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Models of Luteinization¹

^a Centre de recherche en reproduction animale, Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 7C6

	ABSTRACT

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
Luteinization is essential to the success of early gestation. It is the process by which elements of the ovarian follicle, usually including both theca interna and granulosa cells, are provoked by the ovulatory stimulus to develop into the corpus luteum. Although there are significant species differences in luteinization, some elements pervade, including the morphological and functional differentiation to produce and secrete progesterone. There is evidence that luteinization results in granulosa cell exit from the cell cycle. The mechanisms that appear to control luteinization include intracellular signalling pathways, cell adhesion factors, intracellular cholesterol and oxysterols, and perhaps progesterone itself as a paracrine or intracrine regulator. Cell models of luteinization, along with some of the conflicting observations on the luteinization process, are discussed in this review.

corpus luteum function, female reproductive tract, follicle, granulosa cells, ovary, theca cells

	INTRODUCTION

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
Because of its fundamental importance to early pregnancy in mammals, the corpus luteum (CL) has been the subject of considerable research. We know about pituitary support of luteal function, uterine signals for luteal regression, and the role of waxing and waning progesterone secretion in regulation of ovarian cycles. Less is known about luteinization, the process by which the postovulatory follicle differentiates to become the CL. This may be due to the complexity of the process, which engenders differentiation and integration of cells derived from theca, granulosa, vascular, and reticuloendothelial progenitors. It may also be due to the variation in luteinization among species. A number of experimental models have been employed in studies of luteinization, including whole animals, in vitro culture of ovarian cells, and mice bearing null mutations for putative luteal regulators. These have provided insight, often with respect to the individual model, but we lack an overview. This review addresses the problems of luteinization from morphologic, physiologic, and biochemical standpoints.

	LUTEINIZATION IN VIVO

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
Although it is generally accepted that luteinization has a common stimulus, the preovulatory LH surge, there is considerable morphologic and temporal variation in the process among species. The morphologic events in some species have been well described. In the pig, Corner [1] established the sequence of luteinization, confirming the then controversial view that the granulosa cells were an integral component of the CL. Following expulsion of the ovum, the granulosa layer is thrown into folds about the follicular antrum, which contains elements of blood and follicular fluid. Theca cells are borne into the incipient CL by invasion of connective and vascular tissue at these folds. The vascular components soon reach the cavity of the collapsed follicle and invading septa persist as radially oriented strands of connective tissue, carrying the larger blood vessels into the CL. Later, extensive capillary branching completes vascularization of the CL, carrying the theca cells that become dispersed therein as single entities or in small groups. Granulosa cells undergo massive hypertrophy, with eightfold volume increases relative to their preovulatory size.

The carnivore CL displays another variation, due perhaps to intervals between the surge of LH and ovulation, 44 h or more in the dog [2] and 36 to 48 h in the mink [3], which are longer than those in domestic animals or rodents. In carnivores, differentiation of the granulosa and theca populations precedes expulsion of the ovum. In canids, the theca layer invades the follicle prior to ovulation, concomitant with increases in peripheral progesterone, indicating that luteinization precedes expulsion of the ovum [2]. In mink, morphologic luteinization also precedes ovulation [4]. In this and other mustelids with embryonic diapause, there is involution in luteal volume during the delay that precedes implantation, followed by luteal renaissance a few days prior to the attachment of the embryo [4, 5]. Rodents, including the hamster [6] and the rat [7] display yet another pattern of luteinization. The CL forms following ovulation, but requires a mating stimulus and consequent diurnal prolactin secretion to differentiate into the CL of pregnancy. This differentiation is independent of proliferation, because cell numbers differ between the CL of the cycle and that of pregnancy in the rat [8].

