Double-blind trial of oral 1,25-dihydroxy vitamin D3 versus placebo in asymptomatic hyperparathyroidism in patients receiving maintenance haemodialysis.

Fifty-seven patients who had been receiving maintenance haemodialysis for a mean of 4.6 years were given 0.25-0.5 microgram oral 1,25-dihydroxy (1,25-(OH)2) vitamin D3 or a placebo in a double-blind manner for one to two years. In patients with normal radiographs (mean plasma parathyroid hormone concentration 205 microliterEq/ml) 1,25-(OH)2 vitamin D3 prevented the development of the radiological appearances of hyperparathyroidism. In patients with abnormal radiographs (mean plasma parathyroid concentration 709 microliterEq/ml) 1,25-(OH)2 vitamin D3 arrested or reversed the radiological changes of hyperparathyroidism. Nevertheless, the response was slow and the concentration of the hormone remained considerably raised (mean 445 microliterEq/ml). It is concluded from these results that giving 1,25-(OH)2 vitamin D3 to patients receiving maintenance haemodialysis who have normal hand radiographs or minimal erosions is beneficial. In patients with more advanced hyperparathyroidism parathyroidectomy should be considered unless there is a rapid response.     

Vitamin D status and its relation to age and body mass index

BACKGROUND/AIMS: While numerous studies have examined 25(OH)-vitamin D(3) (25-D) concentrations and their relation to parathyroid hormone (PTH) levels there is only limited information on the interrelation between 25-D, 1,25(OH)(2)-vitamin D(3) (1,25-D) and PTH. It was the aim of this study to assess the vitamin D endocrine system and its relation to age and body mass index (BMI). METHODS: This cross-sectional study comprised a convenience sample of 483 adults which attended the endocrinology outpatient service of a university hospital in the years 2002-2004. RESULTS: The mean concentrations of 25-D, 1,25-D, calcium and PTH were 21.0 +/- 10.6 ng/ml, 47.9 +/- 21.7 pg/ml, 9.48 +/- 0.48 mg/dl and 51.0 +/- 27.2 pg/ml, respectively. 25-D was related (p < 0.01) to BMI, age, PTH and 1,25-D. After correction for 25-D, we found no relation between BMI and 1,25-D. PTH was related (p < 0.01) to serum calcium, BMI, age and 1,25-D (p = 0015). There was a seasonal variation in both, 25-D and 1,25-D serum concentrations: 25-D levels were lowest in January and increased until July while the nadir and zenith of 1,25-D were found in April and October, respectively. CONCLUSION: Since BMI was negatively related to 25-D the prevalence of 25-D deficiency (<8.8 ng/ml) increased from 8.8% in subjects with BMI <30 kg/m(2) to 15.0% in subjects with BMI >30 kg/m(2). BMI, age and season should be taken into account when assessing a patients vitamin D status and more aggressive vitamin D supplementation should be considered for obese subjects.     

A new, highly sensitive assay for 1,25-dihydroxyvitamin D not requiring high-performance liquid chromatography: application of monoclonal antibody against vitamin D receptor to radioreceptor assay.

A new, highly sensitive radioreceptor assay, which does not require high-performance liquid chromatography, has been developed for the determination of 1,25-dihydroxyvitamin D3 (1,25-(OH2)D3) in serum. The assay involves rapid extraction of serum, Sep Pak silica purification, and addition of 1,25-dihydroxyvitamin D3 receptor, radiolabeled 1,25-dihydroxyvitamin D3, bovine serum albumin, and monoclonal antibody to specifically precipitate the receptor. This method is sensitive to 0.3-0.6 pg/tube, with B50 occurring at 5.8 pg/tube. This sensitivity combined with overall recovery of 1,25-dihydroxyvitamin D3 (81.5 +/- 5.2%, n = 50, mean +/- SD) allows the measurement of serum 1,25-(OH)2D3 in duplicates with only 0.5 ml of serum. Intra- and interassay coefficient of variation were 9.5 and 14.6%, respectively. Dilution analysis, analytical recovery of added 1,25-dihydroxyvitamin D3, and comparison with a standard method using HPLC have been used to validate the assay. Serum 1,25-dihydroxyvitamin D3 level was for normal adults, 36.6 +/- 10.5 pg/ml (n = 14); in primary hyperparathyroidism, 98.9 +/- 19.9 pg/ml (n = 16); in chronic renal failure, 17.8 +/- 5.1 pg/ml (n = 12). This method allows large numbers of samples to be processed at once. Further, the method is rapid and provides an accurate assay using small amounts of serum.     

