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Establishing lactation

Breast development and control of milk synthesis

Peter E. Hartmann, Robyn A. Owens, David B. Cox, and Jacqueline C. Kent

Abstract

We have developed a computerized breast measurement system that can quantitate both long-term (lactation cycle) and short-term (between breastfeedings) changes in breast volume. The increase in breast volume during pregnancy was not related to milk production at one month of lactation, whereas milk production from one to six months of lactation remained constant and was not controlled directly by the suckling-evoked secretion of prolactin. From the measurement of circadian changes in breast volume, it was concluded that infants rarely emptied the breasts at a single breastfeeding and that short-term variation in the rate of synthesis during the day and between the left and right breasts was closely related to the degree of breast fullness. Furthermore, differences between women in the storage capacity of the breasts dictated their flexibility in frequency of breastfeeding. These observations are consistent with the autocrine (local) control of milk synthesis during established lactation in women.

Introduction

Breastfeeding and breastmilk must be considered in the context of maternal physiology and infant development rather than just the narrow role of optimizing infant nutrition (table 1). The lactating breast has a high metabolic activity. Indeed, the energy output in milk represents approximately 25% of the total energy intake in the maternal diet for women exclusively breastfeeding single infants, and up to 50% for those breastfeeding twins [1]. In addition, milk is a very complex secretion, consisting of cells (leucocytes, macrophages, and epithelial cells), lipids (triacylglycerols, free fatty acids, phospholipids, sterols, hydrocarbons, and fat-soluble vitamins), carbohydrates (lactose, oligosaccharides, galactose, glucose, and glycoproteins), proteins (caseins, a-lactalbumin, lactoferrin, secretory IgA and other immunoglobulins, Iysozyme, enzymes, hormones, and growth factors), non-protein nitrogenous compounds (urea, creatine, creatinine, uric acid, amino acids including glutamine, nucleic acids, nucleotides, and polyamines), water-soluble vitamins, macronutrient elements, and trace elements [2,3]. Furthermore, it is now clear that the proportions of these constituents in breastmilk are uniquely appropriate for the human neonate at a time when growth and development are occurring at near-maximal rates, yet many of the infant's systems (such as the digestive, hepatic, immune, neural, renal, and skeletal systems) are functionally immature. In addition, breastfeeding is an integral component of the complex psychological and metabolic dependencies of the infant on its mother, with single physical functions, such as nursing, providing the stimuli of touch, balance, smell, hearing, and vision, and each having specific effects on the infant [4]. Nevertheless, the magnitude of these benefits of human lactation, by and large, has not been afforded appropriate prominence in either health-professional education or the specialist's medical literature (for example, ref. 5).

Successful lactation requires the development of fully functional mammary glands. Whereas other major organs are morphologically and functionally relatively mature at birth, the mammary gland undergoes very limited structural development in utero, with the most dramatic changes in women occurring during puberty, pregnancy, lactation, and weaning [6]. The latter three stages (pregnancy, lactation, and involution during and after weaning) form the phases of the lactation cycle (fig. 1). This cycle can vary greatly in length from a little over nine months to many years, and it may be repeated many times, depending on female fecundity.

TABLE 1. Functions attributed to breastfeeding and breastmilk

Foetal development

A comprehensive investigation of the foetal development of the human mammary gland was carried out by Dawson in 1934[7]. It was observed that a mammary band (milk streak) appeared as a raised portion of ectoderm on either side of the midline, extending from the axilla to the groin of the human embryo by about the fourth week of intrauterine life. This band contains a narrow ribbon of raised epithelial cells known as the milk line (mammary ridge). Whereas the mammary band generally disappears, the milk line diminishes in length from its caudal end, and the cranial extremity thickens into a small nodule of ectodermal cells in the thoracic region at about 6 to 7 weeks of age. The nodule composed of epidermal cells then sinks into the underlying mesenchymal tissue to form a mammary bud. By 12 to 16 weeks, the overlying skin no longer protrudes, allowing the formation of an indentation that ultimately forms the areola and nipple. From this time to birth, the mammary gland anlage buds to form a number of solid cords, which traverse the underlying mesenchymal and subcutaneous tissue. These cords branch and become canalized to become ducts at 20 to 24 weeks after conception. At the end of gestation, Russo and Russo [6] observed the development of very primitive lobular structures composed of ducts ending in short ductules, lined by one layer of epithelial cells and one layer of myoepithelial cells. The epithelial cells had fine cytoplasmic vacuolization containing lipid droplets and apocrine secretion, which was not confined to the primitive alveolar structures.

