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The Molecular Control of Corpus Luteum Formation, Function, and Regression

Department of Obstetrics, Gynecology and Reproductive Science (C.S.), Yale University School of Medicine, New Haven, Connecticut 06510; Division of Basic Biomedical Sciences (C.T.), Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069; and Department of Physiology and Biophysics (G.G.), University of Illinois College of Medicine, Chicago, Illinois 60612

Correspondence: Address all correspondence and requests for reprints to: Dr. Geula Gibori, Department of Physiology and Biophysics, University of Illinois College of Medicine, 835 South Wolcott Avenue, Chicago, Illinois 60612. E-mail: ggibori{at}uic.edu

	Abstract

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

 
The corpus luteum (CL) is one of the few endocrine glands that forms from the remains of another organ and whose function and survival are limited in scope and time. The CL is the site of rapid remodeling, growth, differentiation, and death of cells originating from granulosa, theca, capillaries, and fibroblasts. The apparent raison d’etre of the CL is the production of progesterone, and all the structural and functional features of this gland are geared toward this end. Because of its unique importance for successful pregnancies, the mammals have evolved a complex series of checks and balances that maintains progesterone at appropriate levels throughout gestation. The formation, maintenance, regression, and steroidogenesis of the CL are among the most significant and closely regulated events in mammalian reproduction. During pregnancy, the fate of the CL depends on the interplay of ovarian, pituitary, and placental regulators. At the end of its life span, the CL undergoes a process of regression leading to its disappearance from the ovary and allowing the initiation of a new cycle. The generation of transgenic, knockout and knockin mice and the development of innovative technologies have revealed a novel role of several molecules in the reprogramming of granulosa cells into luteal cells and in the hormonal and molecular control of the function and demise of the CL. The current review highlights our knowledge on these key molecular events in rodents.

I. Introduction

II. Formation of the Corpus Luteum: Reprogramming of Follicular Cells

A. Exit from the cell cycle

B. Key molecules involved in luteinization

C. Changes in the expression of receptors

D. Activation of signaling pathways

III. Genesis of a New Gland: Structural Changes from the Remnants of the Ovulated Follicle

A. Luteal cell types

B. Tissue remodeling

C. Vascularization

IV. Function of the Corpus Luteum

A. Luteal steroidogenesis

B. Hormonal regulation

V. Regression of the Corpus Luteum: Involution to Resume Cyclicity

A. Functional luteal regression

B. Structural luteal regression

VI. Concluding Remarks

	I. Introduction

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

 
THE CORPUS LUTEUM (CL) plays a central role in the regulation of the estrous cycle and in the maintenance of pregnancy. This function is carried out largely by progesterone, which is the main steroid synthesized by this transient endocrine gland. If the oocyte is not fertilized, the CL regresses, allowing a new cycle to begin. Implantation, mating, or even cervical stimulation in some mammals initiates a complex mechanism geared to maintain CL function, ensuring a continuous supply of progesterone needed for fetal survival.

Four types of CL differing in their life span and steroidogenic output can be found in mammals, i.e., the CL of: 1) the cycle, 2) pseudopregnancy, 3) pregnancy, and 4) lactation. Only the CL of pregnancy is present in all mammalian species, whereas all four types can be found in rodents. The CL of the cycle does not exist in induced ovulators, and the CL of pseudopregnancy does not form in primates, whereas the CL of lactation is seen only in species that ovulate after parturition.

Reviews covering several aspects of the physiology of the primate CL, such as luteal steroidogenesis (1, 2), the process of luteal regression and remodeling (3), and the molecular mechanisms triggered by LH (4) have been published. The mechanism controlling luteal function, principally in ruminants, also has been reviewed by various investigators (5, 6, 7, 8, 9, 10, 11, 12). In addition, an extensive analysis of the role of immune cells and cytokines as mediators of luteal formation and regression has being published recently (7, 13, 14). Other aspects of luteal function such as angiogenesis and overall role of the luteal microvasculature have been also revisited (15, 16, 17). The clinical aspect of the CL function in assisted reproduction has also been discussed (18). Finally, an overview of the contribution of mutant mouse models to the knowledge of luteal development, function, and regression has been reported (19, 20). The present review focuses on the molecular, cellular, and physiological mechanisms underlying the processes of formation, regulation, and regression of the CL, with a particular emphasis on rodent species.

	II. Formation of the Corpus Luteum: Reprogramming of Follicular Cells

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

 
Activation of the LH receptor (LH-R) in follicular cells by the preovulatory LH surge causes ovulation and rapidly initiates a program of terminal differentiation of the ovulated follicle into a CL through a process termed luteinization. Remarkably, transformation of granulosa cells into luteal cells occurs within a few hours (21). There are structural and genomics changes that lead to the terminal differentiation of follicular cells into nondividing progesterone-producing luteal cells. Cells undergoing luteinization must stop dividing and begin expressing a new set of molecules that will allow luteal cells to survive in a different hormonal environment. Thus, the final luteal cell phenotype depends on a specific combination of genes encoding for regulatory proteins such as receptors, transcription factors, and signaling proteins, which ensures the expression of only those genes necessary for luteal cell function. This reprogramming of follicular cells into luteal cells is irreversible and requires first the exit from the cell cycle.

A. Exit from the cell cycle
LH terminates follicular growth by causing granulosa cells of preovulatory follicles to exit the cell cycle. Luteal steroidogenic cells are found arrested predominantly at the G₀/G₁ phase of the cell cycle (22). Cyclin-dependent kinases (Cdks) and several proteins that either stimulate or inhibit their activities regulate the G₁ phase of the cell cycle, governing the transition between proliferation and quiescence (23). Progression through G₁ is controlled largely by Cdks 4/6 and 2 in association with cyclins D and E, respectively. Entry of cells into S-phase involves the cooperation of Cdk 4/6 and D-type cyclins, D1, D2, and D3 with Cdk2/cyclin E. These kinases phosphorylate the retinoblastoma protein (pRb) on multiple sites. Once phosphorylated, pRb frees transcription factor E2 (E2F) that, in turn, activates diverse genes required for S-phase entry and progression (24, 25). Initiation of cell cycle arrest involves the induction of endogenous Cdk inhibitors (e.g., p21^cip1 and p27^kip1), which bind to cyclin/Cdk complexes to inhibit their activity (25). Thus, phosphorylation of pRb does not take place, allowing hypophosphorylated pRb to repress the activity of E2F leading to G₁ cell cycle arrest (reviewed in Ref. 26). Accordingly, in mice (27) and human (22) luteal cells, only unphosphorylated pRb is found and, consistent with this, they contain the Cdk inhibitor protein, p27^Kip1, but not E2F-1, which is normally expressed only in proliferating cells. More recently, the deletion of cyclin D2, p21^cip, p27^kip1, and Cdk4 genes has allowed investigators to clarify the mechanisms by which follicular cells cease to divide. Deletion of the cyclin D2 gene impairs granulosa cell proliferation and prevents follicular development. Follicles remain small, and ovulation does not occur (28). Because cyclin D2 promotes G₁ progression by activating Cdk4, a cyclin D2/Cdk4 complex was thought to be required for proliferation of follicular cells. However, Cdk4-null mice demonstrated intact follicular maturation and revealed no intrinsic irregularities in the exit from the cell cycle of follicular cells after ovulation (29, 30). Deletion of Cdk4 caused rather a rapid demise of the CL due to a profound decrease in the number of pituitary lactotropes, leading to reduced secretion of prolactin (PRL). Thus, restoring serum PRL levels is sufficient to rescue normal formation of the CL in Cdk4-null mice. The selective effect of Cdk4 deficiency on the pituitary but not the ovary suggests that other factors may compensate for its absence in the ovary. Normal cell growth in the ovary of Cdk4-null mice may depend on Cdk6 that is normally coexpressed with Cdk4 in most tissues (31) and has cyclin D-dependent kinase activity in vitro indistinguishable from that of Cdk4 (32).

Cessation of cell proliferation during luteinization is associated with a progressive loss of positive cell cycle regulators, including cyclins and Cdk2, and with increased expression of the Cdk inhibitors p21^cip1 and p27^kip1 (27, 33). Richards et al. (34) have elegantly shown that the LH surge silences, within 2 to 4 h, the expression of cyclin D2 mRNA and protein and induces that of the Cdk inhibitors p21^cip1 and p27^kip1. The expression of p21^cip1 is rapidly induced by LH; however, p27^kip1 stimulation is seen only after 12 to 24 h of treatment; this led the authors to conclude that p27^kip1 may not affect the immediate exit of granulosa cells from the cell cycle but rather contributes to the maintenance of cell cycle arrest. Deletion of p21^cip1 caused no detectable effect on proliferation of luteinized cells and fertility, whereas p27^kip1-null ovaries showed hyperproliferation of granulosa cells during luteinization, which appears to be, at least in part, the cause of the sterility seen in these mice (35). These observations suggest that p27^kip1 is a major limiting factor for successful exit of granulosa cells from the cell cycle during luteinization. The recent generation of p27^kip1, p21^cip1 double knockout (35) revealed that these two Cdk inhibitors play a cooperative role in exit of the cell cycle of granulosa cells. The absence of the two Cdk inhibitors resulted in prolonged proliferative life span of luteinized cells in vivo. This implies that exit from the cell cycle is not an obligatory step for the differentiation of granulosa cells into luteal cells. This possibility is further substantiated by the finding that granulosa cells isolated from mice lacking both Cdk inhibitors have remarkably prolonged proliferation in culture, they continue expressing granulosa cell-specific genes, yet they differentiate into luteal cells after several passages in culture despite their p27^kip1 and p21^cip1 deficiency (35). Interestingly, these cells are neither immortal nor transformed as they undergo senescence and finally die by apoptotic programmed cell death.

B. Key molecules involved in luteinization
Several genes that are rapidly and transiently induced by the LH surge are thought to be involved in ovulation and induction of luteinization. Between the transiently induced genes after the LH surge are progesterone receptor (PR) (36, 37), cyclooxygenase-2 (COX-2) (38), CATT/enhancer binding protein ß (C/EBPß) (39), early growth response protein-1 (Egr-1) (40), and Nur77 (41). Whereas Nur77-null mice are fertile, mice deficient in PR, C/EBPß, or COX-2 are infertile. This latter group of mice develops preovulatory follicles but fails to ovulate. COX-2 and PR knockout female mice do not ovulate even in response to exogenous hormones but form CL containing trapped oocytes, suggesting that luteinization can occur in the absence of these molecules (38, 42). In contrast, C/EBPß-null mice ovulate fertilizable eggs in response to gonadotropin stimulation, yet luteinization does not take place, and the CL are not formed even when the ovaries are transplanted into normal hosts (39). These data indicate that this phenotype is caused by intrinsic ovarian defect(s) and demonstrate a key role for C/EBPß in the process of luteinization. The C/EBPß transcription factor, which belongs to the basic leucine zipper class of DNA binding proteins, is rapidly induced in vivo by LH in granulosa cells (39, 43). The C/EBPß promoter contains two cAMP response elements (CREs) that may be essential for LH-stimulated C/EBPß transcription. This is because LH-R signaling is known to increase intracellular cAMP (37), which activates the CRE binding protein (CREB). The genes targeted by C/EBPß that are specifically involved in follicular cell luteinization are not yet known. Some intriguing findings were obtained with the C/EBPß-null mice, suggesting that this transcription factor does not necessarily mediate stimulation of gene expression by LH during luteinization, but rather may be responsible for silencing the expression of genes after their prior induction by LH. In wild-type mice and rats, P450 cholesterol side-chain cleavage (P450scc), P450 aromatase (P450arom), and COX-2 expressions were stimulated by LH (37, 39). However, whereas P450scc remained highly expressed long after luteinization began, both COX-2 and P450arom expressions declined several hours after LH/human chorionic gonadotropin (hCG) administration. This decrease does not occur in ovaries of C/EBPß-null mice, suggesting that a product of the C/EBPß gene could be responsible for this phenomenon. The C/EBPß gene is transcribed into a single RNA that gives rise to four C/EBPß isoforms: two full-length liver-enriched activator protein (LAP) isoforms (38 and 34 kDa), one truncated 21-kDa liver-enriched inhibitory protein (LIP) isoform, and a second truncated 14-kDa isoform. LIP C/EBPß isoforms function as dominant negative inhibitors of the full-length C/EBPß LAP isoform (reviewed in Ref. 44). Thus, functioning as a transcriptional repressor in luteinized cells, LIP may repress the expression of COX-2 and P450arom. Once luteinization occurs, C/EBPß is no longer expressed in the CL (39), suggesting that the role of this transcription factor is limited to the process of luteinization and is not involved in the maintenance of luteal function.

