Increased Parathyroid Hormone Secretion Research Articles

Cellular and molecular mechanisms of secondary hyperparathyroidism

The objective of this review is to share important basic research insights into the mechanisms of secondary hyperparathyroidism. An understanding of these mechanisms is essential to more effectively treating the disease. Central underlying abnormalities are increased parathyroid hormone (PTH) gene expression and secretion, and parathyroid cell proliferation. Significant progress has been made in understanding these abnormalities at the cellular and molecular level, particularly their regulation. Studies point to a prominent role of calcium, phosphate and vitamin D as regulators of PTH and parathyroid cell proliferation. 1,25[OH]2 vitamin D3 decreases PTH synthesis and secretion. Small decreases in serum calcium and prolonged increases in serum phosphate as may occur in patients with chronic failure, increase PTH secretion, PTH gene expression, and parathyroid cell proliferation. Regulation at the level ofPTH gene expression is particularly significant given the limited amount of preformed mature PTH. It is now known that calcium and phosphate regulate PTH gene expression through changes in protective parathyroid cytosolic proteins that bind to an instability element in the PTH mRNA 3'-untranslated region and influence transcript stability. These findings may help guide the development of novel therapies for secondary hyperparathyroidism.

Pathogenesis of parathyroid dysfunction in end-stage kidney disease

Small decreases in serum calcium (Ca(2+)) and more-prolonged increases in serum phosphate (Pi) stimulate the parathyroid (PT) to secrete parathyroid hormone (PTH). 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2) D(3)] decreases PTH synthesis and secretion. The prolonged decrease in serum Ca(2+) and 1,25(OH)(2) D(3), or increase in serum Pi, observed in patients with chronic renal failure leads to a secondary increase in serum PTH. This secondary hyperparathyroidism involves increases in PTH gene expression, synthesis, and secretion and, if chronic, to proliferation of the PT cells. A low serum Ca(2+) leads to an increase in PTH secretion, PTH mRNA stability, and PT cell proliferation. Pi also regulates the PT in a similar manner. The effect of Ca(2+) on the PT is mediated by a membrane Ca(2+) receptor. 1,25(OH)(2) D(3) decreases PTH gene transcription. Ca(2+) and Pi regulate the PTH gene post transcriptionally by regulating the binding of PT cytosolic proteins, trans factors, to a defined cis sequence in the PTH mRNA 3'-untranslated region, thereby determining the stability of the transcript. The PT trans factors and cis elements have been defined.

Hypophosphatemia in meningococcal sepsis

Sirs, We read with interest the article by Akil et al. [1], presenting a 3-year-old boy with fulminant meningococcemia and acute renal failure. In this patient hypophosphatemia occurred paradoxically in the presence of oliguria. We would like to further expand on the authors’ discussion about this electrolyte abnormality. The pathophysiological mechanisms of hypophosphatemia include internal redistribution (for example in cases of respiratory alkalosis or glucose administration), urinary loss, and decreased intestinal absorption [2]. Hypophosphatemia has long been reported for adult patients in the early phase of sepsis, most often caused by gram-negative bacteria [3]. Serum phosphate levels normalize within days, as the symptoms of acute septicemia subside. Acute renal loss of phosphate was thought to be an unlikely explanation, since many of these patients presented with oliguria or anuria. Severe hypophosphatemia was observed even in the presence of normal blood gases and prior to initiation of intravenous fluid administration [3]. Later, hypophosphatemia was also demonstrated for adult patients with pneumonia and other infections, mostly bacterial [4, 5, 6]. We reported that transient hypophosphatemia is a relatively frequent phenomenon in children admitted with bacterial infections [7]. In most of these studies, factors such as respiratory alkalosis, renal disease, prior intravenous fluid administration, and poor nutritional status were among the exclusion criteria or were not observed for many of the hypophosphatemic patients. The patient presented by Akil et al. [1] already had low serum phosphate (1.68 mg/dl) on admission, with normal blood urea nitrogen and creatinine levels (6 mg/dl and 0.27 mg/dl, respectively) [1]. So, what is the cause of hypophosphatemia in patients with acute infection? Barak et al. [6] investigated the relationship between serum phosphate and cytokine levels in adult patients with sepsis or other bacterial infections. They found that hypophosphatemia in these patients was associated with high levels of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Injection of TNF-a or IL-6 in mice resulted in a marked decrease of their serum phosphate concentrations, suggesting a causative role for these cytokines in the pathogenesis of hypophosphatemia [6]. H glin et al. [5] reported that hypophosphatemic patients had a higher mean C-reactive protein level (CRP) than the normophosphatemic group. The prevalence of hypophosphatemia was higher in pediatric patients with elevated CRP levels, reaching 61% in children with pneumonia and CRP>150 mg/l [7]. Hypophosphatemia occurred before the increase in CRP and resolved before the normalization of CRP levels [7]. These findings were in agreement with those of Barak et al. [6], since TNF-a and IL-6 are the main stimuli for the production of CRP from hepatocytes, and their peak levels in plasma precede those of CRP by 24–48 h. Consequently, the hypophosphatemia in the presented case of meningococcal sepsis could be attributed to the overproduction of cytokines such as TNF-a and IL-6, which are known to play a major role in the pathogenesis of sepsis. Notably, the patient’s CRP level on admission was very high (245 mg/l) [1]. In parallel with these reports, other studies have investigated urinary electrolyte excretion in patients with sepsis. Kalan et al. [8] reported increased urinary loss of phosphate in septic neonates. An increased parathyroid hormone secretion was found in critically ill adult patients, some with septicemia, but was not associated with hypophosphatemia or changes in urinary calcium excretion [9]. There is also a possibility of inadequate or unbalanced (in relation to calcium) phosphate supplementation as a cause of hypophosphatemia associated with infection, C. Antachopoulos First Department of Pediatrics, Athens University, Aghia Sophia Children’s Hospital, Athens, Greece

