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Antral follicle count (AFC) and anti-Müllerian hormone (AMH) concentrations are reflective for ovarian reserve and have been associated with improved reproductive performance in cattle. Key events for regulation of uterine receptivity are orchestrated by progesterone. As progesterone concentrations are greater in animals with high than low AFC, we tested the hypothesis, if the resulting improved uterine environment will lead to improved conceptus elongation and endometrial response to interferon tau. For four years, 10 heifers with lowest and highest AFC, respectively, were selected from 120 heifers. Reproductive tracts and blood samples for progesterone and AMH analysis were collected after synchronization and insemination. For a recovered conceptus, length was determined, and interferon tau (IFNT) transcript abundance was analyzed. Endometrial transcript abundance of interferon-stimulated gene 15 (ISG15) and oxytocin receptor (OXTR) were analyzed. Progesterone concentrations did not differ between low and high AFC groups (P = 0.1). A difference in conceptus length was not observed. Endometrial abundance of ISG15 did not differ between pregnant low and high AFC heifers. Abundance of OXTR was greater in open low AFC than open high AFC heifers (P < 0.01). Interaction of AMH and pregnancy status was determined, with greater AMH in pregnant than open high AFC heifers (P < 0.05). Improved uterine environment in high vs. low AFC heifers did not result in longer conceptuses or improved endometrial response. As the increase in OXTR transcript abundance was only detected in low AFC heifers, reported differences in reproductive performance might be associated with earlier initiation of luteolysis. Summary Sentence Up-regulation of endometrial oxytocin receptor transcription is a prerequisite for the initiation of luteolysis and occurs later in heifers with increased ovarian reserve indicating temporal differences in the initiation of luteolysis. Graphical Abstract

Conceptus-derived interferon-tau (IFNT) initiates maternal recognition of pregnancy in ewes by paracrine actions on the endometrium and endocrine action on the corpus luteum (CL). To examine the effect of IFNT on the CL without inducing IFN-stimulated genes (ISGs) in the endometrium, recombinant ovine IFNT (roIFNT) or bovine serum albumin was delivered directly into CLs via osmotic pumps at a rate of 10, 50, or 100 ng/h from days 9 to 12 of the estrous cycle. Endometrial and CL samples were collected on day 12. 50 ng/h of roIFNT induced ISG15 in the CL on day 12 without affecting endometrial ISG15 concentrations. In a second experiment, roIFNT (50 ng/h) was infused into the CL from days 10 to 17 of the estrous cycle and serum samples were collected daily. Serum progesterone concentrations were significantly higher from days 15 to 17 in roIFNT-infused ewes compared to controls. Levels of LHCGR, STAR, CYP11A1, HSL, OPA1, and protein kinase A mRNA and proteins were higher in the roIFNT-infused CLs compared to the controls. Levels of ISG15 and MX1 mRNA increased in the CLs of roIFNT-infused ewes but not in the endometrium. Endometrial ESR1 mRNA and protein concentrations were higher in the controls compared to roIFNT-infused ewes. In conclusion, intra-luteal delivery of roIFNT induced ISGs, stabilized steroidogenesis in the CL, and delayed luteolysis without inducing endometrial IFN-stimulated genes. Inhibition of ESR1 in the endometrium of roIFNT-infused ewes was observed suggesting that direct delivery of IFNT to the CL has an additional anti-luteolytic effect on the endometrium. Summary Sentence Interferon-tau induces interferon-stimulated genes, delays luteolysis, and stabilizes steroidogenesis in the ovine corpus luteum. Graphical Abstract

