Limitations of the bioactive factors Feedback Inhibitor of Lactation model

Here's what is agreed by researchers and clinicians about the regulation of human milk production

• Human milk is stored in alveoli between episodes of milk removal.

• Lactocytes constantly secrete milk. Milk secretion from the lactocytes is either constant or even upregulates if the lumen is repeatedly and optimally cleared of milk.

• Macronutrient concentrations within milk are largely stable, except for fat. That is, as milk volumes rise, the concentrations stay proportionately stable, though the total load increases. The average macronutrient composition of breastmilk is approximately 1.2 g/dL for protein, 7.4 g/dL for lactose (the main carbohydrate in breastmilk). The other significant carbohydrates in breastmilk are called oligosaccharides, which comprise approximately 1 g/dL in breastmilk.

• The lipid component of breast milk (on average 3.6 g/dL) is the main component of human milk which has a relative decrease in concentration as the total volume of breast milk within the alveoli increases. This is because mechanical effects of rising intra-alveolar pressure stretches lactocytes, making it impossible for the apex to pinch off and produce the fatty globule membranes required to produce fat globules as volumes increase.

Here's an analysis of two studies which have been used to refute the hydrostatic compression Feedback Inhibitor of Lactation model (or NDC mechanobiological model) of milk downregulation

Research in domestic species led to an early theory that the mechanical pressure of high volumes in the mammary glands resulted in downregulation of milk secretion.

But a study in goats's udders in 1971 by Schmidt was said to disprove the mechanical forces theory. Another study in goats by Henderson & Peaker (1984) concluded that a bioactive (not mechanical) factor in milk sent signals to cells in mammary gland to reduce milk synthesis. A further study by Peaker and Wilde in 1996 considered in some depth and then discarded a major role for mechanical forces. This latter paper named the single peptide that was posited to result in decreased milk secretion the Feedback Inhibitor of Lactation (FIL). As a result, I propose that the bioactive factors FIL model has been extrapolated into human milk research

• Without proper consideration of the role of hydrostatic pressures (or mechanical forces) within the human mammary gland

• Despite the very significant differences between diary and other domestic mammalian species udder morphology and function and the lactating human breast.

Analysis of Henderson & Peaker 1984

Henderson and Peaker's study of goats (1984) involved injecting isosmotic sucrose solution into goats' udders. This was done in goats which were being milked three times daily. After the initial milk removal that day, in the treatment group the milk removed was replaced by injected sucrose water.

Because thrice daily milking, regardless of whether the sucrose water was injected or not, was found to make significant more milk than twice-daily milking (without sucrose injection), it was concluded that physical distension does not cause the reduction in milk secretion which normally takes place in the latter part of a long milking interval. The authors write: "Instead, it is concluded that there is in milk a locally-active chemical inhibitor, which reduces milk secretion by negative feed-back during this time."

Weaver & Hernandez claim that "in ruminants, intramammary pressure was definitively disproven as the sole regulator of milk synthesis in a study performed by Henderson and Peaker (1984)."

However, I argue that Henderson and Peaker is methodologically flawed, and its findings cannot be extrapolated to lactating humans because

• Goat udders have substantial gland and teat cisterns or sinuses. Human breast does not have sinuses or cisterns for storage of milk.

• Goats have been bred for the kind of udder morphology which increases milk yields over widely spaced-out milking events, for purposes of human consumption of their milk.

Analysis of Schmidt 1971

Professor Hernandez in Chicago Academy of Breastfeeding Medicine Conference 2024 stated that Schmidt et al 1971 studies showed "it is a true fact" that mechanical forces don't downregulate mammalian milk supply.

Schmidt 1971 measured goat udder pressure by either mechanical stimulation or feeling the udder. Goat udder pressure was at its highest about 40 hours after last milking, but the milk secretion rate had already dropped off by then, and was zero at about 33 hours after last milking. Professor Hernandez says this study shows that udder pressure contributes to production cessation but plays a very secondary role to the dominant role of bioactive factors in milk.

However, the Geddes Hartmann Human Lactation Research Group first demonstrated that, unlike domestic species, the human mammary gland does not have milk sinuses for milk storage, and that minimal milk storage occurs in the lactiferous ducts. This research re-wrote how anatomy text books understood the human mammary glands.

In interpreting the Schmidt study, I would propose

• That udder pressure, measured externally, does not reflect early effects of rising intra-alveolar pressures on milk secretion rates and is a late manifestation of rising milk pressures

• Because of the effects of breeding for high milk production, findings from the goat udder are not appropriately extrapolated to the human mammary gland.

