Vandetanib Tumor Shrinkage in Metastatic Medullary Thyroid Cancer Allowing Surgical Resection of the Primary Site: A Case Report.

Vandetanib has been shown to improve progression-free survival in adults with advanced medullary thyroid cancer. This article describes a pediatric patient with metastatic medullary thyroid cancer secondary to sporadic multiple endocrine neoplasia 2B, treated with vandetanib. At presentation, he had an inoperable primary tumor, with carotid encasement, and pulmonary metastases. Vandetanib induced a significant response: calcitonin and carcinoembryonic antigen levels both fell considerably, primary tumor maximal diameter decreased by 68%, and pulmonary metastases became no longer detectable. This allowed surgical resection of the primary tumor. The patient remains well after over 6 years of vandetanib therapy, with no treatment toxicity.

Effects of Dulaglutide on Thyroid C Cells and Serum Calcitonin in Male Monkeys.

Glucagon-like peptide-1 (GLP-1) receptor agonists, used for the treatment of type 2 diabetes, have caused hyperplasia/neoplasia of thyroid C cells in rodent carcinogenicity studies. Studies in monkeys have not identified an effect of GLP-1 receptor agonists on thyroid C cells; however, group sizes were small. Dulaglutide is a once-weekly, long-acting human GLP-1 receptor agonist recently approved in the United States and the European Union. The objective of this study was to determine whether dulaglutide altered C-cell mass in monkeys. Male cynomolgus monkeys (20 per group) were sc injected with dulaglutide 8.15 mg/kg (∼500-fold maximum human plasma exposure) or a vehicle control twice weekly for 52 weeks. Basal and calcium gluconate-stimulated serum calcitonin concentrations were obtained at 3, 6, 9, and 12 months. Thyroid glands were weighed, fixed, and sectioned at 500-µm intervals. C-cell volumes were measured using an automated image analysis. C-cell proliferation was estimated using Ki67/calcitonin colabeling and cell counting. Administration of dulaglutide 8.15 mg/kg twice weekly for 52 weeks did not increase serum calcitonin in monkeys or affect thyroid weight, histology, C-cell proliferation, or absolute/relative C-cell volume. This study represents a comprehensive evaluation of the monkey thyroid C cells after dosing with a GLP-1 receptor agonist, with a large group size, and measurement of multiple relevant parameters. The lack of effect of dulaglutide on C cells is consistent with other studies in monkeys using GLP-1 receptor agonists and suggests that nonhuman primates are less sensitive than rodents to the induction of proliferative changes in thyroid C cells by GLP-1 receptor agonists.

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents.

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.

Effect of oral N-acetylcysteine treatment on immune system in continuous ambulatory peritoneal dialysis patients.

AIM: to determine the effect of oral N-acetylcysteine (NAC) on plasma levels of inflammatory markers in Continuous Ambulatory Peritoneal Dialysis (CAPD) patients. METHODS: we performed a placebo-controlled study over 8 weeks in 32 patients on regular CAPD. The patients were divided into 2 groups of 16 patients matched for age and gender. The first group was given NAC 2x600 mg/day for 8 weeks and inflammatory parameter was compared with control group. The immune system is determined from the average levels of Procalcitonin, IL-6, IL-1, C3, SICAM, hsCRP, and TNF- before and after treatment with NAC. Student t-test was performed to compare the means between NAC receiving and control groups. All statistics were done using SPSS software (SPSS Ver 16.0). RESULTS: administration of NAC, significantly diminished PCT (-0.38±0.57 vs 0.09±0.14; p=0.004), IL-6 (-1.94±3.03 vs 1.19±1.99; p=0.002), IL-1 (-0.14±0.21 vs 0.01±0.04; p=0.010), C3 (-7.40±12.04 vs 4.60±8.12; p=0.002), sICAM (-80.59±29.18 vs -35.02±46.99; p=0.007), hsCRP (-1.50±1.32 vs 0.81±1.17; p<0.001) and TNF- (-0.73±0.47 vs 0.14±0.74; p<0.001) levels compared control to group. CONCLUSION: short-term oral NAC treatment resulted in reduction of circulating PCT, IL-6, IL-1, C3, sICAM, hsCRP, and TNF- in CAPD patients.

