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Department of Biochemistry, University of Western Australia, Crawley, WA 6009, Australia
3To whom correspondence should be addressed. E-mail: hartmanp{at}cyllene.uwa.edu.au
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONLactation cycleLactogenesis ILactogenesis IILITERATURE CITED |
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KEY WORDS: • lactogenesis • prematurity • diabetes • progesterone
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONLactation cycleLactogenesis ILactogenesis IILITERATURE CITED |
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Lactation cycle |
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TOPABSTRACTINTRODUCTIONLactation cycleLactogenesis ILactogenesis IILITERATURE CITED |
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). Several distinct phases of mammary
development have been defined in macropods (1
). For
example, in the Tammar Wallaby, the mammary gland increases
several-fold in size during a 28-d pregnancy (phase 1)
(2
). After delivery, phase 2 of the lactation cycle is
initiated by the single fetus-like infant attaching to one of four
teats in the pouch. Phase 2 is associated with a high carbohydrate and
low fat and protein milk (3
) and is further subdivided
into two 100-d phases. During phase 2A, the young Tammar Wallaby
remains permanently attached to the teat, whereas in phase 2B the
infant relinquishes the teat and suckles less frequently. The onset of
phase 3 occurs at 
200 d of lactation and continues until 300–350 d
postpartum, with the infant leaving the pouch at 250 d. It is
characterized by increased milk production (4
) and a
change in milk composition to low carbohydrate and high fat and protein
(5
). Furthermore, the Tammar is capable of asynchronous
concurrent lactation, with adjacent mammary glands functioning
independently. Thus, one small gland can be commencing phase 2, with
the young Tammar Wallaby in the pouch attached permanently to the teat,
while another large gland is in phase 3 and suckled by an infant at
foot.
Compared with marsupials, the lactation cycle of eutherian mammals is
relatively simple consisting of mammogenesis, lactogenesis,
galactopoiesis and involution. Lactogenesis refers to the expression of
specific genes required for the synthesis of milk by the lactocytes
(mammary secretory epithelial cells) and occurs in two stages
(6
) in those eutherian mammals that have been studied to
date. Lactogenesis I occurs during pregnancy, whereas lactogenesis II
occurs close to birth (7
).
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Lactogenesis I |
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TOPABSTRACTINTRODUCTIONLactation cycleLactogenesis ILactogenesis IILITERATURE CITED |
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-lactalbumin), and its occurrence has been identified by the
detection of these components in the mammary tissue, mammary secretion,
blood or urine of the mother. There is considerable variation both
between and within species on the timing of lactogenesis I, but it
seems that mammals that produce a placental lactogen tend to initiate
lactogenesis earlier in gestation (8
). With the possible
exception of the ewe (9
), the timing of lactogenesis I
does not seem to greatly influence lactogenesis II. |
Lactogenesis II |
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TOPABSTRACTINTRODUCTIONLactation cycleLactogenesis ILactogenesis IILITERATURE CITED |
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Measurement.
By definition, lactogenesis II is the initiation of copious milk
secretion; therefore, the measurement of the rate of milk synthesis
provides an obvious method of determining the onset of lactogenesis II
(6
). However, it is difficult to use this method to
determine the synchronization of lactogenesis II with parturition
because, in most species, lactogenesis II occurs either just before or
at the time of parturition and the prepartum removal of secretion could
in itself initiate lactogenesis II. In women, where lactogenesis II
occurs after parturition, the measurement of the intake of breast milk
by the infant over the first few days after birth is difficult and it
is possible that the infant may not consume all of the available milk
(colostrum). The exception being women who deliver prematurely, where
(providing their breasts can be successfully expressed by either hand
or breast pump) milk production can be measured.
Lactogenesis II is also associated with large changes in the
composition of the mammary secretion as the transition from colostrum
(high concentration of total protein, immunoglobulins, sodium and
chloride; low concentrations of lactose, potassium, glucose and
citrate) to mature milk with the reverse concentrations of these
constituents. Consequently, changes in the concentration of one or a
combination of these constituents can be used to identify the onset of
lactogenesis II (10
, 11
). However, there is some variation
between species. Although the postnatal increase in the concentration
of citrate in human milk is considered "the harbinger of
lactogenesis" (12
), in the sow, citrate decreases during
lactogenesis II (13
).
Hormonal control.
Birth and lactogenesis II are closely coupled by their mutual
relationship to the withdrawal of progesterone in eutherian mammals.
