Open access peer-reviewed chapter

Beneficial Effect of Omega-3 Fatty Acids on Immune and Reproductive Endometrial Function

Written By

Maria A. Hidalgo, Marcelo Ratto and Rafael A. Burgos

Submitted: May 30th, 2019 Reviewed: August 26th, 2019 Published: June 17th, 2020

DOI: 10.5772/intechopen.89351

Chapter metrics overview

756 Chapter Downloads

View Full Metrics


Omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are known by their anti-inflammatory effects through mechanisms such as formation of specialized pro-resolving mediators (SPM), and more recently a new mechanism dependent on the free fatty acid (FFA) receptors has been studied. DHA and EPA have shown an effect on the release of prostaglandins (PGs) E2 and F2α in endometrial cells, two PGs that have key function in fertility. In addition, other molecules such as cyclooxygenase-2, IL-1β, NF-κB, and intracellular signaling pathways are also affected by omega-3 fatty acids in endometrial cells. In this chapter, we will expose the following issues: eicosanoids in fertility and immune function in the uterus, effect of omega-3 fatty acids on endometrial function: in vivo and in vitro studies, mechanisms of action of omega-3 fatty acids in endometrial cells, and perspectives in health and diseases.


  • omega-3 fatty acids
  • prostaglandin
  • endometrial cells
  • fertility
  • immune function

1. Introduction

Uterine function is key for a suitable reproductive performance and fertility. Endocrine and immune response play important roles for keeping the hormonal levels and the fetal-maternal interface. Hormones such as estrogen and progesterone are released from the ovaries; estrogen release is triggered by the hypothalamic-pituitary axis, and progesterone is secreted from the corpus luteum (CL) after ovulation. Estrogen is essential for uterine growth and cell proliferation and progesterone for endometrial receptivity and successful establishment of pregnancy [1, 2]. Estrogen and progesterone are also considered as regulators of innate immunity and inflammation in the endometrium [3]. Endometrial immune homeostasis plays an important role in the success of implantation and pregnancy, with complex interactions between the innate and adaptive immune system, through cells such as natural killer, antigen-presenting cells (macrophages and dendritic cells), and subtypes of T cells [4].

Prostaglandins (PGs), also known as prostanoids, are bioactive lipids with an important function as regulators of reproductive processes, including ovulation, fertilization, and implantation. PGs are synthesized from arachidonic acid by different cells, and five types of PGs have been described, with specific roles and mechanism in the female reproductive system [5, 6]. Prostaglandin F2α (PGF2α) has a luteolytic effect, whereas prostaglandin E2 (PGE2) is central in ovulation, fertilization, embryo development, and implantation [7, 8]. In addition, PGE2 plays important roles in inflammatory processes, being increased at first phases of inflammation [9].

Inflammation is a complex process with two differentiated steps or conditions: acute and chronic inflammation. A number of lipid mediators act as pro-inflammatory (i.e., leukotriene and prostaglandins) or anti-inflammatory and pro-resolving (lipoxins, resolvins, maresins, and protectins) mediators. Lipid mediators derived from polyunsaturated fatty acids (PUFA) have potent anti-inflammatory effect and promote the resolution of inflammation, through specialized pro-resolving lipid mediators (SPM) [10]. Omega-3 fatty acids are a type of PUFA with known beneficial effect, which, in addition to its pro-resolving mechanism, have shown two additional anti-inflammatory mechanisms: activation of the free fatty acid (FFA)-4 receptor and inflammasome inhibition. Recent evidences have suggested an anti-inflammatory effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in the endometrium. Furthermore, FFA4 receptor was detected in the human, mouse, and bovine uterus [11, 12]. The following sections describe the effect and potential mechanisms of omega-3 fatty acids in the immune cells and endometrium and perspectives of these fatty acids in health and disease.


2. Eicosanoids in fertility and immune function in the uterus

Eicosanoids, which include prostaglandins and leukotrienes, are members of a large family of compounds that are synthesized from arachidonic acid through the cyclooxygenase and lipoxygenase pathways [13]. PGF2α and PGE2 exert opposite actions on the corpus luteum (CL); therefore, control over their synthesis and secretion is critical either for the initiation of luteolysis or maintenance of pregnancy [7, 8].

PGF2α is considered a pro-inflammatory molecule, and it may stimulate the synthesis of pro-inflammatory cytokines that enhance phagocytosis and lymphocyte functions [14]. PGF2α can increase IL1β, IL6, CCL2, and CXCL8 via ERK1/ERK2, PI3K, NFAT, and NF-κB pathways in the myometrial cells from term pregnant women, suggesting that PGF2α induces an inflammatory environment during the late stage of human pregnancy [15]. PGF2α in vitro enhanced neutrophil chemotaxis and the ability of neutrophils to ingest bacteria, and anti-PGF2α antibody blocked the chemotactic effects of PGF2α [16, 17]. Exogenous PGF2α increases uterine secretion of PGF2α through the activation of phospholipase A2 (PLA2) and cyclooxygenase 2 [18, 19, 20]. Also, it has been proposed that exogenous PGF2α increases luteal leukotriene B4 (LTB4) production [21]. LTB4 can stimulate chemotaxis, random migration, and antibody-independent cell-mediated cytotoxicity and may reduce the risk of uterine infections in cows [22].

