Local Regulation Of Milk Production Biology Essay

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Lactogenesis is a series of cellular changes that can convert mammary epithelial cells from a non secretory state to a secretory state. Lactogenesis process is normally associated with the end of pregnancy and during the time of child birth. Mammary gland develops the capacity to make milk during the late pregnancy, but normal milk secretion does not take place until near parturition. Galactopoeisis is defined as the maintenance of lactation once lactation has been established. The changes in mammary cell numbers (by growth or by cell death) and in milk yield per cell are regulated by both galactopoietic hormones and local mammary factors. The role of milk removal complicates interpretation of the hormonal requirements for milk synthesis. Without frequent emptying of the mammary gland, milk synthesis will not persist in spite of adequate hormonal status. Conversely, maintenance of intense suckling or milking stimulus will not maintain lactation indefinitely. Nevertheless, suckling or actual removal of milk is required to maintain lactation [1]

Milk secretion is mainly coordinated by systemic and local feedback mechanisms. Infants can induce prolactin and it is considered as the major positive feedback that produce increased milk secretion in most animals. Both systemic and hormonal factors acts together and regulate alveolar distension, milk synthesis and milk secretion [2]. Mammary glands which are unsuckled gradually stop milk synthesis and undergo partial involution. In humans and rodents, this partial involution causes loss of epithelial cell mass and massive apoptosis. But in dairy cattle, the glands become stagnant during involution and there is no apoptosis condition [3, 4]. The mechanisms involved in milk stasis and involution have not been confirmed, but studies revealed the presence of a feedback inhibitor of lactation compound in milk and these factors decreased milk yield and milk protein synthesis. Regular removal of milk from the mammary gland is essential for the maintenance of milk production and the frequency of milk removal is positively related with milk yield [5, 6]. Milking frequency has significant influence in the milk yield and it was observed that a reduced milking frequency resulted in an immediate decrease in milk yield. Increasing milking frequency during early lactation produced an increase in milk yield that persisted even after lower milking frequency was resumed [7, 8].

Local Control of Mammary Development and Function:

Mammary development and functions are controlled by various hormones. Mammary development is mainly influenced by a variety of steroids and polypeptide mammogens mainly including oestrogen, progesterone and placental lactogen. After the development of mammary glands, lactation process also controlled by numerous hormones, mainly prolactin and growth hormones [9]. There are no prominent evidences to prove that all these hormones can show direct influence on mammary epithelial cells and studies proves that most of these hormone actions are indirectly mediated through local regulation mechanisms. During the period of lactation, growth hormone receptors are not present on mammary glands and it shows that growth hormone action is mediated by increasing the local production of Insulin-like growth factor I (IGF-I) by stromal cells within the mammary gland [10]. IGF-I control the lactation through a passive response that is entirely different from hormonal regulations and perform as a genuine local regulator. Silberstein et al [11] conducted experiments in young mice by implanting anti-oestrogen and found that ductal growth of mice were inhibited in the region of implant. These experiments proved the presence of a mechanism that is inherent to an individual mammary gland and in the absence of external stimuli; this local mechanism can independently regulate the development or function of that mammary gland.

The mammary gland has a complex structure consists of a number of cell types and an extracellular matrix that is responsible for regulatory input [12]. But the most significant feature of the mammary gland is that much of the time the gland is full of its own secretion and this is an unusual characteristic among endocrine glands. But mammary glands of all species shared this feature to a greater or lesser extent. Milk contains a considerable number of bioactive factors [13] and these factors may be interacting with the apical membrane of the secretory cells. Any influence produced by the interaction between these bioactive factors and apical membrane would clearly be local since the alveolar lumen is isolated from external stimuli such as endocrine signals. Christopher H. Knight et al explained that local control is basically used to describe a mechanism that is intrinsic to an individual mammary gland and in the absence of external stimuli; they regulate some aspects of the development or function of that gland independently.

Maule Walker and Peaker [14] conducted studies in pregnant goats which are approaching parturition. In this stage the mammary glands of goats will be ready for secretion and will contain a small quantity of prepartum fluid, but there is no active secretion. If one gland is milked for few days to remove prepartum fluid, only that gland can secrete considerable amount of milk. In lactating goats, if one gland is milked more frequently than other glands, the milk yield of that gland increase significantly [15] and a reduced milking frequency in one gland can cause a drastic decline in milk secretion in that gland. These observations support the concept of local control of both milk secretion (lactogenesis) and maintenance of lactation (Galactopoeisis).

