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      Cross talk between serum Kisspeptin-Leptin during assisted reproduction techniques

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          Abstract

          Background & objective:

          Leptin facilitates onset of puberty by impact on hypothalamic Kisspeptin, gonadotropin releasing hormone, follicle stimulating and luteinizing hormone. The link of peripheral Leptin-Kisspeptin in regulating the ovarian and endometrial tissue in relation to adiposity is unknown. Therefore, we wanted to identify Kisspeptin-Leptin association with body mass index (BMI) and success of assisted reproductive treatments (ART) in infertile females.

          Methods:

          A cross sectional study was carried from August 2014 till May 2016 after receiving ethical approval at Australian Concept Infertility Medical Centre, and Aga Khan University. The study group comprised of females with an age range of 25-37 year who had duration of unexplained infertility for more than two years. They were grouped as; underweight (<18 kg/m 2), normal weight (18-22.9 kg/m 2), overweight 23-24.99 kg/m 2 and obese (>25 kg/m 2). Kisspeptin and Leptin levels were measured by enzyme linked immune sorbent assay before down regulation of ovaries and initiation of treatment protocol of ART. Failure of procedure was detected by beta human chorionic gonadotropin <25mIU/ml (non-pregnant) whereas females with levels >25mIU/ml and cardiac activity on trans-vaginal scan were declared pregnant.

          Results:

          Highest Kisspeptin and Leptin levels were seen in normal weight group (374.80 ± 185.08ng/L; 12.78 ± 6.8 pg/ml) respectively, yet the highest number of clinical pregnancy was observed in overweight group (42%).A strong correlation of Kisspeptin with Leptin (r=0.794, p=0.001) was observed in the overweight females.

          Conclusion:

          Leptin-Kisspeptin-fertility link is expressed by maximum number of clinical pregnancies in the female group that showed strongest relationship between serum Leptin and Kisspeptin levels, irrespective of their BMI.

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          Most cited references21

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          Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54.

          Sophie Messager, Emmanouella Chatzidaki, Dan Ma … (2005)
          We have recently described a molecular gatekeeper of the hypothalamic-pituitary-gonadal axis with the observation that G protein-coupled receptor 54 (GPR54) is required in mice and men for the pubertal onset of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion to occur. In the present study, we investigate the possible central mode of action of GPR54 and kisspeptin ligand. First, we show that GPR54 transcripts are colocalized with gonadotropin-releasing hormone (GnRH) neurons in the mouse hypothalamus, suggesting that kisspeptin, the GPR54 ligand, may act directly on these neurons. Next, we show that GnRH neurons seem anatomically normal in gpr54-/- mice, and that they show projections to the median eminence, which demonstrates that the hypogonadism in gpr54-/- mice is not due to an abnormal migration of GnRH neurons (as occurs with KAL1 mutations), but that it is more likely due to a lack of GnRH release or absence of GnRH neuron stimulation. We also show that levels of kisspeptin injected i.p., which stimulate robust LH and FSH release in wild-type mice, have no effect in gpr54-/- mice, and therefore that kisspeptin acts directly and uniquely by means of GPR54 signaling for this function. Finally, we demonstrate by direct measurement, that the central administration of kisspeptin intracerebroventricularly in sheep produces a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that a key action of kisspeptin on the hypothalamo-pituitary-gonadal axis occurs directly at the level of GnRH release. The localization and GnRH release effects of kisspeptin thus define GPR54 as a major control point in the reproductive axis and suggest kisspeptin to be a neurohormonal effector.
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            KiSS-1 neurones are direct targets for leptin in the ob/ob mouse.

