Advertisement

Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract

      Objective

      To investigate the presence of neurokinin B (NKB)/NK3 receptor (NK3R) and kisspeptin/KISS1 receptor (KISS1R) messenger RNA (mRNA) and proteins throughout the human female genital tract.

      Design

      In vitro study.

      Setting

      Academic research laboratories and academic hospitals.

      Patient(s)

      Fifteen reproductive-age women and 16 postmenopausal women provided fresh samples of uterus, ovary, or oviduct, and 12 women provided archival samples of endometrium or oviduct.

      Intervention(s)

      Fresh and archival samples of uterus, ovary, and oviduct obtained from reproductive-age and postmenopausal women.

      Main Outcome Measure(s)

      Results of reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry to investigate the pattern of expression of NKB/NK3R and kisspeptin/KISS1R in target tissues.

      Result(s)

      Expression of the genes encoding NKB (TAC3) and NK3R (TACR3), and kisspeptin (KISS1) and its receptor (KISS1R) was found in the uterus, ovary, and oviduct. Both NKB and NK3R immunoreactivity was detected in the endometrium, the oviduct, and the ovary, with marked expression in endometrial and oviductal epithelial cells, where intense coexpression of kisspeptin and KISS1R was also detected. Positive staining for NKB and NK3R was found in the myometrium where, in contrast, kisspeptin and KISS1R were absent.

      Conclusion(s)

      NKB/NK3R and kisspeptin/KISS1R are present in female peripheral reproductive tissues with colocalization of both systems in some non-neuronal cell populations of the human female genital tract. Our findings are compatible with a potential modulatory role of NKB and kisspeptin at peripheral reproductive tissues.

