Lack of involution of hyperplastic parathyroid glands in dogs: Adaptation via a decrease in the calcium stimulation set point and a change in secretion profile

Abstract

This study analyzes the parathyroid function in four dogs before and after 2 years of a low-calcium, high-sodium, vitamin D-deficient diet and the involution of the same function following (1) correction of dietary calcium deficiency and administration of i.v. 1,25-(OH)2D (0.25 micrograms twice per day) during 1 month, (2) after an additional month of normal dog chow supplemented with oral vitamin D (25 micrograms per day), and, finally, (3) after 5 and 17 months of a diet with normal levels of calcium and vitamin D. The parathyroid function was evaluated through i.v. infusion of CaCl2 and Na2 EDTA with measurement of intact (I) and carboxyl-terminal (C) immunoreactive parathyroid hormone (iPTH). The C-iPTH/I-iPTH ratio was calculated to assess the modulation of molecular forms of iPTH induced by the various treatments. The 2 years of calcium and vitamin D deprivation lowered ionized calcium (1.23 +/- 0.04, p < 0.05) and 25-OHD (4.02 +/- 2.06 nM, p < 0.005) and tended to decrease 1,25-(OH)2D (80.8 +/- 8.6 pM); it increased basal I- and C-iPTH levels approximately eightfold (I-iPTH, 40.2 +/- 20.7, p < 0.05; C-iPTH, 185.4 +/- 94.9, p < 0.05) and stimulated I-iPTH (60.2 +/- 23.0 pM, p < 0.05) and C-iPTH (239.6 +/- 80.7 pM, p < 0.05) fivefold. A greater rise in nonsuppressible I-iPTH levels than in C-iPTH levels led to a decreased C-iPTH/I-iPTH ratio in hypercalcemia (12.5 +/- 2.8 versus 27.8 +/- 6.05 pM, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Parathyroid hormone fragments inhibit active hormone and hypocalcemia-induced 1,25(OH)2D synthesis

“…When 1,25(OH) 2 D is elevated, the intestinal absorption of calcium is enhanced, the transcription of the PTH gene is reduced, 20 the production and secretion of C-PTH fragments by the parathyroid glands 12 are augmented and measurable in the circulation. 10,11 This should result in a decrease of bone resorption. 6 The reverse would be true when 1,25(OH) 2 D level is low.…”

“…It is well-known that 1,25(OH) 2 D impacts the secretion of PTH(1-84) and the C-PTH/I-PTH ratio in blood. [10][11][12] Here, we report a negative influence of C-PTH fragments on 1,25(OH) 2 D synthesis but not on CYP27B1 mRNA expression in the kidneys. We also explain why it has been difficult to demonstrate an effect of hPTH or preparations on 1,25(OH) 2 D synthesis.…”

Influence of Secondary Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal Failure on Circulating Rat PTH Molecular Forms

“…Furthermore, as sHPT progresses, basal, stimulated, and nonsuppressible Intact (I) PTH increases more than carboxyl-terminal (C) PTH levels, indicating a shift in PTH secretion toward PTH(1-84) [1]. When these dogs were replenished with vitamin D, ionized calcium and 25(OH)D normalized rapidly while 1,25(OH) 2 D initially reached supraphysiological values which progressively regressed to normal with time [2]. While I-PTH normalized to prior vitamin D deficiency values, C-PTH remained elevated with a 2-fold rise in the C-PTH/I-PTH ratio, indicating adaptation to increased parathyroid tissue mass through oversecretion of C-PTH fragments [2].…”

“…When these dogs were replenished with vitamin D, ionized calcium and 25(OH)D normalized rapidly while 1,25(OH) 2 D initially reached supraphysiological values which progressively regressed to normal with time [2]. While I-PTH normalized to prior vitamin D deficiency values, C-PTH remained elevated with a 2-fold rise in the C-PTH/I-PTH ratio, indicating adaptation to increased parathyroid tissue mass through oversecretion of C-PTH fragments [2]. The latter finding was further sustained by low-dose 1,25(OH) 2 D therapy in normal dogs which, without augmenting calcium concentration, caused a decrease in I-PTH but not C-PTH secretion, heightening the C-PTH/I-PTH ratio at all calcium concentrations [3].…”