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Département de Physiologie, Hopital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale U356, Institut Fédératif de Recherche 58, Paris, 75015 France
Address correspondence and requests for reprints to: Pascal Houillier, M.D., Ph.D., Département de Physiologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France. E-mail: pascal.houillier{at}egp.ap-hop-paris.fr.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Several factors have been considered to explain the maintenance of normal serum calcium concentration in primary hyperparathyroidism. It has been proposed that, in the patients with normocalcemic primary hyperparathyroidism, serum total calcium concentration may not reliably reflect the expected increase in the free, biologically relevant fraction of serum calcium (5, 6), thereby justifying the usefulness of direct measurement of serum ionized calcium concentration in the patients with minimal or no increase of the total serum calcium level. Another commonly admitted explanation is that normocalcemic primary hyperparathyroidism may represent an early and/or a mild variety of primary hyperparathyroidism (4, 6, 7, 8). Indeed, when measured, the weight of parathyroid tumors (4, 9) and plasma PTH concentration (4, 8) are lower in hyperparathyroid patients with normal serum calcium concentration than in patients with hypercalcemia. However, no available data support the view that parathyroid gland weight is dependent on the duration of the disease; by contrast, available data suggest that PTH secretion remains steady for years in patients with primary hyperparathyroidism (10).
A previous study by our group has suggested that the maintenance of a normal serum total calcium concentration in patients with primary hyperparathyroidism could be the consequence of a renal tubular resistance to the action of PTH. It was shown that patients with normocalcemic primary hyperparathyroidism had a normal (i.e. not increased) tubular reabsorption of calcium, whereas patients with hypercalcemic primary hyperparathyroidism had a tubular reabsorption of calcium increased in proportion to serum calcium concentration (11). However, in this study, patients were separated between hypercalcemic and normocalcemic subgroups on the basis of serum total calcium value and not serum ionized calcium; among the 20 patients referred to as normocalcemic, four had a high serum ionized calcium value. In addition, serum 1,25 dihydroxyvitamin D values had not been determined and no explanation for the tubular resistance to PTH was apparent.
The aim of the present work was to address three distinct issues: Does normocalcemic primary hyperparathyroidism exist when patients are classified on the basis of serum ionized calcium concentration? Does normocalcemic primary hyperparathyroidism represent a biologically milder form of the disease than hypercalcemic primary hyperparathyroidism? Finally, is it related to a renal or more general peripheral resistance to parathyroid hormone?
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Patients and Methods |
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Selection of patients (Fig. 1
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Four hundred seventy-one patients were excluded from further analysis because of the presence of severe vitamin D deficiency (defined as a 25 OH vitamin D concentration < 15 nmol/liter, 99 patients), magnesium deficiency (defined as a plasma magnesium concentration < 0.71 mmol/liter, 26 patients), impaired renal function (defined as a plasma creatinine value higher than 110 µmol/liter or a creatinine clearance lower than 50 ml/min per 1.73 m2, 49 patients), treatment with a drug interacting with bone and mineral metabolism (bisphosphonates, lithium, loop diuretics or thiazides, corticosteroids, 243 patients), an associated disease (such as a progressive endocrine disorder, neoplasia, or granulomatosis, 66 patients), or because they did not follow a low-calcium diet on the day before the investigation (29 patients). Some patients had more than one cause for exclusion.
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Ninety-four patients in our cohort of patients with primary hyperparathyroidism have been operated on because they met the guidelines of the National Institutes of Health for parathyroidectomy (12). The 84 nonoperated patients, either normocalcemic (n = 13) or hypercalcemic (n = 71) fulfilled the same biological diagnostic criteria as the operated patients. The key comparative data in surgically verified and nonverified cases are summarized in Table 1. No significant difference could be observed between the two groups. Consequently all the patients have been studied together.
