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Egg/Embryo Quality: A Critical Consideration in IVF (Part 2)

Dr. Geoffrey Sher Recommends

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My last post discussed age related factors that affect egg/embryo quality. This post will discuss the other half of the egg/embryo quality equation – the contribution of the woman’s IVF stimulation protocol to egg/embryo quality. The importance of this factor seems to be commonly misunderstood or discounted by some IVF practitioners. They’re approach is to treat patients who are at risk of ending up with eggs/embryos of poor quality using a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COH protocols can greatly improve IVF outcome in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).

While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COH to meet the individual needs of the patient.

During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.

However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian hyperstimulation (COH) should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COH with fertility drugs as well as the precise timing of the “trigger shot” of hCG.

It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce androgens (e.g; testosterone). Only a small amount of testosterone is necessary for optimal estrogen production. Over-production has a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.

In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Folistim, Puregon, Bravelle and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COH, this appears to be more vital in older women, who tend to be more sensitive to LH

It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COH. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.

The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily lupron injections continue, to ensure an “LH-free” environment.

Lupron Flare/Micro-Flare Protocols

Another approach to COH is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron). The intent is to deliberately allow lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” represents “a double edged sword” because while it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially in older women, and in women with diminished ovarian reserve . Accordingly, I do not prescribe them at all.

Estrogen Priming – The SIRM Approach for “Poor Responders”

Our patients who have demonstrated reduced ovarian response to COH as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The aproach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COH is thereupon initiated using a relatively high dosage of FSH-(Folistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “HCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.

Polycystic Ovarian Syndrome and Ovarian Hyperstimulation Syndrome

Women with PCOS who undergo IVF are highly sensitive to gonadotropins and are at risk of developing severe ovarian hyperstimulation syndrome (OHSS). For the reasons cited above, they are also more likely than others to produce poor quality eggs/embryos which, they are often led to believe is attributable to an intrinsic egg defect that is characteristic of their PCOS condition. This is not necessarily so. The most likely reason as to why many women with PCOS develop an excessive number of follicles and then go on to produce poor quality eggs/embryos has to do with the fact that, in an attempt to contain reduce the risk of OHSS they are often administered HCG prematurely – prior to the attainment of optimal egg maturation.

In the early nineties, we introduced “Prolonged Coasting”, a procedure which eliminates the risk of OHSS while allowing the hCG trigger to be deferred for long enough as to allow for optimal follicle/egg maturation to take place. Coasting involves withholding gonadotropin therapy while the administration of GnRH agonist/antagonist is continued. The daily measurement of blood estradiol is continued until the concentration drops below a safe threshold level, at which time HCG is administered (regardless of the number of follicles). When appropriately implemented “coasting” results in the production of good quality eggs/embryos, in circumstances where this might otherwise not have been possible.

The potential of a woman’s eggs to develop into “good quality embryos” following fertilization is largely genetically determined. However, the ultimate ability to optimally express such potential is dependent upon the highly orchestrated interaction of many complex intra-ovarian hormonal events. “Super physiologic” stimulation with exogenous gonadotropins, or COH, by precipitating growth and development of multiple follicles at a time and activating excessive ovarian androgen hormone production can play havoc with this harmonious interplay. This exaggerated induced ovarian hormonal response is capable of compromising the ability of the eggs to optimally express their intrinsic developmental potential. Proper preparation, coupled with an individualized approach to COH protocol selection, would go a long way toward limiting such excesses, promote orderly growth and maturation of multiple mature ovarian follicles (most of which would harbor mature, “good quality eggs”), while at the same time avoiding the development of OHSS.

Tags: Controlled Ovarian Hyperstimulation, egg quality, embryo quality, estrogen priming, IVF Authority, Lupron Flare, Micro Flare, Polycystic Ovarian Syndrome, Polycystic ovary syndrome (PCOS)

10 Responses to “Egg/Embryo Quality: A Critical Consideration in IVF (Part 2)”

Christine says:

December 7, 2012 at 12:19 pm

At 43, I ‘passed’ the Clomid Challenge Test and began an aggressive stimulation protocol with lupron, menopur, and gonal-F. It took me 15 days to get to retrieval, rather than the ‘standard’ 8 – 11. The result was 4 mature eggs but none fertilized! Hubby sperm is not the culprit — the eggs wouldn’t bind. I still haven’t debriefed with my RE yet.

