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REVIEW ARTICLE Role of Kisspeptin in Female Infertility

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REVIEW ARTICLE Role of Kisspeptin in Female Infertility REVIEW ARTICLE Role of Kisspeptin in Female Infertility Bhuiyan MRI1, Khaliduzzaman SM2, Priti KN3 Abstract Background: Kiss1, a noble G protein coupled receptor designated as GPR54, was first identified in rat brain in 1999 and orthologue gene identified in human in 2001 the original niche for the function of kisspeptin was restricted to cancer biology for their ability to suppress tumor metastasis. However, kisspeptin has recently emerged as a key player in the field of reproductive endocrinology. Method: A systematic literature review was done by using PUBMED. Though there is lack of human data, used animal data also hold translational potential for human. Results: Inactivating mutation of GPR54 gene is linked with absence of puberty onset and idiopathic hypogonadotrophic hypogonadism. Furthermore, recent studies support critical role of kisspeptin/GPR54 system on regulation of GnRH neurons, involvement of puberty onset and gonadal steroid feedback. Conclusion: This review will briefly discuss on cellular and molecular level of kisspeptin, their potential effects on human and clinical application of kisspeptin on human reproductive disorder. Introduction axis, revolutionized our current understanding Procreation is an indispensable part of every on control of human reproduction.8 It is believed species. To initiate and control reproduction, that, kisspeptin and functional neural network coordination of neuronal networks play complex KNDY (kisspeptin / neurokinin / dynorphin) role and finally make a common pathway, which system modulate GnRH pulse. Therefore, is well known as Hypothalamic Pituitary Kisspeptin is considered as a key regulator of Gonadal (HPG) axis that synthesize gonadotropin secretion and responsible for gonadotrophic releasing hormone. Since its many physiological phenomenons. Moreover, discovery, adequate pulsatile hypothalamic manipulation of KNDY neural network and gonadotrophic releasing hormone (GnRH) regulation of LH pulse, subsequently control of secretion has been considered as key element for gonadal hormonal secretion may open a new maintaining reproductive function.1-4 During horizon in treatment of infertility. Recently puberty, hypothalamus start synthesis and release reproductive scientists are working for future of GnRH, which acts on anterior pituitary to application of KNDY system by increasing LH secrete FSH and LH, as a result gonads begin to pulse, like wise hypothalamic amenorrhea, 5-7 produce sex steroid and peptide hormone. hypogondotrophic hypogonadism or reduce LH Only a decade ago in 2003, discovery of secretion, such as in polycystic ovary kisspeptin and its role on regulation of the HPG syndrome.9 1. Junior embryologist, Dept. of IVF, Apollo hospitals Dhaka, 2. Embryologist, Dept. of IVF Apollo hospitals Dhaka, 3. Medical officer, Islami Bank hospital Pulse Volume 8 2015 43 second most dense as pre-optic area.21 As on to the median eminence (in rodent, sheep & highlighted above, Kisspeptin neuron has been monkey).22,23,25,33 In 2009, Navarro et al In this review, briefly discussed on cellular and various proteolytic processing.14 In human, detected in the Infundibular / Arcuate Nucleus in discovered that LH secretion was inhibited by molecular level biology of kisspeptin and its kisspeptin precursor encodes 145 amino acid all species. However, availability of Kisspeptin dynorphin and neurokinin B, which act auto potential effect on human, more precisely on including a 54 amino acid region, named as neuron in rostral pre-optic area varies from synaptically on pulsatile release of Kisspeptin female reproduction, and how future clinical kisspeptin 54 (formerly termed as metastin). 12,15 species to species.21-25 For example, in rat model and drive pulsatile release of GnRH and LH.34 application of kisspeptin may resolve neural This segment can be further divided into low Kisspeptin is located in rostral periventricular Role of steroid on Kisspeptin reproductive disorder. A systematic literature molecular weight forms which are termed as KP region of the third ventricle of its brain whereas, Studies with human and various animal models 26-27 review was done by using PUBMED. Though 54, KP13, KP 10 for 14, and 13 and 10 amino it is absent in human brain. Only suggest that pulsatile GnRH secretion followed there is lack of human data, used animal data also acid peptide respectively. In addition, all peptide infundibulum in human, homologous to arcuate by LH secretions is controlled by steroid 36 hold translational potential for human. fragment share c terminal sequence of kisspeptin in rodent express all three KNDY neuron. feedback.35 However, GnRH neuron located in Discovery of Kiss1 Gene