The Role of Arachidonic and Linoleic Acid Derivatives in Pathological Pregnancies and the Human Reproduction Process

Abstract

The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women's ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies.

Keywords: HETE; HODE; arachidonic acid; endometriosis; gestational diabetes mellitus; inflammation; polycystic ovarian syndrome; preeclampsia; pregnancy disorders.

Figure 1

Synthesis of proinflammatory mediators from linoleic acid (LA) and arachidonic acid (AA). LOX—lipoxygenase, HETE—hydroperoxyeicosatetraenoic acid, HPETE—Hydroperoxyeicosatetraenoic acid, HODE—hydroxyoctadecadiene acids, COX—cyclooxygenase, CYP—cytochrome P450, HETEs—hydroxyeicosatetraenoic acids, EETs—epoxyeicosatrienoic acids, PG—prostaglandins, TX—thromboxane.

Figure 2

Participation of AA metabolites in pathological conditions of pregnancy—endometriosis and polycystic ovary syndrome; PCOS: polycystic ovary syndrome; COX: cyclooxygenase; EPA: eicosapentaenoic acid; AA: arachidonic acid; CYP2C19: cytochrome isoform; HODE: hydroxyoctadecadiene acids.

Figure 3

Participation of AA metabolites in pathological conditions of pregnancy—gestational diabetes mellitus and preeclampsia. CYP: cytochrome P450; LOX: lipoxygenase; HETE: hydroperoxyeicosatetraenoic acid; EET: epoxyeicosatrienoic acid.

Figure 4

Flow diagram. Studies included in the review.