Oral Progestin For Ovulation Suppression During IVF

Welcome to Fertility and Serility Journal Club Live, live from the MRSI 2024 meeting. We are live with an audience here in downtown Chicago at the Drake Hotel, but also have hundreds of folks logging in from all over the world to hear what we have to say. And today is a topic that I've actually been wanting to talk about for a long time.

Today's talk's entitled Oral Progestins for Ovulatory Suppression. And I'll add in the colon, because every good talk has a colon. Why the slow uptake? Why are we not all doing this yet? And to discuss this, we have a panel in person, but we also have a special guest joining us from Dubai.

I'll start with our guest from across the globe, Dr. Baris Atta, who's a reproductive endocrinologist and president of the Turkish Society for Reproductive Medicine, is joining us virtually from Dubai. Hi, Baris. Hi, Pietro.

And we also have in-person discussants with us from left to right. We have Dr. Scott Nelson, the Muirhead Professor of Obstetrics and Gynecology at the University of Glasgow. Mild job.

Welcome, Scott. Thank you. And to my left, Dr. Amber Cooper, who's the chief medical officer for genomics and laboratory sciences at KindBody and the IVF practice director at St. Louis.

Welcome, Dr. Cooper. And it brings me an immense amount of joy to also have a fellow on the panel, Dr. Morgan Wilhoyt, who's an R.E.I. fellow from the University of Cincinnati. And it has the unenviable task of summarizing two of the articles that we're going to be discussing.

These are articles that have been discussed earlier in the meeting. But we have just a handful of minutes per article to lay the foundation for why we think this is worth talking about and why we think more of us should be incorporating this into our clinical practice. So Dr. Wilhoyt, will you tell us a little bit about these two articles? I would love to.

Thank you so much for that very warm introduction, Pietro. So there are two articles, as Dr. Bortolato said. One of them is entitled, Oral Medroxyprogesterone Acetate for the Use of Ovulation Suppression and In Vitro Fertilization, a Cohort Trial.

This article is by first author, Dr. Anna Lynn Welp, who is a third year resident at the University of Virginia, and senior author, Dr. Alinea Goodman. So as we all know, IVF cycles are extremely cost prohibited to many of our patients, especially those in non-mandated states. The high cost of GRNH antagonist medications contributes to this financial burden.

There's a trend emerging of using oral progestins to prevent that premature ovulation and IVF freeze-all cycles due to many advantages, some of which include higher patient satisfaction due to fewer injections, reduced protocol complexity, the convenience of use and acquisition, and the reduction of cost and monitoring visits. So the goal of this cohort trial was to establish if the use of oral medroxyprogesterone acetate could allow for the benefits of improved patient and provider satisfaction while preventing premature ovulation and maintaining IVF key outcomes. The investigators accomplished this by analyzing subjects 18 to 44 years old who underwent autologous MPA IVF cycles from April of 2022 through October of 2023, versus their historical control group from the previous 18 months who underwent antagonist protocol cycles.

The authors included all infertility diagnoses but excluded patients using donor oocytes or who planned a fresh embryo transfer. The primary outcomes were rate of premature ovulation and the number of oocytes retrieved. Premature ovulation in their study was defined as the collapse of follicles on ultrasound, a progesterone greater than three in the antagonist cycles, and or no oocytes retrieved with the lab confirmation at time of retrieval.

So control to varying hyper simulation was achieved with recombinant FSH and low-dose HCG with these doses chosen based on clinician discretion and typical clinic protocols. For ovulation suppression, our control group used GRNH antagonists, which was initiated when the lead follicle reached 12 to 14 millimeters or an estradiol reached greater than 400. In the MPA group, the 10 milligrams of medroxyprogesterone acetate was started on simulation by the control group on simulation day one with the sardigonatropins.

A trigger occurred with either HCG and or Lupron based on ovarian response and OHSS concern when at least two follicles reached 18 millimeters or greater. For the patients that had them, FET cycles occurred one to two months following TVR and followed either programmed or natural cycles. Right, for the results.

418 patients in the MPA group compared with 419 antagonist controls. Age was similar between the groups as was the spread of infertility diagnoses and the length of infertility. There were no cases of premature ovulation in the MPA group versus five in the control group.

There was also no difference in outcome parameters for those that underwent FET. There was a similar number of ongoing pregnancies per transfer. Both groups, sorry about that, both groups averaged 10 days of simulation with the patients in the MPA group averaging 1.2 less monitoring visits per cycle.

Patients in the control group averaged about five doses of daily injectable GRNH antagonists and on average at a self-pay price of 99.50 per dose equaling 497.50 per cycle. A 10 day supply of MPA cost the patient $6.44 equaling a cost savings of $491.06 when patients underwent the MPA protocol opposed to the antagonist protocol. Multivariate logistic regression analysis was performed to determine the likelihood of having a usable embryo for transfer and for clinical pregnancy rate for those that underwent FET.