Although the endocrine control of foetal mammary gland development is poorly understood, the higher levels of androgen in male than in female foetal rats have been associated with the suppression of mammary development in the male foetus, and the administration of steroid hormones to pregnant mice and rats can induce abnormal mammary development in their offspring (see ref. 8). These findings strongly suggest that more attention should be given to the foetal environment as a potential cause of subsequent lactation failure.

FIG. 1. Breast development and the lactation cycle

Pre-pubertal development

"Witches' milk" is one of the very few pre-scientific terms still in current use and refers to colostrum-like fluid [9,10] that is secreted from the nipples of newborn infants. It was thought that infants secreting this "milk" were possessed by witches, and these infants were not favoured. It is now clear, however, that this is a normal transient event, as secretion can be expressed from the nipples of most infants by seven days after birth, and involution of the neonatal mammary gland is complete by eight weeks postpartum [10]. Throughout childhood, only isometric growth of the breast occurs, with limited elongation and branching of the ducts [7].

Pubertal development

In humans, unlike other mammals, extensive positive allometric growth of the breast occurs at puberty. From 10 to 12 years of age, girls enter puberty and, over time, develop to sexual maturity. Three phases of puberty have been identified: thelarche (commencement of breast development), pubarche (growth of pubic hair), and menarche (start of menstruation).

At thelarche, the ovaries of the immature female start to secrete oestrogen, which initiates positive allometric growth of the primitive mammary structures. The mammary ducts elongate and extend their epithelial lining, branching dichotomously, resulting in the formation of a branched, treelike structure that extends from the nipple into the mammary connective tissue. In addition, terminal buds form on the ducts in preparation for the development of alveolar and lobular tissue structures.

During thelarche, mammary elasticity, vascularization, connective tissue volume, and fat deposition increase [6], leading to the development of the characteristic shape of the mature human breast [11]. Compared with other mammals, mammary growth in pubescent girls is far in excess of the development required for subsequent successful lactation, and therefore it has been suggested that this growth is not related to lactation but rather provides an indicator of sexual maturity.

During puberty there is accelerated growth of the nipple and development of subareolar tissue leading to the elevation of the areola and nipple. About 15 to 25 lactiferous ducts lead to each nipple from discrete lobes within the mammary parenchymatous tissue. These lactiferous ducts may merge within the nipple so that the number of ductal openings is less than the number of lactiferous ducts. The lactiferous ducts dilate at the base of the nipple to form milk sinuses, which, during lactation, accumulate milk drained from the lobes. Unlike other mammals, the lobes of the human mammary gland are separated by deposits of adipose tissue, and the proportion of adipose to secretory tissue varies between individuals. Each lobe is subdivided into lobules that, in turn, are composed of 10 to 100 alveoli. The alveoli are lined with a single layer of lactocytes (mammary secretory epithelial cells) surrounded by starlike myoepithelial cells, a basement membrane, and a network of blood capillaries [9,12].

Under the cyclic influence of ovarian oestrogen and corpus luteal progesterone, as well as the presence of other metabolic and growth-promoting hormones [8, 12], the mammary glands are stimulated to grow. From three to four days before the onset of menstruation, women may experience swelling, tension, fullness, tightness, heaviness, and pain in their breasts [9]. Fluid retention in the connective tissue and enhanced ductular and lobulo-alveolar tissue growth increase breast volume by 30 ml [6, 9] to 100 ml [13]. Increases up to a doubling of breast size have been observed in some women. After menstruation the mammary gland is characterized by some apoptosis, with minimum breast volume occurring five to seven days post-menstrum [6]. Mammary involution following menstruation never completely returns the mammary gland back to the previous premenstrual morphology and, hence, allows the mammary parenchyma to develop, albeit gradually, during successive menstrual cycles [6] until women reach about 30 years of age. In spite of the functional responsiveness of the breast to stimulation [12], little information is available on breast development in relation to the commencement of sexual activity.

