The Critical Roles of Progesterone Receptor (PGR) in Ovulation, Oocyte Developmental Competence and Oviductal Transport in Mammalian Reproduction

Authors


Author’s address (for correspondence): Rebecca L Robker, Level 3, Medical School South, University of Adelaide, Frome Rd, Adelaide, SA 5005, Australia. E-mail: rebecca.robker@adelaide.edu.au

Contents

Progesterone is critical for successful ovulation in the ovary and for the multi-faceted role of the oviduct in mammalian reproduction. Its effects are mediated by progesterone receptor (PGR), which is highly expressed in the ovary, specifically granulosa cells of preovulatory follicles in response to the luteinizing hormone (LH) surge that occurs just prior to ovulation, and in the oviduct, predominantly luminal epithelial cells but also muscle cells. This review will summarize research which shows that progesterone, via the actions of PGR, plays a key role in the functions of these cells and in the important periovulatory events of oocyte release, acquisition of oocyte developmental competence and oviductal transport of the newly formed embryo. PGR is a nuclear receptor that regulates the expression of many downstream target genes. However, although much is known about its expression characteristics in ovarian and oviductal cells, there is still much to unravel about the mechanisms by which PGR exerts its control over these important reproductive processes, particularly in the oviduct.

Introduction

Progesterone (P4) is commonly allied to pregnancy establishment and maintenance (hence ‘pro-gestation’), but it also plays critical roles in other tissues including the ovary and oviduct/Fallopian tube. Ovarian granulosa-lutein cells are the major sites of P4 production in response to the preovulatory surge in luteinizing hormone (LH), and ovary-derived P4 is involved in autocrine regulation of ovarian function and ovulation (Conneely et al. 2002). Similarly, P4 is involved in modulating the morphology and physiology of the oviduct, providing an optimal environment for oocyte maturation, sperm capacitation, fertilization and bi-directional transport of gametes and embryos (Hunter 1998; Murray et al. 1995). Its effects are mediated by progesterone receptor (PGR), a ligand-activated, nuclear transcription factor that exerts pleiotropic control over many reproductive processes (Lydon et al. 1995). Importantly, however, P4 also binds and activates membrane-bound receptors that have been demonstrated to transmit rapid non-genomic effects in many cells (Gellersen et al. 2009; Peluso 2006).

This review summarizes current knowledge on the role of nuclear PGR specifically in oocyte release (ovulation), oocyte developmental competence or quality and oviductal transport of the newly fertilized oocyte. Much is known on its role in ovulation, particularly in rodents and humans, and so this review will simply highlight the major findings in this area. However, there has been no critical review of studies examining the effect of PGR on oocyte developmental competence, indeed many studies show conflicting results between species. Further, the role of PGR in oviductal function and transport has been relatively neglected compared to comprehensive studies examining its essential roles in implantation and mammary gland function. An understanding of the role of PGR during this early period of oocyte release and embryo transport is crucial for improving the success rates of assisted reproductive technologies in humans and other species, and may provide insight into potential down-stream mediators of PGR action as non-hormonal targets for novel contraceptive agents.

Progesterone Receptor Expression in the Ovary and Oviduct

In the ovary, PGR is expressed specifically in granulosa cells of preovulatory follicles. In rodents, it is rapidly, yet transiently, induced in response to the LH surge or an ovulatory dose of human chorionic gonadotropin (hCG). The PGR mRNA and protein is detectable by 4 h post-hCG, peaks at 8 h post-hCG, but is undetectable by 12 h post-hCG (Ismail et al. 2002; Park and Mayo 1991; Robker et al. 2000; Teilmann et al. 2006). It is primarily localized to nuclei and cytosol of mural granulosa cells and is virtually undetectable in cumulus cells or oocytes, consistent with LH receptor expression (Ismail et al. 2002; Robker et al. 2000; Teilmann et al. 2006; Conneely et al. 2003, 2001). In mammals, the PGR gene gives rise to two functionally distinct protein isoforms, PGR-A and PGR-B. These isoforms arise as a result of translation from alternative initiation sites in the same PGR gene (Graham and Clarke 2002; Kastner et al. 1990; Conneely et al. 1989, 1987) to produce two distinct transcripts. Of the two isoforms, PGR-A predominates in granulosa cells of preovulatory follicles in mice, although PGR-B is co-expressed but at a much lower level (Natraj and Richards 1993; Shao et al. 2003; Teilmann et al. 2006; Gava et al. 2004; Park and Mayo 1991; Conneely et al. 2003).