Relationship between substances in seminal plasma and Acrobeads Test results.

OBJECTIVE: To asses the effects of seminal plasma on sperm function. DESIGN: Retrospective case-control study. SETTING: University hospital. PATIENT(S): One hundred fourteen infertile men. INTERVENTION(S): Acrobeads Test scores (0-4) and measurement of interleukin (IL)-6, soluble IL-6 receptor, epidermal growth factor, insulin-like growth factor-I (IGF-I), transforming growth factor-beta I, superoxide dismutase, calcitonin, and macrophage migration inhibitory factor (MIF) levels in seminal plasma. MAIN OUTCOME MEASURE(S): Kruskal-Wallis test to compare the concentrations of substances as a nonparametric test for differences among Acrobeads Test scores and a multivariable logistic regression model to find independent risk factors associated with abnormal Acrobeads Test results. RESULT(S): The Acrobeads Test score was 0 for 7 samples, 1 for 20 samples, 2 for 18 samples, 3 for 28 samples, and 4 for 41 samples. Age, abstinence period, and semen parameters, except for sperm motility and percentage of sperm with abnormal morphology, had no effect on the Acrobeads Test results. Concentrations of IGF-I and MIF were significantly higher in patients with abnormal Acrobeads Test results. Multivariate analysis indicated that MIF and IGF-I were significantly associated with abnormal Acrobeads Test results (scores 0 to 1). CONCLUSION(S): Although further studies are needed, IGF-I and MIF in seminal plasma may have negative effects on sperm function.

The value of intraoperative pentagastrin testing in medullary thyroid cancer.

BACKGROUND: The decrease of calcitonin levels after curative operation in patients with medullary thyroid cancer is characterized by individual variation; therefore, intraoperative calcitonin measurements to evaluate the completeness of the resection seem to not be feasible. The aim of this study was to evaluate whether an intraoperative pentagastrin test after thyroidectomy and central neck dissection is useful to predict lymph node involvement of the lateral neck. METHODS: A group of 30 consecutive patients underwent primary surgery. After thyroidectomy and dissection of the central lymph node compartment, an intraoperative pentagastrin test was performed. Biochemical and histologic data were compared retrospectively. RESULTS: Of the group, 20 patients (67%) showed no, or only central neck lymph node, involvement and no increase in calcitonin after intraoperative stimulation. Lymph node involvement was documented histologically in the lateral neck of 10 patients (33%), and 8 patients showed an increase of calcitonin as an indication of lymph node involvement. In two patients, each with 1 single micrometastasis in the lateral neck, the intraoperative pentagastrin test was negative. CONCLUSIONS: Intraoperative calcitonin monitoring after pentagastrin stimulation seems promising in predicting lymph node involvement of the lateral neck to aid selection of patients for lateral lymph node dissection. The development of a highly sensitive, quick calcitonin assay is imperative.

Both mercury and cadmium directly influence calcium homeostasis resulting from the suppression of scale bone cells: the scale is a good model for the evaluation of heavy metals in bone metabolism.

To examine the effects of heavy metals such as cadmium and mercury on calcium homeostasis, plasma calcium and calcitonin were measured in goldfish. Cadmium induced hypocalcemia both at 4 and at 8 days. In methylmercury-treated goldfish, the plasma calcium level increased at 2 days and then decreased at 8 days. The plasma calcitonin level increased in correspondence with the increased plasma calcium by methylmercury treatment, although cadmium did not cause a significant change. To elucidate the mechanism in detail, fish scales, which have both osteoclasts and osteoblasts and are similar to mammalian membrane bone, were used in the present study. We measured tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) activity as respective indicators of activity in both types of cells. TRAP activity in the scales decreased by treatment of cadmium and methylmercury at 6 h incubation. Particularly, cadmium (even at 10(-13) M) significantly suppressed TRAP activity, suggesting that this system is utilized as an acute biosensor for cadmium. ALP activity decreased after exposures of 64 and 96 h, although the activity did not change after 6, 18, and 36 h. In addition, mRNA expression of the estrogen receptor and insulin-like growth factor 1, which participate in osteoblastic growth and differentiation, was less than the control values by treatment with both metals. This study demonstrates that mercury directly acts on the bone cells and influences calcium homeostasis and indicates that, in a short-term exposure, mercury has a different action from that of cadmium and induces hypercalcemia.

