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Mothers and Babies Research Center, University of Newcastle and John Hunter Hospital (S.M., E.-C.C., J.T.F., R.S.), Newcastle, New South Wales 2310, Australia; and Singapore KK Women’s and Children’s Hospital (K.K., G.Y.), Singapore 229899
Address all correspondence and requests for reprints to: Dr. Sam Mesiano, Mothers and Babies Research Center, John Hunter Hospital, Locked Bag 1 HRMC, New South Wales 2310, Australia. E-mail: . smesiano{at}mail.newcastle.edu.au
Abstract
In human parturition, progesterone withdrawal and estrogen activation are not mediated by changes in progesterone and estrogen levels. Instead, these events could be facilitated by changes in the responsiveness of the myometrium to progesterone and estrogens via changes in PR and ER expression. We hypothesized that functional progesterone withdrawal occurs by increased expression of the type A PR (PR-A), which suppresses progesterone responsiveness, and that functional estrogen activation occurs by increased myometrial expression of ER
and/or ERß. To test this hypothesis we compared the abundance of mRNAs (assessed by quantitative RT-PCR) encoding PR-A, PR-B, ER, and ERß in nonlaboring (n = 12) and laboring (n = 12) term human myometrium. PR-A, PR-B, the PR-A/PR-B mRNA ratio, and ER mRNA were significantly increased in laboring myometrium, whereas ERß mRNA was low and unchanged. The PR-A/PR-B mRNA ratio correlated positively with ER mRNA levels in nonlaboring myometrium and with HOXA10 mRNA levels in laboring myometrium. Because progesterone inhibits ER and HOXA10 expression, these findings indicate that myometrial progesterone responsiveness is inversely related to the extent of expression of PR-A relative to PR-B. ER mRNA levels correlated positively with cyclooxygenase type 2 and oxytocin receptor mRNA levels in nonlaboring myometrium, indicating that the increase in ER expression is directly associated with the activation of contraction-associated genes and estrogen responsiveness. These data indicate that in the term human myometrium, responsiveness to progesterone is controlled by the expression of PR-A relative to PR-B and that a significant increase in this ratio underlies functional progesterone withdrawal. Our data also indicate that functional estrogen activation occurs by increased expression of ER and is linked to functional progesterone withdrawal. Interaction between the PR and ER systems in the human myometrium may be critical for the control of human parturition and the coordination of progesterone withdrawal and estrogen activation required for parturition.
PROGESTERONE AND estrogens play central roles in the maintenance of pregnancy and the initiation of parturition by modulating myometrial contractility and excitability. Progesterone supports pregnancy and prevents parturition by promoting myometrial quiescence. In the mid-1950s, Csapo (1) proposed that progesterone actively blocks labor and delivery and that parturition requires progesterone withdrawal. Indeed, in all mammals studied to date, including humans, parturition is induced by any intervention that prevents progesterone synthesis or action, and in most mammals the onset of labor is preceded by a rapid fall in maternal progesterone levels. In contrast, estrogens stimulate parturition by increasing the expression of genes that encode factors that augment myometrial contractility and excitability. In most species parturition is associated with increased estrogen levels. Thus, the process of parturition and in particular the transformation of the myometrium from a quiescent to a contractile state, requires progesterone withdrawal and estrogen activation, which in most mammals are achieved by changes in circulating progesterone (decrease) and estrogen (increase) levels (2, 3). However, in humans and higher primates the strategy for progesterone withdrawal and estrogen activation is not readily apparent, because maternal progesterone and estrogens levels are high for most of pregnancy and remain elevated during labor and delivery (4, 5). In the present study we examined the possibility that in human parturition progesterone withdrawal and estrogen activation are mediated by changes in the responsiveness of the myometrium to progesterone and estrogens.