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The investigation was performed as previously described (11, 13, 14). During the day before the test, a 24-h urine sample was collected; patients could eat any food other than cheese and dairy products, and virtually calcium-free drinking water was given (<10 mg/liter of elemental calcium). From the evening before the test, patients fasted until the investigation, which started the following day at 0830 h and lasted for half a day. During the test, patients were given virtually calcium-free drinking water in an amount sufficient to yield adequate urine specimens. One 2-h urine collection period was performed on the basal state. An oral load of 1 g elemental calcium [45 ml calcium gluconate (Calcium, Sandoz, Rueil-Malmaison, France) together with milk] was then given, except in the 18 patients whose baseline serum ionized calcium concentration was higher than 1.60 mmol/liter. Urine collected during the following 90 min was discarded. A subsequent 2-h urine collection period was then performed. Blood was drawn at the midpoint of each period, without a tourniquet, through an indwelling catheter inserted into a large vein of the arm.
The following variables were measured: during the fasting state, in serum, total calcium (normal 2.08–2.52 mmol/liter; 8.3–10.1 mg/dl), ionized calcium (normal 1.14–1.35 mmol/liter; 4.6–5.4 mg/dl), PTH 1–84 (normal 10–58 ng/liter), and osteocalcin (normal 5–14 ng/ml); in plasma, creatinine, phosphate (normal 0.82–1.40 mmol/liter; 2.5–4.3 mg/dl), magnesium (normal 0.71–1.04 mmol/liter; 1.7–2.5 mg/dl), 25 hydroxyvitamin D (normal 15–126 nmol/liter; 6–51 ng/ml), 1,25 dihydroxyvitamin D (normal 45–110 pmol/liter; 19–46 pg/ml), cAMP, total CO2 and pH. Calcium, phosphate, creatinine, and PTH were measured in each blood sample. In urine, creatinine, calcium, phosphate, and cAMP were measured and, in the first urine collection only, deoxypyridinoline (available from April 1993). The 24-h urine sample was analyzed for creatinine, calcium, and sodium.
Total calcium and magnesium were determined by atomic absorption spectrometry (model 3110, Perkin-Elmer, Norwalk, CT), ionized calcium by a specific electrode (model ICA2, Radiometer, Copenhagen, Denmark), creatinine and phosphate by routine colorimetric method, sodium by specific electrodes (model E2A, Beckman, Brea, CA); pH and PCO2 were analyzed using an automated pH and gas analyzer (ABL 330, Radiometer); and plasma and urine cAMP were analyzed by radiocompetition (Amersham, Little Chalfont, UK). PTH was measured by a two-site radioimmunometric method (Allegro PTH, Nichols Institute, San Clemente, CA), 25 hydroxyvitamin D by radiocompetition, and 1,25 dihydroxyvitamin D by radioreceptor assay. Deoxypyridinoline was measured by immunoenzymology (Metra Biosystems, Mountain View, CA). Serum-intact osteocalcin was measured by RIA (B.R.A.H.M.S. Diagnostica GmbH, Berlin, Germany). Coefficients of variation (between-assay) were 0.9 ± 0.2% for total calcium, 1.1 ± 0.4% for ionized calcium, 6.8 ± 0.1% for PTH, 11.3 ± 1.9% for 25 hydroxyvitamin D, and 11.7 ± 2.9% for 1,25 dihydroxyvitamin D.
Diagnosis of primary hyperparathyroidism
Hypercalcemic primary hyperparathyroidism was defined by a supranormal fasting serum ionized calcium concentration (>1.35 mmol/liter; >5.4 mg/dl) together with a serum PTH concentration either supranormal (>58 pg/ml) or in the upper range of normal values. Patients with normocalcemic primary hyperparathyroidism had, on baseline, a serum-ionized calcium concentration in the upper range of normal values. The diagnosis of normocalcemic primary hyperparathyroidism was established when, during the oral calcium tolerance test described above, serum ionized calcium concentration increased to supranormal values, and only a minimal reduction in serum PTH concentration was seen (14, 15, 16).