My question is whether or not ICSI will work in my situation. I think from the stats I’ve read, my chances wouldn’t have been better with ICSI.

So that leaves two other possibilities: 1) change the drug protocol or 2) call it quits (we aren’t doing the donor egg route).

I just can’t tell if changes to the drug protocol will alter my situation for the better. For what it is worth, I conceived naturally at age 40 and have one child.

Reply
- Geoffrey Sher says:
  
  December 7, 2012 at 2:35 pm
  
  We need to talk. This is likely a protocol issue that needs to be individualized for DOR.
  
  Please go to http://www.IVFauthority.com and when you get to the home page find the “search bar” in the right hand column. Type in the following subjects into the bar and it will take you to all the relevant articles I posted there.
  
   “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
   “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
   “Agonist/Antagonist Conversion Protocol”
   “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
   “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
   “IVF success: Factors that influence outcome”
   “Staggered IVF”
   “Embryo Banking”
   “Egg Donation”
  
  Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada). While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
  
  Geoff Sher
  
  Reply
  - Christine says:
    
    December 11, 2012 at 7:08 am
    
    I have to say your customer service is unparallelled from what I’ve seen from IVF clinics so far. I have read several of the articles already and will continue to educate myself. Thanks for being such a thorough resource.
    
    I will call to set up a skype conversation.
    
    Reply
    - Geoffrey Sher says:
      
      December 11, 2012 at 9:26 pm
      
      Thank you Christine! I hope I can help.
      
      Geoff Sher
      
      Reply
Kristine says:

January 2, 2013 at 10:40 am

I have had 3 failed IVF cycles, and now I don’t know what to do. My last cycle I was on Follistim, Menopur, and had my retrieval 15 days after I started the stim meds. I do not produce very many mature eggs (7 at most). I have transferred 3 embryos each time, always fragmented.

I will be reading the posts you recommended above to Christine, but I’m curious if you think I should have some further testing done. I am 32 years old. I have a son already, via IUI 4 years ago. I haven’t been diagnosed with any fertility issues.

We only have enough sperm left to do IVF (my husband had cancer), and will only have the finances to do two more IVF cycles. I don’t want to give up, but its hard not to after 3 IVF failures.

Reply
Yvonne says:

February 28, 2013 at 5:07 am

Hi, I am 41 and have just finished my first round of IVF with no success. Prior to this I tried IUI. My protocol for the IVF cycle consisted of Lupron, Menopure, Gonal F, and then the HCG injection. My doctor thought I had a great cycle from the retrieval because they extracted 19 follicles. However, of the 19, 11 looked healthy, and of the 11, 7 fertilized and by the time they did the transfer on day 3 I had 4 left. Of the 4, 3 were grade 1 quality, and 1 was grade 2 quality. My hysteroscopy and annual PAP didn’t reveal any issues to be concerned with. I am also doing this without a partner so I am using frozen donor sperm, but the donor has had several successful births.
I reviewed the cycle with my doctor yesterday. He said that he was very frustrated because he thought that I should have had success. He feels the issue is poor egg quality. He said the 3 key factors he really looks at are FSH levels, and AMH levels were that of a 30 year old, if that has an relevance, but my age and the egg quality is the issue. He said the rapid drop off from the 19 to 4 was an indicator. He said in a good cycle you have about 80% to 85% that fertilize or are left.
My concern is 2 fold. First and foremost is the cost and expense related to these cycles and treatment. I am not rich by any means ( and I know the other people seeking this solution have made serious financial commitments to this process), single, and if it were not for the fact that my health insurance is covering most of the expense this probably would not even be an option for me. My second concern is the fact that my doctor seems to think a donor egg is the solution when I really would prefer to have a child from my own blood line. He said that for him it is not an issue that I could not get pregnant and carry the baby; the issue is the quality of my eggs. He said that he believes I have a 60% chance of pregnancy with a donor egg. But donor eggs run from $15,000 to $40,000 depending if fresh or frozen.
I read your article and really started to feel like there may be some hope for me in this process and the fact that you were so willing to reach out the Christine as so refreshing. Do you think that the protocol needs to be tweaked from an individual perspective? Right now I am feeling that I got the standard cocktail treatment.

