This manuscript reviews the mechanisms that maintain the corpus luteum (CL) of pregnancy in ruminants. In mammals, ovulation and luteinization of the remaining cells in the CL are due to a surge in Luteinizing Hormone (LH). In cattle, continued secretion of pulses of LH is essential for full development and function of the CL during the estrous cycle (LH pulses), however, the few studies on the CL after d20 of pregnancy do not indicate that LH is essential for maintaining the CL of pregnancy. The first essential step in maintaining the CL of pregnancy in ruminants is overcoming the mechanisms that cause regression of the CL in non-pregnant ruminants (d18-25 in cattle; d13-21 in sheep). These mechanisms have a uterine component involving oxytocin-induced prostaglandin F2α (PGF2A) pulses and a luteal component involving decreased progesterone production and luteal cell death. There is a critical role for embryonic interferon-tau (IFNT) in suppressing the uterine secretion of PGF2A during early pregnancy (d13-21 in sheep; d16-25 in cattle) and preventing luteolysis. There are also effects of IFNT on the expression of interferon-stimulated genes in other tissues including the CL but the physiologic role of these interferon-stimulated genes is not yet clear. After the IFNT period, there is another mechanism that maintains the CL of pregnancy in ruminants since embryonic IFNT is inhibited as attachment occurs and trophoblastic binucleate/giant cells begin secretion of pregnancy-associated glycoproteins. The second mechanism for luteal maintenance has not yet been defined but acts in a local manner (ipsilateral to pregnancy), and remains functional from d25 until just before parturition. The most likely mechanisms mediating later maintenance of the CL of pregnancy are increased uterine blood flow or decreased prostaglandin transporter expression in the utero-ovarian vasculature, preventing PGF2A reaching the CL. Finally, implications of these ideas on pregnancy loss in cattle are explored, highlighting the importance of inappropriate regression of the CL of pregnancy as a mechanism for pregnancy loss in cattle.

Purpose: We examined the effects of travoprost on cell proliferation-related signals and E-cadherin expression in vitro and in situ in order to obtain evidence to support the hypothesis that topical travoprost impairs the integrity of the corneal epithelium.Methods: A human corneal epithelial cell culture was treated with travoprost (0.4 mg/ml) and/or PD168393 (an EGF receptor inhibitor, 10 μM). The culture was then processed for cell proliferation, an mRNA expression analysis of epidermal growth factor (EGF) and E-cadherin, and protein expression analysis of E-cadherin by immunocytochemistry and Western blotting. The eyes of C57/BL6 mice were incubated in serum-free medium plus travoprost (0.4 mg/ml) and/or PD168393 (10 μM). After being cultured for 24 h, the expression patterns of phospho-EGFR, phospho-ERK, E-cadherin, and Ki67 were immunohistochemically examined in paraffin sections.Results: The addition of travoprost up-regulated EGF mRNA expression and cell proliferation in the corneal epithelial cell culture, and this was cancelled by the addition of PD168393. This FP agonist also decreased E-cadherin expression levels in the cell-cell contact zone, and this was cancelled by the addition of PD168393. In the organ culture, the addition of travoprost to the medium up-regulated the expression of phospho-EGFR and phospho-ERK as well as cell proliferation, and down-regulated the expression of E-cadherin in the corneal epithelium, particularly in basal cells, whereas PD168393 reversed these effects.Conclusions: Travoprost activates epithelial cell proliferation by up-regulating an EGF-related signal in association with the suppression of E-cadherin localization in the cell-cell contact zone. Modulation of the EGF signal may be a strategy to minimize the negative impact of this mitogen on reformation of corneal barrier function during epithelial renewal.