Target tissue responsiveness to progesterone and estrogens is principally controlled by the amount and type of cognate receptors. The human PRs exist as two major subtypes, PR-A and PR-B, both encoded by a single gene independently regulated by separate promoters (6). PR-A is a truncated form of PR-B that lacks the first 164 N-terminal amino acids (7). In most human cells types and in the majority of promoter systems examined to date PR-B is the principal ligand-dependent transcriptional activator of progesterone-responsive genes, whereas PR-A is a ligand-activated repressor of the transcriptional activity mediated by PR-B (8, 9, 10). Thus, in vitro studies indicate that PR-A and PR-B comprise a dual system of target tissue-mediated control of progesterone action, whereby PR-B mediates, and PR-A suppresses, progesterone responsiveness. However, studies of PR knockout mice suggest that the roles of PR-A and PR-B in vivo may be more complex. Mice lacking both PRs (11) or just PR-A (12) are infertile, and only a subset of progesterone actions can be attributed to PR-B (12). In contrast, mice lacking only PR-B appear to be fertile and have a normal pregnancy (13), suggesting that in this species the full complement of progesterone’s reproductive actions is mediated through PR-A alone. Whether this pertains to the actions of PRs in human reproductive physiology remains unknown. The human ER also exists as two major subtypes, ER and ERß, derived from separate genes, each having different ligand binding affinities and tissue distributions (14). The selective actions of estrogens and various estrogen agonists and antagonists are thought to be due to differential expression of ER and ERß (14, 15). Based on this understanding we further hypothesized that transformation of the pregnant myometrium from a quiescent to a contractile state involves a decrease in its responsiveness to progesterone via increased expression of PR-A and an increase in its responsiveness to estrogen via increased expression of ER and/or ERß.
PR and ER binding and receptor immunoactivity have been determined in laboring and nonlaboring human myometrium (16, 17, 18, 19). In each of those studies myometrial ER activity was low and did not change with the onset of labor. In contrast, the activity of PR was higher than that of ER and increased further in association with the onset of labor (16, 18). Rezapour et al. (16) interpreted the labor-associated increase in myometrial PR to reflect increased progesterone responsiveness and proposed a role for progesterone in the transition of the myometrium to a contractile phenotype. The possibility that the increased PR activity was due to increased expression of PR-A and that this subtype actually reduces progesterone responsiveness was not considered. Recently, Pieber et al. (20), using immunoblot analysis to discriminate between PR-A and PR-B, reported that PR-A protein abundance increases markedly in the human myometrium in association with the onset of labor. Interestingly, they also found that overexpression of PR-A in primary cultures of human term myometrial cells decreases progesterone responsiveness, thus providing strong mechanistic evidence that PR-A suppresses myometrial progesterone responsiveness. Taken together, these findings support the idea that functional progesterone withdrawal is in part mediated by increased expression of PR-A in the myometrium. However, whether responsiveness of the human myometrium to progesterone actually decreases as part of the parturition cascade and as a result of increased expression of PR-A remains uncertain. Also, the roles of ER and ERß expression in functional estrogen activation are unclear. In the present study we addressed these issues by assessing whether the onset of labor is associated with concordant changes in myometrial expression of PR-A, PR-B, ER, and ERß. We also indirectly examined whether the extent of PR and ER expression in the pregnant human myometrium at term is associated with progesterone and estrogen responsiveness in situ by examining the coexpression of progesterone- and estrogen-responsive genes.
Materials and Methods
Tissue specimens
Biopsies (
0.5 cm3) of term human myometrium were collected from cesarean section deliveries before the onset of labor (n = 12) and during active labor (n = 12). Tissue was removed from the upper margin of the incision made in the lower uterine segment. Myometrium was dissected from decidua and connective tissue, snap-frozen in liquid nitrogen, and stored at -80 C. Mean maternal age (31.4 ± 4 yr) and gestational age (38.2 ± 0.9 wk) did not differ significantly between the nonlaboring and laboring women. The laboring tissues were obtained from deliveries that required cesarean section for reasons independent of uterine contractions, e.g. breech presentations, cephalo-pelvic disproportion, and fetal distress. The nonlaboring samples were from breech presentations and elective cesarean section deliveries, and no cervical changes were evident at the time of surgery. All specimens were obtained after patient consent, and the study was approved by the human research ethics committees of Singapore KK Women’s and Children’s Hospital, John Hunter Hospital and University of Newcastle.