      Key Words

      To read this article in full you will need to make a payment

      References

        • Pennefather J.N.
        • Lecci A.
        • Candenas M.L.
        • Patak E.
        • Pinto F.M.
        • Maggi C.A.
        Tachykinins and tachykinin receptors: a growing family.
        Life Sci. 2004; 74: 1445-1463
        • Satake H.
        • Kawada T.
        Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors.
        Curr Drug Targets. 2006; 7: 963-974
        • Almeida T.A.
        • Rojo J.
        • Nieto P.M.
        • Pinto F.M.
        • Hernandez M.
        • Martin J.D.
        • Candenas M.L.
        Tachykinins and tachykinin receptors: structure and activity relationships.
        Curr Med Chem. 2004; 11: 2045-2081
        • Lasaga M.
        • Debeljuk L.
        Tachykinins and the hypothalamo-pituitary-gonadal axis: an update.
        Peptides. 2011; 32: 1972-1978
        • Topaloglu A.K.
        • Reimann F.
        • Guclu M.
        • Yalin A.S.
        • Kotan L.D.
        • Porter K.M.
        • et al.
        TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction.
        Nature Genet. 2009; 41: 354-358
        • Semple R.K.
        • Topaloglu A.K.
        Neurokinin B and its receptor in hypogonadotropic hypogonadism.
        Front Horm Res. 2010; 39: 1333-1341
        • Young J.
        • Bouligand J.
        • Francou B.
        • Raffin-Sanson M.L.
        • Gaillez S.
        • Jeanpierre M.
        • et al.
        TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans.
        J Clin Endocrinol Metab. 2010; 95: 2287-2295
        • Gianetti E.
        • Tusset C.
        • Noel S.D.
        • Au M.G.
        • Dwyer A.A.
        • Hughes V.A.
        • et al.
        TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood.
        J Clin Endocrinol Metab. 2010; 95: 2857-2867
        • Lehman M.N.
        • Coolen L.M.
        • Goodman R.L.
        Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion.
        Endocrinology. 2010; 151: 3479-3489
        • de Roux N.
        • Genin E.
        • Carel J.C.
        • Matsuda F.
        • Chaussain J.L.
        • Milgrom E.
        Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.
        Proc Natl Acad Sci USA. 2003; 100: 10972-10976
        • Seminara S.B.
        • Messager S.
        • Chatzidaki E.E.
        • Thresher R.R.
        • Acierno Jr., J.S.
        • Shagoury J.K.
        • et al.
        The GPR54 gene as a regulator of puberty.
        N Engl J Med. 2003; 349: 1614-1627
        • Navarro V.M.
        • Castellano J.M.
        • Fernandez-Fernandez R.
        • Barreiro M.L.
        • Roa J.
        • Sanchez-Criado J.E.
        • et al.
        Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide.
        Endocrinology. 2004; 145: 4565-4574
        • Navarro V.M.
        • Tena-Sempere M.
        Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility.
        Nature Rev Endocrinol. 2011; 8: 40-53
        • Rance N.E.
        • Young III, W.S.
        Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women.
        Endocrinology. 1991; 128: 2239-2247
        • Rance N.E.
        Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback.
        Peptides. 2009; 30: 111-122
        • Goodman R.L.
        • Lehman M.N.
        • Smith J.T.
        • Coolen L.M.
        • de Oliveira C.V.
        • Jafarzadehshirazi M.R.
        • et al.
        Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B.
        Endocrinology. 2007; 148: 5752-5760
        • Pinto F.M.
        • Armesto C.P.
        • Magraner J.
        • Trujillo M.
        • Martín J.D.
        • Candenas M.L.
        Tachykinin receptor and neutral endopeptidase gene expression in the rat uterus: characterization and regulation in response to ovarian steroid treatment.
        Endocrinology. 1999; 140: 2526-2532
        • Page N.M.
        • Woods R.J.
        • Gardiner S.M.
        • Lomthaisong K.
        • Gladwell R.T.
        • Butlin D.J.
        • et al.
        Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia.
        Nature. 2000; 405: 797-800
        • Page N.M.
        • Dakour J.
        • Morrish D.W.
        Gene regulation of neurokinin B and its receptor NK3 in late pregnancy and pre-eclampsia.
        Mol Hum Reprod. 2006; 12: 427-433
        • Pennefather J.N.
        • Patak E.
        • Pinto F.M.
        • Candenas M.L.
        Mammalian tachykinins and uterine smooth muscle: the challenge escalates.
        Eur J Pharmacol. 2004; 500: 15-26
        • Pintado C.O.
        • Pinto F.M.
        • Pennefather J.N.
        • Hidalgo A.
        • Baamonde A.
        • Sanchez T.
        • Candenas M.L.
        A role for tachykinins in female mouse and rat reproductive function.
        Biol Reprod. 2003; 69: 940-946
        • Löffler S.
        • Schulz A.
        • Brylla E.
        • Nieber K.
        • Spanel-Borowski K.
        Transcripts of neurokinin B and neurokinin 3 receptor in superovulated rat ovaries and increased number of corpora lutea as a non-specific effect of intraperitoneal agonist application.
        Regul Pept. 2004; 122: 131-137
