Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems

Sally Radovick; Andy V. Babwah

doi:10.1055/s-0039-3400966

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2019; 37(04): 182-190
DOI: 10.1055/s-0039-3400966

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems

Authors

Sally Radovick

¹Department of Pediatrics, Laboratory of Human Growth and Reproductive Development, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey

²Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
Andy V. Babwah

¹Department of Pediatrics, Laboratory of Human Growth and Reproductive Development, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey

²Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey

Abstract

Several studies provide strong evidence suggesting that in addition to central kisspeptin/KISS1R signaling, the peripheral uterine- and placental-based kisspeptin/KISS1R signaling systems are major regulators of pregnancy. Specifically, the evidence suggests that the uterine-based system regulates embryo implantation and decidualization, while both the uterine- and placental-based systems regulate placentation. Uterine kisspeptin and KISS1R regulate embryo implantation by controlling the availability of endometrial glandular secretions, like leukemia inhibitory factor, which are essential for embryo adhesion to the uterine epithelium. As for decidualization, the data suggest that decidualized stromal cells express KISS1R and secrete kisspeptin-inhibiting decidual cell motility and thereby indirectly regulate embryo and placental invasion of the uterus. Similarly, for placentation, placental kisspeptin and KISS1R negatively regulate extravillous trophoblast migration and invasion and thereby directly control placental invasion of the uterus. Having recognized a significant role for the uterine- and placental-based kisspeptin/KISS1R signaling systems regulating pregnancy, the future looks promising for the development of kisspeptin and KISS1R as prognostic and diagnostic markers of pregnancy disorders and the use of kisspeptin as a therapeutic agent in the prevention and treatment of conditions such as recurring implantation failure, recurrent pregnancy loss, and preeclampsia.

