Early effects of parathyroid hormone on rat calvarian bone alkaline phosphatase.

Using a quantitative cytochemical method, explanted calvaria of 1- to 6-day-old male rats were used for the measurement of the in situ effect of parathyroid hormone (PTH) on the activity of alkaline phosphatase (AP) in the calcifying bone. The earliest effect of PTH was observed at 4--7 min. The direction and magnitude of the response of AP was dependent on the age of the animal and on the dose of PTH (50 fg-500 pg/ml). The calvaria of younger animals (2-days old) showed a decrease in AP activity, whereas in 5-day-old rats, AP activity was stimulated by PTH. In 5-day-old animals, the linear dependence of ATP stimulation on the PTH dose in the concentration range 50 fg-50 pg/ml could serve as the basis for a bioassay of a high sensitivity. The age-dependent response of AP to PTH may reflect the difference between the early and late stages of the calcification process. Our observations may reconcile conflicting reports on the effect of PTH on bone AP.

Tumor hypercalcemia and "ectopic hyperparathyroidism".

1. All available evidence for and against the concept of ectopic hyperparathyroidism, including 307 case reports of tumor hypercalcemia, was collated. 2. Of 104 combined cases of tumors of the kidney, lung, liver, head, neck and esophagus, 91 (88%) were in men. 3. The parathyroid glands were examined in 170 of 307 cases and parathyroid hyperplasia or adenoma were described in 34 cases. This high frequency may reflect higher likelihood of reporting such association. 4. Analysis of the histological pattern of tumors associated with humoral hypercalcemia revealed a marked association with certain histological types in different organs, such as clear-cell carcinoma of the kidney and ovary, hepatocarcinoma and cholangiocarcinoma, pheochromocytoma, and squamous-cell carcinoma of the lung, head, neck, esophagus, and urogenital tract. This histological correlation is not compatible with the "random derepression" hypothesis. 5. The existence of tumor humoral hypercalcemia is well documented, as 61 of 74 operated patients sustained remission of hypercalcemia following tumor removal. 6. The evidence for ectopic PTH being produced by tumor is not well documented and is based on conflicting radioimmunoassay results. We have found no case in the literature which fulfilled unequivocally criteria of ectopic production of biologically active PTH. There has been a lack of studies of tumors for the presence of biologically active hypercalcemic factors because only relatively insensitive bioassays are available at present. More information is also required on microscopic bone changes in tumor hypercalcemia as x-ray studies alone are inadequate. 7. On the basis of the present evidence, causes and mechanisms of tumor hypercalcemia are likely to be multiple.

Apparent improvement of antisera for radioimmunoassay by treatment with sodium iodide.

The concept that antisera for radioimmunoassay can be improved by treatment with NaI and dialysis is challenged. Some antisera are little affected by NaI. Even when NaI does dissociate endogenous antigenic material from crude antiserum, in the subsequent dialysis NaI is dialysed at a much faster rate than antigen, allowing reassociation to occur. The reported improvement of antisera by the NaI method cannot be attributed to the effect of NaI but can be explained by the dilution which occurs during dialysis.

Substance P in ovarian carcinoid.

A high content of substance P (124 ng/g wet tissue) was demonstrated by radioimmunoassay in lymph node metastases in a patient with bilateral ovarian carcinoid tumours. The plasma substance P level was elevated but urinary 5-hydroxyindoleacetic acid (5-HIAA) was low. It is suggested that, in some carcinoid patients, an elevated plasma substance P level may help diagnosis and follow-up when urinary 5-HIAA is normal.

Substance P in obstetrics and gynecology.

The occurrence and distribution of the neurohormone substance P in the urogenital tract suggest a role for substance P in regulation of blood flow, smooth-muscle activity, and sensation. The distribution and pharmacologic effects of substance P in the brain suggest an involvement of substance P in regulating the release of gonadotropins and prolactin from the pituitary and in the gonadal-hypothalamic feedback. As substance P is also present in endocrine-like cells of the diffuse endocrine system in the urogenital tract, it may serve as a tumor marker for carcinoid and related tumors, particularly in the ovary and the uterine cervix. This review is limited to the distribution and effects of substance P in the female genital tract and its relevance in female reproduction.

Clinical course and outcome of thirty-five pregnancies in infertile hyperprolactinemic women.

Thirty-five pregnancies occurred during a 21-month follow-up period in 68 women (51%) who presented with infertility and hyperprolactinemia. Bromocriptine was used in 33 patients, of whom 25 (76%) conceived. In the remaining 35 patients who did not receive bromocriptine, there were 10 pregnancies (28%). The presence or absence of menses and galactorrhea in infertile hyperprolactinemic women treated with bromocriptine did not affect significantly the pregnancy rate. No pituitary complication occurred during pregnancy in any hyperprolactinemic patient and there was no change in sellar x-ray appearance, even in two patients whom a plain skull x-ray showed a minor sellar abnormality. Of the 35 pregnancies, 25 occurred after bromocriptine therapy, 2 after thyroxine therapy, 2 after clomiphene therapy, and 6 without any treatment. Five pregnancies ended in first-trimester abortion, including four after bromocriptine treatment. It is concluded that hyperprolactinemia is a good prognostic factor in infertility and that the majority of patients become fertile after a course of bromocriptine. No congenital abnormalities were observed in the offspring of patients treated with bromocriptine, but the abortion rate was higher than average.

