The influence of metabolic hormones on lactation

Thesis

Lactation is regulated by reproductive and metabolic hormones, and critical for infant and maternal health. However, the range of hormones acting on the mammary gland, their mechanisms of action, and concentrations required for milk secretion are unclear. The aims of my DPhil were to conduct clinical and cellular studies to define the normal serum hormone concentrations mediating lactation onset after childbirth, and to investigate how metabolic hormones act on mammary cells to promote lactation.

During my DPhil, I measured serum hormones in n=106 women at the onset of lactation and identified novel hormone changes during this period. Thus, maternal serum prolactin concentrations increase by approximately 20% following birth and are greater in multiparous women, who report earlier lactation onset. Thyroid stimulating hormone (TSH) increases on days 1-2 post-partum and is followed by a rise in free thyroid hormone concentrations. I have also demonstrated a novel post-partum increase in serum growth hormone (GH). Furthermore, I showed that insulin sensitivity increases post-partum, but this is impaired in women with increased BMI, a known risk factor for delayed lactation.

To investigate the mechanisms of hormone action of hormones, I used the HC11 mammary cellular model of lactation. My work showed that GH signals through the Janus kinase 2 (Jak2)- signal transducer and activator of transcription 5 (STAT5) pathway, while transcriptomic evaluation of GH-treated HC11 cells demonstrated that GH promotes synthesis of milk proteins and proteins associated with lipid synthesis. GH is therefore likely to augment the milk-synthesising actions of prolactin at lactation onset.

I also showed that insulin signals through the PI3K-Akt pathway in HC11 cells and promotes mitochondrial oxidative phosphorylation and glycolysis. In keeping with this, transcriptomic assessment of insulin-treated HC11 cells showed upregulation of genes encoding proteins in all mitochondrial electron transport chain subunits, as well as of glycolytic and pentose phosphate pathway enzymes. Insulin therefore may support the bioenergetic requirements of lactation.

In summary, my clinical and basic scientific studies investigating the endocrine regulation of lactation have provided novel insights into serum hormone changes at the onset of lactation and advanced our understanding of hormone action in mammary cells.

Authors: Rostom, H

• DOI: 10.5287/ora-0ordny10m
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: growth hormone; lactation; endocrinology; hormones; insulin; metabolism
• Subjects: Lactation; Hormones; Metabolism