Composition of the CL

The phenomenon of differential size distribution of luteal cells has been confirmed in many mammals [9, 10] and is relevant to an understanding of the process of luteinization. Two cell populations with differing functional characteristics are present in the pig [11, 12], cow [13], sheep [14], and ferret [15]. A common view, based on histologic evidence, is that theca cells persist as the small luteal cells, whereas granulosa cells become large luteal cells [16]. In support of this view is the observation that, under certain conditions of culture, bovine theca cells acquire the small luteal phenotype, whereas granulosa cells display characteristics of large luteal cells [17]. In contrast, quantitative morphologic analysis of the bovine CL of the estrous cycle indicates fluctuation in the ratio of small and large cells, interpreted to indicate that small cells may differentiate into large luteal cells [18]. The premise of two functional cell populations intermixed in the CL does not apply to all species. The marmoset displays but one population of cells rather than the small and large versions [19]. The human CL contains cells of two sizes, the larger form predominates and the smaller cells are restricted to clusters in the periphery of the gland, associated with the vascular septa [20]. These cells are called the granulosa-lutein and theca-lutein cells, respectively, to reflect their purported origin [19].

	LUTEINIZATION IN VITRO

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
Channing and Ledwitz-Rigby [21] first demonstrated structural and functional differentiation in granulosa cells cultured in the presence of serum. Pig granulosa cells attach to the substrate and begin to display an elongated or fibroblastic aspect within the first 24 h of culture [22]. Over the next 48 h, they metamorphose to a pavement-like epithelial phenotype, concomitant with logarithmic increases in progesterone production [22, 23]. In the presence of serum, porcine [24], and bovine [25] theca cells in culture also undergo functional changes indicative of luteinization. This process includes a less pronounced morphologic shift from the fibroblastic to epitheloid phenotype [16, 25–27]. In rat granulosa cells, in vitro luteinization is accompanied by extensive cytoskeletal remodeling [28, 29].

Although the mature corpus luteum is comprised of both theca and granulosa cells, there appear to be few studies to indicate whether they function independently or interact. Preliminary investigation of bovine theca and granulosa cells grown on opposing sides of a collagen membrane demonstrated that coculture alters their morphology [30], but apparently not to the extent that occurs during differentiation of granulosa or theca cell monocultures. The changes include increased cell-cell contact between theca cells, increased frequency of membrane projections in granulosa cells, and increased cell convexity of both cell types. In an earlier report [31], it was demonstrated that coculture of human theca and granulosa cells in serum-supplemented medium results in initial increases in progesterone production relative to production noted in theca or granulosa cells cultured alone. Addition of testosterone increased progesterone synthesis by theca cells alone, whereas it inhibited progesterone synthesis in granulosa cell cultures and in theca-granulosa cell cocultures. The mechanisms of these interactions remain obscure, but may be due to the effects of steroids on activity of steroidogenic enzymes.

	LUTEINIZATION AND CELL DIVISION

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
The nature of the proliferative process in differentiated luteal cells has not been clearly defined. Luteinization may represent exit from the cell cycle and terminal differentiation of the granulosa cell descendents in the CL. In support of this view, Meyer and Bruce [8] found no change in the numbers of cells in the rat CL during early pregnancy. Further, proliferation of rat granulosa cells is arrested [32, 33] by ovulatory doses of LH, within 7 h after the luteinizing stimulus [33]. Christenson and Stouffer [34] found no evidence of concomitant steroidogenesis, (3ß-hydroxysteroid dehydrogenase activity) and proliferation (presence of cell cycle-related protein, Ki67) in primate luteal cells. In addition, the number of large luteal cells is constant throughout the luteal phase in the sheep [35], and their abundance is consistent with the number of granulosa cells in the preovulatory follicle [36, 37].

Nonetheless, there is evidence in some models that luteinization and proliferation are not mutually exclusive. Granulosa cells retain their capacity to proliferate in vitro [38], even after they have undergone luteinization [22]. At low plating density, human granulosa-luteal cells divide; at higher density, they differentiate [39]. In vivo, DNA synthesis and steroidogenesis colocalize in to luteal cells in small numbers of rat [40, 41] and sheep [42]. Steroidogenic cells from the ovine CL divide in vivo [42], and as many as 5% of human granulosa-luteal cells display Ki67, with greatest frequency during the early part of the luteal phase [43]. Mink luteal cells taken from involuted CL of embryonic diapause proliferate rapidly in culture and retain mitotic competence, even at confluence [44]. Mitosis has also been documented in marsupial luteal cells associated with reactivation of the CL at the end of embryonic diapause [45].

