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 pre-ovulatory molecular nuclear-cytoplasmic events, will profoundly influence the ultimate numerical chromosomal integrity of the mature egg, which in turn will largely determine embryo “competency”.

After birth, there is a progressive decline in the number of eggs present in the 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 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). 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 DOR is significant, to the point that it could significantly, adversely affect the yield of follicles and eggs following ovarian stimulation. And, once the AMH falls below 0.5ng/ml (<5pmol/L) 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 (stroma or theca), produces male hormones (androstenedione and 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, an increased prevalence 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, leading to exaggerated ovarian testosterone activity which in turn can compromise IVF outcome.

The above serves to clarify why the use of drugs which increase pituitary LH output (e.g. clomiphene and Letrozole) should in my opinion, preferably be avoided in older women and those who have with DOR or /PCOS/, why “flare-agonist (Lupron/Buserelin/Superfact/Decapeptyl) protocols” that dramatically increase pituitary LH release should also be avoided in such cases and why the amount of LH/hCG containing drugs (e.g. Menopur) should be curtailed.

As stated, 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 is worthwhile to understand that oral fertility drugs such as Letrozole and clomiphene, also cause increased release of LH by the pituitary gland.  It follows that the use of such medications in older women and those with DOR who already have a tendency to over-produce LH-induced ovarian testosterone, is probably not optimal.  It is for this reason that when considering IVF in such women, using “mini-IVF” (where clomiphene or Letrozole are often used) or resorting to  natural cycle (NC)- IVF is in my opinion best avoided. Rather, individualized and strategically designed FSH-dominant and LH-regulated protocols be used in such cases and that these be complimented by PGS/PGT-A testing of blastocysts with the subsequent, selective transfer of chromosomally competent (euploid) blastocysts.