The use of GnRH antagonists, as currently prescribed in ovarian stimulation cycles, i.e. the administration of 250mcg daily from the 6or 7th day of stimulation with gonadotropins, is in my opinion problematic when used in women who have diminished ovarian reserve (DOR) (i.e. are “poor responders” to gonadotropins),. In such cases the commencement of pituitary LH suppression with GnRH antagonists 6-7 days into the stimulation fails to suppress high tonic pituitary LH in the first few days of stimulation and it is at this time , formative (early) stage of follicle/egg development early on in the most the vulnerable stage. One of the roles of LH is to promote androgen (mail hormone) production which in turn is essential (in modest amounts) for optimal follicular growth to take place. In women with high LH and/or ovarian stromal hyperplasia, the failure of conventional GnRH antagonist protocols to address this issue, results in the inevitable excessive exposure of follicles to androgens (mainly testosterone). This can adversely influence egg/embryo quality and endometrial development.
The likely reason for the traditional approach of commencing GnRH- antagonist 6-7 days after stimulation with gonadotropins commences, is to try to block the release of LH (later in the cycle) so as to try to prevent the occurrence of the so called “premature LH surge” (syn; premature luteinization), which is most commonly seen in women with DOR, who tend to be susceptible to LH-induced “follicular exhaustion” resulting in poor egg/embryo quality. But if truth be known, the term “premature LH surge” is a misnomer. Contrary to popular belief, the concept of LH rising as a “terminal event” late in the cycle is erroneous. In fact, rather than representing an isolated event, the so called “premature LH surge” is the end point of a progressive escalation in LH (“a staircase effect”) which results in increasing ovarian stromal activation with commensurate growing androgen (mainly testosterone) production. A more appropriate term would be ”Premature Luteinization.” So, trying to improve ovarian response and protect follicular exhaustion by administering Ganirelix/Cetrotide/Orgalutron starting during the final few days of ovarian stimulation is like trying to prevent a shipwreck by collision, through removing the tip of an iceberg. The use of such late GnRH-antagonist protocols in women who have a normal ovarian reserve (i.e. are “good responders”) will probably not produce such adverse effects because the tonic endogenous LH levels are low (normal) and such women are unlikely to have ovarian stromal hyperplasia.
It is my opinion that some form of pituitary blockade, either in the form of a GnRH agonist (e.g. Lupron, Buserelin, Superfact or Decapeptyl) or a GnRH antagonist (e.g. Orgalutron Cetrotide, and Ganirelix) is an essential component in ovarian stimulation of “poor responders” undergoing IVF. If this is not done, a progressive rise in LH –induced ovarian androgens (male hormones ….mainly testosterone) will often adversely affect follicle/ egg development, resulting in compromised embryo quality. However, when a GnRH antagonist is used in women with DOR, it is my belief (for reasons cited above) that it should preferably be administered from early in the cycle, at the time that gonadotropin stimulation starts and NOT 6-7 days later, as is traditionally done. In such cases, the dosage of the GnRH antagonist can in my opinion be reduced to 125mcg daily.
The long Pituitary agonist down-Regulation approach: With the long Lupron down regulation protocol the administration of the GnRH agonist begins several days in advance of commencing gonadotropin stimulation. As such, by the time gonadotropin stimulation commences, most LH has been expunged from the pituitary gland thereby avoiding over-production of ovarian androgens. However, this protocol involves continued administratio0n of the GnRH agonist throughout the stimulation phase and this is not ideal for women who have DOR where prolonged administration of GnRH agonists could blunt follicular response to ovarian stimulation with gonadotropins (perhaps by competitively binding with ovarian FSH receptors).
The agonist-Antagonist conversion protocol (A/ACP). I introduced the A/ACP for women with DOR, in order to counter the suppression effect of the traditional long Pituitary agonist down-regulation protocol.. With the A/ACP, low dose GnRH-antagonist (Ganirelix/Cetrotide Orgalutron) is commenced at the onset of menstrual bleeding that follows initiation of GnRH agonist therapy using a long-down-regulation protocol approach or at the onset of spontaneous menstruation. I currently prescribe the A/ACP to most of my IVF patients who have DOR. Results suggest that this is an optimal approach in such cases. In such cases I augment the stimulation with human growth hormone.
