An Individualized Approach to Ovarian Stimulation for IVF is Crucial!

Understanding the Basis for Individualizing Protocols for Ovarian Stimulation:
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. post-maturely) 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 orchestrated 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 (predominantly testosterone) are essential to enhance egg and follicle development, over-exposure to excessive amounts of the same hormones can seriously compromise egg (and subsequently, also embryo) quality. It follows that protocols for ovarian stimulation should be geared towards optimizing follicle and egg development while avoiding overexposure to ovarian male hormones. The fulfillment of these objectives requires a very strategic and individualized approach to ovarian stimulation and precise timing of the human chorionic gonadotropin (hCG) “trigger.”

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 at the cells that line the inside of the follicles (i.e. granulosa cells). LH, on the other hand, acts primarily on the connective tissue that surrounds the follicles (i.e. the ovarian stroma or theca) to compel the production of male hormones. Only a small amount of these hormones (predominantly testosterone) is necessary for optimal estrogen production. Overproduction 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 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 Repronex might further aggravate this effect. Thus we strongly recommend against the exclusive use of such products, in PCOS patients, preferring FSH-dominant products such as Folistim and Gonal F. While it would seem prudent to limit LH exposure in all cases of ovarian stimulation, this appears to be more relevant in older women, who tend to be more sensitive to LH

Preparing for Ovarian Stimulation:
Before embarking on ovarian stimulation it is essential to try and define the woman’s ovarian reserve (i.e., the number of eggs still available in her ovaries). Determination of the ovarian reserve will assist in defining the protocol of ovarian stimulation that would most safely yield the optimum number and quality of follicles/eggs in a given case. The ovarian reserve can best be assessed by determining the woman’s blood FSH and estradiol (E2) measurement on the 3rd day of a spontaneous menstrual cycle and by evaluating the manner in which she responded to a most recent cycle of treatment. Other blood tests that can also be selectively used to assist in assessing ovarian reserve are measurement of blood antimullerian hormone and inhibin B levels.
Once the ideal stimulation protocol is selected, the next step is to choose a suitable time for IVF treatment. For women who require a repeated cycle it is advisable that at least one-month be allowed to elapse (“resting cycle”) between IVF treatments, in order to allow the ovaries to fully recover from the preceding stimulation.

It is both clinically beneficial as well as convenient to launch IVF cycles with the woman having been on at least 10 days of combined birth control pill (BCP) such as Desogen or Orthonovum 135. A word of warning: one often hears the expressed opinion that the BCP suppresses response to ovarian stimulation. This is NOT the case, provided that the BCP is overlapped with administration of a GnRH agonist (e.g. Lupron, Buserelin) for several days leading up to the start of menstruation and the initiation of ovarian stimulation cycle with fertility drugs. If the latter precaution is not taken, and the cycle of stimulation is initiated coming directly off the BCP the response will often be blunted and subsequent egg quality could be adversely affected. The explanation for this is that in natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability to properly respond to FSH stimulation is dependent on the recruited follicles having reached the antral phase of development by the time the cycle begins (or similarly, stimulation with fertility dugs is initiated).

The transition of early primary follicles to develop into antral follicles (AF) takes a 3-6 day period of a sustained rise in blood FSH prior to the onset of menstruation.. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise otherwise development will not take place. GnRH agonists (e.g. Lupron, Buserelin, Nafarelin and Synarel) do this by triggering a rapid increase in FSH production. Thus, by overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.

It is also important that there be no functional ovarian cysts at the time ovarian stimulation commences. To insure this, the patients can undergo an ultrasound examination while on the BCP or at the onset of menses immediately prior to initiating ovarian stimulation. At the onset of bleeding a measurement of blood estradiol (E2) is done to insure that it is low enough (under 70 pg/ml) to start administering the fertility drugs. 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 (I personally prefer to aspirate cysts under local anesthesia, on the spot COH.

Unlike GnRH agonists that exert their LH (and FSH) lowering effect by exhausting the pituitary gland of its over 4-7 days GnRH antagonists (such as Ganirelix, Orgalutron, Cetrotide ) do so directly and immediately (within a few hours of administration).Thus both agonists and antagonists of GnRH both serve to establish a “low LH environment” in which follicular and egg development can proceed optimally.

The Choice of Gonadotropin Products to be Prescribed:
The recent availability of DNA-recombinant FSH and LH gonadotropins has made this an easy choice. In my opinion, it is no longer necessary to prescribe urinary-derived menotropins where there could be significant variations in batch to batch biological potency and thus in response to stimulation. There is also (in my opinion) little advantage in using combined FSH/LH urinary-derived products where the additional LH contained in the preparation might in some cases compromise rather than enhance follicle and egg development. Accordingly, with few exceptions I personally only advocate the use of pure DNA-recombinant FSH (Folistim, Puregon and Gonal-F) and LH (Luveris) products for my IVF patients. The exception to this rule is when it comes to prescribing an hCG product. Here I advocate the use of urinary-derived hCG (Profasi, Pregnyl and Novarel) over the DNA recombinant hCG (Ovidrel). In my opinion, at the suggested dosage of administration, Ovidrel lacks the required biological potency. In order to optimize its effect the dosage would have to be doubled and this increases the cost. Besides, the urinary derived hCG products are very effective.

