OVARIAN STIMULATION WITH GONADOTROPINS: AN INDIVIDUALIZED APPROACH.
PREPARING FOR CONTROLLED OVARIAN HYPERSTIMULATION (COH) WITH GONADOTROPINS:
It is advisable that at least one-month be allowed to elapse (the “resting cycle”) between IVF treatment cycles, in order to allow the ovaries to fully recover. It is also important to ensure that the plasma E2 level is below 70 picograms per milliliter following successful pituitary LH suppression (with GnRH agonist or antagonist), prior to initiating COH. The best time to measure the E2 level is soon after (i.e.; within days) the onset of lupron-induced menstruation. The commonest cause of an elevated blood E2 level around this time is the existence of one or more ovarian follicular cysts. These should be allowed to absorb, or be aspirated as soon as possible. Spontaneous absorption will usually occur with continued LH suppression using agonist/antagonist failing which; the cyst should be aspirated under local anesthesia, prior to initiating COH.
http://forums.haveababy.com/lofiversion/index.php?t865.htmlTHE INDIVIDUALIZED APPROACH TO INDUCTION OF
OVULATION
In order for any organism to attain an optimal state of maturation (ripening) it must first undergo full growth and development. A fruit plucked from a tree before having developed fully or a poorly developed fruit might still ripen (mature) on the shelf and might even appear as enticing as one that had previously undergone proper development, but it will lack the same quality. The same principles apply to the development and maturation of human eggs. Proper development as well as precise timing in the initiation of egg maturation with LH or hCG is no less crucial to optimal egg maturation, fertilization and ultimately to embryo quality .In fact, in cases where egg maturation is improperly timed (LH or hCG is released/given too early, i.e. prematurely or too late, i.e. postmaturely) there is an increased risk of aneuploidy (structural and numerical chromosomal abnormalities) leading to compromised reproductive performance.
The potential for a woman’s eggs to undergo orderly maturation, successful fertilization and subsequent progression to “good quality embryos” that are capable of producing healthy offspring, is in large part, genetically determined. However, the expression of such potential is profoundly susceptible to numerous extrinsic influences, especially to intra-ovarian hormonal changes during the pre-ovulatory phase of the cycle.
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, while small amounts of ovarian male hormones (androgens) such as testosterone, enhance egg and follicle development, over-exposure to excessive concentrations of the same hormones can seriously compromise egg ( and subsequently, also embryo) quality . It follows that protocols for controlled ovarian hyperstimulation (COH) should be geared toward optimizing follicle and egg development and avoiding over exposure to androgens The fulfillment of these objectives requires an individualized approach to COH and that the administration of human chorionic gonadotropin (hCG) or recombinant luteinizing hormone (LHr) to “trigger” ovulation, be timed precisely.
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 toward granulosa cell (which line the inside of the follicles) proliferation and estrogen production. LH, on the other hand, acts primarily on the ovarian stroma (the connective tissue that surrounds the follicles) to produce androgens. 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 disease (PCOD), which is characterized by increased blood LH levels, there is also an increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” and inadequate endometrial development are often features of this condition. The use of LH-containing preparations such as Pergonal and Repronex further aggravates this effect. Thus we strongly recommend against the exclusive use of such products, in PCOD patients, preferring FSH-dominant products such as Folistim and Gonal F. While it would seem prudent to limit LH exposure in all cases of COH, this appears to be more relevant in older women, who tend to be more sensitive to LH
It is common practice to administer gonadotropin releasing hormone (GnRH) agonists (e.g. Lupron,Buserelin) and more recently, GnRH-antagonists (e.g. Antagon, Cetrorelix, Cetrotide )to prevent the release of LH with COH. GnRH agonists exert their LH-lowering effect. over a number of days. They act by causing an initial outpouring and then depletion of pituitary gonadotropins. This results in the LH level falling to within negligible concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act by rapidly, within a few hours to block pituitary LH release, so as to achieve the same effect.
Long GnRHa Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Lupron is given, starting a week or so prior to menstruation. This precipitates an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. This is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a relatively “LH-free” environment.