The interval from both spontaneous and prostaglandin (PGF)-induced luteolysis to ovulation is greatly variable in mares. Several reports have shown a positive association between the length of the interval from PGF treatment to ovulation (ITO) and the subsequent pregnancy rate (PR). However, it is not known whether this association also occurs in estrous cycles with spontaneous luteolysis. The main objective of this study was to determine the effect of the duration of estrus-like echotexture of the uterus during the follicular phase on the subsequent PR in both spontaneous and PGF-induced cycles. A total of 768 estrous cycles from 325 thoroughbred mares were analyzed (401 estruses were induced with exogenous PGF and 367 cycles were not treated with PGF). The following factors were taken into account to determine the effect on PR: age of the mare, stallion, year of breeding, month of season, reproductive status of the mare, use of PGF treatment, duration of follicular phase with estrus-like echotexture, interovulatory interval (IOI; in spontaneous cycles), and ITO (in PGF-induced cycles). The age of the mare (P = 0.017), mare status (P = 0.031), the ITO (P = 0.041), and the duration of the follicular phase with estrus-like echotexture (P < 0.001) influenced the PR. The PR increased with the duration of estrus and of endometrial edema in both PGF-induced and spontaneous cycles. The correlation between the duration of endometrial edema and the IOI and ITO was positive (r = 0.5) and significant (P < 0.05).

The objective of the study was to determine the effect of three different PGF2α (PGF) treatments in the 5-day CO-Synch progesterone-based synchronization protocol on artificial insemination (AI) pregnancy rate (PR) in Holstein heifers in Turkey and the United States. We hypothesized that two doses of PGF administered concurrently or 6 hours apart would result in greater AI pregnancy compared with a single dose of PGF on Day 5 at controlled internal drug release (CIDR) removal. In Turkey, Holstein heifers (n = 450) from one farm in the province of Adana and another farm in the province of Bursa were included. In the US, Holstein heifers (n = 483) from two locations in the state of Idaho were included. Heifers within locations were randomly allocated to one of three protocol groups: 1PGF-received 25 mg IM of dinoprost at CIDR removal; 2Co-PGF-received 50 mg IM of dinoprost at CIDR removal, and 2PGF-received 25 mg IM of dinoprost at CIDR removal and an additional 25 mg IM of dinoprost 6 hours later. All heifers received a CIDR (1.38 g of progesterone) and GnRH (10 μg IM of Buserelin [Turkey] or gonadorelin hydrochloride [US]) on Day 0. The CIDRs were removed on Day 5, and each heifer was given PGF according to the assigned treatments. On Day 7, each heifer was given another dose of GnRH and concurrently inseminated at 56 hours after CIDR removal. Heifers in both experiments were examined for pregnancy status between 35 and 45 days after AI. Overall, controlling for age, the heifers in the 2PGF group had greater AI-PR (61.7% [192/311]) than heifers in 2Co-PGF (48.2% [149/309]; P < 0.001) or 1PGF (53.7% [168/313]; P < 0.05) groups. No difference was observed between 2Co-PGF and 1PGF groups (P > 0.1). In Turkey, the heifers in the 2PGF group had a greater AI-PR (60% [90/150]) than 2Co-PGF (45.3% (68/150); P < 0.01] group. No difference was observed between 2PGF and 1PGF (55.3% [83/150]) groups (P > 0.1). There was a trend for AI pregnancy between 1PGF and 2Co-PGF groups (P = 0.08). In the United States, the heifers in the 2PGF group had a greater AI-PR (63.4% [102/161]) than the heifers in 2PGF (50.9 [81/159]; P < 0.05) or 1PGF (52.1% [85/163]; P < 0.05) groups. Heifers that were 15- and 16-month old achieved greater AI-PR than 17- and 18-month-old heifers (59.2 [342/578] vs. 47.0% [168/355]; P < 0.01). In conclusion, administration of 2PGF at 6 hours apart on Day 5 at CIDR removal in a 5-day CO-Synch + CIDR protocol resulted in greater AI pregnancy. A greater number of 15- and 16-month-old heifers became pregnant compared with 17- and 18-month-old heifers.