Calculations
Calculated variables were the following: glomerular filtration rate (GFR) estimated by endogenous creatinine clearance (in milliliters per minute to 1.73 m2 body surface) and the Cockcroft and Gault formula (17); fasting urinary calcium excretion either factored by creatinine excretion (normal 0.03–0.36 mmol/mmol creatinine; 0.01–0.13 mg/mg creatinine) or parametrically expressed as a function of GFR (normal 0.31–2.70 µmol/dl glomerular filtrate; 0.01–0.11 mg/dl glomerular filtrate); and nephrogenous cAMP also was expressed as a function of GFR (normal 0.59–1.99 nmol/dl glomerular filtrate) (18); and renal threshold for phosphate (maximal transport of phosphate/GFR, normal 0.75–1.37 mmol/liter glomerular filtrate; 2.3–4.2 mg/liter glomerular filtrate) was determined using the nomogram from Bijvoët et al. (19). Fasting urinary free deoxypyridinoline was expressed in nanomoles per millimole urinary creatinine (normal 1.8–7.5 nmol/mmol creatinine).
Tubular reabsorption of calcium (TRCa) (factored by GFR, TRCa/GFR) was calculated as the difference between serum calcium (SCa) and urine calcium excretion (UCaV) rate parametrically expressed as a function of GFR:
TRCa/GFR = SCa - UCaV/GFR.
Theoretically, this calculation requires the direct measurement of serum ultrafilterable calcium concentration, GFR, and UCaV. Because serum ultrafilterable calcium concentration and GFR were not measured in the present study, we used total serum calcium instead of ultrafilterable calcium and creatinine clearance instead of GFR. This was done because, in a previous study (20), we simultaneously measured the true tubular reabsorption of calcium (using serum ultrafilterable calcium concentration, and inulin clearance) as well as the estimate of tubular calcium reabsorption, using total serum calcium and creatinine. Both estimates of tubular calcium reabsorption were highly and linearly correlated (r = 0.89, n = 36).
Statistical analysis
Results are reported as mean ± 1 SD. Quantitative values were compared using the t test for unpaired values. Variables that were not normally distributed (25 hydroxyvitamin D and parathyroid gland mass) were expressed as median value and range; the comparisons were then performed with a Mann-Whitney U test. Parathyroid gland weight was also expressed as geometric mean and 95% confidence interval. Correlations between variables have been evaluated by simple or multiple regression analysis (as appropriate). P < 0.05 was considered significant. All calculations were performed with the Statview 5.0 statistical software (SAS Institute, Cary, NC).
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Results |
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A total of 178 patients were studied. On the basis of fasting serum ionized calcium concentration, two distinct subsets of patients could be identified (Table 2). Of the 178 patients, 144 patients had a high serum ionized calcium concentration, ranging from 1.36–1.86 mmol/liter (5.4–7.4 mg/dl). In 27 of these patients, serum total calcium concentration was within the normal range despite the supranormal value of serum-ionized calcium concentration. In the 144 patients, serum PTH concentration was simultaneously elevated or in the upper range of normal values (93 ± 49 pg/ml, range 44–382). Their fasting UCaV was high (0.64 ± 0.37 mmol/mmol creatinine; 0.23 ± 0.13 mg/mg creatinine). Following the oral calcium load that was performed in all patients except in 18 who had a baseline serum ionized calcium concentration higher than 1.60 mmol/liter, the serum PTH concentration only slightly decreased (from 82 ± 28 to 62 ± 24 pg/ml; a -24% change) despite a marked increase in serum ionized calcium concentration (from 1.45 ± 0.07 to 1.53 ± 0.08 mmol/liter; 5.8 ± 0.3 to 6.1 ± 0.3 mg/dl). These data allowed the establishment of the diagnosis of primary hyperparathyroidism. Finally, 73 (51%) of these 144 patients were operated on according to the recommendations of the 1991 consensus conference (12); in all of them, a parathyroid tumor was retrieved (65 single adenomas, two double adenomas, and six diffuse hyperplasia).
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Nine patients from this group of normocalcemic primary hyperparathyroidism patients were investigated at least twice at more than a 1-month interval (median 19 months; range 2–76 months) in our unit. All these patients, five of whom having been operated on, remained normocalcemic over the time of follow-up.
Mean serum PTH concentration was lower in the normocalcemic than in the hypercalcemic subset of patients (Table 2
). However, it was apparent that serum PTH values in normocalcemic and hypercalcemic subgroups largely overlapped (Fig. 2). This overlap suggested that a given increase in PTH secretion was able to induce hypercalcemia in many patients but failed to do so in others. To elucidate this point, we matched each normocalcemic patient with one hypercalcemic patient on the basis of age, gender, and baseline serum PTH concentration.
