Adaptation of parathyroid function to intravenous 1,25-dihydroxyvitamin D3 or partial parathyroidectomy in normal dogs

Abstract

Parathyroid function was studied in 14 normal dogs 1 month before and after daily i.v. administration of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (eight dogs), or about 50% parathyroidectomy (six dogs), to test the hypothesis that degradation of newly synthesized intact parathyroid hormone (I-PTH) is involved in parathyroid gland adjustment to a modified demand for I-PTH. Parathyroid function was studied through i.v. infusions of Na2EDTA and CaCl2 and measurement of ionized calcium (Ca2+), I-PTH and carboxyl-terminal PTH (C-PTH) at various time points. The C-PTH/I-PTH ratio was used as an index for change in the relative proportion of circulating C-PTH vs I-PTH, 1 month prior to and following each intervention. This ratio was further validated by looking at the HPLC profile of I- and C-PTH in hypo- and hypercalcemia under experimental conditions. Basal Ca2+ was unaltered 1 month after surgery, and was maintained constant in the 1,25-(OH)2D3-treated group by gradually decreasing 1,25-(OH)2D3 doses over time from 0.25 to 0.13 microgram twice daily during the last week of the experimental protocol. In this same group, basal 1,25-(OH)2D3 was increased by 65% (P < 0.0001) and basal I-PTH was decreased by 40% (P < 0.05), while basal C-PTH and the C-PTH/I-PTH ratio remained unchanged. Stimulated and non-suppressible I- and C-PTH followed the same pattern with, this time, an increase of stimulated and non-suppressible C-PTH/I-PTH ratio of 60% (P < 0.05) and 85% (P < 0.05) respectively. There was no change in basal I-PTH, C-PTH, or C-PTH/I-PTH ratio after surgery. However, stimulated I- and C-PTH were decreased by 45% (P < 0.005) and 65% (P < 0.005) respectively, with a 30% (P < 0.005) decrease of stimulated C-PTH/I-PTH ratio. There was no change in non-suppressible I-PTH, while non-suppressible C-PTH decreased by 55% (P < 0.005), with a 55% (P < 0.05) decrease in non-suppressible C-PTH/I-PTH ratio. The HPLC profiles of I- and C-PTH obtained in hypo- and hypercalcemia disclosed a similar distribution of the immuno-reactivity into peaks before and after i.v. administration of 1,25-(OH)2D3 as well as partial parathyroidectomy. This indicated that C-PTH/I-PTH ratio changes were related to different circulating levels of I- and C-PTH rather than to a different composition of I- and C-PTH. These data indicate a shift in the circulating PTH profile toward more PTH carboxyl-terminal fragments after 1 month of i.v. 1,25-(OH)2D3, but toward more intact PTH 1 month after about 50% parathyroidectomy, possibly reflecting adjustments in PTH degradation induced by a modified demand for I-PTH. Although these changes are most likely modulated at the parathyroid gland level, we cannot formally eliminate participation of the hormone's peripheral metabolism.