Lutalyse® induces uterine-ovarian PGF₂α release in sheep: a critical component of induced luteolysis
Exogenous PGF2α, (see Appendix I for definitions of abbreviations) is luteolytic in midluteal (1.e., d 9 of a 17 d estrous cycle) sheep. However, the pharmacokinetic responses to PGF2α-induced luteolysis are not known. This study (Exp. 1 and 2) was conducted to determine several pharmacokinetic responses to two dosing regimens of Lutalyse® (PGF2α). Experiment 1 was a 2 x 2 factorial design, with Lutalyse and H/Ox as main effects. Lutalyse (15 mg) was injected i.m., and blood samples were collected, relative to the time of injection, from the vena cava at points cranial and caudal to the uteroovarian vein. Progesterone and PGF2α, were measured in blood plasma. The PGF2α concentrations were greater in H/Ox and sham H/Ox ewes treated-with Lutalyse® than in control ewes. Peak concentrations of PGF2α were greatest in sham H/Ox Lutalyse-treated ewes, indicating that the uterus and(or) ovaries secrete PGF2α, in response to exogenous PGF2α. In Lutalyse-treated ewes, progesterone concentrations decreased by 50% within 8 h after treatment. The design of Exp. 2 was also a 2 x 2 factorial, with Lutalyse (2 x 5mg at 3 h intervals) and H/Ox as main effects. Prostaglandin F2α and PGFM were measured in blood plasma collected, relative to the time of injections, from the vena cava at points cranial and caudal to the uteroovarian vein. The PGF2α concentrations were greater in sham H/Ox ewes treated-with Lutalyse than in control ewes. Peak concentrations of PGF2α were greater in sham H/Ox than in ewes in all other treatment groups, indicating again that the uterus and(or) ovaries secrete PGF2α in response to exogenous PGF2α In general, PGFM concentrations increased in a pattern similar to that of PGF2α after Lutalyse injection; although there was a short delay of approximately 2 min. Caudal vena caval PGF, concentrations in H/Ox Lutalyse-treated ewes were greater than that after saline injection, which indicates that metabolism may depend on the presence or absence of the uterus and(or) ovaries. In Exp. 1, caudal PGF, concentrations were greater in H/Ox ewes injected with 15 mg of Lutalyse than in ewes in all other treatments . However, in response to 5 mg Lutalyse, caudal PGF2α concentrations were greater in sham H/Ox ewes than in all other treatment groups. This indicates that the larger dose in H/Ox ewes supersedes the capacity of the lung and kidney to dispose of PGF2α, and PGF2α is more tightly regulated in intact ewes. The lungs and kidney are capable of metabolizing the smaller dose of Lutalyse but not the resulting PGF2α production in intact ewes.
A short validation experiment was conducted to determine the effects of sampling location on progesterone, PGF2α and PGFM concentrations. Sampling location did not affect the mean concentration of progesterone or PGFM. However, location affected the mean PGF2α concentration. The concentration of PGF2α, was greater (P < .05) in saphenous vein and caudal vena caval blood plasma than in jugular plasma.
In summary, the uterus and(or) ovaries produce and regulate PGF2α concentration in response to Lutalyse. It is speculated that a threshold PGF2α concentration or duration of the PGF2α peak concentration exists because these PGF2α, responses differed in intact Lutalyse-treated and saline-treated ewes in both experiments. The mean cranial PGF2α concentration, peak concentration, duration of the peak, increase in PGF2α and AUC were greater in response to 15 mg of Lutalyse, although the two smaller doses have been shown to be more efficacious in inducing luteolysis. The second dose of PGF2α may act by mimicking pulses of PGF2α and initiate the luteolytic cascade two times.