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Progesterone receptors in the human uterus and their possible role in parturition
Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 397–400
Progesterone receptors in the human uterus and their possible role in parturition Joseph H.H. Thijssen ∗ Laboratory of Endocrinology, University Medical Centre Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands
Abstract An overview is given on the role of progesterone in parturition in the human. Progesterone withdrawal is considered to be a major event for the beginning of parturition. However, in the human, no evidence exists in favour of a decline in placental progesterone production prior to labour. Progesterone actions are mediated by two functionally different but structurally highly related intranuclear proteins, progesterone receptor (PR) A and PRB. In the human, functional progesterone withdrawal is thought to play a role. This may be mediated by a change in the expression of the two isoforms of the PR, with an increase in the PRA:PRB ratio, and this is accompanied by an increase in the expression of the estrogen receptor. These mechanisms are considered to be critical for the endocrine control of parturition. © 2005 Elsevier Ltd. All rights reserved. Keywords: Progesterone receptor A (PRA); Progesterone receptor B (PRB); Labour; Uterus; Actions of progesterone
1. Introduction Progesterone is a very important hormone in the regulation of female reproduction. Several of the major actions of progesterone take place in the uterus: in particular, preparation of the endometrium for implantation after ovulation and fertilisation of an oocyte, and the maintenance of a subsequent pregnancy by promotion of uterine growth and suppression of myometrial contractility [1]. The actions of progesterone in the uterus are thought to be mediated through binding to its receptor, an intranuclear protein known as the progesterone receptor (PR) that can specifically bind progesterone and other progestins. Binding of the steroid to this receptor leads to a sequence of events including conformational changes in the protein and finally results in binding of the steroid-receptor complex to DNA, causing subsequent modulation of gene expression followed by protein synthesis. These processes take time; increases in protein synthesis can be observed a few hours after first binding of the steroid to its receptor. This PR was initially characterised in mammalian uterus [2,3], but was soon demonstrated in the human uterus as well [4]. Later it was shown that the PR exists in two different ∗
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forms [5], PRA and PRB, which both bind progesterone with identical affinity. The two PR proteins in the human are encoded by a single gene under the control of two distinct promoters, each of which gives rise to a distinct mRNA species encoding for either PRA or PRB [6,7]. In addition to the biological effects based on this wellknown genomic pathway, there is ample evidence for a second mechanistic pathway that is not operating via genomic interactions. These so-called nongenomic actions [8] require, in general, a short time frame in which to occur. Evidence has accumulated that rapid effects of progesterone on spermatozoa, hepatocytes and on some specific brain areas are not mediated by PR but by binding sites on or in the membranes of these cells. Furthermore, several progesterone metabolites, which are unable to bind to the PR, are capable of inducing biological effects mediated by other receptors located in the membranes of cells [8]. In the human uterus, the major actions of progesterone are thought to be mediated mainly by so-called “classic” receptors.
2. Progesterone receptors There is some evidence that the two forms of PR are functionally different and that the balance between PRA and PRB may make it possible to affect diverse physiological targets
398
J.H.H. Thijssen / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 397–400
[9]. However, much of this evidence is conflicting and modelspecific, and the true functions of the differences between the receptor forms in normal tissues are yet to be fully understood. Structurally, the two PR forms are identical except that PRA lacks the last 164 amino acids found at the N-terminal end of PRB. This region, which is therefore unique to PRB, contains a third transcription activation factor (AF3), in addition to the two other activation factors, AF1 and AF2, that are common to both PRA and PRB [10]. The PR is a member of a large family of ligandactivated nuclear transcription regulators, which include specific receptors for several other steroid hormones, but also for retinoids, thyroid hormone, the active Vitamin D metabolite and a number of as yet unknown ligands. Like all of these receptors, the PR is made up of a central DNA binding domain, a steroid-specific ligand binding domain and multiple activation and inhibiting function elements. Binding of progesterone to the PR causes conformational change and a dimerisation, resulting in association of the progestincomplexed PR dimer with specific coactivators [11] and general transcription factors. The activated complex of proteins binds to so-called progesterone responsive elements (PREs) in the DNA of promoters of target genes, resulting in modulation of the transcription of those genes [12]. In a number of experiments, all of which were based on co-transfection of a variety of cell lines with PRA and PRB constructs, differences have been observed in the transcriptional activities of PRA and PRB. In all cell types, PRB exhibited hormone-dependent transactivation irrespective of the complexity