Who manages the mammaries: physiology edition

After last week’s post on low milk supply/insufficient milk syndrome and how common medical practices may contribute to these problems, my intention was to move on to looking at additional physiological factors that might contribute to diagnosis of low milk syndrome and general patterns of breastfeeding cessation. However, based on the comments following the post, it appears that a brief interlude would be useful – and so I bring you “who manages the mammaries: physiology edition”, specially looking at how milk synthesis starts and milk supply is maintained. I think this will be useful for the overall trajectory of the multipart series emerging here.

The onset of milk production occurs with lactogenesis. In humans, this is split into two general stages, the first occurring during the transition from pregnancy to lactation and the second characterized by secretory activation of the mammary gland. More than simply the onset of milk production, each discrete physiological phase hallmarks a number of important cellular changes within the mammary epithelium and the mammary ducts. The first phase, secretory differentiation, previously called lactogenesis I is followed by secretory activation, formerly known as lactogenesis 2, is characterized by a shift to full milk production and further cellular level changes (Neville et al., 2012). Secretory activation is usually complete within 72 hours following birth, however there is an increased incidence in delayed activation among American mothers (Nommsen-Rivers et al., 2012) compared to other populations where lactogenesis may occur much sooner. The transition from secretory differentiation to activation also signals the shift from endocrine to autocrine control (Riordan and Wambach, 2010).

The secretory differentiation phase starts during the later half of pregnancy, and is characterized by an overall increase in breast size, reflecting both ductal growth and the terminal differentiation of mammary epithelial cells into mature mammary epithelial cells (lactocytes) capable of producing milk. Lactocytes begin secreting fat, protein, and lactose (Riordan and Wambach, 2010) in small amounts. During this period, the gap junctions between the lactocytes are open, allowing for the passage of larger molecules between the cells and into the milk.  Following the decrease in circulating progesterone levels after the delivery of the infant and placenta, the gap junctions between the lactocytes close.  “Copious” milk production, characteristic of secretory activation, starts with this shift to autocrine regulation. Milk synthesis will be maintained by both galactopoietic hormones and milk removal after day 3-8, depending on individual variation. 

The mammary glands are highly vascularized, with two main arteries – the internal mammary artery (anterior & posterior branches) and the lateral mammary branch of the lateral thoracic artery, although in about 30% of women, other arteries may also contribute to mammary blood flow. Blood supply to the breasts more than doubles during pregnancy and remains stable during lactation. The increase in blood supply is necessary to provide resources to the individual lactocytes and surrounding cells such as myoepthelial cells and adipocytes (fat cells). Aljazaf (2005) estimates that the ratio of milk yield to blood flow is 1:500, highlighting the importance of a large blood supply for these tissues, although Geddes (2012) cautions that there is not clear evidence for a direct link between mammary blood flow and milk synthesis rate. Within the breast, lactocytes line each alveolus with a single layer of cells. Each cluster is surrounded by myoepithelial cells and fat cells (Figure 1). There is little evidence for nerves extending to the individual alveolus, although certainly both larger and smaller nerves are found throughout the breast. However, myoepithelial cells and lactocytes have a constant blood supply, allowing for hormonal signaling as well as cellular uptake of glucose, fatty acids, amino acids, and other substances. 

Figure 1: The new visualization of the mammary gland, thanks to ultrasound techniques (Geddes, 2007) and other methodological breakthroughs. Image from Medela.

Regular – but not scheduled – removal of milk from the breasts is necessary to maintain milk synthesis following secretory activation. Breastfeeding or milk removal is not necessary for the onset of milk synthesis but is necessary for continued synthesis. Often described simply as a “supply-demand response” (Riordan and Wambach, 2010), milk synthesis is in fact an elaborate orchestration.  Infant suckling, through the stimulation of nerves in the nipple, triggers nerve pulses to the supraoptic and paraventricular nuclei of the hypothalamus. Paraventricular neurons project to the posterior pituitary, where stimulation leads to the release of oxytocin (Rinamen 2007); similar neuron projections trigger the release of prolactin from lactotrophic cells in the anterior pituitary (Kiss et al., 1986). Oxytocin and prolactin travel through maternal circulation to the mammary gland, where oxytocin binds to specific receptors on myoepithelial cells and prolactin to prolactin receptors on the lactocytes themselves (Figure 2).

