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Follicle Selection in Primates: "Many Are Called but Few Are Chosen"¹

^a Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

	ABSTRACT

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
During the follicular phase of humans and most nonhuman primates, a single preovulatory follicle usually matures each menstrual cycle. The observation that numerous preovulatory follicles may be stimulated to mature when exogenous gonadotropins are administered indicates that there must be a precise and highly reproducible mechanism by which only one of the many follicles capable of ovulating actually does so. The goal of this review is to summarize past and current research which indicates that follicle selection in primates is the result of an exquisitely sensitive interplay between gonadotropin secretion by the pituitary gland, steroid production by the ovary, and maturation-dependent alterations of the ovary's responsiveness to gonadotropins.

follicle-stimulating hormone, luteinizing hormone, menstrual cycle, ovary

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
The goal of this review is to summarize the current views regarding the regulation of the primate menstrual cycle with particular reference to the physiological and cellular mechanisms involved in the initiation of preovulatory follicular development and the selection of a single preovulatory follicle. For this purpose, the review will focus on the following: the cessation of preovulatory follicular growth during the luteal phase of the menstrual cycle, the initiation of preovulatory follicular growth during the early through midfollicular phase of the menstrual cycle, and the selection of the preovulatory follicle during mid- through late follicular phase of the menstrual cycle.

This review summarizes early work that has also been reviewed elsewhere [1] as well as more recent studies by this laboratory and others. It will focus on answering two simple questions, the answers of which are key to the understanding of follicle selection: "How does the maturing follicle inhibit the development of less mature follicles?" and "How is the selected follicle spared from its own inhibition?"

	CESSATION OF PREOVULATORY FOLLICULAR DEVELOPMENT DURING THE LUTEAL PHASE

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
Unlike other species (cows, horses, and sheep) follicular development does not progress beyond the early antral stages during the luteal phase of the menstrual cycle of monkeys and humans indicating that, in some manner, the presence of a functional corpus luteum inhibits antral follicular development. This inhibition could either be direct or indirect. Direct inhibition would involve a mechanism whereby secretions of the corpus luteum locally inhibit the maturation of preovulatory follicular development. An indirect mechanism would involve feedback inhibition of gonadotropin secretion by secretory products of the corpus luteum.

Evidence for a direct effect of the corpus luteum in inhibiting follicular development came from the studies in monkeys by Goodman, Hodgen, and coworkers [2], which demonstrated that removal of the corpus luteum during the midluteal phase of the menstrual cycle resulted in the initiation of follicular development in the absence of a statistically significant increase in the plasma concentrations of FSH and LH. This observation led to the hypothesis that secretory products of the corpus luteum directly inhibited follicular development by reducing the ability of follicles to respond to FSH. Removal of the source of the inhibition allowed follicular development to proceed without a necessary increase in gonadotropin secretion.

In humans, however, resumption of follicular development following the removal of the corpus luteum was preceded by a clear elevation of FSH concentrations [3, 4], thereby casting doubt as to whether a rise in FSH is not necessary for follicular development following removal of the corpus luteum. Although the hypothesis that the corpus luteum directly inhibits follicular growth has not been disproved, the available evidence to date suggests that the corpus luteum indirectly inhibits preovulatory follicular development by way of its secretions of estrogen, progesterone, and possibly inhibin that suppress FSH secretion. Thus, as reflected by [³H]thymidine incorporation studies [5], granulosa cells of preantral follicles incorporate [³H]thymidine during the luteal phase. In humans, granulosa cells collected from small antral follicles during the late luteal phase are responsive to FSH in vitro with respect to estrogen production [6]. These observations indicate that the early stages of follicular development are not inhibited by the corpus luteum and that the inhibitory influences imposed by the corpus luteum must be confined to the final stages of folliculogenesis. The observations in monkeys that preovulatory follicular development can be readily stimulated during the luteal phase of the menstrual cycle either by direct administration of exogenous gonadotropins [7] or by interfering with the feedback inhibition of estrogen and progesterone upon gonadotropin secretion [8] is consistent with the hypothesis that the failure of follicles to mature beyond the early antral stages during the luteal phase is not due to a direct inhibition of follicular development by the corpus luteum but rather due to insufficient gonadotropin concentrations as a result of feedback inhibition of gonadotropin secretion by the secretory products of the corpus luteum. A final argument against local control mechanisms in the inhibition of follicular development is the fact that, in species that ovulate only a single follicle, follicular development must be suppressed in both ovaries. In the absence of direct circulatory communication between the ovaries, as appears to be the case in primates, it is difficult to conceptualize how a local inhibitor could be active in the ovary contralateral to that which bears either a dominant follicle or a corpus luteum.