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The biological data in the normocalcemic patients and the matched hypercalcemic patients are given in Table 3. It was readily apparent that the mean values of age, sex ratio, and serum PTH concentration were exactly the same in both groups of patients. Therefore, the two groups were appropriately designed to address the following issue: why didn’t an identically increased PTH secretion induce an identical increase in serum calcium concentration in the two subgroups of patients?
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, A and B, serum ionized calcium concentration was positively correlated to both the net entry of calcium into the extracellular fluid as estimated by the fasting urinary calcium excretion (UCa/UCr) and the index of tubular calcium reabsorption (TRCa/GFR). In univariate analysis, these results indicated that, in our population of 68 patients with primary hyperparathyroidism, serum ionized calcium was much more dependent on TRCa/GFR (slope 0.499; 95% confidence interval: 0.406–0.592; r2 0.64) than on UCa/UCr (slope 0.079; 95% confidence interval 0.028–0.130; r2 0.13). In multivariate regression analysis, serum ionized calcium remained independently predicted by both variables; nevertheless, using step-by-step regression analysis, the r2 coefficient was 0.64 when TRCa/GFR was the unique independent variable in the model; it only slightly increased, to 0.68, when UCa/UCr was entered in the model, which means that the contribution of UCa/UCr was only marginal, knowing the value of TRCa/GFR.
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). First, UCa/UCr was significantly lower in normocalcemic than in hypercalcemic patients. Second, the index of TRCa/GFR was also lower in the normocalcemic subgroup than in the hypercalcemic one. In both groups of patients, the mean TRCa/GFR was higher than that calculated in normal subjects (2.23 ± 0.02 mmol/liter glomerular filtrate; 8.9 ± 0.8 mg/dl glomerular filtrate; P < 0.01 for both comparisons). As shown in Fig. 4, for any amount of calcium entering the extracellular fluid, serum calcium was higher in the hypercalcemic than in the normocalcemic group, despite an identically elevated serum PTH concentration.
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) that several other PTH-dependent variables differed between the two subgroups: The renal threshold for phosphate was higher in the normocalcemic patients; conversely, plasma 1,25 dihydroxyvitamin D and osteocalcin concentrations and fasting urine deoxypyridinoline excretion were lower in the normocalcemic subgroup. By contrast, there was no difference in plasma pH and bicarbonate concentration, 25 hydroxyvitamin D and serum magnesium concentrations, and 24-h urine sodium excretion. Finally, and unexpectedly, the mean body mass index (BMI) differed between both subsets of patients: it was higher in the normocalcemic group than in the hypercalcemic one, despite identical sex ratio and age. |
Discussion |
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Cases of patients with a primary increase in PTH secretion together with the maintenance of a normal serum calcium concentration have been repeatedly reported (for review see Refs. 3 ,4). Several explanations have been proposed for this persistently normal serum calcium concentration in these patients with a primary hypersecretion of PTH. First, serum total calcium concentration might be an imperfect estimator of the changes in serum ionized calcium concentration. In fact, when serum total and ionized calcium values in patients with primary hyperparathyroidism are compared, ionized calcium values are more frequently elevated than total calcium values (5, 6). Our data are in perfect agreement with those from these earlier studies: About half of the studied patients with primary hyperparathyroidism and a normal total serum calcium concentration have a false normocalcemic primary hyperparathyroidism; this strengthens the view that the measurement of serum ionized calcium, which is the regulated variable, is more relevant in the diagnosis of mild or subtle primary hyperparathyroidism than the measurement of total serum calcium.
It remains clear, however, that approximately 20% of the patients with primary hyperparathyroidism reported in this study have a normal ionized calcium concentration and are, therefore, truly normocalcemic. The main purpose of the present work was to determine the reason(s) for the maintenance of a true normal calcium concentration in these patients.
