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Centre de Recherche en Reproduction Animale, Faculté de médecine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 7C6
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREGULATION OF PROSTAGLANDIN...REGULATION OF THE OXYTOCIN...REGULATION OF PROSTAGLANDIN...REFERENCES |
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(PGF2) from the endometrium. It has been known for many years that progesterone, estradiol, and oxytocin are the hormones responsible for luteolysis. To achieve luteolysis, two independent processes have to be coordinated; the first is an increase in the prostaglandin synthetic capability of the endometrium and the second is an increase in oxytocin receptor number. Although progesterone and estradiol can modulate the expression of the enzymes involved in prostaglandin synthesis, the primary reason for the initiation of luteolysis is the increase in oxytocin receptor on the endometrial epithelial cells. Results of many in vivo studies have shown that progesterone and estradiol are required for luteolysis, but it is still not fully understood exactly how these steroid hormones act. The purpose of this article is to review the recent data related to how progesterone and estradiol could regulate (initiate and then turn off) the uterine pulsatile secretion of PGF2 observed at luteolysis.
estradiol, female reproductive tract, oxytocin, progesterone, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREGULATION OF PROSTAGLANDIN...REGULATION OF THE OXYTOCIN...REGULATION OF PROSTAGLANDIN...REFERENCES |
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(PGF2) that causes luteolysis [1]. OT, from the pituitary and corpus luteum (CL), stimulates the pulsatile release of PGF2 via the OT receptor (OTR) in the luminal epithelium of the endometrium, resulting in regression of the CL [2–4]. Although there are reports, especially in the cow, that OT might not be involved in luteolysis [5], there is no conclusive evidence for other factors being involved in the pulsatile secretion of PGF2. Thus, the acquisition of responsiveness to OT by the endometrial epithelium determines when endogenous secretion of PGF2 will occur during the estrous cycle, and this appears to require the coordinated action of P4 and E2. Progesterone administered early in the estrous cycle, before the normal rise in plasma P4, results in premature luteolysis [6], whereas delaying the action of P4 on the endometrium by the use of an antagonist delays luteolysis [7]. Thus, the length of time the endometrium is exposed to P4 determines the length of the luteal phase. Progesterone can regulate PGF2 secretion in different ways. Prolonged exposure to P4 promotes the endometrial accumulation of arachidonic acid and cyclooxygenase (COX) necessary for the synthesis of PGF2. Progesterone also exerts a suppressive effect on PGF2 secretion, which wanes after prolonged exposure [1]. This suppressive effect is due to an inhibitory action on OTR gene expression during the early and midluteal phase of the estrous cycle [8–12]. After 12 days of continuous exposure to P4 in sheep [13, 14] and cow [15], the P4 block to OTR up-regulation is lost, possibly due to loss of progesterone receptors (PR) [16], and the endometrium becomes responsive to OT.
Estradiol is also important for the timing of luteolysis because removal of E2 results in a prolonged cycle [17, 18] and administration of E2 in midcycle initiates luteolysis by increasing plasma PGFM (13,14,-dihydro-15-keto-PGF2) concentration [19], presumably by raising endometrial OTR concentration [20]. The effect of E2 is dependent on P4 because it is only observed after the endometrium has been primed with P4 for a certain period of time [15, 21, 22]. E2 can also affect the magnitude, timing, and pattern of PGF2 pulses in response to OT [23, 24]. During the early and midluteal phases, estrogen receptor (ER) expression is suppressed in the ovine endometrium except in the deep glands, presumably by an inhibitory action of rising P4 levels [11, 16]. The profile appears to be different in the cow, where ER is not suppressed throughout the luteal phase [25]. ER number increases at the end of the luteal phase in both the cow and sheep, possible due to E2 up-regulating the expression of its own receptor in endometrial cells [26–28]. This increase in ER has been thought to initiate luteolysis by increasing OTR [26, 29]; however, some studies have shown that the up-regulation of OTR expression in the ovine [11] and bovine [25] endometrial luminal epithelium precedes that of the ER. Thus, although the up-regulation of ER induces an increase in OTR, which is responsible for the large pulses of PGF2 that cause luteolysis, it is possible that an increase in ER does not initiate luteolysis.
