Overriding follicle selection in controlled ovarian stimulation protocols: Quality vs quantity
© Stouffer and Zelinski-Wooten; licensee BioMed Central Ltd. 2004
Received: 25 February 2004
Accepted: 16 June 2004
Published: 16 June 2004
Selection of the species-specific number of follicles that will develop and ovulate during the ovarian cycle can be overridden by increasing the levels of pituitary gonadotropin hormones, FSH and LH. During controlled ovarian stimulation (COS) in nonhuman primates for assisted reproductive technology (ART) protocols, the method of choice (but not the only method) has been the administration of exogenous gonadotropins, either of nonprimate or primate origin. Due to species-specificity of the primate LH (but not FSH) receptor, COS with nonprimate (e.g., PMSG) hormones can be attributed to their FSH activity. Elevated levels of FSH alone will produce large antral follicles containing oocytes capable of fertilization in vitro (IVF). However, there is evidence that LH, probably in lesser amounts, increases the rate of follicular development, reduces heterogeneity of the antral follicle pool, and improves the viability and rate of pre-implantation development of IVF-produced embryos. Since an endogenous LH surge typically does not occur during COS cycles (especially when a GnRH antagonist is added), a large dose of an LH-like hormone (i.e., hCG) may be given to reinitiate meiosis and produce fertilizable oocytes. Alternate approaches using exogenous LH (or FSH), or GnRH agonist to induce an endogenous LH surge, have received lesser attention. Current protocols will routinely yield dozens of large follicles with fertilizable eggs. However, limitations include non/poor-responding animals, heterogeneity of follicles (and presumably oocytes) and subsequent short luteal phases (limiting embryo transfer in COS cycles). However, the most serious limitation to further improvements and expanded use of COS protocols for ART is the lack of availability of nonhuman primate gonadotropins. Human, and even more so, nonprimate gonadotropins are antigenic in monkeys, which limits the number of COS cycles to as few as 1 (PMSG) or 3 (recombinant hCG) protocols in macaques. Production and access to sufficient supplies of nonhuman primate FSH, LH and CG would overcome this major hurdle.
A major factor in the development and application of ARTs to basic and applied aspects of primate reproduction was the use of controlled ovarian stimulation (COS) protocols. These COS cycles generate numerous large antral follicles and hence many oocytes that are available for such ART procedures as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), nuclear transfer (NT), and resultant embryos for transfer (ET) into the reproductive tract, in vitro culture and embryonic stem (ES) cell development, or for genetic evaluation and manipulation (see following chapters). The authors have addressed the development and use of COS protocols in ART research in earlier reviews over the past decade [4–6]. This chapter will review the current status of the field, with particular emphasis on the limitations and controversies associated with follicular stimulation protocols.
Follicular stimulation protocols
In theory, methods which increase the levels of endogenous gonadotropic hormones or administer exogenous gonadotropins should stimulate multiple follicular growth in primates. The former approach is used clinically in women, wherein an anti-estrogen (e.g., clomiphene ) or, more recently, an aromatase inhibitor (i.e., letrozole ) is administered to antagonize or eliminate estrogen's negative feedback control of pituitary gonadotropin secretion, thereby raising endogenous FSH and LH levels. Although clinically successful in ovulation induction (few follicles) and COS (many follicles) cycles, this approach is rarely used in nonhuman primates (NHPs, e.g., ) except to consider the possible local role(s) of estrogen in the primate follicle. Estrogen is believed to promote FSH-stimulated folliculogenesis in some species, notably rodents [10, 11], but there is considerable controversy regarding its actions, if any, in the primate follicle . The reported lack of estrogen receptor (ER)-α in primate follicles supported a minimal role, but the subsequent discovery of the ER-β isoform  and its presence in primate follicles has renewed this controversy [14, 15]. Limited studies employing steroid (including selective estrogen) ablation during gonadotropin-stimulated antral follicle development suggest that oocyte maturation and fertilizability could be suboptimal in rhesus monkeys , but this has not been rigorously addressed in any NHP species or women.
