IVF And Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting the Optimal Protocol for Ovarian Stimulation

Dr. Geoffrey Sher - October 2, 2018
IVF And Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting the Optimal Protocol for Ovarian Stimulation

When it comes to the selection of ovarian stimulation protocols for older women and those who have DOR there is in my opinion, no justification for the use of a “one size fits all” or “recipe approach”. I firmly believe that the time has arrived to reflect seriously on an individualized selection of ovarian stimulation protocols that would optimize egg/embryo quality, rather than simply trying to maximize the total egg yield.

A woman is born with all the eggs she will ever have. The quality, as well as the number of eggs in her ovaries (ovarian reserve), usually begins to decline in the mid- 30’s, becoming more pronounced as she ages beyond 35Y. Typically, very few women retain normal fertility by the time they enter their 40s. It is essential to note that there is no known method by which reverse these age-related effects. There is also an inevitable decline in the number of eggs present in the ovaries.

Maturation is a conclusive developmental event, designed to fine-tune biological systems so as to optimize function. But optimal maturation cannot take place in a vacuum. Without exception, it requires prior, orderly development of numerous preliminary molecular-biological systems. In the case of the egg, optimal development (ovogenesis) requires a perfect functional interaction of countless intracellular microsystems, all designed to effect and regulate orderly chromosomal segregation during reproductive division (meiosis). It follows that factors that are capable of influencing such preovulatory molecular nuclear-cytoplasmic events, will profoundly influence the ultimate numerical chromosomal integrity of the mature egg, which in turn will largely determine embryo “competency”.

A woman is born with all the eggs she will ever have. After birth, there is a progressive decline in the number of eggs present in her ovaries. Following puberty and the onset of regular ovulation, numerous eggs are used up each cycle. Over time, the woman’s the egg population declines below a theoretical threshold (which probably varies from woman to woman). This is the point beyond which the hypothalamus and pituitary gland, progressively increases its production and output of FSH in a futile attempt to reawaken follicle and egg production. Once this threshold is crossed there occurs a progressive reduction in cyclical ovarian follicle development, manifesting as a reduction in antral follicle count (AFC), a slow but steady rise in basal FSH (>9.0MIU/ml), an increase in the biologic activity (and later in the overall production) of LH and a progressive decline in ovarian production of antimullerian hormone (AMH) below the normal value of 2ng/ml (or 15pmol/L). This reduction in AMH coincides with the onset of diminishing ovarian reserve (DOR). While AFC and basal FS/LH levels are relatively good indicators of ovarian reserve, it is the AMH level that is by far the most reliable. Once the AMH level falls below 1.5 ng/ml (11pmol/l) it suggests that the severity of DOR is significant, to the point that it will likely significantly, adversely affect the yield of follicles and eggs following ovarian stimulation. And, once the AMH falls below 0.5ng/ml (<4pmol/L) the DOR should be regarded as advanced and that total ovarian egg depletion is likely to occur within 6months-3 years.

Physiologically, in response to LH, the connective tissue surrounding ovarian follicles, produces male hormones ( predominantly testosterone) which is conveyed to the granulosa cells that line the inside of follicles where  FSH induces enzymatic activity that converts it to estradiol. While a small amount of LH-induced testosterone is essential for orderly follicle and egg development, overexposure to testosterone can be decidedly detrimental leading to dysfunctional follicle and egg development, increasing the likelihood of egg (and thus embryo) aneuploidy and thus, a reduced chance of a successful pregnancy. Typically, women with DOR, older women and those with polycystic ovarian syndrome – (PCOS) have increased LH activity, often leading to exaggerated ovarian testosterone activity which can compromise IVF outcome.

The above serves to clarify why it is my opinion that the use of drugs which increase pituitary LH output (e.g. clomiphene and Letrozole) should preferably be avoided in older women and those who have with DOR/PCOS/older women in such cases, why “flare-agonist (Lupron/Buserelin/Superfact) protocols that dramatically increase pituitary LH release should also be avoided and why the amount of LH/hCG containing drugs (e.g. Menopur) should be curtailed. I hold that women with DOR should preferentially receive robust dosages of FSH-dominant gonadotropins (e.g. Follistim/Gonal-F/Puregon).

Older women and those with DOR often have increased LH-induced ovarian testosterone. The only way to minimize such deleterious influences is to control LH prior to and during the cycle. It follows that the use of low-dosage stimulation protocols (mini-IVF) and natural cycle (NC)- IVF where elevated LH is NOT addressed, are best avoided. 

I propose that aggressive, individualized and strategically designed FSH-dominant and LH-regulated protocol for ovarian stimulation should be used in women with DOR. Such stimulated IVF cycles should in my opinion also best augmented with PGS testing of blastocysts, followed by the selective transfer of chromosomally competent (euploid) blastocysts.  


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