Quantitative RT-PCR
Total RNA was extracted and purified from tissue specimens using the acid-phenol method (21), treated with deoxyribonuclease to remove any contaminating genomic DNA, and quantified, and 1.5 µg reverse transcribed with random primers using Superscript II reverse transcriptase (Life Technologies, Inc., Melbourne, Australia). Primer sets for the human PRs, ER, and ERß; the contraction-associated genes cyclooxygenase type 2 (COX-2) and the oxytocin receptor (OTr); the homeobox gene HOXA10; and the constitutively expressed reference gene 18S rRNA were designed using Primer Express software (PE Applied Biosystems, Foster City, CA) based on published sequences (Table 1
). All primer sets produced amplicons of the expected size and sequence, and all except those for HOXA10 flanked intron/exon junctions. Two primer sets were used to measure PR mRNA abundance. One primer set was directed at the sequence specific for the PR-B (i.e. within the 164 amino acids at the N-terminus) and therefore detected only mRNA transcripts encoding PR-B. The other primer set was directed to the section of the PR common to PR-A and PR-B and therefore detected total PR mRNA. The amount of mRNA encoding PR-A was calculated by subtracting the relative abundance of PR-B mRNA from that of total PR mRNA. This approach was validated using known amounts of PR-A and PR-B cDNAs. Assays were validated for all primer sets by confirming that single amplicons of appropriate size and sequence were generated according to predictions. PCR was performed in the presence of SYBR Green (PE Applied Biosystems), and amplicon yield was monitored during cycling in an ABI PRISM 7700 Sequence Detector (PE Applied Biosystems) that continually measures fluorescence caused by the binding of the dye to double-stranded DNA. The cycling conditions were 50 C for 2 min, 95 C for 10 min, and then 40 cycles of 95 C for 15 sec, 60 C for 1 min. The cycle at which the fluorescence reached a preset threshold (cycle threshold) was used for quantitative analyses. The cycle threshold in each assay was set at a level where the exponential increase in amplicon abundance was approximately parallel between all samples. All mRNA abundance data were expressed relative to the abundance of the constitutively expressed 18S rRNA.
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Differences between mRNA levels in nonlaboring and laboring groups were assessed by t and Mann-Whitney tests. The relationship between parameters was tested by linear regression analysis. Correlation between parameters was tested nonparametrically using the Spearman rank correlation (rs) method. Differences were considered statistically significant at P less than 0.05.
Results
In laboring myometrium, the mean relative abundance of mRNAs encoding PR-A, PR-B, and ER was significantly increased compared with levels in nonlaboring tissue, whereas ERß mRNA was low and not different between groups (Fig. 1). The abundance of PR-A mRNA was greater than that of PR-B mRNA in both labor states, and the magnitude of its increase in the laboring specimens exceeded that of PR-B mRNA. This resulted in a significant 2- to 3-fold increase in the PR-A/PR-B mRNA ratio in laboring compared with nonlaboring specimens (Fig. 1).
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(22, 23, 24) and HOXA10 (25), we used the levels of mRNAs encoding these factors as surrogate markers of progesterone responsiveness. Thus, we assessed whether PR subtype expression influences progesterone responsiveness by determining the relationship between levels of mRNAs encoding PR-A, PR-B, the PR-A/PR-B mRNA ratio, and levels of mRNAs encoding ER and HOXA10 in the two experimental groups (Table 2). ER mRNA correlated with PR-A mRNA (r2 = 0.4798; rs = 0.6713; P < 0.005) only in nonlaboring specimens and did not correlate with PR-B mRNA in either group. A strong and highly significant positive correlation was detected between ER mRNA and the PR-A/PR-B mRNA ratio (r2 = 0.8983; rs = 0.9320; P < 0.001) in nonlaboring myometrium (Fig. 2). Abundance of mRNA encoding HOXA10 was very low in nonlaboring myometrium and increased 7-fold in laboring tissue (Fig. 3A). HOXA10 mRNA correlated positively with the PR-A mRNA (r2 = 0.4813; rs = 0.7483; P < 0.001) and the PR-A/PR-B mRNA ratio (r2 = 0.8159; rs = 0.8601; P < 0.001) only in laboring myometrium (Table 2 and Fig. 3B) and did not correlate with PR-B in either group.
