PROGESTIN-INDUCED GROWTH-HORMONE EXCESS IN THE DOG ORIGINATES IN THE MAMMARY-GLAND

In the dog endogenous progesterone and synthetic progestins may incite overproduction of GH, resulting in acromegaly and insulin resistance. This progrestin-induced excessive GH secretion is characterized by di sappearance of the pulsatile secretion pattern and insensitivity to bo th stimulation with GHRH and inhibition with a somatostatin analog. Th is progestin-induced GH hypersecretion is not associated with neoplast ic transformation at the pituitary level. These observations were the impetus for a search of a possible extrapituitary site of GH productio n. In four ovariohysterectomized dogs elevated plasma GH levels (46.5 +/- 7.7 mu g/liter; mean +/- SEM) were induced by administration of sy nthetic progestins. In these dogs hypophysectomy did not led to a sign ificant decrease in plasma GH levels. Analysis of the GH content of va rious tissue homogenates revealed that the highest GH immunoreactivity was found in extracts of the mammary gland. Ectopic production of GH in the mammary gland was confirmed by lowering of plasma GH concentrat ion to values within the reference range within 2 h after complete mam mectomy in two dogs with progestin-induced elevations of plasma GH lev els. In one of these dogs the arterial and venous GH concentrations ac ross the mammary gland were measured and an arterio-venous GH gradient was demonstrated. Displacement studies in the RIA and analysis by rev ersed-phase HPLC revealed that mammary-derived GH is highly similar to pituitary-derived GH. Immuno-histochemical staining revealed that GH immunoreactivity was localized in focal areas of hyperplastic ductular epithelium. In mammary tissue of healthy untreated female dogs no GH immunoreactivity was found. It is concluded that treatment of dogs wit h synthetic progestins can induce the overproduction of GH in the mamm ary grand. This GH is biologically active, highly similar to pituitary derived GH, and originates from foci of hyperplastic ductular epithel ium of the mammary gland.