The spermatozoon, in the process of its maturation also undergoes meiosis at which time it too reduces its chromosomes by half but instead of discarding 23 chromosomes, it simple diveides into two . Thus in the process of fertilization each immature spermatozoon with 46 chromosomes propagates two mature spermatazoa, each containing 23 chromosomes. The subsequent fertilization of a 23 chromosome-containing egg, by a mature sperm with 23 chromosomes propagates an embryo that has 46 chromosomes (the normal human genome). Thus for an embryo to have exactly 46 chromosomes (the euploid number) and thus be "competent(have the potential to develop into a baby), both the mature egg and mature fertilizing spermatozoon must each contain exactly 23 chromosomes.
Those embryos that bhave an irregular number of chromosomes (i.e. aneuploid) are incapable of developing into healthy babies (“incompetent”). While embryo "incompetence" can result from either egg or sperm aneuploidy, it is usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo increases significantly.
Embryo aneuploidy is by far the most important rate-limiting factor in human reproduction and is the most common cause of “implantation dysfunction” and failed IVF, early miscarriages and many chromosomal birth defects such as X-monosomy and Down’s syndrome.
When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women, at best only 2 out of 5 eggs are chromosomally normal (euploid) and this decreases progressively with the advancing age. By age 35 years, only about 1 in 4 is competent, and by the mid forties only 10-15% are chromosomally normal.
The fertilization of an aneuploid egg will inevitably lead to embryo aneuploidy, and as stated, an aneuploid embryo cannot propagate a normal pregnancy. In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain a large amount of cell debris or “fragments” are usually aneuploid and are thus "incompetent". Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/"incompetent".
At a point in the later stage of a woman's reproductive career, the number of remaining eggs in her ovaries falls below a certain threshold, upon which she is unable to respond optimally to fertility drugs. Often times this is signaled by a rising day 3 blood follicle stimulating hormone (FSH) level. Such women with diminishing ovarian reserve produce fewer eggs in response to ovarian stimulation. While diminished ovarian reserve is most commonly encountered in women over 40 years of age it can and indeed sometimes does occur in much younger women.
A few important (but often overlooked concepts should be considered in this regard:
1. It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood FSH/inhibin B or antimullerian hormone) that results in an increased incidence of egg/embryo "incompetence" due to aneuploidy
2. The ovaries and developing eggs of women with diminished ovarian reserve (regardless of age) are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced overproduction of male hormones (mainly testosterone). A little testosterone produced by the ovary promotes normal follicle growth and orderly egg development but too much testosterone has the opposite effect. That is why (especially in women with diminished ovarian reserve who often have high LH and increased ovarian testosterone production , the use of ovarian stimulation protocols that fail to down-regulate LH production prior to initiating stimulation with gonadotropins, often prejudices egg/embryo quality and IVF outcome.
Simply stated, while age is certainly the most important factor in determining the incidence of egg/embryo aneuploidy, women with diminished ovarian reserve (regardless of their age), unless they receive customized/individualized protocols of ovarian stimulation are less likely to propagate euploid (competent) eggs/embryos.
NOTHING can be done to lower the incidence of age related aneuploidy, however, it is indeed possible to avoid a further increase in egg/embryo aneuploidy by individualizing the protocols of ovarian stimulation used. In my opinion the following ovarian stimulation protocols are best avoided in women with diminished ovarian reserve:
a) Microdose agonist (e.g. Lupron) flare protocols
b) High doses of LH/hCG-containing fertility drugs such as Repronex or Menopur. c) Traditional GnRH antagonist protocols protocols
d) Clomiphene citrate or Letrozole.
3. In 2007, SIRM introduced agonist/antagonist conversion protocols (A/ACP) that optimize the number and quality of oocytes made available for IVF/ICSI and optimize IVF pregnancy rates in women with diminished ovarian reserve and in older women. 4. With the introduction of Comparative Genomic Hybridization (CGH) that for the first time permits identification of all the chromosomes in the egg and embryo we can now far better identify "competent" (euploid) embryos for selective transfer to the uterus, and thereby vastly improve the efficiency and success of the IVF process. This additional tool has better equipped us to manage cases with diminished ovarian reserve.
