THE LOSS OF CIRCADIAN RHYTHM FOR INTACT PARATHYROID HORMONE AND NEPHROGENOUS CYCLIC AMP IN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM

The measurement of serum intact parathyroid hormone (PTH) (1-84) over a 24-h period has shown the existence of a circadian rhythm in normal males which is absent in patients with primary hyperparathyroidism. The physiological significance of this observation is reflected in the presence of parallel changes in nephrogenous cyclic adenosine monophosphate (N-cAMP) in normals which are also absent in primary hyperparathyroidism. Serum calcium, adjusted for variations in albumin concentrations, showed a transient fall in normal subjects prior to the nocturnal rise in PTH (1-84). A similar transient fall in serum adjusted calcium was observed in the hyperparathyroid patients. Serum phosphate showed a circadian rhythm in normal subjects, and an attenuated rhythm persisted in primary hyperparathyroidism. These data suggest that both ionic factors and higher centres play important roles in the fine control of PTH (1-84) secretion.     

Alteration of the circadian rhythm of intact parathyroid hormone following a 96-hour fast

OBJECTIVE PTH(1-84) secretion in normal male subjects follows a circadian rhythm. The control of this rhythm is multifactorial with both neuroendocrine and chemical influences. The aim of this study was to assess the effect of a 96-hour fast on the circadian rhythm of PTH(1 -84), serum calcium, phosphate and nephrogenous cAMP (NcAMP), an index of PTH(1-84) bioactivity. DESIGN Blood samples for estimation of all analytes were obtained over a 24-hour period at 30-minute intervals. Urine samples were obtained 4 hourly during the daytime and overnight. Each subject was studied on two occasions after being randomized to either (a) normal hospital diet or (b) a 96-hour fast with water freely available. SUBJECTS Six healthy adult males aged between 28 and 40 years, mean 32 years. MEASUREMENTS PTH(1-84) was measured by an in-house immunoradiometric assay. Serum calcium, phosphate, albumin, creatinine and urinary creatinine were measured by standard automated techniques. Calcium was adjusted for albumin. Plasma cAMP was estimated by a commercial method and urine cAMP by in-house radioimmunoassay and NcAMP obtained by calculation. Rhythm parameters were analysed by cosinor techniques. RESULTS There were alterations in the circadian rhythms of serum phosphate, PTH(1–84) and NcAMP following a 96-hour fast. Fasting abolished the nocturnal rise in phosphate, PTH(1-84) and NcAMP but had little effect on the pattern of adjusted calcium over a 24-hour period. The mean concentrations of serum phosphate, adjusted calcium and NcAMP decreased significantly following the fast and mean PTH(1-84) increased during day time. CONCLUSIONS Fasting for 96 hours significantly alters the circadian rhythm of PTH(1-84) secretion by lowering the mean calcium concentration and attenuating the circadian rhythm of serum phosphate.     