Other transcription factors such as Egr-1 (also named NGFI-A) and Nur77 (NGFI-B) are also stimulated by LH (40, 41, 45, 46). Both factors are encoded by immediate early genes and are capable of binding regions rich in guanine and cytosine (GC-rich) within the promoter of numerous genes. Egr-1 has been shown to be induced by LH/hCG in granulosa cells of ovulating follicles (40). Egr-1 expression in response to LH is rapid, transient, and dependent on the activation of at least two cellular signaling pathways, protein kinase A (PKA) and MAPK (46). GC-rich enhancer elements that potentially bind Egr-1 are present in many LH-regulated genes, and Egr-1 often binds overlapping sequences with Sp1, an important transcription factor controlling several ovarian-expressed genes. Based in this fact, Russell et al. (46) proposed that Egr-1 can exert either positive or negative transcriptional events by acting on Sp1 sites. Disruption of Egr-1 expression led to fertility problems due to a diminished or complete lack of expression of LHß (47). However, development of a second mutant mouse, in which the lacZ gene was introduced into the Egr-1 locus, showed that infertility results from abnormal function of both the anterior pituitary and the ovary (48). An ovarian defect is supported by the lack of ovulation and formation of CL on Egr-1 knockout mice treated with pregnant mare serum gonadotropin and hCG (48). Egr-1 knockout animals subjected to a superovulation protocol showed, however, an increase in size of both the uterus and antral follicles. These enlarged follicles lacked signs of luteinization or cumulus cells expansion; instead, the follicles appeared highly hemorrhagic. These abnormalities indicate a severe defect in the receptivity of follicular cells to LH. Accordingly, the authors demonstrated a reduction of LH-R expression in the ovary of Egr-1 knockout mice (48), suggesting that Egr-1 controls not only the expression of LHß in the pituitary but also the capacity of granulosa cells to respond to this hormone.

Classified as an orphan nuclear receptor, Nur77 displays the tripartite domain structure of members of the steroid receptor family yet does not bind any known ligand. Nur77 was shown to regulate the transcriptional activity of steroidogenic genes (49, 50, 51) and has been implicated in the regulation of apoptosis in nonovarian cell types (52, 53). Nur77 is a homolog of steroidogenic factor-1 (SF-1), which is constitutively active in many steroidogenic tissues and binds to an element similar yet distinct from Nur77 (54). In contrast to SF-1, Nur77 is present at low levels in preovulatory granulosa cells under basal conditions, but it becomes rapidly and highly expressed in response to hCG/LH stimuli both in vivo and in vitro (45). However, mice deficient in Nur77 have no apparent aberrant phenotype (reproductive or other), suggesting that biological alternative pathways may compensate for the loss of Nur77 (55). Transcription factor Nurr1 may have this function. As Nur77, Nurr1 is also an immediate-early gene with DNA and ligand-binding domains similar to that of Nur77 (56). Whether Nurr1 is expressed in the ovary in the absence of Nur77 remains to be determined.

Several members of the activator protein-1 (AP1) family of transcription factors, such as Fra2 and JunD, are stimulated during luteinization induced by LH (57), suggesting that AP1 signaling may be an important downstream target for LH. JunB, JunD, and Fra2 expression rapidly increases in response to hCG, appearing first in theca cells and thereafter in granulosa cells. JunD and Fra2, but not JunB, persist in the nucleus of luteal cells, suggesting that these factors are selectively associated with terminal differentiation of the granulosa cells (57).

C. Changes in the expression of receptors
One of the most important changes during luteinization is the alteration in the cellular responsiveness to external signals allowing luteal cells to respond to a new set of hormones. The most studied receptors are those for FSH, LH, PRL, estrogen, and progesterone. The LH surge causes the silencing of the FSH receptor (FSH-R), a transient decline in the LH-R, and a sustained stimulation of the PRL receptor (PRL-R). It also induces a rapid yet short-lived increase in PR expression and a shift in the expression of the estrogen receptor (ER) from the predominance of ERß to that of ER.

1. FSH-R.
This receptor plays an essential role during follicular development but becomes unnecessary once follicular cells differentiate. Its expression declines after the LH surge during the process of luteinization (58). This down-regulation appears to be solely due to LH because its administration to rats possessing large preovulatory follicles is sufficient to cause luteinization of granulosa cells and a marked decline in FSH-R content (59). In addition, treatment of granulosa cells with hCG completely abolished FSH-R expression (60). Once the expression of this receptor is inhibited, it does not recover and it is not expressed in the CL (60). The molecular mechanism by which LH silences the expression of the FSH-R gene is unclear, although recent investigations suggest that retinoic acid is involved in this process (61, 62). Retinoic acid, which is stimulated by LH (63), represses the FSH-R gene (62). The finding that the activity of the FSH-R promoter is repressed by retinoic acid receptor (RAR) and stimulated by SF-1, and that RAR and SF-1 bind to overlapping response elements, led Xing and Sairam (62) to propose a model for the mechanism whereby RAR and SF-1 control the overall expression of the FSH-R gene. Upon LH stimulation, RAR may displace SF-1 from the FSH-R promoter and recruit corepressors to inhibit transcription. Therefore, LH stimulation of retinoic acid may be a key step in the suppression of FSH-R during luteinization and throughout the life span of the CL. Recent findings revealed that binding of octamer transcription factor 1 to exon 1 of the FSH-R gene is required for silencing of this gene and that in Sertoli cells GATA-1 binding to the same region attenuates octamer transcription factor 1 repression (64).

2. LH-R.
The preovulatory LH surge causes first activation and thereafter desensitization of the LH-R in luteinized cells. A model for such desensitization involving ADP ribosylation factor 6 (ARF6) and arrestin 2 was recently proposed by Hunzicker-Dunn et al. (65) and shown in Fig. 1. In this model, the switch of the LH-R from an actively signaling module to one uncoupled from Gs is considered to be intimately associated with the formation of larger protein aggregates containing self-associated LH-Rs (66). A marked down-regulation of cell surface LH-R and its cognate mRNA follows desensitization (67, 68, 69). The down-regulation of LH-R mRNA that occurs under these conditions is not due to decreased transcription of the LH-R gene, but rather to increased degradation of LH-R mRNA (70). Menon and colleagues have identified and purified (71, 72) a rat ovarian protein, designated LH-R binding protein, that binds to a region of the open reading frame of the rat LH-R mRNA and enhances its degradation. In contrast to the FSH-R, the expression of the LH-R increases after luteinization and becomes highly abundant in the CL. This up-regulation of LH-R during CL formation has been shown to be due to PRL both in vivo (68, 73) and in vitro (74). However, whereas extensive investigations have defined the mechanism of LH-R down-regulation at the promoter and receptor levels (reviewed in Ref. 75), no information defining the molecular mechanism of PRL-mediated stimulation of LH-R is available to date.

View larger version (48K): [in this window] [in a new window]   FIG. 1. Model of LH-R desensitization. Shown in the top panel is the docking of arrestin 2 at a membrane location distinct from the inactive LH-R and in association with inactive ARF6 GDP. Activation of LH-R upon binding to LH, as shown in the middle panel, promotes not only activation of Gs and consequently AC activation, but also activation of ARF6 and liberation of arrestin 2. Arrestin 2 binding to the third intracellular loop of the active LH/CG-R, shown in the bottom panel, mediates desensitization by interfering with the ability of the agonist-activated receptor to activate Gs. [Adapted by permission of Federation of the European Biochemical Societies from M. Hunzicker-Dunn et al.: FEBS Letters 521:3–8, 2002 (65 ). Copyright 2002.]

The up-regulation of PRL-R during luteinization in rodents appears to depend on LH. A study reported differential stimulation of both PRL-R variants during luteinization because treatment of granulosa cells with hCG caused a 4-fold stimulation of PRL-RL and 10-fold stimulation of PRL-RS (79). Quantitative RT-PCR analysis of mRNA obtained from whole ovaries (79) revealed that levels of PRL-RL mRNA in proestrous ovaries were twice those of PRL-RS, whereas both receptor mRNAs were equally expressed in ovaries at diestrus, which contain newly formed CL. This finding supports the concept that during luteinization PRL-RS is stimulated more than PRL-RL. The molecular mechanism that leads to the increased level of one receptor mRNA over the other is not clear.

Although CL are observed in the ovaries of both wild-type and PRL-R knockout mice (80), their morphology is dramatically different. Two days after mating, wild-type mice had large CL with classical morphology, whereas PRL-R knockout mice exhibited CL undergoing regression displaying strong DNA cleavage associated with extremely low indications of vascularization. Interestingly, 1 d after ovulation, these animals have CL expressing p27^kip1 and steroidogenic enzymes at levels that are not different from the wild-type animals. The major defect seen in the CL of the PRL-R-knockout mice is the premature expression of the 20-hydroxysteroid dehydrogenase (20HSD) enzyme that is present as early as the first day of pregnancy. This enzyme is known to catabolize progesterone to 20-dihydroprogesterone (20DHP), and its expression may be in large part responsible for the lack of implantation observed in the PRL-R knockout mice. Two days after ovulation, the CL of these animals shows an elevated degree of apoptosis together with decreased levels of p27^kip1 and steroidogenic enzymes (80). These data support the importance of PRL and progesterone as antiapoptotic hormones needed for luteal survival.

4. ER.
In rodents, the ovary expresses both ER and ERß genes as single (6.5 kb) and multiple transcripts (ranging from 1.0 kb to approximately 10 kb), respectively (81, 82). Whereas ERß is abundantly expressed in the follicle, especially in the granulosa cell layer (81, 82), ER is the major receptor found in the CL (83) at levels 10-fold higher than that of ERß (Fig. 2). In granulosa cells, a large decline in ERß expression occurs during proestrous. This down-regulation is clearly associated with the LH surge and can be mimicked in vivo and in vitro by hCG stimulation (81, 84). Moreover, agents stimulating LH/hCG receptor-associated intracellular signaling pathways (e.g., forskolin and a phorbol ester) readily mimic the effect of hCG in down-regulating ERß mRNA in cultured granulosa cells (81). LH-induced down-regulation of ERß mRNA levels is not due to an effect on transcription, but rather on mRNA stability. This LH-induced destabilization of the ERß mRNA requires ongoing protein synthesis (85). Although the molecular mechanisms involved in LH-induced destabilization of ERß mRNA await further studies, it may be attributable to the blockade of translation elongation of ERß transcripts themselves or to the interaction between LH-induced new protein(s) and the ERß mRNA, as suggested by Park-Sarge and co-workers (85). These LH-induced protein(s) may alter the tertiary folding of the ERß transcripts, rendering them easy targets for ribonucleases. It is not yet known, however, whether the decrease in ERß during luteinization is essential for the normal development of the CL. It has been shown that ERß can act as ER-dominant negative and repress its transcriptional activity, leading to an overall decrease in the cellular sensitivity to estradiol (86). Because both ER and ERß remain expressed throughout the life span of the CL of the pregnant rodent, mainly because of PRL stimulation (82, 83), a function for both luteal ERs throughout pregnancy remains a possibility.

View larger version (35K): [in this window] [in a new window]   FIG. 2. Expression of ER and ERß mRNAs in the pregnant rat ovary as shown by in situ hybridization. Left panel shows abundant expression of ERß mRNA mainly at the small growing follicles, whereas the right panel shows abundant expression of ER mRNA mainly in the CL of pregnancy. The ovaries were from d 17 pregnant rats. [Adapted from C. M. Telleria et al.: Endocrinology 139:2432–2442, 1998 (82 ). Copyright The Endocrine Society.]

D. Activation of signaling pathways
Differentiation to a luteal phenotype also implies numerous changes in the intracellular signaling network activated upon receptor occupancy. Several signaling pathways participate in the profound changes that take place during luteinization and CL formation. See Fig. 3 for a scheme of the multiple factors affected by the surge of LH and their participation in the different processes induced by this hormone.

View larger version (58K): [in this window] [in a new window]   FIG. 3. Transient and permanent effects of LH on key follicular genes leading to luteinization. See text for details.