Modulation of the inflammatory response to cardiopulmonary bypass by dopexamine and epidural anesthesia.

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory reaction. Microcirculation-dependent alteration of the gut mucosal barrier with subsequent translocation of endotoxins is a postulated mechanism for this inflammatory response. This study was designed to elucidate whether two different approaches to modulate splanchnic perfusion may influence systemic inflammation to CPB. METHODS: We examined 40 patients scheduled for elective coronary bypass surgery in a prospective, randomized study. One group (DPX) received dopexamine (1 micro g. kg-1. min-1) continuously after induction of anesthesia until 18 h after CPB. The control group (CON) received equal volumes of NaCl 0.9% in a time-matched fashion. In a third group (EPI) a continuous epidural infusion of bupivacaine 0.25% [(body height (cm) - 100). 10-1=ml.h-1] was administered for the whole study period. Procalcitonin (PCT), tumor necrosis factor (TNF-alpha), soluble TNF receptor, human soluble intercellular adhesion molecule-1, C-reactive protein (CRP) and leukocyte count were measured as parameters of inflammation. RESULTS: All parameters significantly increased following CPB. Increases of PCT, TNF-alpha and leukocyte count were significantly attenuated in the DPX and EPI groups at different time points. However, neither splanchnic blood flow nor oxygen delivery and consumption were different when compared with the CON-group. CONCLUSION: These results do suggest that mechanisms other than an improved splanchnic blood flow by DPX and EPI treatment have to be considered for the anti-inflammatory effects.

Induction of systemic serum procalcitonin and cardiocirculatory reactions after isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan.

OBJECTIVES: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP. SETTING: University surgical oncology division with an integrated eight-bed intensive care unit. PATIENTS: Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma. INTERVENTIONS: The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel. MEASUREMENTS AND MAIN RESULTS: PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes. CONCLUSIONS: Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.

Surgical treatment of postoperative, incidentally diagnosed small sporadic C-cell carcinomas of the thyroid.

BACKGROUND AND AIMS: The surgical strategy in small sporadic C-cell carcinomas of the thyroid that are incidentally diagnosed after goiter resection for benign disease is controversial. It remains unclear whether a completion thyroidectomy should be performed in every case. PATIENTS AND METHODS: We present nine patients who were operated on between October 1992 and October 1997 in whom an unexpected, small sporadic C-cell carcinoma (seven with pT1, two with pT2) was found in the postoperative histology. RESULTS: All patients were calcitonin negative and there were no signs of the disease being inherited (no familial history, negative RET proto-oncogene). No patient underwent a completion thyroidectomy. All patients had a follow-up with pentagastrin-stimulated calcitonin and carcinoembryonic antigen (CEA) 3 months, 6 months and annually after the operation. No patient became calcitonin positive or showed any other signs of tumor recurrence after a follow-up period of 2-7 years. CONCLUSION: A completion thyroidectomy is not necessary in small sporadic C-cell carcinoma that is incidentally diagnosed after resection for benign disease if there is no sign of familial cancer and if calcitonin is negative. A close follow-up is necessary.

Minimally invasive surgery for recurrent neuroendocrine carcinoma of the supraglottic larynx.