Impaired mineral metabolism in Cushing's syndrome: parathyroid function, vitamin D metabolites and osteopenia

To clarify the mechanism for the impaired mineral metabolism in Cushing's syndrome, the clinical features, biochemical parameters before and after oral calcium load, and vitamin D metabolism were compared between two groups of patients of endogenous Cushing's syndrome (17 cases) with and without osteopenia. The patients with osteopenia [OP (+): 7 cases, all female] were older (42.7 +/- 8.3 y. o.) and had a longer duration (117 +/- 75 M) of the syndrome than those without osteopenia [OP (-): 33.8 +/- 8.9 y. o., 36 +/- 25 M]. OP (-) showed a blunted hypercalciuria after oral calcium load (63.7 +/- 20.4 to 90.9 +/- 36.1 mg/g X Cr), while OP (+) had higher levels of urinary excretion of calcium (fasting: 120.4 +/- 37.5, and after oral calcium load: 235.6 +/- 72.6 mg/g X Cr), of cyclic AMP (7.6 +/- 1.1 nmol/dl X GF), and of plasma 1.25(OH)2D (76.6 +/- 34.0 pg/ml) than OP (-) (u-cAMP: 3.2 +/- 2.0 nmol/dl X GF, 1,25(OH)2D: 27.9 +/- 16.3 pg/ml). These results indicate that 1) elderly female patients with Cushing's syndrome of long duration are susceptible to OP, 2) during the early phases of the syndrome, reduced intestinal calcium absorption with sustained calciuria (probably through the inhibition of calcium reabsorptive effect of PTH by glucocorticoid) induces negative calcium balance, leading to 3) a development of secondary hyperparathyroidism which stimulates 1,25(OH)2D synthesis. Thus, the mechanism involving bone resorption stimulated by excess PTH along with the direct inhibition of bone formation by glucocorticoid seems to play an important role in a progressive development of OP in Cushing's syndrome.     

Subnormal follicular-phase serum progesterone levels and elevated follicular-phase serum estradiol levels in young women with insulin-dependent diabetes

In a search for possible hormonal reasons for the loss of protection from myocardial infarction seen in diabetic women, serum levels of estradiol, progesterone, and luteinizing hormone were compared throughout a menstrual cycle (17 points) in eight healthy nonsmoking women and five otherwise healthy nonsmoking insulin-dependent diabetic women. The total length of the menstrual cycle and the lengths of the follicular and luteal phases did not differ between the groups. During the periovulatory and luteal phases, there was no significant intergroup difference with respect to any of the three hormones. During the follicular phase, in both groups, there was a plateau in serum progesterone concentration, with the level approximately 42% lower in the diabetic group (12.0 +/- 6.6 ng/dl versus 20.7 +/- 5.7; P less than 0.0001). Follicular-phase serum estradiol showed a rising curve in both groups; day-by-day comparison (days -10 to -3 before the luteinizing hormone peak) showed consistently higher levels in the diabetic group (mean, 108 pg/ml versus 95 pg/ml; P less than 0.001). The follicular-phase serum estradiol to progesterone ratio was nearly twice as high in the diabetic group as in the normal group (8.9 versus 4.6), a difference that was highly significant. The finding of elevated serum estradiol and subnormal serum progesterone concentrations during the follicular phase is so far unique to women with insulin-dependent diabetes mellitus. The possibility that this pronounced abnormality in diabetic women may be related to coronary disease merits testing in suitable in vivo and in vitro models of atherogenesis.     

Sex hormones correlated with sex skin swelling and rectal temperature during the menstrual cycle of the pigtail macaque (Macaca nemestrina).