Episodic fluctuation in serum intact parathyroid hormone concentration in men

To evaluate the temporal features of physiological fluctuation in serum PTH concentration, we sampled peripheral blood at 4-min intervals for 24 h from five normal men (32.8 yr; range, 26-40 yr) and measured serum PTH levels using a two-site immunoradiometric assay with the exquisite sensitivity and specificity for human PTH-(1-84) (intact PTH). The resultant 24-h time series of serum intact PTH levels were assessed by contemporary techniques in chronophysiology for rhythmic and episodic peak detection. Cosinor analysis disclosed a significant circadian rhythm in serum intact PTH concentrations in all five men, with the mean circadian amplitude and acrophase of 7.2 +/- 4.4 ng/L and 2305 +/- 401 h, respectively (mean +/- SD; n = 5). No apparent fixed ultradian periodicity was found by autocorrelation and spectral analyses. Evaluation of episodic intact PTH pulsatility by Cluster analysis revealed 23.0 +/- 4.4 discrete PTH pulses/24 h (P less than 0.01 vs. signal-free noise), which occurred at an interpulse interval of 61.6 +/- 11.1 min. The average duration of a serum intact PTH peak was 42.8 +/- 7.3 min, and its mean incremental amplitude was 12.6 +/- 1.3 ng/L, which corresponded to a 31.8 +/- 5.2% increase above the preceding nadir. Discrete PTH peaks were separated by nonpulsatile valleys which lasted for 17.9 +/- 4.4 min. Cross-correlation between the time series of serum intact PTH and whole blood ionized calcium (Ca2+) was at its maximum (-0.5) at concurrent time points in three subjects, while significant positive correlation between serum intact PTH and simultaneous serum inorganic phosphorus concentrations was observed in four of five subjects. There was no apparent correlation between the levels of serum intact PTH and serum magnesium. Our data show that serum levels of intact PTH, the only biologically active form of PTH in the blood, is characterized by a significant circadian periodicity, spontaneous episodic pulsatility with distinct peak properties, and a significant temporal coupling with Ca2+ and inorganic phosphorus concentrations. We conclude that PTH secretion, as judged by the temporal pattern of serum intact PTH levels, is pulsatile in normal men.     

Serum calcium is positively correlated with fasting plasma glucose and insulin resistance, independent of parathyroid hormone, in male patients with type 2 diabetes mellitus

Patients with primary hyperparathyroidism have impaired glucose tolerance more often than do controls, and parathyroid resection sometimes improves this derangement. However, it is unclear whether serum calcium (Ca) or parathyroid hormone (PTH) is more strongly related to impaired glucose metabolism in subjects without primary hyperparathyroidism. In this cross-sectional study, we examined patients with type 2 diabetes mellitus (DM) (271 men and 209 women) and analyzed the relationships between serum concentrations of Ca or intact PTH and DM-related variables. Simple regression analyses showed that the level of serum Ca was significantly and positively correlated with the levels of fasting plasma glucose, immunoreactive insulin, and homeostasis model assessment insulin resistance in men (P < .05), but not in women. In contrast, intact PTH was not significantly correlated with DM-related parameters in either sex. Multiple regression analyses showed that the significant and positive correlations between serum Ca vs fasting plasma glucose and homeostasis model assessment insulin resistance in men still remained after adjustment for intact PTH as well as age, body weight, height, creatinine, albumin, phosphate, bone metabolic markers, and estradiol (P < .05). Serum Ca level is positively associated with impaired glucose metabolism, independent of PTH or bone metabolism, in men with type 2 DM.     

Age-related changes in serum immunoreactive parathyroid hormone and its biological action in healthy men and women

Circulating levels of PTH and related parameters of calcium and phosphate metabolism were measured in healthy free-living elderly and young subjects residing in the Southwest to determine if parathyroid function changes with aging. Serum immunoreactive PTH (iPTH) was measured with two well characterized antisera; an amino (N)-terminal antiserum which cross-reacts with the biologically active domain (1-34) and recognizes intact hormone, and a midregion (44-68) antiserum which cross-reacts with intact hormone and biologically inactive midregion/C-terminal fragments. Serum iPTH in both RIAs was significantly increased in the elderly population. An age-related increase was also found for total urinary cAMP and serum alkaline phosphatase, whereas the tubular reabsorptive maximum for phosphate (TmP/GFR) decreased with age. No difference was found between men and women of the same age group for serum iPTH, urinary cAMP, or serum alkaline phosphatase. TmP/GFR declined with age in men, but not women. Correspondingly, serum phosphate was significantly lower in elderly men than in elderly women. Urinary calcium excretion was higher in elderly women than in men of the same age group. Neither serum total or ionized calcium decreased with age. In conclusion, the age-related increase in N-terminal PTH and alterations in associated parameters of phosphate and calcium metabolism are consistent with increased parathyroid function as men and women age. Factors other than PTH are responsible for the sex-related differences observed in TmP/GFR, calcium excretion, and serum phosphate. The cause of the increased circulating levels of apparently biologically active PTH is unclear, but extends beyond the age-related decrease in renal function.     