of the response elements. The activity of PRA, however, appeared to be cell- and reporter-specific; its transactivation activity varied from very similar to PRB to almost inactive and even to activity as a transdominant inhibitor of PRB activity [9]. Moreover, PRA was able to influence the transcriptional activity of other nuclear factors such as glucocorticoid, mineralocorticoid, androgen and estrogen receptors [13–16]. Thus the ability of PRA to act as a transdominant repressor is highly model-specific and there is considerable variability in this ability according to the different reports. The basic mechanisms by which PRA and PRB can exert such apparently different transcriptional activities in various cell and promoter systems remain largely unknown [9]. The unique AF3 in PRB may confer a difference in activities between the two PRs for coregulators. Experimental evidence suggests that coactivators may bind differently to the two PRs or that each isoform of the PR binds to different subgroups of coactivators [17]. Given that the PR requires interactions with multiple transcriptional factors in order to affect transcription, it is possible that existing variability in tissue-specific expression of the components of this multiprotein complex may result in different PRA and PRB activities [18]. Differential cofactor requirements between gene promoters may lead to differences in the transcriptional efficacy of the two PRs on the same promoter [12]. If the two isoforms are transcriptionally distinct, it also can be expected that changes in the relative amounts of PRA and
PRB in a cell would result in altered gene expression patterns. However, when the relative expression of PRA and PRB was varied in wild-type T47D cells, which already express both isoforms, the impact on transcription was not dramatic unless PRA vastly exceeded PRB [19]. Furthermore, no evidence was obtained of dominant transcriptional inhibition of PRA. These data suggest that co-expression of both isoforms at similar levels is associated with appropriate transcriptional responses to progestins and that changes in PRA and PRB levels must be quite dramatic before physiological changes in progestin effects can be observed. The view that PRB is the active PR, whereas PRA is either inactive or active as an inhibitor of PRB, is largely based on transfection experiments in cell lines that are not progestin targets. There is little evidence in vivo that PRA is a dominant inhibitor of PRB. Data from PRA or PRB gene knockout animals show that PRB knockout mice, which only have PRA, do not have impaired biological responses of the uterus to progesterone [20]. This, plus other evidence, suggests that the two isoforms either work co-operatively to mediate progesterone action or that each isoform has distinct physiological roles that are probably cell- and promoter-specific [9]. A combination of cooperative action and distinct display is probably the best explanation for the complex and divergent pathways of progesterone in physiology.
3. Progesterone receptors in the human uterus Estrogens stimulate the number of PRs and progesterone itself decreases the expression of its receptor in the endometrium and the myometrium. During the follicular phase of the menstrual cycle, PR levels in the uterus increase and reach their highest around ovulation; during the second half of the cycle, as serum progesterone levels increase, total PR levels decrease [21]. Such a decrease can be brought on prematurely by treatment with progestins. It has been demonstrated that the PRs are present in the nuclei of epithelial and stromal cells of the endometrium and in the myometrial smooth muscle cells. In general, PRA and PRB are co-expressed in the same target cells and their relative expression is close to unity [22]. In contrast, most endometrial cancers express mainly one PR isoform and isoform predominance is associated with higher histological grades [23]. There is evidence for a discrete subnuclear location of nuclear receptors, the significance of which is as yet unknown. According to current knowledge, the nucleus of a cell is a highly organized structure containing numerous specialized subnuclear structures and many nuclear components localized in discrete domains. In a recently published study [24], the authors examined PRA and PRB distribution within the nucleus in vivo in normal endometrium during the menstrual cycle. PRs were distributed evenly within the nucleus but were also found localized in discrete subnuclear foci. In the proliferative phase, an even PR distribution was predominant and both PR-isoforms were co-located and distributed
J.H.H. Thijssen / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 397–400
evenly. In the secretory phase, there was a marked increase in the proportion of nuclei containing PRs distributed into discrete foci and PRB was the predominant isoform in these nuclear foci. There was an inverse relationship between even and focal distribution during the menstrual cycle, suggesting that hormonal fluctuations were involved in the movement of PRs into focal nuclear locations. In the normal endometrium, nuclear foci coincide with high progesterone levels. It was concluded that nuclear distribution might be an important component of gene regulation in target tissues [24]. No regional variations in PR distribution have been found in the endometrium or myometrium [25] during the menstrual cycle. However, a high intra-epithelial expression of PRs has been found in the transformation zone of the uterine cervix [26] when compared with the ectocervix. The PRs at this location are thought to be involved in processes at the end of pregnancy.