Daily measurement of serum luteinizing hormone, estradiol-17beta, and progesterone were made during the menstrual cycle in nine pigtail macaques (Macaca nemestrina). All data were normalized to the day of the luteinizing hormone peak. Serum estradiol-17beta increased from approximately 100 pg/ml during the early follicular phase to 442 +/- 156 pg/ml during the maximum midcycle concomitant with the luteinizing hormone peak, and a small increase in serum estradiol-17beta was observed during the luteal phase coincident with the progesterone peak. Serum progesterone values increased slightly at the time of the luteinizing hormone peak and increased from 0.2-0.3 ng/ml during the midfollicular phase to peak levels of 8.3 +/- 1.75 ng/ml 9 days after the luteinizing hormone surge. Serum luteinizing hormone remained low and relatively constant throughout the early and midcycle, then sharply increased approximately four-fold to peak values of 6.25 +/- 0.9 ng/ml. Sex skin swelling increased slowly during the follicular phase and declined slowly throughout the early luteal phase. Rectal temperature did not change significantly throughout the menstrual cycle. The similarity of plasma sex hormone changes during the menstrual cycle between women and the pigtail macaque suggested that this nonhuman primate should be a useful animal model for studying human reproduction.     

Radioimmunoassay of 13, 14-dihydro-15-keto-prostaglandin F2alpha

A simple method is described for the determination of 13, 14-dihydro-15-keto-prostaglandin F2alpha (PGFM), using a highly specific antiserum raised in New Zealand rabbits. It involves extraction of human peripheral venous plasma with diethyl ether after addition of tritiated PGFM and HCl. Radioimmunoassay is performed on appropriate aliquots; after 2 hours or overnight equilibration the bound and free metabolite are separated using dextran-coated charcoal. The mean values +/- S.D. obtained are as follows: healthy males 32 +/- 16 pg/ml, females during follicular phase 48 +/- 18 pg/ml, luteal phase 37 +/- 8 pg/ml, first trimester of pregnancy 66 +/- 33 pg/ml, second trimester 67 +/- 42 pg/ml and third trimester 72 +/- 26 pg/ml.     

An acromegalic patient with recurrent urolithiasis

A 52-year-old man with an acromegalic appearance of prolonged duration suffered abdominal colic attacks and hematuria during the middle of the course of the disease. The patient was diagnosed as having urolithiasis caused by increased urinary calcium. The calcium metabolic disorder was not considered to be due to hyperparathyroidism because serum calcium and PTH levels were within the normal range and no abnormality was observed in a parathyroidal scintigraph. The serum 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels (55.0 and 73.0 pg/ml) were higher than the normal range (27.2-53.8 pg/ml). A selective adenomectomy by the transsphenoidal route (Hardy's method) was performed, resulting in an improvement in the hypercalciuria and urolithiasis, and a decrease in the levels of serum 1,25-(OH)2D (23.0 and 23.0 pg/ml). These findings suggest that GH may promote the activation of vitamin D in the kidney in acromegaly, resulting in an acceleration of calcium absorption in the intestine through the action of activated vitamin D and the induction of increased urinary calcium excretion by the urinary excretion of excessive blood calcium.     

Evidence for calcium-dependent control of 1,25-dihydroxyvitamin D3 production by rat kidney proximal tubules

The role of calcium in the parathyroid hormone-mediated increase in 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) production was evaluated using isolated proximal tubules from rats fed a low calcium diet (0.002% Ca) for 14 days. Tubules were prepared by collagenase digestion and centrifugation through Percoll. Tubules from rats fed a low calcium diet produced 1,25-(OH)2D3 at rates 10 times that of tubules from rats fed normal calcium diet (1.2% Ca). In vitro 1,25-(OH)2D3 biosynthesis was highly dependent upon extracellular calcium with inhibition in the absence of medium calcium and maximal production at 0.25 mM medium calcium (0.9 +/- 0.25 versus 15.1 +/- 2.3 nmol/mg protein/5 min, p less than 0.03). Inhibition of 1,25-(OH)2D3 production was partly due to depressed ATP content (0 versus 1.2 mM calcium, 6.8 +/- 0.6 versus 12.7 +/- 0.6 nmol/mg protein, p less than 0.006). EGTA reduced 1,25-(OH)2D3 synthesis and total cell calcium and ATP production. Ruthenium red blocked the inhibitory effects of EGTA on 1,25-(OH)2D3 production. Barium (1.0 mM) inhibited 1,25-(OH)2D3 production (7.2 +/- 0.5 versus 3.4 +/- 0.3, p less than 0.001) without altering ATP production. The calcium ionophore A23187 increased 1,25-(OH)2D3 production in a calcium-dependent manner. It is concluded that parathyroid hormone-mediated increases in 1,25-(OH)2D3 production, as during low calcium diet, require extracellular calcium. Extracellular calcium maintains mitochondrial calcium at optimal concentrations for normal ATP production, a requirement for 25-hydroxyvitamin D3-1-hydroxylase (25-OH-D3-1-hydroxylase) activity. Inhibition of 25-OH-D3-1-hydroxylase activity by barium without an alteration of ATP suggests calcium may also control 1,25-(OH)2D3 production independent of its effects on oxidative phosphorylation, perhaps through a direct interaction with one or more components of the 25-OH-D3-1-hydroxylase.     

