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BOR - Papers in Press, published online ahead of print February 1, 2006.
Biol Reprod 2006, 10.1095/biolreprod.105.049924
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BIOLOGY OF REPRODUCTION 75, 2–8 (2006)
DOI: 10.1095/biolreprod.105.049924
© 2006 by the Society for the Study of Reproduction, Inc.

Minireview

Multiplicity of Progesterone's Actions and Receptors in the Mammalian Ovary1

John J. Peluso 2 

Department of Cell Biology and Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut 06030


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 INTRAOVARIAN ACTIONS OF...
 POTENTIAL MEDIATORS OF...
 P4 RECEPTORS AND THEIR...
 REFERENCES
 
This minireview summarizes the role that progesterone (P4) plays in regulating granulosa and luteal cell function. These actions include the stimulation of P4 synthesis and the inhibition of estrogen synthesis, mitosis, and apoptosis. P4 also plays a key role in the ovulatory process. Although P4's actions are well documented, the mechanism or mechanisms that mediate all of these actions have not been defined. In addition to P4-induced gene transcription that is mediated by the nuclear P4 receptors (PGR-A and PGR-B), three other receptor/signal transduction pathways could account for P4's intraovarian actions. These pathways could be mediated by 1) the PGR localizing at or near the plasma membrane and activating SRC family kinases, 2) a membrane progestin receptor that responds to P4 by lowering intracellular cAMP and increasing MAPK 3/1 activity, and 3) a membrane receptor complex composed of serpine 1 mRNA binding protein (also known as PAIRBP1 or RDA288) and progesterone receptor membrane component 1. Ligand activation of this complex likely leads to an increase in protein kinase G activity, the maintenance of low basal intracellular free calcium, and the inhibition of granulosa and luteal cell mitosis and apoptosis. Given the complexity of P4's actions within the ovary, it is likely that all of these receptor/signal transduction pathways influence some aspect of ovarian function with the specific P4 response dependent on 1) the expression pattern of these putative P4 receptors, 2) the P4 binding affinity of each receptor system, and 3) the amount of available P4.

corpus luteum, granulosa cells, mechanisms of hormone action, ovary, progesterone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
INTRAOVARIAN ACTIONS OF...
 POTENTIAL MEDIATORS OF...
 P4 RECEPTORS AND THEIR...
 REFERENCES
 
Progesterone (P4) is a steroid hormone that is synthesized by the ovary, with the amount of P4 secreted depending on the level of gonadotropin stimulation and the physiological status of the ovary. Moreover, granulosa cells, thecal/stromal cells, and luteal cells all secrete P4 albeit at different levels [1–3]. Once secreted from the ovary, P4 acts at the level of 1) the hypothalamus-pituitary axis, to regulate gonadotropin secretion [4, 5] and mating behavior [6]; 2) the mammary gland, to stimulate its development [7]; and 3) the uterus [8, 9]. P4 influences numerous aspects of uterine physiology, including the differentiation of the endometrium and the development of the placenta [8, 9]. Because P4 regulates all of these essential physiological processes, considerable research has been focused on the mechanism through which P4 mediates its actions in these tissues. These mechanistic studies have identified two nuclear P4 receptors (PGR-A and PGR-B). These two receptors function as transcription factors, thereby regulating gene cascades that account for many of P4's biological actions [10].

Unlike the well-characterized P4-responsive tissues, it has been difficult to determine whether P4 influences ovarian function, because the ovary synthesizes P4 in such high amounts. However, in his 1981 [11] and 1996 [12] reviews Rothchild put forth the concept that P4 has an intraovarian site of action. Although Rothchild's concept was based on P4's ability to regulate its own secretion in luteal cells, other studies also suggested that P4 influences different aspects of granulosa cell function, specifically those related to follicular growth [13]. Unfortunately, Rothchild's concept has not been extensively tested, in part because of the observations that neither rodent luteal cells nor granulosa cells express PGR before the ovulatory gonadotropin surge [14–18].