MAPKs have been implicated in the phosphorylation of CREB. MAPKs comprise a superfamily of kinases (99) that have been identified in the CL of several species. ERK1 and ERK2 are expressed in porcine, bovine, rat, and human CL (100, 101, 102, 103, 104, 105), and p38/MAPK has been shown to be expressed in the CL of rat and cow (101, 106), whereas Jun N-terminal kinase has been studied mostly in bovine CL (106, 107). Hunzicker-Dunn and colleagues (101) have elegantly demonstrated that activation of LH-R leads to phosphorylation of p38/MAPK and its upstream activator MAPK kinase 6 but has no effect on either MAPK kinase 3 or ERK1/2. The p38/MAPK downstream protein kinase target termed MAPK-activated protein kinase 3 (MAPKAPK3) is induced at both mRNA and protein levels during luteal formation, whereas mRNA and protein expression of the closely related MAPKAPK2 is diminished. MAPKAPK3, activated during luteinization in vivo, readily catalyzed CREB phosphorylation in immune complex kinase assays, and phosphorylation of CREB was shown to depend on an intact p38/MAPK signaling pathway in a cellular model of luteinization. Thus, activation of the MAPKAPK3 seems to be crucial to maintain CREB phosphorylation during luteinization (101). Whether LH activation of this MAPK system is mediated by the increase on cAMP or by growth factors such as IGF-I or vascular endothelial growth factor (VEGF) needs to be investigated.

2. LH/PLC/PKC.
The LH surge not only generates high levels of intracellular cAMP in granulosa cells, but also activates phospholipase C (PLC), leading to the increase in intracellular calcium (108, 109, 110). The actions of ovulatory concentrations of LH can be mimicked by subovulatory doses of LH/hCG plus a protein kinase C (PKC) activator in primary granulosa cell cultures (111, 112), suggesting that the effects of LH are mediated by more than one kinase. However, despite the ability of the LH-R to activate PLC under experimental conditions and the ability of PKC activators to synergize with hCG, the responses to LH appear to be independent from the activation of PKC (113).

3. LH/Wnts/Frizzled.
Wnt proteins are secreted extracellular signaling molecules that act locally to control diverse developmental processes such as proliferation and differentiation. Wnts transduce their signals by binding to G protein-coupled receptors of the Frizzled (Fzd) family (for review, see Ref. 114). In the rodent’s ovary, Wnt-4 performs critical functions during early ovarian development (115). Wnt-4 and Wnt-2 mRNA are expressed in granulosa cells (116, 117). Wnt-4 expression increases after hCG treatment and remains elevated in the CL during pregnancy (117). Luteal cells express Disheveled 1 (Dvl-1) and ß-catenin (117), which are components of Wnt-4 intracellular signaling pathway. Expression of Fzd1 and Fzd4 is also stimulated by LH-R activation. Although the role of both Wnt-4 and Fzd4 in luteinization is not yet clear, the results obtained to date suggest that Wnt-4 may be a ligand for Fzd4 and that Wnt-4/Fzd4 signaling is important for the regulation of luteal cell formation and function. The recent deletion of the Fzd4 gene has revealed that the null mice fail to form functional CL despite normal follicular development and ovulation of fertilizable oocytes. Fzd4–/– ovaries exhibit CL of altered appearance and reduced expression of genes known to be associated with luteinization (118). Because these genes are regulated by PRL and because the phenotype of the Fzd4–/– null mice is similar to that of PRL-R–/– mice, Hsieh et al. (118) speculate that PRL signaling might be defective in the newly formed CL of Fzd4–/– mice.

4. PRL/Jak/Stat.
This pathway, formed by the Janus kinase (Jak) and the signal transducers and activators of transcription (Stat) proteins, is activated after ovulation mainly by PRL. PRL binding to the long form of its cognate receptor (PRL-RL) was thought to induce receptor homodimerization, which leads to immediate transphosphorylation of the associated tyrosine kinase Jak2, followed by phosphorylation of Stat transcription factors Stat5a and Stat5b (119). Recent data indicate, however, ligand-independent dimerization of the PRL-R (120). The increase in PRL-R expression observed during luteinization is accompanied by changes in the activation of the intracellular signaling transduction pathway of PRL (34, 121, 122). The activity of Stat5a and Stat5b is nondetectable in preovulatory follicles (79), but it is induced by PRL after the LH surge (121). PRL activates Stat5b as well as Stat5a; however, Stat5b is the predominant isoform in luteal cells (79). Recent investigations have revealed that there is a difference in the mechanism by which PRL activates Stat5a and Stat5b (123). Whereas PRL activation of Jak2 leads to phosphorylation and activation of Stat5a, Jak2-induced tyrosine phosphorylation of Stat5b can be separated from Stat5b transcriptional activity. PRL appears to activate a second tyrosine kinase that can phosphorylate Stat5b at a place that does not lead to Stat5b transcriptional activity. The high sequence similarity between Stat5a and Stat5b (96%) suggests that there may be redundancy in their signaling pathways, whereas differences in their tissue distribution may lead to distinct functions. Mice knockout for Stat5a do not have major reproductive defects; they suffer only from impaired mammary gland development (124). Stat5b, on the other hand, seems to be essential for luteal function and survival because Stat5b-deficient mice abort beyond d 7 of pregnancy, a phenomenon that could be partially prevented by treatment with progesterone (125). Because abortion occurs after d 7 of pregnancy, it appears that the major role of Stat5b is not in luteinization, but rather in CL maintenance and production of progesterone. Interestingly, only the double knockout Stat5a/b female mice, but not the Stat5a or Stat5b mutants, are totally infertile, demonstrating a functional redundancy of the Stat5 proteins (126). Stat5a/b double mutant mice have normal developing follicles and ovulation, yet few CL are evident in their ovaries, indicating that Stat5 molecules may play a crucial role in the development and survival of the gland (126). However, because the luteal phenotype of Stat5a/b null mice has not been investigated with sufficient detail, it is not clear whether CL formation and luteinization, which occur rapidly after ovulation, are affected by the lack of the Stats. As in the case of the PRL-R null mice, disruption of the Stat5a/b genes results in low levels of p27^kip1, leading to the speculation that the Stat5 proteins control luteal p27^kip1 expression and that this expression is critical for inducing differentiation of follicular cells into luteal cells. Of great interest is the finding that Stat5a/b deletion leads to extensive expression of the progesterone metabolizing enzyme 20HSD in their CL (126), thus explaining the low circulating levels of progesterone found in these animals (see Section IV). As mentioned earlier, lack of Stat5b is associated with early abortions that are due to reduced progesterone levels during midgestation (125). This deficiency is partially corrected in the double knockout for 20HSD and Stat5b (127), supporting the concept that activation of Stat5b is important in suppressing 20HSD gene expression.

Deactivation of the Jak/Stat signaling pathway plays an important role in establishing and maintaining tissue responsiveness to PRL. Negative regulation of cytokine signaling downstream of Stat activation occurs through several families of modulators. Two Src-homology domain-containing protein tyrosine phosphatases (SHP-1 and SHP-2) have been shown to modulate PRL-induced Stat responses. SHP-2 is a substrate for Jak2 and is obligatory for PRL/Stat5 induction of ß-casein (128). On the other hand, SHP-1 binds activated Stat5b, catalyzing its rapid dephosphorylation, leading to the transient activation pattern that is characteristic of this family of transcription factors (129). SHP-1 expression (mRNA and protein) is undetectable in preovulatory follicles, but it is maximally expressed in the nuclei of luteal cells throughout gestation (79), suggesting acquisition of PRL responsiveness and activation of Stat5b. The presence of SHP-1 in the nucleus of luteal cells explains the transient Stat5b activation in PRL-treated CL during early gestation. These results led Russell and Richards (79) to postulate that, at least in rodents, SHP-1 may continuously dephosphorylate activated Stat5b, resulting in a transient activation profile during pulsatile PRL exposure early in pregnancy.

5. PI3K/Sgk/Foxo.
The forkhead family of transcription factors, FKHR (Foxo1), FKHRL1 (Foxo3), and AFX (Foxo4) are regulated by a pathway involving phosphatidylinositol-3-kinase (PI3K) and protein kinase B (PKB/Akt). Direct phosphorylation by PKB or by the PKB-related kinase, serum and glucocorticoid-induced kinase (Sgk), results in translocation to the cytoplasm and inactivation of the forkhead transcription factors (for review, see Ref. 130). As granulosa cells luteinize, they gain increased levels of Sgk, Foxo4, and Foxo3, whereas at the same time, Foxo1 expression declines, possibly affecting the expression of p27^kip1 and p21^cip1 (131). Deletion of Foxo3a led to premature ovarian failure (132), therefore establishing a key role for this transcription factor in the survival of granulosa cells and oocytes.

6. Oocyte/TGFß pathway.
It has long been believed that oocyte-derived regulatory molecules act within the follicle to inhibit premature luteinization and limit progesterone biosynthesis (133). In vitro studies have demonstrated that members of the TGFß superfamily mediate the antiluteinizing effect of the oocyte (134, 135). The TGFß superfamily includes TGFß, activins and inhibins, bone morphogenetic proteins (BMPs), growth/differentiation factors (GDFs), and anti-Müllerian hormone (136). BMP-15 (134) and GDF-9 (135), both produced by the oocyte, have been proposed as luteinization inhibitors. TGFß-related proteins signal through a serine–threonine kinase cascade that results in the cytoplasmic to nuclear translocation of intracellular effector proteins termed "mothers against decapentaplegic homolog (SMADs)." TGFß and activin signal through SMAD2 and SMAD3, whereas the BMPs and GDFs mediate their signals through SMAD1, SMAD5, and SMAD8 (for review, see Ref. 137). In addition, the capacity for the TGFß-related ligands to signal is thought to require SMAD4, the common SMAD that partners with the receptor regulated-SMADs to form the core of a transcriptional complex (138). SMAD4, therefore, is a central component of the TGFß superfamily signaling pathway. Recent generation of SMAD4 and activin granulosa cells conditional knockout resulted in premature luteinization and ovaries full of CL, respectively. This provides clear in vivo evidence that activin prevents premature luteinization of granulosa cells during follicle development (139). Interestingly, these changes are accompanied by a significant increase in serum progesterone levels (139) and high levels of luteal markers such as P450scc, 17ßHSD-7, and steroidogenic acute regulatory protein (StAR).

	III. Genesis of a New Gland: Structural Changes from the Remnants of the Ovulated Follicle

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

 
The formation of the CL not only involves changes in the expression of genes implicated in the cell cycle and signaling in theca and granulosa cells but also the breakdown of the follicular basal membrane necessary for rapid migration of endothelial cells, fibroblasts, and theca cells into the previously avascular granulosa layer. The CL is therefore the product of luteinization of follicular cells, endothelial cell invasion, and tissue remodeling.

A. Luteal cell types
The CL is a heterogeneous gland composed of small and large steroidogenic luteal cells, fibroblasts, endothelial, pericytes, and immune cells. These cells have different morphological, endocrine, and biochemical features. Interactions between these various cell types is essential in maintaining the health and steroidogenic function of the CL (16, 140, 141, 142). Once luteinization takes place, a defined cell population undergoes extensive hypertrophy and differentiates into large steroidogenic luteal cells, whereas another cell population remains much smaller and comprises small steroidogenic luteal cells. In ruminants and rodents, small and large luteal cells differ in their basal rates of progesterone secretion, with the large cells producing 2- to 40-fold more progesterone than the small cells. These two luteal cell types, however, differ in their response to different hormonal and/or second messenger stimuli (140). It is widely believed that the origin of the large luteal cells is the granulosa cells, whereas the theca cells differentiate into small luteal cells; however, although this hypothesis is well supported in domestic animals (for review, see Ref. 6), there is no evidence indicating these cellular origins in rodents (140, 143). In most species there is considerable mixing of large and small cell types during the reorganization of the follicle into the CL leading to a close contact between the two cell types. Primates are an exception, with the two cell populations remaining relatively separate, and therefore are generally called granulosa-lutein cells and theca-lutein cells, respectively (6). These two cell populations can be distinguished in tissue sections by their location; furthermore, whereas theca-lutein cells do not hypertrophy during the luteal phase, the granulosa-lutein cells undergo considerable hypertrophy that significantly contributes to the growth of the CL (144, 145). Additionally in primates, theca-luteal cells are the primary source of androgens (146), whereas granulosa-luteal cells are the site for estrogen synthesis (147), indicating that the two-cells model of estrogen biosynthesis invoked to explain follicular estrogen production is preserved in the CL of primates.

