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.

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.

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):

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.

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.

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.

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].

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.

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.