Because of the greater potential for supraphysiologic response (higher gonadotropin levels and larger follicle numbers), investigators have preferred to administer exogenous gonadotropins, either of nonprimate or primate origin. Following the discovery of two distinct pituitary gonadotropins in the 1940's, the efforts of van Wagenen  and Knobil  demonstrated that follicular growth and ovulation could be stimulated in intact and hypophysectomized monkeys, respectively, using purified preparations of macaque gonadotropins. Nevertheless, because of more general availability, investigators also initially used nonprimate gonadotropins, typically but not exclusively, pregnant mare serum gonadotropin, which resulted in 1984 in the first rhesus monkey infant born after COS, follicle aspiration, IVF and ET . Indeed, investigators around the world continue to use PMSG, now termed equine chorionic gonadotropin (eCG) for COS protocols in NHPs, such as African green monkeys .
With the emergence of clinical ART programs, investigators began to use commercially available preparations of human gonadotropins, initially urinary preparations, such as human menopausal gonadotropin (hMG; containing both FSH and LH) and a more purified preparation of hFSH. With the advent of recombinant (r) DNA technology in the mid-1990s, pure r-hFSH (devoid of LH activity) and r-hLH (devoid of FSH activity) became available for testing in rhesus macaques, and is now the preparation(s) of choice for many physicians treating infertile women in ART clinics. However, a standard or optimal protocol of human gonadotropins has not emerged from clinical protocols in women, or from COS procedures in any NHP species. In macaque species, for example, investigators have employed gonadotropin regimens of hFSH alone [20–22], a combined treatment of hFSH plus hLH , and a sequential protocol of hFSH alone followed by an interval of hFSH plus hLH [24–26]. Despite the issues described in subsequent sections, these protocols can successfully generate multiple large antral follicles with fertilizable oocytes both in adult primates and, more recently, in prepubertal monkeys [6, 27]. The latter is analogous to the immature, PMSG-treated rodent model that is extensively used in basic and applied research [28, 29].
It is noteworthy that a timely LH surge of normal magnitude and duration does not usually occur during COS protocols, presumably due to the supraphysiologic levels of estrogen having a predominantly negative-, rather than positive-, feedback effect at midcycle . Indeed, if one unexpectedly occurs, oocyte collection is usually disrupted or cancelled (see subsequent section). Oocytes from FSH/LH-stimulated follicles may be collected at the immature (germinal vesicle or GV-intact) stage for attempts at in vitro maturation (IVM [20, 30]). However, generally, the actions of the LH surge, notably resumption of meiosis to generate a metaphase II oocyte capable of fertilization, are mimicked by administering a bolus of the LH-like hormone, human chorionic gonadotropin (hCG). Typically, urinary preparations of hCG were employed [18, 31], but more recently, pure r-hCG became available for inducing ovulation events in women and NHPs [21, 32].
Preparations of hCG have been the hormone of choice, particularly because of its general availability and much longer half-life than hLH; hence, one injection is sufficient to maintain surge levels over a 27–36 hr interval to collect a large percentage of maturing (metaphase I or II) oocytes by follicle aspiration prior to ovulation . However, it is possible to produce surge levels of endogenous or exogenous LH for various intervals in women and NHPs by administering either a gonadotropin releasing hormone (GnRH) agonist or urinary/recombinant hLH [33, 34]. Although GnRH agonists are used successfully in some clinical ART programs, and may be indicated in some patients at risk for developing ovarian hyperstimulation syndrome (OHSS ), macaque species appear less sensitive to such GnRH regimens. Up to 3 injections of GnRH or a GnRH agonist only produced a short LH surge of ≤ 14 hrs and was insufficient to reinitiate meiotic maturation of oocytes . In contrast, one injection of hLH produced LH surges of approximately 18–24 hrs that reinitiated oocyte development, but failed to sustain the development and/or function of the macaque corpus luteum. Only after two injections of hLH were administered at 18 hr intervals did one achieve surge levels of LH for 36–48 hrs accompanied by oocyte maturation and corpus luteum development/function comparable to that observed in hCG-treated animals . Although these and other  studies are providing needed information on the strength-duration requirements for ovulatory processes in primate follicles, COS regimens attempting to induce an endogenous LH surge or providing exogenous LH as an ovulatory stimulus have been rare in NHPs .
