Jean-Claude Emperaire1
(1)
Bordeaux, France
Ovulation is simply the focal destruction of the follicular wall that enables extrusion of the oocyte and follicular contents through the breach. A space of some 36–40 h passes from the initial gonadotropin surge to the follicular rupture itself, during which irreversible actions reprogram the entire structure and function of the follicle, reawaken oocyte meiosis, alter the follicular wall, and commence the process of luteinization.
6.1 The Ovulatory Process
6.1.1 Oocyte Maturation
The surge of pituitary gonadotropins provokes a resumption of meiosis in the oocyte nucleus that had been suspended in prophase of the first meiotic division since intrauterine life. As the first polar body is expelled, meiosis arrests once more in metaphase of the second meiotic division, and will be completed only after the ovum is fertilized. Oocyte cytoplasmic maturation develops in the same way, being marked by characteristic granulations that migrate under the cell’s cortical membrane.
6.1.2 Follicular Rupture
This event terminates a process of biochemical transformations that result in an increased internal pressure and a weakened follicular wall. The gonadotropin surge inhibits further synthesis of basal membrane components and stimulates proteolytic enzymes, both of which contribute to a weakening of the follicular wall. Gonadotropins also induce an enzymatic deterioration of large follicular fluid proteins into numerous smaller molecules, a process that augments osmotic pressure and a diffusion of water into the follicle. The combination of follicular swelling acting on a weakened wall leads to a rupture that completes the ovulation [1]. This stepwise chain of events occurring within the follicle explains the latency period between the start of the pre-ovulatory gonadotropin surge and the completed rupture. It also helps understand why a defective component of this process may lead to an unruptured follicle (luteinized unruptured follicle, LUF syndrome).
Follicular luteinization actually commences just before oocyte extrusion, although theca interna vascularity invades the previously avascular granulosa layer only after ovulation. The luteal body, or corpus luteum, continues to secrete a reduced level of estradiol for a few days because of the perturbations of follicular rupture, and then pre-ovulatory levels return only to decline again at the end of the cycle. Primarily the new luteal gland secretes high levels of progesterone (>10 ng/ml in plasma) before declining as well at the end of the luteal phase. Corpus luteum waning is an apoptotic process programmed to start after 12–14 days, unless the gland has been rescued by exponentially rising secretions of hCG from an implanting embryo.
6.2 Spontaneous Triggering of Ovulation
Natural ovulation is triggered by a pre-ovulatory surge of both pituitary gonadotropins FSH and LH, secondary to a rise of GnRH secretion into the hypothalamic-pituitary portal system (Fig. 6.1).
Fig. 6.1
GnRH and gonadotropin pre-ovulatory surges. Note the secondary pituitary desensitization provoked by sustained secretion of GnRH [35]
6.2.1 The Normal Menstrual Cycle
Wave profiles of LH secretion have been analyzed in some detail. Typical pre-ovulatory surges, lasting about 48 h, begin with an ascending phase of 14 h, settle at a plateau for another 10 h, and move through a 24 h declining phase [2]. Although a few cycle-to-cycle variations are possible, each woman seems to have a fairly unique pre-ovulatory surge profile [3]. Profiles can be substantially different between women, particularly with regard to two important parameters (Fig. 6.2):
Fig. 6.2
Comparative characteristics of the spontaneous pre-ovulatory surges of FSH and LH [2]
· Magnitude: Surge levels in blood can vary between 25 and 150 IU/l in different individuals, and the intensity seems to correlate with the chance of achieving pregnancy within that cycle.
· Duration: Often consistent with the surge magnitude, duration correlates even better with the chance of the cycle ending in a pregnancy [4].
The physiologic importance of the synchronous FSH surge, while of a lesser magnitude (5–12 IU/l) than LH, is less completely established, but it is well understood that FSH plays an important role in the follicular expansion leading to ovulation. In fact, it is possible to trigger an ovulation (or at least the resumption of meiosis) in controlled ovarian hyperstimulation (COH) with FSH alone [5]. It has also been claimed that addition of an FSH bolus to the ovulation-triggering hCG administration results in a superior quality of oocyte and embryo [6]. It is probable that the two gonadotropins act in synergy during the pre-ovulatory surge, and concurrently optimize the ovulatory process and development of the corpus luteum.
6.2.2 The Stimulated Cycle
During ovarian stimulation procedures, a normal spontaneous gonadotropin surge of sufficient magnitude may result from the effect of rising estradiol levels in the presence of a mature dominant follicle that is primed to ovulate. This surge event usually occurs during a proper stimulation using pulsatile administration of GnRH or with oral clomiphene citrate, but gonadotropin treatment alone can also trigger a normal ovulation. The only drawback to this event is that it disorganizes plans for an in utero insemination, since the precise moment of the initiating gonadotropin rise becomes uncertain.
