Maternal recognition of pregnancy in the horse: a mystery still to be solved

Maternal recognition of pregnancy in the horse is the sum of events leading to maintenance of pregnancy; in a narrow sense, maternal recognition of pregnancy refers to the physiological process by which the lifespan of the corpus luteum is prolonged. The horse is one of the few domestic species in which the conceptus-derived pregnancy recognition signal has not been identified. The presence of the conceptus reduces pulsatile prostaglandin F2α secretion by the endometrium during early gestation in the mare, partly attributed to the reduced expression of cyclooxygenase-2. Cyclooxygenase-2 has therefore been suggested as one of the regulators of endometrial prostaglandin F2α release modified by the antiluteolytic factor secreted by the conceptus. In addition, altered oxytocin responsiveness has been implicated in the adjustment of prostaglandin release in pregnant mares. While conceptus mobility has proven to be essential for establishment of pregnancy, conceptus-derived oestrogens and prostaglandins, principally prostaglandin E2, have not been confirmed as the critical antiluteolytic factor. Various ways to induce prolonged luteal function in the non-pregnant mare will be highlighted in the current review, specifically, how they may pertain to the process of maternal recognition of pregnancy. Furthermore, recently published microarray experiments comparing the transcriptome of pregnant and non-pregnant endometria and different stages of conceptus development will be reviewed. Findings include the prevention of conceptus adhesion, the provision of nutrients to the conceptus and the avoidance of immunological rejection, among others.

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Pregnancy recognition and conceptus implantation in domestic ruminants: roles of progesterone, interferons and endogenous retroviruses

Reproduction Fertility and Development ◽

10.1071/rd06102 ◽

2007 ◽

Vol 19 (1) ◽

pp. 65 ◽

Cited By ~ 187

Author(s):

Thomas E. Spencer ◽

Greg A. Johnson ◽

Fuller W. Bazer ◽

Robert C. Burghardt ◽

Massimo Palmarini

Keyword(s):

Receptor Gene ◽

Cathepsin L ◽

Prostaglandin F2α ◽

Endogenous Retroviruses ◽

Oxytocin Receptor Gene ◽

Domestic Ruminants ◽

Cell Proliferation And Differentiation ◽

New Information ◽

Conceptus Development ◽

Pregnancy Recognition

The present review highlights new information on pregnancy recognition and conceptus development and implantation in sheep with respect to regulation by progesterone, interferons and endogenous retroviruses. After formation of the corpus luteum, progesterone acts on the endometrium and stimulates blastocyst growth and elongation to a filamentous conceptus (embryo/fetus and associated extra-embryonic membranes). The envelope of endogenous retroviruses related to Jaagsiekte sheep retroviruses appears to intrinsically regulate mononuclear trophectoderm cell proliferation and differentiation into trophoblast giant binucleate cells. The mononuclear trophectoderm cells of elongating sheep conceptuses secrete interferon-τ, which acts on the endometrium to prevent development of the luteolytic mechanism by inhibiting transcription of the gene for the oestrogen receptor α in the luminal and superficial ductal glandular epithelia. These actions prevent oestrogen-induced transcription of the oxytocin receptor gene and, therefore, oxytocin-induced luteolytic pulses of prostaglandin F2α. Progesterone downregulation of its receptors in luminal and glandular epithelia correlates temporally with a reduction in anti-adhesive mucin 1and induction of secreted galectin 15 (LGALS15) and secreted phosphoprotein 1, which are proposed to regulate trophectoderm proliferation and adhesion. Interferon-τ acts on the endometrial lumenal epithelium to induce WNT7A and to stimulate LGALS15, cathepsin L and cystatin C, which are candidate regulators of conceptus development and implantation. The number of potential contributors to maternal recognition and establishment of pregnancy continues to grow and this highlights our limited appreciation of the complexity of the key molecules and signal transduction pathways that intersect during these key developmental processes. The goal of improving reproductive efficiency by preventing embryonic losses that occur during the peri-implantation period of pregnancy in domestic ruminants provides the challenge to increase our knowledge of endometrial function and conceptus development.

