Tachykinins and Kisspeptins in the Regulation of Human Male Fertility

Infertility is a global disease affecting one out of six couples of reproductive age in the world, with a male factor involved in half the cases. There is still much to know about the regulation of human male fertility and thus we decided to focus on two peptide families that seem to play a key role in this function: tachykinins and kisspeptins. With this aim, we conducted an exhaustive review in order to describe the role of tachykinins and kisspeptins in human fertility and their possible implications in infertility etiopathogenesis. Many advances have been made to elucidate the roles of these two families in infertility, and multiple animal species have been studied, including humans. All of this knowledge could lead to new advances in male infertility diagnosis and treatment, but further research is needed to clarify all the implications of tachykinins and kisspeptins in fertility.

[1]  M. Matsuyama,et al.  Subcutaneous administration of Kiss1 pentadecapeptide accelerates spermatogenesis in prepubertal male chub mackerel (Scomber japonicus). , 2013, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[2]  J. Charron,et al.  Reduced Fertility in Male Mice Deficient in the Zinc Metallopeptidase NL1 , 2004, Molecular and Cellular Biology.

[3]  L. Saso,et al.  Immunohistochemical profile of some neurotransmitters and neurotrophins in the seminiferous tubules of rats treated by lonidamine. , 2007, European journal of histochemistry : EJH.

[4]  N. Hooper,et al.  Neurokinin B is hydrolysed by synaptic membranes and by endopeptidase‐24.11 (‘enkephalinase’) but not by angiotensin converting enzyme , 1985, FEBS letters.

[5]  D. Coates,et al.  The neprilysin (NEP) family of zinc metalloendopeptidases: Genomics and function , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[6]  K. Spanel‐Borowski,et al.  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 , 2004, Regulatory Peptides.

[7]  S. Nakanishi Mammalian tachykinin receptors. , 1991, Annual review of neuroscience.

[8]  F. Pinto,et al.  Tachykinin Receptor and Neutral Endopeptidase Gene Expression in the Rat Uterus: Characterization and Regulation in Response to Ovarian Steroid Treatment. , 1999, Endocrinology.

[9]  A. Calogero,et al.  Current and emerging medical therapeutic agents for idiopathic male infertility , 2019, Expert opinion on pharmacotherapy.

[10]  M. Davidoff,et al.  Substance P: immunocytochemical localization and biological role in hamster gonads during ontogenesis. , 1991, Functional and developmental morphology.

[11]  T. Walther,et al.  Effects of kinins on mammalian spermatozoa and the impact of peptidolytic enzymes , 2003, Andrologia.

[12]  J. Irazusta,et al.  Autocrine regulation of human sperm motility by tachykinins , 2010, Reproductive biology and endocrinology : RB&E.

[13]  B. Sastry,et al.  Significance of Substance P— and Enkephalin—Peptide Systems in the Male Genital Tract a , 1991, Annals of the New York Academy of Sciences.

[14]  R. Steiner,et al.  Kisspeptin signaling in the brain. , 2009, Endocrine reviews.

[15]  M. Tena-Sempere The roles of kisspeptins and G protein-coupled receptor-54 in pubertal development , 2006, Current opinion in pediatrics.

[16]  S. Mortimer,et al.  A critical review of the physiological importance and analysis of sperm movement in mammals. , 1997, Human reproduction update.

[17]  C. Maggi,et al.  Tachykinins and tachykinin receptors: effects in the genitourinary tract. , 2005, Life sciences.

[18]  Frank Reimann,et al.  TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction , 2009, Nature Genetics.

[19]  J. Toppari,et al.  Sperm morphological defects related to environment, lifestyle and medical history of 1001 male partners of pregnant women from four European cities. , 2001, Human reproduction.

[20]  S. Garde,et al.  Immunocytochemical localization of bioregulatory peptides in marmoset testes. , 1992, Archives of andrology.

[21]  C. Gerard,et al.  Molecular aspects of the tachykinin receptors , 1993, Regulatory Peptides.

