Ovarian Stimulation in IVF: Why It Is Important to Down-Regulate LH
Suboptimal controlled ovarian stimulation (COS) protocols, especially in older women and those with diminished ovarian reserve, can increase the occurrence of egg/embryo numerical chromosomal abnormalities (aneuploidy), thereby reducing the chance of implantation and increasing the incidence of chromosomal miscarriages and birth defects (e.g., Down syndrome).
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”.
While a small amount of luteinizing hormone (LH)-induced male hormones (androgens, mainly testosterone), produced by ovarian connective tissue (stroma or theca) is essential for orderly follicle and egg development, overexposure to androgen-testosterone can be decidedly detrimental, leading to dysfunctional follicle and egg development, an increased likelihood of egg aneuploidy, and thus a reduced chance of a successful pregnancy. It follows that women who intrinsically manifest with increased endogenous (self-produced) pituitary LH activity as well as those that through medical treatment become overexposed to LH, will have an increased predisposition to producing aneuploid eggs/embryos.
The connective tissue surrounding ovarian follicles (stroma or theca) represents the main site of ovarian androgen production. Here, chronic over-exposure to LH activity can lead to overgrowth (stromal hyperplasia or hyperthecosis). This characteristically is seen in older women, women with diminished ovarian reserve (DOR), and those with polycystic ovarian syndrome (PCOS), who often have exaggerated endogenous LH activity. In such cases, the increased the ovarian stromal tissue/theca presents a “greater target” for LH to act on. Thus, unless in such cases LH levels are kept low prior to and during COS, the exaggerated androgen environment created can result in abnormal follicle growth and egg development, with increased egg/embryo aneuploidy and compromised outcome.
The use of strategically designed, individualized ovarian stimulation protocols that are comprised primarily of purified recombinant FSH (FSHr), (rather that urinary-derived gonadotropins such as Menopur that in addition to FSH, also contain high concentrations of LH/hCG), as well as the preferential use of long pituitary LH down-regulation protocols (that suppress LH prior to and during COS) will in such cases, go a long way towards minimizing the risk of this happening. Conversely, compounds such as clomiphene citrate and Letrozole, as well as microdose “flare” protocols which by their very nature increase pituitary output of LH release, and late antagonist protocols that belatedly block LH several days after the commencement ovarian stimulation, can be particularly harmful to these women in my opinion.
It is certainly time for us to reflect seriously on what and why we use specific COS protocols and drugs in IVF. Perhaps we should focus more upon optimizing ovogenesis rather than simply on how to increase the total egg yield. Personally, I strongly favor the use of FSHr-dominant, long pituitary down-regulation protocols that reduce LH, especially when conducting COS in older women, women with DOR, and those with PCOS.