Suppression of secondary hyperparathyroidism in uraemia: acute and chronic studies.

A study was conducted evaluating the response of serum parathyroid hormone to acute hypercalcaemia and long term administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in patients receiving maintenance haemodialysis. During infusion of elemental calcium 4 mg/kg/h over four hours in 12 patients not receiving vitamin D the concentration of serum amino terminal parathyroid hormone fell by 31-96% (mean 74.8 (SD 17.6)%) while that of carboxy terminal parathyroid hormone changed little. There was a strong inverse correlation between baseline serum calcium concentration and percentage fall in amino terminal parathyroid hormone during infusion (r = 0.88; p less than 0.001). In seven patients who received prolonged treatment with 1,25(OH)2D3 after calcium infusion there was a positive correlation between maximum percentage fall in amino terminal parathyroid hormone during infusion and the percentage fall in amino terminal parathyroid hormone after 1,25(OH)2D3 treatment (r = 0.79; p less than 0.05). The responsiveness of the parathyroid glands to changes in calcium in acute studies may be used to predict the efficacy of long term treatment with 1,25(OH)2D3. Patients in whom calcium infusion does not suppress parathyroid hormone may have true parathyroid autonomy and require early parathyroidectomy.     

Decreased fractional urinary calcium excretion and serum 1,25-dihydroxyvitamin D and IGF-I levels in preeclampsia

During preeclampsia several alterations of calcium metabolism have been described, the most common of them is hypocalciuria, which pathophysiology is still unclear. In order to assess the contribution of calciotropic hormones to urinary calcium excretion, a cross-sectional study was done including 26 preeclamptic Mexican women (PE group) and 26 normotensive control pregnant women (NT group). Total and fractional urinary calcium excretion were significantly lower (P<0.0001) in the PE group than in the NT group (82+/-7 versus 171+/-7 mg/24h and 0.62+/-0.38 versus 1.38+/-0.71%, respectively), without significant differences in creatinine clearance, urinary sodium excretion and phosphate tubular reabsorption. In addition, serum 1,25-(OH)(2)D and IGF-I levels were significantly (P<0.05) lower in the PE than in NT group (43+/-9 versus 50+/-9 pg/mL and 195+/-67 versus 293+/-105 ng/mL, respectively), without significant differences in serum PTH levels. In the NT group, association analysis showed that total and fractional urinary calcium excretions positively correlated with serum levels of 1,25-(OH)(2)D (P<0.01) and IGF-I (P<0.001). In the PE group, total urinary calcium excretion positively correlated only with serum 1,25-(OH)(2)D (P<0.05). In conclusion, the results obtained in this study confirm that PE is associated with hypocalciuria and suggest that 1,25-(OH)(2)D and/or IGF-I may be involved in the regulation of urinary calcium excretion.     

Plasma alpha-melanocyte-stimulating hormone during the menstrual cycle in women

alpha-Melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH) immunoreactivity (IR) was measured in the blood of 22 healthy women with normal ovulatory process in the early and late follicular (near to ovulation) phases and in the early luteal phase of the menstrual cycle. Plasma alpha-MSH IR ranged from undetectable values to 81.3 pg/ml, the highest levels being found in the late follicular phase (15.52 +/- 4.16 pg/ml). In contrast, plasma ACTH IR was always detectable (range: 18.5-63.2 pg/ml), but its concentration did not differ significantly between the 3 phases of the menstrual cycle. High-pressure liquid chromatography fractionation of Sep pak C18-purified alpha-MSH IR revealed in all 3 phases the presence of 3 major peaks of alpha-MSH IR, coeluting with desacetyl-alpha-MSH, alpha-MSH and diacetyl-alpha-MSH, respectively. The most abundant peak always coeluted with authentic desacetyl-alpha-MSH, and the ratio between this deacetylated and the other 2 acetylated forms was similar in the 2 follicular phases (1:1.25 and 1:1.16 in the early and late phase, respectively), but significantly different in the luteal phase (1:0.48). The fluctuations in plasma concentration of the above MSH-related peptides suggest that different rates of alpha-MSH acetylation and release take place in the pituitary gland depending on the phase of the menstrual cycle.     