In cattle, females stimulated with a gonadotropin analogue (GnRH) also display transient expression of PGR in preovulatory follicles, with a rapid increase in PGR mRNA in granulosa and theca cells peaking at 6 h post-GnRH injection, but undetectable by 12 h post-GnRH (Jo et al. 2002). This is followed by a second wave of expression in both granulosa and theca cells at 24 h post-GnRH, just prior to ovulation (Jo et al. 2002). PGR mRNA is also induced in these cells when cultured with a luteinizing dose of LH in vitro (Jo et al. 2002).

Unlike the very transient pattern of PGR expression observed in rodents and cattle, primates, including humans, display more prolonged expression of PGR in the ovary, probably due to the extended luteal phase in these species. In primates, PGR protein has been localized to granulosa cells in primordial and primary follicles, whereas the highest levels were detected in luteinizing granulosa cells of follicles that had responded to the LH surge and in theca cells of follicles at all stages (Hild-Petito et al. 1988). Corpora lutea (CL) from the early and mid-luteal phases expressed PGR protein, but late-luteal and regressing CLs did not (Hild-Petito et al. 1988; Duffy and Stouffer 1997). In humans, there are very few reports of PGR protein localization in the ovary. Consistent with other species, PGR is expressed in the dominant follicle at the time of the LH surge (Iwai et al. 1990) and similar to other primates, PGR expression is maintained in the active CL but not in the late CL (Revelli et al. 1996; Iwai et al. 1990; Suzuki et al. 1994). However, further work is required to clarify the expression patterns of PGR isoforms in the human ovary, particularly during the periovulatory period.

In the oviducts of mice, PGR is highly expressed in both ciliated and non-ciliated columnar epithelial cells that line the lumen (Teilmann et al. 2006; Ismail et al. 2002), as well as some expression in smooth muscle cells in the oviductal wall (Ismail et al. 2002). Both isoforms of PGR are expressed in the oviduct, although PGR-A predominates and PGR-B is restricted to luminal epithelial cells (Teilmann et al. 2006; Gava et al. 2004). In ciliated cells, PGR is specifically localized to the lower half of motile cilia, with adjacent secretory cells displaying PGR staining confined to the nuclei (Teilmann et al. 2006). Constitutive expression of PGR in the oviduct across the oestrous cycle has been suggested by a lacZ-reporter study in mice (Ismail et al. 2002) and has also been reported in human Fallopian tubes (Amso et al. 1994). However, another study has shown that PGR can be induced in the oviduct by an ovulatory dose of hCG in pubertal mice, particularly in ciliated cells (Teilmann et al. 2006), with immunohistochemical staining showing up-regulated expression of PGR protein at 6 h post-hCG that was sustained until 16 h post-hCG (post-ovulation). An earlier in vitro study of human Fallopian tube supports this, with the highest concentrations of PGR during the proliferative phase of the cycle (Pollow et al. 1981). In contrast, another study found that both isoforms of PGR peaked at 48 h post-eCG (equine chorionic gonadotropin) treatment and subsequent administration with hCG gradually decreased PGR protein in parallel with increasing levels of P4 (Shao et al. 2006).

In the bovine oviduct, strong PGR staining has been localized to ciliated and secretory cells of the luminal epithelium and smooth muscle cells, although unlike the predominance of staining to cilia as mentioned above, staining was restricted to nuclei (Valle et al. 2007; Ulbrich et al. 2003; Saruhan et al. 2011). Several studies have demonstrated cell-type and region-specific differences in staining intensity across the bovine reproductive cycle (Kenngott et al. 2011; Ulbrich et al. 2003; Valle et al. 2007), with studies generally reporting increased PGR expression in the epithelium during the follicular phase. However, a recent immunohistochemical study of PGR-B expression found no difference in the intensity of staining between the follicular and luteal phases or in the different regions of the oviduct (Saruhan et al. 2011). Therefore, whether PGR isoforms are indeed induced by the LH surge in the oviduct remains to be clarified and may indeed, as in the ovary, be species-specific.

