The Use of Different Gonadotropin Regimes

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Mark Perloe, MD:  “Hi, we’re at the Ferring meeting and I’m here with Dr. Elkind-Hirsch and Dr. Sharara who presented a Symposium this morning on ‘Advances in the Use of Human Derived Gonadotrophins.’  I’d like them to discuss their work with us and some of the clinical implications that might result from that.” 

Fady I Sharara, MD:  “The use of urinary gonadotrophins have actually been evolving since the beginning of the 1960’s, and I think the first pregnancy was reported in the late sixties.  The norm has been the use of something called hMG which is FSH and LH in equal amounts, and that was the gold standard up until the early part of the 1980’s when urinary FSH became available which is mainly FSH with very little LH activity.  Over the years that has evolved into the 1990’s as a form of using recombinant FSH which are made by recombinant technology not using any urinary products.  The debate over the past few years has been whether the recombinant products are better than any urinary derived products, and I reviewed the whole literature this morning on the use of urinary FSH, urinary hMG, and recombinant FSH.  The bottom line is the recombinant products are definitely not any better or worse than the urinary derived products and this is a very important message because the recombinant derived products are still much more expensive around the world.  Ferring is coming out with a new urinary derived product, a urinary FSH, that has just underwent a multicenter randomized trial in the U.S. showing that it has at least as good of a pregnancy rate when used appropriately - subcutaneously.” 

Mark Perloe, MD:  “I wanted to ask you something about that because we’re all aware of the meta-analysis that showed superiority so you presented some data and talked about that too in your presentation.” 

Fady I Sharara, MD:  “I think this is an extremely controversial paper that came out in 1999 and the companies that make recombinant products have been using this meta-analysis to justify that recombinant FSH is much better than urinary derived products and actually that’s not the case at all.  You have to read that paper extremely carefully and the paper has a number of flaws that really needed to be pointed out.  If you read the message of the paper it shows that recombinant FSH is slightly better and results in about a 3.7% additional increase in pregnancy rates compared to urinary derived products.  But if you read the paper very carefully there have been some data that were included that should not have been included in the beginning in this meta-analysis.  If you look at the ICSI data, there was absolutely no difference between urinary FSH and recombinant FSH. That paper is still being used around the world to justify the use of a much more expensive recombinant product when the data is just not there to support it.” 

Mark Perloe, MD:  “One of the arguments that was used in the switch was there was insufficient volumes of menopausal urine to generate the samples, and we were looking at draining the Gulf of Mexico to get a sufficient supply of urine to generate this.  I guess that’s not a problem.” 

Fady I Sharara, MD:  “It’s not a problem at all and actually we all remember the “shortage” in the urinary supply, now whether it was really true or whether it was something that was just coincidental to the release of recombinant products in the U.S.  Basically, with the shortage and the absence of Metrodin in the U.S. it really pushed most of us who like to use urinary FSH into using recombinant FSH.  Within a matter of two to three years clinicians started finding out that the use of recombinant FSH only has not resulted in a better pregnancy rate, it has resulted actually in a slightly higher cancellation rate.  You have to understand that the way the clinicians in the U.S. stimulate the patients is totally different than in Europe.  Most of us use oral contraceptives first as a way of down regulation then we overlap with Lupron before we start stimulation.  In some of these patients their LH levels become so undetectable that if you use only recombinant FSH you’re not going to have the clinical outcome that you really are looking for.” 

Mark Perloe, MD:  “As a result of that we’ve gone to protocols where we’ll mix the purified FSH or the recombinant FSH with a hMG product either in the same syringe or at various ratios and you presented data that looks at doing that.” 