On the other hand, a triggered ovulation may not occur spontaneously during a cycle stimulated with gonadotropins, even in the presence of a mature follicle. For one thing the hypothalamic-pituitary-gonadal axis may be disrupted by supra-physiologic levels of estradiol. In addition, erratic gonadotropin surges of low magnitude and duration that are still incapable of initiating the complete ovulatory process may induce a premature luteinization of the follicle and/or a secretory transformation of the endometrium. Either event will adversely affect chances for a successful pregnancy. For these important reasons an ovulation should be medically triggered as soon as the follicular maturity criteria have been met.
6.3 Therapeutic Triggering of Ovulation
The triggering of ovulation is a crucial moment of the treatment. If done too early, the selected follicle may be still immature, and follicular rupture may not occur, or it may be difficult to fertilize the oocyte. If done too late, the follicle may be hypermature, leading to the same consequences. Judging follicular maturity criteria requires both morphological and functional assessment.
6.3.1 Sonographic Criteria
6.3.1.1 Follicular Diameter
The mean diameter of a mature follicle is typically between 16 and 23 mm. Although there are no clear-cut data in the literature, it is claimed that this optimal diameter can vary in accordance with the specific gonadotropin preparation used for the stimulation: a bit larger with HMG use (average 18 mm) than with FSH use (average 16 mm), and both being lesser than when clomiphene is used (average >20 mm) [7]. However, one study has shown that the pregnancy rate when using HMG was comparable when the mean dominant follicular diameter was only 16 mm or larger at the time of hCG administration [8].
6.3.1.2 Uterine Mucosa
The endometrium itself must be anechogenic, in three distinct leaves, and with the “coffee bean” appearance. Thickness should optimally reach at least 7 mm, although a successful nidation may occasional settle on a slightly thinner mucosa.
6.3.1.3 Hormonal Criteria
The level of secreted estradiol, by the dominant follicle(s) as well as the smaller ones, depends on the stimulation protocol. Expect levels to be greater than those in the normal physiologic pre-ovulatory phase:
· For a monofollicular stimulation, estradiol should be between 150 and 350 pg/ ml.
· For a paucifollicular stimulation, estradiol levels will be much higher, between 500 and 800–1,000 pg/ml, and are dependent on the number of dominant follicles.
· For multifollicular stimulations (or COH), estradiol level is also a function of the number of follicles to be punctured, and should run between 70 and 140 pg/ml per follicle >14 mm diameter [9]. The only remaining matter of debate concerns these upper values that seem to vary among different clinicians in accordance with their own perception of the risks of hyperstimulation. The upper limit of safety is typically acknowledged to be 2,500 pg/ml, although some clinicians accept upper ranges in excess of 5,000 pg/ml.
6.3.2 Chorionic Gonadotropin
Pituitary LH has never been available in clinical practice for procedures of triggering ovulation. This role has been relegated to placental hCG since the earliest days of ovulation stimulation, when PMSG was the sole available FSH product. Chorionic gonadotropin is without effect on the resting ovary. It may provoke follicular atresia or luteinization when administered during the early part of the menstrual cycle, and of course it exerts a trophic effect on the corpus luteum when administered during the luteal phase. This latter action is able to extend the functional life of a corpus luteum unless it is has already begun to wane. When administered in the presence of a mature follicle, hCG triggers ovulation no matter the gonadotropin that had been used to stimulate development. It is quite paradoxical that, despite considerable progress in strategies for ovulatory stimulation that closely mimic the physiologic process, the use of “nonphysiologic” hCG to trigger the actual ovulation has never been questioned, either in principle or in practice. In fact, the main natural hormone for triggering physiologic ovulation is LH, in association with FSH, and LH indeed exhibits numerous distinctions from hCG.
6.3.3 LH and hCG
Both of these hormones are glycoprotein heterodimers sharing the same alpha subunit but having unique beta subunits, although the primary sequences of beta LH and hCG subunits are actually the most closely homologous (96 %) of all glycoprotein hormones. Both complete hormones also possess a high degree of specificity for the same receptor (LH-hCG-R). The sequence of the hCG-β subunit includes a chain of 31 additional amino acids at the carboxyl-terminal end, and increased sialic acid content also contributes to a greater molecular mass. Because of this hCG has a slower hepatorenal degradation, a slower renal elimination rate and thus a longer plasma half-life. A partial desyalization of hCG brings its pharmacodynamic properties as well as its clinical effects in closer alignment to those of LH [10].
