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Real-time dynamics of prostaglandin F₂ release from uterus and corpus luteum during spontaneous luteolysis in the cow

¹ Department of Agricultural and Life Science and ² The Field Centre of Animal Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan and ³ Department of Animal Science, University of Peradeniya, Peradeniya 20400, Sri Lanka

Correspondence should be addressed to Akio Miyamoto; Email: akiomiya{at}obihiro.ac.jp

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Prostaglandin (PG) F₂ released from the uterus in a pulsatile fashion is essential to induce regression of the corpus luteum (CL) in the cow. In addition to the uterus, the CL has also been recognized as a site of PGF₂ production. Therefore, this study aimed to determine the detailed dynamics of the releasing profile of CL-derived PGF₂ together with uterus-derived PGF₂ during spontaneous luteolysis in the cow. Non-lactating Holstein cows (n = 6) were surgically implanted with a microdialysis system (MDS) on day 15 (oestrus = day 0) of the oestrous cycle. Simultaneously, catheters were implanted to collect ovarian venous plasma ipsilateral to the CL as well as jugular venous plasma. The concentrations of PGF₂, 13,14-dihydro-15-keto-PGF₂ (PGFM) and progesterone in the MDS and plasma samples were determined by enzyme immunoassays. The intra-luteal PGF₂ secretion slightly increased after the onset of luteolysis (0 h) and drastically increased from 24 h, and was maintained at high levels towards the following oestrus. Furthermore, PGF₂ was released from the CL into the ovarian vein in a pulsatile manner during spontaneous luteolysis. Also, the fact that intra-luteal secretion of PGF₂ and PGFM showed a positive correlation indicates the existence of a local metabolic pathway for PGF₂ in the CL. In conclusion, the present study clarified the real-time dynamics of uterus-derived PGF₂ and CL-derived PGF₂ during spontaneous luteolysis in the cow, and gives the first in vivo evidence that the CL releases PGF₂ during spontaneous luteolysis in the cow. Although the physiological relevance of CL-derived PGF₂ appears to be restricted to a local role as an autocrine/paracrine factor in the CL, overall results support the concept that the local release of PGF₂ within the regressing CL amplifies the luteolytic action of PGF₂ from the uterus.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Release of prostaglandin (PG) F₂ from the uterus in a pulsatile fashion on days 17–18 of the oestrous cycle is essential to induce regression of the corpus luteum (CL) in ruminants (McCracken et al. 1984, Wolfenson et al. 1985). In addition to uterus-derived PGF₂, the functional CL of the cow produces and secretes at least three kinds of PGs, such as PGF₂, PGE₂, and 6-keto-PGF₁, the stable inactive metabolite of prostacyclin (PGI₂) (Shemesh & Hansel 1975, Milvae & Hansel 1983, Rodgers et al. 1988, Blair et al. 1997). Also, the receptors for PGF₂ are fully expressed during the lifespan of bovine CL (Rao et al. 1979, Sakamoto et al. 1995, Mamluk et al. 1998). Recently, we and others observed that a luteolytic injection of PGF₂ induces a rapid and transient increase of intra-luteal PGF₂ during the first 4 h, but it increases again from 24 h (Hayashi et al. 2003), and these changes are well supported by the mRNA expression levels of cyclooxygenase 2 (COX-2) (Tsai & Wiltbank, 1998, Levy et al. 2000, Hayashi et al. 2003). Moreover, the addition of PGF₂ to ovine luteal cells in culture increased the expression of COX-2 protein at 4–12 h, and PGF synthase mRNA concentration increased at 24 h after PGF₂ treatment (Tsai & Wiltbank 1997). Thus, PGF₂ synthesis is induced in the CL especially at later stages during PGF₂-induced luteolysis. However, the detailed information of PGF₂ secretion within the CL during spontaneous luteolysis in the cow has not been well clarified.

The findings above imply that PGF₂ secreted in the CL may amplify the luteolytic effect of exogenous PGF₂ or the pulsatile release of PGF₂ from the uterus. It is therefore important to determine the detailed dynamics of the releasing profile of CL-derived PGF₂ together with uterus-derived PGF₂ during spontaneous luteolysis in the cow. For this purpose, we utilized an in vivo microdialysis system (MDS) implanted in the CL to observe the real-time changes in PGF₂, 13,14-dihydro-15-keto-PGF₂ (PGFM), and progesterone concentrations within the regressing CL, along with the changes in the concentration of these substances in ovarian venous plasma (OVP) ipsilateral to the CL as well as in jugular venous plasma (JVP).