When adjusting for agent AMH, the method of ovarian suppression had no effect, or I'm sorry, ovulation suppression had no effect on having an embryo available for transfer or on clinical pregnancy rate. There was a statistically significantly higher odds of having a usable embryo and clinical pregnancy per transfer with a younger age. So in conclusion, this study demonstrated the ability of oral medroxyprogesterone acetate to successfully prevent ovulation and provide comparable outcomes in terms of OSI yield, blastocyst, euploid embryo rate, pregnancy rate, added benefits of cost savings and increased convenience across all infertility diagnoses.

So for the second paper that I'll be discussing, this is almost like a follow-up to the first but not done at the University of Virginia. The second paper is entitled A Randomized Control Trial to Compare the Live Birth Rate of the First Frozen Embryo Transfer Following the Progestin-Primed Ovarian Simulation Protocol Versus the Antagonist Protocol in Women with Anticipated High Ovarian Response. And this paper was by first author Dr. Ziqian Chen and senior author Dr. Ernest Hung-Yu Ng at Shanghai First Maternity and Infant Hospital.

This RCT aimed to compare the live birth rate of the first FET after ovarian suppression by a progestin-primed ovarian simulation protocol, which I'll refer to as the PPOS protocol versus the antagonist protocol in women with an anticipated high ovarian response. The investigators randomized 784 patients who were less than 43 years old with an antral follicle count of greater than 18, undergoing their first IVF cycle from June 2020 through October 2021 to either the PPOS or the antagonist groups. Similarly to the last study, patients utilizing donor gametes were excluded as were those with hydrosalpinges, active baseline cysts, abnormal chromosomes, uterine anomalies, planned PGT, and moderate or severe endometriosis.

Patients with PCOS were not excluded. Ovarian stimulation similarly was achieved in this protocol by FSH and HMG. Starting and titrating doses were based on clinician discretion.

In the PPOS protocol, 10 milligrams of medroxyprogesterone acetate was started again on stem day one with the first day of gonadotropins. And in the antagonist protocol, 0.25 milligrams of antagonist was given on stem day six until the trigger. Trigger occurred with HCG and or tryptorelin based on ovarian response and OHSS concern.

FET of one embryo occurred via natural or modified cycle at least two months after IVF. The groups were comparable in many demographics, age, BMI, duration and causes of infertility, AMH level, antral follicle count, FSH level, and number of ICSI cycles. So there were no differences in the starting and total gonadotropin doses, simulation duration and trigger method.

The estradiol and LH levels on the day of trigger in the PPOS groups was higher than in the antagonist group. However, the progesterone level on the day of trigger was similar between the two. Two women in the PPOS groups had premature LH surges, but early ovulation was not observed in either group.

Endometrial thickness was statistically significantly lower in the PPOS group. There were no cases of moderate severe OHSS. The groups had similar numbers of oocytes retrieved, fertilized, cleaved embryos, good quality day three embryos, blastocysts and embryos frozen.

And no statistically significant differences were found in fertilization failure or the number of cycles without a transferable embryo. During the study period, 330 patients in the PPOS group and 327 patients in the antagonist group underwent their first FET cycle. The method of endometrial preparation, the endometrial thickness, the number and type of embryos or blastocysts transferred and the number of good quality embryos after thawing were all similar.

The primary outcome was live birth rate, which was classified as delivery after 22 weeks of gestation. No statistically significant difference in live birth rate of the first FET cycle was noticed between the two groups on the basis of both the intention of treat and the per protocol analyses. Both groups showed comparable clinical pregnancy ongoing pregnancy, miscarriage multiple pregnancy and ectopic pregnancy rates.

Obstetric characteristics and complication rates were also similar between. A multivariate logistic regression using the backward conditional method revealed that only patient age and duration of infertility were associated with live birth rate following the first FET cycle after adjusting for confounders. So in conclusion, the live birth rates of the first FET following the PPOS and the antagonist protocols were comparable in patients with an anticipated high ovarian response.

So panelists, I'd love to open it up to a discussion on what our thoughts are of the pros and cons of these protocols. I'll start off by saying there's few things in our field that I think have trended in the right direction from idea, evidence and then actually being incorporated to clinical practice. This is one of those things that I think from a field perspective has been a slam dunk.

People have had the idea for a while. They've actually done multiple RCTs now in multiple different populations to answer discrete questions that people have had along the way. I think overwhelmingly the data suggests that it does what we think it does and it appears to be safe and doesn't sacrifice clinical outcomes.

So I'll ask Scott the question, why the hell aren't we all using it? Why are we having to talk to an audience of reproductive endocrinologists about it? So I think that depends where you are in the world whether or not you're using it. We're really fortunate. We've got Baris Atta on the call who uses this every day.

Other populations like Antonio LaMarca, Juan Garcia Velasco in Italy, Spain do use it. But when you come to the UK, for example, we don't really use it. If you go to Denmark, they don't use it either.