Most studies about PGF2α and fertility have been performed in production animals. PGF2α and its analogs have been used to resolve uterine infections in livestock; however, its mechanism of action is not known. Moreover, it is unclear if modulation of sexual steroids levels induced by PGF2α directly alters the immune response in postpartum. Cattle are resistant to uterine infections when progesterone concentrations are basal, and they are susceptible to uterine infections when progesterone concentrations are increased [23, 24]. It has been proposed that exogenous PGF2α is an effective luteolytic factor to reduce progesterone levels and subsequent estrus, with increased estrogen level and myometrial contractions, and would be favorable for clearance of uterine infection [25, 26]. However, other authors report that PGF2α upregulate immune functions reducing vaginal discharge, uterine inflammation, endometrium fibrosis, and infection, which could be independent of progesterone levels [27]. Also, it has been proposed that PGF2α is more effective when progesterone levels are high or a corpus luteum is palpable [28, 29]. Thus, a direct effect of PGF2α on immune system has been proposed. The in vivo effect of exogenous PGF2α suggests that immune functions do not seem entirely independent of progesterone [30]. Fenprostalene, a long-acting PGF2α analog, injected between days 7 and 10 postpartum, when progesterone concentrations are basal, reduced the incidence of endometritis in dairy cows with dystocia and/or retained fetal membranes and reduced the interval from parturition to conception [31]. The studies with cloprostenol and fenprostalene indicate that increased PGF2α during the postpartum period in dairy cattle improves uterine health [27, 31]. Indeed, jugular concentrations of 13,14-dihydro-15-keto-PGF2α, which is a metabolite that seems to reflect uterine production of PGF2α postpartum, were less in postpartum dairy cows that subsequently developed uterine infections, than in cows that did not develop uterine infections [31, 32]. Despite the above antecedents, the evidence is contradictory if exogenous PGF2α can be useful as endometritis therapy in cows [33, 34, 35, 36].

PGE2 is the most abundant eicosanoid lipid in the inflammatory environment. Thus, PGE2 plays a pivotal role in endometriosis-associated inflammation and pain, and its production is augmented in lesions and in the peritoneal cavity [37, 38]. Exogenous PGE2 pretreatment also modulates the innate immune response, increasing the Pam3CSK4-induced inflammatory responses through Toll-like receptor (TLR)-2 signaling in bovine endometrial epithelial cells [39]. PGE2 can increase the lipopolysaccharide (LPS)-induced response on PKA, ERK1/ERK2, and IκBα phosphorylation, as well as COX-2 and IL-6 expression, and downregulate the PGE2 receptor 4 (EP4) and TLR4 in bovine endometrial cells [40]. PGE2 via EP2 and EP4 receptors can reduce the expression of CXCL8, CCL2, and granulocyte macrophage colony-stimulating factor (GM-CSF) induced by IL-1β in primary human myometrial cells [41]. In human uterine epithelial cells, misoprostol, an analog of PGE2, increases cAMP levels via EP4 and reduces the expression of antimicrobial peptides such as β-defensins [42].


3. Effect of omega-3 fatty acids on endometrial function: in vivo and in vitro studies

Several studies have suggested that supplementation of omega-3 fatty acids during pregnancy is beneficial for establishment and maintenance of pregnancy, maintains gestation length and fetal growth, prevents preterm birth, and decreases the rate of gestational diabetes [43]. These effects of omega-3 fatty acids have been mainly studied in animals such as bovine and ovine; however, some recent studies have begun to be performed to demonstrate the beneficial effect of these fatty acids in humans and mice. Consumption of omega-3 fatty acids has been associated with a reduction of the symptoms and lower risk of developing endometriosis in women, a hormone-dependent chronic inflammatory condition [44, 45]. In wild-type mice, the administration of EPA reduced the number of endometriotic lesions, similarly as was observed in a transgenic mouse model with high levels of omega-3 fatty acids [46]. In a rat model of endometriosis, the EPA supplementation reduced the endometriotic lesions and expression of pro-inflammatory gene, suggesting that the EPA supplementation might be a strategy for the treatment of endometriosis [47].

Some studies in vitro have evidenced that the supplementation of mice with omega-3 fatty acids increased implantation markers such as laminin and leukemia inhibitory factor in endometrial epithelium and stroma, which would encourage the endometrium for a favorable environment of implantation [48]. Through an abortion mouse model and human stromal cells, it was suggested that omega-3 fatty acids activate the signaling pathways ERK1/ERK2 and AMPK, which increase FOXO1 and GLUT 1 expression, and the increased glucose uptake would be important for the maintenance of pregnancy [11].