Here are two key critiques of the bioactive factors FIL model

I have two key critiques of the bioactive factors FIL model.

1. I argue that although the association between multiple bioactive factors and downregulation of milk secretion may be true and proven, a causative relationship is not. The bioactive factors FIL model which is used to explain downregulation of milk secretion causatively is not clearly explicated, that is, the mechanism has not yet been explained in a biologically plausible way.

2. This is an example of how we tend to apply a reductionist lens to research which is being conducted upon very complex systems. It's understandable, given the extraordinary amount of money and time invested in a single research study, that researchers may wish to generalise the implications of their study, for example, into a single (marvellous) bioactive factor. Researchers are gradually identifying, one by one, a myriad of extraordinary bioactive factors found in human milk, each with remarkably complex actions both upon other components of milk, upon the mammary epithelial cells, and upon the infant gut. It's noted that these bioactive factors are associated with decreased milk secretion as milk volumes rise. We apply a reductionist lens to assume this is a linear relationship: the rising levels of the bioactive factor which has been isolated in human milk is assumed to be causing (or contributing to cause) decreased milk secretion.

   • In a recent example of the reductionist lens which may be applied by researchers, in November 2024 in a presentation at the Academy of Breastfeeding Medicine conference, Chicago, Professor Laura Hernandez (Animal and Dairy Sciences, University of Wisconsin-Madison) emphasised that the multiple-bioactive-factors FIL mechanism is proven in human milk production. Professor Hernandez reiterated the dominant belief that it "is clearly true" and that "the concept is true". Professor Hernandez stated that numerous chemical factors have this effect, listing the examples of lactoferrin, fatty acids, casein phosphopeptides, TGF beta,and PRHrP. Professor Hernandez also elaborated on her team's studies concerning 5-HT serotonin as a key bioactive factor which downregulates milk secretion. Professor Hernandez stated that serotonin interacts with prolactin as the mammary gland fills, claiming that the more serotinin there is in the mammary gland, the more genetic expression of milk protein secretion is suppressed. Professor Hernandez noted there doesn't appear to be interaction between serotonin and oxytocin.

Here are six questions raised by the bioactive factors FIL model

Here are questions that I propose are raised by the bioactive factors FIL model. It will be interesting to hear what you think, and what questions you might have!

1. As the volume of milk rises within alveoli, does the total load of milk bioactive components increase but their concentration remain stable, as occurs with the macronutrient components? Proponents of the bioactive factors FIL model often talk of "rising concentrations" of the bioactive factors. But is it the total load or the concentration that is increasing?

2. By what mechanism does each of the bioactive factors act to downregulate milk secretion and over what time frame?

3. Does the FIL model propose that the lactocytes are sensitive to total volumes of bioactive factors (rather than proportionate concentrations? But these total volumes are not in contact with lactocytes - only the molecules on the very outer edge of the growing collection of milk, a small proportion of the total volume of any bioactive factor, will directly contact the lactocyte.

4. If milk secretion is directly and immediately controlled by bioactive factors in milk, as the alveoli fill there would be an immediate decrease in rate of milk synthesis. If this were the case, women would not describe tight or tight and painful breasts when their baby goes for a longer period than usual between breastfeeds, because the bioactive factors would be constantly downregulating milk supply in response to rising volumes.

5. Either that, or the multiple bioactive factors operate according to a threshold, and only begin to decrease the rate of milk synthesis once that threshold concentration is crossed as a pattern over time. These thresholds would need to be elucidated for each of the multiple bioactive factors, acting synergistically, as well as their cumulative effects over time.

6. Serotonin is one of many bioactive factors in milk which have also been shown to influence proliferation and apoptosis of the mammary gland. It's stated that serotonin induces calcium into milk from blood vessels. Calcium is important for cell proliferation and apoptosis. However, intracellular calcium is profoundly affected by mechanical forces in muscle cells. Does rising hydrostatic pressure compress the lactocyte and alter intracellular calcium levels, with significant affect on milk secretion?

In summary, the NDC mechanobiological model proposes that the bioactive factors FIL model illustrates confusion between association and causation. The mechanisms by which bioactive factors are proposed to downregulate milk secretion are not elucidated.

You can read why the Okkam's razor principle preferences the NDC hydrostatic compression Feedback Inhibitor of Lactation model here.

The image at the bottom of this page shows goats which have been bred for domestic goat's milk consumption at a milking station. Domestic goats are bred for optimal milk production, which selects out certain kinds of udder morphology including teat and udder sinus or cistern morphology. 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 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.

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