So why is that the case? And that can be due to some specific situations for that country. So for the UK, for example, there's two big issues. One's the cost of the drugs.

So just to put it into context, five days of GNH antagonist will cost you $42 in total. So five days of GNH antagonist costs you $42. To use MPA costs you $21.

So the financial saving is not that great. And then secondly, with Brexit, which I realize is a really unique UK population thing, actually you couldn't get MPA for a while. You couldn't get 10 milligrams of MPA.

And even today, I checked, some 2.5 and 5 milligrams are still not available within the UK. So, and we don't have the Digestron, which is the other one that's been done. So I don't, so the driver to change is not being the same.

So we realize that there's the benefits in terms of the oral medication versus injections, but actually when clinicians have taken such a long time to move to antagonists, and that's really in the UK, that's still the same, actually the further drive to move again is not. But I think in other parts of the world, they have moved, and I think we're really fortunate we've got Baris on the call today to be able to talk about the wealth of literacy. There's now 36 studies.

34 are all positive, and there's two that aren't, yeah. So that's a great transition. Baris is joining us.

I believe in Dubai, I don't know if I misspoke or if he's actually in Turkey right now. But as someone who has published on the topic and someone who uses it routinely in the clinical realm, tell us a little bit about your experience using progesterone, and I'd hope for you to comment specifically on these two studies that have not shown the slam dunk positive response that we've seen in the other 34. All right, Pietro, I hope you can hear me properly.

Thank you. We can hear you perfectly. Okay.

So I've been using it for over five years now, I think, and my experience, like personal experience, has been totally favorable. And as Scott said, the literature is overwhelmingly infection, right? So when you do multiple studies on any subject, you're supposed to see some variation in the effect estimates, right? So there would be some variation around the true effect, okay? So it's not unusual to find some chance negative. The findings, as in the study by Beguera from Spain, which was one of the early papers, and RCT with four side donors, the overwhelming response was same, but they reported a lower pregnancy rate in the recipients.

However, the recipients were not randomized, okay? So there may be a chance finding. Then we published a retrospective study comparing two cycles of the same donors and the pregnancy rate and live birth rate in our recipients were similar. So I don't think there's much of a debate there.

And then the outstandingly negative, there are two papers from China, okay, which report lower euploid rates with PPOS, but these studies have certain methodological limitations, which we mentioned in our recent review on the subject. And one of them is, so not only being retrospective, but there are a lot of subgroup analysis with arbitrary divisions based on age. And then let's say, I mean, they say, euploid rate is lower.

I don't remember exact numbers, but just to explain the concept, in women between 40 and 42, whereas it's similar in younger women. Then the other study says, euploid rates were lower in younger women, but not in the older women. So those negative studies were not consistent among themselves.

And secondly, the number of participants in these subgroups, like retrospectively created subgroups were really pretty small in one that were only 19 participants. And the overall euploid rate in those papers were really much lower than what we observed, I mean, based on age, what you would anticipate based on age, compared to the rest of PGTA literature. So I don't think the results are generalizable.

Then one negative finding study, which was published in FNS, I think two years ago, which is mentioned in the discussion of the paper by Chen, the RCT in hyper-responders, was what, sorry, women with high reserve. In the discussion, they refer to the 2022 paper, in an unselected population, when the retrospectively compared cumulative live birth rate was lower with PPOS compared to antibodies. That study is, I mean, with all due respect, really severely flawed in the analysis, because the reason is the definition of cumulative live birth rate was arbitrary.

So the formal definition would be either until a patient achieves a live birth, or she exhausts all the available embryos, right? So they define live birth as live birth until, sorry, in 16 months after stimulation. And again, arbitrarily, they start the transfers to eat two cycles later, two cycles after the collection in the progestin arm, whereas in the antagonist arm, they did fresh transfers, and then they continued with frozen transfers, even in the immediate cycle. So at the end of the 16th month after stimulation, the patients in the progestin arm had two months, at least two cycles less exposure.

And despite patients in both arms yielding similar number of oocytes, generating similar number of embryos, obviously with two cycles shorter exposure, the patients in the progestin arm did not undergo a similar number of embryo transfers. Indeed, the difference between the total number of embryos transferred in two arms was something around like 250 embryos less in the PPSR. So it wasn't a fair comparison, and there's no way to statistically adjust for this.

So that paper is actually, in my opinion, has been published with a wrong conclusion and wrong interpretation. So these are the studies that comes to my mind with negative results. All the rest, impressively consistently, I mean, in China, in Europe, and now the other paper we are discussing today is completing the puzzle because the U.S. papers were missing.

Now they started appearing as well. Again, I mean, they overwhelmingly support progestins as being equal to performing similarly to GNH analogs. I think that nicely summarizes the state of the literature, and when we say that there were two studies that showed it did not work well, I think the nuance and what Boris's explanation, I think, is helpful.