Figure 2: The brain releases oxytocin and prolactin following stimulation of the nipple – both prolactin and oxytocin have important functions in milk ejection and synthesis.  Image from: VisualMD.com. For more information check out: VisualMDHealthCenters.

The binding of oxytocin to the myoepithelial cells triggers the cells to contract. These contractions force milk into the ducts. Progressive contractions will push milk progressively through the ducts towards the nipple, provided the infant (or breast pump) is maintaining a vacuum (Ramsey et al., 2005). Blood flow to the alveolus decreases just prior to milk ejection followed by an increase 1-2 minutes later (Geddes 2007). 

Meanwhile, prolactin binds to prolactin receptors on the lactocyte, specifically those expressed on the basal membrane side in contact with the maternal blood supply (Figure 3).  Binding activates transcription mechanisms in the lactocyte, leading to the activation of genes for the production of milk proteins and lactose (Mohammad et al., 2012; Rhoads et al., 2009), as well as fatty acid synthesis and assembly of the milk fat globule (Maningat et al., 2009). Although prolactin peaks following nipple stimulation, there does not appear to be a direct association between circulating plasma prolactin levels and the rate of milk synthesis (Cox et al., 1996), and maternal prolactin levels decrease over the course of lactation. It is likely that autocrine regulation is largely responsible for local control of milk synthesis rates. Daly et al., (1996) have shown that breasts holding more milk (with longer interfed intervals) have decreased milk synthesis rates compared to empty breasts, providing an explanatory framework for the 17-33 mL/hr rate proposed by Arthur et al., in 1989.  This may also explain why milk fat increases from fore to hind milk (Daly et al., 1993; Kent et al., 2006) – the cellular machinery for producing milk and the uptake of long chain fatty acids from maternal circulation are increased, facilitating the transfer of fat into milk. Additional hormones, including glucocorticoids such as cortisol, and metabolic hormones such as insulin, appear to also play a role in milk synthesis and mammary function.  Glucocorticoids may prioritize glucose for mammary tissue and amplify the effects of prolactin on milk protein synthesis while insulin appears to play a role in maintaining the integrity of the mammary epithelium itself.  

Figure 3: Association between milk synthesis rate and breast fullness through the changes to prolactin receptors. Image: VisualMD.com

And this system works pretty well – except when it can’t. And one big risk of reducing milk synthesis is letting too much milk accumulate in the ducts and alveoli without regular emptying. As milk accumulates, certain areas of the ducts may distend slightly. This distension leads to two primary problems: 1) increasing concentrations of feedback inhibitor of lactation in the milk in the ducts (Peaker, 1998) and 2) distortion of the lactocytes themselves. This distortion limits the ability of prolactin to bind to its receptor on the lactocyte and decreases milk synthesis (Streuli et al., 1995).

It’s actually a very elegant system, set up to minimize waste. If the infant is eating less, either because of supplemental foods, illness, or infant loss, decreasing milk synthesis is actually not a bad idea. It takes, based on the calculations by Prentice et al., (1988) considerable energy to produce milk – about 77.2-80.3 Calories per 100 milliliters of milk (72.66 Calories received by the infant) or about 90-94% return on investment. Still, if you figure 750mL of milk per day, that’s 579+ calories per day and if the infant is not eating all 750 mL, reducing synthesis saves energy. 

It is only when the system gets out of whack – possibly because of scheduled feedings, supplemental foods (especially formula), infant illness or poor latch/vacuum – that milk synthesis is down regulated when it does not need to be. Essentially, the physiology is responding to the change in demand – the shifting baseline (Olson 2002). And like any shifting baseline, the change is often gradual, tiny decreases accumulating over days. This can lead to an actual decrease in milk supply, as the breast “thinks” the infant is getting enough to eat. The good news is, it is reversible – the same signals that communicated “too much” can signal “not enough” provided the stimulus is there.  The reality is though, that for most women (except that ~5%) with “low milk supply” nursing more can help with milk supply. 