The pioneering work of Kuhn (14
) established that
progesterone withdrawal was the trigger for lactogenesis II in rats,
and this mechanism seems to control the timing of lactogenesis II in a
number of other species, including humans (8
). However, in
contrast to other species, the major fall in progesterone occurs after
birth in women (commencing with the delivery of the placenta);
therefore, lactogenesis II is delayed until 24 h after birth.
Because this is contrary to the infant’s perceived metabolic needs,
there must be a strong selective advantage associated with this delay.
The metabolic resilience of the human infant at birth is probably
related to its significant fat reserves and its slow rate of postnatal
growth. For example, the piglet is born with only 2% body fat
(15
) and doubles it birth weight in the first week of
life, whereas the human infant merely regains it birth weight during
the same period. Furthermore, each piglet consumes approximately three
times more colostrum (50–100 mL) in the first 4 h after birth
(16
) than the human infant consumes (20–30 mL) during
the first 24 h of life (17
). This difference in milk
production clearly demonstrates the difference between these two
species in the timing of lactogenesis II. In women, premature delivery,
insulin-dependent diabetes mellitus
(IDDM),4
obesity, Cesarean section and endocrine disturbances can either delay
or suppress lactogenesis II and affect the successful establishment of
lactation (18
).
Term mothers.
Acute postpartum changes in the composition (e.g., lactose; Fig. 1
) of the mammary secretion concurrent with an increase in milk
production identify the onset of lactogenesis II at between 30 and
40 h after birth in women (10
). Twenty-four hours
after this time, women often experience a sudden feeling of breast
fullness and their milk supply is said to be coming in. It has long
been assumed that this was a marker of the initiation of lactation in
women (19
). Indeed, Cadogan stated: "When a child is
first born, there seems to be no provision at all made for it; for the
mother’s milk seldom comes ’till the 3rd day; so that, according to
nature, a child would be left a day and a half, or two days, without
any food; to me, a very sufficient proof that it wants none." This
conclusion was consistent with the widely held cultural belief at that
time that colostrum was not good for the newborn infant.
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) that retention of
placental fragments inhibited lactogenesis II supported the importance
of progesterone withdrawal in determining the timing of lactogenesis II
in women. Indeed, De Passille et al. (21
) reported reduced
growth rates and increased mortality in piglets from sows that had
slightly higher concentrations of progesterone in their blood after
farrowing, suggesting that a slow withdrawal of progesterone may
compromise the establishment of lactation. If a similar response to
progesterone withdrawal occurs in women, extreme caution should be
exercised with progestagen administration in the perinatal period. Preterm mothers.
Women who have delivered preterm and express their milk seem more
likely to produce less milk than women who deliver full-term
(22
), particularly in those women who do not express their
milk for the first few days after birth (23
). It is
possible that the poor milk production at this time in some expressing
women could be related to large differences among women in the
effectiveness of breast pumps in removing the available milk from some
women’s breasts (24
).
We recently investigated milk production and the concentration of four
markers of lactogenesis II (milk citrate, lactose, sodium and total
protein) at d 5 postpartum in 22 women who were expressing their milk
for their preterm infant (11
). The lactogenesis II markers
for the preterm women had much greater variation about the mean women
on d 5 postpartum than was observed in full-term breastfeeding
women (n = 16). Furthermore, all the full-term
women had all four markers within 3 SD of the
mean for the full-term women and were classified as having
successfully undergone lactogenesis II. However, only 18% of the
preterm women had all four markers within 3 SD of
the mean for full-term women (Fig. 2
). The remaining preterm women had one or more of the markers > 3
SD from the mean concentration for full-term
women. In addition, the preterm women who demonstrated one or more
lactogenesis II marker outside the range for the full-term women
had significantly lower milk productions than did preterm women with
all four markers within the range for full-term women. Therefore,
it was concluded that lactogenesis II had been compromised in 82% of
the preterm women. Similar changes in the concentration of the markers
of lactogenesis II occur in the mammary secretion in full-term
women regardless of whether they choose to feed breast milk to their
infants (25
). Therefore, the efficiency of removal of
available colostrum by breast pumping cannot explain the compromised
lactogenesis II of the preterm women.
|
). Cowie et al. (7
) hypothesized that
during pregnancy, circulating progesterone and corticosteroids compete
for the glucocorticoid receptors on the mammary epithelial cells.
Therefore, any treatment with corticosteroids could override the
progesterone inhibition of lactation during pregnancy. For example, we
have found that the administration of therapeutic doses of
ß-methasone to the fetus or pregnant ewes at 104, 111 and 118 d
of gestation significantly increased the concentration of lactose in
the mammary secretion by d 125 of gestation (Fig. 3
) and resulted in a poor lactation performance at term (Johnson,
S., Newnham, J. P., Moss, T. & Hartmann, P. E., unpublished
observations). Although such a link has not been established in women,
the compromised lactogenesis II in preterm women may be related to the
unintended stimulation of the breast by steroid hormone therapy for
high risk pregnancies, and, thus, causing lactogenesis II to occur
before delivery.