It has been proposed that, in the normal estrous cycle, the concentration of endometrial OTR is initially depressed by P4 and that the marked increase in the concentration of OTR over Days 13–16 of the cycle in sheep is due primarily to the withdrawal of the inhibitory influence of progesterone [30]. Experiments in ewes have also shown that withdrawal of progesterone alone is sufficient to initiate endometrial oxytocin receptor expression but that estradiol administration at the time of progesterone withdrawal can facilitate the up-regulation of oxytocin receptor gene expression [13, 31, 32]. Thus, luteolysis is brought about by coordinated changes in both prostaglandin synthesis and in OTR. Although both of these processes are regulated by E2 and P4, there are significant differences between the two.
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REGULATION OF PROSTAGLANDIN SYNTHESIS |
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TOPABSTRACTINTRODUCTIONREGULATION OF PROSTAGLANDIN...REGULATION OF THE OXYTOCIN...REGULATION OF PROSTAGLANDIN...REFERENCES |
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. In some cell types, a functional linkage between type IIA sPLA2 and COX-2 for catalyzing delayed production of PG after an inflammatory stimulus has been observed [34]. The second subgroup of PLA2 enzymes is best characterized by the type IV cytosolic PLA2 (cPLA2), an 85-kd enzyme without homology with other PLA2 enzymes [35]. The cPLA2, in contrast with sPLA2 s, has a preference for phospholipids containing arachidonate at the sn-2 position. This enzyme is likely to be involved in regulating lipid mediator generation immediately after cell activation [34]. Activity of cPLA2 requires translocation and binding to phospholipid membranes [35]. Although Ca2+ is not required for enzymatic activity, Ca2+ is required for translocation and binding to the phospholipid membrane. The nuclear envelope and endoplasmic reticulum are the primary sites for arachidonic acid (AA) metabolism initiated by cPLA2 in activated cells. These are also the primary subcellular locations for the COX enzymes, 5-LO, and some of the terminal synthases.
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Following its release, arachidonic acid is converted to PGH2 by the action of prostaglandin G/H synthase (PGHS), also known as cyclooxygenase (COX), which is situated on the luminal surface of the endoplasmic reticulum and the inner and outer membranes of the nuclear envelope [36]. Numerous studies have demonstrated the existence of two distinct genes encoding isoforms of COX, COX-1, and COX-2. Both enzymes possess a PGG2-synthetic cyclooxygenase activity and a peroxidase activity that converts PGG2 to PGH2. Despite catalytic and structural similarities, COX-1 and -2 differ in most other respects, including gene structure and regulation and mRNA stability [37, 38]. COX-1 is constitutively expressed and is considered to play a housekeeping role, whereas COX-2 is normally readily induced by hormones, growth factors, cytokines, etc. in a variety of tissues.
After biosynthesis of PGH2, this endoperoxide is converted to one of several possible prostanoids by a terminal synthase. Prostaglandin F2 is synthesized via three pathways from PGD2, PGE2, or PGH2 by PGD 11-ketoreductase, PGE 9-ketoreductase, or PGH 9-, 11-endoperoxide reductase. PGD 11-ketoreductase is the enzyme commonly referred to as PGF synthase and it catalyzes the reduction of the 9-, 11-endoperoxide group of PGH2 to the two hydroxy groups of PGF2. This enzyme also catalyzes the conversion of PGD2 to 9-, 11-PGF2 in the presence of NADPH [39] and, like PGF2, 9-, 11-PGF2 causes contraction of bronchial, vascular, and smooth muscle. PGD 11-ketoreductase was independently discovered in rat liver and rat lung [39]. The enzyme from bovine lung is a monomeric protein with a Mr of 36 666, consisting of 323 amino acids; its amino acid sequence is highly homologous to sequences of aldo-keto reductase (AKR) family members. PGE 9-ketoreductase catalyzes the conversion of PGE2 to PGF2 in the presence of NADH or NADPH [39]. This enzyme is classified as a member of the AKR superfamily, based on the broad substrate specificity, an Mr of about 36 000, NADPH as a cofactor, and high amino acid sequence homology with other members of this family. PGE 9-ketoreductase was reported to be identical to 20-hydroxysteroid dehydrogenase (HSD) [40], which belongs to the AKR1C group, based on its amino acid sequence and substrate specificity. Also, a newly identified enzyme in the bovine endometrium (AKR1B5) is a functional PGFS and is up-regulated at around Day 9 of the cycle [41].