There is one potential draw back to the use of the A/ACP, in that the sustained use of a GnRH antagonist throughout the stimulation phase of the cycle, appears to compromise the predictive value of serial plasma estradiol measurements as a measure of follicle growth and development in that the estradiol levels tend to be much lower in comparison to cases where an agonist (e.g. Lupron) alone is used or where a “conventional” short GnRH antagonist protocol is employed. Rather than this being due to reduced production of estradiol by the ovary(ies), the lower blood concentration of estradiol seen with prolonged exposure to GnRH-antagonist, could be the result of a subtle, agonist-induced alteration in the configuration of the estradiol molecule , such that currently available commercial kits used to measure estradiol levels are rendered much less sensitive/specific. Thus when the A/ACP is employed, we rely much more heavily on ultrasound growth of follicles along with observation of the trend in the rise of estradiol levels, than on absolute estradiol values. For this reason I avoid prescribing the A/ACP in “high responders” who are predisposed to the development of severe ovarian hyperstimulation syndrome (OHSS) where accurate measurement of plasma estradiol plays a very important role in the safe management of their stimulation cycles.
The A/ACP with Estrogen priming: In women who have severe DOR (AMH=<0.1 ng/ml) I modify the A/ACP The A/ACP through incorporation of “estrogen priming” with injections of estradiol valerate (Delestrogen), given twice weekly for about a week following the initiation of the A/ACP, and prior to commencing FSH-dominant gonadotropin stimulation. I then continue this through gonadotropin stimulation. Estrogen Priming appears to further enhance ovarian response….presumably by up-regulating ovarian FSH-receptors. ”.
“Flare Protocols” in women with DOR: With the “Flare” approach, GnRH agonist (e.g. Lupron/Buserelin/Superfact/Decapeptyl) is started with the initiation of gonadotropin stimulation. The agonist causes an immediate surge in pituitary gland LH release. Thus the follicles/ eggs of women on GnRH-agonist “flare protocols” are exposed to an exaggerated Lupron-induced LH release, (the “flare effect” The increased androgen production early on in the stimulation has a deleterious effect on egg development and thus on subsequent embryo quality.
The Traditional GnRH-antagonist , ‘short protocol” in women with DOR: While the follicles/eggs of women, who receive GnRH antagonists starting 6-8 days into the stimulation cycle are exposed to endogenous LH -induced ovarian androgens( especially testosterone). While this might not be problematic in in women who have normal ovarian reserve (i.e. “normal responders”), it could be decidedly prejudicial in women with DOR (“poor responders”) where endogenous tonic LH activity is usually raised and the ovaries may be inordinately sensitive to LH. In such cases excessive exposure of follicles and eggs to androgens (mainly testosterone) could severely compromise egg development and thus embryo quality.
Use of the Birth Control Pill to set up ovarian stimulation with gonadotropins: In my practice, patients are placed on a birth control pill for 10-40 days (depending on circumstance), before commencing a long antagonist protocol (whether conventional or the A/ACP). With this approach, the agonist is overlapped with the BCP in the last few days of its usage. Thereupon daily agonist administration continues until menstruation ensues a few days later at which point, the dosage of the agonist is halved and this is continued throughout stimulation until the hCG “trigger”.
The rise in FSH that occurs in ovulating women 5-6 days prior to menses, initiates recruitment of follicles available for the upcoming cycle. The BCP by suppressing ovulation (and FSH) precludes this premenstrual rise in FSH, suppressing follicle recruitment. Premenstrual GnRH agonist administration overcomes this by inducing a premenstrual FSH surge which then serves to recruits follicles in a timely manner…for the upcoming COH cycle. Following use of the BCP (without prior overlap with agonist) the first 4-6 days of FSH administration must first recruit follicles before growing them.
When the BCP is overlapped with a GnRH agonists towards the end of the BCP cycle, it triggers a pre-menstrual pituitary release of endogenous FSH (and LH). This results in recruitment of follicles to the antral follicle stage, whereupon the initiation of gonadotropin stimulation, while continuing agonist or supplanting this with low dose antagonist (i.e. A/ACP) to prevent further LH release, will induce an uninhibited and prompt follicle growth and development.
Given that FSH is so important to antral follicle “recruitment” , since the BCP suppresses FSH, it is essential (in my opinion) that the contraceptive pill be overlapped with an agonist during the last 3 days of its use to promote FSH production. If this is omitted optimal antral follicle development will not occur, and the response to subsequent ovarian stimulation with gonadotropins will in my opinion, be suboptimal. This could result in discordant egg/follicle development, a longer period of ovarian stimulation and compromised egg/embryo quality. I believe that unless the use of a long pituitary down regulation approach is contemplated, launching ovarian stimulation coming off a BCP should be avoided.