Jean-Claude Emperaire1
(1)
Bordeaux, France
Classic ovulation stimulation involves three successive steps:
1.
2.
3.
It should be noted at this point that most of the effort involving protocol development have essentially concerned the stimulation step. However it is at least as important that the two other steps should progress in a harmonious way that facilitates chances for a successful pregnancy in the selected indication, be it correction of ovulation abnormalities, restoration of ovulation, improvement of cervical mucus, or preparation for an intra-uterine insemination.
9.1 Objectives
The stimulation itself should work toward two principal goals:
· To mimic or adjust the normal menstrual cycle. Stimulation of monofollicular development consists of provoking or facilitating growth of one single follicle in the same manner normally accomplished by physiologic menstrual cycle, whereas a paucifollicular stimulation seeks the growth of two or three follicles. In order to mimic or alter slightly the natural cycle, one should strictly apply the rules already established by nature, i.e., to apply a strategy of gonadotropin administration that follows the basic principles of identifying an FSH threshold and window. Manipulating these parameters should attain the chosen objective, whatever the beginning situation may have been.
· To avoid complications: Insufficient or inadequate stimulation may result in a defective ovulatory process (e.g., abnormalities of oocyte maturation, follicular rupture, or corpus luteum function) that can paradoxically decrease the patient’s chances for successful pregnancy during the treated cycle. This outcome should be considered as a true complication despite the absence of “symptoms.” A succession of treatment failures make it tempting for patients to consider without due cause the more difficult road to assisted procreation, when the reality was simply a poor management of the ovarian stimulation.
Excessive stimulation is much easier to recognize because it is more symptomatic, exposing the patient to risks for ovarian hyperstimulation, multiple pregnancy, or both. The risks for these untoward results are of course greater in paucifollicular than monofollicular stimulations.
Ovarian hyperstimulation might occur only when development of the leading follicle(s) evolves in concert with numerous smaller follicles (<10 mm), a situation that can be easily discovered by ultrasound and plasma estradiol levels that rise abnormally high for one to three mature follicles.
Multiple pregnancy can only occur when a dominant and additional secondary follicles develop together, and become capable of growing and ovulating during the activity lifespan of the hCG injection that was intended to trigger only the lead follicle.
9.2 Methods of Stimulation
The difference between a successful stimulation and a defective stimulation leading to cycle cancellation has less to do with the choice of gonadotropin preparation and more to do with the administration protocol. The somewhat more simple monofollicular stimulation will be described here first, with the means for recruiting and sustaining the development of one or more additional follicles being reserved for the section on paucifollicular stimulation.
Basically, the parameters of “step-up,” “step-down,” or combined protocols are chosen to locate the FSH threshold, to manage the FSH window, and then to sustain appropriate follicular development so that only the optimal follicle continues to mature.
9.2.1 The Starting Dose
The prevailing consensus about an FSH threshold was first described 25 years ago by Brown and his colleagues [1], in an era prior to ultrasound technology. They also stressed the concept of inter-patient variability for this threshold, as well as more limited inter-cycle variations within the same patient. Because the ovarian follicle seems to respond to a particular level of FSH rather than to a particular administered dose, the issue is in fact how to characterize the relationship of injected dosage to resulting blood level. This is a complex multifactorial relationship that depends on severable variables:
· Existing endogenous FSH secretion that occurs in every patient, except for those rare instances of hypogonadotropic hypogonadism
· The route of administration, particularly when thick layers of subcutaneous fat create a “depot” effect at the injection site
· The volume of distribution of injected FSH that is also somewhat related to the patient’s BMI
· The metabolic clearance rate of the FSH preparation that varies according to its isoform composition and degree of sialylation, and also in relation to the patient’s age; these parameters all affect accumulation of hormone in plasma
· Inter-patient variations of FSH threshold related to: (a) individual physiologic parameters specific to each patient, which can account for different FSH plasma levels resulting from identical injections, and (b) variable ovarian sensitivity to FSH within each patient, which explains why patients will react differently to the same FSH level
Relationships between plasma levels and FSH threshold have been extensively investigated by Schoemaker, who monitored plasma levels daily while making very precise adjustments to dosing in order to restrict variations in plasma on the order of 1 IU/l [2]. It was found that the quantity of injected gonadotropin necessary to obtain the same plasma FSH level could vary substantially from one patient to another, but that inter- and intra-patient variations in the ovarian response to a given FSH plasma level are much smaller, save for PCO patients. While “usual” patients can be expected to show no follicular response to blood levels below 7.8 IU/l, the actual FSH threshold can vary from 6.3 to 9.8 IU/l in PCO patients with large inter-individual variations being related to differences in ovarian sensitivity.