	INITIATION OF PREOVULATORY FOLLICULAR GROWTH DURING THE EARLY- THROUGH MIDFOLLICULAR PHASE OF THE MENSTRUAL CYCLE

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
Primates are unique with respect to the long duration required for the maturation of the preovulatory follicle when compared with other species. As presented in the other reviews in this minisymposium, horses and cows exhibit waves of antral follicular development during the luteal phase in which follicles develop to the antral stages but do not ovulate. Sheep also appear to undergo waves of follicular growth during the luteal phase [9]. Baird [10] proposed that the lengthy follicular phase of primates is because the primate corpus luteum, unlike that of sheep, cows, and horses, produces sufficient amounts of estrogen to suppress FSH secretion below the level necessary to advance the development of early antral follicles, and hence more time is required for a follicle to develop to the preovulatory stage. Upon the demise of the corpus luteum, serum levels of FSH and LH increase (the perimenstrual rise), and the process of preovulatory follicular development is initiated. Although the occurrence of a perimenstrual rise in serum FSH concentrations was recognized by Ross et al. [11] in their original descriptions of the hormonal profiles of the human menstrual cycle, the extent to which such a slight (30–50%) rise in FSH concentrations during the early follicular phase participated in follicular development was not fully appreciated until Brown [12] demonstrated that changes in FSH concentrations on the order of 10–30% are sufficient to initiate follicular development in anovulatory women. Based on this finding, Brown introduced the concept of an FSH threshold to indicate that a critical concentration of FSH must be achieved to initiate the process of follicular development.

	MIDFOLLICULAR PHASE THROUGH THE LATE FOLLICULAR PHASE

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
It is during this period that follicular selection is accomplished. Figure 1 presents the pattern of concentrations of FSH and estradiol during the follicular phase of the macaque menstrual cycle. As mentioned in the previous section, a perimenstrual rise in FSH secretion occurs following the regression of the corpus luteum. Thereafter, there is a reciprocal relationship between the plasma concentrations of FSH and estradiol. During the early follicular phase prior to the emergence of a stimulated follicle, serum FSH concentrations are elevated while estradiol concentrations are low. Approximately 5 days before the midcycle gonadotropin surge, serum estrogen concentrations begin to rise as the result of the emergence of a maturing follicle. Associated with the gradual increase in estradiol concentrations is a progressive fall in FSH concentrations due to the feedback actions of estrogen (and possibly inhibin) on gonadotropin secretion [13, 14]. This classical negative feedback relationship between estradiol and FSH is an essential component in the process of follicular selection. Owing to the steady exit of follicles from the primordial pool, there will always be a maturationally distinct population of early antral follicles within the ovaries ready for development to the preovulatory stage under the influence of FSH. Because a growing follicle acquires sufficient aromatase activity as a result of FSH stimulation, its production of estrogen suppresses FSH secretion below that necessary to sustain the development of less mature follicles that consequently undergo atresia.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Relationship between serum FSH and estrogen concentrations during the follicular phase of the menstrual cycle

The estrogen-feedback hypothesis has been tested directly in subhuman primates by manipulating the pattern of estrogen concentrations during the follicular phase of the menstrual cycle. In rhesus monkeys, subcutaneous insertion of estrogen-containing capsules on Days 3–6 of the follicular phase of the menstrual cycle prematurely elevated estrogen concentrations by 50–80 pg/ml and resulted in a slight but significant fall in the plasma concentration of FSH and an interruption of spontaneous follicular development [15]. This negative feedback model for follicle selection would also predict that negating the gonadotropin-suppressing effects of estrogen during the mid- through late follicular phase of the menstrual cycle should prevent the fall in FSH concentrations and override the process of follicle selection. Indeed, passive immunization of rhesus monkeys with antiestradiol antibodies during the mid- through late follicular phase of the menstrual cycle prevented the fall in FSH concentrations and caused the maturation of more than one preovulatory follicle [16]. In humans, it is well known that blockage of the biological actions of estrogen with the antiestrogen clomiphene results in an augmentation of gonadotropin secretion and maturation of more than one preovulatory follicle [17].

