Ovarian Stimulation For IVF: High-Responders vs. Poor Responders

There is a growing body of evidence to suggest that over-stimulation of women who have normal or above normal ovarian reserve (i.e. normal and high responders to gonadotropin fertility drugs), might prejudice egg quality. As a point in fact…younger women who receive above average dosages of gonadotropins and over-respond by producing large numbers of follicles, tend to yield an inordinately high percentage of “immature” as well as chromosomally abnormal (aneuploid) eggs. Such eggs are incapable of making normal “competent” embryos.

It is unlikely that the gonadotropins directly act on the eggs to compromise them. It is more likely that in susceptible cases the “overstimulation “ of connective tissue surrounding follicles (i.e. stroma or theca) causes excessive androgen (male hormone) production. This, upon reaching the follicles in high concentrations, compromises egg development. It follows that in the interest of optimizing egg quality, it is advisable to avoid over-stimulating normal and high responders with gonadotropins.

When it comes to ovarian stimulation of poor responders, it is another matter altogether. Here, the existence of ovarian resistance to gonadotropins necessitates a more aggressive approach in order to try and maximize the number of developing follicles and eggs. At the same time there is a need to try and avoid excessive ovarian stromal/thecal activation. Since “poor responders” are women with diminished ovarian reserve who have an overgrowth of ovarian stroma/theca (i.e. stromal hyperplasia or hyperthecosis) they have a propensity to over-produce androgens in response to gonadotropins. The real challenge in such cases is to strike a balance between optimizing follicle and egg development while avoiding overstimulation of ovarian stroma/theca. To do this requires pituitary down-regulation with a birth control pill (often for 1-2 months) followed by the administration of an agonist (e.g. Lupron). In some cases, we first administer an estrogen (i.e., “estrogen priming”) for a week or longer before initiating ovarian stimulation using a high dosage of Follicle Stimulating Hormone (FSH). The BCP administration is done in an attempt to suppress elevated LH for long enough to effect shrinkage of ovarian stroma/theca and thereby reduce subsequent androgen production in response to gonadotropins.

There is nothing we can do (given current knowledge) to affect the quality of those eggs available for use in a particular ovarian cycle. They will have been genetically preselected and then have gone through an independent 4 month process of preparation. By the time the cycle starts, “the hand will have been shuffled and dealt” However, by individualizing (customizing) the protocol of ovarian stimulation, it is possible to influence the ovarian hormonal environment during the ovarian stimulation cycle in the hope of protecting the eggs during stimulation.

Given the large number of uncontrollable variables that are operative in any IVF cycle and the absolute inability to keep them all constant while measuring variations in just one, is why randomized controlled ("gold standard") studies are virtually impossible to conduct satisfactorily in IVF. It also explains why developments involving the entire field of IVF are generally based on the results of longitudinal studies (trial and error).