The elimination curve of both hormones is bi-exponential. LH shows an initial rapidly decreasing phase of about 45 min half-life (versus 8 h for hCG), followed by a second slower decline of some 10 h (versus 35–56 h for hCG). Recombinant hormone and extracted preparations have the same elimination curves as natural hormone [11]. The slow elimination of hCG explains why the hormone is still detectible for as long as 2 weeks following a 10,000 IU administration, and this property assuredly complicates interpretation of a standard pregnancy test one might conduct following a triggered ovulation [12]. In addition, the slower elimination rate assures that a single administration of hCG will be capable of providing a comparable or longer LH-like action to an endogenous pre-ovulatory gonadotropin surge. Repeated daily injections of hCG will cause a progressive accumulation in plasma, especially when administered by the IM route. Thus repeated hCG administration runs a risk for a hyperstimulation syndrome, without enhancing the clinical efficacy (Fig. 6.3) [13].
Fig. 6.3
Plasma accumulation of hCG following repeated administration [13]
Commercially extracted urinary hCG is very heterogeneous: preparations may contain as much as 45 % chain fragments having little or no activity, with significant batch-to-batch variations [14]. On the other hand, the development of a recombinant hCG has ended with a product consisting of 100 % complete hormone.
6.3.4 Triggering Ovulation with hCG
In the past, programs of ovarian stimulation with gonadotropins would trigger ovulation with one to several hCG doses of 1,000–3,000 IU each, administered either simultaneously with or shortly following the final HMG injection. The only true advance in this design came in the early 1960s when hCG administration was reduced to one single dose, usually on the day after the last FSH injection.
The basic issue regarding the precise dose that is both necessary and sufficient to trigger an adequate ovulation has really never been resolved, undoubtedly because of the absence of recognizable side effects when unnecessarily high hCG doses are used. Nevertheless it has been documented with animal studies that excessive hCG dosing can induce a rather brutal luteinization of the dominant follicle, leading to a LUF syndrome [15]. Brown described an hCG threshold, similar to that for FSH, and did not hesitate to give 40,000–60,000 IU hCG for triggering ovulation in some patients, although this was done prior to the availability of ultrasound monitoring [16]. Nevertheless it would seem useful to address the question of an optimal dose, at least on the theoretical level.
Basic principles of endocrinology practice hold an exact quantity of any administered hormone should be determined in order to produce a precise effect. In other words, what is true for FSH administration should be the same for hCG. It seems archaic to decide that an appropriate dose of hCG to trigger ovulation relies on little more than the patient characteristics and the stimulation intensity.
However, more out of habit than from solid scientific evidence, the typical hCG dosing level has become:
· Approximately 5,000 IU for a mono- or paucifollicular stimulation
· Approximately 5,000–10,000 IU in COH
Work published by Abdallah indicated that although a dose of 10,000 IU does not provide a significant benefit in comparison to 5,000 IU in COH protocols, the lower doses may still be insufficient in some patients [17]. The bioavailable level of hCG is a function of the injected dose but also of the patient’s BMI. A 5,000 IU dose may result in fewer harvested oocytes and diminish the chances for a successful pregnancy in the obese patient [18].
It is nevertheless well established that the different steps of the ovulatory process do require different amounts of hCG for optimal completion. Whereas lesser amounts should be sufficient to resume meiosis and an adequate oocyte maturity, higher doses are required for actual follicular rupture, and still higher levels are needed to establish and maintain a fully functional corpus luteum [19]. This is the reason why stimulation models used for IVF, where follicular puncture for ovum retrieval replaces the hormone-induced rupture, and where the luteal phase is supported by exogenous progesterone administration, have turned out to be inadequate for ovulation triggering in classic stimulation protocols, where lower doses may be sufficient. We have demonstrated that doses of 5,000, 3,000 or even 1,500 IU uhCG can provide comparable results regarding frequency of the follicular rupture, plasma progesterone levels, length of the luteal phase and pregnancy success rates [20]. Indeed, an adequate ovulatory process may even be triggered with 500 IU hCG administered intravenously [21]. In the practical sense, a 5,000 IU dose of extracted hCG seems sufficient for triggering ovulation following a classical (non-COH) stimulation with gonadotropins, and for guarding against possible variations of batch-to-batch bioactivity.
