Hello everyone, welcome. I'm Pietro Bortoletto, Interactive Associate in Chief for Fertility and Sterility, and thank you so much for joining tonight's discussion on the management of porovarian response. As some of you may know, we chose this topic this evening because FNS recently published the six-part views and reviews series on porovarian response, and it's a clinical scenario all of us are familiar with and all of us struggle with, so we thought it'd be a good fodder for a one-hour discussion.
As a special plug, all the articles are available in your control bar. You can link to the main article to read the whole series there, and also in your control bar you have the opportunity to ask myself and the panel any questions that you may have, and we'll try to get to all of them during the course of the next hour. We're hoping that over the next hour we can share the highlights of this excellent views and reviews series, but also some expert clinical commentary, and tonight we have an excellent panel.
Joining us is Dr. Marcel Cedars, current president of the ASRM and division director at UCSF. Dr. Lan Vong, chair of OIJN at the University of Medical and Pharmacy at Ho Chi Minh City, Vietnam. Dr. Kim Thornton, division director at the Beth Israel Deaconess Medical Center and Boston IVF, as well as a board member of the ASRM.
And tonight is a little bit different than our usual journal clubs in that we're being hosted by the Boston IVF and Beth Israel Deaconess CRE-I Fellowship Program. So to kick us off tonight, our last panelist is Dr. Alan Penzias, who's the chair of the ASRM practice committee, board member of the ASRM, and fellowship director at Boston IVF. Alan, welcome, and thank you for hosting us this evening.
Would you please introduce your fellows who are going to be giving us a short summary of tonight's views and reviews articles? Thank you very much, Pietro. It's a pleasure and welcome everyone. Pleasure to host tonight's journal club.
It's a very exciting topic, and giving our presentation, I'd like to introduce our three fellows. From left to right, Dr. Ann Korkadakis, our third-year fellow. In the center, our second-year fellow, Dr. Rewa Sabat.
And on the far right, Dr. Katrell Hayward, our first-year fellow. Fellows, let's hear a little presentation. Thank you for that kind introduction, and we're very excited to be participating in this FNH journal club global.
Next slide. So this series starts with Dr. Seder's review on managing poor ovarian response in the patient with diminished ovarian response, or as we're referring it to, POR in the DOR. It starts off by acknowledging that counseling and treating patients with poor ovarian response is one of the most difficult issues in ART.
It further goes on to describe the two more recent attempts at standardizing the definition. The Bologna Criteria, published by ASHRAE, which aimed to predict a low number of eggs retrieved, and the patient-oriented strategies encompassing individual oocyte number, known as Poseidon, and its aim is to predict prognosis rather than simply egg number. For the Bologna Criteria, it requires at least two of the following three features, advanced maternal age or another risk factor for POR, a prior poor ovarian response classified as three or less oocytes in a conventional simulation protocol, and an abnormal ovarian reserve test with an AFC or AMH in those parameters.
In terms of limitations, because one of the features of the definition is a prior poor ovarian response, it's a retrospective definition and does not really inform on counseling and simulation of the very first cycle. It conflates an appropriate low response reflective of a low intrinsic capacity and a true POR response where the ultimate capacity was not achieved. And this is an important distinction as a later response may benefit from cycle modification whereas a former response was expected and you might consider not canceling a POR response in the former cycle.
Furthermore, this regards impact of oocyte quality. We're all aware that a prognosis for a low egg number is different in a 32-year-old as compared to a 42-year-old. The Poseidon Criteria is based on the chances of achieving a euploid embryo.
It includes oocyte number as well as maternal age. It contributes to counseling prior to cycle start and it improves classification for trials. It establishes more homogeneous groups that are more amenable to meta-analyses.
Furthermore, it distinguishes between the two reasons for low egg yield, either a limited individual capacity or a suboptimal stimulation where an individual did not reach their full capacity. Poseidon Group 1 is young patients with an adequate reserve with an unexpected low response. Poseidon 2 is older patients with an adequate ovarian reserve with an anticipated lower response.
Again, in those two groups, these patients did not achieve their anticipated full potential. Poseidon Group 3 is young patients with poor ovarian reserve parameters and Group 4 is older patients with poor ovarian reserve parameters and we'd expect these later two groups to poorly respond to ovarian stimulation. Now the question remains, once you're like, once you identify a patient that's likely to have a low response, what are the next steps? And so one of the reviews that is discussed by Olvieto goes over pre-treatment strategies for patients with poor ovarian response.
One of these strategies is androgens and the most commonly used androgens are testosterone and DHEA. Their potential role was suggested based on primate studies that showed an increase in the number of follicles, granulose and cell proliferation, as well as an increased response to FSH. But early human studies were encouraging for testosterone using patients with POR, but more recent evidence is not convincing.
DHEA pre-treatment also demonstrated improved outcomes. However, those studies were flawed and definitely an RCT is needed. Androgen modulating agents like incumbent LH, HCG and aromatase inhibitors can also be used as pre-treatment strategies.
