The Role of Kisspeptin Signalling in Human Reproduction and Puberty

Running head: THE ROLE OF KISSPEPTIN SIGNALLING
THE ROLE OF KISSPEPTIN SIGNALLING
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THE ROLE OF KISSPEPTIN SIGNALLING2
Introduction:
The early detection of kisspeptins in the recent era facilitate the present knowledge of the
neuroendocrine axis associated with the human puberty as well as reproduction. As suggested by
a range of researchers, the secretion of gonadotropic release hormone from the hypothalamus
plays a fundamental role in controlling and initiating reproductive function of the human being
(2). However, some functional hindrance further highlighted that an intermediate pathway
controls the hypothalamic-pituitary-gonadal (HPG) axis that in turn enhance the reproductive
function of a human being. In this context, the kisspeptin pathway exhibits regulatory function
which opened a new revenue in the arena of researches focused on the human reproductive
system. kisspeptin is a KiSS1 gene-encoded hypothalamic peptide that acts upstream of
Gonadotropin-releasing hormone and controls the hypothalamic-pituitary-gonadal axis via onset
puberty, regulation of gonadotropin secretion and control of fertility (1). The signalling pathway
also involved in the negative as well as positive sex steroid feedback signals for connecting the
metabolic status of the body and reproductive system. The pathway regulation observed in
various peripheral reproductive organs by mediating placentation, implanting embryo and
modulating the ovarian function. This paper aims to provide an in-depth discussion of the
reproductive role of kisspeptins, functional anatomy, and role in the axis and clinical significance
in the following paragraphs.
Discussion:
Kisspeptin and reproductive role:
Kisspeptin is a hypothalamic peptide that secreted from the hypothalamus and mediated
the initiation of a cell to cell communication followed by the production of reproductive

THE ROLE OF KISSPEPTIN SIGNALLING3
hormones, follicle-stimulating hormones from the pituitary gland. Kiss1 is a gene that encodes
the protein and it is originally discovered as a human metastasis suppressor gene with the ability
for suppressing melanoma (3). Many experimental studies reported that KiSS1 in human being
presented in human chromosome 1 (1q32) that originally produces a 145 amino acid building
block peptide known as prepro-kisspeptin (8). Prepro-kisspeptin is further cleaved into 54 amino
acid protein, known as kisspeptin-54, Kp-45 or formerly called metastin. Kp-54 further cleaved
to produce low molecular weight kisspeptin (4). The kisspeptin peptide directly activates
Gonadotropin-releasing hormone neurones, indicating that it has a direct role in the
hypothalamic-pituitary-gonadal axis which has a clinical significance. The role of Kisspeptine in
the regulation of reproduction was remained unrecognized until 2003 (3). However, the mutation
of GPR54 mutation related to idiopathic hypogonadotropic hypogonadism in mice pointed out
the role of kisspeptin function in the reproduction regulation (5). The researchers suggested that
in order to regulate the puberty, kisspeptin plays a crucial role which further provides a need for
exploration of the detailed function of Kisspeptine in regulating appropriate reproduction in
human being.
The role of kisspeptins in modifying GnRH secretion:
Hypothalamus is the chief site of the action of kisspeptin since it has the ability to
encourage the discharge of Gonadotropin-releasing hormone in the hypothalamus. In the
hypothalamus of rat, it is found that the over three to fourth of the Gonadotropin-releasing
hormone neurons coexpress the receptor for kisspeptin (7). However, it also plays a crucial role
in the metabolic control of the reproductive system.
Kisspeptin is considered as a G protein-coupled receptor ligand for GPR54 that further
facilitate the secretion of gonadotropin-releasing hormone for acting on anterior the anterior

THE ROLE OF KISSPEPTIN SIGNALLING4
pituitary for inducing the secretion of the luteinizing hormone as well as follicle-stimulating
hormone (9). These hormones are responsible for the sexual maturation amongst human being
(3). Hence, it is crucial to study the role of kisspeptin in gonadotropin-releasing hormone pulse
generation, secretion in the human body. Apart from the indirect stimulation, kisspeptin can
directly stimulate pituitary gland for stimulating luteinizing hormone and follicle-stimulating
hormone (10). However, indirect stimulation increases the discharge of gonadotropin-releasing
hormone as well as control the hypothalamic-pituitary-gonadal axis.
Role of kisspeptin in the gonadal system:
Kisspeptin neurons act as a channel for negative feedback as well as positive feedback of
sex steroids. Kisspeptin regulate feedback by increasing mRNA expression in the hypothalamus
of both male and female. The negative feedback in female further impacts the oestrogen level.
This findings further suggested that kisspeptin stimulated by a high level of oestrogen and
progestreton that in turn induct preovulatory surge since kiss1-mRNA expression is increased by
oestrogen. On the other hand, through the negative feedback, oestrogen suppresses luteinizing
hormone by reducing kisspeptin mediated release of gonadotropin-releasing hormone. Hence,
kisspeptin pathway plays an essential role in regulating sex hormones.
Apart from the role in regulating sex hormones, it plays a crucial role in the female
reproductive tract. Kisspeptin modulates the follicular maturation, survival of oocyte and
subsequent ovulation. Majority of the studies were conducted on the mouse and sheep model.
The researchers suggested that kiss1 mRNA expression occurs on the cyclic manners in the
period of the oestrous cycle where a noteworthy increase observed in the preovulatory stage that