While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COH to meet the individual needs of the patient.
During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.
However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian hyperstimulation (COH) should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COH with fertility drugs as well as the precise timing of the “trigger shot” of hCG.
It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce androgens (e.g; testosterone). Only a small amount of testosterone is necessary for optimal estrogen production. Over-production has a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.
In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Folistim, Puregon, Bravelle and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COH, this appears to be more vital in older women, who tend to be more sensitive to LH
It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COH. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.
The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily lupron injections continue, to ensure an “LH-free” environment.
Lupron Flare/Micro-Flare Protocols
Another approach to COH is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron). The intent is to deliberately allow lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” represents “a double edged sword” because while it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially in older women, and in women with diminished ovarian reserve . Accordingly, I do not prescribe them at all.
Estrogen Priming - The SIRM Approach for “Poor Responders”
Our patients who have demonstrated reduced ovarian response to COH as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The aproach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COH is thereupon initiated using a relatively high dosage of FSH-(Folistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “HCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.
Polycystic Ovarian Syndrome and Ovarian Hyperstimulation Syndrome
Women with PCOS who undergo IVF are highly sensitive to gonadotropins and are at risk of developing severe ovarian hyperstimulation syndrome (OHSS). For the reasons cited above, they are also more likely than others to produce poor quality eggs/embryos which, they are often led to believe is attributable to an intrinsic egg defect that is characteristic of their PCOS condition. This is not necessarily so. The most likely reason as to why many women with PCOS develop an excessive number of follicles and then go on to produce poor quality eggs/embryos has to do with the fact that, in an attempt to contain reduce the risk of OHSS they are often administered HCG prematurely – prior to the attainment of optimal egg maturation.
In the early nineties, we introduced “Prolonged Coasting”, a procedure which eliminates the risk of OHSS while allowing the hCG trigger to be deferred for long enough as to allow for optimal follicle/egg maturation to take place. Coasting involves withholding gonadotropin therapy while the administration of GnRH agonist/antagonist is continued. The daily measurement of blood estradiol is continued until the concentration drops below a safe threshold level, at which time HCG is administered (regardless of the number of follicles). When appropriately implemented “coasting” results in the production of good quality eggs/embryos, in circumstances where this might otherwise not have been possible.
The potential of a woman’s eggs to develop into “good quality embryos” following fertilization is largely genetically determined. However, the ultimate ability to optimally express such potential is dependent upon the highly orchestrated interaction of many complex intra-ovarian hormonal events. “Super physiologic” stimulation with exogenous gonadotropins, or COH, by precipitating growth and development of multiple follicles at a time and activating excessive ovarian androgen hormone production can play havoc with this harmonious interplay. This exaggerated induced ovarian hormonal response is capable of compromising the ability of the eggs to optimally express their intrinsic developmental potential. Proper preparation, coupled with an individualized approach to COH protocol selection, would go a long way toward limiting such excesses, promote orderly growth and maturation of multiple mature ovarian follicles (most of which would harbor mature, “good quality eggs”), while at the same time avoiding the development of OHSS.
Posts
0 comments:
Post a Comment