Calcitonin-secreting neuroendocrine carcinomas of the supraglottic larynx are infrequent tumors, making it difficult to agree on treatment plans for recurrent tumors. Furthermore, this rare malignancy is often confused with the more common medullary thyroid carcinoma, resulting in inappropriate thyroidectomies. We present a case report of a calcitonin-secreting recurrent neuroendocrine carcinoma of the supraglottic larynx, in which surgery and pentagastrin stimulation were performed repeatedly at various stages of the disease. The recurrent laryngeal tumor was ultimately identified and, after construction of a protective tracheostomy, resected transorally en bloc with the underlying arytenoid cartilage. Postoperatively, the patient did well and stimulated calcitonin levels never exceeded double baseline values. Laryngoscopic removal of smaller laryngeal carcinomas is both technically feasible and safe, even when tumors are recurrent. In calcitonin-secreting malignancies, pentagastrin stimulation may facilitate the distinction between laryngeal and medullary thyroid carcinoma and thus help avoid unnecessary thyroidectomies.

Influence of laminin substratum on cell proliferation and CALC I gene expression in medullary thyroid carcinoma C cell lines.

Medullary thyroid carcinoma (MTC) originates from C cells, which secrete calcitonin (CT) and CT gene-related peptide (CGRP), the two splice peptide products of the CALC I gene. Normal and hyperplastic C cells are intrafollicular, in contact with the basement membrane (BM) that is maintained around the differentiated tumors. To investigate the relationships between MTC evolution and BM constituents, we examined the modifications induced by laminin-1 and -2 (merosin), two isoforms colocalized in the follicular BM, on three MTC cell lines: murine rMTC 6-23 and CA-77 cells, and human TT cells. Laminin exerted a mitogenic activity on rMTC 6-23 and on TT cells, causing a concurrent decrease in both CT and CGRP mRNA levels and production of the peptides. Conversely, laminin reduced the proliferation rate and enhanced CGRP synthesis and secretion in CA-77 cells. This antiproliferative response, which coincides with an increase in differentiation markers, is comparable to that reported in normal cells and also in the neoplastic Caco-2 cell line. This suggests that laminin could exert opposite effects depending on the stage of tumor evolution.

Regulation of calcitonin secretion by thyroid parafollicular cells in vitro.

The studies were performed on cultured TT cells originating from human thyroid medullary carcinoma (i.e., from parafollicular cells of the thyroid). The amount of released calcitonin was dependent upon calcium level in the medium. Moreover, calcitonin secretion might be regulated by medium supplementation with polypeptide hormones. Somatostatin inhibited while glucagon and pentagastrin stimulated calcitonin secretion to t he medium. Calcitonin secretion was also influenced by biogenic amines and their precursors. Dihydroxy-1-phenylalanine and serotonin augmented while 5-hydroxy-1-tryptophan and dopamine inhibited calcium secretion. This, calcitonin secretion may be controlled by different substances present in the healthy organism. This points to a complex control of calcium ion level in the blood.

Cytotoxic effect of free bleomycin A5-iron (II) complex and its conjugates with concanavalin A, insulin and calcitonin on mouse thymocytes.

The possibility of using the antibiotic bleomycin as a part of a hybrid molecule consisting of a targeting fragment and a generator of reactive oxygen species has been investigated. The bleomycin-iron (II) complex was shown to destroy the plasma membrane of thymocytes by producing reactive oxygen species. Antioxidants protected the cells from destruction thus pointing to its free-radical mechanism. The protective effects of catalase and superoxide dismutase indicate that superoxide radical and hydrogen peroxide being formed during autooxidation of the complex are involved in cell damage. The covalent binding of bleomycin to targeting molecules (concanavalin A, insulin, and calcitonin) enhanced the ability of the bleomycin-iron (II) complex to destroy the plasma membrane of thymocytes.

[Substitutive hormone therapy in postmenopausal osteoporosis. Are there any contraindications?]. / L'hormonothérapie substitutive dans l'ostéoporose post-ménopausique. Existe-t-il des contre-indications?