Biologic Effects of Parathyroid Hormone Metabolites: Implications for Renal Bone Disease

Renal bone disease or renal osteodystrophy is the term used to describe the spectrum of histologic abnormalities encountered in patients with chronic kidney disease (CKD). The patterns of bone histology encountered in the setting of CKD range from states of high bone turnover, such as osteitis fibrosa, the result of hyperparathyroidism, to states of abnormally low bone turnover, such as adynamic bone.1 The major factors involved in the pathogenesis of secondary hyperparathyroidism include phosphate retention as glomerular filtration rate decreases and low levels of calcitriol as renal mass is reduced. Both of these factors may lower serum calcium and therefore stimulate parathyroid hormone (PTH) secretion. In addition to these indirect effects, low levels of calcitriol and high serum phosphorus have been shown to have direct effects on the parathyroid gland to increase PTH secretion. The pathogenetic factors involved in the development of adynamic bone disease are less well understood, but it appears that oversuppression of PTH and the use of vitamin D compounds may play a role. Thus, in the management of renal osteodystrophy, it is important to be able to monitor and treat hyperparathyroidism effectively while at the same time avoiding oversuppression of PTH. In this regard, accurate measurements of circulating PTH levels are an essential guide in the management of renal bone disease. It is well accepted that PTH is present in the circulation in the form of both the intact 84-amino acid peptide and a variety of truncated fragments.2–4 Although the role of the intact PTH molecule as a major regulator of mineral ion homeostasis is well established, the actions of PTH fragments have remained poorly understood. In this review, we discuss the generation of PTH metabolites and the evidence supporting their biologic activity and their potential role in renal bone disease.

Acute effect of pamidronate on PTH secretion in postmenopausal hemodialysis patients with secondary hyperparathyroidism

Background: The purpose of this study is to evaluate the acute effect of pamidronate on plasma ionized calcium (iCa) level reduction and dynamic parathyroid hormone (PTH) secretion in postmenopausal hemodialysis-dependent women with secondary hyperparathyroidism. Methods: Twelve postmenopausal women undergoing regular hemodialysis with serum intact PTH levels greater than 200 pg/mL (200 ng/L) were included in this study. Pamidronate was administered intravenously as a single dose of 15 mg in the last hour of hemodialysis. PTH responses to hypocalcemia and hypercalcemia induced with 1 mEq/L (0.5 mmol/L) and 4 mEq/L (2 mmol/L) of dialysate calcium, respectively, were evaluated before and 1 week after pamidronate therapy. Results: Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (iCabase; P < 0.05) levels and an increase in maximal serum PTH (PTHmax; P < 0.001), basal PTH (PTHbase; P < 0.001), and minimal PTH levels (P < 0.001). The set point of serum calcium and the slope of the PTH-calcium curve were not altered by pamidronate therapy. An inverse correlation was present between iCabase and the PTHbase-PTHmax ratio before (r = −0.66; P < 0.05) and after (r = −0.84; P < 0.001) pamidronate therapy. Conclusion: Our study shows that pamidronate therapy is associated with reduced plasma iCa levels and increased PTH secretion, resulting in aggravated secondary hyperparathyroidism. These findings suggest that secondary hyperparathyroidism may worsen after the administration of pamidronate, at least in the short term, in postmenopausal hemodialysis patients.