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uterus affected differently? Do the reported changes precede or follow the other factors currently thought to play a role in the onset of labour in primates? How different to the levels of progesterone are the available PRs at the time that the balance of steroidal control of pregnancy is turning from progesterone to estrogen? A number of mechanisms have been suggested to account for the functional withdrawal of progesterone. Cervical ripening is related to significant local hormonal changes [38]. In addition to changes in PR isoforms, the regulation of PR responsive genes through nuclear factor kappaB promoter sites and the non-genomic effects of progesterone have been suggested [39,40]. Furthermore, the possible cross talk between steroid hormone receptors and other intracellular signalling pathways offers many new ways for regulation in hormonally responsive tissues [41].
5. Conclusion 4. Progesterone receptors and 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. Parturition is initiated by the fetal-placental unit and involves a cascade of endocrinological and physiological events that ideally culminate in the birth of healthy offspring [27]. Almost 50 years ago, Csapo [28] had already proposed that progesterone actively blocks labour and that parturition requires progesterone withdrawal. The foundations of this hypothesis were the findings in animals that progesterone levels decreased before the onset of normal parturition and that progesterone administration delayed the onset of labour [29]. In the rat, experimental evidence supports this hypothesis [30] but proof that it is relevant in primates has been more elusive [31] as, in these species, progesterone synthesis by the placenta does not decrease before parturition. However, more recently, evidence has been found in humans [32,33] and rhesus macaques [34] that, prior to parturition, there is a shift in the expression of PR from PRB to PRA. These findings have been interpreted as resulting in a functional withdrawal of progesterone and its effects [31,35]. In addition to changes in the relative distribution of PRA and PRB, an increase in estrogen receptor ␣ has been described during the early phase of first stage labour, around cervical dilatation at term [36]. Furthermore, a decline in PR coactivator expression and histone acetylation has been documented in the uterus near term and this also may impair PR function, thus causing a functional progesterone withdrawal [37]. However, considerable additional evidence is required before the findings fulfil the promise of Csapo’s hypothesis in explaining the onset of parturition in primates. Many questions remain [31] such as: Why do these changes in PR expression occur? Why are the different compartments of the
Advances in our understanding of the molecular basis for PR-mediated control of progesterone responsiveness has led to the hypothesis that functional progesterone withdrawal also plays a role in human parturition. The functional withdrawal can be mediated by specific changes in myometrial expression of the isoforms of PR, in their function, or both [42]. Functional progesterone withdrawal is possibly mediated by an increase in the myometrial PRA:PRB expression ratio and/or possibly by modulation of coactivator and corepressor proteins. Functional progesterone withdrawal appears to induce functional estrogen activation by effecting the expression of estrogen receptor ␣. The link between functional progesterone withdrawal and functional estrogen activation may be a critical mechanism for the endocrine control of human parturition.