It has been known for a long time that progesterone stimulates prostaglandin synthesis in the endometrium of the ewe [42]. The early studies of Kindahl also showed that rapid loss of P4 by removing the CL at the time of luteolysis resulted in cessation of PGF2 secretion, whereas maintaining low P4 (around 1–2 ng/ml) resulted in maintenance of the pulsatile secretion of PGF2 that stopped abruptly upon removal of progesterone [43]. Some in vivo studies have been carried out to try to determine the regulation of the enzymes involved in prostaglandin synthesis. cPLA2 is increased at Day 11 of the cycle in sheep [44]. The cPLA2 is probably regulated by steroid hormones because E2 increases PLA2 activity in the rat uterus [45], but no studies on the regulation of PLA2 in the ruminant endometrium have been reported and no studies have examined the possible role of sPLA2. COX-2 is up-regulated during the estrous cycle in sheep and cattle [46, 47]. The expression of COX-1 appears to differ between the two species, in cattle COX-1 is undetectable [47], whereas in sheep, COX-1 is highly expressed but does not change during the cycle [46]. Progesterone up-regulates COX-2, and E2, either alone or together with P4, has no effect [46]. PGFS is also up-regulated during the estrous cycle in the cow [41], but no studies have been performed in vivo to determine if steroid hormones are involved. The 9-keto-PGE reductase is also present in the ovine endometrium and it increases during the late luteal phase [48]. Again, no studies have been performed to determine if it is regulated by steroid hormones.
In vitro studies have been used to try to examine the mechanisms involved in the regulation of prostaglandin synthesis. In general, P4 stimulates PGF2 secretion from endometrial epithelial cells [49, 50] and endometrial strips [51]. The observed stimulation of prostaglandin synthesis by P4 in endometrial epithelial cells was not due to an increase in either COX-2 or PGFS mRNA expression [50]. Thus, the increase in COX-2 induced by P4 in vivo could be due to an action of P4 on other cells of the endometrium. The effect of E2 in vitro is more variable. Although studies on human endometrium have demonstrated that estrogens enhance PG production in epithelial cells by elevating PG synthase activity [52], no stimulatory effect of E2 on the expression of either COX-1 or -2 has been observed in ruminants [50, 53]. This agrees with the in vivo results obtained by Charpigny et al. [46]. E2 inhibits PGF2 secretion from endometrial cells but had no effect on endometrial strips. This inhibitory effect of E2 on isolated cells could be explained by an inhibition of COX-2, but not PGFS, expression [50]. The situation is further complicated by the observation that, in endometrial tissue taken from long-term ovariectomized cows, estradiol stimulates prostaglandin secretion [54]. OT can also increase COX-2, but not COX-1, expression [55–57].
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REGULATION OF THE OXYTOCIN RECEPTOR |
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TOPABSTRACTINTRODUCTIONREGULATION OF PROSTAGLANDIN...REGULATION OF THE OXYTOCIN...REGULATION OF PROSTAGLANDIN...REFERENCES |
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is not necessary for basal OT receptor synthesis but is absolutely necessary for the induction of OT receptor binding in the brain by estrogen [59]. However, it is unclear whether OT receptor gene transcription is predominantly regulated by estrogen. The continuous presence of receptors in certain brain regions after gonadectomy suggests the existence of alternate mechanisms of regulation. The OTR is expressed in the ruminant uterus at high levels at estrus and at term of pregnancy. This expression appears to be controlled mostly at the transcriptional level and correlates with increasing estrogen concentration and progesterone withdrawal. While there is no estrogen response element (ERE) on the bovine or ovine OTR gene promoter region [60], ER can act through SP1 and possibly AP1 sites on gene promoters [61]. This is a possible mechanism by which E2 can up-regulate OTR and is supported by recent findings that ER likely stimulates OTR promoter through both protein-DNA and protein-protein interactions with Sp1 and AP-1 [62].
