Progestins specifically suppress alpha-lactalbumin synthesis and secretion

Mammary gland explants from pregnant (day 12-15) rats were cultured with insulin and prolactin, and their content and secretion of alpha-lactalbumin determined after exposure to a wide range of doses (0.01-300 nM) of the specific synthetic progestin (ORG2058), alone or with a maximally stimulatory dose of the highly specific glucocorticoid RU26988. ORG2058 alone suppressed alpha-lactalbumin synthesis below baseline, with a half-maximal effect at a concentration of less than 0.1 nM; RU26988-stimulated secretion was similarly abrogated by ORG2058, similarly with a half maximally effective dose of less than 0.1 nM. We interpret these data as suggesting that (i) given the specificity and doses of the steroids used the effect of progestins on alpha lactalbumin synthesis is directly via progesterone receptor occupancy, and not by competing with glucocorticoids for glucocorticoid receptors and (ii) given the shift to the left in the alpha-lactalbumin response (half maximal less than 0.1 nM ORG2058) compared with receptor binding (Kd (37 degrees C) greater than 1 nM), one possible model for such sensitivity is that of multiple, independent regulatory elements on the chromatin controlling alpha-lactalbumin gene expression, occupancy of any one of which by an activated progesterone receptor is sufficient to abrogate transcription.