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Interferon-tau and fertility in ruminants

Reproduction ◽

10.1530/rep-17-0432 ◽

2017 ◽

Vol 154 (5) ◽

pp. F33-F43 ◽

Cited By ~ 25

Author(s):

N Forde ◽

P Lonergan

Keyword(s):

Prostaglandin F2α ◽

Threshold Level ◽

Type I ◽

Interferon Tau ◽

Uterine Endometrium ◽

Domestic Ruminants ◽

Oxytocin Receptors ◽

Pregnancy Recognition ◽

Maternal Recognition Of Pregnancy ◽

Primary Agent

Establishment of pregnancy in domestic ruminants includes pregnancy recognition signalling by the conceptus, implantation and placentation. Despite the high fertilisation success rate in ruminants, a significant amount of embryo loss occurs, primarily during early gestation. Interferon-tau (IFNT), a type I interferon that is exclusively secreted by the cells of the trophectoderm of the ruminant conceptus, has been recognised as the primary agent for maternal recognition of pregnancy in ruminants. It produces its antiluteolytic effect on the corpus luteum by inhibiting the expression of oxytocin receptors in the uterine epithelial cells, which prevents pulsatile, luteolytic secretion of prostaglandin F2α by the uterine endometrium. While the importance of IFNT in maternal recognition of pregnancy and prevention of luteolysis in ruminants is unequivocal, important questions, for example, relating to the threshold level of IFNT required for pregnancy maintenance, remain unanswered. This paper reviews data linking IFNT with measures of fertility in ruminants.

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Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

The Journal of Immunology ◽

10.4049/jimmunol.1101600 ◽

2012 ◽

Vol 188 (10) ◽

pp. 5132-5141 ◽

Cited By ~ 24

Author(s):

Soo Jung Park ◽

Jee Hoon Lee ◽

Hee Young Kim ◽

Youn Hee Choi ◽

Jung Sup Park ◽

...

Keyword(s):

Cyclooxygenase 2 ◽

Prostaglandin Release

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Short oestrous cycles in sheep during anoestrus involve defects in progesterone biosynthesis and luteal neovascularisation

Reproduction ◽

10.1530/rep-13-0400 ◽

2014 ◽

Vol 147 (3) ◽

pp. 357-367 ◽

Cited By ~ 10

Author(s):

H M Brown ◽

C Fabre Nys ◽

J Cognié ◽

R J Scaramuzzi

Keyword(s):

Luteal Phase ◽

Regulatory Protein ◽

Prostaglandin F2α ◽

Significant Loss ◽

Short Cycle ◽

Luteal Function ◽

Expression Of Genes ◽

Molecular Events ◽

Cast Doubt ◽

Ram Effect

Anoestrous ewes can be induced to ovulate by the socio-sexual, ‘ram effect’. However, in some ewes, the induced ovulation is followed by an abnormally short luteal phase causing a so-called ‘short cycle’. The defect responsible for this luteal dysfunction has not been identified. In this study, we investigated ovarian and uterine factors implicated in male-induced short cycles in anoestrous ewes using a combined endocrine and molecular strategy. Before ovulation, we were able to detect a moderate loss of thecal expression of steroid acute regulatory protein (STAR) in ewes that had not received progesterone priming (which prevents short cycles). At and following ovulation, we were able to identify a significant loss of expression of genes coding key proteins involved in the biosynthesis of progesterone (STAR,CYP11A1andHSD3B1(HSD3B)) as well as genes coding proteins critical for vascular development during early luteal development (VEGFAandKDR(VEGFR2)), suggesting dysfunction in at least two pathways critical for normal luteal function. Furthermore, these changes were associated with a significant reduction of progesterone production and luteal weight. Additionally, we cast doubt on the proposed uterus-mediated effect of prostaglandin F2α (PGF2α) as a cause of short cycles by demonstrating the dysregulation of luteal expression of the PGF receptor, which mediates the luteal effects of PGF2α, and by finding no significant changes in the circulating concentrations of PGFM, the principal metabolite of PGF2α in ewes with short cycles. This study is the first of its kind to examine concurrently the endocrine and molecular events in the follicular and early luteal stages of the short cycle.Free French abstractA French translation of this abstract is freely available athttp://www.reproduction-online.org/content/147/3/357/suppl/DC1

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EFFECTS OF PROSTAGLANDIN F2α ON OVARIAN BLOOD FLOW AND VASCULAR RESISTANCE IN THE PSEUDOPREGNANT RABBIT

Acta Endocrinologica ◽

10.1530/acta.0.0790337 ◽

1975 ◽

Vol 79 (2) ◽

pp. 337-350 ◽

Cited By ~ 23

Author(s):