Estrogen deficiency is the main cause of postmenopausal osteoporosis. Replacement estrogen therapy protects the bone by reducing bone resorption and activating osteoblasts, as well as by promoting absorption of calcium and production of calcitonin. These preventive effects are especially marked in cancellous bone, provided estrogen therapy is initiated as soon as menstruation stops. Effects are dose-dependent and efficacy of the treatment is noticeable mainly during the period of administration. The rare contra-indications to estrogen therapy include hormone-dependent cancers, cholestatic jaundice, and large uterine myomas (for which surgical treatment is recommended). Metabolic disorders, arterial hypertension, and thyroid function disorders are less common with the new natural estrogens (estradiol) given orally or percutaneously to avoid hepatic passage of the drug. As for treatment induced cancers, sequential administration of a progestagen protects the endometrium and the relative risk seems negligible for breast cancer. Although concomitant use of a progestagen is mandatory, either natural progesterone or norpregnanes should be given to avoid adverse metabolic effects. Emphasis has recently been put on the role of concomitant progestagen therapy which may promote the formation of bone, probably by competing for glucocorticoid receptors in bone. There is still a need for prospective epidemiological studies, although evaluation methods and the long follow-ups needed raise significant problems.

Cholinergic-nicotinic control of growth and secretion of cultured pulmonary neuroendocrine cells.

Dispersed newborn hamster lung cells were established in vitro in a defined, low-serum growth medium. Neuroendocrine markers (immunohistochemistry for bombesin/gastrin-releasing peptide and calcitonin) revealed a cellular predominance of pulmonary neuroendocrine (PNE) cells. While the supernatant concentration remained stable, the concentration of PNE cell immunoreactive calcitonin (iCT) gradually declined over 4 weeks. Supplementation of the medium with nicotine for 3 weeks prevented this decline in cellular iCT. Concurrently, the number of cells and [3H]thymidine incorporation were significantly increased. The stimulatory effect of chronic nicotine was reversed by the coadministration of the nicotinic antagonist hexamethonium. In another set of experiments, prior multiple transplacental nicotine pretreatments resulted in a significant increase in iCT in the lungs of newborns; when these lungs were subsequently placed in cell culture without nicotine, despite the higher concentration of iCT, there was a drop in iCT similar to that observed in the control culture. In contrast, in vivo, the lung iCT remained significantly elevated at 1 week post-parturition. Cell culture supernatants were analyzed at week 4 for the evoked release of iCT; cholinergic-nicotinic agonists promptly increased the supernatant iCT, which was blocked by nicotinic but not by muscarinic antagonists. We suggest that this in vitro system provides a useful tool to study directly the PNE cell. The acute and chronic effects of nicotine are most likely related to stimulation of cholinergic-nicotinic receptors on iCT-containing PNE cells.

Heterogeneity studies of hamster calcitonin following acute exposure to cigarette smoke: evidence for monomeric secretion.

Various acute stimuli, including cigarette smoke, induce hypercalcitonemia in man and hamsters. We have shown that this occurs also in thyroidectomized subjects. In the present study we have further explored this phenomenon of secretion from the lungs by studying, simultaneously, the HPLC characteristics of pulmonary tissue and serum in control hamsters and in animals immediately following short-term exposure to cigarette smoke. In addition, we have studied the immunoheterogeneity of lung calcitonin 24 hours following the acute exposure. Control lungs contained monomeric immunoreactive calcitonin (M-iCT), high molecular mass iCT (H-iCT), and CT fragments. Immediately following smoke exposure, there was an acute decrease of lung iCT by radioimmunoassay (RIA) which consisted primarily of a decrease in M-iCT by HPLC. Simultaneously, the iCT increase in the serum by RIA was shown by HPLC to involve M-iCT. Twenty-four hours after smoke inhalation, the lung iCT by RIA and M-iCT by HPLC had returned towards control levels. These findings document the molecular characteristics of lung iCT following acute cigarette smoke stimulation, and suggest that under certain circumstances M-iCT may be actively secreted by the lung. It remains to be determined whether this type of secretion reflects hemocrine or paracrine release and what the physiological role for such a secretion may be.

[The prognostic importance of calcitonin screening in familial medullary thyroid carcinoma]. / Prognostische Bedeutung des Calcitonin-Screenings beim familiären medullären Schilddrüsenkarzinom.

