The potential physiological significance of milk-borne hormonally active substances for the neonate



This article reviews the presence and potential physiological significance of hormones and hormonally active substances (including growth factors) in human milk. Human milk has been found to contain several nonpeptide hormones and many peptide hormones and growth factors. In contrast to human breast milk, infant formulae lack some hormonally active peptides. There is little data concerning the effects of these agents on human neonates. Studies in immature experimental animals showing effects of orogastically administered hormones are summarized. The problems of supplementation of infant formula are discussed. Since hormones are present in the milk as a “cocktail” of potentially agonistic and antagonistic substances, one question is whether supplementation with a single agent would disturb this balance.

Key words

Nonpeptide hormones peptide hormones growth factors gastrointestinal absorption luminal effects of hormones milk 


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  1. 1.
    K. Heim (1931a). Hormonale wirkungen der frauenmilch.Klin. Wochenschr. 10:357.Google Scholar
  2. 2.
    K. Heim (1931b). Brustdrüse und hypophysenvorderlappen.Klin. Wochenschr. 10:1598.Google Scholar
  3. 3.
    N. Yaida (1929). Ovarial hormone in blood of pregnant women, of pregnant animals; ovarial hormone in urine of pregnant women; ovarial hormone in milk of pregnant animals.Trans. Jpn. Pathol. Soc. 19:39–101.Google Scholar
  4. 4.
    O. Koldovský (1995). Hormones in milk. In G. Litwack (ed.),Vitamins and Hormones (Chap. 2), Academic Press, New York,50:77–149.Google Scholar
  5. 5.
    O. Koldovský (1989). Critical review: Search for role of milkborne biologically active peptides for the suckling.J. Nutr. 119:1543–1551.PubMedGoogle Scholar
  6. 6.
    J. R. Britton and O. Koldovský (1989). The development of luminal protein digestion: Implications for biologically-active dietary polypeptides.J. Pediatr. Gastroenterol. Nutr. 9:144–161.PubMedGoogle Scholar
  7. 7.
    O. Koldovský and W. Thornburg (1987). Hormones in milk: A review.J. Pediatr. Gastroenterol. Nutr. 6:172–196.PubMedGoogle Scholar
  8. 8.
    G. Carpenter (1980). Epidermal growth factor is a major growth-promoting agent in human milk.Science 210:198–199.PubMedGoogle Scholar
  9. 9.
    H. Yagi, S. Suzuki, T. Noji, K. Nagashima, and T. Kuroume (1986). Epidermal growth factor in cow's milk and milk formula.Acta Pediatr. Scand. 75:233–235.Google Scholar
  10. 10.
    B. J. Iaccopetta, F. Grieu, M. Horisberger, and G. I. Sunahara (1992). Epidermal growth factor in human and bovine milk.Acta Pediatr. Scand. 81:287–291.Google Scholar
  11. 11.
    K. Nagashima, K. Itoh, and T. Kuroume (1990). Levels of insulin-like growth factor in full and preterm human milk in comparison to levels in cow's milk and in milk formulas.Biol. Neonate 58:343–346.PubMedGoogle Scholar
  12. 12.
    J. C. Juskevich and C. G. Guyer (1990). Bovine growth hormone: human food safety evaluation.Science 249:875–884.PubMedGoogle Scholar
  13. 13.
    L. C. Read, G. L. Francis, J. C. Wallace, and F. J. Ballard (1985). Growth factor concentrations and growth-promoting activity in human milk following premature birth.J. Devel. Physiol. 7:135–145;Pediatr. Res. 18:133–139.Google Scholar
  14. 14.
    A. A. Budayr, B. P. Halloran, J. C. King, D. Diep, R. A. Nissenson, and G. J. Strewler (1989). High levels of a parathyroid hormone-like protein in milk.Proc. Natl. Acad. Sci. U.S.A. 86:7183–7185.PubMedGoogle Scholar
  15. 15.
