The general goal of this project is to understand the structure, function, and physiology of the human glycoprotein hormones, thyroid-stimulating hormone (TSH), choriogonadotropin (hCG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), and thereby to develop diagnostic and therapeutic clinical applications. Recent research advances include the following: First, a eukaryotic expression system for the production of recombinant human FSH in a human cell line has been developed. The human alpha and beta FSH subunit genes transfected into a human embryonal kidney cell line were expressed as an intact FSH molecule that is three times more potent than FSH extracted from human pituitary. Second, patients with the McCune-Albright syndrome were shown to commonly have thyroid dysfunction that may be clinically occult and not rapidly progressive. They had suppressed serum TSH levels, absence of other bioassayable thyroid- stimulating factors, and thyroid ultrasonographic defects indicative of multifocal autonomous function. Taken together, these results, other characteristics of the syndrome, and its sporadic nature are consistent with a somatic gene defect in the signal transduction pathway for glycoprotein hormones. Third, patients who have been treated for acute lymphoblastic leukemia with craniospinal irradiation were found to acquire subtle primary hypothyroidism, manifested by elevated serum TSH levels. Screening and treatment with thyroid hormone can be expected to improve growth and development and reduce the risk to development of thyroid cancer in these children. The future direction of the project will emphasize investigation of the structure-function relationships of FSH and the human FSH receptor through site- directed mutagenesis of their respective genes.