References [1] J.D. Graham, C.L. Clarke, Physiological action of progesterone in target tissues, Endocr. Rev. 18 (1997) 502–519. [2] E. Milgrom, E.E. Baulieu, Progesterone in uterus and plasma. I. Binding in rat uterus 105,000 g supernatant, Endocrinology 87 (1970) 276–286. [3] E. Milgrom, M. Atger, E.E. Baulieu, Progesterone in uterus and plasma. IV. Progesterone receptor(s) in guinea pig uterus, Steroids 16 (1970) 741–754. [4] B.R. Rao, W.G. Wiest, W.M. Allen, Progesterone “receptor” in human endometrium, Endocrinology 95 (1974) 1275–1281. [5] B.A. Lessey, P.S. Alexander, K.B. Horwitz, The subunit structure of human breast cancer progesterone receptors: characterization by chromatography and photoaffinity labelling, Endocrinology 112 (1983) 1267–1274. [6] P. Kastner, A. Krust, B. Turcotte, U. Stropp, L. Tora, H. Gronemeyer, P. Chambon, Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B, EMBO J. 9 (1990) 1603–1614. [7] P.H. Giangrande, D.P. McDonnell, The A and B isoform of the human progesterone receptor: two functionally different transcription
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[25] M.P. Snijders, A.F. de Goeij, M.J. Debets-Te Baerts, M.J. Rousch, J. Koudstaal, F.T. Bosman, Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause, J. Reprod. Fertil. 94 (1992) 363–371. [26] F. Remoue, N. Jacobs, V. Miot, J. Boniver, P. Delvenne, High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix, Am. J. Obstet. Gynecol. 189 (2003) 1660–1665. [27] F. Bazer, The endocrinology and physiology of parturition: understanding the process through mining genome databases, Endocrinology 144 (2003) 2253. [28] A.I. Csapo, Progesterone block, Am. J. Anat. 98 (1956) 273–291. [29] A.I. Csapo, The “see-saw” theory of parturition, in: M. O’Connor, J. Knight (Eds.), The Fetus and Birth, Elsevier, New York, 1977, pp. 159–210. [30] Y. Saito, H. Sakamoto, N.J. MacLusky, F. Naftolin, Gap junctions and myometrial steroid hormone receptors in pregnant and non-pregnant rats: a possible cellular basis for the progesterone withdrawal hypothesis, Am. J. Obstet. Gynecol. 151 (1985) 805–812. [31] F. Naftolin, Csapo redux, but more veils remain, J. Soc. Gynecol. Investig. 9 (2002) 117. [32] S. Mesiano, C. Eng-Cheng, J.A. Fitter, K. Kwek, G. Yeo, R. Smith, Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium, J. Clin. Endocrinol. Metab. 87 (2002) 2924–2930. [33] Y. Stjernholm-Vladic, H. Wang, D. Stygar, G. Ekman, L. Sahlin, Differential regulation of the progesterone receptor A and B in the human uterine cervix at parturition, Gynecol. Endocrinol. 18 (2004) 41–46. [34] G.J. Haluska, B.S. Wells, J.J. Hirst, R.M. Brenner, D.W. Sadowsky, M.J. Novy, Progesterone receptor localization and isoforms in myometrium, decidua and fetal membranes from rhesus macaques: evidence for functional progesterone withdrawal at parturition, J. Soc. Gynecol. Invest. 9 (2002) 125–136. [35] H.A. Rodriguez, I. Kass, J. Varayoud, J.G. Ramos, H.H. Ortega, M. Durando, M. Munoz-De-Toro, E.H. Luque, Collagen remodelling in the guinea-pig uterine cervix at term is associated with a decrease in progesterone receptor expression, Mol. Hum. Reprod. 9 (2003) 807–813. [36] M. Winkler, B. Kemp, I. Classen-Linke, D.C. Fischer, S. Zlatinsi, J. Neulen, H.M. Beier, W. Rath, Estrogen receptor ␣ and progesterone receptor A and B concentration and localization in the lower uterine segment in term parturition, J. Soc. Gynecol. Invest. 9 (2002) 226–232. [37] J.C. Condon, P. Jeyasuria, J.M. Faust, J.W. Wilson, C.R. Mendelson, A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition, Proc. Nat. Acad. Sci. U.S.A. 100 (2003) 9518–9523. [38] G. Ekman-Ordeberg, Y. Stjernholm, H. Wang, D. Stygar, L. Sahlin, Endocrine regulation of cervical ripening in humans—potential roles for gonadal steroids and insuline-like growth factor-I, Steroids 68 (2003) 837–847. [39] S. Astle, D.M. Slater, S. Thornton, The involvement of progesterone in the onset of human labour, Eur. J. Obstet. Gynecol. Reprod. Biol. 108 (2003) 177–181. [40] C.A. Lange, Minireview. Making sense of cross-talk between steroid hormone receptors and intra-cellular signalling pathways: who will have the last word? Mol. Endocrinol. 18 (2004) 269–278. [41] M. Perusquia, Nongenomic action of steroids in myometrial contractility, Endocrine 15 (2001) 63–72. [42] S. Mesiano, Myometrial progesterone responsiveness and the control of human parturition, J. Soc. Gynecol. Invest. 11 (2004) 193–202.