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Animals and experimental design
Six multiparous, non-lactating Holstein cows were used for this study. They had had at least two oestrous cycles of normal length (21–22 days) before being used. Luteolysis was induced by intramuscular (i.m.) injection of 500 µg of the PGF₂ analogue (cloprostenol: Estrumate; Takeda Co., Osaka, Japan); 100 µg gonadotrophin releasing hormone (GnRH) (Conceral; Takeda Co.) were injected i.m. 60 h after the PGF₂ injection to ensure ovulation. The day of oestrus was designated as day 0. The cows received surgical implants of MDS membranes into the CL, and the ovarian vein and jugular vein were also catheterized simultaneously on day 15 of the oestrous cycle. After surgery, cows were moved to individual stanchions, and were fed with hay and water available ad libitum. Sample collection was started 24 h after surgery and continued until the next oestrus. After the experimental period, the MDS was surgically removed and the cow was ovariectomized. The occurrence of luteolysis was confirmed by macroscopic observation of the dissected CL (Ireland et al. 1980). The time schedule of the present study is shown in Fig. 1.

View larger version (14K): [in this window] [in a new window]   Figure 1 Time schedule of the treatment with the MDS in vivo.

Venous catheterization and collection of OVP and JVP
At surgery, a catheter was placed into the ovarian vein ipsilateral to the CL. The catheter was inserted into the vein about 5 cm away from the ovary, and propelled about 8–10 cm. Catheterization of the jugular vein was also conducted. Blood samples were collected from MDS-implanted cows into sterile 10 ml glass tubes containing 200 µl of a stabilizer solution (0.3 M EDTA, 1% acetyl salicylic acid, pH 7.4) at 4 h intervals until the end of the experiment. All blood samples were immediately chilled in ice water for 10 min, centrifuged at 2000 g for 15 min at 4 °C, and the plasma was frozen at –30°C until further analysis.

Hormone determination
The concentrations of progesterone, PGF₂ and PGFM in the perfusate fractions of the MDS and in plasma were determined in duplicate by second antibody enzyme immunoassays (EIAs) after extraction using 96-well ELISA plates (NUNC-Immuno Plate, NUNC Brand Products, Roskilde, Denmark).

The progesterone concentrations in the perfusate fractions of the MDS were assayed directly (Miyamoto et al. 1992). The standard curve ranged from 0.05 to 50 ng ml^–1, and the ED₅₀ of the assay was 2.4 ng ml^–1. The intra- and interassay coefficients of variation averaged 6.2% and 9.3% respectively.

To extract PGs, the plasma samples (OVP and JVP: 2 ml) and the MDS perfusates (6 ml) were adjusted to pH 3.5 using HCl and extracted using diethyl ether as described previously (Acosta et al. 1999). The residue was dissolved in 2 ml and 200 µl assay buffer (40 mM PBS, 0.1% BSA, pH 7.2) for plasma and MDS samples respectively. Samples were thus concentrated 30-fold for the MDS perfusate. To estimate the recovery rate in the plasma, PGF₂ and PGFM were added to plasma, and the obtained values were 60 and 70% respectively. Likewise, to estimate the recovery rate in the MDS perfusate, PGF₂ and PGFM were added to Ringer’s solution, and the obtained values were 65 and 66% respectively. The EIAs for PGF₂ (Miyamoto et al. 1995) and PGFM (Meyer et al. 1989) were described previously. The standard curve for PGF₂ ranged from 9.5 to 9500 pg ml^–1, and the ED₅₀ of the assay was 145 pg ml^–1. The intra- and interassay coefficients of variation were 7.7 and 9.7% respectively. The standard curve for PGFM ranged from 2.5 to 2500 pg ml^–1, and the ED₅₀ of the assay was 78 pg ml^–1. The intra- and interassay coefficients of variation were 7.7 and 12.5% respectively.