There has been considerable hope that the synthesis of rhCG (choriogonadotropin alpha, Ovidrel®) would finally provide an opportunity for precise characterization of appropriate doses for each type of stimulation protocol, and to modify some old habits long unsupported by scientific validation. Unfortunately this has not occurred, offering more evidence of the complete lack of interest on the part of the clinical-scientific community in menstrual cycle events occurring after the administration of hCG. The strategy of determining appropriate rhCG doses has merely attempted to approximate the plasma elimination curve of uhCG, and has resulted in release of only one dosage size at 250 μg, equivalent to 5,000–6,500 IU uhCG. This has at least pleased both supporters of the 5,000 and 10,000 IU doses. On the other hand, administration of a double-sized dose of rhCG (i.e., 500 μg) significantly enhances the risk for OHSS without bringing a superior clinical outcome [22].
6.3.5 hCG Administration and Follicular Rupture
Complete follicular rupture, as documented by ultrasound, actually takes place over a lengthy period of time following a single I.M. administration of hCG. With a mean time interval of about 40 h, follicular rupture occurs prior to the 36th hour in only 10 % of cycles, and not until after 48 h in another 10 % of cycles [21]. These time intervals following hCG administration are comparable to those observed from the beginning of the endogenous pre-ovulatory surge of gonadotropins, characterized by an LH surge initiating rise (LH-SIR) [3].
In clinical practice, however, the precise knowledge of the very moment of the follicular rupture is paradoxically of little help to assure success of the treatment cycle: other poorly understood parameters seem to be involved in the pregnancy rate, such as the penetration and survival of the spermatozoa within the cervical mucus, the duration of the spermatozoa fertilizing ability in vivo, and of the oocyte fecundability. For example, a large retrospective study reported comparable pregnancy rates if intra-uterine insemination occurred between the 28th and the 48th hours post-hCG (or within that same duration from the beginning of a spontaneous gonadotropin surge). Results were significantly lower for less than 28 h [23]. On the other hand, the pregnancy rate seems higher when performing insemination during the first day rather than the second after the LH rise [24]. Optimal intervals were even less well defined for the intra-cervical insemination, where the behavior of the spermatozoa within the cervical mucus becomes an important factor. Pregnancy rate was comparable when the insemination occurred on the same day or following day after of the hCG administration. Of course, a single programmed intercourse should occur within the same time interval.
6.3.6 Luteinizing Hormone
Using LH itself for triggering ovulation would avoid a number of potential hazards of hCG administration. This could be achieved either by mobilizing the pituitary gonadotroph LH pool, found in essentially all stimulated patients, with gonadorelin (GnRH) or a GnRH agonist (GnRHa), or by administration of recombinant LH itself.
6.3.6.1 Endogenous LH
Administration of hypothalamic GnRH mobilizes an initial burst of stored FSH and LH, and a gonadotropin surge that is capable of triggering ovulation of a mature follicle; this strategy has been studied since GnRH agonists first became available. However, this kind of induced surge is capable of inducing a significant proportion of abnormal luteal phases.
Regardless of the particular short-lived agonist used, a single administration results in a gonadotropin surge with a characteristic profile. Initially, a synchronous peak for both FSH and LH is reached within 4 h, at median levels of 150 and 45 IU/l for LH and FSH, respectively. From that point levels decrease gradually and return to baseline within 24 h in most patients (Fig. 6.4). This profile is quite different from the normal endogenous pre-ovulatory gonadotropin surge in that it begins more quickly, rises to higher peaks, and terminates sooner (Fig. 6.5). Nevertheless, a single administration of a short-lived GnRH agonist provides the same chance for a successful pregnancy as an injection of hCG, whether in a classical or a COH stimulation protocol [25].
Fig. 6.4
FSH and LH surges elicited by a GnRH short-acting agonist in four patients (DTRP 60.1 = Triptorelin, 0.1 mg)
Fig. 6.5
LH effect following administration of a short-acting GnRH agonist or of hCG, contrasted with an endogenous pre-ovulatory gonadotropin surge (in red)
Triggering with a GnRHa is relatively uncomplicated because a maximum gonadotropin surge will likely be elicited with a very modest dose. One vial of triptorelin (Decapeptyl®, 0.1 mg) administered sc, a single nasal spray of nafarelin (Synarel®, 0.2 mg), a single spray (0.1 mg) or sc injection (0.3 mg) of buserelin (Suprefact®), or a 0.2 mg sc dose of leuprolide (Lucrin®) are equally effective [26]. Higher doses than these do not result in a higher gonadotropin surge because the pituitary response is already maximized (Fig. 6.6).