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Using lactose and citrate as markers of lactogenesis II, Arthur et al.
(10
) found that the onset of lactogenesis II was delayed
by between 15 and 28 h in women with IDDM. Subsequently, Neubauer
et al. (27
) confirmed these findings and concluded that in
women with IDDM the onset of lactogenesis II, as defined by the milk
markers, lactose and total nitrogen (an approximation to total
protein), was delayed by 24 h (Fig. 1)
. However, no significant
difference was found between IDDM and control women in the amount of
milk produced over a 24-h period at d 7 postpartum. Because it had been
claimed that better hospital management of the IDDM women had prevented
the delay in the onset of lactogenesis II, Cox (28
)
repeated the study of Arthur et al. (10
), comparing the
initiation of lactation in 10 control women with 8 IDDM women. A
significant delay was found in the timing of the increase in lactose in
the colostrum from IDDM women (Fig. 1)
. Although no differences were
observed in the change in concentration of either sodium or potassium
in colostrum between control and IDDM women, significant differences
were observed in the change in concentration of lactose and total
protein; therefore, these women showed some of the characteristics of
the compromised onset of lactogenesis II observed in preterm women.
Lactose, the most osmotically active component of human milk, draws
water into the lactocyte (29
). Thus, Arthur et al.
(10
) concluded that any delay in the increase in the
concentration of lactose in IDDM women was associated with a decrease
in milk volume in the first 3 d postpartum. Furthermore, in view
of the importance of citrate in generating acetyl CoA from glucose
(30
), they also suggested that the delay in the increase
in the concentration of citrate may be associated with a delay in the
de novo synthesis of medium-chain fatty acids. In this connection,
Bitman et al. (31
) reported that IDDM women who started
pumping at 72 h postpartum initially produced milk with lower
medium-chain fatty acid, total fat and cholesterol but higher
oleic, linoleic and polyunsaturated long-chain fatty acid content
than a reference population. Ferris et al. (32
) observed
that IDDM women commence breastfeeding, on average, 24 h later
than nondiabetic women. Furthermore, it has subsequently been
demonstrated that an increased number of early breastfeeding episodes
(within the first 12 h postpartum) were critically important for
stimulating the onset of lactogenesis II in women with IDDM
(33
).
The cause of the delay in the onset of lactogenesis II in IDDM women is
unclear. Because human Placental Lactogen (hPL) is positively
correlated with breast growth during pregnancy (34
), there
could be a possible involvement of hPL in the delay of the onset of
lactogenesis II in some IDDM women. Previous studies have found that
IDDM had no effect on circulating levels of progesterone, total
estriol, prolactin (35
) estradiol or human Chorionic
Gonadotrophin (36
) when compared with nondiabetic
women. However, Botta et al. (35
) described that
circulating levels of hPL were significantly lower at all latter stages
of pregnancy, compared with nondiabetic women, whereas Stewart et al.
(36
) found no difference between the two groups. There is
no obvious reason for the discrepancy between these two studies.
Furthermore, human hPL has been demonstrated to support lactogenesis II
in the absence of maternal prolactin in rats (37
).
Gestational diabetes mellitus (GDM).
Normal human pregnancy is accompanied by hyperinsulinaemia and normal
to slightly decreased glucose tolerance (38
). However, GDM
occurs in 3% of Western women and is defined as diabetes diagnosed
for the first time during pregnancy that then resolves postpartum
(39
). Obesity is a risk factor for delayed onset of
lactation (18
, 40
), and because GDM is most common in obese
women (41
), it is possible that the diabetes or the
obesity could alter the onset of lactogenesis II. Our preliminary
investigation of noninsulin-dependent gestational diabetic women
suggested that there was not a marked delay in the onset of
lactogenesis II because the concentration of lactose in the colostrum
of GDM women was not significantly different from control women at
40–50 h postpartum (data not shown). However, earlier samples were not
available for GDM women because they had difficulty expressing
colostrum from their breasts during the first 2 d of lactation.
Current maternity practice rightly focuses on the importance of the appropriate positioning and attachment of the infant to the breast. However, the onset of lactogenesis II in women can be influenced by a variety of pathological factors (IDDM, premature delivery, obesity, prolactin deficiency and delayed progesterone withdrawal) as well as hormonal and anesthetic therapeutic agents administered during pregnancy and child birth. Taken together, these findings suggest that additional research is required to determine the causes of delayed onset of lactogenesis II in women and its influence on the establishment of successful breastfeeding. Clinically, delayed onset of lactogenesis II should be considered a potential factor in the perinatal management of human lactation.