A standardized regimen of human gonadotropins has not evolved, but treatment generally begins in the early follicular phase (prior to natural selection of the dominant follicle, which occurs as early as day 5 of the menstrual cycle in macaques and women) and continues for 6–11 days. At ONPRC, the authors currently employ the following regimen for COS cycles after comparing three different protocols in rhesus monkeys . Beginning around menses, adult, cycling females receive twice daily IM injections of 30 IU r-hFSH for 6 days, followed by 30 IU r-hFSH and r-hLH for 3 days. On day 10, the animals then receive a single IM injection of 1000 IU r-hCG to induce ovulatory events. Although ovulatory follicles develop, aspiration by laparoscopy is typically performed ≥ 27 hr after hCG injection to retrieve maturing (M I and II) oocytes before follicle rupture. This regimen can be individualized per animal, based on criteria for desired numbers/size of antral follicles and circulating estrogen levels, by varying the interval of FSH + LH exposure . However, this requires labor-intensive efforts to regularly perform transabdominal ultrasonography and rapid estradiol assays, usually daily from day 7 of treatment. Also, based on their effectiveness and reversibility in macaques, a GnRH agonist [22, 23] or antagonist [32, 39] can be administered concomitantly throughout or during the last part of the gonadotropin stimulation protocol to assure prevention of an endogenous LH surge (see later section).
It should be noted that the functional luteal phase that follows the exogenous gonadotropin treatment (FSH ± LH, followed by hCG) in COS cycles is abnormal as noted in clinical ART  and NHP [32, 41] protocols. Although circulating progesterone levels are often supraphysiologic, due to the presence of multiple luteinized follicles/corpora lutea, the length of the luteal phase is typically shortened. This is likely due to the suppression of circulating pituitary LH levels by the supraphysiologic levels of ovarian steroids and/or the residual action of GnRH analogs administered during multiple follicular development . Thus, once the circulating levels of administered hCG decline to baseline, luteotropic support for luteal structure-function is lost, progesterone secretion declines and early menstruation results . Clinically, luteal phase support in the form of progesterone supplements is the method of choice to allow embryo transfer in COS cycles . However, embryo transfer during COS cycles in NHPs is not routine. The typical approach to date is to cryopreserve embryos and to transfer thawed embryos into monkeys (either the egg donor or a surrogate mother) during the luteal phase of a natural menstrual cycle [4, 42]. This eliminates any potential problem during the luteal phase in COS cycles.
Major limitation – availability and antigenicity of gonadotropins
Availability of suitable gonadotropin preparations for follicular stimulation protocols is the most critical limitation to the use of ARTs in NHPs. Although nonprimate preparations, e.g., eCG, are readily available, these are by far the least desirable gonadotropins for two reasons: species-specificity of action and antigenicity. Following evidence of species specificity of growth hormone action in primates, Van Wagenen speculated from her experience that a similar species specificity applied to LH, but not FSH, action in the primate ovary (see review ). Subsequent studies appear to support this premise; e.g., primate LH and hCG were 500–1000 times more efficient than nonprimate gonadotropins in inhibiting 125I-hLH binding to macaque LH-CG receptors, whereas all gonadotropins were equipotent for rodent LH receptors . These results emphasize the need for primate gonadotropins, at least LH-CG, in studies in NHPs. Investigators should realize that any activity of nonprimate gonadotropins in NHPs is likely due solely to FSH in the preparations, unless very large quantities are used. However, their use especially in large amounts is further contraindicated by the antigenicity.
Antihuman gonadotropin antibodies in macaque serum prior to and following three consecutive controlled ovarian stimulation (COS) cycles with recombinant human gonadotropins .