Several studies in bovines have proposed that omega-3-rich diet improve the reproductive performance. It has been described that incorporation of fatty acids of omega-3, and also omega-6, in the bovine diet influences some of the reproductive process involved in the follicular development [49] and progesterone and PGF2α production [50, 51] regulating embryo survival and implantation.

It has been shown that high intake of omega-6 fatty acid induces a change in membrane phospholipids, increasing the proportion of arachidonic acid, which would favor the synthesis of PG of the series 2, and eicosanoid, so it would turn into a pro-inflammatory environment [52]. By contrast, the dietary increase of the omega-3 fatty acid especially EPA and DHA would increase the proportion of these phospholipids in the cell membranes, which would ultimately result in the decrease of the synthesis of the PG series 2, whereby they would act as an anti-inflammatory mechanism [52]. Based on the effect of fatty acids on PG secretion, several studies conducted in dairy cattle have been addressed to attenuate the endometrium secretion of PG at the time of the embryo-maternal recognition of pregnancy in order to improve embryo survival and pregnancy rate [53, 54, 55]. Dairy cows supplemented with conjugated linoleic acid (CLA) have higher pregnancy rates than their non-supplemented control group, and the probability of pregnancy increases by up to 26% and that the interval of first postpartum ovulation was reduced by 8 days [56].

Also, the supplementation of dairy cows with polyunsaturated omega-3 fatty acids as EPA can inhibit the synthesis of PGF2α through competition with arachidonic acid by COX-1 and COX-2 enzymes or in the case of DHA competing with arachidonic acid with the phospholipase A2 enzymes [57]. For this reason, fish meal included in the bovine diet could reduce PGF2α and delay regression of the CL, improving embryonic survival and female fertility [51]. The supplementation of cows with omega-3 fatty acid from the fish meal not only reduces the endometrial concentration of arachidonic acid but also increases the concentration of both EPA and omega-3 fatty acids in the endometrium [58]. When fish meal was included in the diet in a study conducted with beef cows (Angus), an increase in EPA and DHA in luteal tissue and a reduction of arachidonic acid in the endometrium resulting in an increase in the fertility of cows were observed [59]. However, in addition to its effect on PG secretion, some studies have concluded that diets rich in EPA and DHA can have a direct effect on the growth of the conceptus per se [60]. Others speculate that the delay on CL regression would allow not well-developed embryos to reach their competent size to initiate a maternal dialog before the luteolytic secretion of PG [50, 61].

The roles of omega-3 and omega-6 fatty acids on prostaglandin secretion have been well documented in in vitro and in vivo studies. The production of PGF2 α was suppressed in an endometrial cell culture when the culture medium was supplemented with omega-3 fatty acids [62]. However, when the medium was supplemented with omega-6 fatty acids, the increase in the ratio of omega-6 to omega-3 produced an increase of PGF2α [63]. Similarly, in studies conducted with dairy cows, the supplementation with different ratio of fatty acids from omega-6 to omega-3 altered the secretion on PGF2 α induced by either oxytocin [64] or spontaneous [49]. The production of PGE2 induced by LPS also was inhibited in the cellular line of bovine endometrium BEND treated with DHA [12]. Additionally, recent evidences show an inhibition of the translocation of the transcription factor NF-κB induced by LPS in BEND cells treated with DHA (Figure 1; unpublished data).

Figure 1.

Localization of NF-κB in BEND cells treated with DHA and stimulated with LPS. BEND cells were treated with 50 μM DHA for 15 min, and then 1 μg/ml LPS was added and incubated for 30 min. NF-κB was detected by immunocytochemistry and epifluorescence microscopy. Magnification 40X [65].


4. Mechanisms of action of omega-3 fatty acids in endometrial cells

The first known anti-inflammatory mechanism of omega-3 fatty acids was the formation of specialized pro-resolving mediators (SPMs) derived from DHA. The enzymatic oxygenation of DHA via 12−/15-lipoxygenase (LOX) and 5-LOX leads to the formation of the D-series resolvins (RvD1, RvD2, RvD3, RvD4, RvD5, and RvD6), neuroprotectins/protectins, and maresins in different cells [10, 66], and resolvins have a potent effect on leukocyte migration and also reduce production of pro-inflammatory cytokines [67]. All those evidences have been obtained in different cellular types, but in the uterus or endometrial cells, there are not yet studies about formation of SPM.

Two more recent mechanisms have been described in macrophages and endothelial cells: (1) binding of DHA to FFA4 receptor/β-arrestin and inhibition of TAK1/NF-κB, thus reducing synthesis of pro-inflammatory factors, and (2) inhibition of NLRP3 inflammasome. FFA4 receptor is a G-protein-coupled receptor with high affinity by DHA described first in the intestine and macrophages. Recent studies evidenced the presence of FFA4 receptor in the human, mouse, and bovine endometrium [11, 12]. After ligand binding, FFA4 receptor couples to β-arrestin2, which is followed by receptor endocytosis and inhibition of TAB1-mediated activation of TAK1, a protein activated after inflammatory stimuli such as LPS, which induce signaling through the NF-κB pathway, thus reducing TNF-α, IL-6, and MCP-1 [68, 69]. Other studies have proposed omega-3 fatty acids to reduce the NLRP3 inflammasome activation [70, 71, 72, 73]. The first evidence proposed two mechanisms dependent on FFA4 receptor to the reduction of inflammasome activation: first, DHA stimulation caused FFA4 receptor internalization through β-arrestin2, which reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB, and second, DHA enhanced autophagy, thereby reducing inflammasome complex formation or presenting inflammasome components for destruction [73]. Then, it was demonstrated that DHA reduced NLRP3 inflammasome expression in hepatocytes [70].