Prevention and treatment of secondary hyperparathyroidism: still a challenge for the nephrologist?

Secondary hyperparathyroidism is a well known complication of chronic renal insufficency. It is not only a state of increased parathyroid hormone secre-tion but also a state of parathyroid gland hyperplasia. Prevention and treatment of secondary hyperpara-thyroidism is a huge challenge for the nephrologist, despite new agents for the treatment of hyperphos-phataemia, new vitamin D analogues and calci-mimetics. The importance of parathyroid gland hyperplasia and the possibility of its reduction frequently are neglected issues. Ultrasonography could be very useful in detection of parathyroid gland size and shape and in the management of secondary hyperparathyroidism.

Mechanisms of secondary hyperparathyroidism.

Small decreases in serum Ca(2+) and more prolonged increases in serum phosphate (P(i)) stimulate the parathyroid (PT) to secrete parathyroid hormone (PTH), and 1,25(OH)(2)D(3) decreases PTH synthesis and secretion. A prolonged decrease in serum Ca(2+) and 1,25(OH)(2)D(3), or increase in serum P(i), such as in patients with chronic renal failure, leads to the appropriate secondary increase in serum PTH. This secondary hyperparathyroidism involves increases in PTH gene expression, synthesis, and secretion, and if chronic, to proliferation of the PT cells. Low serum Ca(2+) leads to an increase in PTH secretion, PTH mRNA stability, and PT cell proliferation. P(i) also regulates the PT in a similar manner. The effect of Ca(2+) on the PT is mediated by a membrane Ca(2+) receptor. 1,25(OH)(2)D(3) decreases PTH gene transcription. Ca(2+) and P(i) regulate the PTH gene posttranscriptionally by regulating the binding of PT cytosolic proteins, trans factors, to a defined cis sequence in the PTH mRNA 3'-untranslated region, thereby determining the stability of the transcript. PT trans factors and cis elements have been defined.

Direct effect of acute metabolic and respiratory acidosis on parathyroid hormone secretion in the dog.

Because both metabolic (Met Acid) and respiratory acidosis (Resp Acid) have diverse effects on mineral metabolism, it has been difficult to establish whether acidosis directly affects parathyroid hormone (PTH) secretion. Our goal was to determine whether acute Met Acid and Resp Acid directly affected PTH secretion. Three groups of dogs were studied: control, acute Met Acid induced by HCl infusion, and acute Resp Acid induced by hypoventilation. EDTA was infused to prevent acidosis-induced increases in ionized calcium, but more EDTA was needed in Met Acid than in Resp Acid. The PTH response to EDTA-induced hypocalcemia was evaluated also. Magnesium needed to be infused in groups receiving EDTA to prevent hypomagnesemia. The half-life of intact PTH (iPTH) was determined during hypocalcemia when PTH was measured after parathyroidectomy. During normocalcemia, PTH values were greater (p < 0.05) in Met Acid (92 +/- 19 pg/ml) and Resp Acid (77 +/- 22 pg/ml) than in controls (27 +/- 5 pg/ml); the respective pH values were 7.23 +/- 0.01, 7.24 +/- 0.01, and 7.39 +/- 0.02. The maximal PTH response to hypocalcemia was greater (p < 0.05) in Met Acid (443 +/- 54 pg/ml) than in Resp Acid (267 +/- 37 pg/ml) and controls (262 +/- 48 pg/ml). The half-life of PTH was greater (p < 0.05) in Met Acid than in controls, but the PTH secretion rate also was greater (p < 0.05) in Met Acid than in the other two groups. In conclusion, (1) both acute Met Acid and Resp Acid increase PTH secretion when the ionized calcium concentration is normal; (2) acute Met Acid may increase the bone efflux of calcium more than Resp Acid; (3) acute Met Acid acts as a secretogogue for PTH secretion because it enhances the maximal PTH response to hypocalcemia.