Human, rat, and bovine theca cells undergo hyperplasia in vitro in response to serum, gonadotropins, and growth factors [46]. Rat theca cells proliferate in vivo [32] and 15% of theca-luteal cells show proliferation during the early human luteal phase [43]. Corner [1] reported the occurrence of mitosis in theca-like cells of the septa of the pig CL. Further, Niswender et al. [47] postulated mitosis in small (presumably theca-derived) luteal cells in the sheep CL. If the granulosa component is terminally differentiated and there are increases in the numbers of steroidogenic cells across the luteal phase [35], the theca cell population must provide the new recruits. These may be the theca-derived "stem" cells that are postulated to be present in the bovine CL [46]. Their source is unknown, but may be an undifferentiated layer of the theca, as in the pig follicle [1], where there are small, rounded cells that are devoid of cytochrome P450 17 hydroxylase C17,20 lyase (P450 17) and 3ßHSD [48].

Insight into the mechanism of mitotic arrest of rat granulosa cells comes from recent studies of cell cycle proteins [49, 50]. Targeted deletion of the cyclin-dependent kinase inhibitor p27^Kip1 results in infertility in mice, attributed to a failure of the CL to differentiate into a compact structure [51]. A second cell cycle inhibitor, p21^cip1, has also been implicated in luteinization, based on its induction in the incipient CL of hypophysectomized rats by an ovulatory dose of LH [52]. The Cip/Kip family of kinase inhibitors regulates cyclin D complexes [53]. Cyclin D2 is necessary for granulosa cell proliferation, as its targeted deletion impairs both normal [54] and gonadotropin-induced [52] granulosa cell mitosis. Cyclin D2 expression is downregulated within 4 h in granulosa cells undergoing luteinization [52], which suggests that the LH surge arrests mitosis by concurrent inhibition of cyclin D2 and upregulation of p27^Kip1 and p21^cip1.

	FUNCTIONAL MARKERS OF LUTEINIZATION

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
Interaction of theca, granulosa, vascular, and reticuloendothelial elements in the extensive cellular remodeling in luteinization occasions the coordinated expression of many proteins, of which we know but a few. These have served as tools for characterizing luteinization, investigating control mechanisms, and attempting to map the fates of luteal cell progenitors.

In most species, the theca of the follicle produces androgens that are aromatized to estrogens by cytochrome P450aromatase in granulosa cells [55]. The loss of androgen production and aromatization mark luteinization in some species [26]. The P450 17 enzyme complex is rate limiting and necessary for androgen formation in the follicle [55], and P450 17 is present in the theca, but not the granulosa of developing follicles in the sheep, cow, and pig [48]. Its disappearance at luteinization in the sheep and cow has been employed as a marker for luteinization [26, 56]. Nonetheless, P450 17 remains along the invading vascular tracts following luteinization in primates [57] and is dispersed throughout the mature porcine CL [48]. The disappearance of aromatase, the rate-limiting enzyme in estrogen synthesis, is another potential marker of luteinization in granulosa cells [27, 56]. It is less valuable in pigs where estrogen is synthesized by both theca and granulosa compartments of the follicle [58], and by the mature CL [11]. Nevertheless, in vitro luteinization of pig granulosa cells engenders rapid loss of aromatase expression [22]. Changes in other steroidogenic enzymes mark luteinization; cytochrome P450 side chain cleavage (P450Sscc) is acquired within 7 h of the ovulatory stimulus in the rat CL [32]. Its expression increases during in vitro luteinization of pig granulosa cells [22, 23, 59].