Conceptus estrogens and prostaglandins have long been considered the primary signals for maternal recognition of pregnancy (MRP) in the pig. However, loss-of-function studies targeting conceptus aromatase genes (CYP19A1 and CYP19A2) and prostaglandin–endoperoxide synthase 2 (PTGS2) indicated that conceptuses can not only signal MRP without estrogens or prostaglandins but can maintain early pregnancy. However, complete loss of estrogen production leads to abortion after day 25 of gestation. Although neither conceptus estrogens nor prostaglandins had a significant effect on early maintenance of corpora lutea (CL) function alone, the two conceptus factors have a biological relationship. To investigate the role that both conceptus estrogens and prostaglandins have on MRP and maintenance of pregnancy, a triple loss-of function model (TKO) was generated for conceptus CYP19A1, CYP19A2, and PTGS2. In addition, a conceptus CYP19A2–/– model (A2KO) was established to determine the role of placental estrogen during later pregnancy. Estrogen and prostaglandin synthesis were greatly reduced in TKO concept uses which resulted in a failure to inhibit luteolysis after day 15 of pregnancy despite the presence of conceptuses in the uterine lumen. However, A2KO placentae not only maintained functional CL but were able to maintain pregnancy to day 32 of gestation. Despite the loss of placental CYP19A2 expression, the allantois fluid content of estrogen was not affected as the placenta compensated by expressing CYP19A1 and CYP19A3, which are normally absent in controls. Results suggest conceptuses can signal MRP through production of conceptus PGE or stimulating PGE synthesis from the endometrium through conceptus estrogen. Failure of conceptuses to produce both factors results in failure of MRP and loss of pregnancy. Summary Sentence Triple knockout of conceptus CYP19A1/CYP19A2/PTGS2 results in failure to prevent luteolysis during early pregnancy in the pig. Graphical Abstract

The corpus luteum is a small gland of great importance because its proper functioning determines not only the appropriate course of the estrous/menstrual cycle and embryo implantation, but also the subsequent maintenance of pregnancy. Among the well-known regulators of luteal tissue functions, increasing attention is focused on the role of neuropeptides and adipose tissue hormones—adipokines. Growing evidence points to the expression of these factors in the corpus luteum of women and different animal species, and their involvement in corpus luteum formation, endocrine function, angiogenesis, cells proliferation, apoptosis, and finally, regression. In the present review, we summarize the current knowledge about the expression and role of adipokines, such as adiponectin, leptin, apelin, vaspin, visfatin, chemerin, and neuropeptides like ghrelin, orexins, kisspeptin, and phoenixin in the physiological regulation of the corpus luteum function, as well as their potential involvement in pathologies affecting the luteal cells that disrupt the estrous cycle.

The proposed signal for maternal recognition of pregnancy in pigs is estrogen (E2), produced by the elongating conceptuses between days 11 to 12 of pregnancy with a more sustained increase during conceptus attachment and placental development on days 15 to 30. To understand the role of E2 in porcine conceptus elongation and pregnancy establishment, a loss-of-function study was conducted by editing aromatase (CYP19A1) using CRISPR/Cas9 technology. Wild-type (CYP19A1+/+) and (CYP19A1–/–) fibroblast cells were used to create embryos through somatic cell nuclear transfer, which were transferred into recipient gilts. Elongated and attaching conceptuses were recovered from gilts containing CYP19A1+/+ or CYP19A1–/– embryos on day 14 and 17 of pregnancy. Total E2 in the uterine flushings of gilts with CYP19A1–/– embryos was lower than recipients containing CYP19A1+/+ embryos with no difference in testosterone, PGF2α, or PGE2 on either day 14 or 17. Despite the loss of conceptus E2 production, CYP19A1–/– conceptuses were capable of maintaining the corpora lutea. However, gilts gestating CYP19A1–/– embryos aborted between days 27 and 31 of gestation. Attempts to rescue the pregnancy of CYP19A1–/– gestating gilts with exogenous E2 failed to maintain pregnancy. However, CYP19A1–/– embryos could be rescued when co-transferred with embryos derived by in vitro fertilization. Endometrial transcriptome analysis revealed that ablation of conceptus E2 resulted in disruption of a number biological pathways. Results demonstrate that intrinsic E2 conceptus production is not essential for pre-implantation development, conceptus elongation, and early CL maintenance, but is essential for maintenance of pregnancy beyond 30 days . Summary Sentence Ablation of pig conceptus estrogen production does not affect early maternal recognition of pregnancy and conceptus development but causes a ripple effect in conceptus/endometrial programming resulting in failure to maintain pregnancy beyond 30 days of gestation.

