The IVF “Trigger” Shot: An Important Determinant of Egg Quality

22 Apr
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The egg goes through maturational division (meiosis) during the 36 hour period that precedes ovulation or retrieval. The efficiency of this process will determine the outcome of reproduction. It follows that when it comes to ovulation induction, aside from selecting a suitable protocol for ovarian stimulation, one of the most important decisions the clinician has to make involves choosing and implementing with logic and precision, the “trigger shot” by which to facilitate meiosis.

Here’s how it works: In Ovarian stimulation cycles for IVF, egg development takes place during gonadotropin stimulation. Then, about 36 hours prior to egg retrieval, a “trigger” shot is given. This trigger shot comprises one of three medications: a) urinary-derived hCG (hCGu), e.g., Novarel, Pregnyl and Profasi, b) Recombinant hCG (hCGr), e.g., Ovidrel, or c) an agonist such as Lupron, which upon being injected provokes a surge in the release of pituitary gland-derived, LH) is initiated.

The effect of the “trigger shot” is to send eggs into a reproductive division known as meiosis where the objective end point is a decrease in the number of chromosomes in the egg from 46 to 23 (half) prior to ovulation or egg retrieval. In the process, approximately half of the chromosomes are expelled from the egg nucleus in a membranous envelopment. This so called first polar body comes to lie immediately under the envelopment of the egg (the zona pellucida) in a region known as the perivitelline space where it can be observed microscopically once the cells surrounding the egg are removed microsurgically (or erode away on their own).

While the microscopic visualization of this polar body confirms that the egg is “mature” (i.e., has gone through meiosis), it by no means provides assurance that there are precisely 23 chromosomes (half the original number) remaining in the nucleus. Without there being precisely 23 chromosomes remaining in the nucleus, that egg, upon being fertilized by a sperm (which after also going through meiosis has 23 chromosomes), will be unable to propagate a euploid embryo (one that has 46 chromosomes). An embryo with an irregular quota of chromosomes (more or less than 46) is aneuploid or “incompetent” and is incapable of propagating a healthy baby.

Meiosis, which takes place in the egg following the trigger shot, is thus indispensable to the normal reproductive process. It follows that since the method, dosage and timing of the trigger shot can profoundly affect the efficiency of meiosis and the potential to yield “euploid” mature eggs, it represents a rate-limiting step in ovulation induction in general and IVF in specific.

Urinary versus recombinant hCG: Until quite recently, the standard method used to initiate the “trigger shot” was through the administration of 10,000 units of hCGu. More recently, a recombinant form of hCG (Ovidrel) was introduced and marketed in 250 mcg doses. But clinical experience strongly suggests that 250 mcg of Ovidrel is most likely not equivalent in biological potency to 10,000 units of hCG. It probably only has 50%-70%of the potency of a 10,000U dose of hCGu and as such might not be sufficient to fully promote meiosis, especially in cases where the woman has numerous follicles. For this reason, I firmly believe that when hCGr is selected as the “trigger shot” the dosage should best be doubled to 500 mcg, at which dosage it will probably have an equivalent effect on promoting meiosis as would 10,000 units of hCGu. Having said this, it is my personal opinion that it is unnecessary to supplant hCGu with hCGr since the latter is considerably more expensive and is probably no more biopotent than the former.

The dosage of hCG used: Some clinicians, when faced with a risk of OHSS developing will deliberately elect to reduce the dosage of hCG administered as a trigger in the hope that by doing so, the risk of developing critical OHSS will be lowered. It is my opinion that such an approach is not optimal because a low dose of hCG (e.g., 5000 units hCGu or 25omcg hCGr) is likely inadequate to optimize the efficiency of meiosis, particularly when it comes to cases such as this where there are numerous follicles.

Use of hCG versus an agonist (e.g., Lupron) as the trigger shot: It has been suggested that the use of an “agonist ( Lupron) trigger” in women at risk of developing severe ovarian hyperstimulation syndrome could potentially reduce the risk of the condition becoming critical and thereby placing the woman at risk of developing life-endangering complications. It is for this reason that many RE’s prefer to trigger meiosis in this way rather than through the use of hCG. The agonist promptly causes the woman’s pituitary gland to expunge a large amount of LH over a short period of time and it is this LH “surge” that triggers meiosis. The problem with this approach, in my opinion, is that it is hard to predict how much LH will be released in by the pituitary gland of a given patient receiving an agonist trigger shot, especially if the woman was down-regulated using an agonist, or in cases where an antagonist was used to block pituitary LH release. For this reason, I personally prefer to use hCGu for the trigger, even in cases of ovarian hyperstimulation, with one important proviso…that she underwent “prolonged coasting” in order to reduce the risk of critical OHSS prior to the 10,000 unit hCGu “trigger”.

The timing of the trigger shot to initiate meiosis: This should coincide with the majority of ovarian follicles being >15 mm in mean diameter with several follicles having reached 18-22 mm. Follicles of larger than 22 mm will usually harbor overdeveloped eggs which in turn will usually fail to produce good quality eggs. Conversely, follicles less than 15 mm will usually harbor underdeveloped eggs that are more likely to be aneuploid and incompetent following the trigger.

The protocol selected for ovarian stimulation is undoubtedly one of the most important aspects of IVF because optimal egg maturation is predicated upon prior egg development. Unless follicles and eggs are allowed to develop optimally, no trigger shot will by itself be capable of yielding good quality eggs.