Although these studies are consistent with the hypothesis that feedback inhibition of FSH secretion is the principal mechanism by which the maturing follicle suppresses the development of less mature follicles, it should be noted that the maturing follicle also produces inhibin and extracts of porcine follicular fluid suppress FSH secretion and follicular development in primates [18]. Because both estradiol and inhibin are produced by the preovulatory follicle, it has been difficult to establish the relative importance of estrogen versus inhibin in the control of FSH secretion [19]. In the passive immunization studies [16] mentioned previously, the neutralization of estrogen resulted in the maturation of more than one preovulatory follicle, presumably in the presence of elevated inhibin concentrations that would have resulted from the increased number of maturing follicles. Likewise, the antiestrogen clomiphine, presumably by interfering with the negative feedback effects of estrogen, causes the maturation of more than one preovulatory follicle. Additional evidence for the primacy of estrogen in regulating FSH secretion in primates comes from the analysis of ovarian function of a woman with an inactivating mutation of the aromatase gene [20]. This "experiment of nature" manifested excessive ovarian production of ovarian androgens, multiple large antral follicles, and elevated FSH concentrations, all of which receded upon the administration of ethynyl estradiol. Collectively, these observations suggest that in the absence of estrogen-mediated suppression of FSH secretion, inhibin alone is not able to regulate FSH secretion and hence the number of maturing follicles. However, until similar passive immunization studies are conducted in primates with anti-inhibin antibodies, a definitive conclusion regarding the relative contributions of estrogen and inhibin in the control of FSH secretion cannot be made. Regardless of whether inhibin or estrogen is the primary regulator of FSH secretion during the follicular phase of the menstrual cycle, the important fact is that the maturing follicle inhibits the maturation of other follicles by depriving them of FSH support.

The aforementioned studies answer the first question posed in the Introduction "How does the maturing follicle inhibit the development of less mature follicles?" Given that FSH is essential for follicular development, how is it then that the maturing follicle continues to develop in the presence of FSH concentrations that are unable to maintain the development of less mature follicles? The only explanation for this paradox is that as the follicle matures, it must become less dependent upon FSH such that the concentration of FSH necessary to initiate preovulatory follicular development is greater than the concentration of FSH necessary to maintain preovulatory follicular growth. This hypothesis was tested directly by intravenous infusion of highly purified human FSH (hFSH) and hLH into cynomolgus monkeys whose endogenous gonadotropin secretion was blocked by a GnRH antagonist [21]. Results of this study demonstrated that when plasma FSH levels were maintained at approximately 10 mIU/ml, which is the concentration of FSH seen during the luteal phase of the menstrual cycle, there was no evidence of estrogen secretion. When plasma FSH concentrations were elevated to approximately 20 mIU/ml, which is typical of FSH concentrations during the early follicular phase, preovulatory follicular development was initiated, as reflected by increasing concentrations of estrogen. Once preovulatory follicular growth was apparent, a reduction of plasma FSH concentrations to 10 mIU/ml over a 5-day period was associated with a continued rise in estrogen production. That estrogen secretion continued to rise despite the progressive fall in FSH concentrations demonstrates that the maturing follicle, as a consequence of FSH simulation, acquires increased sensitivity to FSH such that it continues to mature in the presence of FSH concentrations that are unable to initiate the development of less mature follicles.

This finding indicates that there must be specific functional changes in the FSH-stimulated follicle that render it less dependent on FSH than other lesser mature follicles. A hallmark action of FSH during preovulatory follicular development is the induction of LH receptors on granulosa cells [22]. Granulosa cells from early antral follicles possess FSH receptors and stimulation of the cells by FSH results in the activation of adenylyl cyclase and the production of cAMP. In response to FSH stimulation, granulosa cells acquire LH receptors and, like that for the FSH receptor, occupancy of the LH receptor by LH also results in the activation of adenylyl cyclase and the production of cAMP [23]. As would be predicted by the common intracellular cAMP pathway, granulosa cells from FSH-stimulated follicles respond similarly to both FSH and LH, and moreover, at nonsaturating levels of FSH and LH, the responses are additive [24]. The overall significance of these findings is that while granulosa cells from early antral follicles are only responsive to FSH, granulosa cells from FSH-stimulated follicles are responsive to either FSH or LH. Thus, it is possible that the maturing follicle reduces its dependence on FSH by acquiring LH receptors.