    H. Bohles, M. Aschenbrenner, M. Roth, V. Loewenich, F. Ball, and K. H. Usadel (1993). Development of thyroid gland volume during the first 3 months of life in breast-fed versus iodine-supplemented and iodine-free formula-fed infants.Clin. Invest. 71:13–20.Google Scholar
  16. 16.
    J. Mallol, M. J. Obregon, and G. M. Escobar (1982). Analytical artifacts in radioimmunoassay of L-thyroxine in human milk.Clin. Chem. 28:1277–1282.PubMedGoogle Scholar
  17. 17.
    B. Moller, L. Bjorkhem, O. Falk, and A. Larsson (1983). Identification of thyroxine in human breast milk by gas chromatography-mass spectrometry.J. Clin. Endocrinol. Metabol. 30:30–34.Google Scholar
  18. 18.
    L. V. Oberkotter and A. Tenore (1983). Separation and radioimmunoassay of T3 and T4 in human breast milk.Hormone Res. 17:11–18.PubMedGoogle Scholar
  19. 19.
    A. Lucas, S. R. Bloom, and A. A. Green (1985). Gastrointestinal peptides and the adaptation to extrauterine nutrition (Review).Can. J. Physiol. Pharmacol. 63: 527–537.PubMedGoogle Scholar
  20. 20.
    A. E. Schindler (1982). Hormones in human amniotic fluid (Review).Monogr. Endocrinol. 21:1–158.PubMedGoogle Scholar
  21. 21.
    J. T. Boyle (1992). Motility of the upper gastrointestinal tract in the fetus and neonate. In R. A. Polin and W. M. Fox (eds.),Fetal and Neonatal Physiology Vol. 2, W. B. Saunders and Co. Philadelphia, pp. 1028–1032.Google Scholar
  22. 22.
    J. R. Britton, C. George-Nascimento, J. N. Udall, and O. Koldovský (1989). Minimal hydrolysis of epidermal growth factor by gastric fluid of preterm infants.Gut 30:327–332.PubMedGoogle Scholar
  23. 23.
    O. Koldovský (1994). Hormonally active peptides in human milk.Acta Pediatr. (Suppl.)402:89–93.Google Scholar
  24. 24.
    R. J. Playford, T. Marchbank, D. P. Calnan, J. Calam, P. Royston, J. J. Batten, and H. F. Hansen (1995). Epidermal growth factor is digested to smaller, less active forms in acidic gastric juice.Gastroenterology 108:92–101.PubMedGoogle Scholar
  25. 25.
    J. R. Britton, C. George-Nascimento, and O. Koldovský (1988). Luminal hydrolysis of recombinant human epidermal growth factor in the rat gastrointestinal tract: segmental and developmental differences.Life Sci. 43:1339–1347.PubMedGoogle Scholar
  26. 26.
    S. M. Gale, L. C. Read, C. George-Nascimento, J. C. Wallace, and F. J. Ballard (1989). Is dietary epidermal growth factor absorbed by premature human infants?Biol. Neonate 55:104–110.PubMedGoogle Scholar
  27. 27.
    R. Santer, P. Borlinghasu, E. Sievers, E. Segura, and R. Lamerz (1993). Urinary excretion of epidermal growth factor and transforming growth factor-alpha in breast-fed and formula-fed infants.Acta Pediatr. 82:1024–1208.Google Scholar
  28. 28.
    P. Hahn and O. Koldovský (1966).Utilization of Nutrients During Postnatal Development, Pergamon Press, Oxford and London.Google Scholar
  29. 29.
    J. M. Beardmore and R. C. Richards (1983). Concentrations of epidermal growth factor in mouse milk throughout lactation.J. Endocrinol. 96:287–292.PubMedGoogle Scholar
  30. 30.
    E. W. Gresik, H. van der Noen, and T. Barka (1984). Transport of125I-EGF into milk and effect of sialoadenectomy on milk EGF in mice.Am. J. Physiol. 247:E349-E354.PubMedGoogle Scholar
  31. 31.