Acute fasting diminishes the circadian rhythm of biochemical markers of bone resorption

OBJECTIVE: Biochemical markers of bone turnover exhibit circadian rhythms with the peak during the night/early morning and the nadir in the late afternoon. The nocturnal increase in bone resorption could theoretically be caused by the absence of food consumption which brings about a decrease in net calcium absorption and an increase in parathyroid hormone (PTH), followed by increased bone resorption in response to the body's demand for calcium. The aim of the present study was to assess the influence of a 33-h fast on the circadian variation in biochemical markers of bone turnover. DESIGN: Eleven healthy premenopausal women (age: 24+/-5 years) participated in a randomised, cross-over study consisting of two periods: either 33h of fasting (fasting) followed 1 week later by a 33-h period with regular meals eaten at 0800-0830h, 1130-1230h and 1800-1900h (control) or vice versa. METHODS: Urinary CrossLaps (U-CL/Cr) corrected with creatinine, as a marker of bone resorption; serum osteocalcin (sOC) as a marker of bone formation; serum intact PTH (iPTH); serum phosphate; and serum calcium corrected with albumin. RESULTS: Both the fasting and the control periods showed a significant circadian rhythm in U-CL/Cr (P<0.001), but the decrease was significantly less pronounced in the morning hours during the fasting period. Fasting resulted in a significant decrease in serum iPTH (throughout the study period) as compared with the control period (P<0.05-0.001). No change was observed in sOC by fasting. CONCLUSION: Food consumption has a small influence on the circadian variation in bone resorption, independent of PTH. The fall in iPTH during fasting may be secondary to an increased bone resorption produced by fasting.     

Gender variation in leptin circadian rhythm and pulsatility in adult growth hormone deficiency: effects of growth hormone replacement

OBJECTIVES: Adult growth hormone deficiency (AGHD) is characterized by obesity and associated with increased leptin concentration and decreased leptin pulsatility. Growth hormone replacement (GHR) results in a decrease in leptin concentration and increase in leptin pulsatility, followed by reduction in body fat mass (BFM). In both health and AGHD, women exhibit relatively higher leptin concentrations compared to men. The effect of gender on leptin rhythm and pulse parameters in AGHD is yet to be defined and the gender difference in the response of leptin secretory pattern to GHR has not been determined. Therefore the aim of this study was to evaluate the effect of gender on circadian and pulse parameters of leptin secretion in AGHD, and examine the gender variation in response of these parameters to GHR. STUDY DESIGN: A prospective, open treatment design study to determine the effect of gender on leptin rhythm and pulse parameters in untreated and treated AGHD. GH was commenced at a daily dose of 0.5 IU, and titrated up by increments of 0.25 IU at 2-weekly intervals to achieve and maintain IGF-I SDs between the median and upper end of the age-related reference range. PATIENTS: Twelve patients (six men, six women) with severe AGHD following pituitary surgery, defined as peak GH response < 9 mU/l to provocative testing were studied. All patients required additional pituitary replacement hormones following pituitary surgery and were on optimal doses at recruitment. MEASUREMENTS: Plasma leptin was measured at half-hourly intervals for 24 h, before and 1 month after initiation of GHR. Cosinor analysis was used to determine the circadian rhythm parameters: MESOR (rhythm-adjusted mean), acrophase and amplitude; and ULTRA algorithm used for pulse analysis. Body composition was measured using bioelectrical impedance. RESULTS: BFM was higher in women than men at both visits (P < 0.05), but there was no significant change in BFM in either gender following 1 month of GHR. Women had a higher mean 24-h leptin concentration, MESOR, circadian amplitude and pulse amplitude, both before and after GHR (P < 0.05). Following treatment, mean leptin concentration and MESOR decreased significantly in both men and women (P < 0.05), with no significant difference in percentage change between the genders. Pulse frequency increased and duration decreased significantly after GHR in both groups, without any significant gender difference. IGF-I and IGF SDs were similar in both genders at baseline (P = 0.93). However, after 1 month GHR, the increase in both measurements was greater in men than women (P = 0.005) and men had significantly higher IGF-I and IGF SDs than women (P = 0.01). CONCLUSIONS: As in healthy individuals, leptin levels were higher in women with AGHD than men, both prior to and after GHR. Decline in leptin concentrations and increase in leptin pulsatility following 1 month of GH treatment were similar in both genders. Changes in leptin secretory parameters appeared to occur without any significant decrease in BFM, suggesting a regulatory role for GH. Additionally, the action of GH on leptin secretory pattern does not appear to be mediated by IGF-I. Our data suggest that changes in leptin concentration and rhythm parameters following GHR are independent of gender.     

