Recombinant Human Prolactin(Massachusetts General Hospital)

Prolactin is a hormone that is most important for mammary development in swine. It is also essential for both the onset and the maintenance of lactation. In early studies, exogenous recombinant porcine prolactin was used to detect its biological effects on mammary tissue. In these studies, a stimulatory role of prolactin for mammary development of prepubertal gilts was demonstrated. However, when injected throughout lactation, prolactin did not increase sow milk yield likely because mammary receptors were saturated. The secretion of prolactin is largely under negative regulation via dopamine. Inhibition studies using the dopamine agonist bromocriptine showed that prolactin is required in the last third of gestation to sustain mammary development in gilts. When creating a hyperprolactinemic state during that same period, with the dopamine antagonist domperidone, differentiation of mammary epithelial cells was stimulated and milk yield in the subsequent lactation was increased. Domperidone given throughout lactation also led to greater milk yield. A study using domperidone in prepubertal gilts, however, did not reproduce the stimulatory effect of exogenous prolactin on mammary development and demonstrated that timing of the prolactin increase in relation to age of the animals is most important to elicit a response on mammary tissue. Attempts were made to use feed ingredients such as the plant extract from milk thistle, sylimarin, to stimulate prolactin secretion in sows. However, even though prolactin concentrations were increased, this augmentation was not important enough to have an impact on mammary development in late gestation or to increase milk yield. The current knowledge that hyperprolactinemia has beneficial effects for mammary development at various physiological stages and can enhance milk yield in swine leads to new avenues in elaborating strategies that could be used at the farm level to improve sow lactation performance.

Transient Pax8 expression was reported in mouse islets during gestation, whereas a genome-wide linkage and admixture mapping study highlighted PAX8 as a candidate gene for diabetes mellitus (DM). We sought the significance of PAX8 expression in mouse and human islet biology. PAX8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species-specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8. A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her father with type 2 DM but was absent in control patients. The p.T356M variant did not alter protein stability or cellular localization, whereas its transactivation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 affects islet viability and that PAX8 could be considered as a candidate gene for the study of GDM.