Journal of Mammary Gland Biology and Neoplasia

, Volume 12, Issue 4, pp 211–221 | Cite as

Initiation of Human Lactation: Secretory Differentiation and Secretory Activation

  • Wei Wei Pang
  • Peter E. HartmannEmail author


Theories for the origin of milk have been recorded since the time of Ancient Greeks. In those times it was believed that milk was derived from special vessels that connected the uterus to the breasts. The “chyle theory” on the origin of milk was another prominent theory which persisted well into the nineteenth century before the realisation that milk components were derived from blood and some milk constituents were actually synthesized within the breasts. The demonstration that milk ejection was the expulsion of milk that had already been secreted and that milk secretion was a separate continuous process, set the background for the development for the current understanding of milk synthesis and secretion. Today we know that there are two stages in the initiation of lactation- secretory differentiation and secretory activation. Secretory differentiation represents the stage of pregnancy when the mammary epithelial cells differentiate into lactocytes with the capacity to synthesize unique milk constituents such as lactose. This process requires the presence of a ‘lactogenic hormone complex’ of the reproductive hormones, estrogen, progesterone, prolactin and some metabolic hormones. Secretory activation on the other hand, is the initiation of copious milk secretion and is associated with major changes in the concentrations of many milk constituents. The withdrawal of progesterone triggers the onset of secretory activation but prolactin, insulin and cortisol must also be present. This review describes the works of pioneers that have led to our current understanding of the biochemical and endocrinological processes involved in the initiation of human lactation.


Human lactation Secretory differentiation Secretory activation Endocrine control Lactogenesis 



central nervous system


respiratory quotient


Janus kinase


signal transducer and activator of transcription



Our work is supported by Medela AG, Switzerland.