Local Control of Lactogenesis:

The onset of milk secretion during the period parturition is a complex process which requires a combination of hormonal changes. At or around parturition, progesterone level is decreased with increased prolactin and glucocorticoids. During the lactogenesis period, the synthesis of milk components increases rapidly and tight junctions become really tight to prevent paracellular ionic flex. Linzell and Peaker started milk a single gland of goats during the last 3 weeks of pregnancy to study the cellular control of ion movement in to milk. The composition of milk gradually changed during the last stages of pregnancy with expanded tight junction. These changes were visible only in the previously milked glands and the unmilked gland was not at all affected by these changes. After the childbirth, milked gland started secreting mature milk, while the unmilked gland was secreting colostrum. From these observations it is clear that a local feedback mechanism within the gland plays an important role in lactogenesis and the removal of those local inhibitors by frequent milking before parturition can increase the milk yield. Further studies revealed that mammary gland of the late pregnant goat was secreting both oestradiol and prostaglandin F2a (PGF2a) and its metabolites [14]. But the inhibitory action of PGF2a is comparatively week and it can partially inhibit lactogenesis for a short period of time [14].

Local Control of Milk Secretion:

Milking frequency has a direct influence on the rate of milk secretion and it is proved that milk yield can be increased by increasing the number of milking. Even in human lactation, milk secretion is directly correlated with the milking frequency [16]. In dairy farms, the usual milking frequency is two times a day. Pool suggested that three times milking a day can increase milk yield by about 10% [17] and milking a day decreased milking yield by up to 20% [18]. There are number of studies have conducted to explain the real mechanism which can increase milk secretion with an increase in milk frequency. As a part of studies continuous milking was performed on only one gland and the increased milk secretion was limited to that gland. This effect was greatly visible once the milked gland was denervated. Without milk removal, manual stimulation failed to produce milk ejection reflex and it was not useful to increase the milk secretion rate. From all these observations it is clear that milking frequency has significant influence on the rate of milk secretion. Frequent milking can eliminate the pressure within the mammary gland is the most common explanation for the frequent milking response.

Mammary gland is considered to be inactive before milking and milk accumulates inside the mammary gland during this period of time. Once the milking is established, an intramammary pressure is created to regulate the balance between synthesis and secretion. By measuring the blood flow, oxygen consumption and intramammary pressure within mammary gland and comparing these measurements with the secretory rate have given much evidence to conclude that pressure can inhibit milk secretion but not until 24hr after milking. Once pressure has reached at some point, blood flow is restricted by producing an inhibitory effect on milk secretion. Further increase in pressure can produce considerable loss of epithelial integrity and breakdown of tight junctions followed by ionic imbalance [19]. High pressure can induce loss of tight junction integrity and which can cause the inhibition action of milk secretion. But pressure induced inhibition is limited and scientists assumed that there will be another mechanism which can explain the acute regulation of milk secretion. When one gland of goats milked three times a day, the volume of removed milk was replaced by an equivalent volume of iso-osmotic sucrose to maintain its pre milking intramammary pressure value. The interesting fact is that the stimulatory effect of extra milking was clearly visible even after the intramammary pressure is maintained [20].

Sucrose can infuse into unmilked gland to dilute the bioactive components of stored milk and this mechanism can increase the secretion rate [20]. Wilde et al infused partially purified milk whey extract in to mammary glands and observed that milk secretion was reversibly inhibited [21]. All these primary observations are not supporting the pressure hypothesis and revealed that no local neuronal reflexes are involved in this regulation mechanism [22]. Svennersten et al agreed with the concept of Linzell and Peaker [23] who has proposed the possibility of a chemical inhibitory mechanism.

