Clinical relevance of combined FSH and AMH observations in infertile women
Presented by Dr. Norbert Gleicher,
Medical Director and Chief Scientist, Center for Human Reproduction
New York, NY, USA
May 21, 2013
NOTE: We apologize for the echo at the beginning of the recording; the sound improves about four minutes into the recording.
Follicle stimulating hormone (FSH) and anti-Müllerian hormone (AMH) are two of the most common fertility tests used to evaluate a woman’s ovarian function. High FSH and low AMH levels, which usually go together, indicate diminished ovarian reserve (DOR), and reduced pregnancy chances with IVF.
A recent paper by investigators at the Center for Human Reproduction (CHR), published in Journal of Clinical Endocrinology and Metabolism, found that women with the somewhat unusual combination of high FSH and high AMH levels had four times more eggs retrieved, and were almost twice as likely to get pregnant after IVF, than women with all other FSH/AMH combinations.
This webcast, presented by Norbert Gleicher, MD, Medical Director and Chief Scientist of CHR and lead author of the study, provides an overview of the findings and explains what various FSH and AMH levels, combined, may mean to women who are trying to get pregnant.
Title: Webcast: What Do High FSH and High AMH Mean for Your IVF Pregnancy Chances?
Speaker: Dr. Norbert Gleicher
What Do High FSH and High AMH Mean for Your IVF Pregnancy Chances?
In regards to her chances with in vitro fertilization, for women with low ovarian reserve its usually the primary treatment. Before I get into the paper, which is now the abstract and my co-authors, I want to explain quickly what the ovarian reserve is and how it sets.
Ovarian reserve, basically represents a woman’s pregnancy chance. It also represents the number of follicles and eggs she has remaining in her ovaries. The various ways of determining or assessing, approximately what we think is ovarian reserve this is. The most frequently ways to do our assessment of Follicle Stimulating Hormone and Anti-Mullerian. Both of these hormones have been used for decades for this purpose. But both of these hormones are usually utilized in absolute value. Most colleagues use values of approximately 10 million rational units. But, as we obviously all know, at this age, increases as a woman ages. Therefore it is really possible to assess what a normal FSH level should be at any given age, and we call this age-specific ovarian assessment. We can do the same thing with Anti-Müllerian hormone which, in contrast with FSH, declines as a woman ages. But here too, we can establish normal ranges for each age group. What you see here on the slide are the age-specific values that we have established (see 2:55 to 2:58 in video for chart) on the chart, and they’re based on 95% confidence intervals for each age group. So, we can, once we know a woman’s age, we can say what the normal range of FSH for that particular age group is and what the normal range of AMH for that particular age group is.
We define a woman to have low functional ovarian reserve, in other words, older than, she should have older ovaries, if either her FSH is above where it should be for her age, or it is below where it should be for her age. So either FSH too high or FSH too low, or obviously both in combination reflect diminished ovarian reserve. At the same time, it is also known that high Anti-Müllerian hormone level, meaning above the 95 percentile has meaning because it is very frequently associated with a condition which is called Polycystic Ovarian Disease or Polycystic Ovarian Syndrome which itself is a risk factor in association with in vitro fertilization because these patients tend to produce very large egg numbers and are at risk for hyper stimulation syndrome. So, these in regards to AMH, the upper limits are also important. I’m spending too much time on this because I want to explain that based on these normal levels, one therefore can define every patient in a study as either being normal, if she both in FSH is in normal range and in AMH as a normal range for her age, or she can be either, with AMH higher than normal or lower than normal, and she obviously can be with FSH higher than normal or lower than normal. That combined, therefore gives you 9 potential combinations in which patients can fall in.
Correlation of AMH and FSH
Before I get to those combinations, AMH and FSH obviously correlate quite well as this correlation coefficient demonstrates, but they do not do so equally well at all ages as this study we published in 2010 demonstrates where you have different combinations of normal AMH and FSH, normal AMH abnormal FSH, abnormal AMH normal FSH, and both of them are normal at different age groups. We see there are differences between those gaps. But how exactly this plays out in terms of IVF outcomes has really been unknown and we therefore decided in the study to investigate what these different combinations of AMH and FSH mean in terms of how these patients will then behave in an IVF setting.