Karen Elkind-Hirsch, MD:  “Right, and actually the Ferring study I think is unique in the fact that this was a study in which clinical practice actually turned around and had a company ask a scientific question.  It’s usually the other way around, usually we have scientific data and we change our practice and that was a very nice lead into the fact that we have a product with recombinant and the introduction of recombinant of an FSH that is devoid of LH activity.  Many of us found using that type of protocol in the U.S., particularly the suppression of the ovary with an oral contraceptive followed by Lupron suppression, that these patients didn’t have enough LH for normal follicular development and so we all began to use various combinations based on nothing scientific just kind of a gut reaction of ratios.  Ferring sort of saw that happening and said maybe we need to see if there is a good combination, is adding hMG in early better than adding it later, do we have to add just a little, or do we have to add a lot?  So this particular clinical trial was designed to look at that question but I think more importantly which you raised is that people began to add in hMG with recombinant FSH and the problem is these products were not designed to necessarily be mixed together.  The recombinant diluent is specific for the recombinant products, and the urinary diluent is specific for the urinary products.  We don’t know when we use one diluent with the other what we’re really getting in the syringe if we mix them together which classically is what practitioners do to make it easy for patients.  We don’t want them giving multiple injections and an injection of this and injection of that.  So the first thing that we actually did in the Ferring study, which is some very elegant bioassay work, was actually to mix Ferring’s urinary FSH with Ferring’s urinary hMG and clearly showed that there was no loss of either LH activity or FSH activity when we mixed them in the same syringe.  That was the precedent for actually doing the clinical trial, and we kind of did that before we went ahead and said let’s try various ratios.” 

Mark Perloe, MD:  “Now that study was using an FSH product that wasn’t available in the U.S.” 

Karen Elkind-Hirsch, MD:  “Correct.” 

Mark Perloe, MD:  “Does that data then apply to the products that we might have available to us now?” 

Karen Elkind-Hirsch, MD:  “As I said before, the problem is the recombinant technology and the formulation of the recombinant product is different then the formulation of the urinary products so I cannot say that we can take the results from a urinary mixing that are formulated the same way that have been maximized for that diluent and say - yes, now I know I can mix anything together and get a good yield.  So really this is specific to mixing Ferring’s urinary products with each other, and I think the other studies need to probably be done to actually answer whether what we put in that syringe is what we get out of the syringe.” 

Mark Perloe, MD:  “You went on then and next mixed at various ratios and looked at various protocols.” 

Karen Elkind-Hirsch, MD:  “Part of that was because there are a multitude of protocols in the States and they’re trying to sort of address some common ways people do it.  One was to take sort of a two to one ratio of the FSH to LH all the way through the cycle so that’s one thing a lot of people do.  Another thing that practitioners do is they hit them with pure FSH early for recruitment of follicles but then the idea is you recruit them but then once they’re recruited we need that LH for follicle development.  So that’s kind of the second treatment which is adding the LH in at day five, and then the last treatment was sort of another common protocol where you have this basal amount of LH, just this very low level all the way through.  When you want to increase your dosage you just increase your FSH so we call that LH baseline, so those were the three different protocols that were looked at.  The other thing the study did was divide and rightly so divide the patients according to their ages, and the reason is there was a perception that perhaps different ratios may be more important in a younger population versus what might be needed in the older population, different needs and what not.  The data is not completed so this is sort of an interim analysis but the basic take home message was we really didn’t find a difference in our ratios.  I wish I could sit here and tell you here’s the perfect protocol and here’s the perfect mixture but there didn’t seem, at least to date, one that particularly stood out.  We had great outcomes and great egg development but there wasn’t a particular mixing that seemed to be better than the rest.” 

Mark Perloe, MD:  “So it seemed that based on the tools that we have now the urinary derived products are equally effective compared to the recombinant and there are no particular protocols that immediately stand out in terms of looking at what would be the appropriate ratio.” 

Fady I Sharara, MD:  “Correct, this issue has been basically around since the introduction of recombinant products and after nearly ten years of using recombinants it’s very clear that there are no differences or any improvement of using recombinant technology versus urinary derived products.  It only tells us that there is really probably no difference at all in using these products that are either urinary derived or recombinant derived.  Obviously, the recombinant technology is purer, there’s all these issues about the batch to batch but the bottom line is the pregnancy rate is exactly the same and the cost is a major factor when you…” 

Karen Elkind-Hirsch, MD:  “When you’re adding the LH back in anyway.” 