Aside from these variations between patients, the FSH threshold and thus the starting dose are also correlated to other parameters such as patient age, AFC, AMH level, and her BMI. Several attempts for predicting the best FSH starting dose have been proposed: for example, Frieseleben’s algorithm that takes into account only the patient’s AFC and weight [3]. However, these are only probabilities, and for an initial stimulation cycle it seems preferable to lean toward a lower dose if only because an insufficient dosage is easier to handle than an excessive one.
9.2.2 Selecting a Protocol
Schoemaker’s study also confirms that a minimal increase of FSH, as low as 1 IU/L above the threshold, may lead to multifollicular development. This finding illustrates two main basic principles:
· The increment of administered gonadotropin doses must remain small, so that plasma FSH levels do not rise too rapidly. There is indeed a narrow range between the dose which elicits no response, even if administered indefinitely, and the dose responsible for multifollicular development. This dose range may not exceed 25–37.5 IU, and perhaps less.
· The increment of FSH doses must remain progressive, as it takes 4–6 days for plasma hormone levels to stabilize, and also because the follicular recruitment period may spread over 5–15 days. This explains why FSH may be administered in three different types of protocol.
9.2.2.1 The “Step-Up” Protocols
Definitions of the protocols for gonadotropin administration began in the mid-1960s, when monitoring by measuring levels of urinary estrogens became available. The earlier stimulation method originally proposed by Crooke, that utilized very high single dosing or a fractionated 3-dose process was abandoned for one of two “step-up” designs [4]:
· A Lunenfeld-Rabau proposal that each dose increment should be 75 IU (one HMG vial)
· A proposal by Brown that increments should not increase over the previous dose by more than one-third
The Israeli protocol continues as the more frequently used, although many Australian clinicians have held strongly to Brown’s ideas.
9.2.3 The Standard Step Up Protocol
Basically because of its simplicity, this remains the most widely used protocol, particularly for spontaneously ovulating women. The fundamental approach begins with a daily FSH dose of 50–75 IU, with the first monitoring conducted after 5–7 days of administration. If no mature follicle is detected, there are three possible situations (Fig. 9.1):
Fig. 9.1
Step-up standard protocol
· A beginning follicular response, evidenced by the appearance at ultrasound of a follicle of at least 10 mm diameter plus a concomitant rise of plasma estradiol. In this case the stimulation should continue with the same FSH dose, and a second evaluation should be scheduled for 2–3 days later. Experience has shown that the starting dose can be continued throughout the complete stimulation cycle in most cases.
· Absent follicular response: the absence of visual evidence of any developing follicles suggests that the FSH threshold has not been reached. The dose should be increased by 50 or 100 % in line with the plasma estradiol profile. It there is still no response after another 5–7 days, the FSH dose may be increased once or twice more, but if no development ensues, it is preferable to stop the present stimulation cycle and undertake a new cycle with a higher starting dose.
· A plurifollicular response accompanied by rapidly rising estradiol levels. This indicates that the FSH threshold has been overcome. One might consider beginning a “step down” approach, but it may also be prudent to stop the present cycle and undertake a new stimulation cycle using a lower starting dose of FSH, a step-up low dose protocol, or both.
The theoretical drawback of these traditional step-up protocols is that they often move rather distant from the principles of a natural cycle, nevertheless requiring a careful monitoring. On the other hand, this design offers an advantage of dose adaptations over short periods of time. In addition, it is fairly simple to manage, particularly with clinicians who are still relatively inexperienced with ovarian stimulation protocols. Further, the design is relatively simple for patients to follow. Only one or two monitoring controls are required per cycle, and indeed the strategy is quite effective in most spontaneously ovulating women.
9.2.4 The Step-Up Low Dose Protocol
Because of persistent risks for multifollicular development in PCO patients, occurring despite using urinary FSH in a standard step-up protocol, Siebel was led to define the principles for a low dose treatment strategy. It should be pointed out that his initial proposal was simply to reverse the FSH/LH ratio of the injections by administrating “pure” FSH [5]. Polson deserves credit for revisiting the concept of an FSH threshold by folding in an initial administration of low FSH doses [6]. The latter step actually adopted Brown’s initial recommendations for a more progressive increase in the FSH doses, because he had noted that in certain patients, an increment of only 10–30 % was sufficient to move from no response to a plurifollicular reaction. Without the help of ultrasound, this author proposed to start stimulations at 100 IU FSH for 5 days, and if no follicular response were detected, to increase this daily dose by 30 % every 5 days until a response appears. This final level of dosing is then continued until ovulation is triggered [1].
