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