Statistical analysis
For analysis of changes in the concentrations of progesterone, PGF₂, and PGFM in the MDS fractions, the mean concentrations of the first six fractions (24 h) were used for the calculation of an individual proportion of baseline, because of the large variation in the absolute amount of hormones released into each of the microdialysis capillary membranes implanted in different cows. All hormone concentrations in the fractions collected were then expressed as a proportion of this individual baseline. This treatment enables an evaluation of the relative changes of hormonal values between the CL of different animals. The time point when progesterone concentrations in the MDS fractions started to decrease was considered as the onset of spontaneous luteolysis (0 h). Changes in hormonal release after the onset of luteolysis were tested on the basis of individual time points throughout the experiment as compared with the baseline. They were analysed by repeated measures ANOVA followed by t-test with the Bonferroni method. Differences were considered significant at a probability less than 5% (P < 0.05).

Pulsatile releases of PGF₂ in OVP and MDS as well as PGFM in JVP during spontaneous luteolysis were examined. The occurrence of peaks was identified when the proportional changes of PGF₂ or PGFM increased from basal values to at least threefold over that of the intra-assay CV of EIAs. The relationship between peaks of PGF₂ in OVP and PGFM in JVP, and that of PGF₂ peaks between OVP and MDS, were analysed using the Chi-square test of independence for contingency. Probabilities less than 5% (P < 0.05) were considered significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Oestrous signs were observed in all cows between days 21–23 from the last oestrus, and CLs implanted with MDS were collected by ovariectomy after the following oestrus. The regression of CLs was confirmed by macroscopic observation.

Intra-luteal changes in progesterone, PGF₂, and PGFM concentrations during spontaneous luteolysis
The basal levels of release (100%) of progesterone, PGF₂ and PGFM into the MDS were 1546 ± 276 pg ml^–1, 18.52 ± 1.52 pg ml^–1 and 6.61 ± 0.71 pg ml^–1 respectively. Intra-luteal progesterone secretion started to decrease (P < 0.01) immediately after the onset of luteolysis, and declined further to about 20% of the baseline at the end of the experiment. Intra-luteal PGF₂ secretion slightly increased (P < 0.05 to 0.01) after the onset of luteolysis, drastically increased from 24 h to about 300% (P < 0.01), and was maintained at high levels towards the following oestrus. Also, a significant increase (P < 0.05 to 0.01) in intra-luteal PGFM secretion (150% of baseline) was observed from 20 h after the onset of luteolysis (Fig. 2).

View larger version (30K): [in this window] [in a new window]   Figure 2 Local release of (A) progesterone (P), (B) PGF2 and (C) PGFM into the MDS (bars; 18 lines from 6 cows) during spontaneous luteolysis in the cows (n = 6; means±S.E.M.). The MDS data are expressed as a percentage of basal release (baseline) for the first 24 h (100% = 1546 ± 276 pg ml–1 for progesterone, 18.5±2 1.52 pg ml– for PGF2 and 6.61 ± 0.71 pg ml–1 for PGFM). Black bars indicate the onset of luteolysis (0 h). * and •, higher or lower than baseline (P < 0.05 and P < 0.01 respectively).

Relationship between PGF₂ in OVP and PGFM in JVP

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View larger version (24K): [in this window] [in a new window]   Figure 3 Relationship between PGF2 in OVP ipsilateral to the CL and PGFM in JVP. Pattern I was classified as a concomitant appearance of a PGF2 peak in OVP with a PGFM peak in JVP. Pattern II was classified as a PGF2 peak in OVP with basal release of PGFM in JVP. Pattern III was classified as the appearance of a weak PGFM peak in JVP with basal release of PGF2 in OVP.

Characteristics of releasing profiles of PGF₂ (OVP) and PGFM (JVP) prior to and after the onset of spontaneous luteolysis

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View this table: [in this window] [in a new window]   Table 1 Distribution of the occurrence of types I, II and III pulse patterns of PGF2 (OVP) and PGFM (JVP) release prior to (–48 ~ 0 h) and after (0 ~ 72 h) the onset of spontaneous luteolysis. Results are expressed as peak occurrence/cow/day; means±S.E.M., n = 6 cows.

