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Roles and Novel Regimens of Luteinizing Hormone and Follicle-Stimulating Hormone in Ovulation Induction*

Reproductive Endocrinology Center, University of Bologna, 40138 Bologna, Italy

Address correspondence and requests for reprints to: Marco Filicori, M.D., Reproductive Endocrinology Center, University of Bologna, Via Massarenti 13, 40138 Bologna, Italy. E-mail: filicori{at}med.unibo.it

	Abstract

Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 
Although FSH is universally recognized as the key driver of ovarian follicle growth and maturation, the role of LH in these processes is more controversial. LH acts on theca cells to induce androgen substrate for estrogen conversion by the aromatase system; furthermore, LH can affect granulosa cell function starting in the mid- follicular phase, when these cells express LH receptors. The capacity of LH to stimulate granulosa cells in larger follicles (>10 mm diameter) may be the critical mechanism involved in the selection of the dominant follicle in the normal menstrual cycle. Furthermore, the addition of LH activity can shorten and optimize FSH ovulation induction and reduce the development of smaller preovulatory ovarian follicles that are associated with the severe complications of this procedure. Novel mixed gonadotropin administration regimens that incorporate graded amounts of LH and FSH activity may improve efficacy, safety, and cost of ovulation induction, particularly in the area of assisted reproduction.

	Introduction

Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 
THE HUMAN MENSTRUAL cycle integrates a complex series of physiological mechanisms and events that functionally links the hypothalamus, the pituitary gland, and the ovary. Although the gonadotropins are the key drivers of the menstrual cycle, other compounds such as ovarian steroids and inhibins critically affect and modulate hypothalamic and pituitary hormone selection as well as local gonadal function. FSH is, almost by definition, the fundamental component that controls ovarian follicle growth and maturation since early development stages. Furthermore, FSH stimulates the granulosa cell (GC) aromatase system that catalyzes the conversion of androgens into estrogens (1).

LH is also critically involved in the physiologic events that lead to the development of a competent preovulatory dominant follicle. Under the stimulation of LH, ovarian theca cells (TCs) produce androgens that are transferred into GCs and transformed into estrogens through the action of the aromatase enzyme system; this modular action of gonadotropins was named the "two cell-two gonadotropin model" (2). Estrogens in turn play a fundamental role in priming the hypothalamic-pituitary unit in preparation for the preovulatory gonadotropin surge as well as inducing morphologic uterine and endometrial changes needed for embryo implantation. The two cell-two gonadotropin model dictates that each gonadotropin acts solely on a separate set of ovarian follicle cells, FSH on GCs and LH on TCs; nevertheless, this theoretical model is not applicable throughout the entire life span of the ovarian follicle and needs to be revised and reassessed at least for the late part of GC functional life (3). In the course of the follicular phase, FSH stimulates GCs to express LH receptors (4, 5); this action may be facilitated by estrogens (6). Thus, in the late stages of follicle development, once antral ovarian follicle diameter increases beyond roughly 10 mm, GCs become receptive to LH stimulation and LH becomes capable of exerting its actions on both TCs and GCs (7). Most of FSH physiologic actions on GCs, including the stimulation of the aromatase system, can be exerted by LH once its receptors are expressed (8).

The physiologic rationale of this shift in GC receptivity to gonadotropin stimulation is readily evident when the dynamics of hormone secretion in the normal menstrual cycle are examined. Serum FSH levels are reduced during most of the luteal phase, begin to increase only a few days before menses, and are elevated throughout the luteal-follicular transition, thus stimulating ovarian follicle recruitment (9); FSH then progressively declines across the follicular phase until the midcycle gonadotropin surge is triggered by increasing estrogen and progesterone concentrations. Follicular phase LH levels follow an inverse secretory pattern, being low in the early follicular phase and progressively increasing thereafter, as a consequence of LH pulse frequency augmentation (10).

Should ovarian follicle growth and development solely depend on FSH, this process would be arrested in the mid-late follicular phase at the time of FSH decline. The expression of GC LH receptors allows the larger follicle(s) to keep growing and to develop dominance over smaller, GC LH receptor-free follicles (11). An additional mechanism that could contribute to dominant follicle selection is the increase of LH-induced TC intraovarian androgen production that may synergize with late follicular phase FSH deprivation to hasten atresia and, thus, the demise of smaller ovarian follicles (12, 13).

Thus, it is evident that physiologic follicular growth and maturation is dependent on the dynamic interplay between both gonadotropins; key physiologic events such as follicular recruitment and dominant follicle selection rely on both the prevalence of either FSH or LH activity and on GC LH receptor status at different stages of the follicular phase.

	Endocrine features, efficacy, and complications of ovulation induction

Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 
Numerous drugs have been developed and commercially introduced in the ovulation induction area in the last four decades, including clomiphene citrate, pulsatile GnRH, gonadotropins, and GnRH analogs. The specific drug and administration regimen used largely depend on the goal of treatment [i.e. induction of monoovulation in anovulatory patients or stimulation of multifolliculogenesis in assisted reproduction technology (ART) programs].