In contrast to the primate CL, rodent’s small and large luteal cells are intermingled within the CL and do not appear to differentiate from the theca and granulosa cell, respectively. The protein profile of both cell types is largely similar (Fig. 4) with the only major difference being the abundant expression of a 32-kDa protein known as PRAP (for PRL-R associated protein) (148, 149). PRAP is found solely in large luteal cells and is an excellent marker for them. Yet in the follicle, it is the theca cell layer and not the granulosa cell layer that expresses this protein (see Section IV and Fig. 8). This, added to the finding that both the large and small luteal cells express P450 17-hydroxylase/C17–20-lyase and cytochrome P450 aromatase (140, 148, 150) and produce both androgen and estrogen, casts serious doubt to the dual origin of both luteal cell types.

View larger version (29K): [in this window] [in a new window]   FIG. 4. Expression of PRAP in large luteal cells. Large and small luteal cells were isolated from rat CL, and proteins were separated by gel electrophoresis. [Adapted from M. P. McLean et al.: Endocrinology 126:1796–1805, 1990 (148 ). Copyright The Endocrine Society.]

View larger version (34K): [in this window] [in a new window]   FIG. 8. Expression of 17ßHSD-1 and 17ßHSD-7 in ovaries of pregnant rats and the reactions that they catalyze in the rat CL. 17ßHSD-1 (white signal) is expressed only in granulosa cells (from Ref. 274 ). In contrast, 17ßHSD-7 (red staining) is expressed in the CL and the theca (T) and interstitial (I) cells, but not at all in the granulosa cells (C. T. Albarracin and G. Gibori, unpublished observations). Lower left panel, In the follicle, 17ßHSD-1 has dual activity and can convert androstenedione to testosterone as well as estrone to estradiol. Lower right panel, After the LH surge, 17ßHSD-1 is no longer found in the CL, which expresses instead PRAP/17ßHSD-7, an enzyme that only converts estrone to estradiol.

C. Vascularization
The development of capillaries from preexisting blood vessels is essential for the formation and function of the CL (15, 161). Each luteal cell is in direct contact with several capillaries, giving the CL one of the highest rates of blood flow in the organism. The development of a new microcirculatory bed involves ECM degradation, endothelial cell proliferation, expansion of the capillaries, and development of capillary lumen (maturation). The dense capillary network that is formed efficiently supplies nutrients, hormones, and lipoprotein-bound cholesterol to the luteal cells and provides a mechanism for speedy and efficient output of progesterone from the CL. Soon after the LH surge and ovulation, pericytes derived from the theca compartment are the first vascular cells to invade the developing luteal parenchyma. These pericytes rapidly proliferate and populate a large percentage of vessels in the mature CL (162). In the rat CL, collagen type IV and laminin are detected in the granulosa layer approximately 6 h after ovulation, whereas within 16 h, new complete capillaries can be found (163, 164). The molecular regulation of angiogenesis in the CL is complex, with a growing list of regulators including VEGF that are essential for CL angiogenesis (165), basic fibroblast growth factor (bFGF), the newly discovered endocrine gland-derived VEGF (EG-VEGF) (166), and angiopoietins (Ang). LH /hCG appears to stimulate the expression of VEGF, EG-VEGF, Ang, and their receptor and to affect profoundly vascularization of the CL during luteinization (167) (see Fig. 5).

View larger version (34K): [in this window] [in a new window]   FIG. 5. Stages of luteal vascularization and their control by LH. See text for details.

Recently, a novel regulator of ovarian angiogenesis, EG-VEGF or Prokineticin-1 (PK-1), was identified in the ovary and has been proposed as a steroidogenic gland-specific angiogenic regulator. In contrast to VEGF, in human and nonhuman primates, EG-VEGF expression is largely restricted to the steroidogenic glands such as the ovary, testis, adrenal cortex, and placenta (179). Consistent with such an expression pattern, the human EG-VEGF gene promoter has a potential binding site for SF-1, a pivotal element for steroidogenic-specific transcription. Although structurally different, EG-VEGF and VEGF have similar functions; both promote proliferation, survival, and chemotaxis of endothelial cells isolated from steroidogenic tissues (166, 180). G protein-coupled receptors of the neuropeptide Y receptor class have been identified in endothelial cells as the cognate receptors for EG-VEGF (181). The mitogenic and prosurvival activities of EG-VEGF correlate with the ability of this peptide to induce phosphorylation of ERK1/2 and Akt (181). In humans, peak VEGF expression is found in early luteal phase, associated with the initial development of a capillary plexus within the CL, whereas EG-VEGF is low in early stage of the CL but is up-regulated during midluteal to late luteal phase at a time when VEGF expression is considerably reduced (167). When delivered by adenovirus in mouse, EG-VEGF induced extensive angiogenesis in the ovary but not in other tissues (179). Because EG-VEGF and VEGF have an additive response in vitro (166), they may also cooperate in vivo to induce the fenestrated phenotype and to promote angiogenesis, especially because both molecules are produced in the CL in a complementary and coordinated fashion. Taken together, these observations support the notion that VEGF activity is rate limiting for the creation of the capillary plexus within the CL, whereas EG-VEGF may stimulate, together with VEGF, the angiogenesis that accompanies early-to-mid CL development.

The first angiogenic factor identified in the ovary was bFGF, (182) which is produced by steroidogenic and endothelial cells of rat (183), human (184), and ruminant CL (185). bFGFs have been found to stimulate proliferation and motility of luteal endothelial cells (185, 186, 187), and treatment with antibodies to bFGF suppressed approximately 80% of endothelial cell proliferative activity in extracts of CL from cows, sheep, and pigs (185). Surprisingly, however, deletion of the bFGF gene in mice did not result in developmental disruption or loss of fertility (188), raising doubts as to how crucial bFGF is for luteal angiogenesis.

Ang belong to a family of growth factors that appear to be also critical for angiogenesis and vessel integrity. They have been implicated in the regulation of vascular development and regression. Ang-1 and Ang-2 bind the Tie-2 receptor; however, whereas Ang-1 stimulates sprouting and maturation of blood vessels, Ang-2 inhibits this effect, acting as a competitive inhibitor by binding the Tie-2 receptor without activating intracellular signaling pathways (for review, see Ref. 189). Tie-2 or Ang-1 knockout mice are embryonic lethal, with the most prominent defects involving the vasculature (190, 191). Ultrastructural analysis of the blood vessels in these animals reveals defects in endothelial cell interactions with their basement membranes and a marked decrease in the number of periendothelial support cells. Little information on Ang and their receptors is available in the CL despite the specificity of the site of their expression in rodents and primates and their apparent regulation by LH/hCG (192, 193). Ang-2 transcripts were found in close association with blood vessels in the theca interna of the preovulatory follicle and in the front of vessels invading the developing CL. Ang-1 transcripts were also associated with blood vessels but appeared to follow rather than to precede vessel ingrowth into the early CL. These expression patterns have led Maisonpierre et al. (192) to suggest that Ang-2 may collaborate with VEGF at the front of invading vascular sprouts by blocking the function of Ang-1, whereas Ang-1 may have a later role than VEGF in angiogenesis involving vessel maturation and/or stabilization.

	IV. Function of the Corpus Luteum

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

 
A. Luteal steroidogenesis
Severe changes in the expression of steroidogenic enzymes and in the type of steroid produced occur during and after luteinization. In rodents, luteal cells continue to synthesize androstenedione and estradiol, but become a substantial site of progesterone biosynthesis. This is in contrast to the follicle, where progesterone mainly serves as substrate for estradiol production. The CL expresses high levels of key proteins involved in the uptake, synthesis, and transport of cholesterol, and in the processing of cholesterol to progesterone, androgens, as well as estrogens. These proteins are the sites of regulation by tropic hormones such as PRL, LH, and estradiol (see Fig. 6 for summary).

View larger version (29K): [in this window] [in a new window]   FIG. 6. Diagram depicting genes involved in synthesis of progesterone, 20-dh-progesterone (20-DHP), and estradiol and their regulation by different tropic hormones. +, Stimulatory effect; –, inhibitory effect.

View larger version (48K): [in this window] [in a new window]   FIG. 7. Oil-red staining of lipids in ovaries from SR-BI+/+ or SR-BI–/– mice. [Adapted from B. Trigatti et al.: Proc Natl Acad Sci USA 96:9322–9327, 1999 (213 ).]

Once cholesterol reaches the outer mitochondrial membrane, it is transported to the inner mitochondrial membrane through the aqueous intermembrane space. This step involves several proteins, including the StAR (for review, see Refs. 224 and 225), peripheral-type benzodiazepine receptor (PBR) (226, 227), and possibly hormone-sensitive lipase (228). The role of StAR in the ovary was further substantiated by the phenotype of the StAR-null mice (229). Immediately after birth, the ovaries of these mice appear normal. After puberty, however, lipid accumulation occurs, and this is accompanied by incomplete follicular maturation that ultimately ends in premature ovarian failure. In contrast to the StAR-null ovaries, no detectable lipid deposits were present in the interstitial and theca cells of double StAR- and gonadotropin-knockout mice, suggesting that gonadotropin stimulation is essential for lipid accumulation in the ovaries of StAR-deficient mice (230). The impaired ovulation of the double StAR/gonadotropin-null mice cannot be reversed with exogenous progesterone and gonadotropin, suggesting that the compromised steroidogenesis of the StAR-deficient ovaries makes ovulation impossible. The mechanism whereby StAR facilitates cholesterol transport has been under intense investigation. It was originally thought that StAR might act as an intermitochondrial shuttle. However, restriction of StAR to the cytoplasm does not inhibit its activity, whereas importation of StAR into the mitochondria causes its degradation (231), suggesting that StAR acts on the outer surface of the mitochondria.

The expression of StAR in the CL was shown to be up-regulated by LH/cAMP (232) and to be repressed by prostaglandin F2 (PGF2) (233). Transcriptional regulation of the StAR gene is the primary mechanism of control of steroidogenesis and has been the focus of many studies. Comparison of StAR promoters across species indicates that the first 250 bases of the proximal promoter are critical for basal and hormone-stimulated StAR transcription and that the transcription factor response elements are highly conserved in this region (234). Several transcription factors, including SF-1, C/EBPß, SREBP-1a, cFos, GATA-4, Sp-1, and CREB family members have been implicated in the transcriptional stimulation of the StAR gene (for review, see Ref. 235). Conversely, dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene 1 (DAX-1) and forkhead box protein L2 (FOXL2) were shown to play key roles on its repression (236).

The PBR, on the other hand, is a high-affinity, cholesterol-binding protein found in between outer and inner mitochondrial membranes (237). In this location, PBR could function as a pore, allowing for the translocation of cholesterol from the outer to the inner mitochondrial membrane (238). PBR is closely associated with StAR at the outer mitochondrial membrane (239) and appears to be a promising partner for it. The importance of these two proteins in luteal steroidogenesis is suggested from the studies of Sridaran et al. (240, 241). These investigators have demonstrated that PBR and StAR are coexpressed in the pregnant rat CL and that their coordinated suppression by GnRH agonists leads to reduced progesterone production followed by luteal cell death (242). Recently, the hormone-sensitive lipase that is responsible for the neutral cholesteryl ester hydrolase activity in steroidogenic tissues was shown to interact with StAR and to facilitate cholesterol movement from lipid droplets to the mitochondria for steroidogenesis (228).

3. Biosynthesis of progesterone by the CL.
Once cholesterol reaches the inner mitochondrial membrane, its transformation into steroid hormones begins. The capacity to transform cholesterol to progesterone is a universal characteristic of the CL and involves the mitochondrial P450scc and one of the six isoforms of the 3ßHSD, 3ßHSD type II (3ßHSD-II), which is located in the smooth endoplasmic reticulum (243). Formation of the CL is accompanied by a dramatic increase in the expression of both enzymes (214, 244, 245) and in the organelles that house them (246, 247), allowing the CL to synthesize large amounts of progesterone. Both enzymes remain highly expressed in the CL throughout pregnancy and are considered to be constitutively expressed (245, 248), yet various investigators have shown that they can be regulated by PRL and gonadotropin (245, 249, 250, 251, 252, 253). In the case of 3ßHSD-II, PRL stimulation is at the level of transcription and is mediated by transcription factor Stat5 (254).