Per Olof Janson ◽

Ivan Albrecht ◽

Kurt Ahrén

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Cardiac Output ◽

Vascular Resistance ◽

Prostaglandin F2α ◽

Interstitial Tissue ◽

Corpora Lutea ◽

Luteal Function ◽

Direct Measurements ◽

Before And After

ABSTRACT In the search for data supporting the hypothesis that the luteolytic effect of prostaglandins (PG) is initiated by a vascular mechanism, some haemodynamic parameters including ovarian blood flow and vascular resistance were measured in pseudopregnant anaesthetized rabbits before and after exogenous administration of PGF2α. The measurements were performed on days 5–10 of pseudopregnancy induced by 500 IU HCG iv. Infusion of 50 μg/kg PGF2α iv over a one-minute period caused significant falls in cardiac output, heart rate and blood pressure after 1–3 min. Blood pressure and cardiac output were normalized after 16–49 min. Blood flow in the ovarian vein (direct measurements) decreased and returned to initial values parallel to the blood pressure and no change in resistance in the vascular bed drained by the vein was noted. Total ovarian blood flow and resistance, as measured in surgically intact ovaries before and after PG infusion, using 35 or 15 μm 169Yb and 46Sc-labelled microspheres, changed and remained constant respectively, according to the same pattern as in the direct measurements. The distribution of blood flow between the corpora lutea and the interstitial tissue of the ovary measured by 15 μm radioactive microspheres. PGF2α caused an interstitial vasodilation whereas no significant change in luteal vascular resistance was noted. Since luteal blood flow represented a predominant part of total ovarian flow in the type of ovary studied, the interstitial vasodilatation caused only negligible changes in blood flow to the whole ovary. The present study does not support the hypothesis of a PG-induced luteal blood flow reduction preceding luteolysis. The possible significance of the interstitial vasodilatation for luteal function remains to be elucidated.

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49 Collection of Day 7 equine embryos in aluteal cycles in mares

Reproduction Fertility and Development ◽

10.1071/rdv31n1ab49 ◽

2019 ◽

Vol 31 (1) ◽

pp. 150 ◽

Cited By ~ 1

Author(s):

C. K. Mak ◽

V. Medina ◽

M. Markle ◽

C. R. F. Pinto

Keyword(s):

Developmental Stage ◽

Statistical Significance ◽

Prostaglandin F2α ◽

Control Group ◽

Developmentally Delayed ◽

Luteal Function ◽

Acceptable Quality ◽

Uterine Flushing ◽

Lactated Ringer's Solution ◽

Long Acting

Serial administration of prostaglandin F2α (PGF2) in early diestrus has been recently shown to prevent luteal function in mares and is associated with delayed embryo development in induced aluteal cycles (progesterone deprived environment; <1.0ng mL−1; Leisinger et al. 2018 Theriogenology 105, 178-183). We hypothesised that embryos collected on Day 7 during induced aluteal cycles would be developmentally delayed compared with those collected from control cycles (progesterone deprived environment but supplemented with exogenous progestogen). Mares were monitored until a preovulatory follicle=35mm and the presence of uterine oedema were detected by ultrasonography. Mares were treated IV once with 2000IU of human chorionic gonadotropin and artificially inseminated every other day with total motile spermatozoa from one stallion of known fertility until ovulation. Mares were examined twice daily to determine the occurrence of ovulation. After ovulation, mares were randomly assigned to the control group (serial PGF2 treatment+long-acting altrenogest) or AL group (serial PGF2 treatment only). Using a protocol to induce aluteal cycles (Leisinger et al. 2018 Theriogenology 105, 178-183), mares in the AL group (n=7) were treated twice daily with 10mg of PGF2 (Lutalyse, dinoprost tromethamine, Zoetis, Florham Park, NJ, USA) IM on Days 0, 1, 2, and then once daily on Days 3 and 4. Mares in the control group (n=4) were treated with serial PGF2 treatment as mentioned before, and treated with a single injection of 225mg altrenogest (BioRelease Altrenogest LA 150; BET Pharm, Lexington, KY, USA) IM at the time of ovulation. On Day 7 post-ovulation, embryo collection was performed by uterine flushing using lactated Ringer’s solution. The developmental stage of embryos, diameter, and quality were determined using a stereomicroscope and photographed. Embryos were washed 3 times in commercial embryo holding medium (EmCare™ Holding Solution, ICP Bio, Spring Valley, WI) and stained with 1µg mL−1 of 4’,6-diamidino-2-phenylindole at 38.5°C for 15min to determine the number of nonviable cells. Data were analysed using t-test or Mann-Whitney U test where appropriate. Statistical significance was set at P=0.05. Data are reported as mean±s.e.M. Overall, the developmental stage of control embryos differed from AL embryos (P<0.03). In the control group, all embryos (n=4) collected were classified as expanded blastocysts. In contrast, embryos (n=7) collected from the AL group were all early blastocysts. Furthermore, the mean embryo diameter differed in control v. AL groups, 401±8mm v. 166±2mm, respectively (P<0.001). The quality grades of control embryos (1.3±0.3) were not different from the AL group (1.3±0.2; P>0.05). All embryos of both groups had less than 10% of blastomeres stained with 4’,6-diamidino-2-phenylindole. This study showed that morphologically normal equine embryos of acceptable quality can be collected on Day 7 in aluteal cycles.