In the endometrium, only two lines of evidences about potential mechanisms of action of omega-3 have been studied. In human stromal cells, FFA4 receptor promoted decidualization through the upregulation of the GLUT1-mediated glucose uptake and glucose-6-phosphate dehydrogenase-mediated pentose-phosphate pathway [11]. In mice, FFA4 receptor protects LPS or RU486-induced abortion [11]. In summary, omega-3 fatty acids via FFA4 receptor increase ERK1/ERK2 and AMPK signaling and upregulate FOXO1 and GLUT1 expression, which increases glucose uptake and activates the pentose-phosphate pathway, promoting decidualization and maintenance of pregnancy. In addition, it was also shown that FFA4 receptor upregulates the expression of chemokines and cytokines such as CXCL12, TGFβ, and IL-15 [11]. In bovine endometrial cells, it was evidenced the presence of mRNA and protein of FFA4 receptor as well as an increase of intracellular calcium mobilization induced by DHA or a synthetic agonist (TUG891) of FFA4 receptor, which was inhibited by AH7614, a FFA4 receptor antagonist [12]. Also, DHA reduced NF-κB activation and PGE2 production induced by LPS; however, AH7614 did not modify these effects, suggesting that other mechanisms would be involved in the anti-inflammatory effect of DHA, which should be studied [12].


5. Perspectives in health and diseases

Until now, omega-3 fatty acids have been only used as dietary supplements, or DHA-rich diet has been recommended by their beneficial effects for health. However, although the mechanism of action of DHA has begun to be elucidated, it has not been recommended yet as an anti-inflammatory drug. The recent studies have described several possible anti-inflammatory mechanisms and propose omega-3 fatty acids as potential treatment for spontaneous abortion for its effect on decidualization and the maintenance of pregnancy [11]. Also, omega-3 fatty acids would be useful for the prevention and treatment of endometriosis because this disorder is characterized by a chronic inflammation [44, 46, 47]. In veterinary medicine, omega-3 fatty acids have potential use in fertility of dairy cows. Omega-3- rich supplements have been associated with improved reproductive performance, and the recent evidence of the presence of FFA4 receptor in the endometrium [12] could contribute to understand the mechanism as omega-3 fatty acids exert its effects, and open new possibilities for the prevention and treatment of the endometrial inflammation associated with infectious diseases, such as metritis or endometritis.


6. Conclusions

Omega-3 fatty acids have anti-inflammatory effects through different mechanisms, described in macrophages and endothelial cells: formation of SPMs, activation of the FFA4 receptor, inhibition of TAK1/NF-κB activation, and inflammasome inhibition. These mechanisms have not yet been demonstrated in the endometrium, but the presence of the FFA4 receptor and the inhibition of NF-κB, PGE2, and PGF2α suggest that similar anti-inflammatory mechanism could occur in the endometrium. Furthermore, omega-3 fatty acids could be useful for the treatment of disorders such as endometriosis or metritis/endometritis, as well as the prevention of spontaneous abortion and improvement of fertility.



Funded by Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt No. 1151047).


Conflict of interest

The authors declare no conflict of interest.


