Can peri-ovulatory putrescine supplementation improve egg quality in older infertile women?

  • Yong Tao
  • Alina Tartia
  • Maralee Lawson
  • Mary B. Zelinski
  • Wei Wu
  • Jia-Yin Liu
  • Johan Smitz
  • Marie-Claude Léveillé
  • Arthur Leader
  • Hongmei Wang
  • Timothy Ramsay
  • X. Johné LiuEmail author
Commentary Review


The aging-related decline in fertility is an increasingly pressing medical and economic issue in modern society where women are delaying family building. Increasingly sophisticated, costly, and often increasingly invasive, assisted reproductive clinical protocols and laboratory technologies (ART) have helped many older women achieve their reproductive goals. Current ART procedures have not been able to address the fundamental problem of oocyte aging, the increased rate of egg aneuploidy, and the decline of developmental potential of the eggs. Oocyte maturation, which is triggered by luteinizing hormone (LH) in vivo or by injection of human chorionic gonadotropin (hCG) in an in vitro fertilization (IVF) clinic, is the critical stage at which the majority of egg aneuploidies arise and when much of an egg’s developmental potential is established. Our proposed strategy focuses on improving egg quality in older women by restoring a robust oocyte maturation process. We have identified putrescine deficiency as one of the causes of poor egg quality in an aged mouse model. Putrescine is a biogenic polyamine naturally produced in peri-ovulatory ovaries. Peri-ovulatory putrescine supplementation has reduced egg aneuploidy, improved embryo quality, and reduced miscarriage rates in aged mice. In this paper, we review the literature on putrescine, its occurrence and physiology in living organisms, and its unique role in oocyte maturation. Preliminary human data demonstrates that there is a maternal aging-related deficiency in ovarian ornithine decarboxylase (ODC), the enzyme responsible for putrescine production. We argue that peri-ovulatory putrescine supplementation holds great promise as a natural and effective therapy for infertility in women of advanced maternal age, applicable in natural conception and in combination with current ART therapies.


Putrescine Ornithine decarboxylase Oocyte maturation Aneuploidy Infertility Aging Embryo development 