Lactation cycle

The lactation cycle begins at conception (fig. 1). During the lactation cycle, there is further growth of the breast (mammogenesis), the initiation of milk synthesis and secretion (lactogenesis 1 and lactogenesis 2), lactation (galactopoiesis), regression of the breast during and after weaning (involution), and relative quiescence during subsequent menstrual cycles.

Mammogenesis

The mammary gland develops the histologic and biochemical capacity to synthesize and secrete milk during pregnancy. Histologic studies have separated mammary development during pregnancy into two distinct phases: mammogenesis and lactogenesis 1. Mammogenesis occurs from early pregnancy and is characterized by proliferation of the distal elements of the ductal tree, creating multiple alveoli (acini) of variable size and shape [14]. Lactogenesis 1 occurs in the later stages of pregnancy and is characterized by the differentiation of resting mammary cells into lactocytes, with the potential to secrete the unique fats, carbohydrates, and proteins characteristic of milk [15].

Initially, mammary development during pregnancy appears to be an acceleration of the parenchymal hypertrophy associated with the menstrual cycle. Indeed, an increase in the sensitivity and tenderness of the breast, and nipple sensitivity in particular, is often one of the first indications of pregnancy, and this can occur within a few days of conception and before the due date of the next menstrual period. Thus, the factors initiating mammogenesis at this time must be closely related to those responsible for the mother's recognition of her pregnancy. Subsequently, the subcutaneous veins become enlarged and visible through the skin, and the areola usually enlarges and becomes more darkly pigmented [14]. Extensive lobulo-alveolar growth occurs during the first half of pregnancy, and in the third trimester there is a further increase in lobular size associated with hypertrophy of the lactocytes and the accumulation of secretion in the lumina of the alveoli [6].

Although there is little precise information on the hormonal control of mammary development in women during pregnancy, the changes in the patterns of circulating hormones are now well established. The implantation of the blastocyst in the uterine wall is associated with the secretion of human chorionic gonadotrophin (hCG), which maintains and increases the steroidogenic activity of the corpus luteum, until hCG secretion decreases at about 8 to 10 weeks of gestation. In the later stages of pregnancy, the maternal serum concentrations of progesterone and oestrogens are increased by de novo synthesis in the placenta [16].

In classical studies on ovariectomized-hypophysectomized-adrenalectomized rats and mice, Lyons [17] and others have shown that ductal mammogenesis is promoted by oestrogens, growth hormone, and corticosteroids. In addition, lobulo-alveolar development occurred at maximal rates in the presence of oestrogen, progesterone, prolactin, growth hormone, corticosteroids, and placental lactogen. Studies on isolated human mammary tissue in culture suggest that insulin, cortisol, growth hormone, prolactin, oestrogens, progesterone, and epidermal growth factor (EGF) are involved in the proliferation and differentiation of human mammary cells in tissue culture [18-22]. Relaxin has been implicated in the proliferation of porcine mammary parenchyma [23]. The action of oestrogen and progesterone on mammary parenchyma leads to the secretion of EGF and transforming growth factor-a (TGF-a), both of which are potent mammary mitogens [22]. In contrast, TGF-b₁ inhibits mammary growth [22, 24, 25]. These studies imply that the development of the human mammary gland during pregnancy is controlled by a complex sequence of stimuli and inhibition similar to the hormonal mechanisms that control the growth and development of the mammary glands of common laboratory animals.

