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The Making of a Milk Factory Objectives . List the major factors necessary for good milk production . Describe the role of the placenta in mammary gland development during pregnancy. Explain two ways that environmental The Making of a Milk Factory contaminants may interfere with reproductive hormones © 2019 Lisa Marasco MA, IBCLC, FILCA Hormones and Receptors The Milk Supply Equation SUFFICIENT GLANDULAR TISSUE + INTACT NERVE PATHWAYS & DUCTS + ADEQUATE HORMONES & RECEPTORS + ADEQUATE LACTATION-CRITICAL NUTRIENTS + ADEQUATE & EFFECTIVE MILK REMOVAL (Good management, effective baby) = GOOD MILK SUPPLY Directors of the process Important players by stage Hormones important to milk production Puberty Pregnancy Lactation Insulin Estrogen Estrogen Cortisol Lactogenic Progesterone Progesterone Complex HPL Prolactin Chorionic Gonadotropin Maintains metabolism; Growth Hormone Growth Hormone Thyroxine - Supports & directs IGF-1 IGF-1 PTPRF pituitary Prolactin Prolactin Insulin Insulin Regulate mammary blood Cortisol Cortisol PTHrP - flow; calcium transport and Thyroxine Thyroxine homeostasis PTHrP PTHrP Oxytocin Oxytocin - milk delivery With permission: Andaluz Waterbirth Center © Lisa Marasco 2019 1 The Making of a Milk Factory Hormone receptors 101 Hormone Receptors 201 Hormones- travel thru blood or synthesized locally Dynamic: Expressed by genes ER α, β Expressed PR α, β R Up & down regulation where and PRLR L, S Can be resistant as needed OTR H Can be hypersensitive Can be influenced positively or negatively by other hormones Receptors: Integral to hormone function, located on “target tissues,” on or in cells Can be influenced by environment The Big Construction Picture PR-A Phase I ER PR-B ERα Series of stages of organo-genesis lasting until ERβ PRLrL adulthood that are irreversible (fetal through puberty) PR-B Phase II Series of changes involving growth and secretory differentiation of the lobulo-alveolar system that are reversible Estrogen Prolactin Progesterone (Preg, lactation, involution) Horseman, N. D. (1999). Prolactin and mammary gland development. J Mammary Gland Biol Neoplasia, 4(1), 79-88. Hormones can have multiple receptors for different effects Fat Pad: the scaffolding of breast development Sufficient lactation tissue starts during Fetal Development Primitive framework Macias et al. WIREs Dev Biol 2012. DOI: 10.1002/ wdev.35, Copyright © 2012 Wiley Periodicals, Inc. © Lisa Marasco 2019 2 The Making of a Milk Factory Pubertal 1 Development Puberty 2 3 Development of fad pad 4 Elongation of ducts into pad Growth velocity Skeleton team of alveoli vs 5 Tanner stages Tanner Staging Marshall, W., & Tanner, J. (1969). Variations in pattern of pubertal changes in girls. Archives of Disease in Childhood, 44(235), 291. Pubertal breast growth window ~10 yrs to 14-16 yrs The completed breast End of Puberty: Completion of the Milk Factory clavicle Vertical span 1 ~ ribs 2 to 6 Basic structure is in place 2 Awaiting start-up 3 Horizontal span 4 ~midaxillary 5 to sternum 6 ~50% glandular up to age 35 Shermak, 2010 Phase II Starts with a new pregnancy Pregnancy hormones Pituitary: “Mammotropic” Prolactin Proliferation hormones synthesized Milk making locally in breast Thyroid: cells multiply Prolactin, Progesterone, Thyroxine Estrogen, relaxin, epidermal GF, PTHrP Differentiation Placental: Milk-making cells enlarge and mature, HPL, HCG, Ovarian: developing Terminal estrogen, Estrogen End Buds (TEBs) progesterone Progesterone © Lisa Marasco 2019 3 The Making of a Milk Factory PTHrP - an unsung hero Pregnancy Development: The Critical Role of the Placenta *Present in mammary gland, human milk, mother and baby’s blood Progesterone after 3mo all from placenta Glandular development: Human Placental Lactogen Stimulates mammary branching morphogenesis (HPL) only produced in Essential for proper development placenta Lactation: Level of HPL correlates most Increases Ca+ transport from blood to milk closely with breast volume change Regulates mammary blood flow Regulates myoepithelial cell tone illustration courtesy of T. John Martin FRS Influence of multiples pregnancy Normal Pregnancy Development Image courtesy of Triumph International and bubhub.com.au General signs of successful mammogenesis: More placenta = more mammary gland growth Increased breast sensitivity, nipple changes, enlargement, expressible colostrum at end of pregnancy Ukrainian research 245 VIRGINS AND NULLIPAROUS WOMEN- OBSERVATIONS: Development occurs at an uneven rate Some parts of breast mature while others lag in intermediate stage During pregnancy these parts continue uneven growth, and not all are “sufficiently complete” by labor Conclusion: This may contribute to some cases of “primary hypogalactia” in first time mothers Used with permission Morozova, M. G. (1961). [The significance of underdeveloped tissue of the mammary gland in the development Hennighausen, L., & Robinson, G. W. (2005). Information networks of the so-called primary hypolactation.]