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10 comments:
I am 42 years old, I have just finished a protocol with 56 menopure, I had 2 folicules, doctor said they very "empty", my AMH is very low, what would your recomend me for the next time? No stimulation at all?
Thank you
No stimulation at all would be a mistake in your case, You probably need an agonist/antagonist conversion protocol (A/ACP) with estrogen priming. Read elsewhere on this blog about this protocol.
Feel free to set up a consultation by phone if you want to discuss further.
Geoff Sher
Thanks for writing this.
I did five IVF cycles, age 33-34. The first two I don't think I stimmed long enough (RE was worried about hyperstim) and had a lower number of mature eggs, but decent fert rates but then not a great number of on target embryos (but a few). Third one was antagonist and we added Menopur and had AWFUL fert rates. Fourth one went to a 'famous' clinic and was put on MDL which made no sense to me. My E2 was way too high right away (2600 on day 4 of stims with FSH) and I think the LH ruined my eggs. Only 2 out of 12 fertilized and they looked dark and grainy with fragmented polar bodies (which previous embryologist had never detected). Fifth cycle I begged for no LH to be added and the clinic relented initially, but ended up pushing for Menopur added in on day 3 of stims because my E2 was low (of course it ended up hitting near 7,000, which I knew would happen--I'm always slow). We had better maturity rates and better fert rates and more on target embryos and actually had a chemical--the further we'd ever come and the only happiness we'd ever had from IVF (getting a positive HPT was incredible.) We also did two uterine biopsies prior and an FET (of day 3 embryos) and I do think those two things significantly helped my uterine receptivity, as I have a history of borderline uterine hyperplasia. We've always done day 3 transfers.
If I had unlimited funds I'd try one more time and do NO LH until later in the stim phase because I do think we have a few good eggs in there, it's just a matter of finding them and being delicate with their stimulation. I'd repeat the biopsies too, which I think helped. But we're out of funds and it it just breaks my heart that we're at the end of our A.R.T. road and still have empty arms (and wallets!).
Now if only there were a study studying patients crazy enough to do a sixth IVF :)
I understand fully and would advise you to contact INCIID and apply for their INCIID the Heart program thatoffers free IVF to qualifying couples.
Frankly I think their could be something else afoot too...namely an implantation issue...but I agree with your opinion.
Geoff Sher
Hi, I would absolutely love your feedback as I think your article speaks to my situation... I started at 36 and am now 38. I had 6 failed IUIs, 3 failed IVFs, plus 2 frozen IVF cycles. I froze the last 2 cycles as we discovered I had immune issues. After being treated for that (LIT, NK, TNF, plus anti-ovarian antibodies which are supposedly untreatable) we actually have opted to go the route of a surrogate focusing on egg quality for now! Also as an fyi, I have produced 2 perfect and high quality embryos, 2 decent quality embryos, and 1 genetic swing - average quality embryo - out of 2 IVFs (first IVF got nothing, and #4 and 5 are frozen and untested).
My first IVF was a Lupron, Bravelle, Repronex cycle in which we only got 1 fertilized and genetically tested very poor. 2nd and 3rd IVF which were the best, I did natural antigon with Bravelle and Menapur (adding ganirelix at the end). 4th IVF (frozen) I did a microdose flare Lupron again with Bravelle and Menapur. 5th IVF (frozen) I did precycle ganirelix and estrace then did the regular Bravelle and Menapur which was my worst cycle along with IVF #1.
So it seems to me I do good on a natural antigon where we use Bravelle and Menapur with no ganirelix up front (it is used at the end to keep me from ovulating for 2 to 3 days).
At most I have about 7 antrofollicles. So I am a low ovarian reserve and I have a terribly low AMH number while my FSH has tested at a high of 14.5 and a low of 7.5.
