Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein

Pseudohypoparathyroidism type I is characterized by resistance (defined as a deficient urinary cAMP response) to parathyroid hormone and, in most cases, hypocalcemia and hyperphosphatemia. Many patients with pseudohypoparathyroidism type I snow a peculiar somatic phenotype termed Albright's hereditary osteodystrophy, but patients without this feature who show identical parathyroid hormone resistance have been described. Parathyroid hormone resistance in pseudohypoparathyroidism type I has been attributed to a defective parathyroid hormone receptor-adenylate cyclase complex. Recent studies have demonstrated deficient activity of the guanine nucleotide regulatory protein (G unit) of adenylate cyclase in many patients with Pseudohypoparathyroidism. Since the G unit is common to all tissues, as opposed to hormone receptors, which are tissue specific, a defective G unit should lead to resistance to multiple hormones that act by stimulating adenylate cyclase. To test this hypothesis, we studied erythrocyte G unit activity and clinical endocrine function in 29 patients with pseudohypoparathyroidism type I. Thirteen patients had deficient erythrocyte G unit activity (43 ± 9 percent of control [mean ± 1 SD]); 16 patients had normal G unit activity (92 ± 8 percent of control) (p < 0.001). Patients with deficient erythrocyte G unit activity had significantly greater (p < 0.001) basal and thyrotropin-releasing hormonestimulated thyrotropin levels than patients with normal erythrocyte G unit activity or normal control subjects (15.0 ± 6.5 and 54.3 ±22.7; 4.5 ± 2.0 and 19.5 ± 6.6; 2.0 ± 1.1 and 16.5 ± 6.7 μU/ml, respectively). In the absence of goiter or antithyroid antibody, an elevated thyrotropin level in patients with deficient erythrocyte G unit activity is consistent with thyroid resistance to thyrotropin. Furthermore, patients with deficient erythrocyte G unit activity had significantly lower (p < 0.02) integrated plasma cAMP increases to glucagon stimulation than either patients with normal erythrocyte G unit activity or normal subjects (5.1 ± 2.2 versus 8.6 ± 3.9 versus 8.6 ± 3.6 μ M × minutes), consistent with impaired hepatic cyclase responsiveness to glucagon. Clinical evidence of gonadal dysfunction was common in patients with deficient erythrocyte G unit activity, but was not observed in patients with normal erythrocyte G unit activity. These observations suggest that patients with Pseudohypoparathyroidism and deficient erythrocyte G unit activity have a disorder that is generalized to cyclase-dependent tissues, and not limited to parathyroid hormone-sensitive tissues. Moreover, it appears that patients with pseudohypoparathyroidism and normal erythrocyte G unit activity may have a defect limited to parathyroid hormone-sensitive tissues. These data support the hypothesis that a deficiency of G units is the basis for multiple hormone resistance in pseudohypoparathyroidism.