Uterine and placental KISS1 regulate pregnancy: what we know and the challenges that lie ahead

Abstract

Hypothalamic KISS1 and its derivatives (kisspeptins) are now well recognized as potent stimulators of GnRH secretion and thereby major regulators of the neuroendocrine-reproductive axis. Recent studies in the mouse strongly suggest that independent of the hypothalamus and pituitary, peripherally derived KISS1 also regulates fertility, and disruption of local KISS1 signaling in the ovary and uterus is sufficient to trigger infertility. With this increasing recognition that peripherally derived KISS1 regulates fertility, the first goal of this review is to critically discuss the data that have led to this conclusion, focusing on uterine-and placental-derived KISS1. Given that a significant amount of this data was generated in animals such as the mouse and rat, a second goal of this review is to identify and discuss the limitations of the animal data in the context of better understanding KISS1 as a regulator of human pregnancy. The growing evidence suggests that in both man and mouse, KISS1 plays an important role in regulating very early pregnancy events such as embryo implantation. However, as pregnancy advances, although it seems that KISS1 continues to play important roles in regulating human pregnancy, it might not do so in the mouse. This surprising functional dichotomy between human females and mice appears also to exist between women and a large number of animal species, including lower primates. These findings are of tremendous significance and will greatly shape how KISS1 will be developed as a therapeutic agent in augmenting the reproductive potential of both women and important livestock species.Reproduction (2015) 150 R121-R128

Deregulation of miR-324/KISS1/kisspeptin in early ectopic pregnancy: mechanistic findings with clinical and diagnostic implications

“…Human placentation is an intricate process of fetal-maternal interaction that shares some similarities with cancer migration and metastasis (35). In this context, kisspeptins, initially identified as potential metastasis-suppressing factors abundantly expressed in the placenta, were suspected as important players for the fine control of trophoblast invasion and placentation (17,18). This placental dimension of kisspeptins was further attested by the proven elevation of kisspeptin levels already at early stages of human gestation (21).…”

“…In our study, the observed drop in KISS1 expression might have an impact on the whole process of trophoblast invasion, which is inhibited by locally produced kisspeptins (20,37), and might facilitate nidation at an ectopic site. Interestingly, Kisspeptin and miR-324-3p in Ectopic Pregnancy kisspeptins have been suggested also to facilitate initial embryo adhesion/implantation at proper endometrial sites (18,38), while high tubal expression of Kiss1/kisspeptin has been proposed as mechanism to prevent ectopic implantation in rats (39). Whether early deregulation of kisspeptin production might facilitate adherence at extra-uterine sites in human pregnancy is yet to be elucidated.…”

“…Despite the overwhelming evidence supporting a major function of brain (hypothalamic) kisspeptin signaling in the control of reproduction, mainly via its capacity to stimulate gonadotropin-releasing hormone (GnRH) neurons (16), additional functions of kisspeptins have been reported at peripheral levels of the reproductive axis, including the ovary and the uterus (17,18). On the latter, mounting evidence has demonstrated that the elements of Kiss1 system are expressed in human endometrium and placenta (18), and kisspeptins have been proposed to play an important role in endometrial gland development and function (19), as well as in human placentation (17,18). Notably, expression and functional analyses have suggested that kisspeptin signaling is an important (negative) regulator of human trophoblast migration and invasion (20), as well as a (positive) regulator of embryo implantation (18).…”

“…On the latter, mounting evidence has demonstrated that the elements of Kiss1 system are expressed in human endometrium and placenta (18), and kisspeptins have been proposed to play an important role in endometrial gland development and function (19), as well as in human placentation (17,18). Notably, expression and functional analyses have suggested that kisspeptin signaling is an important (negative) regulator of human trophoblast migration and invasion (20), as well as a (positive) regulator of embryo implantation (18). Altogether, these findings attest a relevant function of kisspeptins in human placentation, which is further suggested by the fact that circulating levels of kisspeptins dramatically increase during gestation (21), with abundant expression of KISS1 in human trophoblast, especially in the first trimester (20).…”

Kisspeptin: new biomarker of pregnancy

“…15 It is most likely that the increase in the total number of trophoblast cells throughout the course of gestation is responsible for the dramatic increase in serum kisspeptin levels. 16 Kisspeptin are mainly derived from placenta, the levels of plasma or serum kisspeptin can probably act as a biomarker for the function of the placenta and therefore viability of pregnancy. [17][18][19] Dhillo et al, showed that Circulating kisspeptin levels fell again 5 days post-delivery to comparable concentrations prior to pregnancy, implicating a placental source.…”