Fig. 6.6
Gonadotropin surges elicited by two different doses of a short-acting GnRH agonist (DTRP6 = Triptorelin). The responses were not greater when the dose was doubled, from 0.1 to 0.2 mg
The principal benefit of triggering ovulation using GnRH is the significant reduction of risk for early ovarian hyperstimulation, due to the relatively shorter duration of LH effect upon the stimulated ovary. Some authors have reported no reluctance to trigger ovulation in IVF cycles when plasma estradiol was in excess of 15,000 pg/ml, and with no instances of early OHSS being observed [27]. The risk for multiple pregnancies also appears to be significantly decreased for the same reason: the gonadotropin surge triggers ovulation exclusively on a follicle of optimal maturity, whereas the prolonged duration of administered hCG action enables a greater number of dominant follicles to arrive at this critical maturity level and then to ovulate.
However, although the literature contains many reports as just described, it must be kept in mind that total elimination of the hyperstimulation hazard has not been completely validated through prospective studies, evidently for reasons of feasibility. Another point of caution is that while triggering with GnRH seems to avoid early hyperstimulation, this approach has only a minimal ability to prevent a late hyperstimulation following the appearance of hCG from an implanting embryo. Furthermore, the main drawback of triggering ovulation with a GnRH agonist is the tendency to produce a shortened or inadequate luteal phase in about one-third of the cycles, at least in some patients [28]. This insufficiency may be secondary to the shorter duration of the induced gonadotropin surge in comparison with the normal physiologic pre-ovulatory peak, or it may be caused by a temporary refractoriness of pituitary gonadotrophs and/or the luteal gland. Use of micronized oral progesterone seems to offers little improvement in these cases, and correction of this disorder is best accomplished through the administration of a low dose (750 to 1500 IU) of hCG. This, however, returns the risk of hyperstimulation.
6.3.6.2 Recombinant LH
The ability to trigger ovulation with exogenous pituitary LH following HMG stimulation has been established since 1964. However, extracted, purified human pituitary hormone has never been made available for clinical use, and the question of LH administration in the clinic has appeared only in recent years following the announced synthesis of recombinant LH. This synthetic hormone has identical pharmacokinetic properties as extracted urinary and human pituitary LH. However, the issue of appropriate dosage has yet to be resolved. It has been established for LH, as it has for hCG, that progressively increasing quantities are needed to stimulate in turn the resumption of meiosis, follicular rupture, and then its transformation into a corpus luteum.
It appears that any single dose between 15,000 and 30,000 IU rLH will be sufficient to resume meiosis in a COH protocol [29]. In a classical stimulation, however, where LH must support the complete ovulatory process, results from studies in nonhuman primates suggested that a second administration of 2,500 IU 18 h after the first was necessary to complete an LH effect over the 48–50 h required to rupture a follicle and develop a functional luteal gland [30]. Obviously, these results suggest that inadequate LH exposure may lead to a luteal insufficiency or a LUF syndrome. In contrast, an excessive or a prolonged LH exposure creates the potential for the same risks as an hCG overdose. In one notable case, a quintuple pregnancy occurred after repeated high dosing with pituitary LH over 5 days [31].
It should also be mentioned that the practical question of using rLH to trigger ovulation is essentially moot because of high cost. Thus it seems highly unlikely that rLH, the only physiological product capable of reducing the risks for ovarian hyperstimulation as well as multiple pregnancy will ever be commercially available for triggering ovulation.
6.3.6.3 Oxytocin
This posterior pituitary hormone has a vast range of physiological effects outside its well-known actions to promote labor and milk ejection; among them is a possible role in fertility, particularly in the ovulatory process. Oxytocin receptors are present in cumulus and luteal cells of the ovary, and a 7-fold rise of plasma oxytocin occurs simultaneously with the pre-ovulatory LH surge. Administration of 5 IU oxytocin in the presence of a mature follicle in anovulatory women yields the same pregnancy rates as 5,000 IU hCG, apparently by triggering an endogenous LH surge [32]. This recent report was only a feasibility study, and the true value of this triggering mode, as well as its ability to prevent OHHS, particularly important in COH protocols, remains to be determined.
6.4 Conclusion
The process of triggering of ovulation is most assuredly as important as that of stimulating follicular growth, and it definitely requires as much care. Both a post-ovulatory measure of plasma progesterone and an ultrasound procedure to verify follicular rupture are recommended in order to reveal any hidden ovulatory dysfunctions that might help explain repeated failure to conceive following apparently successful ovarian stimulation cycles. To this point, nearly all of the research and developmental advances in ovulation induction have concerned exclusively the follicular stimulation, and the ovulation triggering step using hCG remains as an archaic reminder of an earlier era. Unfortunately, an endogenous LH surge cannot occur in every stimulation protocol, and recombinant LH will not likely ever be available for this indication. Thus the road remains open for continued use of hCG, either as an extracted or a recombinant product, along with its untoward trail of hazards and misfortune [33, 34].
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