OBJECTIVE: The aim of this systematic review and metaanalysis was to determine the efficacy and safety of cervical ripening agents in the second trimester of pregnancy in patients with previous cesarean delivery.
METHODS: Data sources were PubMed, EMBASE, CINAHL, LILACS, Google Scholar, and clinicaltrials.gov (1983 through 2015). Eligibility criteria were cohort or cross-sectional studies that reported on efficacy and safety of cervical ripening agents in patients with previous cesarean delivery. Efficacy was determined based on the proportion of patients achieving vaginal delivery and vaginal delivery within 24 hours following administration of a cervical ripening agent. Safety was assessed by the risk of uterine rupture and complications such as retained placental products, blood transfusion requirement, and endometritis, when available, as secondary outcomes. Of the 176 studies identified, 38 met the inclusion criteria. Of these, 17 studies were descriptive and 21 studies compared the efficacy and safety of cervical ripening agents between patients with previous cesarean and those with no previous cesarean. From included studies, we abstracted data on cervical ripening agents and estimated the pooled risk differences and risk ratios with 95% confidence intervals. To account for between-study heterogeneity, we estimated risk ratios based on underlying random effects analyses. Publication bias was assessed via funnel plots and across-study heterogeneity was assessed based on the I(2) measure.
RESULTS: The most commonly used agent was PGE1. In descriptive studies, PGE1 was associated with a vaginal delivery rate of 96.8%, of which 76.3% occurred within 24 hours, uterine rupture in 0.8%, retained placenta in 10.8%, and endometritis in 3.9% in patients with ≥1 cesarean. In comparative studies, the use of PGE1, PGE2, and mechanical methods (laminaria and dilation and curettage) were equally efficacious in achieving vaginal delivery between patients with and without prior cesarean (risk ratio, 0.99, and 95% confidence interval, 0.98-1.00; risk ratio, 1.00, and 95% confidence interval, 0.98-1.02; and risk ratio, 1.00, and 95% confidence interval, 0.98-1.01; respectively). In patients with history of ≥1 cesarean the use of PGE1 was associated with higher risk of uterine rupture (risk ratio, 6.57; 95% confidence interval, 2.21-19.52) and retained placenta (risk ratio, 1.21; 95% confidence interval, 1.03-1.43) compared to women without a prior cesarean. However, the risk of uterine rupture among women with history of only 1 cesarean (0.47%) was not statistically significant (risk ratio, 2.36; 95% confidence interval, 0.39-14.32), whereas among those with history of ≥2 cesareans (2.5%) was increased as compared to those with no previous cesarean (0.08%) (risk ratio, 17.55; 95% confidence interval, 3.00-102.8). Funnel plots did not demonstrate any clear evidence of publication bias. Across-study heterogeneity ranged from 0-81%.
CONCLUSIONS: This systematic review and metaanalysis provides evidence that PGE1, PGE2, and mechanical methods are efficacious for achieving vaginal delivery in women with previous cesarean delivery. The use of prostaglandin PGE1 in the second trimester was not associated with significantly increased risk for uterine rupture among women with only 1 cesarean; however, this risk was substantially increased among women with ≥2 cesareans although the absolute risk appeared to be relatively small.

Prostanoids and PGE2 in particular have been long viewed as one of the major mediators of inflammation in arthritis. However, experimental data indicate that PGE2 can serve both pro- and anti-inflammatory functions. We have previously shown (Kojima et al., J. Immunol. 180 (2008) 8361-8368) that microsomal prostaglandin E synthase-1 (mPGES-1) deletion, which regulates PGE2 production, resulted in the suppression of collagen-induced arthritis (CIA) in mice. This suppression was attributable, at least in part, to the impaired generation of type II collagen autoantibodies. In order to examine the function of mPGES-1 and PGE2 in a non-autoimmune form of arthritis, we used the collagen antibody-induced arthritis (CAIA) model in mice deficient in mPGES-1, thereby bypassing the engagement of the adaptive immune response in arthritis development. Here we report that mPGES-1 deletion significantly increased CAIA disease severity. The latter was associated with a significant (~3.6) upregulation of neutrophil, but not macrophage, recruitment to the inflamed joints. The lipidomic analysis of the arthritic mouse paws by quantitative liquid chromatography/tandem mass-spectrometry (LC/MS/MS) revealed a dramatic (~59-fold) reduction of PGE2 at the peak of arthritis. Altogether, this study highlights mPGES-1 and its product PGE2 as important negative regulators of neutrophil-mediated inflammation and suggests that specific mPGES-1 inhibitors may have differential effects on different types of inflammation. Furthermore, neutrophil-mediated diseases could be exacerbated by inhibition of mPGES-1.