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expression are associated with changes in myometrial estrogen responsiveness and its transformation from a quiescent to a contractile state, we examined the relationship between levels of ER mRNA with COX-2 and OTr mRNAs. COX-2 and OTr are contraction-associated genes that are activated in the myometrium at parturition. OTr is known to be up-regulated by estrogen (26, 27, 28, 29). Levels of mRNAs encoding COX-2 and OTr increased 115- and 6-fold, respectively, in laboring compared with nonlaboring specimens (Fig. 4A). ER mRNA levels correlated positively with COX-2 (r2 = 0.8543; rs = 0.7483; P < 0.001) and OTr (r2 = 0.3573; rs = 0.6643; P < 0.005) mRNAs only in nonlaboring specimens (Fig. 4B).
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Our data show that in term human myometrium, the onset of labor is associated with increased expression of PR-A (18- to 19-fold), PR-B (4- to 5-fold), and ER (6- to 7-fold), whereas ERß expression is very low and is not affected by labor status. The increase in PR-A mRNA in laboring myometrium confirms a similar increase in PR-A protein abundance (assessed by immunoblot analysis) reported by Pieber et al. (20) and in total PR immunoactivity reported by Rezapour et al. (16) in laboring compared with nonlaboring term human myometrium. These findings indicate that PR mRNA levels reflect PR proteins levels. However, we cannot be certain of this, as biopsies were not large enough to allow parallel protein analyses. Clearly, steady state mRNA abundance may not be directly indicative of functional protein in all cases, because posttranslational modifications, such as phosphorylation, and interaction with other coactivators/repressors could modulate a protein’s function without affecting its levels. Therefore, we consider that the mRNA data for each of the genes examined provide a direct measurement of gene activity and are only indicative of the potential level of functional protein.
The labor-associated increase in PR-A gene activity was greater than that of PR-B and resulted in a significant increase in the PR-A/PR-B mRNA ratio. This ratio is important because the amount of PR-A relative to PR-B is thought to determine the extent of progesterone responsiveness, because PR-A blocks progesterone action by inhibiting the transcriptional activity of PR-B (9). This has been demonstrated in primary cultures of term human myometrial cells in which overexpression of PR-A relative to PR-B repressed progesterone activation of a cotransfected reporter cDNA driven by a progesterone response element (20). Thus, in cultured human myometrial cells derived from term pregnancies, PR-A suppresses progesterone action when its level exceeds that of PR-B. However, whether this mechanism underlies desensitization of the pregnant human myometrium to progesterone in vivo remains uncertain. To address this issue, we indirectly assessed the level of myometrial progesterone responsiveness in vivo by measuring the extent of ER and HOXA10 expression and their relationship with PR expression. We chose ER because it is generally accepted that uterine ER expression is inhibited by progesterone (22, 23, 24). The homeobox gene, HOXA10, was examined because its expression in the nonpregnant human myometrium is also inhibited by progesterone (25). Although HOXA10 is thought to be involved in steroid hormone-induced myometrial growth and differentiation, its role in myometrial function during human pregnancy and parturition remains uncertain. We found that mean levels of ER and HOXA10 mRNAs were 7- and 6-fold greater, respectively, in laboring compared with nonlaboring myometrium. These data indicate that progesterone responsiveness of the myometrium decreases in the laboring tissue in vivo because progesterone inhibits the expression of these genes, and the level of myometrial exposure to circulating progesterone does not decrease at term. Interestingly, ER and HOXA10 mRNAs correlated positively with the PR-A/PR-B mRNA ratio. Thus, as the amount of PR-A mRNA increases relative to PR-B mRNA, so too does ER and HOXA10 mRNA levels. This positive association supports the concept that progesterone responsiveness