The level of progesterone secreted by the CL in rodents depends not only on the amount of progesterone synthesized by the luteal cells but also on the expression of the enzyme 20HSD that catabolizes progesterone into the inactive progestin, 20-DHP. Once 20HSD becomes expressed in the CL, progesterone secretion drops and 20-DHP becomes the major steroid secreted by luteal cells (255, 256). Due to the detrimental effect of 20HSD on luteal progesterone secretion, its pattern of expression/activity greatly contributes to the changes in the circulating levels of progesterone during gestation, ultimately controlling the progression of pregnancy. Indeed, it has been known for years that little, if any, 20HSD activity is found in the rat CL throughout pregnancy; however, elevated activity is found just before parturition concomitant with the rapid decrease in the concentration of progesterone in serum. In rodents, this decrease in serum progesterone is essential for parturition to take place. Accordingly, mice deficient for 20HSD sustain high progesterone levels and display a delay in parturition for several days (127). The development of a specific antibody against rat 20HSD (257) and the cloning of its gene (258, 259) led to the demonstration that the lack of enzyme activity throughout pregnancy and its appearance just before parturition are not due to activation/deactivation of an already present enzyme but rather to changes in gene expression (255, 257, 260). The crystalline structures of human and rabbit 20HSD have been recently obtained (261). Although 20HSD is one of the most important players in the regulation of luteal progesterone secretion in rodents, the role of this enzyme in the control of progesterone production and/or action in other species needs further investigation.

Two other enzymes have been implicated in the reduction of progesterone secretion by the CL at the end of pregnancy. P450c26, which catalyzes the conversion of cholesterol to 26-hydroxycholesterol, also rises at the end of pregnancy and could reduce progesterone secretion by limiting substrate availability (262). Luteal 5-reductase, which converts testosterone to dihydrotestosterone (DHT), has also been implicated in the functional demise of the CL. This is supported by the secretion of DHT from the rat CL at the end of pregnancy and by the fact that exogenous DHT can decrease progesterone biosynthesis (263, 264). However, although deletion of the 5-reductase type I gene impairs cervical ripening, causing parturition defects, it does not affect the decline in serum progesterone concentration at the end of pregnancy (265), raising doubts about the physiological role of DHT during luteal regression in rodents.

4. Biosynthesis of androgen and estradiol by the CL.
In rodents as in humans, the CL also produces androgens and estrogens in addition to progesterone. The major androgen produced by the ovary is the weak androgen, androstenedione (266). Conversion of progesterone to androstenedione is mediated by the enzyme P45017-hydroxylase/C17–20 lyase (P450c17 or CYP17). In preovulatory follicles, P450c17 is expressed in the theca interna and interstitial cells but not in granulosa cells (267), whereas in the CL both luteal cell types express P450c17 (140) and synthesize aromatizable androgens (268, 269, 270). Khan et al. (271) have demonstrated that LH stimulation of estradiol biosynthesis by luteal cells is the consequence of selective stimulation of P450c17. However, LH-mediated stimulation of this enzyme plays a key role only during the first half of pregnancy in the CL of the rat. After midpregnancy, luteal P450c17 expression drops as consequence of the fall in circulating levels of LH. At this stage, the rodent’s placenta starts secreting very high levels of androstenedione, which serves as substrate for estradiol biosynthesis (for review, see Ref. 272). In the follicle, androstenedione produced by the theca cells is converted to estrone in the granulosa cells upon the action of the cytochrome P450 aromatase (P450arom or CYP19), and thereafter to estradiol by 17ß-hydroxysteroid dehydrogenase type 1 (17ßHSD-1) (273). 17ßHSD-1 also catalyzes the conversion of androstenedione to testosterone (274), which can be aromatized to estradiol directly. In the CL, high levels of P450arom expression were reported years ago (252); yet the luteal 17ßHSD responsible for converting estrone to estradiol and/or androstenedione to testosterone remained totally unknown. Serendipitously, we discovered in the rat CL a protein that was several years later identified as being a 17ßHSD enzyme. We originally identified a 32-kDa protein abundantly expressed in large luteal cells and absent in small luteal cells (148). Subsequently, we cloned the cDNA (149), developed specific antibody against this protein (275), and isolated and characterized the promoter region of this gene (276). Most interestingly, this protein was found to be phosphorylated on tyrosine and to associate with the intracellular domain of the short form of the PRL-R (PRL-RS), but not with the long form of the PRL-R (PRL-RL) (149). Originally, the protein was named PRAP (for prolactin receptor-associated protein). It was thereafter established that PRAP was a novel 17ßHSD (276, 277) that was consequently renamed PRAP/17ßHSD-7. This enzyme is a potent converter of estrone to estradiol but does not convert androstenedione to testosterone (Fig. 8). Several 17ßHSD enzymes have been cloned; however only 17ßHSD-1 and PRAP/17ßHSD-7 are capable of converting estrone, a weak estrogen, to estradiol. 17ßHSD-1 is specific to the granulosa cells (274, 278, 279) and disappears after luteinization, whereas PRAP/17ßHSD-7 is highly specific to the CL and is found at low levels in theca/interstitial cells (see Fig. 8 and Ref. 148). Interestingly, the transcription of 17ßHSD-1 and PRAP/17ßHSD-7 is regulated by LH in opposite manners; LH stimulates 17ßHSD-1 (279) and inhibits PRAP/17ßHSD-7 (276). During pregnancy, PRAP/17ßHSD-7 becomes highly expressed only when circulating LH levels drop to nadir. The opposite effect of LH on the follicular 17ßHSD-1 and on the luteal PRAP/17ßHSD-7 most probably prevents the production of high levels of estradiol in early pregnancy, which in rodents can induce termination of pregnancy. In the CL, the expression of 17ßHSD-7 is inhibited by LH but markedly stimulated by estradiol (275, 280). PRAP/17ßHSD-7 has been found in the CL of every species investigated to date, including ruminants and humans (275), revealing the possibility that the CL has a universal capacity to convert estrone to estradiol.

B. Hormonal regulation
The CL is not an autonomous organ; in contrast, its function is controlled by the interaction of several tropic hormones secreted by the pituitary, the decidua, and the placenta. The key factors are PRL (or PRL-related proteins) and estradiol. The source of PRL/PRL-related protein stimulation changes from the pituitary to the decidua first, and thereafter to the trophoblast as pregnancy progresses. Similarly, the source of androgen substrates for estradiol biosynthesis switches over time from the ovary itself to the trophoblast. In addition to the direct regulatory control elicited by PRL and estradiol, new data support the contribution of androgens and progesterone as autocrine regulatory hormones within the rodent CL. Finally, LH also plays a role in the regulation of CL function in rodents, although this hormone does not have the same central role that it has in other mammalian species (see Fig. 9 for a scheme of the tropic hormones, their signaling mechanism, and the genes they control).

View larger version (86K): [in this window] [in a new window]   FIG. 9. Hormones controlling luteal function: their signaling mechanisms and targets genes. See text for details.

Although PRL support is essential for normal CL function throughout pregnancy, PRL is secreted from the pituitary until midpregnancy only (reviewed in Ref. 283). Moreover, inhibition of pituitary PRL secretion after d 6 of pregnancy has no deleterious effect on progesterone production by the CL (284). This is most probably because in rodents (285), as in humans (286, 287), the decidua expresses the PRL gene and secretes sufficient PRL to sustain CL function for a few additional days until the trophoblast begin producing PRL-like hormones.

The physiological role of decidual PRL in the normal function of the CL during pregnancy is not clear because at the time pituitary PRL ceases to be secreted the placenta starts outpouring placental lactogen (PL) I and II. These PRL-related hormones are secreted by the trophoblast sequentially and in large amounts. Both PL-I and PL-II bind to the PRL-R and sustain CL function until parturition (for review, see Ref. 288). Although a tropic action for PL-I secreted at midpregnancy was widely accepted, it was not until recently that PL-II secreted later during pregnancy was shown to have identical actions to PRL (289, 290) and to be responsible for the maintenance of the CL of late pregnancy.

PRL enhances progesterone production by luteal cells in a wide variety of species (reviewed in Ref. 283). Its main role in rodents is to prevent the catabolism of progesterone in luteal cells by repressing the expression of the 20HSD gene, leading to the virtual disappearance of this enzyme from the CL (257, 291, 292). The 20HSD promoter has several putative binding sites for the transcription factor Stat5 (293), and deletion of either the PRL-R (80) or the Stat5a/b genes (126) causes premature expression of this enzyme in the CL, supporting the involvement of the Jak2/Stat5 pathway in the PRL-mediated inhibition of 20HSD. The 5' flanking region of the 20HSD gene also has several response elements for nuclear factor-B (NFB) (293). The recent finding that PRL activates this transcription factor and that overexpression of NFB in luteal cells suppresses both 20HSD promoter activity and the levels of its endogenous mRNA (294) suggests a role for NFB in the suppression of 20HSD triggered by PRL.

Although the main action of PRL in the CL is to prevent the transformation of progesterone into an inactive metabolite, there are several other sites of PRL action. This hormone was identified early on as a factor that could elevate luteal stores of cholesterol (295, 296, 297). Subsequently, PRL was shown to increase the number of lipoprotein binding sites (298), to enhance cholesterol uptake by luteal cells (299), and to activate cholesteryl ester hydrolase (300, 301, 302). Microarray analysis has recently revealed that many of these effects of PRL, including the increase in the abundance of HDL receptor (SR-BI), hormone-sensitive lipase, and SCP-2 are at the level of transcription (253). PRL also has been shown to up-regulate the expression of P450scc and 3ßHSD (250, 251, 252).

Recent investigations showed that, in addition to its essential role in progesterone production, PRL plays an important role in the production and action of estrogen by the CL. PRL enhances the level of expression of the two enzymes involved in estradiol biosynthesis, P450arom (252, 303, 304) and PRAP/17ßHSD-7 (305). In contrast to its effect on P450arom, PRL treatment enhances PRAP/17ßHSD-7 protein without affecting its mRNA levels (305). The finding that PRAP/17ßHSD-7 associates specifically with PRL-RS and becomes phosphorylated on tyrosine residues (149) led to the suggestion that PRL may cause the phosphorylation and stabilization of this enzyme. To our knowledge, PRAP/17ßHSD-7 is the first steroidogenic enzyme known to associate with a membrane-bound receptor and to be phosphorylated on tyrosine. This may represent a novel mechanism whereby a membrane-bound receptor affects the cellular levels of a steroidogenic enzyme.

The ability of the rat CL to respond to estrogen formed locally also requires PRL, which stimulates the expression of the ERs (for review, see Ref. 123). Transcription of the genes encoding both ER and ERß is stimulated by PRL through the Jak2-Stat5 pathway and Stat5 response elements that are located within each one of the ER promoters (306). A single nucleotide difference between Stat5 response elements located on the ER and ERß promoters is responsible for the observation that either Stat5a or Stat5b can stimulate ER transcription, whereas only Stat5b can activate transcription of ERß (83). The tyrosine kinase Jak2 is required for PRL activation of ER promoter activity; however, additional pathways, downstream of PI3K, are involved in PRL-induced Stat5b phosphorylation, nuclear translocation, and DNA binding (306).

PRL may have a protective role on the CL through stimulation of superoxide dismutases, enzymes that scavenge free radicals (253, 307), and inhibition of annexin 5 expression (253, 308), a protein that may play a role in luteal cell death. In addition, PRL has been implicated in the vascularization of the CL. However, although full length and proteolytically cleaved PRL has direct angiogenic effects in some tissues (for review, see Ref. 309), in the CL, the action of PRL on vascular development is most likely mediated by estradiol. PRL also stimulates the production of the broad-spectrum protease inhibitor 2M (310), which may play a role in regulating angiogenesis by inactivating proteases or by binding antiangiogenic factor(s) (311). cDNA microarray studies have revealed that PRL affects the expression of several additional genes. It down-regulates ADP-ribosylation factor 3 and c-Jun and stimulates TIMP2, cytochrome oxidase IV, cathepsin H and L, heat shock protein (HSP) 60, and mitochondrial ATP synthase (253). The particular role of each one of these genes, as well as how critical is their regulation by PRL in the correct functioning of the CL, remains unknown.

2. Estradiol.
In rodents, estradiol produced locally by luteal cells is a potent tropic hormone that stimulates progesterone biosynthesis, vascularization, and hypertrophy of the CL (reviewed in Ref. 272). Both ER and ERß are expressed in the rat CL throughout pregnancy (82), although ER is expressed at much higher levels (83). Generation of mice lacking one or the other of these receptors has indicated that whereas estrogen is critical for CL formation and maintenance, it can act through either receptor to carry out its actions (312). Estradiol enhances cholesterol supply in luteal cells by stimulating cholesterol synthesis (313, 314, 315), uptake of cholesterol from circulation (211), and intracellular cholesterol mobilization (217). Recent investigations have revealed that these effects of estradiol are due, at least in part, to transcriptional stimulation of the SR-BI gene (212). In rabbits, estradiol has also been linked with elevated production of StAR (316) and with greater cholesterol accumulation in mitochondria (317).