Keywords

kisspeptin - KISS1R - implantation - decidualization - placentation

Full Text

References

References
1 Whynott RM, Vaught KCC, Segars JH. The effect of uterine fibroids on infertility: a systematic review. Semin Reprod Med 2017; 35 (06) 523-532
2 Fainberg J, Kashanian JA. Recent advances in understanding and managing male infertility. F1000 Res 2019; 8: 8
3 Spinella F, Fiorentino F, Biricik A. , et al. Extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments. Fertil Steril 2018; 109 (01) 77-83
4 Seminara SB, Messager S, Chatzidaki EE. , et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
5 de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
6 Dorfman MD, Garcia-Rudaz C, Alderman Z. , et al. Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology 2014; 155 (08) 3098-3111
7 Gaytan F, Garcia-Galiano D, Dorfman MD. , et al. Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology 2014; 155 (08) 3088-3097
8 Comninos AN, Demetriou L, Wall MB. , et al. Modulations of human resting brain connectivity by kisspeptin enhance sexual and emotional functions. JCI Insight 2018; 3 (20) 121958
9 Liu X, Herbison AE. Kisspeptin regulation of neuronal activity throughout the central nervous system. Endocrinol Metab (Seoul) 2016; 31 (02) 193-205
10 Herbison AE, de Tassigny Xd, Doran J, Colledge WH. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 2010; 151 (01) 312-321
11 Pineda R, Plaisier F, Millar RP, Ludwig M. Amygdala kisspeptin neurons: putative mediators of olfactory control of the gonadotropic axis. Neuroendocrinology 2017; 104 (03) 223-238
12 Stephens SBZ, Di Giorgio NP, Liaw RB. , et al. Estradiol-dependent and -independent stimulation of Kiss1 expression in the amygdala, BNST, and lateral septum of mice. Endocrinology 2018; 159 (09) 3389-3402
13 Wolfe A, Hussain MA. The emerging role(s) for kisspeptin in metabolism in mammals. Front Endocrinol (Lausanne) 2018; 9: 184
14 Song WJ, Mondal P, Wolfe A. , et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 2014; 19 (04) 667-681
15 Bowe JE, King AJ, Kinsey-Jones JS. , et al. Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats. Diabetologia 2009; 52 (05) 855-862
16 Prague JK, Dhillo WS. Potential clinical use of kisspeptin. Neuroendocrinology 2015; 102 (03) 238-245
17 Cetković A, Miljic D, Ljubić A. , et al. Plasma kisspeptin levels in pregnancies with diabetes and hypertensive disease as a potential marker of placental dysfunction and adverse perinatal outcome. Endocr Res 2012; 37 (02) 78-88
18 Nijher GM, Chaudhri OB, Ramachandran R. , et al. The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy. Br J Clin Pharmacol 2010; 70 (05) 674-681
19 Nijher GM, Baxter JE, Chaudhri OB. , et al. Identification of the hormone kisspeptin in amniotic fluid. Clin Chem 2010; 56 (06) 1029-1031
20 Hu KL, Zhao H, Yu Y, Li R. Kisspeptin as a potential biomarker throughout pregnancy. Eur J Obstet Gynecol Reprod Biol 2019; 240: 261-266
21 Jayasena CN, Comninos AN, Narayanaswamy S. , et al. The identification of elevated urinary kisspeptin-immunoreactivity during pregnancy. Ann Clin Biochem 2015; 52 (Pt 3): 395-398
22 Dhillo WS, Savage P, Murphy KG. , et al. Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment. Am J Physiol Endocrinol Metab 2006; 291 (05) E878-E884
23 Jayasena CN, Abbara A, Izzi-Engbeaya C. , et al. Reduced levels of plasma kisspeptin during the antenatal booking visit are associated with increased risk of miscarriage. J Clin Endocrinol Metab 2014; 99 (12) E2652-E2660
24 Finn CA, Martin L. The control of implantation. J Reprod Fertil 1974; 39 (01) 195-206
25 McCormack JT, Greenwald GS. Evidence for a preimplantation rise in oestradiol-17beta levels on day 4 of pregnancy in the mouse. J Reprod Fertil 1974; 41 (02) 297-301
26 Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology 2000; 141 (12) 4365-4372
27 Tabibzadeh S. Molecular control of the implantation window. Hum Reprod Update 1998; 4 (05) 465-471
28 Kobayashi R, Terakawa J, Omatsu T. , et al. The window of implantation is closed by estrogen via insulin-like growth factor 1 pathway. J Reprod Infertil 2017; 18 (02) 231-241
