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Objective: To report the high prevalence of increased parathyroid hormone-related peptide (PTHrP) in patients with islet cell carcinoma and associated hypercalcemia., Design: We conducted a retrospective study of PTHrP levels in patients with hypercalcemia and eucalcemia associated with islet cell carcinoma and compared these findings with those in healthy subjects., Material and Methods: Using a sensitive PTHrP immunochemiluminometric assay, we measured PTHrP levels in 17 patients with islet cell carcinoma and 110 healthy subjects. The differences between PTHrP levels in patients with normal and those with high serum calcium concentrations were analyzed statistically., Results: PTHrP levels were significantly higher (P < 0.01) in 10 patients with hypercalcemia and islet cell carcinoma (median, 14.0 pmol/L; range, undetectable to 40.1) than in 7 patients with eucalcemia and islet cell carcinoma (median, undetectable; range, undetectable to 1.3 pmol/L) or in the 110 healthy subjects (median, undetectable; range, undetectable to 4.2 pmol/L). The range of increased PTHrP levels in hypercalcemic islet cell carcinoma was 2 to 20 times the upper normal limit (2.0 pmol/L). Decreased PTHrP and serum calcium and increased parathyroid hormone levels were demonstrated in two patients after effective therapy. For all seven eucalcemic patients with islet cell carcinoma, PTHrP levels did not differ significantly from those in healthy subjects., Conclusion: PTHrP levels are increased in a substantial proportion of patients with hypercalcemia and islet cell carcinoma and seem to decrease after treatment of the underlying tumor. Measurement of PTHrP levels may be useful for confirming the diagnosis of hypercalcemia associated with malignant disease and for monitoring of therapy.

Objective: To report the clinical responses and mediator-release profiles of an aspirin-sensitive man with systemic mast cell disease during aspirin desensitization., Material and Methods: We quantified the release of six mediators during aspirin desensitization., Results: Although aspirin was administered cautiously with an initial dose of 20 mg, successful aspirin desensitization necessitated complete monitoring and resuscitation capabilities of a medical intensive-care unit for 4.5 days because of frequent, severe anaphylactoid responses. To our knowledge, this is the first report of a pronounced increase in plasma levels of the vasodilator peptide calcitonin gene-related peptide during episodes of aspirin-induced hypotension. Increases in plasma levels of calcitonin and serum levels of tryptase paralleled those of calcitonin gene-related peptide, but plasma levels of calcitonin remained increased for up to 18 hours. Urinary excretion of histamine and 1-methyl-4-imidazoleacetic acid also showed precipitous, although delayed, increases. Excretion of the prostaglandin D2 metabolite 11 beta-prostaglandin F2 alpha followed a bimodal pattern during aspirin desensitization; after severe hypotensive responses, the maximal value was more than 490,000 pg/mL, but the level decreased to less than 100 pg/mL after therapeutic serum levels of salicylate were attained., Conclusion: These data suggest that the hypotensive responses to aspirin in some patients with systemic mast cell disease may result from the combined effects of several mediators.

Objective: To report the recent development and validation of a sensitive 15-minute immunochemiluminometric assay (ICMA) of parathyroid hormone (PTH)., Design: The characteristics and applications of a new "rapid" PTH ICMA are described, and the advantages in comparison with other assays are discussed., Material and Methods: The 15-minute PTH ICMA was achieved by using a higher incubation temperature (45 degrees C rather than room temperature) and a concentration of tracer antibodies that was 5 times that in the regular 18-hour assay. The sensitivity, recovery, and linearity of dilution of the rapid ICMA were assessed, as was its ability to reflect intraoperative changes in PTH concentration after parathyroidectomy in patients with hyperparathyroidism., Results: The sensitivity of the ICMA was 0.3 pmol/L in comparison with 0.08 pmol/L for the regular 18-hour assay (normal range, 1.0 to 5.0). The recovery of added PTH was 84% by using ethylene-diaminetetraacetic acid-plasma as the specimen. Moreover, the linearity of specimens after dilution was good. The assay demonstrated a rapid response to parathyroid gland removal. In most patients, PTH levels declined precipitously (to less than 30% of basal values) within 5 minutes after parathyroid resection. PTH levels remained low to undetectable at 10 and 20 minutes after excision., Conclusion: This rapid PTH ICMA may be of assistance to endocrine surgeons in the monitoring of PTH function after both parathyroid and thyroid surgical procedures.