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Diestrous Ovulations in Pregnant Mares as a Response to Low Early Postovulatory Progestogen Concentration

Animals ◽

10.3390/ani10122249 ◽

2020 ◽

Vol 10 (12) ◽

pp. 2249

Author(s):

Carolina T. C. Okada ◽

Martim Kaps ◽

Javier Perez Quesada ◽

Camille Gautier ◽

Jörg Aurich ◽

...

Keyword(s):

Corpus Luteum ◽

Prostaglandin F2α ◽

Tissue Response ◽

P Value ◽

Luteal Function ◽

Luteal Tissue ◽

Underlying Causes ◽

Hypothalamic Pituitary Axis ◽

Effect Of Treatment ◽

Response Detection

Spontaneous prolongation of the luteal phase has been described in horses, but the underlying causes are still unclear. The present study investigated details of gonadotrophin and progestogen secretion in pregnant mares (n = 11) with or without experimentally reduced early postovulatory luteal function. From days 0 to 3 after ovulation, they were treated with the prostaglandin F2α (PGF2α) analogue cloprostenol or left untreated. After conceptus collection on day 34, they were assigned to the opposite treatment. Mares were affiliated to the group primary corpus luteum (n = 6) or diestrous corpus luteum (n = 5) depending on diestrous corpus luteum (CL) detection in the PGF pregnancy. For statistical comparisons, a p-value < 0.05 was significant. There was an effect of treatment (p < 0.01), but not of group on progestogen concentration. The concentration of LH was higher in PGF-treated than in untreated pregnancies (p < 0.05), but did not differ between groups. The FSH concentration did not differ between groups nor treatments. The total luteal tissue area was greater in mares with a diestrous ovulation during the PGF treatment pregnancy. Low progestogen concentration in the early postovulatory phase diminish the negative feedback on the hypothalamic-pituitary axis in early pregnancy and, thus, stimulate a luteal tissue response. Detection of secondary CL at the time of pregnancy examination in mares may reflect that early post-ovulatory progestogen concentrations were low.

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Post-ovulation nutritional status in ewes does not influence early conceptus development in vivo or luteotrophic protein secretion in vitro.

Proceedings of the British Society of Animal Production (1972) ◽

10.1017/s0308229600023850 ◽

1993 ◽

Vol 1993 ◽

pp. 58-58

Author(s):

J.M. Wallace ◽

R.P. Aitken ◽

M.A. Cheyne

Keyword(s):

Pregnancy Rate ◽

Immunosuppressive Agents ◽

Maternal Environment ◽

Embryo Survival ◽

Domestic Species ◽

Progesterone Secretion ◽

Conceptus Development ◽

In Pregnancy

Overfeeding during early pregnancy compromises pregnancy establishment and /or embryo survival in a variety of domestic species including sheep, cattle and pigs (reviewed by Robinson, 1990). Embryo survival was reduced in recipient ewes receiving a high as opposed to a low plane of nutrition from embryo transfer on day 5 post-ovulation to day 60 of gestation (McKelvey & Robinson, 1988).Similarly high plane feeding for only 12 days starting on day 2 after mating significantly reduced pregnancy rates at day 60 ( Parr et al .,1987). Although not extensively monitored in either study, peripheral progesterone concentrations were inversely correlated with feed intake. Indeed, the reduction in pregnancy rate in high plane ewes in Parr's study was reversed by progesterone supplementation on days 8-14 after mating.The inhibition of luteolysis and maintenance of adequate progesterone secretion by the corpus luteum is central to the maternal recognition of pregnancy in sheep ( Bazer et al .,1991 ). Progesterone plays a major role in controlling maternal secretion of nutrients, growth factors , immunosuppressive agents .enzymes and steroids required for successful embryo development. It seems likely therefor that the mechanisms underlying nutritionally induced differences in pregnancy rate and embryo survival may operate via changes in progesterone levels which in turn alter the secretory dialogue between the conceptus and its maternal environment.

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