In practice, the low-dose step-up protocols usually begin with 50–75 IU FSH daily for 7 days (Fig. 9.2). If a 10 mm diameter follicle appears by this point, the same dose is maintained until the triggering criteria are met. If there is no follicular response after 7 days of stimulation, the dose is increased by half the initial dose for another 7 days, and so on. When a follicular response does appear, this dose is maintained until ovulation is triggered.
Fig. 9.2
Step-up low-dose protocol
In case of an excessive response, it is still possible to diminish the FSH dose, or to stop the treatment cycle altogether, and start another one with a lower initial dose, and/or to proceed with only 25 % increments of the initial dose. If hyper-responsive difficulties persist, move to an even lower dose protocol.
The more physiologic design of this step-up low-dose protocol avoids many hyper-responses, and monitoring is not more demanding. For this reason the protocol has progressively replaced the standard step up in non ovulatory patients.
9.2.5 The Step Up Chronic Low-Dose Protocol
This design begins in similar fashion to the low dose protocol by starting with 50–75 IU FSH for 7 days. If a response does not appear, the same dose is maintained for another 7 days, in contrast to the low dose protocol, because this treatment interval is closer to the recruitment duration that may run between 5 and 15 days (Fig. 9.3).
Fig. 9.3
Step-up chronic low-dose protocol
If no response appears after 14 days, then the FSH dose is increased by half of the initial dose for another 7 days, and then increased similarly at weekly intervals, as with the low-dose protocol. When a follicular response finally occurs, the FSH dose remains unchanged until ovulation triggering.
If no response is observed after 35 days of stimulation, the cycle should be abandoned, and the next one initiated at 150 % of the previous starting dose. On the other hand, if the response becomes excessive, the stimulation cycle must be halted and the next treatment cycle begun with a lower starting dose of FSH.
The low-dose and chronic low-dose step-up protocols yield comparable results in anovulatory patients [7]. In contrast to the standard step-up protocol, the step-up low-dose designs represent a true advance for some PCO patients because they combine a high rate monofollicular cycles and of successful pregnancy together with a substantial reduction of risks for multiple pregnancy and/or OHHS. On the other hand, a drawback to this protocol is the need for continuous monitoring during stimulation that may potentially go on for several weeks. This can lead to problems of feasibility or compliance, although only some 10 % of patients appear to discontinue treatment because of lack of ovarian response after 35 days of stimulation. To avoid these overly lengthy stimulation phases, one may consider starting a new cycle with a slightly higher FSH dose than the dose level that reached the FSH threshold in the previous cycle, even if that leads to a decreased dose later on. On the other hand, if the chronic low-dose level remains too high, it is still possible to decrease the starting dose and/or the dose increment (e.g., by one-fourth of the initial dose), thereby creating a sort of step-up, chronic, ultra-low dose protocol.
All the step-up protocols do vary somewhat from the physiologic spontaneous menstrual cycle. While they usually reach the FSH threshold in a more or less progressive fashion, they also maintain this elevated dose throughout the whole stimulation period. In a normal physiologic cycle, levels of FSH elevate rapidly during the first few cycle days, and then decline throughout the remainder of the follicular phase. Maintaining a dose regimen that achieves an FSH plasma level higher than the threshold may hold the FSH window open for recruitment of additional follicles, thus producing a plurifollicular response. Repeated daily administration of a fixed FSH dose will cause an over-abundance of hormone in plasma by the end of the stimulation phase. All of these potential drawbacks are taken into account in the design of the step-down protocols.
9.2.5.1 The Step-Down Protocol
This protocol initially designed by Mizunuma et al. was later extensively studied and refined by Fauser et al. [8, 9]. It was initially confirmed that the early rise of FSH in normal menstrual cycles reached a mean of 6 IU/l on cycle day 5, with a variance factor of 2.5 between women. Hormone levels were then observed to diminish by 0.5 IU/l per day to a mean nadir of 2.9 IU/l on cycle day 13. They also reported that the first detectable rise of the plasma estradiol coincides with the ultrasound appearance of a 9–10 mm diameter structure, namely the emerging dominant follicle.
The principle of the step down protocol is to start the stimulation with an FSH dose tailored to overcome the FSH threshold so that several of the most sensitive elements of the ovarian follicular pool begin to grow. Once the dominant follicle has appeared, the daily FSH dose is then progressively reduced so that only the most sensitive follicle continues to develop (Fig. 9.4).
Fig. 9.4
Step-down protocol
In practice the stimulation sequence begins with 150 IU FSH daily for 5 days:
· If monitoring shows the beginning of an ovarian response, the FSH dose is decreased by a fourth every 3 days until a minimum of 75 IU, and this dose is maintained until ovulation triggering.
· If there is no ovarian response after 5 days of stimulation, the daily dose is increased by 37.5 IU every 5 days, for a maximum of two additional increases.
