Kisspeptin: Role in Female Infertility

*Abdulsamed Kükürt, Mushap Kuru, Ömer Faruk Başer and Mahmut Karapehlivan*

#### **Abstract**

Kisspeptin is a neuropeptide encoded by the kisspeptin gene (Kiss1) and located in different brain regions, primarily in the hypothalamus. Kisspeptin and its receptor G-protein-coupled receptor-54 (GPR54), are also found in behavioural brain regions such as the hippocampus and cortex. Kisspeptin, a very powerful neuropeptide that stimulates the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary, does this by increasing gonadotropin-releasing hormone (GnRH) levels. In recent studies, it has been noted that kisspeptin is effective on reproductive functions. Globally 8 to 12% of couples have infertility problems, and the majority are residents of developing countries. Approximately 70% of infertility cases are caused by fertility problems in women. The frequency of infertility in women continues to increase every year and the underlying factors require further research. Bearing this problem in mind, this review examines the possible role of kisspeptin in female infertility. In doing so, it aims to find out how future application of kisspeptin may potentially unravel the neural reproductive disorder.

**Keywords:** kisspeptin, metastin, GPR54, Kiss1, Kiss1r, infertility, nitric oxide, sex streoid, progesterone, GnRH, LH, FSH

#### **1. Introduction**

Infertility is the inability to get pregnant despite regular sexual intercourse for one year or more (without contraception or the impairment of a person's or a couple's fertility) [1]. Fertility and pregnancy rates decrease due to ageing in women. For this reason, it is recommended that women aged 35 and above start receiving infertility treatment after 6 months of conception attempt. After the age of 40, this period should not be waited for treatment. Many factors cause female infertility. These can be listed as medical history (family history, previous treatments, menstrual history, sexual history, etc.), physical factors (weight, body mass index, etc.), diminished ovarian reserves, ovulatory dysfunction (hypothalamic–pituitary axis (HPG axis) disorders, ovarian disorders, thyroid disorders and hyperprolactinemia, etc.), tubal factors, uterine factors and unexplained causes [2, 3]. More than 186 million people worldwide suffer from infertility, and the majority of them are residents of developing countries [4].

Kisspeptin was discovered in 1996 as the product of the kisspeptin gene (Kiss1), which is a metastatic tumour suppressor gene; therefore, it was initially called

metastin [5]. Kisspeptins are a family of neuropeptides in RF-Amide structure [(neuropeptides containing arginine-phenylalanine (Arg-Phe) at the C-terminal are defined as RF-Amides)] [6]. Two years later, the connection between kisspeptin-54 and G-protein-coupled receptor-54 (GPR54) was shown for the first time [7]. In 2003, inactivating mutations of GPR54 were found in people with hypogonadotropic hypogonadism [8]. The respective receptor was previously called the GPR54, it is also identified as the kisspeptin receptor (Kiss1r) nowadays [9].

The detection of the role of the kisspeptin receptor mutation in leading to idiopathic hypogonadotropic hypogonadism paved the way for further investigations about the roles played by the kisspeptin, Kiss1, and Kiss1r systems in the field of reproductive endocrinology [10]. Many studies have shown that kisspeptin plays key roles in the regulation of different aspects of reproduction [11–17]. This review examines the possible role of kisspeptin in female infertility. In doing so, it aims to find out how future application of kisspeptin may potentially unravel the neural fertility disorder.