Progesterone receptors in the human uterus and their possible role in parturition Joseph H.H. Thijssen ∗ Laboratory of Endocrinology, University Medical Centre Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands
Abstract An overview is given on the role of progesterone in parturition in the human. Progesterone withdrawal is considered to be a major event for the beginning of parturition. However, in the human, no evidence exists in favour of a decline in placental progesterone production prior to labour. Progesterone actions are mediated by two functionally different but structurally highly related intranuclear proteins, progesterone receptor (PR) A and PRB. In the human, functional progesterone withdrawal is thought to play a role. This may be mediated by a change in the expression of the two isoforms of the PR, with an increase in the PRA:PRB ratio, and this is accompanied by an increase in the expression of the estrogen receptor. These mechanisms are considered to be critical for the endocrine control of parturition. © 2005 Elsevier Ltd. All rights reserved. Keywords: Progesterone receptor A (PRA); Progesterone receptor B (PRB); Labour; Uterus; Actions of progesterone
1. Introduction Progesterone is a very important hormone in the regulation of female reproduction. Several of the major actions of progesterone take place in the uterus: in particular, preparation of the endometrium for implantation after ovulation and fertilisation of an oocyte, and the maintenance of a subsequent pregnancy by promotion of uterine growth and suppression of myometrial contractility [1]. The actions of progesterone in the uterus are thought to be mediated through binding to its receptor, an intranuclear protein known as the progesterone receptor (PR) that can specifically bind progesterone and other progestins. Binding of the steroid to this receptor leads to a sequence of events including conformational changes in the protein and finally results in binding of the steroid-receptor complex to DNA, causing subsequent modulation of gene expression followed by protein synthesis. These processes take time; increases in protein synthesis can be observed a few hours after first binding of the steroid to its receptor. This PR was initially characterised in mammalian uterus [2,3], but was soon demonstrated in the human uterus as well [4]. Later it was shown that the PR exists in two different ∗
Tel.: +31 30 250 4264; fax: +31 30 250 5376. E-mail address: [email protected].
0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.08.011
forms [5], PRA and PRB, which both bind progesterone with identical affinity. The two PR proteins in the human are encoded by a single gene under the control of two distinct promoters, each of which gives rise to a distinct mRNA species encoding for either PRA or PRB [6,7]. In addition to the biological effects based on this wellknown genomic pathway, there is ample evidence for a second mechanistic pathway that is not operating via genomic interactions. These so-called nongenomic actions [8] require, in general, a short time frame in which to occur. Evidence has accumulated that rapid effects of progesterone on spermatozoa, hepatocytes and on some specific brain areas are not mediated by PR but by binding sites on or in the membranes of these cells. Furthermore, several progesterone metabolites, which are unable to bind to the PR, are capable of inducing biological effects mediated by other receptors located in the membranes of cells [8]. In the human uterus, the major actions of progesterone are thought to be mediated mainly by so-called “classic” receptors.