Number of animals
125I-hCG bounda Beforeb
125I-hCG bounda Afterb
Number of animals
125I-FSH bounda Beforeb
125I-FSH bounda Afterb
Clearly, the availability of nonhuman primate – especially macaque – gonadotropins would overcome the limited ability to perform repeated COS protocols and greatly facilitate experimentation. In the late 1980s, the National Institutes of Health contracted for the production of cynomolgus macaque FSH and LH by recombinant DNA technology. However, the small amounts generated serve primarily as antigen or reference hormone for gonadotropin assays (distributed by the U.S. National Hormone and Peptide Program). Although in rare instances they can be used for in vivo studies in macaques , the limited supply precludes their use in COS protocols. Generation of ample supplies of recombinant macaque gonadotropins to permit current and future use of COS protocols in ART programs would clearly facilitate research in the NHP model, e.g., permit repetitive use of optimal or "genetically-selected" monkeys for oocyte/embryo production, including sequential experimental protocols on individual animals. NHP gonadotropins would permit ART-related procedures to preserve or modify genetic-defined animals and to maintain endangered species or genetic lines of macaques or other primates.
Until NHP gonadotropins are available, programs are largely dependent on the sale or donation of human gonadotropins from a few pharmaceutical companies (e.g., Ares Serono, Organon). Their product donations to NHP ART programs in the past decade were critical to many research and development efforts; the authors estimate that the ART program at ONPRC annually consumes human gonadotropins (r-hFSH, r-hLH, r-hCG) having a commercial value of over $200,000. During the development of clinical ART programs and the testing of recombinant preparations, companies recognized the value of research efforts in NHPs as preclinical trials for their products. However, with the world-wide approval, use and great demand for r-hFSH, LH and CG now established, it is not clear that this source of materials will continue to be available and is unlikely to allow expansion. The unsettling scenario of limited availability of human gonadotropins as a product donation for NHP research provides further impetus for the creation of ample supplies of macaque gonadotropin preparations.
Ongoing controversy – the need, or lack thereof, for LH in COS protocols
One of the major reasons that a standard regimen of gonadotropin hormones has not evolved for promoting multiple follicular development in COS cycles is the unresolved issue regarding the need for LH in the protocol. It is generally recognized that LH secreted during the follicular phase of the menstrual cycle is essential for the steroidogenic function of the dominant follicle destined to ovulate at midcycle in primates . This is exemplified by the two-cell, two-gonadotropin model for estrogen production by the follicle, wherein (a) theca interna cells contain LH receptors and respond to circulating LH with increased production of androgen, whereas (b) granulosa cells contain FSH receptors and respond to FSH by increasing the conversion of androgen to estrogen. The rising levels of circulating estradiol act on various target tissues, including the hypothalamic-pituitary axis to elicit the midcycle gonadotropin surge which causes periovulatory events in the mature follicle. However, it is less clear whether LH has additional vital roles in the developing follicle in primates , either independent of its steroidogenic actions or via local steroid effects analogous to androgen or estrogen actions in rodent follicles .
As expected, based on the two-cell, two-gonadotropin model, the levels and patterns of circulating estradiol differed during the two treatment protocols . Serum levels remained at baseline (<20 pg/ml) during the first five days of r-hFSH treatment, then increased and plateaued at levels (~200 pg/ml) that were markedly less (p < 0.05) than those in r-hFSH + r-hLH-treated animals. In contrast, serum estradiol levels rose steadily following initiation of r-hFSH + r-hLH treatment, and peaked at levels (~1000 pg/ml) that were 5-fold higher than those in r-hFSH-treated animals. Nevertheless, either gonadotropin treatment regimen could stimulate the growth of numerous antral follicles (~24 follicles ≥ 2 mm diameter; Fig. 3, right panel), and a greater proportion of mature (metaphase II), fertilizable eggs were obtained at 27 hrs post-hCG injection from FSH- versus FSH + LH-treated animals. These findings support the concept that in pharmacologic COS protocols, FSH alone is adequate for the folliculogenic and gametogenic events required to produce viable embryos in NHPs. This finding is consistent with retrospective meta-analyses finding little if any difference in ovulatory and/or pregnancy rates between hFSH and hFSH + hLH protocols for ovulation induction or ART-ET in women [49–51].