Steroidogenic acute regulatory protein (StAR) imports cholesterol into mitochondria, and is essential for steroidogenesis [60]. It is present in theca but not granulosa cells of follicles and is acquired during in vitro and in vivo luteinization of granulosa cells in the pig [22, 61], cow [62, 63], and mare [64]. Its expression pattern renders it an important marker of the luteinization process.

Oxytocin is expressed in the CL of cows, primates, and pigs [65, 66]. There is evidence for both beneficial and detrimental effects of this nonapeptide on luteal steroidogenesis [67] and it may be involved in the formation of gap junctions in the CL [68]. Notwithstanding the lack of a clear indication of its function, oxytocin appears to be a useful marker for investigation of cell lineages during luteinization. Its expression is confined to the granulosa layer of large follicles in the cow [69] and marmoset [70]. It is upregulated during ovulation [71] and strongly expressed during in vivo [71] and in vitro [72, 73] luteinization of bovine granulosa cells. Its expression is confined to large luteal cells of the bovine CL [74], lending credence to the view that these cells are granulosa derived.

	CHOLESTEROL TRAFFICKING AND LUTEINIZATION

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
The human CL has been estimated to secrete 10–40 mg/day of progesterone [75], and the principal source of substrate for this immense synthetic activity is extracellular, lipoprotein-borne cholesterol [76, 77]. Comparison of circulating concentrations of the follicular products, androgens and estrogens [55] with progesterone, indicates that luteinization increases total ovarian steroidogenesis by orders of magnitude. The role of cholesterol trafficking in luteinization is just beginning to be investigated. Luteinization engenders upregulation of the cholesterol-trafficking pathways (lipoprotein receptors, cholesterol transport proteins, and the enzymes that catalyze cholesterol synthesis, cholesterol ester lytic enzymes) to meet a dramatically elevated substrate requirement [77].

Lavoie et al. [78] demonstrated prominent increases in expression of the porcine low density lipoprotein (LDL) receptor in the follicle, beginning soon after the ovulatory stimulus and persisting through the luteal phase, correlating with luteal progesterone content. Expression of StAR has also been shown to undergo luteinization-dependent upregulation in both the pig [22, 78, 79] and the cow [63]. Less pronounced, but probably real, are elevations of the sterol carrier protein-2, which ferries hydrophobic cholesterol through the aqueous cytoplasmic milieu [77, 78]. Circulating high density lipoproteins (HDL) contribute cholesterol to luteal steroid synthesis, and are the principal cholesterol supply in murine rodents [77]. The mechanism of cellular importation of HDL via a scavenger receptor type 1, class B (SR-B1) has been elucidated [80]. The abundance of its expression correlates with luteinization of rat granulosa cells in vivo [81], and SR-B1 content is directly correlated with the acquisition of cholesterol by granulosa cells in vitro [82]. Expression of SR-B1 increases sevenfold in the CL during luteinization in vivo and fivefold during luteinization of bovine granulosa cells in vitro [83].

Following uptake, LDL-derived cholesterol resides briefly in late endosomes or lysosomes before it undergoes dispersion to membranes, esterification, or metabolism [84]. Its exit from lysosomes depends on the Niemann-Pick protein (NPC-1) [85, 86], which appears to affect bulk transport of cholesterol between the lysosome and the Golgi apparatus [84]. Testicular steroidogenesis is disrupted in mice bearing a spontaneous mutation that inactivates the NPC-1 gene [87]. Expression of NPC-1 has been noted in the porcine ovary and its mRNA abundance increases with luteinization, both in vivo and in vitro [88].

Not all of the proteins that regulate cholesterol economy show marked variation in relation to luteal differentiation. The expression (mRNA abundance) of the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-reductase) does not change with luteinization in the pig ovary [78]. The mRNA for hormone-sensitive lipase, the principal cholesteryl esterase in steroidogenic tissue [89], increases twofold during luteinization of the rat CL [90]. It shows no pattern of variation associated with luteinization of porcine granulosa cells in vitro [unpublished results].