An extraction radioimmunoassay of calcitonin (CT) was used to replace the direct radioimmunoassay, in which false-negative results (normal basal CT values but above normal ["positive"] results after pentagastrin stimulation) occurred in 26 to 30% of cases. During the past 6 years, 170 pentagastrin stimulation tests were performed in 135 patients at our institution. We reviewed the results to determine whether extraction radioimmunoassay yielded improvement. Of the 135 patients, 6 (4.4%) had indeterminate results of pentagastrin stimulation tests that consisted of normal basal levels but increased values after pentagastrin stimulation, a considerable improvement over the results with direct assay. Six other patients had indeterminate results of pentagastrin testing--increased basal CT levels but normal values after pentagastrin stimulation. Indeterminate results of pentagastrin tests occurred primarily in postoperative or preoperative patients with a family history of medullary thyroid carcinoma (MTC). The reasons for the indeterminate results were unclear, as was their importance as a prelude to disease, but two preoperative patients with indeterminate results eventually had positive results and were found to have MTC at operation. We conclude that extraction radioimmunoassay is more reliable than direct radioimmunoassay for the diagnosis of MTC. Determination of a basal CT value and of the CT value after pentagastrin stimulation is sufficient for diagnosing MTC.

The efficacy of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the new analogue calcipotriene (MC 903) in the treatment of psoriasis was investigated. Eight patients with psoriasis were enrolled in a pilot study with systemically administered vitamin D3 and were given 1,25(OH)2D3 (Rocaltrol; Hoffmann-La Roche) in dosages from 0.5 microgram to 2 micrograms/day for a 6-month trial. In one patient, the psoriatic plaques resolved within 2 months after treatment (0.5 microgram/day) was initiated. Moderate improvement was noted in one other patient (1 microgram/day). The serum level of 1,25(OH)2D before treatment was not less than the normal range of the adult population. Side effects of systemically administered 1,25(OH)2D3 included a dose-dependent increase in the 24-hour urinary calcium excretion and a decrease in the total number of platelets. Seven patients with symmetric plaque-type psoriasis were treated topically with 2 micrograms/g of 1,25(OH)2D3 in petrolatum. During 3 months of follow-up, mild improvement was noted in three patients. Five patients in the calcipotriene study were part of a nationwide double-blind placebo-controlled trial by Bristol-Myers Squibb. Moderate to marked improvement was noted in the two patients who received 50 micrograms/g of calcipotriene topically. The three patients who received placebo showed no response. We conclude that a subset of patients with psoriasis responds well to 1,25(OH)2D3. Calcipotriene is efficacious and an excellent alternative to topically applied corticosteroids.

In this study, we reviewed the diagnostic efficiency of laboratory tests that are performed for assessment of patients with Cushing's syndrome or adrenal insufficiency. Baseline laboratory data from patients subsequently diagnosed with adrenal dysfunction were analyzed for tests performed between 1987 and 1989 at our institution. Results were analyzed for 36 patients diagnosed with pituitary-dependent Cushing's syndrome, 15 with ectopic Cushing's syndrome, 12 with adrenal-dependent Cushing's syndrome, 20 with primary adrenal insufficiency, and 7 with secondary adrenal insufficiency. Tests reviewed were plasma cortisol, plasma corticotropin, urinary free cortisol, urinary 17-ketosteroids, urinary ketogenic steroids, low-dose and high-dose dexamethasone suppression, and metyrapone stimulation. Our findings suggest that a substantial proportion of diagnoses could be based on the results of three tests--plasma corticotropin, plasma cortisol, and urinary free cortisol. We present a nomogram that combines the results of plasma corticotropin and plasma cortisol testing to enhance the diagnostic efficiency of these tests.

Three immunometric assays of parathyroid hormone (PTH)--a commercial immunoradiometric assay, an in-house immunoradiometric assay, and an immunochemiluminometric assay--were evaluated in 50 patients with surgically proven primary hyperparathyroidism. Of these patients, 43 had increased values with the commercial assay (sensitivity, 86%), whereas 45 patients had increased concentrations with both the in-house immunoradiometric and the in-house immunochemiluminometric assays (sensitivities, 90%). Because of the results of this comparison study, we confidently chose the immunochemiluminometric assay as our routine assay; this assay was evaluated retrospectively in 361 patients with surgically proven primary hyperparathyroidism. In 45 patients, PTH values were below the upper limit of normal (sensitivity, 88%). The results indicate that the sensitivities of current immunometric assays are approximately 90%. Twenty patients who had hypercalcemia associated with malignant involvement were assessed with the immunochemiluminometric assay. Of these 20 patients, 19 had subnormal PTH values, and 1 had a value within the normal range. In contrast, in the past, PTH values determined with radioimmunoassays have often been in the normal range for such patients. Thus, an immunometric PTH assay is superior to a radioimmunoassay in the differential diagnosis of hypercalcemia associated with malignant disease.

