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The Importance of Individualizing Ovarian Stimulation Protocols in IVF “Poor responders” and “High Responders”

by Dr. Geoffrey Sher on July 23, 2017

Indiscriminate selection and use of protocols of Controlled Ovarian Stimulation (COS) can be decidedly detrimental to egg and embryo competency/quality especially when it comes to IVF conducted in women on opposite sides of the spectrum of response to fertility drugs …i.e. ” high responders and “low responders. It is in such cases that protocols must be individualized.

“High responders” tend to have increased ovarian reserve (high blood levels of AMH) and produce large numbers of ovarian follicles as well as eggs while “low responders’” have tend to have low AMH levels (diminished ovarian reserve-DOR) and produce few follicles/eggs. High responders have a tendency to over-stimulate in response to even modest gonadotropin stimulation and as such are often at risk of developing a life-endangering condition known a severe ovarian hyperstimulation syndrome (OHSS)… while poor responders produce few follicles (even in response to high dosage COS protocols) and as such are clearly not at risk of developing OHSS, regardless of the ovarian COS protocol prescribed (see elsewhere on this blog).

High and poor responders have one characteristic in common, namely that in both cases, there is an increased tendency for their eggs to be chromosomally abnormal (aneuploid /”incompetent”) that are incapable of propagating viable pregnancies (i.e. “incompetent”). Thus in both cases egg quality is often compromised, thereby adversely impacting embryo “competency” and IVF outcome.

Many high responders, especially those who have a condition known as polycystic ovarian syndrome (PCOS) have overgrowth of ovarian connective tissue known as stroma or theca (ovarian stromal hyperplasia or hyperthecosis). This is due to inherent over-activity of pituitary Luteinizing Hormone (LH). With PCOS, the ovarian stroma often over-produces he stroma produces male hormones (mainly testosterone) which upon reaching the follicles in excess, has a damaging effect on egg development. While a small amount of testosterone is essential to orderly follicle and egg development and estrogen production, excessive ovarian testosterone compromises both follicle and egg development. Such eggs will, upon the subsequent administration of hCG (intended to “trigger” reproductive, maturational division or meiosis” to promote orderly separation of egg chromosomes in preparation for egg maturation) will be more likely to end up having an irregular quota of chromosomes (aneuploidy). Aneuploid eggs will upon fertilization, inevitably propagate aneuploid embryos that will either fail to implant in the uterine lining (endometrium) or will spontaneously be lost as a “chemical pregnancy or an early miscarriage.

Unlike high responders who have a tendency to over-produce follicles and eggs, poor responders fail to produce an adequate number of follicles even when an aggressive high-dosage protocol of ovarian stimulation is used. In spite of this major difference, the two conditions have one thing in common namely that they are both associated with high pituitary LH activity, ovarian stromal hyperplasia (or hyperthecosis), increased ovarian testosterone and the fact that an inordinately high percentage of eggs produces turn out to be aneuploid.

Since both many high and poor responders often have increased LH-induced ovarian testosterone production, they both require pituitary down-regulation with an agonist in advance of initiating ovarian stimulation. To do this requires pituitary down regulation with a birth control pill (for a few weeks) prior to COS, followed by the administration of an agonist such as Lupron/Buserelin/Superfact/aminopeptidyl a few days before initiating COS (gonadotropin stimulation). Poor responders often do better with a modification of this approach the agonist/antagonist conversion protocol –A/ACP and in some cases the addition of estrogen “priming and human grow the hormone (hGH). High-responders require low dosage COS with gonadotropins while poor responders require higher dosage protocols.
As stated, poor responders with DOR and high responders with PCOS often both manifest with exaggerated ovarian LH bioactivity and it is thus this group of patients where special attention needs to be given to selecting an optimal ovarian stimulation protocol that would minimize the effects of exaggerated ovarian LH-induced egg/embryo damage.

Eggs are recruited genetically for a given cycle, 3-4 months before the cycle in which they are to use. There is absolutely nothing we can do to influence the egg recruitment process or their development during their 3-4 month journey. No nutritional supplements or treatments will help improve their quality. All that we can do is protect their development (oogenesis) during COS by individualizing/ (customizing) the protocol of ovarian stimulation in such a way as to control/regulate LH-induced ovarian male hormone (mainly testosterone) production. This, in my opinion, requires:
1. Prior pituitary LH down-regulation using agonists (Lupron/Buserelin/Superfact/Aminopeptidyl) starting 5-10 days prior to initiating ovarian stimulation.
2. Avoiding “flare protocols” (where agonists are 1st administered with the onset of gonadotropin administration (i.e. without prior LH-down-regulation) that causes increased pituitary release of LH at the very time that ovarian stimulation with gonadotropins commences.
3. Limiting the use of menotropins such as Menopur, (gonadotropins such as Menopur) that contain LH/hCG
4. Avoiding supplementing early ovarian stimulation with hCG (which similar to LH, augments pituitary LH release) or testosterone
5. Limiting admistration of clomiphene and Letrozole for ovarian stimulation which promote the release of additional pituitary LH. This is especially applies to women with DOR.

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