Physiologic Regulation of Parathyroid Hormone Release

Several endogenous substances, including peptides, steroid hormones, and amines, have been found to influence PTH release.12 It is apparent, however, that calcium is the most potent regulator of PTH secretion. Analyses of normal parathyroid cells have shown that acute changes in extracellular calcium concentration induce rapid changes in PTH release.3,4 Studies in vitro and in vivo5 9 support the concept that the dose-response relationship between calcium and PTH is inversely sigmoidal, with the steepest part of the curve corresponding to the physiologic concentration range for ionized calcium (Ca2+¡) (Fig. 39-1 A). Minor alterations within the physiologic calcium concentration range can thus induce considerable secretory responses (Fig. 39-2), and reduction of ionized plasma calcium by 0.04 mmol/L may elevate serum PTH by 100% or more. Orcadian variation in serum PTH values differs between men and women, and blunting of this variation in HPT seems to occur in vivo,1011 whereas the presence and pathophysiologic significance of rapid pulsations in the release of PTH await clarification.12'13

Stepwise alterations in extracellular calcium concentration have suggested that more sudden changes may elicit greater PTH responses, whereas rapid decreases in plasma calcium may be counteracted most effectively.14 The amplitude and direction of the change in calcium concentration also influence the magnitude of the secretory response.1516 A nonsuppressible component of PTH secretion persists even when the extracellular calcium concentration is markedly elevated (see Figs. 39-1A and 39-2). The extent of this component is partly related to discrepant sensitivities of PTH assays to different portions of the PTH molecule. Under normal circumstances, the basal serum PTH value is positioned closer to the level of maximal suppression than stimulation, which implies a potential to counteract decreased plasma calcium levels.15 The steep slope of the dose-response relationship between external calcium and PTH release in euparathyroid patients also supports the notion that shifts in the position and slope of the dose-response curve significantly influence the steady-state serum PTH value.5'17 Chronic changes in serum calcium lead to a shift in the calcium-PTH dose-response curve, whereas acute changes in serum calcium move the PTH secretory responses along the prevailing dose-response curve.7'8,14,18 Moreover, chronic hypocalcemia is characterized by a maintained, albeit numerically reduced, stimulation of PTH secretion in response to a further reduction of the calcium concentration (Fig. 39-3).

The rapid effect of extracellular calcium on PTH release suggests that calcium directly interferes with the PTH release process, but the nature of this interference has been

—A— Bovine - -O - Adenoma • - - C- - Primary hyperplasia ■ MEN-I hyperplasia 4 Uremic hyperplasia

1 2 Extracellular calcium (mM)

1 2 Extracellular calcium (mM)

FIGURE 39-1. Effects of increases in extracellular ionized calcium on parathyroid hormone (PTH) release (A) and steady-state Ca2+j (B) of dispersed parathyroid cells from normal glands of adult cattle, parathyroid adenomas (n = 22), hyperplastic glands of sporadic primary hyperparathyroidism (HPT) (n = 9), and familial HPT of multiple endocrine neoplasia (MEN) type 1 (n = 8), as well as hyperplastic glands of uremic patients with hypercalcemic HPT (n = 23). PTH release is expressed in percentages of the release at 0.5 mmol extracellular calcium, and cytoplasmic calcium is measured with quin-2 in a cuvette system. Values represent mean ± standard error and are recalculated and extended from Wallfelt and colleagues.6

only partially clarified. It has been demonstrated that external calcium mainly regulates secretion of newly synthesized hormone, which may bypass the relatively few secretory granules in the parathyroid cells.19 Intracellular degradation with release of carboxyterminal PTH fragments occurs especially at high extracellular calcium concentrations. This attenuates the biologic activity of the secretory product because the calcium-regulating properties of PTH reside in its aminoterminal portion. The secretion of PTH is also modulated by transcription of the PTH gene, which consists of three exons and is located in chromosome 11 (llpl5).20 PTH is synthesized as a precursor molecule (pre-pro-PTH) and undergoes sequential cleavage.21 The pre-pro-signal

FIGURE 39-2. Inverse sigmoidal relationship between ionized plasma calcium and intact serum parathyroid hormone (S-PTH) in 22 healthy controls (O) and 26 patients with sporadic primary hyperparathyroidism (•) subjected to sequential citrate and calcium infusions. Values represent mean ± standard deviation. (From Schwartz P, Sorensen HA, Transbol I. Interrelations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: A sequential citrate and calcium clamp study. Eur J Clin Invest 1994;24:553. © 1994 by Blackwell Science.)

FIGURE 39-2. Inverse sigmoidal relationship between ionized plasma calcium and intact serum parathyroid hormone (S-PTH) in 22 healthy controls (O) and 26 patients with sporadic primary hyperparathyroidism (•) subjected to sequential citrate and calcium infusions. Values represent mean ± standard deviation. (From Schwartz P, Sorensen HA, Transbol I. Interrelations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: A sequential citrate and calcium clamp study. Eur J Clin Invest 1994;24:553. © 1994 by Blackwell Science.)

peptide is important for cellular transport and extrusion of the intact (1-84) PTH molecule. A single amino acid mutation in this sequence has been found to cause insufficient PTH secretion in familial hypoparathyroidism.22 Similar actions have also been ascribed to PTH itself, and this may partially explain the existence of the carboxyterminal portion of PTH.

Messenger RNA (mRNA) levels for PTH are increased within hours by low extracellular calcium, consistent with

3 CD CO

Plasma ionized calcium (mM)

FIGURE 39-3. Intact serum parathyroid hormone (PTH) in relation to the ionized plasma calcium concentration during a constant infusion of edetic acid as well as an oral calcium load in 18 patients with primary hyperparathyroidism before parathyroid surgery, as well as 5 days, 1 month, and 1 year postoperatively. Values represent mean ± standard error and are recalculated and extended from Graf and colleagues.18

the effects of calcium on PTH secretion.23"25 Furthermore, calcitriol lowers PTH mRNA levels and inhibits PTH secretion.26,27 This action is associated with a shift of the calcium dependence of PTH secretion toward lower calcium values rather than interference with the slope of the dose-response curve.28 Calcitriol binds to its receptor (vitamin D receptor) and interacts with the 5'-flanking promoter region of the PTH gene.29 The PTH gene also contains cyclic adenosine monophosphate (cAMP)-responsive elements,30 whereby its transcription may be regulated by, for example, corticosteroids, vasoactive intestinal polypeptides, and estrogen.

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