We developed and validated a radioimmunoassay for circulating human parathyroid hormone-related peptide (PTHrP), based on a commercial antiserum to the synthetic 1-34 fragment of PTHrP, 125I-Tyr degrees-PTHrP(1-34) as radioligand, and prior extraction of the native peptide from plasma with C-2 cartridges. We determined immunoreactive PTHrP concentrations in plasma samples from 48 healthy persons (mean +/- SD, 3.1 +/- 1.0 pmol/liter; range, less than 2 to 5 pmol/liter), 8 patients with primary hyperparathyroidism, 36 patients with hypercalcemia and a concurrent malignant lesion, and 9 normocalcemic patients with cancer and increased serum levels of carcinoembryonic antigen or prostate-specific antigen. PTHrP was normal in samples from patients with primary hyperparathyroidism (3.2 +/- 1.1 pmol/liter), secondary hyperparathyroidism (2.5 +/- 1.3 pmol/liter), and cancer without hypercalcemia (2.4 +/- 1.0 pmol/liter). In contrast, plasma immunoreactive PTHrP levels were increased (6.0 to 85.0 pmol/liter) in 47% of patients with hypercalcemia and cancer of various types, with or without bone metastatic lesions. Large amounts of PTHrP were also found in conditioned medium from cultured human prostatic carcinoma cells. Thus, PTHrP may be a causative factor for hypercalcemia associated with a malignant lesion in at least half of the cases. Measurement of circulating PTHrP may be of differential diagnostic help in hypercalcemic states.

Parathyroid hormone-related peptide (PTHrP) is expressed in lactating rat mammary glands after suckling, as a result of increases in prolactin rather than suckling per se. In addition, PTHrP produced in the fetal parathyroid glands and placenta may be responsible for stimulation of placental calcium transport. In the current study, we used a radioimmunoassay for human PTHrP to measure levels of the peptide in (1) human breast milk, cow's milk, and two infant formulas; (2) sequential plasma samples in prepartum and postpartum lactating women; (3) women with pathologic hyperprolactinemia; and (4) human umbilical cord blood. In normal subjects, plasma PTHrP levels ranged from less than 2 to 5 pmol/liter. In contrast, human breast milk contained substantially increased levels of immunoreactive PTHrP. Similar elevations were found in cow's milk and in one infant formula. Column chromatography of breast milk demonstrated that PTHrP immunoreactivity included a region of adenylate cyclase stimulating activity, consistent with the presence of biologically active PTHrP. Plasma prepartum PTHrP values did not differ from corresponding postpartum values in lactating women. Women with hyperprolactinemia had a mean plasma PTHrP value in the high-normal range. Umbilical cord blood had considerably suppressed parathyroid hormone values but PTHrP levels that were indistinguishable from those in normal human plasma. Thus, PTHrP is present in high concentrations in breast milk but apparently does not gain access to the maternal circulation in significant amounts. In addition, women with pathologic hyperprolactinemia seem not to have increased levels of circulating PTHrP.(ABSTRACT TRUNCATED AT 250 WORDS)

We determined the pituitary-adrenal response to 1 microgram/kg of ovine corticotropin releasing hormone (oCRH) administered as an intravenous bolus injection in 50 normal subjects. Brief facial flushing was noted in 44% of the subjects; no other side effects were reported. Plasma corticotropin levels increased from a median of 30.2 pg/ml at baseline to a median peak level of 77.8 pg/ml after administration of oCRH; the peak response occurred at the 30- to 45-minute or the 45- to 60-minute time point. Plasma cortisol levels increased from a median of 10.8 micrograms/dl at baseline to a median peak level of 22.0 micrograms/dl after administration of oCRH; the peak response occurred at the 45- to 60-minute time point. Plasma beta-endorphin levels increased from a median of 9.5 pg/ml at baseline to a median peak level of 23.0 pg/ml after administration of oCRH; the peak response occurred at the 15- to 30-minute or the 30- to 45-minute time point. The responsiveness to oCRH was unaffected by age, sex, or body mass index of the subjects.

