We measured human chorionic gonadotropin (hCG) and its subunits in 76 patients with islet-cell tumors. Seventeen of 27 patients with functioning islet-cell carcinomas had elevated plasma levels of hCG or one of its subunits (hCG-alpha and hCG-beta). Secretion was often discordant; the most frequent finding was an elevated level of hCG-alpha alone. In one patient responding to streptozocin, changes in hCG-alpha correlated with the clinical course. Studies of tumor extracts suggested that the markers observed in the circulation were being produced in the tumor itself. In contrast, none of the 43 patients with benign disease or the six patients with nonfunctioning malignant tumors had elevated levels of hCG, hCG-alpha or hCG-beta. These data show that hCG and its subunits are prevalent and specific markers for islet-cell carcinoma, and suggest that ectopic secretion results from malignant derepression of the genome rather than overproduction by an aberrant "cell rest."

The rate of formation of human chorionic gonadotropin from its alpha and beta subunits has been measured at neutral pH and 37 degrees C as a function of subunit concentration, using the fluorescence probe, 1,8-anilinoaphthalene-sulfonate (ANS), to monitor the reaction. The subunits were prepared by acid dissociation of the intact hormone (pH less than or equal to 2, 37 degrees C). Following neutralization, the rate of appearance of ANS fluorescence was identical with the rate of recovery of receptor binding activity and both of these properties were completely recovered. Kinetic data obtained over a 100-fold range of subunit concentrations (1.5 to 146 muM) were not compatible with a simple second-order reaction scheme, but required at least one additional step. The data were best fit by a model in which the subunits reversibly form an intermediate complex (alpha + beta in equilibrium alphabeta) which then undergoes a conformational rearrangement to form the native structure (alphabeta leads to H). Ultraviolet difference absorption measurements suggest that most of the change in the environment of the tyrosyl residues occurs during this second step.

Thyroid-stimulating hormone (TSH) in tumor and serum of mice with thyrotropic tumors was studied by radioimmunoassay (RIA), radioreceptor assay (RRA) and thyroid adenylate cyclase assay (ACA). In unfractionated samples, serum TSH displayed significantly higher ACA/RIA (0.69 +/- 0.10) and ACA/RRA ratios (0.79 +/- 0.04) than TSH in tumor extracts (0.45 +/- 0.05 and 0.31 +/- 0.01, respectively). After gel chromatography, both tumor and serum TSH activity measured in RIA and RRA eluted in broad, heterogeneous peaks with an apparent molecular weight range of 26,000 - 44,000 daltons. The ACA activity of tumor TSH eluted in 2 sharp peaks (26,000 and 44,000) while that of serum TSH eluted in 3 peaks (26,000, 33,000 and 44,000). The ACA/RIA and ACA/RRA ratios varied greatly among the chromatography fractions, the lowest ratios being detected in the tumor TSH of 33,000 daltons (0.02 for each) and the highest ratios in both tumor and serum TSH of 26,000 (ACA/RIA = 1.60 - 1.90, ACA/RRA = 1.12 - 1.20). Since previous biosynthetic studies have suggested that such heterogeneous forms of mouse tumor TSH differ solely in carbohydrate content, our data suggest that the biologic activity of TSH may be modulated by its glycosylation.