Unmodified Prolactin (PRL) Promotes PRL Secretion and Acidophil Hypertrophy and Is Associated with Pituitary Hyperplasia in Female Rats

Abstract

In this study, we have tested the hypothesis that unmodified prolactin (U-PRL) and phosphorylated prolactin (P-PRL) have differential roles in the autoregulation of PRL secretion in vivo. Recombinant human U-PRL and a molecular mimic of P-PRL (S179D PRL) were administered to male rats and to female rats in different physiological states and the effect on rat PRL release was measured. Administration of U-PRL elevated rat PRL in all female animals, but was without effect in males. By contrast, S179D PRL was inactive in females, but inhibited PRL release in males. Morphometric and immunohistochemical analyses demonstrated acidophil hypertrophy and evidence of increased PRL secretion in the pituitaries of U-PRL-treated females. Analysis of the two forms of PRL during prolactinoma induction in two differentially susceptible strains of rats found a strong temporal correlation among increased ratios of U-PRL: P-PRL, increased circulating PRL, and increased cell proliferation. We conclude (1). that the autoregulatory mechanism(s) can distinguish between the two major forms of PRL and that higher proportions of U-PRL not only allow for higher circulating levels of PRL, but are also autostimulatory, (2). that the autoregulatory mechanism( s) are set differently in males and females such that females are more sensitive to autostimulation by U-PRL and less sensitive to inhibition by P-PRL, and (3). that U-PRL and P-PRL may also have differential roles in the regulation of pituitary cell proliferation.

S179D prolactin: Antagonistic agony!

“…In addition, treatment of primary anterior pituitary cells with estrogen decreases phosphorylation (Liu and Walker, 1994), and treatment of rats with estrogen results in the coincident appearance of pituitary tumors and loss of PRL phosphorylation (Johnson et al, 2003). GH3 pituitary tumor cells do not normally phosphorylate PRL, but can be induced to do so by incubation in phosphorylated PRL (see later section including autoregulation) or by high concentrations of insulin .…”

“…a proportion as normally extracted from the pituitary) inhibits cell proliferation (Krown et al, 1992).This is in addition to the induction of intracellular phosphorylation of endogenous PRL and the production of secretory granules described above. Phosphorylated PRL also acts as an autocrine inhibitor of further PRL release from primary pituitary cells in culture (an ultra short loop feedback mechanism), whereas unmodified PRL has a feed-forward loop Krown et al, 1992;Johnson et al, 2003). Moreover, dephosphorylation of partially phosphorylated pituitary extract PRL stimulates GH3 cell proliferation (Krown et al, 1992).…”

Intracerebroventricular administration of the prolactin (PRL) receptor antagonist, S179D PRL, disrupts parturition in rats

“…S179D PRL reduces endogenous PRL release when administered peripherally to male animals (Johnson et al 2003). Female animals are somewhat more resistant to this effect (Johnson et al 2003), but central rather than peripheral administration may well have resulted in greater sensitivity in the current experimental animals.…”

“…S179D PRL reduces endogenous PRL release when administered peripherally to male animals (Johnson et al 2003). Female animals are somewhat more resistant to this effect (Johnson et al 2003), but central rather than peripheral administration may well have resulted in greater sensitivity in the current experimental animals. Although for the sake of simplicity S179D PRL has been referred to throughout as a PRL receptor antagonist, it achieves this activity both by blockade of signaling from PRL (Schroeder et al 2003) and by the generation of an alternate signal (Wu et al 2003).…”

S179D prolactin diminishes the effects of UV light on epidermal gamma delta T cells

“…Also unknown at present is the ratio of unmodified to phosphorylated PRL found under conditions of hyperprolactinemia or chronic stress in the human population. What is known in rodents is that hyperprolactinemia due to prolactinomas is characterized by a lack of phosphorylation of the released PRL (Johnson et al, 2003;Krown et al, 1992).…”