One critical action of estradiol in the rodent’s CL is the stimulation of vascularization, particularly at midpregnancy (318). In these species, increased angiogenic activity occurs at two stages during pregnancy: the first during luteinization, and the second at midpregnancy in coincidence with a rapid increase in the size and in the progesterone producing capacity of the CL (272). At midpregnancy, estradiol induces a remarkable proliferation of vascular endothelial cells (318), apparently because of the stimulation of VEGF and VEGF receptor expression (169). Estradiol also mediates luteal cell hypertrophy, contributing to the increase in the size of the CL that occurs at midpregnancy (reviewed in Ref. 319). Estradiol elicits this action by stimulating overall protein synthesis (280) through a mechanism that involves an increase in the levels of elongation factor-2, a protein that is an essential component of the protein synthesis machinery (320).

3. Androgens.
There is evidence that androgens play an important role in CL function both as substrates for estrogen synthesis and as direct stimulators of progesterone production. The rodents CL express androgen receptors (321, 322, 323), and treatment of either mouse (289) or rat (324) luteal cells with both aromatizable and nonaromatizable androgens leads to an increase in progesterone synthesis. The finding that an aromatase inhibitor did not prevent this androgen-mediated stimulation of progesterone (289) supports the contention of a direct action of androgens independently from their conversion to estradiol. In vivo experiments provide further evidence for a luteotropic function of androgens. DHT administration at the end of pseudopregnancy prevents the drop in progesterone that normally occurs at this stage in rodent (325), whereas intraovarian administration of androstenedione raises serum levels of progesterone (324). Moreover, androstenedione can prevent the decline in serum progesterone and the loss of luteal weight induced by the antiprogesterone mifepristone despite the presence of an aromatase inhibitor or a specific estrogen-receptor blocker (326). In addition to the stimulation of progesterone production, androstenedione has a direct antiapoptotic effect in the rat CL (323). However, the molecular mechanism mediating the action of androgens in the CL and the genes that they regulate remains unknown.

4. Progesterone.
The possibility that progesterone produced in the CL may act locally to sustain luteal cell function in all mammalian species was originally proposed by Rothchild (327). Investigations from several laboratories have provided evidence in support of this hypothesis and have shown that progesterone can stimulate its own secretion and protect the CL from cell death. Intraovarian administration of either a progesterone antibody or a PR antagonist inhibited luteal progesterone production in pregnant rats (328), whereas luteal cells cultured in the presence of the synthetic progesterone R5020 secrete more progesterone than do cells cultured in the presence of vehicle control (91). In rodents, the main site of action for progesterone appears to be its ability to down-regulate the basal (329, 330) as well as the LH (331) and PGF2-stimulated (91) expression of 20HSD. Progesterone also inhibits the expression of IL-6, a cytokine detrimental to steroidogenesis (332), and protects the CL from cell death (333) most probably by suppressing Fas expression (334). Despite all the evidence supporting a local effect of progesterone, the cognate PR is not expressed in the CL of rodents (90, 91), being only transiently expressed in the follicle just before ovulation (37). Therefore, the molecular mechanism by which progesterone affects luteal function remains largely unknown. Because glucocorticoids mimicked progesterone inhibition of 20HSD in a luteal cell line that does not express the PR but expresses the glucocorticoid receptor (GR), and considering the relatively high affinity of progesterone for the GR, Sugino et al. (329) suggested that progesterone could act through a GR-mediated mechanism. The reported ability of mifepristone to inhibit the action of progesterone in the CL could also be due to its role as GR antagonist (335). Recently, Cai and Stocco (92) established the expression of membrane PR in the rat CL. The authors demonstrated that rat luteal membranes contain proteins that bind progesterone with high affinity and specificity and that these proteins localize exclusively on luteal microsomal fractions. Another important finding presented in this report is that these genes are differentially expressed during pregnancy and that their expression is regulated by PRL. Nevertheless, despite these findings, the specific role of these membrane PRs on luteal cells is still unknown.

5. LH.
In several species, LH is essential and sufficient for the stimulation and maintenance of progesterone production by the CL. In rodents, there is no question that LH acutely enhances progesterone synthesis. It is also clear, however, that the sustained effect of LH in pregnant rodents: 1) is not sufficient by itself to sustain steroidogenesis and is dependent on previous exposure of the CL to PRL or PRL-related hormones; 2) is not necessary throughout pregnancy; and 3) is mediated by estradiol. The acute effect of LH appears to involve cAMP/PKA-dependent and cAMP-guanine nucleotide exchange factors PKA-independent (336) pathways, as well as the PLC pathway (337). LH action is directed primarily at the delivery of cholesterol to the mitochondrial cholesterol side-chain cleavage system, mediated principally by StAR (338). The molecular mechanism whereby LH/CG stimulates StAR transcriptional activity has been the subject of extensive investigations (233, 339). Although regulating StAR is probably the most critical function of LH, this hormone has also been shown to increase SR-BI and HDL uptake (207, 338). In contrast to the short-term actions, the sustained effect of LH on luteal progesterone synthesis in the pregnant rat appears to be due to its effect on yet another site in the steroidogenic pathway, the P450c17. By enhancing the expression/activity of this enzyme, LH stimulates the synthesis of androgens, which are converted readily to estradiol by the active luteal P450arom enzyme. The synthesis of luteal estradiol, however, is not completely regulated by LH throughout gestation. Thus, after midgestation, LH levels decrease markedly (340), and the placenta begins to express P450c17 and secrete androgens to circulation which are used by the CL for estradiol biosynthesis (reviewed in Ref. 319).

	V. Regression of the Corpus Luteum: Involution to Resume Cyclicity

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

 
The CL must be regularly eliminated from the body to allow normal reproductive function. In rodents, regression of the CL occurs in two phases, the first of which is known as functional regression and is associated with marked decrease in progesterone production. The second phase, termed structural regression, occurs after the initial decline in progesterone output. It is during this phase that the luteal cells die through programmed cell death. During the process of luteal regression as during luteinization, the CL undergoes substantial changes in its steroidogenic capacity, vascularization, and remodeling, resulting in a gland formed principally by connective tissue and known as corpus albicans.

A. Functional luteal regression
Functional regression of the CL occurs before discernible morphological changes in luteal cell integrity are observed. There is evidence indicating that during functional regression the luteal cells are still steroidogenically active, although the principal steroid secreted during this period is not progesterone, but rather a metabolite of progesterone (see below in this section). In rodents, as in many other species, the decline in progesterone secretion at the end of pregnancy takes an even more important role in view of the fact that levels of circulating progesterone must fall to allow parturition to occur. Several factors including PGF2 and LH have been implicated in shutting off luteal progesterone production.

1. PGF2 role in functional regression.
Early on it became clear that administration of PGF2 can induce a fall in levels of circulating progesterone and abortion in rodents (341, 342). The finding that inhibition of PGF2 synthesis at the end of pregnancy delays both the fall in circulating progesterone and parturition (343, 344) has led to the conclusion that PGF2 is essential for the inhibition of progesterone synthesis in the CL. The generation of mice lacking the PGF2 receptor brought support to this hypothesis. Indeed, progesterone levels do not decline in PGF2 null mice, and parturition does not take place unless the ovaries are removed (345). The role of PGF2 in the curtailment of progesterone before parturition is further supported by the phenotype observed in mice defective in enzymes involved in prostaglandin biosynthesis such as cytosolic phospholipase A2 (cPLA2), which catalyzes the formation of arachidonic acid from membrane glycerophospholipids, and COX-1, which allows conversion of arachidonic acid to prostaglandins. cPLA2-null females failed to undergo labor at term (i.e., 18.5 to 20.5 d), instead delivering at 21.5–22.5 d and with the majority of offspring being dead (346). Viable neonates were obtained, however, only by administering a PR antagonist (347). Similarly to the cPLA2-null mice, progesterone levels did not decrease in COX-1-null mice at the end of pregnancy, and a delay in the initiation of labor was observed (348). Administration of PGF2 to COX-1-null mice reduced circulating progesterone concentration and restored parturition. From the reproductive performance of cPLA2- and COX-1-null mice, it is apparent that cPLA2 couples with COX-1 to synthesize PGF2, which in turn induces functional regression of the CL.

The uterus seems to be the main producer of PGF2 in a large number of species including rodents, where the removal of the uterus leads to prolonged secretion of progesterone by the CL (for review, see Refs. 5, 6, 8 , and 13). The role of COX-1, COX-2, and cPLA2 in the production of uterine PGF2 has been extensively investigated. In rodents, COX-1 is expressed in the endometrial epithelium, myometrium, and decidua in late pregnancy (349, 350, 351), whereas COX-2 expression is low in intrauterine tissues throughout pregnancy and becomes highly expressed on d 20, the day of parturition (349). This rise in uterine COX-2 expression depends on the physiological drop of serum progesterone levels that precede parturition (349), suggesting that COX-2 does not play a role in the luteolytic process. Interestingly, no changes in cPLA2 mRNA expression, protein levels, or activity were observed during gestation in mice uterus (352), suggesting that whereas constant levels of cPLA2 are essential, it is the rise in COX-1 expression that leads to the higher uterine PGF2 production seen before parturition.

Although the uterus is a source of PGF2, there is solid information indicating that the CL itself also produces PGF2 (353, 354, 355). Both cPLA2 activity and PGF2 content within the CL increase remarkably at the end of pregnancy (331, 353, 356, 357, 358) and without any change in COX-1 expression. This suggests that, in the mouse ovary, the rise in luteal cPLA2 activity at the end of pregnancy liberates the substrates necessary for PGF2 synthesis. In the bovine, injection of PGF2 induces a rapid and transient increase in luteal COX-2 (355, 359) and PGF2 content (355). This effect is well supported by an increase in the cox-2 mRNA (355, 359). These results suggest that in the ovary, most probably COX-2, but not COX-1, is involved in luteal PGF2 synthesis. Considering that PGF2 stimulates its own synthesis in the CL, it is possible to hypothesize that the pulsatile release of PGF2 from the uterus increases luteal PGF2 synthesis, leading to an amplification of the luteolytic process.

2. Effect of PGF2 on luteal steroidogenesis.
In luteal cells, PGF2 signals through a Gq-coupled receptor that has been detected in the CL of multiple mammalian species (for review, see Ref. 13). Activation of this receptor causes PLC-mediated generation of inositol triphosphate and diacylglycerol (360), followed by increased free intracellular calcium and PKC activity (361, 362). In addition to PLC, there is evidence that in luteal cells PGF2 activates 1) the phospholipase D pathway, producing phosphatidic acid in addition to diacylglycerol (363); and 2) the MAPK signaling cascade (103, 105, 364). It has been shown in rat luteinized cells that activation of the ERK1/2 signaling pathway by PGF2 is mediated by an increase in free intracellular calcium in a calmodulin-dependent manner (105). In rats, the PGF2- and calcium-dependent ERK1/2 activation results in phosphorylation of the transcription factor JunD (105), which is constitutively expressed in luteal cells (57).

Extensive investigations have been performed to determine the mechanism by which PGF2 reduces the level of progesterone secreted by the CL. It is clear that in rodents PGF2 does not inhibit the synthesis of progesterone, but instead causes its metabolism to 20DHP. Consequently, at the end of pregnancy, the CL secretes principally 20DHP instead of progesterone. That PGF2 stimulates the activity of the 20HSD enzyme was known for years (365, 366, 367). Once the 20HSD gene was cloned (258, 259) and its promoter isolated (293), it became apparent that PGF2 does not activate the enzyme already present in the CL, but causes a remarkable increase in the expression of the 20HSD mRNA. Using mice lacking PGF2 receptor and pregnant rats, Stocco et al. (255) demonstrated that PGF2 is responsible for the rapid and massive expression of the 20HSD gene at the end of pregnancy. This group explored the molecular mechanism underlying PGF2-induced 20HSD gene expression and presented evidence that PGF2 enhances the activity of the 20HSD promoter. They have determined the upstream region in the 20HSD promoter that confers regulation by PGF2 in primary ovarian cells. This region encompasses a unique transcription factor-binding site with a sequence of a Nur77 response element. Deletion of this motif or overexpression of a Nur77 dominant negative protein caused a complete loss of 20HSD promoter activation by PGF2. Nur77 also transactivated the 20HSD promoter in transient transfection experiments using a luteal cell line. This induction required the Nur77-transactivating domain. Stocco et al. (255) have shown that PGF2 induces a very rapid expression of Nur77 that binds to a distal response element but does not interact with another proximal putative Nur77 response element located downstream in the promoter. A rapid increase in Nur77 mRNA was observed in mice CL just before parturition at a time when 20HSD becomes expressed. This increase in the expression of both genes was not seen in PGF2 receptor knockout mice. It was also shown that inhibition of Nur77 DNA binding in vivo prevents PGF2 from inducing the expression of the 20HSD gene in the CL. Taken together, these results demonstrate that in the CL, PGF2 induces the expression of the nuclear orphan receptor and transcription factor Nur77, which in turn leads to the transcriptional stimulation of 20HSD, triggering the decrease in serum progesterone essential for inducing parturition. Furthermore, the induction of Nur77 expression by PGF2 in luteal cells was shown to be mediated by JunD, a member of the AP1 family of transcription factors (105).