Cumulus-oocyte complex


Decarboxylased SAM




Gamma-aminobutyric acid


Germinal vesicle or oocyte nucleus


Human chorionic gonadotropin


Oocyte in vitro maturation


In vitro fertilization


Luteinizing hormone


Ornithine decarboxylase


Reactive oxygen species


Phosphodiesterase 3A




SAM decarboxylase


Spermidine/spermine N1 acetyltransferase


Funding information

Supported by a research grant from March of Dimes (6-FY13-126) (to XJL), and by the Office of the Director, National Institutes of Health under Award Number P51OD011092 (to ONPRC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  1. 1.
    American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee opinion no. 589. Fertil Steril. 2014;101:633–4.CrossRefGoogle Scholar
  2. 2.
    Angell RR. Predivision in human oocytes at meiosis I: a mechanism for trisomy formation in man. Hum Genet. 1991;86:383–7.CrossRefGoogle Scholar
  3. 3.
    Bastida CM, Cremades A, Castells MT, Lopez-Contreras AJ, Lopez-Garcia C, Tejada F, et al. Influence of ovarian ornithine decarboxylase in folliculogenesis and luteinization. Endocrinology. 2005;146:666–74.CrossRefGoogle Scholar
  4. 4.
    Bell MR, Belarde JA, Johnson HF, Aizenman CD. A neuroprotective role for polyamines in a Xenopus tadpole model of epilepsy. Nat Neurosci. 2011;14:505–12.CrossRefGoogle Scholar
  5. 5.
    Ben-Meir A, Burstein E, Borrego-Alvarez A, Chong J, Wong E, Yavorska T, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14:887–95.CrossRefGoogle Scholar
  6. 6.
    Brown HM, Dunning KR, Sutton-McDowall M, Gilchrist RB, Thompson JG, Russell DL. Failure to launch: aberrant cumulus gene expression during oocyte in vitro maturation. Reproduction. 2017;153:R109–20.CrossRefGoogle Scholar
  7. 7.
    Bruun L, Houen G. In situ detection of diamine oxidase activity using enhanced chemiluminescence. Anal Biochem. 1996;233:130–6.CrossRefGoogle Scholar
  8. 8.
    Cayre M, Strambi C, Charpin P, Augier R, Strambi A. Specific requirement of putrescine for the mitogenic action of juvenile hormone on adult insect neuroblasts. Proc Natl Acad Sci U S A. 1997;94:8238–42.CrossRefGoogle Scholar
  9. 9.
    Cohen SS. Pathways of polyamine metabolism in animals. In: A guide to the polyamines. Oxford: Oxford University Press; 1998. p. 208–30.Google Scholar
  10. 10.
    Conti M, Franciosi F. Acquisition of oocyte competence to develop as an embryo: integrated nuclear and cytoplasmic events. Hum Reprod Update. 2018;24:245–66.CrossRefGoogle Scholar
  11. 11.
    De Vos M, Smitz J, Thompson JG, and Gilchrist RB. The definition of IVM is clear-variations need defining. Hum Reprod. 2016;31:2011–2015.Google Scholar
  12. 12.
    Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11:1305–14.CrossRefGoogle Scholar
  13. 13.
    Eppig JJ. The relationship between cumulus cell-oocyte coupling, oocyte meiotic maturation, and cumulus expansion. Dev Biol. 1982;89:268–72.CrossRefGoogle Scholar
  14. 14.
    Eppig JJ, Schultz RM, O'Brien M, Chesnel F. Relationship between the developmental programs controlling nuclear and cytoplasmic maturation of mouse oocytes. Dev Biol. 1994;164:1–9.CrossRefGoogle Scholar
  15. 15.
    Fenelon JC, Banerjee A, Lefevre P, Gratian F, Murphy BD. Polyamine-mediated effects of prolactin dictate emergence from mink obligate embryonic diapause. Biol Reprod. 2016;95:6.CrossRefGoogle Scholar
  16. 16.
    Fozard JR, Part ML, Prakash NJ, Grove J, Schechter PJ, Sjoerdsma A, et al. L-ornithine decarboxylase: an essential role in early mammalian embryogenesis. Science. 1980a;208:505–8.CrossRefGoogle Scholar
  17. 17.
    Fozard JR, Prakash NJ, Grove J. Ovarian function in the rat following irreversible inhibition of L-ornithine decarboxylase. Life Sci. 1980b;27:2277–83.CrossRefGoogle Scholar