is inversely related to the PR-A/PR-B gene expression ratio. Interestingly, PR-A/PR-B correlated with ER mRNA only in nonlaboring myometrium, whereas it correlated with HOXA10 mRNA only in laboring myometrium. A possible explanation for this is that a higher PR-A/PR-B expression ratio is required to block progesterone suppression of HOXA10 than is required to block progesterone suppression of ER. This difference may reflect variation in the sensitivity of target genes to progesterone inhibition and determine the sequence of genes modulated as the myometrial PR-A/PR-B expression ratio increases during parturition. That is, ER could be an early gene that responds to small increases in the PR-A/PR-B expression ratio, whereas HOXA10 is a late gene requiring larger increases in the PR-A/PR-B expression ratio. A likely explanation for the lack of correlation between ER and PR-A/PR-B in the laboring myometrium is that at this late stage of the parturition process one or both of the parameters becomes maximally expressed, and therefore, any positive correlation between the two is lost. The possibility that changes in the expression of ER and HOXA10 induce changes in PR expression (i.e. the reverse interpretation of the correlation) is unlikely because ER and HOXA10 mRNAs correlated only weakly with PR-A and not with PR-B mRNAs. Rather, our data indicate that the expression of ER and HOXA10 was associated with, and possibly influenced by, the PR-A/PR-B expression ratio. Taken together, these findings provide important indirect evidence that responsiveness of the term pregnant human myometrium to progesterone decreases in association with the onset of labor and is determined at least in part by the PR-A/PR-B expression ratio. Furthermore, we demonstrate a link between the PR-A/PR-B expression ratio and ER gene expression, which may have important implications for the control of myometrial responsiveness to estrogens.
Estrogen activation is thought to transform the myometrium to a contractile phenotype by modulating the expression of a specific cohort of genes encoding contraction-associated proteins (3). To indirectly assess the level of estrogen responsiveness, we examined the expression of the contraction-associated protein genes, COX-2, which encodes the inducible form of cyclooxygenase thought to be responsible for the increase in PG production by the gestational tissues at parturition, and OTr, which encodes the OTr whose increased expression augments myometrial responsiveness to oxytocin, a potent uterotonin. As expected, the abundance of mRNAs encoding these proteins increased significantly in laboring myometrium, indicating that estrogen responsiveness increased in association with labor onset. We also found that ER mRNA correlated positively with COX-2 and OTr mRNAs in nonlaboring myometrium. The lack of correlation in laboring myometrium could be due to ER and/or COX-2 and OTr being maximally expressed at this stage of parturition. The positive association between ER and OTr indicates that estrogen responsiveness is related to ER levels, because OTr expression is known to be up-regulated by estrogen (26, 27, 28, 29). The strong positive association between ER and COX-2 mRNA levels suggests that COX-2 gene expression also is influenced by estrogen responsiveness. However, COX-2 is not known to be up-regulated by estrogen in the pregnant human myometrium, and therefore, the mechanistic basis for the association remains unclear. Slater et al. (30) found that COX-2 expression by the human myometrium increases at term before the onset of labor. Our present findings confirm this and show that prelabor levels of COX-2 gene expression are closely associated with the ER gene expression. The strong association between ER gene expression and activity of the COX-2 and OTr genes in nonlaboring myometrium suggests that the process of human parturition is initiated within myometrial cells well before the onset of active labor. Clearly, it is impossible to know when labor would have occurred in the nonlaboring patients; however, we speculate that nonlaboring women with higher myometrial expression of ER, COX-2, and OTr were closer to labor onset than those with lower levels.