Materials & Methods
As I already mentioned, one therefore can come to 9 combinations of FSH and AMH where either FSH is normal and AMH is low, FSH is normal AMH is high, FSH is normal AMH is also normal, or obviously all the other combinations. And as you can see, since we are dealing with an infertile population, by far the most frequent patient population that we are encountering in the study are those women who have high FSH and low AMH. So, in both parameters, they have abnormally low ovarian reserve. The second frequent one are those that have high FSH and normal AMH. The third frequent one, however to our surprise, is in total about 10% of the patient population, is a group of women representing high FSH and high AMH which, based on what I have told you, in a way is kind of predictory because high FSH obviously means low ovarian reserve while high AMH usually means high functional ovarian reserve. We have been for quite a while quite puzzled about this patient population because of this (8:59) Our sense has been clinically that these patients, did better than what we would expect from high FSH levels but we never had the opportunity to investigate that either, and that’s obviously what this study is for.
For outcome measures we look for number of eggs produced in those IVF cycles, obviously all statistical assessment with them are adjusted for age, implantation rates, again adjusted for age, pregnancy rate. And our center has a long-standing interest in the gene which is called the FMR1 gene that some also call the cyro-x gene for which we have shown significant effects on various reproductive aspects including IVF pregnancy rates. And so we in the study wanted to see whether this gene in any way effects what we are seeing otherwise in the general population.
And coming to the study we looked at a total of 544 pregnancies, 544 first IVF cycles, which led to 142 pregnancies. So, considering the patient population in which the study was done which was quite adversely selected as we will be seeing in a moment, the established clinical pregnancy rate is therefore quite, quite remarkable. What we found in a statistical analysis performed by our statisticians quite significant differences between all those 9 FSH/AMH combinations. That is, in itself, a very important observation because it obviously tells you that if there are significant differences between those 9 combinations, the assessment of this combination of FSH and AMH has statistical importance. And, those differences were quite significant. Those 9 groups differed to a very significant degree in the gonadotropin dosage that they required, in egg numbers, in the number of embryos that they transferred, which is obviously reflected in how many embryos one gets in the population, and also the number of embryos cyropreserved, which again is a reflection of how many embryos the woman had, and a statistically to a much more marginal degree, implantation rate. So, the fact that implantation rate is so differently effected from all these other aspects does not surprise because obviously FSH and AMH representing the ovarian reserve population mostly relate to egg numbers and egg quality, and therefore embryo numbers and embryo quality.
Summary of the Demographic, Clinical and IVF Cycle Data per AMH/FSH Catagories
And here you see the hard data, and I don’t want to waste to much time to go into the detail, but I just want to point out that all those 9 groups here, in terms of the typical patient characteristics like age, BMI, really did not differ statistically. The difference between these groups, in terms of statistical differences, came into play in all the clinically relevant issues. So, again showing us that these different combinations of FSH and AMH have clinically significant meaning and significant clinical relevance in predicting how well or how poorly the patient may do.
So, what our results show that pregnancy, in other words, being pregnant or not pregnant, differed significantly between all 9 categories or 9 groups. The most interesting finding for us was that the group of FSH high and AMH high, in other words this predictory group, amongst all 9 patient groupings had really the mot favorable IVF outcomes. So our clinical sense with this patient populations representing approximately 10% of all IVF cycles, in other words was proven, and to a much significant degree than we had even had expected. These women who had the combination of abnormally high FSH and the abnormally high AMH had over 4 times the odds of having better ooctye, in other words better egg numbers, than the other 8 categories and this finding was preserved by adjusting for gonadotropin dosage as well as patient age. And even more interestingly, this patient group of high FSH and high AMH had practically twice the odds of pregnancy than all other 8 categories, and indeed with age adjustment the numbers remain almost identical. So, the finding of having a high FSH and a high AMH is prognostically a very favorable finding. Here you see the significant difference that I alluded to in terms of ooctyes between groups with high FSH and high AMH and the rest of the patients.