  1. 1. Groothuis PG, Dassen HH, Romano A, Punyadeera C. Estrogen and the endometrium: Lessons learned from gene expression profiling in rodents and human. Human Reproduction Update. 2007;13(4):405-417. DOI: 10.1093/humupd/dmm009
  2. 2. Young SL, Lessey BA. Progesterone function in human endometrium: Clinical perspectives. Seminars in Reproductive Medicine. 2010;28(1):5-16. DOI: 10.1055/s-0029-1242988
  3. 3. Turner ML, Healey GD, Sheldon IM. Immunity and inflammation in the uterus. Reproduction in Domestic Animals. 2012;47(Suppl 4):402-409. DOI: 10.1111/j.1439-0531.2012.02104.x
  4. 4. Liu S, Diao L, Huang C, Li Y, Zeng Y, Kwak-Kim JYH. The role of decidual immune cells on human pregnancy. Journal of Reproductive Immunology. 2017;124:44-53. DOI: 10.1016/j.jri.2017.10.045
  5. 5. Niringiyumukiza JD, Cai H, Xiang W. Prostaglandin E2 involvement in mammalian female fertility: Ovulation, fertilization, embryo development and early implantation. Reproductive Biology and Endocrinology. 2018;16(1):43. DOI: 10.1186/s12958-018-0359-5
  6. 6. Jabbour HN, Sales KJ. Prostaglandin receptor signalling and function in human endometrial pathology. Trends in Endocrinology and Metabolism. 2004;15(8):398-404. DOI: 10.1016/j.tem.2004.08.006
  7. 7. Bennegard B, Hahlin M, Wennberg E, Noren H. Local luteolytic effect of prostaglandin F2 alpha in the human corpus luteum. Fertility and Sterility. 1991;56(6):1070-1076
  8. 8. Hahlin M, Dennefors B, Johanson C, Hamberger L. Luteotropic effects of prostaglandin E2 on the human corpus luteum of the menstrual cycle and early pregnancy. The Journal of Clinical Endocrinology and Metabolism. 1988;66(5):909-914. DOI: 10.1210/jcem-66-5-909
  9. 9. Jabbour HN, Sales KJ, Catalano RD, Norman JE. Inflammatory pathways in female reproductive health and disease. Reproduction. 2009;138(6):903-919. DOI: 10.1530/REP-09-0247
  10. 10. Serhan CN, Petasis NA. Resolvins and protectins in inflammation resolution. Chemical Reviews. 2011;111(10):5922-5943. DOI: 10.1021/cr100396c
  11. 11. Huang J, Xue M, Zhang J, Yu H, Gu Y, Du M, et al. Protective role of GPR120 in the maintenance of pregnancy by promoting decidualization via regulation of glucose metabolism. eBioMedicine. 2019;39:540-551. DOI: 10.1016/j.ebiom.2018.12.019
  12. 12. Valenzuela P, Teuber S, Manosalva C, Alarcon P, Figueroa CD, Ratto M, et al. Functional expression of the free fatty acids receptor-1 and -4 (FFA1/GPR40 and FFA4/GPR120) in bovine endometrial cells. Veterinary Research Communications. 2019;43(3):179-186. DOI: 10.1007/s11259-019-09758-8
  13. 13. Higgins AJ. The biology, pathophysiology and control of eicosanoids in inflammation. Journal of Veterinary Pharmacology and Therapeutics. 1985;8(1):1-18
  14. 14. Lewis GS. Steroidal regulation of uterine immune defenses. Animal Reproduction Science. 2004;82-83:281-294. DOI: 10.1016/j.anireprosci.2004.04.026
  15. 15. Xu C, Liu W, You X, Leimert K, Popowycz K, Fang X, et al. PGF2alpha modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways. Molecular Human Reproduction. 2015;21(7):603-614. DOI: 10.1093/molehr/gav018
  16. 16. Arnould T, Thibaut-Vercruyssen R, Bouaziz N, Dieu M, Remacle J, Michiels C. PGF(2alpha), a prostanoid released by endothelial cells activated by hypoxia, is a chemoattractant candidate for neutrophil recruitment. The American Journal of Pathology. 2001;159(1):345-357. DOI: 10.1016/s0002-9440(10)61701-4
  17. 17. Hoedemaker M, Lund LA, Wagner WC. Influence of arachidonic acid metabolites and steroids on function of bovine polymorphonuclear neutrophils. American Journal of Veterinary Research. 1992;53(9):1534-1539
  18. 18. Binelli M, Guzeloglu A, Badinga L, Arnold DR, Sirois J, Hansen TR, et al. Interferon-tau modulates phorbol ester-induced production of prostaglandin and expression of cyclooxygenase-2 and phospholipase-a(2) from bovine endometrial cells. Biology of Reproduction. 2000;63(2):417-424. DOI: 10.1095/biolreprod63.2.417
  19. 19. Narayansingh RM, Senchyna M, Carlson JC. Treatment with prostaglandin F2alpha increases expression of prostaglandin synthase-2 in the rat corpus luteum. Prostaglandins & Other Lipid Mediators. 2002;70(1-2):145-160
  20. 20. Wade DE, Lewis GS. Exogenous prostaglandin F2 alpha stimulates utero-ovarian release of prostaglandin F2 alpha in sheep: A possible component of the luteolytic mechanism of action of exogenous prostaglandin F2 alpha. Domestic Animal Endocrinology. 1996;13(5):383-398