Circadian variation in ionized calcium and intact parathyroid hormone: evidence for sex differences in calcium homeostasis

The rate of bone loss with age and the incidence of osteoporosis are greater in women than men, which led us to question whether subtle sex differences may occur in the circadian variation of serum ionized calcium (iCa) and PTH. We measured iCa hourly and intact PTH every 2 h for 26 h in 25 women (21-69 yr) and 24 men (20-67 yr) consuming self-selected diets. Urine was collected at 0800-1600, 1600-2400, and 2400-0800 h. Serum iCa levels followed a circadian rhythm in both sexes (P less than or equal to 0.01), and the patterns differed between sexes, notably during early morning, when serum iCa levels were lower in women (P = 0.02). Urinary calcium excretion and fractional excretion of calcium declined in both sexes at night (2400-0800 h), but the decline in men was significantly greater (P = 0.02). Similarly, the percent reduction in urinary calcium excretion at night was greater in men than in women (34% vs. 17%; P less than or equal to 0.05). In women, 26-h mean serum iCa values correlated significantly with total daily calcium intake (r = 0.44; P = 0.03). Serum intact PTH levels showed a significant circadian pattern in both sexes (P less than or equal to 0.001). The patterns of serum intact PTH differed between the sexes (P = 0.05), with an earlier and greater increase at night in men. This blunted nocturnal rise in PTH in women may explain the poor nocturnal adaptation to fasting found in women who, despite lower calcium intake, did not reduce urinary calcium loss at night as effectively as men.     

Effects of cigarette smoking on the circadian rhythm of heart rate variability

BACKGROUND: The effects of cigarette smoking on the circadian rhythm of heart rate variability (HRV) are not known. METHODS: We studied the effects of cigarette smoking on the circadian rhythm of HRV in 24 smoking and 21 non-smoking healthy subjects. Twenty-four hour ambulatory electrocardiograms were recorded and time domain parameters of HRV (SDNN [standard deviation of all R-R intervals], SDANN [standard deviation of the averages of R-R intervals in all 5-minute segments of the entire recording], RMSSD [the square root of the mean of the sum of the squares of differences between adjacent R-R intervals]) were determined for the entire 24-hour period and for each 3-hour period. RESULTS: In total, SDNN and SDANN were significantly lower in smokers than non-smokers (116 +/- 26 vs 136 +/- 27, p < 0.05 for SDNN, 109 +/- 25 vs 121 +/- 24, p < 0.05 for SDANN). However, there were no statistical differences between smokers and non-smokers in heart rate (81 +/- 9 vs 76 +/- 10, p > 0.05) and RMSSD (32 +/- 12 vs 37 +/- 18, p > 0.05). These HRV parameters showed a circadian variation: they increased at night and decreased during the day in both groups. The parameters were lower in smokers than non-smokers during daytime (especially, between 8-14 hours). However, no differences were detected during night-time. CONCLUSIONS: Time domain parameters of HRV (SDNN, SDANN and RMSSD) in both smoking and non-smoking healthy subjects have a circadian rhythm. SDNN and SDANN were lower in smokers than non-smokers during daytime.     