  1. 1.
    Folley SJ. Symposium on lactogenesis: chairman’s introduction. In: Reynolds M, Folley SJ, editors. Lactogenesis: the initiation of milk secretion at parturition. Philadelphia: Pennsylvania Press; 1969. p. 1–3.Google Scholar
  2. 2.
    Folley SJ. The physiology and biochemistry of lactation. Edinburgh: Oliver and Boyd; 1956.Google Scholar
  3. 3.
    Hartmann PE. Changes in the composition and yield of the mammary secretion of cows during the initiation of lactation. J Endocrinol 1973;59(2):231–47.PubMedGoogle Scholar
  4. 4.
    Hartmann PE, Trevethan P, Shelton JN. Progesterone and estrogen and the initiation of lactation in ewes. J Endocrinol 1973;59(2):249–59.PubMedGoogle Scholar
  5. 5.
    Fleet IR, Goode JA, Hamon MH, Laurie MS, Linzell JL, Peaker M. Secretory activity of goat mammary glands during pregnancy and the onset of lactation. J Physiol 1975;251(3):763–73.PubMedGoogle Scholar
  6. 6.
    Neville MC. Determinants of milk volume and composition. A. Lactogenesis in women: a cascade of events revealed by milk composition. In: Jensen RG, editor. Handbook of milk composition. San Diego: Academic; 1995. p. 87–98.Google Scholar
  7. 7.
    Anderson SM, Rudolph MC, McManaman JL, Neville MC. Key stages in mammary gland development. Secretory activation in the mammary gland: it’s not just about milk protein synthesis! Breast Cancer Res 2007;9(1):204.PubMedGoogle Scholar
  8. 8.
    Cowie AT. The hormonal control of milk secretion. In: Kon SK, Cowie AT, editors. Milk: the mammary gland and its secretion. London: Academic; 1961. p. 163–203.Google Scholar
  9. 9.
    Cowie AT, Forsyth IA, Hart IC. Hormonal control of lactation. Monogr Endocrinol 1980;15:I–XIV, 1–275.PubMedGoogle Scholar
  10. 10.
    Folley SJ. Lactation. In: Parkes AS, editor. Marshall’s physiology of reproduction. 3rd ed. London: Longmans; 1952. p. 525–649.Google Scholar
  11. 11.
    Calder R. Leonardo and the age of the eye. London: Heinemann; 1970.Google Scholar
  12. 12.
    Cooper AP. 1768–1841, On the anatomy of the breast. London: Longman, Orme, Green, Brown, and Longmans; 1840.Google Scholar
  13. 13.
    Ramsay DT, Kent JC, Hartmann RA, Hartmann PE. Anatomy of the lactating human breast redefined with ultrasound imaging. J Anat 2005;206(6):525–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Glencross BD, Mullan BP, Tuckey RC, Hartmann PE. A simplification of the deuterium oxide dilution technique using FT-IR analysis of plasma, for estimating piglet milk intake. Aust J Agric Res 1997;48(8):1099–1104.CrossRefGoogle Scholar
  15. 15.
    Gaines WL. A contribution to the physiology of lactation. Am J Physiol 1915;38(2):285–312.Google Scholar
  16. 16.
    Gaines WL, Sanmann FP. The quantity of milk present in the udder of the cow at milking time. Am J Physiol 1927;80(3):691–701.Google Scholar
  17. 17.
    Ely F, Petersen WE. Factors involved in the ejection of milk. J Dairy Sci 1941;24(3):211–23.CrossRefGoogle Scholar
  18. 18.
    Richardson KC. Contractile tissues in the mammary gland, with special reference to myoepithelium in the goat. Proc R Soc Lond Ser B Biol Sci 1949;136(882):30–45.Google Scholar
  19. 19.
    Gunther M. Lactation in women. Can Med Assoc J 1942;47(5):410–14.PubMedGoogle Scholar
  20. 20.
    Newton M, Newton NR. The let-down reflex in human lactation. J Pediatr 1948;33(6):698–704.CrossRefPubMedGoogle Scholar
  21. 21.
    Shennan DB, Peaker M. Transport of milk constituents by the mammary gland. Physiol Rev 2000;80(3):925–51.PubMedGoogle Scholar
  22. 22.
    Neville MC, Allen JC, Watters C. The mechanisms of milk secretion. In: Neville MC, Neifert MR, editors. Lactation: physiology, nutrition, and breast-feeding. New York: Plenum; 1983. p. 49–92.Google Scholar
  23. 23.
    Fetherston CM, Lai CT, Hartmann PE. Relationships between symptoms and changes in breast physiology during lactation mastitis. Breastfeed Med 2006;1(3):136–45.PubMedCrossRefGoogle Scholar
  24. 24.
    Kulski JK, Hartmann PE. Changes in human milk composition during the initiation of lactation. Aust J Exp Biol Med Sci 1981;59(1):101–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Prentice A, Paul A, Prentice A, Black A, Cole T, Whitehead R. Cross-cultural differences in lactational performance. In: Hamosh M, Goldman AS, editors. Human lactation 2: maternal and environmental factors. New York: Plenum; 1986. p. 13–44.Google Scholar