  21. 21. Steadman LE, Murdoch WJ. Production of leukotriene B4 by luteal tissues of sheep treated with prostaglandin F2 alpha. Prostaglandins. 1988;36(5):741-745
  22. 22. Slama H, Vaillancourt D, Goff AK. Leukotriene B4 in cows with normal calving, and in cows with retained fetal membranes and/or uterine subinvolution. Canadian Journal of Veterinary Research. 1993;57(4):293-299
  23. 23. Hawk HW, Brinsfield TH, Turner GD, Whitmore GW, Norcross MA. Effect of ovarian status on induced acute inflammatory responses in cattle uteri. American Journal of Veterinary Research. 1964;25:362-366
  24. 24. Lewis GS. Role of ovarian progesterone and potential role of prostaglandin F2alpha and prostaglandin E2 in modulating the uterine response to infectious bacteria in postpartum ewes. Journal of Animal Science. 2003;81(1):285-293. DOI: 10.2527/2003.811285x
  25. 25. LeBlanc SJ. Postpartum uterine disease and dairy herd reproductive performance: A review. Veterinary Journal. 2008;176(1):102-114. DOI: 10.1016/j.tvjl.2007.12.019
  26. 26. McClary DG, Putnam MR, Wright JC, Sartin JL Jr. Effect of early postpartum treatment with prostaglandin F2alpha on subsequent fertility in the dairy cow. Theriogenology. 1989;31(3):565-570
  27. 27. Bonnett BN, Etherington WG, Martin SW, Johnson WH. The effect of prostaglandin administration to Holstein-Friesian cows at day 26 postpartum on clinical findings, and histological and bacteriological results of endometrial biopsies at day 40. Theriogenology. 1990;33(4):877-890
  28. 28. LeBlanc SJ, Duffield TF, Leslie KE, Bateman KG, Keefe GP, Walton JS, et al. The effect of treatment of clinical endometritis on reproductive performance in dairy cows. Journal of Dairy Science. 2002;85(9):2237-2249. DOI: 10.3168/jds.S0022-0302(02)74303-8
  29. 29. Sheldon IM, Noakes DE. Comparison of three treatments for bovine endometritis. The Veterinary Record. 1998;142(21):575-579. DOI: 10.1136/vr.142.21.575
  30. 30. Lewis GS, Wulster-Radcliffe MC. Prostaglandin F2alpha upregulates uterine immune defenses in the presence of the immunosuppressive steroid progesterone. American Journal of Reproductive Immunology. 2006;56(2):102-111. DOI: 10.1111/j.1600-0897.2006.00391.x
  31. 31. Nakao T, Gamal A, Osawa T, Nakada K, Moriyoshi M, Kawata K. Postpartum plasma PGF metabolite profile in cows with dystocia and/or retained placenta, and effect of fenprostalene on uterine involution and reproductive performance. The Journal of Veterinary Medical Science. 1997;59(9):791-794. DOI: 10.1292/jvms.59.791
  32. 32. Seals RC, Matamoros I, Lewis GS. Relationship between postpartum changes in 13, 14-dihydro-15-keto-PGF2alpha concentrations in Holstein cows and their susceptibility to endometritis. Journal of Animal Science. 2002;80(4):1068-1073. DOI: 10.2527/2002.8041068x
  33. 33. Haimerl P, Heuwieser W, Arlt S. Therapy of bovine endometritis with prostaglandin F2alpha: A meta-analysis. Journal of Dairy Science. 2013;96(5):2973-2987. DOI: 10.3168/jds.2012-6154
  34. 34. Haimerl P, Heuwieser W, Arlt S. Short communication: Meta-analysis on therapy of bovine endometritis with prostaglandin F2alpha-an update. Journal of Dairy Science. 2018;101(11):10557-10564. DOI: 10.3168/jds.2018-14933
  35. 35. Lima FS, Bisinotto RS, Ribeiro ES, Greco LF, Ayres H, Favoreto MG, et al. Effects of 1 or 2 treatments with prostaglandin F(2)alpha on subclinical endometritis and fertility in lactating dairy cows inseminated by timed artificial insemination. Journal of Dairy Science. 2013;96(10):6480-6488. DOI: 10.3168/jds.2013-6850
  36. 36. Wagener K, Gabler C, Drillich M. A review of the ongoing discussion about definition, diagnosis and pathomechanism of subclinical endometritis in dairy cows. Theriogenology. 2017;94:21-30. DOI: 10.1016/j.theriogenology.2017.02.005
  37. 37. Sacco K, Portelli M, Pollacco J, Schembri-Wismayer P, Calleja-Agius J. The role of prostaglandin E2 in endometriosis. Gynecological Endocrinology. 2012;28(2):134-138. DOI: 10.3109/09513590.2011.588753
  38. 38. Wu MH, Lu CW, Chuang PC, Tsai SJ. Prostaglandin E2: The master of endometriosis? Experimental Biology and Medicine (Maywood, N.J.). 2010;235(6):668-677. DOI: 10.1258/ebm.2010.009321
  39. 39. Shen Y, Feng S, Liu B, Mao W, Gao R, Wu J, et al. Prostaglandin E2 promotes Pam3CSK4-induced inflammation in endometrial epithelial cells of cattle. Animal Reproduction Science. 2019;200:51-59. DOI: 10.1016/j.anireprosci.2018.11.010