Now also very interesting, I mentioned to you very briefly that our center has had a long-standing interest in the FMR1 gene, and so we added the FMR1 gene to our statistical model and something very interesting happened. All the positive findings associated with high FSH and high AMH completely disappeared and indeed turn to a negative of 0.75 times lower pregnancy chances if the woman had what were calling a het-norm/low FMR1. I don’t want to diverge the subject too much just yet about the FMR1, only so much. The FMR1 gene publications show, seems to be quite intimately involved in how ovarian aging progresses, in other words, different genetic forms of this gene seem to be aging ovaries in a different way. And the worst gene to have is this het-norm/low FMR1 gene we have previously described in a number of publications, which is characterized by having 1 allele, in other words one X-chromosome with CTG repeats in a normal range between 26 and 34, while the other one is in low range, which means it lower. We have, in other studies, demonstrated that this FMR1 is associated with a lot of different very significant clinical findings, amongst them significantly lower IVF pregnancy rates. As this study demonstrates, this is exactly what comes back again.
Patient Demographics and IVF Outcomes in High AMH Categories and Patients with PCOS.
Finally, high AMH levels are, as I previously mentioned, are associated with Polycystic Ovaries. So what we also did in the study, we looked at the 3 categories where AMH was high, combination with lower FSH, normal FSH, and high FSH and we compared those to patients which we defined amongst all our other patients as PCOS patients, based on large oocytes. In other words, anywhere where we considered clinical PCOS patients, we wanted to see what the difference was between these categories and outright PCOS patients. We see that, in the population like ours 2 PCOS patients are here, the other numbers are relatively small. We see that they were much, much younger than all the other groups. This is a very important point which recently was made in other publications in the literature because what this observation suggests is, PCOS is not a static condition. Women at young age can be very frequently showing PCOS but as the get older, that PCOS will disappear. In other words, that PCOS is not a static condition that a woman carries into older age. That is very important to understand, because that brings me back to the FMR1 gene because this this sub-genotype of her-norm/low, we a number of years ago associated with the PCOS at very young ages, but which very quickly leaves the ovaries and then at mid-age develops diminished ovarian reserves. And so, this sub-genotype of FMR1 gives you this kind of ovarian aging pattern that we see quite frequently in women with infertility. As many of you will know, that question, how PCOS patients do in IVF is a quite controversial one with a number of papers suggesting that they do just as well as anyone else, other papers suggesting that they are doing worse. This may very well be part of the answer in these discrepancies in studies because of that, and then you do your IVF cycle in these patients and base them on their FMR1 genotype.
So, in conclusion, what we think our manuscript or paper demonstrates is that we now understand what the high/high FSH/AMH means. It means good prognosis, but only if that patient does not also carry the FMR1 het-norm/low genotype. So once again, we emphasizing the importance of FMR1 but also suggesting that FSH may be more important in earlier follicle maturation stages that we have seen, and once again, its very well into another theme that were currently investigating in our laboratory which is this cynogistic action of FSH and androgen at very early stages of follicle maturation. Again, the importance of FMR1 in collaboration. The changing of the phenotype of PCOS I already alluded to, very important in clinical consultation. Thank you very much, I will be happy to take questions.
Questions and Answers
Speaker: Thank you Dr. Gliecher. Now I’m going to un-mute everyone so you will be able to ask questions. I’m sure you have some questions. Now, Gloria do you have a question?
Gloria: Yes I have a question. I just wanted to find out, in reference to conversation ( 24:45 ???) and talk some more about high FSH and high AMH, what are in the presence of low AMH and high FSH? Does the same apply, or what is the difference in the situation because from what I understand, with the high FSH and the high AMH, there’s better chances of pregnancy. What about, when in the case of the opposite, low AMH and high FSH.
