My IVF Cycle Failed – What Went Wrong? Question #8: Was the Timing, Dosage and Type of hCG “Trigger” Optimal?
Why did my IVF cycle fail?
This is the 8th in a series of answers to common questions about failed IVF.
The precise timing to administer the hCG “trigger” that will launch a cycle of controlled ovarian stimulation (COS) for both IVF and non-IVF cycles is very important. If mis-timed by even one day, it can compromise egg/embryo quality and lead to IVF failure.
Those of us who have been in this field for some time will recall how (prior to the introduction of “prolonged coasting”), we would often administer hCG prematurely (i.e. prior to optimal follicle development) in an attempt to reduce the risk of life-endangering severe ovarian hyperstimulation syndrome (OHSS). This was done in a deliberate attempt to cut the cycle short, and more often than not we would end up with poor quality eggs/embryos and a failed IVF cycle. Many of us in years past also attempted to force the development of larger follicles in “poor responders” by delaying the hCG trigger shot, which also frequently netted poor quality eggs/embryos and failed IVF cycles.
Yes, indeed when it comes to the hCG trigger shot, timing is critical! However, knowing precisely when to give it requires both a high level of experience and a great deal of finesse! And, while there are certainly guidelines that are helpful in determining such timing (follicle size, blood estradiol level and number of days of ovarian stimulation, these are often inexact. The decision thus requires a clinical judgment call which is part of the essential “art” aspect of reproductive medicine, rather than the science. This article outlines some important roles of hCG both in terms of triggering ovulation and in the nurturing of early pregnancy.
Human chorionic gonadotropin (hCG) is a hormone produced by the cells that envelop the “root system” (trophoblast) of the early embryo. It reaches the mother’s circulatory system in a sufficient amount to be detectable in her blood within 5-7 days of implantation. Thereafter, hCG blood concentrations tend to double every 48 hours for several weeks, whereupon the levels rise more slowly throughout pregnancy. hCG reaches the urine in sufficient amounts to be detectable by most urine pregnancy tests about 10-12 days following implantation (about 14-16 days after ovulation).
The Role of hCG in Ovarian Stimulation and in the Ensuing Pregnancy
Maturing the egg in preparation for ovulation: As a prelude to ovulation which usually occurs within 38-42 hours of the intramuscular administration of a dose of hCG (usually 10,000U) to women who have undergone controlled ovarian stimulation (COS), the egg begins a process known as meiosis (also known as reduction division or maturational division). Here, the egg, which to this point contains 46 chromosomes (23 pairs aligned in a spiral arrangement) sets out to halve its number of chromosomes from 46 to 23. The meiotic process is usually completed within 28-24 hours. Survival of the human species is totally dependent on the orderly occurrence of meiosis so that subsequent fertilization of the mature egg by a mature spermatozoon (which has also undergone meiosis to halve its number of 23 chromosomes) will result in the propagation of a chromosomally normal embryo (euploid embryo) with precisely 46 chromosomes (the normal human genomic make-up).
An egg that, following meiosis, ends up with an irregular quota of chromosomes is incapable of propagating an embryo with a regular number of 46 chromosomes. In this regard, it is important to recognize that it is the egg, rather than the sperm that plays the dominant role. An embryo that has more or less than 46 chromosomes is aneuploid (“incompetent”) and incapable of propagating a healthy pregnancy. It will not divide or implant properly, resulting in a failed pregnancy or miscarriage and in some cases, the birth of an aneuploid baby (e.g. Down syndrome).
Unfortunately, aneuploidy of human eggs/embryos is quite common. In fact, even in young women, only about two in five mature eggs will have a regular number of chromosomes (23), and the incidence of aneuploidy increases rapidly with advancing age. By the mid-forties, more than nine-in-ten are aneuploid, which serves to explain why the incidence of infertility, pregnancy loss/miscarriage, and Down syndrome all increase with advancing age of the egg provider. When only one or two of the 23 chromosome pairs of the embryo have an extra or missing copy, the condition is referred to as “simple aneuploidy,” whereas when three or more chromosome pairs are involved, we term it “complex aneuploidy” (see later).