Reply
- Geoffrey Sher says:
  
  February 28, 2013 at 7:31 am
  
  I agree that this was an egg/embryo issue. However, there are two possible interacting variables here. The one is the inevitability of age impacting on egg chromosomal integrity”. At your age, only about one in 8 eggs will chromosomally normal (euploid). The second (an the one we CAN influence) is the protocol used for ovarian stimulation. When I say that we can influence i, am implying that if the wrong protocol is inadvertently applied, or the timing, dosage and type of hCG given is suboptimal, then the likelihood of normal eggs declines significantly (and you will not necessarily know this from the microscopic appearance of the eggs or embryos. Finally, I am NOT in favor of day 3 transfers because we know that embryos that fail to reach blastocyst by day 5-6 are chromosomally abnormal/aneuploid (“incompetent”) and not worthy of transferring, anyway.
  
  The fact that you respond so well and make many eggs, tells me that provided the ideal stimulation is used and you select embryos based on their chromosomal integrity, for transfer, you can do this with your own eggs. I understand that you have economic constraints, but the cost relates to having a baby and OT to the cost of an IVF procedure. You ideally need “staggered IVF” with “Embryo Banking”….see below. P
  
  Please go to the home page of this blog, (www.IVFauthority.com). When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
  
  1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
  
  2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
  
  3. “Agonist/Antagonist Conversion Protocol”
  
  4.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  5. “IVF success: Factors that influence outcome”
  
  6. “Staggered IVF”
  
  7.“Embryo Banking”
  
  8. “Egg Donation”
  
  Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.. While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.
  
  Geoff Sher
  
  Reply
globetrottermd says:

March 10, 2013 at 9:40 am

I’ve done multiple cycles of IVF. On antagonist protocol, had only 3-4 eggs; converted to IUI on one cycle. Then did microlupron flare; e2 to 5000 but only 5 eggs, 4 fertilized. frozen eggs did not thaw well. Changed practices, had a microflare protocol with fsh/menopur, overall half the dose, got 9 eggs, 8 fertilized, 3 4-6 cell on day 3 and one blast; none implanted. Did another cycle with similar protocol, had 17 follicles (16 on one ovary, other ovary very sluggish) and only 8 fertilized,4 frozen at day 3 due to poor quality. 4 thawed, but only one looked really good at 4 cell grade 1, others had more cells but fragmented. E2 was very high 7500+ so fresh transfer not attempted. All confused at the very variable response. Only change was prior to 3rd cycle, Testosterone ws 125, started metformin about 3 weeks prior. Eventually testosterone down to 12

Reply
- Geoffrey Sher says:
  
  March 10, 2013 at 3:22 pm
  
  Clearly this has something to do with the protocol for ovarian stimulation. I might be able to help here. So, consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.
  
  In thew meanwhile, I suggest that you to the home page of this blog at http://www.IVFauthority.com . When you get to home page, look for a “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
  
  1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
  
  2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
  
  3. “Agonist/Antagonist Conversion Protocol”
  
  4. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
  
  5.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
  
  6. “IVF success: Factors that influence outcome”
  
  Geoff Sher
  
  Reply
- Geoffrey Sher says:
  
  March 12, 2013 at 12:38 pm
  
  Answered above!
  
  Geoff Sher
  
  Reply

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My IVF Cycle Failed – What Went Wrong? Question #12: Might the Timing of Embryo Transfer – Day 2-3 (Cleaved) vs. Day 5-6 (Blastocyst) Play a Role?

This is the 12th in a series of answers to common questions about failed IVF. (Note: I’ll be hosting a live video chat on Aug. 2 on the topic of Failed IVF where I’ll discuss the issues addressed in this series of posts and take your ques... more

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