I’m so excited to be interviewing Dr. John Norian on today’s show. John is with HRC Fertility. He has an office in Pasadena and Rancho Cucamonga in Southern California. He is board certified in OBGYN and reproductive endocrinology, and went to UC Berkeley with a medical degree from The Royal College of Surgeons, and he finished his residency at Albert Einstein College of Medicine in New York and with a fellowship at the NIH. Not only that, he was a Lieutenant Commander in the U.S. Public Health Service and he has had the privilege of providing care to military families.
Dr. Aimee: Hi, John. Welcome to the show!
Dr. John Norian: Hey. It’s great to see you, Dr. Aimee. Thank you so much for having me.
Dr. Aimee: We’re going to get to the meat of this, which is challenging IVF cases and what we can do. John, did I leave anything out that you want to share with our audience about yourself?
Dr. John Norian: You hit all of the main points. I’m a real advocate for all people struggling with fertility, whether you have male parts, female parts, whether you’re single, in a same sex relationship, or just walking the walk of fertility. It’s so nice to be chatting about it.
Dr. Aimee: The first IVF challenge that I want to talk about is this: You’re doing an egg retrieval or you have a patient who presents this case to you as a second opinion consult, and there are no eggs at the time of egg retrieval. What is the process that you go through?
Join Dr. Aimee for The IVF ClassDr. John Norian: No eggs at retrieval… Sometimes as a reproductive specialist we have a little bit of an idea if they’re going to be a low responder, medium responder, or a high responder. This is because we’re monitoring the follicles and we’re seeing how they’re growing and developing. If I have a woman who has 15 follicles and I get no eggs, that’s totally different than a woman who has 1 or 2 follicles and gets no eggs.
Let’s go with the 15, because that’s super rare. What would I do? Number one, I would be disappointed. Let’s just call a spade a spade. I’m so particular at retrieval. When I’m doing a retrieval, I’m doing little techniques to try to release the egg from that follicle. We’re doing different techniques to help with egg yield, number one.
Number two is in the PACU (post anesthesia care unit) I would check a blood level, an HCG and a progesterone level, because I want to see if there was an issue with the trigger. By chance, did I use an HCG trigger, like a full 10,000 units, or did I use a Lupron trigger? I’d want to know the type of trigger and then check a level to see did she take her medications correctly and that sort of thing.
Those are two starting points right there.
Dr. Aimee: So, it could be a medication issue?
Dr. John Norian: It could be a medication issue. A group at the NIH and other groups around the U.S. have published about empty follicle syndrome, and it’s super rare.
Believe it or not, in well done research studies they’ve looked at it and two-thirds of the time there is a medication issue. About one-third of the time, though, people have rare situations where the egg just doesn’t release from the follicle. What are reasons for that, or what are ways we can fix it?
I guess that’s maybe a two-part thing. It gets into really complicated delicate steroid biology. We’re talking about things like the cyclooxygenase pathway. We’re talking about different apoptotic pathways. Is the collagen breaking down from the follicles? Are we going through the proper hormonal steps to allow that egg to release?
Dr. Aimee: What about if the patient actually has ovulated? Is that something that you could actually see when you’re doing the egg retrieval, if that’s the reason why they have no eggs?
Dr. John Norian: You can. That’s of course a huge reason. That’s rare, but it can happen, especially in women who are low responders. Sometimes they break through, especially if we’re using an antagonist cycle where their own body’s FSH and LH are really just high, they have diminished ovarian reserve, and sometimes they break through the antagonist, the Ganirelix or the Cetrotide that we use.
Dr. Aimee: If someone has ovulated, what would you do next time?
Dr. John Norian: It depends on the reason, of course. If she broke through, I would probably use a different protocol. I would be monitoring her maybe a bit more closely. Usually, I see people at the end of a cycle every other day, but maybe I would start monitoring her every day. I would be monitoring LH levels. If I was doing an antagonist cycle, maybe I would give an antagonist on the morning of the trigger shot. So, there are some other little things that we would do.
I might even use a Lupron cycle, a long Lupron cycle, as a way to better prevent ovulation if that were the cause.
Dr. Aimee: I agree. It’s kind of like if your pants are falling off even though you’re wearing a belt, sometimes you even need suspenders! Sometimes you can use Lupron and the antagonist, use a whole bunch of the antagonist for people who do that. I’ve seen it before and those are some really challenging cases.