  26. 26.
    Lyons W. The direct mammotrophic action of lactogenic hormone. Proc Soc Exp Biol Med 1942;51:308–11.Google Scholar
  27. 27.
    Meites J, Turner CW. Studies concerning the induction and maintenance of lactation. I. The mechanism controlling the initiation of lactation at parturition. Res Bull Mo Agric Exp Stn 1948;415:1–65.Google Scholar
  28. 28.
    Meites J, Turner CW. Studies concerning the induction and maintenance of lactation. II. The normal maintenance and experimental inhibition and augmentation of lactation. Res Bull Mo Agric Exp Stn 1948;416:1–36.Google Scholar
  29. 29.
    Popjak G, Beeckmans M-L. Synthesis of cholesterol and fatty acids in fetuses and in mammary glands of pregnant rabbits. Appendix 1. Water bath suitable for the maintenance of temperature to within. Biochem J 1950;46(5):547–61.PubMedGoogle Scholar
  30. 30.
    Balmain JH, Folley SJ, Glascock RF. Relative utilization of glucose and acetate carbon for lipogenesis by mammary-gland slices, studied with tritium, 13C and 14C. Biochem J 1954;56(2):234–9.PubMedGoogle Scholar
  31. 31.
    Folley SJ, Greenbaum AL. Changes in the arginase and alkaline phosphatase contents of the mammary gland and liver of the rat during pregnancy, lactation and mammary involution. Biochem J 1947;41(2):261–9.PubMedGoogle Scholar
  32. 32.
    Folley SJ, French TH. The intermediary metabolism of the mammary gland; respiration and acid production of mammary tissue during pregnancy, lactation and involution in the rat. Biochem J 1949;45(3):270–5.PubMedGoogle Scholar
  33. 33.
    Baldwin RL, Milligan LP. Enzymatic changes associated with the initiation and maintenance of lactation in the rat. J Biol Chem 1966;241(9):2058–66.PubMedGoogle Scholar
  34. 34.
    Baldwin RL. Enzymic and metabolic changes in mammary tissue at lactogenesis. In: Reynolds M, Folley SJ, editors. Lactogenesis: the initiation of milk secretion at parturition. Philadelphia: University of Pennsylvania Press; 1969. p. 85–95.Google Scholar
  35. 35.
    Denamur R. Changes in the ribonucleic acids of mammary cells at lactogenesis. In: Reynolds M, Folley SJ, editors. Lactogenesis: the initiation of milk secretion at parturition. Philadelphia: University of Pennsylvania Press; 1969. p. 53–64.Google Scholar
  36. 36.
    Kronfeld DS. Biosynthesis of milk constituents at lactogenesis. In: Reynolds M, Folley SJ, editors. Lactogenesis: the initiation of milk secretion at parturition. Philadelphia: University of Pennsylvania Press; 1969. p. 109–20.Google Scholar
  37. 37.
    Kronfeld DS, Ramberg CF. Whole animal studies using tracer kinetics. Proc Nutr Soc 1981;40(1):129–38.PubMedCrossRefGoogle Scholar
  38. 38.
    Hardwick DC, Linzell JL. Some factors affecting milk secretion by the isolated perfused mammary gland. J Physiol 1960;154:547–71.PubMedGoogle Scholar
  39. 39.
    Hardwick DC, Linzell JL, Price SM. The effect of glucose and acetate on milk secretion by the perfused goat udder. Biochem J 1961;80:37–45.PubMedGoogle Scholar
  40. 40.
    Linzell JL. Transplantation of mammary glands. Nature 1960;188:596–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Cox DB, Kent JC, Casey TM, Owens RA, Hartmann PE. Breast growth and the urinary excretion of lactose during human pregnancy and early lactation: endocrine relationships. Exp Physiol 1999;84(2):421–34.PubMedCrossRefGoogle Scholar
  42. 42.
    Saint L, Smith M, Hartmann PE. The yield and nutrient content of colostrum and milk of women from giving birth to 1 month post-partum. Br J Nutr 1984;52(1):87–95.PubMedCrossRefGoogle Scholar
  43. 43.
    Arthur PG, Smith M, Hartmann PE. Milk lactose, citrate, and glucose as markers of lactogenesis in normal and diabetic women. J Pediatr Gastroenterol Nutr 1989;9(4):488–96.PubMedCrossRefGoogle Scholar
  44. 44.
    Arthur PG, Kent JC, Hartmann PE. Microanalysis of the metabolic intermediates of lactose synthesis in human milk and plasma using bioluminescent methods. Anal Biochem 1989;176(2):449–56.PubMedCrossRefGoogle Scholar