  18. 18.
    Gerner EW, Meyskens FL Jr. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004;4:781–92.CrossRefGoogle Scholar
  19. 19.
    Grant AL, Holland RE, Thomas JW, King KJ, Liesman JS. Effects of dietary amines on the small intestine in calves fed soybean protein. J Nutr. 1989;119:1034–41.CrossRefGoogle Scholar
  20. 20.
    Grant AL, Thomas JW, King KJ, Liesman JS. Effects of dietary amines on small intestinal variables in neonatal pigs fed soy protein isolate. J Anim Sci. 1990;68:363–71.CrossRefGoogle Scholar
  21. 21.
    Guzman L, Ortega-Hrepich C, Albuz FK, Verheyen G, Devroey P, Smitz J, et al. Developmental capacity of in vitro-matured human oocytes retrieved from polycystic ovary syndrome ovaries containing no follicles larger than 6 mm. Fertil Steril. 2012;98:503–7.CrossRefGoogle Scholar
  22. 22.
    Halonen T, Sivenius J, Miettinen R, Halmekyto M, Kauppinen R, Sinervirta R, et al. Elevated seizure threshold and impaired spatial learning in transgenic mice with putrescine overproduction in the brain. Eur J Neurosci. 1993;5:1233–9.CrossRefGoogle Scholar
  23. 23.
    Icekson I, Kaye AM, Lieberman ME, Lamprecht SA, Lahav M, Lindner HR. Stimulation by luteinizing hormone of ornithine decarboxylase in rat ovary: preferential response by follicular tissue. J Endocrinol. 1974;63:417–8.CrossRefGoogle Scholar
  24. 24.
    Iorgulescu JB, Patel SP, Louro J, Andrade CM, Sanchez AR, Pearse DD. Acute putrescine supplementation with Schwann cell implantation improves sensory and serotonergic axon growth and functional recovery in spinal cord injured rats. Neural Plast. 2015;2015:186385.CrossRefGoogle Scholar
  25. 25.
    Johnson RF, Beltz TG, Thunhorst RL, Johnson AK. Investigations on the physiological controls of water and saline intake in C57BL/6 mice. Am J Physiol Regul Integr Comp Physiol. 2003;285:R394–403.CrossRefGoogle Scholar
  26. 26.
    Kaye AM, Icekson I, Lamprecht SA, Gruss R, Tsafriri A, Lindner HR. Stimulation of ornithine decarboxylase activity by luteinizing hormone in immature and adult rat ovaries. Biochemistry. 1973;12:3072–6.CrossRefGoogle Scholar
  27. 27.
    Kobayashi Y, Kupelian J, Maudsley DV. Ornithine decarboxylase stimulation in rat ovary by luteinizing hormone. Science. 1971;172:379–80.CrossRefGoogle Scholar
  28. 28.
    Kong X, Wang X, Yin Y, Li X, Gao H, Bazer FW, et al. Putrescine stimulates the mTOR signaling pathway and protein synthesis in porcine trophectoderm cells. Biol Reprod. 2014;91:106.CrossRefGoogle Scholar
  29. 29.
    Lefevre PL, Palin MF, Chen G, Turecki G, Murphy BD. Polyamines are implicated in the emergence of the embryo from obligate diapause. Endocrinology. 2011;152:1627–39.CrossRefGoogle Scholar
  30. 30.
    Liang XH, Zhao ZA, Deng WB, Tian Z, Lei W, Xu X, et al. Estrogen regulates amiloride-binding protein 1 through CCAAT/enhancer-binding protein-beta in mouse uterus during embryo implantation and decidualization. Endocrinology. 2010;151:5007–16.CrossRefGoogle Scholar
  31. 31.
    Liu D, Mo G, Tao Y, Wang H, Liu XJ. Putrescine supplementation during in vitro maturation of aged mouse oocytes improves the quality of blastocysts. Reprod Fertil Dev. 2017;29:1392–1400.CrossRefGoogle Scholar
  32. 32.
    Liu D, Mo G, Tao Y, Wang H, Liu XJ. Putrescine supplementation during in vitro maturation of aged mouse oocytes improves the quality of blastocysts. Reprod Fertil Dev. 2017;29:1392–400.CrossRefGoogle Scholar
  33. 33.
    Liu M, Yin Y, Ye X, Zeng M, Zhao Q, Keefe DL, et al. Resveratrol protects against age-associated infertility in mice. Hum Reprod. 2013;28:707–17.CrossRefGoogle Scholar
  34. 34.
    Maudsley DV, Kobayashi Y. Induction of ornithine decarboxylase in rat ovary after administration of luteinizing hormone or human chorionic gonadotrophin. Biochem Pharmacol. 1974;23:2697–703.CrossRefGoogle Scholar
