IVF Ovarian Stimulation: The GnRH Agonist/Antagonist Protocol

GnRH antagonists (e.g. Ganirelix, Cetrotide, Cetrorelix and Orgalutron) are currently used with many controlled ovarian hyperstimulation (COH) protocols. They are traditionally prescribed at the dosage of 250mcg daily from the 6th or 7th day of stimulation with gonadotropins. This is completely acceptable for younger patients (under 39 years) and for good responders to COH who have normal ovarian reserve (i.e. normal day 3 FSH, AMH, and Inhibin B blood levels). However, it can be disadvantageous in women who have elevated baseline luteinizing hormone (LH) levels (e.g. those with polycystic ovarian syndrome [PCOS], women over 40 years of age, and poor responders who have diminished ovarian reserve). In such cases, the abrupt pituitary suppression that rapidly follows administration of the GnRH antagonist, (when it is first administered several days after the COH begins), occurs too late in the cycle of stimulation to suppress LH before it begins adversely affect follicle and egg development

Background Information: One of the roles of LH is to promote male hormone (androgen) production through the connective tissue that surrounds follicles (the stroma or theca). The androgens (maily testosterone) represent the building blocks from which the follicle granulosa cells manufacture estrogen. While a small amount of stromal androgen is essential for optimal follicular growth and egg development, too much can compromise their development. Accordingly, unless the LH levels are regulated by the GnRH antagonist from early in the cycle of COH, the developing follicles and eggs of women who have chronically elevated LH levels can be overexposed to stromal androgens for several days before GnRH antagonist suppression is in effect. This can and does adversely influence egg/embryo quality and perhaps even endometrial proliferation in response to estrogen .

The “Premature LH Surge”: Presumably, the reason for the suggested mid-follicular initiation of high dose GnRH antagonist is to prevent the occurrence of the so called "premature LH surge", a condition where high LH levels cause “follicular exhaustion” resulting in poor egg/embryo quality. But the term “premature LH surge” is a misnomer since it suggests a sudden unanticipated rise in LH that occurs as a “terminal event” or an isolated occurrence. In actuality, what happens is the result of a progressive escalation in LH (the so called “staircase effect”) that through a persistent rise in stromal androgens, ultimately exhausts the follicle and damages the egg irreparably.

A more accurate term might be “premature luteinization.” Against this background, trying to improve ovarian response and prevent follicular exhaustion through administration of GnRH antagonist initiated late in the cycle of COH is like shutting the gate after the horse has already left the stable.

As stated, the use of such “late–follicular” GnRH antagonist protocols in younger women or in women with normal LH and ovarian reserve will probably not produce such adverse effects. However, the more appropriate question might be: since such women are not at risk of premature luteinization, would they even require pituitary LH suppression? I doubt that they do! It is my position that some form of pituitary blockade, either in the form of a premenstrual GnRH agonist administration (e.g. Lupron, Buserelin, Nafarelin, Synarel. Decapeptyl) or GnRH antagonist (e.g. Cetrotide, Cetrorelix, Orgalutron, Ganirelix) is beneficial for older women, women with elevated LH, and for those with diminished ovarian reserve, undergoing COH for IVF. Only in this manner can the adverse effects of LH –induced ovarian androgen elevation on follicle/ egg development be averted.

With GnRH agonist (e.g Lupron) down-regulation protocols (where the pituitary gland is first largely exhausted of LH before COH begins) the residual amount of LH in the circulation is minimal by the time COH with gonadotropins is initiated. The above-mentioned adverse LH-induced androgen effect is thereby largely negated.

The agonist/antagonist conversion protocol
The downside of prolonged GnRHa (e.g. Lupron) administration throughout the cycle of COH is that the GnRHa, by competitively binding with ovarian follicle stimulating hormone (FSH) receptors, can suppress ovarian response to gonadotropins. To counter this effect, we introduced the Agonist/Antagonist Conversion Protocol (A/ACP).

With the A/ACP, only a low dosage (125mcg/day) of GnRH antagonist is injected daily. It is commenced at the onset of spontaneous menstruation, or after the onset of menstruation that follows the initiation of GnRH agonist (e.g. Lupron) therapy that is administered in a long-pituitary down-regulation protocol arrangement. We currently prescribe some form of the A/ACP for most of our IVF patients regardless of whether they are “normal responders” or “poor responders”. Results suggest a significant improvement in egg number, egg/embryo quality, as well as implantation and viable IVF pregnancy rates.

The A/ACP for poor responders
The A/ACP has, however, proven to be most advantageous in “poor responders” with diminished ovarian reserve, where additional enhancement of ovarian response to gonadotropins may be achieved through incorporation of “estrogen priming”. We have reported on the fact that the administration of intramuscular estradiol starting about a week prior to commencement of COH often markedly enhances ovarian response (presumably by enhancing the sensitivity of ovarian FSH-receptors), and improves egg/embryo quality. We refer to l this as the A/ACP+ E2V.

It is remarkable that while using the A/ACP + E2V in poor responders whose FSH levels were often well above threshold limits, the cycle cancellation has consistently been maintained below 10% (much lower than expected). Many such patients who previously were told that they should give up on using their own eggs and switch to ovum donation because of “poor ovarian reserve”, have subsequently gone on to achieve viable pregnancies using the A/ACP with “estrogen priming”.

What are the downsides of the A/ACP? There is one potential drawback to the use of the A/ACP, in that prolonged administration of GnRH antagonist throughout the stimulation phase of the cycle compromises the predictive use of serial plasma estradiol measurements as an indication of ovarian response to COH. The estradiol levels tend to be much lower in comparison with cases where GnRHa alone is used, or where a “conventional” GnRH antagonist protocol is commenced 6-8 days following initiation of gonadotropin stimulation. The reason for the lower blood concentration of estradiol seen with prolonged exposure to GnRH-antagonist could be the result of subtle, antagonist-induced alterations in the configuration of the estradiol molecule, such that currently available commercial test used to measure estradiol levels are rendered less sensitive/specific.

Accordingly, when the A/ACP protocols are employed, we rely much more heavily on the measurement of follicle growth by ultrasound than on the estradiol levels. Because of this downside, we confine the use of A/ACP protocols to normal and poor responders - refraining from using this approach in “high responders” who may be at risk of developing of severe ovarian hyperstimulation syndrome (OHSS) and in whom the accurate measurement of plasma estradiol plays a very important role in the safe management of their COH cycles.