Dr. John Norian: One other thing sometimes as far as the trigger goes. Actually, this data came from UCSF. Their end point, to be fair, wasn’t egg yield or egg number, but I think it was egg maturity. It gets into when you do a co-trigger, when you trigger not just with HCG but you trigger with FSH. When I trigger, I would for sure give a 10,000 HCG trigger, I might even do a 20,000, a couple of my partners do that, and then also give it with a good bolus of follicle stimulating hormone.
Naturally, the way the human body works is it’s not just an LH surge. The idea of trying to do the LH (aka HCG) with a little bit of Follistim or Gonal-F may benefit a little bit. There you go, belt and suspenders.
Dr. Aimee: Exactly. I do that, too. I sometimes add 300 or 600 IUs of Gonal-F or FSH, based on that exact same study that you just shared with us. It’s like we’re the same person. We should be in the same city.
Next is mature eggs. You brought it up. What if you do an egg retrieval and you get a certain number of eggs, let’s say five eggs, and none are mature? That’s a challenge. What would you do next?
Dr. John Norian: Right. A couple of things. Number one is of course you have to sit down and go through the protocol with a fine-tooth comb.
What I typically do is I’ll push another day. Even though I historically have done well with triggering when I have three follicles 18 millimeters or greater — by the way, I measure in two dimensions, not just one dimension — then I might for this unique patient trigger at a 20 or trigger at a 22 as a way to help push egg maturity.
The other thing is it gets to that HCG. It depends on her diagnosis. If she’s a hard core PCO patient or a hard core hypothalamic… Remember, I’ve taken care of people who are super fit, I was an old military doctor, so people who have gone to Hawaii, Ironman and Ironwoman athletes. Fertility is not a time to be bone rail thin. We need healthy fats. When you’re super lean or hypothalamic, and that may be a food issue or it may just be a biology issue, and again we need some coffee to talk about that. Then I would never trigger with Lupron. I would trigger with HCG, because they need that LH. That may also help push the egg maturity.
Those are some tools that I use. We also just talked about that FSH thing.
Dr. Aimee: I agree. I do the same thing. Now you have mature eggs and no fertilization. What do you think about when you have that challenge in front of you?
Dr. John Norian: That’s always really upsetting. That’s a tough call. Back in the old days of IVF, when we didn’t have ICSI — ICSI has been around for a while, it was developed in the ’90s in Paris and then the Americans really optimized the technique. A few things. I’d want to look at the fertilization method.
If we’re doing ICSI, remember that’s when we get the best sperm and we inseminate it directly into the egg, just a single sperm. We learn about the egg, we learn about the membrane of the egg, we learn if the egg is dark or granular, are there a lot of inclusion bodies, a lot of oxidative stress I guess you might say. We’re trying to get a sense is this more of an egg issue of no fertilization or is this more of a sperm issue for no fertilization? Sometimes ICSI helps us that way.
Other things, going back to the future, which is sort of a funny concept. We’ve used in our laboratory in HRC Fertility in Pasadena an old calcium ionophore. Calcium is two positive ions. I know everyone is thinking it’s for your bones. But it’s these two positive ions, and putting that changes the electrical membrane of the egg slightly, and then arguably it may help the sperm better at getting in.
One of the cool things biologically, I know this is a tangent, I’m sorry, but whoever designed this as humans, it is awesome. Biologically, once the sperm hits, even naturally one sperm fertilizes the egg, then there’s a ‘whoosh,’ a huge electrical cascade of ions that kick all of the other sperm out from around the egg. This idea of loosening the shell of the egg may help a little bit with fertilization.
Anyway, those are some thoughts. I’m not sure, do you have other ideas as well?
Dr. Aimee: I’m right there with you. That’s exactly what I would do, too. Sometimes I also consider PICIS.
Dr. John Norian: I’m glad you brought this up. I think PICSI, regionally, is a little more of a Bay Area thing. I’ve traveled, I did my residency in New York, so I know the fertility guys there, and I did my fellowship in DC, and now I’m in Los Angeles.
PICSI, that’s where you place the sperm on a membrane, on a gel, and then you pick it out, and ideally you’re picking the best sperm that’s going to be the super sperm that can fertilize it. My understanding is it’s only somewhat effective. I think people believe in it a little more than others. I don’t know.
Dr. Aimee: I don’t think that it’s going to be a superhero for every case. Most of my patients are over the age of 39, so we’re so lucky to even get one egg, and I want to make sure I pick that winner sperm with the little superhero cape on its back.
How about no sperm on the day of egg retrieval?
Dr. John Norian: That’s a great question. I’ve been in this situation before. Some of it is a little more anticipated. Other times it’s not.