So to take a step back, we have a lot of studies that have shown benefit. Why do you think we haven't, we've been slow to incorporate it in the United States? Amber, in your clinic, I remember you telling me that you use it in a select group of patients. Why a select group and not the larger group of patients in your clinic who are gonna be freezing eggs or embryos up front? I think it's a great question, and I think in the United States, most states, right, most patients are paying out of pockets.

You could say this is exactly why we should be using it because there's, unlike in the UK, there's a drastic difference in cost. On the other hand, there's a drastic difference in cost out of pocket of the entire cycle. So if she were to break through and ovulate, so I think the place to start is in these cohorts, right? They're average or higher than average responders.

Younger patients, generally thin, I think the mean BMI in this study out of China was 21. I wonder sometimes, you know, when you take an oral medication, what's the difference in absorption and the volume of distribution? And all of those other things, I particularly worry about women with lower ovarian reserve breaking through. In my practice, I actually use it in addition to the antagonist in women with diminished ovarian reserve who break through their cycles.

So I actually, I think we will adapt. We will start using it more and more and more in the US, but I think we will step into it is my opinion. We will start with patients more likely to benefit and less likely to break through.

Baris, in your experience in Turkey, patients, Amber suggested that she worries about patients with a higher BMI in their response to the medication. Any comments on what you've seen having used it consistently now for five years? So the average BMI in Turkey compared to the US population is, I mean, lower, not as low as Chinese, but still lower than US population. However, we've been using in the UAE as well, where BMI is not as high as maybe US, but pretty high.

So in both settings, it performs well. And if you look at the studies, I mean, even comparing in, say, progestins with GNH analogs in overweight or obese women, they still seem to perform, I mean, fine. But I think I'll join Amber.

That's something that I would like to highlight. I mean, we can't really stress it enough. Progestins and antagonists work through different mechanisms of action.

So the progestins, I mean, act on hypothalamus to slow down the GNH pulse generator, whereas the antagonists competitively admit the receptors on the pituitary. So in theory, at least, they would have an additive effect. So we've recently started also, I mean, for the last year, using them in combination for patients who are under the highest risk of premature ovulation, like women of advanced age, patients with extremely decreased ovarian reserve.

So it just expands options. And in response to Scott, I mean, any progestin just looks fine. I mean, if you don't have MPA, if you don't have either gestron, I mean, macronized progesterone just looks well.

Even Colombid, you could take Colombid continuously throughout the cycle and achieve a similar oral ovulatory suppression. Let's talk specifically about the progesterone. And I know this is a concern that people raised early in the development of this kind of technique for ovarian suppression.

So medroxyprogesterone is a 17-alpha hydroxyprogesterone derivative, which means also is a weak antiandrogen. Barsh, should we have any concerns with regard to egg quality or fetal outcomes from that antiandrogen exposure during those 10 to 14 days? And what has the literature borne out for us when they've tried to answer that question? That's a wonderful and very relevant question. So progestins are not exactly progesterone.

They are progestins. I mean, if we use micronized progesterone itself, I wouldn't have any worries at all because the follicular fluid has pretty high progesterone levels even in the early follicular phase. So I don't think the systemic addition of a small dose of progestin would not affect the oocyte.

If you look at the laboratory performance, I mean, consistently with any progesterone, progestin, sorry, including MPA, or the other, I mean, lidro, fertilization rates, phosphorylation rates, and employer rates are similar. So I don't think so. And there are a lot of reports on neonatal and obstetric outcomes in different contexts.

I mean, both from progestin cycles for pituitary suppression, and as well as if you consider, I mean, other users. So, so far the data is reassuring. There's no, like, always trend.

And I would be surprised if it appears later on. So we've talked a little bit about scientific rationale, clinical rationale. Let's talk a little bit about the patient experience for a second.

So you, we've all heard headlines of needleless IVF, and can we truly achieve it? I think oral progestins are a way kind of headed in that direction. But I want to ask Morgan specifically, if you put yourself in the patient's chair, you're typically asking them to give themselves recombinant FSH, a menopure, and an antagonist. This reduces three shots down to two shots.

Is that enough to really improve the patient experience? Do you think the patients notice that this is a patient-friendly option for them, aside from cost? Yeah, I think that's a great question. Not only are you reducing two shot, or three shots down to two shots with this protocol, but the complexity of when to start that shot, I think, is really important from the patient perspective. They're mixing medications, depending on how much menopure they're on.

They are, they have a pharmacy with them, right? They're used to taking oral pills, so that's easy, and then when you start it on the first day of simulation, there's not a whole lot of error the patient can make, and we all know, well, at least as a fellow, I get all those first calls of, shoot, I forgot to take my antagonist tonight. Or we are bringing patients back specifically to figure out when we're starting the antagonist. So I do think from the patient perspective, it reduces a lot of complexity of when to start medications, and that's just in addition to one fewer shot.