PGR and Ovulation

Progesterone receptor antagonist studies in both humans and rodents, as well as knockout mouse studies, have demonstrated the critical role of PGR in ovulation (see Robker et al. 2009 for detailed review). PRKO mice have a profound and complete anovulatory phenotype, even when given exogenous gonadotropins, resulting in oocytes entrapped within follicles ((Robker et al. 2000; Lydon et al. 1995) and Fig. 1). This is despite apparently normal growth and development of follicles and oocytes throughout the preovulatory period (Fig. 1). Granulosa cells from preovulatory follicles of PRKO mice respond to the LH surge as demonstrated by the presence of cumulus expansion (Lydon et al. 1995) and undergo normal luteinization as demonstrated by the expression of the luteal marker P450 side-chain cleavage enzyme (Robker et al. 2000). Thus, PGR is required specifically for LH-induced follicular rupture leading to ovulation but not subsequent luteinization of granulosa cells to form CL. Interestingly, mice deficient in either PGR-A (PRAKO) or PGR-B (PRBKO) have different phenotypes, with only PRAKO mice showing severely reduced ovulation rates and implantation defects, suggesting an obligatory role for PGR-A in mouse female fertility (Mulac-Jericevic et al. 2000).

Figure 1.

 Morphology of the PRKO ovary during the periovulatory period. Representative sections are shown of a heterozygous (PR+/−) and knockout (PRKO) ovary at 8, 10, 12 and 14 h post-human chorionic gonadotropin (hCG). Scale bars = 200 μm. At 8 h post-hCG, there are numerous large preovulatory follicles in both genotypes. By 10 h post-hCG, cumulus cells are expanded in the cumulus oocyte complex (COC). By 12 h post-hCG, COCs are fully expanded, and thinning of the apical follicle wall is evident in large follicles. At 14 h post-hCG, the heterozygous ovary shows corpora lutea indicating ovulation has occurred; and the knockout ovary shows numerous entrapped, expanded, COCs within follicles. Bottom panels show the oviducts post-ovulation, with COCs evident in the oviduct of PR+/− (arrow) but not PRKO mice

From genomic approaches, PGR has been identified as an important regulator of gene transcription, specifically of genes found to be necessary for successful oocyte release from the preovulatory follicle (Kim et al. 2009a; Sriraman et al. 2010; Robker et al. 2009). Those currently identified include genes coding for proteases, growth factors, signal transduction components and transcription factors, but few have been demonstrated to play a direct role in ovulation. One of the PGR-regulated genes unequivocally linked to ovulatory success is the extracellular matrix protease, ADAMTS1. This gene is selectively induced by the LH surge in preovulatory follicles (Russell et al. 2003; Espey et al. 2000), is activated via PGR stimulation of promoter activity in vitro (Doyle et al. 2004) and is absent when P4 synthesis or PGR expression is inhibited or lost (Espey et al. 2000; Sriraman et al. 2008; Robker et al. 2000; Russell et al. 2003), and knockout mouse models display a severely reduced ovulation rate with entrapped oocytes reminiscent of the PRKO phenotype (Brown et al. 2010; Mittaz et al. 2004). The vasoconstrictive peptide, endothelin-2 (EDN2), also appears to be an important PGR-regulated gene essential for ovulation. It is specifically induced by LH in mural granulosa cells and is thought to be involved in smooth muscle contraction and follicular constriction, contributing to follicle rupture at the time of ovulation (Bridges et al. 2011, 2010). It is undetectable in ovaries from gonadotropin-stimulated PRKO mice, and treatment with specific endothelin receptor antagonists decreases ovulation rate and results in unruptured preovulatory follicles (Ko et al. 2006; Palanisamy et al. 2006). Similarly, endothelin-1 (EDN1) has been found to be specifically induced by PGR-A in granulosa cells in vitro in the absence of LH (Sriraman et al. 2010), as well as in vivo in response to hCG treatment in mice (Kawamura et al. 2008). It is also significantly reduced in hormonally primed PRKO mice (Sriraman et al. 2010). However, the mechanism by which PGR regulates endothelins remains to be determined as progesterone response elements (PREs) in these genes have not been identified. Epidermal growth factor-like (EGF-like) ligands amphiregulin (AREG) and epiregulin (EREG) are also dysregulated in PRKO granulosa cells (Shimada et al. 2006), and these ligands normally play key roles in triggering cumulus expansion and meiotic resumption in response to ovulatory LH (Park et al. 2004; Ashkenazi et al. 2005). Mice with mutations in EREG or epidermal growth factor receptor (EGFR) have severely reduced ovulation rates (Hsieh et al. 2007). Cumulus expansion, which is required for ovulation (reviewed in (Russell and Robker 2007)), is morphologically normal in PRKO mice (Fig. 1). However, PGR regulation of AREG, EREG and EDN2 may impact functional aspects of cumulus expansion that influence follicular rupture.