Honestly, just a personal story. I was taking care of a wonderful couple that were immigrants from the Middle East running away from the troubles. They spoke pretty darn good English, but they weren’t perfect, I guess you might say.
The gentleman went to his primary care doctor and was like, “My wife is going through fertility. I’m feeling a little sluggish, a little slow.” The primary care, well-meaning, was like, “Well, why don’t you just take a little bit of testosterone?” So, he was. He didn’t share it with me, he just didn’t mention it to me. He was on testosterone for a couple of months while his wife was getting ready to go through egg retrieval.
We go to sperm retrieval. The semen analysis beforehand was great, but he ejaculates and there’s no sperm, nada. We thought maybe it was just a bad thing, we didn’t anticipate it, I looked at the sperm analysis. He had to ejaculate twice on the same day, the poor guy. He did it and no sperm again. What do we do? We froze eggs. Thank god we live now.
We talked to him more, “What’s going on?” He took the testosterone, so that just shut his sperm production down. There’s a happy story at the end. He stopped testosterone, we got him on some vitamins, I think he took some Clomid. They actually had two children, because he ultimately produced sperm, which was great.
That’s the unexpected. Sometimes we can also force retrieve sperm. I myself am trained to do basic sperm retrieval, like a PESA (percutaneous epididymal sperm aspiration), or just a testicular biopsy. In other situations, you really want to know what’s the cause for no sperm and that sort of thing. It is super rare to have an unexpected no sperm.
One thing also I’ve had, which is really nerve-wracking, is when one of my male patients just can’t produce a specimen. It’s not that he doesn’t have sperm, but just the room is hectic for a lot of guys. I know we make light of it, but most men don’t interact with healthcare until we ask them to do the most private intimate act, and that private intimate act is in a medical room with dirty magazines and things. Well, dirty videos, no magazines anymore because of the pandemic. That’s a situation. Sometimes we give what we call emergent Viagra as a way to maybe help the production of an erection. That doesn’t always work. Again, freeze eggs, come back on another day and go from there.
Dr. Aimee: I call them sperm emergencies (I’m trying to make a joke) and there’s no ambulance that comes with that. I wish that there was a kiosk where you could go.
Dr. John Norian: In our field there are very few emergencies. My emergencies are literally like yesterday I saw a patient, a young woman who had a new diagnosis of breast cancer. “John, can you see her?” Of course. We saw her within a day. She’s a really nice person. We’re going to be starting meds in just a couple of days. The other is the sperm emergency. Rarely, a ruptured ectopic.
Dr. Aimee: We talked about no sperm. What about when you have sperm, you’ve made embryos, but then no blastocysts, so there’s no embryo progression and there’s no blastocyst for them? What would you think about, how would you help a person in that situation?
Dr. John Norian: I think that’s a great question. It comes up. This is where I think when you’re working with your fertility doctor you really need to powwow afterwards, you need that 20-minute conversation with the doctor, you have to get their insight.
That’s what I do. We go through their pre-cycle testing labs, what’s their AMH, what’s their sperm analysis, did you do a DNA fragmentation of the sperm, things like that. Also, you go through the nitty-gritty of the embryology and you try to get a sense is this an egg issue or is this a sperm issue.
I also want to know where the embryo stopped developing. In our literature there’s a thing called a day three arrest. What’s a day three arrest? You go from day one where it’s a fertilized egg to day two there’s typically two cells, four cells. Day three there’s six, seven, eight, nine cells. Then the embryo does this crazy thing where it becomes a blob, like a morula, a compacting cell, and then it goes through this beautiful, remarkable, chariots of fire music in the background embryonic expansion.
The egg is sort of the boss, by the way, from day one to day three. The egg is sort of always the boss, but that’s another thing. The egg is the boss because the size of the embryo is the size of the egg on day one, day two, day three, and you just get different cells within that egg’s shell, I guess you would say. Then the shell sort of morphs and becomes a glob and expands.
When you have a day three arrest, people think historically that it’s more of a sperm issue, because that’s when you need the sperm genome to really activate and go through this expansion process. My understanding of the literature is there’s a growing body of evidence that the egg quality also plays a big role. Changing egg quality is difficult. All these supplements and different things of trying to get that engine of the cell better, eat healthy, sleep, low inflammatory diet, all the stuff we talk about. Realistically, that only takes us so far.
Dr. Aimee: Now we have blastocysts, but what if none of them have normal chromosomes, what do you do then?
