**Abstract**

Kisspeptins are a group of neuropeptides with regulatory functions related to puberty, fertility, and reproduction. They are primarily produced by hypothalamic nuclei and are thought to regulate the activity of neurons that produce gonadotropinreleasing hormone. They are also expressed by placental syncytiotrophoblasts in developing pregnancies and are likely involved in the processes of trophoblast invasion and placentation. Similarly to beta-hCG, kisspeptins are found in maternal plasma during the first trimester of pregnancy and increase proportionately with gestational age. Because of their role in implantation, there is currently interest in the use of kisspeptins as minimally invasive biomarkers. It is suspected that maternal kisspeptin levels have diagnostic potential in identifying viable early pregnancies.

**Keywords:** kisspeptin, reproduction, fertility, placentation, biomarker

#### **1. Introduction**

Kisspeptins are a family of neuropeptides with diverse functions in humans. They are cleaved from a precursor peptide encoded by the *KISS-1* gene, which was originally identified in melanoma cells as a metastasis suppressor gene [1]. Expression of KISS-1 has subsequently been identified in many other cell lines, including those of the placenta, ovaries, and testes [2]. It is now known that kisspeptin plays a critical role in reproduction and fertility [3]. Kisspeptin is believed to regulate the secretion of gonadotropin-releasing hormone (GnRH) by integrating central and peripheral signals [4]. During the menstrual cycle, gonadal sex steroid concentrations impact the secretion of GnRH from neurons located in the hypothalamus. It is hypothesized that kisspeptin mediates this hypothalamic feedback because 1) GnRH neurons lack gonadal sex steroid receptors but some express kisspeptin receptors [5–7] and 2) kisspeptin neurons express sex steroid receptors [8, 9]. This review will focus on the role of kisspeptins throughout the menstrual cycle and their potential use as a biomarker of viable pregnancy.

#### **2. Kisspeptin in the follicular phase and periovulation**

Kisspeptin neurons are primarily located in the preoptic area and hypothalamic arcuate nucleus and function as upstream regulators of GnRH neurons [10]. In

both of these anatomic locations, serum estrogen and progesterone concentrations have been shown to regulate kisspeptin-mediated GnRH secretion [11]. During the early follicular phase of the menstrual cycle, estrogen exerts negative feedback on GnRH stimulation of luteinizing hormone (LH) secretion. As the follicular phase progresses, rising estrogen levels result in pulsatile secretion of GnRH, which then stimulates the pulsatile release of follicle-stimulating hormone (FSH) and LH [10]. This pulsatile secretion pattern is likely mediated by kisspeptin through regulation of GnRH neurons. Involvement of kisspeptin in this regulatory pathway is suspected because GnRH neurons lack estrogen and progesterone receptors, and thus cannot directly respond to serum sex steroid concentrations [12, 13]. The absence of a direct biochemical connection between the gonads and hypothalamus suggests the presence of an intermediary signal. This "missing link" is thought to be kisspeptin neurons, which express estrogen receptors and secrete a ligand that can bind to GnRH [12].

During the early follicular phase when follicles are underdeveloped, kisspeptin levels are low [4, 14]. A study by Zhai et al. showed that kisspeptin levels sharply increase when the dominant follicle reaches 1.2 cm in diameter [14]. Kisspeptin levels during the periovulatory period are then high [4, 14, 15], and may have potential in predicting development of the dominant ovarian follicle [14]. A study by Dhillo et al. demonstrated that administration of exogenous kisspeptin to healthy women results in increased gonadotropin secretion; this response is most potent during the preovulatory phase [16].

A study by Meczekalski et al. demonstrated that kisspeptin and LH are cosecreted (i.e. each kisspeptin pulse is accompanied by a pituitary LH pulse in response to a hypothalamic GnRH pulse) [11]. Another study demonstrated that blockade of the kisspeptin receptor (GPR54) resulted in blockade of pulsatile LH secretion [17]. There is also topographical evidence of the connection between GnRH and kisspeptin neurons – in several species, it has been shown that GnRH neuronal axons extend from the arcuate nucleus, where kisspeptin neurons are located, to the median eminence, where GnRH is secreted [12]. Human studies have not reproducibly demonstrated this neuroanatomy for all GnRH neurons, which may suggest that kisspeptin neuronal connections in humans are more complex [11, 18].