They potentially enhance follicular response to exogenous gonadotropins and in normal responders, they showed improved ovarian stimulation characteristics without an increase in pregnancy rates. And the evidence is very confusing in patients with poor ovarian response and large prospective studies are needed. Pituitary suppression with GnRH antagonists estradiol or OCPs can also be used as a pre-treatment strategy.
It aims to achieve endogenous gonadotropin suppression and a uniform follicular recruitment and synchronization. However, those studies are either small retrospective or with patients serving as their own control and there was no clear benefit on the life birth rate. A combination of pituitary suppression and androgen modulating agents can be used as well, achieving higher number of follicles on the day of trigger and higher number of oocytes retrieved.
For growth hormones, IGF-1 has a synergistic effect with FSH on granulosa cell differentiation and studies are encouraging with improvement in ovarian stimulation variables, but there were no differences in clinical pregnancy rate. Coenzyme Q10 was hypothesized to reverse the age related decline in oocyte quality and quantity, but there was no clear advantage regarding pregnancy and life birth rate. And similarly, platelet-rich plasma that showed a benefit with an increased number of oocyte retrieved in 2p in embryos, but again, no differences in life birth rates.
Next, LVG discusses mild to moderate stimulation versus full stimulation in patients with poor ovarian response. Milestone stimulation has gained recognition because of its reduced costs, better patient compliance, and reduced risk of ovarian hyperstimulation syndrome. It is widely recognized that the number of oocytes collected is, in fact, the most reliable predictor of life birth rate.
And so the risks associated with mild stimulation are a reduced number of oocytes obtained and cycle cancellation, which can be seen in around 40% of patients. It was also hypothesized that mild stimulation could reduce the aneuploidy rate, but this is not supported by most recent evidence, and therefore, mild stimulation does not appear to improve oocyte quality. The current literature does not support the use of mild stimulation instead of a conventional protocol in women with low prognosis, and the risks of collecting less oocyte is not balanced by any beneficial effect on oocyte quality.
So collecting as many oocytes as possible is the only practical strategy to counteract the age-related negative effects on embryo quality and ovarian reserve. Next, Hart discusses a review looking at adjuvant therapies for low responders. And so the majority of adjuvant treatments are not licensed for such use, and the evidence for their use in this context may be lacking.
It is essential to examine the effectiveness of such interventions before their widespread adoption, and this can be limited by the low chance of conception in this patient population, and many of these studies are underpowered for a primary outcome of live birth. The adjuvant therapies he goes over are growth hormone, clomiphene citrate, and letrozole. In terms of growth hormone, there is good evidence that growth hormone increases the number of oocytes retrieved at the clinical pregnancy rate, but a limited number of studies report live birth rate as the primary outcome, and as we know, growth hormone therapy is very expensive.
For clomiphene citrate, there seems to be an economic benefit for its use for POR patients by reducing gonadotropin requirement, but again, no improvement in live birth rate. And similarly, for letrozole, there is a reduction in systemic estradiol, which may be more conducive to embryo implantation, and it has the telophase progesterone secretion due to a less platonic pituitary LH suppression can lead to a better implantation. However, economic benefit for the use of letrozole is also beneficial because of reducing gonadotropin requirements, similarly to clomiphene citrate, but again, no improvement in live birth rate.
We then move on to Dr. Fuan's review on strategies to improve final maturation, as well as laboratory techniques of low responders. She acknowledges that the majority of ART strategies, as discussed by Rewa, for low responders tend to focus on increasing egg yield. However, in this patient population, a low egg yield can be anticipated.
Therefore, one should focus on oocyte quality and the number of embryos, as this is critical in this population and directly related to live birth rates. In terms of size of follicle at trigger, there's no criteria in terms of size that is provided. However, she suggests that consideration should be given to retrieving small to medium sized follicles.
Despite them having a lower chance of having a mature egg from these follicles, given the anticipated low overall number of eggs we anticipate, it might provide a benefit overall. In terms of dual trigger, which consists of a gene or agonist trigger in combination with HCG, there's low to moderate evidence for its use in the general ART population. However, there's a lack of data in low responders.
Artificial oocyte activation has shown promise in terms of improving fertilization and quality of embryos, but there's still data lacking. Blastocyst transfer, there's no consensus in this patient population. And in fact, using exclusive blastocyst transfer will certainly increase the number of canceled embryo transfer cycles.
PGTA, it's controversial if a low reserve is predictive of a higher age-based aneuploidy rate. And the STAR trial suggested that PGTA may get benefit in terms of a higher clinical pregnancy rate in women with more advanced reproductive age. However, there's no subgroup analysis in women with a diminished ovarian reserve.
Therefore, there's no consensus in this population. You also need to factor in the potential for loss of viable embryos using this technique in terms of extended culture, biopsy, freezing, and misclassification. We conclude with when is the right time to stop the autologous and IVF cycles in poor responders by Dr. Kaplan.