  45. 45.
    Folley SJ, Young FG. The effect of anterior pituitary extracts on established lactation in the cow. Proc R Soc Lond Ser B Biol Sci 1938;126(842):45–76.Google Scholar
  46. 46.
    Lyons WR. Hormonal synergism in mammary growth. Proc R Soc Lond Ser B Biol Sci 1958;149(936):303–25.CrossRefGoogle Scholar
  47. 47.
    Cowie AT, Lyons WR. Mammogenesis and lactogenesis in hypophysectomized, ovariectomized, adrenalectomized rats. J Endocrinol 1959;19:29–32.PubMedGoogle Scholar
  48. 48.
    Meites J. Recent studies on the mechanisms controlling the initiation of lactation. Rev Can Biol 1954;13(4):359–70.PubMedGoogle Scholar
  49. 49.
    Forsyth IA. The endocrinology of lactation. In: Mepham TB, editor. Biochemistry of lactation. Amsterdam: Elsevier Science; 1983. p. 309–49.Google Scholar
  50. 50.
    Pasteels JL. Morphological and experimental research on prolactin secretion. Arch Biol (Liege) 1963;74:439–553.Google Scholar
  51. 51.
    Bryant GD, Greenwood FC. The concentrations of human prolactin in plasma measured by radioimmunoassay: experimental and physiological modifications. In: Wolstenholme GEW, Knight J, editors. Lactogenic hormones. Edinburgh: Churchill Livingstone; 1972. p. 197–206.Google Scholar
  52. 52.
    Neville MC, McFadden TB, Forsyth I. Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia 2002;7(1):49–66.PubMedCrossRefGoogle Scholar
  53. 53.
    Tucker HA. Hormones, mammary growth, and lactation: a 41-year perspective. J Dairy Sci 2000;83(4):874–84.PubMedCrossRefGoogle Scholar
  54. 54.
    Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000;80(4):1523–631.PubMedGoogle Scholar
  55. 55.
    Gunther M. Infant feeding. London: Methuen; 1970.Google Scholar
  56. 56.
    Kuhn NJ. Progesterone withdrawal as the lactogenic trigger in the rat. J Endocrinol 1969;44(1):39–54.PubMedGoogle Scholar
  57. 57.
    Kuhn NJ. Specificity of progesterone inhibition of lactogenesis. J Endocrinol 1969;45(4):615–6.PubMedGoogle Scholar
  58. 58.
    Neifert MR, McDonough SL, Neville MC. Failure of lactogenesis associated with placental retention. Am J Obstet Gynecol 1981;140(4):477–8.PubMedGoogle Scholar
  59. 59.
    Kulski JK, Hartmann PE, Martin JD, Smith M. Effects of bromocriptine mesylate on the composition of the mammary secretion in non-breast-feeding women. Obstet Gynecol 1978;52(1):38–42.PubMedGoogle Scholar
  60. 60.
    Hale TW. Medications and mothers’ milk. 12st ed. Amarillo: Hale; 2006.Google Scholar
  61. 61.
    Burke CW, Roulet F. Increased exposure of tissues to cortisol in late pregnancy. Br Med J 1970;1(5697):657–9.PubMedGoogle Scholar
  62. 62.
    Florensa E, Harrison R, Johnson M, Youssefnejadian E. Plasma 20 alpha-dihydroprogesterone, progesterone and 17-hydroxyprogesterone in normal human pregnancy. Acta Endocrinol (Copenh) 1977;86(3):634–40.Google Scholar
  63. 63.
    Peterson R. Cortisol. In: Fuchs F, Klopper A, editors. Endocrinology of pregnancy. 2nd ed. New Yok, Evanston, London: Harper & Row; 1977. p. 157–176.Google Scholar
  64. 64.
    Cowie AT, Knaggs GS, Tindal JS, Turvey A. The milking stimulus and mammary growth in the goat. J Endocrinol 1968;40(2):243–52.PubMedGoogle Scholar
  65. 65.
    Brown RE. Relactation: an overview. Pediatrics 1977;60(1):116–20.PubMedGoogle Scholar
  66. 66.
    Nicholas KR, Hartmann PE. Progesterone control of the initiation of lactose synthesis in the rat. Aust J Biol Sci 1981;34(4):435–43.PubMedGoogle Scholar
  67. 67.
    Kulski JK, Smith M, Hartmann PE. Perinatal concentrations of progesterone, lactose and alpha-lactalbumin in the mammary secretion of women. J Endocrinol 1977;74(3):509–10.PubMedGoogle Scholar
  68. 68.
    Oliver G, Detmar M. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev 2002;16:773–83.PubMedCrossRefGoogle Scholar
  69. 69.
    Rendle-Short J, Rendle-Short M. The father of child care. Life of William Cadogan (1711–1797). Bristol: John Wright and Sons Ltd; 1966.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.School of Biomedical, Biomolecular and Chemical Sciences, M310, Faculty of Life and Physical SciencesThe University of Western AustraliaCrawleyAustralia

Personalised recommendations