  40. 40. Shen Y, Liu B, Mao W, Gao R, Feng S, Qian Y, et al. PGE2 downregulates LPS-induced inflammatory responses via the TLR4-NF-kappaB signaling pathway in bovine endometrial epithelial cells. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2018;129:25-31. DOI: 10.1016/j.plefa.2018.01.004
  41. 41. Mosher AA, Rainey KJ, Giembycz MA, Wood S, Slater DM. Prostaglandin E2 represses interleukin 1 beta-induced inflammatory mediator output from pregnant human myometrial cells through the EP2 and EP4 receptors. Biology of Reproduction. 2012;87(1):7, 1-10. DOI: 10.1095/biolreprod.112.100099
  42. 42. Aronoff DM, Hao Y, Chung J, Coleman N, Lewis C, Peres CM, et al. Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii. Journal of Immunology. 2008;180(12):8222-8230. DOI: 10.4049/jimmunol.180.12.8222
  43. 43. Saccone G, Berghella V, Maruotti GM, Sarno L, Martinelli P. Omega-3 supplementation during pregnancy to prevent recurrent intrauterine growth restriction: Systematic review and meta-analysis of randomized controlled trials. Ultrasound in Obstetrics & Gynecology. 2015;46(6):659-664. DOI: 10.1002/uog.14910
  44. 44. Jurkiewicz-Przondziono J, Lemm M, Kwiatkowska-Pamula A, Ziolko E, Wojtowicz MK. Influence of diet on the risk of developing endometriosis. Ginekologia Polska. 2017;88(2):96-102. DOI: 10.5603/GP.a2017.0017
  45. 45. Signorile PG, Viceconte R, Baldi A. Novel dietary supplement association reduces symptoms in endometriosis patients. Journal of Cellular Physiology. 2018;233(8):5920-5925. DOI: 10.1002/jcp.26401
  46. 46. Tomio K, Kawana K, Taguchi A, Isobe Y, Iwamoto R, Yamashita A, et al. Omega-3 polyunsaturated fatty acids suppress the cystic lesion formation of peritoneal endometriosis in transgenic mouse models. PLoS One. 2013;8(9):e73085. DOI: 10.1371/journal.pone.0073085
  47. 47. Netsu S, Konno R, Odagiri K, Soma M, Fujiwara H, Suzuki M. Oral eicosapentaenoic acid supplementation as possible therapy for endometriosis. Fertility and Sterility. 2008;90(4 Suppl):1496-1502. DOI: 10.1016/j.fertnstert.2007.08.014
  48. 48. Sarsmaz K, Goker A, Micili SC, Ergur BU, Kuscu NK. Immunohistochemical and ultrastructural analysis of the effect of omega-3 on embryonic implantation in an experimental mouse model. Taiwanese Journal of Obstetrics & Gynecology. 2016;55(3):351-356. DOI: 10.1016/j.tjog.2016.04.011
  49. 49. Greco LF, Neves Neto JT, Pedrico A, Lima FS, Bisinotto RS, Martinez N, et al. Effects of altering the ratio of dietary n-6 to n-3 fatty acids on spontaneous luteolysis in lactating dairy cows. Journal of Dairy Science. 2018;101(11):10536-10556. DOI: 10.3168/jds.2018-15065
  50. 50. Mattos R, Staples CR, Thatcher WW. Effects of dietary fatty acids on reproduction in ruminants. Reviews of Reproduction. 2000;5(1):38-45
  51. 51. Staples CR, Burke JM, Thatcher WW. Influence of supplemental fats on reproductive tissues and performance of lactating cows. Journal of Dairy Science. 1998;81(3):856-871. DOI: 10.3168/jds.S0022-0302(98)75644-9
  52. 52. Calder PC. Long-chain fatty acids and inflammation. The Proceedings of the Nutrition Society. 2012;71(2):284-289. DOI: 10.1017/S0029665112000067
  53. 53. Ambrose DJ, Kastelic JP, Corbett R, Pitney PA, Petit HV, Small JA, et al. Lower pregnancy losses in lactating dairy cows fed a diet enriched in alpha-linolenic acid. Journal of Dairy Science. 2006;89(8):3066-3074. DOI: 10.3168/jds.S0022-0302(06)72581-4
  54. 54. Silvestre FT, Carvalho TS, Francisco N, Santos JE, Staples CR, Jenkins TC, et al. Effects of differential supplementation of fatty acids during the peripartum and breeding periods of Holstein cows: I. uterine and metabolic responses, reproduction, and lactation. Journal of Dairy Science. 2011;94(1):189-204. DOI: 10.3168/jds.2010-3370
  55. 55. Sinedino LD, Honda PM, Souza LR, Lock AL, Boland MP, Staples CR, et al. Effects of supplementation with docosahexaenoic acid on reproduction of dairy cows. Reproduction. 2017;153(5):707-723. DOI: 10.1530/REP-16-0642
  56. 56. de Veth MJ, Bauman DE, Koch W, Mann GE, Pfeiffer AM, Butler WR. Efficacy of conjugated linoleic acid for improving reproduction: A multi-study analysis in early-lactation dairy cows. Journal of Dairy Science. 2009;92(6):2662-2669. DOI: 10.3168/jds.2008-1845