References

IMAGES: All images from the VisualMD.com

Arthur PG, Jones TJ, Spruce J, Hartmann PE. (1989) Measuring short-term rates of milk synthesis in breast-feeding mothers. Q J Exp Physiol. 1989 Jul;74(4):419-28.

Cox DB, Owens RA, Hartmann PE. (1996) Blood and milk prolactin and the rate of milk synthesis in women. Exp Physiol. 81(6):1007-20.

Daly SE, Di Rosso A, Owens RA, Hartmann PE. (1993) Degree of breast emptying explains changes in the fat content, but not fatty acid composition, of human milk. Exp Physiol. 78(6):741-55.

Daly SE, Kent JC, Owens RA, Hartmann PE. (1996) Frequency and degree of milk removal and the short-term control of human milk synthesis. Exp Physiol. 81(5):861-75.

Geddes DT. (2007) Inside the lactating breast: the latest anatomy research. J Midwifery Womens Health. 52(6):556-63.

Geddes DT, Aljazaf KM, Kent JC, Prime DK, Spatz DL, Garbin CP, Lai CT, Hartmann PE. (2012) Blood flow characteristics of the human lactating breast. J Hum Lact. 28(2):145-52. doi: 10.1177/0890334411435414.

Kent JC, Mitoulas LR, Cregan MD, Ramsay DT, Doherty DA, Hartmann PE. (2006) Volume and frequency of breastfeedings and fat content of breast milk throughout the day. Pediatrics 117(3):e387-95.

Kiss JZ, Kanyicska B, Nagy GY. (1986) The hypothalamic paraventricular nucleus has a pivotal role in regulation of prolactin release in lactating rats. Endocrinology. 119(2):870-3.

Maningat PD, Sen P, Rijnkels M, Sunehag AL, Hadsell DL, Bray M, Haymond MW. (2009) Gene expression in the human mammary epithelium during lactation: the milk fat globule transcriptome. Physiol Genomics. 37(1):12-22.

Mohammad MA, Hadsell DL, Haymond MW. (2012) Gene regulation of UDP-galactose synthesis and transport: potential rate-limiting processes in initiation of milk production in humans. Am J Physiol Endocrinol Metab. 303(3):E365-76. doi: 10.1152/ajpendo.00175.2012. 

Neville MC, Anderson SM, McManaman JL, Badger TM, Bunik M, Contractor N, Crume T, Dabelea D, Donovan SM, Forman N, Frank DN, Friedman JE, German JB, Goldman A, Hadsell D, Hambidge M, Hinde K, Horseman ND, Hovey RC, Janoff E, Krebs NF, Lebrilla CB, Lemay DG, MacLean PS, Meier P, Morrow AL, Neu J, Nommsen-Rivers LA, Raiten DJ, Rijnkels M, Seewaldt V, Shur BD, VanHouten J, Williamson P. (2012) Lactation and neonatal nutrition: defining and refining the critical questions. J Mammary Gland Biol Neoplasia 17(2):167-88. doi: 10.1007/s10911-012-9261-5.

Nommsen-Rivers LA, Dolan LM, Huang B. (2012) Timing of stage II lactogenesis is predicted by antenatal metabolic health in a cohort of primiparas. Breastfeed Med. 7(1):43-9. doi: 10.1089/bfm.2011.0007.

Olson, R. (2002) Shifting Baselines: the truth about ocean decline. LA TIMES, Sunday Opinion Section.

Peaker M, Wilde CJ, Knight CH. (1998) Local control of the mammary gland. Biochem Soc Symp. 63:71-9.

Prentice AM, Prentice A (1988) Energy costs of lactation. Ann. Rev. Nutr. 8:63-79.