and Receptor 54, which is the characteristics feature of RF Physiological Action of KNDY Neuron hypothalamus are devoid of estrogen receptor Kiss1, a noble G protein coupled receptor amide group of peptide, collectively known as GnRH pulse is mainly mediated by gonadal that suggests another group of neuron is essential 12 designated as GPR54, was first identified in rat kisspeptin. Kiss 1R, upon binding its ligand steroid, (steroid sensitive receptor).30 In a study to convey message of ovulation induction to GnRH neuron.9 After discovery of physiological brain in 1999.10 This newly identified molecule kisspeptin activates phospholipase C and convert by Goodman et al revealed that Kisspeptin / role of KNDY it is suggested as <missing link> catalogued as a suppressor of metastasis in secondary intracellular messengers, inositol 1,4, Neurokinin / Dynorphin are in same functional of gonadal steroid feedback. melanoma cell line, therefore it is widely 5 triphosphate (IP3) and diacyl glycerol, that neuronal network, collectively known as KNDY Various animal data collection suggests that known as metastin. Hershey, (PA, USA) which induce calcium release and finally activation of network which is steroid sensitive and play as a estrogen derived negative feedback has been was famous for Hershey kisses chocolate and protein kinase C to proceed kisspeptins crucial regulator for GnRH pulse.29 In a 11,16-17 mediated by Kisspeptin neuron and neurokinin B birthplace of kiss I gene, also named as kiss function. schematic overview published by Skoroupskate of arcuate nucleus. In ovariectomised animal after this exclusive sweets. However, 2 years et al 2014 to correlate KNDY-GnRH pathway Distribution of Kisspeptin model (rodents, sheep, monkey etc.)32 express later, in 2001, orthologue gene AXOR12 and and sex steroid feedback system9 which is In 2001, different independent study group high level of kiss1 mRNA in arcuate nucleus, hOT7T175 identified in human and termed as adapted in this article. (Fig:1) It was not until isolated kiss1 mRNA from placenta, spinal cord, which supports high level of kiss1 mRNA and KISSIR.10-12 Three independent research groups 2003, that GPR54 mutation in men was identified pancreas, and pituitary gland by using reverse neurokinin B in infundibulum of post to be associated factor for hypogonadotrophic explore endogenous ligand of GPCR named as transcriptase polymerase chain reaction.11-13 In menopausal women than in premenopausal 13 11 12 hypogonadism and subsequently absent/delayed GPR54 , AXOR12 , HOT7T175 by using addition, northern blotting test has revealed kiss1 women.20 13, HEK 29311 and puberty, made a revolutionary understanding in different model, CHO K1 and GPR54 genes in peripheral area, such as In the late follicular phase estrogen feedback B16-B2612 role of Kisspeptin and KNDY neuron GnRH consecutively. Therefore, heart, liver, kidney, placenta and Immune switches to positive, ultimately induce LH surge pulse. Furthermore, subsequent research has international pharmacology association Reactivity (IR) found in different areas of the for ovulation. Though arcuate Kisspeptin (widely revealed that KNDY subpopulation in various displaced metastin to kisspeptin considering brain.18,19 Thus in 2005, specific population of known as KNDY) mediates negative feedback, species range from rodent to human play a key structural similarities and origin of kiss1 kiss1 neuron has been recognized in the positive steroid feedback mediated role in GnRH secretion by controlling neuro derivative peptides. hypothalamus.11-12 Infundibulum as source of Kisspeptins are species specific (figure). Apart activity of KNDY cells.30-32 These reciprocally Biology of Kisspeptin kiss1 neuron has been isolated from autopsy from Kisspeptin, other KNDY neuron originating inter connected KNDY cells are very sensitive to Kisspeptin, a noble neuromodulator, which is samples of premenopausal and post-menopausal from arcuate nucleus do not participate in steroid and act by direct contact with GnRH cell 31,34 peptide in nature and encoded by the kiss 1 gene women.20 Furthermore another study done in positive feedback. bodies and neuro secretory terminal (in human) that activate G protein coupled receptor and 2010 including both male and female autopsy upstream GnRH secretion. Kisspeptins are sample support the location of most dense generated from a single precursor through Kisspeptin neuron area as infundibulum and Clinical Aspects of Kisspeptin in Reproductive which is characterized by high level of LH due to Health neuro endocrine feedback defect and relative Since discovery of inactivating point mutation in high insulin lead to metabolic defect.43 KNDY gene GPR54 is associated with impaired puberty neurons are believed to be potential regulator of and idiopathic hypo gonadotrophic steroid mediated negative
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