Parathyroid hormone secretion in chronic human endogenous hypercortisolism.

Osteoporosis is a common manifestation of Cushing's syndrome, but the mechanisms responsible for this abnormality have not been defined. With the objective of analyzing parathyroid hormone (PTH) secretion in chronic hypercortisolism (CH), we evaluated 11 healthy subjects and 8 patients with CH, 6 with Cushing's disease and 2 with adrenal adenoma. These volunteers were submitted to tests of PTH stimulation through hypocalcemia (EDTA), PTH suppression through hypercalcemia (iv and oral calcium), and evaluation of bone mineral density (BMD) by DEXA. During the test of PTH stimulation, the calcium and magnesium concentrations of the normal and CH groups were similar. Patients with CH showed an increased PTH response to the hypocalcemic stimulus compared to controls. PTH values were significantly higher in the CH group at 70 (17.5 +/- 3.5 vs 10.2 +/- 1.3 pmol/l, P = 0.04), and 120 min (26.1 +/- 5.9 vs 11.3 +/- 1.9 pmol/l, P = 0.008) of EDTA infusion. The area under the curve for PTH during EDTA infusion was also significantly higher in patients with CH than in normal subjects (1867 +/- 453 and 805 +/- 148 pmol l(-1) 2 h(-1), P = 0.02). During the test of PTH suppression, calcium, magnesium and PTH levels of the patients with hypercortisolism and controls were similar. BMD was decreased in patients with hypercortisolism in the spine (0.977 +/- 0.052 vs 1.205 +/- 0.038 g/cm2 in controls, P<0.01). In conclusion, our results show that subjects with CH present decreased bone mass mainly in trabecular bone. The use of dynamic tests permitted the detection of increased PTH secretion in response to a hypocalcemic stimulus in CH patients that may probably be involved in the occurrence of osteoporosis in this state.

Effect of high extracellular phosphate concentration on arachidonic acid production by parathyroid tissue in vitro.

Recent in vivo and in vitro studies show that high phosphate directly stimulates parathyroid hormone (PTH) secretion. However, little is known about the intracellular signaling system involved in the regulation of PTH secretion by extracellular phosphate. High extracellular calcium is coupled to the activation of phospholipase A(2) (PLA(2)) and the formation of arachidonic acid (AA), a potent inhibitor of PTH release. The present study was designed to evaluate whether a high phosphate concentration has an effect on the PLA(2)-AA pathway in parathyroid cells. In vitro experiments were performed in parathyroid tissue obtained from normal rats and dogs. AA production was measured in parathyroid tissue in response to 1- and 4-mM phosphate concentration and after addition of PLA(2) to the medium. To determine whether the effect of phosphate on AA production in parathyroid cells was tissue specific, separate experiments were performed to test the effect of phosphate in rat adrenal glomerulosa cells, which are known to increase AA production in response to angiotensin II. The effect of sulfate, an ion with chemical characteristics similar to phosphate, on PTH secretion was also evaluated. In parathyroid tissue, a high phosphate concentration decreased the high calcium-induced AA production. This effect of phosphate was associated with an increase in PTH secretion. The addition of AA reversed the stimulatory effect of phosphate on PTH secretion. In another type of AA-responsive tissue, the adrenal glomerulosa, a high phosphate concentration did not affect the production of AA when stimulated by angiotensin II. In a normal phosphate concentration, the addition of PLA(2) stimulated AA production and decreased the PTH secretion. However, in a 4-mM phosphate concentration, the addition of PLA(2) did not reduce PTH secretion and did not stimulate AA production. Finally, sulfate did not affect PTH secretion. In conclusion, a high phosphate concentration affects the production of AA by parathyroid tissue. This effect of phosphate may be the mechanism by which a high phosphate concentration stimulates PTH secretion.

