Plasma Levels of Parathyroid Hormone (1–84) Whole Molecule and Parathyroid Hormone (7–84)-Like Fragments in Pseudohypoparathyroidism Type I

Abstract

PTH (7-84) has antagonistic effects on the calcemic and phosphaturic actions of PTH (1-84) whole molecule (bioPTH). Human plasma contains bioPTH and PTH (7-84)-like fragments. Using bioPTH-specific and nonspecific assays, we found that the patients with pseudohypoparathyroidism (PHP) type I with PTH-resistant hypocalcemia and hyperphosphatemia had the increased plasma levels of bioPTH and PTH (7-84)-like fragments than normal subjects (26.8 +/- 13.2 vs. 2.37 +/- 0.75 pmol/liter, P < 0.01 and 16.2 +/- 8.8 vs. 0.82 +/- 0.47 pmol/liter, P < 0.01, respectively). Calcitriol treatment increased phosphaturic response to PTH (1-34) (P < 0.05), and there was a negative correlation between phosphaturic response and the PTH levels (P < 0.05). These results suggested that the increased bioPTH and PTH (7-84)-like fragment levels may be related to the impaired phosphaturic response to PTH (1-34) in PHP type I. We also examined bioPTH-calcium dynamics in PHP type Ib patients and found that set-point calcium was 0.928 +/- 0.045 mmol/liter and the baseline to maximal ratio of bioPTH was 0.96 +/- 0.04. Calcitriol treatment increased set-point calcium to 1.129 +/- 0.028 mmol/liter (P < 0.01) and suppressed baseline to maximal ratio of bioPTH to 0.35 +/- 0.21 (P < 0.01). These bio-PTH calcium dynamics studies revealed the maximally stimulated baseline PTH secretion in PHP type Ib and demonstrated the effects of calcitriol on PTH-calcium curve shift and the degree of relative stimulation of baseline secretion.

The administration of an active vitamin D3 analogue reduced the serum concentrations of 1-84 and truncated parathyroid hormone in pseudohypoparathyroidism type Ib patients

“…Alfacalcidol also decreased serum PTH levels in the PHP patients in this study, and similar results were observed in previous studies [11,19,22]. Therefore, the mechanisms by which active vitamin D 3 regulates PTH secretion are functional in PHP patients.…”

“…If serum calcium is a major factor in the production of truncations, the W-PTH/T-PTH ratios in untreated PHP patients should be higher than those in normal subjects because of hypocalcemia in the PHP patients. However, a previous study also revealed significantly reduced ratios in PHP I patients [11], even though their serum calcium levels were Correlations between doses of alfacalcidol and serum PTH levels in PHP Ib patients. For all four PHP Ib patients, the alfacalcidol doses were plotted against the serum levels of W-PTH (A) and T-PTH (B), and against the W-PTH/T-PTH ratios (C).…”

“…The setpoint for PTH secretion was lower than normal in untreated PHP patients [11,19], suggesting the over function of CaR in their parathyroid glands. Again, if the pathways of PTH secretion and N-terminal truncation in the abnormal parathyroid glands are same, the truncation could enhance as well as the secretion.…”

“…In PHP type I patients, the N-terminal truncation of PTH is accelerated even though their serum calcium levels are lower than those in normal subjects. [11] In addition, their PTH N-terminal truncation ratios remain unchanged when their serum calcium levels are normalized by calcitriol treatments.…”

“…The elevated serum calcium levels might have enhanced the PTH N-terminal truncations in these patients, however, the W-PTH/T-PTH ratios remained unchanged. In patients with PHP and idiopathic hypoparathyroidism, the administration of active vitamin D 3 normalized their reduced setpoints for PTH secretion [11,19]. It is possible that the effects of the elevated serum calcium levels were counteracted by an alteration in setpoints for the truncation induced by the active vitamin D 3 analogue, resulting in stable truncation rates.…”