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The endocannabinoid system (eCS), is a complex system, comprising the main endogenous ligands anandamide and 2-arachidonoyl glycerol, the cannabinoid receptors CB1 and CB2 and the biosynthetic and degrading enzymes. Cumulative evidence shows that the eCS plays an important role in reproduction, from egg fertilization to parturition. Therefore, alterations in this system, either by recreation/therapeutic use of cannabis or deregulation of the endogenous cannabinoids, might lead to adverse pregnancy outcomes, including retardation in embryo development, poor blastocyst implantation, inhibition of decidualization, miscarriage and compromised placentation. Nevertheless, the molecular mechanisms by which the eCS participates in different stages of pregnancy remain poorly understood. In this review, we will examine the evidence from animal and human studies to support the role of the eCS in implantation, early-to-late pregnancy and placentation as well as the difficulties of targeting this system for treatment of female infertility.

Fertility of lactating dairy cows is associated with reduced progesterone (P₄) concentration compared with nonlactating animals. The objective of the current study was to determine whether P₄ during growth of the first follicular wave (FFW) affects embryo quality. Lactating Holstein cows at 33±3 days post partum were allocated to one of three treatments. Cows in the FFW and FFW with P₄ (FFWP) treatments started the superstimulation protocol on day 1 of the estrous cycle and second follicular wave (SFW) cows started the superstimulation protocol on estrous cycle day 7. Cows were superstimulated with 400 mg of NIH-FSH-P1 (FSH) given twice daily for 5 days, two prostaglandin F_2α (PGF_2α) injections given with the ninth and tenth injections of FSH, GNRH given 48 h after the first PGF_2α injection, and timed insemination 12 and 24 h after the GNRH injection. Cows in the FFWP treatment received two intravaginal P₄ inserts during the superstimulation. Embryos were recovered 6.5 days after artificial insemination and excellent/good and fair embryos were frozen and transferred. Blood was sampled daily from estrous cycle day 0 until insemination from donor cows. During the superstimulation protocol, P₄ was (P<0.01) greatest for SFW cows followed by FFWP and FFW cows respectively. The percentage of embryos–oocytes from SFW and FFWP cows classified as excellent/good and fair embryos was (P=0.02) greater than those of FFW cows. Pregnancy per embryo transfer was not (P≥0.73) affected by embryo donor treatment. Reduced embryo quality of cows induced to ovulate the follicles from the first follicular wave is a consequence of reduced P₄ during follicle growth.

Maternal lifestyle affects both mother health and pregnancy outcome in humans. Several studies have demonstrated that interventions oriented toward reducing stress and anxiety have positive effects on pregnancy complications such as preeclampsia, excessive gestational weight, gestational diabetes and preterm birth. In this work, we showed that the environmental enrichment (EE), defined as a noninvasive and biologically significant stimulus of the sensory pathway combined with voluntary physical activity, prevented preterm birth (PTB) rate by 40% in an inflammatory mouse model induced by the systemic administration of bacterial lipopolysaccharide (LPS). Furthermore, we found that EE modulates maternal metabolism and produces an anti-inflammatory environment that contributes to pregnancy maintenance. In pregnant mice uterus, EE reduces the expression of TLR4 and CD14 (the LPS receptor and its coactivator protein), preventing the LPS-induced increase in PGE2 and PGF2α release and nitric oxide synthase (NOS) activity. In cervical tissue, EE inhibits cervical ripening events, such as PGE2 release, matrix metalloproteinase (MMP)-9 increased activity and neutrophil recruitment, therefore conserving cervical function. It seems that EE exposure could mimic the stress and anxiety-reducing techniques mentioned above, explaining, at least partially, the beneficial effects of having a healthy lifestyle before and during gestation. Furthermore, we propose that designing an EE protocol for humans could be a noninvasive and preventive therapy for pregnancy complications, averting pre-term birth occurrence and dreaded sequelae that are present in the offspring born too soon.