. I prefer Letrozole over Clomiphene because patients tend to tolerate it better. Clomiphene has been around now for literally 52 years as a very safe drug. But it has a side effect profile that can be pretty rough for people so hot flushes, headaches, irritability, also seems to have a slightly higher rate of twinning. Letrozole, the only side effect that I hear about most or with any frequency is fatigue. So I like people to take it at bedtime or about an hour before bedtime. And we’ll use doses up to 10 milligrams a day for that. And the goal with all of it is to make the person make more than one egg so that there’s a better chance of an egg being picked up that’s normal genetically and getting fertilized and then creating a baby! 

Certainly, you probably heard me talking about how at age 35, the proportion of genetically normal eggs is less than the proportion that are abnormal. And so especially in that over age 35 group, making the person make two or three large follicles–the containers for eggs–so that they can ovulate two or three eggs is really kind of the goal. Oddly enough, ovulating four or five or six does not really increase the risk of conception much at all, the curve is very, very, very, very gentle on the upslope of that. Really making two large follicles is really where it’s at and then it kind of levels off from there. But if you make four or five large follicles your risks of having twins or potentially even triplets, especially if the woman is under 30 years old, can really kind of creep into the picture. 

The other main avenue for explained infertility treatment is IVF. But before we get to that we used to do multiple cycles of what’s called Superovulation with Gonadotropins. So we would actually use an injectable fertility drug like FSH or FSH with an Lh component. And we would do those either sometimes in daily doses depending on how aggressive we were being, sometimes in combination with the pill form fertility drugs, sometimes using say Clomiphene for five days and then doing, you know, cycle days three through seven and then we would do injectable FSH cycle days 6, 8, 10 or different protocols and that would make people reliably make 3, 4, 5 follicles. But then there were two large randomized multicenter multiple arm multiple treatments or studies that came out that showed that those were not helpful for actually improving the chance of pregnancy compared to pill form, fertility drug and insemination alone. They just made the risk of triplets was about 5% if they did get pregnant. And as you all know, triplets are much more dangerous and have about an 80% divorce rate, which I think is a pretty significant statistic, and the twins rate was about 15%. So really pretty high. So, you know, when we talk about just using the pill form stuff we’re talking about, give or take 10% chance of getting pregnant with about a 7% risk of twinning. And virtually no, I have not seen any triplets and people over 35 with pill-form fertility drug and IUI. So doing that middle step and adding the extra $600 or so for the injectable fertility drugs was really not of any benefit in two randomized trials. So I would strongly recommend that you don’t go down that path.

But anyway, getting into IVF–IVF is the kind of the ultimate treatment for unexplained infertility because it allows us to do a whole bunch of things that we can’t do otherwise. One is that we can assure that we get eggs or, hopefully, we can get eggs out. But a lot of the time, the thought is that some people don’t have a very good robust ovulatory response and the eggs are not really leaving the ovary very well or they’re not getting picked up by the fallopian tube. So with IVF, we can go in and we can actually remove or aspirate the eggs out of the ovaries so that we make sure that we get them, then we can make sure that they’re being fertilized appropriately. Because some people–the old saying used to be IVF is not just therapeutic but diagnostic. Meaning that occasionally in the days before we were injecting sperm into eggs–or could do that–that you would put a bunch of sperm like 100,000 sperm with each egg and the sperm would look great, eggs would look great and nothing would fertilize. And so nowadays, typically what we’ll do is we’ll inject at least half of the eggs with the sperm, so that we know for sure that they’re going to fertilize. 

The other thing about IVF is you can control the culture environment. So some people, especially say, endometriosis patients, may have a lot of toxic protein messengers or cytokines that are circulating that may hurt those embryos in the early part of their life. And in this case, we can control that and make that a cleaner environment for them. And then we can pick out the embryos that actually make it to that 200 cell stage, give or take, which is called the blastocyst stage. And then if people want to, they can have those embryos tested genetically, biopsied, where you remove cells, test them, freeze the embryo and then when you get back your test results, then you can move ahead with embryo transfer of a tested embryo. 

The other thing that IVF now lets us do is we can personalize the time to transfer. So it turns out, and this is still fairly controversial, but there are large camps of reproductive endocrinologists that kind of feel different ways about this testing of the uterine lining to see how receptive it is. But we have had patients who had repetitive IVF failure, where we go ahead and do that testing and we find out that truly their best time for transfer is sometimes a day or two later than the standard time. And so we’ve moved that transfer time back and then the patient has gotten pregnant and had a baby. That testing is called the ERA testing or ERA from Igenomix––and you can look up the ERA Receptivity Test and see if that feels like it would be something that you would want to do. It’s not very expensive, but it does require an endometrial biopsy. And basically what we call a sham transfer, or not a sham transfer, but a mock transfer cycle to where we’re going to, you know, treat you exactly the way that we would do an embryo transfer, but then instead of doing the transfer that day, we do the endometrial biopsy. So that costs give or take around $1,000, and then another month it’s costing, before you actually get to transfer so some people want to do it, some don’t. I strongly counsel patients who we suspect or know have endometriosis of going in that direction.

But I had Eva give me our pregnancy rates for IVF for the last three months. And we don’t have–we were shut down for April, but in the under 34 group, we had 23 transfers and we had a 48% pregnancy rate. And, and I don’t think we’ve got any losses in that group that–I don’t think we’ve had any biochemicals. In the 35 to 37 year old group, we had six transfers and it was 67%. So four out of the six conceived. In the over 38 group, we had seven transfers, five pregnancy, so 71%. So, as always, you know, it’s, you take it with a grain of salt, looking at numbers like that, but that’s pretty much what we see. Most of these patients, if I’m recalling correctly, had done the endometrial receptivity testing beforehand. So keep that in mind. So we do think that that adds about a 10% chance of pregnancy to it. But if you glob all those together, not only under 34 should have a better chance of pregnancy, but you’ll see that bounce around and sometimes the over 38 have a better chance. But overall, you know, a 56% out of the 36 that got embryo transfers conceived. So, that’s really the difference between IVF and superovulation IUI is a pretty, pretty big gap there.

