The NDC mechanobiological model explains downregulation of breast milk production

Previous explanatory models for the regulation of human milk production

In 1987, Wilde hypothesised that a protein in the whey fraction, named the Feedback Inhibitor of Lactation, acted as a master key in the synthesis and suppression of milk synthesis. However, it’s now understood that milk synthesis and suppression are not controlled by a single entity, but are complex systems.2

It is possible that bioactive factors within milk (such as growth factors, parathyroid hormone-related protein, and serotonin) act as inhibitors, regulating milk secretion. It is also accepted that progesterone, prolactin, oxytocin, and leukemia inhibitory factor modulate cell signalling and function in the mammary gland.

But these modulatory factors appear to have indirect and time-delayed effects, relative to the immediate and powerful local control exerted by pressure and stretching negative-feedback mechanisms.

Three-dimensional time lapse imaging of the mammary gland of lactating mice supports the existence of a multifaceted system of mechanical sensing through chemical signals in the mammary gland.1, 2

The NDC mechanobiological model of milk production and breast inflammation draws on findings in the new field of mechanobiology

The NDC mechnoabiological model of the downregulation of milk synthesis in the lactating human breast is a clinical interpretation of the work emerging out of the field of mechanobiology, discussed here and here, and draws on four research studies:

1. Weaver and Hernandez’s 2016 proposal that mammalian species downregulate milk by apoptosis,2 with

2. Jindal et al’s 2020 proposal that partial gland involution occurs prior to the complete cessation of breastfeeding in response to decreasing milk removal 8 and

3. Stewart et al’s pioneering 2021 publication on mechanosensing in the mammary gland.1

4. Kobayashi et al's findings, working with in vitro mice lactocytes, that milk-production-related signaling pathways in lactocytes change in response to hydrostatic compression. Kobayashi et al conclude that hydrostatic ompression of the alveolar lumen may directly regulate milk production in the alveolar mammary epithelial cells, corroborating the NDC mechanobiological model which was published the previous year.

The NDC mechanobiological model of regulation of milk production

Before an alveolus fills, lactocytes present rounded apices to the lumen.

When a lactocyte takes this columnar or triangular shape, fat droplets bud off from the apical cell membrane. As intra-alveolar pressure builds due to milk accumulation, lactocyte calcium-permeable ion channels are activated, and lactocytes absorb the increasing mechanical load by stretching and losing their apices. This protects inter-lactocyte tight junction integrity but prevents fat droplet extrusion.

The mechanical effects of severe stretching of the lactocyte cell membrane are not yet clearly elucidated. It is not known if mechanical forces exert an immediate downregulatory effect upon lactocyte cell membrane’s capacity to exocytose protein and lactose in Golgi-derived secretory vesicles or upon cell membrane permeability to water and ions.

It seems most likely that lactocytes steadily secrete lactose and proteins into alveolar lumens, with continued passage of ions and water across the cell membrane in response, even as tight junctions stretch.

Tight junction strain triggers chemical signals, such as cytokines, chemokines, and adhesion molecules, which warn the host immune system of early cell and tissue damage, recruiting local hyperemia and increased leukocytes. Sodium, chloride and albumin from the plasma may pass directly through the tight junctions as they open up under mechanical strain, increasing intra-alveolar volume.9

Increasing milk accumulation exerts shearing or compression forces on tight junctions, which stretch and may finally break under severe mechanical stress, so that the alveolus and its basement membrane rupture. This precipitates a dynamic wound-healing inflammatory response in the stroma and milk, proteolytic degradation of the alveolar basement membrane, and lactocyte apoptosis. Immune cells and perhaps more importantly, other mammary epithelial cells, phagocytose debris from these small subclinical areas of involution.

Lactocytes are irreversibly replaced with adipocytes as tissue is repaired and remodelled.1, 2, 7, 8

The healthy lactating mammary gland is a proinflammatory environment.7, 8 Lactation and the body’s inflammatory response share many common mechanisms. Applying the mechanobiological theory of breast inflammation in lactation, normal wound-healing processes occur microscopically throughout the course of a healthy and successful lactation in response to intermittent excessively high intra-alveolar and intra-ductal pressures, without the development of clinical signs and symptoms.

The NDC mechanobiological model of milk production regulation builds on new research about the mechanobiology of the lactating breast and the role of mechanosensing in the mammary gland immune response,2 to propose a complex biological systems perspective. The mechanical effects of high intra-alveolar and intra-ductal pressure are proposed to be the dominant regulator of the dynamic homeostasis of the lactating breast.