Acting in synergy with PGR, but also PGR-regulated, two key transcription factors, hypoxia inducible factors (HIFs) and peroxisome proliferator-activated receptor gamma (PPARG) are emerging as co-activators of a suite of PGR-regulated genes (Kim et al. 2008, 2009b). Administration of a specific antagonist (for HIFs) and conditional knockout mice (for PPARG) results in abundant unruptured follicles and severely reduced ovulation rates. These models also result in reduced expression of genes previously attributed to PGR regulation (e.g. ADAMTS1, EDN2, IL6 and cGKII). In contrast to other reproductive tissues in which direct PGR-regulated genes have been identified, the molecular mechanisms in the ovary whereby PGR regulates the transcription of its periovulatory gene cohort are not known. PGR-regulated genes in granulosa cells lack PGR binding response elements in their upstream promoters, and therefore unique transcriptional mechanisms are believed to play a role, either interacting directly with PGR or acting as transcriptional co-activators to regulate a distinct gene expression signature (see Robker et al. 2009, for review). Alternatively, by inducing the expression of additional transcription factors, such as HIFs and PPARG, PGR could trigger the ovulatory cascade of gene expression. Thus, through sequential cascades of genes initiated by PGR, biomechanical events including protease activation, cumulus expansion, smooth muscle contraction, vascular permeability and angiogenesis may all contribute to follicle rupture and oocyte release.

PGR and Oocyte Developmental Competence

Although the role for PGR in ovulation is clear, the possible influence of PGR on oocyte developmental competence, that is, the ability of the oocyte to produce a viable embryo following fertilization, does not appear to be resolved. The increase in P4 production by preovulatory follicles, concomitant with resumption of meiosis and maturation of the oocyte, might suggest a role for P4 and/or PGR in this process; however, the low expression of PGR in cumulus cells relative to granulosa cells may similarly indicate it is not involved in COC maturation or oocyte viability. In support of this, oocytes isolated from PRKO follicles can be successfully matured and fertilized in vitro and exhibit normal blastocyst development rates and produce pups following uterine transfer (Robker and Richards 2000). Further, in vitro application of steroid antagonists, including the PGR antagonists mifepristone (RU486) and Org 31710, prevented neither LH-triggered germinal vesicle breakdown (GVBD) of rat or mouse follicle-enclosed oocytes nor the spontaneous maturation of COCs (Motola et al. 2007). Similarly in vivo, two PGR antagonists (RU486 and ZK98734) did not impair pre-implantation development in mice (Vinijsanun and Martin 1990). However, other studies are indicative of a role for P4 in oocyte maturation and developmental competence. A recent study has demonstrated that oocytes from follicles isolated from PRKO mice do not mature in response to exogenous progestin in vitro, with only 20% undergoing GVBD, while those from heterozygous mice showed >80% GVBD (Deng et al. 2009). An early study also showed that treatment of mice with RU486 24 h after eCG resulted in a 50% decrease in the number of two-cell embryos that progressed to the blastocyst stage (Loutradis et al. 1991). Further, in vitro work demonstrated that culture of either mouse preovulatory follicles or isolated COCs with P4 promoted oocyte maturation, assessed as GVBD, but not cumulus expansion, and treatment with mifepristone inhibited maturation (Jamnongjit et al. 2005; Ning et al. 2008).