Recent studies conducted in humans using recombinant FSH and LH by Sullivan et al. [25] support the hypothesis that the acquisition of LH receptors on granulosa cells protect the follicle from the decline in FSH concentrations during the mid- through late follicular phase of the menstrual cycle. Women were treated with recombinant FSH to stimulate follicular development to the antral stages (ca. 14 mm diameter), following which FSH treatment was terminated. In subjects who received no additional gonadotropin treatment, peripheral estrogen concentrations declined within 48 h after the cessation of FSH treatment. However, subjects who received recombinant LH following the cessation of FSH treatment exhibited rising estrogen concentrations over the subsequent 48 h, indicating that LH was able to substitute for FSH in supporting the growth of FSH-stimulated follicles. This observation is further supported by the studies in women by Willis et al. [26] in which estrogen and progesterone production in response to FSH and LH by granulosa cells from different-sized follicles was assessed. They observed that LH responsiveness (estradiol and progesterone production) became apparent in follicles with diameters 10 mm, a size attained by the maturing follicle during the midfollicular phase of the menstrual cycle when estradiol levels just begin to increase [27]. A similar role for LH in follicle selection in sheep has recently been described [28].

A working model for follicle selection is presented in Figure 2. During the luteal phase of the menstrual cycle, preovulatory follicular development is curtailed because the corpus luteum, via its secretions of estrogen, progesterone, and possibly inhibin suppress FSH secretion below that necessary to stimulate the maturation of follicles beyond the early antral stage of development. Upon the regression of the corpus luteum, feedback inhibition of FSH secretion is relieved, and FSH concentrations rise and stimulate the progression of follicles beyond the early antral stages. Two hallmark responses of granulosa cells to FSH are the induction of aromatase and the induction of LH receptors. The induction of aromatase results in the rise in peripheral levels of estrogen which, as noted earlier, suppress FSH secretion such that plasma concentrations of FSH fall below the threshold that is necessary to stimulate the maturation of other less mature follicles. The concurrent induction of LH receptors may provide the maturing follicle with an additional source of gonadotropic support that enables it to continue to mature in the presence of FSH concentrations that are insufficient to support the development of other follicles.

View larger version (27K): [in this window] [in a new window]   FIG. 2. Schematic model for follicle selection in primates. An explanation is presented in the text.

If correct, this model also indicates that estrogen is the principal organizer of the timing of the follicular phase. The initial rise in estrogen secretion is responsible for the suppression of FSH and hence the ultimate selection of the preovulatory follicle. In addition, the estrogen produced by the maturing follicle is responsible for the proliferation of the endometrium in anticipation of subsequent ovulation and fertilization. Finally, during the late follicular phase as the follicle completes its maturation, the rising concentrations of estrogen provide a positive feedback signal to the hypothalamic-pituitary axis that results in the initiation of the midcycle LH, ovulation, and formation of the corpus luteum [29].

	CELLULAR ASPECTS OF FOLLICLE SELECTION

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
It is well established that FSH stimulation of granulosa cells results in the induction of numerous genes that are involved in steroidogenesis as well as cell surface receptors for LH. Over the past decade it has become apparent that in addition to controlling the differentiation of the granulosa cell, FSH also acts as a survival factor that prevents follicular atresia by stimulating cellular proliferation and inhibiting apoptosis [30]. Recent studies in other systems have linked the nuclear transcription factor CREB (cAMP response element binding protein) to a number of genes involved in cell proliferation and cell survival including proliferating cell nuclear antigen [31], bcl-2 [32], and mcl-1 [33]. Moreover, it is known that CREB is phosphorylated (activated) in response to FSH stimulation [34]. It is likely that the genes regulated by FSH involved in cell proliferation and cell survival will soon be identified thus furthering our knowledge on the mechanisms of follicle selection.

In addition to proteins directly involved in granulosa cell function, follicular development is associated with the production of paracrine factors that influence neighboring cells. One such protein is vascular endothelial growth factor (VEGF). Previous studies have demonstrated that the density of capillaries surrounding the maturing follicle is greater that that of other smaller follicles and that this is associated with increased delivery of gonadotropins to the maturing follicle, suggesting that angiogenesis may play a role in the maturation of the preovulatory follicle [35]. Subsequent studies demonstrated that VEGF mRNA is expressed in large preantral follicles [36] and that FSH stimulates VEGF production by primate granulosa cells [37]. Direct evidence for a role of VEGF in follicular development has been obtained by the recent demonstration that passive immunization of monkeys with anti-VEGF during the follicular phase of the menstrual cycle interrupts preovulatory follicular development [38].