Approaching six months post-birth, an infant begins to ingest solids. At this time, maternal milk secretion decreases through the same mechanism of elevated intraluminal pressures, tight junction rupture, alveolar collapse and lactocyte death.

Complete cessation of breastfeeding, whenever this occurs, triggers one of the largest cascades of programmed cell death to occur in mammals: 80-90% of remaining lactocytes switch from milk secretion to apoptosis. During complete weaning, breast stroma is characterised by a heightened inflammatory or wound-healing environment, including activation of macrophages, lymphangiogenesis, and fibroblasts for tissue repair and remodelling.

The post-weaning cascade of inflammatory activity and cell death peaks two weeks after the last breastfeed and is largely resolved by 4 weeks after the last breastfeed.7, 8, 10

You can find out about how the NDC mechanobiological model of milk production regulation also explains breast inflammation, here.

Selected references

Please note that the referencing in this module is still under development. Comprehensive citations are found in the two research publications which the breast inflammation module is built (Douglas 2022 mechanobiological mode; Douglas 2022 classification, prevention, management; Douglas 2023)

Douglas P. Re-thinking benign inflammation of the lactating breast: a mechanobiological model. Women's Health. 2022;18:17455065221075907.

Douglas PS. Re-thinking benign inflammation of the lactating breast: classification, prevention, and management. Women's Health. 2022;18:17455057221091349.

Douglas PS. Does the Academy of Breastfeeding Medicine Clinical Protocol #36 'The Mastitis Spectrum' promote overtreatment and risk worsened outcomes for breastfeeding families? Commentary. International Breastfeeding Journal. 2023;18:Article no. 51 https://doi.org/10.1186/s13006-13023-00588-13008.

Kim T-J. Mechanobiology: a new frontier in biology. Biology. 2021;10(570):https://doi.org/10.3390/biology10070570.

Kobayashi K, Han L, Lu S-N, Ninomiya K, Isobe N, Nishimura T. Effects of hydrostatic ompression on milk production-related signaling pathways in mouse mammary epithelial cells. Experimental Cell Research. 2023;432:113762.

Noam Zuela-Sopilniak, Lammerding J. Can’t handle the stress? Mechanobiology and disease. Trends in Molecular Medicine. 2022;28(9):710-725.

1. Stewart TA, Hughes K, Stevenson AJ, Marino N, Ju AL, Morehead M, et al. Mammary mechanobiology - investigating roles for mechanically activated ion channels in lactation and involution. Journal of Cell Science. 2021;134:doi:10.124/jcs.248849.
2. Weaver SR, Hernandez LL. Autocrine-paracrine regulation of the mammary gland. Journal of Dairy Science. 2016;99:842-53.
3. Douglas PS, Geddes DB. Practice-based interpretation of ultrasound studies leads the way to less pharmaceutical and surgical intervention for breastfeeding babies and more effective clinical support. Midwifery. 2018;58:145–55.
4. Douglas PS, Keogh R. Gestalt breastfeeding: helping mothers and infants optimise positional stability and intra-oral breast tissue volume for effective, pain-free milk transfer. Journal of Human Lactation. 2017;33(3):509–18.
5. Douglas PS, Perrella SL, Geddes DT. A brief gestalt intervention changes ultrasound measures of tongue movement during breastfeeding: case series. BMC Pregnancy and Childbirth. 2022;22(94):https://doi.org/10.1186/s12884-021-04363-7.
6. Mogensen N, Portman A, Mitchell K. Nonpharmacologic approaches to pain, engorgement, and plugging in lactation. Clinical Lactation. 2020;11(1):http://dx.doi.org/10.1891/2158-0782.11.1.35.
7. Zaragoza R, Garcia-Trevijano ER, Lluch A, Ribas G, Vina JR. Involvement of different networks in the mammary gland involution after the pregnancy/lactation cycle: implications in breast cancer. International Union of Biochemistry and Molecular Biology. 2015;67(4):227-38.
8. Jindal S, Narasimhan J, Vorges VF, Schedin P. Characterization of weaning-induced breast involution in women: implications for young women's breast cancer. Breast Cancer. 2020;6(55):https://doi.org/10.1038/s41523-020-00196-3.
9. Fetherstone C. Mastitis in lactating women: physiology or pathology? Breastfeeding Review. 2001;9:5-12.
10. Ingman WV, Glynn DJ, Hutchinson MR. Inflammatory mediators in mastitis and lactation insufficiency. Journal of Mammary Gland Biology and Neoplasia. 2014;19:161-7.
11. Basree M, Shinde N, Koivisto C. Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer. Breast Cancer Research. 2019;21(80):https://doi.org/10.1186/s31058-019-1163-7.