Normocalcemic hyperparathyroidism in Vietnamese immigrants living in southern California

OBJECTIVE: To characterize the normocalcemic hyperparathyroidism in Vietnamese immigrants living in southern California. METHODS: Of 14 Vietnamese patients with primary hyperparathyroidism who were observed between 1991 and 1996, 50% (7 patients; 2 men and 5 women) had normal and/or fluctuating levels of serum total calcium. When the serum calcium was corrected for the albumin, the "corrected" calcium was lower than the measured serum total calcium. Their mean age was 56.4 +/- 11.4 years. All patients had normal serum levels of albumin and serum phosphate. RESULTS: Women were affected more often than men by a ratio of 5:2. The serum-ionized calcium as well as intact PTH were increased in all patients. Five patients underwent surgery with confirmation of parathyroid adenomas. Two patients refused surgery. They did not have osteitis fibrosa cystica by radiological examination. One patient had low plasma levels of 25-hydroxyvitamin D. Five of 7 normocalcemic patients (70%) were born in the month of December compared with 2 of seven hypercalcemic patients (30%). CONCLUSION: The blood ionized calcium and intact parathyroid hormone are necessary for confirmation of normocalcemic hyperparathyroidism. Most of our normocalcemic hyperparathyroid patients (70%) were born in the month of December. We postulate that a combination of exposure to solar ultraviolet light during the formation of the fetal parathyroid glands and stimulation from low vitamin D levels in the wintertime may be related to the development of hyperparathyroidism. However, it is difficult to prove a definite correlation between normocalcemic hyperparathyroidism and their month of birth (December), especially when these observations were seen in a small group of patients.     

Effect of 22-oxacalcitriol on secondary hyperparathyroidism in hemodialysis patients

OBJECTIVE: A synthetic analogue of calcitriol, 22-oxacalcitriol (OCT), strongly suppresses parathyroid hormone (PTH) secretion. This study investigated the influence of OCT on PTH secretion and bone metabolism in 12 hemodialysis patients with secondary hyperparathyroidism. METHODS: OCT was intravenously injected after every hemodialysis session (three times weekly) for 22 weeks. The levels of the following parameters were measured: intact PTH, whole PTH, whole PTH/7-84 PTH ratio, adjusted calcium, phosphorus, alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP), intact osteocalcin (OC), type I collagen carboxyterminal propeptide, tartrate-resistant acid phosphatase (TRAP), cross-linked C-terminal telopeptides of type I collagen, and interleukin-6. PATIENTS: The subjects were 12 hemodialysis patients (8 men and 4 women) with an intact PTH level of more than 460 pg/ml, a normal serum calcium level, and a serum phosphorus of less than 7 mg/dl. RESULTS: The levels of intact PTH, whole PTH, whole PTH/7-84 PTH ratio, ALP, BAP, OC, and TRAP were significantly decreased after OCT administration, while adjusted calcium was significantly increased. Serum phosphorus and the other parameters showed no significant changes. CONCLUSION: OCT effectively suppressed the PTH level and bone metabolism parameters in hemodialysis patients with secondary hyperparathyroidism.     

Increasing parathyroid hormone concentrations in untreated primary hyperparathyroidism.

Twenty-four patients with mild to moderate primary hyperparathyroidism were followed for an average of 2.45 years with serial determinations of serum ionized calcium and intact parathyroid hormone (PTH). For the entire group serum ionized calcium remained stable, whereas serum PTH increased significantly. Eleven patients (group 1) demonstrated a significant increase in PTH with time. The remaining 13 patients formed group 2. Comparison of the changes (%) in each subgroup showed a small but significant increase in serum ionized calcium of 2.6% with time in group 1, while serum PTH increased by 78%. In group 2 serum ionized calcium remained stable whereas PTH increased modestly by 22%. Serum concentrations of creatinine were stable throughout the follow-up period in both groups. Despite the greater precision of serum ionized calcium, measurements of intact PTH are evidently more sensitive than measurements of serum ionized calcium for the detection of progression in primary hyperparathyroidism.     

