The Declining Phase of Lactation: Peripheral or Central, Programmed or Pathological?

Abstract

In most species the functional activity of the mammary gland during lactation follows a biphasic developmental pattern. This pattern starts with a rapid increase in milk output that occurs with secretory activation and continues with a more gradual increase until the point of peak lactation is reached. Following this gain-of-function phase, the ability of the gland to produce milk decreases. This decrease occurs even if the lactation is prolonged by the presence of continued suckling stimulus and complete milk removal. This review describes the current state of our knowledge concerning the factors that regulate milk synthesis capacity by the mammary gland during the lactation cycle. The review describes four potential alternatives as mechanisms governing the process, which we refer to as secretory diminution. These alternatives are not presented as mutually exclusive of each other or other possible mechanisms, but are proposed as potential contributing mechanisms.

Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression

“…Surprisingly, neither the expression of SOCS3 nor the phosphorylation of STAT5 was increased in the mammary glands of PRL-injected dams. Our own previous work on PRL signaling has shown that the recombinant murine PRL used in the present study is capable of inducing mammary STAT5 phosphorylation when administered intravenously to lactating mice (Hadsell et al 2007). In addition, others have demonstrated that exogenous GH and PRL increased the expression of SOCS3 in the mammary tissue of virgin mice (Le Provost et al 2005).…”

“…The second caveat is that mammary gland morphology and wet weight could have been influenced by the timing of tissue sampling relative to the last nursing event between each dam and its pups. While this is meritorious, published data on maternal behavior in rodents, including our own analysis of maternal behavior in mice during prolonged lactation, suggest that because sample collection took place during the day (1000-1200 h), the time period of separation between the dam and its litter would have been no longer than 20 min and was probably much shorter (Sodersten & Eneroth 1984, Hoshino et al 2006, Hadsell et al 2007). These observations strongly support the conclusion that the effects of GH and LR3 were mediated through changes in milk production.…”

“…This enhancement of lactation persistence has been suggested to be a valuable means of improving the well-being of dairy animals as well as enhancing profitability of dairy operations (van Amburgh et al 1997). To take advantage of the power of mouse genetics, our laboratory has developed a litter cross-fostering approach that allows for studies on lactation persistence to be conducted using mice as a model for dairy animals (Hadsell et al 2006(Hadsell et al , 2007. Following this approach, we demonstrated increased lactation persistence in a strain of transgenic mice (WAP-DES) that overexpress des(1-3)human IGF-I (hIGF-I) within the mammary gland (Hadsell et al 2005).…”

“…Studies in our own laboratory have demonstrated that i.v. injection of recombinant murine PRL into the tail vein of a lactating mouse profoundly increases mammary STAT5 phosphorylation within minutes (Hadsell et al 2007). On the other hand, IGF-I signals through several pathways including the phosphoinositide 3 (PI3)-kinase/Akt and JAK/STAT pathways (Dudek et al 1997, Gual et al 1998).…”

“…Our own studies using i.v. injections of the long-R3 (LR3) analog of IGF-I, a form that has enhanced potency due to an inability to interact with IGF-binding proteins, demonstrated increased phosphorylation of both Akt and STAT5 within the mammary gland within minutes of injection (Lee et al 2003, Hadsell et al 2007. Although these observations suggest that both ligands have the capacity to activate shortterm signaling events within the mammary tissue of lactating mice, the effects of chronic treatment via s.c. injections have not been studied.…”