	FACTORS CONTROLLING LUTEINIZATION

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
The proximal event that initiates luteinization is the preovulatory gonadotropin surge that provokes ovulation [91, 92]. Ovulation is not a sina qua non for luteinization; there are numerous examples of luteinization in unruptured follicles, including follicles of rodents [93, 94], humans [95], and subhuman primates [96]. Disruption of ovulation does not affect luteinization in the pig [97] and luteinization appears to be the fate of all large, unovulated follicles in the mink [4].

Both granulosa [21] and theca [25] cells spontaneously luteinize in vitro in serum-supplemented cultures. It was originally believed that the physical presence of the oocyte inhibited luteinization of mammalian follicles [98]. Nonetheless, incubation of the granulosa cells with oocytes did not impair in vitro luteinization; rather, follicular fluid from small follicles (but not from large follicles) proved inhibitory [99]. More recent studies provide convincing evidence for an inhibitory effect of oocytes on steroidogenesis in granulosa cells derived from the cumulus oophorus [100]. The disparate results may perhaps be explained by the number and stage of development of oocytes used: Channing and Tsafriri [101] employed 50 oocytes of an unknown state of maturation per 10⁶ pig granulosa cells, whereas Vanderhyden and MacDonald [100] used multiple oocytes per oocytectomized cumulus complex. In the latter study, oocytes that had acquired meiotic competence proved the most potent inhibitors of the synthesis of progesterone by cumulus cells.

Candidate molecules for inhibition of luteinization include endothelin 1, which is found in porcine follicular fluid [102]. It is capable of inhibiting gonadotropin-induced progesterone production in rat [103] and pig [102] granulosa cell cultures. Alternatively, epidermal growth factor (EGF) inhibits steroidogenic capacity and alters the differentiated phenotype in luteinized granulosa cells [22].

Culture conditions that prevent spontaneous luteinization provide a paradigm for investigation of the factors that control the process. The presence or absence of serum appears to be a principal determinant. Demeter-Arlotto et al. [26] demonstrated that androgen production and 17-hydoxylase could be maintained in bovine theca cells in serum-free culture. Bovine granulosa cells maintained without serum maintain basal and FSH-induced estrogen production [56] and morphology characteristic of follicular granulosa cells [104]. Ovine theca cells likewise avoid spontaneous luteinization in serum-free culture, as indicated by cell shape and androgen production in response to LH for periods of up to 48 h [27].

The serum component employed in most culture systems, usually fetal calf serum, is undefined, and may contain gonadotrophins [105]. It is therefore possible that the LH present in serum drives luteinization of granulosa cells in vitro. This association notwithstanding, serum contains growth factors and cytokines and has plieotropic effects on cells in culture. Insulin and insulin-like growth factors (IGF) have a variety of tropic effects on granulosa and theca cells [106]. It has been shown that IGF-1 hastens the appearance of StAR during in vitro luteinization and augments gonadotropin-induced StAR expression [22, 61].

Adhesion Factors and Luteinization

Bovine granulosa cells grown in anchorage-independent conditions do not spontaneously acquire luteal morphology, which suggests luteinization requires attachment [107]. Serum may provide adhesion proteins that induce or modulate luteinization, including fibronectin, laminin, and collagen. These glycoproteins increase attachment of pig granulosa cells [108]. In some species, including the rat, granulosa cells attach readily to culture wells without addition of serum, most likely because they produce endogenous attachment factors, including fibronectin [109, 110].