2. Progesterone receptors There is some evidence that the two forms of PR are functionally different and that the balance between PRA and PRB may make it possible to affect diverse physiological targets
398
J.H.H. Thijssen / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 397–400
[9]. However, much of this evidence is conflicting and modelspecific, and the true functions of the differences between the receptor forms in normal tissues are yet to be fully understood. Structurally, the two PR forms are identical except that PRA lacks the last 164 amino acids found at the N-terminal end of PRB. This region, which is therefore unique to PRB, contains a third transcription activation factor (AF3), in addition to the two other activation factors, AF1 and AF2, that are common to both PRA and PRB [10]. The PR is a member of a large family of ligandactivated nuclear transcription regulators, which include specific receptors for several other steroid hormones, but also for retinoids, thyroid hormone, the active Vitamin D metabolite and a number of as yet unknown ligands. Like all of these receptors, the PR is made up of a central DNA binding domain, a steroid-specific ligand binding domain and multiple activation and inhibiting function elements. Binding of progesterone to the PR causes conformational change and a dimerisation, resulting in association of the progestincomplexed PR dimer with specific coactivators [11] and general transcription factors. The activated complex of proteins binds to so-called progesterone responsive elements (PREs) in the DNA of promoters of target genes, resulting in modulation of the transcription of those genes [12]. In a number of experiments, all of which were based on co-transfection of a variety of cell lines with PRA and PRB constructs, differences have been observed in the transcriptional activities of PRA and PRB. In all cell types, PRB exhibited hormone-dependent transactivation irrespective of the complexity of the response elements. The activity of PRA, however, appeared to be cell- and reporter-specific; its transactivation activity varied from very similar to PRB to almost inactive and even to activity as a transdominant inhibitor of PRB activity [9]. Moreover, PRA was able to influence the transcriptional activity of other nuclear factors such as glucocorticoid, mineralocorticoid, androgen and estrogen receptors [13–16]. Thus the ability of PRA to act as a transdominant repressor is highly model-specific and there is considerable variability in this ability according to the different reports. The basic mechanisms by which PRA and PRB can exert such apparently different transcriptional activities in various cell and promoter systems remain largely unknown [9]. The unique AF3 in PRB may confer a difference in activities between the two PRs for coregulators. Experimental evidence suggests that coactivators may bind differently to the two PRs or that each isoform of the PR binds to different subgroups of coactivators [17]. Given that the PR requires interactions with multiple transcriptional factors in order to affect transcription, it is possible that existing variability in tissue-specific expression of the components of this multiprotein complex may result in different PRA and PRB activities [18]. Differential cofactor requirements between gene promoters may lead to differences in the transcriptional efficacy of the two PRs on the same promoter [12]. If the two isoforms are transcriptionally distinct, it also can be expected that changes in the relative amounts of PRA and
PRB in a cell would result in altered gene expression patterns. However, when the relative expression of PRA and PRB was varied in wild-type T47D cells, which already express both isoforms, the impact on transcription was not dramatic unless PRA vastly exceeded PRB [19]. Furthermore, no evidence was obtained of dominant transcriptional inhibition of PRA. These data suggest that co-expression of both isoforms at similar levels is associated with appropriate transcriptional responses to progestins and that changes in PRA and PRB levels must be quite dramatic before physiological changes in progestin effects can be observed. The view that PRB is the active PR, whereas PRA is either inactive or active as an inhibitor of PRB, is largely based on transfection experiments in cell lines that are not progestin targets. There is little evidence in vivo that PRA is a dominant inhibitor of PRB. Data from PRA or PRB gene knockout animals show that PRB knockout mice, which only have PRA, do not have impaired biological responses of the uterus to progesterone [20]. This, plus other evidence, suggests that the two isoforms either work co-operatively to mediate progesterone action or that each isoform has distinct physiological roles that are probably cell- and promoter-specific [9]. A combination of cooperative action and distinct display is probably the best explanation for the complex and divergent pathways of progesterone in physiology.
