**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 [18–20]. 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

**215**

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

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

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

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

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].

*DOI: http://dx.doi.org/10.5772/intechopen.89351*

as endometritis therapy in cows [33–36].

antimicrobial peptides such as β-defensins [42].

**in vitro studies**

#### *Beneficial Effect of Omega-3 Fatty Acids on Immune and Reproductive Endometrial Function DOI: http://dx.doi.org/10.5772/intechopen.89351*

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 [33–36].

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].