Certain patients have a very low, and in some cases, non-existent chance of becoming pregnant using autologous eggs. It's therefore our responsibility to determine when treatment is truly futile, which is defined by the ethics committee as a chance of life birth of less than 1%. At times, this puts our professional duty at odds with patient autonomy.
When making these decisions, it's important to look at maternal age, ovarian reserve, prior treatment outcomes, and a center-specific success rates for a particular patient profile. We're all aware that maternal age is the most important determinant of IVF treatment success. The cumulative live birth rates at 40 years old are 28%, compared to 0% at 45 years old or older, and it's consistent across studies.
In terms of ovarian reserve, it is certainly conflicting the literature as to whether or not ovarian reserve parameters are reflective or predictive of live birth rates in the ART population, but it's clear that it's a critical determinant in this DOR population. In terms of 4 mature oocytes leading to a cumulative live birth, it results in 16% live birth rate in those 38 to 39 years old, as compared to 1% in those 44 years old or older. There's strong evidence that 45 years old can be used as a maximum threshold for autologous IVF cycles, and after that should be considered futile and be discouraged.
For those under 45, recommendations should be based on female age, unexpected ovarian response. You need at least three to four embryos to have at least a chance of a live birth at 44 to 45 years old, which would likely require multiple cycles. It may be more appropriate to try more autologous IVF cycles in younger patients before recommending egg donation, and you need to take financial and emotional distress into consideration with decision making.
Fertility practices should develop patient-centered policies to guide these decision making, making these decisions, and that provides some support for the healthcare providers in the practice. Furthermore, you should counsel patients on alternative ways of achieving parenthood through egg donation, embryo donation, and adoption. Mitochondrial enrichment, telomerase reactivation, Cas9 were described, however, it's clear that they're not ready for clinical use at this time.
And so we wanted to start the discussion with a question directed to you, Dr. Cedars. And so it seems like there's some variation among providers, among different organizations as to what poor ovarian response actually is, and so we were wondering if you can give us some insight into how you define a poor ovarian response in your own personal practice. Thank you, and that was a great introduction to the session, so I appreciate that.
Yes, I think it's very important, and Poseidon has done this, to separate the patient who has a low egg number. Is that diminished ovarian reserve, that her intrinsic capacity is low, or does she have a higher capacity that she has not achieved in that cycle? And I think it's very important, and this is one of the problems with prior studies, that those two things have been grouped together, and so it's very hard to know whether a change in protocol is going to have an improvement. If someone's antral follicle count is three, a change in protocol is not going to make you get more than three or four eggs, compared to somebody whose antral follicle count is 10, and so I think one of the strengths of Poseidon was separating those with an expected lone response, which I would term diminished ovarian reserve, which is separate from a poor ovarian response, which is someone with capacity who responds less well.
Oftentimes I think these definitions are, there's the clinical aspect of the definition, there's the research aspect of the definition, but practicing in a state that's mandated, there's also the insurance coverage aspect of a definition. Kim and Alan, when you are dealing with the DOR, POR, and insurance, how do you navigate that kind of very careful dancing that happens with making sure that patients continue to have access to more treatment, if you really think that they have a shot at having an improved response in the subsequent cycle? Great question. You know, I think in a mandated state, I think one of the challenges that we have is that patients expect that they have the coverage where they should go forward.
So I think it's really critical to get ovarian reserve testing to make the appropriate diagnosis, and then advocate for patients if you think that they have a really good chance of success. So I think it's much easier in younger patients, if ovarian reserve is decreased, to justify a number of IVF cycles because we know that the quality of the eggs that they produce and the likelihood that they will produce a euploid embryo is much higher than in your patient with advanced maternal age and very, very low ovarian reserve where that's not the case. You know, we have the response to the insurance companies, if you will, where they have such clear guidelines as to who we can treat and who we can't treat that, you know, we have to be... we end up following a lot of those guidelines, which is sometimes... Yeah, and I had to expand on that exactly, that same point.
The insurance companies will often use published literature, sometimes ASRM guidelines, sometimes just other medical literature, and a lot of it is really based on ovarian reserve testing and the expectation for number of eggs as opposed to the expectation of having a baby as a result of treatment. So if somebody who is 32 years old who may fit into that Poseidon 1 category has true diminished ovarian reserve, so low capacity, and responds as expected with three eggs, they may not... and a low estrogen at the time of IVF, they may be found by their insurance company, well, she didn't make more than X number of eggs, more than X number of high elevated estrogen, so therefore we're not going to approve. So it is incumbent upon us to go back and say, no, she actually has a fairly substantial chance of achieving a pregnancy, even with only one or two embryos.
So I think that this is where customization and physician advocacy, knowledge of the literature and knowledge of our patients can be super helpful. Let's continue down that theme now, that we have a patient who fits this definition and their insurance has decided you can go ahead and try again. You've identified a poor response in your first attempt.
