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Hormonal regulation of mammary gland development and lactation

Abstract

Lactation is critical to infant short-term and long-term health and protects mothers from breast cancer, ovarian cancer and type 2 diabetes mellitus. The mammary gland is a dynamic organ, regulated by the coordinated actions of reproductive and metabolic hormones. These hormones promote gland development from puberty onwards and induce the formation of a branched, epithelial, milk-secreting organ by the end of pregnancy. Progesterone withdrawal following placental delivery initiates lactation, which is maintained by increased pituitary secretion of prolactin and oxytocin, and stimulated by infant suckling. After weaning, local cytokine production and decreased prolactin secretion trigger large-scale mammary cell loss, leading to gland involution. Here, we review advances in the molecular endocrinology of mammary gland development and milk synthesis. We discuss the hormonal functions of the mammary gland, including parathyroid hormone-related peptide secretion that stimulates maternal calcium mobilization for milk synthesis. We also consider the hormonal composition of human milk and its associated effects on infant health and development. Finally, we highlight endocrine and metabolic diseases that cause lactation insufficiency, for example, monogenic disorders of prolactin and prolactin receptor mutations, maternal obesity and diabetes mellitus, interventions during labour and delivery, and exposure to endocrine-disrupting chemicals such as polyfluoroalkyl substances in consumer products and other oestrogenic compounds.

Key points

  • Reproductive and metabolic hormones coordinate the transformation of the mammary gland from a rudimental ductal structure at the onset of puberty into a milk-secreting organ by the end of pregnancy.

  • Lactation onset is mediated by a combination of progesterone withdrawal, circulating and mammary gland-derived prolactin, and glucocorticoids; delayed lactation onset is a major cause of early breastfeeding cessation.

  • Established lactation requires prolactin and oxytocin for milk synthesis and let-down and involves mammary autocrine and paracrine mechanisms triggered by breast emptying; these local mechanisms remain to be elucidated.

  • The mammary gland is an endocrine organ that secretes hormones into the maternal circulation and milk; hormones in milk influence infant development, body composition and the microbiome.

  • Lactation insufficiency is caused by genetic and acquired endocrine disturbances; maternal factors with potential endocrine effects on lactation include primiparity, obesity, preterm birth, Caesarean section and retained placental fragments.

  • Endocrine-disrupting chemicals are environmental pollutants that might affect lactation by altering hormone secretion or mammary gland hormone responsiveness; epidemiological studies highlight potential population-wide effects on breastfeeding.

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Fig. 1: Reproductive and metabolic hormones involved in mammary gland development, lactation and involution.
Fig. 2: Hormones involved in secretory activation and the establishment of lactation.
Fig. 3: Prolactin signalling in MECs.
Fig. 4: Mammary gland PTHrP secretion and effects on maternal calcium mobilization.
Fig. 5: EDCs affect organs that support lactation as well as the developing fetus.

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Acknowledgements

The support of the Family Larsson-Rosenquist Foundation (to F.M.H. and S.H.K.) is gratefully acknowledged. R.V.T. has received a Wellcome Trust Investigator Award (grant number 106995/Z/15/Z); National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme, and NIHR Senior Investigator Award (grant number NF- SI-0514–10091). L.N.V. has received a National Institutes of Health (NIH) grant (grant number U01ES026140). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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F.M.H., T.E. and L.N.V. researched data for the article and wrote the manuscript. S.H.K. and R.V.T. reviewed and edited the manuscript. All authors made substantial contributions to discussion of the content.

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Correspondence to Fadil M. Hannan.

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Competing interests

L.N.V. has been reimbursed for travel expenses by numerous organizations, including SweTox, Israel Environment Fund, the Mexican Endocrine Society, Advancing Green Chemistry, ShiftCon, US EPA, CropLife America, BeautyCounter, and many universities, to speak about endocrine-disrupting chemicals. L.N.V. also serves as a paid scientific adviser to SUDOC, LLC. S.H.K. holds a grant from the Family Larsson-Rosenquist Foundation to help the global dissemination of the INTERGROWTH-21st Preterm Postnatal Growth Standards and feeding recommendations, which include the use of human milk. The other authors declare no competing interests.

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Glossary

Mammary rudiment

Small mammary ductal tree that develops in utero.

Secretory differentiation

Alveolar luminal cells begin to synthesize milk components and accumulate cytoplasmic lipid droplets.

Secretory activation

The initiation of copious milk secretion.

Galactopoiesis

The continued synthesis and secretion of milk.

Colostrum

Initial mammary secretions produced after childbirth that are rich in immunological components.

Alactogenesis

Absence of lactation postpartum.

2,3,7,8-Tetrachlorodibenzo-p-dioxin

(TCDD). A persistent organic pollutant and toxic compound produced during the synthesis of chlorophenol and chlorophenoxy acid herbicides.

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Hannan, F.M., Elajnaf, T., Vandenberg, L.N. et al. Hormonal regulation of mammary gland development and lactation. Nat Rev Endocrinol 19, 46–61 (2023). https://doi.org/10.1038/s41574-022-00742-y

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