Effects of prostaglandin E and F receptor agonists in vivo on luteal function in ewes
Introduction
Luteinizing hormone (LH) regulates luteal progesterone secretion during the estrous cycle or early pregnancy in ewes [1], [2], [3], [4], [5]. Receptors for LH are on both small (SLC) and large (LLC) steroidogenic cells in the corpus luteum [6]; however, LH increases SLC progesterone secretion via adenylate cyclase activity, cAMP, and protein kinase A (PKA), but not by LLC [2], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Loss of progesterone secretion at the end of the estrous cycle in ewes is via uterine PGF2α secretion [16], [17], [18], [19], [20]. However, PGF2α in endometrium 31 [21], uterine [22], [23], [24], [25], [26], [27], [28], [29], [30] or ovarian venous blood [22], [23], luteal tissue [22], [30], binding of PGF2α to luteal membranes [31], or transport of PGF2α from the uterine vein to the adjacent ovarian artery of the luteal-containing ovary [22], [23], [32], are not decreased to explain prevention of luteolysis during early pregnancy. In addition, ovine placental secretion of PGF2α in vitro [33] or PGF2α in medium of luteal tissue cultured from pregnant ewes [34] does not decrease until day-50 of pregnancy. Instead, the embryo–endometrial interaction provides resistance to PGF2α-induced luteolysis during early pregnancy [35], [36], [37]. This resistance to PGF2α is due to the 2-fold increase in PGE1 and PGE2 in the endometrium on day-13 of pregnancy in ewes [21]. Concentrations of PGE2 are increased in uterine venous blood [25], [26], [27], [28], [29] and the PGE:PGF2α ratio increases from 0.1:1 on day-8 to 1:1 during early pregnancy in ewes [28], [29]. Furthermore, chronic intrauterine infusion of PGE1 or PGE2 adjacent to the luteal-containing ovary prevents spontaneous [16], [17], [18], [19], [38], [39], [40] or premature luteolysis induced by estradiol-17β [41], [42], IUD [43], [44], or PGF2α [45], [46]. In addition, PGE1 given intramuscularly in cows increased progesterone for 72 h [47]. Acute treatment with PGE1 in the interstitial tissue of the ovarian vascular pedicle of the luteal-containing ovary of ewes increases occupied and unoccupied luteal LH receptors, while PGE2 does not increase occupied or unoccupied LH receptors in luteal tissue [46]. Moreover, chronic intrauterine treatment with PGE1 from days-10 to 16 post-estrus increased luteal occupied and unoccupied LH receptors, mRNA for LH receptors, and circulating progesterone, while PGE2 only prevented a decrease in mRNA for LH receptors, occupied and unoccupied luteal LH receptors, and circulating progesterone [46], [48] in ewes. These data indicate differences in PGE1 and PGE2 actions to prevent luteolysis. Four subtypes of PGE receptors (EP1, EP2, EP3, and EP4) and an FP receptor have been identified [48], [49], [50], [51], [52]. Data on PGE receptor subtypes have been primarily from in vitro binding [47], [48], [49], [50], [51], [52], [53] rather than in vivo functional studies. The objective of this experiment was to determine the effects of acute treatment with EP1, EP2, EP3, or FP receptor agonists in the interstitial tissue of the ovarian vascular pedicle adjacent to the luteal-containing ovary on occupied and unoccupied luteal LH receptors, mRNA for LH receptors, and circulating progesterone during the estrous cycle of ewes.
Section snippets
Animals, treatments, and sample collection
The experimental protocol was approved by the University of Hawaii IACUC. Merino crossbred ewes were checked twice daily (0800 and 1700 h) for estrus with brisket-painted vasectomized rams. Estrus was designated as day-0 of the estrous cycle. Only ewes with two consecutive interestrous intervals of 16–17 days were used. Ewes were fasted for 12 h before surgery and received 1 cc (0.54 mg) atropine sulfate (Phoenix Pharmaceuticals, Inc., St. Joseph, MO) intramuscularly as a preanesthetic. Ewes were
Results
Luteal weights were decreased (P ≤ 0.05) at 48 h in PGF2α and sulprostone-treated ewes when compared to vehicle, 17-phenyl-tri-Nor-PGE2, butaprost, or 19-(R)-OH-PGE2-treated ewes, which did not differ (P ≥ 0.05) amongst each other (Fig. 1). Profiles of progesterone in PGF2α or sulprostone-treated ewes were lower (P ≤ 0.05) compared to vehicle, 17-phenyl-tri-Nor-PGE2, butaprost, or 19-(R)-OH-PGE2-treated ewes, while progesterone profiles did not differ (P ≥ 0.05) between vehicle and 17-phenyl-tri-Nor-PGE2
Discussion
Weights of corpora lutea and concentrations of circulating progesterone of vehicle, 17-phenyl-tri-Nor-PGE2, butaprost, or 19-(R)-OH-PGE2-treated ewes were not decreased, which indicates that these treatments did not initiate luteal regression. However, the decrease in luteal weights and concentrations of circulating progesterone of ewes treated with PGF2α or sulprostone over the 48 h treatment period is indicative that these treatments initiated regression of the corpora lutea. Luteal regression
Acknowledgements
The authors would like to thank Mr. Wayne Toma (University of Hawaii) for assistance with statistical analysis and graphics and Mr. Armand Unabia and Mr. Alan Umaki, Waialee Livestock Research Center for care of animals and detection of estrus. Antisera for progesterone were kindly provided by Dr. R.L. Butcher, West Virginia University, Morgantown, West Virginia; antisera for PGF2α were kindly provided by Dr. L. Levine, Brandeis University, Waltham, MA, and antiserum for PGE was kindly supplied
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2017, TheriogenologyCitation Excerpt :An EP2R agonist given into the interstitial tissue of the ovarian vascular pedicle adjacent to the luteal-containing ovary increased mRNA expression of luteal LHR and occupied and unoccupied LHR, while an EP3R agonist or PGF2α decreased circulating progesterone, luteal mRNA for LH receptors, and luteal unoccupied and occupied LHR [22]. An EP1R agonist had no effect on luteal function in vivo in ewes [22]. In cows, intraluteal silastic implants inserted on Day-13 postestrus containing PGE1 or PGE2 prevented loss of circulating progesterone, luteal mRNA expression for LHR and luteal unoccupied and occupied LHR on Day-19 postestrus, [23].
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2015, Knobil and Neill's Physiology of Reproduction: Two-Volume SetIn vivo intra-luteal implants of prostaglandin (PG) E <inf>1</inf> or E <inf>2</inf> (PGE <inf>1</inf>, PGE <inf>2</inf>) prevent luteolysis in cows. II: MRNA for PGF <inf>2α</inf>, EP1, EP2, EP3 (A-D), EP3A, EP3B, EP3C, EP3D, and EP4 prostanoid receptors in luteal tissue
2012, Prostaglandins and Other Lipid MediatorsCitation Excerpt :Support for both FP as well as EP3 receptors being involved in luteolysis has been reported in ewes [30]. Treatment with an EP3 receptor agonist was as effective as exogenous PGF2α in inducing luteolysis in ewes [30] and PGF2α does not affect expression of mRNA for EP3 receptors in ewes [37]. A single treatment with an EP3 receptor agonist given at mid-cycle into the interstitial tissue of the ovarian vascular pedicle adjacent to the luteal-containing ovary of ewes was as effective as a luteolytic dose of PGF2α given via the same route in decreasing luteal weight, circulating progesterone, luteal mRNA for LH receptors, and luteal unoccupied and occupied receptors for LH over the 48 h treatment period [30].