  35. 35.
    Meldrum DR, Casper RF, Diez-Juan A, Simon C, Domar AD, Frydman R. Aging and the environment affect gamete and embryo potential: can we intervene? Fertil Steril. 2016;105:548–59.CrossRefGoogle Scholar
  36. 36.
    Metcalf BW, Bey P, Danzin C, Jung MJ, Casara P, Vevert JP. Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C. by substrate and product analogues. J Am Chem Soc. 1978;100:2551–3.CrossRefGoogle Scholar
  37. 37.
    Moor RM, Dai Y, Lee C, Fulka J Jr. Oocyte maturation and embryonic failure. Hum Reprod Update. 1998;4:223–36.CrossRefGoogle Scholar
  38. 38.
    Muller M, Cleef M, Rohn G, Bonnekoh P, Pajunen AE, Bernstein HG, et al. Ornithine decarboxylase in reversible cerebral ischemia: an immunohistochemical study. Acta Neuropathol. 1991;83:39–45.CrossRefGoogle Scholar
  39. 39.
    Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, et al. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature. 1992;360:597–9.CrossRefGoogle Scholar
  40. 40.
    Nehra D, Le HD, Fallon EM, Carlson SJ, Woods D, White YA, et al. Prolonging the female reproductive lifespan and improving egg quality with dietary omega-3 fatty acids. Aging Cell. 2012;11:1046–54.CrossRefGoogle Scholar
  41. 41.
    Niiranen K, Keinanen TA, Pirinen E, Heikkinen S, Tusa M, Fatrai S, et al. Mice with targeted disruption of spermidine/spermine N1-acetyltransferase gene maintain nearly normal tissue polyamine homeostasis but show signs of insulin resistance upon aging. J Cell Mol Med. 2006;10:933–45.CrossRefGoogle Scholar
  42. 42.
    Nishimura K, Shiina R, Kashiwagi K, Igarashi K. Decrease in polyamines with aging and their ingestion from food and drink. J Biochem (Tokyo). 2006;139:81–90.CrossRefGoogle Scholar
  43. 43.
    Nogueira D, Sadeu JC, Montagut J. In vitro oocyte maturation: current status. Semin Reprod Med. 2012;30:199–213.CrossRefGoogle Scholar
  44. 44.
    Ortega-Hrepich C, Stoop D, Guzman L, Van LL, Tournaye H, Smitz J, et al. A “freeze-all” embryo strategy after in vitro maturation: a novel approach in women with polycystic ovary syndrome? Fertil Steril. 2013;100:1002–7.CrossRefGoogle Scholar
  45. 45.
    Paschen W, Csiba L, Rohn G, Bereczki D. Polyamine metabolism in transient focal ischemia of rat brain. Brain Res. 1991;566:354–7.CrossRefGoogle Scholar
  46. 46.
    Pegg AE, Casero RA Jr. Current status of the polyamine research field. Methods Mol Biol. 2011;720:3–35.CrossRefGoogle Scholar
  47. 47.
    Pegg AE, McGovern KA, Wiest L. Decarboxylation of alpha-difluoromethylornithine by ornithine decarboxylase. Biochem J. 1987;241:305–7.CrossRefGoogle Scholar
  48. 48.
    Pendeville H, Carpino N, Marine JC, Takahashi Y, Muller M, Martial JA, et al. The ornithine decarboxylase gene is essential for cell survival during early murine development. Mol Cell Biol. 2001;21:6549–58.CrossRefGoogle Scholar
  49. 49.
    Persson L, Isaksson K, Rosengren E, Sundler F. Distribution of ornithine decarboxylase in ovaries of rat and hamster during pro-oestrus. Acta Endocrinol. 1986;113:403–9.CrossRefGoogle Scholar
  50. 50.
    Quinn MC, McGregor SB, Stanton JL, Hessian PA, Gillett WR, Green DP. Purification of granulosa cells from human ovarian follicular fluid using granulosa cell aggregates. Reprod Fertil Dev. 2006;18:501–8.CrossRefGoogle Scholar
  51. 51.
    Raina A, Eloranta T, Kajander O. Biosynthesis and metabolism of polyamines and S-adenosylmethionine in the rat. Biochem Soc Trans. 1976;4:968–71.CrossRefGoogle Scholar
  52. 52.
    Sakakibara Y, Hashimoto S, Nakaoka Y, Kouznetsova A, Hoog C, Kitajima TS. Bivalent separation into univalents precedes age-related meiosis I errors in oocytes. Nat Commun. 2015;6:7550.CrossRefGoogle Scholar