    A. Grueters, J. Alm, J. Lakshmanan, and D. A. Fisher (1985). Epidermal growth factor in mouse milk during early lactation: Lack of dependency on submandibular glands.Pediatr. Res. 19:853–856.PubMedGoogle Scholar
  32. 32.
    L. Raaberg, E. Nexo, L. Tollund, S. S. Poulsen, S. B. Christensen, and M. S. Christensen (1990). Epidermal growth factor activity in rat milk.Reg. Pept. 30:149–157.Google Scholar
  33. 33.
    R. P. Schaudies, J. Grimes, T. Davis, R. K. Rao, and O. Koldovský (1989). EGF content in the gastrointestinal tract of rats: Effect of age and fasting/refasting.Am. J. Physiol. 256:G856-G861.PubMedGoogle Scholar
  34. 34.
    R. P. Schaudies, J. Grimes, H. L. Wray, and O. Koldovský (1990). Identification and partial characterization of multiple forms of biologically active EGF in rat milk.Am. J Physiol. 259:G1056-G1061.PubMedGoogle Scholar
  35. 35.
    W. Thornburg, L. Matrisian, B. Magun, and O. Koldovský (1984). Gastrointestinal absorption of epidermal growth factor in suckling rats.Am. J. Physiol. 246:G80-G85.PubMedGoogle Scholar
  36. 36.
    J. Thulesen, L. Raaberg, E. Nexo, E. L. Madsen, and S. S. Poulsen (1993). Epidermal growth factor in mammary glands and milk from rats, the influence of insulin.Diabet. Res. Clin. Pract. 21:11–18.Google Scholar
  37. 37.
    J. Thulesen, E. Nexo, L. Raaberg, and S. S. Poulsen (1994). Decreased levels of epidermal growth factor in milk from diabetic rats.Pediatr. Res. 35:107–111.PubMedGoogle Scholar
  38. 38.
    K. Opleta and D. G. Gall (1992). Personal communication.Google Scholar
  39. 39.
    S. Toyoda, P. C. Lee, and E. Lebenthal (1986). Interaction of epidermal growth factor with specific binding sites of enterocytes isolated from rat small intestine during development.Biochim. Biophys. Acta 886:295–301.PubMedGoogle Scholar
  40. 40.
    R. K. Rao, W. Thornburg, M. Korc, L. Matrisian, B. E. Magun, and O. Koldovský (1986). Processing of epidermal growth factor by suckling and adult rat intestinal cells.Am. J. Physiol. 250:G850-G855.PubMedGoogle Scholar
  41. 41.
    N. Gallo-Payet, P. Pothier, and J. S. Hugon (1987). Ontogeny of EGF receptors during postnatal development of mouse small intestine.J. Pediatr. Gastroenterol. Nutr. 6:114–120.PubMedGoogle Scholar
  42. 42.
    J. F. Thompson (1988). Specific receptors for epidermal growth factor in rat intestinal microvillus membranes.Am. J. Physiol. 254:G429-G435.PubMedGoogle Scholar
  43. 43.
    J. F. Thompson, R. M. Lamprey, and P. C. F. Stokkers (1993). Orogastric EGF enhances c-neu and EGF receptor phosphorylation in suckling rats jejunumin vivo.Am. J. Physiol. 265:G63-G72.PubMedGoogle Scholar
  44. 44.
    J. F. Thompson, M. van den Berg, and P. C. Stokkers (1994). Developmental regulation of epidermal growth factor receptor kinase in rat intestine.Gastroenterology 107:1278–1287.PubMedGoogle Scholar
  45. 45.
    M. Popliker, A. Shatz, A. Avivi, A. Ullrich, J. Schlessinger, and C. G. Webb (1987). Onset of endogenous synthesis of epidermal growth factor in neonatal mice.Devel. Biol. 119:38–44.Google Scholar
  46. 46.