Let's go through the views and reviews article topics because I think they follow a nice longitudinal arc where we can really think about the patient in front of us. So the fellows nicely pointed out that there are kind of three broad classes of medications that we can consider when we're pre-treating patients who we know have identified as have had a poor ovarian response. Not all of these are created equal in terms of their cost, patient friendliness, and even potential for a positive effect, but a lot of them do have some biologic plausibility.
I want to specifically talk about testosterone and growth hormone pre-treatment because I think at least in North America they get outsized attention from patients from certain centers in the U.S. but are certainly cumbersome financially for patients. My question for the panel, and I'll open this up to anyone, is are there situations in which you would recommend either of these treatments given that there is lack of data to really substantiate their use in POR, and if so, in which patients? That's a challenging question. From the standpoint of the androgens, I tend not to recommend the androgen supplementation as pre-treatment just because I think that there is not enough compelling evidence that there's an improvement in live birth rates.
There are some side effects with DHEA. That having been said, many of the patients that I see search the internet and are taking it anyway. I don't think that we do a good job of capturing that because I think a lot of patients are taking supplements that we don't know about.
I don't use growth hormone. It's very expensive. I think I've used it in one patient.
In reviewing that particular patient, I didn't see a specific difference in her outcome. She was not a poor responder, however, so she was just grasping at straws. I think that you might, based on the data, get a few more eggs, but if you're not improving clinical pregnancy rate, that patient will have spent thousands of dollars on growth hormone supplementation.
Moreover, there is the FDA black box or warning for the use of off-label growth hormone that is very daunting, so not something that I would recommend. Dr. Vuong, is the situation different in Vietnam where some of these medications may be more accessible and more affordable? Yeah, I don't give free treatment if it's not a proven benefit. In Vietnam, the situation is very different.
Insurance does not cover the IVF cost and although, to me, the cost of one IVF cycle here in Vietnam is among the lowest in the world. However, if we compare to the average salary of the Vietnamese people, it may be around two to three times higher than the average salary per month, monthly salary, so I only consider to give anything that is proven benefit to patients and especially for poor responders, I think time is the important factor for them. If they are around 39, 38 years old, so we don't bother to take their time to take this kind of pre-treatments that are not like we just think that it may be beneficial to patients, so I don't give the pre-treatment if it's not proven benefit.
But sometimes, for the main treatment, because there's lack of data and lack of data does not mean that it's not beneficial, so then sometimes I still go ahead with the main treatment even though I don't have enough data for it. Continuing with the topic of pre-treatment, one of the things that I think is more commonly used in North America is luteal estradiol in various forms, both orally, patch form, in combination with oral contraceptive pills. Kim, Al, and Marcel, do you routinely use luteal phase estradiol in your patients who you have identified have had a previous response in a previous cycle before stimulating them again, or is that something that doesn't really factor into your management? It definitely factors in, and in terms of duration, I think what Dr. Wang was mentioning is that when you're talking about androgens, the current accepted number is three months of pre-treatment, which is quite long and actually may be not only not beneficial but harmful to somebody who is trying to get pregnant, especially at older ages.
With the luteal phase estradiol, we think of either using a birth control pill or estrogen or nothing, just entering the cycle directly. And the luteal estradiol, because typically by convention it's about a week prior to the expected period, seems reasonable enough. And as an alternative to make a difference, whether we've done a OCP cycle first or a direct entry previously, it's something else to do that seems to have little negative impact.
And if it has a little bit of positive, it may be beneficial. Yeah, I think there's biological plausibility for estradiol in the luteal phase, particularly in women who have DOR, because their late luteal rise of FSH is actually shifted earlier in the luteal phase. And so their drive to select a dominant follicle is by the time you come in on day two of their cycle, that dominant follicle is very well already selected.
And we know now from random starts that you can start any time in the cycle. However, if you're in that follicular phase where you've selected that dominant follicle, I think you are going to get lower egg number. And for the person with DOR, you don't really want to write off that one follicle, because maybe she's only got one or two other ones.
And so just thinking of the biology, I think estrogen priming for women with diminished ovarian reserve can be very helpful. I would echo that. I guess one other caveat is I tend to shy away from using OCPs for just that very reason.
I think that the OCPs, a protocol, we used to use this a lot with the microdose Lupron protocol, and I've even transitioned to pretreatment with a luteal estrogen instead of OCP, because I think the OCPs are quite depressive and the response is even less than I would like. It feels like you spent at least a day or two getting the ovaries to wake up after you put a patient with diminished reserve on OCPs. And then by a show of hands, thinking about CoQ10, DHEA, some of the things that you could order on Amazon and have show up in your doorstep the next day, our patients are showing up on it.
Is anyone telling patients to stop it, or are you just saying, go ahead, it's fine, it's unlikely to be detrimental? I'm not encouraging people, let's put it that way, because if they're using it already, you know, I explain kind of the absence of evidence isn't evidence of absence, but CoQ10 has been around for a while and still doesn't have a lot of positive data. If it makes them feel better, if they've invested in it, I don't see a harm, but I'm not advocating for it. It may have the mental effect, you know, because patients can go on internet, they can get all the information, and unless it's harm, so then I'll advise them to stop.