Over the last decade several different potential P4 receptors that localize to the plasma membrane have been detected in either nonmammalian species [19, 20] or in nonovarian tissues [21, 22]. Some of these putative receptors for P4 are expressed in mammalian ovaries, which raises the possibility that they mediate some of P4's intraovarian effects. A summary of the major biological effects of P4 on the mammalian ovary will now be presented, followed by a discussion of the different membrane P4 receptors and how they might influence ovarian function.


   INTRAOVARIAN ACTIONS OF PROGESTERONE
TOP
 ABSTRACT
 INTRODUCTION
 INTRAOVARIAN ACTIONS OF...
POTENTIAL MEDIATORS OF...
 P4 RECEPTORS AND THEIR...
 REFERENCES
 
P4 is known to influence follicular growth, ovulation, and luteinization. Some of the studies that illustrate P4's actions in each of these physiological events will be briefly reviewed in the following section.

Follicular Development

It has been known for a long time that P4 inhibits the development of ovarian follicles. Specifically, in vivo studies have demonstrated a negative correlation between serum P4 levels and the rate of follicular growth (i.e., the rate of granulosa cell mitosis) [23, 24]. This relationship is observed during the estrous cycle, as well as pregnancy [23, 24]. P4's ability to inhibit follicular development is a generalized phenomenon observed in hypophysectomized hamsters [25], gonadotropin-primed hamsters [26], rabbits [27], and cycling rats [28]. The most compelling in vivo model to assess the effect of intraovarian P4 is that of the monkey. To assess the effect of intraovarian P4 in primates, DiZerga et al. [29] implanted P4 in one ovary and control vehicle in the other ovary. Under these conditions, the gonadotropin levels are not affected, but follicular development is inhibited in the P4-treated ovary and not in the control ovary. The findings of DiZerga et al. [29] are also supported by the more recent observations that periovulatory P4 surge accounts for the reduction in granulosa cell mitosis and apoptosis [30].

Given that P4 inhibits granulosa cell proliferation in vivo independent of its ability to influence gonadotropin levels, it is likely that P4 acts directly on granulosa cells. In vitro studies confirm this hypothesis, revealing that P4 enhances granulosa cell P4 secretion [31], suppresses granulosa cell estrogen secretion [31, 32], and slows the rate of mitogen-induced proliferation [33–35]. Interestingly, P4 also prevents apoptosis of granulosa cells [13, 18, 35–37]. Thus, the in vivo and in vitro studies support the idea that P4 acts as an intraovarian "governor" by slowing the rate at which antral follicles grow and undergo atresia.

Progesterone, Ovulation, and Luteal Function

As a consequence of the ovulatory gonadotropin surge and the resulting PGR-induced gene cascade, the granulosa cells of preovulatory follicles differentiate into luteal cells [38–40]. In luteal cells intraovarian P4 seems to function as a "universal luteotropin," as evidenced by its ability to promote its own secretion [11, 12, 30]. P4 also acts to maintain luteal cells by suppressing apoptosis [13, 41–45]. Although this concept of a universal luteotropin was initially based on indirect evidence, recent studies provide a more mechanistic foundation for P4's luteotropic action [30]. These studies demonstrate the presence of a high-affinity, low-capacity binding site for progestin (R5020) in monkey luteal cells. The Kd for the P4 binding site is 1–5 nM, which is consistent with the Kd of the PGR [30]. Interestingly, P4 also promotes P4 synthesis [12] and prevents apoptosis of rat luteal cells [13, 41, 42], which do not express PGR [16, 17]. Given these findings it cannot be concluded with certainty that all of P4's luteotropic actions are due to PGR-mediated events.


   POTENTIAL MEDIATORS OF PROGESTERONE'S BIOLOGICAL ACTIONS
TOP
 ABSTRACT
 INTRODUCTION
 INTRAOVARIAN ACTIONS OF...
 POTENTIAL MEDIATORS OF...
P4 RECEPTORS AND THEIR...
 REFERENCES
 
From the previous discussion two important points are evident. First, in both granulosa and luteal cells P4 plays a major role in regulating steroidogenesis, mitosis, and apoptosis. Second, the cellular and molecular mechanism or mechanisms involved in mediating P4's intraovarian actions are relatively unknown. Insights into P4's mechanism of action are provided by studies with PGR-A/PGR-B null mice [46]. Studies with these animals conclusively show that the PGRs are required for ovulation. This is consistent with the findings that PGR is only detected in granulosa cells after the gonadotropin surge.