Serum osteocalcin levels do not change during rapidly induced hypercalcemia in healthy subjects.

Since osteocalcin has been suggested to play a role in calcium homeostasis, we investigated its serum levels in 6 healthy subjects during a rapid calcium infusion. Serum levels of intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25-(OH) D3] and 1,25-dihydroxyvitamin D [1,25-(OH)2 D3] were also determined. The calcium infusion increased plasma-ionized calcium levels from 1.25 +/- 0.04 to 1.54 +/- 0.07 mmol/l at 30 min (p less than 0.05). Concomitantly, serum levels of intact PTH declined from 2.1 +/- 0.9 to 0.2 +/- 0.3 mmol/l (p less than 0.05). In contrast, serum osteocalcin levels did not change. Further, during calcium infusion, serum levels of 1,25-(OH)2 D3 decreased from 81 +/- 17 to 75 +/- 15 pmol/l (p less than 0.05) whereas serum levels of 25-(OH) D3 did not change. The results therefore suggest that calcium per se does not influence osteocalcin secretion.     

1,25-Dihydroxyvitamin D production after stimulation with synthetic human parathyroid hormone (1-34) in hypoparathyroid and renal tubular disorders

1,25-dihydroxyvitamin D production in response to two successive infusions of synthetic active 1-34 fragment of human PTH [hPTH-(1-34)] was evaluated in order to develop an understanding of the vitamin D metabolism and the rationale of vitamin D therapy in calcium disorders. Five normal controls, six hypoparathyroid patients, two patients with hypophosphatemic vitamin-D-resistant rickets, one patient with Lowe's synd. and one patient with primary Fanconi's synd. were investigated, and the following results were obtained. All normal controls showed a significant increase in serum 1,25(OH)2D[43 +/- 3.8 (m +/- SEM, n = 5, basal), 53 +/- 4.3 (three hours after the first PTH infusion), 65 +/- 7.7 (six hours) and 66 +/- 4.4 (nine hours) pg/ml]. All patients with PTH-deficient hypoparathyroidism showed a significant increase in serum 1,25(OH)2D, and serum 1,25(OH)2D values were within the normal range after hPTH-(1-34) stimulation. Serum 1,25(OH)2D remained low after hPTH-(1-34) infusions in a patient with pseudohypoparathyroidism type I who showed a significant increase in this value after infusion of dibutyryl cyclic AMP. On the other hand, a patient with normocalcemic pseudohypoparathyroidism type I had a high basal 1,25(OH)2D value, which increased further after hPTH-(1-34) infusions. An almost normal increase in serum 1,25(OH)2D was observed in two patients with hypophosphatemic vitamin-D-resistant rickets, one with Lowe's syndrome and the other with primary Franconi's syndrome. We conclude that these results ae important in obtaining an understanding of calcium and vitamin D metabolism in these disorders and that this PTH stimulation test is a useful method to use in evaluating renal responsiveness in 1,25(OH)2D production to PTH in various calcium disorders.     

IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release

IL-6 enhances the differentiation of pluripotent hematopoietic stem cells but predominantly affects the differentiation of hematopoietic cells in the granulocyte-macrophage lineage. We have previously shown that multinucleated cells (MNC) with many features of the osteoclast phenotype form in long term human marrow cultures. Addition of rhIL-6 (10 to 100 pg/ml) to these cultures significantly increased MNC formation, with greater than 80% of the MNC expressing an Ag that cross-reacts with the mAb 23c6. This antibody preferentially binds to osteoclasts. rhIL-6 did not enhance MNC formation in marrow cultures treated with 1,25 dihydroxyvitamin D3, a potent stimulator of MNC formation, but significantly increased the percentage of MNC that cross-reacted with the 23c6 mAb. Addition of antihuman IL-1 to cultures treated with rhIL-6 totally inhibited the increase in MNC formation stimulated by rhIL-6. In contrast, anti-IL-1 did not affect MNC formation stimulated by 1,25 dihydroxyvitamin D3. Further, conditioned media from marrow cultures exposed to rhIL-6 contained elevated levels of IL-1 beta (500 pg/ml compared to 23 pg/ml in control cultures 15 h after IL-6 addition). These results suggest that the capacity of rhIL-6 to stimulate formation of MNC which cross-react with 23c6 is mediated by induction of release of IL-1 beta.     

