Endocrine and local cellular signaling of hormones involved in the regulation of the transition from cyclicity to pregnancy in livestock

Early pregnancy loss is one of the biggest drawbacks in agriculture today and causes economic, ecologic and ethical burden on farms. In cattle, losses occur mainly during the preimplantation period and are hypothesized to be a result of an inadequate embryo maternal communication leading to failures in pregnancy recognition. Consequently, the regression of the corpus luteum (CL), which is the primary source for the pregnancy maintaining hormone progesterone (P4), is not inhibited. In cattle and swine, the regulation of the estrous cycle as the basis for reproduction and especially the initiation of luteolysis during the estrous cycle is not completely understood. In addition, the factors and mechanisms necessary for the inhibition of the latter during pregnancy as an essential part in the process of pregnancy recognition are not fully known to date. During the estrous cycle, estrogens trigger ovulation and P4 is produced by the CL during the subsequent luteal phase. If pregnancy does not establish, the luteal phase of the estrous cycle is terminated by luteolysis, which is triggered by pulses of prostaglandin F2α (PGF2α) resulting in the regression of the CL. Metabolites of the steroids P4 and estradiol-17β (E2) have for long been thought to serve only as excretory products. Nowadays, this assumption is outdated. It is hypothesized that steroid metabolites take part in regulating the estrous cycle and are potentially involved in the initiation of luteolysis. Therefore, we determined ten different P4 metabolites and estrogen conjugates during the estrous cycle of cattle and swine. We found that the profiles of P4 metabolites correlated well with P4 except for the period around luteolysis. During luteolysis, P4 levels dropped more rapidly leading to an increased P4 metabolite to P4 ratio thereafter. Estrogen conjugate levels in serum were found to be rather constant during the estrous cycle, whereas conjugated E2 levels in the endometrium were high at ovulation, decreased thereafter and began to transiently increase again beginning at day 12 post ovulation. The observed increase is probably due to an endometrial estradiol synthesis in swine and might be involved in the initiation of luteolysis. In case of pregnancy in cattle and swine, luteolysis must be inhibited to maintain P4 secretion by the CL. Since prostaglandin E2 (PGE2) is thought to play a luteoprotective role, it is suggested that a reorientation of PGF2α towards PGE2 production within the reproductive tract is a prerequisite for a successful establishment of pregnancy in ruminants and in swine. A previous study in cattle however revealed that intrauterine prostacyclin (PGI2) and PGF2α highly exceed intrauterine PGE2. Consequently, we hypothesized that in addition to PGE2, other prostaglandins might contribute to a successful establishment of pregnancy. Within the framework of this thesis, we aimed at determining the prostaglandin secretome of the bovine embryo during different stages of the preimplantation period from blastocyst hatching until embryo elongation. For this purpose, we developed a liquid chromatography–mass spectrometry (LC-MS) based approach for the quantification of 30 different prostaglandins and metabolites and measured prostaglandins in embryo culture supernatants. We found that bovine embryos predominantly secrete PGE2 and Δ12-PGD2 until day 12 post insemination. iv Thereafter, prostaglandins of the F-series (6keto-PGF1α, > PGF2α > PGE2) are the most abundant prostaglandins produced by the embryo. These findings suggest that the prostaglandin secretion of the bovine embryo changes dynamically with the advancing development. Thus, a complex mixture of prostaglandins influences endometrial secretion generating an optimal uterine environment for the developing embryo. The quantification of novel players during the estrous cycle and early pregnancy found the basis for a better understanding of the transition from cyclicity to pregnancy in livestock. Yet, their specific role in fine-tuning the endometrial function during the estrous cycle and the preimplantation period needs to be unraveled in follow-up studies