View this table: [in this window] [in a new window]   Table 2 Characteristics of releasing profiles of PGF2 and PGFM in types I, II and III pulse patterns prior to (–48 ~ 0 h) and after (0 ~ 72 h) the onset of spontaneous luteolysis. The peaks involve all identified values that increased over threefold from basal values of the intra-assay CV of EIAs. Results are expressed as pg ml–1; means±S.E.M., n = 6 cows.

Relationship of PGF₂ between OVP and MDS

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View larger version (27K): [in this window] [in a new window]   Figure 4 An example of changes in PGF2 concentrations in OVP and MDS fractions in an individual cow. Luteolysis is represented by the black bars (0 h).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

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It is well known that the CL during the oestrous cycle is identified as a site of PG production (Shemesh & Hansel 1975, Milvae & Hansel 1983, Rodgers et al. 1988) and it expresses mRNA for COX-2 (Tsai & Wiltbank 1998, Levy et al. 2000, Silva et al. 2000, Kobayashi et al. 2002) and PGF synthase (Tsai & Wiltbank 1997), as well as PGF receptors (Rao et al. 1979, Wiepz et al. 1992, Sakamoto et al. 1995). In the present study, the basal release of PGF₂ into MDS was about 20 pg ml^–1, which increased to about 60 pg ml^–1 during the later period of luteolysis. The transfer capacity of the MDS capillary membrane was previously examined to be 1% for PG (Miyamoto et al. 1997). Thus, the absolute concentration of PGF₂ in the inter-cellular fluid of the CL could be expected to be 100-fold higher than the substance diffused into MDS, which is calculated as around 2000 to 6000 pg ml^–1. Thus, this observation provides strong evidence that CL produces high amounts of PGF₂ during spontaneous luteolysis.

The bovine CL contains relatively large amounts of arachidonic acid that is comparable to the endometrial cells (Lukaszewska & Hansel 1980), and a functional arachidonic acid–PG metabolic pathway is identified in the bovine CL (Shemesh & Hansel 1975, Milvae & Hansel 1983). In fact, intra-luteal implants of indomethacin, a potent PG synthase inhibitor, on day 11 of the oestrous cycle in ewes resulted in heavier CL on day 18 than that in untreated control ewes (Griffeth et al. 2002), suggesting that intra-luteal production of PGF₂ is required for structural luteolysis. Furthermore, the systemic administration of PG synthesis inhibitors delayed the structural luteolysis in rats (Kurusu et al. 2001). In the present study, the intra-luteal PGF₂ secretion was drastically increased from 24 h after the onset of luteolysis. These findings suggest that the intra-luteal PGF₂ may mediate structural rather than functional luteolysis.

In the systemic circulation, PGF₂ is inactivated by metabolizing into PGFM during the first passage through the lungs (Piper et al. 1970). Hence, the changes in PGFM in peripheral plasma can be considered as an accurate reflection of changes in the uterine PGF₂ secretion. On the other hand, it was reported that PGF₂ can be converted to PGFM in ovine CL (Silva et al. 2000). In the present study, the increases in PGF₂ and PGFM secretion in CL were positively correlated with each other after the onset of luteolysis. The data support the concept that PGF₂ is catabolysed to PGFM in the CL, and thus, a PGF₂ metabolic pathway exists in the CL of the cow. The fact that PGF₂ increased to about 300% while PGFM increased to only about 150% during luteolysis may imply that the active synthesis, but not catabolism, of PGF₂ accelerates the luteolytic cascade by interactions with other local regulators such as endothelin-1 (Girsh et al. 1996a,b, Miyamoto et al. 1997, Ohtani et al. 1998) and angiotensin II (Hayashi & Miyamoto 1999) within the bovine CL. Therefore, it is most likely that luteal PGF₂ plays a role as an autocrine/paracrine modulator of CL function (Miyamoto & Schams 1994, Olofsson & Leung 1994). The increased PGF₂ within the CL after the onset of luteolysis may act as an amplifier of uterine PGF₂ during spontaneous luteolysis.