In the pig, unlike the mouse, PGR is abundantly expressed in cumulus cells in response to FSH and LH and treatment with RU486 significantly impairs cumulus expansion in vitro (Shimada et al. 2004a,b). Treatment with RU486 also blocks porcine oocyte progression to MII and blastocyst development (Shimada et al. 2004b).

In the bovine COC, PGR-A is present in both the cumulus cells and oocyte while PGR-B is induced in cumulus cells during oocyte maturation to MII (Aparicio et al. 2011). Interestingly, multiple non-genomic progesterone receptors were also identified in bovine oocytes and cumulus cells, and inhibition of P4 production by the cumulus cells using trilostane impaired cumulus expansion and reduced blastocyst development rates, an effect reversed by the addition of exogenous P4 (Aparicio et al. 2011). Treatment with RU486 during in vitro maturation (IVM) also impaired bovine cumulus expansion and reduced blastocyst development (Aparicio et al. 2011), indicating an important role for PGR in COC maturation and oocyte quality. In contrast, a previous study reported that treatment of COCs with P4 during oocyte IVM reduced the proportion of blastocyst-stage embryos developing, an effect partially reversed by the addition of RU486 (Silva and Knight 2000). Although these studies are seemingly contradictory with respect to the effects of P4, overall they may indicate a role for P4 and PGR in determining oocyte quality in this species.

The role of P4 and specifically PGR in the regulation of cumulus expansion in humans has not been adequately examined. In a single study, analysis of 135 cumulus cell populations collected from 44 IVF patients at the time of oocyte collection found no relationship between PGR expression and oocyte fertilization or cleavage rate (Hasegawa et al. 2005). However, low expression levels of PGR mRNA, regardless of follicular fluid P4 levels, were correlated with subsequent good embryo quality, defined as embryos with ≥7 blastomeres and ≤5% fragmentation (Hasegawa et al. 2005). In primates, in vitro culture of oocytes with progestin/P4 has been shown to improve blastocyst rates compared to vehicle-treated controls (Borman et al. 2004; Zheng et al. 2003).

Cumulatively, these studies indicate that a better understanding of the role of PGR in the peri-conception COC and its impact on oocyte developmental competence is needed as its regulatory effects may in fact be species-specific, given its varied expression profiles in preovulatory COCs.

PGR and Oviductal Transport of Oocytes and Embryos

While the function of PGR in the ovary, uterus and mammary gland has been well studied, its role and mode of action in the oviduct have not been definitively defined. Ovarian steroid hormones, including P4, have an impact on the oviduct by influencing the morphology and function of oviduct luminal epithelium, regulating muscular and nerve function and regulating the volume and composition of fluids in the lumen (see Hunter 2011 for review). All of these influence and optimize oviductal transport of the newly ovulated COC, as well as transport and nourish the early embryo, to maximize the chance for successful implantation in the uterus. The role of PGR in many of these processes is implied, but is often not explicitly known. Here, we review what is known about P4/PGR regulation of ciliary function, muscular contraction and luminal fluids in the oviduct.

