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Department of Physiology, University of Colorado Health Sciences Center, Denver CO 80262 and
Stanford University School of Medicine, Palo Alto Medical Foundation, Palo Alto, CA 94028
*
3To whom correspondence should be addressed. peggy.neville@uchsc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONStage II lactogenesis in...Regulation of stage II...Does milk removal play...LITERATURE CITED |
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KEY WORDS: • lactogenesis • mammary development • milk composition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONStage II lactogenesis in...Regulation of stage II...Does milk removal play...LITERATURE CITED |
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), which guides the elongation, branching and spacing of
the ducts. In women, with the onset of menses, and in those rodents in
which there is a significant luteal phase, alveolar structures begin to
sprout from the sides of the duct stimulated by progesterone and
probably prolactin. The mature breast resembles a flowering tree in
springtime with lobular alveolar complexes, called terminal duct
lobular units
(TDLU)4
by pathologists, sprouting regularly from the major ducts. The breast
reaches a stage of quiescence marked by some waxing and waning of the
TDLU driven by the hormonal changes of the menstrual cycle
(2
–5
).
The next stage of development begins in pregnancy. As the levels of
progesterone, prolactin and placental lactogen rise, the TDLU undergo a
remarkable expansion so that each lobule comes to resemble a large
bunch of grapes. During mid-pregnancy, secretory differentiation
begins with a rise in mRNA for many milk proteins and enzymes important
to milk formation. Fat droplets begin to increase in size in the
mammary cells, becoming a major cell component at the end of pregnancy.
This switch to secretory differentiation is called stage I lactogenesis
(6
, 7
). The gland remains quiescent but poised to initiate
copious milk secretion around parturition. This period of quiescence
depends on the presence of high levels of circulating progesterone;
when this hormone falls around the time of birth, stage II lactogenesis
or the onset of copious milk secretion ensues. As long as prolactin
secretion is maintained and milk is removed from the gland, the mature
function of the breast, milk secretion, is maintained. After weaning,
the TDLU involute with the apoptosis of a large proportion of the
alveolar cells and a remodeling of the gland so that it returns to the
mature quiescent state (8
).
This brief outline of a complex series of hormonally regulated developmental events shows that mammary development is governed by a series of switches. Most of these developmental switches are instigated by external hormonal influences, but lactogenesis stage I may be simply the consequence of the inherent program of alveolar development and involution is most often initiated by a failure of milk removal. In this short article we discuss the developmental switch represented by lactogenesis stage II. The changes in milk composition and volume attendant on this switch in women are outlined first, followed by a discussion of the role of hormones in its initiation. Finally, the scanty findings concerning the role of milk removal and a hypothesis for a role of an inhibitor of lactogenesis are presented as a guide to future research.
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Stage II lactogenesis in women |
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TOPABSTRACTINTRODUCTIONStage II lactogenesis in...Regulation of stage II...Does milk removal play...LITERATURE CITED |
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shows the time course of the increase in milk volume that occurs during
the 1st wk postpartum (9
–11
). Milk transfer to the
suckling infants starts at a volume of <100 mL/d on d 1 postpartum,
begins to increase 
36 h after birth and levels off at an average of
500 mL at 4 d. Milk composition also changes dramatically during
this period, with a fall in the sodium and chloride concentrations and
an increase in the lactose concentration that start immediately after
birth and are largely complete by 72 h postpartum
(12
). These changes precede the onset of the large
increase in milk volume by at least 24 h and are explained by
closure of the tight junctions that block the paracellular pathway
(7
). Next, the concentrations of secretory immunoglobulin
A and lactoferrin increase dramatically and remain high to
48 h after birth (13
). Their concentrations fall
rapidly after d 2, in part because of dilution as milk volume secretion
increases, but their secretion rate is still substantial (2–3 g/d for
each protein throughout lactation). Oligosaccharide concentrations are
also high in early lactation, comprising as much as 20 g/kg of milk on
d 4 (14
, 15
), falling significantly to a level of 14 g/L
on d 30. These complex sugars are also considered to have substantial
protective effect against a variety of infections (16
).