Ensuring hormonal support for the early pregnancy:
During the immediate post-implantation period and during very early stages of pregnancy, hCG ensures survival of the ovarian corpus luteum, which produces progesterone and estrogen to sustain the implanting pregnancy. This indispensable role of hCG continues up until about the 7th-8th week of pregnancy. In fact were the corpus luteum to die prior to this stage, the pregnancy would almost certainly die. However, after the 8th week, placental development has reached the stage where ovarian hormone production is no longer indispensable to the survival of the pregnancy, and even removal of both ovaries would not likely lead to pregnancy loss.
The immunologic role of hCG, hCG Also plays a crucial role in promoting and modulating the immune acceptance of the fetal allograft (the implanting embryo). This function is most pronounced during early implantation but continues and protects placental growth and development throughout gestation.
Preparing the follicle for ovulation:
As is the case with the LH surge, hCG, among other things, signals the well-developed egg to alert the cumulus cells that bind it to the inner wall of the follicle to release enzymes that will cause these cells to segregate or disperse, allowing the egg to become very loosely attached to the lining of the follicle. Thereupon, through a combination of pressure changes in the fluid of the follicle and erosion of the follicle wall, the egg is extruded and released (ovulation has occurred).
What is not often well appreciated is that in order for the egg to interact properly with surrounding cumulus cells, it must have the required genetic ability. It so happens that severely (complex) aneuploid eggs often lack this ability, causing the cell dispersion mechanism to fail, and resulting in the egg being retained within the follicle. Such eggs will often fail to be retrieved during needle aspiration with IVF. In such cases, the patient is often led to believe that her follicle(s) was/were “empty”. Since no follicle can develop unless there is an egg to “direct” the process, this is a misleading conclusion. This is unfortunately sometimes still referred to as “empty follicle syndrome”. In such cases the unfortunate patient often reaches the erroneous conclusion that she had no eggs in the first place when the failure to harvest eggs might instead have been due to other factors that lead to complex egg aneuploidy, such as advanced age and/or a suboptimal protocol for ovarian stimulation.
The precise timing of administering the hCG trigger following COS is indeed critical. If the hCG injection is administered too early (prior to optimal follicle/egg development) or too late (when the egg is “over-developed) it is far more likely to result in disorderly meiosis and egg/embryo aneuploidy. Such an aneuploid egg, especially if it is complex aneuploid, might not come free at egg retrieval, it may not fertilize, or will result in an incompetent embryo.
What type of hCG should be used, and what about using an agonist “trigger” instead:
Then there is the issue of the type of hCG administered (urinary derived [Profasi, Pregnyl, Novarel] or recombinant DNA-derived hCG [Ovidrel]), whether the dosage of hCG should be lowered in cases of threatening OHSS, and/or whether hCG should be supplanted by the administration of an agonist (Lupron) – which by triggering in the body’s own pituitary LH is thought to potentially lower the risk of OHSS.
First, there is no advantage in giving Ovidrel instead of urinary-derived hCG. Furthermore, in my opinion, at the recommended dosage, Ovidrel has a much lower biopotency (and is less effective) than 10,000U of urinary-derived hCG. It is also much more expensive. If Ovidrel is to be used to “trigger” ovulation, I believe that it should be prescribed at double the recommended dosage.
Second, in my opinion, administering urinary hCG at a reduced dosage from the usual 10,000U to lower the risk of OHSS in hyperstimulated women, will often result in an inadequate biological response, a low percentage of follicles that will yield eggs, and poorer quality eggs/embryos.
Third, initiating an LH surge with an agonist can be effective if used selectively since women who have had their pituitary reserves depleted by prior administration of an agonist during COS might not have enough left in reserve to surge after the agonist “trigger.” Besides, there is currently no consensus that doing so will lower the risk of OHSS.