Common and specific effects of the two major forms of prolactin in the rat testis

1 Division of Biomedical Sciences, University of California, Riverside, California; 2 Laboratory of Veterinary Physiology, School of Veterinary Medicine and Animal Sciences, Kitasato University, Towada, Aomori, Japan; 3 Center for Plant Cell Biology, Department of Botany and Plant Sciences, University of California, Riverside, California Submitted 18 August 2007 ; accepted in final form 30 September 2007 Prolactin (PRL) has both stimulatory and inhibitory effects on testicular function, a finding we hypothesized may be related in some part to the form of the hormone present or administered. In the analysis of the pituitary secretion profiles of early pubescent vs. mature male rats, we found PRL released from early pubescent pituitaries had about twice the degree of phosphorylation. Treatment of mature males with either unmodified PRL (U-PRL) or phosphorylated PRL (via the molecular mimic S179D PRL) for a period of 4 wk (circulating level of 50 ng/ml) showed serum testosterone decreased by 35% only by treatment with the phospho-mimic S179D PRL. Given the specificity of this effect, it was initially surprising that both forms of PRL decreased testicular expression of 3β-hydroxysteroid dehydrogenase and steroidogenic acute regulatory protein. Both forms also increased expression of the luteinizing hormone receptor, but only S179D PRL increased the ratio of short to long PRL receptors. Endogenous PRL and luteinizing hormone levels were unchanged in all groups in this time frame, suggesting that effects on steroidogenic gene expression were directly on the testis. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling analysis combined with staining for 3β-hydroxysteroid dehydrogenase and morphometric analysis showed that S179D PRL, but not U-PRL, increased apoptosis of Leydig cells, a finding supported by increased staining for Fas and Fas ligand in the testicular interstitium, providing an explanation for the specific effect on testosterone. S179D PRL, but not U-PRL, also increased apoptosis of primary spermatogonia, and U-PRL, but not S179D PRL, decreased apoptosis of elongating spermatids. Thus, in mature males, hyperprolactinemic levels of both forms of PRL have common effects on steroidogenic proteins, but specific effects on the apoptosis of Leydig and germ cells. phosphorylated prolactin; S179D prolactin; apoptosis; Leydig cells; testosterone; 3β-hydroxysteroid dehydrogenase; steroidogenic acute regulatory protein; lu