Thus, during the first 2 d postpartum, large molecules with
significant protective power dominate in the mammary secretion; the
total nutrient value is low, simply because the amount of milk
transferred to the infant is small.
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), including but not
limited to lactose, protein (primarily casein) (17
, 18
),
lipid, calcium, sodium, magnesium and potassium (Fig. 1)
. Considering
the secretion patterns for each of the milk components shown in Figure 1
, the coordination achieved by the mammary epithelial cell among the
activity of the various pathways that contribute all these different
milk components is a marvel. The question we need to ask next is:
"How is this remarkable degree of coordination achieved?" |
Regulation of stage II lactogenesis |
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TOPABSTRACTINTRODUCTIONStage II lactogenesis in...Regulation of stage II...Does milk removal play...LITERATURE CITED |
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). That the
fall in progesterone is the lactogenic trigger is supported by evidence
from many species. For example, exogenous progesterone prevents lactose
and lipid synthesis in the mammary gland after removal of the source of
progesterone, namely, the ovary, in pregnant rats (20
, 21
),
mice (22
) and ewes (23
). In humans removal of
the placenta, the source of progesterone during pregnancy in this
species, has long been known to be necessary for the initiation of milk
secretion (24
, 25
). Furthermore, retained placental
fragments with the potential to secrete progesterone have been reported
to delay lactogenesis in humans (25
). Thus, without a fall
in progesterone, lactogenesis does not occur.
However, other hormones must be present for this trigger to be
effective. Either prolactin or placental lactogen are necessary for
mammary development in pregnancy, and, with the fall in placental
lactogen after removal of the placenta, prolactin is necessary for
sustained lactation in most species, although cows may be an exception.
Bromocriptine and other analogs of dopamine (drugs that effectively
prevent prolactin secretion) inhibit lactogenesis when given in
appropriate doses (26
, 27
). Furthermore, prolactin was not
necessary for lactogenesis in mice that had not yet given birth, the
placental lactogen from the placenta providing the necessary
stimulation of prolactin receptors (22
). These data
support the concept that a surge in prolactin is not the trigger for
lactogenesis. It has long been known that glucocorticoids are necessary
for milk secretion and lactogenesis, a postulate recently confirmed in
our laboratory in mice (22
). However, a surge of
glucocorticoids is not necessary and a high dose of glucocorticoid does
not promote lactogenesis. Insulin is generally required for induction
and maintenance of milk protein gene expression in cultured mammary
cells and glands, and deficiencies in plasma insulin led to decreased
milk production in rats and goats. However, short-term deficiencies
in insulin did not interfere with lactogenesis in rats
(28
). Thus, the available literature rules out acute
changes in the concentrations of prolactin, glucocorticoids or insulin
as triggering lactogenesis, although glucocorticoids and prolactin are
necessary at some level for a fall in progesterone to act as the
lactogenic trigger.
In summary, interpretation of the data available from both animal and
human studies is that the physiological trigger for lactogenesis is a
fall in progesterone; however, maintained prolactin and cortisol are
necessary for the trigger to be effective. The caveat is, of course,
that the mammary epithelium must be sufficiently prepared by the
hormones of pregnancy to respond with milk synthesis. Postpartum
prolactin levels are similar in both breastfeeding and nonbreastfeeding
women, so that the basic process occurs regardless of whether
breastfeeding is initiated (27
). Similarly,
glucocorticoids are necessary at some level, but their role is
currently far from defined and, indeed, has received little study in
the past two decades. Likewise, the role of insulin in vivo is not
well-defined, although it is likely to be important in maintaining
a metabolic state that allows flux of nutrients to the mammary gland.