[22]  M. Correia,et al.  The non-genomic effects of endocrine-disrupting chemicals on mammalian sperm. , 2016, Reproduction.

[23]  P. Nieto,et al.  Tachykinins and tachykinin receptors: structure and activity relationships. , 2004, Current medicinal chemistry.

[24]  D. Ashby,et al.  Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. , 2014, The Journal of clinical investigation.

[25]  A. Berger,et al.  Tachykinins in the immune system. , 2006, Current drug targets.

[26]  E. Génin,et al.  Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Holstein,et al.  Are Leydig cells of neural origin? Substance P-like immunoreactivity in human testicular tissue. , 1987, Acta endocrinologica.

[28]  A. Rubin,et al.  Airway smooth muscle cells express functional neurokinin-1 receptors and the nerve-derived preprotachykinin-a gene: regulation by passive sensitization. , 2003, American journal of respiratory cell and molecular biology.

[29]  C. Caligioni,et al.  Uncovering novel reproductive defects in neurokinin B receptor null mice: closing the gap between mice and men. , 2012, Endocrinology.

[30]  M. Tena-Sempere,et al.  Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility , 2012, Nature Reviews Endocrinology.

[31]  I. Z. Qureshi,et al.  Intraperitoneal kisspeptin-10 administration induces dose-dependent degenerative changes in maturing rat testes. , 2011, Life sciences.

[32]  R. Harlan,et al.  Gonadal steroid regulation of substance P (SP) and SP-encoding messenger ribonucleic acids in the rat anterior pituitary and hypothalamus. , 1990, Endocrinology.

[33]  S. Douglas,et al.  Neurokinin 1 receptor isoforms and the control of innate immunity. , 2009, Trends in immunology.

[34]  G. Watanabe,et al.  Effect of kisspeptin antagonist on goat in vitro Leydig cell steroidogenesis. , 2018, Theriogenology.

[35]  A. Bartke,et al.  Tachykinins and their possible modulatory role on testicular function: a review. , 2003, International journal of andrology.

[36]  A. Sanbuissho,et al.  Testicular toxicity induced by a triple neurokinin receptor antagonist in male dogs. , 2011, Reproductive toxicology.

[37]  M. Candenas,et al.  A Role for Tachykinins in Female Mouse and Rat Reproductive Function1 , 2003, Biology of reproduction.

[38]  R. Quinton,et al.  The kisspeptin signaling pathway and its role in human isolated GnRH deficiency , 2011, Molecular and Cellular Endocrinology.

[39]  C. Maggi Principles of tachykininergic co-transmission in the peripheral and enteric nervous system , 2000, Regulatory Peptides.

[40]  W. Ho,et al.  Quantification of substance P mRNA in human mononuclear phagocytes and lymphocytes using a mimic-based RT-PCR. , 1999, Journal of immunological methods.

[41]  F. Valladares,et al.  Differentially regulated expression of neurokinin B (NKB)/NK3 receptor system in uterine leiomyomata. , 2013, Human reproduction.

[42]  P. Seeburg,et al.  Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase) , 1988, FEBS letters.

[43]  W. Colledge,et al.  Does Kisspeptin Signaling have a Role in the Testes? , 2013, Front. Endocrinol..

[44]  A. Turner,et al.  Human neprilysin‐2 (NEP2) and NEP display distinct subcellular localisations and substrate preferences , 2008, FEBS letters.

[45]  N. Page Hemokinins and endokinins , 2004, Cellular and Molecular Life Sciences CMLS.

[46]  C. Maggi,et al.  Tachykinins and tachykinin receptors: a growing family. , 2004, Life sciences.

[47]  F. Monsma,et al.  The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. , 2003, Biochemical and biophysical research communications.

[48]  N. Page Neurokinin B and pre-eclampsia: a decade of discovery , 2010, Reproductive biology and endocrinology : RB&E.

[49]  M. Patterson,et al.  Kisspeptin‐54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms , 2009, British journal of pharmacology.