Pulsatile GnRH is an elegant example of how monofolliculogenesis can be achieved by ovulation-inducing drugs when the physiologic control mechanisms of endogenous gonadotropin secretion are preserved. When pulsatile GnRH is administered to profoundly hypogonadotropic patients, an early selective FSH rise ensues; however, within a few days, despite continued pulsatile GnRH administration, FSH levels begin to decline as estrogens (and presumably inhibins) rise and a progressive increment of LH begins (14). This pattern closely recapitulates the endocrine events of the physiologic spontaneous follicular phase and is associated with the detection at pelvic ultrasound of single dominant follicle development in most treatment cycles. Although pulsatile GnRH is infrequently used in clinical practice worldwide, this ovulation induction method is renowned for its lack of severe complications such as the ovarian hyperstimulation syndrome (OHSS) and a low incidence of multiple gestations (15), thus indirectly confirming a limited occurrence of multiple follicle development.

Conversely, current regimens of exogenous gonadotropin administration usually result in follicular phase endocrine profiles highly dissimilar from the one of the normal menstrual cycle; this is particularly true in the case of controlled ovarian stimulation (COS) for ART, which is conducted with high-dose gonadotropin regimens. In the majority of COS cycles patients also receive GnRH agonists to suppress endogenous LH secretion, in preparation for exogenous gonadotropin administration (16). The starting exogenous FSH dose is high and often increased if folliculogenesis is inadequate and is maintained elevated until ovulation is triggered with urinary human (h) CG (5–10,000 IU), recombinant (r-) hCG (17, 18, 19), or r-hLH (20). The net result of these regimens is that a counterphysiologic increment of FSH levels occurs across the follicular phase whereas endogenous LH is maintained low by GnRH agonists. Although these regimens induce the desired development of many large mature follicles yielding multiple oocytes for ART, a cohort of smaller, less mature antral follicles also develops in several cycles; this follicular pattern predisposes patients to develop OHSS and multiple gestation (21).

Several procedures have been proposed to prevent or limit the occurrence of these complications. Preovulatory hCG administration can be avoided in patients showing signs of excessive ovarian stimulation (22); while effective, this maneuver often amounts to cycle cancellation because oocyte pickup may not be achievable. Coasting consists of delaying preovulatory hCG administration by a few days in patients at risk for complications (23); this procedure may be effective in some patients but can result in reduced oocyte quality. Step-down FSH regimens attempt to recreate the FSH concentration pattern of the normal follicular phase by progressively decreasing exogenous FSH administration during ovulation induction (24); these regimens do not attempt to modulate LH input and, although effective in terms of safety, are not applicable in ART ovulation induction because of the limited oocyte yield obtained. The replacement of hCG with r-hLH has been recently advocated and may be made possible by the commercial availability of this drug in the near future (20). The shorter half-life of LH vs. hCG may reduce midcycle ovarian stimulation and, thus, lower the occurrence of OHSS. Nevertheless, clinical experience with this drug is still very limited, and it is noteworthy that many of the worst OHSS cases ensue not after midcycle hCG administration but rather in early gestation when very high and progressively increasing amounts of endogenous hCG begin to be secreted and stimulate already enlarged ovaries. These latter cases would not be prevented by midcycle r-hLH administration. Finally, when OHSS is threatened, embryos can be frozen and transferred in later cycles rather than being immediately used. It is, thus, clear that none of the described approaches is totally satisfactory in combining efficacy (obtainment of a large yield of mature oocytes) and safety (prevention of COS-related complications). The optimal COS clinical outcome would be the stimulation of a moderate number of large mature preovulatory follicles, concurrent with a severe curtailment in the development of medium and small-size ovarian follicles; is this an achievable goal of COS?

	Ovulation induction with exogenous gonadotropins

Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 
A large number of different gonadotropin preparations are currently clinically available or are in the development pipeline for treatment of anovulation and COS (Table 1). One clear trend that has emerged in the recent past is the replacement of menotropin preparations containing roughly equal unit amounts of LH and FSH with urinary or recombinant compounds virtually or completely devoid of LH activity [highly purified (HP) FSH or r-hFSH]. This strategy apparently derived from the perception that LH plays no fundamental positive role in follicle development and maturation or could actually be detrimental to this process and to oocyte quality (25). For instance, the concomitance of high serum LH levels and of elevated miscarriage rates in patients with the polycystic ovary syndrome (PCOS) had suggested a causative role of LH in this untoward event (26). Nevertheless, recent evidence failed to confirm a causal relationship between elevated LH levels and spontaneous abortion (27). Furthermore, the amounts of LH contained in human menopausal gonadotropin (hMG) preparations barely affect serum LH concentrations even in PCOS patients (28), and no difference in treatment outcome or in the occurrence of complications was ever found between hMG and FSH administration (29).