Growth hormone replacement is important for the restoration of parathyroid hormone sensitivity and improvement in bone metabolism in older adult growth hormone-deficient patients

Alterations in PTH circadian rhythm and PTH target-organ sensitivity exist in adult GH-deficient (AGHD) patients and may underlie the pathogenesis of AGHD-related osteoporosis. GH replacement (GHR) results in increased bone mineral density, but its benefit in AGHD patients over 60 yr old has been debated. To examine the effect of age on changes in PTH circadian rhythm and target-organ sensitivity after GHR, we recruited 22 AGHD patients (12 were <60 yr of age, and 10 were >60 yr of age). Half-hourly blood samples were collected for PTH, calcium, phosphate, nephrogenous cAMP (marker of renal PTH activity), type-I collagenbeta C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker) before and after 1, 3, 6, and 12 months of treatment with GHR. Significant PTH circadian rhythms were present in both age groups throughout the study. After GHR, PTH decreased and nephrogenous cAMP, adjusted calcium, and bone turnover markers increased in both groups, suggesting increased PTH target-organ sensitivity. In younger patients, the changes were significant after 1 month of GHR, but, in older patients, the changes were delayed until 3 months, with maximal changes at 12 months. Older AGHD patients derive benefit from GHR in terms of improvement in PTH sensitivity and bone metabolism. Their response appears delayed and may explain why previous studies have not shown a positive effect of GHR on bone mineral density in older AGHD patients.     

Parathyroid hormone gene polymorphisms in primary hyperparathyroidism

OBJECTIVE: Genetic contributions to bone mineral density (BMD) and bone turnover are well known. In the present study, we analysed the relationship between restriction fragment length polymorphisms of the PTH gene and the development of primary hyperparathyroidism (pHPT) as well as its severity. PATIENTS: Seventy-nine pHPT patients and 104 age-matched healthy controls were analysed. DESIGN AND MEASUREMENTS: PTH genotypes were determined by polymerase chain reaction and BstB I or Dra II restriction fragment length polymorphisms. The presence and absence of BstB I or Dra II restriction sites of the PTH gene were indicated by B and b or D and d, respectively. BMD levels at the lumbar spine and at the radius were measured in all subjects. Serum levels of calcium, phosphorus, alkaline phosphatase and intact PTH were measured in pHPT patients. RESULTS: There were no differences in the frequencies of these PTH genotypes between pHPT patients and controls. In control subjects, lumbar BMD was significantly higher in BB genotype than in Bb/bb genotypes. In pHPT patients, there was no difference of BMD between BB and Bb/bb genotypes. In pHPT patients, serum calcium level was significantly higher in those with the BB genotype than Bb/bb genotypes. On the other hand, there was no association between Dra II polymorphism and BMD in both controls and pHPT patients, but serum intact PTH level was significantly higher in DD genotype than Dd/dd genotype in pHPT patients. Moreover, serum levels of ALP and intact PTH were significantly higher in the PTH BBDD haplotype, compared to those in haplotypes other than BBDD. CONCLUSIONS: The present study suggests that the BstB I polymorphism of PTH gene is closely related to bone mineral density and that PTH gene polymorphisms do not seem to affect the development of primary hyperparathyroidism but may relate to the severity of primary hyperparathyroidism.     