PGF2 was also shown to reduce cholesterol transport in the rat ovary by decreasing SCP-2 (368) and StAR expression (233, 369, 370). Inhibition of StAR by PGF2 has been associated with increased expression of DAX-1 (233), c-Fos (371), and ying yang 1 (372) transcription factors. Administration of PGF2 on d 19 of pregnancy was also reported to reduce luteal 3ßHSD activity (91). However, this inhibitory effect of PGF2 does not appear to be at the level of gene expression (253). The physiological significance of the down-regulation of protein involved in cholesterol transport and processing is not clear because the drop in progesterone secretion at the end of pregnancy in rodents is not due to the decrease in progesterone biosynthesis but rather to the catabolism of progesterone (255, 373).

3. Anti-LH effect of PGF2.
Original work by Behrman et al. demonstrated that PGF2 may prevent both LH and PRL stimulation of progesterone biosynthesis (374). The anti-LH action of PGF2 (reviewed in Ref. 5) was shown to involve two interrelated actions, the blockage of LH-induced cAMP accumulation and the inhibition of the response of the luteal cells to cAMP (374, 375). Activation of PKC and rise in intracellular calcium were suggested to play a role in the anti-LH effect of PGF2 (221, 376); however, neither the blockage of the PGF2-induced increase in intracellular calcium (377, 378, 379, 380) nor the treatment with PKC inhibitors had any effect on the antigonadotropic action of PGF2 (381). A more recent study presented interesting evidence of a possible mechanism of interaction between PGF2 and LH signaling pathways, merging at the level of the StAR gene and involving DAX-1 transcription factor. Sandhoff and McLean (233) demonstrated that PGF2 inhibits StAR expression by activating DAX-1, which in turn reduces the responsiveness of the StAR promoter to cAMP. Thus, by reducing StAR expression, PGF2 may prevent LH from stimulating progesterone biosynthesis. Taken together, all these results indicate that PGF2 prevents LH signaling in the CL. However, because LH is neither secreted nor does it have tropic action after midpregnancy in rodents, a physiological role for such a mechanism in the normal induction of luteal regression by PGF2 at the end of pregnancy appears remote.

4. Anti-PRL effect of PGF2.
There are contradictions in the early literature as to the anti-PRL effect of PGF2 in the rodent CL. PRL was shown either to reverse (374) or to have no effect on the PGF2-mediated decrease in both progesterone and LH-R expression (382). There has also been a report suggesting that the antisteroidogenic effect of PGF2 depends on PRL (383). However, more recent investigations have shown clearly that PGF2 and PRL act in opposite manner to regulate the expression of key luteal genes (see Fig. 10 and Ref. 253). Moreover, PGF2 inhibits the expression of the PRL-R and curtails PRL signaling through the Jak/Stat pathway (384, 385). Using PGF2-R knockout mice, as well as pregnant rats and luteal cell culture, Stocco et al. (384) found that PGF2 rapidly inhibits the expression of both forms of the PRL-R and that the physiological drop in PRL-R expression seen at the end of pregnancy is caused by PGF2. PGF2 was also shown to stimulate the expression of suppressors of cytokine signaling-3 that inhibits the Jak/Stat signaling pathway and prevents PRL-induced Stat5 activation (385).

View larger version (16K): [in this window] [in a new window]   FIG. 10. Effect of PGF2 and PRL on luteal gene expressions. The scale indicates the values of expression as a ratio between PGF2/control or PRL/control for positive values (stimulation) or –1 x control/PGF2 or control/PRL for negatives values (inhibition). The bars represent the average of three different experiments ± SEM. Open bars, PGF2; closed bars, PRL. [Adapted from C. Stocco et al.: Endocrinology 142:4158–4161, 2001 (253 ). Copyright The Endocrine Society.]

5. Antiestradiol effect of PGF2.

6. Effect of PGF2 on oxidative stress.
PGF2-induced and naturally occurring functional luteal regression is associated with accumulation of reactive oxygen species (ROS) and/or with decrease in protective enzymes, antioxidant vitamins, and radical scavengers. The role of ROS in the ovary has been reviewed recently (387). PGF2 treatment rapidly depletes luteal antioxidants such as ascorbic acid (388), increases superoxide radicals (389, 390, 391), and down-regulates genes involved in the elimination of free radicals (392). In the CL, generation of ROS causes invasion of leukocytes (391) and stimulation of ROS scavengers, such as superoxide dismutase and catalase, and prevents the invasion of leukocytes and the decrease in serum progesterone induced by PGF2 (391). The precise source of ROS within the CL remains unclear. There is, however, evidence to support three possible sources: 1) steroidogenic cells; 2) phagocytic leukocytes; and 3) endothelial cells of the microvasculature. PGF2 has been shown to stimulate production of ROS by rat luteal cells in vitro (393) and to cause an increase in hydrogen peroxide in regressing rat CL in vivo (394). Nonsteroidogenic cells of luteinized ovaries were also shown to produce ROS in response to PGF2 via a PKC-activated pathway (389). The authors further suggested that most likely the nonluteal cells producing ROS are phagocytic leukocytes. Finally, ROS generation by endothelial cells can be induced by the ischemia/reperfusion process (395), resulting in neutrophile activation and adhesion. However, induction of luteal regression by PGF2 in rodents does not alter the hemodynamics of the microvasculature (391), suggesting that most likely microvascular endothelial cells are not the major source of ROS in the CL. Luteal blood flow is also not affected by PGF2 (396, 397). The finding that pretreatment with either superoxide dismutase or catalase, which are large molecules that do not easily penetrate cell membranes, prevents luteal regression triggered by PGF2 suggests the possibility that neutrophiles are the major source of ROS during functional luteal regression (391).

Nitric oxide and HSP70 have also been implicated in PGF2 action (398, 399). Nitric oxide appears to have a protective effect on CL function or to mimic the regressive effect induced by PGF2 depending on the developmental status of the CL (400). As for HSP70, it has been shown to increase in rat luteal cells in response to PGF2 in coincidence with the inhibition of progesterone synthesis (399). PGF2 induction of HSP70 is preceded by a rapid activation of the heat shock transcription factor, which binds to its transcriptional control element in target genes (401). The mechanism of heat shock transcription factor activation by PGF2, however, remains largely unknown. The suggestion that HSP70 might have an important role in mediating PGF2 inhibition of steroidogenesis during luteal regression is based on the fact that, resembling PGF2, heat shock causes complete abrogation of LH-sensitive progesterone production and blocks steroidogenesis in response to 8-bromo-cAMP and forskolin (402). Moreover, antisense oligodeoxynucleotide against HSP70 partially reversed heat stress- and PGF2-induced inhibition of LH-stimulated steroidogenesis and cAMP accumulation (399, 401).

7. LH role in functional regression.
Despite the well-known tropic effect of LH, evidence has been accumulated for many years indicating that LH may have a deleterious effect in the rat CL. LH can curtail luteal function in rats during the estrous cycle (403), at the end of pregnancy (404, 405), and during lactation (406). LH levels rise at the end of pregnancy (340), and their neutralization with a blocking antibody prevents serum progesterone levels from dropping (405). Intraovarian administration of LH to d 19 pregnant rats induces a premature down-regulation of luteal 3ßHSD activity and mRNA expression (330). LH was also shown to inhibit the conversion of pregnenolone to progesterone in cultured luteal cells obtained from d 19 pregnant rats (407) and to stimulate 20HSD activity (405) and mRNA expression (330). Interestingly, the fall in progesterone synthesis induced by LH occurs several hours before any change in the activity/expression of the 20HSD enzyme is detected (330, 405). This is in contrast to the luteolytic events induced by PGF2, characterized by an abrupt increase in 20HSD expression (255). It has been postulated that a progressive decline in 3ßHSD activity and the consequent decrease in progesterone production may trigger the synthesis of prostaglandins and subsequent increase in luteal 20HSD activity to accelerate luteal regression (331). Indeed, intraovarian administration of progesterone prevented the LH-mediated increase in luteal PGF2 content as well as that of 20HSD, whereas administration of an inhibitor of the synthesis of prostaglandin prevented only 20HSD activity (331). This series of experiments allows us to conclude that: 1) LH favors luteal regression at the end of pregnancy in rats; 2) LH-induced luteal regression has a different dynamics compared with that induced by PGF2; and 3) locally produced progesterone may act as a "buffer" to allow a controlled regression of the CL.

B. Structural luteal regression
The structural regression of the CL is grossly characterized by a decrease in size and weight of the gland, which eventually becomes a scar within the ovarian stroma known as corpus albicans. The involution of the CL is due not only to luteal cell death but also to the replacement of the vascular supply and supporting connective tissue with bundles of collagen fibers, scattered fibroblasts, and macrophages. Most corpora albicans are eventually reabsorbed and replaced by ovarian stroma.

1. Programmed cell death.
The major event that causes the regression of the CL is death by apoptosis of luteal and vascular cells. In the CL of pregnancy, this process is lengthy and takes place several days after the initial decrease in progesterone production (functional regression). The involution or reduction in the size of the gland (structural regression) takes place only after parturition in the rodent (333). Several signals have been implicated in the induction of cell death including PRL, PGF2, TNF, and Fas ligand (FasL).

It is by now well established that there are two major apoptotic signaling pathways: the death receptor mediated or extrinsic pathway and the mitochondrial or intrinsic pathway (reviewed in Refs. 408 and 409). In the extrinsic pathway, the signal is provided by the interaction between a ligand and "death receptors" including Fas and TNF receptor (TNFR-3, -4, and -5). The ligand for Fas, FasL, initiates the activation of initiator caspases (e.g., caspase-8). The intrinsic apoptotic signaling cascade, on the other hand, is activated by stress stimuli that change the mitochondrial permeability leading to the release of cytochrome c, which binds to apoptotic protease-activating factor-1 and procaspase-9 to form a complex named apoptosome leading to caspase-9 activation. Both pathways lead to activation of the final effectors of the system or executioner caspases such as caspase-3, -6, and -7. These caspases cleave a variety of intracellular polypeptides including major structural elements of the cytoplasm such as actin, components of the DNA repair machinery such as poly (ADP-ribose) polymerase, a number of protein kinases, and the inhibitor of caspase-activated deoxyribonuclease (ICAD) among others (reviewed in Ref. 410).

Apoptosis is tightly regulated by members of the Bcl-2 family of proteins, which can either block (e.g., Bcl-2, Bcl-xL, Mcl-1) or promote (e.g., Bad, Bax, Bak, Bid, Puma) cell death mainly by regulating the permeability of the mitochondria (reviewed in Ref. 411). The participation of the mitochondria in the process of cell death in the ovary was reported by several groups. Human luteinized cells treated with the protein kinase inhibitor staurosporine showed reduced levels of mitochondrial cardiolipin, cleavage of procaspase-9, and activation of caspase-3 (412). Another group (242) showed a drop in mitochondrial levels of protective Bcl-xL associated with increased mitochondrial damaging Bax, as well as DNA fragmentation in luteal cells exposed to a GnRH agonist. In a model of luteal cells induced to die by microgravity, a loss of the mitochondrial membrane potential was observed in parallel with features of apoptosis (413). Finally, using rat luteal cells in culture, apoptotic programmed death was shown to be associated with cleavage of Bid and caspase-9, confirming the involvement of the mitochondria in luteal cell death (414).

Caspase-3 has been localized in the CL of rat (415, 416) and mice (417). The importance of caspase-3 as mediator of apoptosis in luteal regression has been further demonstrated by studies performed with caspase-3 null mice. The CL obtained from these animals showed attenuated rates of apoptosis and delay in the process of involution (417); yet the CL of caspase-3 null mice finally involutes, indicating that caspase-3 is not the sole factor leading to cell death in this gland.