Hytten [26] used a water-displacement technique to measure the volume of the left breast of 11 women at three months of gestation and seven days postpartum. In 10 women breast volume increased by 60 to 480 ml, and in one woman the volume decreased by 20 ml. The relationship, however, between breast volume at the end of pregnancy and the volume of the "empty" breast on the seventh postpartum day is unknown. We [27] have developed a computerized breast measurement (CBM) system that uses video images of structured light stripes projected onto the breast to quantitate both long-term (throughout the lactation cycle) and short-term (during the day) changes in breast volume (figs. 1 and 2). Preliminary findings for breast development (fig. 3) from preconception until just before delivery [28] have demonstrated that significant growth can occur during the first trimester and that this growth can either continue throughout pregnancy or reach a plateau during the second trimester. The six mothers studied to date have had a successful lactation outcome irrespective of their pattern of breast growth during pregnancy.

Lactogenesis 1

The timing of lactogenesis 1 (development of potentially functional lactocytes) in women has not been precisely defined. In mid-pregnancy the true lobulo-alveolar system develops, the proliferative changes are reduced, and there is increasing cellular differentiation with the accumulation of cellular organelles and secretory products [6, 15, 29]. Lactose is the most osmotically active component of the colostrum, and hence excess lactose synthesis during pregnancy could lead to breast distension. Nevertheless, the tight junctions between the lactocytes are open during pregnancy, and thus lactose can escape across the mammary epithelium into the bloodstream and then be excreted in the urine. The concentration of lactose in the blood of pregnant women increases during mid-pregnancy [30], and this coincides with an increase in the excretion of lactose in the urine [28, 31]. These findings suggest that in women lactogenesis 1 occurs approximately halfway through pregnancy. Studies using an increase in the concentration of lactose in the blood or mammary secretion as an indicator of the occurrence of lactogenesis 1 have suggested that lactogenesis 1 occurs at different stages of pregnancy in different species. Whereas lactogenesis 1 occurs in late pregnancy in rats [32], ewes [33], and sows [34, 35], it occurs earlier in pregnancy in cows [36], goats [37], and women [30]. These species differences in the timing of lactogenesis 1 during pregnancy make it difficult to speculate on the control of the development of the functional lactocyte. A greater knowledge of the control of mammogenesis and lactogenesis 1 in women is important not only for the understanding of normal lactation, but also because early pregnancy [13] and lactation [38] have been associated with a reduced risk of breast cancer.

Lactogenesis 2

Whereas the umbilical cord couples the developing foetus to continuous life support from its mother's placenta, nursing after birth provides the growing infant with comparable but intermittent life support from its mother's breasts. Thus, it is essential for the breast to develop its unique synthetic capacity during pregnancy, so that the initiation of an adequate supply of milk accompanies the birth of the infant. The occurrence of lactogenesis 1 halfway through pregnancy in women permits lactogenesis 2 to occur, even if the infant is delivered prematurely, although the milk composition is different from that of full term mothers, possibly because of incomplete hypertrophy of the mammary gland or incomplete exposure to prolactin and other hormones [39].

FIG. 2. Computerized breast measurement system assessment of function for right and left breasts of two mothers (A and B) over 24 hour periods. The degree of fullness is the volume of the breast at the end of a breastfeeding minus the minimum volume of the breast during the 24-hour period, divided by the storage capacity of the breast, expressed as a percentage. The rate of milk synthesis is calculated from the difference between the breast volume at the end of a breastfeeding and the breast volume just before the beginning of the next breastfeeding, divided by the time between the measurements [60]

In women the control of lactogenesis 2 (the initiation of copious milk secretion) appears to be under endocrine regulation similar to that in other mammals. The pioneering work of Kuhn [40] established that progesterone withdrawal was the trigger for lactogenesis 2 in the rat, and subsequently Nicholas and Hartmann [32] established the temporal relationship between the withdrawal of progesterone approximately 24 hours before parturition and the increased rate of lactose synthesis (a measure of lactogenesis 2) coinciding with birth. This pattern appears to be consistent for most mammals studied to date.