Crude substance P from brain contains a cholecystokinin-like peptide.

The subfractions Fa, Fb, and Fc of crude substance P (SP) preparations made from human and bovine brains were analysed for SP and the COOH-terminal octapeptide of cholecystokinin (CCK-8). The methods were specific radioimmunoassays (RIAs) for SP and CCK-8, and bioassays on isolated organs of the guinea pig: the ileum, the gallbladder and the field-stimulated vas deferens. 1. In bioassays of synthetic peptides the vas deferens reacted specifically to SP and the gallbladder to CCK-8. 2. RIAs and bioassays revealed unequivocally that most of SP-like activity was present in Fb, while Fc contained mainly CCK-8-like activity. Varying results were obtained with Fa. 3. The pharmacologically active principle of Fc is CCK-8 or a closely related peptide. Earlier results concerning the pharmacological and neurochemical properties of Fc must be ascribed to this peptide.

Substance P in human cord blood and its degradation by placenta in vitro.

Plasma immunoreactive substance P (iSP) was measured by radioimmunoassay in 12 paired samples of maternal and cord blood, and in placental extracts. The mean plasma iSP concentration in the cord vein was 42.5 pg/ml, as compared to 77.3 pg/ml in the maternal peripheral vein plasma. There was no difference in the mean iSP concentration in the cord vein and artery. Although no iSP was detected in placental tissue, the placenta could not be excluded as the source of iSP in cord blood in view of the rapid degradation of synthetic SP by the placental in vitro.

Catecholamines cause the hypercalciuria and hypercalcaemia in phaeochromocytoma and in hyperthyroidism.

Catecholamines induce bone resorption and hypercalcaemia by the beta-adrenergic effect in bone and hypercalciuria by the alpha adrenergic effect in kidney. The interplay between the alpha-adrenergic hypercalciuria and beta-adrenergic hypercalcaemia explains why in some, but not all, phaeochromocytomas hypercalcaemia occurs. The hypothesis predicts hypercalciuria in both phaeochromocytoma and neuroblastoma. In hyperthyroidism, negative calcium balance and hypercalcaemia cannot be attributed to the direct effect of thyroid hormones on the bone but can be explained by augmentation of the catecholamine effects on bone and kidney by thyroid hormones. The hypothesis offers a solution for an apparent paradox in hyperthyroidism of increased urinary cAMP while nephrogenous cAMP is decreased. It also explains why propranolol corrects hypercalcaemia without influencing renal calcium loss.

Is the evidence for ectopic antidiuretic hormone watertight?

The clinical syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with malignancy cannot be distinguished from a similar metabolic abnormality found in patients with non-malignant conditions. It is, nevertheless, widely accepted that SIADH associated with malignancy is due to the "ectopic" tumour production of arginine vasopressin (AVP). This view is challenged after scrutiny of available data. Since some malignant or non-malignant tissues may produce neurophysins, the presence of "ectopic" AVP in tumour tissue may be explained by active binding of AVP from the circulation by neurophysins. On the other hand, the absence of detectable AVP in tumour accompanied with SIADH suggests excess AVP secretion from the posterior pituitary or hyponatraemia due to other, as yet unidentified, antidiuretic factors. The concept of "ectopic" AVP may be false.

High-sensitivity radioimmunoassay for substance P.

Optimisation of a non-equilibrium radioimmunoassay for substance P is described. The assay has a sensitivity of 2 pg (1.5 fmole), sufficient for substance P determinations in unexcepted human plasma and other biological material. The specificity of antisera used was tested with closely related peptides, physalaemin and eledoisin. Crossreaction of 1 per cent for eledoisin and 0.1 per cent for physalaemin was found. The assay is easy to perform, has a precision of 5 per cent, and takes only 24 hours.

Circulating immunoreactive substance P in man.

Immunoreactive substance P (iSP) has been measured in plasma in 77 normal subjects and in 125 hospital patients. Factors affectingin-vitro degradation of iSP were studied.In vivo, iSP is degraded in the liver and its level in the circulation is independent of kidney excretory function.During insulin-induced hypoglycaemic stress and also during glucose-tolerance test, iSP in plasma decreased transiently. No circadian rhythm of iSP was observed, but in a study in sleeping volunteers episodic secretory bursts were seen, separated by one- to two-hour intervals, the first peak appearing about 90 minutes after the subjects fell asleep.In a patient with carcinoid metastases in the liver, an elevated level of iSP was found in the general circulation with a marked gradient at the hepatic venous effluent.