        • Pinto F.M.
        • Almeida T.A.
        • Hernandez M.
        • Devillier P.
        • Advenier C.
        • Candenas M.L.
        mRNA expression of tachykinins and tachykinin receptors in different human tissues.
        Eur J Pharmacol. 2004; 494: 233-239
        • Candenas L.
        • Lecci A.
        • Pinto F.M.
        • Patak E.
        • Maggi C.A.
        • Pennefather J.N.
        Tachykinins and tachykinin receptors: effects in the genitourinary tract.
        Life Sci. 2005; 76: 835-862
        • Ravina C.G.
        • Seda M.
        • Pinto F.M.
        • Orea A.
        • Fernandez-Sanchez M.
        • Pintado C.O.
        • Candenas M.L.
        A role for tachykinins in the regulation of human sperm motility.
        Hum Reprod. 2007; 22: 1617-1625
        • Hamlin G.P.
        • Williams M.J.
        • Nimmo A.J.
        • Crane L.H.
        Hormonal variation of rat uterine contractile responsiveness to selective neurokinin receptor agonists.
        Biol Reprod. 2000; 62: 1661-1666
        • Cintado C.G.
        • Pinto F.M.
        • Devillier P.
        • Merida A.
        • Candenas M.L.
        Increase in neurokinin B expression and in tachykinin NK(3) receptor-mediated response and expression in the rat uterus with age.
        J Pharmacol Exp Ther. 2001; 299: 934-938
        • Candenas M.L.
        • Magraner J.
        • Armesto C.P.
        • Anselmi E.
        • Nieto P.M.
        • Martín J.D.
        • et al.
        Changes in the expression of tachykinin receptors in the rat uterus during the course of pregnancy.
        Biol Reprod. 2001; 65: 538-543
        • Patak E.
        • Candenas M.L.
        • Pennefather J.N.
        • Ziccone S.
        • Lilley A.
        • Martin J.D.
        • et al.
        Tachykinins and tachykinin receptors in human uterus.
        Br J Pharmacol. 2003; 139: 523-532
        • Patak E.
        • Pinto F.M.
        • Story M.E.
        • Pintado C.O.
        • Fleming A.
        • Page N.M.
        • et al.
        Functional and molecular characterization of tachykinins and tachykinin receptors in the mouse uterus.
        Biol Reprod. 2005; 72: 1125-1133
        • Pinto F.M.
        • Pintado C.O.
        • Pennefather J.N.
        • Patak E.
        • Candenas L.
        Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus.
        Reprod Biol Endocrinol. 2009; 7: 77
        • Castellano J.M.
        • Gaytan M.
        • Roa J.
        • Vigo E.
        • Navarro V.M.
        • Bellido C.
        • et al.
        Expression of KiSS-1 in rat ovary: putative local regulator of ovulation?.
        Endocrinology. 2006; 147: 4852-4862
        • Gaytán M.
        • Castellano J.M.
        • Roa J.
        • Sánchez-Criado J.E.
        • Tena-Sempere M.
        • Gaytán F.
        Expression of KiSS-1 in rat oviduct: possible involvement in prevention of ectopic implantation?.
        Cell Tiss Res. 2007; 329: 571-579
        • Gaytán F.
        • Gaytán M.
        • Castellano J.M.
        • Romero M.
        • Roa J.
        • Aparicio B.
        • et al.
        KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction.
        Am J Physiol Endocrinol Metab. 2009; 296: E520-E531
        • Pinto F.M.
        • Cejudo-Román A.
        • Ravina C.G.
        • Fernández-Sánchez M.
        • Martín-Lozano D.
        • Illanes M.
        • et al.
        Characterization of the kisspeptin system in human spermatozoa.
        Int J Androl. 2012; 35: 63-73
        • Kawada T.
        • Sekiguchi T.
        • Sakai T.
        • Aoyama M.
        • Satake H.
        Neuropeptides, hormone peptides, and their receptors in Ciona intestinalis: an update.
        Zoolog Sci. 2010; 27: 134-153
        • Aoyama M.
        • Kawada T.
        • Fujie M.
        • Hotta K.
        • Sakai T.
        • Sekiguchi T.
        • et al.
        A novel biological role of tachykinins as an up-regulator of oocyte growth: identification of an evolutionary origin of tachykininergic functions in the ovary of the ascidian, Ciona intestinalis.
        Endocrinology. 2008; 149: 4346-4356
        • McGuire N.L.
        • Bentley G.E.
        Neuropeptides in the gonads: from evolution to pharmacology.
        Front Pharmacol. 2010; 1: 114
        • Colledge W.H.
        GPR54 and kisspeptins.
        Results Probl Cell Differ. 2008; 46: 117-143
        • Mayer C.
        • Boehm U.
        Female reproductive maturation in the absence of kisspeptin/GPR54 signaling.
        Nat Neurosci. 2011; 14: 704-710
        • Wray S.
        Insights into the uterus.
        Exp Physiol. 2007; 92: 621-631
        • Casañ E.M.
        • Raga F.
        • Bonilla-Musoles F.
        • Polan M.L.
        Human oviductal gonadotropin-releasing hormone: possible implications in fertilization, early embryonic development, and implantation.
        J Clin Endocrinol Metab. 2000; 5: 1377-1381
        • Xiao Y.
        • Ni Y.
        • Huang Y.
        • Wu J.
        • Grossmann R.
        • Zhao R.
        Effects of kisspeptin-10 on progesterone secretion in cultured chicken ovarian granulosa cells from preovulatory (F1–F3) follicles.
        Peptides. 2011; 32: 2091-2097