Calcitonin and parathyroid hormone: an evening seminar of the 17th Annual Meeting of the Japanese Society for Bone and Mineral Research, July 29, 1999.

and neurodegenerative diseases as a consequence of the paradoxical calcium overload due to age-related calcium deficiency. The main biologic action of calcitonin has resulted from its successful use in disease states characterized by increased bone resorption. Calcitonin is approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis. The main biologic effect of calcitonin is to inhibit osteoclastic bone resorption. This effect is mediated by a calcitonin receptor, which is strongly expressed by osteoclasts. Thyroid C cells, which are neural crest derivatives, are the primary source of calcitonin in mammals. However, other tissue sources of calcitonin have been described, notably the pituitary cells and widely distributed neuroendocrine cells. Since the concentration of calcitonin at its several sites of biosynthesis may be sufficiently high, calcitonin may be expected to have paracrine effects at these sites. The demonstration of calcitonin and its receptors at intracranial sites may qualify calcitonin as a neurotransmitter. Most investigators find that women have lower calcitonin levels than men. The mechanism for this difference may be accounted for in part by a stimulating effect of gonadal steroids on calcitonin secretion. Analgesia is a commonly reported effect of calcitonin treatment in osteoporosis and bone malignant metastasis. In experimental studies using animals, calcitonin has acute antinociceptive effects when administered into the central nervous system. However, the effects of centrally administered calcitonin do not necessarily explain the clinical effects of intramuscular calcium injections. In this symposium, Dr. Yoshimura further focuses on the modulation of pain sensation at the level of the spinal cord in cases where there is an estrogen deficiency. By using a rat model, he initially observed the inducement of hyperalgesia after ovariectomy and the antinociceptive effect after intramuscular injections of elcatonin. He confirmed the involvement of the Parathyroid hormone and calcitonin are the principal regulators of bone and calcium metabolism in humans and most likely all terrestrial vertebrates. In bone, parathyroid hormone stimulates the resorption of bone, releasing calcium and phosphate. In the kidney, this hormone stimulates the reabsorption of calcium and inhibits the reabsorption of phosphate. Parathyroid hormone stimulates the activity of renal 1-αhydroxylase, thereby enhancing synthesis of the active form of vitamin D, which in turn increases intestinal calcium and phosphate. As a result of these parathyroid hormone-dependent actions, blood calcium concentration increases and phosphate concentration decreases. The extracellular calcium concentration is the most important regulator of parathyroid hormone secretion, and it is maintained at a constant level despite variation in the amount of daily calcium intake. In chronic calcium-deficient conditions, however, the homeostatic regulation of extracellular calcium level by parathyroid hormone seems to threaten the skeleton and nonskeletal soft tissues as well. Increased parathyroid hormone secretion readily leads to osteoporosis, which is a decrease in bone calcium content. On the other hand, a variety of cells in the extraskeletal soft tissues are exposed to the constant calcium overflow from bone so their intracellular calcium levels tend to increase. As a consequence, serious disturbance of cell function occurs, giving rise to various diseases. While systemic calcium deficiency is certainly expected to cause skeletal calcium deficiency, the associated increase of calcium within cells of nonskeletal tissue may appear to be paradoxical. In this symposium, Dr. Fujita focuses on this paradoxical calcium overload of the nonskeletal tissues and relates it to calcium deficiency. He attempts to explain the cause of various soft tissue disorders including cardiovascular diseases

Perinatal metabolism of vitamin D

During pregnancy, maternal serum concentrations of 25-hydroxyvitamin D, the circulating form of vitamin D, correlate with dietary vitamin D intake. Maternal serum concentrations of 1,25-dihydroxyvitamin D, the hormonal circulating and active form of vitamin D, are elevated during pregnancy; 1,25-dihydroxyvitamin D is synthesized mainly by the decidual cells of the placenta and allows for increased calcium absorption. The fetus is entirely dependent on the mother for its supply of 25-hydroxyvitamin D, which is believed to cross the placenta. Hypocalcemia and increased parathyroid hormone secretion induce synthesis of 1,25-dihydroxyvitamin D after birth in both full-term and preterm neonates. Nevertheless, serum concentrations of 25-hydroxyvitamin D are a rate-limiting factor in the synthesis of 1,25-dihydroxyvitamin D. In vitamin D-replete infants, circulating 1,25-dihydroxyvitamin D concentrations are higher than those observed in older infants. In countries where dairy products are not routinely supplemented with vitamin D, maternal vitamin D supplementation during pregnancy is necessary. However, there is no indication for the use of pharmacologic doses of vitamin D or its metabolites in the perinatal period.