I have been off for 4 months (last IVF 9/09) trying to line up a surrogate and we should be ready to go mid January. Though I am nervous because my periods / cycles have been weird. I am ovulating early and then my cycle starts around day 30ish. While this last month I ovulated early (day 9ish) and then my cycle started on day 25. This inconsistency makes me worry that my body is changing while I had hoped that the 4 months off would do good???
If you have any comments on the protocols, I would be amazingly greatful as I embark on my last effort to get good eggs. Seems that my sticking with Bravelle and Menpur goes against what you think my group would do well with? What should I consider looking at as a protocol???
I frankly need much more information about the exact immunologic issue being dealt with. I recognize from your post that you have been found to have autoimmune issues but did you have a natural killer cell activity (NKa) test done (i.e. the K-562 target cell test)? AND did you and your husband get an alloimmune panel done for DQa/HLA matching? THEN, how did this get treated. Did you receive IL or IVIG and if so when was the 1st dosage given.
These are important issues because if you do and your husband does not have an alloimmune "clash" with DQa/HLA matching + NKa, then you do NOT need a gestational surrogate at all.
My suspicion is that you have produced poor quality eggs and using a gestational surrogate won’t address this issue at all. It sounds as if you do have diminished ovarian reserve, in which case a "microflare protocol" is not optimal and taking high dosages of LH/hCG containing gonadotropins such as Repronex and/or Menopur won't help either.
I think you need an agonist/antagonist conversion (long) protocol wit estrogen priming (A/ACP+E2V.
Might I suggest that you read up on all these issues in this blog and that you consider talking to me about your problem? Simply call 800-780-7437 and set this up.
Geoff Sher
Thank you very much for your response. I will try to answer. I do have immune issues. I have had high TNF, high NK, and I have had the DQa/HLA issue. I have done 2 doses of IVIG and 2 intralipids (over a period of time) which very successfully brought my TNF and my NK numbers to normal after an adverse flare from doing Humira. With regards to the DQa/HLA my husband and I have done LIT twice. As of November, all of these immune factors are line with being cleared for cycle. The one that I seemingly can't change is the anti-ovarian antibodies which is the highest the immune doctor had ever seen. I am on 1mg dexamethasone for that for 2 months now and continuing until mid January with surrogate.
So we think we are dealing with potential egg quality issues along with knowing about immune issues. We have taken a different approach than many intended parents would do. We have jumped to a surrogate immediately even though it seems my immune issues are in check. At our age, we feel we don't have time to continue to try and potentally fail. If the issue is egg quality and not immune, than we will KNOW for sure and move to an egg donor on try 3. If it is not, then we will have a child. There is logic in there just different!
So my last protocol I was on estrace and ganirelix before the cycle started, then went to the bravelle and menapur after my cycle started. I will look into this and see if this is what you are talking about. The last cycle did not go well. I will also have to check on what "high doses" means. I know I have taken 3 Bravelle and 1 Menapur vials morning and night (= 6+2 total for day) but I don't have any more to look at actual dosage.
Again, thanks so much!!! I will look more into this and read more of your blog.
I think you have made a wise decision with regard to using a gestational surrogate, given the combined autoimmune +alloimmune components operative here.
However, I respectfully submit that you would be far better off without a microflare protocol and/or a heavy dosage of LH-containing medications (see my article .."An Individualized aproach to ovarian stimulation ..." elsewhere on this blog. I further think that you would do best on an agonist/antagonist conversion (long) protocol with estrogen priming (see the relevant article on this protocol, esewhere on this blog).
Good luck!
Geoff Sher
Hi. I am 32 and I have recently been told that I have low ovarian reserve and that I have "eggs of a 46 year old" I realize this is an issue with the quantity of the eggs I have left. Does this also affect the quality? How much does this increase my chances of having a child with a chromosonal disorder/special needs?
It affects accessibility to eggs but with optimal stimulation it should not affect egg quality. See the article on this blod on an individualized aproach to ovarian stimulation for IVF. The one caviat is that it is much more difficult to achieve optimal ovarian stimulation in women with diminished ovarian reserve.
Give me a call at 702-892-9696 and we can discuss your situation indepth.
Geoff Sher
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