Regulation of 1,25(OH)₂D synthesis in hypoparathyroidism and pseudohypoparathyroidism

We examined the regulation of 1,25-dihydroxyvitamin D [1,25(OH)₂D] synthesis in patients with hypoparathyroidism (n = 5) and pseudohypoparathyroidism (n = 5) by administration of parathyroid extract (PTE) and N⁶,O²-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP) and by phosphorus deprivation with antacids. In response to PTE, patients with hypoparathyroidism increased serum 1,25(OH)₂D from 17 ± 5 to 30 ± 5 (SD) pg/ml (P < 0.01). An approximate doubling of the 1,25(OH)₂D concentration also occurred following dbcAMP infusion or phosphorus deprivation (serum phosphorus 4.4 ± 0.5 to 2.6 ± 1.1, P < 0.01). Serum phosphorus and 1,25(OH)₂D concentrations were inversely correlated (r = -0.73, P < 0.001). Patients with pseudohypoparathyroidism had negligible responses to PTE with respect to urinary adenosine 3',5'-cyclic monophosphate excretion, serum phosphorus concentration, or 1,25(OH)₂D synthesis. They did show a rise in serum 1,25(OH)₂D from 17 ± 4 to 44 ± 5 pg/ml (P < 0.001) in response to dbcAMP infusion. During phosphorus deprivation, serum phosphorus decreased from 4.1 ± 0.8 to 3.2 ± 1.2 mg/dl (P < 0.05), but there was no change in serum 1,25(OH)₂D concentration or any correlation between serum phosphorus and 1,25(OH)₂D levels. Although reduction in mean serum phosphorus levels was generally not as great in patients with pseudohypoparathyroidism, one such patient attained serum phosphorus of 1.2 mg/dl and still did not increase serum 1,25(OH)₂D concentration. In addition to an abnormal parathyroid hormone receptor-adenylate cyclase complex, patients with pseudohypoparathyroidism appear to have an abnormal renal 1α-hydroxylase, which does not respond appropriately to phosphate deprivation.