A second insight into the influence of PGR is that follicular development proceeds normally in PGR-A/PGR-B null mice [46]. This is intriguing, given that granulosa cells of immature follicles respond to P4 in a steroid-specific dose-dependent manner, with the doses being in the physiological (i.e., nM) range [47, 48]. This contradiction suggests that receptors other than the PGR may be involved in mediating P4's actions in granulosa cells before the gonadotropin surge. Additionally, luteal cells isolated from animals with short estrous cycles, such as mice and rats [16, 17, 37, 41, 42, 49], do not express PGR, which again raises the question about the receptor that transduces P4's action in luteal cells.

Early attempts to identify other receptors through which P4 acts focused on known receptors to which P4 binds promiscuously. For example, GABAA receptors can bind P4 and its metabolites [50]. Although GABAA receptor subunits are present within the ovary [51], they do not appear to transduce P4's biological effects in granulosa cells [48]. This is based in part on the findings that GABAA inhibitors do not block P4's actions in spontaneously immortalized granulosa cells [48]. Similarly, P4 binds the ovarian glucocorticoid receptor [52]. This receptor is also expressed in both granulosa and luteal cells, but it is not involved in P4's granulosa cell anti-apoptotic and anti-mitotic actions [53]. In luteal cells P4 binding to the glucocorticoid receptor may account for P4's ability to suppress 20{alpha}-hydroxysteroid dehydrogenase, an enzyme that metabolizes P4. This action could account in part for the capacity of P4 to increase its own synthesis and act as a luteotropic factor [54]. A third possibility could involve the oxytocin receptor, because P4 can displace oxytocin binding to its own receptor and thereby attenuate P4's action in the uterus [55]. Although oxytocin influences granulosa and luteal cell function [56, 57], it is unlikely that this mechanism accounts for P4's action, because P4's action in vitro occurs in the absence of oxytocin. Finally, it has been suggested that P4 binds to a subunit of the sodium-potassium ATPase, which in turn stimulates frog oocytes to enter meiosis [58]. P4 could influence function of the mammalian ovary through an interaction with a sodium-potassium ATPase, but this possibility has not been assessed.

As indicated various receptors can promiscuously bind P4, but their ligand-induced activation cannot account for the majority of P4's actions within granulosa and luteal cells. Recently, there have been major advances in identifying putative P4 receptors that transduce P4's actions independent of the genomic action of PGR. These mechanisms involve rapid responses that could be activated through P4 binding to either 1) PGR that localizes at or near the plasma membrane, 2) a family of membrane progestin receptors (MPR{alpha}, MPRß, and MPR{gamma}) that were initially identified in fish oocytes, and 3) a membrane complex composed of serpine 1 mRNA binding protein (SERBP1) and progesterone receptor membrane component 1 (PGRMC1). The expression and potential role that each of these putative receptors play in mediating the intraovarian actions of P4 will be presented in the following sections.

PGR and Rapid P4 Responses

One of the best-known biological actions of P4 is its ability to induce the maturation of Xenopus oocytes. In 2000 two groups cloned a P4 receptor from the Xenopus oocyte that is similar to the mammalian PGR [59, 60]. Overexpression of this receptor results in an increased sensitivity to P4 [59, 60], and PGR antisense oligonucleotide treatment ablates P4's action [60]. It appears that PGR associates with MAPK 3/1 kinase and induces oocyte maturation by activating the phosphoinositide 3 kinase pathway [61].

Taken together these findings indicate that PGR can localize at or near the plasma membrane, providing another possible pathway through which P4 could influence ovarian function. However, PGR is only expressed in granulosa cells after the ovulatory gonadotropin surge and in corpora lutea of species that have a long luteal phase (i.e., sheep, cattle, and humans) [62, 63]. On the basis of this expression pattern, the rapid actions of PGR cannot account for P4's effects before and after the gonadotropin surge.