In 34 of 139 patients (63 men, 76 women, mean age 41.2 +/- 15.6 years) with medullary thyroid carcinoma (MTC) the disease was of the familial variety. 13 of the 34 cases were discovered in the preclinical stage by screening (calcitonin stimulation with pentagastrin). This group was on average younger (16.8 +/- 10.7 years) than the 21 clinically manifest patients with MTC (28.0 +/- 11.9 years) or the 105 patients with sporadic MTC (45.7 +/- 13.6 years). The patients diagnosed through the screening programme had a more favourable tumour stage (12 in stage I or II) and were thus more likely to be cured. Their survival rate was higher (100% at both 5 and 10 years) than the survival rate of the patients with clinically manifest tumour (94 and 87%, respectively). But the group with manifest familial MTC did not differ from those with sporadic occurrence as regards the tumour stage (predominantly advanced stages), limited chance of cure and survival rate (5 years: 94%, 10 years: 81%). These data show that screening of family members decisively improves the prognosis of MTC of the familial variety.

The mechanism involved in the central effect of 5-leu enkephalin on the calcitonin secretion.

Calcitonin (CT) secretion is not exclusively under the control of calcium levels in the plasma, but also depends on the sympathetic-adrenergic tone. In previous experiments we stressed out the possible role played by 5-leu enkephalin (5-LE) in the nervous regulation of the CT secretion. Intracerebroventricular (i.c.v.) 5-LE in doses of 100 micrograms could act at a central level through a mechanism independent from the noradrenergic pathways, since i.c.v. 6-OHDA and propranolol could not interfere with its stimulatory effect on the CT content of the thyroid. In the present experiments, performed in anaesthetized Wistar-Bratislava rats, we studied the involvement of mu and delta receptors in the central effect of 5-LE on the CT content of the thyroids and the CT levels in the plasma. These parameters were measured in parallel, by means of a competitive radioimmunoassay with double antibodies (Peninsula Lab.). 5-LE probably bound to both mu and delta receptors, since its effect on the CT secretion was reversed by 13 micrograms of naloxone (i.c.v.). A partial blockade, comparable to naloxone, was noticed after 382 micrograms of CTOP (i.c.v.), a specific antagonist of the mu receptors--stressing out their involvement in the stimulatory effect of 5-LE on the CT secretion. 250 Ug of ICI 174864 (i.c.v.), a selective antagonist the the delta receptors completely blocked the stimulation induced by 5-LE on the CT secretion to values significantly lower as compared to the controls and even to the sympathectomized group. This suggests the tonic role played by enkephalins in the CT secretion, through the central activation of delta receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of estrogen replacement therapy on endogenous calcitonin production rates.

Calcitonin is now a well-accepted therapy for inhibition of bone loss, both in the first years of menopause and in established osteoporosis. However, its exact role in the pathogenesis of that disease as well as the interactions between calcitonin production and estrogen metabolism remain unsolved. In order to clarify the influence of estrogen replacement therapy (ERT) on calcitonin secretory capacity, we measured whole plasma immunoreactive calcitonin basal levels, metabolic clearance rates and production rates in a group of postmenopausal women, before and after a daily intake for 28 days of 0.625 mg/day of conjugated equine estrogens, and again 4 weeks after the withdrawal of that estrogen replacement therapy. No significant changes appeared in immunoreactive calcitonin or immunoreactive calcitonin metabolic clearance rate but the production rate significantly increased over the 28 days (mean +/- SEM, from 21.3 +/- 5.1 pg/ml to 25.2 +/- 5.9 pg/ml, p less than 0.05), and then decreased 4 weeks after therapy was withdrawn to the initial level (17.9 +/- 3.6 pg/ml). We concluded that estrogen replacement therapy significantly increases calcitonin secretory capacity. This confirms the interactions between calcitonin production and estrogen metabolism, and may provide an explanation concerning the mode of action of estrogen replacement therapy in prevention of postmenopausal bone loss.