Remodeling associated with luteinization includes changes in extracellular matrix adhesion molecules. Integrin 5 is not present on human granulosa cells of follicles, but is acquired during luteinization [111]. Integrin 2 is present in the early CL, and its ligand, collagen type IV, increases in granulosa cells at ovulation, and persists on their surface through luteinization [112]. Integrin 6ß1 is present in early corpora lutea [113] and is associated with CD9, a glycoprotein involved with cell adhesion and migration [114]. Integrin 6ß1 interacts with its ligand, laminin [115]. There is conflicting evidence on the role of this integrin in luteinization. Treatment of human granulosa cell cultures with laminin interferes with progesterone synthesis, an effect that can be reversed by antisera that block laminin-integrin binding [116]. In contrast, laminin upregulates progesterone synthesis in vitro in rat granulosa cells luteinized in vivo, and neutralization of integrin ß1 with antibodies resulted in loss of progesterone synthesis [117]. Pig granulosa cells plated on laminin had increased ligand-induced progesterone synthesis relative to cells grown in serum-free cultures [108]. In overview, the temporal and differentiation-dependent expression of adhesion molecules is evidence that they play a role in luteinization and may be among the serum factors that allow or induce its spontaneous occurrence.

	INTRACELLULAR SIGNALING AND LUTEINIZATION

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
The Protein Kinase A Pathway

Oonk et al. [33] reported phenotypic differentiation and mitotic arrest of rat granulosa cells at 7 h after an ovulatory dose of LH. It is well known that LH stimulates cAMP formation and activation of the protein kinase A (PKA) pathway. It has been postulated that cAMP serves as the initial signal for luteinization of granulosa cells, which then become refractory to cAMP stimulation. This view is consistent with in vivo models including the rat [33, 118] and sheep [119], that display constitutive expression of P450scc and cAMP insensitivity of P450scc during the luteal phase. The pattern of luteal P450scc expression in the cow [79] and pig [61] and in luteinized bovine granulosa cells in vitro [120] fits this model. Recent studies have revealed luteinization-associated differences in components of the cAMP pathway. In the rabbit CL, luteinization increases the stability of the R1 PKA subunit [121], which may limit PKA responses. In the rat, the PKA catalytic subunit shifts from nuclear to cytoplasmic localization following luteinization in vivo [122]. The PKA-driven transcriptional protein, CREB undergoes a transient phosphorylation early in luteinization of rat granulosa cells, followed by insensitivity to phosphorylation in response to continued cAMP (forskolin) stimulation [119]. Expression of at least one CREB isoform disappears during luteinization in the macaque CL [123].

The hypothesis of initial cAMP stimulation, followed by cAMP refractivity does not fit observations made in all species. Incubation of mink luteal cells from both postovulatory and postimplantation periods with a cAMP analogue elevates StAR and P450scc mRNA and progesterone [44], indicating that the PKA system may not be refractory in these cells. In addition, there is marked divergence of in vitro and in vivo models of luteal function, such that in vitro luteinized porcine granulosa cells are not refractory to cAMP stimulation, they display acute increases in P450scc expression in response a cAMP challenge [22, 61, 124]. Further, both LH and its second messenger, cAMP, hasten the appearance of the luteal marker, StAR expression, during luteinization of porcine granulosa cells in vitro [22, 61].

The Protein Kinase C Pathway

The family of enzymes known as protein kinase C (PKC), contains several isoforms with differing downstream targets [125]. The PKC system transduces signals for both cell proliferation and differentiation. Few data exist on its role in luteinization; given the variety of effects of PKC antagonists and agonists, it is not surprising that there is no unifying model. Activation of the PKC pathway by a phorbol ester downregulates induction of aromatase expression in rat granulosa cells [126] and, in concert with LH, induces P450scc, progesterone production, and morphologic markers of luteinization [127]. Likewise, inhibition of PKC abrogates luteinization in rat granulosa cells [128]. In stark contrast, induction of PKC activity both prevents [129] and reverses [22] structural luteinization of porcine granulosa cells. It further eliminates cAMP-induced StAR expression in luteinized pig granulosa cells [22]. Its effects on P450scc mRNA abundance in luteinized cells appear biphasic: initial stimulation is followed by downregulation [22, 130]. These differences demonstrate the peril in generalizing from a single model species.