Estradiol treatment in vivo induces an initial up-regulation of endometrial OTR expression in ewes [13, 23, 63], but if estradiol treatment is continued over several days, OTR concentration decreases [14, 32]. Taken together, these results indicate that estradiol can induce a short-term up-regulation in OTR expression but that the effect cannot be maintained for more than 1–2 days. However, the exact mechanism of action of E2 has been difficult to elucidate. It is generally accepted that E2 increases PGF2 secretion by increasing OTR, but the action of E2 in vivo can vary depending on the time and duration of treatment. For example, administration of E2 to ewes during the midluteal phase causes premature luteal regression [64], whereas daily injection of E2 initiated early during the cycle prolongs the lifespan of the CL [65], and this is thought to be due to a suppression of endometrial OTR [66].
In vitro, E2 inhibits the OTR numbers in cells exposed to P4 for 10 days or less and thus it is possible that E2 together with P4 plays a role in maintaining low responsiveness of the endometrium to OT by decreasing OTR [53]. After a more prolonged exposure to P4, the effect of E2 changes from inhibitory to stimulatory, and E2 increases OTR number with a peak observed at 24 h [53], which coincides with the maximum effect of E2 on OT stimulation of PGF2. These results are in agreement with others studies showing that estradiol facilitates endometrial OTR expression only for 12–24 h after exposure [67].
Inhibition would appear to play an important role in the regulation of the OTR gene in ruminants. OTR is highly expressed in prepubertal heifers [68] and treatment with progesterone, but not estradiol, causes a considerable down-regulation of the OTR [69]. There is also a spontaneous up-regulation of the OTR when endometrial tissue is removed and incubated in vitro [67, 70]. Although P4 is believed to down-regulate OTR during the luteal phase, this action is difficult to reproduce in primary cultures of bovine endometrial epithelial cells, which naturally express high levels of OTRs as well as progesterone receptors [27, 71]. In isolated cells, no inhibitory effect of P4 was observed on OTR [53, 71]. When endometrial explant culture was used, P4 was able to decrease OTR when tissue was taken from long-term ovariectomized cows [54]; however, OT stimulation of PGF2 secretion was not affected. In sheep, treatment of endometrial explants with P4 as they were placed in culture reduced the spontaneous up-regulation of OTR, but this effect was not observed when P4 treatment was postponed for 4 h [72]. Thus, although P4 appears to be responsible for the down-regulation of OTR in vivo, this effect is either indirect or some other, as yet unidentified, factor down-regulates the OTR. This indirect effect of P4 is also supported by the fact that there is no P4 response element on the promoter region of the OTR gene in bovine [60] or other species [73]. However, there is increasing evidence that many steroid response target genes are not regulated by direct binding of receptor to classic hormone response elements but through receptor interaction with other sequence-specific transcription factors to either enhance or suppress their activity. Most examples of negative gene regulation by steroid receptors appear to use this nonclassic mode of regulation [74]. A contributing factor to the potency of RU486 to antagonize P4 is the ability of PR to recruit corepressors to promoters in the presence of RU486. Nuclear receptor corepressor interacts with RU486-bound PR but not agonist-bound PR [75]. We have recently shown that treatment of bovine endometrial epithelial cells with RU486 resulted in decreased prostaglandin secretion and decreased OTR [76]. Thus, a possibility that needs to be investigated further is that corepressors are involved in OTR suppression in vivo.
While there is no evidence at present to show that P4 is acting at the genomic level to regulate the bovine OTR, there has been a report to suggest that it might be acting at the cell membrane directly on the rat OTR protein [77]. A similar effect of P4 has been observed in the cow [78] and the sheep [79]. However, this nongenomic action of P4 on OTR is somewhat controversial because other groups have been unable to reproduce this effect of P4 or a variety of other naturally occurring progesterone metabolites on the human OTR and the natural bovine OTR [69, 80]. Thus, the role of a nongenomic action of P4 in the regulation of OT action in ruminants during the estrous cycle remains to be elucidated.