Regulation of renal vitamin D receptor is an important determinant of 1alpha,25-dihydroxyvitamin D(3) levels in vivo

The synthesis of 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is most strongly regulated by dietary calcium and the action of parathyroid hormone to increase 1alpha-hydroxylase (1alpha-OHase) and decrease 24-hydroxylase (24-OHase) in kidney proximal tubules. This study examines the hypothesis that 1,25-(OH)(2)D(3) synthesis, induced by dietary calcium restriction, is also the result of negative feedback regulation blockade. Rats fed a low calcium (0.02%, -Ca) diet and given daily oral doses of vitamin D (0, 0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 microg) remained hypocalcemic despite increasing levels of serum calcium in relation to the vitamin D dose. Plasma levels of 1,25-(OH)(2)D(3) rose to high levels (1200 pg/ml) at the high vitamin D dose levels. As expected, thyroparathyroidectomy caused a rapid fall in serum 1,25-(OH)(2)D(3). In rats fed a 0.47% calcium diet (+Ca) supplemented with vitamin D (4 microg/day), exogenous 1,25-(OH)(2)D(3) suppressed renal 1alpha-OHase and stimulated the 24-OHase. In rats fed the -Ca diet, vitamin D was unable to suppress the renal 1alpha-OHase or stimulate the renal 24-OHase. In contrast, vitamin D was fully able to stimulate intestinal 24-OHase. Intestinal vitamin D receptor (VDR) was present under all circumstances, while kidney VDR was absent under hypocalcemic conditions and present under normocalcemic conditions. It appears that tissue-specific down-regulation of VDR by hypocalcemia blocks the 1,25-(OH)(2)D(3) suppression of the 1alpha-OHase and upregulation of the 24-OHase in the kidney, causing a marked accumulation of 1,25-(OH)(2)D(3) in the plasma.     

Evaluation of the parathyroid function in six patients with hypophosphatemic osteomalacia,including a case of tertiary hyperparathyroidism developing during combined oral phosphate and vitamin D therapy

AIM: To describe a case of tertiary hyperparathyroidism after long-term phosphate and vitamin D therapy and the retrospective evaluation of parathyroid function in 6 patients with hypophosphatemic osteomalaica. METHODS: We evaluated the parathyroid function by measuring iPTH before and during treatment and divided the patients into normal and elevated serum iPTH groups. RESULTS: In the normal serum iPTH group, the 4 patients were all males, whereas the 2 patients in the elevated serum iPTH group were females. Clinical characteristics and biochemical results showed no differences between the two groups. One of the women with an elevated iPTH level (224 pg/ml) had a normal serum calcium level and no evidence of increasing parathyroid uptake by (99m)Tc-MIBI scan 52 months after treatment. The other woman also had an elevated iPTH level (483 pg/ml) and a normal serum calcium level 56 months after treatment. However, in this latter case both her iPTH (1,447 pg/ml) and serum calcium (11.3 mg/dl) levels were elevated 113 months after treatment, when a (99m)Tc-MIBI scan showed increased uptake in all four parathyroid glands during early and delayed phases of the scan. Parathyroidectomy was performed after the diagnosis of tertiary hyperparathyroidism was made, and the histological findings showed adenomatous hyperplasia. CONCLUSIONS: Our findings indicate that even with vitamin D therapy, long-term phosphate therapy may lead to the development of secondary or tertiary hyperparathyroidism in hypophosphatemic osteomalacia and, therefore, suggest that it is important to carefully monitor the parathyroid function during therapy in those with hypophosphatemic osteomalacia.     

Evaluation of brain-derived neurotrophic factor in menstrual blood and its identification in human endometrium