28 Comments

  • Kelly says:

    Hello Dr. Sher,
    I’m very curious about the effects of trigger choice on ultimate egg quality. Thank you for your post above. I just completed round 4 of IVF, and depending on how this goes, might need to try again. I have DOR (lowest AMH of 0.25, highest day 3 FSH of 29), so knowing that I won’t be able to make as many follicles / eggs as other women, the quality side becomes extra critical. My 4 rounds have resulted in the following outcomes:
    – round 1 (single Ovidrel trigger): 7 follicles, 7 eggs, 6 mature, 5 fertilized, 1 blast frozen (not PGS tested)
    – round 2 (double Ovidrel trigger): 2 follicles, 2 eggs, 1 mature, 0 blasts
    – round 3 (double Ovidrel trigger): 4 follicles, 2 eggs, 2 mature, 1 blast (PGS – Turners Syndrome)
    – round 4 (double Ovidrel + Lupron triggers 12h apart): 5 follicles, 4 eggs, 4 mature, waiting on results now…

    My RE explained that the Ovidrel + Lupron trigger was to try to hit the maturity of the eggs from both angles…have you heard of this and/or do you agree? My biggest frustration is that we are able to produce follicles and mature eggs, but can’t seem to get many blasts to succeed to freeze / bank / PGS test. It feels like this final step might be impacting our final blast numbers…i.e we are producing mature eggs, but maybe not euploid mature eggs?

    I would love and appreciate your thoughts on this!

    Many thanks,
    Kelly (Houston, TX)

    • Geoffrey Sher says:

      My website has changed. The new site is at http://www.sherIVF.com where I host and populate new and updated blog articles . The blog can also be accessed directly by going to http://goo.gl/4hvjoP. I now only respond to posts on this new site.

      To find and follow updated and new blog articles and to post questions or comments, please use this new venue. I promise to respond promptly.

      In the interim, please re-post this question or comment on my new website-blog.

      Geoff Sher

  • Jaclyn says:

    Dr. Sherr,

    I am 37 years old and about to begin my second round of IVF. I am a carrier of Fragile X (78 repeat on one X chromosome), so I am primarily doing IVF for testing purposes. I previously got pregnant and miscarried after trying for 4 months.

    My first round of IVF I had 19 eggs retrieved, 14 mature, 10 fertilized. I only got 2 blastocysts and both came back with poor results from PGS/PGD. I was most disappointed by my blast rate (10 fertilized to only 2 blasts). A Lupron trigger was used the first time. This time the doctor is proposing HCG trigger. I am also using Gonal F (instead of Bravelle) this time. I am doing a frozen transfer due to testing, and last time my levels were at 3000 before the trigger (so my risk of hyperstimulation was not outrageous).

    Do you think things would have been different if I used the HCG? My doctor seems to say no. I consulting with another doctor in the area and she said I was the 6th patient she had seen this month alone with the same story from the same clinic (Lupron trigger). She believed Lupron was not the right choice, and it would have made a difference.

    • Geoffrey Sher says:

      I respectfully disagree with your doctor. In my opinion, while a Lupron trigger protects most women with overstimulation from getting OHSS, this comes at the cost of egg quality.The reason is that the magnitude of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the risk of egg aneuploidy.

      Down-reguWhen it comes to stimulating high-responders, my approach is consistently to use a long pituitary DR protocol with an agonist, coming off 1-2 months on the BCP. The latter is intended to lower LH and thereby reduce stromal activation (hyperthecosis) in the hope of controlling ovarian androgen release. I then stimulate with low dosage FSHr to which I add a smidgeon of LH/hCG (Luveris/Menopur) from the 3rd day and watch for the # of follicles and [E2] starting on the 7th day of COS. If there are > 25 follicles, I keep stimulating (regardless of the [E2] until 50% of all follicles reach 14mm. Then, provided the [E2] is >2500pg/ml, I stop the agonist and the gonadotropin stimulation and follow the E2 (only) daily, without doing further US examinations. The [E2] will almost invariably climb and I watch it go up (regardless of how high the concentration of E2reaches) and track it coming down again. As soon as the [E2] drops below 2500pg/ml (and not before then ever), I administer 10,000U hCGu or hCGf (Ovidrel/Ovitrel-500mcg) as the “trigger” and perform an egg retrieval 36h later. ICSI is a MUST because “coasted” eggs usually have no cumulus oophoris and eggs without a cumulus will not readily fertilize on their own. All fertilized eggs are cultured to blastocyst (up to 6 days). And up to two (2) are transferred transvaginally under US guidance.

      The success of this approach depends on precise timing of the initiation and conclusion of “prolonged coasting”. If you start too early, follicle growth will stop and the cycle will be lost. If you start too late, you will encounter too many post-mature/cystic follicles (>22mm) that usually harbor abnormally developed eggs.

      Use of the above approach avoids unnecessary cycle cancellation, severe OHSS, and optimizes egg/embryo quality. The worst you will encounter is mild to moderate OHSS and this too is uncommon.

      Please go to the home page of 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 for IVF: The most important determinant of IVF Outcome” (Nov. 2103)

      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 “ (Parts 1 & 2 (posted March, 2012)

      6. “IVF success: Factors that influence outcome”

      7. “Use of the Birth Control Pill in IVF”

      Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization: The ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

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