Reports of LH-induced expression of PGR in ciliated cells of the oviduct luminal epithelium suggest a regulatory role for P4 on ciliary beat frequency (CBF), and potentially embryo transport. Cyclic changes in CBF are controlled by estrogen (E2) and P4 levels which fluctuate throughout the cycle (Nishimura et al. 2010), as does expression of their cognate receptors in oviductal epithelial cells (Amso et al. 1994; Teilmann et al. 2006; Pollow et al. 1981). These steroids have been shown to have opposing effects on oviduct transport of ova and embryos, with E2 accelerating and P4 decelerating movement (Nakahari et al. 2011; Orihuela and Croxatto 2001; Orihuela et al. 2003; Mahmood et al. 1998). Administration of mifepristone in vitro prevents the P4-induced reduction in CBF (Mahmood et al. 1998) and in vivo increases the transport of ova and embryos through the oviduct resulting in their premature arrival into the uterus (Fuentealba et al. 1987; Psychoyos and Prapas 1987). Molecular targets of PGR involved in CBF are not known, but might include prostaglandins (Hermoso et al. 2001; Verdugo et al. 1980) or angiotensin II (Saridogan et al. 1996) and/or their cognate receptors, which are known to be produced by the oviduct and can regulate CBF in vitro. Similarly, Ca2+-activated transient receptor potential ion channels are up-regulated in ciliated oviductal epithelial cells following hCG stimulation (Teilmann et al. 2005) and may be a mechanism by which P4 elicits its well-known rapid responses in ciliated cells. Again, however, genomic and non-genomic progesterone receptors may be involved. For example, progesterone membrane receptor component 1 (PGRMC1) has been localized to the luminal epithelia and muscle cells of the bovine oviduct, although unlike classical PGR, it remains at similar levels across the estrous cycle (Luciano et al. 2011). Also, the newly described membrane progesterone receptors beta and gamma (mPR-beta and mPR-gamma) have been found to be exclusively expressed in ciliated cells of the oviduct and to be hormonally regulated (Nutu et al. 2009). Several studies have suggested that P4 may be acting in the oviduct via these non-genomic pathways (Wessel et al. 2004; Luconi et al. 2004; Peluso 2006). For example, Wessel et al. (2004) showed that CBF was inhibited in bovine oviductal explants as soon as 15 min after treatment with P4, but pre-treatment with mifepristone did not affect this result in the short-term but nonetheless prevented the inhibitory influence of P4 after 24 h. The co-expression of classical PGR and membrane receptors in oviductal cells provides the possibility of a co-operative relationship in mediating cilia function.

Ab-ovarian waves of smooth muscle contraction in the oviductal wall are also believed to contribute to oviductal transport of the COC towards the ampulla and the embryo through the isthmus towards the uterus (Croxatto 2002; Hunter 2011). Changes to the myosalpinx or muscular layer occur across the cycle, with increasing muscular tone a feature of the follicular phase or preovulatory phase and relaxation typical in the luteal phase. These changes are coordinated by ovarian steroids, with E2 resulting in muscular contraction and high levels of P4 or progestagens promoting relaxation (Wanggren et al. 2006, 2008; Helm et al. 1982). Prostaglandin E2 and F2α (PGE2 and PGF2α) receptors are expressed in luminal epithelial cells, muscle wall and vessels in the human Fallopian tube (Wanggren et al. 2006), and a subset of these receptors (specifically PTGER1, PTGER2 and PTGFR) was down-regulated in these cells and tissues after treatment with RU486 (Wanggren et al. 2006). Muscular contractions were increased after treatment with PGE2 and PGF2α (Wanggren et al. 2008), and thus muscular contractility in the oviduct appears to be induced by prostaglandins and regulated by P4 and PGR. Endothelins (EDNs) have also been reported to play a role in both oviductal muscular contraction (by EDN1 and EDN2) as well as epithelial cell secretions (by EDN3) (see Bridges et al. 2011 for review). Both EDN1 and EDN3 are locally produced by epithelial cells in the oviduct (Sakamoto et al. 2001; Rosselli et al. 1994), and the endothelin receptor isoform EDNRA has been specifically localized to the muscle layer while EDNRB is localized to the luminal epithelial cells (Jeoung et al. 2010; Sakamoto et al. 2001). E2 but not P4 has been shown to stimulate production of EDN1 in vitro (Wijayagunawardane et al. 1999), but studies examining P4/PGR regulation of endothelin isoforms and their receptors in the oviduct are currently lacking. PGR in smooth muscle cells may also modulate the response by these cells to other myotropic agents, such as neurotransmitters produced distally (e.g. noradrenaline) or locally (e.g. neuropeptide Y, vasoactive intestinal polypeptide and substance P) (Croxatto 2002), but regulation of these factors or their receptors by PGR in the oviduct has not been examined.