            J T Smith, B V Acohido, D K Clifton … (2006)
            Leptin is an adipocyte-derived hormone that acts on the hypothalamus to influence feeding, metabolism and reproduction, but the cellular and molecular targets for the action of leptin in the brain have yet to be fully elucidated. Kisspeptins are encoded by the Kiss1 gene, which is expressed in the hypothalamus and has been implicated in the neuroendocrine regulation of gonadotrophin-releasing hormone secretion. We tested the hypothesis that kisspeptin-expressing neurones are targets for leptin. First, we examined whether leptin regulates the expression of Kiss1 by comparing levels of KiSS-1 mRNA in the arcuate nucleus among groups of mice having different circulating levels of leptin: (i) wild-type (WT); (ii) leptin-deficient ob/ob; and (iii) ob/ob mice treated with leptin. All mice were castrated to control for endogenous concentrations of gonadal steroids. KiSS-1 mRNA was significantly reduced in ob/ob compared to WT mice and levels of KiSS-1 mRNA in ob/ob mice treated with leptin were increased, but not fully restored to that found in WT animals. Second, we performed double-label in situ hybridisation for KiSS-1 mRNA and the leptin receptor (Ob-Rb) mRNA and found that almost one-half (approximately 40%) of KiSS-1 mRNA-expressing cells in the arcuate nucleus expressed Ob-Rb mRNA. These results demonstrate that KiSS-1 neurones are direct targets for regulation by leptin and suggest that the reproductive deficits associated with leptin-deficient states may be attributable, in part, to diminished expression of Kiss1.
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              Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells.

              Javed Iqbal Kazi, Kathryn Backholer, Andrew T. Smith … (2010)
              Kisspeptin stimulates reproduction, and kisspeptin cells in the arcuate nucleus (ARC) express Ob-Rb in the mouse. Herein we report studies in ewes to determine whether kisspeptin cells express Ob-Rb and respond to leptin and whether reciprocal connections exist between kisspeptin cells and proopiomelanocortin (POMC) or neuropeptide Y (NPY) cells to modulate reproduction and metabolic function. Kiss1 mRNA was measured by in situ hybridization in ovariectomized ewes that were normal body weight, lean, or lean with leptin treatment by intracerebroventricular (icv) infusion (4 microg/h, 3 d). Kiss1 expression in the ARC and the preoptic area was lower in hypogonadotropic lean animals than animals of normal weight, and icv infusion of leptin partially restored Kiss1 expression in lean animals. Single-cell laser capture microdissection coupled with real-time PCR showed that Kiss1 cells in the preoptic area and ARC express Ob-Rb. Double-label fluorescent immunohistochemistry showed that reciprocal connections exist between kisspeptin cells and NPY and POMC cells. Accordingly, we treated ovariectomized ewes with kisspeptin (5 microg/h, icv) or vehicle for 20 h and examined POMC and NPY gene expression by in situ hybridization. Kisspeptin treatment reduced POMC and increased NPY gene expression. Thus, kisspeptin neurons respond to leptin and expression of Kiss1 mRNA is affected by leptin status. Kisspeptin cells communicate with NPY and POMC cells, altering expression of the relevant genes in the target cells; reciprocal connections also exist. This network between the three cell types could coordinate brain control of reproduction and metabolic homeostatic systems.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pak J Med Sci
                Journal ID (iso-abbrev): Pak J Med Sci
                Title: Pakistan Journal of Medical Sciences
                Publisher: Professional Medical Publications (Pakistan )
                ISSN (Print): 1682-024X
                ISSN (Electronic): 1681-715X
                Publication date (Print): Mar-Apr 2018
                Volume: 34
                Issue: 2
                Pages: 342-346
                Affiliations
                [1 ]Rehana Rehman, Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan
                [2 ]Zehra Jamil, Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan
                [3 ]Aqsa Khalid, Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan
                [4 ]Syeda Sadia Fatima, Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan
                Author notes
                Correspondence: Dr. Syeda Sadia Fatima, Assistant Professor (Physiology), Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi-74800, Pakistan. Email: sadia.fatima@ 123456aku.edu
                Article
                Publisher ID: PJMS-34-342
                DOI: 10.12669/pjms.342.14078
                PMC ID: 5954376
                PubMed ID: 29805405
                SO-VID: b28d2140-77e4-4a96-a20c-88b8c15dcb5d
                Copyright © Copyright: © Pakistan Journal of Medical Sciences
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 18 October 2017
                Date revision received : 26 February 2018
                Date revision received : 28 February 2018
                Categories
                Subject: Original Article

                Keywords: assisted reproductive techniques,kisspeptin,leptin,body mass index
                Data availability:
                Keywords: assisted reproductive techniques, kisspeptin, leptin, body mass index

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