Nevertheless, there are indications that addition of LH has some positive effects in COS protocols. In our macaque study, the FSH + LH treatment regimen required a shorter interval than FSH alone (9 vs 12 days, p < 0.05) to stimulate follicles to the stage of administering the ovulatory hCG bolus. Also, all FSH + LH-treated animals achieved the follicular development required for hCG administration, whereas 2 of 7 monkeys receiving FSH alone failed to display adequate folliculogenesis. Although fertilized oocytes from both treatment regimens were capable of in vitro development to hatched blastocysts and in vivo development to normal offspring after ET, there were some differences . Notably, embryos from FSH-only treatment protocols were less likely to survive cryopreservation and thawing, and required longer to develop to the morula-to-hatched blastocyst stage than those from FSH + LH protocols. It is intriguing to note that the slower preimplantation development rate in vitro correlated with evidence of delayed rescue of corpus luteum function (16 days post-LH surge) following ET of embryos derived from FSH-only protocols. These data suggest that inclusion of LH in COS protocols improves the efficiency and rate of preovulatory follicle development, embryo "viability" and the rate of preimplantation embryo development in macaques. Whether these parameters are influenced by the greater estrogen milieu provided by LH exposure is unknown. These results are consistent with several published reports from clinical programs, notably those of Filicori and colleagues [52, 53], that inclusion of LH has practical (e.g., shortens treatment and therefore hormone costs) and theoretical (e.g., reduces heterogeneity in follicle size) benefits in ovarian stimulation protocols.
Nevertheless, this issue remains controversial, as well as the related question regarding how much LH is sufficient for optimal folliculogenesis. It seems likely that less LH than FSH is required; studies in hypogonadotropic, hypogonadal women suggest that a ratio of 2 IU r-hFSH:1 IU r-hLH is optimal for promoting follicular development . Likewise, our recent study evaluating LH requirements for final ovulatory maturation of the naturally selected dominant follicle during the menstrual cycle in macaques indicates that a 2:1 ratio (but not 1:0 ratio) is as capable as a 1:1 ratio of FSH-LH in producing an ovulatory follicle . It is likely that some of the controversy in this field is related to the lack of control or analysis of endogenous LH levels during protocols, and that endogenous LH combined with exogenous FSH is sufficient for follicular development. It is important that researchers employing NHPs are aware that different GnRH analog/gonadotropin treatment regimens do not necessarily produce similar follicles, oocytes or embryos. Moreover, their similarity to those generated in the natural menstrual cycle awaits rigorous analysis.
Ongoing problem – heterogeneity of animal and follicle response
Despite the success in developing COS protocols in NHPs, it is apparent the response in terms of multiple follicular development is quite variable. We reported earlier  that rhesus monkeys displayed four types of responses to our gonadotropin treatment protocols in terms of patterns and levels of circulating estradiol: (a) classical responders with continuously rising estradiol levels throughout treatment, (b) biphasic responders with estradiol levels transiently declining by >20%, but rebounding thereafter, (c) abbreviated responders with estradiol declining after more than five days of treatment, and (d) nonresponders with estradiol levels never rising above those observed in spontaneous cycles. Our standard sequential regimen of hFSH followed by hFSH + hLH resulted in the greatest frequency (17 of 25 protocols or 67% of animals) of classical responders. However, a significant percentage of animals (8 of 25 or 33%) fell into categories b-d and either did not reach follicle aspiration (e.g., nonresponders) or provided oocytes that fertilized and cleaved in vitro at a much lower percentage than those from classical responders (13% vs 41%). However, even in classical responders the variation in peak estrogen levels (e.g., 4480 ± 1012 pg/ml, mean ± SEM, n = 17) and numbers of oocytes retrieved (which is positively correlated with peak estradiol levels; p < 0.05) is remarkable.