Dr. Gleicher: Yes, Gloria low AMH and high FSH is obviously what we expect in infertile women who have low ovarian reserve, in other words, who have aging ovaries. Whether due to the fact that they are older, or whether due to the fact that their pregnancy, this is not as good as a pervasive situation. You will have much, much lower egg numbers, therefore lower embyro numbers and lower pregnancy rates. But in many ways, these are probably the patients who are most in need of appropriate clinical care. Our center has been working on women with severely diminished ovarian reserve now for many, many years and we have gained a lot of important insights in recent years about how you can still improve their ovarian performance. Once again, this is not the topic of today’s program, but women who have very low ovarian reserve usually have very low male hormone levels as we recently published in Human Reproduction. Therefore restoring their male hormone level, their testosterone level, will improve their performance. That needs to be done for weeks to months before your IVF cycle. Okay?
Speaker: Anyone else do you have a question? Hello? Let’s move to Lisa. Do you have a question, Lisa?
Lisa: Yes, how about low FSH and low AMH? What is the prognosis there?
Dr. Gleicher: Sorry, Lisa?
Lisa: Okay, how about someone with a low FSH and low AMH? Can you comment on the chances of pregnancy there?
Dr. Gleicher: Yea, that’s a very good question and that is a also not infrequent combination of findings. A low FSH is obviously a good sign, while a low AMH is a bad sign. So, your question comes down to how old the woman will be. If that woman is young, meaning under age 40, the AMH is the much more important and accurate predictor of what’s really going on. But if the woman is older, meaning above age 40, and especially about age 42, or even if she’s younger and has extremely low ovarian reserve, then the question becomes more of FSH important. So, I can’t answer your question directly because it really depends on the age of the patient and how bad her AMH is. IF her AMH is undetectable at a young age, then paradoxically loses importance if one uses the FSH in prognosis. The same applies with age 42.
Speaker: Thank you, I see Maya’s hand is up. One second. Maya do you have a question? This will be the last one.
Gordon: Hello? Can you hear me?
Dr. Gleicher: Ya.
Gordon: It’s Gordon, Maya’s husband. We’ve been working on getting the FSH down and reduced it now, the last blood test showed its lower, its under 10 now. It’s 9. The AMH, of course, we’d like to see it go a little higher. What I’m asking is, should we continue efforts to lower FSH or should we just leave it well enough alone? Because it sounds like higher FSH with lower AMH is more positive in making more effort to get the FSH down.
Dr. Gleicher: We here at CHR do not subscribe to what many of our colleagues do which is to wait for the FSH to come down. We don’t subscribe to it because the FSH is not the disease, it’s not the cause. The FSH is just the symptom. The problem is the ovary. I can bring any woman’s FSH down within days to a normal level by giving her estrogen. That will not change her chances in getting pregnant. What requires treatment is not the FSH, it’s the ovary and again that’s a completely different subject. Your wife seems to have diminished ovarian reserve, so my suspicion is that she has very low male hormone levels and androgen levels. She will probably benefit from having her androgen levels raised. That will improve her ovarian performance. That what it needs to go after, not lowering the FSH level.
Speaker: Okay, we have time for just 1 more question and there’s 1 that came in the Question Chat. This is from Nicole. I’m gonna read. Dr. Gleicher I have a normal FSH, but AMH just tested is 0.7. I’m 45 years old. What is your prognosis for me?
Dr. Gleicher: Uh, let’s see. At age 45, pregnancy chances are obviously limited, but some 45 year old women can still get pregnant and from the little I know from your test, if you have normal FSH at age 45, then you may still have a chance with using your own ovaries. As I said before in answer to one of the prior questions, at that age, FSH is much more important than AMH. So, the fact that your AMH is low really does not bother me. The fact that your FSH is “normal” is somewhat encouraging, but again with a cautionary note that at age 45 it’s always an uphill battle.
Speaker: Alright, thank you so much everybody for attending the first-ever fertility insight today. If you would like to receive a reprint of the paper that was just discussed, please email me at [email protected] that you are seeing on your screen. If you have any follow-up questions, please feel free to e-mail me as well. Hope you have a great rest of the day. We hope to see you again!
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