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Does milk removal play a role in the timing or extent of lactogenesis? |
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TOPABSTRACTINTRODUCTIONStage II lactogenesis in...Regulation of stage II...Does milk removal play...LITERATURE CITED |
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, 11
, 29
) and stress during
parturition (18
). The mechanism is unknown but the delay
did correlate with high cord blood glucose and cortisol. The delay
occurred in women who put the infant to the breast during the first
2 d postpartum, suggesting that poor milk removal is not the cause
of stress-related delayed lactogenesis. In another study high
breast milk sodium concentrations on or before d 3 were observed in
clinical situations in which the infant failed to latch on properly
(Fig. 2
) (30
, 31
). These high sodium concentrations were
statistically related to impending lactation failure and could be
reversed by the use of a breast pump to obtain effective milk removal.
These observations suggest that milk removal and/or effective suckling
are necessary to obtain junctional closure and potentially an increase
in milk volume secretion, at least in some women. Evidence on this
point is mixed. Careful evaluation of milk composition and
breast-filling in nonbreastfeeding women by Kulski et al.
(27
) suggested that milk removal is not needed for the
programmed physiological changes that bring about lactogenesis stage
II. In contrast, Chapman and Perez-Escamilla (32
)
found that formula feeding before lactogenesis was associated with a
delay in the perception of lactogenesis. Furthermore, the time of first
feeding and the breastfeeding frequency on d 2 postpartum were
positively correlated with milk volume on d 5 postpartum
(18
), suggesting that milk removal at early times after
birth increases the efficiency of milk secretion. In the last decade
local factors dependent on milk removal have been implicated in the
regulation of milk secretion during lactation (33
). The
question is: "What are these local factors and when do their effects
become apparent?" It is possible to speculate that they are present
in high concentration in the scant prepartum secretion product of the
breast and that if not removed early in the prepartum period, they
contribute to inhibition of lactogenesis stage II, even with adequate
hormonal changes. Although Kulski and coworkers were unable to
detect any delay in the change in milk composition in their study of
nonbreastfeeding women, it is possible that even the small changes in
the amount of milk remaining in the breast engendered by removal of 5
or 10 mL of secretion product per day by manual expression could
stimulate lactogenesis stage II.
|
). An example
of preglandular would be hormonal causes, such as retained placenta or
lack of pituitary prolactin. Glandular causes might be surgical
procedures, such as reduction mamoplasty or, possibly, insufficient
mammary tissue. Postglandular would be any cause for ineffective or
infrequent milk removal. This latter aspect has received insufficient
attention. A neonatal intensive care nursery where careful correlation
between early milk removal and subsequent lactation performance is
possible would be ideal for such a study. In these studies milk volume
would be most easily measured in women who are using a breast pump to
provide milk for their infants. Very small samples could be taken for
determination of milk sodium and casein on a daily basis to allow a
true distinction to be made between failure of tight junction closure
and reopening of the junctions due to lack of milk removal. Such data
will be valuable in determining how to manage the initiation of
breastfeeding in mothers of sick infants as well as in sick mothers of
well infants. It would also be of great value to determine, using
techniques developed at the Hannah Research Institute in Ayr, Scotland
in collaboration with Prentice et al. (34
), whether a
chemical present in colostrum inhibits milk secretion in an in vitro
model system. Identification of such a chemical and precise
measurements of its concentration could provide a new index for
predicting which women are likely to have problems initiating stage II
lactogenesis.
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FOOTNOTES |
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2 Preparation of this article was supported in
part by National Institutes of Health Grants R37-HD19547 and
PO1-HD38129.
4 Abbreviation used: TDLU, terminal duct lobular
units.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONStage II lactogenesis in...Regulation of stage II...Does milk removal play...LITERATURE CITED |
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18. Chen, D. C., Nommsen-Rivers, L., Dewey, K. G. & Lonnerdal, B. (1998) Stress during labor and delivery and early lactation performance. Am. J. Clin. Nutr. 68:335-344.[Abstract]
19. Kuhn, N. J. (1983) The biochemistry of lactogenesis. Mepham, T. B. eds. Biochemistry of Lactation 1983:351-380 Elsevier Amsterdam, The Netherlands. .
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30. Aperia, A., Broberger, O., Herin, P. & Zetterstroem, R. (1979) Salt content in human breast milk during the first three weeks after delivery. Acta Paediatr. Scand. 68:441-442.[Medline]
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