Pregnancy loss (PL) in lactating dairy cows disrupts reproductive and productive efficiency. We evaluated the expression of interferon-stimulated genes (ISG) in blood leukocytes, vaginal and cervical epithelial cells, luteolysis-related genes, progesterone, and pregnancy-associated glycoprotein (PAG) profiles in lactating dairy cows (n = 86) to gain insight about PL. Expression of ISG on d17, d19, and d21 was greater in cows that maintained the pregnancy (P33) compared to nonpregnant with no PL (NP). Greater ISG differences between groups were observed in the cervix (96.7-fold) than vagina (31.0-fold), and least in blood leukocytes (5.6-fold). Based on individual profiles of ISG and PAG, PL was determined to occur either before (∼13%) or after (∼25%) d22. For cows with PL before d22, ISG expression was similar on d17 but by d21 was lower and OXTR was greater than P33 cows and similar to NP; timing of luteolysis was similar compared to NP cows suggesting embryonic failure to promote luteal maintenance and to attach to the endometrium (no increase in PAG). For cows with PL after d22, ISG expression was similar to P33 cows on d17, d19, and d21 and luteolysis, when it occurred, was later than NP cows; delayed increase in PAG suggested later or inadequate embryonic attachment. In conclusion, PL before d22 occurred due to embryonic demise/failure to signal for luteal maintenance, as reflected in reduced ISG expression by d21. Alternatively, embryos with PL between d22 and 33 adequately signaled for luteal maintenance (ISG) but had delayed/inadequate embryonic attachment and/or inappropriate luteolysis causing PL. Summary Sentence Evaluation of interferon-stimulated genes in multiple tissues showed that the cervix had the greatest expression and revealed that ∼13% of pregnancy loss occurred between d17 and 22, whereas ∼25% of pregnancy loss occurred between d22 and 33. Graphical Abstract

The study aimed to evaluate the mRNA expression levels of various local novel adipokines, including vaspin, adiponectin, visfatin, and resistin, along with their associated receptors, heat shock 70 protein 5, adiponectin receptor 1, and adiponectin receptor 2, in the corpus luteum (CL) during luteal regression, also known as luteolysis, in dairy cows. We selected Fleckvieh cows in the mid-luteal phase (days 8–12, control group) and administered cloprostenol (PGF analog) to experimentally induce luteolysis. We collected CL samples at different time points following PGF application: before treatment (days 8–12, control group) and at 0.5, 2, 4, 12, 24, 48, and 64 h post-treatment (n = 5) per group. The mRNA expression was measured via real-time reverse transcription polymerase chain reaction (RT-qPCR). Vaspin was characterized by high mRNA levels at the beginning of the regression stage, followed by a significant decrease 48 h and 64 h after PGF treatment. Adiponectin mRNA levels were elevated 48 h after PGF. Resistin showed upregulation 4 h post PGF application. In summary, the alterations observed in the adipokine family within experimentally induced regressing CL tissue potentially play an integral role in the local regulatory processes governing the sequence of events culminating in functional luteolysis and subsequent structural changes in the bovine ovary.

Early embryonic loss is a major cause of reproductive inefficiency in cattle, primarily due to premature luteolysis. Interferon tau (IFN-τ), secreted by the trophoblast, plays a critical role in maternal recognition of pregnancy by maintaining corpus luteum function. However, its practical application has been limited by its rapid degradation and short half-life in vivo. Here, we developed a novel formulation of recombinant bovine IFN-τ, combining chitosan-based microencapsulation with starch–chitosan hydrogel delivery, enabling sustained intrauterine release. This dual-delivery strategy offers a significant improvement over conventional IFN-τ administration methods that rely on repeated intrauterine infusions of soluble protein. The rbIFN-τ was expressed in Pichia pastoris, purified to 90.1% homogeneity, and structurally validated via homology modeling and molecular docking, confirming its interaction with type I interferon receptors. The encapsulated formulation retained antiviral activity, stimulated transcription of interferon-stimulated genes (PKR, OAS1, OAS2), and showed sustained release in vitro for up to 26 days. In vivo evaluation demonstrated safety and biological efficacy, with treated cattle showing inhibited luteolysis, sustained serum progesterone levels, and preserved corpus luteum integrity. This formulation represents a promising biotechnological approach to improve reproductive efficiency through a long-acting, species-specific IFN-τ delivery system.