Dr. John Norian: Then we think about the age of the female, how many blastocysts did you have, is this more of a chance thing where we know that as women get older the likelihood of having a chromosomally normal embryo does decline, so it may just be I’m human. Those are sort of the main things, or it may just be a numbers issue where if I just had more numbers then I would have had a higher chance of having a chromosomally normal embryo.
Let’s say in women under 35, what I tell people under 35, the likelihood of having a chromosomally normal blastocyst, the early studies suggested about 60–65% normal per embryo. I think that number is lower. I’d love your thoughts on that. When we’re using the better sequencing platforms that we’re using now, I usually see it at about 55% in that age. What do you think about that?
Dr. Aimee: I think it’s anywhere between 35% and 45%. I’d say 50% is probably closer to age 30.
Dr. John Norian: I think that’s fair. So, it depends on the age of the woman. A woman who is older, let’s say over 42, and she has a few blastocysts, the likelihood of normal per embryo is going to be about 15%, maybe 20% per embryo. It just may be a numbers thing.
Remember, it’s per embryo. Even something that’s 50%, like flipping a coin, it’s 50% each time, it’s not 50% overall.
The other thing, just to highlight your question a little bit, what if there are no normal chromosomes. Especially with a couple who has had recurrent miscarriages, I might even do a karyotype to just make sure there’s not a translocation. What’s a translocation? I probably should comment on that.
A translocation is where you have a little bit of one chromosome do a switcheroo with another chromosome. That’s where let’s say the end of chromosome one goes on the end of chromosome four, and four goes on one and one goes on four. That person, if the break point was at the right spot, they can go live a nice, happy, productive life, because they have all their genes. Remember, genes are different than chromosomes. The problem is when they go to reproduce, if they have a translocation, it can be difficult making normal embryos or balanced embryos. That’s something.
I will say with the next generation sequencing that we’re doing a lot of now when we do PGT, sometimes you do pick up translocation. It depends how big it is, where it is, things like that.
Dr. Aimee: Now we have normal blastocysts, and you want to transfer into the uterus, but the lining is just not thick enough. How do you deal with that challenge?
Dr. John Norian: How do we deal with thin linings? Those are tricky, and they are a certain percentage of all of our patients.
Number one is you want to talk to the patient. That’s always huge. Has this person had procedures? Has she had a D&C? Did she have a delivery and then had an infection right after labor, they couldn’t remove the whole placenta and she had an infection? Does she have scar tissue? Is there a mechanical cause for having a thin lining? If there is, then maybe repairing the uterus might help a little bit. That’s one thing.
One other big thing, the question is not just thickness, but what’s the pattern? I’m more of a pattern person versus a thickness person. Typically, doctors like myself and yourself, we like the lining to be greater than 7 or 7.5 millimeters. Once you hit 8, I’m pretty happy. I think my sweet spot is between 9 and 14 millimeters. Is it triple lined? Is it pretty darn close to triple lined or a mixed pattern? If it’s a good pattern…
I’ve even had a surrogate. I could not get her lining thicker than 6 millimeters, but it was gorgeously triple lined. I just closed my eyes and I looked at that pattern, and I was like, “I’m doing this.” It ended up being effective.
Doctors like us, we try to thicken the lining. What are some things that we do? Usually, I use injectable cycles. I know it’s a total pain, and I’m sorry for that, the half-life of estrogen and progesterone is better if it’s injectable. Sometimes using different routes of estrogen, people’s linings thicken better.
The reason for that is the estrogen receptor DNA is highly conserved in humans. We all have the same DNA for the estrogen receptor. The deal is that upstream / downstream of that receptor are these enhancers, silencers, transcription factors, modifiers. That’s where sometimes the different route of estrogen may help thicken that lining a little bit better.
That’s why certain women, even my sister included, are like, “John, I hate Ortho Tri-Cyclen, but I love this other one,” or vice-versa, “I’m totally an Ortho Tri-Cyclen girl.” It’s not because of the estrogen, because remember the estrogen receptor they all have estradiol or ethinyl estradiol, but it’s how they fit on the receptor.
That was sort of a long answer. Different routes of estrogen and progesterone. Other things, sometimes I use Pentoxifylline. That also can help improve blood flow to the lining. Believe it or not, Viagra, there is some evidence there as a way to improve blood flow. Remember, forming an erection is a blood flow issue, it’s not like this whole other thing. It’s just trying to improve blood flow to the endometrium.
Dr. Aimee: I agree. Then also some vitamins, like Vitamin E and L-arginine, I’ve seen help, and aspirin. There’s a study looking at HGH, for example. I’ve also used hyperbaric oxygen therapy in patients with thin linings and I’ve seen that help, too.
