Local homeostatic mechanisms maintain galactopoiesis in the human mammary gland

What is galactopoiesis?

Galactopoiesis is maintenance of milk production after secretory activation. Galactopoiesis can be conceptualised as a homeostatic process. Homeostasis is the self-regulating biological mechanism by which complex adaptive systems maintain stability amongst interdependent elements. Multiple feedback loops are constantly adjusting to changes, both internal and external, in order to maintain homeostasis.

• You can read about complex adaptive systems and NDC here.

• You can also read about complex adaptive systems here.

The metabolism of the mammary gland is unique amongst human exocrine glands for two reasons: milk secretion is continuous, and the milk is stored in the alveoli (with only small amounts of milk stored in the ducts).

It's agreed in the research literature that to ensure a continous and optimal supply of breast milk, galactopoiesis requires a complex interplay of

• Hormones

• Milk removal

• Genetic factors

• Other factors including

  • Basic nutrition

  • Hydration

  • Supportive environment.

It's also widely agreed in the research literature that milk removal is the fundamental driver of galactopoiesis. It's widely agreed that the homeostasis of galactopoiesis is a balance between mammary epithelial cell apoptosis and stem cell differentiation and proliferation. From the NDC perspective, galactopoiesis in the human mammary gland is a complex adaptive system in a state of dynamic equilibrium or homeostasis.

• In maintenance and upregulation of milk secretion, cell proliferation is dominant, although cell apoptosis constantly occurs.

• In downregulation of milk secretion, cell apoptosis is dominant, although cell differentiation and proliferation also constantly occur.

Endocrine control (systemic hormones)

A quick overview of endocrine control

Galactopoiesis is unable to proceed without elevation of specific systemic hormones from the hypothalmic pituitary axis, which maintain the mammary gland in a secretory state. These hormones include prolactin and oxytocin.

• Three hypothalmic nuclei communicate with hypophyseal portal vessels, releasing prolactin, growth hormone and IGF-1. These hormones respond to milk removal.

• Production of ACTH (signalling the adrenal gland to result in cortisol secretion), TSH (signalling the thyroid to result in T3/T4 secretion), and also FSH, LH (signalling the ovary), + oestradiol and progesterone are critical to development of tissue and production of milk.

The endocrine control of breast milk production will be dealt with in greater detail in a different Lactation Module.

Endocrine secretions prepare the terrain but don't control milk yield

One way of thinking about these endocrine secretions is that they prepare the terrain. However, prolactin and oxytocin have little effect upon amounts of milk produced.

• Prolactin levels help build milk proteins systemically, but don't correlate with milk volumes. You can find out more about prolactin here.

• It's been shown in domestic species that oxytocin secretion won't maintain milk production if milk is allowed to accumulate in the glands for long periods of time. That is, unless there is milk removal, oxytocin secretion alone isn't enough to maintain production.

Pregnancy itself is not a prerequisite for the initiation of lactation. This has been understood for decades in the research literature (and indeed for millenia in traditional human cultures.) You can find out about induction of lactation here. For example

• Virgin ovariectomized goats can be brought into lactation simply by the application of the milking stimulus in the presence of a functional pituitary gland (Cowie et al 1968).

• Breast massage and suckling are successful in allowing women to breastfeed adopted babies (Brown 1977).

You can find out more about how endocrine secretions not only prepare the terrain but support ongoing upregulation of milk secretion here.

Autocrine or paracrine control (local control)

Autocrine signaling involves a cell signaling to itself, while paracrine signaling is cell-to-cell communication where a cell signals to nearby cells.

It can be taken as proven in the research literature that after secretory activation, the mammary gland itself controls the homeostatic process by which milk is produced, by autocrine and paracrine processes.

Two factors have been known from the 1960s in domestic species (with a focus on dairy cows), also confirmed in humans, to be critical to milk yield volumes. These are

1. The amount of milk removed from the alveoli lumens

2. Frequency of milk removal.

These two critical factors are not species dependent and are true in all mammalian species, including marsupials. Although these two factors are biologically fundamental to the success of Homo sapiens breastfeeding, the clinical implications remain poorly understood within our health systems.

Local homeostatic principle #1: Mammary epithelial cell proliferation needs to outpace cell death for optimal milk secretion

The mammary gland has a very high cell turnover because it is very metabolically active. Mammary epithelial cells (lactocyctes, myoepithelial cells, ductal mammary epithelial or luminal cells) are constantly dying - that is, becoming apoptotic.

When mammary epithelial cells die they either

• Shed into the milk (some live mammary epithelial cells also shed into milk) or

• Are mopped up by the stroma's inflammatory processes, which are part of the lactating mammary gland's healthy immune function. These inflammatory processes 'sweep' the stroma clean of cell and other debri. You can find out about the protective role of inflammatory processes in the human mammary gland here, in the Lactation module on Breast Inflammation.

Homeostasis in milk production requires that the number of cells resulting from cell proliferation remains higher than the number of cells which are dying or apoptotic. Other ways of saying this are that

• Having an ongoing milk yield which exclusively meets an infant's caloric needs depends on tilting this dynamic homeostatic mechanism towards cell proliferation, or

• An increase in frequency of milk removal increases the rate of cell proliferation compared to cell death so that cell proliferation dominates, generating more milk rather than less.

Local homeostatic principle #2: something acts to inhibit milk secretion when milk volumes rise in the mammary gland

The nature of this local feedback which inhibits milk secretion as milk volumes rise remains contested. Proponents of the Feedback Inhibitor of Lactation (FIL) model claim that their model is proven. But the NDC mechanobiological model disputes the bioactive factor FIL model and shows why the bioactive fator FIL model is not proven.

The mechanobiological model proposes that hydrostatic stretching and compression within the alveoli is also a form of Feedback Inhibitor of Lactation, and for clarity, I distinguish between the bioactive factors Feedback Inhibitor of Lactation vs the mechanical (or hydrostatic pressure) Feedback Inhibitor of Lactation models.

• You can find out about the Feedback Inhibitor of Lactation (FIL) model here.

• You can find out about the NDC mechanobiological model of downregulation of milk secretion here.

Selected references

Brown RE. Relactation: an overview. Pediatrics 1977;60(1):116–20.

Cowie AT, Knaggs GS, Tindal JS, Turvey A. The milking stimulus and mammary growth in the goat. J Endocrinol 1968;40(2):243–52.

Ingthorsson S, Traustadottir GA, Gudjonsson T. Breast morphogenesis: from normal development to cancer. Advances in Experimental Medicine and Biology. 2025;1464:29-44.

Peaker, M., C. J. Wilde, and C. H. Knight. 1998. Local control of the mammary gland. Biochem. Soc. Symp. 63:71–79.

Schmidt, G. H. 1971. Biology of Lactation. San Francisco: W. H. Freeman.

Weaver SR, Hernandez LL. Autocrine-paracrine regulation of the mammary gland. Journal of Dairy Science. 2016;99:842-853.