Not to mention, that shot is one that burns, and a lot of patients call with that complication, too. Yeah, I think the elephant in the room for why there's some cycle-to-cycle variability is that I think patients, unfortunately, mess up their shots an insignificant amount, because they're doing it in the comfort of their own home at night, and I think there's a, it's probably happening a lot more than I think we think in a daily oral medication that's easier to administer, and probably easier to remember to take, particularly when there's kind of meds coming in and out throughout the cycle, probably is a way to reduce some of that. What about from the clinical perspective now? If you say, my clinic right now does not use oral progestins but I'd like to start using it, like Amber said, in my egg donation program, my egg freezers, my good prognosis patients, how does that affect your clinical workflow for your nurses who are now having to make some of these phone calls, or not making some of these phone calls? Right, we're talking about starting medications on day one, and does that patient need to come back again on day five or day six to see if they're ready for an antagonist start, if they're already on a suppressive medication from the beginning? Do you see this as a way of improving clinic throughput and minimizing points of contact during the cycle? I see it as probably an easy transition, especially if you are starting it on cycle day one.

I think most instructions, especially from our nurses, are on day one. That's one of their longest phone calls, right? And if you can avoid having to give new instructions, just like Morgan said, on day four, five, six of a new drug, I think it's gonna be an easier transition, in my opinion. I think that it's a new medication, it's a change, like anything else.

We've changed over time to random starts, and we do start in the luteal phase. We were nervous about all this progesterone exposure. 20 years ago, we wouldn't stimulate a donor with an IUD, a progesterone IUD, a progestin IUD in place.

We've changed over time. I think our fear of the exposure's changed, and I think the clinical transition is a doable one, in my opinion. For your monitoring, Scott, that patient who's on an oral progestin now, what do you think you could get rid of? Do you need to now check LH and progesterone levels during stimulation for these patients if you were checking them before? Do they need one ultrasound at the end of the cycle to time the trigger shot? What do you think you can peel back? I think this probably reflects the difference between U.S. and Europe in terms of the monitoring, because what we could, I think what we probably could do is start, use a fixed dose of gonadotropin.

We tend to use mono drugs in general, so you could start with your oral progesterone, single drug dose, and probably bring them back. Well, we know the average duration of stimulation, and you could say, well, let's bring them back after eight days, one scan, and actually, you can predict follicles grow at 1.3 millimeters a day. Trigger tomorrow, trigger two days from now.

Exactly, so it's possible to do that. The estuary guideline would suggest that there's not a huge value in biochemistry monitoring, so I guess, but we don't, I appreciate you could do all of that, but we don't even do that, but the reality is if we really wanted to be super convenient for people, that would be the approach that you could take, and I think the evidence is for that today, and people are doing that around the world, where essentially it's baseline, then one scan later on, and then planning that triggering, whether it be today, tomorrow, or the next day, based on that follicular development. I think it is possible to do that.

I think that would be a relatively easy paradigm shift in how physical it is to be an IVF patient, right? Having to come, get your blood drawn, have the ultrasound done by a stranger in the morning multiple times over the course of two weeks. This is not only now a cost savings for the patient, but also, I think, a time saver for the patient. Once you build enough clinical confidence in how to do this and who to do it in, Baris, in your practice in Turkey and in Dubai, have you noticed that your approach to monitoring has changed at all over the last five years, or are you kind of still using the same antagonist cycle monitoring approach? As Amber said, intending to use progestins means you have freeze-all cycle enemies, right? And it brings the opportunity of random start.

What I'm increasingly doing nowadays is I'm starting stimulations peri-ovulatory, which means right before ovulation or right after ovulation, and then the patient's endogenous progesterone rises with corpus luteum. And if sometimes I combine it with the depo-FSH, so going back to your needles IVF, so one injection, then I see them on day eight, measure their progesterone to see if their endogenous progesterone is high enough to suppress the hypothalamus endoterm. And what's that number for you? What number are you looking for? You know, depending on the time of the cycle, I mean, like if it's now mid-luteal, so I would expect to see something at least like eight to 12, I mean, somewhere around eight to 12 nanograms per mL.

And in the subsequent monitoring, if it starts dropping, then depending on how far the trigger is, I either supply with progestin or an antagonist. So I wouldn't say the stimulation takes much longer if you start peri-ovulatory as opposed to mid-luteal starts. And some of them don't require any additional injections.

And I mean, so far it's been working pretty good. The only negative thing about patients, I mean, patients experienced with progesterone, I mean, if you use it, I mean, you know the doses are arbitrary, right? I mean, they're not proper dose-finding studies. And any studies comparing different dosages of the same progesterone, almost invariably found the lower dose was as effective as the higher dose.

So if you use like three times a day or twice a day regimen, sometimes the patient complains about nausea as expected. So if you switch to a single dose progestin at bedtime, I think that also helps with the patient experience. Yeah, that's a great point.