To test the hypothesis that deficiencies in hypothalamic-pituitary function in genetic hemochromatosis result from cellular injury by iron deposits, we conducted provocative tests in 11 men with genetic hemochromatosis before and after iron depletion by serial phlebotomy and in 10 control subjects. We gave combination intravenous injections of insulin (0.15 U/kg), luteinizing hormone releasing hormone (LHRH, 100 micrograms), and thyrotropin releasing hormone (400 micrograms) and then measured plasma glucose, growth hormone, corticosteroids, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone at 30-minute intervals for 90 minutes. Phlebotomy caused a substantial decrease in median values for serum ferritin, deferoxamine-chelatable iron, and hepatic iron concentration. Before phlebotomy, stimulation by hypoglycemia and thyrotropin releasing hormone caused significantly less secretion of growth hormone (P = 0.004) and prolactin (P = 0.03) in patients than in control subjects. No significant improvement was noted, however, in growth hormone or prolactin secretion after phlebotomy. Of the 11 patients, 7 had secondary hypogonadism, and phlebotomy did not improve the serum testosterone, follicle-stimulating hormone, luteinizing hormone, or responses to LHRH in any case. Chlorpromazine injections failed to elevate serum prolactin in all patients, and administration of levodopa caused a partial reduction in serum prolactin; thus, the hypothalamus may be an important locus of endocrine malfunction in these patients. We conclude that abnormal hypothalamic-pituitary function in genetic hemochromatosis is not substantially improved by iron-depletion therapy.

Immunohistochemical studies were performed on the tumors of 97 of 100 patients who had undergone an operation for a presumed prolactin-secreting pituitary adenoma; no tissue was available for study in the other 3 patients. Appropriate immunohistochemical studies were done to identify the presence of growth hormone, prolactin, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone within the adenoma cells. The presence of a prolactin-producing pituitary adenoma was confirmed in 91 patients, 3 of whom had an adenoma that consisted of cells that contained prolactin and growth hormone. One other patient, not counted among the 91 with prolactinoma, had lactotrope and thyrotrope hyperplasia. Among the five patients whose adenoma did not contain prolactin cells, four had a null cell adenoma and one had a tumor consisting of follicle-stimulating hormone and luteinizing hormone immunoreactive cells. On the basis of preoperative serum prolactin values in these patients, we concluded that moderately increased values (30 to 200 ng/ml) of serum prolactin are not a reliable guide for determining whether a prolactin-producing pituitary adenoma is present, whereas levels exceeding 200 ng/ml are usually associated with a prolactin-secreting tumor.

Radioimmunoassays for human calcitonin in whole plasma are limited in sensitivity and specificity; basal values of calcitonin are often undetectable in normal plasma, and nonspecific increases are occasionally found in seemingly healthy persons. We avoided these problems by applying a silica-cartridge extraction-concentration technique for calcitonin assay, and the effectiveness of two calcitonin stimulation tests in healthy volunteers and patients with medullary thyroid carcinoma was compared. The radioimmunoassay was improved by using a new antiserum and a sequential incubation procedure that reduced the previously used sample-volume requirement and incubation period substantially. This method was used to measure mean basal plasma levels of calcitonin (+/-SD) in 45 normal men (8.2 +/- 5 pg/ml) and 47 normal women (4.8 +/- 4 pg/ml) (P less than 0.001). Calcium infusions (2 mg/kg over 5 minutes) in 18 normal men and 37 normal women yielded a significantly greater secretory response than did pentagastrin (0.5 micrograms/kg as a bolus). Among 12 patients with medullary thyroid carcinoma, pentagastrin seemed to be a better secretagogue than calcium (P less than 0.001). We recommend routine measurement of plasma silica-extractable calcitonin and pentagastrin injection as the provocative test of choice for the detection and management of medullary thyroid carcinoma. The short calcium-infusion test is a good alternative.

One hundred patients, 84 females and 16 males, with presumed prolactin-producing pituitary adenomas were treated with transsphenoidal microsurgery. Criteria for success of the operation were return of serum prolactin values to normal and reversal of the endocrine effects of hyperprolactinemia, eradication of the adenoma, and preservation of anterior pituitary function. Of the 84 females, 54 had a microadenoma (a noninvasive adenoma 10 mm or less in diameter), and of the 32 with preoperative values of serum prolactin of less than 100 ng/ml, 28 (88%) had a successful operative result, whereas 11 of 22 (50%) with preoperative values of 100 ng/ml or more had a successful result. Five of 10 patients (50%) with a diffuse adenoma (a noninvasive adenoma more than 10 mm in diameter) and 5 of 20 (25%) with an invasive adenoma had a successful result. Of the 16 males, 3 of 7 (43%) with diffuse adenoma and 3 of 16 (19%) with invasive adenoma had a successful result. There were no males with microadenoma. The largest success rate (88%) was among female patients with microadenoma and preoperative serum prolactin values of less than 100 ng/ml.