In women, however, progesterone withdrawal is delayed until after the delivery of the placenta; thus, there is a frame shift to the post-partum period in the dose temporal relationship between the fall in progesterone and the increase in the concentration of lactose in the colostrum [41].

Lactogenesis 2 is delayed by more than a day to between 30 and 40 hours post-partum (fig. 4). Although this delay may seem inconsistent with the perceived energy requirements of the human infant, it is consistent with the acquisition of mucous membrane protection from maternal colostrum, as well as the remarkable resilience of the human neonate to nutritional abuse and the unusual weight loss m human infants after birth.

FIG. 3. The development of the left breast of one mother depicted by models generated using the computerized breast measurement system

Lactogenesis 2 also occurs 30 to 40 hours after delivery in mothers who have had a Caesarean section [42], since the timing of placenta removal in relation to birth is the same as in those who delivered normally. This is fortunate for human lactation, as Caesarean section delivery in other species, such as ewes, results in a delay in lactogenesis 2 of more than a day when compared with normal delivery [33].

The involvement of the placenta in the initiation of lactation has been further substantiated by the finding that if a fragment of placenta is retained after delivery, lactogenesis 2 occurs only after its removal [43]. These observations also are consistent with progesterone withdrawal acting as the trigger for lactogenesis 2 in women, as it does in other mammals.

Although lactogenesis 2 in women does not require either the suckling stimulus or milk removal [44], it does require the presence of adequate concentrations of lactogenic hormones. The concentration of prolactin in a woman's blood is high at parturition, and suppression of prolactin secretion by the administration of bromocriptine results in the inhibition of lactogenesis 2 [44]. Nevertheless, undesirable side-effects and the potential role of prolactin in facilitating maternal behaviour have cautioned against the use of this drug for the suppression of lactation in women who choose not to breastfeed.

Close assessment of the initiation of lactation in mothers with type I diabetes shows that the increase in the concentration of lactose in the colostrum is delayed by about 24 hours compared with normal mothers [45-47]. Since this delay coincides with the reduction in insulin therapy after birth and the reestablishment of control of glucose homeostasis, permissive amounts of insulin also may be required for lactogenesis 2. Notwithstanding this delay, diabetic women with perseverance can establish successful lactation.

Milk "coming in," which is sensed by mothers as a sudden enlargement of their breasts with milk, is a post-lactogenesis 2 event occurring two to three days after delivery [42]. The physiological significance of the sensation of milk coming in is not clear, but it may represent the time when the mother's capacity to synthesize milk first exceeds the infant's appetite. That is, it may represent the transition from an endocrine-promoted lactogenesis 2 to another form of control during established lactation. Despite these considerations, severe engorgement can be associated with milk coming in, and this is a very painful event of short duration but long remembered by mothers. The risk of severe engorgement is reduced if mothers avoid timed schedules for breasfeeding and fully breastfeed their babies to appetite, day and night, from birth. The implications for lactogenesis 2 and milk coming in are important when considering the design of programmes for the early discharge of mothers from maternity hospitals [48].

FIG. 4. Peripartum milk lactose expressed as a percentage of the maximum lactose concentration for the cow, rat, and woman

Galactopoiesis

The maintenance of galactopoiesis appears to be under a combination of endocrine, autocrine (local), and metabolic control, which varies according to the species and the stage of lactation. The relative importance of these mechanisms, however, depends on whether the species has been selected for dairy production. Nevertheless, the removal of milk from the mammary gland is of the utmost importance for the maintenance of milk secretion in all mammals. In women, frequent suckling not only stimulates the release of oxytocin and thereby elicits milk ejection, but also stimulates the release of prolactin [49] and results in the removal, inactivation, or both of local inhibitory factors [50].

The finding in the early 1970s that the sucking stimulus evoked the release of prolactin [49] provided a potential explanation for the regulation of milk synthesis. We have not, however, found any relation between the suckling-evoked release of prolactin and milk yield. Although the prolactin response decreases in later stages of lactation, there is no decrease in milk yield [28]. Therefore, the concept that demand feeding regulates the rate of milk synthesis by evoking the release of prolactin must be seriously questioned.

