How the bioactive factors Feedback Inhibitor of Lactation model was developed

The chemical Feedback Inhibitor of Lactation hypothesis is currently used to explain the regulation of breast milk production in humans

Since the 1960s, we have learnt a great deal about mammalian lactation from industry-driven explorations of milk production in domestic species, in particular dairy cows and goats. Much of the work on the Feedback Inhibitor of Lactation model has been conducted in domestic species.

The Feedback Inhibitor of Lactation model, which emerged out of this research, proposes that local factors (under autocrine or paracrine control) provide feedback at the level of mammary gland tissue, independent of the hypothalamus and pituitary gland and systemic hormones.

The following effects of elevated milk volumes on milk secretion, including in humans, can be taken as proven. As milk fills the alveoli

• Milk secretion is rapidly downregulated

• Changes in rate of milk secretion can be detected within hours

• Protein gene expression is suppressed, and

• Involution is initiated.

You can find out more about local control of human galactopoiesis here.

The chemical Feedback Inhibitor of Lactation model was initially believed to be a single peptide but this hypothesis is outdated

Levy in 1963 first hypothesised that chemical hormones in milk inhibited milk secretion locally. Then in 1987 Wilde et al conducted research in which the whey fraction of goat's milk was injected into goats' udders, resulting in decreased milk yield. In other research studies in rabbits, goats, mice, and marsupials, the whey protein fraction was also shown to inhibit both casein expression and secretion and fatty acid synthesis.

Wilde et al 1987 hypothesised that a protein in the whey fraction, named the Feedback Inhibitor of Lactation (FIL), acted as a master key in the synthesis and suppression of human milk synthesis.

In 1995 Wilde et al conducted experiments using the whey fraction of goat's milk on tissue explant culture, theorising that FIL was a small glyoprotein with a novel N-terminal amino acid sequence, found in the 10-30 kDa protein in the whey fraction of milk.

• The authors argued that this glycoprotein was inhibitory at the level of the alveoli, because of resultant decreased milk protein expression and decreased fatty acid synthesis.

• However, the same paper acknowledges the limitations of mammary cell tissue explant cultures.

Peaker & Wilde 1996 acknowledged the importance of mechanical factors and calcium in milk secretion

In 1996 Peaker & Wilde also discuss the role of intracellular calcium in lactocyte milk secretion, suggesting there may be two pathways

• One which secretes milk protein and lipids in a way that is calcium independent, and

• A regulatory pathway that is stimulated by a rise in intracellular calcium concentration, noting that "a physiological signal for calcium-stimulated protein secretion has not yet been identified".

• Importantly, the authors note that "calcium influx into cultured mammary cells is stimulated by mechanical deformation of the cells."

• They note: "This raises the intriguing possibility that oxytocin-stimulated myoepithelial contraction, resulting in deformation of adjacent secretory cells, may serve not only to expel milk from alveoli but also to evacuate the secretory cells of unsecreted milk constitutents." They further hypothesise: "Indeed it may be that calcium influx acts at the level of exocytosis."

• The authors note: "There is now evidence to suggest that frequent milking may maintain the mammary cell population by reducing the rate of programmed cell death by apoptosis."

• "Programmed cell death is a normal physiological event in lactating ruminant mammary tissue, and is regulated not only by systemic hormones as in rodents but by a mechanism sensitive to mik stasis."

Since the publication of this paper, however, it hasn't proven possible to isolate or identify the sequence of this hypothesised peptide or small glycoprotein.

It is nevertheless accepted that there will need to be a mechanism for apical uptake of the peptide or for binding with the lactocyte cell membrane, with subsequent transduction of the signal, but the actual proposed mechanisms by which a chemical Feedback Inhibitor of Lactation might act remain unclear.

The chemical Feedback Inhibitor of Lactation model now proposes that multiple bioactive factors in milk downregulation milk secretion

The multiple bioactive factors Feedback Inhibitor of Lactation model is now wrongly claimed to be 'true'or proven by researchers and educators. However, this is an example of confusion between association and causation.

As new studies have emerged showing associations between a whole variety of bioactive chemical factors and decreased milk secretion, and the inaccuracy of the single glycoprotein or peptide model became apparent, the chemical FIL model was adapted, to hypothesise

• That multiple chemicals in breast milk downregulate milk secretion as their concentration in the breast milk increases, and

• That removal of these factors by removal of milk ensures their concentration doesn't build up in the milk, so that milk continues to be secreted.

As a result of this evolving interpretation (wrongly claimed to be a fact), the chemical Feedback Inhibitor of Lactation model has dominated beliefs about the downregulation of human mammary gland milk production for a number of decades.

Weaver & Haernandez 2016

In Professor Hernandez's article published with Professor Weaver in 2016, reviewing the autocrine-paracrine regulation of the mammary gland and focussing predominantly on research in dairy cows, a number of statements are made which pertain to this debate. The authors write

• "The mechanisms underpinning increased milk production with increased milking frequency have been developed over the past 50 yr and are still not conclusively defined for any given species."

• "Arresting milk secretion through mammary distension is critical in the goat for the complete cessation of lactation, but is not the sole regulator of milk synthesis throughout lactation in other species. In early studies, it was tempting to attribute milk secretion control to a rise in intramammary pressure; mechanoreceptors would theoretically sense the elevated pressure of the retained milk, resulting in suppression of milk synthesis. ... In dairy cows, however, mammary pressure is not the driving force in regulating milk cessation. Increases in pro-apoptotic gene expression, key indicators of involution, are not observed until 24 to 48 h after milk stasis and MEC number does not decrease until 72 h."

• "Multiple factors increase in concentration as milk builds up, then tissue effects occur: such as apoptosis or remodelling in extracellular matrix. These are triggered under conditions of high concentrations as milk builds up."

• "Local control occurs at the level of the mammary epithelial cell through pressure and stretching negative-feedback mechanisms, and also in an autocrine fashion through bioactive factors within the milk which act as inhibitors, regulating milk secretion within the alveoli themselves."

You can find a critical analysis of the bioactive factors FIL model here.

The image at the bottom of this page shows someone milking a goat. Goats have been bred for domestic milk consumption, optimising milk production by selecting out certain kinds of udder morphology including size of teat and udder sinus or cistern. The same is true of the udders of dairy cows, pictured above, which have been bred for large teat and udder cisterns. These very large storage cisterns in domestic species alter pressure dynamics, relative to the human mammary gland, which lacks any sinuses or cisterns (first demonstrated by the Geddes Hartmann Human Lactation Research Group).

Selected references

Hernandez LL. ADSA Foundation Scholar Award: A role for serotonin in lactation physiology - where do we go from here? Journal of Dairy Science. 2018;101:5671-5678.

Hernandez LL. Mammary gland control of milk production. Academy of Breastfeeding Medicine Conference 2024 Chicago.

Peaker M, Wilde CJ. Feedback control of milk secretion from milk. Journal of Mammary Gland Biology and Neoplasia. 1996;1(3):307-315.

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