The pulsatile pattern of prostaglandin F2alpha (PGF) secretion during spontaneous luteolysis is well documented, with multiple pulses of exogenous PGF necessary to induce regression using physiologic concentrations of PGF. However, during spontaneous regression, the earliest pulses of PGF are small and not associated with detectable changes in circulating progesterone (P4), bringing into question what, if any, role these early, subluteolytic PGF pulses have during physiologic regression. To investigate the effect of small PGF pulses, luteal biopsies were collected throughout natural luteolysis in conjunction with bihourly blood samples to determine circulating P4 and PGF metabolite to retrospectively assign biopsies to early and later regression. Whole transcriptome analysis was conducted on CL biopsies. Early PGF pulses altered the luteal transcriptome, inducing differential expression of 210 genes (Q < 0.05) during early regression, compared with 4615 differentially expressed genes during later regression. In early regression, few of these differentially expressed genes were directly associated with luteolysis, rather there were changes in local steroid and glutathione metabolism. Most (94%) differentially expressed genes from early regression were also differentially expressed during later regression, with 98% of these continuing to be altered in the same direction compared with CL at a similar stage of the cycle that had not yet been exposed to PGF. Thus, early, subluteolytic PGF pulses impact the luteal transcriptome, though not by altering steroidogenesis or causing direct inhibition of cellular function. Rather, small pulses alter pathways resulting in the removal of cellular support systems, which may sensitize the CL to later pulses of PGF. Summary sentence Early stages of spontaneous luteolysis involve prostaglandin F2alpha pulses too small to impact steroidogenesis; nonetheless, these pulses are capable of removing cellular support systems such as local progesterone signaling and glutathione-based anti-oxidant metabolism that may sensitize the CL to later pulses of PGF.

In heifers and mares, multiple pulses of prostaglandin F2alpha (PGF) are generally associated with complete luteal regression. Although PGF pulses occur before and during luteolysis, little is known about the role of minor PGF pulses during preluteolysis on subsequent luteal and endometrial PGF production that may initiate luteolysis. Heifers (n = 7/group) and mares (n = 6/group) were treated with a single minor dose of PGF (3.0 and 0.5 mg, respectively) during mid-luteal phase (12 and 10 days postovulation respectively). After treatment, a transient decrease in progesterone (P4) concentrations occurred in heifers between Hours 0 and 2 but at Hour 4 P4 was not different from pretreatment. In mares, P4 was unaltered between Hours 0 and 4. Concentrations of P4 decreased in both species by Hour 24 and complete luteolysis occurred in mares by Hour 48. Luteal and endometrial gene expression were evaluated 4 h posttreatment. In heifers, luteal mRNA abundance of PGF receptor and PGF dehydrogenase was decreased, while PTGS2, PGF transporter, and oxytocin receptor were increased. In the heifer endometrium, receptors for oxytocin, P4, and estradiol were upregulated. In mares, luteal expression of PGF receptor was decreased, while PGF transporter and oxytocin receptor were increased. The decrease in P4 between Hours 4 and 24 and changes in gene expression were consistent with upregulation of endogenous synthesis of PGF. The hypotheses were supported that a single minor PGF treatment upregulates endogenous machinery for PGF synthesis in heifers and mares stimulating endogenous PGF synthesis through distinct regulatory mechanisms in heifers and mares. Summary Sentence A minor PGF pulse causes a transient decrease in P4 in heifers but not in mares and upregulates endogenous machinery for PGF synthesis in both species through distinct endometrial, luteal, and hormonal responses to PGF. Graphical Abstract