Aside from apoptotic cell death, other means of cell death have been described in the CL. Gaytan et al. (418) showed that apoptosis of luteal endothelial cells was followed by necrosis of luteal steroidogenic cells. These investigators suggested that the structural regression of the CL in cycling rats may begin with apoptosis of endothelial cells that surround blood vessels leading to secondary ischemia of the CL followed by necrosis of the steroidogenic luteal cells. Other evidence showing luteal cell death other than apoptosis arises from studies in primates (419). Morphometric studies conducted in CL, in which regression was induced by either a PGF2 analog or a GnRH antagonist, revealed that apoptosis of luteal cells was associated with autophagocytosis, a form of programmed cell death characterized by formation of cytoplasmic vacuoles (419). Likewise, degenerative changes that were not in accord with the morphological features of apoptosis were observed during luteal regression of the cyclic human CL (420). Further studies are needed to understand these nonapoptotic forms of cell death in the CL. It was recently suggested (13) that various forms of programmed cell death (i.e. apoptotic, necrotic, autophagic) may be triggered in the regressing CL depending upon the mammalian specie, the physiological or pathological condition evaluated, and/or the nature of the luteolytic trigger.

It is important to mention that most of the data on luteal cell death in rodents were obtained from models that are not representative of the physiological luteolytic process that takes place at the end of pregnancy in rats and mice. For instance, most in vivo models use superovulated rats; in this model the CL has not been exposed to the luteotropic effect of PLs that profoundly alter luteal function, as well as the response of luteal cells to luteolytic factors. Studies oriented to examine the apoptotic pathways during the physiological luteolytic process that take place at the end of pregnancy and after parturition in rodents should be conducted to establish the molecular events that lead to apoptosis of luteal cells at this time.

2. Role of PGF2 in structural luteolysis.
Fas and FasL have been described in the rat CL during luteal regression (421, 422). Administration of either a Fas-activating antibody or PGF2 after ovulation in mice induced activation of caspase-8 and caspase-3 together with DNA fragmentation in the CL. Interestingly, these changes were completely absent in caspase-3-deficient mice (423). Because the receptor for PGF2 has not been shown to be directly coupled to caspase-8 recruitment and activation, the authors hypothesized that PGF2 initiates luteal regression in vivo, at least in part, by increasing the bioactivity or bioavailability of cytokines such as FasL, which activates caspase-3-driven apoptosis. Indeed, FasL has been shown to be highly expressed in the regressing postpartum CL of rats (421). Recently Yadav et al. (424) investigated the relative contribution of the intrinsic and extrinsic apoptotic signaling cascades in PGF2-induced luteal apoptosis in pseudopregnant rats and demonstrated that it was associated with an up-regulation in the activities of caspases-9, -8, and -3 as well as an increase in the expression of Bax and FasL. When a caspase-8 inhibitor was used before the administration of PGF2, the activation of caspase-3 induced by PGF2 was completely blocked, whereas the inhibition was only partial when a caspase-9 inhibitor was used. This suggests a greater importance of the extrinsic pathway in mediating PGF2-induced apoptosis of luteal cells. Finally, another condition associated with structural regression of the CL that has been attributed to PGF2 is the degradation of ECM mediated by MMPs (155, 425).

3. The role of PRL in structural luteolysis of the CL of the cycle.
Early studies by Malven and Sawyer (426) identified PRL as an important physiological molecule involved in the induction of structural luteal regression. The authors described a marked reduction in ovarian weight, a rise in the total number of connective tissue or stromal elements in the "corpus" and a decrease in "recognizable lutein cells." It was also recognized early that regression of the CL of the previous cycle in rats is induced by the proestrous preovulatory PRL surge (427, 428) and that hypophysectomy after CL formation, or blockage of the preovulatory surge of PRL with a dopaminergic agonist, maintains the structure of the CL intact for more than 1 month (426, 429, 430). These animals secrete predominantly 20-DHP instead of progesterone from their CL (431), and if treated with PRL their CL undergo rapid structural regression (427, 431). In rats, the PRL-induced structural regression of the CL of the cycle seems to be due to an apoptotic process (432). From these findings, it appears clear that PRL administration can cause structural luteal regression only in CL that were not previously exposed to PRL for at least 2 d and are producing 20-DHP. Because PRL is an antiapoptotic agent in many tissues (433), including functional CL (434, 435), it is perplexing as to why it acts in the opposite manner in functionally regressed CL. Several investigations indicate that the apoptotic effect of PRL appears not to be direct on luteal cells but to involve the participation of other cell types, namely cells of the immune system that are known to express the PRL-R (436). One cell type identified as a potential regulator is the monocyte/macrophage. These cells are normal components of cell-mediated immunity and are capable of inducing apoptosis through a number of mechanisms. Monocytes/macrophages have been associated with luteal involution in a wide variety of species (437, 438, 439), and in the rat CL this invasion has been shown to be initiated by PRL (427, 440).

In addition to chemoattraction, the migration of monocytes into tissues also requires the vascular endothelial bed of the destination tissue to express the proper adhesion proteins. One such protein is the intercellular adhesion molecule-1 (ICAM-1) that is expressed mainly on endothelial cells, facilitating the recruitment and migration of monocytes/macrophages to sites of inflammation (441, 442). Because ICAM-1 is stimulated by PRL in regressing CL of hypophysectomized rats (441), it is tempting to suggest that PRL may facilitate recruitment and binding of monocytes/macrophages to luteal endothelial cells inducing monocyte chemoattractant protein-1 and ICAM-1.

Other cells of the immune system that may be involved in mediating luteal regression are the lymphocytes. Although these cells are capable of inducing apoptosis through a number of mechanisms, investigations in the CL have been focused on Fas-mediated apoptosis. Expression of FasL is enhanced by PRL, whereas treatment with a blocking anti-FasL antibody inhibits the ability of PRL to induce apoptosis in culture (422). Participation of immune cells in Fas/FasL-induced luteal apoptosis is supported by the fact that Fas is expressed only in luteal steroidogenic cells, whereas FasL is expressed only in nonsteroidogenic CD3-positive luteal immunocytes (443). Moreover, the removal of immune cells inhibits PRL-induced luteal cell apoptosis, indicating that FasL-expressing immunocytes mediate, at least in part, the effect of PRL. Taken together, these findings suggest that PRL stimulates FasL in immune cells and that FasL interacts with its cognate receptor expressed in luteal cells leading to cell death. The mechanism by which PRL induces FasL in luteal immunocytes is not yet understood and needs further investigation.

A number of other changes have been shown to occur during PRL-induced luteal regression. Studies have demonstrated increased MMP-1 and MMP-2 activity during PRL-induced luteal regression (444, 445, 446), which may mediate some of the structural changes by regulating collagen synthesis and degradation. Another factor associated with luteal regression is the formation of oxygen radicals. In a functional CL, ROS formed are scavenged most probably by ascorbic acid, which is very abundant in this gland (388). Interestingly, PRL has been shown to induce depletion of ascorbic acid in regressing CL (444), therefore favoring ROS-mediated luteal damage.

Although several lines of evidence demonstrated that PRL plays a role in the removal of the CL of the cycle, whether this hormone also participates in the luteolytic process at the end of pregnancy remains a subject of investigation.

4. Progesterone and structural luteolysis.
Progesterone plays a protective role against apoptosis is the CL of rodents. This steroid has been shown to suppress apoptosis induced by PRL in luteal cells (334). In another study, exogenous administration of progesterone was capable of preventing the decline in CL weight postpartum and to decrease the number of cells undergoing apoptosis (333). Furthermore, in vivo administration of progesterone delayed the occurrence of DNA fragmentation in CL incubated in serum-free conditions (333). Because progesterone can suppress Fas expression in a large variety of cells, including rodent’s luteal cells, Takahashi and collaborators (443) proposed that progesterone may suppress PRL-induced luteal cell apoptosis by inhibiting the expression of Fas in the functional CL.

Although the chain of events that lead to luteal cell apoptosis is not totally understood, the current data suggest that PGF2 induces 20HSD expression directly by activation of the 20HSD promoter and indirectly by inhibiting PRL signaling. Once luteal cells express 20HSD, they lose their capacity to secrete progesterone, facilitating the expression of Fas on their surface and the invasion of the CL by immune cells. In turn, binding of FasL expressed by immune cells to the Fas receptor present on luteal cells results in the activation of the initiator caspase-8/9 and executioner caspase-3. Caspase-3 then cleaves ICAD, releasing of CAD, which translocates to the nucleus where it proceeds to fragment the DNA (Fig. 11).

View larger version (28K): [in this window] [in a new window]   FIG. 11. An integrative model for luteal regression. Based on the findings from many laboratories, we propose a model of apoptotic signaling pathways in the rodent CL. In this model, PGF2-induced apoptosis involves stimulation of both 20HSD and Fas in luteal cells. PGF2 inhibits PRL-R expression (1), preventing PRL’s repression of 20HSD (2), and stimulates the transcriptional activity of the 20HSD gene (3) leading to a decline in progesterone production (4). This allows a rise in Fas expression (5) and invasion of immune cells that were under repressive control by progesterone. FasL stimulated by PRL in immune cells binds to Fas receptor on luteal cells (6), resulting in activation of the initiator caspase-8 (7) and executioner caspase-3 (8). Caspase-3 then cleaves ICAD, resulting in the release of CAD and its translocation to the nucleus where it proceeds to fragment the DNA. These apoptotic luteal cells are then recognized and cleared by immune cells that infiltrate the CL during luteolysis. Numerals in parentheses refer to numerals on figure.

	VI. Concluding Remarks

Top Abstract I. Introduction II. Formation of the... III. Genesis of a... IV. Function of the... V. Regression of the... VI. Concluding Remarks References

	Footnotes

 
This work was supported by National Institutes of Health Grant HD11119 (to G.G.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 31, 2006

¹ C.S. and C.T. contributed equally to this work.

Abbreviations: AC, Adenylyl cyclase; Ang, angiopoietins; AP1, activator protein-1; ARF6, ADP ribosylation factor 6; bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; Cdk, cyclin-dependent kinase; C/EBP, CATT/enhancer binding protein; CL, corpus luteum; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; CRE, cAMP response element; CREB, CRE binding protein; DAX-1, dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene; 20DHP, 20-dihydroprogesterone; DHT, dihydrotestosterone; E2F, transcription factor E2; ECM, extracellular matrix; Egr-1, early growth response protein-1; EG-VEGF, endocrine gland-derived VEGF; ER, estrogen receptor; FasL, Fas ligand; FSH-R, FSH receptor; Fzd, Frizzled; GATA-1, GATA-binding factor 1; GDF, growth/differentiation factor; GR, glucocorticoid receptor; hCG, human chorionic gonadotropin; HDL, high-density lipoprotein; HSD, hydroxysteroid dehydrogenase; 17ßHSD-1, 17ß-hydroxysteroid dehydrogenase type 1; HSP, heat shock protein; ICAD, inhibitor of caspase-activated deoxyribonuclease; ICAM-1, intracellular adhesion molecule-1; Jak, Janus kinase; LAP, liver-enriched activator protein; LDL, low-density lipoprotein; LH-R, LH receptor; LIP, liver-enriched inhibitory protein; 2M, 2-macroglobulin; MAPKAPK, MAPK-activated protein kinase; MMP, matrix metalloproteinase; NFB, nuclear factor-B; P450arom, P450 aromatase; P450scc, P450 cholesterol side-chain cleavage; PBR, peripheral-type benzodiazepine receptor; PGF2, prostaglandin F2; PI3K, phosphatidylinositol-3-kinase; PKA, protein kinase A; PKB, protein kinase B; PKC, protein kinase C; PL, placental lactogen; PLC, phospholipase C; PR, progesterone receptor; PRAP, PRL-R associated protein; pRb, retinoblastoma; PRL, prolactin; PRL-R, PRL receptor; RAR, retinoic acid receptor; ROS, reactive oxygen species; SCP-2, sterol carrier protein-2; SF-1, steroidogenic factor-1; Sgk, serum and glucocorticoid-induced kinase; SHP, Src-homology domain-containing protein tyrosine phosphatase; SMADs, mothers against decapentaplegic homolog; SR-BI, scavenger receptor class B type I; StAR, steroidogenic acute regulatory protein; Stat, signal transduction and activation of transcription; TIMP, tissue inhibitors of metalloproteinases; VEGF, vascular endothelial growth factor.

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