I think Amber and I, before we got onto the live event, we were talking a little bit about the burden of having to take an oral progestin and what that feels like on the stomach. Not just on the stomach, but it makes you sleepy. It's, some women are, they are more sensitive to the side effects of oral MPA.

You know, it's, as someone who's taken HRT, you do want to take it at bedtime. I think there's less side effects. And I think about when we give the antagonist, we often give them in the morning, right? If you think about timing, when we trigger, when we monitor.

So there are some patients you might want twice daily dosing but they may not like the side effects, right? So it's probably, there's so many positive things about what we're talking about. It's one of the few negative things. Can I just add? So when we're talking about the sort of profound suppression that you can get by us in terms of that LH, there is some data suggesting that you may be, it may be so profound that actually you're worried about your LH max if you're using a GNH agonist trigger.

And then in one of these papers, they use the, you know, in some patients, they use a dual trigger with a lower dose. They use 2,000 units with an agonist trigger. Have you got any feel for where you think that might be beneficial? Because there's other studies that are suggesting that there's no role, there's no improvement with using a dual trigger versus a normal trigger in a PPOS population.

And should we be at all worried about those who have got really profound LH suppression in terms of trying to get an LH max or do we monitor it in any way? My answer was, I thought no, but I'd be interested to get your views on it as well just from a practical perspective. Yeah, Baris, how do you trigger your cycles using progestin parabolatory suppression? Any tips for the audience? As usual for our current cycle, so our routine practice is dual trigger, so which could be 5,000 HCG or the recombinant HCG. 6,500 combined to it in like a peptide like 0.3. I mean, not that it's necessarily beneficial, but it's our practice.

I mean, anyways, if the patient is deemed to be at high risk of hyperstimulation, then I would go for an agonist trigger. What I do, I mean, almost routinely, I know it's not necessary all the time, but if it is possible for the patient, if it's not too difficult for her, we prefer to measure LH levels the next day. So the data on that is also a bit, say, shaky.

I mean, if the patient obviously is not hypo-hypo, if she's not been on long-term contraceptives, or if she hasn't recently lost a lot of weight, and if she's not under risk of hypothalamic insufficiency, I think it just works fine. And actually, we published this a few years ago. What we did was we compared HCG trigger, sorry, we compared agonist-triggered antagonist cycles with agonist-triggered progestin cycles.

So the oocyte yield, oocyte performance was same. And in a number of patients, we had measured LH levels the next day, and the response was similar. Indeed, the trend was even towards higher LH levels in progestin cycles after the trigger.

So my indications are the same as anyone. Let's talk about the scenario on what happens next. So one of these papers talked about the first frozen embryo transfer afterwards.

We can imagine a world in which high-dose progestin exposure for 10 to 14 days may do something to the lining. And I think this study used a two-month washout period before cycling again. Part of the complaint that we have with PGT is just how long it takes from first shot to actually having that embryo happening, coming back to your uterus.

Do you think that there is a real or theoretical concern that you need to have a washout period after progestin exposure is the very first cycle if you have PGT results in hand appropriate for transfer? I think, if I remember right, the half-life of oral MPA is two days or less. And I think about, I mean, take our PCOS patients. We use MPA commonly to induce a bleed before another cycle, before a frozen embryo transfer.

We go right into that transfer, and we are transferring that embryo two to three weeks later. I think that it was safe to do that in the study. I don't think we need to delay things that long, in my opinion.

No, I think you completely agree that the biological rationale isn't there for that, and you can just go straight into it. And in the context of your sort of what will be, we now think it's probably a modified natural cycle is gonna be the best type of transfer for them, and they're going to continue to get high-dose progesterone exposure, probably for the whole of the first trimester. So I think, yeah, I don't think we need to worry about the individual effects there.

Boris, in your practice, do you have a washout period from the? No, not at all, not at all. In the anterovenous context, actually, you know, there are multiple studies consistently showing the immediate next cycle gives you, I mean, higher pregnancy rates compared to subsequent cycles for frozen embryo transfers, even though the mechanism is unclear. So we do not necessarily have a washout.

And our first choice is a natural cycle if the patient is over three. So while you're waiting for the PGTA results, when the patient has her period, we start monitoring. So by the second monitoring visit, which is around cycle day 10, we already have the PGTA result.

We move forward if she has a new transferable embryo. And our overall rates are actually, yeah, that's what I told when I read the paper by that, is very similar to what they published. So I don't think there's any, I don't think there's a concern here, and I don't think we necessarily need to have a washout.

I agree with Scott and Amber. We are coming up at the end of our time. I wanna make sure that we leave a little bit of room for questions from the audience if there are any.

And Jeff's gonna be going around with the microphone, so just raise your hand. And as questions come in, I wanna start to put together this concept for the audience, both in person and virtually. Let's think a little bit towards the future.

