Disadvantages of Leuprolide Trigger Shot

Traditionally, IVF egg retrievals are timed for about 36 hours after a 10,000U hCG “trigger”. The hCG hormone thereupon remains in the system for up to a week. When patients who overstimulate following ovarian stimulation experience prolonged exposure to hCG have a risk of developing severe ovarian hyperstimulation syndrome (OHSS), with its incumbent life-endangering complications.

Ways to Reduce the Risk of OHSS

Attempts to mitigate this risk have included:

  1. Withholding the hCG trigger altogether thereby preventing luteinization of follicle granulosa cells and preventing the production of vasoactive substances (e.g. VEGF) which when overproduced escalate the risk/severity of OHSS,
  2. Prematurely administering the hCG trigger to arrest further follicular growth and escalation in blood estradiol levels,
  3. Reducing the dosage of hCG by half to 5,000U in the hope of limiting/restricting the luteinization process and,
  4. Supplanting the “hCG trigger’ by a Leuprolide (e.g. Lupron) trigger” that causes promotes meiotic egg maturation buy causing a surge in the release of pituitary LH.

All of the options above do indeed reduce the risk of developing OHSS. The first completely prevents egg maturation from occurring and thus virtually precludes the harvesting of “competent” eggs, while numbers two through four all adversely affect egg “competency” to a degree, thereby compromising both embryo quality and IVF outcome.

Advantages of Leuprolide Trigger Shot

Use of the Leuprolide trigger shot bears further mention: Since its recent introduction, this approach has really gained popularity and caught on in a big way. In truth, there can be little argument that it markedly reduces the incidence, severity and risk of complications associated with severe ovarian hyperstimulation. However, use of the “Lupron trigger” often comes at the expense of egg/embryo quality as well as IVF outcome. Thus, the question arises as to whether this approach is advisable, and if not, what the best alternative to its use would be. The reason why the “Lupron trigger” is in my opinion ill-advised, is that in cases of ovarian hyperstimulation, where there are numerous follicles with eggs that need to undergo meiosis following the “trigger”, the magnitude of the LH surge, induced by a “Lupron GnRHa trigger” is often insufficient. This can result in suboptimal egg maturation (meiosis), leading to the generation of an inordinate number of immature/dysmature eggs as well as in an increase in the number of large follicles that fail to yield eggs at all (so-called “empty follicles”). For this reason, I do not employ the “Lupron trigger” approach in my practice, preferring instead to use the long pituitary down-regulation, along with “prolonged coasting” in women who are deemed to be at risk for developing OHSS. My position is further supported by a recent publication showing that for this very reason, the use of a GnRHa-induced “trigger is not helpful. In this case, Prolonged Coasting is my preferred choice.

Prolonged Coasting Protocol

My approach is consistently to have my patients who are at risk of developing OHSS, launch their ovarian stimulation, coming off a monophasic birth control pill (BCP).

  • Initiating Stimulation: The last few days on the BCP is accompanied by the addition of Leuprolide or Lupron. Thereupon the BCP is stopped and Lupron therapy is continued.
  • Dosage Adjustment:  After 3-7 days menstruation usually ensues, at which point the dosage of Lupron is reduced and low dosage FSHr (Follistim/Gonal-F/Puregon) dominant ovarian stimulation is commenced. Lupron and gonadotropins are then continued together. This approach is referred to as the “Long Pituitary Down-regulation protocol.” Use of the BCP is intended to lower LH and thereby reduce stromal activation (hyperthecosis) in the hope of controlling ovarian androgen (mainly testosterone) release (too much ovarian testosterone is harmful to egg development).
  • Monitoring and Adjustment: Seventy-five (75) units of LH/hCG (Luveris/Menopur) are added from the 3rd day of gonadotropin stimulation.
  • Coasting Criteria: Starting on the 7th day of ovarian stimulation with gonadotropins, I start watching daily for the number and size of follicles developing and for the rise in blood [E2]. If there are > 25 follicles, the patient becomes a candidate for “prolonged coasting,” at which point I keep stimulating with gonadotropins (regardless of the [E2]) until a) 50% of all follicles reach 14mm and b) the [E2] reaches 2500pg/ml. At that point, gonadotropin stimulation is discontinued abruptly while daily Leuprolide trigger shots continue. Thereupon, I follow the daily blood [E2] without doing further US examinations. The [E2] will almost invariably continue to rise. I carefully plot the rise in [E2] (regardless of how high it goes). Usually, within 1-3 days it will plateau and then start to decline.
  • Timing and Retrieval: As soon as the [E2] drops below 2500pg/ml (and not before then), I administer the 10,000U hCGu (Novarel/Pregnyl/Profasi) “trigger” or 500mcg of hCGr (Ovidrel) and then schedule an egg retrieval for 36h later. ICSI is a MUST because “coasted” eggs usually have few or no surrounding cumulus cells and eggs without a cumulus layer will not readily fertilize on their own. All fertilized eggs are cultured to the blastocyst (up to 6 days) whereupon I transfer up to two into the uterus, or vitrify all expanded blastocysts for subsequent dispensation at the directive of the patient. In some cases, the embryos are biopsied for PGS testing prior to being cryostored. Subsequent frozen embryo transfers are conducted as per the wishes of the patients.

It is important to point out that the success of this “prolonged coasting” approach depends on precise timing of the initiation and the 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 might encounter is mild to moderate OHSS, and this too is uncommon. The use of an agonist or GNRH trigger, while reducing the risk of severe OHSS developing, comes at the expense of egg/embryo quality and could compromise IVF outcome.