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FOOTNOTES |
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2 Studies conducted by the authors were supported
by MEDELA, the Women and Infants Research Foundation, the National
Health and Medical Research Council and the Lotteries
commission of Western Australia. All studies were approved by the
Committee for Human Ethics, The University of Western Australia.
4 Abbreviations used: GDM, gestational diabetes
mellitus; IDDM, insulin-dependent diabetes mellitus.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONLactation cycleLactogenesis ILactogenesis IILITERATURE CITED |
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1. Tyndale-Biscoe, C. H. & Janssens, P. A. (1988) The Developing Marsupial: Models for Biomedical Research 1988 Springer-Verlag Heidelberg, Germany. .
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3. Green, B. (1984) Composition of milk and energetics of growth in marsupials. Peaker, M. Vernon, R. G. Knight, C. H. eds. Physiological Strategies in Lactation 1984:369-387 Academic Press London, UK. .
4. Dove, H. & Cork, S. J. (1989) Lactation in the tammar wallaby (Macropus eugenii): milk composition and the algebraic description of the lactation curve. J. Zool. London 219:385.
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15. Mellor, D. J. & Cockburn, F. (1986) A comparison of energy metabolism in the new-born infant, piglet, and lamb. Q. J. Exp. Physiol. 71:361-379.
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22. Cregan, M. D. & Hartmann, P. E. (1999) Computerized breast measurement from conception to weaning: clinical implications. J. Hum. Lact. 15:89-96.
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24. Hartmann, P. E., Mitoulas, L. R. & Gurrin, L. C. (2000) Physiology of breast milk expression using an electric breast pump 2000 Proceedings of the 10th International Conference of the Research on Human Milk and Lactation (ISRHML) Tucson, Arizona. .
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32. Ferris, A. M., Dalidowitz, C. K., Ingardia, C. M., Reece, E. A., Fumia, F. D., Jensen, R. G. & Allen, L. H. (1988) Lactation outcome in insulin-dependent diabetic women. J. Am. Diet. Assoc. 88:317-322.[Medline]
33. Ferris, A. M., Neubauer, S. H., Bendel, R. R., Green, K. W., Ingardia, C. M. & Reece, E. A. (1993) Perinatal lactation protocol and outcome in mothers with and without insulin-dependent diabetes mellitus. Am. J. Clin. Nutr. 58:43-48.
34. Cox, D. B., Kent, J. C., Casey, T. M., Owens, R. A. & Hartmann, P. E. (1999) Breast growth and the urinary excretion of lactose during human pregnancy and early lactation: endocrine relationships. Exp. Physiol. 84:421-434.[Abstract]
35. Botta, R. M., Donatelli, M., Bucalo, M. L., Bellomonte, M. L. & Bompiani, G. D. (1984) Placental lactogen, progesterone, total estriol and prolactin plasma levels in pregnant women with insulin-dependent diabetes mellitus. Eur. J. Obstet. Gynecol. Reprod. Biol. 16:393-401.[Medline]
36. Stewart, M. O., Whittaker, P. G., Persson, B., Hanson, U. & Lind, T. (1989) A longitudinal study of circulating progesterone, oestradiol, hCG and hPL during pregnancy in type 1 diabetic mothers. Br. J. Obstet. Gynaecol. 96:415-423.[Medline]
37. Nicholas, K. R. & Hartmann, P. E. (1981) The foetoplacental unit and the initiation of lactation in the rat. Aust. J. Biol. Sci. 34:455-461.[Medline]
38. Kuhl, C. (1977) Serum insulin and plasma glucagon in human pregnancy on the pathogenesis of gestational diabetes. Acta Diabetologica Latina 14:1-8.[Medline]
39. Bell, A. W., Petterson, J. A. & Ehrhardt, R. A. (1995) Insulin resistance in pregnancy: implication for gestational diabetes. Proc. Nutr. Soc. Aust. 19:11-19.
40. Rasmussen, K. M. & Hilson, J. A. (2000) Obesity as a risk factor for failure to initiate and sustain lactation 2000 Abstract from the 10th International Conference of the International Society for Research on Human Milk and Lactation (ISRHML) Tucson, Arizona. .
41. Galtier-Dereure, F., Boegner, C. & Bringer, J. (2000) Obesity and pregnancy: complications and cost. Am. J. Clin. Nutr. 71:1242-1248.
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, Cox
(28
and Neubauer et al. (27