Using our armamentarium of medications that we currently have at our disposal, how could you put together a cycle that maximizes being patient-friendly while minimizing cost and preserving a clinical outcome? We've talked about oral progestins as a piece to the puzzle, but are there other things that we could be doing in parallel to do even better? And I'll start with Scott. So I think the first decision that we have to make is why are we doing the cycle, and are we aiming for a fresh transfer or for a freeze-all? And all of these have different tools that we've got at our disposal to be able to create that. And then, if we're aiming... Let's take a fresh transfer first.

If we're aiming for a fresh transfer, where do they sit on the ovarian reserve spectrum? Because if they have a low ovarian reserve, one approach that you could do is that you could give day two a GnRH agonist depo, so that'll give you quite a profound flare. That will then also suppress any luteinization. You could then give them a long-acting FSH as a depo, so cortopropan-alpha.

That will take you all the way through your follicular phase. You then give them an HCG trigger, and then you could give them an HCG for luteal support. And you avoid progesterone and vaginal progesterone as well.

So, essentially, you've made your IVF cycle... Three shots. Four, including luteal support. So, four, including luteal support, and no other drugs.

And you could do that, say, why don't you use AMH and artifolic? You could at least predict that percentage of the population with probably, for a large proportion, that would work. So, that's for a fresh transfer. I think that's one extreme.

I don't think we can get it less than that, or you have to give more stuff. You can give progesterone and so on to get rid of that fourth shot, so you're replacing, but that's, as far as I conceptualize, that's the minimum I could get it to. And then, could I twist your arm and make you use clomid and letrozole instead of your long-acting FSH? No.

So, I think the reality is that you're getting the biggest response from that GNH agonist, because the massive flare that you're gonna get, you're gonna get FSH values well above 40, and so, it's then that continued support that you're going to get in the second part of the cycles. And so, I think there are some advantages of that, because that will still get you to 10 days of high-dose FSH exposure, you know, reality. And you wouldn't achieve that with using clomid, phenol, or letrozole in the second part of the cycle.

You know, you'll get much lower levels. So, that's why I would suggest not. And I think you still want as many eggs as possible in these patients for that.

And I think, say, that's just one part of the population. But if you're thinking about these other approaches, I think, for, we were doing freezoles for those with the fertility preservation, for oocyte, you know, donation, for PGTA cycles, I think, you know, Baris mentioned this already, it's a combination of using these oral medications with long-acting FSH if you really want to reduce your treatment burden in terms of number of injections. But those of us who were exposed to, we'll remember when they tried to market, actually, you could go from seven injections down to one injection.

That didn't really work as a marketing ploy because, in reality, what we realized was that it was the doctors who were probably the drug company's clients, not the patients. And actually, they didn't really care why not the patients were getting seven injections or one injection because it's not them that are doing it themselves and so on. But I'll let others talk about other approaches, you know, in terms of Amber or Baris, to think about how they could reduce the burden for patients.

Sometimes I think it might be easier in the UK. Access to care is such an issue in the US that, you know, you're often trying to get multiple babies out of one cycle, right? So we have an inclination to push harder and do less mild cycles or mild stimulation, if you will. European stimulation.

Yes, correct, correct. You know, another drug we haven't really talked about is indomethacin. Using that, I use it sometimes, 50 milligrams TID, in addition to some of these patients with diminished ovarian reserve who break through, and that's a cheaper drug that we can use as well.

And I think we can use clomiphene citrate or letrozole in good responders if we're gonna go in that direction. I think the bigger problem still is access to care and trying to get or maximize one really good cycle. So I think Europe is recognizing that we've been behind and actually they've won and done, although there's not a huge amount of actual evidence for that, but the conceptual came out of Boston IVF from your group, Pietro.

But the reality is that we're all moving towards that. We accept that we should probably be getting more, and it's just because we've been doing fresh transfers for so long, but we recognize that actually for many patients, we've probably been doing a disservice by focusing on that. So everyone who's got a good response, probably should be getting maximal stimulation, freeze all, and then the first transfer being that frozen one.

I think Europe is transitioning to that, or learning from the US. I'll turn to our live audience here. Do you have any questions for our panelists on stage or Dr. Atta joining virtually? We have one question in the back.

Microphone making its way towards him. Hi, I'm Andres Rich. I'm a fellow at Armour, New Jersey.

I just had a question, perhaps more for Barish, related to, you mentioned that you would potentially give progestin in combination with an antagonist for patients at a higher risk of premature LH surge. Are there any patients, or is there any particular population that you think this is not good for, that you think they should not be using progestin, or is there no population to which this does not apply? Hi, Andres. Thank you, great question.

The only contraindication for using progestins for ovarian stimulation would be in fertility preservation in patients with progesterone receptor-positive breast cancer. I doubt how much that would affect, but I mean, except for those patients, I can't think of anyone who would be harmed by using progestins for pituitary suppression or combined suppression with progestin and antagonist as long as they receive adequate exogenous concentrotans. Other questions from the audience? Dr. Young, up front, Steve, or Jeff's getting his work up.

