Retrobulbar Modifications in Experimental Exophthalmos: The Effect of Thyrotropin and an Exophthalmos-Producing Substance Derived from Thyrotropin on the35SO4Incorporation and Glycosaminoglycan Content of Harderian Glands
Thyrotropin-induced exophthalmos in the guinea pig is associated with a 2-fold increase in the glycosaminoglycan content of the predominant tissue of the retro-orbital space, the Harderian gland. Hyaluronic acid is the major glycosaminoglycan of the normal gland and accounts for over 90% of the 2-fold increase. Sulfated glycosaminoglycans account for the remainder. Since the increase in sulfated glycosaminoglycans is proportional to the increase in hyaluronic acid, nondialyzable [35S]sulfate incorporation into the Harderian gland is a sensitive index of these glycosaminoglycan increases. Dialyzable [35S]sulfate incorporation measures an early effect of thyrotropin administration, i.e., the conversion of inorganic sulfate to an activated sulfate derivative, phosphoadenosinephosphosulfate. The glycosaminoglycan increases in exophthalmos can be induced by crude thyrotropin preparations, by purified and homogeneous preparations of thyrotropin, or by a proteolytic derivative of the thyrotropin molecule which has effectively no thyroid stimulating activity but is still exophthalmogenic in fish bioassays. This 20,000 molecular weight thyrotropin derivative is composed of an intact or nearly intact P subunit of the thyrotropin molecule and a 6,000 molecular weight fragment from the amino terminus of its a subunit. These findings indicate that thyrotropin is exophthalmogenic but that the determinant responsible for the exophthalmogenic activity is not the same as that responsible for thyroid stimulation. They suggest that the absence of thyroid stimulating activity in the serum of patients with exophthalmos does not exclude a role for thyrotropin in the pathogenesis of this disease. (Endocrinology93: 670, 1973)