Non-autonomy of parathyroid hormone secretion in acute primary hyperparathyroidism

A patient with acute primary hyperparathyroidism treated with mithramycin preoperatively, underwent neck exploration and two enlarged parathyroid glands were excised: one huge adenoma (6g) and another smaller gland. Mithramycin was administered preoperatively to lower life-threatening hypercalcaemia, and parathyroid slices from the huge adenoma removed at surgery were submitted in vitro to various calcium concentrations in the media to determine the influence of calcium on parathyroid adenoma secretory pattern in acute primary hyperparathyroidism. Mithramycin induced a significant decline in calcium levels and significant elevations of calciotrophic hormones (intact PTH, mid-region specific PTH, calcitonin and calcitriol). Significant suppression in PTH output in vitro was achieved by increasing calcium levels in the media. These results exclude autonomous PTH secretion (non-calcium dependent) as a possible aetiology of acute primary hyperparathyroidism. We suggest that a sudden increase in the set-point of the diseased parathyroid cells in the presence of a huge cell mass accounts, in large part, for both the marked hypercalcaemia and elevated PTH levels in this patient.     

Temporal interrelationships between the circadian rhythms of serum parathyroid hormone and calcium concentrations

The temporal relationships between the circadian rhythms of serum PTH, total calcium (Cat), and phosphate (Pi) and plasma ionized calcium (Cai) concentrations were determined in 9 normal men. Blood samples were collected every half hour for 24 h. Serum PTH was measured by an RIA specific for the midregion of the molecule. The mean circadian pattern for each variable was derived by calculating the average value across all men at concurrent time points. After the data were smoothed by the method of running means, the correlations between PTH and mineral values from concurrent time points were calculated, as were cross-correlations to 12 lag periods (6 h). Spectral and cross-spectral analyses were performed on the same data set. Both statistical methods yielded consistent results: 1) at concurrent time points (0 lag), high correlations were found between serum PTH and Cat (r = -0.74), PTH and Pi (r = 0.79), and PTH and Cai (r = -0.53); and 2) when the PTH series was lagged by 2 h, the PTH/Cai correlation improved to -0.70. A direct PTH/Cai correlation of 0.50 was found when the Cai series was lagged about 4.5 h. No improvement in the correlations were found when the other series were lagged. Spectral analyses also detected significant interrelations between PTH and Cai at 2 and 3.5 h. These data describe the timing of the bidirectional interaction between serum PTH and plasma Cai under steady state conditions in normal adult men; changes in Cai concentrations precede inverse changes in PTH levels by 2 h, whereas changes in PTH precede similar directional alterations in Cai by about 4 h.     

Diagnostic applicability of intact and midregion/C-terminal parathyroid hormone assays in calcium metabolic disorders

We compared measurements of parathyroid hormone (PTH) using two assays, in order to detect intact PTH and midregion/C-terminal PTH (M/C-PTH) in a variety of calcium metabolic disorders. The series consisted of a total of 101 patients, including subjects with primary hyperparathyroidism (n = 24), hypoparathyroidism (n = 18), hypercalcaemia of malignancy (n = 10), moderate chronic renal failure (n = 14), chronic renal failure undergoing haemodialysis (n = 19), and small bowel disorders (n = 16). The intact PTH assay was superior to the M/C-PTH assay in reflecting parathyroid function in primary hyperparathyroidism, hypoparathyroidism and hypercalcaemia of malignancy. In patients with chronic renal failure, both assays were indicators of a comparable number of patients with elevated PTH levels. Intact PTH proved most reliable in detecting changes in parathyroid hormone secretion in response to variations in ionized calcium induced by haemodialysis. In patients with extensive intestinal resection, both assays showed increased levels of PTH. It is concluded that measurement of intact PTH is a more reliable index of parathyroid function than measurement of midregion/C-terminal PTH. Thus such an approach should be the one of choice for clinical evaluation of calcium homeostasis.     