· If there is still no ovarian response after 15 days of stimulation, the cycle should be halted, and the next treatment cycle should start with a dose of 187.5 IU (125 % of the previous starting dose).
This protocol, while attractive in theory, may in fact be somewhat difficult to manage:
For one thing, the precise moment for reducing the FSH dose, marked by the appearance of a 9–10 mm follicle together with an estrogenic response, is not always easy to recognize, and problems of interpretation may occur. Diminishing the FSH dose too early might lead to an irreversible follicular atresia, and reducing the dose too late may lead to plurifollicular stimulation, two opposing causes leading to the same outcome, i.e., abandoning the treatment cycle.
Another problem is that the proposed starting dose of 150 IU FSH is arbitrary and does not take into account the FSH threshold of each patient. 150 IU may be quite excessive for some patients, and provoke a plurifollicular development that the successive dose reductions may not be able to control. This again can lead to having to stop the cycle and start another one at 50 % of the previous starting dose.
9.2.6 Step-Up and Step-Down (Sequential) Protocol
This approach combining the step-up and step-down protocols was first made by JN Hughes, in order to benefit from the advantages of each. The stimulation begins similarly to a step-up low-dose protocol, so that the FSH dose does not overcome ovarian sensitivity. Once the dominant follicle is recognized, the same dose is maintained for a few days, and then is decreased in order to prevent development of secondary and tertiary follicles. This secondary reduction in the FSH dose is thus delayed, in contrast to the regular step-down protocol [10].
Specifically, the sequential protocol should be conducted as follows (Fig. 9.5):
Fig. 9.5
Sequential step-up/step-down protocol
· Begin stimulation with a 50–75 IU FSH dose for 6–7 days, then increase by half of the starting dose (25–37.5 IU) at intervals of the same duration until a 9–10 mm diameter follicle appears
· Maintain the same FSH dose until the dominant follicle reaches the empirically chosen diameter of 14 mm
· Reduce the FSH dose by half and maintain this level until the ovulation is triggered
This attractive protocol, like the step-down protocol, may also encounter problems, mainly being able to recognize with certainty the crucial moment when the FSH dose should be reduced.
9.2.7 Summary
Clinicians finally have at hand a variety of therapeutic plans that should resolve every sort of challenging problem posed by the stimulation process.
Step-up protocols continue to be the most widely used to initial trials, and remain the standard approach for ovulatory women. On the other hand, nonovulatory patients should be initially started with a low-dose schedule.
Step-down and sequential protocols share the same difficulties regarding the decision point for reducing the FSH dose. More experience may be necessary before undertaking these protocols because they are more operator-dependent as well as harder to reproduce. They are especially tailored for the very few patients who are hypersensitive to FSH, especially following failures with low dose and ultra low dose protocols. Furthermore, abandonment of several consecutive stimulation cycles after many daily injections and monitoring controls may lead even the most dedicated patient to relinquish her treatment.
9.3 Stimulation Monitoring
Monitoring must be conducted using both hormonal and ultrasound parameters. Conventional 2D ultrasound is quite adequate for measuring the mean diameter of one or several follicles. The plasma estradiol assay is mandatory, as estradiol production reaches a maximum 6 h after FSH administration and is maintained at this level for at least 24 h [11]; it also helps to distinguish a functional follicle from a follicular cyst. A progesterone assay is useful for detection of a possible premature luteinization, and the LH assay is necessary to locate the best moment for a single intercourse or insemination.
There are three basic principles for adapting FSH doses to the ovarian response. All are related to the dynamics of estradiol levels and ultrasound data, and all are fairly intangible:
· Decrease the FSH dose when estradiol increases faster than follicular growth
· Maintain the same FSH dose when the estradiol rise and follicular growth are at the same rate
· Increase the FSH dose when the estradiol level lags behind follicular growth; when this type of response repeats itself on the next cycle, consider to add LH to FSH administration
These principles underlie the reason why protocols that rely only on ultrasound data are merely indicative and incomplete. At similar ultrasound readings, measures of estradiol patterns will lead to different clinical decisions.
For example, in cases of discrepancy between ultrasound evaluation and estrogen responses:
· A beginning estrogen response without a recognizable ultrasound reaction may lead to a decision to delay the FSH dose increase
· A beginning ultrasound response with no sign of an estradiol rise may lead to increasing the FSH dose sooner than originally scheduled.
Finally, the rhythm and number of monitoring controls should of course be suited to the selected protocol, and also to the patient’s possibilities. While it remains true that conducting more frequent controls brings more precision to the monitoring process, the rules should sometimes be softened, and whenever possible consider the situation, sensibility, and availability of each patient.
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