29 Ruiz-Alonso M, Galindo N, Pellicer A, Simón C. What a difference two days make: “personalized” embryo transfer (pET) paradigm: a case report and pilot study. Hum Reprod 2014; 29 (06) 1244-1247
30 Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: key pieces of the development puzzle. Science 1994; 266 (5190): 1508-1518
31 Dey SK, Lim H, Das SK. , et al. Molecular cues to implantation. Endocr Rev 2004; 25 (03) 341-373
32 Tanyapanyachon P, Amelkina O, Chatdarong K. The expression of kisspeptin and its receptor in the domestic cat ovary and uterus in different stages of the ovarian cycle. Theriogenology 2018; 117: 40-48
33 Cejudo Roman A, Pinto FM, Dorta I. , et al. Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. Fertil Steril 2012; 97 (05) 1213-1219
34 Fayazi M, Calder M, Bhattacharya M, Vilos GA, Power S, Babwah AV. The pregnant mouse uterus exhibits a functional kisspeptin/KISS1R signaling system on the day of embryo implantation. Reprod Biol Endocrinol 2015; 13: 105
35 Schäfer-Somi S, Ay SS, Kaya D. , et al. Kisspeptin-10 and the G protein-coupled receptor 54 are differentially expressed in the canine pregnant uterus and trophoblast cells. Reprod Domest Anim 2017; 52 (Suppl. 02) 123-129
36 León S, Fernandois D, Sull A. , et al. Beyond the brain—peripheral kisspeptin signaling is essential for promoting endometrial gland development and function. Sci Rep 2016; 6: 29073
37 Calder M, Chan YM, Raj R. , et al. Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor. Endocrinology 2014; 155 (08) 3065-3078
38 Zhang P, Tang M, Zhong T. , et al. Expression and function of kisspeptin during mouse decidualization. PLoS One 2014; 9 (05) e97647
39 Schäfer-Somi S, Kaya D, Sözmen M, Kaya S, Aslan S. Pre-pubertal treatment with a GnRH agonist in bitches—effect on the uterus and hormone receptor expression. Reprod Domest Anim 2018; 53 (Suppl. 03) 103-109
40 Baba T, Kang HS, Hosoe Y. , et al. Menstrual cyclic change of metastin/GPR54 in endometrium. Med Mol Morphol 2015; 48 (02) 76-84
41 Wu HM, Huang HY, Soong YK, Leung PCK, Wang HS. Kisspeptin regulation of human decidual stromal cells motility via FAK-Src intracellular tyrosine kinases. Hum Reprod 2019; 34 (07) 1291-1301
42 Hugon-Rodin J, Yoshii K, Lahlou N, Flandrin J, Gompel A, de Roux N. Complete kisspeptin receptor inactivation does not impede exogenous GnRH-induced LH surge in humans. J Clin Endocrinol Metab 2018; 103 (12) 4482-4490
43 d'Anglemont de Tassigny X, Fagg LA, Dixon JP. , et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A 2007; 104 (25) 10714-10719
44 Lapatto R, Pallais JC, Zhang D. , et al. Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 2007; 148 (10) 4927-4936
45 Taylor J, Pampillo M, Bhattacharya M, Babwah AV. Kisspeptin/KISS1R signaling potentiates extravillous trophoblast adhesion to type-I collagen in a PKC- and ERK1/2-dependent manner. Mol Reprod Dev 2014; 81 (01) 42-54
46 Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci U S A 1991; 88 (24) 11408-11412
47 Stewart CL, Kaspar P, Brunet LJ. , et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 1992; 359 (6390): 76-79
48 Marwood M, Visser K, Salamonsen LA, Dimitriadis E. Interleukin-11 and leukemia inhibitory factor regulate the adhesion of endometrial epithelial cells: implications in fertility regulation. Endocrinology 2009; 150 (06) 2915-2923
49 Filant J, Lydon JP, Spencer TE. Integrated chromatin immunoprecipitation sequencing and microarray analysis identifies FOXA2 target genes in the glands of the mouse uterus. FASEB J 2014; 28 (01) 230-243
50 Qi QR, Xie QZ, Liu XL, Zhou Y. Osteopontin is expressed in the mouse uterus during early pregnancy and promotes mouse blastocyst attachment and invasion in vitro. PLoS One 2014; 9 (08) e104955
51 Liu N, Zhou C, Chen Y, Zhao J. The involvement of osteopontin and β3 integrin in implantation and endometrial receptivity in an early mouse pregnancy model. Eur J Obstet Gynecol Reprod Biol 2013; 170 (01) 171-176