    B. Dvorak, H. Holubec, A. V. LeBouton, J. M. Wilson, and O. Koldovský (1995). Epidermal growth factor and transforming growth factor-α mRNA in rat small intestine:In situ hybridization study.FEBS Lett. 352:291–295.Google Scholar
  47. 47.
    J. Grimes, P. Schaudies, D. Davis, C. Williams, B. J. Curry, M. D. Walker, and O. Koldovský (1992). Effect of short-term fasting/refeeding on epidermal growth factor content in the gastrointestinal tract of suckling rats.Proc. Soc. Exp. Biol. Med. 199:75–80.PubMedGoogle Scholar
  48. 48.
    R. K. Rao, K. Lam, A. F. Philipps, C. Williams, M. Lake, and O. Koldovský (1993). Presence of multiple forms of peptidase inhibitors in rat milk.J. Pediatr. Gastroenterol. Nutr. 17:414–420.PubMedGoogle Scholar
  49. 49.
    P. A. Gonnella, K. Siminoski, R. A. Murphy, and M. R. Neutra (1987). Transepithelial transport of epidermal growth factor by absorptive cells of suckling rat ileum.J. Clin. Invest. 80:22–32.PubMedGoogle Scholar
  50. 50.
    R. K. Rao, O. Koldovský, M. Korc, P. F. Pollack, S. Wright, and T. P. Davis (1990). Processing and transfer of epidermal growth factor in developing rat jejunum and ileum.Peptides 11:1093–1102.PubMedGoogle Scholar
  51. 51.
    F. Puccio and T. Lehy (1988). Oral administration of epidermal growth factor in suckling rats stimulates cell DNA synthesis in fundic and antral gastric mucosae as well as in intestinal mucosa and pancreas.Reg. Pept. 20:53–64.Google Scholar
  52. 52.
    E. V. O'Loughlin, M. Chung, M. Hollenberg, J. Hayden, I. Zahavi, and D. G. Gall (1985). Effect of epidermal growth factor on ontogeny of the gastrointestinal tract.Am. J. Physiol. 249:G674-G678.PubMedGoogle Scholar
  53. 53.
    K. Opleta, E. V. O'Loughlin, E. A. Shaffer, J. Hayden, M. Hollenberg, and D. G. Gall (1987). Effect of epidermal growth factor on growth and postnatal development of the rabbit liver.Am. J. Physiol. 253:G622-G626.PubMedGoogle Scholar
  54. 54.
    C. L. Berseth and V. L. M. Go (1987). Enhancement of neonatal somatic and hepatic growth by orally administered epidermal growth factor in rats.J. Pediatr. Gastroenterol. Nutr. 7:889–893.Google Scholar
  55. 55.
    J. Falconer (1987). Oral epidermal growth factor is trophic for the stomach in the neonatal rat.Biol. Neonate 52:347–350.PubMedGoogle Scholar
  56. 56.
    P. F. Pollack, T. Goda, P. C. Colony, J. Edmond, W. Thornburg, M. Korc, and O. Koldovský (1987). Effects of enterally fed epidermal growth factor on the small and large intestine of the suckling rat.Reg. Pept. 17:121–132.Google Scholar
  57. 57.
    R. S. McCuskey, J. Nishida, D. McDonnell, and O. Koldovský (1995). Effect of milk-borne EGF on the hepatic microcirculation and Kupffer cell functions in suckling rats.Pediatr. Res. 37:313.Google Scholar
  58. 58.
    L. A. Ellis, A. M. Mastro, and M. F. Picciano (1996). Milkborne prolactin and neonatal development.J. Mam. Gland Biol. Neoplasia 1(3):259–269.Google Scholar
  59. 59.
    Y. Koch, H. Werner, and M. Fridkin (1991). Hypothalamic hormones in milk.Endocrinol. Exp. 25:128–133.Google Scholar
  60. 60.
    R. K. Rao, O. Koldovský, and T. P. Davis (1990). Inhibition of intestinal degradation of somatostatin by rat milk.Am. J. Physiol. 258:G426-G431.PubMedGoogle Scholar
  61. 61.