Otherwise, they can just like, yeah, I think it may have a mental effect. So you've decided that you're either pre-treating or not pre-treating a patient. You've picked what is likely some form of luteal estradiol to start a patient.
I think we've generally agreed that growth hormone, testosterone pre-treatment, probably not really in our armamentarium. Now you'd have to decide which protocol to start this patient on and what dose to select, and one of these articles nicely goes over mild stimulation versus kind of a conventional 300, 150, or a 450 max dose of gonadotropin protocol. The fellows nicely pointed out that pretty consistently, mild dose protocols have produced fewer eggs and lead to higher cancellation rates, which stands in contrast with what you're hoping to accomplish in a patient who's previously had a poor ovarian response.
I think a lot of us utilize some version of a milder stimulation, but usually couple it with things like letrozole or clomiphene, at least in North America. If you use this approach, do you use it upfront or do you use this as a second or third line protocol after they've had a poor response with antagonist or a microdose lupron protocol? I think I used to use it as a second line if they had a limited response, because sometimes I think if you come in with a really high dose, you can almost downregulate the receptors, and I've seen people not respond at all. But I've shifted, and the problem with the data in that article, that again, most of the studies looking at minimal stims or moderate stims have been in normal responders, and I think you absolutely will get less.
But if I have somebody who's got less than five follicles, they don't get less. And so I have actually shifted to my primary protocol and someone who has less than five follicles being a clomid low dose gonadotropin protocol. And that endogenous rise of FSH early in the cycle, I also, for reasons I really can't understand, there as patients age, they tend to respond better to their own FSH than they do exogenous FSH.
So I think there's benefit of that endogenous rise of FSH to start the stimulation and then adding exogenous FSH still in a low dose to maintain growth. And when you say low dose, you mean 150 and 75? 150. 150.
And then when you think about mild stimulation, be it with just mild stim or with clomid or letrozole, does it then change your approach to how you're going to transfer these embryos? Because I think so often, at least here in the States, we've moved towards a frozen upfront biopsy everything approach. And maybe for patients with poor ovarian response or diminished reserve, that may not be the best approach. Do you link the mild stimulation with the fresh transfer, Dr. Cedars, or do you still consider the potential for freezing and biopsy in these patients? True, true, unrelated.
So to me, those two things don't have anything related. The decision to grow to blast, to do biopsy, to do fresh, to do frozen, to me is unrelated to what my type of stimulation is. Because in a lot of these people I have not seen, you're not necessarily looking at repetitive cycles if you're going to do this.
And if the lining's adequate, and not everybody with clomid, particularly with clomid gonadotropin, is going to have a thin lining. So my decision about fresh versus frozen, or blast versus, you know, PGT versus day three, doesn't really have that much to do with my stimulation. And it might be, is this her first stimulation or is this her last stimulation? So one of the potential problems with doing fresh transfers is if they get pregnant and miscarry, they potentially lose time.
So for patients with DOR who are older, they'll sometimes say, well, I want to bank some embryos, and then they'll do their fresh transfer in a last cycle. But I don't think you're going to go fresh, fresh, fresh, fresh, because you run that risk of losing time with a miscarriage. And in terms of the selection of the mild protocol versus a full dose traditional protocol, again, it's a little bit of counseling that goes into it, because if we can talk reasonably, depending on the patient's age, depending on what prior history they come into the clinic with, about what the expectations are, and if we're really only looking to achieve a few eggs, I think that the saved cost of the medicines, because sometimes that's an out-of-pocket expense, even in an insurance environment.
Also, the number of shots, just thinking about the volume. If you're using 450 units of gonadotropin, using two different gonadotropins, adding an antagonist, you're talking about three shots a day, potentially, for upwards of two weeks, so you're talking about 45, 50 injections, which may be so daunting that it makes a patient who fails to become pregnant just walk away from the whole thing, when in fact, if they just came back for that one more cycle, got that next embryo in the next cycle, they might succeed. So like Marcel, I think I'm a little bit more inclined to use the milder protocols when I truly believe that it's a diminished capacity, not the diminished response to an errant response with good capacity.
Kim and Len, does duostim have a role here when we're thinking about stimulation? We've talked about mild versus conventional, but we're seeing a lot of being written about the back-to-back stimulation for patients who have had a previous poor response. What's your experience, your thoughts, both from Vietnam and here in Massachusetts? I can comment on my experience in someone who's had a poor response. Oftentimes, I will still, my go-to might be the antagonist protocol or luteal pretreatment, but more recently, I've been going back to older protocols with the microdose luteal protocol.