Ramsay DT, Kent JC, Hartmann RA, Hartmann PE. (2005) Anatomy of the lactating human breast redefined with ultrasound imaging. J Anat. 206(6):525-34.

Rhoads RE, Grudzien-Nogalska E. (2007) Translational regulation of milk protein synthesis at secretory activation. J Mammary Gland Biol Neoplasia. 12(4):283-92.

Rinaman L. (2007) Visceral sensory inputs to the endocrine hypothalamus. Front Neuroendocrinol. 28(1):50-60.

Riordan J, Wambach K. (2010) Breastfeeding and Human Lactation, 4^th edition. Sudbury: Jones and Barlett.

Streuli CH, Edwards GM, Delcommenne M, Whitelaw CB, Burdon TG, Schindler C, Watson CJ. (1995) Stat5 as a target for regulation by extracellular matrix. J Biol Chem. 15;270(37):21639-44.

Wilde CJ, Addey CV, Bryson JM, Finch LM, Knight CH, Peaker M. (1998) Autocrine regulation of milk secretion. Biochem Soc Symp. 63:81-90.

Go check out . . .

You should go check out Mammals Suck . . .Milk; this month's topic is stem cells in human milk. I will probably be looking at this topic as well in March!

http://mammalssuck.blogspot.com/2013/02/human-breast-milk-contains-pluripotent.html

Who manages the mammaries?

One of the really excellent points that have come up in the recent discussions of medicine failing breastfeeding is an appreciation that human breasts, like all other organ systems, can have physiological dysregulation and difficulties. There are a small percentage of women with physiological inability to produce milk (estimated at 2-5% of the population), just as there are individuals with beta cell dysfunction (Type 1 diabetics), thyroid issues, and problems with really every other organ in the body. By comparison, including types 1 & 2, the incidence of diabetes was 8.3% in 2011 (CDC, 2011). To put it simply, breasts are organs, and have about the same rate of physiological issues as other organs (I borrowed this from the ongoing conversations). 

However, there has been a tremendous increase in recent years in the number of women diagnosed with insufficient milk syndrome (or insufficient milk supply syndrome) or “low milk production”.  While there was an overall consensus the problem was becoming more common, concrete data were hard to find.  The best I can do is the Infant Feeding Practices Study from 2006, wonderfully indexed on http://www.cdc.gov/ifps/results/. I recommend checking it out, as you can see tables for every possible variable and even download the raw data. But, here are the numbers:

	Month stopped breastfeeding
Reason for stopping breastfeeding 3	< 1	1 to 2	3 to 5	6 to 9	>=9
My baby had trouble sucking or latching on	53.7	27.1	11	2.6	1.5
Breast milk alone did not satisfy my baby	49.7	55.6	49.1	49.5	43.5
I thought that my baby was not gaining enough weight	23	18.3	11	14.1	8.4
A health professional said my baby was not gaining enough weight	19.8	15.2	8.6	9.9	5
I had trouble getting the milk flow to start	41.4	23.2	19.6	14.6	5.7
I didn't have enough milk	51.7	52.1	54	43.8	26

Table 1: Reasons for breastfeeding cessation, as reported by US women participating in the 2005-06 Infant Feeding Practices Study. More than 2500 women participated in the initial survey; approximately 1400 women completed the survey through the first year (Shealy et al., 2008).

I think, based on the numbers presented above, it is reasonable to say that of the number of women who stopped breastfeeding during the first five months of life, more than 50% identified insufficient milk supply as a contributing factor. While this is not an overall incidence, it does support the overall idea that IMS is increasingly common.  We can also not know the number of women who were told this by a medical professional versus self-diagnosed. If we use medical diagnosis of poor infant weight gain as a measure of medical diagnosis (again, not ideal) we end up with 8.6-19.8%. Still, much higher than the 2-5% who likely have actual insufficient milk supply. 