For most of human pregnancy the myometrium is exposed to very high levels of estrogens (5). However, for most of that time the myometrium is refractory to estrogenic actions. This insensitivity is probably due to progesterone suppression of ER expression. In the pregnant rhesus monkey the progesterone antagonist RU486 not only induces parturition, but also increases myometrial ER expression, suggesting that progesterone decreases myometrial ER expression during pregnancy (22). Our present finding that ER expression positively correlates with the PR-A/PR-B expression ratio supports this idea. This interaction between the ER and PR systems in the myometrial cell may have important implications for estrogen and progesterone control of the pregnant myometrium. Numerous studies in various species have shown that progesterone and estrogen actions on the uterus are influenced by feedback interactions between the PR and ER systems, whereby progesterone decreases estrogen responsiveness by decreasing ER expression, and estrogen increases progesterone responsiveness by increasing PR expression (23, 24). In the context of endometrial function this interaction may ensure an optimum physiological outcome (i.e. an intrauterine environment conducive for implantation) during each menstrual cycle despite variability in the circulating estrogen and progesterone levels between cycles. As in the menstrual cycle, this association may serve to control progesterone and estrogen actions during pregnancy. Indeed, during human pregnancy the myometrium is exposed to elevated and highly variable levels of progesterone and estrogens, yet outcome is usually consistent, i.e. delivery at term. Our data and those in the rhesus monkey (22) suggest that progesterone withdrawal induces estrogen activation. Thus, the interaction between the ER and PR systems may be a central mechanism controlling myometrial function during pregnancy and at parturition. We speculate (Fig. 5) that for most of human pregnancy, progesterone inhibits myometrial ER expression and therefore desensitizes this tissue to high levels of circulating estrogens. At term, myometrial progesterone responsiveness decreases due to increased expression of PR-A relative to PR-B. This causes a coordinated increase in ER expression, as demonstrated by the strong positive association between PR-A/PR-B and ER expression. Eventually progesterone responsiveness is suppressed to a level that results in sufficient ER expression to increase myometrial responsiveness to circulating estrogens, i.e. estrogen activation which increase the expression of contraction-associated genes. Induction of estrogen activation by progesterone withdrawal would explain why human parturition is induced by artificial progesterone withdrawal with antagonists such as RU486, but is not affected by increased estrogen production. In conclusion, our data indicate that in human parturition functional progesterone withdrawal is mediated by increased myometrial expression of PR-A, and functional estrogen activation is mediated by increased expression of ER. Furthermore, we provide indirect evidence that interaction between the myometrial PR and ER systems prevents estrogen actions during most of pregnancy and coordinates progesterone withdrawal with estrogen activation at parturition. Induction of PR-A expression in human myometrial cells may be a pivotal event in the hormonal regulation of human parturition.
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Acknowledgments
We thank Mr. Aaron Pezely for technical assistance.
Footnotes
This work was supported by the National Health and Medical Research Council of Australia and the Hunter Medical Research Institute.
Abbreviations: COX-2, Cyclooxygenase type 2; OTr, oxytocin receptor; PR-A, PR type A; PR-B, PR type B.
Received December 14, 2001.
Accepted March 6, 2002.
References
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P. M. Sheehan, G. E. Rice, E. K. Moses, and S. P. Brennecke 5{beta}-Dihydroprogesterone and steroid 5{beta}-reductase decrease in association with human parturition at term Mol. Hum. Reprod., July 1, 2005; 11(7): 495 - 501. [Abstract] [Full Text] [PDF]
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E. Hirsch and H. Wang The Molecular Pathophysiology of Bacterially Induced Preterm Labor: Insights From the Murine Model Reproductive Sciences, April 1, 2005; 12(3): 145 - 155. [Abstract] [PDF]
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S. Goldman, A. Weiss, I. Almalah, and E. Shalev Progesterone receptor expression in human decidua and fetal membranes before and after contractions: possible mechanism for functional progesterone withdrawal Mol. Hum. Reprod., April 1, 2005; 11(4): 269 - 277. [Abstract] [Full Text] [PDF]
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J. C. Havelock, P. Keller, N. Muleba, B. A. Mayhew, B. M. Casey, W. E. Rainey, and R. A. Word Human Myometrial Gene Expression Before and During Parturition Biol Reprod, March 1, 2005; 72(3): 707 - 719. [Abstract] |