Membrane Progestin Receptor

Zhu et al. [19, 20] identified a family of membrane progestin receptor proteins from the sea trout ovary. These proteins are referred to as membrane progestin receptors (MPR) and are structurally different from the PGR family. These receptors possess characteristics of seven-transmembrane G protein-coupled receptors. To date three isoforms have been identified (MPR{alpha} , MPRß, and MPR{gamma}). The MPR{alpha} isoform binds P4 with high affinity (the Kd is approximately 30 nM) but has little or no capacity to bind RU486. This is in contrast to the PGR [64]. Moreover, ligand activation of MPR{alpha} increases MAPK 3/1 kinase activity and decreases adenylate cyclase activity [19, 20].

Recently, Cai and Stocco [65] have shown that all three MPRs are expressed within the rat ovary and that MPR{alpha} and MPR{gamma} levels increase in corpora lutea throughout pregnancy, whereas MPRß levels remain constant (Fig. 1). Interestingly, MPR{alpha} and MPRß levels decrease just before the end of pregnancy. Similarly, MPR{alpha} mRNA levels decrease just before the porcine corpora lutea regresses [66].


Figure 1
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  		FIG. 1. The relative expression of MPR{alpha} (A), MPRß (B), MPR{gamma} (C), and PGRMC1 (D) in the rat corpus luteum during pregnancy. Quantitative real-time PCR was used to determine copies per nanogam of total RNA of each transcript. The ratio between copies per nanogram of each receptor and that of ß-actin are shown in each graph. Means with SEM are shown in A–D, whereas only means are shown in E. Bars with different letters are statistically different (P < 0.05). For details see Cai and Stocco [59]. This figure is a modification of Figure 7 from Cai and Stocco [65] and is provided with permission of Drs. Cai and Stocco and the Endocrine Society. Copyright 2005, The Endocrine Society.

P4 Membrane Receptor Component 1

P4 also binds to a membrane protein that has been cloned from porcine liver [21, 67]. This protein, now referred to as PGRMC1 [68], is composed of 194 amino acids and possesses a single membrane-spanning domain [21, 67]. Binding studies indicate that PGMRC1 has a high-affinity binding site (Kd = 11 nM) and a low-affinity binding site (Kd = 286 nM) [21, 67]. Furthermore, mRNA encoding PGRMC1 is detected in preovulatory mouse follicles [49], porcine granulosa cells [69], and human granulosa/luteal cells maintained in culture [70]. Immunohistochemical studies reveal that PGRMC1 is also expressed in rat granulosa cells, with its cellular localization within granulosa cells being regulated by gonadotropins. In preantral and antral follicles before eCG treatment, PGRMC1 is detected in a limited number of granulosa cells, with PGRMC1 apparently localizing to the nuclei of many PGRMC1-expressing granulosa cells (Fig. 2, B and C). After eCG treatment the localization dramatically changes, such that PGRMC1 expression is almost exclusively at or near select regions of the plasma membrane (Fig. 2D). With hCG-induction of ovulation and luteinization, PGRMC1 expression increases, as assessed by both immunohistochemical analysis (Fig. 2, E and F) and Western blot (unpublished observation). Unlike granulosa cells, 100% of the luteal cells expressed high levels of PGRMC1, which is localized throughout the cell. Moreover, treatment with an antibody to PGRMC1 blocks P4's anti-apoptotic action (unpublished results). These observations support the possibility that PGRMC1 is involved in regulating P4's antiapoptotic actions in both granulosa and luteal cells.