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REGULATION OF PROSTAGLANDIN SECRETION DURING LUTEOLYSIS |
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TOPABSTRACTINTRODUCTIONREGULATION OF PROSTAGLANDIN...REGULATION OF THE OXYTOCIN...REGULATION OF PROSTAGLANDIN...REFERENCES |
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Secretion
That treatment of ovariectomized ruminants with P4 alone can induce OTR and OT-stimulated PGF2 secretion, together with the fact that neither plasma E2 concentration nor ER in the endometrial epithelium increases before the increase in OTR, suggest that estradiol is not involved in the initial up-regulation of OTR. The molecular mechanisms involved in this increase in OTR are not known but it is likely due to the removal of a suppressive effect of P4. One possibility that needs further investigation is that the increase in the prostaglandin synthetic capability of the endometrium leads to the initial increase in OTR. There are two ways in which this could be accomplished. 1) There is an increase in PGFS during the luteal phase and this enzyme also has 20-hydroxysteroid dehydrogenase activity [41]. The authors have proposed that this could bring about a local metabolism of P4 to its inactive metabolite in the endometrium and reduce its effect. 2) There are PG receptors, especially PGE2, on the endometrial cells [81] and treatment of cows with prostaglandin can increase PGF2 output from the uterus [82, 83]. Because we have shown that there is a decrease in OTR when PG synthesis is decreased [76], it is possible that prostaglandins act in an autocrine or paracrine manor to stimulate OTR.
Luteolysis
There is much evidence to show that the large amplitude pulses of PGF2, which cause luteolysis, result from decreasing progesterone and increasing estradiol concentrations analogous to that seen at parturition. The driving force behind this is the increase in E2 and ER whereby the activated ER stimulates the up-regulation of OTR. In the pregnant animal, luteolysis is prevented predominantly by interferon-
inhibiting this up-regulation of the ER [63, 84]. There is no classical ERE on the promoter of the bovine and ovine OTR gene, and ER is believed to act via protein-DNA and protein-protein interactions [62].
Cessation of PGF2 Secretion
Almost as important as the increase in PGF2 secretion that causes luteolysis is the cessation of PGF2 secretion once luteolysis is complete. The decline in PGF2 secretion is not caused by a lack of substrate or of oxytocin because pulsatile PGF2 secretion is prolonged if P4 concentration is maintained at 1–2 ng/ml [43]. It is also not due to a decrease in OTR because OTR number is highest at estrus, when pulsatile PGF2 secretion has ceased. The decrease is due to a decline in enzymatic activity caused by a decrease in progesterone below 1 ng/ml and an inhibitory effect of E2 on COX-2 [50]. Thus, it appears that it is the regulation of OTR that causes luteolysis and the regulation of PG synthesis that terminates PGF2 secretion.
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FOOTNOTES |
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2 Correspondence. FAX: 450 778 8103; goffak{at}medvet.umontreal.ca
Received: 25 November 2003.
First decision: 22 December 2003.
Accepted: 22 January 2004.
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TOPABSTRACTINTRODUCTIONREGULATION OF PROSTAGLANDIN...REGULATION OF THE OXYTOCIN...REGULATION OF PROSTAGLANDIN...REFERENCES |
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during luteolysis in ruminants. Biol Reprod 1991 45:655-663[Abstract] in bovine uterine endometrial cells. Endocrinology 1998 139:2293-2299This article has been cited by other articles:
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  K. Mitko, S. E Ulbrich, H. Wenigerkind, F. Sinowatz, H. Blum, E. Wolf, and S. Bauersachs Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle Reproduction, February 1, 2008; 135(2): 225 - 240. [Abstract] [Full Text] [PDF]
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 S Bauersachs, S E Ulbrich, K Gross, S E M Schmidt, H H D Meyer, R Einspanier, H Wenigerkind, M Vermehren, H Blum, F Sinowatz, et al. Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes J. Mol. Endocrinol., June 1, 2005; 34(3): 889 - 908. [Abstract] [Full Text] [PDF]
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