[50]  Steven J. Greco,et al.  Tachykinins in the emerging immune system: relevance to bone marrow homeostasis and maintenance of hematopoietic stem cells. , 2004, Frontiers in bioscience : a journal and virtual library.

[51]  S. O’Rahilly,et al.  The GPR54 Gene as a Regulator of Puberty , 2003 .

[52]  B. Bonici,et al.  Distribution of neurokinin B in rat spinal cord and peripheral tissues: Comparison with neurokinin A and substance P and effects of neonatal capsaicin treatment , 1992, Neuroscience.

[53]  M. Candenas,et al.  Mammalian tachykinins and uterine smooth muscle: the challenge escalates. , 2004, European journal of pharmacology.

[54]  A. E. Curtis,et al.  Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. , 2006, American journal of physiology. Endocrinology and metabolism.

[55]  Peter Holzer,et al.  Newly discovered tachykinins raise new questions about their peripheral roles and the tachykinin nomenclature. , 2004, Trends in pharmacological sciences.

[56]  A. Pellicer,et al.  Expression of KiSS-1 in rat ovary: putative local regulator of ovulation? , 2006, Endocrinology.

[57]  Claire V. Harper,et al.  Mobilisation of stored calcium in the neck region of human sperm--a mechanism for regulation of flagellar activity. , 2008, The International journal of developmental biology.

[58]  A. Agarwal,et al.  A Schematic Overview of the Current Status of Male Infertility Practice , 2019, The world journal of men's health.

[59]  T. Nishigaki,et al.  Calcium channels in the development, maturation, and function of spermatozoa. , 2011, Physiological reviews.

[60]  J. Overstreet,et al.  Best practice policies for male infertility. , 2002, The Journal of urology.

[61]  L. Giojalas,et al.  Continuous behavioural ‘switching’ in human spermatozoa and its regulation by Ca2+-mobilising stimuli , 2019, Molecular human reproduction.

[62]  A. Agarwal,et al.  Role of antioxidants in the treatment of male infertility , 2009, International journal of urology : official journal of the Japanese Urological Association.

[63]  J. Irazusta,et al.  Expression of enkephalin-degrading enzymes in human semen and implications for sperm motility. , 2008, Fertility and sterility.

[64]  S. Sangiao-Alvarellos,et al.  Deregulation of miR-324/KISS1/kisspeptin in early ectopic pregnancy: mechanistic findings with clinical and diagnostic implications. , 2019, American journal of obstetrics and gynecology.

[65]  A. Pellicer,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. , 2009, American journal of physiology. Endocrinology and metabolism.

[66]  B. Yılmaz,et al.  The effect of kisspeptin on spermatogenesis and apoptosis in rats. , 2017, Turkish journal of medical sciences.

[67]  Haibin Kuang,et al.  Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery , 2019, Reproductive Biology and Endocrinology.

[68]  M. Fernández-Sánchez,et al.  Expression of Tachykinins and Tachykinin Receptors and Interaction with Kisspeptin in Human Granulosa and Cumulus Cells1 , 2016, Biology of reproduction.

[69]  L. Debeljuk,et al.  Tachykinins and the hypothalamo–pituitary–gonadal axis: An update , 2011, Peptides.

[70]  J. Irazusta,et al.  Peptidase activities in human semen , 2002, Peptides.

[71]  K. Cox,et al.  Neurokinin B is critical for normal timing of sexual maturation but dispensable for adult reproductive function in female mice. , 2015, Endocrinology.

[72]  R. Chianese,et al.  Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian. , 2017, Reproduction.

[73]  Hongkui Zeng,et al.  The Role of Kisspeptin–GPR54 Signaling in the Tonic Regulation and Surge Release of Gonadotropin-Releasing Hormone/Luteinizing Hormone , 2007, The Journal of Neuroscience.

[74]  S. Suarez,et al.  Rethinking the Relationship Between Hyperactivation and Chemotaxis in Mammalian Sperm1 , 2010, Biology of reproduction.