About 20 years ago, it was generally accepted that the nutrition of the mother was the most important determinant of milk synthesis. This assumption was based on numerous studies demonstrating the dependence of milk production on the level of nutrition in dairy cows and goats. As a result, it was concluded that feeding the malnourished mother would thereby feed the child [51]. Nevertheless, subsequent studies by Prentice et al. [52] have shown that improving the nutritional status of malnourished mothers does not increase milk production. This, together with extensive studies on milk production in women from both developing and developed countries, has led to the conclusion that maternal nutrition is not an important determinant of milk production in women (see ref. 53).

The demand-fed infant consumes irregular quantities of milk at irregular intervals during the day [53]. These feeding patterns also are consistent with mothers' awareness [54] and with recent studies that indicate that it is the baby's appetite that determines milk yield [53]. Indeed, a comprehensive consideration of the literature leads to the conclusion that ensuring that the infant has sufficient access to the breast to satisfy its appetite for milk optimizes milk production. The basic question, however, remains: How does the breast regulate milk synthesis to meet this unpredictable external demand for milk by the infant?

In 1984 Neil Matterson [55] provided a practical answer to this question: "The more he cries the less milk he drinks, so less milk is produced, so there's less for him to drink, so he cries because he didn't get a drink. Do you understand that?" Perhaps this confusing explanation of the control of milk synthesis underlies epidemiologic results showing that many mothers give up breastfeeding in the belief that they cannot produce enough milk for their babies [56].

A prerequisite for investigating the control of milk synthesis during galactopoiesis in any suckling mammal is to measure the rate of milk synthesis accurately. The classical means of determining the daily rate of milk synthesis in women has been the "weigh-suckle-weigh" or "test-weighing" method [57], which conventionally records the combined milk output from both breasts and sums the milk consumed during all breastfeedings over a period of 24 hours. If correction is made for evaporative water loss during each breastfeeding, test weighing is a very accurate method of determining milk transfer between the mother and her infant [58]. But neither test weighing nor alternative methods of measuring milk production [59] measure the short-term (between breastfeedings) rates of milk synthesis in individual breasts.

Our CBM system measures the short-term rates of milk synthesis in women by determining the rate of increase in breast volume between breastfeedings [27]. We installed the CBM system in the homes of seven mothers so that we could measure their milk production and changes in breast volume while they breastfed on demand in their normal environment. In addition to the short-term rate of milk synthesis, we were able to calculate two new parameters for the assessment of breast function from the progressive changes in breast volume over the 24-hour period. First, the storage capacity of the breast was calculated, that is, the demonstrated capacity of the breast to store milk that was available to the infant. This was calculated as maximum breast volume minus minimum breast volume observed over the 24-hour period [60]. Second, the degree of fullness of the breast was calculated as the volume of the breast at the end of a breastfeeding minus the minimum volume of the breast during the 24-hour period, divided by the storage capacity of the breast. Thus, the degree of fullness varied from one when the breast was full to zero when the breast was empty.

To illustrate our findings using the CBM system, the results for two of the seven mothers who participated in this study [60] are presented (table 2 and fig. 2). Mothers A and B were fully breastfeeding their babies and had similar levels of milk production: 912 and 950 g/24 hours, respectively. Nevertheless, as with most other women we have studied, this production was not divided equally between the mother's breasts, emphasizing the importance of investigating the regulation of milk synthesis in individual breasts rather than in individual women.

TABLE 2. Computerized breast measurement system assessment of breast function for two mothers

Source: ref. 60.

A detailed review of the results of our investigations of human lactation over the 24-hour period using the CBM system is given by Daly and Hartmann [61], and a summary of our observations and conclusions is given in table 3. These studies clearly demonstrated that the infant's appetite determined the milk intake at a particular breastfeeding. The breast storage capacity varied greatly between women (table 2), and this factor significantly influenced the breastfeeding frequency required to maintain an adequate milk supply. In addition to these observations, we were unable to show a relation between the increase in blood prolactin at a breastfeeding and the subsequent rate of milk synthesis between breastfeedings [62]. Furthermore, the short-term rates of milk synthesis of a woman's right and left breasts often responded independently from breastfeeding to breastfeeding. For example, after the first feeding, the milk synthesis rate of the right breast could be higher than that of the left breast, but after the next feeding, the reverse could be true, with the left breast now showing the higher rate of milk synthesis.