Sterol Signaling

Cholesterol is metabolized to oxysterols by hydroxylation at sites on the sterol nucleus or side chain by specific cytochrome P450 hydroxylases [131] and, in at least one case, by an enzyme (25-hydroxylase) that is not of the P450 motif [132]. Nonenzymatic oxidation has also been reported [131]. Hydroxylation confers hydrophilicity on cholesterol, facilitating its movement between membranes and compartments of the cell [133]. Oxysterols are potent modulators of expression of cholesterol synthetic, degrading, and transporting proteins functioning in part by regulation of transcription of sterol-sensitive elements [134, 135]. When intracellular sterol concentrations are low, sterol-regulatory element binding proteins (SREBPs) are released from the membranes of the endoplasmic reticulum by sterol cleavage activating protein (SCAP) [132]. The promoter regions of HMG-CoA reductase and the LDL receptor [134], HMG-CoA synthase [136], hormone sensitive lipase [137], and others, contain 10 nucleotide sequences designated sterol regulatory elements 1 and 2 (SRE-1 and SRE-2). The SREBP product of SCAP cleavage migrates to the nucleus where it interacts with coregulatory factors and associated DNA binding sites to upregulate transcription of the genes that increase intracellular cholesterol [138]. Several coregulators have been recognized, including SP-1 and NF-Y [139].

Oxysterols suppress endogenous cholesterol synthesis [140] and downregulate the LDL pathway [141] in granulosa cells. There appears to be intracrine regulation of oxysterol formation in rat luteal tissue. Upregulation of the expression of 26-hydroxylase, the enzyme that forms 26-OH cholesterol, reduces progesterone synthesis [142]. In turn, progesterone is a negative regulator of the formation of 26-OH cholesterol, both at the level of enzyme activity [143] and at the level of mRNA production [142].

Other mechanisms of sterol regulation have been postulated. The promoter region of numerous endocrine genes, including the cytochrome P450 family that regulate steroidogenesis [144], StAR [61, 145, 146–148], and SR-B1 [149], contains a consensus sequence for the orphan nuclear receptor, SF-1. Mutation and deletion analyses of SF-1 consensus sites in StAR promoter regions, along with cotransfection of SF-1, indicate that this protein plays an important role in cAMP-induced expression of StAR [146, 148]. Lala et al. [150] reported that oxysterols, particularly 25-OHC and 27-OHC, may serve as ligands for SF-1. Thus, the potential exists for positive oxysterol regulation of luteinization, via a stimulation and induction of StAR and progesterone synthetic enzymes.

Subsequent exploration of the hypothesis that oxysterols are ligands for SF-1 yielded conflicting results. Mellon and Bair [151] reported that 25-OHC failed to modulate transcription of six SF-1-dependent genes in mouse MA-10 Leydig tumor cells. Christenson et al. [152] demonstrated stimulatory effects of both 25- and 27-OHC on expression of the StAR gene promoter constructs in CV-1 cells but not COS-1 or CHO cells. Surprisingly, there was an inverse effect on inhibition of StAR promoter activity in adrenal-derived Y-1 cells. In primary cultures of human theca and granulosa cells, 27-OHC induced fivefold increases in StAR protein in the absence of changes in StAR mRNA [152], interpreted as indicative of posttranscriptional regulation.

There are additional pathways for oxysterol regulation of cholesterol metabolism and cellular function. Cholesterol oxygenated at the 22 or 24 position is a ligand for orphan nuclear receptors LXR and LXRß, and thereby regulates metabolism of cholesterol and bile acids in the liver [153]. In luteinized pig granulosa cells, the oxysterol, 22(R)-OHC reduces abundance of StAR and NPC-1 mRNAs [Gévry, Dobias and Murphy, unpublished], but it is not known whether this occurs via LXR, SF-1, SRE, or some other mechanism.