52 Chaen T, Konno T, Egashira M. , et al. Estrogen-dependent uterine secretion of osteopontin activates blastocyst adhesion competence. PLoS One 2012; 7 (11) e48933
53 O'Sullivan CM, Ungarian JL, Singh K, Liu S, Hance J, Rancourt DE. Uterine secretion of ISP1 & 2 tryptases is regulated by progesterone and estrogen during pregnancy and the endometrial cycle. Mol Reprod Dev 2004; 69 (03) 252-259
54 Chen W, Han BC, Wang RC, Xiong GF, Peng JP. Role of secretory protease inhibitor SPINK3 in mouse uterus during early pregnancy. Cell Tissue Res 2010; 341 (03) 441-451
55 Mumtaz A, Khalid A, Jamil Z, Fatima SS, Arif S, Rehman R. Kisspeptin: a potential factor for unexplained infertility and impaired embryo implantation. Int J Fertil Steril 2017; 11 (02) 99-104
56 Jamil Z, Fatima SS, Arif S, Alam F, Rehman R. Kisspeptin and embryo implantation after ICSI. Reprod Biomed Online 2017; 34 (02) 147-153
57 Bhattacharya M, Babwah AV. Kisspeptin: beyond the brain. Endocrinology 2015; 156 (04) 1218-1227
58 Babwah AV. Uterine and placental KISS1 regulate pregnancy: what we know and the challenges that lie ahead. Reproduction 2015; 150 (04) R121-R128
59 Ramathal CY, Bagchi IC, Taylor RN, Bagchi MK. Endometrial decidualization: of mice and men. Semin Reprod Med 2010; 28 (01) 17-26
60 Dean M. Glycogen in the uterus and fallopian tubes is an important source of glucose during early pregnancy. Biol Reprod 2019; 101 (02) 297-305
61 Pollheimer J, Vondra S, Baltayeva J, Beristain AG, Knöfler M. Regulation of placental extravillous trophoblasts by the maternal uterine environment. Front Immunol 2018; 9: 2597
62 Mori M, Bogdan A, Balassa T, Csabai T, Szekeres-Bartho J. The decidua-the maternal bed embracing the embryo-maintains the pregnancy. Semin Immunopathol 2016; 38 (06) 635-649
63 Szwarc MM, Hai L, Gibbons WE. , et al. Human endometrial stromal cell decidualization requires transcriptional reprogramming by PLZF. Biol Reprod 2018; 98 (01) 15-27
64 Schwenke M, Knöfler M, Velicky P. , et al. Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors. PLoS One 2013; 8 (01) e54336
65 Silver RM, Barbour KD. Placenta accreta spectrum: accreta, increta, and percreta. Obstet Gynecol Clin North Am 2015; 42 (02) 381-402
66 El-Azzamy H, Balogh A, Romero R. , et al. Characteristic changes in decidual gene expression signature in spontaneous term parturition. J Pathol Transl Med 2017; 51 (03) 264-283
67 Wu S, Zhang H, Tian J, Liu L, Dong Y, Mao T. Expression of kisspeptin/GPR54 and PIBF/PR in the first trimester trophoblast and decidua of women with recurrent spontaneous abortion. Pathol Res Pract 2014; 210 (01) 47-54
68 Bilban M, Ghaffari-Tabrizi N, Hintermann E. , et al. Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. J Cell Sci 2004; 117 (Pt 8): 1319-1328
69 Wang Y, Zhao S. , eds. Vascular Biology of the Placenta. San Rafael, CA: Morgan & Claypool Life Sciences; 2010
70 Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol 2000; 157 (06) 2111-2122
71 National Institute for Health and Care Excellence (NICE). Hypertension in pregnancy: diagnosis and management. NICE Guideline 2019: 1-54
72 Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367 (9516): 1066-1074
73 Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33 (03) 130-137
74 Say L, Chou D, Gemmill A. , et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014; 2 (06) e323-e333
75 Horikoshi Y, Matsumoto H, Takatsu Y. , et al. Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans. J Clin Endocrinol Metab 2003; 88 (02) 914-919
76 Lee JH, Miele ME, Hicks DJ. , et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996; 88 (23) 1731-1737
77 Kotani M, Detheux M, Vandenbogaerde A. , et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276 (37) 34631-34636
78 Muir AI, Chamberlain L, Elshourbagy NA. , et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 2001; 276 (31) 28969-28975
79 Janneau JL, Maldonado-Estrada J, Tachdjian G. , et al. Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells. J Clin Endocrinol Metab 2002; 87 (11) 5336-5339
