Using Agonists and Antagonists in IVF: An Opinion
The main objective in controlled ovarian stimulation (COS) is of course, to safely optimize egg quantity without compromising quality. For this to be achieved, COS must of necessity strike a balance in the administration of the pituitary gland-derived hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH).
When it comes to influencing IVF outcome, the protocol selected for COS is the most critical decision that the treating fertility doctor can make. There is no more a standard protocol applicable to all IVF candidates than there is a standard height or weight for any individual. Each woman should be independently evaluated for the optimal COS protocol. Such an assessment should take into account the woman’s age, her ovarian reserve (as assessed by basal blood FSH, LH, estradiol and in many cases also the AMH), her previous response to ovarian stimulation, and the cause of the infertility. This article seeks to establish a rational basis for how the interaction between pituitary gonadotropins (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) and agonists/antagonists can affect egg/embryo quality and ultimately impact IVF outcome.
How LH and FSH promote follicle growth and egg development: LH causes the connective tissue (theca/stroma) that surrounds the ovarian follicles to produce and release androgens (male hormones)…mainly testosterone. These androgens are then transported to the (granulosa) cells that line the inner ovarian follicles, where FSH then causes the conversion of (predominantly) testosterone to estradiol. As a result, the follicles grow, blood estrogen levels rise, and eggs undergo the developmental change (ovogenesis) necessary to allow proper preovulatory maturation triggered by the LH surge or by the administration of human chorionic gonadotropins (hCG).
While some androgen-testosterone is an essential prerequisite for normal follicular development, estradiol production and ovogenesis, an excess of androgens can overload and exhaust granulosa cells, overtax egg development and ultimately lead to egg chromosomal irregularities (i.e., aneuploidy). Upon being fertilized, aneuploid eggs invariably propagate embryos that are aneuploid and “incompetent” (i.e., incapable of developing normally). Such aneuploid embryos will invariably either arrest during development, fail to implant in the uterus, miscarry, or develop into chromosomally compromised offspring (e.g., Down Syndrome).
Long agonist pituitary down-regulation protocols: Within a few hours of administering an agonist (e.g., leuprolide, Buserelin, Nafarelin, Synarel), most LH is promptly expunged from pituitary gland reservoirs. The result….high blood LH concentrations, and consequential release of large amounts of androgens (mainly testosterone). The continued administration of agonists will ultimately exhaust pituitary LH reservoirs such that within a few days, blood LH concentration will decline, and over-production of ovarian androgens will thereby be avoided.
Long pituitary down-regulation protocols involve the administration of an agonist over four or more days prior to initiating ovarian stimulation with FSH-containing gonadotropins (e.g., Follistim, Gonal-F, Puregon). These protocols take advantage of this LH-depleting effect such that by the time COS with gonadotropins is initiated, the blood LH will be low enough to avoid over-production of ovarian androgens and thereby help protect follicle and egg development.
Short (flare/microflare) agonist protocols: This type of protocol involves commencing agonist administration at the time that FSH-gonadotropin therapy is initiated. This will usually result in a high (excessive) concentration of androgens bombarding follicle- granulosa cells from the very onset of COS…to the ultimate determent of egg/embryo “competency.” Since older women, those who have diminished ovarian reserve (DOR) and those with polycystic ovarian syndrome (PCOS) tend to have exaggerated pituitary LH production and/or activity leading to overgrowth of androgen-producing ovarian theca/stroma (hyperthecosis), they are the ones who are most susceptible to the adverse effects of agonist-induced, exaggerated LH-testosterone production caused by short (flare/microflare) protocols. Thus, in my opinion, it is prudent to avoid using this protocol, especially in such vulnerable individuals.
Antagonist protocols: There is another group of drugs that rapidly blocks the release of gonadotropins (FSH/LH) by the pituitary gland. These so called antagonists (e.g., Ganirelix, Cetrotide, Orgalutron) are traditionally administered starting 6-8 days after the initiation of controlled ovarian stimulation (COS). I believe that this might be all well and good with COS in younger women that have normal ovarian reserve and in whom LH activity is not excessive. However, the initiation of an antagonist LH blockade starting as late as 6-8 days after COS is started fails to protect early developing follicles and eggs from the potentially ravaging effects of over exposure to LH-induced ovarian androgens. Thus, in my opinion, it is preferable to commence antagonist therapy at the point that COS with gonadotropins is initiated, rather than starting a week or so thereafter.
Clomiphene and Letrozole: Similarly, since fertility drugs such as Clomiphene (Serophene/Clomid) and Letrazole (Femara) also cause increased release of pituitary LH, they are, in my opinion, best avoided in the IVF setting.
LH-containing menotropins: For the same reasons , the use of gonadotropins such as Menopur, that have a considerable amount of LH activity should in my opinion be limited in IVF, especially when it comes to older women, those with DOR and women who have PCOS. I submit that it is at all times preferable to predominantly use FSH-dominant, recombinant DNA-derived Follistim, Puregon and Gonal-F than to use LH-containing menotropins.