The maintenance of a normal serum calcium concentration might be accounted for by milder excess in serum PTH concentration. In fact, a lower mean serum PTH concentration is observed in patients with normocalcemic primary hyperparathyroidism than in patients with the hypercalcemic form of the disease. The first explanation may be that a lower parathyroid tumor mass explains the lower mean serum PTH concentration (21). Indeed, when comparing the parathyroid tumor mass in the patients of the present study who have been operated on, the mean tumor weight is lower in the normocalcemic than in the hypercalcemic patients. Second, normocalcemic primary hyperparathyroidism might be an earlier form of the disease than hypercalcemic primary hyperparathyroidism. Although we cannot rule out this possibility, it must be noticed that, in both groups of patients, the diagnosis of primary hyperparathyroidism has been made at a similar age. In addition, prospective follow-up of some normocalcemic patients shows that serum calcium concentration can remain within the normal range over a time period reaching 76 months, consistent with the fact that normocalcemic primary hyperparathyroidism may not represent a transitional phase toward the hypercalcemic form of the disease.
Although maintenance of a normal serum calcium concentration in a subset of patients with primary hyperparathyroidism may be explained, in part, by a lower mean PTH secretion, it clearly appears that a major overlap exists between PTH concentration values measured in patients with the hypercalcemic form and those with the normocalcemic form of the disease. This indicates that a similarly increased PTH secretion is able to induce hypercalcemia in most patients but is unable to do so in others. To address this issue, we matched patients with either normocalcemic or hypercalcemic primary hyperparathyroidism on the basis of fasting PTH concentration, age, and gender. Despite the identically elevated PTH concentration in both groups, the immediate determinants of serum ionized calcium concentration significantly differ. First, the net bone calcium release (as assessed by fasting UCa/UCr) is lower in the normocalcemic than in the hypercalcemic subgroup. The markers of bone turnover are also lower in the normocalcemic than in the hypercalcemic subgroup. Taken together, these results indicate that in the subgroup of patients with normocalcemic primary hyperparathyroidism, PTH induces milder biological bone effects than in hypercalcemic patients. Second, the renal tubular effect of PTH differs in the patients with the normocalcemic or hypercalcemic form of the disease. The ability of the renal tubule to reabsorb calcium is lower in the former than the latter group of patients. In addition, the ability of PTH to decrease tubular phosphate reabsorption and stimulate synthesis of 1,25 dihydroxyvitamin D is also blunted in the patients who remain normocalcemic, compared with those who are hypercalcemic. Therefore, at least three PTH-dependent functions of the kidney are attenuated in the normocalcemic hyperparathyroid patients despite an identical primary hypersecretion of PTH, demonstrating a partial renal resistance to the physiological actions of PTH.
Recently the existence of an N-terminally truncated PTH fragment measured together with full-length PTH by the intact PTH assay (Nichols Institute) has been demonstrated (22). Furthermore, this peptide could antagonize the biological effect of 1–84 PTH either in vivo or in vitro (23). This truncated peptide, if it is proportionally more expressed in the normocalcemic than in the hypercalcemic patients, could explain, at least partly, our results. However, the nephrogenous cAMP secretion is indistinguishable between normocalcemic and hypercalcemic matched subgroups, indicating that the amount of serum bioactive 1–84 PTH is the same in both subsets of patients. However, the definitive demonstration that the N-truncated PTH fragment does not play a role in the resistance to the bone, and kidney effects of PTH will require the direct measurement of 1–84 and 7–84 peptides in both groups of patients.
The next point to be addressed is the reason for the difference in biological response of target organs to a same excessive concentration of PTH. It might be considered that an additional factor, besides PTH concentration, could mitigate the overall action of PTH on bone and kidney tubule. For example, it is established that, independently of PTH level, sodium intake and extracellular fluid volume, acid-base status, extracellular calcium and magnesium concentrations can affect the renal tubular calcium handling. However, in our study, both groups of patients had identical urinary sodium excretions, plasma pH and bicarbonate concentrations, and serum magnesium concentrations. In addition, because tubular calcium reabsorption is decreased by high extracellular calcium concentration, the lower tubular calcium reabsorption observed in patients who remain normocalcemic cannot be accounted for by the extracellular calcium concentration.
