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

Michael A. Levine, Robert W. Downs, Arnold M. Moses, Neil A. Breslau, Stephen J. Marx, Roz D. Lasker, Rene E. Rizzoli, Gerald D. Aurbach, Allen M. Spiegel

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209 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)545-556
Number of pages12
JournalThe American Journal of Medicine
Volume74
Issue number4
DOIs
StatePublished - Apr 1983
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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