The negative relationship between the degree of breast fullness and the short-term rate of milk synthesis (fig. 2) was of particular interest. In this respect, the right breasts of mothers A and B represent two extremes. Mother A, with a large storage capacity, had high rates of milk synthesis when her breast contained the least milk (fullness approximately zero) and low rates of milk synthesis when her breast was nearly full (fullness approximately one). In contrast, mother B. with a small breast storage capacity, achieved a high level of milk production by more frequent breastfeedings with relatively consistent short-term rates of milk synthesis, as her degree of fullness was low after each breastfeeding.

TABLE 3. Observations and conclusions from computerized breast measurements of the circadian changes in breast volume in lactating women

Our results for women are consistent with the autocrine theory of milk synthesis control during established lactation, which has been recently proposed for dairy goats by Peaker and Wilde [50]. These workers have isolated a protein called feedback inhibitor of lactation (FIL) that appears to suppress milk synthesis as milk accumulates in the mammary gland between breastfeedings by reversibly inhibiting the transfer of newly synthesized protein from the endoplasmic reticulum to the Golgi vesicles.

We also have shown that the difference in the fat content of breastmilk between the beginning and the end of a breastfeeding is related to the degree of fullness of the breast, rather than to whether it is either fore or hind milk [63]. Furthermore, Heesom et al. [64] have demonstrated that medium-chain-length fatty acids inhibit glucose metabolism and lipid synthesis in isolated mammary acini of rats. The presence of lipases in breastmilk and the nature of the accumulation of triacylglycerol in the alveolus suggest that autocrine control of milk fat synthesis by free fatty acids also is mechanistically plausible in lactating women [65]. In vitro studies have shown that free fatty acids may act as messenger and modulator molecules, mediating responses of the cell to extracellular signals [66].

A further interesting development arises from studies by Molenaar et al. [67]. They used ³⁵S-labelled cRNA probes to localize the sites of a-lactalbumin, a-S1-casein, and lactoferrin mRNA synthesis in sheep. Early in lactation, mammary gland expression of a-lactalbumin and a-S1-casein was high in some alveoli but not in others. Those alveoli with high expression of a-lactalbumin and a-S1-casein contained few fat globules in their cells and lumina, whereas those in which expression of these proteins was absent contained abundant fat globules. These latter alveoli also almost exclusively expressed lactoferrin. These findings suggest that milk secretion either is heterogeneous across lobules or occurs sequentially with time in the alveolus as newly secreted milk accumulates. The latter concept seems more plausible.

It is tempting to speculate that the FIL and free fatty acids may act locally to sequentially regulate the short-term rates of milk constituent synthesis, either within a mammary gland or, more likely, within lobules according to the degree of emptying of the lobules in each breast.

Involution

Studies of lactation in village women and the few remaining hunter-gatherer societies suggest that the normal duration of lactation in women is three to four years. In these societies, and more recently in a number of developed countries, weaning is prolonged and gradual (that is, child-led weaning). The cessation of sucking results in distension of the gland with milk and atrophy of the epithelial structures. Finally, milk secretion is greatly suppressed, and the lactocytes disintegrate and desquamate. Phagocytosis of the degenerated alveoli reduces the lobulo-alveolar structures, and ductal systems become predominant. It seems that the involution of the human breast occurs much more gradually than that of the mammary glands of other mammals [68], and this may explain the relative ease of relactation in women.

Acknowledgements

We would like to thank the mothers who kindly volunteered for our studies and the Nursing Mothers' Association of Australia. The work from our laboratory was supported by the National Health and Medical Research Council of Australia.

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