Progesterone as an Autocrine or Intracrine Signal

The venerable Dr. Rothchild [7] postulated that progesterone stimulates its own secretion, thereby providing positive feedback for a free-running CL. There is evidence from some models to support to this view. Mice bearing the null mutation for the progesterone receptor are anovulatory and ovulation is not successfully induced by gonadotrophin treatment, suggesting an essential role of progesterone in early granulosa cell differentiation [154]. Progesterone receptor expression is induced in rat granulosa cells by the LH surge [155] and is dependent on cAMP and granulosa cell differentiation [156]. Progesterone receptors localize to the nuclei of luteal cells during early and midluteal phases in monkeys [157, 158] and to luteinized monkey granulosa cells [159]. Blockade of the conversion of pregnenolone to progesterone reduces the mass of the monkey CL [160]. Progesterone receptor antagonists inhibit luteinization in bovine granulosa cells, as indicated by loss of oxytocin gene upregulation [161]. In immortalized porcine granulosa cells, synthetic progestins act in synergy with cAMP to increase progesterone synthesis, and progesterone and other progestins upregulate P450scc [162]. Progesterone further promotes differentiation and inhibits proliferation of human granulosa-luteal cells in vitro [39].

Contrasting data include the observations that progesterone receptors are undetectable in the CL of the rat estrous cycle [163] and not consistently present in the rabbit CL [164]. Furthermore, progesterone and pregnenolone are potent inhibitors of lysosomal export of cholesterol [165], impairing the function of the LDL-substrate pathway in luteinized human granulosa cells [166]. Studies with specific agents that block progesterone synthesis and with receptor antagonists will allow for better characterization of the role of progesterone as a signal in luteinization.

	SUMMARY AND UNRESOLVED ISSUES

TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 
Luteinization of elements of the postovulatory follicle is essential to the success of pregnancy in mammals. Although the diversity of mechanisms precludes a unifying model, there are elements common to most species. Figure 1 presents a summary of the luteinization process and hypotheses about the elements that control it, based on the observations reviewed herein. Our understanding of this crucial step in differentiation is not profound, and thus it may not yet be possible to arrive at an integrated perspective. However, the available information provides the basis for a number of questions. First, given the morphological and apparent mechanistic diversity of luteinization, are there common pathways of luteal differentiation among mammals? Recent studies have shown that luteal angiogenesis and vascularization arise from the theca interna [167]. Are the steroidogenic theca cells simply passengers in the angiogenic process, or are they actively translocated? If the latter case is true, what is the mechanism? Are luteinization and proliferation mutually exclusive in species other than the rat? If so, what is the source of dividing cells in corpora lutea? As the in vitro model of granulosa cells shows some fidelity to the in vivo process in terms of steroidogenesis, what are the differences in cell cycle control in vivo and in vitro? What are the mechanisms that prevent spontaneous luteinization of follicles in vivo? How do signaling pathways interact to regulate the expression of luteinization-specific events? Are the changes in adhesion proteins associated with luteinization the cause or the effect of differentiation? Do cholesterol and its steroid hormone metabolites, particularly progesterone, have regulatory effects on the process of luteinization?

View larger version (50K): [in this window] [in a new window]   FIG. 1. Schematic representation of the changes that take place during luteinization and their potential regulatory mechanisms

In conclusion, it is our challenge is to develop both models of luteinization and the methods needed to investigate these questions.

	ACKNOWLEDGMENTS

 
Thanks are extended to Mira Dobias and Sandra Ledoux for technical assistance. Figure 1 was drawn by Sandra Ledoux.

	FOOTNOTES

 
First decision: 6 December 1999.

¹ Experiments in the author's laboratory were supported by grants from MRC and NSERC of Canada.

² Correspondence. FAX: 450 778 8103; murphyb{at}medvet.umontreal.ca

Accepted: February 16, 2000.

Received: November 2, 1999.

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TOP ABSTRACT INTRODUCTION LUTEINIZATION IN VIVO LUTEINIZATION IN VITRO LUTEINIZATION AND CELL DIVISION FUNCTIONAL MARKERS OF... CHOLESTEROL TRAFFICKING AND... FACTORS CONTROLLING... INTRACELLULAR SIGNALING AND... SUMMARY AND UNRESOLVED ISSUES REFERENCES

 

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