Hypercalcemia and neoplasia. Biologic, biochemical, and ultrastructural studies of a hypercalcemia-producing Leydig cell tumor of the rat.

A localized, transplantable testicular tumor of the Fischer rat regularly produces hypercalcemia and increased phosphorus clearance in host animals. Light and electron microscopic examinations of the tumor indicate that it is of Leydig origin. There is no evidence that the tumor secretes any biologically active sex steroids, judges by weights of target tissues, when the tumor is grown in castrated or spayed rats. No radioactive steroid hormone formation in vitro was detected using 1-14C-acetate as a precursor although 14C was incorporated into the "C27" sterol fraction. Mass (micrograms) amounts of sex steroids were not detected after purifying large amounts of tumor extracts. The phytosterols, beta-sitosterol, stigmasterol, campesterol, were tentatively identified in tumor extracts but were also found in other tissues and in tumors not associated with hypercalcemia. Administered in vivo, human chorionic gonadotropin caused an acute rise in serum calcium in 3 to 5 hours in tumor-bearing hypercalcemic rats. Only trophic hormones with luteinizing hormone activity were found to compete with 125I-human chorionic gonadotropin for binding to the tumor homogenate in vitro indicating the tumor possessed luteinizing hormone receptors. When the tumor was transplanted intrasplenically, hypercalcemia did not occur unless adhesions formed, suggesting that the tumor hormone was rapidly metabolized by the liver and was probably of small molecular weight. Secretory granules, usually thought to be associated with peptide hormone secretion, were not detected at the ultrastructure level. Cortisol, conjugated estrogen, and an inhibitor of sterol biosynthesis (AY-9944) were effective in lowering the elevated serum calcium. Definitive identification of the agent causing lethal hypercalcemia has not been accomplished. The available data suggest it is not parathyroid hormone or vitamin D. The Leydig cell origin of the tumor, its response to human chorionic gonadotropin in vivo, the lack of secretory granules at the ultrastructural level, and biologic characteristics, all lead to the speculation that the secretory product of the tumor is a new hormonal substance, possibly a steroid precursor or related substance not previously described or is a known substance of small molecular weight whose calcium-mobilizing properties have not been fully characterized. This transplantable tumor may represent a model for one form of neoplastic hypercalcemia occurring in man and may have important implications in the general area of calcium and phosphorus homeostasis.