Kisspeptins are a family of neuropeptides that are critical for initiating puberty and regulating ovulation in sexually mature females via the central control of the hypothalamic–pituitary–gonadal axis. Recent studies have shown that kisspeptin and its receptor kisspeptin receptor (KISS1R) are expressed in the mammalian ovary. Convincing evidence indicates that kisspeptins can activate a wide variety of signals via its binding to KISS1R. Experimental data gathered recently suggest a putative role of kisspeptin signaling in the direct control of ovarian function, including follicular development, oocyte maturation, steroidogenesis, and ovulation. Dysregulation or naturally occurring mutations of the kisspeptin/KISS1R system may negatively affect the ovarian function, leading to reproductive pathology or female infertility. A comprehensive understanding of the expression, actions, and underlying molecular mechanisms of this system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in reproductive diseases and infertility.

BACKGROUND Initially identified as suppressors of metastasis in various types of cancer, kisspeptins are a family of neuropeptides that are key regulators of the mammalian reproductive axis. Accumulating evidence has shown that kisspeptin is able to control both the pulsatile and surge GnRH release, playing fundamental roles in female reproduction, which include the secretion of gonadotropins, puberty onset, brain sex differentiation, ovulation and the metabolic regulation of fertility. Furthermore, recent studies have demonstrated the involvement of the kisspeptin system in the processes of implantation and placentation. This review summarizes the current knowledge of the pathophysiological role and utility of these local placental regulatory factors as potential biomarkers during the early human gestation. OBJECTIVE AND RATIONALE A successful pregnancy, from the initiation of embryo implantation to parturition, is a complex process that requires the orchestration of a series of events. This review aims to concisely summarize what is known about the role of the kisspeptin system in implantation, placentation, early human pregnancy and pregnancy-related disorders, and to develop strategies for predicting, diagnosing and treating these abnormalities. SEARCH METHODS Using the PubMed and Google Scholar databases, we performed comprehensive literature searches in the English language describing the advancement of kisspeptins and the kisspeptin receptor (KISS1R) in implantation, placentation and early pregnancy in humans, since its initial identification in 1996 and ending in July 2018. OUTCOMES Recent studies have shown the coordinated spatial and temporal expression patterns of kisspeptins and KISS1R during human pregnancy. The experimental data gathered recently suggest putative roles of kisspeptin signaling in the regulation of trophoblast invasion, embryo implantation, placentation and early pregnancy. Dysregulation of the kisspeptin system may negatively affect the processes of implantation as well as placentation. Clinical studies indicate that the circulating levels of kisspeptins or the expression levels of kisspeptin/KISS1R in the placental tissues may be used as potential diagnostic markers for women with miscarriage and gestational trophoblastic neoplasia. WIDER IMPLICATIONS Comprehensive research on the pathophysiological role of the kisspeptin/KISS1R system in implantation and placentation will provide a dynamic and powerful approach to understanding the processes of early pregnancy, with potential applications in observational and analytic screening as well as the diagnosis, prognosis and treatment of implantation failure and early pregnancy-related disorders.

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Objective: To study whether melatonin treatment can increase clinical pregnancy rate and live birth rate in assisted reproductive technology (ART) cycles. Methods: Literature searches were conducted to retrieve randomized trials that reported the effect of melatonin treatment on ART outcomes. Databases searched included PubMed, EMBASE, Cochrane Library, Web of Science, and Google Scholar. Results: Ten studies matched the inclusion criteria. Clinical pregnancy was reported in all of the included studies and live birth was reported in three studies. Melatonin treatment significantly increased the clinical pregnancy rate [OR = 1.43 (1.11, 1.86), power = 0.98, 10 RCTs, low-quality evidence] but not the live birth rate [OR = 1.38 (0.78, 2.46), power = 0.34, 3 RCTs, low-quality evidence]. Melatonin treatment increased the number of oocyte collected [SMD = 0.34 (0.01, 0.67), 7 RCTs, low-quality evidence], the number of maturated oocyte [SMD = 0.56 (0.27, 0.85), 7 RCTs, low-quality evidence], and the number of good quality embryo [MD = 0.36 (0.18, 0.55), 3 RCTs, low-quality evidence]. Melatonin treatment significantly increased the biochemical pregnancy rate [OR = 1.65 (1.14, 2.38), 6 RCTs, low-quality evidence] and had no significant effect on the miscarriage rate [OR = 1.28 (0.65, 2.51), 5 RCTs, low-quality evidence]. Conclusion: Melatonin treatment significantly increases the clinical pregnancy rate but not live birth rate in ART cycles. Melatonin treatment also increases the number of oocyte collected, maturated oocyte, and good quality embryo. No clear evidence suggested that melatonin treatment increased the adverse events in ART cycles. The actual findings may be compromised due to the wide heterogeneity of the included IVF patients, from PCOS to low ovarian reserve.