Figure 2
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  		FIG. 2. The localization of PGRMC1 in the ovary of gonadotropin-primed immature rats. A) Section taken from an immature 23-day-old rat is shown that was stained as a negative control. B) Adjacent section stained for PGRMC1. Note that numerous granulosa cells of both preantral and antral follicles express PGRMC1, with the majority of granulosa cells showing apparent nuclear localization. C) High magnification of a follicle shown in panel B. The arrow points to granulosa cells in which PGRMC1 is localized to the extreme periphery of the cell. D) Antral follicle taken 24 h after eCG is shown. Note that PGRMC1 is localized to the extreme periphery of a select number of granulosa cells. E) Corpus lutea collected 96 h after hCG. In these structures all of the cells express PGRMC1 with PGRMC1 observed throughout the luteal cell (F). Bar = 60 µm (A, B); 20 µm (C, D); 150 µm (E); 40 µm (F).

Although PGRMC1 has been implicated as a mediator of P4's action in sperm [68], virtually nothing is known about the signal transduction pathways that are activated when it binds P4. Interestingly, PGRMC1 has a very short cytoplasmic domain. Structural analysis with Motif Scan (available at: http://scansite.mit.edu/motifscan_seq.phtml) revealed the presence of three Src homology domains. Whether these domains are involved in the transduction of the ligand-activated signal associated with PGRMC1 remains to be determined.

SERBP1 and P4's Action

The fourth protein that is involved in regulating P4's intraovarian action was initially detected by a PGR receptor antibody referred to as C-262. Interestingly, Bramley [62] detected a 55–60-kDa protein in bovine luteal cells by use of the C-262 antibody. Similarly, the C-262 antibody detected a 55–60-kDa protein that localizes to the extracellular surface of the plasma membranes of rat granulosa cells [48]. The C-262 antibody antagonizes the antiapoptotic action of P4 in these cells [48].

Because these studies suggest that the 55–60-kDa C-262 detectable protein is involved in mediating P4's antiapoptotic actions, the C-262 detectable protein was affinity purified and its sequence determined using LC-MS/MS [71]. This analysis identified the C-262 detectable protein as SERBP1. Immunohistochemical analysis revealed that SERBP1 is expressed in thecal/stromal cells, ovarian surface epithelial cells, and luteal cells. In addition its level increases within granulosa cells during follicular development [13]. Overexpression of SERBP1 increases the capacity of spontaneously immortalized granulosa cells to respond to P4 [71]. Finally, SERBP1 localizes to the extracellular surface of the plasma membrane, and its antibody interferes with P4's antiapoptotic action [13, 71]. These findings suggest that SERBP1 is an essential component of P4's mechanism of action.

Although the expression analysis and in vitro studies implicate SERBP1 in P4's mechanism of action, its structure does not support a role in signal transduction, because SERBP1 does not possess a transmembrane domain. Moreover, SERBP1 antibody treatment does not affect 3H-P4 binding [13]. One possible resolution to this contradiction would be for SERBP1 to bind to another protein that binds P4. Immunoprecipitation experiments using the SERBP1 antibody revealed that SERBP1 interacts with PGRMC1 [13]. Taken together, these findings suggest that SERBP1 forms a complex with PGRMC1. This complex, which is localized to the extracellular surface of the plasma membrane, could function as a membrane receptor complex through which P4 mediates its antiapoptotic and antimitotic action.


   P4 RECEPTORS AND THEIR SIGNAL TRANSDUCTION PATHWAYS
TOP
 ABSTRACT
 INTRODUCTION
 INTRAOVARIAN ACTIONS OF...
 POTENTIAL MEDIATORS OF...
 P4 RECEPTORS AND THEIR...
REFERENCES
 
From the previous discussion it is obvious that P4 influences ovarian function but the receptor-mediated mechanisms through which P4 acts remain to be elucidated. There are at least four potential receptor signal transduction pathways that could regulate P4's actions. These pathways are summarized in Table 1.


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  		TABLE 1. The expression and characteristics of receptors that could mediate progesterone's actions in ovarian cells.