	CONCLUSION

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 
One of the enigmas in understanding the regulation of folliculogenesis is that both FSH and LH, at least in part, regulate follicular function through the cAMP signaling system. If both FSH and LH stimulate cAMP, why is there a need for FSH to induce LH receptors on granulosa cells? Recent findings indicate that the process of preovulatory follicular development, including the selection of a single follicle and ovulation, may be regulated by a single intracellular message (cAMP) which, in turn, is controlled in succession by two different messengers, FSH and LH. These observations, in addition to furthering our basic understanding of ovarian function, may also provide a novel approach for controlled ovarian stimulation in humans. If a specific cutoff point could be identified below which follicles are unresponsive to LH in vivo, it may be possible to develop a sequential FSH-LH stimulation regimen that would be effective in limiting follicular recruitment and thereby reduce the risk of unplanned multiple gestations and ovarian hyperstimulation.

	FOOTNOTES

 
First decision: 14 November 2000.

¹ The author's research reported in this review was supported by National Institutes of Health grants HD 12014, HD 16842, HD 08610, and Research Career Development Award HD 00531.

² Correspondence: Anthony J. Zeleznik, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, S327 Biomedical Science Tower, 3500 Terrace St., Pittsburgh, PA 15261. FAX: 412 383 7159; zeleznik+{at}pitt.edu

Accepted: March 19, 2001.

Received: October 13, 2000.

	REFERENCES

TOP ABSTRACT INTRODUCTION CESSATION OF PREOVULATORY... INITIATION OF PREOVULATORY... MIDFOLLICULAR PHASE THROUGH THE... CELLULAR ASPECTS OF FOLLICLE... CONCLUSION REFERENCES

 

1. Zeleznik AJ, Benyo DF. Control of follicular development, corpus luteum function, and recognition of pregnancy in higher primates. In: Knobil E, Neill JD (eds.), Physiology of Reproduction, vol. 2, 2nd ed. New York: Raven Press; 1994: 751–782
2. Goodman AL, Hodgen GD. The ovarian triad of the primate menstrual cycle. Recent Prog Horm Res 1983; 39:1-73
3. Nilsson L, Wikland M, Hamberger L. Recruitment of an ovulatory follicle in the human following follicle-ectomy and lute-ectomy. Fertil Steril 1982; 37:30-34[Medline]
4. Baird DT, Bäckström T, McNeilly AS, Smith SK, Wathen CG. Effect of enucleation of the corpus luteum at different stages of the luteal phase of the human menstrual cycle on subsequent follicular development. J Reprod Fertil 1984; 70:615-624[Abstract]
5. Zeleznik AJ, Wildt L, Schuler HM. Characterization of ovarian folliculogenesis during the luteal phase of the menstrual cycle in rhesus monkeys using [³H]thymidine autoradiography. Endocrinology 1980; 107:982-988[Abstract]
6. McNatty KP, Hillier SG, van den Boogaard AM, Trimbos-Kemper TC, Reichert LE Jr, van Hall EV. Follicular development during the luteal phase of the human menstrual cycle. J Clin Endocrinol Metab 1983; 56:1022-1031[Abstract]
7. Zeleznik AJ, Resko JA. Progesterone does not inhibit gonadotropin-induced follicular maturation in the female rhesus monkey. Endocrinology 1980; 106:1820-1826[Abstract]
8. Zeleznik AJ, Hutchison JS, Schuler HM. Passive immunization with anti-estradiol antibodies during the luteal phase of the menstrual cycle potentiates the perimenstrual rise in serum gonadotropin concentrations and stimulates follicular growth in the cynomolgus monkey. J Reprod Fertil 1987; 80:403-410[Abstract]
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34. Mukherjee A, Park-Sarge OK, Mayo KE. Gonadotropins induce rapid phosphorylation of the 3',5'-cyclic adenosine monophosphate response element binding protein in ovarian granulosa cells. Endocrinology 1996; 137:3234-3245[Abstract]
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