The role of insulin-like growth factor I in age-related changes in calcium homeostasis in men

The aim of this study was to evaluate hormonal influences on age-related changes in calcium homeostasis in men. We recruited 178 healthy men, ages 20-79 (about 30 per decade). We measured serum calcium, phosphate, urinary calcium, and creatinine clearance. Dietary calcium intake and use of fish oils were determined by questionnaire. Fractional calcium absorption was estimated using the stable strontium technique in a subgroup of 60 men. PTH, 1, 25-dihydroxyvitamin D [1,25(OH)(2)D], 25-hydroxyvitamin D (25OHD), serum insulin-like growth factor I (IGF-I), and testosterone were measured in all men. There was no change in serum calcium with age. There were decreases in serum phosphate, urinary calcium, and creatinine clearance with age (P: < 0.02). Dietary calcium was unchanged. Strontium absorption decreased (P: < 0.01), and PTH increased (P: < 0.001) with age. The data for 1,25OH(2)D were biphasic, reaching a peak at age 55 yr (P: = 0.003). There was a linear increase in 25OHD with age (P: = 0.009) that persisted after correcting for seasonal variation and was positively associated with fish oil use, therefore, the age-related changes in 25OHD were masked by self medication. There were log-linear decreases in IGF-I and testosterone with age (P: < 0.0001). Strontium absorption was not related to 25OHD or 1,25(OH)(2)D, but was positively correlated with IGF-I. 1,25(OH)(2)D correlated negatively with serum phosphate and calcium, but not PTH or creatinine clearance. IGF-I was positively associated with creatinine clearance, serum calcium, and phosphate and negatively associated with PTH (P: < 0.001). In this cross-sectional study of otherwise healthy, normally aging men, age-related decreases in IGF-I seem to have a greater impact on mineral absorption than does vitamin D status.     

Effect of acute cimetidine administration on indices of parathyroid hormone action in healthy subjects and patients with primary and secondary hyperparathyroidism

To evaluate the acute effect of histamine H2-receptor blockade with cimetidine on PTH concentrations and its endogenous biological activity, we studied the effect of iv administration of cimetidine (50-mg bolus followed by 500 mg/60 min infusion) in normal subjects and patients with primary and secondary hyperparathyroidism. No significant changes in serum concentrations of calcium, phosphate, or immunoreactive C-terminal PTH were found in any group. However, the control group had decreased calciuria, increased phosphaturia, and decreased tubular reabsorption of phosphate, while the primary hyperparathyroid group had increased phosphaturia, increased nephrogenous cAMP excretion, and decreased tubular reabsorption of phosphate. In both of these groups, the finding suggest an increase in PTH-like biological activity. These findings suggest that cimetidine is not useful in the diagnosis or medical management of hyperparathyroidism. In fact, the changes in renal calcium and phosphorous excretion indicative of PTH-like biological activity along with a decrease in creatinine clearance in the primary hyperparathyroid group suggest a relative contraindication to the use of this drug in these patients.     

Relationships with serum parathyroid hormone in old institutionalized subjects

OBJECTIVE AND BACKGROUND: Old people in residential care are at the highest risk of any group for hip fracture. This may relate to their high prevalence of hyperparathyroidism. There are few data, however, on relationships with serum parathyroid hormone (PTH) in these individuals. This study therefore examined complex associations with serum PTH in nursing home and hostel residents. DESIGN: Cross-sectional analysis. PATIENTS: One hundred and forty-three nursing home and hostel residents of median age 84 years. MEASUREMENTS: Serum PTH, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25-(OH)2D), plasma creatinine, phosphate, calcium, albumin, Bsm-1 vitamin D receptor genotype, age, weight and use of frusemide or thiazide. RESULTS: The statistical models determined accounted for half the interindividual variation in serum PTH. Heavier weight was associated with both the prevalence of secondary hyperparathyroidism and the serum concentration of PTH. Novel interactions with serum PTH were identified between: weight and 25OHD; 25OHD and phosphate; and phosphate and thiazide diuretic use. Plasma phosphate was associated with PTH independently of calcium and 1,25-(OH)2D. There was no independent association between PTH and nuclear vitamin D receptor genotype. CONCLUSIONS: Heavier weight is associated with both the prevalence and severity of secondary hyperparathyroidism and consistent with animal models of secondary hyperparathyroidism, phosphate may relate to serum PTH independently of 1,25-(OH)2D or calcium.