Hypocalcemia and parathyroid hormone secretion in critically ill patients

To investigate possible causes of hypocalcemia and to assess parathyroid hormone (PTH) secretion in intensive care unit (ICU) patients. Combined cross-sectional and prospective study. ICU in a university hospital. Thirteen patients with sepsis and 13 patients who underwent major surgery. None. Calcium metabolic indices were investigated during the first 24 hrs in the ICU and after 2 days. Eight of the surgical patients and five of the septic patients were subjected to a citrate/calcium infusion on day 1 in the ICU, to study the dynamics of PTH secretion. The blood ionized calcium (Ca2+) concentration was generally low in the septic patients (mean +/- SD, 1.03+/-0.08 mmol/L; reference value, 1.10-1.30) and increased, but not normalized, after 2 days. Hypocalcemia was only occasionally seen in the surgical patients. In the septic patients, urinary excretion of calcium was low; and, in both patient groups, elevated concentrations of two markers of bone resorption, deoxypyridinoline and ICTP (serum carboxy-terminal cross-linked telopeptide of type I collagen), were found. In cases of sepsis, the concentrations of proinflammatory cytokines were high (394+/-536 pg/mL for tumor necrosis factor-alpha and 5676+/-5190 pg/mL for interleukin-6, both normally <10-20). The Ca2+ concentration was inversely related to tumor necrosis factor-alpha and interleukin-6 (r2 = .35-.42; p<.01), as well as to procalcitonin (r2 = .71; p<.01). Despite normocalcemia in the surgical patients, serum PTH concentrations were elevated in both patient groups (97 and 109 ng/L) (reference value, <55 ng/L), both on day 1 and day 3 in the ICU. The citrate/calcium infusion revealed an increased secretory response of PTH to lowered Ca2+ concentrations in both groups of patients (p<.05), when compared with matched healthy controls. Hypocalcemia was common in septic ICU patients and was not the result of an increased urinary excretion of calcium or of an attenuated bone resorption, but seemed related to the inflammatory response. An increased PTH secretion was found in both patient groups.

Effect of phosphate on parathyroid hormone secretion in vivo.

Alterations in phosphate homeostasis play an important role in the development of secondary hyperparathyroidism in renal failure. Until recently, it was accepted that phosphate retention only increased parathyroid hormone (PTH) secretion through indirect mechanisms affecting calcium regulation and calcitriol synthesis. However, recent in vitro studies have suggested that phosphate may directly affect PTH secretion. Our goal was to determine whether in vivo an intravenous phosphate infusion stimulated PTH secretion in the absence of changes in serum calcium. Three different doses of phosphate were infused intravenously during 120 minutes to increase the serum phosphate concentration in dogs. Sulfate was also infused intravenously as a separate experimental control. A simultaneous calcium clamp was performed to maintain a normal ionized calcium concentration throughout all studies. At the lowest dose of infused phosphate (1.2 mmol/kg), serum phosphate values increased to approximately 3 mM, but PTH values did not increase. At higher doses of infused phosphate (1.6 mmol/kg and 2.4 mmol/kg), the increase in serum phosphate to values of approximately 4 mM and 5 mM, respectively, was associated with increases in PTH, even though the ionized calcium concentration did not change. Increases in PTH were not observed until 30-60 minutes into the study. These increases were not sustained, since by 120 minutes PTH values were not different from baseline or controls despite the maintenance of marked hyperphosphatemia. During the sulfate infusion, serum sulfate values increased by approximately 3-fold, but no change in PTH values were observed. In conclusion, an acute elevation in serum phosphate stimulated PTH secretion in the intact animal, but the magnitude of hyperphosphatemia exceeded the physiologic range. Future studies are needed to determine whether PTH stimulation is more sensitive to phosphate loading in states of chronic phosphate retention. Moreover, the mechanisms responsible for the delay in PTH stimulation and the failure to sustain the increased PTH secretion need further evaluation.