. Akush Ginekol (Mosk), 37, 43-50. in the mammary gland. Nat Rev Mol Cell Biol, 6(9), 715-725. © Lisa Marasco 2019 4 The Making of a Milk Factory More Ukrainian research Findings ~1:1 ~2:1 N= 58 pregnant & 21 pp c-sect non-lactating Fat progressively displaced by lactating glandular & connective tissue Measured changes in mammary gland composition during pregnancy (started at 6- 12wks gestation) Classified women by prevalence of glandular, Speed and intensity of changes varied mixed or adipose in ≥ 3 of 4 quadrants “Proportion of secretory and fat tissues in the breasts can be used for prognosis of lactation activity….” Morozova N, OM P. Clinical ultrasonographic correlations of lactation. Pediatria, akusherstvo ta gynekologia. 1997(5):64-65. Morozova N, OM P. Clinical ultrasonographic correlations of lactation. Pediatria, akusherstvo ta gynekologia. 1997(5):64-65. Ramsay et al. (2005). Anatomy of the lactating human breast redefined with ultrasound imaging. Journal of Anatomy, 206(6), 525-534. Influence of Age Anatomy of a lactating breast Glandular tissue gradually regresses, Parenchyma replaced by fatty/stromal tissue Glandular portion Left: 63% ± 9% (range 46-83%) Right: 65 ± 11% (range 45-83%) Interesting side notes: Age ≥ 30 Large proportion of glandular associated with delayed lactation tissue located within 30mm Nommsen-Rivers, 2010 of nipple base Stroma Milk intake decreased 25g for each 5-year Connective tissue increment of age Marquis, 2002 Adipose tissue Ligaments Ramsay et al. (2005). Anatomy of the lactating human breast redefined with ultrasound imaging. Journal of Anatomy, 206(6), 525-534. Anatomy of a lactating breast Phase II end: Involution Dismantling and disposal of equipment Macias 2012 no longer needed Remodeling Ramsay et al. (2005). Anatomy of the lactating human breast redefined H Macias et al. WIREs Dev Biol 2012. with ultrasound imaging. Journal of Anatomy, 206(6), 525-534. DOI: 10.1002/ wdev.35, Copyright © 2012 Wiley Periodicals, Inc. © Lisa Marasco 2019 5 The Making of a Milk Factory Stages of postnatal mammary gland development In human women, lasts up to 2 weeks Shore, A. N., & Rosen, J. M. (2014). Regulation of H Macias et al. WIREs Dev Biol 2012. mammary epithelial cell homeostasis by lncRNAs. DOI: 10.1002/ wdev.35, Copyright © 2012 Wiley Periodicals, Inc. Illustration depicting the two Life cycle of the breast in reproduction stages of mammary gland involution. Upon weaning, the gland is remodeled back Winter: Dormant breast to its prepregnancy state. Stage 1 is reversible and is regulated largely by STAT3 Fall: Spring: Involution & Pregnancy Stage 2 is irreversible and “remodeling” blossoming characterized by alveolar of the breast of breast collapse and adipocyte differentiation Lactation: the fruit H Macias et al. WIREs Dev Biol 2012. DOI: 10.1002/ wdev.35, Copyright © 2012 Wiley Periodicals, Inc. of summer Influence of parity Glands from parous animals reacted more robustly to a subsequent pregnancy dos Santos, et al. (2015). An epigenetic memory of pregnancy in Used with permission. the mouse mammary gland. Cell Reports, 11(7), 1102-1109. http://www.veltmaatlab.net/research.html © Lisa Marasco 2019 6 The Making of a Milk Factory Response to pseudo-pregnancy hormones after 6 & 12 days tx Factors that can disrupt development: Construction gone awry “Pregnancy leaves an epigenetic memory Effects of uteroplacental insufficiency O'Dowd et al, 2008. Progesterone Tx rescues mammary impairment L6 Mammary wt ↓, Control, Restricted, Restricted + P Reduced Litter to Wlodek, 2009 PTHrP ↓ Na/K ↑ . Uterine restriction induced GD18 Sham Control 5 pups after birth Pup milk intake ↓ . Progesterone 1mg/kg on GD20 Normal levels, .Restricted- less alveoli, fewer blood Sham Control lactation vessels, more adipose stroma control Maternal mammary PTHrP content was correlated with control milk lactose concentration, which directly relates to volume GD22: BWs ↓ 16%, GD 20 Lier # ↓ 25%; litter size ↓ 36% control P ↓ 46%, α-lac mRNA control Restricted Group ↑ 113% L6 Mammary wt ↓, milk lactose ↓, PTHrP ↓ ↓, control Day 22 Ligation GD 18 birth Premature Lact II triggered Na/K ↑ Subsequent involution Pump milk intake ↓ control Used with permission of Dr. Paul Kenyon Growth restricted 28% Day 22 *Milk production gradually picked up for RG birth Body wt reduct ↑ to 36% Impact of pregnancy problems Risk factors Effects of early delivery on mammary growth Baby SGA/IUGR Hypertension Implications of SGA baby for placental function © Lisa Marasco 2019 7 The Making of a Milk Factory Impact of pregnancy
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