Fady I Sharara, MD:  “Right.” 

Karen Elkind-Hirsch, MD:  “Because in a large proportion of patients we can’t predict which patients needs that LH, that’s one of the hardest things.  Having some on board even if they have enough isn’t going to be a bad thing but if you don’t have it on board it is going to be a bad thing.” 

Fady I Sharara, MD:  “There was a paper that was published from the University of Pennsylvania clearly showing that the percentage of biochemical pregnancies and cancellation rate is higher when recombinant FSH is used without the addback of any LH, especially in these women I told you use the pill and then are down regulated.  Obviously, the patients buy the medications before they start the cycle.  You’re not going to test them the day they’re going to start and then call them at four in the afternoon and tell them they have to go buy some hMG because their LH is so low.  A lot of centers either don’t measure LH or if they do measure the LH they don’t even look at it to decide if they’re going to change their clinical way of practice.” 

Mark Perloe, MD:  “There are studies that have also looked at the day three LH values, and it doesn’t seem that that predicts what’s going to happen on day ten so looking early in the cycle and measuring LH doesn’t help you predict later on what you should be administering.  One of the things we’ve heard in the past and I’d be interested in your comments, it’s certainly not data that you looked at in the study, we were always told that the LH had such short bioactivity that it was gone before you knew that you had given it and we had heard data that perhaps HCG may be sufficient to maintain follicular development.  Do you want to comment on your thoughts about that when you’re considering using LH?” 

Fady I Sharara, MD:  “Dr. Filicori presented some very elegant data and actually published on it a couple of years back.  As we all know, LH has a very short half-life and we use HCG to trigger ovulation exactly for that reason because HCG can be around easily for about thirty-six hours.  With the LH, even though the half-life is extremely short, we have to remember that there’s endogenous LH still being secreted even in down regulated patients only in small amounts that may be totally sufficient to get the cycle going.  We’re trying to improve on nature, and nature has been evolving over millions of years.  There’s the two-cell gonadotrophin theory that has really stood the test of time that you really need some FSH and some LH.  When we tried to remove one of these very important products, obviously, we could not totally mimic the natural cycle or get the pregnancy rates we really wanted to have so we’re back and we made a full swing from the days of urinary FSH only to coming back full swing and adding hMG.  If you look at the percentage of physicians, at least in the U.S., using mixed protocols every year this percentage is rising and it was about 50% last year.  My predictions in 2001 and 2002 are going to be at least about 70%.” 

Karen Elkind-Hirsch, MD:  “Some of the LH and hMG is actually a low dose of HCG as well.  I can tell you that one of the reasons Dr. Filicori actually started using HCG addback was hMG was not available to him in Italy when he began that and he needed a mechanism to add LH back and that’s why he used the HCG as an addback.” 

Mark Perloe, MD:  “That’s certainly a considerably cheaper option than going after the gonadotrophins.” 

Karen Elkind-Hirsch, MD:  “But the nice thing with hMG is you get your FSH and LH all in one vial so it isn’t added; you’re going to be giving that FSH anyway.  You need that FSH and now you get the LH with it.” 

Mark Perloe, MD:  “There was data presented that as time goes by and in the past few years we’ve seen an increasing number of American physicians switching to the protocol, as you said.  Is it because of expense or because of personal experience?” 

Fady I Sharara, MD:  “Actually it became very clear when people started noticing at least not an improvement in pregnancy rates and in most cases a lower pregnancy rate in recombinant only products and people started adding back to get to the rates that they are comfortable with.  You have a lot of physicians around the country who would not go back to using recombinant only because their pregnancy rates definitely improved when they started doing mixed protocols.” 

Mark Perloe, MD:  “Thank you so much for coming and visiting with us and sharing your studies, I appreciate it.” 

Fady I Sharara, MD:  “Thank you for having us.” 

Karen Elkind-Hirsch, MD:  “Thank you.”