Now you have a beautiful lining, but there’s a little bit of fluid in the lining. What would you do then?
Dr. John Norian: Fluid in the lining, first, it may not be too big a deal if it’s a small amount of fluid. If it’s one millimeter, your doctor may ride it and may tell you some basic things as a way to slightly help improve blood flow to the uterus and maybe help extrude the fluid.
Play along with me, it’s actually something I don’t love talking about, even as a reproductive specialist. Number one, I tell people to do some jumping jacks, just get that blood flowing through your body.
I think improving blood flow through the body may help a little bit. There’s very minimal evidence.
The other idea is do you aspirate it? Do you just place a thin little piece of angel hair pasta floppy IUI catheter into the uterus and gently remove it? Those are some things that I’ve seen done.
Dr. Aimee: What if a woman cannot tolerate injections, what would you do for a patient like that? She can’t tolerate looking at needles, giving herself shots. How would you manage that challenge?
Dr. John Norian: I’ve been in that situation and I’m sure you have as well. Number one, in order to retrieve eggs, we use these hormones that are very small peptides. We just can’t take FSH and LH orally, because our stomach acids will just shred it apart and we won’t be able to stimulate the ovaries well. There are some other medications, like Clomid or Letrozole, oral medications that instead of one dominant follicle maybe we’ll get two or three. This idea of doing these mini stims, you just don’t do as well. You just don’t get as many eggs, they don’t fertilize as well, you don’t create as many embryos, but that’s something.
The other is going through an IVF cycle. Believe it not, you’re just doing these small injections. Usually, most people can do it. Sometimes we have injection nurses that can help the patient if she can’t do it herself or have her spouse or a family member do it. Those are some ways that we do it. Sometimes a little behavioral therapy can also help. That sort of thing.
Dr. Aimee: There’s this cool little thing, I don’t know if you’ve heard of it, the Buzzy Bee. It’s this little device that can cool the skin down with a little gel pack and then it vibrates, and you don’t even feel the needle. It’s really a great solution for some patients.
Dr. John Norian: That’s cool. There’s another one that we’ve used, Synera, that’s a topical pain numbing medicine that can work, and when you do the injection it just doesn’t hurt as much.
The other injections, when we’re doing the frozen embryo transfer cycle, I usually do programmed cycles. You can also do a natural cycle transfer and avoid injections too.
Injectables tend to be more steady state absorption, but if you’re on it and you’re not going to miss your dose at 2:00 in the afternoon, then you can maybe do the noninjectable ones.
Dr. Aimee: I agree. I feel like the vaginal suppositories are just as good as the injectable. If you skip one though, your efforts are done. I don’t think people realize how important it is to keep to the schedule. In these studies that show that the injectables are better, I don’t really believe that. I think in a certain patient population, vaginal or oral administration of some of this stuff is just as good. I’m glad you said that.
Dr. John Norian: I’m a little bit of a wimp. I’d love to ask you. When I use my progesterone,I usually give vaginal Endometrin or a vaginal progesterone suppository, and usually an oral. It’s the belt and suspenders thing. I know the studies show just straight vaginal is what was effective in theory.
Dr. Aimee: Okay, last challenge for you. You have a patient and she can’t take hormones. She’s so allergic or she has a blood clotting history, or something that makes it so that she cannot take hormones. How would you handle that IVF challenge?
Dr. John Norian: A lot of times I have patients who can’t take birth control pills. Remember, we use birth control to help regulate, plan, and synchronize the cycle. Those are where we do what we call a day two start. We just do that, we can avoid birth control pills very easily.
I try not to use synthetic hormones. Especially if someone has a blood clot, then we really are hyper aware of that. We’ll do a full thrombophilia panel. I’ll try to really understand what’s going on with their biology and that sort of thing.
Dr. Aimee: I love it. John, thank you for joining us today on our show about challenging IVF cases. You did such a great job sharing all your brilliant tips with us. I know that you are known to be a fabulous communicator, so your patients are so lucky to have you at HRC.
Thank you, John. I appreciate you so much. We’ll see you soon. Thanks again.
Dr. John Norian: Thank you for having me.Catch more of me and topics like this through The Egg Whisperer Show. Episodes are live-streamed on YouTube, Facebook, Twitter, IGTV and Apple Podcasts . Sign up to get my newsletter. Tune in to The Egg Whisperer Show on YouTube. and Sign up for The Egg Whisperer School.