1α,25‐Dihydroxy‐3‐Epi‐vitamin D3, a natural metabolite of 1α,25‐dihydroxyvitamin D3, is a potent suppressor of parathyroid hormone secretion

1α,25(OH)2D3 is an important negative regulator of parathyroid hormone (PTH) gene transcription. In parathyroid cells, as in other target tissues, 1α,25(OH)2D3 is degraded by side chain oxidation by the inducible 24-hydroxylase. We have previously shown that one metabolite of this pathway, 1α,23(S),25-(OH)3-24-oxo-D3, potently suppresses PTH synthesis and secretion in cultured bovine parathyroid cells (bPTC). Further examination of the metabolites of 1α,25(OH)2D3 in bPTC has revealed another compound that is less polar than 1α,25(OH)2D3. By HPLC analysis and mass spectrometry, this metabolite was identified as 1α,25(OH)2-3-epi-D3. The activity of this metabolite on PTH gene transcription was assessed by the steady-state PTH secretion by bPTC after 72-h treatment with concentrations from 10−11 M to 10−7 M. 1α,25(OH)2-3-epi-D3 was found to be only slightly, but not significantly, less active than the native 1α,25(OH)2D3 in suppressing PTH secretion despite having 30 times lower affinity for the bPTC VDR. Both 1α,25(OH)2D3 and 1α,25(OH)2-3-epi-D3 maximally suppressed PTH secretion by 50%. Along with 1α,25(OH)2-3-epi-D3, the activities of the other two A-ring diastereomers were assessed. 1β,25(OH)2D3 suppressed PTH only at 10−7 M with a decrease of only 30%, in good agreement with its low VDR affinity. Surprisingly, 1β,25(OH)2-3-epi-D3 stimulated PTH secretion by 30–50% at concentrations from 10−11 M to 10− 8M and fell to control (untreated) rates at 10−7M. The mechanism for this increase in PTH secretion is under investigation. Metabolism studies performed in bPTC cells using high concentrations of 1α,25(OH)2D3 substrate showed that in some incubations, the concentration of 1α,25(OH)2-3-epi-D3 was even higher than that of the parent substrate 1α,25(OH)2D3. This finding indicates a slower rate of metabolism for this diastereomer. Thus, production and accumulation of 1α,25(OH)2-3-epi-D3, as a major stable metabolite of 1α,25(OH)2D3 in parathyroid glands, may contribute to the prolonged suppressive effect of 1α,25(OH)2D3 on PTH gene transcription. J. Cell. Biochem. 73:106–113, 1999. © 1999 Wiley-Liss, Inc.

1?,25-Dihydroxy-3-Epi-vitamin D3, a natural metabolite of 1?,25-dihydroxyvitamin D3, is a potent suppressor of parathyroid hormone secretion

1Alpha,25(OH)2D3 is an important negative regulator of parathyroid hormone (PTH) gene transcription. In parathyroid cells, as in other target tissues, 1alpha,25(OH)2D3 is degraded by side chain oxidation by the inducible 24-hydroxylase. We have previously shown that one metabolite of this pathway, 1alpha,23(S),25-(OH)3-24-oxo-D3, potently suppresses PTH synthesis and secretion in cultured bovine parathyroid cells (bPTC). Further examination of the metabolites of 1alpha,25(OH)2D3 in bPTC has revealed another compound that is less polar than 1alpha,25(OH)2D3. By HPLC analysis and mass spectrometry, this metabolite was identified as 1alpha,25(OH)2-3-epi-D3. The activity of this metabol ite on PTH gene transcription was assessed by the steady-state PTH secretion by bPTC after 72-h treatment with concentrations from 10(-11) M to 10(-7) M. 1Alpha,25(OH)2-3-epi-D3 was found to be only slightly, but not significantly, less active than the native 1alpha,25(OH)2D3 in suppressing PTH secretion despite having 30 times lower affinity for the bPTC VDR. Both 1alpha,25(OH)2D3 and 1alpha,25(OH)2-3-epi-D3 maximally suppressed PTH secretion by 50%. Along with 1alpha,25(OH)2-3-epi-D3, the activities of the other two A-ring diastereomers were assessed. 1beta,25(OH)2D3 suppressed PTH only at 10(-7) M with a decrease of only 30%, in good agreement with its low VDR affinity. Surprisingly, 1beta,25(OH)2-3-epi-D3 stimulated PTH secretion by 30-50% at concentrations from 10(-11) M to 10(-8)M and fell to control (untreated) rates at 10(-7) M. The mechanism for this increase in PTH secretion is under investigation. Metabolism studies performed in bPTC cells using high concentrations of 1alpha,25(OH)2D3 substrate showed that in some incubations, the concentration of 1alpha,25(OH)2-3-epi-D3 was even higher than that of the parent substrate 1alpha,25(OH)2D3. This finding indicates a slower rate of metabolism for this diastereomer. Thus, production and accumulation of 1alpha,25(OH)2-3-epi-D3, as a major stable metabolite of 1alpha,25(OH)2D3 in parathyroid glands, may contribute to the prolonged suppressive effect of 1alpha,25(OH)2D3 on PTH gene transcription.