Microflare GnRHa protocols: Another approach to COH, is by way of so-called “microflare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist. The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release so as to augment ovarian response to the gonadotropin medication. Unfortunately, this approach represents “a double edged sword” as the resulting increased release of FSH is likely to be accompanied by a similar rise in blood LH levels that could evoke excessive ovarian stromal androgen production. The latter could potentially compromise egg quality, especially in older women, and to women with conditions like polycystic ovarian syndrome (PCOS) whose ovaries have increased sensitivity to LH. We believe that in this way, “microflare protocols” potentially; can hinder endometrial development; compromise egg/embryo quality and reduce IVF success rates. Accordingly, we prefer to avoid “flare protocols”.
GnRH antagonist protocols: The use of GnRH antagonists as currently prescribed in ovarian stimulation cycles, i.e. the administration of 250mcg daily from the 6or 7th day of stimulation with gonadotropins may be problematic, especially in women with high LH and overgrowth (hyperplasia) of ovarian stroma e.g. women over 40yrs, women with raised cycle day 3 FSH and/or low Inhibin B, other “poor responders” to gonadotropins, and in some women with PCOS. In such cases the initiation of pituitary suppression with GnRH antagonists so late in the cycle of stimulation fails to suppress high tonic pituitary LH in the most formative (early) stage of folliculogenesis. One of the roles of LH is to promote androgen (mail hormone) production which in turn is essential (in small amounts) for optimal follicular growth to take place. In women with high LH and/or ovarian stromal hyperplasia, the failure of conventional GnRH antagonist protocols to address this issue, results in the inevitable excessive exposure of follicles to androgens (mainly testosterone). This can adversely influence egg/embryo quality and endometrial development.
Presumably, the reason for the suggested mid-follicular initiation of high dose GnRH antagonist is to prevent the occurrence of the so called "premature LH surge", which is known to be associated with “follicular exhaustion” and poor egg/embryo quality. However the term “premature LH surge” is a misnomer and the concept of this being a “terminal event” or an isolated insult is, erroneous. In fact the event results from a culmination (end point) of the progressive escalation in LH (“a staircase effect”) which results in increasing ovarian stromal activation with commensurate growing androgen production. Trying to improve ovarian response and protect follicular exhaustion by administering Antagon/Cetrotide during the final few days of ovarian stimulation is like trying to prevent a shipwreck by collision, through removing the tip of an iceberg.
The use of such mid-follicular Antagon/Cetrotide protocols in younger women or in normal responders will probably not produce such adverse effects because the tonic endogenous LH levels are low (normal) in such cases and such normally ovulating women rarely have ovarian stromal hyperplasia . The better question would be: Do such women in fact require any form of pituitary suppression or down regulation at all? ---I doubt that they do.
So, at SIRM we almost always prescribe 125mg Antagon or Cetrotide (i.e. half the usual dosage) starting on the day that FSH-dominant gonadotropins (Follistim, Gonal F and Bravelle) stimulation is initiated. The intent is to purposefully allow only a very small amount of the woman's own pituitary LH to enter her blood while preventing a large amount of LH from reaching her circulation. This is because while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg maturation a large concentration of LH can trigger over-production of ovarian stromal testosterone with an adverse effect of follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the endometrium, an excess of testosterone can also have an adverse effect on endometrial growth.
Estrogen priming protocols: Older women (over 40 yrs), women who have demonstrated a prior reduced ovarian response to COH and those who by way of significantly raised cycle day 3 FSH and reduced Inhibin B levels are considered likely to be “poor responders”, are first given GnRH agonist for a number of days to effect pituitary down-regulation. Upon menstruation and confirmation by ultrasound blood estradiol measurement that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered (or the agonist is replaced with a GnRH antagonist) and the woman is givens twice-weekly injections of estradiol for a period of 7-10 days. COH is then initiated using a relatively high dosage of FSH-dominant gonadotropins such as Folistim or Gonal F that is continued along with daily administration of GnRH agonist/antagonist until the “hCG trigger”. A recently completed study has demonstrated the efficacy of this protocol and the ability to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients
The GnRH Agonist/Antagonist Conversion Protocol (A/ACP) : It is our position that some form of pituitary blockade, either in the form of a GnRH agonist (e.g. Lupron, Buserelin, Nafarelin, and Synarel. Decapeptyl) or a GnRH antagonist (e.g. Antagon, Cetrotide, Cetrorelix, and Ganarelix) is an essential component in ovarian stimulation of “poor responders” undergoing IVF. If this is not done, a progressive rise in LH –induced ovarian androgens (male hormones ….mainly testosterone) will inevitably affect follicle/ egg development, resulting in compromised embryo quality.