In the present study, three kinds of relationship were observed between the PGF₂ peaks in OVP and the PGFM peaks in JVP during spontaneous luteolysis. Pattern I was classified as a concomitant appearance of a PGF₂ peak in OVP with a PGFM peak in JVP (Fig. 5a). Presumably, uterine PGF₂ was released into the uterine vein, and then branched into two pathways. In the first pathway PGF₂ is transferred to the ovary by utero-ovarian local counter-current transfer mechanisms, and reaches the CL (Barrett et al. 1971, Ginther et al. 1973, Kawakami et al. 1955). After circulating the ovary, the transferred PGF₂ moves into the ovarian vein and is detected as a peak in OVP. In the second pathway PGF₂ flows to the systemic circulation, and is inactivated by metabolizing into PGFM during the first passage through the lungs, so that it is detected as a peak in JVP. Thus, pattern I is interpreted as the uterus-derived PGF₂ pulse.

View larger version (34K): [in this window] [in a new window]   Figure 5 Diagrammatic illustration of the relationship between PGF2 in OVP ipsilateral to the CL and PGFM in JVP. (a) Pattern I was classified as a concomitant appearance of a PGF2 peak in OVP with a PGFM peak in JVP. Presumably, uterine PGF2 was released into the uterine vein, and then branched into two pathways. In the first path-way PGF2 transfers to the ovary via the local countercurrent transfer mechanism, and then appears in OVP. In the second pathway PGF2 flows to the systemic circulation, and is inactivated by metabolizing into PGFM, so that it is detected as a peak in JVP. (b) Pattern II was classified as a peak of PGF2 in OVP together with basal release of PGFM in JVP. The observation that PGFM in the systemic circulation does not show a peak at that time strongly suggests that the PGF2 peak in OVP is not derived from the uterus. (c) Pattern III was classified as the appearance of a weak PGFM peak in JVP with basal release of PGF2 in OVP. The weak PGFM peak may be due to a small amount of PGF2 released from the uterus, which is an insufficient amount to be reflected in the OVP via local countercurrent transfer.

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Pattern III was classified as the appearance of a weak PGFM peak in JVP with basal release of PGF₂ in OVP (Fig. 5c). The observation that PGF₂ in the ovarian vein does not show a peak suggests that the CL does not release PGF₂ at that time. Thus, the weak PGFM peak may be due to a small amount of PGF₂ released from the uterus, which is an insufficient amount to be reflected in the OVP via local countercurrent transfer. The observations noted above suggest that the source of PGF₂ during spontaneous luteolysis is not only the uterus but also the CL. In the present study, it was observed that the distribution of pulse patterns I, II and III, or peak concentrations of PGF₂ and PGFM in pulse patterns I, II and III were constant prior to and after initiation of spontaneous luteolysis.

In the present study, there was no relationship between profiles of local secretion of PGF₂ within the CL (PGF₂ in MDS) and the PGF₂ released from the CL into the ovarian vein (PGF₂ in OVP) during spontaneous luteolysis. Even though PGF₂ detected in the ovarian vein may contain both uterus- (pattern I) and CL-derived (pattern II) PGF₂, the changing profiles of PGF₂ within the CL and in OVP do not coincide. Therefore, it is unlikely that the production of PGF₂ within CL tissue is reflected in circulating PGF₂ in the whole body, and hence different mechanisms may regulate these two phenomena.

Taken together, the results of the present study show the real-time dynamics of uterine- and CL-derived PGF₂ during spontaneous luteolysis, and provide the first in vivo evidence that the CL releases PGF₂ during spontaneous luteolysis in the cow. Although the physiological relevance of CL-derived PGF₂ appears to be restricted to a local role as an autocrine/paracrine factor in the CL, overall results support the concept that the local release of PGF₂ within the regressing CL amplifies the luteolytic action of PGF₂ from the uterus.

	Acknowledgements

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
The authors thank Dr K Okuda, Okayama University, Japan, for progesterone antiserum, Dr S Ito, Kansai University of Medicine, Japan, for PG antiserum, and Fresenius AG, St Wendel, Germany for the microdialysis capillary membranes. This study was supported by the Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science (JSPS), the Novartis Foundation (Japan) for the Promotion of Science, and the 21st Century COE Program (A-1), Ministry of Education, Culture, Science and Technology, Japan. T J A and M P B W are postdoctoral fellows supported by Japan Society for the Promotion of Science. M M is supported by the COE Program.

	Footnotes

 
Received 23 January 2004
First decision 24 March 2004
Revised manuscript received 13 May 2004
Accepted 14 May 2004

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