The Protocols:
1. Long GnRH Agonist Protocols: The most commonly prescribed protocol for agonist/gonadotropin administration is the so-called “long protocol”. An agonist (usually, Lupron) is given either in a natural cycle, starting a 5-7 days prior to menstruation or is overlapped with the BCP for two days whereupon the latter is stopped and the Lupron, continued until menstruation ensues. The agonist precipitates a rapid rise in FSH and LH level, which is rapidly followed by a precipitous decline in the blood level of both, to near zero. This is followed by uterine withdrawal bleeding (menstruation) within 5-7 days of starting the agonist treatment, whereupon gonadotropin treatment is initiated (preferably within 7-10 days of the onset of menses) while daily Lupron injections continue, to ensure a relatively “low LH- environment”. Gonadotropin administration continues until the hCG trigger.

2. GnRH-agonist(“micro-flare”) protocols: Another approach to COH is by way of so-called “microflare protocols”. This involves initiating gonadotropin therapy simultaneously 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 concomitant (excessive) rise in LH levels that could evoke excessive production of male hormone by the ovarian stroma. The latter in turn could potentially compromise egg quality, especially in women over 39 years of age, women with diminished ovarian reserve, and in women with polycystic ovarian syndrome (PCOS) - all of whose ovaries have increased sensitivity to LH. In this way, “microflare protocols” can potentially hinder egg/embryo development and reduce IVF success rates. While microflare protocols usually are not harmful in younger women and those with normal ovarian reserve, I personally avoid this approach altogether for safety sake.

3. GnRH antagonist protocols: The use of GnRH antagonists as currently prescribed in ovarian stimulation cycles (i.e. the administration of 250mcg daily starting on the 6th or 7th day of stimulation with gonadotropins) may be problematic, especially in women over 39 yrs., women with diminished ovarian reserve (i.e. “poor responders” to gonadotropins), and women with PCOS. Such women tend to have higher levels of LH to start with and as such the initiation of LH suppression with GnRH antagonists so late in the cycle (usually on day 6-7) of stimulation fails to suppress LH early enough to avoid compromising egg development. This can adversely influence egg/embryo quality and endometrial development. As is the case with the “microflare”approach (see above) the use of GnRH antagonist protocols in younger women who have normal ovarian reserve, is acceptable. Again, for reasons of caution, and because I see no benefit in doing so, I personally never prescribe this approach for my patients.

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 is the 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 against follicular exhaustion by administering GnRH antagonists during the final few days of ovarian stimulation is like trying to prevent a shipwreck by by removing the tip of an iceberg.

4. The agonist/antagonist conversion protocol (A/ACP): With a few (notable) exceptions I preferentially advocate this protocol for many of my patients. With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by taking a BCP for at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days later her menstruation starts, she supplants the agonist with a half dosage (125mg) of an antagonist (e.g. Ganirelix, Orgalutron or Cetrotide).Within a few days of this switch-over, gonadotropin stimulation is commenced. Both the antagonist and the gonadotropins are then continued until the hCG trigger. The purpose in switching from agonist to antagonist is to intentionally allow only a very small amount of the woman's own pituitary LH to enter her blood and reach her ovaries, while at the same time preventing a large amount of LH from reaching her ovaries. 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. Also, since agonists might suppress some ovarian response to the gonadotropin stimulation, antagonists do not do so. It is for this reason that the A/ACP is so well suited to older women and those with some degree of diminished ovarian reserve.

The follicles/eggs of women on GnRH-agonist “micro-flare protocols” can be exposed to exaggerated agonist-induced LH release, (the “flare effect”) while the follicles/eggs of women, who receive GnRH antagonists starting 6-8 days following the initiation of stimulation with gonadotropins can likewise be exposed to pituitary LH-induced ovarian male hormones (especially testosterone). While this is not necessarily problematic in younger women and those with adequate ovarian reserve (“normal responders”) it could be decidedly prejudicial in “poor responders” and older women where there is increased follicle and egg vulnerability to high local male hormone levels.

5. Long protocol (or A/ACP) with estrogen priming: Women who have a significant degree of diminished ovarian reserve are first given GnRH agonist for a number of days to effect pituitary down-regulation. Upon post-BCP/agonist-induced menstruation, the dosage of GnRH agonist is drastically lowered (or commonly is supplanted by 125mg daily of an antagonist) and the woman is given twice-weekly injections of 2-4mg of estradiol valerate (E2V) for a period of 7-10 days. Ovarian stimulation is then initiated using a relatively high dosage of an FSH-dominant gonadotropins such as Folistim, Puregon or Gonal F for a few days, whereupon the dosage is reduced and a small amount of DNA-recombinant LH (Luveris) is added daily. Both the FSH and the LH are then continued along with daily administration of GnRH agonist (or antagonist) until the “hCG trigger”. The reason for the “estrogen priming” is because it enhances follicle response to FSH and also helps optimize the uterine lining.
We recently reported in a prestigious medical Journal on results using the A/ACP with estrogen priming in older women and women with diminished ovarian reserve where the approach has proven to be most advantageous.

There is one potential drawback to the use of the A/ACP. We have learned that prolonged use of a GnRH antagonist throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements to evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation, the blood E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment is only commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear. Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to assess progress. Also, younger women (under 30 years) and women with absent, irregular or dysfunctional ovulation, and those with polycystic ovarian syndrome are at risk of developing life-threatening severe ovarian hyperstimulation. The prediction of this condition requires daily access to accurate blood E2 levels. Accordingly we currently tend to refrain from prescribing the A/ACP in such cases, preferring instead use the “standard long-protocol” approach.