There are numerous physiological conditions that are associated with decreased milk supply, and we cannot discount that the increase in the incidence of these conditions may be contributing to the increase in the number of women with insufficient milk syndrome. These conditions include: polycystic ovarian syndrome; maternal postpartum hemorrhage, retained placenta/placental fragments, thyroid conditions, insufficient glandular tissue (Anderson 2001; Willis and Livingston, 1995; Speller and Brodribb, 2012; Neifert et al., 1985 – in topical order), and mammary reduction, although this is not an exhaustive list (refs). Other conditions, such as obesity and diabetes may also interfere with lactation (Turcksin et al., 2012), particularly the onset of milk production, known as lactogenesis (Nommsen-Rivers et al., 2010). 

However, while these biological conditions may explain the initial 2-5%, and perhaps a small increase in the incidence of these conditions, it is unlikely they explain the dramatic difference we see in Table 1, with more than 50% of women who stop breastfeeding by five months reporting problems with supply.  Based on the 2009 Healthy People Data (released in 2012), 76.9% of women are initiating breastfeeding and 47.2% of infants are breastfed to 6 months! So of the babies who start breastfeeding, 61.4% are still breastfeeding at 6 months (but only 47.2%) of all infants. And, extrapolating from the 52.6% (average over the 3 categories) of women who report lack of milk as a reason for breastfeeding cessation, we end up with a crude estimate of 32.3% for IMS. Again, this is a crude estimate based on linking several different sources of numbers together and should be considered an approximation, not a set in stone number and should be viewed as a “back of the envelope calculation”. I’m using it as it is better than anything else I can find (if you know of something let me know and I will adjust the post accordingly). 

So, we have an estimated occurrence of IMS at 32.3% compared to an estimated biological frequency of 2-5%. That’s an excess of 27.3-30.3% women reporting low milk supply. Add in the nearly 4 million infants born in the same year, and we’re talking about more than 1 million women identifying with low milk supply.

It seems unlikely then, that this difference can be explained only by physiological issues, even adding in possible physiological factors with infants as well, including tongue tie (Kumar and Kalke, 2012), palate, latch, or vacuum issues (Geddes et al., 2008; Geddes et al., 2012). Certainly, it would be an oversight to suggest that these factors are not very real, not uncommon, and not contributing to overall increases in IMS. But these factors along cannot explain the difference.

Difficulties with breastfeeding, including poor latch, poor positioning, pain, nipple confusion, nipple cracking/bleeding, mastitis, are very real realities for breastfeeding mothers.  How many of these issues are the result of limited exposure to other breastfeeding women and a medical community largely unfamiliar with breastfeeding issues? Osband et al., (2011) reported that pediatric residents in the United States received an average of 9 hours of breastfeeding education (over a 3 year residency). Anchondo et al., (2012), in a survey of pediatricians, obstetricians, gynecologists, and family medicine physicians, reported that although physicians in their study had positive attitudes towards breastfeeding and information on the health benefits, hands-on knowledge was considerably lacking. Physicians also reported low breastfeeding rates and short durations themselves. Freed (1995) in a survey of more than 3000+ medical residents and physicians (68% response rate) reported that while 90% endorsed breastfeeding, less than 50% felt like they had the skills for counseling mothers. And the scariest information: for treating jaundice, clinical management was wrong more than 50% of the time and for insufficient milk syndrome, wrong about 30% of the time.  

Nine hours of training, and probably a little extra (maybe a half day at most) of training during medical school, is the sum total of the “average” physicians training in breastfeeding. I would suspect too, that some of that medical school time is allocated towards mammary anatomy (not that this is not important for understanding how breastfeeding works). And the vast majority of that time will probably be fair more theoretical than hands on/practical, if the reports from Anchondo et al., (2012) are any indication.

