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Colony-Stimulating Factor-1 Plays a Major Role in the Development of Reproductive Function in Male Mice

Department of Developmental and Molecular Biology (P.E.C., J.W.P.), Department of Obstetrics and Gynecology (J.W.P.), Albert Einstein College of Medicine, Bronx, New York 10461,
Population Council and The Rockefeller University (M.P.H.), New York, New York 10021

Colony-stimulating factor-1 (CSF-1) is the principal regulator of cells of the mononuclear phagocytic lineage that includes monocytes, tissue macrophages, microglia, and osteoclasts. Macrophages are found throughout the reproductive tract of both males and females and have been proposed to act as regulators of fertility at several levels. Mice homozygous for the osteopetrosis mutation (csfm^op) lack CSF-1 and, consequently, have depleted macrophage numbers. Further analysis has revealed that male csfm^op/csfm^op mice have reduced mating ability, low sperm numbers, and 90% lower serum testosterone levels. The present studies show that this low serum testosterone is due to reduced testicular Leydig cell steroidogenesis associated with severe ultrastructural abnormalities characterized by disrupted intracellular membrane structures. In addition, the Leydig cells from csfm^op/csfm^op males have diminished amounts of the steroidogenic enzyme proteins P450 side chain cleavage, 3ß-hydroxysteroid dehydrogenase, and P450 17-hydroxylase-lyase, with associated reductions in the activity of all these steroidogenic enzymes, as well as in 17ß-hydroxysteroid dehydrogenase. The CSF-1-deficient males also have reduced serum LH and disruption of the normal testosterone negative feedback response of the hypothalamus, as demonstrated by the failure to increase LH secretion in castrated males and their lack of response to exogenous testosterone. However, these males are responsive to GnRH and LH treatment. These studies have identified a novel role for CSF-1 in the development and/or regulation of the male hypothalamic-pituitary-gonadal axis.

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