	LH activity in gonadotropin ovulation induction

Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 
The issue of whether LH activity should be added to FSH for COS in ART is still highly controversial (29). Retrospective meta-analysis studies have provided conflicting results (39, 40). Recently published protocols combining 75 IU r-hLH with r-hFSH in patients undergoing COS have not evidenced any advantage of this procedure (41, 42). Conversely, it was recently shown that r-hLH administration (75 IU/day) to patients poorly responding to FSH-only COS can improve treatment outcome (43). Furthermore, when compared with FSH only, the administration of LH-containing menotropins dramatically improved implantation and pregnancy rates after blastocyst transfer (44).

Our group has investigated this issue from different angles. We demonstrated that the supplementation of HP FSH with low-dose hCG (50 IU/day) to provide LH activity can hasten large ovarian follicle development, shorten treatment duration, and reduce the HP FSH dose needed to achieve optimal folliculogenesis (45). This amount of hCG (50 IU) corresponds to roughly 250–350 IU of LH activity (46) and was highly effective also in the treatment of HH (35). More recently, we examined endocrine and ultrasound outcome of ovulation induction conducted in GnRH agonist-suppressed normo-ovulatory patients treated with HP FSH or hMG (47). We confirmed that the LH-containing menotropin (hMG) was associated with reduced treatment duration and drug dose; an additional critical finding of this study was the relationship between LH activity and reduced small follicle development in the late follicular phase, as evidenced by ultrasound, inhibin measurements, and clinical outcome.

In another series of studies, selective LH activity administration in the mid- and late stages of FSH ovulation induction was tested both in COS and in anovulatory patients. Low-dose (75 IU/day) r-hLH administration after at least one 14-mm follicle had developed did not significantly affect oocyte yield and pregnancy rates in ART ovulation induction (48). The use of higher-dose LH in the late follicular phase was recently tested in HH (49) and PCOS patients (50) in the attempt of reducing exuberant folliculogenesis in these patients; in both studies high-dose r-hLH administration (225–450 IU/day) was capable of limiting small antral follicle development. The hypothesis that LH activity alone could be capable of sustaining follicular estrogen secretion in the absence of an FSH input was recently tested by Sullivan et al. (51). They demonstrated that, while discontinuation of FSH administration at the end of follicular stimulation caused a decline in serum estradiol concentrations, replacement of FSH with r-hLH (150 or 375 IU, twice daily) was capable of maintaining follicle estradiol production. Although the duration of this study was too short (2 days) to fully assess the effect of this type of biphasic stimulation regimen on follicle development, Sullivan et al. (51), for the first time, demonstrated that ovarian follicle function can be maintained by selective LH activity administration in the human. In a recent series of unpublished studies, we recently determined that in women, after FSH priming, low-dose hCG can be used to provide large follicle stimulation and support for several days while FSH administration is reduced or altogether discontinued; the occurrence of small ovarian follicles in the preovulatory stage was also markedly reduced (Filicori et al., unpublished observation). Most of these studies, thus, point toward a potential application of LH activity to selectively stimulate and support large ovarian follicle development in the late stages of gonadotropin ovulation induction while at the same time reducing small follicle growth; nevertheless, to achieve this goal, relatively elevated amounts of LH activity seem to be needed, because low-dose LH activity administration may not be adequate to provide clinically meaningful results. These regimens may have a profound impact for the optimization and improved safety of these procedures both for the treatment of anovulation and in COS.

	Conclusions

Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 
Recent developments in ovulation induction regimens raise the issue of how LH activity can be applied for optimizing gonadotropin treatment outcome in terms of efficacy, safety, and cost. The capacity of LH to stimulate and modulate follicle function, particularly in the mid-late follicular phase, opens the way for new regimens that could reduce treatment duration while at the same time promoting the selective development of large and mature ovarian follicles. These regimens could consist of early-mid follicular phase administration of gonadotropin preparations with prevailing FSH activity (although not completely devoid of LH activity to stimulate steroidogenesis) followed in the mid-follicular phase and onward by the administration of LH activity-rich gonadotropin preparations (Fig. 1). This type of regimen could be applicable, with proper dose adjustments, to both the treatment of anovulation and for COS in ART programs. The goal of such schemes would be to induce multiple folliculogenesis by using therapeutic dosages of exogenous gonadotropins to partly override the physiologic control mechanisms of the normal menstrual cycle while at the same time controlling the follicle crop by modulating with different LH/FSH ratios the development and demise of follicles of different size and maturity. If successful, this approach might achieve the gold standard of ovulation induction, i.e. providing a limited number of mature oocytes for spontaneous fertilization or ART procedures while markedly limiting the occurrence of smaller, less mature follicles, that are linked to the troublesome and potentially fatal complications of ovulation induction (52).

View larger version (45K): [in this window] [in a new window]   Figure 1. Schematic representation of biphasic ovulation induction gonadotropin regimens composed by prevailing FSH activity in the early-mid follicular phase, followed by LH-prevailing activity in the later stages of ovarian stimulation.

Received September 19, 2000.

Revised October 27, 2000.

Accepted November 9, 2000.

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Top Abstract Introduction Endocrine features, efficacy,... Ovulation induction with... LH activity in gonadotropin... Conclusions References

 

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