PGR clearly plays essential roles in ovulation and the induction of genes associated with the differentiation of luteal cells, and there are two potential mechanisms through which PGRs could act. The first mechanism involves the well-characterized ligand induction of transcriptional activity by the PGR [10]. Recently, a second PGR-dependent mechanism has come to light. In this mechanism P4 binding can activate the SH3 domain within the PGR and, in turn, promote the binding and activation of Src kinases [72]. This was demonstrated by transfecting COS-7 cells with PGR-B and SRC. Treatment of these cells with P4 induces a transient increase in Src activity within 2–5 min. This response is mediated by the PGR-B, because it is not observed in cells only transfected with SRC. Moreover, the activation of SRC is not dependent on PGR-induced transcription [64]. By activating Src kinase, P4 has the capacity to influence numerous signal transduction pathways that ultimately regulate specific gene cascades [73]. The identity of the genes involved in luteinization that are induced directly via the transcriptional activity of the PGR versus those induced by the PGR activating the SRC kinase remains to be determined.

The third P4 mechanism uses members of the MPR family. To date these MPRs have been shown to be expressed in luteal cells [65] and act to suppress intracellular cAMP levels and increase MAPK 3/1 activity [19, 20]. The net effect of MPR activation is unknown. However, because a decrease in intracellular cAMP would suppress steroidogenesis [74] and MAPK 3/1 activation is part of an apoptotic mechanism in many cell types [13], expression and activation of MPR in the luteal cells could initiate changes that would make the luteal cell more susceptible to apoptosis and could promote the regression of the corpus luteum. Moreover, the levels of PGRMC1 begin to decrease during the middle of pregnancy, whereas MPR{alpha} continues to increase until just before luteolysis (i.e., when the P4 levels decrease) (Fig. 1). This alteration in the ratio of PGRMC1 and MPR{alpha}, coupled with the fact that Kd for the MPR{alpha} (30 nM) [19, 20] is 10 times greater than the low affinity site for PGRMC1 (approximately 300 nM) [21, 67], would also promote conditions that could lead to luteolysis. However, this concept is based on expression data and remains to be rigorously tested.

As indicated previously, the fourth potential P4-regulated signal transduction pathway involves the interaction of PGRMC1 and SERBP1. The role of SERBP1 in this complex is unknown but could involve localizing PGRMC1 to the plasma membrane and/or influencing whether the high-affinity and/or low-affinity binding sites within PGRMC1 are available to bind P4. Given its structure, PGRMC1 likely binds P4 and thereby promotes the activation of various kinases through an interaction with the Src homology domains that are present within its cytoplasmic tail. Activation of protein kinase G and the phosphorylation of numerous but undefined proteins could be downstream events associated with ligand activation of PGRMC1 [75]. The increase in protein kinase G activity has not been directly attributed to activation of PGRMC1 but rather is induced by P4 in spontaneously immortalized granulosa cells, which express only PGRMC1.

Finally, it is important to appreciate that none of these signal transduction pathways are mutually exclusive. In fact, the overall effect of P4 may be dependent on 1) the expression pattern of these putative P4 receptors, 2) the P4 binding affinity of each receptor system, and 3) the amount of available P4. Importantly, intraovarian levels of P4 are always relatively high (i.e., in the µM range) throughout the rat estrous cycle [76], making it likely that the action of P4 is mostly dependent on the level at which each receptor is expressed.

In summary, P4 has numerous intraovarian actions, but neither the receptors nor the signal transduction pathways that mediate the action of P4 have been completely defined. As indicated, some of the potential P4 receptors and their signal transduction components have been identified. Hopefully, their identification will stimulate research that will provide a molecular mechanism to explain Rothchild's 25-yr-old concept of the intraovarian action of P4.


   ACKNOWLEDGMENTS
 
I thank Dr. Fred Stomshak for the invitation to write this review and Dr. Stomshak and Jonathan Romak for their careful review of this manuscript. Finally, because of page limitations, not all of the work implicating the action of P4 within the ovary was cited. I regret these omissions.


   FOOTNOTES
 
1 Supported by the NIH (grants HD 34383, HD 047205, and HD 050298). Back

2 Correspondence: FAX: 860 679 1269; peluso{at}nso2.uchc.edu Back

Received: 1 December 2005.

First decision: 14 January 2006.

Accepted: 26 January 2006.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 INTRAOVARIAN ACTIONS OF...
 POTENTIAL MEDIATORS OF...
 P4 RECEPTORS AND THEIR...
 REFERENCES
 

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