However, even though IVF has gotten a lot more cost effective, and the cost of even transferring or biopsying embryos fell–last year was $350. And this year, it’s 250 per embryo, so it really has fallen quite a bit, making IVF more and more cost effective over time. But there are some downsides to it. One is the cost. So around here, our first cycle, depending on how much medicine you’re going to use, is going to be $13 or 14,000. For everything, then sometimes you may make more embryos than you want to use. And a lot of patients, it’s always interesting to me because I’ve had over the years, I’ve had many, many people who’ve said, that’s a good problem to have. I’m gonna know if I have, however many children, say two or three kids, I’m not going to have any trouble throwing away those embryos because those embryos aren’t people to me. But then on the other end of it, after they have a baby from one of those embryo transfers, their perception of those embryos then can shift quite a bit, and they can be left thinking, wow, you know, I really need to transfer all of those embryos. And I will say that happens–that I am transferring embryos to people several times per year, who’ve actually completed their family building. So take it with a grain of salt, but that’s the kind of the way, you know, we look at it. So be careful saying, Oh yeah, I wouldn’t have a problem with it, until you get there it can be kind of an issue. 

And there were some other questions. And one of them was what’s the hardest thing about unexplained infertility for patients? And I’d say it’s just not know–they just don’t know. You know, you’d like to identify a problem that you could fix. You know, like, we always rejoice like if we have a guy with a sperm problem, and then we send him to the urologist and they find it you know, a couple of big varicoceles or varicose veins in his scrotum and they can fix that. Because a fair amount of those guys are going to at least improve their sperm production. When you can’t find anything at all and you’re just left kind of rudderless. You’re sitting there thinking, well is it my tubes, is it the uterine lining, is it the sperm not working, all of that ovulation stuff and so on. So it’s just the uncertainty is really a tough one. 

There was a question, are there recommendations for those with unexplained infertility would like to try naturally, but may still be nervous about coming into the office during her cycle due to COVID? Well, first of all, we think that we’re mitigating that COVID risk to patients pretty well. And how we’re doing that is we’re just having one patient in the office at a time. It’s very cumbersome. But on the other hand, I’m one doctor. So what we try to do is, you know, more or less run on time, do most of the discussion outside of exam room, because it really does look like transmission is closest, or is more common in close spaces where there’s a lot of laughing, singing, yelling, all that kind of stuff, which hopefully no yell in the office, but if everybody’s wearing masks and we’re just sort of doing the exam, breathing quietly, and then we can do more of the discussion either in a larger room or outside around the telephone, that’s what we do. So I think that and then also, we’re all being tested for COVID on a regular basis, as are the anesthesiologists and anybody who’s going to be in close contact with you. So I think that’s pretty good. But as far as going ahead and trying on your own and getting pregnant, I think it’s pretty reassuring that thus far, COVID is not super, super bad for babies. I know that there’s a American Journal of Obstetrics and Gynecology, the Gray Journal, article on that, that’s like the number two article if you want to go look that up, that just came out today. But I would encourage you, because we don’t know how long this is going to go on, so if you want to try to go ahead and get pregnant, I would do so. 

There was a question, is my partner able to come to testing with me or should they remain at home? So they have to remain at home. We’re trying to minimize the number of people in the office and the number of contacts. However, bring your phone and you can do FaceTiming or you can make a video say–today, we’re doing a couple of pregnancy ultrasounds, it’s always fun for people to be able to, if everything looks normal for them, to take videos back because then they can share that with not just their husband, but with their parents and everybody else. 

And then somebody said, if I suspect to have infertility issues, would you recommend I do a telemedicine visit? And of course, yeah, if you if you think there’s something going on, then definitely, yeah, let us know. Yeah, I had a guy with a semen analysis today that had no sperm, I always hate making that phone call because it’s like, oh, you know, this could really be, you know, a big, big burden for this guy. And I’m trying to break it to him gently and he says, Well, that’s what I’m looking for because I had a vasectomy. So. Yeah. So anyway, if you suspect you’ve got an issue, like having had a vasectomy, definitely make your appointment with your local reproductive endocrinologist. 

Anyway, if anybody has any other questions, and it’s nice to see who is listening. You all have a great night and I will let you go. And feel free to look at our other Hutchison’s Huddles that we’ve done over time with some of my colleagues who are much more entertaining than I am. And you can look back on many different topics with regard to fertility and the nutrition part of things, especially. I feel like that has been glazed over far, far, far too much. The lack of nutritional recommendations, plus the lack of clinics telling people to stop drinking, stop smoking, stop smoking pot or using CBD oil, that really you know, you really need to watch that stuff. So if your clinic has not told you to clean up your diet and avoid substances, please do so, because it’s going to make a huge difference for your eggs and sperm and embryos. 

So anyway, with that, have a great night and if you have any questions, you can always email them to us or give us a call and stay safe. And if you–I think I mentioned it last time–but the Erin Bromage blog about COVID transmission and how to stay safe I think is really, really worthwhile. So I would encourage you to peruse that. And especially if you have any family members or you need to travel by airplane, I want you to look at that. So anyway, have a great night, stay safe, eat healthy, get asleep, and we’ll see you next week!

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