    B. Kacsoh, L. C. Terry, J. S. Meyers, W. R. Crowley, and C. E. Grosvenor (1989). Maternal modulation of growth hormone secretion in the neonatal rat. I. Involvement of milk factors.Endocrinology 125:1326–1336.PubMedGoogle Scholar
  62. 62.
    C. M. Kuhn, J. Pauk, and S. M. Schanberg (1990). Endocrine responses to mother-infant separation in developing rats.Dev. Psychobiol. 23:395–410.PubMedGoogle Scholar
  63. 63.
    G. Nagy, B. Kacsoh, B. Kanyicska, B. E. Toth, and E. Korausz (1986). Separation and suckling induced changes in serum growth hormone levels of lactating rats and their pups.Endocrinol. Exp. 20:217–222.PubMedGoogle Scholar
  64. 64.
    T. Baram, Y. Koch, E. Hazum, and M. Fridkin (1977). Gonadotropin-releasing hormone in milk.Science 198:300–302.PubMedGoogle Scholar
  65. 65.
    V. Raghavan, P. R. Sheth, T. D. Nandekar, and A. R. Sheth (1982). Effect of weaning on gonadotropin levels in plasma and pituitary of female mice.Ind. J. Exp. Biol. 20:252.Google Scholar
  66. 66.
    S. S. Smith-White and S. R. Ojeda (1984). Maternal modulation of infantile ovarian development and available ovarian luteinizing hormone-releasing hormone (LHRH) receptors via milk LHRH.Endocrinology 115:1973–1984.PubMedGoogle Scholar
  67. 67.
    W. C. Grant (1952). Influence of anoxia of a lactating rat on the blood of normal baby rats.Am. J. Physiol. 171:728–729.Google Scholar
  68. 68.
    R. D. Carmichael, A. S. Gordon, and J. Lobue (1978). The effects of maternal phlebotomy and orally-administered erythropoietin (EP) on erythropoiesis in the suckling rat.Biol. Neonate 33:119–131.PubMedGoogle Scholar
  69. 69.
    R. D. Carmichael, A. S. Gordon, and J. Lobue (1986). Effects of the hormone erythropoietin in milk on erythropoiesis in neonatal rats.Endocrinol. Exp. 20:67–188.PubMedGoogle Scholar
  70. 70.
    T. E. Porter, L. E. Chapman, F. M. Van Dolah, and L. S. Frawley (1991). Normal differentiation of prolactin cells in neonatal requires a maternal signal specific to early lactation.Endocrinology 128:792–796.PubMedGoogle Scholar
  71. 71.
    T. E. Porter and L. S. Frawley (1991). Stimulation of prolactin cell differentiationin vitro by a milk-borne peptide.Endocrinology 129:2707–2713.PubMedGoogle Scholar
  72. 72.
    T. E. Porter, C. D. Wiles, and L. S. Frawley (1993). Lactotrope differentiation in rats is modulated by a milk-borne signal transferred to the neonatal circulation.Endocrinology 133:1284–1291.PubMedGoogle Scholar
  73. 73.
    S. J. Konturek, T. Radecki, T. Brzozowski, I. Piastucki, A. Dembinski, A. Dembinska-Kiec, R. Zmuda, R. Gryglewski, and H. Gregory (1981). Gastric cytoprotection by epidermal growth factor. Role of endogenous prostaglandins and DNA synthesis.Gastroenterology 81:438–443.PubMedGoogle Scholar
  74. 74.
    S. J. Konturek, A. Dembinski, Z. Warzecha, T. Brzozowski, and H. Gregory (1988). Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats.Gastroenterology 94:1300–1307.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  1. 1.Departments of Pediatrics and Physiology and Steele Memorial Research Center, Furrow Research Laboratory and Cosden Neonatology Research WingUniversity of Arizona, College of MedicineTucson

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