A Structural Approach to Renal Bone Disease

A Structural Approach to Renal Bone Disease

Prospective evaluation of parathyroid graft function after total parathyroidectomy and heterotopic autotransplantation in renal hyperparathyroidism by bilateral determination of intact parathormone in cubital venous blood.

The value of gradients for intact parathyroid hormone (PTH) in the assessment of graft function after total parathyroidectomy/autotransplantation for renal hyperparathyroidism was evaluated in a prospective follow-up study. Altogether 99 patients who underwent operation from August 1, 1987 to December 31, 1996 were prospectively investigated and reexamined postoperatively, including analyses of serum calcium, alkaline phosphatase, and intact PTH in the antecubital venous blood of both arms. The postoperative course is known for all patients. Of the 99 patients included in the study, 95 underwent one to nine reexaminations (median three) over follow-up periods of 1 month to 5 years (median 24 months). Reproducible PTH gradients were established during follow-up. Ninety percent of the calculated gradients were < or = 20. Intermittent postoperative hypocalcemia, due to calcium deficiency of the skeleton in renal osteopathy, led to an increase in PTH secretion and gradients. Increasing gradients > 20 during follow-up make graft-dependent recurrence probable. The presence of a gradient of approximately 1 in bilaterally elevated PTH levels may be an indication of hyperfunctioning parathyroid tissue in the neck or mediastinum. The combined assessment of the course of gradients for intact PTH, hormone levels in both arms, and serum calcium permits an objective evaluation of parathyroid graft function.

Ultraviolet light may contribute to geographic and racial blood pressure differences.

Mean systolic and diastolic pressures and the prevalence of hypertension vary throughout the world. Published data suggest a linear rise in blood pressure at increasing distances from the equator. Similarly, blood pressure is higher in winter than summer. Blood pressure also is affected by variations in skin pigmentation. Altered calcium, vitamin D, and parathyroid hormone status is associated with hypertension and may vary with latitude and season. Since changes in UV light affect vitamin D and parathyroid hormone status and UV light intensity are influenced by seasonal change and latitude, these disparate observations suggest an association between blood pressure and ultraviolet light. This discussion presents the hypothesis that reduced epidermal vitamin D3 photosynthesis associated with high skin melanin content and/or decreased UV light intensity at distances from the equator, alone or when coupled with decreased dietary calcium and vitamin D, may be associated with reduced vitamin D stores and increased parathyroid hormone secretion. These changes may stimulate growth of vascular smooth muscle and enhance its contractility by affecting intracellular calcium, adrenergic responsiveness, and/or endothelial function. Thus, UV light intensity and efficiency of epidermal vitamin D3 photosynthesis may contribute to geographic and racial variability in blood pressure and the prevalence of hypertension.

Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro

Phosphorus retention is an important factor in the development of hyperparathyroidism secondary to renal failure. In vivo manipulation of phosphorus is associated with changes in serum calcium and calcitriol levels which in turn can modify parathyroid hormone synthesis and secretion. The present in vitro study evaluates whether high extracellular phosphorus has a direct effect on parathyroid hormone secretion. Fresh rat parathyroid glands were incubated in a media with phosphorus concentrations of 1, 2, 3, and 4 mM and subsequently exposed to calcium levels ranging from 0.4 to 1.35 mM. In 1.25 mM calcium, the parathyroid hormone secretion rate was similar in 1 and 2 mM phosphorus; however, a phosphorus concentration of 3 and 4 mM produced a 3- and 4-fold increase in the parathyroid hormone secretion, respectively, as compared with 1 mM phosphorus. While in 1 or 2 mM phosphorus an increase in calcium from 0.6 to 1.35 mM reduced parathyroid hormone secretion to 37%, in 4 mM phosphorus the same increase in calcium only inhibited parathyroid hormone secretion to 75%. Furthermore, the addition of arachidonic acid 20 microM, a substrate for inhibitory intracellular signal pathway, to the 4 mM phosphorus-1.35 mM calcium incubation media reduced the parathyroid hormone secretion to 34.5% (p < 0.05). In conclusion, our results indicate that in vitro, high phosphorus directly increases parathyroid hormone secretion.