80 Francis VA, Abera AB, Matjila M, Millar RP, Katz AA. Kisspeptin regulation of genes involved in cell invasion and angiogenesis in first trimester human trophoblast cells. PLoS One 2014; 9 (06) e99680
81 Armstrong RA, Reynolds RM, Leask R, Shearing CH, Calder AA, Riley SC. Decreased serum levels of kisspeptin in early pregnancy are associated with intra-uterine growth restriction and pre-eclampsia. Prenat Diagn 2009; 29 (10) 982-985
82 Whitehead CL, Walker SP, Ye L. , et al. Placental specific mRNA in the maternal circulation are globally dysregulated in pregnancies complicated by fetal growth restriction. J Clin Endocrinol Metab 2013; 98 (03) E429-E436
83 Smets EM, Deurloo KL, Go AT, van Vugt JM, Blankenstein MA, Oudejans CB. Decreased plasma levels of metastin in early pregnancy are associated with small for gestational age neonates. Prenat Diagn 2008; 28 (04) 299-303
84 Qiao C, Cheng DL, Zhang SL, Wang CH, Lin QD. The role of KiSS-1 and matrix metalloproteinase-9 in regulation of invasion of trophoblasts [in Chinese]. Zhonghua Yi Xue Za Zhi 2005; 85 (12) 839-842
85 Brew O, Sullivan MH, Woodman A. Comparison of normal and pre-eclamptic placental gene expression: a systematic review with meta-analysis. PLoS One 2016; 11 (08) e0161504
86 Horng HC, Yeh CC, Wang PH. Kisspeptin and preeclampsia. Taiwan J Obstet Gynecol 2017; 56 (03) 420-421
87 Ziyaraa MA, Hamdan FB, Mousa LR. Correlation of kisspeptin-10 level and fetal well-being in preeclamptic patients. Taiwan J Obstet Gynecol 2016; 55 (06) 840-846
88 Matjila M, Millar R, van der Spuy Z, Katz A. Elevated placental expression at the maternal-fetal interface but diminished maternal circulatory kisspeptin in preeclamptic pregnancies. Pregnancy Hypertens 2016; 6 (01) 79-87
89 Qiao C, Wang C, Zhao J, Liu C, Shang T. Elevated expression of KiSS-1 in placenta of Chinese women with early-onset preeclampsia. PLoS One 2012; 7 (11) e48937
90 Adali E, Kurdoglu Z, Kurdoglu M, Kamaci M, Kolusari A, Yildizhan R. Metastin levels in pregnancies complicated by pre-eclampsia and their relation with disease severity. J Matern Fetal Neonatal Med 2012; 25 (12) 2671-2675
91 Cartwright JE, Williams PJ. Altered placental expression of kisspeptin and its receptor in pre-eclampsia. J Endocrinol 2012; 214 (01) 79-85
92 Logie JJ, Denison FC, Riley SC. , et al. Evaluation of kisspeptin levels in obese pregnancy as a biomarker for pre-eclampsia. Clin Endocrinol (Oxf) 2012; 76 (06) 887-893
93 Zhang H, Long Q, Ling L, Gao A, Li H, Lin Q. Elevated expression of KiSS-1 in placenta of preeclampsia and its effect on trophoblast. Reprod Biol 2011; 11 (02) 99-115
94 Farina A, Sekizawa A, Purwosunu Y. , et al. Quantitative distribution of a panel of circulating mRNA in preeclampsia versus controls. Prenat Diagn 2006; 26 (12) 1115-1120
95 Madazli R, Bulut B, Tuten A, Aydin B, Demirayak G, Kucur M. First-trimester maternal serum metastin, placental growth factor and chitotriosidase levels in pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2012; 164 (02) 146-149
96 Vazquez-Alaniz F, Galaviz-Hernandez C, Marchat LA. , et al. Comparative expression profiles for KiSS-1 and REN genes in preeclamptic and healthy placental tissues. Eur J Obstet Gynecol Reprod Biol 2011; 159 (01) 67-71
97 Carter AM. Animal models of human placentation–a review. Placenta 2007; 28: 41-47
98 Tanaka A, Nakata D, Masaki T, Kusaka M, Watanabe T, Matsui H. Evaluation of pharmacokinetics/pharmacodynamics and efficacy of one-month depots of TAK-448 and TAK-683, investigational kisspeptin analogs, in male rats and an androgen-dependent prostate cancer model. Eur J Pharmacol 2018; 822: 138-146
99 Nishizawa N, Takatsu Y, Kumano S. , et al. Design and synthesis of an investigational nonapeptide KISS1 receptor (KISS1R) agonist, Ac-d-Tyr-hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH₂ (TAK-448), with highly potent testosterone-suppressive activity and excellent water solubility. J Med Chem 2016; 59 (19) 8804-8811
100 Millar RP, Babwah AV. KISS1R: hallmarks of an effective regulator of the neuroendocrine axis. Neuroendocrinology 2015; 101 (03) 193-210