The lack of training, and the invisibility of possible issues related to breastfeeding, may be contributing to those excess sufferers of IMS. How many physicians for example, upon hearing that a woman has “low milk supply,” will address the feeding and not the supply issue?  One of the most common “treatments” for low milk supply is to supplement the infant with formula. Here, the focus is on the infant, and meeting the metabolic needs of the infant, without thinking about how the situation could be addressed from the maternal side.  Milk production is driven by milk removal and suckling from the breast. A complex series of hormones and neuropeptides regulate milk synthesis, and include Feedback-inhibitor of lactation (FIL), oxytocin, and prolactin. Suckling stimulates prolactin release, and while plasma prolactin does not scale to milk synthesis rate (Cox et al., 1999), prolactin promotes mRNA synthesis and the production of milk proteins.  More suckling stimulates more prolactin and maintains circulating plasma levels and milk synthesis (Cregan et al., 2002). FIL works in a different manner – FIL accumulates in milk as feeding intervals increase and the breast becomes increasingly full; increasing FIL down regulates milk synthesis within the mammary epithelial cells (Peaker et al., 1998). 

By providing the infant with formula, the entire process above is interrupted.  Infant hunger is met by formula and the amount of time spent on the breast, actively sucking, decreases. The decrease reduces the secretion of prolactin, accumulating milk increases local FIL and milk synthesis is down regulated.  Production decreases, increasing the need for formula because the mother is now making less milk. It becomes a self-fulfilling prophecy and compounds issues that may or may not have been present. The ideal solution here would be to use the system, not disrupt it. Instead of supplemental formula, increase the frequency and duration (a minimum of 3-5 minutes) of the feeds.  Not enough milk? Feed more – in most cases, the body will respond accordingly. If it does not, and the infant starts losing weight, then there is likely more troubleshooting needed. But here, the clinical practice (30% of the time) is a wrench in the physiology and likely contributes to further development of low milk supply. Poor clinical management may not explain all instances of low milk supply, but it cannot be discounted as a major player.

Thus far, we have been limited the emphasis to frequently used clinical strategies for managing self- perceived low milk supply. Here, perception of low supply has driven a specific treatment; this has further contributed to the problem.  And that is just clinical management – what about other common problems influencing breastfeeding, on both the mother and the baby’s side of things, that contribute to low milk supply?

Next time (week): tongue tie, poor latch, and other breastfeeding challenges  . . .

References

Anchondo I, Berkeley L, Mulla ZD, Byrd T, Nuwayhid B, Handal G, Akins R. (2012) Pediatricians', obstetricians', gynecologists', and family medicine physicians' experiences with and attitudes about breast-feeding. South Med J. 105(5):243-8.

Anderson AM. (2001) Disruption of lactogenesis by retained placental fragments. J Hum Lact 17(2):142-4.

Cox DB, Owens RA, Hartmann PE. (1996) Blood and milk prolactin and the rate of milk synthesis in women. Exp Physiol.  81(6):1007-20.

Peaker M, Wilde CJ. (1996) Feedback control of milk secretion from milk. J Mammary Gland Biol Neoplasia 1(3):307-15.

Cregan MD, Mitoulas LR, Hartmann PE. (2002) Milk prolactin, feed volume and duration between feeds in women breastfeeding their full-term infants over a 24 h period. Exp Physiol. 87(2):207-14

Freed GL, Clark SJ, Lohr JA, Sorenson JR. (1995) Pediatrician involvement in breast-feeding promotion: a national study of residents and practitioners.  Pediatrics 96(3 Pt 1):490-4.

Geddes DT, Langton DB, Gollow I, Jacobs LA, Hartmann PE, Simmer K. (2008) Frenulotomy for breastfeeding infants with ankyloglossia: effect on milk removal and sucking mechanism as imaged by ultrasound. Pediatrics 122(1):e188-94. doi: 10.1542/peds.2007-2553.

Geddes DT, Sakalidis VS, Hepworth AR, McClellan HL, Kent JC, Lai CT, Hartmann PE. (2012) Tongue movement and intra-oral vacuum of term infants during breastfeeding and feeding from an experimental teat that released milk under vacuum only. Early Hum Dev. 88(6):443-9. doi: 10.1016

Infant Feeding Practice Study II. http://www.cdc.gov/ifps/results/, accessed Jan 24, 2013. Page last updated October 1, 2009.

Kumar M, Kalke E. (2012) Tongue-tie, breastfeeding difficulties and the role of Frenotomy. Acta Paediatr. 101(7):687-9.