  57. 57. Mattos R, Staples CR, Arteche A, Wiltbank MC, Diaz FJ, Jenkins TC, et al. The effects of feeding fish oil on uterine secretion of PGF2alpha, milk composition, and metabolic status of periparturient Holstein cows. Journal of Dairy Science. 2004;87(4):921-932. DOI: 10.3168/jds.S0022-0302(04)73236-1
  58. 58. Bilby TR, Guzeloglu A, MacLaren LA, Staples CR, Thatcher WW. Pregnancy, bovine somatotropin, and dietary n-3 fatty acids in lactating dairy cows: II. Endometrial gene expression related to maintenance of pregnancy. Journal of Dairy Science. 2006;89(9):3375-3385. DOI: 10.3168/jds.S0022-0302(06)72374-8
  59. 59. White NR, Burns PD, Cheatham RD, Romero RM, Nozykowski JP, Bruemmer JE, et al. Fish meal supplementation increases bovine plasma and luteal tissue omega-3 fatty acid composition. Journal of Animal Science. 2012;90(3):771-778. DOI: 10.2527/jas.2011-4208
  60. 60. Ribeiro ES. Symposium review: Lipids as regulators of conceptus development: Implications for metabolic regulation of reproduction in dairy cattle. Journal of Dairy Science. 2018;101(4):3630-3641. DOI: 10.3168/jds.2017-13469
  61. 61. Santos JE, Bilby TR, Thatcher WW, Staples CR, Silvestre FT. Long chain fatty acids of diet as factors influencing reproduction in cattle. Reproduction in Domestic Animals. 2008;43(Suppl 2):23-30. DOI: 10.1111/j.1439-0531.2008.01139.x
  62. 62. Mattos R, Guzeloglu A, Badinga L, Staples CR, Thatcher WW. Polyunsaturated fatty acids and bovine interferon-tau modify phorbol ester-induced secretion of prostaglandin F2 alpha and expression of prostaglandin endoperoxide synthase-2 and phospholipase-A2 in bovine endometrial cells. Biology of Reproduction. 2003;69(3):780-787. DOI: 10.1095/biolreprod.102.015057
  63. 63. Caldari-Torres C, Rodriguez-Sallaberry C, Greene ES, Badinga L. Differential effects of n-3 and n-6 fatty acids on prostaglandin F2alpha production by bovine endometrial cells. Journal of Dairy Science. 2006;89(3):971-977. DOI: 10.3168/jds.S0022-0302(06)72162-2
  64. 64. Mattos R, Staples CR, Williams J, Amorocho A, McGuire MA, Thatcher WW. Uterine, ovarian, and production responses of lactating dairy cows to increasing dietary concentrations of menhaden fish meal. Journal of Dairy Science. 2002;85(4):755-764. DOI: 10.3168/jds.S0022-0302(02)74133-7
  65. 65. Valenzuela P. Modulación de la respuesta inmune mediante la activación de receptores de ácidos grasos de cadena larga en tejido endometrial bovino [thesis]. Valdivia: Universidad Austral de Chile; 2019
  66. 66. Serhan CN, Yang R, Martinod K, Kasuga K, Pillai PS, Porter TF, et al. Maresins: Novel macrophage mediators with potent antiinflammatory and proresolving actions. The Journal of Experimental Medicine. 2009;206(1):15-23. DOI: 10.1084/jem.20081880
  67. 67. Spite M, Norling LV, Summers L, Yang R, Cooper D, Petasis NA, et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;461(7268):1287-1291. DOI: 10.1038/nature08541
  68. 68. Liu KL, Yang YC, Yao HT, Chia TW, Lu CY, Li CC, et al. Docosahexaenoic acid inhibits inflammation via free fatty acid receptor FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 expression in EA.hy926 cells. Molecular Nutrition & Food Research. 2016;60(2):430-443. DOI: 10.1002/mnfr.201500178
  69. 69. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142(5):687-698. DOI: 10.1016/j.cell.2010.07.041
  70. 70. Sui YH, Luo WJ, Xu QY, Hua J. Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation. World Journal of Gastroenterology. 2016;22(8):2533-2544. DOI: 10.3748/wjg.v22.i8.2533
  71. 71. Garay-Lugo N, Dominguez-Lopez A, Miliar Garcia A, Aguilar Barrera E, Gomez Lopez M, Gomez Alcala A, et al. n-3 fatty acids modulate the mRNA expression of the Nlrp3 inflammasome and Mtor in the liver of rats fed with high-fat or high-fat/fructose diets. Immunopharmacology and Immunotoxicology. 2016;38(5):353-363. DOI: 10.1080/08923973.2016.1208221
  72. 72. Lin C, Chao H, Li Z, Xu X, Liu Y, Bao Z, et al. Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. Experimental Neurology. 2017;290:115-122. DOI: 10.1016/j.expneurol.2017.01.005
  73. 73. Williams-Bey Y, Boularan C, Vural A, Huang NN, Hwang IY, Shan-Shi C, et al. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-kappaB activation and enhancing autophagy. PLoS One. 2014;9(6):e97957. DOI: 10.1371/journal.pone.0097957

Written By

Maria A. Hidalgo, Marcelo Ratto and Rafael A. Burgos

Submitted: May 30th, 2019 Reviewed: August 26th, 2019 Published: June 17th, 2020