The follicles/ eggs of women on GnRH-agonist “flare protocols” are exposed to an exaggerated Lupron-induced LH release, (the “flare effect” while the follicles/eggs of women, who receive GnRH antagonists starting 6-8 days into the stimulation cycle are exposed to endogenous LH -induced ovarian androgens( especially testosterone). This might not be problematic in “normal responders” but could be decidedly prejudicial in “poor responders” and older women where endogenous basal LH levels are often raised and the ovaries may be inordinately sensitive to LH and where excessive exposure of follicles and eggs to testosterone could severely compromise egg development and thus embryo quality.
exhausted of its LH and residual minimal LH is present in the circulation by the time stimulation with gonadotropins begins, the above mentioned adverse testosterone-effect is largely negated. On the down side is the fact that prolonged administration of GnRH agonists such as Lupron (such as with the GnRH agonist down-regulation protocol could suppress subsequent ovarian response to ovarian stimulation with gonadotropins, by competitively binding with ovarian FSH receptors. We introduced of our Agonist/Antagonist Conversion Protocol (A/ACP) more than a year ago in an effort to counter this effect.
With the A/ACP, low dose Antagon/Cetrotide is commenced at the onset of spontaneous menstruation or following bleeding that follows initiation of GnRH agonist (e.g. Lupron) therapy using a long-down-regulation protocol arrangement. We currently prescribe the A/ACP to most of our IVF patients regardless of whether they are “normal responders” or “poor responders”. Preliminary results suggest a significant improvement in egg number, egg/embryo quality as well as in implantation and viable IVF pregnancy rates. The A/ACP has however, proven to be most advantageous in “poor responders” where additional enhancement of ovarian response to gonadotropins may be achieved through incorporation of “estrogen priming”. We have reported on the fact that the addition of estradiol for about a week following the initiation of the A/ACP, prior to commencing FSH-dominant gonadotropin stimulation appears to further enhance ovarian response, presumably by up-regulating ovarian FSH-receptors.
There is one potential draw back to the use of the A/ACP, in that the sustained use of a GnRH antagonist ( e.g. Antagon/Cetrotide) throughout the stimulation phase of the cycle, appears to compromise the predictive value of serial plasma estradiol measurements as a measure of follicle growth and development in that the estradiol levels tend to be much lower in comparison to cases where agonist (Lupron) alone is used or where a “ conventional” GnRH antagonist protocol is employed ( i.e. antagonist administration is commenced 6-8 days following initiation of gonadotropin stimulation). Rather than being due to reduced production of estradiol by the ovary(ies), the lower blood concentration of estradiol seen with prolonged exposure to GnRH-antagonist, could be the result of a subtle, agonist-induced alteration in the configuration of the estradiol molecule , such that currently available commercial kits used to measure estradiol levels are rendered much less sensitive/specific. Thus when the A/ACP is employed, we rely much more heavily on ultrasound growth of follicles along with observation of the trend in the rise of estradiol levels, than on absolute estradiol values. Thus we commonly refrain from prescribing the A/ACP in “high responders” who are predisposed to the development of severe ovarian hyperstimulation syndrome (OHSS) and accordingly where the accurate measurement of plasma estradiol plays a very important role in the safe management of their stimulation cycles.
It is remarkable, that while using the A/ACP + "estrogen priming " in “poor responders “ whose FSH levels were often well above threshold limits, the cycle cancellation has consistently been maintained below 10% ( i.e. much lower than expected). Many of these patients who had previously been told that they should give up on using their own eggs, and switch to ovum donation because of “poor ovarian reserve”, have subsequently achieved viable pregnancies at SIRM using the A/ACP with “estrogen priming”.