  53. 53.
    Schwartz B, Hittelman A, Daneshvar L, Basu HS, Marton LJ, Feuerstein BG. A new model for disruption of the ornithine decarboxylase gene, SPE1, in Saccharomyces cerevisiae exhibits growth arrest and genetic instability at the MAT locus. Biochem J. 1995;312(Pt 1):83–90.CrossRefGoogle Scholar
  54. 54.
    Selesniemi K, Lee HJ, Muhlhauser A, Tilly JL. From the cover: prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A. 2011;108:12319–24.CrossRefGoogle Scholar
  55. 55.
    Stouffer RL, Zelinski-Wooten MB. Overriding follicle selection in controlled ovarian stimulation protocols: quality vs quantity. Reprod Biol Endocrinol. 2004;2:32.CrossRefGoogle Scholar
  56. 56.
    Sunkara PS, Wright DA, Nishioka K. An essential role for putrescine biosynthesis during meiotic maturation of amphibian oocytes. Dev Biol. 1981;87:351–5.CrossRefGoogle Scholar
  57. 57.
    Tao Y, Liu D, Mo G, Wang H, Liu XJ. Peri-ovulatory putrescine supplementation reduces embryo resorption in older mice. Hum Reprod. 2015;30:1867–75.CrossRefGoogle Scholar
  58. 58.
    Tao Y, Liu XJ. Deficiency of ovarian ornithine decarboxylase contributes to aging-related egg aneuploidy in mice. Aging Cell. 2013;12:42–9.CrossRefGoogle Scholar
  59. 59.
    Til HP, Falke HE, Prinsen MK, Willems MI. Acute and subacute toxicity of tyramine, spermidine, spermine, putrescine and cadaverine in rats. Food Chem Toxicol. 1997;35:337–48.CrossRefGoogle Scholar
  60. 60.
    Wagner J, Claverie N, Danzin C. A rapid high-performance liquid chromatographic procedure for the simultaneous determination of methionine, ethionine, S-adenosylmethionine, S-adenosylethionine, and the natural polyamines in rat tissues. Anal Biochem. 1984;140:108–16.CrossRefGoogle Scholar
  61. 61.
    Washkowitz AJ, Schall C, Zhang K, Wurst W, Floss T, Mager J, et al. Mga is essential for the survival of pluripotent cells during peri-implantation development. Develop. 2015;142:31–40.CrossRefGoogle Scholar
  62. 62.
    Younglai EV, Godeau F, Mester J, Baulieu EE. Increased ornithine decarboxylase activity during meiotic maturation in Xenopus laevis oocytes. Biochem Biophys Res Commun. 1980;96:1274–81.CrossRefGoogle Scholar
  63. 63.
    Yun Y, Lane SI, Jones KT. Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes. Develop. 2014;141:199–208.CrossRefGoogle Scholar
  64. 64.
    Zhang M, Pickart CM, Coffino P. Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate. EMBO J. 2003;22:1488–96.CrossRefGoogle Scholar
  65. 65.
    Zhou Y, Ma C, Karmouch J, Katbi HA, Liu XJ. Antiapoptotic role for ornithine decarboxylase during oocyte maturation. Mol Cell Biol. 2009;29:1786–95.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yong Tao
    • 1
    • 2
  • Alina Tartia
    • 1
  • Maralee Lawson
    • 3
  • Mary B. Zelinski
    • 3
  • Wei Wu
    • 4
  • Jia-Yin Liu
    • 4
  • Johan Smitz
    • 5
  • Marie-Claude Léveillé
    • 1
    • 6
  • Arthur Leader
    • 1
    • 6
  • Hongmei Wang
    • 7
  • Timothy Ramsay
    • 2
  • X. Johné Liu
    • 2
    • 6
    Email author
  1. 1.Ottawa Fertility CenterOttawaCanada
  2. 2.Ottawa Hospital Research InstituteThe Ottawa Hospital-General CampusOttawaCanada
  3. 3.Oregon National Primate Research CenterBeavertonUSA
  4. 4.Clinical Center of Reproductive Medicine, The First Affiliated HospitalNanjing Medical UniversityNanjingChina
  5. 5.Center for Reproductive Medicine, Academisch ZiekenhuisVrije Universiteit BrusselBrusselsBelgium
  6. 6.Department of Obstetrics and GynecologyUniversity of OttawaOttawaCanada
  7. 7.State Key Laboratory of Stem Cell and Reproductive Biology, Institute of ZoologyChinese Academy of SciencesBeijingChina

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