And the reason is oftentimes with poor responders, if I do plan on doing a fresh transfer, I don't see as much of the late luteal or the late follicular rise in progesterone levels, which in our practice is pushing people to cryo-all, and then we end up doing a cryo-all cycle, but patients only have one or two embryos and they never have an embryo to freeze. So that has been my go-to. I think I do less minimal stimulation, unless I've previously demonstrated that increasing the dose hasn't made a difference.
What about duostim? Dual trigger or? Duostim, where you stimulate the patient back-to-back. Oh, back-to-back. I can't comment on that because we have insurance constraints, so we have to get authorization, so it's almost impossible to do that.
In the cases where patients are paying out of pocket, you know, I don't know if I can comment because I don't think we do it enough. What about in Vietnam? Yeah, so I will base on the ovarian testing result. So if I think that the patient has extremely low, I think that when I see the patients having extremely low ovarian results, so then I will consider to do mild stimulation and duostim, mild stimulation.
So one cycle after another, we just go ahead with the egg collection. Then five days later, start again, another stimulation, and we will accumulate the oocytes for embryo generation. And how do you trigger the patients for that first ovulation trigger? We can use either SCG or antagonist, agonist triplet.
And thinking a little bit more about the stimulation before we move on about how to complete the cycle, oftentimes these patients with a diminished ovarian reserve for producing a poor response run the risk of premature ovulation, breaking through their antagonist, which tends to be kind of our workhorse protocol in the U.S. Do any of you use BID antagonist or have any of you utilized oral progesterones as a suppression during the cycle to avoid that premature ovulation? I've found that when people are breaking through, it's really, there are times when you don't even notice an LH surge, so that you'll see that the LH is remaining low. So I'm not convinced that it's necessarily a pituitary breakthrough of LH surging causing luteinization of the follicles that are there. There may be some other paracrine or autocrine factor going on in some of those cases.
And I Kim was mentioning such a case to me today, we were talking a little bit about in the office. So those are fortunately far and few between, but it does seem to be some of the older patients with diminished reserve and who that happens. So I'm not convinced that adding other adjuvants to further suppress the pituitary, which is what the addition of oral progesterone or something else, a birth control pill, anything else in between would necessarily alleviate from that problem.
Yeah. And I agree with that. And I, I think it does lend at least in my hands to triggering earlier in older patients.
And it's not even so much, it might be a little bit more in older and DOR, but older patients in general. And I, and I think of it sort of the way I think of it and the way they behave is it's their granulosa cells just like kind of burn out and you know, their estrogens plateau, their progesterone may go up. And I don't think it's an LH surge either.
I think you just can't push them as far as you can with someone who's younger. So I think you need, or at least in my hands, we would trigger them a little bit earlier rather than something to prevent opulation. Tell us what early means at UCSF.
What is early on an antagonist protocol? So early on, so it depends. I mean, if she's really DOR, she's not on an antagonist protocol. She's on a clomid protocol, which are larger follicles.
But if she's on an antagonist protocol, then, you know, that might be somebody I'm going to trigger 16, 16 to 17. I'm certainly not going to push her past 17. And Kim, what do you do when they're on a lupron-based protocol? I might go 17, 19, you know, 18, 19, that type of thing.
And Kim, what do you do if you're on a lupron-based protocol? On a microdose lupron protocol? Well, first off, I would monitor them earlier and more frequently. And the reason being is, you know, I feel like sometimes you can catch these subtle rises in LH if it's in fact occurring. Um, but if it's a microdose lupron protocol, I will trigger probably around 17, 18 millimeters.
I'm not going to push them to 20 millimeters. That's kind of what I do. Yeah, my microdose lupron, I don't use it very much, but I actually trigger those people at 60.
Yeah, I've just started using it more often, but I think it's mainly to avoid the late luteal progesterone rise, which I mentioned earlier. And when we think about triggering these patients, what kind of trigger do you think makes the most amount of sense when the patient has the opportunity for solo HCG, solo lupron, or a dual trigger strategy? Is there one that you lean towards because you're trying to exploit some potential benefit? In an initial cycle, you know, I'll stick with usually recombinant HCG because it's a pre-mixed syringe, it's easy to administer, it's cost effective, and seems to be quite effective clinically as well. If somebody has had an experience where they've gotten eggs that are not mature, sometimes I will go to generic urinary HCG or the dual trigger with a combination of the GnRH agonist plus HCG to try to avail myself and her ovaries of all the mechanisms for completing the maturation of the eggs.
Dr. Cedars, do you add FSH based off of the recent UCSF papers? So, we did until pricing went up. I do think there's benefit to dual trigger in terms of increasing maturity, oocyte maturity, getting more mature, more fertilized eggs, which for our poor responders is really important. It's actually more cost effective to do HCG and an agonist trigger than to do FSH.