A primary renal calcium leak leading to secondary hyperparathyroidism and eventually autonomous hyperparathyroidism has been proposed to explain the absence of hypercalcemia in some cases of primary hyperparathyroidism (24). In the present study, this hypothesis does not explain the apparent biological skeletal resistance to PTH action and the lower ability of PTH to decrease tubular phosphate reabsorption and stimulate synthesis of 1,25 dihydroxyvitamin D observed in the normocalcemic group. Moreover, only a minority of the normocalcemic patients with primary hyperparathyroidism have an increased urinary calcium excretion; these patients with fasting hypercalciuria have been operated on, and in all cases a single adenoma (and not a diffuse hyperplasia as it may be expected in secondary hyperparathyroidism) was retrieved. Finally in a previous study by our group (11), hypercalciuria when present in patients with normocalcemic primary hyperparathyroidism did not persist after surgery.
Finally, a hormonal interference able to mitigate the end-organ effect of PTH must be considered. Concomitant vitamin D deficiency has been proposed to account for persistent normocalcemia during primary hyperparathyroidism (25). In our study, several patients in the two groups with primary hyperparathyroidism had vitamin D insufficiency as it is observed in people without primary hyperparathyroidism, living in southern or western European countries (26, 27). However, recent evidence indicates that patients with primary hyperparathyroidism and vitamin D insufficiency have a similarly elevated serum calcium concentration, a higher serum PTH concentration, a lower serum phosphate value, and higher markers of bone turnover (28, 29) and parathyroid gland mass (29) than patients with normal vitamin D stores. In the present study, no difference in 25 hydroxyvitamin D concentrations was observed between the normocalcemic group and the hypercalcemic one. Therefore it is very unlikely that maintenance of a normal serum calcium concentration in one group could be ascribed to vitamin D deficiency.
The observation that most patients with primary hyperparathyroidism are postmenopausal women (30, 31) suggests that estrogen deficiency could play a role in the unmasking of hypercalcemia. Several clinical studies have shown that estrogen supply to postmenopausal women with primary hyperparathyroidism induces a significant decrease in serum and urine calcium (32, 33, 34, 35) and the biological markers of bone turnover (33, 34, 35). These effects occur despite no change (33, 34) or an increase (35) in serum PTH concentration (i.e. the ability of PTH to stimulate bone turnover and resorption decreases in the presence of estrogens). This is in agreement with an experimental study in postmenopausal women (36), which revealed an estrogen-induced protection against bone-resorbing effects of PTH infusion. Finally, tubular calcium reabsorption in the patients with primary hyperparathyroidism could also be decreased during estrogen treatment (32). As a whole, estrogen supply appears to induce some degree of bone and kidney resistance to the effects of PTH in women with primary hyperparathyroidism, similar to what is observed in the patients with normocalcemic primary hyperparathyroidism. Serum estrogen concentration was not prospectively measured in our patients. However, patients with normocalcemic primary hyperparathyroidism had a higher BMI than hypercalcemic patients. This higher BMI could explain a higher residual estrogen production related to a greater mass of adipose tissue, which is an important site of estrogen biosynthesis in postmenopausal women (37). A possible explanation for the increased apparent incidence of primary hyperparathyroidism in postmenopausal women is that the estrogen deficiency allows target tissues to become more sensitive to the action of PTH. Therefore, women with mild primary hyperparathyroidism who remain normocalcemic before the menopause may become hypercalcemic after menopause, which renders the diagnosis easier. A minority of these women with mild primary hyperparathyroidism could remain normocalcemic because of a sufficient endogenous estrogen production. Whether serum estrogens concentration actually differs between patients with normocalcemic and hypercalcemic primary hyperparathyroidism and plays a significant role in determining the biological presentation of the disease remains to be settled.
In summary, this study demonstrates that a significant proportion of patients with primary hyperparathyroidism remains normocalcemic because of a lower sensitivity of bone and kidney tubule to the biological effect of PTH. The identification of the reason(s) for this lower sensitivity requires further investigations but putatively implicates the endogenous estrogen synthesis. It potentially provides an interesting model for the study of modulations of biological effects of PTH by interacting factors.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; GFR, glomerular filtration rate; TRCa, tubular reabsorption of calcium; UCaV, urine calcium excretion.
Received September 6, 2002.
Accepted June 23, 2003.
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