Yeah, thanks. That was wonderful. Thank you, everybody.

I just wondered, are there any synthetic progestins that you would avoid using? You know, one of the obvious ones that I would think of would be northendrone, you know, H. estin. It's very well-tolerated, you can get, five milligrams are quite potent, and there may be a little bit of cost increase, but I find my patients do really well on it for other reasons. Just wondered if there are any classes of progestins that you would avoid using.

I have to imagine with northendrone, there's a little bit of peripheral conversion to estrogen, and does that negate a little bit of your stimulation? I think that's a good point, but I think in a high-responding patient probably not. I don't think there's enough for you to see it to affect your FSH dosing. It's a very small amount of conversion.

Boris and Turkey, you guys are exclusively using medroxyprogesterone, or do you have experience with other oral progestins routinely? When I started, I started with MPA, because that was easily available, that was in the first publications, and then in the UAE, we're using an indigestron all the time, because MPA is not available, and I mean, we've tried micronized progesterone, that also works fine. I think we can really use any progesterone, and when we're stimulating, the patient is not pregnant yet, so the embryo is not there, embryo is not exposed to any of those, and then it's really a very short exposure, so I can't think of any progesterone to exclude for any concern, and that may sound superficial, but yeah. Dr. Luis Hoyos.

Would you have any concerns in terms of response for DOR patients? You know, because the way I see it is, you know, we're starting the progesterone from steam start, so there are basically no endogenous gonadotropins, whereas in the antagonist cycle, at least during the first six days, there is some contribution, and then you start your antagonist, so is there a concern? I mean, because we know, for example, we don't do long lupron cycles, we know the response is way worse in DOR patients, and again, they're suppressed from the get, so is that a concern in this case, and if it is, then if we're gonna use progestins for DOR patients, should we start them with an antagonist criteria instead from steam start? May I? Please. I mean, 2021, we published something called the flexible PPOS, and PPOS part is in this number, but the idea was to start progestins just like you would start antagonists in a flexible antagonist protocol, so the original study was done on oocyte donors with high ovarian reserve, but then we also used it in women with normal as well as low ovarian reserve, and we published multiple comparisons, flexible versus what I call conventional progestin protocol, where you start at the beginning with gonadotropins, or flexible progestin versus flexible antagonist. I mean, there weren't any significant differences, so I wouldn't rule out progestins just because the patient has low ovarian reserve, because even if, assume like as in a long protocol, even if we shut down pituitary toll, as long as we dose with exogenous gonadotropins adequately, that wouldn't be a problem, and particularly in women with POI, who would be at the highest risk of premature ovulation, in my opinion, what I could do, or what I do at times, so I mean, those patients typically do not have regular periods, so you monitor them.

Whenever you see a follicle, depending on what is its size, what are the hormone levels at the time, you just tailor to the patient, but if you expect follicle growth, I would take every precaution to prevent premature ovulation, so that would be progestins, antagonists, indomethazine, and as we recently published, triggering at a much smaller follicle size, and so I wouldn't rule out progestin just because she has low ovarian reserve. So, I was thinking about, given the wealth of literature that we've got, and it's all aligned, Baris, you know, I say there's 36 studies I could see, apart from the two that you've discussed in detail, given their study limitations, I was trying to think, what are their remaining unanswered questions? And I was really struggling, apart from these practical ones we're talking about, like how to facilitate uptake, what are the unanswered scientific questions? I appreciate there's some data on the children, you know, it's all super reassuring, but you would obviously need much larger sample sizes for that, so that's not come for any period of time, so I wasn't sure if the panel had actually any unanswered scientific questions, because I was really struggling, you know, thinking that we should just be moving on, accepting it, and adopting it routinely. I think the paper that's missing to me is the how do you operationalize this in your clinic paper, it's a white paper talking about how do you talk to patients about it, how do you teach your nurses about it, how does this modify your monitoring schedule, and which are the patients that you should start using it with to build confidence in.

I think that's potentially a paper that this panel could write with Baris, just kind of teach people how to take something that's solidly evidence-based now, with 36 papers and counting, and actually put it into practice, rather than the other way around, with many notable examples in our field where we started doing it, and then tried to prove that it works, and realized it didn't. So this is an opportunity, I think, to get it right, and I think this is hopefully the start of this conversation in North America, and we'll see more and more uptake of it as we go on. We're at the end of our time, I know this is a discussion we could have for a lot longer, I wanted to thank Baris for logging in after hours, remotely, I wanted to thank my panel, Scott, Amber, Morgan, for being here, and for presenting those articles, and thank our live and virtual audience for being at the MRSI 2024 meeting with us for the FNS Journal Club.

That's all the time we have for today, we'll see you again next year at this meeting, and online for subsequent Journal Club Globals. Thank you. Thank you.