The presence of high-affinity brain-derived neurotrophic factor receptor Trk B in mouse and in human fetal oocytes, together with the presence of neurotrophins in human follicular fluid suggests a paracrine role for brain-derived neurotrophic factor (BDNF) in female biology. This study aims to evaluate if BDNF is present and quantitatively determined in human menstrual blood and endometrium. Twenty-one women were studied and subdivided in two groups: A, 11 fertile women (27 ± 2 days cycle length) and B, 10 anovulatory women and/or women with inadequate luteal phase (36 ± 2 days cycle length). In fertile women menstrual BDNF levels was higher than plasma (679.3 ± 92.2 vs 301.9 ± 46.7 pg/ml p <0.001). Similarly, in Group B, BDNF in menstrual blood was higher than plasma (386.1 ± 85.2 vs 166.8 ± 24.1 pg/ml p < 0.001). Moreover, both menstrual and plasma BDNF concentrations in Group A were significantly higher respect to Group B (679.3 ± 92.2 vs 386.1 ± 85.2 pg/ml p < 0.001; 301.9 ± 46.7 vs 166.8 ± 24.1 pg/ml p < 0.001). Immunohistochemistry evidence of BDNF in endometrium, during follicular and luteal phase, was also shown. The detection of BDNF in the human menstrual blood and endometrium further supports the role of this neurotrophin in female reproductive function.     

Sex differences in osmotic regulation of AVP and renal sodium handling.

To determine sex differences in osmoregulation of arginine vasopressin (AVP) and body water, we studied eight men (24 +/- 1 yr) and eight women (29 +/- 2 yr) during 3% NaCl infusion [hypertonic saline infusion (HSI); 120 min, 0.1 ml. kg body wt(-1). min(-1)]. Subjects then drank 15 ml/kg body wt over 30 min followed by 60 min of rest. Women were studied in the early follicular (F; 16.1 +/- 2.8 pg/ml plasma 17beta-estradiol and 0.6 +/- 0.1 ng/ml plasma progesterone) and midluteal (L; 80.6 +/- 11.4 pg/ml plasma 17beta-estradiol and 12.7 +/- 0.7 ng/ml plasma progesterone) menstrual phases. Basal plasma osmolality was higher in F (286 +/- 1 mosmol/kgH(2)O) and in men (289 +/- 1 mosmol/kgH(2)O) compared with L (280 +/- 1 mosmol/kgH(2)O, P < 0.05). Neither menstrual phase nor gender affected basal plasma AVP concentration (P([AVP]); 1.7 +/- 4, 1.9 +/- 0.4, and 2.2 +/- 0.5 pg/ml for F, L, and men, respectively). The plasma osmolality threshold for AVP release was lowest in L (x-intercept, 263 +/- 3 mosmol/kgH(2)O, P < 0.05) compared with F (273 +/- 2 mosmol/kgH(2)O) and men (270 +/- 4 mosmol/kgH(2)O) during HSI. Men had greater P([AVP])-plasma osmolality slopes (i.e., sensitivity) compared with F and L (slopes = 0.14 +/- 0.04, 0.09 +/- 0.01, and 0.24 +/- 0.07 for F, L, and men, respectively, P < 0.05). Despite similar Na+-regulating hormone responses, men excreted less Na+ during HSI (0.7 +/- 0.1, 0.7 +/- 0.1, and 0.5 +/- 0.1 meq/kg body wt for F, L, and men, respectively, P < 0.05). Furthermore, men had greater systolic blood pressure (119 +/- 5, 119 +/- 5, and 132 +/- 3 mmHg for F, L, and men, respectively, P < 0.05) than F and L. Our data indicate greater sensitivity in P([AVP]) response to changes in plasma osmolality as the primary difference between men and women during HSI. In men, this greater sensitivity was associated with an increase in systolic blood pressure and pulse pressure during HSI, most likely due to a shift in the pressure-natriuresis curve.     

Estrone sulfate and dehydroepiandrosterone sulfate concentrations in normal subjects and men with cirrhosis.

Circulation levels of estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHAS) have been measured in plasma using a radioimmunoassay for estrone and dehydroepiandrosterone following extraction and hydrolysis of the sulfate. The mean +/- SE concentrations of E1S and DHAS in normal men were 458 +/- 25 pg/ml and 1.45 +/- 0.19 micrograms/ml, respectively. In normal women the values for days 5-7 of the cycle were 880 +/- 117 pg/ml and 1.25 +/- 0.12 micrograms/ml which were not different than the values for days 20-22 of 1195 +/- 176 pg/ml and 1.58 +/- 0.29 micrograms/ml. The mean values in post-menopausal women were 250 +/- 33 pg/ml and 0.47 +/- 0.07 micrograms/ml, both lower than the values in young women. In a group of cirrhotic men the mean values were 325 +/- 55 pg/ml and 0.38 +/- 0.12 micrograms/ml, both significantly lower than the normal values. This suggests a defect in sulfurylation in men with hepatic cirrhosis.