3. Progesterone receptors in the human uterus Estrogens stimulate the number of PRs and progesterone itself decreases the expression of its receptor in the endometrium and the myometrium. During the follicular phase of the menstrual cycle, PR levels in the uterus increase and reach their highest around ovulation; during the second half of the cycle, as serum progesterone levels increase, total PR levels decrease [21]. Such a decrease can be brought on prematurely by treatment with progestins. It has been demonstrated that the PRs are present in the nuclei of epithelial and stromal cells of the endometrium and in the myometrial smooth muscle cells. In general, PRA and PRB are co-expressed in the same target cells and their relative expression is close to unity [22]. In contrast, most endometrial cancers express mainly one PR isoform and isoform predominance is associated with higher histological grades [23]. There is evidence for a discrete subnuclear location of nuclear receptors, the significance of which is as yet unknown. According to current knowledge, the nucleus of a cell is a highly organized structure containing numerous specialized subnuclear structures and many nuclear components localized in discrete domains. In a recently published study [24], the authors examined PRA and PRB distribution within the nucleus in vivo in normal endometrium during the menstrual cycle. PRs were distributed evenly within the nucleus but were also found localized in discrete subnuclear foci. In the proliferative phase, an even PR distribution was predominant and both PR-isoforms were co-located and distributed
J.H.H. Thijssen / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 397–400
evenly. In the secretory phase, there was a marked increase in the proportion of nuclei containing PRs distributed into discrete foci and PRB was the predominant isoform in these nuclear foci. There was an inverse relationship between even and focal distribution during the menstrual cycle, suggesting that hormonal fluctuations were involved in the movement of PRs into focal nuclear locations. In the normal endometrium, nuclear foci coincide with high progesterone levels. It was concluded that nuclear distribution might be an important component of gene regulation in target tissues [24]. No regional variations in PR distribution have been found in the endometrium or myometrium [25] during the menstrual cycle. However, a high intra-epithelial expression of PRs has been found in the transformation zone of the uterine cervix [26] when compared with the ectocervix. The PRs at this location are thought to be involved in processes at the end of pregnancy.
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uterus affected differently? Do the reported changes precede or follow the other factors currently thought to play a role in the onset of labour in primates? How different to the levels of progesterone are the available PRs at the time that the balance of steroidal control of pregnancy is turning from progesterone to estrogen? A number of mechanisms have been suggested to account for the functional withdrawal of progesterone. Cervical ripening is related to significant local hormonal changes [38]. In addition to changes in PR isoforms, the regulation of PR responsive genes through nuclear factor kappaB promoter sites and the non-genomic effects of progesterone have been suggested [39,40]. Furthermore, the possible cross talk between steroid hormone receptors and other intracellular signalling pathways offers many new ways for regulation in hormonally responsive tissues [41].
5. Conclusion 4. Progesterone receptors and 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. Parturition is initiated by the fetal-placental unit and involves a cascade of endocrinological and physiological events that ideally culminate in the birth of healthy offspring [27]. Almost 50 years ago, Csapo [28] had already proposed that progesterone actively blocks labour and that parturition requires progesterone withdrawal. The foundations of this hypothesis were the findings in animals that progesterone levels decreased before the onset of normal parturition and that progesterone administration delayed the onset of labour [29]. In the rat, experimental evidence supports this hypothesis [30] but proof that it is relevant in primates has been more elusive [31] as, in these species, progesterone synthesis by the placenta does not decrease before parturition. However, more recently, evidence has been found in humans [32,33] and rhesus macaques [34] that, prior to parturition, there is a shift in the expression of PR from PRB to PRA. These findings have been interpreted as resulting in a functional withdrawal of progesterone and its effects [31,35]. In addition to changes in the relative distribution of PRA and PRB, an increase in estrogen receptor ␣ has been described during the early phase of first stage labour, around cervical dilatation at term [36]. Furthermore, a decline in PR coactivator expression and histone acetylation has been documented in the uterus near term and this also may impair PR function, thus causing a functional progesterone withdrawal [37]. However, considerable additional evidence is required before the findings fulfil the promise of Csapo’s hypothesis in explaining the onset of parturition in primates. Many questions remain [31] such as: Why do these changes in PR expression occur? Why are the different compartments of the
Advances in our understanding of the molecular basis for PR-mediated control of progesterone responsiveness has led to the hypothesis that functional progesterone withdrawal also plays a role in human parturition. The functional withdrawal can be mediated by specific changes in myometrial expression of the isoforms of PR, in their function, or both [42]. Functional progesterone withdrawal is possibly mediated by an increase in the myometrial PRA:PRB expression ratio and/or possibly by modulation of coactivator and corepressor proteins. Functional progesterone withdrawal appears to induce functional estrogen activation by effecting the expression of estrogen receptor ␣. The link between functional progesterone withdrawal and functional estrogen activation may be a critical mechanism for the endocrine control of human parturition.
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