If researchers are monitoring daily estradiol levels and follicle numbers/diameters, it is possible to individualize the treatment regimen, as in clinical ART protocols, to reduce variability in follicular stimulation in NHPs . However, an individualized approach does not eliminate the occurrence of nonclassical responders. Many of the abbreviated and biphasic estradiol responses in monkeys appear associated with a spontaneous LH surge (>100 ng/ml) or "mini-surge" (<100 ng/ml) on the day before declining estrogen levels . The addition of GnRH analogs (first agonists, and more recently, antagonists) is used clinically to prevent endogenous LH surges during COS protocols. In addition, ART patients are often treated with these drugs prior to starting gonadotropin treatment to permit arbitrary initiation of protocols independent of the menstrual cycle, thereby projecting follicle aspiration for a convenient time during the work week. With the development of second- and third-generation GnRH analogs, these drugs have been administered to macaques prior to , throughout [23, 32] or in the latter part (unpublished) of the gonadotropin treatment regimen for these purposes. However, effective methods are needed to identify potential nonresponders prior to initiating follicular stimulation protocols. Attempts in the clinic include evaluation of basal FSH levels and ultrasound monitoring of the pool of small antral follicles  in ART patients. However, these are not easily monitored in macaques, and one report suggests that FSH levels are not predictive of a poor response to gonadotropin stimulation in cynomolgus monkeys . Anecdotal reports suggest that estradiol levels below those expected at the onset of the follicular phase (or a poor estrogen response to GnRH agonist ) portend a poor follicular response in NHPs, but this has not been rigorously evaluated.
Over the past 15 years, the remarkable increase in use of COS-ART protocols in clinical practice to treat infertile couples  has been paralleled by applications of this technology to numerous NHP species, from great apes  to baboons [62, 63], and various Old World monkeys [19, 22, 64–66] to New World monkeys . Reports from zoological settings [61, 65] as well as many NHP research centers (see also following chapters) illustrate the potential value of this approach to preserve and foster reproduction of endangered primate species or primates of a known genetic character that are valuable for applied research of direct relevance to human health. A large supply of competent gametes (notably oocytes) and embryos will also facilitate basic and applied research on primate gametogenesis, fertilization, early embryogenesis and pregnancy initiation – areas that logistically and ethically are difficult or cannot be performed in humans. However, limitations remain, including the lack of availability of NHP gonadotropins which seriously curtails current ovarian stimulation protocols in the predominant research model, the Old World macaque. Also, the heterogeneity of response between and within COS protocols, in terms of the antral follicle population, oocyte quality and embryo potential, should be recognized by primate researchers. The latter is a significant issue for NHP studies where every oocyte/embryo is a valuable commodity and distributed arbitrarily between treatment groups in research protocols. A standard gonadotropin treatment regimen may never by generally accepted, either clinically or experimentally, due to the controversial need for LH in antral follicle maturation. Nonetheless, further progress in the described research areas is likely – especially if adequate sources of NHP gonadotropins become available for in vivo studies, including COS protocols.
A special thanks to Dr. Don Wolf, Director of the ART Core Laboratory, and all current and past members of the IVF-ET and ART programs at ONPRC for their valuable contributions to this research field. The assistance of Dr. David Hess and his associates in the Endocrine Services Laboratory, Dr. John Fanton and his assistants in the Surgery Unit, the animal care technicians in the Division of Animal Resources, and Ms. Carol Gibbins, Administrative Assistant in the Division of Reproductive Sciences is gratefully acknowledged. We also thank Ares-Serono and the Serono Reproductive Biology Institute for their generous donations of urinary and recombinant human gonadotropins (hMG, hFSH, hLH, hCG) and GnRH antagonist (Antide) that made our studies possible. This work was supported by NIH grants funding ONPRC (RR00163), the Specialized Cooperative Center Program in Reproduction Research (HD18185), and individual investigators (HD20869, HD22408; RLS) and contractual projects awarded by Serono Laboratories, Inc. (RLS, MZ-W).
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