The volume and composition of oviductal fluids change across the oestrous cycle. Fluid accumulation occurs during the follicular phase and the relative contributions of transudate from capillaries and active secretions by the luminal epithelium differs according to the stage of the cycle and the region of the duct (Hunter 2011). The regulation of oviductal fluid accumulation by ovarian steroids has been demonstrated in ovariectomized animals (McDonald and Bellve 1969), but the relative contributions of E2 and P4 and the role that PGR may play in this regulation has not been addressed. Also, although the composition of oviductal fluid has been examined in detail (Leese et al. 2008; Aviles et al. 2010) and secretory products are known to vary across the reproductive cycle, the specific roles that P4 and PGR play in regulating these secretions has not been adequately addressed.

A recent review (Aviles et al. 2010) compiled a comprehensive list of molecules expressed and/or secreted by the oviduct across several mammalian species. Many of these constituents, like the well-known oviduct-specific glycoproteins, are probably E2-dependent (Buhi et al. 2000); however, P4 may also plays a role, as many of these products are at high concentrations during the periovulatory period and during the first days of pregnancy. Very few studies have examined PGR regulation of these products in the oviduct. One study, examining the regulation of cytokine expression in the human Fallopian tube after administration of mifepristone 2 days after the ovulatory LH surge (Li et al. 2004), measured IL8, TNFα, TGFβ and LIF in the ampulla and isthmus regions using immunohistochemistry. Mifepristone had no effect on expression of TGFβ or LIF, but increased expression of TNFα in the epithelial cells of the isthmus and decreased expression of IL8 in the epithelium of the ampulla. However, this study had small sample sizes (n = 7 per group) and used a simple scoring system for staining intensity which is difficult to analyse statistically. Other studies have examined the actions of P4 on oviductal genes and products, but not the role of PGR per se. For example, exogenous P4 regulated complement component 3 (C3) mRNA and protein expression in oviducts of ovariectomized mice but not in human oviductal epithelial cells from intact women in vitro (Lee et al. 2009). The expression of C3 mRNA was the highest in oviductal cells of pregnant mice at day 2 of pregnancy (Lee et al. 2009). C3 is converted into the embryotrophic derivatives iC3b and C3b in the presence of embryos and oviductal cells (Tse et al. 2008). Similarly, both plasminogen activator inhibitor 1 (PAI1) (Kouba et al. 2000) and tissue inhibitor of metalloproteinase 1 (TIMP1) (Buhi et al. 1997) were shown to be stimulated in oviductal cells by exogenous P4 in ovariectomized gilts and were highest at day 2 of pregnancy. PAI1 is hypothesized to play a role in protecting the oocyte/embryo from enzymatic degradation while the role for TIMP1 is unknown. Thus, there is some evidence that P4 regulates production of oviductal secretory products; however, additional studies are needed, for instance in mouse models lacking PGR, to identify any regulatory roles that PGR may play in the expression/secretion and function of oviductal molecules in the luminal milieu during the earliest stages of embryogenesis.

Conclusion

The critical role that the ovarian steroid hormone P4 plays in modulating the function of the ovary and oviduct is indisputable. It is essential for release of the oocyte from the preovulatory ovarian follicle at ovulation, potentially plays a role in acquisition of oocyte developmental competence and controls the passage of the oocyte and embryo through the oviduct via its effects on ciliary beating, muscular contraction and oviductal fluid volume and composition. However, the specific role that its cognate intracellular receptor, PGR, plays in these processes, particularly in the oviduct, is still to be resolved. Given that PGR acts as a nuclear transcription factor, its effects are likely mediated via direct or indirect regulation of a specific suite of downstream target genes. There has been much progress in determining these downstream targets in the ovary; however, there is a large gap in knowledge with respect to PGR-regulated effectors in the oviduct, although prostaglandins and endothelins are emerging as important. Further examination of the molecular actions of PGR in both the ovary and oviduct is required to elucidate the potentially complex web of gene regulation occurring in these tissues and their essential roles in female reproduction.

Acknowledgements

Funding was provided by the National Health & Medical Research Council (NHMRC) to RLR and scholarships to LKA from NHMRC, Healthy Development Adelaide and The Robinson Institute.

Conflicts of interest

None of the authors have any conflicts of interest to declare.

Author contributions

LK Akison reviewed the literature, particularly with regard to the oviduct, wrote the initial draft of the manuscript and collected the samples for histology. RL Robker drafted the outline for the manuscript and contributed to and edited later drafts of the manuscript.

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