We did the original study because it was in a Lupron based protocol with an FSH trigger, because obviously with a Lupron suppression protocol, they're not going to respond to an agonist trigger. So, the original study was with FSH co-trigger, but with Lupron, the goal is just to get an FSH rise in addition to the LH rise. Lan, in Vietnam where these medications can still be quite cost prohibitive for patients, what are you using for triggering patients with a poor response in a previous cycle? Yeah, I normally give them just HCG as a very traditional way, because I think for poor responders, anything you do, the improvement is not a lot.
And one of another way to do is try to make it simple, try to make it not so costly for the patients. So, I mostly just give them HCG, but in some cases, like Dr. Penzias said before, if they have low maturation rate in the previous cycle, so I may consider to do dual trigger, HCG and agonist trigger. Speaking of expensive things with questionable benefit, how does PGT factor in to the management of patients with a prior poor response? Is it something that you discuss with patients up front? Are they asking for it? How do you navigate that conversation, Dr. Cedars? I mean, I'd love to get the answer to what to do with the 42-year-old who has an antral follicle count of two or three, because the question is, you know, there's one argument that says just do a bunch of stimulations and grow them all out to blast, and ultimately, you'll get the same number of blasts as if you had somebody who got 10 eggs in a cycle.
But that's, I think, we don't know that that necessarily is the best strategy. So, those are the people I struggle with the most, because from an age perspective, they're the people who would benefit the most from PGTA, but they're also the people who have the highest risk of having nothing. And one argument is, well, look at all those transfers, you've saved them.
But for the reasons that were brought up in the introduction, I don't care how good anybody's lab is, I don't think you can tell me every embryo that has capacity makes a blast, and that putting a hole in an embryo and taking cells out, the embryo is just as healthy as if you hadn't done that. So, I honestly don't know what the right answer is. So, I discuss it with patients, and we sort of make a shared decision.
It's not something where I say, you're 42, you must do PGT, or we do PGT on everybody, therefore, you must do it. I think it's really, it's complicated for those DOR older patients. And the question is, what is the value proposition for the individual patient, or couple if there happens to be? And that is, do they value information that they'd rather know that the embryo either failed to become a blastocyst in the laboratory, or became a blastocyst, was biopsied, and is aneuploid, and that gives them the satisfaction of knowing that with high likelihood that embryo would not have resulted in a baby, or they've avoided a miscarriage, which would then set them back further.
That's one approach that a patient may value, where the other is, let me just get an egg out, let's put it back on day three after it's fertilized, so I know I've had my bite at the apple. And if it works, fantastic. If it doesn't, I can get closure, because emotionally, I value the opportunity, because as Dr. Cedar said, not every embryo that can't become a blastocyst in our lab wouldn't become a baby.
So, it's presenting that dichotomy, and seeing what the patient values, because ultimately, at the end of the day, we can promise effort, but not outcome. And if the patient feels heard, and that their values have been respected during this process, and it's not my value that I have to have the highest pregnancy rate, or the most euploid embryos that I biopsy, if I'm valuing what is important to her, that she's the center of everything that we do, I think that regardless of whether she has a baby or not, she'll feel the satisfaction of having been treated appropriately, and with respect. You know, I would echo that, and very oftentimes, what I will find with my older patients, is that we might have done PGT with the first cycle, and either not gotten to the point where biopsy, or biopsy didn't gotten an aneuploid embryo, but they've not had an embryo transfer.
And so, in their closure cycle, we make the decision, we're not going to do PGTA, we're going to do, you know, a day three transfer, and give them, you know, if they're 42, they might take two, or even three embryos back, just because the implantation rate is so low, but at least they've had embryos in the uterus. And that allows them to have that closure to then move on. Speaking of closure, all these things must eventually end, and one of the things that we talk about with patients is when to start treatment, but also when to stop, or at least to change directions, away potentially from autologous oocytes to donor oocytes, or donor embryos.
I want to ask the group here, do your centers have age or number of failed cycle cutoffs, whereby you would not recommend additional cycling of that patient? We don't have, like, a policy. I think it really is very patient dependent, and like Alan said, it's going to depend very much on what that patient values, and where they're coming from. And I think as long as you're being honest about what their chances for conception are, and they choose to go forward, I do think just sort of at each interface between cycles, we talk about the failure, and again, what the chances for success are.
And, you know, progressively, as Kim said at the beginning, you plant that seed for donor or adoption very early, and you bring it up at each sort of inter-cycle discussion. And, you know, I think, you know, in the three range, around three to four, depending on the patient, if they haven't pulled the trigger already, it starts to sink in. But we don't have a policy, because some people will stop after one, and one of my partners had a patient who did 10, and took home a baby.
So, you know, you never know. There's anecdotal stories, and you really have to try to have some shared decision making. I think our practice generally has guidelines that we follow, and have recommended no further treatment after the age of 45.
A lot of it's aligned with insurance. We have a patient care committee, and anybody who is cycling over the age of 45 is presented to the committee, so we can review their previous cycles, etc. And, you know, oftentimes, we'll give one more, make recommendations for one more treatment cycle, even though, you know, we know that the likelihood of conception, in most instances, your patient aside, Marcel, is futile.