[75]  L. Coolen,et al.  KNDy Cells Revisited. , 2018, Endocrinology.

[76]  N. Hooper,et al.  The metabolism of neuropeptides. Neurokinin A (substance K) is a substrate for endopeptidase-24.11 but not for peptidyl dipeptidase A (angiotensin-converting enzyme). , 1985, The Biochemical journal.

[77]  M. Tena-Sempere,et al.  Kisspeptins and reproduction: physiological roles and regulatory mechanisms. , 2012, Physiological reviews.

[78]  P. Devillier,et al.  mRNA expression of tachykinins and tachykinin receptors in different human tissues. , 2004, European journal of pharmacology.

[79]  M. Shahab,et al.  Immunocytochemical localization of kisspeptin and kisspeptin receptor in the primate testis , 2016, Journal of medical primatology.

[80]  T. Klassert,et al.  Differential expression of neurokinin B and hemokinin-1 in human immune cells , 2008, Journal of Neuroimmunology.

[81]  F. Pinto,et al.  Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus , 2009, Reproductive biology and endocrinology : RB&E.

[82]  S. Ziccone,et al.  Tachykinins and tachykinin receptors in human uterus , 2003, British journal of pharmacology.

[83]  F. Gaytán,et al.  Expression of KiSS-1 in rat oviduct: possible involvement in prevention of ectopic implantation? , 2007, Cell and Tissue Research.

[84]  M. Tena-Sempere,et al.  Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. , 2012, Fertility and sterility.

[85]  J. Qiao,et al.  Potential roles for the kisspeptin/kisspeptin receptor system in implantation and placentation , 2019, Human reproduction update.

[86]  C. Maggi,et al.  Peripheral tachykinin receptors as potential therapeutic targets in visceral diseases , 2003, Expert opinion on therapeutic targets.

[87]  M. Vine Smoking and male reproduction: a review. , 1996, International journal of andrology.

[88]  Jia Cao,et al.  Kisspeptin Protein in Seminal Plasma Is Positively Associated with Semen Quality: Results from the MARHCS Study in Chongqing, China , 2019, BioMed research international.

[89]  L. Kanchev,et al.  Substance P‐induced inhibition of Leydig cell steroidogenesis in primary culture , 2009, Andrologia.

[90]  K. Tsutsui,et al.  Localization of gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin and GnRH receptor and their possible roles in testicular activities from birth to senescence in mice. , 2012, Journal of experimental zoology. Part A, Ecological genetics and physiology.

[91]  M. Tena-Sempere,et al.  Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. , 2014, Human reproduction.

[92]  M. Fernández-Sánchez,et al.  A role for tachykinins in the regulation of human sperm motility. , 2007, Human reproduction.

[93]  S. Bloom,et al.  Investigating the KNDy Hypothesis in Humans by Coadministration of Kisspeptin, Neurokinin B, and Naltrexone in Men , 2016, The Journal of clinical endocrinology and metabolism.

[94]  R. Chianese,et al.  Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: a study carried out in ex vivo testes. , 2015, General and comparative endocrinology.

[95]  Michael N Lehman,et al.  Kisspeptin / Neurokinin B / Dynorphin ( KNDy ) Cells of the Arcuate Nucleus : A Central Node in the Control of Gonadotropin-Releasing Hormone Secretion , 2010 .

[96]  Teng Zong,et al.  Kisspeptin stimulates progesterone secretion via the Erk1/2 mitogen-activated protein kinase signaling pathway in rat luteal cells. , 2013, Fertility and sterility.

[97]  M. Tena-Sempere,et al.  Characterization of the kisspeptin system in human spermatozoa. , 2012, International journal of andrology.

[98]  W. Schulze,et al.  Tachykinin (substance-P) gene expression in Leydig cells of the human and mouse testis. , 1991, Endocrinology.

[99]  A. Pacey,et al.  Sperm transport in the female reproductive tract. , 2006, Human reproduction update.

[100]  Occupational risks for male fertility: an analysis of patients attending a tertiary referral centre. , 2001 .