Feedback mechanism:

An in vitro study conducted by Wilde et al observed that milk fat or milk casein is not producing any specific inhibitory action [22]. They reported that milk whey proteins of nominal size are involved in specific inhibitory activity. The effect produced by 10- 30 kDa whey proteins was rapid and reversible and this way protein fraction can induce the same inhibitory activity was also effective in vivo. Wilde et al purified the 10- 30 kDa fraction using anion exchange chromatography and produced a single protein fraction that can show inhibitory activities to both casein and lactose synthesis (wilde et al95) and called feedback inhibitor of lactation (FIL). FIL or analogous proteins are found in milk from goats [24], cows [25] and humans [26]. After the analysis of the content taken from the lumen, the presence of FIL was visible in lumen content at a noticeably higher concentration than in the culture medium [27]. Milk present in alveolar lumen is only associated with secretory cells, and thus it is clear that FIL are produced by the secretory cells. So, FIL can apply its action on the same cells that produced it and this mechanism is considered as truly autocrine.

Action of feedback inhibitor of lactation:

Henderson and Peaker suggested that frequent drainage of milk from the udder cistern do not produce increases milk yield. Only frequent milking can produce a favorable increase in the milk yield [20]. FIL action is found mainly within alveolar tissue and the accurate action site must be the apical surface of the secretory cell. Rennison et al [28] suggested that the action of FIL occurs at early stages of protein secretory pathway and further pulse-chase experiments shows that FIL inhibits the trafficking of radiolabelled proteins through Golgi apparatus. The later stages of secretory processes were not influenced by FIL action. Once FIL is added in to the culture medium, the morphology of Golgi and endoplasmic reticulum were considerably affected and the protein secretion was drastically reduced. But after the removal of FIL, the culture medium regains its original stage within one hour and protein secretion becomes normal.

Normal milking does not remove all milk from the gland and remaining milk will be within the secretory alveoli. So, FIL will be present in the gland even after each milking with the residual milk. Dewhurst (1994) explained that a portion of milk should be present in alveoli at one hour after milking and it suggest that the secretory cell is always exposed to FIL. Concentration dependent FIL mechanism is not well studied and scientists believed that some kind of mechanism must be there to reduce the concentration of FIL in residual milk soon after milking. Wilde et al found the existence of multiple forms of the biological inactive molecules and from these observations it can be predicted that FIL may be secreted in an inactive form and it can become active within the alveolar lumen or an active form of FIL can be secreted and metabolized to inactive forms after milking. Milk secretion is a continuous process and after each milking, newly synthesized milk is distributed between secretory tissue storage and cisternal storage [29]. The action of FIL is manly based on secretory cells and FIL will be highly active when the milk content in the secretory tissue storage is higher than that of cisternal storage. Animals with large cistern are able to produce more milk than those with a small cistern.

Serotonin as a Feedback Inhibitor of Lactation in the Bovine:

Stimulation of milk synthesis by PRL can be suppressed by the introduction of negative feedback inhibitors such as suppressors of cytokines Signaling (SOCS) genes [30]. There are many other feedback inhibition mechanisms are present within the gland that regulate milk production. Tryptophan hydroxylase 1 (TPH1) is an enzyme which catalyzes the rate-limiting step in serotonin biosynthesis [31]. Studies proposed that serotonin produced by the action of TPH1 can act as a feedback inhibitor of lactation [32]. Serotonin (5-HT) is a hormone and neurotransmitter synthesized from L-tryptophan. Serotonin can resist endocrine stimulation of mammary development and milk secretion by acting as a feedback inhibitor of lactation [32]. Recent studies conducted by Matsuda et al observed that prolactin can induce biosynthesis of 5-HT in rodent mammosphere culture and b- casein mRNA expression can be suppressed by an external addition of 5-HT. Previous studies carried out by Zia et al have reported that 5-HT was present in cow milk [33]. 5-HT can act as vasoconstrictor in mammary gland [34] and it can cause constriction of the smooth muscle in teat wall [35]. In spite of all these factors, no evidence are available to support that serotonin has influence on milk yield.


Regular milking is important to maintain milk secretion. Early studies proposed that milking frequency can influence the mammary blood flow as well as mammary cell number and activity. Recent studies proposed the possibility of another mechanism in which the milk secretion was regulated locally within the mammary gland. Furthermore, increased milking frequency during early lactation stimulated an increase in milk yield. The local mechanism involved in the regulating the mammary response to increased milking frequency is poorly understood. But the understanding of feedback inhibitor of lactation provides information about this phenomenon. Regular removal of these inhibitory factors from mammary gland through milk is important for further milk secretion and frequent milking can increase milk yield by removing inhibitory components from the gland.