And, you know, take that approach, so that patients are aware of the guidelines, and the physicians in the practice are aware of the guidelines, so we try not to run into a situation where we're doing, you know, cycles ad nauseum, if you will. No, we do have a cutoff of 45. I'm, in my mind, I was thinking of the 42-year-old with low numbers, or 43-year-old, but we do have an age cutoff of 45.
Except for the person who's, you know, 45 and 26 antral follicles, the prior PCO who's now 45, but yes, we do have an age cutoff. Then, Dr. Vuong, in Vietnam. Yeah, in Vietnam, I think about 10 years ago, the Ministry of Health issued regulations on the limitation of age for infertile treatment, which is 45.
But then, after a while, there's no more limitation on age for treatment for patients. So, I think advanced age female is a very challenging situation, because sometimes they come in, maybe a couple coming in, the wife, they just married like one year ago, and the wife now is 46, 47 years old. We cannot just tell them that, oh, the cutoff is 45, and you have no more chance, things like that.
So, in Vietnam, in my real practice, I will give a thorough discussion, counseling to the patients, and get them to share the decision-making process. And what is the oldest patient that you have had success with autologous oocytes in Vietnam, given that you may potentially go above 45? 48. 48? So, yeah.
And can you share with us, how did that cycle go? What was your protocol, and what was your approach to transfer? Okay, antagonist protocol, five cycles. Five cycles, 300 IU per day, as initial dose of viral token. And one after another, just like that, we accumulate the oocytes, and then we thaw all the oocytes to generate the embryos.
And she finally got three embryos, but we transfer two embryos on day three. So, in Vietnam, it's difficult to counsel, to consult patients, convince patients to grow the embryos up to day five, because there's a risk of losing all embryos. And yeah, although I know that the success rate with day three might be lower than day five, and there's a risk of miscarriage too, if we don't do PGT.
But in Vietnam, PGT is not common. It's not common, we don't do for everyone. We just do in patients who have indications for it.
Let's say they have recurrent miscarriage, repeated implantation failure, or advanced age, female age, and patients agree to do it. So, I think that's it, 45 years old, and she's like married just two years before, two years before she comes and came for treatment. I don't know that there are many patients who listen to this podcast or this journal club, but I think a lot of them would be excited to hear that 48 was the highest number that achieved a live birth.
But Vietnamese people may be different from other population. Yeah, because we don't have obese patients. Most of our patients have normal BMI 21 to 23.
Most have 21, and no smoking, no drinking, things like that. I think maybe the characteristics of the population may have an impact on the results. Well said, well said.
So, we've covered a lot of ground, and we had so much to talk about in these views and reviews, articles that Dr. Cedars put together. Alan, can you summarize for me what you think are your big takeaways if you're faced with a patient with a poor ovarian response, and how you would approach and counsel that patient on what we should do next? Thank you very much. And first, I want to thank everybody and our fellows for the presentation, and also comment that all the things we've been teaching you in private, now we're saying in public too, and it's all recorded.
So, you can say that we're being consistent. And I think that part of those takeaways are a couple of things. Number one is that low ovarian reserve is not poor ovarian response.
They're not synonymous. Number two, I think that when we're thinking about poor ovarian response, there are a category of people who are unintended poor ovarian response that you didn't expect. And I think of those differently, and we have to approach them differently than those with low capacity, who then respond as we would expect with few eggs.
It's clear that from the different strategies that we do, whether it's pretreatment, whether it's adjuvants, whether it's mild stem or high dose conventional, that the number of eggs may vary with these things, but the number of babies tends not to. So that I think that the take-home message for everybody is that customization with good patient counseling is really kind of the key here. Because when we're dealing with very few eggs and ultimately few embryos, how we achieve those embryos, what the expectations that the patient has, whether it will result in a freeze cycle using an adjuvant therapy like a PGTA or not, it's really important to incorporate what the value to the patient is, so that at the end of the day, if they have a baby, everybody's excited.
But if they don't, they can feel that they did everything that they can do, and that we did everything in an evidence-based way and in a rational and humane way, so that they've been treated properly. Okay, I think that sums up exactly what I think the views and reviews was trying to convey and how so many of us practice and manage these patients. Thank you, Alan.
And thank you, panelists and fellows, for what I think was a really rich discussion tonight. The discussion tonight is going to be recorded and available for later. If you missed tonight or want to re-watch it or want to have your fellows watch it, I think there was a lot that was discussed here that's of value.
I want to also plug our next Journal Club, which is happening live from the ASRM in Anaheim, California on Monday, October 24th at 3 p.m. Eastern, or noon if you're on the West Coast, where we're going to be discussing polygenic risk scoring and PGT specifically for polygenic risk scoring, which I think will be a fun debate to have in front of a big audience. Thank you, all of you, for joining before a long weekend, wherever you are in the United States or abroad. And that's all the time that we have for today.
Thank you so much, and until we see you next time, bye-bye.
